Skip to content

Instantly share code, notes, and snippets.

@jure

jure/gists.json

Created June 29, 2015 09:55
Show Gist options
  • Star 0 You must be signed in to star a gist
  • Fork 0 You must be signed in to fork a gist
  • Save jure/7092587d3a63d06994d5 to your computer and use it in GitHub Desktop.
Save jure/7092587d3a63d06994d5 to your computer and use it in GitHub Desktop.
Download ZIP
ScienceGist - All gists
Raw
gists.json
This file has been truncated, but you can view the full file.
{
"gists": [
{
"id": 3,
"content": "Biostar enables bioinformatics knowledge-discovery and knowledge-sharing in an open, online ecosystem. ",
"content_html": "<p>Biostar enables bioinformatics knowledge-discovery and knowledge-sharing in an open, online ecosystem. <\/p>\n",
"user": {
"email": "plindenbaum@yahoo.fr"
},
"paper": {
"identifier": "doi: 10.1371\/journal.pcbi.1002216",
"title": "BioStar: An Online Question Answer Resource for the Bioinformatics Community",
"metadata": {
"authors": "Laurence D. Parnell, Pierre Lindenbaum, Khader Shameer, Giovanni Marco Dall'Olio, Daniel C. Swan, Lars Juhl Jensen, Simon J. Cockell, Brent S. Pedersen, Mary E. Mangan, Christopher A. Miller, Istvan Albert, Philip E. Bourne",
"journal": "PLoS Comput Biol 2011"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-06T16:03:07Z",
"updated_at": "2013-07-06T16:03:07Z"
},
"created_at": "2013-07-06T16:03:07Z",
"updated_at": "2013-07-13T12:52:51Z"
},
{
"id": 1,
"content": "Piecing together genomes from sequencing data without the aid of a previously assembled reference, is technically very challenging and requires a huge amount of computational power and resources. The latest version of BGI's popular SOAPdenovo assembly tool tackles this problem, and is designed with a new algorithm optimized for larger genomes. Undergoing a number of tests it is shown to be competitive with other similar tools in both accuracy and length of the genome assembly produced.",
"content_html": "<p>Piecing together genomes from sequencing data without the aid of a previously assembled reference, is technically very challenging and requires a huge amount of computational power and resources. The latest version of BGI\u2019s popular SOAPdenovo assembly tool tackles this problem, and is designed with a new algorithm optimized for larger genomes. Undergoing a number of tests it is shown to be competitive with other similar tools in both accuracy and length of the genome assembly produced.<\/p>\n",
"user": {
"email": "me@juretriglav.si"
},
"paper": {
"identifier": "doi: 10.1186\/2047-217X-1-18",
"title": "SOAPdenovo2: an empirically improved memory-efficient short-read de novo assembler",
"metadata": {
"authors": "Ruibang Luo, Binghang Liu, Yinlong Xie, Zhenyu Li, Weihua Huang, Jianying Yuan, Guangzhu He, Yanxiang Chen, Qi Pan, Yunjie Liu, Jingbo Tang, Gengxiong Wu, Hao Zhang, Yujian Shi, Yong Liu, Chang Yu, Bo Wang, Yao Lu, Changlei Han, David W Cheung, Siu-Ming Yiu, Shaoliang Peng, Zhu Xiaoqian, Guangming Liu, Xiangke Liao, Yingrui Li, Huanming Yang, Jian Wang, Tak-Wah Lam, Jun Wang",
"journal": "Giga SciGigaScience 2012"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-06T15:33:36Z",
"updated_at": "2013-07-06T15:33:36Z"
},
"created_at": "2013-07-06T15:33:36Z",
"updated_at": "2013-07-12T10:37:15Z"
},
{
"id": 2,
"content": "A review on how non-biological nanopores (extremely tiny holes) are made and used by the latest technology. Tiny things are moved through nanopores by creating an electrical gradient across either side of the hole. We can sequence DNA by measuring the electrical conductance inside the hole as an ATCG base passes through it.\u00a0",
"content_html": "<p>A review on how non-biological nanopores (extremely tiny holes) are made and used by the latest technology. Tiny things are moved through nanopores by creating an electrical gradient across either side of the hole. We can sequence DNA by measuring the electrical conductance inside the hole as an ATCG base passes through it.\u00a0<\/p>\n",
"user": {
"email": "me@juretriglav.si"
},
"paper": {
"identifier": "DOI:\u00a010.1039\/C2CS35286A",
"title": "Single molecule sensing with solid-state nanopores: novel materials, methods, and applications",
"metadata": {
"authors": "Benjamin N. Miles, Aleksandar P. Ivanov, Kerry A. Wilson, Fatma Do\u011fan, Deanpen Japrung, Joshua B. Edel",
"journal": "Chem. Soc. Rev. 2012"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-06T15:52:02Z",
"updated_at": "2013-07-06T15:52:02Z"
},
"created_at": "2013-07-06T15:52:02Z",
"updated_at": "2013-07-11T15:42:05Z"
},
{
"id": 8,
"content": "This paper explores the impacts of climatic change on marine fisheries around the world. Examples are drawn from tropical, temperate, and arctic marine ecosystems. Likely changes to fisheries fall within five categories: range shifts (northward and\/or deeper); declines in production; changes in organism growth rates; habitat loss; and declines in recruitment (survivorship & fecundity). Some general principles are provided regarding how human communities can learn to respond (adapt) to these changes. Adaptive strategies proposed include: diverting fishing effort from imperiled fisheries to more stable options; protecting key functional groups; investing in communities and societies to lessen the impacts of change; and divesting and\/or diversifying from fishing to additional livelihood strategies. ",
"content_html": "<p>This paper explores the impacts of climatic change on marine fisheries around the world. Examples are drawn from tropical, temperate, and arctic marine ecosystems. Likely changes to fisheries fall within five categories: range shifts (northward and\/or deeper); declines in production; changes in organism growth rates; habitat loss; and declines in recruitment (survivorship &amp; fecundity). Some general principles are provided regarding how human communities can learn to respond (adapt) to these changes. Adaptive strategies proposed include: diverting fishing effort from imperiled fisheries to more stable options; protecting key functional groups; investing in communities and societies to lessen the impacts of change; and divesting and\/or diversifying from fishing to additional livelihood strategies. <\/p>\n",
"user": {
"email": "ploring@alaska.edu"
},
"paper": {
"identifier": "doi: 10.1098\/rstb.2010.0289",
"title": "Transitional states in marine fisheries: adapting to predicted global change",
"metadata": {
"authors": "M. A. MacNeil, N. A. J. Graham, J. E. Cinner, N. K. Dulvy, P. A. Loring, S. Jennings, N. V. C. Polunin, A. T. Fisk, T. R. McClanahan",
"journal": "Philosophical Transactions of the Royal Society B: Biological Sciences 2010"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-07T23:35:15Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-07T23:35:15Z",
"updated_at": "2013-07-11T15:42:27Z"
},
{
"id": 9,
"content": "This paper explores the history of gardening by Alaska Native communities of the Interior Alaska, upper-Yukon River area. In the mid-20th century, the Alaska Native Service and Bureau of Indian Affairs instituted a school gardening program as a mechanism of education and promotion of more \"civilized\" foodways for these primarily hunter-gatherer communities. Officials considered the program a failure, but records explored by the authors, in combination with interviews with elders who participated in the gardening program, suggest a different story. Many Alaska Native families in fact were trying to find ways to incorporate back-yard gardens as just a part of a flexible and diverse subsistence calendar. Officials, because they wanted to \"convert\" local Alaska Natives to more agrarian ways, did not recognize this local experimentation and innovation. The gist is that it is important to not conflate \"traditional\" practices with \"historical\" practices, for fear of locking indigenous peoples into some imagined construction of their identity and culture.",
"content_html": "<p>This paper explores the history of gardening by Alaska Native communities of the Interior Alaska, upper-Yukon River area. In the mid-20th century, the Alaska Native Service and Bureau of Indian Affairs instituted a school gardening program as a mechanism of education and promotion of more \u201ccivilized\u201d foodways for these primarily hunter-gatherer communities. Officials considered the program a failure, but records explored by the authors, in combination with interviews with elders who participated in the gardening program, suggest a different story. Many Alaska Native families in fact were trying to find ways to incorporate back-yard gardens as just a part of a flexible and diverse subsistence calendar. Officials, because they wanted to \u201cconvert\u201d local Alaska Natives to more agrarian ways, did not recognize this local experimentation and innovation. The gist is that it is important to not conflate \u201ctraditional\u201d practices with \u201chistorical\u201d practices, for fear of locking indigenous peoples into some imagined construction of their identity and culture.<\/p>\n",
"user": {
"email": "ploring@alaska.edu"
},
"paper": {
"identifier": "DOI:10.1215\/00141801-2009-060",
"title": "Outpost Gardening in Interior Alaska: Food System Innovation and the Alaska Native Gardens of the 1930s through the 1970s",
"metadata": {
"authors": "P. A. Loring, S. C. Gerlach",
"journal": "Ethnohistory 2010"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-07T23:44:14Z",
"updated_at": "2013-07-07T23:44:14Z"
},
"created_at": "2013-07-07T23:44:14Z",
"updated_at": "2013-07-11T15:42:29Z"
},
{
"id": 4,
"content": "ngs workflow xml bioinformatics make makefile",
"content_html": "<p>ngs workflow xml bioinformatics make makefile<\/p>\n",
"user": {
"email": "plindenbaum@yahoo.fr"
},
"paper": {
"identifier": "doi: 10.6084\/m9.figshare.736442",
"title": "XML4NGS : A XML-based description of a Next-Generation sequencing project allowing the generation of a \u2019Makefile\u2019-driven workflow.",
"metadata": {
"authors": "Pierre Lindenbaum, Raluca Teusan, Richard Redon, Audrey Bihou\u00e9e, Solena LeScouarnec",
"journal": "FigShare"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-23T13:44:13Z",
"updated_at": "2013-07-24T12:36:49Z"
},
"created_at": "2013-07-06T16:17:46Z",
"updated_at": "2013-10-13T17:33:39Z"
},
{
"id": 205,
"content": "Seedlings are more sensitive to severe environmental conditions than both adult plants and seeds of the same species, making germination a risky one-way transition in the plant life cycle. Consequently, strong selection pressures act on germination, resulting in a range of strategies to time germination to places or times that are suitable for seedling survival and onward growth. A range of environmental conditions tell seeds whether or not they are in a place suitable for germination, such as light conditions, smoke after burning and moisture. Timing strategies for germination are often cued by temperature and cold stratification. It is often argued that life under severe and unfavourable climatic conditions will select for increased environmental tolerance in local populations. \r\nCalluna is the keystone species of Europe\u2019s heathland systems and occurs throughout a broad geographical and climatic range, being found along Europe\u2019s western coast from the Strait of Gibraltar to northern Norway, from sea level into the alpine zone (Pyrenees, Alps, Scottish Highlands and Scandinavian Mountains) and even in continental Western Russia. This paper investigates germination behaviour along climatic gradients in heather, Calluna vulgaris. The discovery of a conditional cold-avoidance strategy for Calluna germination together with previous records from Scotland, France and Spain support a theory of gradual replacement of cold as the main hazard for seedlings as we move south in Europe by first competition and then, further south, possibly drought, that explains varying germination patterns in relation to temperature. The results suggest that Calluna in Northern Europe generally avoids hazards imposed by cold climates by cueing germination towards the relatively warm frost-free late spring to early summer season. In populations from less adverse climates, the species\u2019 cold-avoidance strategy seems to be weakened in favour of earlier germination, which would allow the species to address other limitations of, for example, light and space as a consequence of higher competition under warmer climates. \r\n \r\nThis information first appeared on AoBBlog.com: http:\/\/aobblog.com\/2013\/11\/cold-avoidance-germination-calluna-vulgaris\/ ",
"content_html": "<p>Seedlings are more sensitive to severe environmental conditions than both adult plants and seeds of the same species, making germination a risky one-way transition in the plant life cycle. Consequently, strong selection pressures act on germination, resulting in a range of strategies to time germination to places or times that are suitable for seedling survival and onward growth. A range of environmental conditions tell seeds whether or not they are in a place suitable for germination, such as light conditions, smoke after burning and moisture. Timing strategies for germination are often cued by temperature and cold stratification. It is often argued that life under severe and unfavourable climatic conditions will select for increased environmental tolerance in local populations. \nCalluna is the keystone species of Europe\u2019s heathland systems and occurs throughout a broad geographical and climatic range, being found along Europe\u2019s western coast from the Strait of Gibraltar to northern Norway, from sea level into the alpine zone (Pyrenees, Alps, Scottish Highlands and Scandinavian Mountains) and even in continental Western Russia. This paper investigates germination behaviour along climatic gradients in heather, Calluna vulgaris. The discovery of a conditional cold-avoidance strategy for Calluna germination together with previous records from Scotland, France and Spain support a theory of gradual replacement of cold as the main hazard for seedlings as we move south in Europe by first competition and then, further south, possibly drought, that explains varying germination patterns in relation to temperature. The results suggest that Calluna in Northern Europe generally avoids hazards imposed by cold climates by cueing germination towards the relatively warm frost-free late spring to early summer season. In populations from less adverse climates, the species\u2019 cold-avoidance strategy seems to be weakened in favour of earlier germination, which would allow the species to address other limitations of, for example, light and space as a consequence of higher competition under warmer climates. <\/p>\n\n<p>This information first appeared on AoBBlog.com: http:\/\/aobblog.com\/2013\/11\/cold-avoidance-germination-calluna-vulgaris\/ <\/p>\n",
"user": {
"email": "alan.cann@gmail.com"
},
"paper": {
"identifier": "doi:10.1093\/aob\/mct142",
"title": "Conditional cold avoidance drives between-population variation in germination behaviour in Calluna vulgaris",
"metadata": {
"authors": "J. P. Spindelbock, Z. Cook, M. I. Daws, E. Heegaard, I. E. Maren, V. Vandvik",
"journal": "Annals of Botany 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-11-11T18:32:41Z",
"updated_at": "2013-11-11T18:32:41Z"
},
"created_at": "2013-11-11T18:32:41Z",
"updated_at": "2013-11-11T18:32:41Z"
},
{
"id": 17,
"content": "Neural stem cells are known to continue to undergo neurogenesis postnatally within specialized niches. Although it is assumed that neuronal activity modulates multiple stages of adult neurogenesis, it is unknown whether local circuitry directly regulates adult quiescent neural stem cells (NSCs) through neurotransmitter release. In a recent study, Song et al used electrophysiology to record NSCs gabaergic response. The authors found that conditional deletion of a GABA receptor subunit enhanced stem cell renewal. Using optogenetics, they pinpointed the endogenous source of GABA to parvalbumin-positive interneurons which when activated were able to restore NSC quiescence after social isolation. This study provides exciting evidence that direct synaptic input regulates hippocampal NSC division.",
"content_html": "<p>Neural stem cells are known to continue to undergo neurogenesis postnatally within specialized niches. Although it is assumed that neuronal activity modulates multiple stages of adult neurogenesis, it is unknown whether local circuitry directly regulates adult quiescent neural stem cells (NSCs) through neurotransmitter release. In a recent study, Song et al used electrophysiology to record NSCs gabaergic response. The authors found that conditional deletion of a GABA receptor subunit enhanced stem cell renewal. Using optogenetics, they pinpointed the endogenous source of GABA to parvalbumin-positive interneurons which when activated were able to restore NSC quiescence after social isolation. This study provides exciting evidence that direct synaptic input regulates hippocampal NSC division.<\/p>\n",
"user": {
"email": "e.rod.89@gmail.com"
},
"paper": {
"identifier": "doi: 10.1038\/nature11306",
"title": "Neuronal circuitry mechanism regulating adult quiescent neural stem-cell fate decision",
"metadata": {
"authors": "Juan Song, Chun Zhong, Michael A. Bonaguidi, Gerald J. Sun, Derek Hsu, Yan Gu, Konstantinos Meletis, Z. Josh Huang, Shaoyu Ge, Grigori Enikolopov, Karl Deisseroth, Bernhard Luscher, Kimberly M. Christian, Guo-li Ming, Hongjun Song",
"journal": "Nature 2012"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-10T01:56:21Z",
"updated_at": "2013-07-10T01:56:21Z"
},
"created_at": "2013-07-10T01:56:21Z",
"updated_at": "2013-07-11T15:42:51Z"
},
{
"id": 5,
"content": "John Searle and Susanna Siegel have argued that cases of aspect-switching show that visual experience represents a richer range of properties than colours, shapes, positions and sizes. In this paper, Richard Price responds that cases of aspect-switching can be explained without holding that visual experience represents rich properties. Price also argues that even if Searle and Siegel are right, and aspect-switching does require visual experience to represent rich properties, there is reason to think those properties do not include natural-kind properties, such as being a tomato.",
"content_html": "<p>John Searle and Susanna Siegel have argued that cases of aspect-switching show that visual experience represents a richer range of properties than colours, shapes, positions and sizes. In this paper, Richard Price responds that cases of aspect-switching can be explained without holding that visual experience represents rich properties. Price also argues that even if Searle and Siegel are right, and aspect-switching does require visual experience to represent rich properties, there is reason to think those properties do not include natural-kind properties, such as being a tomato.<\/p>\n",
"user": {
"email": "richard@academia.edu"
},
"paper": {
"identifier": "doi: 10.1111\/j.1467-9213.2009.610.x",
"title": "ASPECT-SWITCHING AND VISUAL PHENOMENAL CHARACTER",
"metadata": {
"authors": "Richard Price",
"journal": " 2009"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-23T10:53:40Z",
"updated_at": "2013-07-23T10:53:40Z"
},
"created_at": "2013-07-06T22:36:03Z",
"updated_at": "2013-07-23T10:53:40Z"
},
{
"id": 10,
"content": "The article illustrates AlmaDL Journals, the open access e-publishing service supporting scientific peer reviewed journals edited by Departments and research groups of the University of Bologna. AlmaDL Journals use OJS as publishing platform, and make use of social and academic networks to spread and promote research. OAI-PMH allow dissemination in several databases and aggregators. Moreover, WIkipedia is used when possible to cite articles. ",
"content_html": "<p>The article illustrates AlmaDL Journals, the open access e-publishing service supporting scientific peer reviewed journals edited by Departments and research groups of the University of Bologna. AlmaDL Journals use OJS as publishing platform, and make use of social and academic networks to spread and promote research. OAI-PMH allow dissemination in several databases and aggregators. Moreover, WIkipedia is used when possible to cite articles. <\/p>\n",
"user": {
"email": "zanni.andrea84@gmail.com"
},
"paper": {
"identifier": "doi: 10.6092\/issn.1973-9494\/3396",
"title": "AlmaDL Journals: Quality Services for Open Access Scientific Publications at the University of Bologna",
"metadata": {
"authors": "Marialaura Vignocchi, Roberta Lauriola, Andrea Zanni, Antonio Puglisi, Raffaele Messuti",
"journal": "DataCite"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-08T07:08:59Z",
"updated_at": "2013-07-23T12:58:21Z"
},
"created_at": "2013-07-08T07:08:59Z",
"updated_at": "2013-07-23T13:07:41Z"
},
{
"id": 15,
"content": "This is about stroke, and the (lack of) effect of aspirin treatment in some people. It deals with how platelets are \"recruited\" to participate in a thrombus (\"clot\"), and how in some people aspirin does not have as much of the expected beneficial effects. In addition, it describes how red blood cells can make things worse for the patient.\r\n\r\nThis paper is by colleagues with whom I have had a very good working relationship in the past. I am now retired and not active anymore.",
"content_html": "<p>This is about stroke, and the (lack of) effect of aspirin treatment in some people. It deals with how platelets are \u201crecruited\u201d to participate in a thrombus (\u201cclot\u201d), and how in some people aspirin does not have as much of the expected beneficial effects. In addition, it describes how red blood cells can make things worse for the patient.<\/p>\n\n<p>This paper is by colleagues with whom I have had a very good working relationship in the past. I am now retired and not active anymore.<\/p>\n",
"user": {
"email": "broek.njus@gmail.com"
},
"paper": {
"identifier": "doi: 10.1016\/j.thromres.2013.06.010",
"title": "TXA2 synthesis and COX1-independent platelet reactivity in aspirin-treated patients soon after acute cerebral stroke or transient ischaemic attack",
"metadata": {
"authors": "Juana Valles, Aida Lago, Antonio Moscardo, Jose I.Tembl, Vera Parkhutik, Maria T. Santos",
"journal": "Thrombosis Research 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-23T13:46:26Z",
"updated_at": "2013-07-23T13:46:26Z"
},
"created_at": "2013-07-09T20:24:37Z",
"updated_at": "2013-07-23T13:46:26Z"
},
{
"id": 252,
"content": "The innate immune system can detect and destroy viruses, bacteria and other pathogens that enter the human body. In particular, inside cells, viral RNA can bind to and activate a protein called RIG-I. This protein switches on another protein, called MAVS, which can activate other copies of itself. These MAVS molecules then aggregate together on the membrane of mitochondria and send a signal that leads to the production of small proteins, called cytokines, which stimulate an inflammatory response and ultimately neutralize the virus.Although many of the proteins that are activated by MAVS in the innate immunity signaling pathway have been identified, precisely how MAVS transmits this signal is unknown. Now, Liu et al. explore how this protein can propagate signals in the innate immune response by monitoring activation of the transcription factors IRF3 and NF-\u03baB, which transcribe cytokine genes.Previous studies have suggested that a protein known as ubiquitin is needed to activate RIG-I, and that this protein collaborates with MAVS to signal through the innate immunity pathway. Liu et al. found that a group of proteins including TRAF2, TRAF5, TRAF6 and LUBAC relay the antiviral signal by binding to MAVS. These so-called \u2018E3 ligases\u2019 string ubiquitin together in chains called polyubiquitin, which is essential for activating signaling after, or downstream of, MAVS; however, the association of these E3 ligases with MAVS also requires that multiple copies of MAVS cluster together.MAVS, the TRAF proteins and LUBAC collectively recruit other innate immunity pathway proteins to activate IRF3 and NF-\u03baB, and thus transcription of the genes that control the innate immunity response. Together, these results show the intricate interplay of proteins needed to eliminate viruses from the body.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00785.002",
"content_html": "<p hwp:id=\"p-5\">The innate immune system can detect and destroy viruses, bacteria and other pathogens that enter the human body. In particular, inside cells, viral RNA can bind to and activate a protein called RIG-I. This protein switches on another protein, called MAVS, which can activate other copies of itself. These MAVS molecules then aggregate together on the membrane of mitochondria and send a signal that leads to the production of small proteins, called cytokines, which stimulate an inflammatory response and ultimately neutralize the virus.<\/p>\n<p hwp:id=\"p-6\">Although many of the proteins that are activated by MAVS in the innate immunity signaling pathway have been identified, precisely how MAVS transmits this signal is unknown. Now, Liu et al. explore how this protein can propagate signals in the innate immune response by monitoring activation of the transcription factors IRF3 and NF-&#x3BA;B, which transcribe cytokine genes.<\/p>\n<p hwp:id=\"p-7\">Previous studies have suggested that a protein known as ubiquitin is needed to activate RIG-I, and that this protein collaborates with MAVS to signal through the innate immunity pathway. Liu et al. found that a group of proteins including TRAF2, TRAF5, TRAF6 and LUBAC relay the antiviral signal by binding to MAVS. These so-called &#x2018;E3 ligases&#x2019; string ubiquitin together in chains called polyubiquitin, which is essential for activating signaling after, or downstream of, MAVS; however, the association of these E3 ligases with MAVS also requires that multiple copies of MAVS cluster together.<\/p>\n<p hwp:id=\"p-8\">MAVS, the TRAF proteins and LUBAC collectively recruit other innate immunity pathway proteins to activate IRF3 and NF-&#x3BA;B, and thus transcription of the genes that control the innate immunity response. Together, these results show the intricate interplay of proteins needed to eliminate viruses from the body.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00785.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00785.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00785.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00785",
"title": "MAVS recruits multiple ubiquitin E3 ligases to activate antiviral signaling cascades",
"metadata": {
"authors": "S. Liu, J. Chen, X. Cai, J. Wu, X. Chen, Y.-T. Wu, L. Sun, Z. J. Chen",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2014-01-13T00:39:10Z",
"updated_at": "2014-01-13T00:39:10Z"
},
"created_at": "2014-01-13T00:39:10Z",
"updated_at": "2014-01-13T00:39:10Z"
},
{
"id": 6,
"content": "This paper challenges assessments of sustainability that are limited to single species and\/or that do not incorporate social and cultural values. Alaska's commercial fisheries are presented as a case study; these fisheries are widely touted as sustainable, yet many rural Alaska residents, including in fishing communities, suffer poor quality of life, food insecurity, and have lost or are losing their rights to participate in commercial fishing. According to the authors, this facade of sustainability limits the opportunities for meaningful improvements to be made in how Alaska fisheries are managed, and also threatens the fish stocks themselves. Alternative ideas for managing fisheries for food security and social well-being are presented. ",
"content_html": "<p>This paper challenges assessments of sustainability that are limited to single species and\/or that do not incorporate social and cultural values. Alaska\u2019s commercial fisheries are presented as a case study; these fisheries are widely touted as sustainable, yet many rural Alaska residents, including in fishing communities, suffer poor quality of life, food insecurity, and have lost or are losing their rights to participate in commercial fishing. According to the authors, this facade of sustainability limits the opportunities for meaningful improvements to be made in how Alaska fisheries are managed, and also threatens the fish stocks themselves. Alternative ideas for managing fisheries for food security and social well-being are presented. <\/p>\n",
"user": {
"email": "ploring@alaska.edu"
},
"paper": {
"identifier": "doi: 10.1111\/j.1523-1739.2012.01938.x",
"title": "Alternative Perspectives on the Sustainability of Alaska's Commercial Fisheries",
"metadata": {
"authors": "PHILIP A. LORING The Alaska Center for Climate Assessment and Policy; University of Alaska Fairbanks; PO Box 755910; Fairbanks; AK 99775; U.S.A.",
"journal": "Conservation Biology 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-07T23:25:21Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-07T23:25:21Z",
"updated_at": "2013-07-11T15:42:20Z"
},
{
"id": 16,
"content": "Inputs from midbrain dopaminergic neurons are known to modulate striatal output during motor action. These neurons extend from both the ventral tegmental area (VTA) and substantia nigra pars compacta (SNpc) and release dopamine to regulate the activity of striatal projection neurons. Recent findings have demonstrated that a subset of these neurons co-release glutamate. However, as Tritsch et al. point out, these recent findings are based on experiments conducted in the presence of GABA receptor antagonists. Through the use of optogenetics and electrophysiology, the authors revealed that the dopaminergic neurons from the VTA and SNpc inhibit activity of striatal neurons through the release of GABA. Using a conditional knockout of vesicular GABA transporter VGAT and a pharmacological blockade of vesicular monoamine transporter VMAT2, the authors suggest that GABA release requires activity of only VMAT2, and not VGAT. Furthermore, the authors found that exogenous expression of VMAT2 is sufficient to sustain GABA release in GABAergic neurons lacking VGAT. This study expands the range of synaptic mechanisms available to monoaminergic cells by revealing that GABA functions as a co-transmitter.",
"content_html": "<p>Inputs from midbrain dopaminergic neurons are known to modulate striatal output during motor action. These neurons extend from both the ventral tegmental area (VTA) and substantia nigra pars compacta (SNpc) and release dopamine to regulate the activity of striatal projection neurons. Recent findings have demonstrated that a subset of these neurons co-release glutamate. However, as Tritsch et al. point out, these recent findings are based on experiments conducted in the presence of GABA receptor antagonists. Through the use of optogenetics and electrophysiology, the authors revealed that the dopaminergic neurons from the VTA and SNpc inhibit activity of striatal neurons through the release of GABA. Using a conditional knockout of vesicular GABA transporter VGAT and a pharmacological blockade of vesicular monoamine transporter VMAT2, the authors suggest that GABA release requires activity of only VMAT2, and not VGAT. Furthermore, the authors found that exogenous expression of VMAT2 is sufficient to sustain GABA release in GABAergic neurons lacking VGAT. This study expands the range of synaptic mechanisms available to monoaminergic cells by revealing that GABA functions as a co-transmitter.<\/p>\n",
"user": {
"email": "e.rod.89@gmail.com"
},
"paper": {
"identifier": "doi: 10.1038\/nature11466",
"title": "Dopaminergic neurons inhibit striatal output through non-canonical release of GABA",
"metadata": {
"authors": "Nicolas X. Tritsch, Jun B. Ding, Bernardo L. Sabatini",
"journal": "Nature 2012"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-10T01:54:55Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-10T01:54:56Z",
"updated_at": "2013-07-11T18:37:10Z"
},
{
"id": 19,
"content": "This is a nuclear astrophysics paper that describes some new nuclear physics measurements that help us understand how heavy elements are made in core-collapse supernovae. A brand new facility provided radioactive nuclei from nuclear fission---some of the same nuclei which exist during supernovae like those which may have made the heavy elements in the Earth. These nuclei were trapped in a magnetic field, and their masses were measured to a precision of around 0.000007%, which tells us their binding energies. Theoretical physicists haven't figured out how to calculate what the binding energies of different nuclei are from theory yet, so we only have rough guesses called \"mass models\" unless we go out and measure them like this.\r\n\r\nWe know that supernovae only last about 1 second, but there's a lot we don't know like exactly how hot and dense it is in the center where these nuclear reactions happen. The authors used the new binding energy measurements to figure out how fast nuclear reactions with these nuclei would happen in supernovae at various temperatures and densities. This tells us whether or not there is enough time during a supernova to make the heaviest elements in those different conditions.\r\n\r\nThe gist is that in order for a core-collapse supernova to make elements heavier than tin, the supernova has to be less hot and\/or more dense than most mass models have been telling us for years.",
"content_html": "<p>This is a nuclear astrophysics paper that describes some new nuclear physics measurements that help us understand how heavy elements are made in core-collapse supernovae. A brand new facility provided radioactive nuclei from nuclear fission\u2014some of the same nuclei which exist during supernovae like those which may have made the heavy elements in the Earth. These nuclei were trapped in a magnetic field, and their masses were measured to a precision of around 0.000007%, which tells us their binding energies. Theoretical physicists haven\u2019t figured out how to calculate what the binding energies of different nuclei are from theory yet, so we only have rough guesses called \u201cmass models\u201d unless we go out and measure them like this.<\/p>\n\n<p>We know that supernovae only last about 1 second, but there\u2019s a lot we don\u2019t know like exactly how hot and dense it is in the center where these nuclear reactions happen. The authors used the new binding energy measurements to figure out how fast nuclear reactions with these nuclei would happen in supernovae at various temperatures and densities. This tells us whether or not there is enough time during a supernova to make the heaviest elements in those different conditions.<\/p>\n\n<p>The gist is that in order for a core-collapse supernova to make elements heavier than tin, the supernova has to be less hot and\/or more dense than most mass models have been telling us for years.<\/p>\n",
"user": null,
"paper": {
"identifier": "arXiv:1307.0429",
"title": "First Results from the CARIBU Facility: Mass Measurements on the r-Process Path",
"metadata": {
"authors": "J. Van Schelt, D. Lascar, G. Savard, J. A. Clark, P. F. Bertone, S. Caldwell, A. Chaudhuri, A. F. Levand, G. Li, G. E. Morgan, R. Orford, R. E. Segel, K. S. Sharma, M. G. Sternberg",
"journal": "Physical Review Letters"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-11T22:43:12Z",
"updated_at": "2013-07-11T22:43:12Z"
},
"created_at": "2013-07-11T22:43:12Z",
"updated_at": "2013-08-06T23:56:04Z"
},
{
"id": 11,
"content": "There are a significant number of projects developing guidelines for reporting scientific research in particular areas. This paper describes a collaboration between such projects to ensure that they don't repeat each others' work, to avoid confusing scientists looking for guidance on how to report their research.",
"content_html": "<p>There are a significant number of projects developing guidelines for reporting scientific research in particular areas. This paper describes a collaboration between such projects to ensure that they don\u2019t repeat each others\u2019 work, to avoid confusing scientists looking for guidance on how to report their research.<\/p>\n",
"user": {
"email": "chrisftaylor@gmail.com"
},
"paper": {
"identifier": "doi: 10.1038\/nbt.1411",
"title": "Promoting coherent minimum reporting guidelines for biological and biomedical investigations: the MIBBI project",
"metadata": {
"authors": "Chris F Taylor, Dawn Field, Susanna-Assunta Sansone, Jan Aerts, Rolf Apweiler, Michael Ashburner, Catherine A Ball, Pierre-Alain Binz, Molly Bogue, Tim Booth, Alvis Brazma, Ryan R Brinkman, Adam Michael Clark, Eric W Deutsch, Oliver Fiehn, Jennifer Fostel, Peter Ghazal, Frank Gibson, Tanya Gray, Graeme Grimes, John M Hancock, Nigel W Hardy, Henning Hermjakob, Randall K Julian, Matthew Kane, Carsten Kettner, Christopher Kinsinger, Eugene Kolker, Martin Kuiper, Nicolas Le Nov\u00e8re, Jim Leebens-Mack, Suzanna E Lewis, Phillip Lord, Ann-Marie Mallon, Nishanth Marthandan, Hiroshi Masuya, Ruth McNally, Alexander Mehrle, Norman Morrison, Sandra Orchard, John Quackenbush, James M Reecy, Donald G Robertson, Philippe Rocca-Serra, Henry Rodriguez, Heiko Rosenfelder, Javier Santoyo-Lopez, Richard H Scheuermann, Daniel Schober, Barry Smith, Jason Snape, Christian J Stoeckert, Keith Tipton, Peter Sterk, Andreas Untergasser, Jo Vandesompele, Stefan Wiemann",
"journal": "Nat Biotechnol 2008"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-23T10:53:53Z",
"updated_at": "2013-07-23T10:53:53Z"
},
"created_at": "2013-07-08T12:08:55Z",
"updated_at": "2013-07-23T10:53:53Z"
},
{
"id": 13,
"content": "A novel single celled (protist) marine flagellate was isolated and characterized in the light microscope and by 18S rDNA sequencing. The BLAST results of the 18S rDNA sequence showed that it belonged to a well known environmental clade (in particular, MAST-3) of Heterokont sequences that are often talked about in the literature because the physical identities of the sequences are unknown. These data from the novel flagellate spurred on further reclassification of other flagellates of uncertain placement placing them within the Heterokont part of the eukaryotic tree. This large paper takes an in-depth look at the current 18S rDNA analyses of heterokonts (stramenopile).",
"content_html": "<p>A novel single celled (protist) marine flagellate was isolated and characterized in the light microscope and by 18S rDNA sequencing. The BLAST results of the 18S rDNA sequence showed that it belonged to a well known environmental clade (in particular, MAST-3) of Heterokont sequences that are often talked about in the literature because the physical identities of the sequences are unknown. These data from the novel flagellate spurred on further reclassification of other flagellates of uncertain placement placing them within the Heterokont part of the eukaryotic tree. This large paper takes an in-depth look at the current 18S rDNA analyses of heterokonts (stramenopile).<\/p>\n",
"user": {
"email": "jojoscoble@gmail.com"
},
"paper": {
"identifier": "doi: 10.1016\/j.ejop.2012.09.002",
"title": "Phylogeny of Heterokonta: Incisomonas marina, a uniciliate gliding opalozoan related to Solenicola (Nanomonadea), and evidence that Actinophryida evolved from raphidophytes",
"metadata": {
"authors": "Thomas Cavalier-Smith, Josephine Margaret Scoble",
"journal": "European Journal of Protistology 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-23T10:54:01Z",
"updated_at": "2013-07-23T10:54:01Z"
},
"created_at": "2013-07-08T15:50:40Z",
"updated_at": "2013-07-23T10:54:01Z"
},
{
"id": 12,
"content": "This paper explains what the authors have learned from setting up super computing and storage systems to work well for analyzing DNA\/RNA and similar data, from the new kind of DNA\/RNA sequencing machines that are called \"Next generation sequencers\". The special thing with this new technology is that it typically produces enormous amounts of data (more often counted in terabytes than gigabytes), which is hard or impossible to manage on a normal desktop computer. The kind of lessons learned include typical usage patterns for this kind of computational analysis, and how one can select the appropriate type of computing and storage hardware, as well as more organizational aspects, such as how to organize support staff in a well-functioning way.",
"content_html": "<p>This paper explains what the authors have learned from setting up super computing and storage systems to work well for analyzing DNA\/RNA and similar data, from the new kind of DNA\/RNA sequencing machines that are called \u201cNext generation sequencers\u201d. The special thing with this new technology is that it typically produces enormous amounts of data (more often counted in terabytes than gigabytes), which is hard or impossible to manage on a normal desktop computer. The kind of lessons learned include typical usage patterns for this kind of computational analysis, and how one can select the appropriate type of computing and storage hardware, as well as more organizational aspects, such as how to organize support staff in a well-functioning way.<\/p>\n",
"user": {
"email": "samuel.lampa@gmail.com"
},
"paper": {
"identifier": "doi: 10.1186\/2047-217X-2-9",
"title": "Lessons learned from implementing a national infrastructure in Sweden for storage and analysis of next-generation sequencing data",
"metadata": {
"authors": "Samuel Lampa, Martin Dahl\u00f6, Pall I Olason, Jonas Hagberg, Ola Spjuth",
"journal": "Giga SciGigaScience 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-23T10:54:51Z",
"updated_at": "2013-07-23T10:54:51Z"
},
"created_at": "2013-07-08T12:23:15Z",
"updated_at": "2013-07-23T10:54:51Z"
},
{
"id": 21,
"content": "XML4NGS is a schema describing a [NGS](http:\/\/en.wikipedia.org\/wiki\/Next-generation_sequencing#Next-generation_methods) experiment in [XML](https:\/\/en.wikipedia.org\/wiki\/XML). It provides a [XSLT](https:\/\/en.wikipedia.org\/wiki\/XSLT) stylesheet transforming the XML into a [Makefile](https:\/\/en.wikipedia.org\/wiki\/Makefile)-driven workflow allowing a parallel analysis ([alignment](https:\/\/en.wikipedia.org\/wiki\/Sequence_alignment), [calling](http:\/\/en.wikipedia.org\/wiki\/Base_calling), [annotation](https:\/\/en.wikipedia.org\/wiki\/DNA_annotation) ...) on a cluster.",
"content_html": "<p>XML4NGS is a schema describing a <a href=\"http:\/\/en.wikipedia.org\/wiki\/Next-generation_sequencing#Next-generation_methods\">NGS<\/a> experiment in <a href=\"https:\/\/en.wikipedia.org\/wiki\/XML\">XML<\/a>. It provides a <a href=\"https:\/\/en.wikipedia.org\/wiki\/XSLT\">XSLT<\/a> stylesheet transforming the XML into a <a href=\"https:\/\/en.wikipedia.org\/wiki\/Makefile\">Makefile<\/a>-driven workflow allowing a parallel analysis (<a href=\"https:\/\/en.wikipedia.org\/wiki\/Sequence_alignment\">alignment<\/a>, <a href=\"http:\/\/en.wikipedia.org\/wiki\/Base_calling\">calling<\/a>, <a href=\"https:\/\/en.wikipedia.org\/wiki\/DNA_annotation\">annotation<\/a> \u2026) on a cluster.<\/p>\n",
"user": {
"email": "me@juretriglav.si"
},
"paper": {
"identifier": "doi: 10.6084\/m9.figshare.736442",
"title": "XML4NGS : A XML-based description of a Next-Generation sequencing project allowing the generation of a \u2019Makefile\u2019-driven workflow.",
"metadata": {
"authors": "Pierre Lindenbaum, Raluca Teusan, Richard Redon, Audrey Bihou\u00e9e, Solena LeScouarnec",
"journal": "FigShare"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-23T13:44:13Z",
"updated_at": "2013-07-24T12:36:49Z"
},
"created_at": "2013-07-23T14:12:29Z",
"updated_at": "2013-07-23T14:12:45Z"
},
{
"id": 182,
"content": "We investigated the effect of oxidative stress on male infertility in Prdx 6 knockout mice by examining the oxidative stress marker parameters and sperm functional assays. Our results show that Prdx6 knockout males were more sensitive to oxidative stress more than wild type males not only in vitro but also in vivo, demonstrating more oxidative damage on lipids and proteins in spermatozoa also showing low sperm motility and count and incomplete sperm maturation. Therefore, the lack of Peroxiredoxin 6 affects the sperm function detrimentally in mice.",
"content_html": "<p>We investigated the effect of oxidative stress on male infertility in Prdx 6 knockout mice by examining the oxidative stress marker parameters and sperm functional assays. Our results show that Prdx6 knockout males were more sensitive to oxidative stress more than wild type males not only in vitro but also in vivo, demonstrating more oxidative damage on lipids and proteins in spermatozoa also showing low sperm motility and count and incomplete sperm maturation. Therefore, the lack of Peroxiredoxin 6 affects the sperm function detrimentally in mice.<\/p>\n",
"user": {
"email": "buraktango@twitter.oauth"
},
"paper": {
"identifier": "doi:10.1016\/j.freeradbiomed.2012.10.345",
"title": "Detrimental Effects of Oxidative Stress on Spermatozoa Lacking Peroxiredoxin 6",
"metadata": {
"authors": "Burak Ozkosem, Cristian O'Flaherty",
"journal": "Free Radical Biology and Medicine 2012"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-10-10T03:29:58Z",
"updated_at": "2013-10-10T03:29:58Z"
},
"created_at": "2013-10-10T03:29:58Z",
"updated_at": "2013-10-10T03:30:38Z"
},
{
"id": 7,
"content": "This paper reports on a survey conducted in 2011 of seafood consumption and food security in the Kenai Peninsula region of Alaska. It finds that access to locally-caught seafood, especially salmon, provides food security for many Alaska residents, and is especially important for low-income households. Many people at the lowest income levels do not have access to local seafood, however, as it is not available for purchase from local grocers. Some barter and\/or trade for fish. The gist is that local seafood can be an important part of local food systems, but improvements can still be made to bring more seafood to local consumers through small-scale commercial marketing. ",
"content_html": "<p>This paper reports on a survey conducted in 2011 of seafood consumption and food security in the Kenai Peninsula region of Alaska. It finds that access to locally-caught seafood, especially salmon, provides food security for many Alaska residents, and is especially important for low-income households. Many people at the lowest income levels do not have access to local seafood, however, as it is not available for purchase from local grocers. Some barter and\/or trade for fish. The gist is that local seafood can be an important part of local food systems, but improvements can still be made to bring more seafood to local consumers through small-scale commercial marketing. <\/p>\n",
"user": {
"email": "ploring@alaska.edu"
},
"paper": {
"identifier": "Doi:10.5304\/jafscd.2013.033.006",
"title": "Seafood as Local Food: Food Security and Locally Caught Seafood on Alaska&#x2019;s Kenai Peninsula",
"metadata": {
"authors": "Philip Loring, S. Craig Gerlach, Hannah Harrison",
"journal": "JAFSCD 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-07T23:28:37Z",
"updated_at": "2013-07-07T23:28:37Z"
},
"created_at": "2013-07-07T23:28:37Z",
"updated_at": "2013-07-23T14:46:54Z"
},
{
"id": 256,
"content": "In all multicellular plants and animals, cells are continuously dying and being replaced. There are a number of different types of cell death, but two of the best studied are apoptosis and necrosis. Apoptosis, sometimes referred to as \u2018cell suicide\u2019, is a form of programmed cell death that is generally beneficial to the organism. Necrosis, however, occurs whenever cells are damaged\u2014for example, due to a lack of oxygen\u2014and can trigger harmful inflammation in surrounding tissue. Although the processes leading up to apoptosis and necrosis are very different, they both involve regulated changes in mitochondria\u2014the organelles that supply cells with chemical energy.Mitochondria have a distinctive appearance, being enclosed by two membranes, the innermost of which is highly folded. During apoptosis, large pores form in the outer membranes of mitochondria. These pores are generated by two proteins\u2014Bax and Bak\u2014and they enable the mitochondrion to release proteins that activate processes involved in apoptosis. Pores also form in the mitochondrial membrane during necrosis. However, these mitochondrial permeability transition pores (MPTPs) occur simultaneously in both the inner and outer membranes and are thought to lead to swelling and rupture of mitochondria.Now, Karch et al. have shown that Bax and Bak are also involved in the formation of these permeability pores that underlie necrosis. When mouse cells that had been genetically modified to lack Bak and Bax were grown in cell culture, they were found to be resistant to substances that normally induce necrosis. Instead, their mitochondria continued to function normally, suggesting that MPTPs cannot form in the absence of Bak and Bax.Karch et al. then generated mice with heart cells that lack Bax and Bak, and deprived their hearts of oxygen to simulate a heart attack. Compared to normal mice, the genetically modified animals experienced less damage to their heart muscle, suggesting that the absence of Bax and Bak prevents cell death due to necrosis. If Bax and Bak are involved in both apoptosis and necrosis, inhibiting them could be a powerful therapeutic approach for preventing all forms of cell death during heart attacks or in certain degenerative diseases.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00772.002",
"content_html": "<p hwp:id=\"p-4\">In all multicellular plants and animals, cells are continuously dying and being replaced. There are a number of different types of cell death, but two of the best studied are apoptosis and necrosis. Apoptosis, sometimes referred to as &#x2018;cell suicide&#x2019;, is a form of programmed cell death that is generally beneficial to the organism. Necrosis, however, occurs whenever cells are damaged&#x2014;for example, due to a lack of oxygen&#x2014;and can trigger harmful inflammation in surrounding tissue. Although the processes leading up to apoptosis and necrosis are very different, they both involve regulated changes in mitochondria&#x2014;the organelles that supply cells with chemical energy.<\/p>\n<p hwp:id=\"p-5\">Mitochondria have a distinctive appearance, being enclosed by two membranes, the innermost of which is highly folded. During apoptosis, large pores form in the outer membranes of mitochondria. These pores are generated by two proteins&#x2014;Bax and Bak&#x2014;and they enable the mitochondrion to release proteins that activate processes involved in apoptosis. Pores also form in the mitochondrial membrane during necrosis. However, these mitochondrial permeability transition pores (MPTPs) occur simultaneously in both the inner and outer membranes and are thought to lead to swelling and rupture of mitochondria.<\/p>\n<p hwp:id=\"p-6\">Now, Karch et al. have shown that Bax and Bak are also involved in the formation of these permeability pores that underlie necrosis. When mouse cells that had been genetically modified to lack Bak and Bax were grown in cell culture, they were found to be resistant to substances that normally induce necrosis. Instead, their mitochondria continued to function normally, suggesting that MPTPs cannot form in the absence of Bak and Bax.<\/p>\n<p hwp:id=\"p-7\">Karch et al. then generated mice with heart cells that lack Bax and Bak, and deprived their hearts of oxygen to simulate a heart attack. Compared to normal mice, the genetically modified animals experienced less damage to their heart muscle, suggesting that the absence of Bax and Bak prevents cell death due to necrosis. If Bax and Bak are involved in both apoptosis and necrosis, inhibiting them could be a powerful therapeutic approach for preventing all forms of cell death during heart attacks or in certain degenerative diseases.<\/p>\n<p hwp:id=\"p-8\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00772.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00772.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00772.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00772",
"title": "Bax and Bak function as the outer membrane component of the mitochondrial permeability pore in regulating necrotic cell death in mice",
"metadata": {
"authors": "J. Karch, J. Q. Kwong, A. R. Burr, M. A. Sargent, J. W. Elrod, P. M. Peixoto, S. Martinez-Caballero, H. Osinska, E. H.-Y. Cheng, J. Robbins, K. W. Kinnally, J. D. Molkentin",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2014-01-13T00:39:26Z",
"updated_at": "2014-01-13T00:39:26Z"
},
"created_at": "2014-01-13T00:39:26Z",
"updated_at": "2014-01-13T00:39:26Z"
},
{
"id": 23,
"content": "As the population of the world continues to increase beyond 7 billion, and agricultural pests continue to rapidly evolve resistance to pesticides, it is becoming ever more important to cultivate arable land in a way that is sustainable for both humans and the environment. A better understanding of the different mechanisms used by wild plants to deter herbivores will help to increase crop production without harming the environment.Plants use both direct and indirect methods to fend off herbivores. Direct defense methods include the production of chemicals that are toxic to herbivores or give them indigestion, and the growth of sticky prickles and spines that can injure or kill the herbivore. Indirect defense methods, on the other hand, generally rely on the plant attracting organisms that are either predators or parasites of the herbivore.Plants produce odors known as herbivory-induced plant volatiles (HIPVs) that are thought to offer indirect defense against herbivores by betraying their location to predators and parasites. However, HIPVs also influence other members of the ecological community, sometimes in ways that are detrimental to plants. Moreover, despite 30 years of research, no study has demonstrated that HIPVs increase the fitness of a plant, so it is unclear what they have evolved to do.Now, a 2-year field study by Schuman et al. has shown plants that emit green leaf volatiles (which are a type of HIPV) produce twice as many buds and flowers\u2014a measure of fitness\u2014as plants that have been genetically engineered not to emit green leaf volatiles. This study was conducted with Nicotiana attenuata, which is a wild tobacco plant that is often targeted by Manduca sexta, a type of moth that is also known as the tobacco hornworm. Green leaf volatiles only increased plants' fitness when various species of Geocoris\u2014a bug that preys on Manduca sexta\u2014reduced the number of herbivores by a factor of two. This is the first evidence that HIPVs offer indirect defense against herbivores.Schuman et al. also studied the effects of molecules called protease inhibitors that are thought to function as direct defenses by making it difficult for herbivores to digest plants. They found that the ability to produce protease inhibitors did not increase the fitness of plants under herbivore attack; however, tobacco hornworms that had been fed plants containing protease inhibitors were found to be more sluggish in response to attack, which suggests that protease inhibitors can enhance the indirect defenses of plants. The results suggest that employing both direct and indirect defenses\u2014such as a combination of biological pesticides and genetic engineering to produce both HIPVs and protease inhibitors\u2014is the best approach for defending agricultural plants against pests.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00007.002",
"content_html": "<p hwp:id=\"p-5\">As the population of the world continues to increase beyond 7 billion, and agricultural pests continue to rapidly evolve resistance to pesticides, it is becoming ever more important to cultivate arable land in a way that is sustainable for both humans and the environment. A better understanding of the different mechanisms used by wild plants to deter herbivores will help to increase crop production without harming the environment.<\/p>\n<p hwp:id=\"p-6\">Plants use both direct and indirect methods to fend off herbivores. Direct defense methods include the production of chemicals that are toxic to herbivores or give them indigestion, and the growth of sticky prickles and spines that can injure or kill the herbivore. Indirect defense methods, on the other hand, generally rely on the plant attracting organisms that are either predators or parasites of the herbivore.<\/p>\n<p hwp:id=\"p-7\">Plants produce odors known as herbivory-induced plant volatiles (HIPVs) that are thought to offer indirect defense against herbivores by betraying their location to predators and parasites. However, HIPVs also influence other members of the ecological community, sometimes in ways that are detrimental to plants. Moreover, despite 30 years of research, no study has demonstrated that HIPVs increase the fitness of a plant, so it is unclear what they have evolved to do.<\/p>\n<p hwp:id=\"p-8\">Now, a 2-year field study by Schuman <italic>et al.<\/italic> has shown plants that emit green leaf volatiles (which are a type of HIPV) produce twice as many buds and flowers&#x2014;a measure of fitness&#x2014;as plants that have been genetically engineered not to emit green leaf volatiles. This study was conducted with <italic>Nicotiana attenuata<\/italic>, which is a wild tobacco plant that is often targeted by <italic>Manduca sexta<\/italic>, a type of moth that is also known as the tobacco hornworm. Green leaf volatiles only increased plants' fitness when various species of <italic>Geocoris<\/italic>&#x2014;a bug that preys on <italic>Manduca sexta<\/italic>&#x2014;reduced the number of herbivores by a factor of two. This is the first evidence that HIPVs offer indirect defense against herbivores.<\/p>\n<p hwp:id=\"p-9\">Schuman <italic>et al.<\/italic> also studied the effects of molecules called protease inhibitors that are thought to function as direct defenses by making it difficult for herbivores to digest plants. They found that the ability to produce protease inhibitors did not increase the fitness of plants under herbivore attack; however, tobacco hornworms that had been fed plants containing protease inhibitors were found to be more sluggish in response to attack, which suggests that protease inhibitors can enhance the indirect defenses of plants. The results suggest that employing both direct and indirect defenses&#x2014;such as a combination of biological pesticides and genetic engineering to produce both HIPVs and protease inhibitors&#x2014;is the best approach for defending agricultural plants against pests.<\/p>\n<p hwp:id=\"p-10\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00007.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00007.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00007.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00007",
"title": "Herbivory-induced volatiles function as defenses increasing fitness of the native plant Nicotiana attenuata in nature",
"metadata": {
"authors": "M. C. Schuman, K. Barthel, I. T. Baldwin",
"journal": "eLife 2012"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:27:32Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:27:32Z",
"updated_at": "2013-07-25T09:27:32Z"
},
{
"id": 20,
"content": "This exciting microbiology-related paper describes the discovery of a substance that is capable of killing the bacteria responsible for the dreaded disease, anthrax. This anti-bacterial substance is produced and released by a deep sea-inhabiting microscopic organism called Streptomyces. Scientists from the Scripps Institution of Oceanography of the University of California at San Diego, who discovered this powerful antibiotic, have named it 'anthracimycin'; in laboratory tests, very small doses of anthracimycin were able to kill certain disease-causing bacteria, which are responsible for diseases such as anthrax, strep throat, pneumonia, and bacterial infection of the heart. It was even effective against bacteria which were immune to other conventional antibiotics, such as methicillin-resistant Staphylococcus aureus (a.k.a. MRSA), which is notorious for causing diseases in enclosed spaces (such as hospitals and prisons).\r\n\r\nThe mechanism by which this antibiotic acts is not fully understood yet, but it appears that anthracimycin is able to stop a vital function of the bacterial cell, namely, synthesis of fresh DNA or RNA, by inserting itself into existing DNA - like throwing a monkey wrench into the cellular machinery. Anthracimycin was found to be less effective against certain other types of bacteria known to have a thick wall covering them, such as E. coli, the bacteria responsible for diarrhea and urinary tract infection. However, the scientists took a leaf out of the play-book of a soil-inhabiting bacterium (known as myxobacterium), which produces a substance similar to anthracimycin, but chemically slightly different - in that it contains chlorine atoms in its structure. They took anthracimycin, and chemically attached two chlorine atoms to it. Et voil\u00e0! The modified, chlorine-containing anthracimycin was now able to go through the thick wall of E. coli and other bacteria of this second type, and do some damage to those bugs, too.\r\n\r\nThe scientists are now conducting animal experiments to see how well this antibiotic performs in the living system. The prospect of this new drug is particularly appealing for combating the anthrax-causing bacteria, which has been used as a bioterrorism weapon, as well as a few other problematic drug-resistant bacterial diseases.",
"content_html": "<p>This exciting microbiology-related paper describes the discovery of a substance that is capable of killing the bacteria responsible for the dreaded disease, anthrax. This anti-bacterial substance is produced and released by a deep sea-inhabiting microscopic organism called Streptomyces. Scientists from the Scripps Institution of Oceanography of the University of California at San Diego, who discovered this powerful antibiotic, have named it \u2018anthracimycin\u2019; in laboratory tests, very small doses of anthracimycin were able to kill certain disease-causing bacteria, which are responsible for diseases such as anthrax, strep throat, pneumonia, and bacterial infection of the heart. It was even effective against bacteria which were immune to other conventional antibiotics, such as methicillin-resistant Staphylococcus aureus (a.k.a. MRSA), which is notorious for causing diseases in enclosed spaces (such as hospitals and prisons).<\/p>\n\n<p>The mechanism by which this antibiotic acts is not fully understood yet, but it appears that anthracimycin is able to stop a vital function of the bacterial cell, namely, synthesis of fresh DNA or RNA, by inserting itself into existing DNA - like throwing a monkey wrench into the cellular machinery. Anthracimycin was found to be less effective against certain other types of bacteria known to have a thick wall covering them, such as E. coli, the bacteria responsible for diarrhea and urinary tract infection. However, the scientists took a leaf out of the play-book of a soil-inhabiting bacterium (known as myxobacterium), which produces a substance similar to anthracimycin, but chemically slightly different - in that it contains chlorine atoms in its structure. They took anthracimycin, and chemically attached two chlorine atoms to it. Et voil\u00e0! The modified, chlorine-containing anthracimycin was now able to go through the thick wall of E. coli and other bacteria of this second type, and do some damage to those bugs, too.<\/p>\n\n<p>The scientists are now conducting animal experiments to see how well this antibiotic performs in the living system. The prospect of this new drug is particularly appealing for combating the anthrax-causing bacteria, which has been used as a bioterrorism weapon, as well as a few other problematic drug-resistant bacterial diseases.<\/p>\n",
"user": {
"email": "kausik.datta@gmail.com"
},
"paper": {
"identifier": "doi: 10.1002\/anie.201302749",
"title": "Anthracimycin, a Potent Anthrax Antibiotic from a Marine-Derived Actinomycete",
"metadata": {
"authors": "Kyoung Hwa Jang, Sang-Jip Nam, Jeffrey B. Locke, Christopher A. Kauffman, Deanna S. Beatty, Lauren A. Paul, William Fenical",
"journal": "Angew. Chem. Int. Ed. 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-22T21:37:17Z",
"updated_at": "2013-07-22T21:37:17Z"
},
"created_at": "2013-07-22T22:54:16Z",
"updated_at": "2013-09-11T16:16:17Z"
},
{
"id": 24,
"content": "All animals, including humans, evolved in a world filled with bacteria. Although bacteria are most familiar as pathogens, some bacteria produce small molecules that are essential for the biology of animals and other eukaryotes, although the details of the ways in which these bacterial molecules are beneficial are not well understood.The choanoflagellates are water-dwelling organisms that use their whip-like flagella to move around, feeding on bacteria. They can exist as one cell or a colony of multiple cells and, perhaps surprisingly, are the closest known living relatives of animals. This means that experiments on these organisms have the potential to improve our understanding of animal development and the transition from egg to embryo to adult.Alegado et al. have explored how the morphology of Salpingoeca rosetta, a colony-forming choanoflagellate, is influenced by its interactions with various species of bacteria. In particular, they find that the development of multicellularity in S. rosetta is triggered by the presence of the bacterium Algoriphagus machipongonensis as well as its close relatives. They also identify the signaling molecule produced by the bacteria to be C32H64NO7S; this lipid molecule is an obscure relative of the sphingolipid molecules that have important roles in signal transmission in animals, plants, and fungi. Moreover, Alegado et al. show that S. rosetta can respond to this molecule \u2013 which they call rosette-inducing factor (RIF-1) \u2013 over a wide range of concentrations, including concentrations as low as 10\u221217 M.The work of Alegado et al. suggests that interactions between S. rosetta and Algoriphagus bacteria could be a productive model system for studying the influences of bacteria on animal cell biology, and for investigating the mechanisms of signal delivery and reception. Moreover, the molecular mechanisms revealed by this work leave open the possibility that bacteria might have contributed to the evolution of multicellularity in animals.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00013.002",
"content_html": "<p hwp:id=\"p-5\">All animals, including humans, evolved in a world filled with bacteria. Although bacteria are most familiar as pathogens, some bacteria produce small molecules that are essential for the biology of animals and other eukaryotes, although the details of the ways in which these bacterial molecules are beneficial are not well understood.<\/p>\n<p hwp:id=\"p-6\">The choanoflagellates are water-dwelling organisms that use their whip-like flagella to move around, feeding on bacteria. They can exist as one cell or a colony of multiple cells and, perhaps surprisingly, are the closest known living relatives of animals. This means that experiments on these organisms have the potential to improve our understanding of animal development and the transition from egg to embryo to adult.<\/p>\n<p hwp:id=\"p-7\">Alegado <italic>et al<\/italic>. have explored how the morphology of <italic>Salpingoeca rosetta,<\/italic> a colony-forming choanoflagellate, is influenced by its interactions with various species of bacteria. In particular, they find that the development of multicellularity in <italic>S. rosetta<\/italic> is triggered by the presence of the bacterium <italic>Algoriphagus machipongonensis<\/italic> as well as its close relatives. They also identify the signaling molecule produced by the bacteria to be C<sub>32<\/sub>H<sub>64<\/sub>NO<sub>7<\/sub>S; this lipid molecule is an obscure relative of the sphingolipid molecules that have important roles in signal transmission in animals, plants, and fungi. Moreover, Alegado <italic>et al<\/italic>. show that <italic>S. rosetta<\/italic> can respond to this molecule &#x2013; which they call rosette-inducing factor (RIF-1) &#x2013; over a wide range of concentrations, including concentrations as low as 10<sup>&#x2212;17<\/sup> M.<\/p>\n<p hwp:id=\"p-8\">The work of Alegado <italic>et al<\/italic>. suggests that interactions between <italic>S. rosetta<\/italic> and <italic>Algoriphagus<\/italic> bacteria could be a productive model system for studying the influences of bacteria on animal cell biology, and for investigating the mechanisms of signal delivery and reception. Moreover, the molecular mechanisms revealed by this work leave open the possibility that bacteria might have contributed to the evolution of multicellularity in animals.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00013.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00013.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00013.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00013",
"title": "A bacterial sulfonolipid triggers multicellular development in the closest living relatives of animals",
"metadata": {
"authors": "R. A. Alegado, L. W. Brown, S. Cao, R. K. Dermenjian, R. Zuzow, S. R. Fairclough, J. Clardy, N. King",
"journal": "eLife 2012"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:27:35Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:27:35Z",
"updated_at": "2013-07-25T09:27:35Z"
},
{
"id": 25,
"content": "Protein folding\u2014the process by which a sequence of amino acids adopts the precise shape that is needed to perform a specific biological function\u2014is one of the most important processes in all of biology. Any sequence of amino acids has the potential to fold into a large number of different shapes, and misfolded proteins can lead to toxicity and other problems. For example, all cells rely on signaling proteins in the membranes that enclose them to monitor their environment so that they can adapt to changing conditions and, in multicellular organisms, communicate with neighboring cells: without properly folded signaling proteins, chaos would ensue. Moreover, many diseases\u2014including diabetes, cancer, viral infection and neurodegenerative disease\u2014have been linked to protein folding processes. It is not surprising, therefore, that cells have evolved elaborate mechanisms to exert exquisite quality control over protein folding.One of these mechanisms, called the unfolded protein response (UPR), operates in a compartment within the cell known as the endoplasmic reticulum (ER). The ER is a labyrinthine network of tubes and sacs within all eukaryotic cells, and most proteins destined for the cell surface or outside the cell adopt their properly folded shapes within this compartment. If the ER does not have enough capacity to fold all of the proteins that are delivered there, the UPR switches on to increase the protein folding capacity, to expand the surface area and volume of the compartment, and to degrade misfolded proteins. If the UPR cannot adequately adjust the folding capacity of the ER to meet the demands of the cell, the UPR triggers a program that kills the cell to prevent putting the whole organism at risk.Researchers have identified the cellular components that monitor the protein folding conditions inside the ER. All eukaryotic cells, from unicellular yeasts to mammalian cells, contain a highly conserved protein-folding sensor called Ire1. In all species analyzed to date, Ire1 is known to activate the UPR through an messenger RNA (mRNA) splicing mechanism. This splicing event provides the switch that drives a gene expression program in which the production of ER components is increased to boost the protein folding capacity of the compartment.Kimmig, Diaz et al. now report the first instance of an organism in which the UPR does not involve mRNA splicing or the initiation of a gene expression program. Rather, the yeast Schizosaccharomyces pombe utilizes Ire1 to an entirely different end. The authors find that the activation of Ire1 in S. pombe leads to the selective decay of a specific class of mRNAs that all encode proteins entering the ER. Thus, rather than increasing the protein folding capacity of the ER when faced with an increased protein folding load, S. pombe cells correct the imbalance by decreasing the load.The authors also show that a lone mRNA\u2014the mRNA that encodes the molecular chaperone BiP, which is one of the major protein-folding components in the ER\u2014uniquely escapes this decay. Rather than being degraded, Ire1 truncates BiP mRNA and renders it more stable. By studying the UPR in a divergent organism, the authors shed new light on the evolution of a universally important process and illustrate how conserved machinery has been repurposed.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00048.002",
"content_html": "<p hwp:id=\"p-8\">Protein folding&#x2014;the process by which a sequence of amino acids adopts the precise shape that is needed to perform a specific biological function&#x2014;is one of the most important processes in all of biology. Any sequence of amino acids has the potential to fold into a large number of different shapes, and misfolded proteins can lead to toxicity and other problems. For example, all cells rely on signaling proteins in the membranes that enclose them to monitor their environment so that they can adapt to changing conditions and, in multicellular organisms, communicate with neighboring cells: without properly folded signaling proteins, chaos would ensue. Moreover, many diseases&#x2014;including diabetes, cancer, viral infection and neurodegenerative disease&#x2014;have been linked to protein folding processes. It is not surprising, therefore, that cells have evolved elaborate mechanisms to exert exquisite quality control over protein folding.<\/p>\n<p hwp:id=\"p-9\">One of these mechanisms, called the unfolded protein response (UPR), operates in a compartment within the cell known as the endoplasmic reticulum (ER). The ER is a labyrinthine network of tubes and sacs within all eukaryotic cells, and most proteins destined for the cell surface or outside the cell adopt their properly folded shapes within this compartment. If the ER does not have enough capacity to fold all of the proteins that are delivered there, the UPR switches on to increase the protein folding capacity, to expand the surface area and volume of the compartment, and to degrade misfolded proteins. If the UPR cannot adequately adjust the folding capacity of the ER to meet the demands of the cell, the UPR triggers a program that kills the cell to prevent putting the whole organism at risk.<\/p>\n<p hwp:id=\"p-10\">Researchers have identified the cellular components that monitor the protein folding conditions inside the ER. All eukaryotic cells, from unicellular yeasts to mammalian cells, contain a highly conserved protein-folding sensor called Ire1. In all species analyzed to date, Ire1 is known to activate the UPR through an messenger RNA (mRNA) splicing mechanism. This splicing event provides the switch that drives a gene expression program in which the production of ER components is increased to boost the protein folding capacity of the compartment.<\/p>\n<p hwp:id=\"p-11\">Kimmig, Diaz <italic>et al.<\/italic> now report the first instance of an organism in which the UPR does not involve mRNA splicing or the initiation of a gene expression program. Rather, the yeast <italic>Schizosaccharomyces pombe<\/italic> utilizes Ire1 to an entirely different end. The authors find that <italic>the<\/italic> activation of Ire1 in <italic>S. pombe<\/italic> leads to the selective <italic>decay<\/italic> of a specific class of mRNAs that all encode proteins entering the ER. Thus, rather than increasing the protein folding capacity of the ER when faced with an increased protein folding load, <italic>S. pombe<\/italic> cells correct the imbalance by decreasing the load.<\/p>\n<p hwp:id=\"p-12\">The authors also show that a lone mRNA&#x2014;the mRNA that encodes the molecular chaperone BiP, which is one of the major protein-folding components in the ER&#x2014;uniquely escapes this decay. Rather than being degraded, Ire1 truncates BiP mRNA and renders it more stable. By studying the UPR in a divergent organism, the authors shed new light on the evolution of a universally important process and illustrate how conserved machinery has been repurposed.<\/p>\n<p hwp:id=\"p-13\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00048.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00048.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00048.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00048",
"title": "The unfolded protein response in fission yeast modulates stability of select mRNAs to maintain protein homeostasis",
"metadata": {
"authors": "P. Kimmig, M. Diaz, J. Zheng, C. C. Williams, A. Lang, T. Aragon, H. Li, P. Walter",
"journal": "eLife 2012"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:27:38Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:27:38Z",
"updated_at": "2013-07-25T09:27:38Z"
},
{
"id": 26,
"content": "In 1934, in a famous experiment at Cornell University, it was discovered that laboratory mice could live twice as long as expected if they were fed a low-calorie diet that included enough nutrients to avoid malnutrition. This phenomenon has since been observed in species ranging from worms to primates, but not in humans. Reducing calorie intake leads to longer lives by modifying a number of the biochemical pathways that sense nutrients, including pathways that involve insulin and various other biomolecules. Chemical and genetic methods can also increase longevity by modifying these pathways, which suggests that it might be possible to develop drugs that can increase lifespan without reducing calorie intake.Mice, humans and other creatures respond to prolonged fasting through a number of adaptive changes that include mobilizing and burning fatty acids. The liver has an important role in this response, secreting a hormone called fibroblast growth factor-21 (FGF21) that coordinates these processes among tissues. Previous experiments on transgenic mice with high levels of this hormone have shown that it suppresses the activity of growth hormone and reduces the production of insulin-like growth factor, which prevents growth and can lead to hibernation-like behavior.Here Zhang et al. compare groups of wild-type mice and transgenic mice with high levels of FGF21. They find that the transgenic mice have a longer median survival time than wild-type mice (38 months vs 28 months), and that the transgenic female mice on average live for 4 months longer than their male counterparts. However, unlike in other examples of increased longevity, they find that decreased food intake is not required. Instead, they find that transgenic mice eat more food than wild-type mice, yet remain profoundly insulin-sensitive. The results suggest that the longer survival times are caused by a reduction in the production of insulin-like growth factor, but they also suggest that the mechanism responsible for the increased longevity is independent of the three pathways that are usually associated with such increases. Further research is needed to understand this mechanism in greater detail and could, perhaps, pave the way for the use of FGF21-based hormone therapy to extend lifespan without the need for a low-calorie diet.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00065.002",
"content_html": "<p hwp:id=\"p-4\">In 1934, in a famous experiment at Cornell University, it was discovered that laboratory mice could live twice as long as expected if they were fed a low-calorie diet that included enough nutrients to avoid malnutrition. This phenomenon has since been observed in species ranging from worms to primates, but not in humans. Reducing calorie intake leads to longer lives by modifying a number of the biochemical pathways that sense nutrients, including pathways that involve insulin and various other biomolecules. Chemical and genetic methods can also increase longevity by modifying these pathways, which suggests that it might be possible to develop drugs that can increase lifespan without reducing calorie intake.<\/p>\n<p hwp:id=\"p-5\">Mice, humans and other creatures respond to prolonged fasting through a number of adaptive changes that include mobilizing and burning fatty acids. The liver has an important role in this response, secreting a hormone called fibroblast growth factor-21 (FGF21) that coordinates these processes among tissues. Previous experiments on transgenic mice with high levels of this hormone have shown that it suppresses the activity of growth hormone and reduces the production of insulin-like growth factor, which prevents growth and can lead to hibernation-like behavior.<\/p>\n<p hwp:id=\"p-6\">Here Zhang et al. compare groups of wild-type mice and transgenic mice with high levels of FGF21. They find that the transgenic mice have a longer median survival time than wild-type mice (38 months vs 28 months), and that the transgenic female mice on average live for 4 months longer than their male counterparts. However, unlike in other examples of increased longevity, they find that decreased food intake is not required. Instead, they find that transgenic mice eat more food than wild-type mice, yet remain profoundly insulin-sensitive. The results suggest that the longer survival times are caused by a reduction in the production of insulin-like growth factor, but they also suggest that the mechanism responsible for the increased longevity is independent of the three pathways that are usually associated with such increases. Further research is needed to understand this mechanism in greater detail and could, perhaps, pave the way for the use of FGF21-based hormone therapy to extend lifespan without the need for a low-calorie diet.<\/p>\n<p hwp:id=\"p-7\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00065.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00065.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00065.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00065",
"title": "The starvation hormone, fibroblast growth factor-21, extends lifespan in mice",
"metadata": {
"authors": "Y. Zhang, Y. Xie, E. D. Berglund, K. C. Coate, T. T. He, T. Katafuchi, G. Xiao, M. J. Potthoff, W. Wei, Y. Wan, R. T. Yu, R. M. Evans, S. A. Kliewer, D. J. Mangelsdorf",
"journal": "eLife 2012"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:27:40Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:27:40Z",
"updated_at": "2013-07-25T09:27:40Z"
},
{
"id": 27,
"content": "Protein complexes\u2014stable structures that contain two or more proteins\u2014have an important role in the biochemical processes that are associated with the expression of genes. Some help to silence genes, whereas others are involved in the activation of genes. The importance of such complexes is emphasized by the fact that mice die as embryos, or are born with serious defects, if they do not possess the protein complex known as Polycomb Repressive Complex 2, or PRC2 for short.It is known that the core of this complex, which is found in species that range from Drosophila to humans, is composed of four different proteins, and that the structures of two of these have been determined with atomic precision. It is also known that PRC2 requires a particular protein co-factor (called AEBP2) to perform this function. Moreover, it has been established that PRC2 silences genes by adding two or three methyl (CH3) groups to a particular amino acid (Lysine 27) in one of the proteins (histone H3) that DNA strands wrap around in the nucleus of cells. However, despite its biological importance, little is known about the detailed architecture of PRC2.Ciferri et al. shed new light on the structure of this complex by using electron microscopy to produce the first three-dimensional image of the human PRC2 complex bound to its cofactor. By incorporating various protein tags into the co-factor and the four subunits of the PRC2, and by employing mass spectrometry and other techniques, Ciferri et al. were able to identify 60 or so interaction sites within the PRC2-cofactor system, and to determine their locations within the overall structure.The results show that the cofactor stabilizes the architecture of the complex by binding to it at a central hinge point. In particular, the protein domains within the PRC2 that interact with the histone markers are close to the site that transfer the methyl groups, which helps to explain how the gene silencing activity of the PRC2 complex is regulated. The results should pave the way to a more complete understanding of how PRC2 and its cofactor are able to silence genes.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00005.002",
"content_html": "<p hwp:id=\"p-5\">Protein complexes&#x2014;stable structures that contain two or more proteins&#x2014;have an important role in the biochemical processes that are associated with the expression of genes. Some help to silence genes, whereas others are involved in the activation of genes. The importance of such complexes is emphasized by the fact that mice die as embryos, or are born with serious defects, if they do not possess the protein complex known as Polycomb Repressive Complex 2, or PRC2 for short.<\/p>\n<p hwp:id=\"p-6\">It is known that the core of this complex, which is found in species that range from <italic>Drosophila<\/italic> to humans, is composed of four different proteins, and that the structures of two of these have been determined with atomic precision. It is also known that PRC2 requires a particular protein co-factor (called AEBP2) to perform this function. Moreover, it has been established that PRC2 silences genes by adding two or three methyl (CH3) groups to a particular amino acid (Lysine 27) in one of the proteins (histone H3) that DNA strands wrap around in the nucleus of cells. However, despite its biological importance, little is known about the detailed architecture of PRC2.<\/p>\n<p hwp:id=\"p-7\">Ciferri et al. shed new light on the structure of this complex by using electron microscopy to produce the first three-dimensional image of the human PRC2 complex bound to its cofactor. By incorporating various protein tags into the co-factor and the four subunits of the PRC2, and by employing mass spectrometry and other techniques, Ciferri et al. were able to identify 60 or so interaction sites within the PRC2-cofactor system, and to determine their locations within the overall structure.<\/p>\n<p hwp:id=\"p-8\">The results show that the cofactor stabilizes the architecture of the complex by binding to it at a central hinge point. In particular, the protein domains within the PRC2 that interact with the histone markers are close to the site that transfer the methyl groups, which helps to explain how the gene silencing activity of the PRC2 complex is regulated. The results should pave the way to a more complete understanding of how PRC2 and its cofactor are able to silence genes.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00005.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00005.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00005.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00005",
"title": "Molecular architecture of human polycomb repressive complex 2",
"metadata": {
"authors": "C. Ciferri, G. C. Lander, A. Maiolica, F. Herzog, R. Aebersold, E. Nogales, K. Struhl",
"journal": "eLife 2012"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:27:45Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:27:45Z",
"updated_at": "2013-07-25T09:27:45Z"
},
{
"id": 28,
"content": "A central feature of the immune system is the ability to detect bacteria, viruses and other pathogens so that they can be repelled or neutralized before they cause lasting damage to an organism. Cells employ a number of different receptors that can detect these pathogens or the molecules they produce. Many of these are called pattern recognition receptors because they recognize certain signatures of microorganisms such as nucleic acids or carbohydrates. An important class of pattern recognition receptor is the toll-like receptor: there are many different families of the receptors, each recognizing a unique feature of bacteria or viruses. (The word toll, which means \u2018great\u2019 in German, refers to a gene whose mutations lead to striking phenotypes in flies, and has nothing to do with road and bridge tolls.)Toll-like receptors have two parts that perform two different functions: when one part binds the relevant microbial molecules, the other part sends a signal that results in the production of effector proteins. These proteins include interleukin-1\u03b2, which helps to fight infection by causing the inflammation of tissue. To date, 12 different types of toll-like receptors have been found in mice, including three\u2014known as TLR11, TLR12 and TLR13\u2014that are not present in humans. Very little is known about the functions of TLR12 and TLR13. Humans, on the other hand, possess 10 different TLRs, only one of which, TLR10, is not found in mice.Li and Chen have now discovered that TLR13 is responsible for detecting a certain type of ribosomal RNA called 23S ribosomal RNA that are present in bacteria but not in eukaryotic cells. Moreover, they have shown that a short sequence of 13 residues within the 23S ribosomal RNA triggers this pathway and leads to the production of interleukin-1\u03b2. The sequence of 13 residues is located at an active site in the RNA that catalyzes the synthesis of peptide bonds, and changing just one of these residues stops the production of interleukin-1\u03b2. Other forms of ribosomal RNA are unable to trigger the production of interleukin-1\u03b2. These results show that TLR13 differs from all other pattern recognition receptors because it is able to recognize a specific RNA sequence. Li and Chen went on to generate mice lacking TLR13 and showed that immune cells isolated from these mice failed to respond to bacterial RNA. These mice can be used to investigate the role of TLR13 in immune responses to bacterial infections in vivo.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00102.002",
"content_html": "<p hwp:id=\"p-4\">A central feature of the immune system is the ability to detect bacteria, viruses and other pathogens so that they can be repelled or neutralized before they cause lasting damage to an organism. Cells employ a number of different receptors that can detect these pathogens or the molecules they produce. Many of these are called pattern recognition receptors because they recognize certain signatures of microorganisms such as nucleic acids or carbohydrates. An important class of pattern recognition receptor is the toll-like receptor: there are many different families of the receptors, each recognizing a unique feature of bacteria or viruses. (The word toll, which means &#x2018;great&#x2019; in German, refers to a gene whose mutations lead to striking phenotypes in flies, and has nothing to do with road and bridge tolls.)<\/p>\n<p hwp:id=\"p-5\">Toll-like receptors have two parts that perform two different functions: when one part binds the relevant microbial molecules, the other part sends a signal that results in the production of effector proteins. These proteins include interleukin-1&#x3B2;, which helps to fight infection by causing the inflammation of tissue. To date, 12 different types of toll-like receptors have been found in mice, including three&#x2014;known as TLR11, TLR12 and TLR13&#x2014;that are not present in humans. Very little is known about the functions of TLR12 and TLR13. Humans, on the other hand, possess 10 different TLRs, only one of which, TLR10, is not found in mice.<\/p>\n<p hwp:id=\"p-6\">Li and Chen have now discovered that TLR13 is responsible for detecting a certain type of ribosomal RNA called 23S ribosomal RNA that are present in bacteria but not in eukaryotic cells. Moreover, they have shown that a short sequence of 13 residues within the 23S ribosomal RNA triggers this pathway and leads to the production of interleukin-1&#x3B2;. The sequence of 13 residues is located at an active site in the RNA that catalyzes the synthesis of peptide bonds, and changing just one of these residues stops the production of interleukin-1&#x3B2;. Other forms of ribosomal RNA are unable to trigger the production of interleukin-1&#x3B2;. These results show that TLR13 differs from all other pattern recognition receptors because it is able to recognize a specific RNA sequence. Li and Chen went on to generate mice lacking TLR13 and showed that immune cells isolated from these mice failed to respond to bacterial RNA. These mice can be used to investigate the role of TLR13 in immune responses to bacterial infections in vivo.<\/p>\n<p hwp:id=\"p-7\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00102.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00102.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00102.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00102",
"title": "Sequence specific detection of bacterial 23S ribosomal RNA by TLR13",
"metadata": {
"authors": "X.-D. Li, Z. J. Chen",
"journal": "eLife 2012"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:27:47Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:27:47Z",
"updated_at": "2013-07-25T09:27:47Z"
},
{
"id": 33,
"content": "Histones are proteins found in large numbers in most animal cells, where their primary job is to help DNA strands fold into compact and robust structures inside the nucleus. In vitro, histones are very effective at killing bacteria, and there is some evidence that histones secreted from cells provide protection against bacteria living outside cells. However, many types of bacteria are able to enter cells, where they can avoid the immune system and go on to replicate.In principle histones could protect cells against such bacteria from the inside, but for many years this was thought to be unlikely because most histones are bound to DNA strands in the cell nucleus, whereas the bacteria replicate in the cytosol. Moreover, free histones can be extremely damaging to cells, so most species have developed mechanisms to detect and degrade free histones in the cytosol.Recently, however, it was discovered that histones can bind to lipid droplets\u2014organelles in the cytosol that are primarily used to store energy\u2014in various animal cells and tissues. Now, Anand et al. have demonstrated that histones bound to lipid droplets can protect cells against bacteria without causing any of the harm normally associated with the presence of free histones. In in vitro experiments with lipid droplets purified from Drosophila embryos, they showed that histones bound to lipid droplets could be released to kill bacteria. The histones were released by lipopolysaccharide or lipoteichoic acid produced by the bacteria.The effect was also observed in vivo: using four different bacterial species, Anand et al. injected similar numbers of bacteria into Drosophila embryos that contained histones bound to lipid droplets, and also into embryos that had been genetically modified so that they did not contain such droplet-bound histones. While most of the normal embryos survived, the vast majority of the embryos without droplet-bound histones died. Similar results were also found in experiments on adult flies, along with evidence which suggests that histones might also provide defenses against bacteria in mice.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00003.002",
"content_html": "<p hwp:id=\"p-5\">Histones are proteins found in large numbers in most animal cells, where their primary job is to help DNA strands fold into compact and robust structures inside the nucleus. In vitro, histones are very effective at killing bacteria, and there is some evidence that histones secreted from cells provide protection against bacteria living outside cells. However, many types of bacteria are able to enter cells, where they can avoid the immune system and go on to replicate.<\/p>\n<p hwp:id=\"p-6\">In principle histones could protect cells against such bacteria from the inside, but for many years this was thought to be unlikely because most histones are bound to DNA strands in the cell nucleus, whereas the bacteria replicate in the cytosol. Moreover, free histones can be extremely damaging to cells, so most species have developed mechanisms to detect and degrade free histones in the cytosol.<\/p>\n<p hwp:id=\"p-7\">Recently, however, it was discovered that histones can bind to lipid droplets&#x2014;organelles in the cytosol that are primarily used to store energy&#x2014;in various animal cells and tissues. Now, Anand et al. have demonstrated that histones bound to lipid droplets can protect cells against bacteria without causing any of the harm normally associated with the presence of free histones. In in vitro experiments with lipid droplets purified from <italic>Drosophila<\/italic> embryos, they showed that histones bound to lipid droplets could be released to kill bacteria. The histones were released by lipopolysaccharide or lipoteichoic acid produced by the bacteria.<\/p>\n<p hwp:id=\"p-8\">The effect was also observed in vivo: using four different bacterial species, Anand et al. injected similar numbers of bacteria into <italic>Drosophila<\/italic> embryos that contained histones bound to lipid droplets, and also into embryos that had been genetically modified so that they did not contain such droplet-bound histones. While most of the normal embryos survived, the vast majority of the embryos without droplet-bound histones died. Similar results were also found in experiments on adult flies, along with evidence which suggests that histones might also provide defenses against bacteria in mice.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00003.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00003.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00003.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00003",
"title": "A novel role for lipid droplets in the organismal antibacterial response",
"metadata": {
"authors": "P. Anand, S. Cermelli, Z. Li, A. Kassan, M. Bosch, R. Sigua, L. Huang, A. J. Ouellette, A. Pol, M. A. Welte, S. P. Gross",
"journal": "eLife 2012"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:28:05Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:28:05Z",
"updated_at": "2013-07-25T09:28:05Z"
},
{
"id": 209,
"content": "Almost every cell in the human body contains the complete sequence of the [human genome](http:\/\/en.wikipedia.org\/wiki\/Human_genome), written in [DNA](http:\/\/en.wikipedia.org\/wiki\/Dna). Every time a cell divides, it creates a copy of this DNA before it splits up, so that each of the two daughter cells inherits a whole copy. At the same time, the cell's DNA is being constantly attacked by chemicals which can damage the genetic information. Although such damage is usually rapidly repaired, if the cell divides just after damage occurs then the damage can be passed on to future cells. These [mutations](http:\/\/en.wikipedia.org\/wiki\/Mutation) can build up over time and can eventually cause cancer. In order to prevent mutations from being passed on, the cell contains a protein called [P53](http:\/\/en.wikipedia.org\/wiki\/P53), which prevents the cell from dividing if it detects any damage to the cell's DNA.\r\n\r\nP53 is part of a group of proteins called [transcription factors](http:\/\/en.wikipedia.org\/wiki\/Transcription_factor), which work by binding directly to the DNA of a gene and turning it on. However, previous work has identified all the regions in the genome bound by P53 and shown that much of this binding occurs outside of genes. In this paper, the authors investigate binding of P53 outside genes and ask whether these regions might be enhancers. [Enhancers](http:\/\/en.wikipedia.org\/wiki\/Enhancer_%28genetics%29) are regions of DNA that direct which genes should be turned on (transcribed) in any given cell type. They can be very far away from genes, but often appear to control specific groups of genes by physically touching their DNA sequence.\r\n\r\nFirst they identify several regions outside of genes which are bound by other proteins known to mark enhancers. They use an experiment called a [luciferase assay](http:\/\/en.wikipedia.org\/wiki\/Luciferase#Applications) to fuse these potential enhancers to a gene and demonstrate that the enhancer region is indeed switching the gene on. They then go on to confirm that these regions do make physical contacts with nearby genes. To demonstrate that the binding of P53 to these enhancer regions might activate these nearby genes, they treat the cells with a chemical that increases the amount of P53 and show that the activity of nearby genes increases.\r\n\r\nWhen a gene is \"active\", the cell produces a copy of the gene's DNA in a slightly different chemical called [RNA](http:\/\/en.wikipedia.org\/wiki\/Rna). It is now known that many enhancers can also be active in this way, and can produce RNA. The authors show that their enhancer regions do produce RNA. They then use a modified luciferase assay where they add RNA and not DNA to show that the RNA produced by the enhancer regions can actually stimulate activation of the nearby gene on it's own. Finally, they show that removing these RNAs interferes with the ability of P53 to stop the cell from dividing when the DNA is damaged. In summary, this paper shows that as well as directly activating genes by binding to them when DNA is damaged, P53 can also activate genes indirectly by activating the production of enhancer RNAs.",
"content_html": "<p>Almost every cell in the human body contains the complete sequence of the <a href=\"http:\/\/en.wikipedia.org\/wiki\/Human_genome\">human genome<\/a>, written in <a href=\"http:\/\/en.wikipedia.org\/wiki\/Dna\">DNA<\/a>. Every time a cell divides, it creates a copy of this DNA before it splits up, so that each of the two daughter cells inherits a whole copy. At the same time, the cell\u2019s DNA is being constantly attacked by chemicals which can damage the genetic information. Although such damage is usually rapidly repaired, if the cell divides just after damage occurs then the damage can be passed on to future cells. These <a href=\"http:\/\/en.wikipedia.org\/wiki\/Mutation\">mutations<\/a> can build up over time and can eventually cause cancer. In order to prevent mutations from being passed on, the cell contains a protein called <a href=\"http:\/\/en.wikipedia.org\/wiki\/P53\">P53<\/a>, which prevents the cell from dividing if it detects any damage to the cell\u2019s DNA.<\/p>\n\n<p>P53 is part of a group of proteins called <a href=\"http:\/\/en.wikipedia.org\/wiki\/Transcription_factor\">transcription factors<\/a>, which work by binding directly to the DNA of a gene and turning it on. However, previous work has identified all the regions in the genome bound by P53 and shown that much of this binding occurs outside of genes. In this paper, the authors investigate binding of P53 outside genes and ask whether these regions might be enhancers. <a href=\"http:\/\/en.wikipedia.org\/wiki\/Enhancer_%28genetics%29\">Enhancers<\/a> are regions of DNA that direct which genes should be turned on (transcribed) in any given cell type. They can be very far away from genes, but often appear to control specific groups of genes by physically touching their DNA sequence.<\/p>\n\n<p>First they identify several regions outside of genes which are bound by other proteins known to mark enhancers. They use an experiment called a <a href=\"http:\/\/en.wikipedia.org\/wiki\/Luciferase#Applications\">luciferase assay<\/a> to fuse these potential enhancers to a gene and demonstrate that the enhancer region is indeed switching the gene on. They then go on to confirm that these regions do make physical contacts with nearby genes. To demonstrate that the binding of P53 to these enhancer regions might activate these nearby genes, they treat the cells with a chemical that increases the amount of P53 and show that the activity of nearby genes increases.<\/p>\n\n<p>When a gene is \u201cactive\u201d, the cell produces a copy of the gene\u2019s DNA in a slightly different chemical called <a href=\"http:\/\/en.wikipedia.org\/wiki\/Rna\">RNA<\/a>. It is now known that many enhancers can also be active in this way, and can produce RNA. The authors show that their enhancer regions do produce RNA. They then use a modified luciferase assay where they add RNA and not DNA to show that the RNA produced by the enhancer regions can actually stimulate activation of the nearby gene on it\u2019s own. Finally, they show that removing these RNAs interferes with the ability of P53 to stop the cell from dividing when the DNA is damaged. In summary, this paper shows that as well as directly activating genes by binding to them when DNA is damaged, P53 can also activate genes indirectly by activating the production of enhancer RNAs.<\/p>\n",
"user": {
"email": "robbeagrie@twitter.oauth"
},
"paper": {
"identifier": "doi:10.1016\/j.molcel.2012.11.021",
"title": "eRNAs Are Required for p53-Dependent Enhancer Activity and Gene Transcription",
"metadata": {
"authors": "Carlos\u00a0A. Melo, Jarno Drost, Patrick\u00a0J. Wijchers, Harmen van\u00a0de\u00a0Werken, Elzo de\u00a0Wit, Joachim\u00a0A.F.\u00a0Oude Vrielink, Ran Elkon, S\u00f3nia\u00a0A. Melo, Nicolas L\u00e9veill\u00e9, Raghu Kalluri, Wouter de\u00a0Laat, Reuven Agami",
"journal": "Molecular Cell 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-11-19T08:56:35Z",
"updated_at": "2013-11-19T08:56:35Z"
},
"created_at": "2013-11-19T08:56:35Z",
"updated_at": "2013-11-19T08:56:35Z"
},
{
"id": 30,
"content": "Embryonic stem cells have two characteristic properties: they are able to differentiate into any type of cell, a property known as pluripotency, and they are able to replicate themselves indefinitely to produce an endless supply of new stem cells. Different genes code for the various proteins associated with these two properties, and understanding the behaviour and properties of stem cells in detail is a major challenge in developmental biology. In human embryonic stem cells that have not yet differentiated, the genes that code for the transcription factors involved in the self-renewal process are expressed, whereas the genes associated with differentiation are not active. However, if the expression of the genes for self-renewal is reduced, the process of differentiation will begin, and the embryonic stem cells will be able to produce any one of the 200 or so different types of cell found in the human body.All of this activity is orchestrated by proteins that oversee the transcription of specific regions of DNA into messenger RNA. Transcription is the first step in the process by which genes are expressed as proteins, and it cannot start until the relevant transcription factor binds to a stretch of DNA near the gene called the promoter. These transcription factors are complex structures that contain a central protein called TBP, which binds to the promoter, and 14 or so other proteins called TAFs.Maston et al. now report that the transcription machinery that regulates gene expression and self-renewal in human embryonic stem cells is different from that found in other types of cells, including embryonic stem cells taken from mice. In particular, they found that undifferentiated human embryonic stem cells contain only 6 of the 14 TAFs observed in other cells, although all 14 are present after differentiation. Moreover, for many active genes the transcription factors contained only two of these TAFs. There was also evidence for a new complex that contained the other four TAFs plus TBP.Maston et al. also demonstrated that the removal of just one of the six TAFs, or the addition of just one extra TAF, caused the process of differentiation to begin. This shows, they argue, that the unusual transcription machinery they have discovered is essential for the proper workings of human embryonic stem cells.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00068.002",
"content_html": "<p hwp:id=\"p-4\">Embryonic stem cells have two characteristic properties: they are able to differentiate into any type of cell, a property known as pluripotency, and they are able to replicate themselves indefinitely to produce an endless supply of new stem cells. Different genes code for the various proteins associated with these two properties, and understanding the behaviour and properties of stem cells in detail is a major challenge in developmental biology. In human embryonic stem cells that have not yet differentiated, the genes that code for the transcription factors involved in the self-renewal process are expressed, whereas the genes associated with differentiation are not active. However, if the expression of the genes for self-renewal is reduced, the process of differentiation will begin, and the embryonic stem cells will be able to produce any one of the 200 or so different types of cell found in the human body.<\/p>\n<p hwp:id=\"p-5\">All of this activity is orchestrated by proteins that oversee the transcription of specific regions of DNA into messenger RNA. Transcription is the first step in the process by which genes are expressed as proteins, and it cannot start until the relevant transcription factor binds to a stretch of DNA near the gene called the promoter. These transcription factors are complex structures that contain a central protein called TBP, which binds to the promoter, and 14 or so other proteins called TAFs.<\/p>\n<p hwp:id=\"p-6\">Maston et al. now report that the transcription machinery that regulates gene expression and self-renewal in human embryonic stem cells is different from that found in other types of cells, including embryonic stem cells taken from mice. In particular, they found that undifferentiated human embryonic stem cells contain only 6 of the 14 TAFs observed in other cells, although all 14 are present after differentiation. Moreover, for many active genes the transcription factors contained only two of these TAFs. There was also evidence for a new complex that contained the other four TAFs plus TBP.<\/p>\n<p hwp:id=\"p-7\">Maston et al. also demonstrated that the removal of just one of the six TAFs, or the addition of just one extra TAF, caused the process of differentiation to begin. This shows, they argue, that the unusual transcription machinery they have discovered is essential for the proper workings of human embryonic stem cells.<\/p>\n<p hwp:id=\"p-8\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00068.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00068.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00068.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00068",
"title": "Non-canonical TAF complexes regulate active promoters in human embryonic stem cells",
"metadata": {
"authors": "G. A. Maston, L. J. Zhu, L. Chamberlain, L. Lin, M. Fang, M. R. Green",
"journal": "eLife 2012"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:27:52Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:27:52Z",
"updated_at": "2013-07-25T09:27:52Z"
},
{
"id": 31,
"content": "Proteases are enzymes that break the peptide bonds that hold proteins together, and have a central role in many physiological processes, including digestion, blood clotting and programmed cell death. An important characteristic of proteases is that they are highly selective, only cutting proteins that contain well-defined sequences of amino acids in accessible regions. Proteases that are soluble in water have been studied for over a century and are now well understood, as are proteases that need to be tethered to the membrane of a cell to work properly.In 1997 researchers discovered a protease that was immersed in the cell membrane, and it soon became clear that these intramembrane proteases were widespread and involved in a wide range of processes in cells. Examples of intramembrane proteases include \u03b3-secretase, which is implicated in Alzheimer's disease, and various site-2 proteases that regulate pathogenic circuits in bacteria.There are many similarities between soluble and intramembrane proteases. However, given that intramembrane proteases evolved within the hydrophobic environment of the membrane, whereas soluble proteases evolved in an aqueous environment, there should there should also be significant differences between them. The best understood intramembrane proteases in terms of their biochemistry are probably the rhomboid proteases. However, most studies of their function have been performed in detergent systems rather than in real membranes.Moin and Urban now report that the main strategy used by rhomboid proteases to identity the proteins that they selectively cut is completely different from that used by soluble proteases. Through a combination of biochemical and spectroscopic methods, they have discovered that rhomboid proteases identify the proteins they act on mainly by detecting changes in dynamic behavior: only those proteins that lose a stable helical structure when they exit the lipid phase to interact with the rhomboid protease will be cut by the rhomboid protease. Soluble proteases, on the other hand, achieve specificity by looking for proteins with a particular sequence of amino acids. The novel strategy used by rhomboid proteases allows them to patrol the membrane for unstable helices and selectively cut them. This discovery provides the first explanation of why these complicated enzymes evolved to have active sites immersed within the cell membrane.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00173.002",
"content_html": "<p hwp:id=\"p-5\">Proteases are enzymes that break the peptide bonds that hold proteins together, and have a central role in many physiological processes, including digestion, blood clotting and programmed cell death. An important characteristic of proteases is that they are highly selective, only cutting proteins that contain well-defined sequences of amino acids in accessible regions. Proteases that are soluble in water have been studied for over a century and are now well understood, as are proteases that need to be tethered to the membrane of a cell to work properly.<\/p>\n<p hwp:id=\"p-6\">In 1997 researchers discovered a protease that was immersed in the cell membrane, and it soon became clear that these intramembrane proteases were widespread and involved in a wide range of processes in cells. Examples of intramembrane proteases include &#x3B3;-secretase, which is implicated in Alzheimer's disease, and various site-2 proteases that regulate pathogenic circuits in bacteria.<\/p>\n<p hwp:id=\"p-7\">There are many similarities between soluble and intramembrane proteases. However, given that intramembrane proteases evolved within the hydrophobic environment of the membrane, whereas soluble proteases evolved in an aqueous environment, there should there should also be significant differences between them. The best understood intramembrane proteases in terms of their biochemistry are probably the rhomboid proteases. However, most studies of their function have been performed in detergent systems rather than in real membranes.<\/p>\n<p hwp:id=\"p-8\">Moin and Urban now report that the main strategy used by rhomboid proteases to identity the proteins that they selectively cut is completely different from that used by soluble proteases. Through a combination of biochemical and spectroscopic methods, they have discovered that rhomboid proteases identify the proteins they act on mainly by detecting changes in dynamic behavior: only those proteins that lose a stable helical structure when they exit the lipid phase to interact with the rhomboid protease will be cut by the rhomboid protease. Soluble proteases, on the other hand, achieve specificity by looking for proteins with a particular sequence of amino acids. The novel strategy used by rhomboid proteases allows them to patrol the membrane for unstable helices and selectively cut them. This discovery provides the first explanation of why these complicated enzymes evolved to have active sites immersed within the cell membrane.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00173.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00173.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00173.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00173",
"title": "Membrane immersion allows rhomboid proteases to achieve specificity by reading transmembrane segment dynamics",
"metadata": {
"authors": "S. M. Moin, S. Urban",
"journal": "eLife 2012"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:27:54Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:27:54Z",
"updated_at": "2013-07-25T09:27:54Z"
},
{
"id": 32,
"content": "Many biological processes oscillate with a period of roughly 24 hr, and the ability of organisms as diverse as bacteria and humans to maintain such circadian rhythms, even under conditions of continuous darkness, influences a range of phenomena, including sleep, migration and reproduction. One characteristic of circadian rhythms is that they can adjust to local time (with humans suffering from jet lag as they wait for this to happen).Experiments have shown that the circadian system in mammals relies on feedback loops that operate at the level of individual cells. These loops are controlled by two particular proteins, which comprise the transcription factor complex called BMAL1:CLK. Transcription factors cause particular sequences of bases in the DNA of cells to be transcribed into messenger RNA, thus starting the process by which target genes are expressed as proteins. In the case of BMAL1:CLK, these proteins are then modified, which inhibits any further transcription of the target genes. A reversal of these modifications is then followed by the synthesis of new proteins, which allows a new cycle of the transcription process to begin.The amounts of many messenger RNAs (mRNAs) in a cell also increases and decreases with a period of 24 hr, and it was generally assumed that this was due to the changes in the level of transcription. More recently, however, it was suggested that other processes, such as splicing and translation, might also contribute to rhythmic changes in the amount of mRNA associated with particular genes. Such post-transcriptional processes are known to have a role in other areas of cell biology, including aspects of the circadian system, but until very recently this had not been studied in detail for all genes.Now Menet et al. have directly assayed rhythmic transcription by measuring the amount of nascent mRNA being produced at a given time, six times a day, across all the genes in mouse liver cells using a high-throughput sequencing approach called Nascent-Seq. They compared this with the amount of liver mRNA expressed at six time points of the day. Although the authors found that many genes exhibit rhythmic mRNA expression in the mouse liver, about 70% of them did not show comparable transcriptional rhythms. Post-transcriptional regulation must, therefore, have a major role in the circadian system of mice and, presumably, other mammals.Menet et al. also found that the influence of CLK:BMAL1 differed from what was expected, which suggests that it collaborates with a number of other transcription factors to effect transcription of most target genes. In addition to showing that circadian systems of mammals are more complex than previously believed, the results also illustrate the potential of Nascent-Seq as a genome-wide assay technique for exploring a range of questions related to gene expression and gene regulation.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00011.002",
"content_html": "<p hwp:id=\"p-4\">Many biological processes oscillate with a period of roughly 24 hr, and the ability of organisms as diverse as bacteria and humans to maintain such circadian rhythms, even under conditions of continuous darkness, influences a range of phenomena, including sleep, migration and reproduction. One characteristic of circadian rhythms is that they can adjust to local time (with humans suffering from jet lag as they wait for this to happen).<\/p>\n<p hwp:id=\"p-5\">Experiments have shown that the circadian system in mammals relies on feedback loops that operate at the level of individual cells. These loops are controlled by two particular proteins, which comprise the transcription factor complex called BMAL1:CLK. Transcription factors cause particular sequences of bases in the DNA of cells to be transcribed into messenger RNA, thus starting the process by which target genes are expressed as proteins. In the case of BMAL1:CLK, these proteins are then modified, which inhibits any further transcription of the target genes. A reversal of these modifications is then followed by the synthesis of new proteins, which allows a new cycle of the transcription process to begin.<\/p>\n<p hwp:id=\"p-6\">The amounts of many messenger RNAs (mRNAs) in a cell also increases and decreases with a period of 24 hr, and it was generally assumed that this was due to the changes in the level of transcription. More recently, however, it was suggested that other processes, such as splicing and translation, might also contribute to rhythmic changes in the amount of mRNA associated with particular genes. Such post-transcriptional processes are known to have a role in other areas of cell biology, including aspects of the circadian system, but until very recently this had not been studied in detail for all genes.<\/p>\n<p hwp:id=\"p-7\">Now Menet et al. have directly assayed rhythmic transcription by measuring the amount of nascent mRNA being produced at a given time, six times a day, across all the genes in mouse liver cells using a high-throughput sequencing approach called Nascent-Seq. They compared this with the amount of liver mRNA expressed at six time points of the day. Although the authors found that many genes exhibit rhythmic mRNA expression in the mouse liver, about 70% of them did not show comparable transcriptional rhythms. Post-transcriptional regulation must, therefore, have a major role in the circadian system of mice and, presumably, other mammals.<\/p>\n<p hwp:id=\"p-8\">Menet et al. also found that the influence of CLK:BMAL1 differed from what was expected, which suggests that it collaborates with a number of other transcription factors to effect transcription of most target genes. In addition to showing that circadian systems of mammals are more complex than previously believed, the results also illustrate the potential of Nascent-Seq as a genome-wide assay technique for exploring a range of questions related to gene expression and gene regulation.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00011.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00011.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00011.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00011",
"title": "Nascent-Seq reveals novel features of mouse circadian transcriptional regulation",
"metadata": {
"authors": "J. S. Menet, J. Rodriguez, K. C. Abruzzi, M. Rosbash",
"journal": "eLife 2012"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:28:00Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:28:00Z",
"updated_at": "2013-07-25T09:28:00Z"
},
{
"id": 34,
"content": "Liver diseases related to the human hepatitis B virus (HBV) kill about 1 million people every year, and more than 350 million people around the world are infected with the virus. Some 15 million of these people are also infected with the hepatitis D virus (HDV), which is a satellite virus of HBV, and this places them at an even higher risk of liver diseases, including cancer. The viruses are known to enter liver cells by binding to receptors on their surface before being engulfed.Both HBV and HDV have outer coats that consist of three kinds of envelope proteins, and a region called the pre-S1 domain in one of them is known to have a central role in the interaction between the viruses and the receptors and, therefore, in infecting the cells. However, the identity of the HBV receptor has remained a mystery. Now Yan et al. have identified this receptor to be sodium taurocholate cotransporting polypeptide. This protein, known as NTCP for short, is normally involved in the circulation of bile acids in the body.In addition to humans, only two species are known to be susceptible to infection by human HBV and HDV\u2014chimpanzees and a small mammal known as the treeshrew. Yan et al. started by isolating primary liver cells from treeshrews, and then used a combination of advanced purification and mass spectrometry analysis to show that the NTCP on the surface of the cells interacts with the pre-S1 domain in HBV.The authors then performed a series of gene knockdown experiments on liver cells of both human and treeshrew origin: when the gene that codes for NTCP was silenced, HBV infection was greatly reduced. Moreover, they were able to transfect HepG2 cells\u2014which are widely used in research into liver disease, but are not susceptible to HBV and HDV infection\u2014with NTCP from humans and treeshrews to make them susceptible. Similarly, although monkeys are not susceptible to HBV, replacing just five amino acids in monkey NTCP with their human counterparts was enough to make the monkey NTCP a functional receptor for the viruses.In the past, basic research into HBV and the development of antiviral therapeutics have both been hindered by the lack of suitable in vitro infection systems and animal models. Now, the work of Yan et al. means that it will be possible to use NTCP-complemented HepG2 cells for challenges as diverse as fundamental studies of basic viral entry\/replication mechanisms and large-scale drug screening. It is also possible that HBV and HDV infection might interfere with some of the important physiological functions carried out by NTCP, so the latest work could also be of interest to medical scientists working on other diseases related to these infections.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00049.002",
"content_html": "<p hwp:id=\"p-5\">Liver diseases related to the human hepatitis B virus (HBV) kill about 1 million people every year, and more than 350 million people around the world are infected with the virus. Some 15 million of these people are also infected with the hepatitis D virus (HDV), which is a satellite virus of HBV, and this places them at an even higher risk of liver diseases, including cancer. The viruses are known to enter liver cells by binding to receptors on their surface before being engulfed.<\/p>\n<p hwp:id=\"p-6\">Both HBV and HDV have outer coats that consist of three kinds of envelope proteins, and a region called the pre-S1 domain in one of them is known to have a central role in the interaction between the viruses and the receptors and, therefore, in infecting the cells. However, the identity of the HBV receptor has remained a mystery. Now Yan et al. have identified this receptor to be sodium taurocholate cotransporting polypeptide. This protein, known as NTCP for short, is normally involved in the circulation of bile acids in the body.<\/p>\n<p hwp:id=\"p-7\">In addition to humans, only two species are known to be susceptible to infection by human HBV and HDV&#x2014;chimpanzees and a small mammal known as the treeshrew. Yan et al. started by isolating primary liver cells from treeshrews, and then used a combination of advanced purification and mass spectrometry analysis to show that the NTCP on the surface of the cells interacts with the pre-S1 domain in HBV.<\/p>\n<p hwp:id=\"p-8\">The authors then performed a series of gene knockdown experiments on liver cells of both human and treeshrew origin: when the gene that codes for NTCP was silenced, HBV infection was greatly reduced. Moreover, they were able to transfect HepG2 cells&#x2014;which are widely used in research into liver disease, but are not susceptible to HBV and HDV infection&#x2014;with NTCP from humans and treeshrews to make them susceptible. Similarly, although monkeys are not susceptible to HBV, replacing just five amino acids in monkey NTCP with their human counterparts was enough to make the monkey NTCP a functional receptor for the viruses.<\/p>\n<p hwp:id=\"p-9\">In the past, basic research into HBV and the development of antiviral therapeutics have both been hindered by the lack of suitable in vitro infection systems and animal models. Now, the work of Yan et al. means that it will be possible to use NTCP-complemented HepG2 cells for challenges as diverse as fundamental studies of basic viral entry\/replication mechanisms and large-scale drug screening. It is also possible that HBV and HDV infection might interfere with some of the important physiological functions carried out by NTCP, so the latest work could also be of interest to medical scientists working on other diseases related to these infections.<\/p>\n<p hwp:id=\"p-10\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00049.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00049.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00049.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00049",
"title": "Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus",
"metadata": {
"authors": "H. Yan, G. Zhong, G. Xu, W. He, Z. Jing, Z. Gao, Y. Huang, Y. Qi, B. Peng, H. Wang, L. Fu, M. Song, P. Chen, W. Gao, B. Ren, Y. Sun, T. Cai, X. Feng, J. Sui, W. Li",
"journal": "eLife 2012"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:28:07Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:28:07Z",
"updated_at": "2013-07-25T09:28:07Z"
},
{
"id": 35,
"content": "Single-celled microorganisms called archaea are one of the three domains of cellular life, along with bacteria and eukaryotes. Archaea are similar to bacteria in that they do not have nuclei, but genetically they have more in common with eukaryotes. Archaea are found in a wide range of habitats including the human colon, marshlands, the ocean and extreme environments such as hot springs and salt lakes.It has been known since the 1990s that the DNA of archaea is wrapped around histones to form complexes that closely resemble the nucleosomes found in eukaryotes, albeit with four rather than eight histone subunits. Nucleosomes are the fundamental units of chromatin, the highly-ordered and compact structure that all the DNA in a cell is packed into. Now we know exactly how many nucleosomes are present in a given cell for some eukaryotes, notably yeast, and to a good approximation we know the position of each nucleosome during a variety of metabolic states and physiological conditions. We can also quantify the nucleosome occupancy, which is measure of the length of time that the nucleosomes spend in contact with the DNA: this is a critical piece of information because it determines the level of access that other proteins, including those that regulate gene expression, have to the DNA. These advances have been driven in large part by advances in technology, notably high-density microarrays for genome wide-studies of nucleosome occupancy, and massively parallel sequencing for direct nucleosome sequencing.Ammar et al. have used these techniques to explore how the DNA of Haloferax volcanii, a species of archaea that thrives in the hyper-salty waters of the Dead Sea, is organized on a genome-wide basis. Despite some clear differences between the genomes of archaea and eukaryotes\u2014for example, genomic DNA is typically circular in archaea and linear in eukaryotes\u2014they found that the genome of Hfx. volcanii is organized into chromatin in a way that is remarkably similar to that seen in all eukaryotic genomes studied to date. This is surprising given that the chromatin in eukaryotes is confined to the nucleus, whereas there are no such constraints in archaea. In particular, Ammar et al. found that those regions of the DNA near the ends of genes that mark where the transcription of the DNA into RNA should begin and end contain have lower nucleosome occupancy than other regions. Moreover, the overall level of occupancy in Hfx. volcanii was twice that of eukaryotes, which is what one would expect given that nucleosomes in archaea contain half as many histone subunits as nucleosomes in eukaryotes. Ammar et al. also confirmed that that the degree of nucleosome occupancy is correlated with gene expression.These two findings\u2014the similarities between the chromatin in archaea and eukaryotes, and the correlation between nucleosome occupancy and gene expression in archaea\u2014raise an interesting evolutionary possibility: the initial function of nucleosomes and chromatin formation might have been for the regulation of gene expression rather than the packaging of DNA. This is consistent with two decades of research that has shown that there is an extraordinary and complex relationship between the structure of chromatin and the process of gene expression. It is possible, therefore, that as the early eukaryotes evolved, nucleosomes and chromatin started to package DNA into compact structures that, among other things, helped to prevent DNA damage, and that this subsequently enabled the early eukaryotes to flourish.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00078.002",
"content_html": "<p hwp:id=\"p-4\">Single-celled microorganisms called archaea are one of the three domains of cellular life, along with bacteria and eukaryotes. Archaea are similar to bacteria in that they do not have nuclei, but genetically they have more in common with eukaryotes. Archaea are found in a wide range of habitats including the human colon, marshlands, the ocean and extreme environments such as hot springs and salt lakes.<\/p>\n<p hwp:id=\"p-5\">It has been known since the 1990s that the DNA of archaea is wrapped around histones to form complexes that closely resemble the nucleosomes found in eukaryotes, albeit with four rather than eight histone subunits. Nucleosomes are the fundamental units of chromatin, the highly-ordered and compact structure that all the DNA in a cell is packed into. Now we know exactly how many nucleosomes are present in a given cell for some eukaryotes, notably yeast, and to a good approximation we know the position of each nucleosome during a variety of metabolic states and physiological conditions. We can also quantify the nucleosome occupancy, which is measure of the length of time that the nucleosomes spend in contact with the DNA: this is a critical piece of information because it determines the level of access that other proteins, including those that regulate gene expression, have to the DNA. These advances have been driven in large part by advances in technology, notably high-density microarrays for genome wide-studies of nucleosome occupancy, and massively parallel sequencing for direct nucleosome sequencing.<\/p>\n<p hwp:id=\"p-6\">Ammar et al. have used these techniques to explore how the DNA of <italic>Haloferax volcanii<\/italic>, a species of archaea that thrives in the hyper-salty waters of the Dead Sea, is organized on a genome-wide basis. Despite some clear differences between the genomes of archaea and eukaryotes&#x2014;for example, genomic DNA is typically circular in archaea and linear in eukaryotes&#x2014;they found that the genome of <italic>Hfx. volcanii<\/italic> is organized into chromatin in a way that is remarkably similar to that seen in all eukaryotic genomes studied to date. This is surprising given that the chromatin in eukaryotes is confined to the nucleus, whereas there are no such constraints in archaea. In particular, Ammar et al. found that those regions of the DNA near the ends of genes that mark where the transcription of the DNA into RNA should begin and end contain have lower nucleosome occupancy than other regions. Moreover, the overall level of occupancy in <italic>Hfx. volcanii<\/italic> was twice that of eukaryotes, which is what one would expect given that nucleosomes in archaea contain half as many histone subunits as nucleosomes in eukaryotes. Ammar et al. also confirmed that that the degree of nucleosome occupancy is correlated with gene expression.<\/p>\n<p hwp:id=\"p-7\">These two findings&#x2014;the similarities between the chromatin in archaea and eukaryotes, and the correlation between nucleosome occupancy and gene expression in archaea&#x2014;raise an interesting evolutionary possibility: the initial function of nucleosomes and chromatin formation might have been for the regulation of gene expression rather than the packaging of DNA. This is consistent with two decades of research that has shown that there is an extraordinary and complex relationship between the structure of chromatin and the process of gene expression. It is possible, therefore, that as the early eukaryotes evolved, nucleosomes and chromatin started to package DNA into compact structures that, among other things, helped to prevent DNA damage, and that this subsequently enabled the early eukaryotes to flourish.<\/p>\n<p hwp:id=\"p-8\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00078.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00078.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00078.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00078",
"title": "Chromatin is an ancient innovation conserved between Archaea and Eukarya",
"metadata": {
"authors": "R. Ammar, D. Torti, K. Tsui, M. Gebbia, T. Durbic, G. D. Bader, G. Giaever, C. Nislow",
"journal": "eLife 2012"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:28:18Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:28:18Z",
"updated_at": "2013-07-25T09:28:18Z"
},
{
"id": 36,
"content": "If all of the DNA in a human cell was stretched out, it would be about 2 m long. The nucleus of a human cell, on the other hand, has a diameter of just 6 \u03bcm, so the DNA molecules that carry all the genetic information in the cell need to be carefully folded to fit inside the nucleus. Cells meet this challenge by combining their DNA molecules with proteins to form a compact and highly organized structure called chromatin. Packaging DNA into chromatin also reduces damage to it.But what happens when the cell needs to express the genes carried by the DNA as proteins or other gene products? The answer is that the compact structure of chromatin relaxes and opens up, which allows the DNA to be transcribed into messenger RNA. Indeed, packing DNA into chromatin makes this process more reliable, thus ensuring that the cell only produces proteins and other gene products when it needs them. However, because cross-talk between neighboring genes could potentially disrupt or change gene expression patterns, cells evolved special elements called boundaries or insulators to stop this from happening. These elements subdivide eukaryotic chromosomes into functionally autonomous chromatin domains.Since the protein factors implicated in boundary function seemed to be active in all tissues and cell types, it was assumed for many years that these boundaries and the resulting chromatin domains were fixed. However, a number of recent studies have shown that boundary activity can be subject to regulation, and thus chromatin domains are dynamic structures that can be defined and redefined during development to alter patterns of gene expression.Aoki et al. report the isolation and characterization of a new fruit fly boundary factor that, unlike previously characterized factors, is active only during a specific stage of development. The Elba factor is also unusual in that it is made of three different proteins, known as Elba1, Elba2, and Elba3, and all three must be present for it to bind to DNA. While Elba2 is present during most stages of development, the other two Elba proteins are only present during early embryonic development, so the boundary factor is only active in early embryos. In addition to revealing a new mechanism for controlling boundary activity as an organism develops, the studies of Aoki et al. provide further evidence that chromatin domains can be dynamic.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00171.002",
"content_html": "<p hwp:id=\"p-4\">If all of the DNA in a human cell was stretched out, it would be about 2 m long. The nucleus of a human cell, on the other hand, has a diameter of just 6 &#x3BC;m, so the DNA molecules that carry all the genetic information in the cell need to be carefully folded to fit inside the nucleus. Cells meet this challenge by combining their DNA molecules with proteins to form a compact and highly organized structure called chromatin. Packaging DNA into chromatin also reduces damage to it.<\/p>\n<p hwp:id=\"p-5\">But what happens when the cell needs to express the genes carried by the DNA as proteins or other gene products? The answer is that the compact structure of chromatin relaxes and opens up, which allows the DNA to be transcribed into messenger RNA. Indeed, packing DNA into chromatin makes this process more reliable, thus ensuring that the cell only produces proteins and other gene products when it needs them. However, because cross-talk between neighboring genes could potentially disrupt or change gene expression patterns, cells evolved special elements called boundaries or insulators to stop this from happening. These elements subdivide eukaryotic chromosomes into functionally autonomous chromatin domains.<\/p>\n<p hwp:id=\"p-6\">Since the protein factors implicated in boundary function seemed to be active in all tissues and cell types, it was assumed for many years that these boundaries and the resulting chromatin domains were fixed. However, a number of recent studies have shown that boundary activity can be subject to regulation, and thus chromatin domains are dynamic structures that can be defined and redefined during development to alter patterns of gene expression.<\/p>\n<p hwp:id=\"p-7\">Aoki et al. report the isolation and characterization of a new fruit fly boundary factor that, unlike previously characterized factors, is active only during a specific stage of development. The Elba factor is also unusual in that it is made of three different proteins, known as Elba1, Elba2, and Elba3, and all three must be present for it to bind to DNA. While Elba2 is present during most stages of development, the other two Elba proteins are only present during early embryonic development, so the boundary factor is only active in early embryos. In addition to revealing a new mechanism for controlling boundary activity as an organism develops, the studies of Aoki et al. provide further evidence that chromatin domains can be dynamic.<\/p>\n<p hwp:id=\"p-8\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00171.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00171.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00171.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00171",
"title": "Elba, a novel developmentally regulated chromatin boundary factor is a hetero-tripartite DNA binding complex",
"metadata": {
"authors": "T. Aoki, A. Sarkeshik, J. Yates, P. Schedl",
"journal": "eLife 2012"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:28:21Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:28:21Z",
"updated_at": "2013-07-25T09:28:21Z"
},
{
"id": 37,
"content": "Most cells are surrounded by a semipermeable membrane, and although this membrane allows very few molecules to pass through it, cells can use transmembrane proteins to overcome this barrier. Some of these proteins import glucose, amino acids and other nutrients into the cell, while others transport ions into or out of the cell. Ion transport across the cell membrane is essential for a wide variety of biological processes, including signal transduction and the generation of electrical impulses in nerve cells.The pores that allow ions to travel through the cell membrane are known as ion channels, and most channels allow only one type of ion\u2014usually sodium, calcium or potassium (K+) ions\u2014to pass through them. There are many different types of ion channels and they are classified according to the type of ion they allow to pass through them, and by the gating mechanism that is used to open and close the channel. For example, ligand-gated K+ channels facilitate the passage of potassium ions and are opened and closed by ligands binding and unbinding to and from the channel.Most K+ channels are made up of four identical subunits, and in the majority of ligand-gated K+ channels in prokaryotes, each of these subunits will have one or two ligand-binding RCK domains (where RCK stands for regulating the conductance of K+). This is also true for some K+ channels in eukaryotes. While it is known that RCK domains are responsible for regulating the transport of potassium ions across the cell membranes of diverse organisms, little is known about the structure or gating mechanisms of K+ channels that are gated by more than one ligand.Kong et al. have studied a ligand-gated K+ channel called GsuK that has two RCK domains per subunit and is found in the bacterium G. sulfurreducens. They found that the opening process was mediated by a ligand that contains adenine, such as NAD+ or ADP, and the channel was closed by the presence of calcium ions. And by determining multiple crystal structures, Kong et al. were able to understand, from a structural point of view, how these ligands regulate this channel, and to propose a gating mechanism that is distinct from the mechanisms that are known to control other potassium channels. DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00184.002",
"content_html": "<p hwp:id=\"p-5\">Most cells are surrounded by a semipermeable membrane, and although this membrane allows very few molecules to pass through it, cells can use transmembrane proteins to overcome this barrier. Some of these proteins import glucose, amino acids and other nutrients into the cell, while others transport ions into or out of the cell. Ion transport across the cell membrane is essential for a wide variety of biological processes, including signal transduction and the generation of electrical impulses in nerve cells.<\/p>\n<p hwp:id=\"p-6\">The pores that allow ions to travel through the cell membrane are known as ion channels, and most channels allow only one type of ion&#x2014;usually sodium, calcium or potassium (K<sup>+<\/sup>) ions&#x2014;to pass through them. There are many different types of ion channels and they are classified according to the type of ion they allow to pass through them, and by the gating mechanism that is used to open and close the channel. For example, ligand-gated K<sup>+<\/sup> channels facilitate the passage of potassium ions and are opened and closed by ligands binding and unbinding to and from the channel.<\/p>\n<p hwp:id=\"p-7\">Most K<sup>+<\/sup> channels are made up of four identical subunits, and in the majority of ligand-gated K<sup>+<\/sup> channels in prokaryotes, each of these subunits will have one or two ligand-binding RCK domains (where RCK stands for regulating the conductance of K<sup>+<\/sup>). This is also true for some K<sup>+<\/sup> channels in eukaryotes. While it is known that RCK domains are responsible for regulating the transport of potassium ions across the cell membranes of diverse organisms, little is known about the structure or gating mechanisms of K<sup>+<\/sup> channels that are gated by more than one ligand.<\/p>\n<p hwp:id=\"p-8\">Kong et al. have studied a ligand-gated K<sup>+<\/sup> channel called GsuK that has two RCK domains per subunit and is found in the bacterium <italic>G. sulfurreducens<\/italic>. They found that the opening process was mediated by a ligand that contains adenine, such as NAD<sup>+<\/sup> or ADP, and the channel was closed by the presence of calcium ions. And by determining multiple crystal structures, Kong et al. were able to understand, from a structural point of view, how these ligands regulate this channel, and to propose a gating mechanism that is distinct from the mechanisms that are known to control other potassium channels. <\/p><p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00184.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00184.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00184.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00184",
"title": "Distinct gating mechanisms revealed by the structures of a multi-ligand gated K+ channel",
"metadata": {
"authors": "C. Kong, W. Zeng, S. Ye, L. Chen, D. B. Sauer, Y. Lam, M. G. Derebe, Y. Jiang",
"journal": "eLife 2012"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:28:24Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:28:24Z",
"updated_at": "2013-07-25T09:28:24Z"
},
{
"id": 38,
"content": "In 1975 Samuel Preston published a classic paper that showed life expectancy was related to national income. When plotted as a graph, with national income on the horizontal axis and life expectancy on the vertical axis, the Preston curve shows that an increase in national income leads to an increase in life expectancy, with the increases in life expectancy becoming proportionally smaller as income increases. Moreover, Preston showed that innovations in healthcare (such as vaccinations, public health education, and sanitation systems) were increasing the maximum life expectancy that can be achieved for any given national income (defined as GDP per capita): this can be seen by comparing the Preston curves from 1960 and 2000 shown in Figure 1A. Indeed, global life expectancy increased by about 25 years over the course of the 20th century, which suggests that the level of daily income needed to achieve a certain life expectancy should be falling over time.To explore this in greater detail, Hum et al. have constructed a mathematical model to investigate the relationship between health and income across different age groups and income levels. They found that most of the gains in life expectancy for low- and middle-income countries have been achieved by reducing child mortality, with gains in life expectancy for adults being restricted mostly to high-income countries. The model, which is based on the mathematical equations used to describe the kinetics of enzymatic reactions, makes it possible to estimate the improvements of health that can be made over time, and also the level of income that is needed to achieve these improvements.In particular, Hum et al. have established a new parameter, the critical income, which is the level of income needed to achieve half of the maximal health found in high-income countries for the year in question. Based on available data from over 150 countries, they found that critical incomes fell by half for children between 1970 and 2007, but doubled for adult males during the same period. The rise in critical income for adults was due partly to the HIV epidemic and increases in smoking in low- and middle-income countries, reflecting the growing problems presented by noncommunicable diseases. Hum et al. conclude that increasing the survival among adults will require increased use of proven cost-effective interventions, most notably tobacco control, plus new research to identify low-cost drugs, diagnostics, and other public health strategies.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00051.002",
"content_html": "<p hwp:id=\"p-4\">In 1975 Samuel Preston published a classic paper that showed life expectancy was related to national income. When plotted as a graph, with national income on the horizontal axis and life expectancy on the vertical axis, the Preston curve shows that an increase in national income leads to an increase in life expectancy, with the increases in life expectancy becoming proportionally smaller as income increases. Moreover, Preston showed that innovations in healthcare (such as vaccinations, public health education, and sanitation systems) were increasing the maximum life expectancy that can be achieved for any given national income (defined as GDP per capita): this can be seen by comparing the Preston curves from 1960 and 2000 shown in Figure 1A. Indeed, global life expectancy increased by about 25 years over the course of the 20th century, which suggests that the level of daily income needed to achieve a certain life expectancy should be falling over time.<\/p>\n<p hwp:id=\"p-5\">To explore this in greater detail, Hum et al. have constructed a mathematical model to investigate the relationship between health and income across different age groups and income levels. They found that most of the gains in life expectancy for low- and middle-income countries have been achieved by reducing child mortality, with gains in life expectancy for adults being restricted mostly to high-income countries. The model, which is based on the mathematical equations used to describe the kinetics of enzymatic reactions, makes it possible to estimate the improvements of health that can be made over time, and also the level of income that is needed to achieve these improvements.<\/p>\n<p hwp:id=\"p-6\">In particular, Hum et al. have established a new parameter, the critical income, which is the level of income needed to achieve half of the maximal health found in high-income countries for the year in question. Based on available data from over 150 countries, they found that critical incomes fell by half for children between 1970 and 2007, but doubled for adult males during the same period. The rise in critical income for adults was due partly to the HIV epidemic and increases in smoking in low- and middle-income countries, reflecting the growing problems presented by noncommunicable diseases. Hum et al. conclude that increasing the survival among adults will require increased use of proven cost-effective interventions, most notably tobacco control, plus new research to identify low-cost drugs, diagnostics, and other public health strategies.<\/p>\n<p hwp:id=\"p-7\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00051.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00051.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00051.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00051",
"title": "Global divergence in critical income for adult and childhood survival: analyses of mortality using Michaelis-Menten",
"metadata": {
"authors": "R. J. Hum, P. Jha, A. M. McGahan, Y.-L. Cheng",
"journal": "eLife 2012"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:28:31Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:28:31Z",
"updated_at": "2013-07-25T09:28:31Z"
},
{
"id": 39,
"content": "The DNA molecules in cells are continuously bombarded with radiation, chemicals and other agents, and it is important for cells to repair the damage caused by these before the process of cell division begins. Most DNA molecules consist of two single strands of DNA that are held together by hydrogen bonds in the familiar double-helix structure. Of the various types of damage that DNA molecules are prone to, double-strand breaks are among the most dangerous because they can lead to cancer if they are not repaired.DNA molecules use four bases\u2014adenine, cytosine, guanine, and thymine\u2014to store genetic information. In single-stranded DNA these bases are attached to a backbone made of alternating sugar and phosphate groups. A crucial feature of double-stranded DNA is that the sequences of bases in the two strands are complementary to each other\u2014adenine is always paired with thymine, and cytosine is always paired with guanine. However, the hydrogen bonds that hold the pairs of bases together are quite weak, which means that the two strands of the double helix can be pulled apart quite easily. The ease with which these bonds can be formed and broken is crucial for many genetic processes.One way to repair a double strand break is to replace the damaged stretch of DNA with an undamaged stretch from another DNA molecule. This process of swapping DNA molecules, which is called strand exchange, is catalyzed by a protein that is able to interact with two DNA molecules at the same time. An important first step within this process is identifying the stretch of DNA that can be used to repair the break.Ragunathan et al. now report evidence from experiments on Escherichia coli that support a model in which the protein catalyst (RecA in the case of E. coli) combines with a single strand of DNA to form a filamentous DNA\u2013protein complex (RecA filament) that can then slide along a double-stranded DNA molecule to search for a complementary sequence of base pairs. High-resolution fluorescent imaging reveals that the RecA filament is able to sample several hundred base pairs before the filament dissociates from the DNA and rebinds at a different location. The sliding was largely driven by electrostatic interactions between the RecA filament and the double-stranded DNA, and the filament was capable of identifying matching sequences that contained as few as six matching bases.Ragunathan et al. estimate that sliding is about two orders of magnitude faster at finding matching sequences compared to mechanisms that do not involve sliding, such as models that rely solely on chance encounters between DNA molecules and the RecA filament. By showing that a DNA\u2013protein complex can slide along another DNA molecule to search for a target, these results could lead to new insights into other systems in which it is necessary for protein-nucleic acid complexes to locate a particular sequence of bases.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00067.002",
"content_html": "<p hwp:id=\"p-6\">The DNA molecules in cells are continuously bombarded with radiation, chemicals and other agents, and it is important for cells to repair the damage caused by these before the process of cell division begins. Most DNA molecules consist of two single strands of DNA that are held together by hydrogen bonds in the familiar double-helix structure. Of the various types of damage that DNA molecules are prone to, double-strand breaks are among the most dangerous because they can lead to cancer if they are not repaired.<\/p>\n<p hwp:id=\"p-7\">DNA molecules use four bases&#x2014;adenine, cytosine, guanine, and thymine&#x2014;to store genetic information. In single-stranded DNA these bases are attached to a backbone made of alternating sugar and phosphate groups. A crucial feature of double-stranded DNA is that the sequences of bases in the two strands are complementary to each other&#x2014;adenine is always paired with thymine, and cytosine is always paired with guanine. However, the hydrogen bonds that hold the pairs of bases together are quite weak, which means that the two strands of the double helix can be pulled apart quite easily. The ease with which these bonds can be formed and broken is crucial for many genetic processes.<\/p>\n<p hwp:id=\"p-8\">One way to repair a double strand break is to replace the damaged stretch of DNA with an undamaged stretch from another DNA molecule. This process of swapping DNA molecules, which is called strand exchange, is catalyzed by a protein that is able to interact with two DNA molecules at the same time. An important first step within this process is identifying the stretch of DNA that can be used to repair the break.<\/p>\n<p hwp:id=\"p-9\">Ragunathan et al. now report evidence from experiments on <italic>Escherichia coli<\/italic> that support a model in which the protein catalyst (RecA in the case of <italic>E. coli<\/italic>) combines with a single strand of DNA to form a filamentous DNA&#x2013;protein complex (RecA filament) that can then slide along a double-stranded DNA molecule to search for a complementary sequence of base pairs. High-resolution fluorescent imaging reveals that the RecA filament is able to sample several hundred base pairs before the filament dissociates from the DNA and rebinds at a different location. The sliding was largely driven by electrostatic interactions between the RecA filament and the double-stranded DNA, and the filament was capable of identifying matching sequences that contained as few as six matching bases.<\/p>\n<p hwp:id=\"p-10\">Ragunathan et al. estimate that sliding is about two orders of magnitude faster at finding matching sequences compared to mechanisms that do not involve sliding, such as models that rely solely on chance encounters between DNA molecules and the RecA filament. By showing that a DNA&#x2013;protein complex can slide along another DNA molecule to search for a target, these results could lead to new insights into other systems in which it is necessary for protein-nucleic acid complexes to locate a particular sequence of bases.<\/p>\n<p hwp:id=\"p-11\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00067.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00067.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00067.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00067",
"title": "RecA filament sliding on DNA facilitates homology search",
"metadata": {
"authors": "K. Ragunathan, C. Liu, T. Ha",
"journal": "eLife 2012"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:28:34Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:28:34Z",
"updated_at": "2013-07-25T09:28:34Z"
},
{
"id": 40,
"content": "A hallmark of the nervous systems of all mammals is their capacity to undergo changes in function that are shaped by experience. This phenomenon underlies the ability of our brains to develop properly and to learn, and also enables various sensory systems\u2014including the visual, auditory and olfactory systems\u2014to perform optimally in diverse environments.In most mammals, a high-functioning olfactory system is essential for carrying out tasks that are crucial for survival, such as finding food, avoiding predators and mating. In general, sensory systems have to decipher only a limited collection of stimuli, but the olfactory system must be able to process information from thousands of distinct odors that are found in a given environment and which may vary dramatically from one environment to the next. Each odor-sensing neuron in the nose of a mammal contains just one kind of odorant receptor protein, although mammalian genomes typically encode 1000 or so different kinds of receptor proteins. This suggests that it might be possible to \u2018tune\u2019 the olfactory system to a particular environment by changing the relative numbers of the different types of neurons. Indeed, it is known that the relative abundance of each type of odor-sensing neuron changes with age and experience, and that these changes might be caused by variations in the lifespans of the neurons.Although our understanding of how these experience-dependent changes are orchestrated at the molecular level is far from complete, it is clear that adjustments in the levels of specific gene products is necessary. But how do experiences alter the levels of gene products to give rise to lasting changes in the brain? One hypothesis is that changes to a structure called chromatin are key to this process: chromatin is an assembly of DNA molecules, which are quite long, and organizing proteins, mostly proteins known as histones, that together form a compact structure that can fit inside the nucleus of a cell.Santoro and Dulac have now discovered a previously uncharacterized protein called H2BE that is found only in the odor-sensing neurons of mice. H2BE is a variant of a protein called H2B, which is a well-known histone. They found that in odor-sensing neurons, H2BE replaces H2B to an extent that depends on the amount of activity experienced by the neuron: H2BE is nearly undetectable in highly active neurons, but almost completely replaces H2B in neurons that are inactive. Moreover, genetic manipulation showed that the deletion of H2BE significantly extended the lifespan of neurons, whereas elevated levels of H2BE shortened their lifespan. These findings reveal an extraordinary process that involves inactive odor-sensing neurons being depleted relative to active ones over time.How does H2BE, which differs from H2B by just five amino acids, cause such dramatic changes in neuronal composition? One hint comes from evidence that these amino acids disrupt interactions between chromatin and \u2018effector\u2019 proteins, which modulate gene activity. Consistent with this, Santoro and Dulac have found that the replacement of H2B by H2BE strongly alters gene activity, although the precise mechanism by which these alterations regulate neuronal lifespans remains to be determined. Understanding this process in detail, and exploring if similar phenomena are involved in experience-dependent changes elsewhere in the nervous system, are fascinating areas of future research.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00070.002",
"content_html": "<p hwp:id=\"p-4\">A hallmark of the nervous systems of all mammals is their capacity to undergo changes in function that are shaped by experience. This phenomenon underlies the ability of our brains to develop properly and to learn, and also enables various sensory systems&#x2014;including the visual, auditory and olfactory systems&#x2014;to perform optimally in diverse environments.<\/p>\n<p hwp:id=\"p-5\">In most mammals, a high-functioning olfactory system is essential for carrying out tasks that are crucial for survival, such as finding food, avoiding predators and mating. In general, sensory systems have to decipher only a limited collection of stimuli, but the olfactory system must be able to process information from thousands of distinct odors that are found in a given environment and which may vary dramatically from one environment to the next. Each odor-sensing neuron in the nose of a mammal contains just one kind of odorant receptor protein, although mammalian genomes typically encode 1000 or so different kinds of receptor proteins. This suggests that it might be possible to &#x2018;tune&#x2019; the olfactory system to a particular environment by changing the relative numbers of the different types of neurons. Indeed, it is known that the relative abundance of each type of odor-sensing neuron changes with age and experience, and that these changes might be caused by variations in the lifespans of the neurons.<\/p>\n<p hwp:id=\"p-6\">Although our understanding of how these experience-dependent changes are orchestrated at the molecular level is far from complete, it is clear that adjustments in the levels of specific gene products is necessary. But how do experiences alter the levels of gene products to give rise to lasting changes in the brain? One hypothesis is that changes to a structure called chromatin are key to this process: chromatin is an assembly of DNA molecules, which are quite long, and organizing proteins, mostly proteins known as histones, that together form a compact structure that can fit inside the nucleus of a cell.<\/p>\n<p hwp:id=\"p-7\">Santoro and Dulac have now discovered a previously uncharacterized protein called H2BE that is found only in the odor-sensing neurons of mice. H2BE is a variant of a protein called H2B, which is a well-known histone. They found that in odor-sensing neurons, H2BE replaces H2B to an extent that depends on the amount of activity experienced by the neuron: H2BE is nearly undetectable in highly active neurons, but almost completely replaces H2B in neurons that are inactive. Moreover, genetic manipulation showed that the deletion of H2BE significantly extended the lifespan of neurons, whereas elevated levels of H2BE shortened their lifespan. These findings reveal an extraordinary process that involves inactive odor-sensing neurons being depleted relative to active ones over time.<\/p>\n<p hwp:id=\"p-8\">How does H2BE, which differs from H2B by just five amino acids, cause such dramatic changes in neuronal composition? One hint comes from evidence that these amino acids disrupt interactions between chromatin and &#x2018;effector&#x2019; proteins, which modulate gene activity. Consistent with this, Santoro and Dulac have found that the replacement of H2B by H2BE strongly alters gene activity, although the precise mechanism by which these alterations regulate neuronal lifespans remains to be determined. Understanding this process in detail, and exploring if similar phenomena are involved in experience-dependent changes elsewhere in the nervous system, are fascinating areas of future research.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00070.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00070.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00070.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00070",
"title": "The activity-dependent histone variant H2BE modulates the life span of olfactory neurons",
"metadata": {
"authors": "S. W. Santoro, C. Dulac",
"journal": "eLife 2012"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:28:37Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:28:37Z",
"updated_at": "2013-07-25T09:28:37Z"
},
{
"id": 41,
"content": "The central nervous system relies on electrical signals travelling along neurons and through synapses at high speeds. Signals often have to pass between two neurons, or from a neuron to a muscle fiber, and the nervous system relies on a process called membrane fusion to ensure that the neurotransmitter molecules that carry the signal across the synapses are released as quickly as possible. Membrane fusion is an important process in many areas of biology, including intracellular transport and fertilization, but it occurs much faster (millisecond time scale) in the nervous system than anywhere else in the body. The reasons for this have long been a mystery, although calcium ions are known to trigger the fusion process.The fusion of two biological membranes is similar in many regards to the way that small soap bubbles merge together to form large bubbles. Just as soap bubbles can form a variety of discernible intermediate structures when they merge, so can biological membranes. This means that it is possible to produce a so-called hemifusion intermediate in which the outer layers of the membranes have merged, but the inner layers have not, so it is not possible for anything\u2014such as serotonin, dopamine and other neurotransmitter molecules\u2014to transfer from one membrane to the other.Diao et al. have used a combination of advanced optical imaging and cryogenic electron microscopy to explore membrane fusion between synthetic membranes that contained reconstituted synaptic proteins, including synaptotagmin and a family of protein receptors called SNAREs. When calcium ions were injected into the synthetic system, the basic characteristics of neurotransmitter release\u2014such as membrane fusion on a millisecond time scale\u2014was observed. Contrary to some theories of membrane fusion, the fastest fusion events did not begin or proceed via a discernible hemifusion intermediate state. Rather, these events proceeded from a \u2018point contact\u2019 state in which the membranes were close to each other (just 1\u20135 nm apart) without being fused, and were ready to undergo fast fusion once the calcium ions had been injected. And when Diao et al. introduced a protein called complexin, which is known to be important for fast neurotransmitter release in vivo, they observed more immediate fusion events and fewer events that involved a hemifusion intermediate.With a synthetic system it is possible to perform experiments that are currently not possible with live neurons, and this has allowed Diao et al. to clarify the roles of the individual components in the process of membrane fusion, and could prove useful in efforts to develop novel therapeutic treatments to combat neurological disorders.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00109.002",
"content_html": "<p hwp:id=\"p-6\">The central nervous system relies on electrical signals travelling along neurons and through synapses at high speeds. Signals often have to pass between two neurons, or from a neuron to a muscle fiber, and the nervous system relies on a process called membrane fusion to ensure that the neurotransmitter molecules that carry the signal across the synapses are released as quickly as possible. Membrane fusion is an important process in many areas of biology, including intracellular transport and fertilization, but it occurs much faster (millisecond time scale) in the nervous system than anywhere else in the body. The reasons for this have long been a mystery, although calcium ions are known to trigger the fusion process.<\/p>\n<p hwp:id=\"p-7\">The fusion of two biological membranes is similar in many regards to the way that small soap bubbles merge together to form large bubbles. Just as soap bubbles can form a variety of discernible intermediate structures when they merge, so can biological membranes. This means that it is possible to produce a so-called hemifusion intermediate in which the outer layers of the membranes have merged, but the inner layers have not, so it is not possible for anything&#x2014;such as serotonin, dopamine and other neurotransmitter molecules&#x2014;to transfer from one membrane to the other.<\/p>\n<p hwp:id=\"p-8\">Diao et al. have used a combination of advanced optical imaging and cryogenic electron microscopy to explore membrane fusion between synthetic membranes that contained reconstituted synaptic proteins, including synaptotagmin and a family of protein receptors called SNAREs. When calcium ions were injected into the synthetic system, the basic characteristics of neurotransmitter release&#x2014;such as membrane fusion on a millisecond time scale&#x2014;was observed. Contrary to some theories of membrane fusion, the fastest fusion events did not begin or proceed via a discernible hemifusion intermediate state. Rather, these events proceeded from a &#x2018;point contact&#x2019; state in which the membranes were close to each other (just 1&#x2013;5 nm apart) without being fused, and were ready to undergo fast fusion once the calcium ions had been injected. And when Diao et al. introduced a protein called complexin, which is known to be important for fast neurotransmitter release in vivo, they observed more immediate fusion events and fewer events that involved a hemifusion intermediate.<\/p>\n<p hwp:id=\"p-9\">With a synthetic system it is possible to perform experiments that are currently not possible with live neurons, and this has allowed Diao et al. to clarify the roles of the individual components in the process of membrane fusion, and could prove useful in efforts to develop novel therapeutic treatments to combat neurological disorders.<\/p>\n<p hwp:id=\"p-10\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00109.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00109.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00109.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00109",
"title": "Synaptic proteins promote calcium-triggered fast transition from point contact to full fusion",
"metadata": {
"authors": "J. Diao, P. Grob, D. J. Cipriano, M. Kyoung, Y. Zhang, S. Shah, A. Nguyen, M. Padolina, A. Srivastava, M. Vrljic, A. Shah, E. Nogales, S. Chu, A. T. Brunger",
"journal": "eLife 2012"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:28:40Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:28:40Z",
"updated_at": "2013-07-25T09:28:40Z"
},
{
"id": 42,
"content": "For multicellular organisms, the innate immune system is the first immunological defence against infection, rapidly recognizing and responding to the presence of any pathogen. Many different cell types contribute to the innate immunity, including fibroblasts, epithelial cells, dendritic cells and macrophages. Once alerted to injury or infection, these cells release proteins called cytokines, interferons and chemokines into the blood or directly into tissue. These proteins act as messengers and interact with receptors on the surfaces of other cells in the immune system, stimulating them to join the battle against the infection.Detecting nucleic acids such as DNA is an important part of recognizing pathogens and infectious agents, particularly viruses, and activating the innate immune system. However, while the presence of DNA in the cytoplasm is known to initiate an innate immune response, we do not fully understand how this foreign DNA is sensed, or how the innate immune system is activated once foreign DNA has been detected.Here Ferguson et al. report that a well-known complex of three proteins, collectively called DNA-dependent protein kinase, is able to activate an innate immune response when it detects foreign DNA. This enzyme, called DNA-PK for short, is best known for its ability to repair broken DNA inside the nucleus. Now Ferguson et al. have found that it is also present at high levels within fibroblasts, cells that are often primary targets of viral infection, and they go on to explain how the detection of DNA by DNA-PK triggers a sequence of events that leads to the innate immune response being activated. These events include the transcription of type I interferon, chemokines and cytokines in a manner that depends on the presence IRF-3, a transcription factor that has a central role in the response of the immune system to viral infection.By identifying a role for DNA-PK in the cytoplasm as a DNA sensor, the work of Ferguson et al. increases our understanding of innate immunity. It may also, in the future, lead to an improved understanding of autoimmunity, and might also assist in the development of more immunogenic vaccines based on DNA or microbes that contain DNA.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00047.002",
"content_html": "<p hwp:id=\"p-6\">For multicellular organisms, the innate immune system is the first immunological defence against infection, rapidly recognizing and responding to the presence of any pathogen. Many different cell types contribute to the innate immunity, including fibroblasts, epithelial cells, dendritic cells and macrophages. Once alerted to injury or infection, these cells release proteins called cytokines, interferons and chemokines into the blood or directly into tissue. These proteins act as messengers and interact with receptors on the surfaces of other cells in the immune system, stimulating them to join the battle against the infection.<\/p>\n<p hwp:id=\"p-7\">Detecting nucleic acids such as DNA is an important part of recognizing pathogens and infectious agents, particularly viruses, and activating the innate immune system. However, while the presence of DNA in the cytoplasm is known to initiate an innate immune response, we do not fully understand how this foreign DNA is sensed, or how the innate immune system is activated once foreign DNA has been detected.<\/p>\n<p hwp:id=\"p-8\">Here Ferguson et al. report that a well-known complex of three proteins, collectively called DNA-dependent protein kinase, is able to activate an innate immune response when it detects foreign DNA. This enzyme, called DNA-PK for short, is best known for its ability to repair broken DNA inside the nucleus. Now Ferguson et al. have found that it is also present at high levels within fibroblasts, cells that are often primary targets of viral infection, and they go on to explain how the detection of DNA by DNA-PK triggers a sequence of events that leads to the innate immune response being activated. These events include the transcription of type I interferon, chemokines and cytokines in a manner that depends on the presence IRF-3, a transcription factor that has a central role in the response of the immune system to viral infection.<\/p>\n<p hwp:id=\"p-9\">By identifying a role for DNA-PK in the cytoplasm as a DNA sensor, the work of Ferguson et al. increases our understanding of innate immunity. It may also, in the future, lead to an improved understanding of autoimmunity, and might also assist in the development of more immunogenic vaccines based on DNA or microbes that contain DNA.<\/p>\n<p hwp:id=\"p-10\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00047.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00047.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00047.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00047",
"title": "DNA-PK is a DNA sensor for IRF-3-dependent innate immunity",
"metadata": {
"authors": "B. J. Ferguson, D. S. Mansur, N. E. Peters, H. Ren, G. L. Smith",
"journal": "eLife 2012"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:28:42Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:28:42Z",
"updated_at": "2013-07-25T09:28:42Z"
},
{
"id": 210,
"content": "The paper focuses on Snowflake, a Western lowland gorilla, who happened to be albino, leading to his rise to fame. Snowflake died of skin cancer in 2003. Scientists investigated Snowflake's genome after death. \r\n\r\nIt was found that approximately 12 % of Snowflake\u2019s genome contained stretches of DNA where the two copies inherited from each parent were identical. Such large amounts of genomic overlap is usually a good indication that that the parents are closely related \u2013 which in the case of Snowflake, points to an illicit union between either an uncle and a niece, or an aunt and a nephew. Researchers were fairly certain that this inbreeding led to the subsequent albinism of Snowflake. The reduction in genetic variation that comes about when these similar genomes combine often allows otherwise recessive traits to be expressed. In this case, Snowflake\u2019s gene for albinism \u2013 known as SLC45A2\u2014was the most striking product of this effect.\r\n\r\nIt's also important to add that gorillas rarely engage in inbreeding. Females often move from group to group to avoid advances from relatives, preventing inbreeding. Therefore this is a rather surprising finding - and reveals evidence of this activity occurring in the wild. ",
"content_html": "<p>The paper focuses on Snowflake, a Western lowland gorilla, who happened to be albino, leading to his rise to fame. Snowflake died of skin cancer in 2003. Scientists investigated Snowflake\u2019s genome after death. <\/p>\n\n<p>It was found that approximately 12 % of Snowflake\u2019s genome contained stretches of DNA where the two copies inherited from each parent were identical. Such large amounts of genomic overlap is usually a good indication that that the parents are closely related \u2013 which in the case of Snowflake, points to an illicit union between either an uncle and a niece, or an aunt and a nephew. Researchers were fairly certain that this inbreeding led to the subsequent albinism of Snowflake. The reduction in genetic variation that comes about when these similar genomes combine often allows otherwise recessive traits to be expressed. In this case, Snowflake\u2019s gene for albinism \u2013 known as SLC45A2\u2014was the most striking product of this effect.<\/p>\n\n<p>It\u2019s also important to add that gorillas rarely engage in inbreeding. Females often move from group to group to avoid advances from relatives, preventing inbreeding. Therefore this is a rather surprising finding - and reveals evidence of this activity occurring in the wild. <\/p>\n",
"user": {
"email": "james.balm@biomedcentral.com"
},
"paper": {
"identifier": "doi:10.1186\/1471-2164-14-363",
"title": "The genome sequencing of an albino Western lowland gorilla reveals inbreeding in the wild",
"metadata": {
"authors": "Javier Prado-Martinez, Irene Hernando-Herraez, Belen Lorente-Galdos, Marc Dabad, Oscar Ramirez, Carlos Baeza-Delgado, Carlos Morcillo-Suarez, Can Alkan, Fereydoun Hormozdiari, Emanuele Raineri, Jordi Estell\u00e9, Marcos Fernandez-Callejo, M\u00f2nica Valles, Lars Ritscher, Torsten Sch\u00f6neberg, Elisa de la Calle-Mustienes, S\u00f2nia Casillas, Raquel Rubio-Acero, Marta Mel\u00e9, Johannes Engelken, Mario Caceres, Jose Gomez-Skarmeta, Marta Gut, Jaume Bertranpetit, Ivo G Gut, Teresa Abello, Evan E Eichler, Ismael Mingarro, Carles Lalueza-Fox, Arcadi Navarro, Tomas Marques-Bonet",
"journal": "BMC GenomicsBMC Genomics 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-11-19T13:35:57Z",
"updated_at": "2013-11-19T13:35:57Z"
},
"created_at": "2013-11-19T13:35:57Z",
"updated_at": "2013-11-19T14:50:41Z"
},
{
"id": 321,
"content": "Septins are proteins that provide structural support for cells as they divide. Yeast cells are known to have seven types of septins, which have been widely studied, and 13 different septins have been identified in human cells, although they all seem similar to those found in yeast. Mutations in the genes that carry the genetic code for septins lead to a range of debilitating conditions in humans, including neurodegenerative diseases and male infertility.An enzyme called Cdc42 is thought to have a key role in the formation of ring-like structures by septins before a cell divides, and in the subsequent dismantling of these rings after the cell has divided. A pair of proteins, called Gic1 and Gic2, is known to be critical for the formation of the septin rings, but the details of the interactions between these two proteins, Cdc42 and the septins are sketchy.Now Sadian et al. have used two imaging approaches\u2014electron microscopy and cryo-electron tomography\u2014to scrutinise the role of Gic1 in greater detail in yeast cells. Gic1 interacts with specific subunits within adjacent septins, and these interactions have the effect of crosslinking the septins and stabilizing them in long filaments. However, high concentrations of the enzyme Cdc42 block the interaction between the Gic1 proteins and the subunits, causing the filaments to be dismantled. A future challenge will be to elucidate the interaction of these proteins in molecular detail using other techniques, in particular X-ray crystallography.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.01085.002",
"content_html": "<p hwp:id=\"p-5\">Septins are proteins that provide structural support for cells as they divide. Yeast cells are known to have seven types of septins, which have been widely studied, and 13 different septins have been identified in human cells, although they all seem similar to those found in yeast. Mutations in the genes that carry the genetic code for septins lead to a range of debilitating conditions in humans, including neurodegenerative diseases and male infertility.<\/p>\n<p hwp:id=\"p-6\">An enzyme called Cdc42 is thought to have a key role in the formation of ring-like structures by septins before a cell divides, and in the subsequent dismantling of these rings after the cell has divided. A pair of proteins, called Gic1 and Gic2, is known to be critical for the formation of the septin rings, but the details of the interactions between these two proteins, Cdc42 and the septins are sketchy.<\/p>\n<p hwp:id=\"p-7\">Now Sadian et al. have used two imaging approaches&#x2014;electron microscopy and cryo-electron tomography&#x2014;to scrutinise the role of Gic1 in greater detail in yeast cells. Gic1 interacts with specific subunits within adjacent septins, and these interactions have the effect of crosslinking the septins and stabilizing them in long filaments. However, high concentrations of the enzyme Cdc42 block the interaction between the Gic1 proteins and the subunits, causing the filaments to be dismantled. A future challenge will be to elucidate the interaction of these proteins in molecular detail using other techniques, in particular X-ray crystallography.<\/p>\n<p hwp:id=\"p-8\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.01085.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.01085.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.01085.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.01085",
"title": "The role of Cdc42 and Gic1 in the regulation of septin filament formation and dissociation",
"metadata": {
"authors": "Y. Sadian, C. Gatsogiannis, C. Patasi, O. Hofnagel, R. S. Goody, M. Farkasovsky, S. Raunser",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2014-01-13T00:43:19Z",
"updated_at": "2014-01-13T00:43:19Z"
},
"created_at": "2014-01-13T00:43:19Z",
"updated_at": "2014-01-13T00:43:19Z"
},
{
"id": 44,
"content": "Cancer is a broad term to describe over 200 diseases that are caused by cells proliferating in an out-of-control manner. Cell replication and division are normally very tightly regulated, and as cells become old, damaged or mutated, they are either repaired or undergo programmed cell death (apoptosis). However, if defective cells continue to replicate, the resulting clusters of abnormal cells can become cancerous.With so many different types of cancer, there is no \u2018magic bullet\u2019 to cure all of them. Many cancer therapies are targeted, relying on drugs that block the spread of cancer by interfering with specific molecules involved in the growth and progression of certain tumors. However, the fact that diseased cells replicate faster than normal cells in many forms of cancer makes it possible to use non-specific drugs, such as doxorubicin, to treat tumors when targeted therapies are not available.Doxorubicin can induce DNA breaks in a variety of different cancers by inhibiting the activity of topoisomerase II but a consistent relationship between the inhibition of this enzyme and the blocking of cell proliferation has not been established. This lack of understanding of the mechanism through which doxorubicin inhibits cell proliferation makes it difficult to identify cancer patients who are most likely to benefit from doxorubicin treatment.Denard et al. have now shown that doxorubicin blocks cell replication by cleaving a transcription factor called CREB3L1. This latest work builds on previous work in which they showed that cleavage of this transcription factor can inhibit the replication of cells infected with hepatitis C virus. It has been known since 2000 that CREB3L1 is a membrane protein with one end inside the lumen of the endoplasmic reticulum, and the other end (which is terminated with an NH2 group) in the cytosol of the cell. When CREB3L1 is cleaved, the NH2-terminal domain travels into the nucleus of the cell, where it drives the transcription of genes that suppress the cell cycle. Denard et al. clearly show that doxorubicin triggers the cleavage of CREB3L1 by stimulating the production of ceramide molecules. Thus, It might be possible, with further research, to use CREB3L1 as a biomarker to identify tumors that are suitable for treatment by doxorubicin.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00090.002",
"content_html": "<p hwp:id=\"p-4\">Cancer is a broad term to describe over 200 diseases that are caused by cells proliferating in an out-of-control manner. Cell replication and division are normally very tightly regulated, and as cells become old, damaged or mutated, they are either repaired or undergo programmed cell death (apoptosis). However, if defective cells continue to replicate, the resulting clusters of abnormal cells can become cancerous.<\/p>\n<p hwp:id=\"p-5\">With so many different types of cancer, there is no &#x2018;magic bullet&#x2019; to cure all of them. Many cancer therapies are targeted, relying on drugs that block the spread of cancer by interfering with specific molecules involved in the growth and progression of certain tumors. However, the fact that diseased cells replicate faster than normal cells in many forms of cancer makes it possible to use non-specific drugs, such as doxorubicin, to treat tumors when targeted therapies are not available.<\/p>\n<p hwp:id=\"p-6\">Doxorubicin can induce DNA breaks in a variety of different cancers by inhibiting the activity of topoisomerase II but a consistent relationship between the inhibition of this enzyme and the blocking of cell proliferation has not been established. This lack of understanding of the mechanism through which doxorubicin inhibits cell proliferation makes it difficult to identify cancer patients who are most likely to benefit from doxorubicin treatment.<\/p>\n<p hwp:id=\"p-7\">Denard et al. have now shown that doxorubicin blocks cell replication by cleaving a transcription factor called CREB3L1. This latest work builds on previous work in which they showed that cleavage of this transcription factor can inhibit the replication of cells infected with hepatitis C virus. It has been known since 2000 that CREB3L1 is a membrane protein with one end inside the lumen of the endoplasmic reticulum, and the other end (which is terminated with an NH<sub>2<\/sub> group) in the cytosol of the cell. When CREB3L1 is cleaved, the NH<sub>2<\/sub>-terminal domain travels into the nucleus of the cell, where it drives the transcription of genes that suppress the cell cycle. Denard et al. clearly show that doxorubicin triggers the cleavage of CREB3L1 by stimulating the production of ceramide molecules. Thus, It might be possible, with further research, to use CREB3L1 as a biomarker to identify tumors that are suitable for treatment by doxorubicin.<\/p>\n<p hwp:id=\"p-8\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00090.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00090.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00090.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00090",
"title": "Doxorubicin blocks proliferation of cancer cells through proteolytic activation of CREB3L1",
"metadata": {
"authors": "B. Denard, C. Lee, J. Ye",
"journal": "eLife 2012"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:28:55Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:28:55Z",
"updated_at": "2013-07-25T09:28:55Z"
},
{
"id": 45,
"content": "Malaria is an infectious disease that is estimated to kill more than half a million people every year, mostly young children in Africa. It is spread by mosquitos that are infected with Plasmodium parasites that attack red blood cells in the human body. Plasmodium falciparum, the species that is responsible for most of these deaths, causes malaria by entering red blood cells and releasing antigens that travel to the surface of the cells, where they change the adhesion properties. This causes the infected red blood cells to accumulate in small blood vessels, surface capillaries or the brain, which can have severe consequences for the person infected.P. falciparum is particularly dangerous because of its ability to vary the antigens displayed on the cell surface: this process, known as antigenic variation, helps to maintain infections for extended periods of time by allowing the antigens to stay one step ahead of the immune system (a process known as immune escape). The origins of antigenic variation lie in the fact that each P. falciparum genome has a repertoire of between 50 and 60 var genes that code for the variability of a major antigen that is responsible for immune escape in malaria. Molecular sequencing has shown that local parasite populations contain thousands of different types of var genes: hence, meiotic recombination in the mosquito can create a vast number of combinations of var repertoires.Artzy-Randrup et al. have developed a computational model of this highly diverse and complex system to address the following question: is a local pathogen population composed of largely random and ephemeral repertoires of these genes, or is it structured into independently circulating strains? Their model goes beyond previous models by including interactions within the local host population that arise as a result of indirect competition between different strains of the pathogen for available hosts: this competition is influenced by the history of infection and, therefore, by the patterns of immunity within the host population. Previous models included within-host processes but not these higher, local population-level interactions.The model simulates the dynamics of all the unique combinations of var genes in a population of hosts, and shows that even with high rates of reproduction, the parasite population self-organizes into a limited number of coexisting strains: the distinct var repertoires of these strains only weakly overlap, suggesting that the immune response of the host population has been partitioned into distinct niches. By investigating genetic variation at both antigenic sites and regions of the genome that do not code for antigens, Artzy-Randrup et al. suggest that immune selection\u2014the selection imposed on var repertoires by the build up of specific immunity at the population level\u2014plays a central role in structuring parasite diversity.The new model should lead to a better understanding of the epidemiology of Plasmodium and other pathogens that work in similar ways, including Trypanosoma brucei (sleeping sickness), Borellia burgdorferi (Lyme disease) and Giardia lamblia (gastroenteritis), and help with global efforts to eliminate malaria and other diseases.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00093.002",
"content_html": "<p hwp:id=\"p-4\">Malaria is an infectious disease that is estimated to kill more than half a million people every year, mostly young children in Africa. It is spread by mosquitos that are infected with <italic>Plasmodium<\/italic> parasites that attack red blood cells in the human body. <italic>Plasmodium falciparum<\/italic>, the species that is responsible for most of these deaths, causes malaria by entering red blood cells and releasing antigens that travel to the surface of the cells, where they change the adhesion properties. This causes the infected red blood cells to accumulate in small blood vessels, surface capillaries or the brain, which can have severe consequences for the person infected.<\/p>\n<p hwp:id=\"p-5\"><italic>P. falciparum<\/italic> is particularly dangerous because of its ability to vary the antigens displayed on the cell surface: this process, known as antigenic variation, helps to maintain infections for extended periods of time by allowing the antigens to stay one step ahead of the immune system (a process known as immune escape). The origins of antigenic variation lie in the fact that each <italic>P. falciparum<\/italic> genome has a repertoire of between 50 and 60 <italic>var<\/italic> genes that code for the variability of a major antigen that is responsible for immune escape in malaria. Molecular sequencing has shown that local parasite populations contain thousands of different types of <italic>var<\/italic> genes: hence, meiotic recombination in the mosquito can create a vast number of combinations of <italic>var<\/italic> repertoires.<\/p>\n<p hwp:id=\"p-6\">Artzy-Randrup et al. have developed a computational model of this highly diverse and complex system to address the following question: is a local pathogen population composed of largely random and ephemeral repertoires of these genes, or is it structured into independently circulating strains? Their model goes beyond previous models by including interactions within the local host population that arise as a result of indirect competition between different strains of the pathogen for available hosts: this competition is influenced by the history of infection and, therefore, by the patterns of immunity within the host population. Previous models included within-host processes but not these higher, local population-level interactions.<\/p>\n<p hwp:id=\"p-7\">The model simulates the dynamics of all the unique combinations of <italic>var<\/italic> genes in a population of hosts, and shows that even with high rates of reproduction, the parasite population self-organizes into a limited number of coexisting strains: the distinct <italic>var<\/italic> repertoires of these strains only weakly overlap, suggesting that the immune response of the host population has been partitioned into distinct niches. By investigating genetic variation at both antigenic sites and regions of the genome that do not code for antigens, Artzy-Randrup et al. suggest that immune selection&#x2014;the selection imposed on <italic>var<\/italic> repertoires by the build up of specific immunity at the population level&#x2014;plays a central role in structuring parasite diversity.<\/p>\n<p hwp:id=\"p-8\">The new model should lead to a better understanding of the epidemiology of <italic>Plasmodium<\/italic> and other pathogens that work in similar ways, including <italic>Trypanosoma brucei<\/italic> (sleeping sickness), <italic>Borellia burgdorferi<\/italic> (Lyme disease) and <italic>Giardia lamblia<\/italic> (gastroenteritis), and help with global efforts to eliminate malaria and other diseases.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00093.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00093.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00093.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00093",
"title": "Population structuring of multi-copy, antigen-encoding genes in Plasmodium falciparum",
"metadata": {
"authors": "Y. Artzy-Randrup, M. M. Rorick, K. Day, D. Chen, A. P. Dobson, M. Pascual",
"journal": "eLife 2012"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:28:58Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:28:58Z",
"updated_at": "2013-07-25T09:28:58Z"
},
{
"id": 46,
"content": "Diploid organisms contain two sets of chromosomes, one set inherited from the mother and the other from the father. Humans, for example, have 23 pairs of chromosomes, and the chromosomes within each pair are said to be homologous because they are similar to each other in a number of ways, including length and shape. When it comes time for one of these cells to duplicate, each chromosome is first replicated to generate a pair of identical chromosomes called sister chromatids, which subsequently separate in a cell division process known as mitosis to produce two identical daughter cells.While most cells proliferate via mitotic cell division, the germ cells that generate gametes in the form of sperm or eggs undergo a different cell division known as meiosis. This process reduces the number of chromosomes by a factor of two, so that the original number of chromosomes is restored by the fusion of gametes during sexual reproduction. During meiotic cell division, a single round of DNA replication is followed by two consecutive rounds of nuclear division called meiosis I and meiosis II. During meiosis I, homologous chromosomes are separated. Subsequently, during meiosis II, the sister chromatids separate to produce a total of four products, each with half the number of chromosomes as the original cell.The separation of homologous chromosomes or sister chromatids relies on them being pulled apart by microtubules. One end of each microtubule is attached to a protein-based structure called a kinetochore, which is assembled onto the centromere of each chromosome. The other end of each microtubule is attached to a structure that is called a centrosome in human cells and a spindle pole body in yeast cells. Human cells have two centrosomes, which reside on the opposite poles of the cell, and likewise for the spindle pole bodies in yeast cells. In mitotic cells and in meiosis II, microtubules attach to kinetochores in a way that means the sister chromatids are pulled apart. During meiosis I, on the other hand, they attach to kinetochores in a manner so the homologous chromosomes are pulled apart.Miller et al. now show how the timing of the interaction between the kinetochore and microtubules is critical to ensure that the homologous chromosomes are separated during meiosis I. They found that premature interactions resulted in the separation of sister chromatids (as happens in mitosis) rather than the separation of homologous chromosomes, as is supposed to happen in meiosis I. They also showed that cells prevent such premature interactions by dismantling the outer regions of the kinetochore and reducing the levels of enzymes called CDKs in the cell. These results demonstrate that preventing premature microtubule\u2013kinetochore interactions is essential for establishing a meiosis I-specific chromosome architecture, and they also provide fresh insights into how the molecular machinery that is responsible for mitotic chromosome segregation can be modulated to achieve meiosis.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00117.002",
"content_html": "<p hwp:id=\"p-5\">Diploid organisms contain two sets of chromosomes, one set inherited from the mother and the other from the father. Humans, for example, have 23 pairs of chromosomes, and the chromosomes within each pair are said to be homologous because they are similar to each other in a number of ways, including length and shape. When it comes time for one of these cells to duplicate, each chromosome is first replicated to generate a pair of identical chromosomes called sister chromatids, which subsequently separate in a cell division process known as mitosis to produce two identical daughter cells.<\/p>\n<p hwp:id=\"p-6\">While most cells proliferate via mitotic cell division, the germ cells that generate gametes in the form of sperm or eggs undergo a different cell division known as meiosis. This process reduces the number of chromosomes by a factor of two, so that the original number of chromosomes is restored by the fusion of gametes during sexual reproduction. During meiotic cell division, a single round of DNA replication is followed by two consecutive rounds of nuclear division called meiosis I and meiosis II. During meiosis I, homologous chromosomes are separated. Subsequently, during meiosis II, the sister chromatids separate to produce a total of four products, each with half the number of chromosomes as the original cell.<\/p>\n<p hwp:id=\"p-7\">The separation of homologous chromosomes or sister chromatids relies on them being pulled apart by microtubules. One end of each microtubule is attached to a protein-based structure called a kinetochore, which is assembled onto the centromere of each chromosome. The other end of each microtubule is attached to a structure that is called a centrosome in human cells and a spindle pole body in yeast cells. Human cells have two centrosomes, which reside on the opposite poles of the cell, and likewise for the spindle pole bodies in yeast cells. In mitotic cells and in meiosis II, microtubules attach to kinetochores in a way that means the sister chromatids are pulled apart. During meiosis I, on the other hand, they attach to kinetochores in a manner so the homologous chromosomes are pulled apart.<\/p>\n<p hwp:id=\"p-8\">Miller et al. now show how the timing of the interaction between the kinetochore and microtubules is critical to ensure that the homologous chromosomes are separated during meiosis I. They found that premature interactions resulted in the separation of sister chromatids (as happens in mitosis) rather than the separation of homologous chromosomes, as is supposed to happen in meiosis I. They also showed that cells prevent such premature interactions by dismantling the outer regions of the kinetochore and reducing the levels of enzymes called CDKs in the cell. These results demonstrate that preventing premature microtubule&#x2013;kinetochore interactions is essential for establishing a meiosis I-specific chromosome architecture, and they also provide fresh insights into how the molecular machinery that is responsible for mitotic chromosome segregation can be modulated to achieve meiosis.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00117.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00117.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00117.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00117",
"title": "Meiosis I chromosome segregation is established through regulation of microtubule-kinetochore interactions",
"metadata": {
"authors": "M. P. Miller, E. Unal, G. A. Brar, A. Amon",
"journal": "eLife 2012"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:29:01Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:29:01Z",
"updated_at": "2013-07-25T09:29:01Z"
},
{
"id": 47,
"content": "Sensory neurons carry information from sensory cells in the eyes, ears and other sensory organs to the brain and spinal cord so that they can coordinate the body's response to its environment and various stimuli. The sensory organs responsible for four of the traditional senses\u2014vision, hearing, smell and taste\u2014are relatively small and self-contained: however, the sensory organ responsible for touch is as big as the body itself. Moreover, a variety of many different types of sensory cells in the skin allow the body to respond to temperature, pain, itches and a range of other external stimuli.Despite more than a century of research, relatively little is known about the morphology of the complex networks (arbors) of sensory neurons that send signals towards the central nervous system. This is mainly due to difficulties involved in imaging intact skin, the way that different arbors overlap and intermingle, and the relatively large distances that separate the bodies of neuronal cells and the farthest reaches of their arbors.Wu et al. employed an imaging method that exploits the Cre-Lox system that is already widely used in genetics. In this approach a Cre enzyme is used to remove a region of DNA that is flanked by two genetically engineered Lox sequences. Wu et al. used a gene that codes for an enzyme marker (alkaline phosphatase) that previous investigators had into the DNA of mice. The gene was inserted in such a way that it was only expressed in sensory neurons that innervate the skin when Cre-Lox recombination had removed an adjacent segment of DNA. Moreover, Wu et al. used this reporter gene in combination with a modified Cre enzyme that only enters the nuclei of cells in the presence of a drug (Tamoxifen), so the probability that the marker gene is expressed is determined by the concentration of Tamoxifen. By administering a low level of Tamoxifen to pregnant mice, it was possible to label a very small number of sensory neurons in each embryo. Individual neurons that express the alkaline phosphatase marker were visualized with a histochemical reaction that rendered them dark purple. The remainder of the tissue remained unstained.Based on quantitative analyses of the morphologies of more than 700 arbors, Wu et al. identified 10 distinct types of neurons. Of the two types of neurons with the largest arbors, one makes contact with \u223c200 hair follicles, with the nerve endings completely encircling the follicles; the other type of arbor contains several thousand branches, with a total length for all of the branches summing to as much as one meter in length. The next challenge is to study the morphologies of neurons in tissues other than the skin, and also the neurons involved in other sensory systems, and to explore the cellular and developmental mechanisms responsible for the morphological diversity found in these initial experiments.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00181.002",
"content_html": "<p hwp:id=\"p-4\">Sensory neurons carry information from sensory cells in the eyes, ears and other sensory organs to the brain and spinal cord so that they can coordinate the body's response to its environment and various stimuli. The sensory organs responsible for four of the traditional senses&#x2014;vision, hearing, smell and taste&#x2014;are relatively small and self-contained: however, the sensory organ responsible for touch is as big as the body itself. Moreover, a variety of many different types of sensory cells in the skin allow the body to respond to temperature, pain, itches and a range of other external stimuli.<\/p>\n<p hwp:id=\"p-5\">Despite more than a century of research, relatively little is known about the morphology of the complex networks (arbors) of sensory neurons that send signals towards the central nervous system. This is mainly due to difficulties involved in imaging intact skin, the way that different arbors overlap and intermingle, and the relatively large distances that separate the bodies of neuronal cells and the farthest reaches of their arbors.<\/p>\n<p hwp:id=\"p-6\">Wu et al. employed an imaging method that exploits the Cre-Lox system that is already widely used in genetics. In this approach a Cre enzyme is used to remove a region of DNA that is flanked by two genetically engineered Lox sequences. Wu et al. used a gene that codes for an enzyme marker (alkaline phosphatase) that previous investigators had into the DNA of mice. The gene was inserted in such a way that it was only expressed in sensory neurons that innervate the skin when Cre-Lox recombination had removed an adjacent segment of DNA. Moreover, Wu et al. used this reporter gene in combination with a modified Cre enzyme that only enters the nuclei of cells in the presence of a drug (Tamoxifen), so the probability that the marker gene is expressed is determined by the concentration of Tamoxifen. By administering a low level of Tamoxifen to pregnant mice, it was possible to label a very small number of sensory neurons in each embryo. Individual neurons that express the alkaline phosphatase marker were visualized with a histochemical reaction that rendered them dark purple. The remainder of the tissue remained unstained.<\/p>\n<p hwp:id=\"p-7\">Based on quantitative analyses of the morphologies of more than 700 arbors, Wu et al. identified 10 distinct types of neurons. Of the two types of neurons with the largest arbors, one makes contact with &#x223C;200 hair follicles, with the nerve endings completely encircling the follicles; the other type of arbor contains several thousand branches, with a total length for all of the branches summing to as much as one meter in length. The next challenge is to study the morphologies of neurons in tissues other than the skin, and also the neurons involved in other sensory systems, and to explore the cellular and developmental mechanisms responsible for the morphological diversity found in these initial experiments.<\/p>\n<p hwp:id=\"p-8\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00181.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00181.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00181.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00181",
"title": "Morphologic diversity of cutaneous sensory afferents revealed by genetically directed sparse labeling",
"metadata": {
"authors": "H. Wu, J. Williams, J. Nathans",
"journal": "eLife 2012"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:29:03Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:29:03Z",
"updated_at": "2013-07-25T09:29:03Z"
},
{
"id": 48,
"content": "Gene expression in eukaryotic cells can be controlled in a number of different ways, including various epigenetic mechanisms that do not involve making changes to DNA sequences that define the genes themselves. A well-known epigenetic mechanism for silencing genes in vertebrates is DNA methylation\u2014the addition of a methyl group (CH3) to cytosine, which is one of the four bases found in the DNA. Methylation is thought to silence genes by preventing transcription factors from binding to the DNA, and also by recruiting proteins that inhibit the transcription of DNA.DNA methylation occurs naturally throughout the genome, mostly at positions where cytosine is bonded to guanine to form a CpG dinucleotide. While the cytosine bases in most CpG dinucleotides are methylated, there are short stretches of DNA known as CpG islands that contain a high proportion of unmethylated CpG dinucleotides. These islands contain a large number of cytosine and guanine bases, and they are often found at or near transcription start sites.The lack of methylation at CpG islands has long been assumed to have a passive role in gene expression, leaving the DNA easily accessible and available for transcription factors to bind and initiate transcription. However, recent work suggests that CpG islands may have a more active role. In particular, it has been shown that specific proteins bind to CpG islands to create chromatin environments that are more favourable for the initiation of gene expression. Moreover, a subset of CpG islands can also bind polycomb-group proteins, including the polycomb repressive complex 1 (PRC1) that silence gene expression. These complexes have an important role in the regulation of genes during early development in animals, but the mechanism by which PRC1 recognizes CpG islands in mammals has remained enigmatic.Farcas et al. now reveal that a protein, KDM2B (FBXL10), can recognize CpG islands and recruit PRC1 to them. To achieve this, KDM2B encodes a DNA binding domain that specifically recognizes non-methylated CpG dinucleotides. By interacting biochemically with a variant PRC1 complex, KDM2B then nucleates PRC1 at CpG islands, and PRC1 activity silences certain polycomb target genes in embryonic stem cells. Surprisingly, Farcas et al. also find low but appreciable levels of PRC1 at most CpG islands genome-wide, in addition to the high levels of PRC1 at selected islands: this suggests that KDM2B may sample the whole genome to find CpG islands where PRC1 can establish silencing. An improved understanding of the polycomb repressive system, and the role of CpG islands within it, could lead to new insights into the role of epigenetic mechanisms in mammalian development.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00205.002",
"content_html": "<p hwp:id=\"p-5\">Gene expression in eukaryotic cells can be controlled in a number of different ways, including various epigenetic mechanisms that do not involve making changes to DNA sequences that define the genes themselves. A well-known epigenetic mechanism for silencing genes in vertebrates is DNA methylation&#x2014;the addition of a methyl group (CH<sub>3<\/sub>) to cytosine, which is one of the four bases found in the DNA. Methylation is thought to silence genes by preventing transcription factors from binding to the DNA, and also by recruiting proteins that inhibit the transcription of DNA.<\/p>\n<p hwp:id=\"p-6\">DNA methylation occurs naturally throughout the genome, mostly at positions where cytosine is bonded to guanine to form a CpG dinucleotide. While the cytosine bases in most CpG dinucleotides are methylated, there are short stretches of DNA known as CpG islands that contain a high proportion of unmethylated CpG dinucleotides. These islands contain a large number of cytosine and guanine bases, and they are often found at or near transcription start sites.<\/p>\n<p hwp:id=\"p-7\">The lack of methylation at CpG islands has long been assumed to have a passive role in gene expression, leaving the DNA easily accessible and available for transcription factors to bind and initiate transcription. However, recent work suggests that CpG islands may have a more active role. In particular, it has been shown that specific proteins bind to CpG islands to create chromatin environments that are more favourable for the initiation of gene expression. Moreover, a subset of CpG islands can also bind polycomb-group proteins, including the polycomb repressive complex 1 (PRC1) that silence gene expression. These complexes have an important role in the regulation of genes during early development in animals, but the mechanism by which PRC1 recognizes CpG islands in mammals has remained enigmatic.<\/p>\n<p hwp:id=\"p-8\">Farcas et al. now reveal that a protein, KDM2B (FBXL10), can recognize CpG islands and recruit PRC1 to them. To achieve this, KDM2B encodes a DNA binding domain that specifically recognizes non-methylated CpG dinucleotides. By interacting biochemically with a variant PRC1 complex, KDM2B then nucleates PRC1 at CpG islands, and PRC1 activity silences certain polycomb target genes in embryonic stem cells. Surprisingly, Farcas et al. also find low but appreciable levels of PRC1 at most CpG islands genome-wide, in addition to the high levels of PRC1 at selected islands: this suggests that KDM2B may sample the whole genome to find CpG islands where PRC1 can establish silencing. An improved understanding of the polycomb repressive system, and the role of CpG islands within it, could lead to new insights into the role of epigenetic mechanisms in mammalian development.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00205.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00205.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00205.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00205",
"title": "KDM2B links the Polycomb Repressive Complex 1 (PRC1) to recognition of CpG islands",
"metadata": {
"authors": "A. M. Farcas, N. P. Blackledge, I. Sudbery, H. K. Long, J. F. McGouran, N. R. Rose, S. Lee, D. Sims, A. Cerase, T. W. Sheahan, H. Koseki, N. Brockdorff, C. P. Ponting, B. M. Kessler, R. J. Klose",
"journal": "eLife 2012"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:29:06Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:29:06Z",
"updated_at": "2013-07-25T09:29:06Z"
},
{
"id": 212,
"content": "A fertilised egg is a single cell that can grow into a complex animal with many different types of cell. The specialised cells are formed through a process known as cell <a href=\"http:\/\/en.wikipedia.org\/wiki\/Cellular_differentiation\">differentiation<\/a>. During differentiation sets of genes are switched on and off, but sometimes the control system can fail. When this happens to cells that are part of the <a href=\"http:\/\/en.wikipedia.org\/wiki\/Immune_system\">immune system<\/a>, the result can be an <a href=\"http:\/\/en.wikipedia.org\/wiki\/Autoimmune_disease\">autoimmune disease<\/a>.\r\n<p> \r\nT-helper (Th) cells can activate other cells in the immune system. The <a href=\"http:\/\/en.wikipedia.org\/wiki\/T_helper_17_cell\">Th17<\/a> sub-group of helper cells become specialised in defending mucous membranes from bacteria and fungi. They are also thought to be involved in autoimmune diseases, such as psoriasis and Crohn's disease. Better understanding of the differentiation of these cells might help in the identification of targets for therapeutic interventions.\r\n<p>\r\nDifferentiation is controlled by proteins called <a href=\"http:\/\/en.wikipedia.org\/wiki\/Transcription_factor\">transcription factors<\/a> (TFs) that can bind to specific sections of the DNA sequence. <a href=\"http:\/\/en.wikipedia.org\/wiki\/RAR-related_orphan_receptor_gamma\">ROR&gamma;t<\/a> is understood to be a master regulator of transcription, but several other TFs are also required for activation of the full differentiation programme. In this study data obtained from different experimental approaches were integrated to obtain a network of the TFs, and the genes under their control.\r\n<p>\r\nThe work involved a study of <a href=\"http:\/\/en.wikipedia.org\/wiki\/Naive_T_cell\">Th0<\/a> cells, which are na\u00efve T-helper cells, yet to undergo differentiation. Differentiation of cultured cells was investigated at several timepoints up to 48 hours. TF binding was detected using a method known as <a href=\"http:\/\/en.wikipedia.org\/wiki\/ChIP-sequencing\">ChIP-seq<\/a>. The groups of TFs found to bind together were assumed to co-operate in the regulation of genes.\r\n<p>\r\nTo find out which TFs are responsible for the regulation of which genes, single TFs were '<a href=\"http:\/\/en.wikipedia.org\/wiki\/Gene_knockout\">knocked out<\/a>'. In a knockout cell line the TF was not present, so the effects of the loss of the TF could be measured. The effects on gene expression was estimated using another sequencing technique called <a href=\"http:\/\/en.wikipedia.org\/wiki\/RNA-Seq\">RNA-seq<\/a>.\r\n<p>\r\nThe data from all the experiments were used to build a model that can be used to predict the effects of a drug targetted at Th17 cells. ",
"content_html": "<p>A fertilised egg is a single cell that can grow into a complex animal with many different types of cell. The specialised cells are formed through a process known as cell <a href=\"http:\/\/en.wikipedia.org\/wiki\/Cellular_differentiation\">differentiation<\/a>. During differentiation sets of genes are switched on and off, but sometimes the control system can fail. When this happens to cells that are part of the <a href=\"http:\/\/en.wikipedia.org\/wiki\/Immune_system\">immune system<\/a>, the result can be an <a href=\"http:\/\/en.wikipedia.org\/wiki\/Autoimmune_disease\">autoimmune disease<\/a>.<\/p>\n<p> \nT-helper (Th) cells can activate other cells in the immune system. The <a href=\"http:\/\/en.wikipedia.org\/wiki\/T_helper_17_cell\">Th17<\/a> sub-group of helper cells become specialised in defending mucous membranes from bacteria and fungi. They are also thought to be involved in autoimmune diseases, such as psoriasis and Crohn's disease. Better understanding of the differentiation of these cells might help in the identification of targets for therapeutic interventions.\n<p>\nDifferentiation is controlled by proteins called <a href=\"http:\/\/en.wikipedia.org\/wiki\/Transcription_factor\">transcription factors<\/a> (TFs) that can bind to specific sections of the DNA sequence. <a href=\"http:\/\/en.wikipedia.org\/wiki\/RAR-related_orphan_receptor_gamma\">ROR&gamma;t<\/a> is understood to be a master regulator of transcription, but several other TFs are also required for activation of the full differentiation programme. In this study data obtained from different experimental approaches were integrated to obtain a network of the TFs, and the genes under their control.\n<p>\nThe work involved a study of <a href=\"http:\/\/en.wikipedia.org\/wiki\/Naive_T_cell\">Th0<\/a> cells, which are na\u00efve T-helper cells, yet to undergo differentiation. Differentiation of cultured cells was investigated at several timepoints up to 48 hours. TF binding was detected using a method known as <a href=\"http:\/\/en.wikipedia.org\/wiki\/ChIP-sequencing\">ChIP-seq<\/a>. The groups of TFs found to bind together were assumed to co-operate in the regulation of genes.\n<p>\nTo find out which TFs are responsible for the regulation of which genes, single TFs were '<a href=\"http:\/\/en.wikipedia.org\/wiki\/Gene_knockout\">knocked out<\/a>'. In a knockout cell line the TF was not present, so the effects of the loss of the TF could be measured. The effects on gene expression was estimated using another sequencing technique called <a href=\"http:\/\/en.wikipedia.org\/wiki\/RNA-Seq\">RNA-seq<\/a>.\n<p>\nThe data from all the experiments were used to build a model that can be used to predict the effects of a drug targetted at Th17 cells. \n<\/p><\/p><\/p><\/p><\/p>\n",
"user": {
"email": "heather.vincent@manchester.ac.uk"
},
"paper": {
"identifier": "doi:10.1016\/j.cell.2012.09.016",
"title": "A Validated Regulatory Network for Th17 Cell Specification",
"metadata": {
"authors": "Maria Ciofani, Aviv Madar, Carolina Galan, MacLean Sellars, Kieran Mace, Florencia Pauli, Ashish Agarwal, Wendy Huang, Christopher\u00a0N. Parkurst, Michael Muratet, Kim\u00a0M. Newberry, Sarah Meadows, Alex Greenfield, Yi Yang, Preti Jain, Francis\u00a0K. Kirigin, Carmen Birchmeier, Erwin\u00a0F. Wagner, Kenneth\u00a0M. Murphy, Richard\u00a0M. Myers, Richard Bonneau, Dan\u00a0R. Littman",
"journal": "Cell 2012"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-11-21T16:37:52Z",
"updated_at": "2013-11-21T16:37:52Z"
},
"created_at": "2013-11-21T16:37:52Z",
"updated_at": "2013-11-21T16:37:52Z"
},
{
"id": 50,
"content": "Most cells in multicellular organisms possess a property known as polarity that is reflected, in part, in the organization of the cell surface into distinct domains. One well-known axis in epithelial cells, such as those in the skin, divides the cell into an apical domain, which faces out, and a basal domain, which faces the underlying tissue. These cells rely on the distribution of structural components inside the cell, or within the cell membrane, to tell the difference between these two directions. Epithelial cells also possess a second type of polarity, planar cell polarity, that ensures that cells adjacent to each other in the plane parallel to the skin tissue are oriented correctly with respect to each other during development. This ensures, in turn, that hairs, scales, feathers and so on are all aligned.All eukaryotic cells sort and process proteins within an organelle called the Golgi apparatus, and proteins that are required at a specific destination within the cell, such as the cell surface membrane, carry specific molecular sorting signals that act as address labels to convey the protein into and within the secretory pathway. As one of these proteins moves through the Golgi apparatus, its sorting signals are recognized by coat proteins, such as clathrin, that subsequently form a vesicle around it. The assembly of this vesicle is initiated by an enzyme from the Arf family, but the enzyme must first undergo a conformational change (by exchanging a molecule of GDP for one of GTP) before formation can begin. The resulting vesicle can then be sent on its way to the address indicated by its Golgi-to-cell-surface sorting signal. These sorting signals also help to establish planar cell polarity in cells by ensuring that proteins called signaling receptors are distributed asymmetrically within the cell membrane.Guo et al. have now examined the mechanism behind the asymmetric sorting of two proteins that are involved in planar cell polarity: Vangl2 and Frizzled 6. In an effort to understand why these proteins are localized to opposite surfaces of epithelial cells, Guo et al. used genetic techniques to reduce the expression of Golgi-localized Arf proteins in epithelial cell cultures. They found that knockdown of a protein called Arfrp1 caused Vangl2 to accumulate in the last station of the Golgi complex instead of being transported to the cell surface membrane. Then, using a technique called affinity chromatography, they demonstrated that a coat protein called the clathrin adaptor complex (AP-1) had to be present for the formation of vesicles around Vangl2. Moreover, disrupting AP-1 and Arfrp1 did not prevent Frizzled 6 being transported to the cell surface membrane. This suggests that cells use several distinct adaptor proteins and coat complexes to ensure that proteins from the Golgi apparatus go to specific locations on the cell surface and, thus, help to establish planar cell polarity.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00160.002",
"content_html": "<p hwp:id=\"p-5\">Most cells in multicellular organisms possess a property known as polarity that is reflected, in part, in the organization of the cell surface into distinct domains. One well-known axis in epithelial cells, such as those in the skin, divides the cell into an apical domain, which faces out, and a basal domain, which faces the underlying tissue. These cells rely on the distribution of structural components inside the cell, or within the cell membrane, to tell the difference between these two directions. Epithelial cells also possess a second type of polarity, planar cell polarity, that ensures that cells adjacent to each other in the plane parallel to the skin tissue are oriented correctly with respect to each other during development. This ensures, in turn, that hairs, scales, feathers and so on are all aligned.<\/p>\n<p hwp:id=\"p-6\">All eukaryotic cells sort and process proteins within an organelle called the Golgi apparatus, and proteins that are required at a specific destination within the cell, such as the cell surface membrane, carry specific molecular sorting signals that act as address labels to convey the protein into and within the secretory pathway. As one of these proteins moves through the Golgi apparatus, its sorting signals are recognized by coat proteins, such as clathrin, that subsequently form a vesicle around it. The assembly of this vesicle is initiated by an enzyme from the Arf family, but the enzyme must first undergo a conformational change (by exchanging a molecule of GDP for one of GTP) before formation can begin. The resulting vesicle can then be sent on its way to the address indicated by its Golgi-to-cell-surface sorting signal. These sorting signals also help to establish planar cell polarity in cells by ensuring that proteins called signaling receptors are distributed asymmetrically within the cell membrane.<\/p>\n<p hwp:id=\"p-7\">Guo et al. have now examined the mechanism behind the asymmetric sorting of two proteins that are involved in planar cell polarity: Vangl2 and Frizzled 6. In an effort to understand why these proteins are localized to opposite surfaces of epithelial cells, Guo et al. used genetic techniques to reduce the expression of Golgi-localized Arf proteins in epithelial cell cultures. They found that knockdown of a protein called Arfrp1 caused Vangl2 to accumulate in the last station of the Golgi complex instead of being transported to the cell surface membrane. Then, using a technique called affinity chromatography, they demonstrated that a coat protein called the clathrin adaptor complex (AP-1) had to be present for the formation of vesicles around Vangl2. Moreover, disrupting AP-1 and Arfrp1 did not prevent Frizzled 6 being transported to the cell surface membrane. This suggests that cells use several distinct adaptor proteins and coat complexes to ensure that proteins from the Golgi apparatus go to specific locations on the cell surface and, thus, help to establish planar cell polarity.<\/p>\n<p hwp:id=\"p-8\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00160.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00160.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00160.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00160",
"title": "A novel GTP-binding protein-adaptor protein complex responsible for export of Vangl2 from the trans Golgi network",
"metadata": {
"authors": "Y. Guo, G. Zanetti, R. Schekman",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:29:12Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:29:12Z",
"updated_at": "2013-07-25T09:29:12Z"
},
{
"id": 51,
"content": "Actin is a multi-functional protein that is found in almost all eukaryotic cells. When polymerized, it forms robust filaments that participate in a variety of cellular processes. For example, actin filaments are involved in the contraction of muscles, and they are also a major component in the various structures that maintain and control the shape of cells as they move and divide. These structures include the cell cortex, a meshwork of actin filaments that is bound to the inner surface of the plasma membrane by anchor proteins. However, both the cell cortex and the plasma membrane must undergo dramatic changes when a cell divides, and the forces that drive these changes are generated by another protein, myosin II.Myosin II contains three domains: a head domain, also known as the motor domain, that binds to actin; a neck domain; and a tail domain. Like actin, myosin II proteins also form filaments, but these myofilaments have a distinctive structure: the tail domains of two Myosin II proteins join together, with the motor domains being found at both ends of the filament. When activated, the motor domains grab actin filaments and pull against them in a \u2018powerstroke\u2019. However, the details of the interactions between the myofilament motor domains and the actin filaments in the cell cortex, which are bound to the plasma membrane, are not fully understood.Studying these processes in living cells is extremely challenging, so Vogel et al. have built an in vitro model of the cell cortex, and then used single-molecule imaging to watch the interactions between the myofilaments and the actin filaments in this model. They show that the myofilaments move along the actin in the cortex, breaking up the filaments and compressing them in the process. They propose that tension builds up between the ends of the myofilaments, leading to compressive stress being exerted on the actin filaments. Computer simulations confirm that the forces generated are high enough to cause the actin filaments to buckle and break. The in vitro model developed by Vogel et al. should allow researchers to clarify the basic biophysical principles that underpin the structure and function of the cell cortex.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00116.002",
"content_html": "<p hwp:id=\"p-4\">Actin is a multi-functional protein that is found in almost all eukaryotic cells. When polymerized, it forms robust filaments that participate in a variety of cellular processes. For example, actin filaments are involved in the contraction of muscles, and they are also a major component in the various structures that maintain and control the shape of cells as they move and divide. These structures include the cell cortex, a meshwork of actin filaments that is bound to the inner surface of the plasma membrane by anchor proteins. However, both the cell cortex and the plasma membrane must undergo dramatic changes when a cell divides, and the forces that drive these changes are generated by another protein, myosin II.<\/p>\n<p hwp:id=\"p-5\">Myosin II contains three domains: a head domain, also known as the motor domain, that binds to actin; a neck domain; and a tail domain. Like actin, myosin II proteins also form filaments, but these myofilaments have a distinctive structure: the tail domains of two Myosin II proteins join together, with the motor domains being found at both ends of the filament. When activated, the motor domains grab actin filaments and pull against them in a &#x2018;powerstroke&#x2019;. However, the details of the interactions between the myofilament motor domains and the actin filaments in the cell cortex, which are bound to the plasma membrane, are not fully understood.<\/p>\n<p hwp:id=\"p-6\">Studying these processes in living cells is extremely challenging, so Vogel et al. have built an in vitro model of the cell cortex, and then used single-molecule imaging to watch the interactions between the myofilaments and the actin filaments in this model. They show that the myofilaments move along the actin in the cortex, breaking up the filaments and compressing them in the process. They propose that tension builds up between the ends of the myofilaments, leading to compressive stress being exerted on the actin filaments. Computer simulations confirm that the forces generated are high enough to cause the actin filaments to buckle and break. The in vitro model developed by Vogel et al. should allow researchers to clarify the basic biophysical principles that underpin the structure and function of the cell cortex.<\/p>\n<p hwp:id=\"p-7\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00116.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00116.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00116.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00116",
"title": "Myosin motors fragment and compact membrane-bound actin filaments",
"metadata": {
"authors": "S. K. Vogel, Z. Petrasek, F. Heinemann, P. Schwille",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:29:15Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:29:15Z",
"updated_at": "2013-07-25T09:29:15Z"
},
{
"id": 52,
"content": "The development of a single fertilized egg into a highly complex animal is determined by its genome, with a process called differential gene regulation exerting exquisite control over gene expression to ensure that various specialized cells are generated and that many types of tissue are produced. However, the mechanisms responsible for controlling gene expression and, therefore mammalian development, are poorly understood.Researchers have developed a number of in vitro cell culture models to elucidate the details of differential gene regulation, and this approach has been used to characterize adipocytes\u2014cells that store energy in the form of fat\u2014for close to two decades. The formation of adipocytes, a process known as adipogenesis, has been extensively studied, but there remain major gaps in our knowledge: for example, the identities of many of the transcriptional regulators that are responsible for the differentiation of mesenchymal stem cells into adipocytes remain a mystery. This task is complicated by the fact that some of these regulators are involved in the differentiation of multiple cell lines, and that some of them also have multiple roles in the generation of a single cell type. In addition to being of fundamental interest, improving our knowledge of the properties and behavior of adipocytes is essential for tackling the increasing prevalence of obesity in the developed world.Zhou et al. now report that TAF7L\u2014a gene that was previously thought to be involved only in the production of sperm cells\u2014has two roles in the differentiation of stem cells to form adipocytes. Using a combination of cellular, biochemical, genetic and genomic techniques, they show that TAF7L interacts with PPAR\u03b3, an important adipocyte transcriptional regulator at enhancer sites on the genome to increase the transcription of genes that are involved in adipogenesis. They also show that TAF7L interacts with a general transcription factor called TBP (short for TATA-binding protein) at promoter sequences, again to increase the expression of genes involved in adipogenesis. Moreover, they show that the expression of TAF7L in myoblasts\u2014precursor cells that usually become muscle cells\u2014can induce the formation of fat cells rather than muscle cells. Furthermore, mice lacking TAF7L are lean compared to their normal littermates. A clearer understanding of the underlying causes of fat cell formation could lead to the development of new approaches for the treatment of obesity and associated diseases.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00170.002",
"content_html": "<p hwp:id=\"p-4\">The development of a single fertilized egg into a highly complex animal is determined by its genome, with a process called differential gene regulation exerting exquisite control over gene expression to ensure that various specialized cells are generated and that many types of tissue are produced. However, the mechanisms responsible for controlling gene expression and, therefore mammalian development, are poorly understood.<\/p>\n<p hwp:id=\"p-5\">Researchers have developed a number of in vitro cell culture models to elucidate the details of differential gene regulation, and this approach has been used to characterize adipocytes&#x2014;cells that store energy in the form of fat&#x2014;for close to two decades. The formation of adipocytes, a process known as adipogenesis, has been extensively studied, but there remain major gaps in our knowledge: for example, the identities of many of the transcriptional regulators that are responsible for the differentiation of mesenchymal stem cells into adipocytes remain a mystery. This task is complicated by the fact that some of these regulators are involved in the differentiation of multiple cell lines, and that some of them also have multiple roles in the generation of a single cell type. In addition to being of fundamental interest, improving our knowledge of the properties and behavior of adipocytes is essential for tackling the increasing prevalence of obesity in the developed world.<\/p>\n<p hwp:id=\"p-6\">Zhou et al. now report that TAF7L&#x2014;a gene that was previously thought to be involved only in the production of sperm cells&#x2014;has two roles in the differentiation of stem cells to form adipocytes. Using a combination of cellular, biochemical, genetic and genomic techniques, they show that TAF7L interacts with PPAR&#x3B3;, an important adipocyte transcriptional regulator at enhancer sites on the genome to increase the transcription of genes that are involved in adipogenesis. They also show that TAF7L interacts with a general transcription factor called TBP (short for TATA-binding protein) at promoter sequences, again to increase the expression of genes involved in adipogenesis. Moreover, they show that the expression of TAF7L in myoblasts&#x2014;precursor cells that usually become muscle cells&#x2014;can induce the formation of fat cells rather than muscle cells. Furthermore, mice lacking TAF7L are lean compared to their normal littermates. A clearer understanding of the underlying causes of fat cell formation could lead to the development of new approaches for the treatment of obesity and associated diseases.<\/p>\n<p hwp:id=\"p-7\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00170.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00170.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00170.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00170",
"title": "Dual functions of TAF7L in adipocyte differentiation",
"metadata": {
"authors": "H. Zhou, T. Kaplan, Y. Li, I. Grubisic, Z. Zhang, P. J. Wang, M. B. Eisen, R. Tjian",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:29:18Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:29:18Z",
"updated_at": "2013-07-25T09:29:18Z"
},
{
"id": 53,
"content": "Most animals need to be able to move to survive. Animals without limbs, such as snakes, move by generating by wave-like contractions along their bodies, whereas limbed animals, such as vertebrates and arthropods, walk by coordinating the movements of multi-jointed arms and legs. Locomotion in limbed animals involves bending each joint within each arm or leg in a coordinated manner, while also ensuring that the movements of all the limbs are coordinated with each other. In bipeds such as humans, for example, it is critical that one leg is in the stance phase when the other leg is in the swing phase. The rules that govern the coordination of limbs also depend on the gait, so the rules for walking are not the same as the rules for running.The nervous systems of bipeds and other animals that walk solve these problems by using complex neural circuits that coordinate the firing of the relevant motor neurons. Two general mechanisms are used to coordinate the firing of motor neurons. In one mechanism, local interneurons within the central nervous system coordinate motor neuron activities: in vertebrates these interneurons are found in the spinal cord. A second mechanism, termed proprioception, relies on sensory neurons that report the load and joint angles from the arms and legs back to the central nervous system, and thereby influence the firing of the motor neurons. Remarkably, both of these mechanisms, and also the types of neurons that comprise motor neuron circuits, are conserved from arthropods to vertebrates.Mendes et al. describe a new approach that can be used to analyze how the fruit fly, D. melanogaster, walks on surfaces. They use a combination of an optical touch sensor and high-speed video imaging to follow the body of the fly as it walks, and also to record when and where it places each of its six feet on the surface as it moves. Then, using a software package called FlyWalker, they are able to extract a large of number of parameters that can be used to describe locomotion in adult fruit flies with high temporal and spatial resolution. Many of these parameters have never been measured or studied before.Mendes et al. show that fruit flies do not display the abrupt transitions in gait that are typically observed in vertebrates. However, they do modify their neural circuits depending on their speed: indeed it appears that flies use subtly different neural circuitry for walking at slow, medium and fast speeds. Moreover, when genetic methods are used to block sensory feedback, the fly is still able to walk, albeit with reduced coordination and precision. Further, the data suggest that proprioception is less important when flies walk faster compared to when they walk more slowly. The next step in this research will be to combine this new method for analyzing locomotion in flies with the wide range of genetic tools that are available for the study of Drosophila: this will allow researchers to explore in greater detail the components of the motor neuron circuitry and their role in coordinated walking.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00231.002",
"content_html": "<p hwp:id=\"p-4\">Most animals need to be able to move to survive. Animals without limbs, such as snakes, move by generating by wave-like contractions along their bodies, whereas limbed animals, such as vertebrates and arthropods, walk by coordinating the movements of multi-jointed arms and legs. Locomotion in limbed animals involves bending each joint within each arm or leg in a coordinated manner, while also ensuring that the movements of all the limbs are coordinated with each other. In bipeds such as humans, for example, it is critical that one leg is in the stance phase when the other leg is in the swing phase. The rules that govern the coordination of limbs also depend on the gait, so the rules for walking are not the same as the rules for running.<\/p>\n<p hwp:id=\"p-5\">The nervous systems of bipeds and other animals that walk solve these problems by using complex neural circuits that coordinate the firing of the relevant motor neurons. Two general mechanisms are used to coordinate the firing of motor neurons. In one mechanism, local interneurons within the central nervous system coordinate motor neuron activities: in vertebrates these interneurons are found in the spinal cord. A second mechanism, termed proprioception, relies on sensory neurons that report the load and joint angles from the arms and legs back to the central nervous system, and thereby influence the firing of the motor neurons. Remarkably, both of these mechanisms, and also the types of neurons that comprise motor neuron circuits, are conserved from arthropods to vertebrates.<\/p>\n<p hwp:id=\"p-6\">Mendes et al. describe a new approach that can be used to analyze how the fruit fly, <italic>D. melanogaster<\/italic>, walks on surfaces. They use a combination of an optical touch sensor and high-speed video imaging to follow the body of the fly as it walks, and also to record when and where it places each of its six feet on the surface as it moves. Then, using a software package called FlyWalker, they are able to extract a large of number of parameters that can be used to describe locomotion in adult fruit flies with high temporal and spatial resolution. Many of these parameters have never been measured or studied before.<\/p>\n<p hwp:id=\"p-7\">Mendes et al. show that fruit flies do not display the abrupt transitions in gait that are typically observed in vertebrates. However, they do modify their neural circuits depending on their speed: indeed it appears that flies use subtly different neural circuitry for walking at slow, medium and fast speeds. Moreover, when genetic methods are used to block sensory feedback, the fly is still able to walk, albeit with reduced coordination and precision. Further, the data suggest that proprioception is less important when flies walk faster compared to when they walk more slowly. The next step in this research will be to combine this new method for analyzing locomotion in flies with the wide range of genetic tools that are available for the study of <italic>Drosophila<\/italic>: this will allow researchers to explore in greater detail the components of the motor neuron circuitry and their role in coordinated walking.<\/p>\n<p hwp:id=\"p-8\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00231.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00231.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00231.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00231",
"title": "Quantification of gait parameters in freely walking wild type and sensory deprived Drosophila melanogaster",
"metadata": {
"authors": "C. S. Mendes, I. Bartos, T. Akay, S. Marka, R. S. Mann",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:29:22Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:29:22Z",
"updated_at": "2013-07-25T09:29:22Z"
},
{
"id": 54,
"content": "After the DNA in a gene has been transcribed into messenger RNA, portions of the mRNA called introns are removed, and the remaining stretches of mRNA, which are known as exons, are spliced together. Within eukaryotic cells, a process known as alternative splicing allows a single gene to encode for multiple protein variants by ensuring that some exons are included in the final, modified mRNA, while other exons are excluded. This modified mRNA is then translated into proteins.Eukaryotic cells also contain proteins that bind to RNA to regulate alternative splicing. These RNA-binding proteins are often found in both the cytoplasm and nucleus of cells, and their involvement in splicing may be linked to other processes in the cell such as mRNA localization and translation. It has also become clear over the past two decades that certain types of RNA-binding proteins, including NOVA proteins, are only found in neurons, and that these proteins have been best characterized as alternative splicing regulators. Recent work has also suggested that they also have important roles in regulating neuronal activity and development, and that their actions in neuronal nuclei and cytoplasm might be coordinated.Now Eom et al. use the predictive power of a high throughput sequencing and crosslinking method termed HITS-CLIP to show that NOVA proteins can indirectly regulate cytoplasmic mRNA levels by regulating the process of alternative splicing in the nucleus to produce \u2018cryptic\u2019 exons in the brains of mice. The presence of these exons in the mRNA leads to the production of premature termination codons in the cytoplasm. These codons trigger a process called nonsense-mediated decay that involves identifying mRNA transcripts that contain nonsense mutations, and then degrading them. These cryptic exons were seen in mice missing the NOVA proteins, where they are expressed in abnormally high levels; in normal mice, these exons have not been seen before, hence they were termed \u2018cryptic\u2019.Eom et al. also show that these cryptic exons are physiologically relevant by inducing epileptic seizures in mice. Following the seizures, they find that the NOVA proteins up-regulate and down-regulate the levels of different cryptic exons, leading to changes in the levels of the proteins encoded by these mRNAs, including proteins that inhibit further seizures. Overall the results indicate that, by controlling the production of various proteins in neurons, these previously unknown cryptic exons have important roles in the workings of the brain.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00178.002",
"content_html": "<p hwp:id=\"p-4\">After the DNA in a gene has been transcribed into messenger RNA, portions of the mRNA called introns are removed, and the remaining stretches of mRNA, which are known as exons, are spliced together. Within eukaryotic cells, a process known as alternative splicing allows a single gene to encode for multiple protein variants by ensuring that some exons are included in the final, modified mRNA, while other exons are excluded. This modified mRNA is then translated into proteins.<\/p>\n<p hwp:id=\"p-5\">Eukaryotic cells also contain proteins that bind to RNA to regulate alternative splicing. These RNA-binding proteins are often found in both the cytoplasm and nucleus of cells, and their involvement in splicing may be linked to other processes in the cell such as mRNA localization and translation. It has also become clear over the past two decades that certain types of RNA-binding proteins, including NOVA proteins, are only found in neurons, and that these proteins have been best characterized as alternative splicing regulators. Recent work has also suggested that they also have important roles in regulating neuronal activity and development, and that their actions in neuronal nuclei and cytoplasm might be coordinated.<\/p>\n<p hwp:id=\"p-6\">Now Eom et al. use the predictive power of a high throughput sequencing and crosslinking method termed HITS-CLIP to show that NOVA proteins can indirectly regulate cytoplasmic mRNA levels by regulating the process of alternative splicing in the nucleus to produce &#x2018;cryptic&#x2019; exons in the brains of mice. The presence of these exons in the mRNA leads to the production of premature termination codons in the cytoplasm. These codons trigger a process called nonsense-mediated decay that involves identifying mRNA transcripts that contain nonsense mutations, and then degrading them. These cryptic exons were seen in mice missing the NOVA proteins, where they are expressed in abnormally high levels; in normal mice, these exons have not been seen before, hence they were termed &#x2018;cryptic&#x2019;.<\/p>\n<p hwp:id=\"p-7\">Eom et al. also show that these cryptic exons are physiologically relevant by inducing epileptic seizures in mice. Following the seizures, they find that the NOVA proteins up-regulate and down-regulate the levels of different cryptic exons, leading to changes in the levels of the proteins encoded by these mRNAs, including proteins that inhibit further seizures. Overall the results indicate that, by controlling the production of various proteins in neurons, these previously unknown cryptic exons have important roles in the workings of the brain.<\/p>\n<p hwp:id=\"p-8\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00178.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00178.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00178.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00178",
"title": "NOVA-dependent regulation of cryptic NMD exons controls synaptic protein levels after seizure",
"metadata": {
"authors": "T. Eom, C. Zhang, H. Wang, K. Lay, J. Fak, J. L. Noebels, R. B. Darnell",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:29:27Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:29:27Z",
"updated_at": "2013-07-25T09:29:27Z"
},
{
"id": 55,
"content": "Nerve cells, called neurons, are one of the core components of the brain and form complex networks by connecting to other neurons via long, thin \u2018wire-like\u2019 processes called axons. Axons can extend across the brain, enabling neurons to form connections\u2014or synapses\u2014with thousands of others. It is through these complex networks that incoming information from sensory organs, such as the eye, is propagated through the brain and encoded.The basic unit of communication between neurons is the action potential, often called a \u2018spike\u2019, which propagates along the network of axons and, through a chemical process at synapses, communicates with the postsynaptic neurons that the axon is connected to. These action potentials excite the neuron that they arrive at, and this excitatory process can generate a new action potential that then propagates along the axon to excite additional target neurons. In the visual areas of the cortex, neurons respond with action potentials when they \u2018recognize\u2019 a particular feature in a scene\u2014a process called tuning. How a neuron becomes tuned to certain features in the world and not to others is unclear, as are the rules that enable a neuron to change what it is tuned to. What is clear, however, is that to understand this process is to understand the basis of sensory perception.Memory storage and formation is thought to occur at synapses. The efficiency of signal transmission between neurons can increase or decrease over time, and this process is often referred to as synaptic plasticity. But for these synaptic changes to be transmitted to target neurons, the changes must alter the number of action potentials. Although it has been shown in vitro that the efficiency of synaptic transmission\u2014that is the strength of the synapse\u2014can be altered by changing the order in which the pre- and postsynaptic cells are activated (referred to as \u2018Spike-timing-dependent plasticity\u2019), this has never been shown to have an effect on the number of action potentials generated in a single neuron in vivo. It is therefore unknown whether this process is functionally relevant.Now Pawlak et al. report that spike-timing-dependent plasticity in the visual cortex of anaesthetized rats can change the spiking of neurons in the visual cortex. They used a visual stimulus (a bar flashed up for half a second) to activate a presynaptic cell, and triggered a single action potential in the postsynaptic cell a very short time later. By repeatedly activating the cells in this way, they increased the strength of the synaptic connection between the two neurons. After a small number of these pairing activations, presenting the visual stimulus alone to the presynaptic cell was enough to trigger an action potential (a suprathreshold response) in the postsynaptic neuron\u2014even though this was not the case prior to the pairing.This study shows that timing rules known to change the strength of synaptic connections\u2014and proposed to underlie learning and memory\u2014have functional relevance in vivo, and that the timing of single action potentials can change the functional status of a cortical neuron.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00012.002",
"content_html": "<p hwp:id=\"p-4\">Nerve cells, called neurons, are one of the core components of the brain and form complex networks by connecting to other neurons via long, thin &#x2018;wire-like&#x2019; processes called axons. Axons can extend across the brain, enabling neurons to form connections&#x2014;or synapses&#x2014;with thousands of others. It is through these complex networks that incoming information from sensory organs, such as the eye, is propagated through the brain and encoded.<\/p>\n<p hwp:id=\"p-5\">The basic unit of communication between neurons is the action potential, often called a &#x2018;spike&#x2019;, which propagates along the network of axons and, through a chemical process at synapses, communicates with the postsynaptic neurons that the axon is connected to. These action potentials excite the neuron that they arrive at, and this excitatory process can generate a new action potential that then propagates along the axon to excite additional target neurons. In the visual areas of the cortex, neurons respond with action potentials when they &#x2018;recognize&#x2019; a particular feature in a scene&#x2014;a process called tuning. How a neuron becomes tuned to certain features in the world and not to others is unclear, as are the rules that enable a neuron to change what it is tuned to. What is clear, however, is that to understand this process is to understand the basis of sensory perception.<\/p>\n<p hwp:id=\"p-6\">Memory storage and formation is thought to occur at synapses. The efficiency of signal transmission between neurons can increase or decrease over time, and this process is often referred to as synaptic plasticity. But for these synaptic changes to be transmitted to target neurons, the changes must alter the number of action potentials. Although it has been shown in vitro that the efficiency of synaptic transmission&#x2014;that is the strength of the synapse&#x2014;can be altered by changing the order in which the pre- and postsynaptic cells are activated (referred to as &#x2018;Spike-timing-dependent plasticity&#x2019;), this has never been shown to have an effect on the number of action potentials generated in a single neuron in vivo. It is therefore unknown whether this process is functionally relevant.<\/p>\n<p hwp:id=\"p-7\">Now Pawlak et al. report that spike-timing-dependent plasticity in the visual cortex of anaesthetized rats can change the spiking of neurons in the visual cortex. They used a visual stimulus (a bar flashed up for half a second) to activate a presynaptic cell, and triggered a single action potential in the postsynaptic cell a very short time later. By repeatedly activating the cells in this way, they increased the strength of the synaptic connection between the two neurons. After a small number of these pairing activations, presenting the visual stimulus alone to the presynaptic cell was enough to trigger an action potential (a suprathreshold response) in the postsynaptic neuron&#x2014;even though this was not the case prior to the pairing.<\/p>\n<p hwp:id=\"p-8\">This study shows that timing rules known to change the strength of synaptic connections&#x2014;and proposed to underlie learning and memory&#x2014;have functional relevance in vivo, and that the timing of single action potentials can change the functional status of a cortical neuron.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00012.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00012.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00012.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00012",
"title": "Changing the responses of cortical neurons from sub- to suprathreshold using single spikes in vivo",
"metadata": {
"authors": "V. Pawlak, D. S. Greenberg, H. Sprekeler, W. Gerstner, J. N. Kerr",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:29:34Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:29:34Z",
"updated_at": "2013-07-25T09:29:34Z"
},
{
"id": 56,
"content": "Viruses are infectious agents that can replicate only inside a living host cell. When a virus infects an animal or plant, it introduces its own genetic material and tricks the host cells into producing viral proteins that can be used to assemble new viruses. An essential step in the life cycle of any virus is transmission to a new host: understanding this process can be crucial in the fight against viral epidemics.Many viruses use living organisms, or vectors, to move between hosts. In the case of plant viruses such as cauliflower mosaic virus, the vectors are often aphids. When an aphid sucks sap out of a leaf, virus particles already present in the leaf become attached to its mouth, and these viruses can be transferred to the next plant that the insect feeds on. However, in order for cauliflower mosaic virus particles to become attached to the aphid, structures called transmission bodies must form beforehand in the infected plant cells. These structures are known to contain helper proteins that bind the viruses to the mouth of the aphid, but the precise role of the transmission body has remained obscure.Now Martini\u00e8re et al. show that the transmission body is in fact a dynamic structure that reacts to the presence of aphids and, in so doing, boosts the efficiency of viral transmission. In particular, they show that the action of an aphid feeding on an infected leaf triggers a rapid and massive influx of a protein called tubulin into the transmission body. The transmission body then bursts open, dispersing helper protein-virus particle complexes throughout the cell, where they become more accessible to aphids. This series of events increases viral transmission rates twofold to threefold.The results show that a virus can detect insect vectors, likely by using the sensory system of its host, and trigger a response that boosts viral uptake and thus transmission. This is a novel concept in virology. It will be important to discover whether similar mechanisms are used by other viruses, including those that infect animals and humans.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00183.002",
"content_html": "<p hwp:id=\"p-5\">Viruses are infectious agents that can replicate only inside a living host cell. When a virus infects an animal or plant, it introduces its own genetic material and tricks the host cells into producing viral proteins that can be used to assemble new viruses. An essential step in the life cycle of any virus is transmission to a new host: understanding this process can be crucial in the fight against viral epidemics.<\/p>\n<p hwp:id=\"p-6\">Many viruses use living organisms, or vectors, to move between hosts. In the case of plant viruses such as cauliflower mosaic virus, the vectors are often aphids. When an aphid sucks sap out of a leaf, virus particles already present in the leaf become attached to its mouth, and these viruses can be transferred to the next plant that the insect feeds on. However, in order for cauliflower mosaic virus particles to become attached to the aphid, structures called transmission bodies must form beforehand in the infected plant cells. These structures are known to contain helper proteins that bind the viruses to the mouth of the aphid, but the precise role of the transmission body has remained obscure.<\/p>\n<p hwp:id=\"p-7\">Now Martini&#xE8;re et al. show that the transmission body is in fact a dynamic structure that reacts to the presence of aphids and, in so doing, boosts the efficiency of viral transmission. In particular, they show that the action of an aphid feeding on an infected leaf triggers a rapid and massive influx of a protein called tubulin into the transmission body. The transmission body then bursts open, dispersing helper protein-virus particle complexes throughout the cell, where they become more accessible to aphids. This series of events increases viral transmission rates twofold to threefold.<\/p>\n<p hwp:id=\"p-8\">The results show that a virus can detect insect vectors, likely by using the sensory system of its host, and trigger a response that boosts viral uptake and thus transmission. This is a novel concept in virology. It will be important to discover whether similar mechanisms are used by other viruses, including those that infect animals and humans.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00183.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00183.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00183.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00183",
"title": "A virus responds instantly to the presence of the vector on the host and forms transmission morphs",
"metadata": {
"authors": "A. Martiniere, A. Bak, J.-L. Macia, N. Lautredou, D. Gargani, J. Doumayrou, E. Garzo, A. Moreno, A. Fereres, S. Blanc, M. Drucker",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:29:39Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:29:39Z",
"updated_at": "2013-07-25T09:29:39Z"
},
{
"id": 57,
"content": "Ribosomes are complex molecular machines that translate the sequence of bases in a messenger RNA (mRNA) transcript into a polypeptide that subsequently folds to form a protein. Each ribosome is composed of two major subunits: the small subunit reads the mRNA transcript, and the large subunit joins amino acids together to form the polypeptide. This process stops when the ribosome encounters a stop codon and releases the completed polypeptide.It is critical that cells perform some form of quality control on the polypeptides as they are translated to prevent a build up of incomplete, incorrect or toxic proteins in cells. Problems can occur if a ribosome stalls while translating the mRNA transcript, or if the mRNA transcript is defective. For example, most mRNA transcripts contain a stop codon, but some do not, and these non-stop mRNA transcripts result in a non-stop polypeptide that remains tethered to the ribosome. It is important that the cell identifies and removes these faulty polypeptides so as to leave the ribosome free to translate other (non-faulty) mRNA transcripts. A regulatory protein called ubiquitin is responsible for marking and sending proteins that are faulty, or are no longer needed by the cell, to a molecular machine called the proteasome, where they are degraded by a process called proteolysis. In 2010 researchers identified Ltn1 as the enzyme that attaches ubiquitin to non-stop proteins in yeast.Now, building on this work, Verma et al. identify additional proteins involved in this process. In particular, an ATPase enzyme called Cdc48 (known as p97 or VCP in human cells) and two co-factors\u2014Ufd1 and Npl4\u2014promote release of the ubiquitinated non-stop polypeptides from the ribosomes, thus committing the marked polypeptide to destruction by the proteasome. Verma et al. also show that the Cdc48-Ufd1-Npl4 complex is involved in other aspects of quality control of newly synthesized proteins within cells. Collectively these processes are known as ribosome-associated degradation.Mutations of the gene that codes for human p97 can cause a number of diseases, including Paget's disease of the bone and frontotemporal dementia, so an improved understanding of ribosome-associated degradation could provide new insights into these diseases.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00308.002",
"content_html": "<p hwp:id=\"p-4\">Ribosomes are complex molecular machines that translate the sequence of bases in a messenger RNA (mRNA) transcript into a polypeptide that subsequently folds to form a protein. Each ribosome is composed of two major subunits: the small subunit reads the mRNA transcript, and the large subunit joins amino acids together to form the polypeptide. This process stops when the ribosome encounters a stop codon and releases the completed polypeptide.<\/p>\n<p hwp:id=\"p-5\">It is critical that cells perform some form of quality control on the polypeptides as they are translated to prevent a build up of incomplete, incorrect or toxic proteins in cells. Problems can occur if a ribosome stalls while translating the mRNA transcript, or if the mRNA transcript is defective. For example, most mRNA transcripts contain a stop codon, but some do not, and these non-stop mRNA transcripts result in a non-stop polypeptide that remains tethered to the ribosome. It is important that the cell identifies and removes these faulty polypeptides so as to leave the ribosome free to translate other (non-faulty) mRNA transcripts. A regulatory protein called ubiquitin is responsible for marking and sending proteins that are faulty, or are no longer needed by the cell, to a molecular machine called the proteasome, where they are degraded by a process called proteolysis. In 2010 researchers identified Ltn1 as the enzyme that attaches ubiquitin to non-stop proteins in yeast.<\/p>\n<p hwp:id=\"p-6\">Now, building on this work, Verma et al. identify additional proteins involved in this process. In particular, an ATPase enzyme called Cdc48 (known as p97 or VCP in human cells) and two co-factors&#x2014;Ufd1 and Npl4&#x2014;promote release of the ubiquitinated non-stop polypeptides from the ribosomes, thus committing the marked polypeptide to destruction by the proteasome. Verma et al. also show that the Cdc48-Ufd1-Npl4 complex is involved in other aspects of quality control of newly synthesized proteins within cells. Collectively these processes are known as ribosome-associated degradation.<\/p>\n<p hwp:id=\"p-7\">Mutations of the gene that codes for human p97 can cause a number of diseases, including Paget's disease of the bone and frontotemporal dementia, so an improved understanding of ribosome-associated degradation could provide new insights into these diseases.<\/p>\n<p hwp:id=\"p-8\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00308.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00308.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00308.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00308",
"title": "Cdc48\/p97 promotes degradation of aberrant nascent polypeptides bound to the ribosome",
"metadata": {
"authors": "R. Verma, R. S. Oania, N. J. Kolawa, R. J. Deshaies",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:29:42Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:29:42Z",
"updated_at": "2013-07-25T09:29:42Z"
},
{
"id": 58,
"content": "Microorganisms such as bacteria, archaea and tiny eukaryotes are found throughout the biosphere. Some of these microorganisms are pathogens that cause diseases in animals, while others provide nutrients, including essential amino acids and vitamins; there are also microorganisms that have critical roles in recycling elements such as carbon, nitrogen and oxygen in the biosphere. In the natural world, microorganisms interact with their environment and with each other, often competing for space, light and nutrients, but sometimes they act cooperatively, which benefits all parties involved.Microbial communities exhibit spatial patterns that reflect the relative positioning of different microbes in a community. These patterns can be critical for the proper functioning of a microbial community. For example, in the microbial granules that digest organic compounds in waste water, the stratified pattern of different microbial species can be thought of as a sequence of catalysts needed to perform a series of biochemical processing steps. Thus, it is important to understand the mechanisms that drive pattern formation in multispecies communities.Now, through a combination of simulations and experiments, Momeni et al. have identified two features of spatial patterns in two-population microbial communities when pattern formation is driven by fitness effects related to the ecological interactions between cells. First, interactions that confer significant advantages to at least one of the populations can potentially result in the generation of a stable community; the community is stable in the sense that if it is disturbed, it will return to its stable population composition following the disturbance. Indeed, in engineered Saccharomyces cerevisiae communities, very different initial population ratios converged to the same value over time when one strain depended on the other strain, or when the two strains depended on each other, but not when the two strains competed.The second feature applies to microbial communities composed of two cooperating populations: whereas two populations that compete with each other tend to segregate, cooperation results in the members of the two populations mixing together. Momeni et al. observe the formation of such an \u201cintermixed\u201d community in simulations, and also in two experimental systems that involve cooperation\u2014a community containing two different strains of yeast cooperating through metabolite exchange, and a biofilm in which Methanococcus maripaludis, an archaeon that produces methane, cooperates with the bacterium Desulfovibrio vulgaris.These two features of spatial patterning are conceptually similar to the competitive exclusion principle, which states that two species competing for the same resources cannot stably coexist if competition is the sole force at work. This principle has, therefore, encouraged scientists to search for the other forces that must be responsible for the coexistence of different species. Similarly, by predicting the sorts of patterns that will form when the fitness effects of ecological interactions between cells are the only forces at work, Momeni et al. lay the groundwork for investigations into other mechanisms, such as cell\u2013environment interactions and active cell motility, that can govern pattern formation in microbial communities.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00230.002",
"content_html": "<p hwp:id=\"p-4\">Microorganisms such as bacteria, archaea and tiny eukaryotes are found throughout the biosphere. Some of these microorganisms are pathogens that cause diseases in animals, while others provide nutrients, including essential amino acids and vitamins; there are also microorganisms that have critical roles in recycling elements such as carbon, nitrogen and oxygen in the biosphere. In the natural world, microorganisms interact with their environment and with each other, often competing for space, light and nutrients, but sometimes they act cooperatively, which benefits all parties involved.<\/p>\n<p hwp:id=\"p-5\">Microbial communities exhibit spatial patterns that reflect the relative positioning of different microbes in a community. These patterns can be critical for the proper functioning of a microbial community. For example, in the microbial granules that digest organic compounds in waste water, the stratified pattern of different microbial species can be thought of as a sequence of catalysts needed to perform a series of biochemical processing steps. Thus, it is important to understand the mechanisms that drive pattern formation in multispecies communities.<\/p>\n<p hwp:id=\"p-6\">Now, through a combination of simulations and experiments, Momeni et al. have identified two features of spatial patterns in two-population microbial communities when pattern formation is driven by fitness effects related to the ecological interactions between cells. First, interactions that confer significant advantages to at least one of the populations can potentially result in the generation of a stable community; the community is stable in the sense that if it is disturbed, it will return to its stable population composition following the disturbance. Indeed, in engineered <italic>Saccharomyces cerevisiae<\/italic> communities, very different initial population ratios converged to the same value over time when one strain depended on the other strain, or when the two strains depended on each other, but not when the two strains competed.<\/p>\n<p hwp:id=\"p-7\">The second feature applies to microbial communities composed of two cooperating populations: whereas two populations that compete with each other tend to segregate, cooperation results in the members of the two populations mixing together. Momeni et al. observe the formation of such an &#x201C;intermixed&#x201D; community in simulations, and also in two experimental systems that involve cooperation&#x2014;a community containing two different strains of yeast cooperating through metabolite exchange, and a biofilm in which <italic>Methanococcus maripaludis<\/italic>, an archaeon that produces methane, cooperates with the bacterium <italic>Desulfovibrio vulgaris<\/italic>.<\/p>\n<p hwp:id=\"p-8\">These two features of spatial patterning are conceptually similar to the competitive exclusion principle, which states that two species competing for the same resources cannot stably coexist if competition is the sole force at work. This principle has, therefore, encouraged scientists to search for the other forces that must be responsible for the coexistence of different species. Similarly, by predicting the sorts of patterns that will form when the fitness effects of ecological interactions between cells are the only forces at work, Momeni et al. lay the groundwork for investigations into other mechanisms, such as cell&#x2013;environment interactions and active cell motility, that can govern pattern formation in microbial communities.<\/p><p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00230.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00230.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00230.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00230",
"title": "Strong inter-population cooperation leads to partner intermixing in microbial communities",
"metadata": {
"authors": "B. Momeni, K. A. Brileya, M. W. Fields, W. Shou",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:29:44Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:29:44Z",
"updated_at": "2013-07-25T09:29:44Z"
},
{
"id": 59,
"content": "The ability to make specific changes to DNA\u2014such as changing, inserting or deleting sequences that encode proteins\u2014allows researchers to engineer cells, tissues and organisms for therapeutic and practical applications. Until now, such genome engineering has required the design and production of proteins with the ability to recognize a specific DNA sequence. The bacterial protein, Cas9, has the potential to enable a simpler approach to genome engineering because it is a DNA-cleaving enzyme that can be programmed with short RNA molecules to recognize specific DNA sequences, thus dispensing with the need to engineer a new protein for each new DNA target sequence.Now Jinek et al. demonstrate the capability of RNA-programmed Cas9 to introduce targeted double-strand breaks into human chromosomal DNA, thereby inducing site-specific genome editing reactions. Cas9 assembles with engineered single-guide RNAs in human cells and the resulting Cas9-RNA complex can induce the formation of double-strand breaks in genomic DNA at a site complementary to the guide RNA sequence. Experiments using extracts from transfected cells show that RNA expression and\/or assembly into Cas9 is the limiting factor for the DNA cleavage, and that extension of the RNA sequence at the 3\u2032 end enhances DNA targeting activity in vivo.These results show that RNA-programmed genome editing is a straightforward strategy for introducing site-specific genetic changes in human cells, and the ease with which it can programmed means that it is likely to become competitive with existing approaches based on zinc finger nucleases and transcription activator-like effector nucleases, and could lead to a new generation of experiments in the field of genome engineering for humans and other species with complex genomes.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00471.002",
"content_html": "<p hwp:id=\"p-4\">The ability to make specific changes to DNA&#x2014;such as changing, inserting or deleting sequences that encode proteins&#x2014;allows researchers to engineer cells, tissues and organisms for therapeutic and practical applications. Until now, such genome engineering has required the design and production of proteins with the ability to recognize a specific DNA sequence. The bacterial protein, Cas9, has the potential to enable a simpler approach to genome engineering because it is a DNA-cleaving enzyme that can be programmed with short RNA molecules to recognize specific DNA sequences, thus dispensing with the need to engineer a new protein for each new DNA target sequence.<\/p>\n<p hwp:id=\"p-5\">Now Jinek et al. demonstrate the capability of RNA-programmed Cas9 to introduce targeted double-strand breaks into human chromosomal DNA, thereby inducing site-specific genome editing reactions. Cas9 assembles with engineered single-guide RNAs in human cells and the resulting Cas9-RNA complex can induce the formation of double-strand breaks in genomic DNA at a site complementary to the guide RNA sequence. Experiments using extracts from transfected cells show that RNA expression and\/or assembly into Cas9 is the limiting factor for the DNA cleavage, and that extension of the RNA sequence at the 3&#x2032; end enhances DNA targeting activity in vivo.<\/p>\n<p hwp:id=\"p-6\">These results show that RNA-programmed genome editing is a straightforward strategy for introducing site-specific genetic changes in human cells, and the ease with which it can programmed means that it is likely to become competitive with existing approaches based on zinc finger nucleases and transcription activator-like effector nucleases, and could lead to a new generation of experiments in the field of genome engineering for humans and other species with complex genomes.<\/p>\n<p hwp:id=\"p-7\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00471.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00471.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00471.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00471",
"title": "RNA-programmed genome editing in human cells",
"metadata": {
"authors": "M. Jinek, A. East, A. Cheng, S. Lin, E. Ma, J. Doudna",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:29:46Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:29:46Z",
"updated_at": "2013-07-25T09:29:46Z"
},
{
"id": 60,
"content": "Although our health depends on our immune system's ability to recognize and attack foreign material, this same response can cause the body to reject an organ transplant or even to spontaneously attack itself (this is called autoimmune disease). To help prevent rejection, patients who receive donated organs are given immunosuppressant drugs, with a compound called FK506, or Tacrolimus, the most commonly used. However, FK506 can have a number of serious side effects, including high blood pressure, kidney damage and diabetes.The job of starting an immune response falls in large part to a type of white blood cell called the dendritic cell, which patrols the body in search of cells in trouble\u2014such as those infected with viruses. Dendritic cells are efficient at engulfing dying cells, which they break down and display fragments of on their cell surface. These fragments\u2014which are known as antigens\u2014are presented directly to T cells, which trigger a cascade of additional immune responses leading ultimately to the destruction of infected cells.In some cases of autoimmune disease, however, T cells begin to mistake the body's own cells for infected cells and to launch attacks against healthy tissue. Evidence suggests that immunosuppressive drugs such as FK506 can help to tone down these inappropriate immune responses. However, the use of FK506 to treat autoimmune disease has been limited by its side effects.Now, Orange et al. have shown that dendritic cells can be exploited to deliver drugs such as FK506 in a targeted and controlled manner. When the researchers loaded dendritic cells with FK506, they found that the cells sequestered the drug and then released it slowly in quantities that were sufficient to inhibit T-cell responses for at least 72 hr.Using a mouse model of rheumatoid arthritis\u2014an autoimmune disease characterized by inflammation and destruction of joint tissue\u2014Orange and co-workers demonstrated that their novel drug delivery system could be therapeutically useful. They loaded dendritic cells displaying the antigen that triggers the mouse immune system to attack joint tissue, with FK506, and used the resulting cells to treat arthritic mice. Mice that received these cells showed less severe arthritis than control animals treated with dendritic cells that had not been loaded with FK506. Moreover, the total dose of FK506 that the mice were exposed to was very low, with the result that they showed no evidence of the side effects typically seen with this drug.This proof-of-concept study suggests that dendritic cells could be used for the gradual and controlled delivery of drugs to specific target cells within the immune system. By precisely targeting relevant immune cells, it should be possible to use much lower drug doses, and thereby reduce side effects. Follow-up studies are now required to determine whether dendritic cells can be used as vehicles for the delivery of other drugs to treat a range of diseases.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00105.002",
"content_html": "<p hwp:id=\"p-4\">Although our health depends on our immune system's ability to recognize and attack foreign material, this same response can cause the body to reject an organ transplant or even to spontaneously attack itself (this is called autoimmune disease). To help prevent rejection, patients who receive donated organs are given immunosuppressant drugs, with a compound called FK506, or Tacrolimus, the most commonly used. However, FK506 can have a number of serious side effects, including high blood pressure, kidney damage and diabetes.<\/p>\n<p hwp:id=\"p-5\">The job of starting an immune response falls in large part to a type of white blood cell called the dendritic cell, which patrols the body in search of cells in trouble&#x2014;such as those infected with viruses. Dendritic cells are efficient at engulfing dying cells, which they break down and display fragments of on their cell surface. These fragments&#x2014;which are known as antigens&#x2014;are presented directly to T cells, which trigger a cascade of additional immune responses leading ultimately to the destruction of infected cells.<\/p>\n<p hwp:id=\"p-6\">In some cases of autoimmune disease, however, T cells begin to mistake the body's own cells for infected cells and to launch attacks against healthy tissue. Evidence suggests that immunosuppressive drugs such as FK506 can help to tone down these inappropriate immune responses. However, the use of FK506 to treat autoimmune disease has been limited by its side effects.<\/p>\n<p hwp:id=\"p-7\">Now, Orange et al. have shown that dendritic cells can be exploited to deliver drugs such as FK506 in a targeted and controlled manner. When the researchers loaded dendritic cells with FK506, they found that the cells sequestered the drug and then released it slowly in quantities that were sufficient to inhibit T-cell responses for at least 72 hr.<\/p>\n<p hwp:id=\"p-8\">Using a mouse model of rheumatoid arthritis&#x2014;an autoimmune disease characterized by inflammation and destruction of joint tissue&#x2014;Orange and co-workers demonstrated that their novel drug delivery system could be therapeutically useful. They loaded dendritic cells displaying the antigen that triggers the mouse immune system to attack joint tissue, with FK506, and used the resulting cells to treat arthritic mice. Mice that received these cells showed less severe arthritis than control animals treated with dendritic cells that had not been loaded with FK506. Moreover, the total dose of FK506 that the mice were exposed to was very low, with the result that they showed no evidence of the side effects typically seen with this drug.<\/p>\n<p hwp:id=\"p-9\">This proof-of-concept study suggests that dendritic cells could be used for the gradual and controlled delivery of drugs to specific target cells within the immune system. By precisely targeting relevant immune cells, it should be possible to use much lower drug doses, and thereby reduce side effects. Follow-up studies are now required to determine whether dendritic cells can be used as vehicles for the delivery of other drugs to treat a range of diseases.<\/p>\n<p hwp:id=\"p-10\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00105.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00105.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00105.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00105",
"title": "Dendritic cells loaded with FK506 kill T cells in an antigen-specific manner and prevent autoimmunity in vivo",
"metadata": {
"authors": "D. E. Orange, N. E. Blachere, J. Fak, S. Parveen, M. O. Frank, M. Herre, S. Tian, S. Monette, R. B. Darnell",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:29:51Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:29:51Z",
"updated_at": "2013-07-25T09:29:51Z"
},
{
"id": 61,
"content": "A little over 10 years ago, researchers discovered that a brain region called the hippocampus is larger in London taxi drivers than it is in the general population. This tied in with results from animal studies, which had revealed a key role for the hippocampus in spatial navigation and memory. However, other work has shown that the hippocampus is equally important for remembering personal experiences\u2014a form of memory known as episodic memory.Many neurons in the hippocampus display \u2018place fields', which means that they fire bursts of action potentials whenever an animal is in a specific location. Place fields tend to remain stable during repeated visits to an environment: the same cells fire whenever the animal returns to a particular place. However, if the animal enters a new environment, a neuron might adopt a different place field or not show any place field at all. This phenomenon is known as remapping.Now, Takahashi has provided further insight into the circumstances under which such remapping occurs. He recorded from large numbers of neurons in the rat hippocampus\u2014in a subregion called CA1\u2014as the animals moved through a maze shaped like a digital figure \u20188'. The rats had to perform three tasks within the maze: one guided by visual cues, and two that were memory-based.In the visual task, a light informed the rats to turn either left or right to obtain a reward. In the first memory task, the rats had to alternate their choices to obtain the reward, running through the maze from right-to-left and then from left-to-right (non-delayed spatial alternation). The second memory task worked the same way, except that the rats had to wait 5 s before turning left or right (delayed spatial alternation).Takahashi compared the responses of hippocampal CA1 neurons as rats performed the three tasks. As expected, he found that neurons tended to remap their place fields based on the animal's initial and final locations in the maze, regardless of which task the animal was performing. Surprisingly, however, neurons with specific place fields distinguished between the three tasks by firing at different rates in each.By combining information about the locations and rates at which large assemblies of neurons fired, Takahashi found that he could accurately predict which task a rat had been performing, where it had come from, and where it had ended up, because the place field remapping was hierarchically organized. Moreover, the prediction could be made even before the rat had completed the task. Overall, these results add to our understanding of how the hippocampus performs its dual roles in spatial navigation and episodic memory.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00321.002",
"content_html": "<p hwp:id=\"p-4\">A little over 10 years ago, researchers discovered that a brain region called the hippocampus is larger in London taxi drivers than it is in the general population. This tied in with results from animal studies, which had revealed a key role for the hippocampus in spatial navigation and memory. However, other work has shown that the hippocampus is equally important for remembering personal experiences&#x2014;a form of memory known as episodic memory.<\/p>\n<p hwp:id=\"p-5\">Many neurons in the hippocampus display &#x2018;place fields', which means that they fire bursts of action potentials whenever an animal is in a specific location. Place fields tend to remain stable during repeated visits to an environment: the same cells fire whenever the animal returns to a particular place. However, if the animal enters a new environment, a neuron might adopt a different place field or not show any place field at all. This phenomenon is known as remapping.<\/p>\n<p hwp:id=\"p-6\">Now, Takahashi has provided further insight into the circumstances under which such remapping occurs. He recorded from large numbers of neurons in the rat hippocampus&#x2014;in a subregion called CA1&#x2014;as the animals moved through a maze shaped like a digital figure &#x2018;8'. The rats had to perform three tasks within the maze: one guided by visual cues, and two that were memory-based.<\/p>\n<p hwp:id=\"p-7\">In the visual task, a light informed the rats to turn either left or right to obtain a reward. In the first memory task, the rats had to alternate their choices to obtain the reward, running through the maze from right-to-left and then from left-to-right (non-delayed spatial alternation). The second memory task worked the same way, except that the rats had to wait 5 s before turning left or right (delayed spatial alternation).<\/p>\n<p hwp:id=\"p-8\">Takahashi compared the responses of hippocampal CA1 neurons as rats performed the three tasks. As expected, he found that neurons tended to remap their place fields based on the animal's initial and final locations in the maze, regardless of which task the animal was performing. Surprisingly, however, neurons with specific place fields distinguished between the three tasks by firing at different rates in each.<\/p>\n<p hwp:id=\"p-9\">By combining information about the locations and rates at which large assemblies of neurons fired, Takahashi found that he could accurately predict which task a rat had been performing, where it had come from, and where it had ended up, because the place field remapping was hierarchically organized. Moreover, the prediction could be made even before the rat had completed the task. Overall, these results add to our understanding of how the hippocampus performs its dual roles in spatial navigation and episodic memory.<\/p>\n<p hwp:id=\"p-10\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00321.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00321.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00321.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00321",
"title": "Hierarchical organization of context in the hippocampal episodic code",
"metadata": {
"authors": "S. Takahashi",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:29:53Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:29:53Z",
"updated_at": "2013-07-25T09:29:53Z"
},
{
"id": 62,
"content": "While most animals experience a physiological decline as they age, the underlying cause of this decline is not fully understood. According to the free radical theory of aging, chemicals known as reactive oxygen species build up in the body and then cause damage to various components within cells, including DNA and proteins. These species, which include hydrogen peroxide and peroxynitrite, can cause substantial oxidative damage. However, while there is definitely a relationship between aging and reactive oxygen species, it remains possible that oxidative damage is a byproduct of aging rather than the cause of it.In the past researchers have measured the carbonylation of proteins (that is, the oxidation of certain amino acids in proteins) as a proxy for damage caused by reactive oxygen species, but this method has a number of shortcomings. More recently, it has become possible to quantify the oxidation state of cysteine, an amino acid that contains sulfur, in proteins using a technique based on mass spectrometry. Building on previous work in which they used this technique to measure the oxidation state of 300 proteins in vivo in the yeast Saccharomyces cerevisiae, Brandes et al. have now determined how the oxidation state of these proteins changes over the lifespan of S. cerevisiae, which is a popular model system for analyzing aging in cells that are in a high metabolic state but are no longer dividing. This made it possible to identify protein targets that might\u2014as a result of changes in their oxidation state caused by reactive oxygen species\u2014contribute to the physiological alterations observed in aging organisms. It was also possible to establish a clear connection between the onset and extent of oxidative stress and lifespan.Brandes et al. discovered that several days before the yeast cells died, they underwent a sudden and global \u2018redox collapse\u2019 in which \u223c80% of the 300 proteins being studied experienced an increase in their oxidation state (i.e., they lost electrons). This event was preceded by a large drop in the level of NADPH, a coenzyme that, by being a source of electrons, helps to counterbalance the removal of electrons by reactive oxygen species within cells. The drop in the concentration of NADPH occurred very early in the life cycle of the yeast, and set in motion a series of events that down-regulated most cellular processes. Intriguingly, these findings are consistent with the effect of caloric restriction, a condition that is known to extend the lifespan of animals. Caloric restriction increases cellular NADPH and delays the down-regulation of cellular processes.Brandes et al. propose that the underlying cause of aging is not the accumulation of reactive oxygen species: rather, these results suggest that aging is caused by a sudden and substantial decrease in available NADPH, which means that cells cannot maintain a stable oxidation state. If borne out by further work, these findings could have a significant impact on how we think about the aging process, and could require researchers to rethink how they study aging.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00306.002",
"content_html": "<p hwp:id=\"p-6\">While most animals experience a physiological decline as they age, the underlying cause of this decline is not fully understood. According to the free radical theory of aging, chemicals known as reactive oxygen species build up in the body and then cause damage to various components within cells, including DNA and proteins. These species, which include hydrogen peroxide and peroxynitrite, can cause substantial oxidative damage. However, while there is definitely a relationship between aging and reactive oxygen species, it remains possible that oxidative damage is a byproduct of aging rather than the cause of it.<\/p>\n<p hwp:id=\"p-7\">In the past researchers have measured the carbonylation of proteins (that is, the oxidation of certain amino acids in proteins) as a proxy for damage caused by reactive oxygen species, but this method has a number of shortcomings. More recently, it has become possible to quantify the oxidation state of cysteine, an amino acid that contains sulfur, in proteins using a technique based on mass spectrometry. Building on previous work in which they used this technique to measure the oxidation state of 300 proteins in vivo in the yeast <italic>Saccharomyces cerevisiae<\/italic>, Brandes et al. have now determined how the oxidation state of these proteins changes over the lifespan of <italic>S. cerevisiae<\/italic>, which is a popular model system for analyzing aging in cells that are in a high metabolic state but are no longer dividing. This made it possible to identify protein targets that might&#x2014;as a result of changes in their oxidation state caused by reactive oxygen species&#x2014;contribute to the physiological alterations observed in aging organisms. It was also possible to establish a clear connection between the onset and extent of oxidative stress and lifespan.<\/p>\n<p hwp:id=\"p-8\">Brandes et al. discovered that several days before the yeast cells died, they underwent a sudden and global &#x2018;redox collapse&#x2019; in which &#x223C;80% of the 300 proteins being studied experienced an increase in their oxidation state (i.e., they lost electrons). This event was preceded by a large drop in the level of NADPH, a coenzyme that, by being a source of electrons, helps to counterbalance the removal of electrons by reactive oxygen species within cells. The drop in the concentration of NADPH occurred very early in the life cycle of the yeast, and set in motion a series of events that down-regulated most cellular processes. Intriguingly, these findings are consistent with the effect of caloric restriction, a condition that is known to extend the lifespan of animals. Caloric restriction increases cellular NADPH and delays the down-regulation of cellular processes.<\/p>\n<p hwp:id=\"p-9\">Brandes et al. propose that the underlying cause of aging is not the accumulation of reactive oxygen species: rather, these results suggest that aging is caused by a sudden and substantial decrease in available NADPH, which means that cells cannot maintain a stable oxidation state. If borne out by further work, these findings could have a significant impact on how we think about the aging process, and could require researchers to rethink how they study aging.<\/p>\n<p hwp:id=\"p-10\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00306.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00306.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00306.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00306",
"title": "Time line of redox events in aging postmitotic cells",
"metadata": {
"authors": "N. Brandes, H. Tienson, A. Lindemann, V. Vitvitsky, D. Reichmann, R. Banerjee, U. Jakob",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:29:56Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:29:56Z",
"updated_at": "2013-07-25T09:29:56Z"
},
{
"id": 63,
"content": "Many species, including our own, show a preference for familiar foods over novel ones. This behavior probably evolved to reduce the risk of consuming items that turn out to be poisonous, but the mechanisms that underlie a preference for familiar foods are largely unknown.The nematode worm, C. elegans, is a useful organism in which to study such processes. Having only around 1000 cells and a simple anatomy, C. elegans is an attractive model system for studying molecular biology, and was the first multicellular organism to have its genome fully sequenced.C. elegans feeds on bacteria, which it detects using a pair of sensory cells called ADF neurons, which sense extrinsic cues. When the ADF neurons detect bacteria, they release the transmitter serotonin. Serotonin stimulates the worm to consume the bacteria by pumping them into the pharynx, its feeding organ, and then transporting them to its intestine after crushing them.Now, Song et al. have demonstrated that C. elegans consumes familiar bacteria more rapidly than it does novel ones, and have identified the molecular mechanism behind this behavior. They found that familiar bacteria stimulated the release of serotonin from the ADF cells: this activated SER-7 receptors on a specific type of motor neuron in the pharynx and this, in turn, triggered the worms' feeding response. Novel bacteria, on the other hand, failed to either activate ADF or to trigger feeding. Moreover, when Song et al. offered the worms familiar bacteria in medium that had previously contained novel bacteria, the residual traces of the novel bacteria stopped the worms from responding to familiar food.Further research is needed to determine whether the mechanisms that underpin the more active consumption of familiar food by C. elegans can also explain the preference for familiar foods shown by other species. A better understanding of the mechanisms by which different foods elicit feeding could also offer important insights into factors that contribute to obesity.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00329.002",
"content_html": "<p hwp:id=\"p-4\">Many species, including our own, show a preference for familiar foods over novel ones. This behavior probably evolved to reduce the risk of consuming items that turn out to be poisonous, but the mechanisms that underlie a preference for familiar foods are largely unknown.<\/p>\n<p hwp:id=\"p-5\">The nematode worm, <italic>C. elegans<\/italic>, is a useful organism in which to study such processes. Having only around 1000 cells and a simple anatomy, <italic>C. elegans<\/italic> is an attractive model system for studying molecular biology, and was the first multicellular organism to have its genome fully sequenced.<\/p>\n<p hwp:id=\"p-6\"><italic>C. elegans<\/italic> feeds on bacteria, which it detects using a pair of sensory cells called ADF neurons, which sense extrinsic cues. When the ADF neurons detect bacteria, they release the transmitter serotonin. Serotonin stimulates the worm to consume the bacteria by pumping them into the pharynx, its feeding organ, and then transporting them to its intestine after crushing them.<\/p>\n<p hwp:id=\"p-7\">Now, Song et al. have demonstrated that <italic>C. elegans<\/italic> consumes familiar bacteria more rapidly than it does novel ones, and have identified the molecular mechanism behind this behavior. They found that familiar bacteria stimulated the release of serotonin from the ADF cells: this activated SER-7 receptors on a specific type of motor neuron in the pharynx and this, in turn, triggered the worms' feeding response. Novel bacteria, on the other hand, failed to either activate ADF or to trigger feeding. Moreover, when Song et al. offered the worms familiar bacteria in medium that had previously contained novel bacteria, the residual traces of the novel bacteria stopped the worms from responding to familiar food.<\/p>\n<p hwp:id=\"p-8\">Further research is needed to determine whether the mechanisms that underpin the more active consumption of familiar food by <italic>C. elegans<\/italic> can also explain the preference for familiar foods shown by other species. A better understanding of the mechanisms by which different foods elicit feeding could also offer important insights into factors that contribute to obesity.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00329.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00329.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00329.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00329",
"title": "Recognition of familiar food activates feeding via an endocrine serotonin signal in Caenorhabditis elegans",
"metadata": {
"authors": "B.-m. Song, S. Faumont, S. Lockery, L. Avery",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:29:59Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:29:59Z",
"updated_at": "2013-07-25T09:29:59Z"
},
{
"id": 64,
"content": "Influenza is caused by viruses that infect birds and mammals. These viruses enter cells when two lipid bilayers\u2014one surrounding the virus, the other enclosing the cellular compartment into which the virus has been engulfed\u2014merge to form a single unified membrane. This process, known as membrane fusion, allows the RNA of the virus to gain access to the host cell's molecular machinery, which it commandeers to produce multiple copies of itself and to direct the assembly of new virus particles. The process of membrane fusion generally includes an intermediate hemifused state in which only the adjacent monolayers from each bilayer have merged. In addition to its role in virology, membrane fusion is critical for many other biological processes, including exocytosis, protein trafficking and the fertilization of eggs by sperm.Efficient membrane fusion requires a catalyst, and a glycoprotein known as the influenza hemagglutinin performs this role for the influenza virus. The hemagglutinin is found on the surface of the virus, and a typical influenza virus particle can have a few hundred such molecules on its surface. When an influenza virus particle binds to the surface of a cell (as a result of these hemagglutinin molecules interacting with cellular receptor molecules), the cell engulfs the virus into an internal compartment called an endosome. Acidification of the endosome, part of the cell's normal activity, triggers a sequence of conformational changes in the hemagglutinin molecules on the surface of the virus. One part of the hemagglutinin inserts itself into the endosomal membrane, and further conformational changes draw the endosomal and viral membranes together into an intermediate, hemifused state; the process then continues until fusion of the two membranes is complete.Previous work has suggested that an average of three hemagglutinin molecules are required to fuse the endosomal and viral membranes. Ivanovic et al. have now investigated the molecular details of this process and described the time course of conformational changes undergone by the hemagglutinin molecules from the moment the pH is lowered within the endosome until the time when hemifusion of the endosomal and viral membranes is complete. They find, among other things, that hemifusion proceeds rapidly only when three or four immediately adjacent hemagglutinin molecules have inserted into the endosomal membrane. Since membrane fusion is a very general cellular process, the findings of Ivanovic et al. are relevant to many areas of cell biology, in addition to having potential applications in virology.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00333.002",
"content_html": "<p hwp:id=\"p-5\">Influenza is caused by viruses that infect birds and mammals. These viruses enter cells when two lipid bilayers&#x2014;one surrounding the virus, the other enclosing the cellular compartment into which the virus has been engulfed&#x2014;merge to form a single unified membrane. This process, known as membrane fusion, allows the RNA of the virus to gain access to the host cell's molecular machinery, which it commandeers to produce multiple copies of itself and to direct the assembly of new virus particles. The process of membrane fusion generally includes an intermediate hemifused state in which only the adjacent monolayers from each bilayer have merged. In addition to its role in virology, membrane fusion is critical for many other biological processes, including exocytosis, protein trafficking and the fertilization of eggs by sperm.<\/p>\n<p hwp:id=\"p-6\">Efficient membrane fusion requires a catalyst, and a glycoprotein known as the influenza hemagglutinin performs this role for the influenza virus. The hemagglutinin is found on the surface of the virus, and a typical influenza virus particle can have a few hundred such molecules on its surface. When an influenza virus particle binds to the surface of a cell (as a result of these hemagglutinin molecules interacting with cellular receptor molecules), the cell engulfs the virus into an internal compartment called an endosome. Acidification of the endosome, part of the cell's normal activity, triggers a sequence of conformational changes in the hemagglutinin molecules on the surface of the virus. One part of the hemagglutinin inserts itself into the endosomal membrane, and further conformational changes draw the endosomal and viral membranes together into an intermediate, hemifused state; the process then continues until fusion of the two membranes is complete.<\/p>\n<p hwp:id=\"p-7\">Previous work has suggested that an average of three hemagglutinin molecules are required to fuse the endosomal and viral membranes. Ivanovic et al. have now investigated the molecular details of this process and described the time course of conformational changes undergone by the hemagglutinin molecules from the moment the pH is lowered within the endosome until the time when hemifusion of the endosomal and viral membranes is complete. They find, among other things, that hemifusion proceeds rapidly only when three or four immediately adjacent hemagglutinin molecules have inserted into the endosomal membrane. Since membrane fusion is a very general cellular process, the findings of Ivanovic et al. are relevant to many areas of cell biology, in addition to having potential applications in virology.<\/p>\n<p hwp:id=\"p-8\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00333.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00333.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00333.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00333",
"title": "Influenza-virus membrane fusion by cooperative fold-back of stochastically induced hemagglutinin intermediates",
"metadata": {
"authors": "T. Ivanovic, J. L. Choi, S. P. Whelan, A. M. van Oijen, S. C. Harrison",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:30:06Z",
"updated_at": "2013-10-09T14:38:25Z"
},
"created_at": "2013-07-25T09:30:06Z",
"updated_at": "2013-07-25T09:30:06Z"
},
{
"id": 65,
"content": "Toll-like receptors (TLRs) are proteins that are responsible for recognizing specific molecules associated with invading pathogens, known as pathogen-associated molecular patterns. Upon detecting these signals, TLRs activate the body's immune response, which fights the infection.A subset of TLRs recognizes nucleic acids, including DNA and RNA, enabling the immune system to respond to foreign material from a diverse range of bacteria and viruses. However, some of the body's own DNA and RNA is also found outside cells (e.g., in the bloodstream) and TLRs must be able to discriminate between these nucleic acids and those belonging to pathogens, because failure to tell the difference between the two could result in autoimmune disease. To reduce this risk, TLRs are sequestered inside the cell within membrane-bound compartments known as endosomes.UNC93B1 is a transmembrane protein that is known to control the movement of TLRs from the endoplasmic reticulum\u2014where TLRs are assembled\u2014to endosomes. However, the exact mechanisms by which this protein controls TLR trafficking were unclear. Now Lee et al. reveal that it directly controls the packaging of at least six TLRs at the endoplasmic reticulum: it helps to load these TLRs into vesicles, which are in turn processed by the Golgi apparatus\u2014the organelle wherein proteins are sorted and packaged en route to their final destinations. Surprisingly, UNC93B1 remains associated with the TLRs even after Golgi processing.Lee et al. also reveal that specific endosomal TLRs are subject to distinct post-Golgi trafficking mechanisms. In order for TLR9 to be delivered to the endosome, UNC93B1 must recruit an adaptor protein called AP-2, whereas other TLRs appear to require different actions by UNC93B1. By defining the mechanisms that underlie the differential trafficking of endosomal TLRs, Lee et al. suggest that we may learn how to manipulate distinct aspects of TLR activation, and also gain insights into the causes of certain autoimmune diseases.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00291.002",
"content_html": "<p hwp:id=\"p-4\">Toll-like receptors (TLRs) are proteins that are responsible for recognizing specific molecules associated with invading pathogens, known as pathogen-associated molecular patterns. Upon detecting these signals, TLRs activate the body's immune response, which fights the infection.<\/p>\n<p hwp:id=\"p-5\">A subset of TLRs recognizes nucleic acids, including DNA and RNA, enabling the immune system to respond to foreign material from a diverse range of bacteria and viruses. However, some of the body's own DNA and RNA is also found outside cells (e.g., in the bloodstream) and TLRs must be able to discriminate between these nucleic acids and those belonging to pathogens, because failure to tell the difference between the two could result in autoimmune disease. To reduce this risk, TLRs are sequestered inside the cell within membrane-bound compartments known as endosomes.<\/p>\n<p hwp:id=\"p-6\">UNC93B1 is a transmembrane protein that is known to control the movement of TLRs from the endoplasmic reticulum&#x2014;where TLRs are assembled&#x2014;to endosomes. However, the exact mechanisms by which this protein controls TLR trafficking were unclear. Now Lee et al. reveal that it directly controls the packaging of at least six TLRs at the endoplasmic reticulum: it helps to load these TLRs into vesicles, which are in turn processed by the Golgi apparatus&#x2014;the organelle wherein proteins are sorted and packaged en route to their final destinations. Surprisingly, UNC93B1 remains associated with the TLRs even after Golgi processing.<\/p>\n<p hwp:id=\"p-7\">Lee et al. also reveal that specific endosomal TLRs are subject to distinct post-Golgi trafficking mechanisms. In order for TLR9 to be delivered to the endosome, UNC93B1 must recruit an adaptor protein called AP-2, whereas other TLRs appear to require different actions by UNC93B1. By defining the mechanisms that underlie the differential trafficking of endosomal TLRs, Lee et al. suggest that we may learn how to manipulate distinct aspects of TLR activation, and also gain insights into the causes of certain autoimmune diseases.<\/p>\n<p hwp:id=\"p-8\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00291.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00291.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00291.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00291",
"title": "UNC93B1 mediates differential trafficking of endosomal TLRs",
"metadata": {
"authors": "B. L. Lee, J. E. Moon, J. H. Shu, L. Yuan, Z. R. Newman, R. Schekman, G. M. Barton",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:30:09Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:30:09Z",
"updated_at": "2013-07-25T09:30:09Z"
},
{
"id": 66,
"content": "Determining the structure of proteins and other biomolecules at the atomic level is central to understanding many aspects of biology. X-ray crystallography is the best-known technique for structural biology but, as the name suggests, it works only with samples that can be crystallized. Electron cryo-microscopy (cryo-EM) could, potentially, be used to determine the atomic structures of biomolecules that cannot be crystallized, but at present the resolution that can be achieved with this approach is sufficient only for imaging certain types of viruses.In cryo-EM, a solution of the biomolecule of interest is frozen in a thin layer of ice, and this layer is imaged in an electron microscope. By combining images of many identical biomolecules in many different orientations, it is possible to work backwards and determine their 3D structure. However, in order to determine this structure at high resolution, it is necessary to make repeated measurements to reduce high levels of noise in the images.Cryo-EM images are usually recorded on a photographic film or a CCD (charge-coupled device) camera. However, photographic film is unsuitable for high-throughput methods because it has to be handled manually, while the efficiency of CCD cameras is limited because the electrons have to be converted into visible light to be detected. Digital cameras that can detect electrons directly have become available recently, and these are more efficient than both film and CCD cameras. They are also much faster, which means that it is possible to record videos of the sample during the time (typically \u223c1 s) it is being exposed to the electron beam. Processing these videos could then\u2014in theory\u2014compensate for any movements of the biomolecules that are induced by the electron beam. Along with radiation damage caused by the electrons, these beam-induced movements have been a major limitation on the resolution that can be achieved with cryo-EM.Bai et al. demonstrate the potential of direct-electron detectors in cryo-EM by determining the structures of two ribosomes. Using a novel statistical algorithm to accurately follow the movements of the ribosomes during the time they are exposed to the electron beam, they are able to compensate for these movements, and this makes it possible to determine the structures of the ribosomes with near-atomic precision. Moreover, the resolution they achieve with just \u223c30,000 ribosomes is better than that previously achieved with more than a million ribosomes, allowing small details inside the ribosome \u2013 such as \u00df-strands and bulky amino-acid side chains \u2013 to be resolved with cryo-EM for the first time. The work of Bai et al. could, therefore, allow researchers to use cryo-EM to determine the structure of many more biomolecules with atomic precision.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00461.002",
"content_html": "<p hwp:id=\"p-4\">Determining the structure of proteins and other biomolecules at the atomic level is central to understanding many aspects of biology. X-ray crystallography is the best-known technique for structural biology but, as the name suggests, it works only with samples that can be crystallized. Electron cryo-microscopy (cryo-EM) could, potentially, be used to determine the atomic structures of biomolecules that cannot be crystallized, but at present the resolution that can be achieved with this approach is sufficient only for imaging certain types of viruses.<\/p>\n<p hwp:id=\"p-5\">In cryo-EM, a solution of the biomolecule of interest is frozen in a thin layer of ice, and this layer is imaged in an electron microscope. By combining images of many identical biomolecules in many different orientations, it is possible to work backwards and determine their 3D structure. However, in order to determine this structure at high resolution, it is necessary to make repeated measurements to reduce high levels of noise in the images.<\/p>\n<p hwp:id=\"p-6\">Cryo-EM images are usually recorded on a photographic film or a CCD (charge-coupled device) camera. However, photographic film is unsuitable for high-throughput methods because it has to be handled manually, while the efficiency of CCD cameras is limited because the electrons have to be converted into visible light to be detected. Digital cameras that can detect electrons directly have become available recently, and these are more efficient than both film and CCD cameras. They are also much faster, which means that it is possible to record videos of the sample during the time (typically &#x223C;1 s) it is being exposed to the electron beam. Processing these videos could then&#x2014;in theory&#x2014;compensate for any movements of the biomolecules that are induced by the electron beam. Along with radiation damage caused by the electrons, these beam-induced movements have been a major limitation on the resolution that can be achieved with cryo-EM.<\/p>\n<p hwp:id=\"p-7\">Bai et al. demonstrate the potential of direct-electron detectors in cryo-EM by determining the structures of two ribosomes. Using a novel statistical algorithm to accurately follow the movements of the ribosomes during the time they are exposed to the electron beam, they are able to compensate for these movements, and this makes it possible to determine the structures of the ribosomes with near-atomic precision. Moreover, the resolution they achieve with just &#x223C;30,000 ribosomes is better than that previously achieved with more than a million ribosomes, allowing small details inside the ribosome &#x2013; such as &#xDF;-strands and bulky amino-acid side chains &#x2013; to be resolved with cryo-EM for the first time. The work of Bai et al. could, therefore, allow researchers to use cryo-EM to determine the structure of many more biomolecules with atomic precision.<\/p>\n<p hwp:id=\"p-8\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00461.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00461.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00461.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00461",
"title": "Ribosome structures to near-atomic resolution from thirty thousand cryo-EM particles",
"metadata": {
"authors": "X.-c. Bai, I. S. Fernandez, G. McMullan, S. H. Scheres",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:30:11Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:30:11Z",
"updated_at": "2013-07-25T09:30:11Z"
},
{
"id": 71,
"content": "The cell membrane is a busy place, with cell-surface proteins continually added and removed according to the needs of the cell. Each protein extends a polypeptide tail into the cell cytoplasm. When a protein is to be removed from the cell surface, its tail recruits a protein complex known as the AP2 adaptor to the membrane. AP2 then recruits a coat protein called clathrin, which forms a spherical scaffold around the adaptor, the target protein and the surrounding membrane, enclosing them inside a vesicle that breaks off from the membrane and enters the cell.Endocytosis is particularly common in neurons, which use it as a means of recycling proteins at synapses\u2014the contact points between nerve cells. However, it is unclear whether synaptic-vesicle recycling also involves clathrin and AP2. To address this question, Gu et al. examined mutant nematode worms (C. elegans) in which the composition of AP2 had been altered.AP2 has four subunits, called \u03b1, \u03b22, \u03bc2 and \u03c32, and Gu et al. produced worms that lack either the \u03b1- or \u03bc2-subunit, or both. Few worms that lacked both subunits survived. Surprisingly, however, worms that lacked just one subunit were viable, despite previous evidence that AP2 requires all four subunits to be functional. Nevertheless, these single mutants produced 30% fewer synaptic vesicles compared to wild-type worms. To examine the consequences of both subunits being absent, Gu et al. rescued the double mutants by selectively expressing AP2 in their skin. These animals\u2014which still lack AP2 in their nervous systems\u2014produced 70% fewer synaptic vesicles than their wild-type counterparts.The results show that AP2 does not need all four of its subunits and that it can exist as two semi-independent hemicomplexes. Moreover, Gu et al. show that C. elegans uses at least two endocytotic mechanisms (AP2-dependent and independent) to recycle vesicles and so maintain synaptic function.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00190.002",
"content_html": "<p hwp:id=\"p-4\">The cell membrane is a busy place, with cell-surface proteins continually added and removed according to the needs of the cell. Each protein extends a polypeptide tail into the cell cytoplasm. When a protein is to be removed from the cell surface, its tail recruits a protein complex known as the AP2 adaptor to the membrane. AP2 then recruits a coat protein called clathrin, which forms a spherical scaffold around the adaptor, the target protein and the surrounding membrane, enclosing them inside a vesicle that breaks off from the membrane and enters the cell.<\/p>\n<p hwp:id=\"p-5\">Endocytosis is particularly common in neurons, which use it as a means of recycling proteins at synapses&#x2014;the contact points between nerve cells. However, it is unclear whether synaptic-vesicle recycling also involves clathrin and AP2. To address this question, Gu et al. examined mutant nematode worms (<italic>C. elegans<\/italic>) in which the composition of AP2 had been altered.<\/p>\n<p hwp:id=\"p-6\">AP2 has four subunits, called &#x3B1;, &#x3B2;2, &#x3BC;2 and &#x3C3;2, and Gu et al. produced worms that lack either the &#x3B1;- or &#x3BC;2-subunit, or both. Few worms that lacked both subunits survived. Surprisingly, however, worms that lacked just one subunit were viable, despite previous evidence that AP2 requires all four subunits to be functional. Nevertheless, these single mutants produced 30% fewer synaptic vesicles compared to wild-type worms. To examine the consequences of both subunits being absent, Gu et al. rescued the double mutants by selectively expressing AP2 in their skin. These animals&#x2014;which still lack AP2 in their nervous systems&#x2014;produced 70% fewer synaptic vesicles than their wild-type counterparts.<\/p>\n<p hwp:id=\"p-7\">The results show that AP2 does not need all four of its subunits and that it can exist as two semi-independent hemicomplexes. Moreover, Gu et al. show that <italic>C. elegans<\/italic> uses at least two endocytotic mechanisms (AP2-dependent and independent) to recycle vesicles and so maintain synaptic function.<\/p>\n<p hwp:id=\"p-8\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00190.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00190.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00190.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00190",
"title": "AP2 hemicomplexes contribute independently to synaptic vesicle endocytosis",
"metadata": {
"authors": "M. Gu, Q. Liu, S. Watanabe, L. Sun, G. Hollopeter, B. D. Grant, E. M. Jorgensen",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:30:36Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:30:36Z",
"updated_at": "2013-07-25T09:30:36Z"
},
{
"id": 67,
"content": "In the earliest stages of development, animal cells undergo multiple rounds of division without growth via a process known as mitosis. Over the course of just 12 rounds of cell division, a single fertilized egg is transformed into more than 4000 smaller cells.Before dividing, the cell must first replicate its chromosomes. A structure called the mitotic spindle then separates the members of each chromosome pair and distributes them evenly between the two daughter cells. Given that the daughter cells become smaller with each round of division, the spindle must also become smaller to ensure that the chromosomes are pulled apart an appropriate distance. However, it has been unclear how the cell achieves this.Now, Wilbur and Heald report insights into the mechanism by which spindle size is coordinated with cell size, using the model organism Xenopus laevis\u2014a frog that produces large embryos that are easy to manipulate. They began by preparing extracts of cytoplasm from X. laevis embryos at two different developmental stages: one set of embryos contained 4 cells each and the other set contained \u223c4000 cells. They found that the spindle, which is composed largely of microtubules\u2014hollow filaments that can become longer or shorter through the addition or removal of tubulin building blocks\u2014was almost twice as large in the four-cell embryos as in the more developed embryos.Moreover, spindle size was determined by the actions of two proteins: kif2a and importin-\u03b1. Binding of kif2a destabilized microtubules and caused them to shorten; importin-\u03b1 blocked this process by binding to kif2a and preventing it from interacting with microtubules. Wilbur and Heald found that over the course of development, importin-\u03b1 became increasingly localized to the cell membrane, meaning that there was less available to bind to kif2a in the cytoplasm. This freed up kif2a to interact with and destabilize microtubules, and led ultimately to a reduction in spindle size.Given that the overall ratio of cell surface membrane to cytoplasm increases as cells undergo division without growth, interaction between kif2a and importin-\u03b1 could be the long-sought mechanism by which spindle and cell sizes are coordinated early in development.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00290.002",
"content_html": "<p hwp:id=\"p-4\">In the earliest stages of development, animal cells undergo multiple rounds of division without growth via a process known as mitosis. Over the course of just 12 rounds of cell division, a single fertilized egg is transformed into more than 4000 smaller cells.<\/p>\n<p hwp:id=\"p-5\">Before dividing, the cell must first replicate its chromosomes. A structure called the mitotic spindle then separates the members of each chromosome pair and distributes them evenly between the two daughter cells. Given that the daughter cells become smaller with each round of division, the spindle must also become smaller to ensure that the chromosomes are pulled apart an appropriate distance. However, it has been unclear how the cell achieves this.<\/p>\n<p hwp:id=\"p-6\">Now, Wilbur and Heald report insights into the mechanism by which spindle size is coordinated with cell size, using the model organism <italic>Xenopus laevis&#x2014;<\/italic>a frog that produces large embryos that are easy to manipulate. They began by preparing extracts of cytoplasm from <italic>X. laevis<\/italic> embryos at two different developmental stages: one set of embryos contained 4 cells each and the other set contained &#x223C;4000 cells. They found that the spindle, which is composed largely of microtubules&#x2014;hollow filaments that can become longer or shorter through the addition or removal of tubulin building blocks&#x2014;was almost twice as large in the four-cell embryos as in the more developed embryos.<\/p>\n<p hwp:id=\"p-7\">Moreover, spindle size was determined by the actions of two proteins: kif2a and importin-&#x3B1;. Binding of kif2a destabilized microtubules and caused them to shorten; importin-&#x3B1; blocked this process by binding to kif2a and preventing it from interacting with microtubules. Wilbur and Heald found that over the course of development, importin-&#x3B1; became increasingly localized to the cell membrane, meaning that there was less available to bind to kif2a in the cytoplasm. This freed up kif2a to interact with and destabilize microtubules, and led ultimately to a reduction in spindle size.<\/p>\n<p hwp:id=\"p-8\">Given that the overall ratio of cell surface membrane to cytoplasm increases as cells undergo division without growth, interaction between kif2a and importin-&#x3B1; could be the long-sought mechanism by which spindle and cell sizes are coordinated early in development.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00290.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00290.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00290.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00290",
"title": "Mitotic spindle scaling during Xenopus development by kif2a and importin &#xA0;",
"metadata": {
"authors": "J. D. Wilbur, R. Heald",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:30:19Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:30:19Z",
"updated_at": "2013-07-25T09:30:19Z"
},
{
"id": 68,
"content": "Learning a new motor skill, from riding a bicycle to eating with chopsticks, involves the cerebellum\u2014a structure located at the base of the brain underneath the cerebral hemispheres. Although its name translates as \u2018little brain' in Latin, the cerebellum contains more neurons than all other regions of the mammalian brain combined.Most cerebellar neurons are granule cells which, although numerous, are simple neurons with an average of only four excitatory inputs, from axons called mossy fibers. These inputs are diverse in nature, originating from virtually every sensory system and from command centers at multiple levels of the motor hierarchy. However, it is unclear whether individual granule cells receive inputs from only a single sensory source or can instead mix modalities. This distinction has important implications for the functional capabilities of the cerebellum.Now, Huang et al. have addressed this question by mapping, at extremely high resolution, the projections of two pathways onto individual granule cells\u2014one carrying sensory feedback from the upper body (the proprioceptive stream), and another carrying motor-related information (the pontine stream). Using a combination of genetic and viral techniques to label the pathways, Huang and co-workers identified regions where the two types of fiber terminated in close proximity. They then showed that around 40% of proprioceptive granule cells formed junctions, or synapses, with two (or more) fibers carrying different types of input. These cells were not uniformly distributed throughout the cerebellum but tended to occur in \u2018hotspots\u2019.Lastly, Huang et al. examined the type of information conveyed by the sensory and motor-related input streams whenever they contacted a single granule cell. They confirmed that when the sensory input consisted of feedback from the upper body, the motor input consisted of copies of motor commands related to the same body region. Because it is thought that the cerebellum converts sensory information into representations of the body's movements, directing motor commands to these same circuits may allow the cerebellum to predict the consequences of a planned movement prior to, or without, the actual movement occurring.The work of Huang et al. provides evidence to support the previously controversial idea that granule cells in the mammalian cerebellum receive both sensory and motor-related inputs. The labeling technique that they used could also be deployed to study the inputs to the cerebellum in greater detail, which should yield new insights into the functioning of this part of the brain.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00400.002",
"content_html": "<p hwp:id=\"p-4\">Learning a new motor skill, from riding a bicycle to eating with chopsticks, involves the cerebellum&#x2014;a structure located at the base of the brain underneath the cerebral hemispheres. Although its name translates as &#x2018;little brain' in Latin, the cerebellum contains more neurons than all other regions of the mammalian brain combined.<\/p>\n<p hwp:id=\"p-5\">Most cerebellar neurons are granule cells which, although numerous, are simple neurons with an average of only four excitatory inputs, from axons called mossy fibers. These inputs are diverse in nature, originating from virtually every sensory system and from command centers at multiple levels of the motor hierarchy. However, it is unclear whether individual granule cells receive inputs from only a single sensory source or can instead mix modalities. This distinction has important implications for the functional capabilities of the cerebellum.<\/p>\n<p hwp:id=\"p-6\">Now, Huang et al. have addressed this question by mapping, at extremely high resolution, the projections of two pathways onto individual granule cells&#x2014;one carrying sensory feedback from the upper body (the proprioceptive stream), and another carrying motor-related information (the pontine stream). Using a combination of genetic and viral techniques to label the pathways, Huang and co-workers identified regions where the two types of fiber terminated in close proximity. They then showed that around 40% of proprioceptive granule cells formed junctions, or synapses, with two (or more) fibers carrying different types of input. These cells were not uniformly distributed throughout the cerebellum but tended to occur in &#x2018;hotspots&#x2019;.<\/p>\n<p hwp:id=\"p-7\">Lastly, Huang et al. examined the type of information conveyed by the sensory and motor-related input streams whenever they contacted a single granule cell. They confirmed that when the sensory input consisted of feedback from the upper body, the motor input consisted of copies of motor commands related to the same body region. Because it is thought that the cerebellum converts sensory information into representations of the body's movements, directing motor commands to these same circuits may allow the cerebellum to predict the consequences of a planned movement prior to, or without, the actual movement occurring.<\/p>\n<p hwp:id=\"p-8\">The work of Huang et al. provides evidence to support the previously controversial idea that granule cells in the mammalian cerebellum receive both sensory and motor-related inputs. The labeling technique that they used could also be deployed to study the inputs to the cerebellum in greater detail, which should yield new insights into the functioning of this part of the brain.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00400.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00400.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00400.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00400",
"title": "Convergence of pontine and proprioceptive streams onto multimodal cerebellar granule cells",
"metadata": {
"authors": "C.-C. Huang, K. Sugino, Y. Shima, C. Guo, S. Bai, B. D. Mensh, S. B. Nelson, A. W. Hantman",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:30:26Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:30:26Z",
"updated_at": "2013-07-25T09:30:26Z"
},
{
"id": 69,
"content": "DNA methylation\u2014the addition of a methyl group to cytosine, one of the four bases found in DNA\u2014is a central process in genetics. By preventing genes from being expressed as proteins, DNA methylation is one of a number of epigenetic mechanisms that can determine which proteins are made in different cell types without changing the underlying DNA sequence.In warm-blooded vertebrates such as mammals most of the genome is methylated, however short regions of non-methylated DNA are known to be associated with gene promoters (regions of DNA that act as binding sites for the enzymes and transcription factors that transcribe the DNA in the gene into RNA). Much of our current understanding of the role of these islands of non-methylated DNA is based on computational predictions rather than experimental data. In cold-blooded vertebrates, for example, computer models often predict that non-methylated islands are not associated with gene promoters, which potentially suggests an evolutionary divergence in the role of methylation amongst vertebrates. However, this idea has not been confirmed by experimental data.Long et al. have performed experiments to compare the location of non-methylated islands in seven different vertebrate species. In general they find that computational models are not a reliable method for identifying non-methylated islands. Moreover they find that non-methylated islands are a central epigenetic feature of gene promoters in all vertebrates analysed\u2013including three mammals, a bird, a lizard, a frog and a fish\u2014and not just in warm-blooded vertebrates as suggested by computational models. This shows that the epigenetic function of these non-methylated islands has been conserved over more than 450 million years of evolution.In addition to the non-methylated islands associated with gene promoters, Long et al. identify two other types: intergenic non-methylated islands that are found away from gene promoters and are said to be \u2018plastic\u2019 because the DNA in these islands can acquire methyl groups, and \u2018broad\u2019 non-methylated islands that span many of the genes that are involved in embryonic development.By showing that the epigenetic role of non-methylated islands has been conserved over time, and identifying three specific types of island, the work of Long et al. marks an important change in our understanding of epigenetics in vertebrates.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00348.002",
"content_html": "<p hwp:id=\"p-5\">DNA methylation&#x2014;the addition of a methyl group to cytosine, one of the four bases found in DNA&#x2014;is a central process in genetics. By preventing genes from being expressed as proteins, DNA methylation is one of a number of epigenetic mechanisms that can determine which proteins are made in different cell types without changing the underlying DNA sequence.<\/p>\n<p hwp:id=\"p-6\">In warm-blooded vertebrates such as mammals most of the genome is methylated, however short regions of non-methylated DNA are known to be associated with gene promoters (regions of DNA that act as binding sites for the enzymes and transcription factors that transcribe the DNA in the gene into RNA). Much of our current understanding of the role of these islands of non-methylated DNA is based on computational predictions rather than experimental data. In cold-blooded vertebrates, for example, computer models often predict that non-methylated islands are not associated with gene promoters, which potentially suggests an evolutionary divergence in the role of methylation amongst vertebrates. However, this idea has not been confirmed by experimental data.<\/p>\n<p hwp:id=\"p-7\">Long et al. have performed experiments to compare the location of non-methylated islands in seven different vertebrate species. In general they find that computational models are not a reliable method for identifying non-methylated islands. Moreover they find that non-methylated islands are a central epigenetic feature of gene promoters in all vertebrates analysed&#x2013;including three mammals, a bird, a lizard, a frog and a fish&#x2014;and not just in warm-blooded vertebrates as suggested by computational models. This shows that the epigenetic function of these non-methylated islands has been conserved over more than 450 million years of evolution.<\/p>\n<p hwp:id=\"p-8\">In addition to the non-methylated islands associated with gene promoters, Long et al. identify two other types: intergenic non-methylated islands that are found away from gene promoters and are said to be &#x2018;plastic&#x2019; because the DNA in these islands can acquire methyl groups, and &#x2018;broad&#x2019; non-methylated islands that span many of the genes that are involved in embryonic development.<\/p>\n<p hwp:id=\"p-9\">By showing that the epigenetic role of non-methylated islands has been conserved over time, and identifying three specific types of island, the work of Long et al. marks an important change in our understanding of epigenetics in vertebrates.<\/p>\n<p hwp:id=\"p-10\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00348.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00348.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00348.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00348",
"title": "Epigenetic conservation at gene regulatory elements revealed by non-methylated DNA profiling in seven vertebrates",
"metadata": {
"authors": "H. K. Long, D. Sims, A. Heger, N. P. Blackledge, C. Kutter, M. L. Wright, F. Grutzner, D. T. Odom, R. Patient, C. P. Ponting, R. J. Klose",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:30:28Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:30:28Z",
"updated_at": "2013-07-25T09:30:28Z"
},
{
"id": 101,
"content": "Mitochondria generate most of the energy used by cells, and they also play key roles in cellular growth, death, and differentiation. They are evolutionarily derived from bacteria and have retained their own DNA and protein translation system, but they are also dependent on the cell for their growth and replication.A significant portion of the outer membrane of a mitochondrion is in contact with the endoplasmic reticulum (ER)\u2014an organelle that is the starting point for the synthesis of secreted proteins, and is also critical for the synthesis of lipids and other organelles. Recent work suggests that mitochondria\u2013ER contact points mark sites of mitochondrial division, but it is unclear exactly how this process occurs.Here, Murley et al. use the budding yeast and model organism Saccharomyces cerevisiae to show that at mitochondrial division sites, a multiprotein complex called ERMES promotes the formation of ER\u2013mitochondrial contact points, while an evolutionarily conserved enzyme, Gem1, antagonizes these contacts to aid mitochondrial segregation. The contact points are found adjacent to nucleoids (which are complexes of mitochondrial DNA and proteins)\u2014an observation suggesting that ER-associated mitochondrial division evolved to help distribute nucleoids between newly formed mitochondria.The present study also reveals a novel role for the conserved protein Gem1 and could lead researchers to reinvestigate the functions of Miro1\/2\u2014the equivalent of Gem1 in higher eukaryotes. Miro1\/2 is thought to connect mitochondria to motor proteins, which transports them through the cell along microtubules. Dysfunction of Miro1\/2 reduces the mobility of mitochondria, and the work of Murley et al. suggests that this could be a consequence of enhanced contacts between mitochondria and the ER.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00422.002",
"content_html": "<p hwp:id=\"p-5\">Mitochondria generate most of the energy used by cells, and they also play key roles in cellular growth, death, and differentiation. They are evolutionarily derived from bacteria and have retained their own DNA and protein translation system, but they are also dependent on the cell for their growth and replication.<\/p>\n<p hwp:id=\"p-6\">A significant portion of the outer membrane of a mitochondrion is in contact with the endoplasmic reticulum (ER)&#x2014;an organelle that is the starting point for the synthesis of secreted proteins, and is also critical for the synthesis of lipids and other organelles. Recent work suggests that mitochondria&#x2013;ER contact points mark sites of mitochondrial division, but it is unclear exactly how this process occurs.<\/p>\n<p hwp:id=\"p-7\">Here, Murley et al. use the budding yeast and model organism <italic>Saccharomyces cerevisiae<\/italic> to show that at mitochondrial division sites, a multiprotein complex called ERMES promotes the formation of ER&#x2013;mitochondrial contact points, while an evolutionarily conserved enzyme, Gem1, antagonizes these contacts to aid mitochondrial segregation. The contact points are found adjacent to nucleoids (which are complexes of mitochondrial DNA and proteins)&#x2014;an observation suggesting that ER-associated mitochondrial division evolved to help distribute nucleoids between newly formed mitochondria.<\/p>\n<p hwp:id=\"p-8\">The present study also reveals a novel role for the conserved protein Gem1 and could lead researchers to reinvestigate the functions of Miro1\/2&#x2014;the equivalent of Gem1 in higher eukaryotes. Miro1\/2 is thought to connect mitochondria to motor proteins, which transports them through the cell along microtubules. Dysfunction of Miro1\/2 reduces the mobility of mitochondria, and the work of Murley et al. suggests that this could be a consequence of enhanced contacts between mitochondria and the ER.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00422.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00422.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00422.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00422",
"title": "ER-associated mitochondrial division links the distribution of mitochondria and mitochondrial DNA in yeast",
"metadata": {
"authors": "A. Murley, L. L. Lackner, C. Osman, M. West, G. K. Voeltz, P. Walter, J. Nunnari",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:32:44Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:32:44Z",
"updated_at": "2013-07-25T09:32:44Z"
},
{
"id": 253,
"content": "In many cells, genomic DNA is wrapped around proteins known as histones to produce particles called nucleosomes. These particles then join together\u2014like beads on a string\u2014to form a highly periodic structure called chromatin. In the nucleus, chromatin is further folded and condensed into chromosomes. However, many important processes, including the replication of DNA and the transcription of genes, require access to the DNA. The cell must therefore be able to disassemble chromatin and remove the histones, and then, once these processes are complete, to reassemble the chromatin. Enzymes known as chromatin assembly factors are responsible for the disassembly and reassembly of chromatin.There are two main types of chromatin assembly factors in eukaryotic cells (i.e., cells with nuclei)\u2014histone chaperones and motor proteins. The histone chaperones escort histones from the cytoplasm, where they are made, to the nucleus. The motor proteins\u2014using energy supplied by ATP molecules\u2014then catalyze the formation of nucleosomes. This involves two activities: the motor proteins assemble nucleosomes by helping the DNA to wrap around the histones, and they also remodel chromatin by altering the positions of nucleosomes along the DNA to ensure that they are periodic\u2014that is, regularly spaced.A conserved motor protein called Chd1 performs chromatin assembly and remodeling in eukaryotic cells. Chd1 works in conjunction with histone chaperones\u2014both are needed for chromatin assembly, and so are DNA, histones and ATP. However, whether or not chromatin assembly and chromatin remodeling by Chd1 are identical or distinct processes is not well understood.Torigoe et al. have now discovered a mutant Chd1 protein that has nucleosome assembly activity (i.e., it can make nucleosomes) but cannot remodel chromatin (i.e., it is unable to move nucleosomes), and thus have demonstrated that these two processes are functionally distinct. Torigoe et al. additionally have found that the mutant Chd1 proteins produce randomly distributed nucleosomes rather than the periodic arrays normally found in chromatin. Further analysis then revealed that the wild-type Chd1 protein, which can remodel chromatin, is able to convert randomly distributed nucleosomes into periodic arrays.These findings have led to a new model for chromatin assembly in which Chd1 initially generates randomly distributed nucleosomes (via its assembly function), and then converts them into periodic arrays of nucleosomes (via its remodeling function). Together, these studies shed light on the mechanisms by which chromatin is created and manipulated in cells.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00863.002",
"content_html": "<p hwp:id=\"p-4\">In many cells, genomic DNA is wrapped around proteins known as histones to produce particles called nucleosomes. These particles then join together&#x2014;like beads on a string&#x2014;to form a highly periodic structure called chromatin. In the nucleus, chromatin is further folded and condensed into chromosomes. However, many important processes, including the replication of DNA and the transcription of genes, require access to the DNA. The cell must therefore be able to disassemble chromatin and remove the histones, and then, once these processes are complete, to reassemble the chromatin. Enzymes known as chromatin assembly factors are responsible for the disassembly and reassembly of chromatin.<\/p>\n<p hwp:id=\"p-5\">There are two main types of chromatin assembly factors in eukaryotic cells (i.e., cells with nuclei)&#x2014;histone chaperones and motor proteins. The histone chaperones escort histones from the cytoplasm, where they are made, to the nucleus. The motor proteins&#x2014;using energy supplied by ATP molecules&#x2014;then catalyze the formation of nucleosomes. This involves two activities: the motor proteins assemble nucleosomes by helping the DNA to wrap around the histones, and they also remodel chromatin by altering the positions of nucleosomes along the DNA to ensure that they are periodic&#x2014;that is, regularly spaced.<\/p>\n<p hwp:id=\"p-6\">A conserved motor protein called Chd1 performs chromatin assembly and remodeling in eukaryotic cells. Chd1 works in conjunction with histone chaperones&#x2014;both are needed for chromatin assembly, and so are DNA, histones and ATP. However, whether or not chromatin assembly and chromatin remodeling by Chd1 are identical or distinct processes is not well understood.<\/p>\n<p hwp:id=\"p-7\">Torigoe et al. have now discovered a mutant Chd1 protein that has nucleosome assembly activity (i.e., it can make nucleosomes) but cannot remodel chromatin (i.e., it is unable to move nucleosomes), and thus have demonstrated that these two processes are functionally distinct. Torigoe et al. additionally have found that the mutant Chd1 proteins produce randomly distributed nucleosomes rather than the periodic arrays normally found in chromatin. Further analysis then revealed that the wild-type Chd1 protein, which can remodel chromatin, is able to convert randomly distributed nucleosomes into periodic arrays.<\/p>\n<p hwp:id=\"p-8\">These findings have led to a new model for chromatin assembly in which Chd1 initially generates randomly distributed nucleosomes (via its assembly function), and then converts them into periodic arrays of nucleosomes (via its remodeling function). Together, these studies shed light on the mechanisms by which chromatin is created and manipulated in cells.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00863.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00863.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00863.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00863",
"title": "ATP-dependent chromatin assembly is functionally distinct from chromatin remodeling",
"metadata": {
"authors": "S. E. Torigoe, A. Patel, M. T. Khuong, G. D. Bowman, J. T. Kadonaga",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2014-01-13T00:39:13Z",
"updated_at": "2014-01-13T00:39:13Z"
},
"created_at": "2014-01-13T00:39:13Z",
"updated_at": "2014-01-13T00:39:13Z"
},
{
"id": 72,
"content": "Many microbes grow by producing methane gas from carbon dioxide and hydrogen gas, and enzymes known as hydrogenases play important roles in this metabolic process. The production of methane in these microbes depends on a nickel\u2013iron hydrogenase called Frh adding electrons to a coenzyme called F420. This hydrogenase cleaves a hydrogen molecule into two electrons, which are transferred to the F420 coenzyme, and two protons. The reduced form of F420 is then used for several reactions in the methane production process. This process, which is known as methanogenesis, provides the microbes with energy.Nickel\u2013iron hydrogenases can be divided into five different groups, but researchers have been able to determine the detailed structures of the enzymes in just one of these groups. All nickel\u2013iron hydrogenases contain at least two subunits: a large subunit with a catalytic center composed of both nickel and iron ions and a small subunit that contains three iron\u2013sulfur clusters. Frh\u2014which is short for F420-reducing nickel\u2013iron hydrogenase\u2014is known to have a third subunit comprising an extra iron\u2013sulfur cluster and a coenzyme called FAD that allows it to interact with the F420 coenzyme. However, until now, little was known about the detailed structure of the Frh enzyme.Mills et al. have used electron cryo-microscopy (cryo-EM) to determine the structure of Frh when it is on its own, and also when it is bound to F420. This technique involves freezing a solution of the enzyme in a thin layer of ice and recording an image of this layer in an electron microscope. By combining a large number of images, each of which contains many identical enzymes in different orientations, it is possible to determine the 3-dimensional structure of the enzyme.Mills et al. found that Frh forms a very large tetrahedral complex that contains six Frh dimers. And by comparing the structure with and without F420, they identify a pocket near the FAD coenzyme that the F420 coenzyme binds to. They also identify a fold in the third subunit that allows proteins to bind both FAD and F420. The work demonstrates the potential of cryo-EM to elucidate structures that cannot be determined by other approaches.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00218.002",
"content_html": "<p hwp:id=\"p-6\">Many microbes grow by producing methane gas from carbon dioxide and hydrogen gas, and enzymes known as hydrogenases play important roles in this metabolic process. The production of methane in these microbes depends on a nickel&#x2013;iron hydrogenase called Frh adding electrons to a coenzyme called F<sub>420<\/sub>. This hydrogenase cleaves a hydrogen molecule into two electrons, which are transferred to the F<sub>420<\/sub> coenzyme, and two protons. The reduced form of F<sub>420<\/sub> is then used for several reactions in the methane production process. This process, which is known as methanogenesis, provides the microbes with energy.<\/p>\n<p hwp:id=\"p-7\">Nickel&#x2013;iron hydrogenases can be divided into five different groups, but researchers have been able to determine the detailed structures of the enzymes in just one of these groups. All nickel&#x2013;iron hydrogenases contain at least two subunits: a large subunit with a catalytic center composed of both nickel and iron ions and a small subunit that contains three iron&#x2013;sulfur clusters. Frh&#x2014;which is short for F<sub>420<\/sub>-reducing nickel&#x2013;iron hydrogenase&#x2014;is known to have a third subunit comprising an extra iron&#x2013;sulfur cluster and a coenzyme called FAD that allows it to interact with the F<sub>420<\/sub> coenzyme. However, until now, little was known about the detailed structure of the Frh enzyme.<\/p>\n<p hwp:id=\"p-8\">Mills et al. have used electron cryo-microscopy (cryo-EM) to determine the structure of Frh when it is on its own, and also when it is bound to F<sub>420<\/sub>. This technique involves freezing a solution of the enzyme in a thin layer of ice and recording an image of this layer in an electron microscope. By combining a large number of images, each of which contains many identical enzymes in different orientations, it is possible to determine the 3-dimensional structure of the enzyme.<\/p>\n<p hwp:id=\"p-9\">Mills et al. found that Frh forms a very large tetrahedral complex that contains six Frh dimers. And by comparing the structure with and without F<sub>420<\/sub>, they identify a pocket near the FAD coenzyme that the F<sub>420<\/sub> coenzyme binds to. They also identify a fold in the third subunit that allows proteins to bind both FAD and F<sub>420<\/sub>. The work demonstrates the potential of cryo-EM to elucidate structures that cannot be determined by other approaches.<\/p>\n<p hwp:id=\"p-10\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00218.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00218.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00218.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00218",
"title": "De novo modeling of the F420-reducing [NiFe]-hydrogenase from a methanogenic archaeon by cryo-electron microscopy",
"metadata": {
"authors": "D. J. Mills, S. Vitt, M. Strauss, S. Shima, J. Vonck",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:30:39Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:30:39Z",
"updated_at": "2013-07-25T09:30:39Z"
},
{
"id": 73,
"content": "The rates at which many genes are expressed as proteins are limited by the efficiency of a process called transcriptional elongation. This process takes place as the stretch of DNA that defines the gene is transcribed into an RNA molecule and it is catalyzed by an enzyme called RNA polymerase II. However, this enzyme can become trapped, and another enzyme called P-TEFb (positive transcription elongation factor b) is needed to release it. P-TEFb and other elongation factors therefore have an important role in gene expression.The human immunodeficiency virus (HIV) is a retrovirus that hijacks the gene expression processes in human immune cells to replicate the RNA genome of the virus. To do this, the virus produces a protein called Tat that recruits P-TEFb as part of a multi-protein machine called the super elongation complex. This ensures that the process of transcriptional elongation, and hence the overall replication process, is highly efficient. There are gaps, however, in our knowledge of the architecture of the super elongation complex, which is known to be organized on a flexible scaffold. In turn, the molecular basis for the interaction between HIV-1 Tat and P-TEFb within the super elongation complex is not well understood.Now Schulze-Gahmen et al. show that only one of the two subunits in P-TEFb\u2014a cyclin known as CycT1\u2014binds to the AFF4 scaffold protein in the super elongation complex. In addition to assisting with the expression of hundreds of human genes, super elongation complexes containing P-TEFb-AFF4 are hijacked in various forms of cancer and viral infections, including HIV\/AIDS. Schulze-Gahmen et al. show that AFF4 can directly contact HIV-1 Tat, which binds to the P-TEFb-AFF4 complex much more strongly than it binds to P-TEFb alone. This suggests that HIV-1 Tat evolved to work within the super elongation complex. Moreover, Schulze-Gahmen et al. reveal that HIV-1 Tat binds to a cleft between the P-TEFb enzyme and the AFF4 protein, which raises the possibility that this cleft could be used as a target for anti-HIV\/AIDS drugs.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00327.002",
"content_html": "<p hwp:id=\"p-6\">The rates at which many genes are expressed as proteins are limited by the efficiency of a process called transcriptional elongation. This process takes place as the stretch of DNA that defines the gene is transcribed into an RNA molecule and it is catalyzed by an enzyme called RNA polymerase II. However, this enzyme can become trapped, and another enzyme called P-TEFb (positive transcription elongation factor b) is needed to release it. P-TEFb and other elongation factors therefore have an important role in gene expression.<\/p>\n<p hwp:id=\"p-7\">The human immunodeficiency virus (HIV) is a retrovirus that hijacks the gene expression processes in human immune cells to replicate the RNA genome of the virus. To do this, the virus produces a protein called Tat that recruits P-TEFb as part of a multi-protein machine called the super elongation complex. This ensures that the process of transcriptional elongation, and hence the overall replication process, is highly efficient. There are gaps, however, in our knowledge of the architecture of the super elongation complex, which is known to be organized on a flexible scaffold. In turn, the molecular basis for the interaction between HIV-1 Tat and P-TEFb within the super elongation complex is not well understood.<\/p>\n<p hwp:id=\"p-8\">Now Schulze-Gahmen et al. show that only one of the two subunits in P-TEFb&#x2014;a cyclin known as CycT1&#x2014;binds to the AFF4 scaffold protein in the super elongation complex. In addition to assisting with the expression of hundreds of human genes, super elongation complexes containing P-TEFb-AFF4 are hijacked in various forms of cancer and viral infections, including HIV\/AIDS. Schulze-Gahmen et al. show that AFF4 can directly contact HIV-1 Tat, which binds to the P-TEFb-AFF4 complex much more strongly than it binds to P-TEFb alone. This suggests that HIV-1 Tat evolved to work within the super elongation complex. Moreover, Schulze-Gahmen et al. reveal that HIV-1 Tat binds to a cleft between the P-TEFb enzyme and the AFF4 protein, which raises the possibility that this cleft could be used as a target for anti-HIV\/AIDS drugs.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00327.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00327.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00327.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00327",
"title": "The AFF4 scaffold binds human P-TEFb adjacent to HIV Tat",
"metadata": {
"authors": "U. Schulze-Gahmen, H. Upton, A. Birnberg, K. Bao, S. Chou, N. J. Krogan, Q. Zhou, T. Alber",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:30:43Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:30:43Z",
"updated_at": "2013-07-25T09:30:43Z"
},
{
"id": 74,
"content": "Neurons, or nerve cells, are excitable cells that transmit information using electrical and chemical signals. Nerve cells are generally composed of a cell body, multiple dendrites, and a single axon. The dendrites are responsible for receiving inputs and for transferring these signals to the cell body, whereas the axon carries signals away from the cell body and relays them to other cells.Like all cells, nerve cells have a cytoskeleton made up of microtubules, which help to determine cellular shape and which act as \u2018highways' for intracellular transport. Microtubules are long hollow fibers composed of alternating \u03b1- and \u03b2-tubulin proteins: each microtubule has a \u2018plus'-end, where the \u03b2 subunits are exposed, and a \u2018minus'-end, where the \u03b1 subunits are exposed. Nerve cells are highly polarized: within the axon, the microtubules are uniformly oriented with their plus-ends pointing outward, whereas in dendrites, there are many microtubules with their minus-ends pointing outward. This arrangement is conserved across the animal kingdom, but the mechanisms that establish it are largely unknown.Yan et al. use the model organism Caenorhabditis elegans (the nematode worm) to conduct a detailed in vivo analysis of dendritic microtubule organization. They find that a motor protein called kinesin-1 is critical for generating the characteristic minus-end-out pattern in dendrites: when the gene that codes for this protein is knocked out, the dendrites in microtubules undergo a dramatic polarity shift and adopt the plus-end-out organization that is typical of axons. The mutant dendrites also show other axon-like features: for example, they lack many of the proteins that are usually found in dendrites. Based on these and other data, Yan et al. propose that kinesin-1 determines microtubule polarity in dendrites by moving plus-end-out microtubules out of dendrites.These first attempts to explain, at the molecular level, how dendritic microtubule polarity is achieved in vivo could lead to new insights into the structure and function of the neuronal cytoskeleton.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00133.002",
"content_html": "<p hwp:id=\"p-4\">Neurons, or nerve cells, are excitable cells that transmit information using electrical and chemical signals. Nerve cells are generally composed of a cell body, multiple dendrites, and a single axon. The dendrites are responsible for receiving inputs and for transferring these signals to the cell body, whereas the axon carries signals away from the cell body and relays them to other cells.<\/p>\n<p hwp:id=\"p-5\">Like all cells, nerve cells have a cytoskeleton made up of microtubules, which help to determine cellular shape and which act as &#x2018;highways' for intracellular transport. Microtubules are long hollow fibers composed of alternating &#x3B1;- and &#x3B2;-tubulin proteins: each microtubule has a &#x2018;plus'-end, where the &#x3B2; subunits are exposed, and a &#x2018;minus'-end, where the &#x3B1; subunits are exposed. Nerve cells are highly polarized: within the axon, the microtubules are uniformly oriented with their plus-ends pointing outward, whereas in dendrites, there are many microtubules with their minus-ends pointing outward. This arrangement is conserved across the animal kingdom, but the mechanisms that establish it are largely unknown.<\/p>\n<p hwp:id=\"p-6\">Yan et al. use the model organism <italic>Caenorhabditis elegans<\/italic> (the nematode worm) to conduct a detailed in vivo analysis of dendritic microtubule organization. They find that a motor protein called kinesin-1 is critical for generating the characteristic minus-end-out pattern in dendrites: when the gene that codes for this protein is knocked out, the dendrites in microtubules undergo a dramatic polarity shift and adopt the plus-end-out organization that is typical of axons. The mutant dendrites also show other axon-like features: for example, they lack many of the proteins that are usually found in dendrites. Based on these and other data, Yan et al. propose that kinesin-1 determines microtubule polarity in dendrites by moving plus-end-out microtubules out of dendrites.<\/p>\n<p hwp:id=\"p-7\">These first attempts to explain, at the molecular level, how dendritic microtubule polarity is achieved in vivo could lead to new insights into the structure and function of the neuronal cytoskeleton.<\/p>\n<p hwp:id=\"p-8\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00133.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00133.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00133.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00133",
"title": "Kinesin-1 regulates dendrite microtubule polarity in Caenorhabditis elegans",
"metadata": {
"authors": "J. Yan, D. L. Chao, S. Toba, K. Koyasako, T. Yasunaga, S. Hirotsune, K. Shen",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:30:45Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:30:45Z",
"updated_at": "2013-07-25T09:30:45Z"
},
{
"id": 75,
"content": "Neurons have crucial roles in both the peripheral and central nervous systems. The role of the neurons in the sensory organs (the eyes, ears, and nose) is to sense stimuli\u2014including light, sound, and odor\u2014and transmit this sensory information to the neurons of the central nervous system for processing. The first step in sensing an odor relies on the peripheral nerves of the olfactory epithelium. This tissue, which lines the inside of the nasal cavity, includes two main types of olfactory sensory neurons: ciliated sensory neurons that detect volatile or easily evaporated substances and microvillous sensory neurons that detect pheromones, nucleotides, and\/or amino acids.During vertebrate embryogenesis, an embryo develops three distinct germ layers, the ectoderm, mesoderm, and endoderm, each of which gives rise to the different tissues of the body. The ectoderm has three parts\u2014the external ectoderm, the neural crest, and the neural tube\u2014and together they give rise to the neurons of the peripheral and central nervous systems. The neurons within the eye and ear are known to originate from a thickened portion of the ectoderm, and it has been proposed that olfactory neurons develop in a similar manner.Now, Saxena et al. show that, unlike what happens in the eye and ear, some olfactory sensory neurons originate from the neural crest. By studying the development of the olfactory system in zebrafish, Saxena et al. discovered that microvillous neurons, but not ciliated neurons, develop from neural crest cells, and that the transcription factor Sox10 is critical for the development of microvillous neurons. By establishing that neural crest cells are involved in the development of a substantial proportion of olfactory sensory neurons, this work sets the stage for future studies of olfactory nerve growth and regeneration. It may also assist researchers working on anosmia (the inability to smell).DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00336.002",
"content_html": "<p hwp:id=\"p-4\">Neurons have crucial roles in both the peripheral and central nervous systems. The role of the neurons in the sensory organs (the eyes, ears, and nose) is to sense stimuli&#x2014;including light, sound, and odor&#x2014;and transmit this sensory information to the neurons of the central nervous system for processing. The first step in sensing an odor relies on the peripheral nerves of the olfactory epithelium. This tissue, which lines the inside of the nasal cavity, includes two main types of olfactory sensory neurons: ciliated sensory neurons that detect volatile or easily evaporated substances and microvillous sensory neurons that detect pheromones, nucleotides, and\/or amino acids.<\/p>\n<p hwp:id=\"p-5\">During vertebrate embryogenesis, an embryo develops three distinct germ layers, the ectoderm, mesoderm, and endoderm, each of which gives rise to the different tissues of the body. The ectoderm has three parts&#x2014;the external ectoderm, the neural crest, and the neural tube&#x2014;and together they give rise to the neurons of the peripheral and central nervous systems. The neurons within the eye and ear are known to originate from a thickened portion of the ectoderm, and it has been proposed that olfactory neurons develop in a similar manner.<\/p>\n<p hwp:id=\"p-6\">Now, Saxena et al. show that, unlike what happens in the eye and ear, some olfactory sensory neurons originate from the neural crest. By studying the development of the olfactory system in zebrafish, Saxena et al. discovered that microvillous neurons, but not ciliated neurons, develop from neural crest cells, and that the transcription factor Sox10 is critical for the development of microvillous neurons. By establishing that neural crest cells are involved in the development of a substantial proportion of olfactory sensory neurons, this work sets the stage for future studies of olfactory nerve growth and regeneration. It may also assist researchers working on anosmia (the inability to smell).<\/p>\n<p hwp:id=\"p-7\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00336.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00336.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00336.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00336",
"title": "Sox10-dependent neural crest origin of olfactory microvillous neurons in zebrafish",
"metadata": {
"authors": "A. Saxena, B. N. Peng, M. E. Bronner",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:30:52Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:30:52Z",
"updated_at": "2013-07-25T09:30:52Z"
},
{
"id": 76,
"content": "Rice is one of the most important food crops and is estimated to provide more than a fifth of the calories consumed by the world's population. For several decades, rice has been modified by conventional breeding methods to produce plants with increased yields and greater resistance to pests and harsh weather conditions. Efforts are also being made to create rice plants with superior yield traits and resistance to biotic and abiotic stresses using genetic engineering techniques.Genetically modified plants are usually produced using tissue culture. New genes are introduced into plant cells that are growing in a dish, and each cell then replicates to form a mass of genetically identical cells. The application of plant hormones triggers the tissue to produce roots and shoots, giving rise to plantlet clones.In addition to the genes that comprise its genome, the genetic make-up of an organism also includes its epigenome\u2014a collection of chemical modifications that influence whether or not a given gene is expressed as a protein. The addition of methyl groups to specific sequences within the DNA, for example, acts as an epigenetic signal to reduce the transcription, and thus expression, of the genes concerned.Now, Stroud et al. reveal that the techniques used to modify a plant's genome\u2014in particular, the process of tissue culture\u2014also affect its epigenome. They prepared high-resolution maps of DNA methylation in several regenerated rice lines, and found that regenerated plants produced in culture showed less methylation than control plants. The changes were relatively over-represented around the promoter sequences of genes\u2014regions of DNA that act as binding sites for the enzymes that transcribe DNA into RNA\u2014and were accompanied by changes in gene expression. Crucially, the plants' descendants frequently also inherited the changes in methylation status. These results are likely part of the explanation for a phenomenon called somaclonal variation, first observed before the era of modern biotechnology, in which plants regenerated from tissue culture sometimes show heritable alterations in the phenotype of the plant.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00354.002",
"content_html": "<p hwp:id=\"p-4\">Rice is one of the most important food crops and is estimated to provide more than a fifth of the calories consumed by the world's population. For several decades, rice has been modified by conventional breeding methods to produce plants with increased yields and greater resistance to pests and harsh weather conditions. Efforts are also being made to create rice plants with superior yield traits and resistance to biotic and abiotic stresses using genetic engineering techniques.<\/p>\n<p hwp:id=\"p-5\">Genetically modified plants are usually produced using tissue culture. New genes are introduced into plant cells that are growing in a dish, and each cell then replicates to form a mass of genetically identical cells. The application of plant hormones triggers the tissue to produce roots and shoots, giving rise to plantlet clones.<\/p>\n<p hwp:id=\"p-6\">In addition to the genes that comprise its genome, the genetic make-up of an organism also includes its epigenome&#x2014;a collection of chemical modifications that influence whether or not a given gene is expressed as a protein. The addition of methyl groups to specific sequences within the DNA, for example, acts as an epigenetic signal to reduce the transcription, and thus expression, of the genes concerned.<\/p>\n<p hwp:id=\"p-7\">Now, Stroud et al. reveal that the techniques used to modify a plant's genome&#x2014;in particular, the process of tissue culture&#x2014;also affect its epigenome. They prepared high-resolution maps of DNA methylation in several regenerated rice lines, and found that regenerated plants produced in culture showed less methylation than control plants. The changes were relatively over-represented around the promoter sequences of genes&#x2014;regions of DNA that act as binding sites for the enzymes that transcribe DNA into RNA&#x2014;and were accompanied by changes in gene expression. Crucially, the plants' descendants frequently also inherited the changes in methylation status. These results are likely part of the explanation for a phenomenon called somaclonal variation, first observed before the era of modern biotechnology, in which plants regenerated from tissue culture sometimes show heritable alterations in the phenotype of the plant.<\/p>\n<p hwp:id=\"p-8\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00354.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00354.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00354.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00354",
"title": "Plants regenerated from tissue culture contain stable epigenome changes in rice",
"metadata": {
"authors": "H. Stroud, B. Ding, S. A. Simon, S. Feng, M. Bellizzi, M. Pellegrini, G.-L. Wang, B. C. Meyers, S. E. Jacobsen",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:30:55Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:30:55Z",
"updated_at": "2013-07-25T09:30:55Z"
},
{
"id": 77,
"content": "The development of the nervous system involves the formation of complex networks of connections between diverse cell types, such as motor neurons, interneurons and pyramidal cells. However, the mechanisms by which individual cells are programmed to acquire particular identities, and how they are instructed to form connections with other specific cells, remain unclear.In many species, the Notch signaling pathway has a role in setting up these networks. Notch is a transmembrane protein, which means that it has one component inside the cell and another outside. When a ligand binds to the extracellular part of Notch, this causes the receptor to break in two. The intracellular domain then travels to the nucleus where it can influence gene expression.The nematode worm (C. elegans), which has two Notch receptors, is often used to study the formation of neuronal networks because each worm has only around 300 neurons, and they are connected in roughly the same way in each worm. C. elegans relies on two types of cell that are very similar to each other\u2014type-1 and type-2 vulval muscle cells\u2014to lay eggs, and the neurons that trigger egg-laying form synaptic connections on specialized structures called muscle arms. However, these structures are found only in type-2 vulval muscle.To investigate the mechanisms underlying the formation of the egg-laying circuit, Li et al. screened large numbers of mutant worms to find animals that lacked muscle arms. They identified a number of such mutants, which laid fewer eggs compared to wild-type worms, and found that they all had mutations in genes that encode for proteins or ligands that are involved in the LIN-12\/Notch pathway. This pathway mediates cell\u2013cell interactions that help to specify cell fates.Li et al. showed that type-2 vulval muscle cells develop muscle arms when their neighbors\u2014type-1 vulval muscle cells and vulval epithelial cells\u2014produce enough ligand to activate the LIN-12 Notch receptor on the type-2 vulval muscle cells. They also identified two of the downstream targets of LIN-12, and found that artificially expressing one of these in type-1 vulval muscle cells is sufficient to trigger the formation of muscle arms.The work of Li et al. provides further evidence that the Notch signalling pathway, which is well known for its role in early development, also acts at later developmental stages to determine cell fate and patterns of connectivity.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00378.002",
"content_html": "<p hwp:id=\"p-4\">The development of the nervous system involves the formation of complex networks of connections between diverse cell types, such as motor neurons, interneurons and pyramidal cells. However, the mechanisms by which individual cells are programmed to acquire particular identities, and how they are instructed to form connections with other specific cells, remain unclear.<\/p>\n<p hwp:id=\"p-5\">In many species, the Notch signaling pathway has a role in setting up these networks. Notch is a transmembrane protein, which means that it has one component inside the cell and another outside. When a ligand binds to the extracellular part of Notch, this causes the receptor to break in two. The intracellular domain then travels to the nucleus where it can influence gene expression.<\/p>\n<p hwp:id=\"p-6\">The nematode worm (<italic>C. elegans<\/italic>), which has two Notch receptors, is often used to study the formation of neuronal networks because each worm has only around 300 neurons, and they are connected in roughly the same way in each worm. <italic>C. elegans<\/italic> relies on two types of cell that are very similar to each other&#x2014;type-1 and type-2 vulval muscle cells&#x2014;to lay eggs, and the neurons that trigger egg-laying form synaptic connections on specialized structures called muscle arms. However, these structures are found only in type-2 vulval muscle.<\/p>\n<p hwp:id=\"p-7\">To investigate the mechanisms underlying the formation of the egg-laying circuit, Li et al. screened large numbers of mutant worms to find animals that lacked muscle arms. They identified a number of such mutants, which laid fewer eggs compared to wild-type worms, and found that they all had mutations in genes that encode for proteins or ligands that are involved in the LIN-12\/Notch pathway. This pathway mediates cell&#x2013;cell interactions that help to specify cell fates.<\/p>\n<p hwp:id=\"p-8\">Li et al. showed that type-2 vulval muscle cells develop muscle arms when their neighbors&#x2014;type-1 vulval muscle cells and vulval epithelial cells&#x2014;produce enough ligand to activate the LIN-12 Notch receptor on the type-2 vulval muscle cells. They also identified two of the downstream targets of LIN-12, and found that artificially expressing one of these in type-1 vulval muscle cells is sufficient to trigger the formation of muscle arms.<\/p>\n<p hwp:id=\"p-9\">The work of Li et al. provides further evidence that the Notch signalling pathway, which is well known for its role in early development, also acts at later developmental stages to determine cell fate and patterns of connectivity.<\/p>\n<p hwp:id=\"p-10\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00378.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00378.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00378.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00378",
"title": "LIN-12\/Notch signaling instructs postsynaptic muscle arm development by regulating UNC-40\/DCC and MADD-2 in Caenorhabditis elegans",
"metadata": {
"authors": "P. Li, K. M. Collins, M. R. Koelle, K. Shen",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:30:57Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:30:57Z",
"updated_at": "2013-07-25T09:30:57Z"
},
{
"id": 78,
"content": "Being able to keep memories of similar events separate in your mind is an essential part of remembering. If you use the same carpark every day, recalling where you left your car this morning is challenging, not because you have to remember an event from long ago, but because you have to distinguish between many similar memories.Keeping memories distinct is one of the functions of a subregion of the hippocampus called the dentate gyrus. The process of taking complex memories and converting them into representations that are less easily confused is known as pattern separation. Exactly how the dentate gyrus achieves this, however, is unclear.Computational models predict that a different population of dentate gyrus cells will be active when an animal is in different environments. However, previous experiments have instead shown that the same population of cells is active in multiple environments, and that cells distinguish between environments by firing at different rates.Now, Deng et al. have added to our understanding of pattern separation. The researchers used a type of genetically modified mouse in which it is possible to identify or \u2018tag' the activity of a population of hippocampal neurons at multiple time points. They placed each mouse in a box and noted which hippocampal neurons were active as the animal learned about its new environment. After several such learning episodes, the animal received a mild electric shock inside the box. When it was returned to the box the next day, the mouse remembered receiving the shock, enabling the researchers to note which neurons were active during the retrieval process.Deng et al. found that in a subregion of the hippocampus called CA1, the particular neurons that were active during the initial learning episode were also likely to be active when the animals remembered receiving the shock. However, this was not the case for the dentate gyrus: in this subregion, distinct groups of cells were active during learning and during retrieval. Moreover, exposing the mice to two subtly different environments activated two distinct groups of cells in the dentate gyrus.The work of Deng et al. reveals that memory retrieval does not always involve reactivation of the same neurons that were active during encoding. More importantly, the results indicate that the dentate gyrus performs pattern separation by using distinct populations of cells to represent similar but non-identical memories. Overall the findings add to our understanding of the mechanisms that underpin memory formation.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00312.002",
"content_html": "<p hwp:id=\"p-4\">Being able to keep memories of similar events separate in your mind is an essential part of remembering. If you use the same carpark every day, recalling where you left your car this morning is challenging, not because you have to remember an event from long ago, but because you have to distinguish between many similar memories.<\/p>\n<p hwp:id=\"p-5\">Keeping memories distinct is one of the functions of a subregion of the hippocampus called the dentate gyrus. The process of taking complex memories and converting them into representations that are less easily confused is known as pattern separation. Exactly how the dentate gyrus achieves this, however, is unclear.<\/p>\n<p hwp:id=\"p-6\">Computational models predict that a different population of dentate gyrus cells will be active when an animal is in different environments. However, previous experiments have instead shown that the same population of cells is active in multiple environments, and that cells distinguish between environments by firing at different rates.<\/p>\n<p hwp:id=\"p-7\">Now, Deng et al. have added to our understanding of pattern separation. The researchers used a type of genetically modified mouse in which it is possible to identify or &#x2018;tag' the activity of a population of hippocampal neurons at multiple time points. They placed each mouse in a box and noted which hippocampal neurons were active as the animal learned about its new environment. After several such learning episodes, the animal received a mild electric shock inside the box. When it was returned to the box the next day, the mouse remembered receiving the shock, enabling the researchers to note which neurons were active during the retrieval process.<\/p>\n<p hwp:id=\"p-8\">Deng et al. found that in a subregion of the hippocampus called CA1, the particular neurons that were active during the initial learning episode were also likely to be active when the animals remembered receiving the shock. However, this was not the case for the dentate gyrus: in this subregion, distinct groups of cells were active during learning and during retrieval. Moreover, exposing the mice to two subtly different environments activated two distinct groups of cells in the dentate gyrus.<\/p>\n<p hwp:id=\"p-9\">The work of Deng et al. reveals that memory retrieval does not always involve reactivation of the same neurons that were active during encoding. More importantly, the results indicate that the dentate gyrus performs pattern separation by using distinct populations of cells to represent similar but non-identical memories. Overall the findings add to our understanding of the mechanisms that underpin memory formation.<\/p>\n<p hwp:id=\"p-10\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00312.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00312.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00312.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00312",
"title": "Selection of distinct populations of dentate granule cells in response to inputs as a mechanism for pattern separation in mice",
"metadata": {
"authors": "W. Deng, M. Mayford, F. H. Gage",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:31:04Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:31:04Z",
"updated_at": "2013-07-25T09:31:04Z"
},
{
"id": 79,
"content": "Like animals, plants go through several stages of development before they reach maturity, and it has long been thought that some of the transitions between these stages are triggered by changes in the nutritional status of the plant. Now, based on experiments with the plant Arabidopsis thaliana, Yu et al. and, independently, Yang et al. have provided fresh insights into the role of sugar in \u2018vegetative phase change'\u2014the transition from the juvenile form of a plant to the adult plant.The new work takes advantage of the fact that vegetative phase change is controlled by two genes that encode microRNAs (MIRNAs). Arabidopsis has eight MIR156 genes and both groups confirmed that supplying plants with sugar reduces the expression of two of these\u2014MIR156A and MIR156C\u2014while sugar deprivation increases their expression. Removing leaves also leads to upregulation of both genes, and delays the juvenile-to-adult transition. Given that this effect can be partially reversed by providing the plant with sugar, it is likely that sugar produced in the leaves\u2014or one of its metabolites\u2014is the signal that triggers the juvenile-to-adult transition through the reduction of miR156 levels.Yu and co-workers confirmed that sugar also reduces the expression of MIR156 in tobacco, moss, and tomato plants, suggesting that this mechanism is evolutionarily conserved. Consistent with the work of Yang and colleagues, Yu and co-workers revealed that sugar is able to reduce the transcription of MIR156A and MIR156C genes into messenger RNA. Moreover, they showed that sugar can also suppress MIR156 expression by promoting the breakdown of MIR156A and MIR156C primary messenger RNA transcripts.The work of Yu et al. and Yang et al. has thus provided key insights into the mechanisms by which a leaf-derived signal controls a key developmental change in plants. Just as fruit flies use their nutritional status to regulate the onset of metamorphosis, and mammals use it to control the onset of puberty, so plants use the level of sugar in their leaves to trigger the transition from juvenile to adult forms.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00269.002",
"content_html": "<p hwp:id=\"p-4\">Like animals, plants go through several stages of development before they reach maturity, and it has long been thought that some of the transitions between these stages are triggered by changes in the nutritional status of the plant. Now, based on experiments with the plant <italic>Arabidopsis thaliana<\/italic>, Yu et al. and, independently, Yang et al. have provided fresh insights into the role of sugar in &#x2018;vegetative phase change'&#x2014;the transition from the juvenile form of a plant to the adult plant.<\/p>\n<p hwp:id=\"p-5\">The new work takes advantage of the fact that vegetative phase change is controlled by two genes that encode microRNAs (MIRNAs). <italic>Arabidopsis<\/italic> has eight <italic>MIR156<\/italic> genes and both groups confirmed that supplying plants with sugar reduces the expression of two of these&#x2014;<italic>MIR156A<\/italic> and <italic>MIR156C<\/italic>&#x2014;while sugar deprivation increases their expression. Removing leaves also leads to upregulation of both genes, and delays the juvenile-to-adult transition. Given that this effect can be partially reversed by providing the plant with sugar, it is likely that sugar produced in the leaves&#x2014;or one of its metabolites&#x2014;is the signal that triggers the juvenile-to-adult transition through the reduction of miR156 levels.<\/p>\n<p hwp:id=\"p-6\">Yu and co-workers confirmed that sugar also reduces the expression of <italic>MIR156<\/italic> in tobacco, moss, and tomato plants, suggesting that this mechanism is evolutionarily conserved. Consistent with the work of Yang and colleagues, Yu and co-workers revealed that sugar is able to reduce the transcription of <italic>MIR156A<\/italic> and <italic>MIR156C<\/italic> genes into messenger RNA. Moreover, they showed that sugar can also suppress <italic>MIR156<\/italic> expression by promoting the breakdown of <italic>MIR156A<\/italic> and <italic>MIR156C<\/italic> primary messenger RNA transcripts.<\/p>\n<p hwp:id=\"p-7\">The work of Yu et al. and Yang et al. has thus provided key insights into the mechanisms by which a leaf-derived signal controls a key developmental change in plants. Just as fruit flies use their nutritional status to regulate the onset of metamorphosis, and mammals use it to control the onset of puberty, so plants use the level of sugar in their leaves to trigger the transition from juvenile to adult forms.<\/p>\n<p hwp:id=\"p-8\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00269.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00269.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00269.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00269",
"title": "Sugar is an endogenous cue for juvenile-to-adult phase transition in plants",
"metadata": {
"authors": "S. Yu, L. Cao, C.-M. Zhou, T.-Q. Zhang, H. Lian, Y. Sun, J. Wu, J. Huang, G. Wang, J.-W. Wang",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:31:13Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:31:13Z",
"updated_at": "2013-07-25T09:31:13Z"
},
{
"id": 80,
"content": "Like animals, plants go through several stages of development before they reach maturity, and it has long been thought that some of the transitions between these stages are triggered by changes in the nutritional status of the plant. Now, based on experiments with the plant Arabidopsis thaliana, Yang et al. and, independently, Yu et al. have provided fresh insights into the role of sugar in \u2018vegetative phase change'\u2014the transition from the juvenile form of a plant to the adult plant.The new work takes advantage of the fact that vegetative phase change is controlled by two genes that encode microRNAs (MIRNAs). Arabidopsis has eight MIR156 genes and both groups confirmed that supplying plants with sugar reduces the expression of two of these\u2014MIR156A and MIR156C\u2014whereas sugar deprivation increases their expression. Removing leaves also leads to upregulation of both genes, and delays the juvenile to adult transition. Given that this effect can be partially reversed by providing the plant with sugar, it is likely that sugar produced in the leaves\u2014or one of its metabolites\u2014is the signal that triggers the juvenile to adult transition through the reduction of miR156 levels.Consistent with this idea, Yang and co-workers revealed that mutant plants that are deficient in chlorophyll show elevated levels of miR156 and a delayed transition to the adult form. In addition, they showed that a gene called HXK1, which encodes a glucose signaling protein, helps to keep plants in the juvenile form under conditions of low sugar availability. HXK1 also contributes to the glucose-induced decrease in miR156 levels and does so, at least in part, by regulating the transcription of MIR156A and MIR156C genes into messenger mRNA. HXK1 is not solely responsible for the juvenile to adult transition, however, because plants that lack this protein are only slightly precocious in their transition to the adult form.The works of Yang et al. and Yu et al. have thus provided key insights into the mechanisms by which a leaf-derived signal controls a key developmental change in plants. Just as fruit flies use their nutritional status to regulate the onset of metamorphosis, and mammals use it to control the onset of puberty, so plants use the level of sugar in their leaves to trigger the transition from juvenile to adult forms.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00260.002",
"content_html": "<p hwp:id=\"p-4\">Like animals, plants go through several stages of development before they reach maturity, and it has long been thought that some of the transitions between these stages are triggered by changes in the nutritional status of the plant. Now, based on experiments with the plant <italic>Arabidopsis thaliana<\/italic>, Yang et al. and, independently, Yu et al. have provided fresh insights into the role of sugar in &#x2018;vegetative phase change'&#x2014;the transition from the juvenile form of a plant to the adult plant.<\/p>\n<p hwp:id=\"p-5\">The new work takes advantage of the fact that vegetative phase change is controlled by two genes that encode microRNAs (MIRNAs). <italic>Arabidopsis<\/italic> has eight <italic>MIR156<\/italic> genes and both groups confirmed that supplying plants with sugar reduces the expression of two of these&#x2014;<italic>MIR156A<\/italic> and <italic>MIR156C<\/italic>&#x2014;whereas sugar deprivation increases their expression. Removing leaves also leads to upregulation of both genes, and delays the juvenile to adult transition. Given that this effect can be partially reversed by providing the plant with sugar, it is likely that sugar produced in the leaves&#x2014;or one of its metabolites&#x2014;is the signal that triggers the juvenile to adult transition through the reduction of miR156 levels.<\/p>\n<p hwp:id=\"p-6\">Consistent with this idea, Yang and co-workers revealed that mutant plants that are deficient in chlorophyll show elevated levels of miR156 and a delayed transition to the adult form. In addition, they showed that a gene called <italic>HXK1<\/italic>, which encodes a glucose signaling protein, helps to keep plants in the juvenile form under conditions of low sugar availability. HXK1 also contributes to the glucose-induced decrease in miR156 levels and does so, at least in part, by regulating the transcription of <italic>MIR156A<\/italic> and <italic>MIR156C<\/italic> genes into messenger mRNA. HXK1 is not solely responsible for the juvenile to adult transition, however, because plants that lack this protein are only slightly precocious in their transition to the adult form.<\/p>\n<p hwp:id=\"p-7\">The works of Yang et al. and Yu et al. have thus provided key insights into the mechanisms by which a leaf-derived signal controls a key developmental change in plants. Just as fruit flies use their nutritional status to regulate the onset of metamorphosis, and mammals use it to control the onset of puberty, so plants use the level of sugar in their leaves to trigger the transition from juvenile to adult forms.<\/p>\n<p hwp:id=\"p-8\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00260.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00260.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00260.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00260",
"title": "Sugar promotes vegetative phase change in Arabidopsis thaliana by repressing the expression of MIR156A and MIR156C",
"metadata": {
"authors": "L. Yang, M. Xu, Y. Koo, J. He, R. S. Poethig",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:31:19Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:31:19Z",
"updated_at": "2013-07-25T09:31:19Z"
},
{
"id": 81,
"content": "All living organisms use enzymes called replicative DNA polymerases to produce copies of their genome during cell division. These enzymes promote the formation of new DNA strands by catalyzing the polymerization of deoxyribonucleotides, the single units that make up DNA. In humans these polymerases contain multiple protein subunits, as well as a specific cofactor\u2014a magnesium ion\u2014that is required for the enzyme to be active.DNA polymerases are able to add several nucleotides at once because they are anchored to ring-shaped protein complexes called sliding clamps that encircle the DNA template. This structure, known as the holoenzyme, is able to slide freely along the DNA template, which allows the polymerase to promote the addition of nucleotides in a highly efficient manner.Protein complexes called clamp loaders are responsible for attaching the holoenzyme to the DNA template, and also for detaching it. Studies of model organisms, including bacteria, viruses and yeast, have provided insights into the assembly of the holoenzyme in humans, but the exact mechanism behind this process has remained unknown.Now, Hedglin et al. use fluorescence resonance energy transfer (FRET), a powerful microscopy technique that can monitor interactions between proteins, and also between proteins and DNA, to study the assembly of the holoenzyme. Whenever a sliding clamp is loaded onto a DNA template in the absence of polymerase, the clamp loaders quickly remove it. Whenever a polymerase is present, however, it captures the sliding clamps; the clamp loaders then dissociate from the newly assembled holoenzyme and DNA replication begins.By revealing that clamp loaders recycle scarce sliding clamps, and that they boost the efficiency of holoenzyme assembly by preventing clamps from accumulating on DNA in the absence of polymerase, Hedglin et al. have redefined our understanding of human holoenzyme assembly.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00278.002",
"content_html": "<p hwp:id=\"p-4\">All living organisms use enzymes called replicative DNA polymerases to produce copies of their genome during cell division. These enzymes promote the formation of new DNA strands by catalyzing the polymerization of deoxyribonucleotides, the single units that make up DNA. In humans these polymerases contain multiple protein subunits, as well as a specific cofactor&#x2014;a magnesium ion&#x2014;that is required for the enzyme to be active.<\/p>\n<p hwp:id=\"p-5\">DNA polymerases are able to add several nucleotides at once because they are anchored to ring-shaped protein complexes called sliding clamps that encircle the DNA template. This structure, known as the holoenzyme, is able to slide freely along the DNA template, which allows the polymerase to promote the addition of nucleotides in a highly efficient manner.<\/p>\n<p hwp:id=\"p-6\">Protein complexes called clamp loaders are responsible for attaching the holoenzyme to the DNA template, and also for detaching it. Studies of model organisms, including bacteria, viruses and yeast, have provided insights into the assembly of the holoenzyme in humans, but the exact mechanism behind this process has remained unknown.<\/p>\n<p hwp:id=\"p-7\">Now, Hedglin et al. use fluorescence resonance energy transfer (FRET), a powerful microscopy technique that can monitor interactions between proteins, and also between proteins and DNA, to study the assembly of the holoenzyme. Whenever a sliding clamp is loaded onto a DNA template in the absence of polymerase, the clamp loaders quickly remove it. Whenever a polymerase is present, however, it captures the sliding clamps; the clamp loaders then dissociate from the newly assembled holoenzyme and DNA replication begins.<\/p>\n<p hwp:id=\"p-8\">By revealing that clamp loaders recycle scarce sliding clamps, and that they boost the efficiency of holoenzyme assembly by preventing clamps from accumulating on DNA in the absence of polymerase, Hedglin et al. have redefined our understanding of human holoenzyme assembly.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00278.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00278.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00278.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00278",
"title": "Stepwise assembly of the human replicative polymerase holoenzyme",
"metadata": {
"authors": "M. Hedglin, S. K. Perumal, Z. Hu, S. Benkovic",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:31:24Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:31:24Z",
"updated_at": "2013-07-25T09:31:24Z"
},
{
"id": 82,
"content": "The Chikungunya virus is carried by mosquitos and can cause a number of diseases in humans including encephalitis, which can be fatal in some cases, and severe arthritis. A recent mutation in the E1 protein of the virus has allowed it to efficiently reproduce in a different species of mosquitos, leading to a Chikungunya epidemic in R\u00e9union Island in 2005 and the subsequent infection of millions of individuals in Africa and Asia. The virus also has the potential to spread to many areas of Europe and the Americas.Chikungunya virus has a single-stranded RNA genome that codes for four non-structural proteins and five structural proteins. Based on this knowledge it has been possible to develop virus-like particles that can be used to immunise non-human primates against Chikungunya infection by inducing antibody production. However, the development of vaccines for Chikungunya in humans will require a deeper understanding of how these antibodies produced by the vaccine interact with the virus and more detailed information about the structures of the virus and antibodies.Sun et al. have used two techniques \u2013 X-ray crystallography and electron cryo-microscopy \u2013 to determine the structure of Chikungunya virus-like particles, and to obtain new insights into the interactions of these particles with four related antibodies. Electron cryo-microscopy was used to figure out the structure of the particles at near atomic resolution, and X-ray crystallography was used to determine the atomic resolution structures of two of the four Fab antibodies that neutralize the Chikungunya virus. Electron cryo-microscopy was also used to probe the complex formed by the interactions between the virus-like particles and the antibodies.Sun et al. were able to identify the likely viral receptor site that is blocked by three of the antibodies when they neutralize the virus; the fourth antibody is thought to act by immobilizing one of the domains of protein E2, thereby hiding the \u201cfusion loop\u201d that allows the virus to enter and infect human tissue. It is hoped that these findings will contribute to efforts to combat the spread of the Chikungunya virus worldwide.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00435.002",
"content_html": "<p hwp:id=\"p-8\">The Chikungunya virus is carried by mosquitos and can cause a number of diseases in humans including encephalitis, which can be fatal in some cases, and severe arthritis. A recent mutation in the E1 protein of the virus has allowed it to efficiently reproduce in a different species of mosquitos, leading to a Chikungunya epidemic in R&#xE9;union Island in 2005 and the subsequent infection of millions of individuals in Africa and Asia. The virus also has the potential to spread to many areas of Europe and the Americas.<\/p>\n<p hwp:id=\"p-9\">Chikungunya virus has a single-stranded RNA genome that codes for four non-structural proteins and five structural proteins. Based on this knowledge it has been possible to develop virus-like particles that can be used to immunise non-human primates against Chikungunya infection by inducing antibody production. However, the development of vaccines for Chikungunya in humans will require a deeper understanding of how these antibodies produced by the vaccine interact with the virus and more detailed information about the structures of the virus and antibodies.<\/p>\n<p hwp:id=\"p-10\">Sun <italic>et al.<\/italic> have used two techniques &#x2013; X-ray crystallography and electron cryo-microscopy &#x2013; to determine the structure of Chikungunya virus-like particles, and to obtain new insights into the interactions of these particles with four related antibodies. Electron cryo-microscopy was used to figure out the structure of the particles at near atomic resolution, and X-ray crystallography was used to determine the atomic resolution structures of two of the four Fab antibodies that neutralize the Chikungunya virus. Electron cryo-microscopy was also used to probe the complex formed by the interactions between the virus-like particles and the antibodies.<\/p>\n<p hwp:id=\"p-11\">Sun <italic>et al.<\/italic> were able to identify the likely viral receptor site that is blocked by three of the antibodies when they neutralize the virus; the fourth antibody is thought to act by immobilizing one of the domains of protein E2, thereby hiding the &#x201C;fusion loop&#x201D; that allows the virus to enter and infect human tissue. It is hoped that these findings will contribute to efforts to combat the spread of the Chikungunya virus worldwide.<\/p>\n<p hwp:id=\"p-12\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00435.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00435.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00435.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00435",
"title": "Structural analyses at pseudo atomic resolution of Chikungunya virus and antibodies show mechanisms of neutralization",
"metadata": {
"authors": "S. Sun, Y. Xiang, W. Akahata, H. Holdaway, P. Pal, X. Zhang, M. S. Diamond, G. J. Nabel, M. G. Rossmann",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:31:26Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:31:26Z",
"updated_at": "2013-07-25T09:31:26Z"
},
{
"id": 83,
"content": "During mitosis, a cell duplicates its DNA and then divides, ultimately generating two genetically identical daughter cells. In eukaryotes, the process of DNA duplication occurs at multiple sites throughout the genome: at each site, the antiparallel strands of the parental DNA separate and provide a template for DNA polymerase (Pol), the enzyme that synthesizes the two new DNA strands. Duplication of the DNA proceeds in both directions from each site through the polymerization of nucleotides to form new strands of DNA that are complementary to the template strands. However, since DNA polymerases can only polymerize nucleotides in one direction, the 5\u2032 to 3\u2032 direction, synthesis of the so-called leading strand proceeds continuously, whereas the other, lagging strand is synthesized in fragments.The task of duplicating the bulk of the DNA is shared between Pol \u03b4, which is primarily responsible for synthesis of the lagging strand, and Pol \u03b5, which fulfils the same role for the leading strand. However, Pols \u03b4 and \u03b5 cannot initiate DNA synthesis by themselves; short RNA-DNA chains called primers must also be paired to each template strand. Production of the primers requires the concerted action of two more enzymes: an RNA polymerase known as primase, and another DNA polymerase called Pol \u03b1. It is known that completion of the RNA-DNA primer requires Pol \u03b1 to increase the length of the RNA segment by adding extra nucleotides, but the details of this process are poorly understood.Perera et al. combined crystallographic, biochemical and computational evidence to describe how Pol \u03b1 first recognizes and then extends the RNA strand in the primer. They found that Pol \u03b1 recognizes the particular shape of double helix\u2014an A-form helix\u2014that is formed by the DNA template and the RNA primer. The geometry of this helix prompts the Pol \u03b1 enzyme to start adding nucleotides to the RNA in the primer. Perera et al. determined that once a full turn of double-helix DNA has been synthesized, Pol \u03b1 is no longer in direct contact with the A-form helix, which causes the enzyme to disengage and terminate polymerization, leaving behind the now complete RNA-DNA primer.Perera et al. offer a new paradigm for understanding the initiation of DNA synthesis in eukaryotic replication. Their work suggests that Pol \u03b1 has the ability to discriminate between different shapes of the primer-template helix, thus providing a mechanistic understanding of primer release. The spontaneous release of the primer offers a simple and elegant way to limit DNA synthesis by Pol \u03b1, a polymerase that is prone to error, and to make the RNA-DNA primer directly available for extension by Pol \u03b4 and Pol \u03b5.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00482.002",
"content_html": "<p hwp:id=\"p-5\">During mitosis, a cell duplicates its DNA and then divides, ultimately generating two genetically identical daughter cells. In eukaryotes, the process of DNA duplication occurs at multiple sites throughout the genome: at each site, the antiparallel strands of the parental DNA separate and provide a template for DNA polymerase (Pol), the enzyme that synthesizes the two new DNA strands. Duplication of the DNA proceeds in both directions from each site through the polymerization of nucleotides to form new strands of DNA that are complementary to the template strands. However, since DNA polymerases can only polymerize nucleotides in one direction, the 5&#x2032; to 3&#x2032; direction, synthesis of the so-called leading strand proceeds continuously, whereas the other, lagging strand is synthesized in fragments.<\/p>\n<p hwp:id=\"p-6\">The task of duplicating the bulk of the DNA is shared between Pol &#x3B4;, which is primarily responsible for synthesis of the lagging strand, and Pol &#x3B5;, which fulfils the same role for the leading strand. However, Pols &#x3B4; and &#x3B5; cannot initiate DNA synthesis by themselves; short RNA-DNA chains called primers must also be paired to each template strand. Production of the primers requires the concerted action of two more enzymes: an RNA polymerase known as primase, and another DNA polymerase called Pol &#x3B1;. It is known that completion of the RNA-DNA primer requires Pol &#x3B1; to increase the length of the RNA segment by adding extra nucleotides, but the details of this process are poorly understood.<\/p>\n<p hwp:id=\"p-7\">Perera et al. combined crystallographic, biochemical and computational evidence to describe how Pol &#x3B1; first recognizes and then extends the RNA strand in the primer. They found that Pol &#x3B1; recognizes the particular shape of double helix&#x2014;an A-form helix&#x2014;that is formed by the DNA template and the RNA primer. The geometry of this helix prompts the Pol &#x3B1; enzyme to start adding nucleotides to the RNA in the primer. Perera et al. determined that once a full turn of double-helix DNA has been synthesized, Pol &#x3B1; is no longer in direct contact with the A-form helix, which causes the enzyme to disengage and terminate polymerization, leaving behind the now complete RNA-DNA primer.<\/p>\n<p hwp:id=\"p-8\">Perera et al. offer a new paradigm for understanding the initiation of DNA synthesis in eukaryotic replication. Their work suggests that Pol &#x3B1; has the ability to discriminate between different shapes of the primer-template helix, thus providing a mechanistic understanding of primer release. The spontaneous release of the primer offers a simple and elegant way to limit DNA synthesis by Pol &#x3B1;, a polymerase that is prone to error, and to make the RNA-DNA primer directly available for extension by Pol &#x3B4; and Pol &#x3B5;.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00482.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00482.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00482.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00482",
"title": "Mechanism for priming DNA synthesis by yeast DNA Polymerase &#xA0;",
"metadata": {
"authors": "R. L. Perera, R. Torella, S. Klinge, M. L. Kilkenny, J. D. Maman, L. Pellegrini",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:31:31Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:31:31Z",
"updated_at": "2013-07-25T09:31:31Z"
},
{
"id": 84,
"content": "Life first appeared on Earth more than 3 billion years ago in the form of single-celled microorganisms. The diverse array of complex life forms that we see today evolved from these humble beginnings, but it is not clear what triggered the evolution of multicellular organisms from single cells.One of the simplest multicellular eukaryotes is the yeast, Saccharomyces cerevisiae\u2014a fungus that has been used for centuries in baking and brewing and, more recently, as a model organism in molecular biology. Yeast cells feed on sugar (sucrose), but are unable to absorb it directly from their surroundings. Instead they secrete an enzyme called invertase, which breaks down the sucrose into simpler components that cells can take up with the help of sugar transporters.However, single yeast cells living in a low-sucrose environment face a problem: most of the simple sugars that they produce diffuse out of reach. To overcome this difficulty, the cells could form multicellular clumps, which would enable each cell to consume the sugars that drift away from its neighbours. Alternatively, the cells could increase their production of invertase, or they could begin to take up sucrose directly.Using genetic engineering, Koschwanez et al. produced three strains of yeast, each with one of these traits, and confirmed that all three strategies do indeed help fungi to grow in low sucrose. But could any of these traits evolve spontaneously? To test this possibility, Koschwanez et al. introduced wild-type yeast cells into a low-sucrose environment and studied any populations of cells that managed to survive. Of 12 that did, 11 had acquired the ability to form multicellular clumps, while 10 had increased their expression of invertase. Surprisingly, none had evolved the ability to import sucrose. However, 11 of the populations that survived also displayed an adaptation that the researchers had not predicted beforehand: they all expressed higher levels of the sugar transporters that take up sucrose breakdown products.The work of Koschwanez et al. suggests that the benefits of being able to share invertase and, therefore, simple sugars, may have driven the evolution of multicellularity in ancient organisms. Moreover, their use of rational design (engineered mutations) combined with experimental evolution (allowing colonies to grow under selection pressure and studying the strategies that they adopt) offers a new approach to studying evolution in the lab.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00367.002",
"content_html": "<p hwp:id=\"p-4\">Life first appeared on Earth more than 3 billion years ago in the form of single-celled microorganisms. The diverse array of complex life forms that we see today evolved from these humble beginnings, but it is not clear what triggered the evolution of multicellular organisms from single cells.<\/p>\n<p hwp:id=\"p-5\">One of the simplest multicellular eukaryotes is the yeast, <italic>Saccharomyces cerevisiae<\/italic>&#x2014;a fungus that has been used for centuries in baking and brewing and, more recently, as a model organism in molecular biology. Yeast cells feed on sugar (sucrose), but are unable to absorb it directly from their surroundings. Instead they secrete an enzyme called invertase, which breaks down the sucrose into simpler components that cells can take up with the help of sugar transporters.<\/p>\n<p hwp:id=\"p-6\">However, single yeast cells living in a low-sucrose environment face a problem: most of the simple sugars that they produce diffuse out of reach. To overcome this difficulty, the cells could form multicellular clumps, which would enable each cell to consume the sugars that drift away from its neighbours. Alternatively, the cells could increase their production of invertase, or they could begin to take up sucrose directly.<\/p>\n<p hwp:id=\"p-7\">Using genetic engineering, Koschwanez et al. produced three strains of yeast, each with one of these traits, and confirmed that all three strategies do indeed help fungi to grow in low sucrose. But could any of these traits evolve spontaneously? To test this possibility, Koschwanez et al. introduced wild-type yeast cells into a low-sucrose environment and studied any populations of cells that managed to survive. Of 12 that did, 11 had acquired the ability to form multicellular clumps, while 10 had increased their expression of invertase. Surprisingly, none had evolved the ability to import sucrose. However, 11 of the populations that survived also displayed an adaptation that the researchers had not predicted beforehand: they all expressed higher levels of the sugar transporters that take up sucrose breakdown products.<\/p>\n<p hwp:id=\"p-8\">The work of Koschwanez et al. suggests that the benefits of being able to share invertase and, therefore, simple sugars, may have driven the evolution of multicellularity in ancient organisms. Moreover, their use of rational design (engineered mutations) combined with experimental evolution (allowing colonies to grow under selection pressure and studying the strategies that they adopt) offers a new approach to studying evolution in the lab.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00367.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00367.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00367.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00367",
"title": "Improved use of a public good selects for the evolution of undifferentiated multicellularity",
"metadata": {
"authors": "J. H. Koschwanez, K. R. Foster, A. W. Murray",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:31:34Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:31:34Z",
"updated_at": "2013-07-25T09:31:34Z"
},
{
"id": 85,
"content": "Circadian rhythms are biochemical, physiological and behavioral processes that follow a 24-hr cycle, responding primarily to the periods of light and dark, and they have been observed in bacteria, fungi, plants and animals. The circadian clock that drives these rhythms\u2014which dictate our sleep patterns and other processes\u2014involves a set of genes and proteins that participate in a collection of positive and negative feedback loops.Previous research has mainly focused on identifying core clock genes\u2014that is, genes that make up the molecular clock\u2014and studying the functions of these genes and the proteins they code for. However, it has become clear that other clock genes are also involved in circadian behavior, and it has been proposed that polymorphisms in these non-core clock genes could contribute to the variations in circadian behavior displayed by different mammals.One important feedback loop in mammals involves two key transcription factors, CLOCK and BMAL1, that combine to form a complex that initiates the transcription of the negative feedback genes, Period and Cryptochrome. Shimomura et al. discovered that Usf1, a gene that codes for a transcription factor that is typically involved in lipid and carbohydrate metabolism, as well as other cellular processes, is also important. In particular, this transcription factor is capable of partially rescuing an abnormal circadian rhythm caused by a mutation in the Clock gene in mice.Shimomura et al. showed that the proteins expressed by the mutant Clock gene can bind to the same regulatory sites in the genome as the normal CLOCK:BMAL1 complex, but that gene expression of these targets is reduced because transcriptional activation is lower and binding of the complex is not as strong. However, proteins expressed by the Usf1 gene are able to counter this by binding to the same sites in the genome and compensating for the mutant CLOCK protein. Further experiments are needed to explore how the interactions between the USF1 and CLOCK:BMAL1 transcriptional networks regulate circadian rhythms and, possibly, carbohydrate and lipid metabolism as well.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00426.002",
"content_html": "<p hwp:id=\"p-8\">Circadian rhythms are biochemical, physiological and behavioral processes that follow a 24-hr cycle, responding primarily to the periods of light and dark, and they have been observed in bacteria, fungi, plants and animals. The circadian clock that drives these rhythms&#x2014;which dictate our sleep patterns and other processes&#x2014;involves a set of genes and proteins that participate in a collection of positive and negative feedback loops.<\/p>\n<p hwp:id=\"p-9\">Previous research has mainly focused on identifying core clock genes&#x2014;that is, genes that make up the molecular clock&#x2014;and studying the functions of these genes and the proteins they code for. However, it has become clear that other clock genes are also involved in circadian behavior, and it has been proposed that polymorphisms in these non-core clock genes could contribute to the variations in circadian behavior displayed by different mammals.<\/p>\n<p hwp:id=\"p-10\">One important feedback loop in mammals involves two key transcription factors, CLOCK and BMAL1, that combine to form a complex that initiates the transcription of the negative feedback genes, <italic>Period<\/italic> and <italic>Cryptochrome<\/italic>. Shimomura et al. discovered that <italic>Usf1<\/italic>, a gene that codes for a transcription factor that is typically involved in lipid and carbohydrate metabolism, as well as other cellular processes, is also important. In particular, this transcription factor is capable of partially rescuing an abnormal circadian rhythm caused by a mutation in the <italic>Clock<\/italic> gene in mice.<\/p>\n<p hwp:id=\"p-11\">Shimomura et al. showed that the proteins expressed by the mutant <italic>Clock<\/italic> gene can bind to the same regulatory sites in the genome as the normal CLOCK:BMAL1 complex, but that gene expression of these targets is reduced because transcriptional activation is lower and binding of the complex is not as strong. However, proteins expressed by the <italic>Usf1<\/italic> gene are able to counter this by binding to the same sites in the genome and compensating for the mutant CLOCK protein. Further experiments are needed to explore how the interactions between the USF1 and CLOCK:BMAL1 transcriptional networks regulate circadian rhythms and, possibly, carbohydrate and lipid metabolism as well.<\/p>\n<p hwp:id=\"p-12\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00426.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00426.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00426.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00426",
"title": "Usf1, a suppressor of the circadian Clock mutant, reveals the nature of the DNA-binding of the CLOCK:BMAL1 complex in mice",
"metadata": {
"authors": "K. Shimomura, V. Kumar, N. Koike, T.-K. Kim, J. Chong, E. D. Buhr, A. R. Whiteley, S. S. Low, C. Omura, D. Fenner, J. R. Owens, M. Richards, S.-H. Yoo, H.-K. Hong, M. H. Vitaterna, J. Bass, M. T. Pletcher, T. Wiltshire, J. Hogenesch, P. L. Lowrey, J. S. Takahashi",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:31:43Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:31:43Z",
"updated_at": "2013-07-25T09:31:43Z"
},
{
"id": 90,
"content": "Cells have evolved elaborate mechanisms for the detection of misfolded or damaged proteins, and for targeting their degradation. Since the accumulation of misfolded proteins is toxic to the cell, these protein quality control systems are critical for the maintenance of normal cellular function over the lifetime of an organism. The breakdown of this quality control correlates with the progression of neurodegenerative disorders including Alzheimer's, Huntington's and Parkinson's disease. Normal function of the protein quality control machinery can also cause disease: this is the case with channelopathies such as cystic fibrosis, in which mutant ion channels are targeted for degradation and therefore cannot function correctly at the cell surface. Understanding how protein quality control systems recognize misfolded proteins and target their degradation, and designing ways to stabilize or destabilize specific targets, particularly at the cell surface, could thus lead to the development of new therapeutic strategies.While protein quality control mechanisms in the cytosol and endoplasmic reticulum (ER) have been studied extensively, much less is known about quality control of integral membrane proteins after they exit the ER. Maintaining the quality of cell surface proteins impacts many critical biological functions including nutrient uptake, signaling and the functioning of specialized surface structures such as cell junctions.Here, Zhao et al. describe a new quality control mechanism that prevents misfolded proteins from accumulating in the plasma membrane. Building upon earlier work describing a network of adaptor proteins (called ARTs) for the Rsp5 ubiquitin ligase, Zhao et al. show that subjecting cells to proteotoxic stress, particularly thermal stress, triggers ART-Rsp5-mediated clearance of misfolded plasma membrane proteins. When ART-Rsp5-mediated clearance is abrogated, misfolded proteins accumulate at the cell surface, resulting in a rapid loss of cellular integrity. In the brain, such proteotoxicity can lead to cell death and neurodegeneration, thereby highlighting the importance of this plasma membrane quality control system.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00459.002",
"content_html": "<p hwp:id=\"p-5\">Cells have evolved elaborate mechanisms for the detection of misfolded or damaged proteins, and for targeting their degradation. Since the accumulation of misfolded proteins is toxic to the cell, these protein quality control systems are critical for the maintenance of normal cellular function over the lifetime of an organism. The breakdown of this quality control correlates with the progression of neurodegenerative disorders including Alzheimer's, Huntington's and Parkinson's disease. Normal function of the protein quality control machinery can also cause disease: this is the case with channelopathies such as cystic fibrosis, in which mutant ion channels are targeted for degradation and therefore cannot function correctly at the cell surface. Understanding how protein quality control systems recognize misfolded proteins and target their degradation, and designing ways to stabilize or destabilize specific targets, particularly at the cell surface, could thus lead to the development of new therapeutic strategies.<\/p>\n<p hwp:id=\"p-6\">While protein quality control mechanisms in the cytosol and endoplasmic reticulum (ER) have been studied extensively, much less is known about quality control of integral membrane proteins after they exit the ER. Maintaining the quality of cell surface proteins impacts many critical biological functions including nutrient uptake, signaling and the functioning of specialized surface structures such as cell junctions.<\/p>\n<p hwp:id=\"p-7\">Here, Zhao et al. describe a new quality control mechanism that prevents misfolded proteins from accumulating in the plasma membrane. Building upon earlier work describing a network of adaptor proteins (called ARTs) for the Rsp5 ubiquitin ligase, Zhao et al. show that subjecting cells to proteotoxic stress, particularly thermal stress, triggers ART-Rsp5-mediated clearance of misfolded plasma membrane proteins. When ART-Rsp5-mediated clearance is abrogated, misfolded proteins accumulate at the cell surface, resulting in a rapid loss of cellular integrity. In the brain, such proteotoxicity can lead to cell death and neurodegeneration, thereby highlighting the importance of this plasma membrane quality control system.<\/p>\n<p hwp:id=\"p-8\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00459.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00459.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00459.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00459",
"title": "The ART-Rsp5 ubiquitin ligase network comprises a plasma membrane quality control system that protects yeast cells from proteotoxic stress",
"metadata": {
"authors": "Y. Zhao, J. A. MacGurn, M. Liu, S. Emr",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:31:56Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:31:56Z",
"updated_at": "2013-07-25T09:31:56Z"
},
{
"id": 86,
"content": "Prostate cancer is the most commonly diagnosed cancer in men, and the second most lethal. All stages of prostate cancer depend upon male sex hormones, also known as androgens, to grow because these hormones bind and activate androgen receptors. A class of drugs termed \u2018antiandrogens\u2019 can effectively treat prostate cancer because they bind to androgen receptors without activating them, thereby preventing androgens from binding. However, the efficacy of even highly potent antiandrogen drugs, such as enzalutamide is short-lived in many patients, and understanding the biological mechanisms that cause drug resistance is one of the major objectives in translational prostate cancer research.Resistance can arise through mutations of the androgen receptor that result in the receptor being activated, rather than inhibited, by antiandrogen drugs. However, no such mutations are known yet for enzalutamide, and researchers are keen to understand whether they exist and, if so, to generate new drugs for prostate cancer that overcome them. To identify mutations that may lead to resistance, Balbas et al. designed a new screening method in human prostate cancer cells and showed that androgen receptors with a specific mutation (called F876L) can be activated by enzalutamide. More comprehensive biological studies showed that prostate cancer cells harboring the mutation continued to grow when treated with the drug. Balbas et al. also showed that this mutation can arise spontaneously in human prostate cancer cells treated long term with enzalutamide.Balbas et al. reasoned that the mutation likely altered the way enzalutamide binds to the androgen receptor, and used computer-guided structural modeling of the complex formed by the receptor and the drug to investigate how this might occur. These studies indicated that the region of the androgen receptor containing the F876L mutation comes into direct contact with the drug, and provided a structural explanation for the loss of inhibition. Because these studies showed how enzalutamide might bind to the androgen receptor, they also suggested ways in which enzalutamide could be chemically modified to restore its inhibitory activity against the mutant receptor.Balbas et al. then designed and synthesized a set of novel compounds, which the modeling data suggested could act as inhibitors of the mutant receptor. Several of these compounds inhibited the activity of both mutant and wild-type forms of the androgen receptor, and suppressed the growth of both enzalutamide-resistant and nonresistant prostate cancer cells.The work of Balbas et al. outlines a general screening strategy for the discovery of clinically relevant mutations in cancer genes, and shows how in silico technologies can accelerate drug discovery in the absence of a crystal structure of a protein\u2013drug complex. It also emphasizes how understanding the manner in which a drug binds its target can stimulate rational design of improved drug candidates.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00499.002",
"content_html": "<p hwp:id=\"p-4\">Prostate cancer is the most commonly diagnosed cancer in men, and the second most lethal. All stages of prostate cancer depend upon male sex hormones, also known as androgens, to grow because these hormones bind and activate androgen receptors. A class of drugs termed &#x2018;antiandrogens&#x2019; can effectively treat prostate cancer because they bind to androgen receptors without activating them, thereby preventing androgens from binding. However, the efficacy of even highly potent antiandrogen drugs, such as enzalutamide is short-lived in many patients, and understanding the biological mechanisms that cause drug resistance is one of the major objectives in translational prostate cancer research.<\/p>\n<p hwp:id=\"p-5\">Resistance can arise through mutations of the androgen receptor that result in the receptor being activated, rather than inhibited, by antiandrogen drugs. However, no such mutations are known yet for enzalutamide, and researchers are keen to understand whether they exist and, if so, to generate new drugs for prostate cancer that overcome them. To identify mutations that may lead to resistance, Balbas et al. designed a new screening method in human prostate cancer cells and showed that androgen receptors with a specific mutation (called F876L) can be activated by enzalutamide. More comprehensive biological studies showed that prostate cancer cells harboring the mutation continued to grow when treated with the drug. Balbas et al. also showed that this mutation can arise spontaneously in human prostate cancer cells treated long term with enzalutamide.<\/p>\n<p hwp:id=\"p-6\">Balbas et al. reasoned that the mutation likely altered the way enzalutamide binds to the androgen receptor, and used computer-guided structural modeling of the complex formed by the receptor and the drug to investigate how this might occur. These studies indicated that the region of the androgen receptor containing the F876L mutation comes into direct contact with the drug, and provided a structural explanation for the loss of inhibition. Because these studies showed how enzalutamide might bind to the androgen receptor, they also suggested ways in which enzalutamide could be chemically modified to restore its inhibitory activity against the mutant receptor.<\/p>\n<p hwp:id=\"p-7\">Balbas et al. then designed and synthesized a set of novel compounds, which the modeling data suggested could act as inhibitors of the mutant receptor. Several of these compounds inhibited the activity of both mutant and wild-type forms of the androgen receptor, and suppressed the growth of both enzalutamide-resistant and nonresistant prostate cancer cells.<\/p>\n<p hwp:id=\"p-8\">The work of Balbas et al. outlines a general screening strategy for the discovery of clinically relevant mutations in cancer genes, and shows how in silico technologies can accelerate drug discovery in the absence of a crystal structure of a protein&#x2013;drug complex. It also emphasizes how understanding the manner in which a drug binds its target can stimulate rational design of improved drug candidates.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00499.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00499.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00499.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00499",
"title": "Overcoming mutation-based resistance to antiandrogens with rational drug design",
"metadata": {
"authors": "M. D. Balbas, M. J. Evans, D. J. Hosfield, J. Wongvipat, V. K. Arora, P. A. Watson, Y. Chen, G. L. Greene, Y. Shen, C. L. Sawyers",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:31:46Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:31:46Z",
"updated_at": "2013-07-25T09:31:46Z"
},
{
"id": 87,
"content": "The endoplasmic reticulum (ER) is a structure that performs a variety of functions within eukaryotic cells. It can be divided into two regions: the surface of the rough ER is coated with ribosomes that manufacture various proteins, while the smooth ER is involved in activities such as lipid synthesis and carbohydrate metabolism. Proteins synthesized by the ribosomes attached to the rough ER are generally transferred to another structure within the cell, the Golgi apparatus, where they undergo further processing and packaging before being secreted or transported to another location within the cell.Proteins are shuttled from the ER to the Golgi apparatus by vesicles covered with coat protein complex II (COPII). This complex is composed of an inner and outer coat, each of which is assembled primarily with two different SEC proteins: the SEC23\/SEC24 protein heterodimer forms the inner coat of the COPII vesicle, and plays a key role in recruiting the appropriate protein cargos to the transport vesicle, while the SEC13\/SEC31 protein heterotetramer forms the outer coat and is generally responsible for regulating vesicle size and rigidity.Previous work found that mammals, including humans and mice, harbor multiple copies of several SEC protein genes, including two copies of SEC23 and four copies of SEC24. Both copies of SEC23 are derived from the same ancestral gene, and all four copies of SEC24 are derived from a different ancestral gene, and the availability of these copies potentially expands the range of properties that the vesicles can have. Insight into the roles of each SEC protein has come from work with SEC mutants. For example, a mutation in SEC23A was found to cause skeletal abnormalities in humans.Here, Chen et al. report the results of experiments which showed that mice with an inactive Sec24a gene could develop normally. However, these mice experienced a 45% reduction in their plasma cholesterol levels because they were not able to recruit and transport a secretory protein called PCSK9, which is a critical regulator of blood cholesterol levels.The work of Chen et al. reveals a previously unappreciated complexity in the recruitment of secretory proteins to the COPII vesicle and suggests that the various combinations of SEC proteins influence the proteins selected for transport to the Golgi apparatus. The work also identifies Sec24a as a potential therapeutic target for the reduction of plasma cholesterol, a finding that could be of interest to researchers working on heart disease and other conditions exacerbated by high cholesterol.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00444.002",
"content_html": "<p hwp:id=\"p-4\">The endoplasmic reticulum (ER) is a structure that performs a variety of functions within eukaryotic cells. It can be divided into two regions: the surface of the rough ER is coated with ribosomes that manufacture various proteins, while the smooth ER is involved in activities such as lipid synthesis and carbohydrate metabolism. Proteins synthesized by the ribosomes attached to the rough ER are generally transferred to another structure within the cell, the Golgi apparatus, where they undergo further processing and packaging before being secreted or transported to another location within the cell.<\/p>\n<p hwp:id=\"p-5\">Proteins are shuttled from the ER to the Golgi apparatus by vesicles covered with coat protein complex II (COPII). This complex is composed of an inner and outer coat, each of which is assembled primarily with two different SEC proteins: the SEC23\/SEC24 protein heterodimer forms the inner coat of the COPII vesicle, and plays a key role in recruiting the appropriate protein cargos to the transport vesicle, while the SEC13\/SEC31 protein heterotetramer forms the outer coat and is generally responsible for regulating vesicle size and rigidity.<\/p>\n<p hwp:id=\"p-6\">Previous work found that mammals, including humans and mice, harbor multiple copies of several SEC protein genes, including two copies of <italic>SEC23<\/italic> and four copies of <italic>SEC24<\/italic>. Both copies of <italic>SEC23<\/italic> are derived from the same ancestral gene, and all four copies of <italic>SEC24<\/italic> are derived from a different ancestral gene, and the availability of these copies potentially expands the range of properties that the vesicles can have. Insight into the roles of each SEC protein has come from work with <italic>SEC<\/italic> mutants. For example, a mutation in <italic>SEC23A<\/italic> was found to cause skeletal abnormalities in humans.<\/p>\n<p hwp:id=\"p-7\">Here, Chen et al. report the results of experiments which showed that mice with an inactive <italic>Sec24a<\/italic> gene could develop normally. However, these mice experienced a 45% reduction in their plasma cholesterol levels because they were not able to recruit and transport a secretory protein called PCSK9, which is a critical regulator of blood cholesterol levels.<\/p>\n<p hwp:id=\"p-8\">The work of Chen et al. reveals a previously unappreciated complexity in the recruitment of secretory proteins to the COPII vesicle and suggests that the various combinations of SEC proteins influence the proteins selected for transport to the Golgi apparatus. The work also identifies <italic>Sec24a<\/italic> as a potential therapeutic target for the reduction of plasma cholesterol, a finding that could be of interest to researchers working on heart disease and other conditions exacerbated by high cholesterol.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00444.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00444.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00444.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00444",
"title": "SEC24A deficiency lowers plasma cholesterol through reduced PCSK9 secretion",
"metadata": {
"authors": "X.-W. Chen, H. Wang, K. Bajaj, P. Zhang, Z.-X. Meng, D. Ma, Y. Bai, H.-H. Liu, E. Adams, A. Baines, G. Yu, M. A. Sartor, B. Zhang, Z. Yi, J. Lin, S. G. Young, R. Schekman, D. Ginsburg",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:31:48Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:31:48Z",
"updated_at": "2013-07-25T09:31:48Z"
},
{
"id": 88,
"content": "A little stress can be good for you. Just over 100 years ago, psychologists Robert Yerkes and John Dodson suggested that cognitive performance improves as stress increases, although it falls off again if stress levels continue to rise. The hippocampus is a key brain region for both memory and the regulation of emotion, and is highly sensitive to the main class of stress hormones, glucocorticoids. One particular subregion of the hippocampus, the dentate gyrus, contains a high density of glucocorticoid receptors, and is also notable for being one of only two regions in the adult mammalian brain that can give rise to new neurons via a process called neurogenesis.Chronic stress is known to impair memory and to reduce neurogenesis. However, the effects of acute stress are less clear-cut: early studies suggested that it suppressed the generation of new neurons, whereas several recent studies have observed no effect. Other work has shown that acute stress increases the expression of growth factors\u2014substances that stimulate cellular growth and proliferation\u2014which would seem to suggest that stress could enhance neurogenesis.Now Kirby et al. have obtained further insights into the effects of acute stress on the proliferation of cells in the dentate gyrus. Exposing rats to a moderate acute stressor, namely being restrained for a few hours, led to increased neurogenesis in the dorsal, but not ventral, hippocampus. Injecting rats with the stress hormone corticosterone had the same effect. In both cases, the enhanced neurogenesis was accompanied by increased expression of a growth factor called FGF2, which is produced by glial cells called astrocytes.Intriguingly, Kirby and co-workers found that the stressed rats performed better than control animals in a memory test. Moreover, the beneficial effects were seen if the rats performed the task 2 weeks after their stressful experience, but not if they performed the task 2 days after being stressed. This is pertinent because new neurons in the dentate gyrus become functional 2 weeks after being generated, which suggests that the stress-induced increase in neurogenesis could account for the rats' improved memory.The work of Kirby and co-workers has thus identified a mechanism by which moderate acute stress could have beneficial effects on cognition. Given that acute stress can be harmful in other instances\u2014leading, for example, to post-traumatic stress disorder\u2014further work is required to identify the factors that determine whether a response to stress is adaptive or pathological.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00362.002",
"content_html": "<p hwp:id=\"p-5\">A little stress can be good for you. Just over 100 years ago, psychologists Robert Yerkes and John Dodson suggested that cognitive performance improves as stress increases, although it falls off again if stress levels continue to rise. The hippocampus is a key brain region for both memory and the regulation of emotion, and is highly sensitive to the main class of stress hormones, glucocorticoids. One particular subregion of the hippocampus, the dentate gyrus, contains a high density of glucocorticoid receptors, and is also notable for being one of only two regions in the adult mammalian brain that can give rise to new neurons via a process called neurogenesis.<\/p>\n<p hwp:id=\"p-6\">Chronic stress is known to impair memory and to reduce neurogenesis. However, the effects of acute stress are less clear-cut: early studies suggested that it suppressed the generation of new neurons, whereas several recent studies have observed no effect. Other work has shown that acute stress increases the expression of growth factors&#x2014;substances that stimulate cellular growth and proliferation&#x2014;which would seem to suggest that stress could enhance neurogenesis.<\/p>\n<p hwp:id=\"p-7\">Now Kirby et al. have obtained further insights into the effects of acute stress on the proliferation of cells in the dentate gyrus. Exposing rats to a moderate acute stressor, namely being restrained for a few hours, led to increased neurogenesis in the dorsal, but not ventral, hippocampus. Injecting rats with the stress hormone corticosterone had the same effect. In both cases, the enhanced neurogenesis was accompanied by increased expression of a growth factor called FGF2, which is produced by glial cells called astrocytes.<\/p>\n<p hwp:id=\"p-8\">Intriguingly, Kirby and co-workers found that the stressed rats performed better than control animals in a memory test. Moreover, the beneficial effects were seen if the rats performed the task 2 weeks after their stressful experience, but not if they performed the task 2 days after being stressed. This is pertinent because new neurons in the dentate gyrus become functional 2 weeks after being generated, which suggests that the stress-induced increase in neurogenesis could account for the rats' improved memory.<\/p>\n<p hwp:id=\"p-9\">The work of Kirby and co-workers has thus identified a mechanism by which moderate acute stress could have beneficial effects on cognition. Given that acute stress can be harmful in other instances&#x2014;leading, for example, to post-traumatic stress disorder&#x2014;further work is required to identify the factors that determine whether a response to stress is adaptive or pathological.<\/p>\n<p hwp:id=\"p-10\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00362.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00362.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00362.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00362",
"title": "Acute stress enhances adult rat hippocampal neurogenesis and activation of newborn neurons via secreted astrocytic FGF2",
"metadata": {
"authors": "E. D. Kirby, S. E. Muroy, W. G. Sun, D. Covarrubias, M. J. Leong, L. A. Barchas, D. Kaufer",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:31:51Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:31:51Z",
"updated_at": "2013-07-25T09:31:51Z"
},
{
"id": 91,
"content": "The human body is home to many different microorganisms, with a range of bacteria, fungi and archaea living on the skin, in the intestine and at various other sites in the body. While many of these microorganisms are beneficial to their human hosts, we know very little about most of them. Early research focused primarily on comparing the microorganisms found in healthy individuals with those found in individuals suffering from a particular illness. More recently researchers have become interested in more general issues, such as understanding how these collections of microorganisms, which are also known as the human microbiota or the human microbiome, become established, and exploring the causes of similarities and differences between the microbiota of individuals.We now know that the communities of microorganisms found in the intestines of genetically related people tend to be more similar than those of people who are not related. Moreover, the communities of microorganisms found in the intestines of non-related adults living in the same household are more similar than those of unrelated adults living in different households. We also know that the range of microorganisms found in the intestine changes dramatically between birth and the age of 3 years. However, these studies have focused on the intestine, and little is known about the effect of relatedness, cohabitation and age on the microbiota at other body sites.Song et al. compared the microorganisms found on the skin, on the tongue and in the intestines of 159 people\u2014and 36 dogs\u2014in 60 families. They found that co-habitation resulted in the communities of microorganisms being more similar to each other, with those on the skin being the most similar. This was true for all comparisons, including human pairs, dog pairs and human\u2013dog pairs. This suggests that humans probably acquire many of the microorganisms on their skin through direct contact with their surroundings, and that humans tend to share more microbes with individuals, including their pets, with which they are in frequent contact. Song et al. also discovered that, unlike what happens in the intestine, the microbial communities on the skin and tongue of infants and children were relatively similar to those of adults. Overall, these findings suggest that the communities of microorganisms found in the intestine changes with age in a way that differs significantly from those found on the skin and tongue.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00458.002",
"content_html": "<p hwp:id=\"p-6\">The human body is home to many different microorganisms, with a range of bacteria, fungi and archaea living on the skin, in the intestine and at various other sites in the body. While many of these microorganisms are beneficial to their human hosts, we know very little about most of them. Early research focused primarily on comparing the microorganisms found in healthy individuals with those found in individuals suffering from a particular illness. More recently researchers have become interested in more general issues, such as understanding how these collections of microorganisms, which are also known as the human microbiota or the human microbiome, become established, and exploring the causes of similarities and differences between the microbiota of individuals.<\/p>\n<p hwp:id=\"p-7\">We now know that the communities of microorganisms found in the intestines of genetically related people tend to be more similar than those of people who are not related. Moreover, the communities of microorganisms found in the intestines of non-related adults living in the same household are more similar than those of unrelated adults living in different households. We also know that the range of microorganisms found in the intestine changes dramatically between birth and the age of 3 years. However, these studies have focused on the intestine, and little is known about the effect of relatedness, cohabitation and age on the microbiota at other body sites.<\/p>\n<p hwp:id=\"p-8\">Song et al. compared the microorganisms found on the skin, on the tongue and in the intestines of 159 people&#x2014;and 36 dogs&#x2014;in 60 families. They found that co-habitation resulted in the communities of microorganisms being more similar to each other, with those on the skin being the most similar. This was true for all comparisons, including human pairs, dog pairs and human&#x2013;dog pairs. This suggests that humans probably acquire many of the microorganisms on their skin through direct contact with their surroundings, and that humans tend to share more microbes with individuals, including their pets, with which they are in frequent contact. Song et al. also discovered that, unlike what happens in the intestine, the microbial communities on the skin and tongue of infants and children were relatively similar to those of adults. Overall, these findings suggest that the communities of microorganisms found in the intestine changes with age in a way that differs significantly from those found on the skin and tongue.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00458.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00458.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00458.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00458",
"title": "Cohabiting family members share microbiota with one another and with their dogs",
"metadata": {
"authors": "S. J. Song, C. Lauber, E. K. Costello, C. A. Lozupone, G. Humphrey, D. Berg-Lyons, J. G. Caporaso, D. Knights, J. C. Clemente, S. Nakielny, J. I. Gordon, N. Fierer, R. Knight",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:31:59Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:31:59Z",
"updated_at": "2013-07-25T09:31:59Z"
},
{
"id": 92,
"content": "The genomes of cancer cells contain mutations that are not present in normal cells. Some of these prevent cells from repairing their DNA, while others give rise to tumours by causing cells to multiply uncontrollably. Moreover, some of the mutations in breast cancer cells occur in clusters\u2014a phenomenon known as kataegis (from the Greek for \u2018thunderstorm\u2019).Kataegic mutations occur almost exclusively at a cytosine preceded by a thymine. This suggests that a family of proteins called AID\/APOBEC enzymes\u2014which remove amine groups from cytosines\u2014may be involved in generating these mutations. In this study, Taylor et al. confirm this possibility by showing that expressing individual members of the AID\/APOBEC family of enzymes in yeast cells increases the mutation frequency and induces kataegis.The kataegis triggered by the AID\/APOBEC enzymes could be localised through the introduction of double-stranded breaks into the DNA: Taylor et al. suggest that this might happen because repairing the breaks exposes single-stranded DNA, which the AID\/APOBEC enzymes then act upon. By comparing the mutations induced in the yeast cells with those observed in breast cancer cells, Taylor et al. identified APOBEC3B as the enzyme most likely to be responsible for kataegis in breast cancer (with APOBEC3A also a strong candidate in some cancers). Moreover, they showed that APOBEC3B was highly expressed in breast cancer cell lines, and that APOBEC3B and APOBEC3A can also cause DNA damage in human cells.Taken together, the findings provide key insights into the mechanism by which kataegis arises, and identify two proteins likely to contribute to the mutations seen in breast cancer. Further work is now required to determine whether these enzymes also give rise to mutations in other forms of cancer.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00534.002",
"content_html": "<p hwp:id=\"p-5\">The genomes of cancer cells contain mutations that are not present in normal cells. Some of these prevent cells from repairing their DNA, while others give rise to tumours by causing cells to multiply uncontrollably. Moreover, some of the mutations in breast cancer cells occur in clusters&#x2014;a phenomenon known as kataegis (from the Greek for &#x2018;thunderstorm&#x2019;).<\/p>\n<p hwp:id=\"p-6\">Kataegic mutations occur almost exclusively at a cytosine preceded by a thymine. This suggests that a family of proteins called AID\/APOBEC enzymes&#x2014;which remove amine groups from cytosines&#x2014;may be involved in generating these mutations. In this study, Taylor et al. confirm this possibility by showing that expressing individual members of the AID\/APOBEC family of enzymes in yeast cells increases the mutation frequency and induces kataegis.<\/p>\n<p hwp:id=\"p-7\">The kataegis triggered by the AID\/APOBEC enzymes could be localised through the introduction of double-stranded breaks into the DNA: Taylor et al. suggest that this might happen because repairing the breaks exposes single-stranded DNA, which the AID\/APOBEC enzymes then act upon. By comparing the mutations induced in the yeast cells with those observed in breast cancer cells, Taylor et al. identified APOBEC3B as the enzyme most likely to be responsible for kataegis in breast cancer (with APOBEC3A also a strong candidate in some cancers). Moreover, they showed that APOBEC3B was highly expressed in breast cancer cell lines, and that APOBEC3B and APOBEC3A can also cause DNA damage in human cells.<\/p>\n<p hwp:id=\"p-8\">Taken together, the findings provide key insights into the mechanism by which kataegis arises, and identify two proteins likely to contribute to the mutations seen in breast cancer. Further work is now required to determine whether these enzymes also give rise to mutations in other forms of cancer.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00534.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00534.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00534.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00534",
"title": "DNA deaminases induce break-associated mutation showers with implication of APOBEC3B and 3A in breast cancer kataegis",
"metadata": {
"authors": "B. J. Taylor, S. Nik-Zainal, Y. L. Wu, L. A. Stebbings, K. Raine, P. J. Campbell, C. Rada, M. R. Stratton, M. S. Neuberger",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:32:02Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:32:02Z",
"updated_at": "2013-07-25T09:32:02Z"
},
{
"id": 93,
"content": "Mammalian oviducts, or Fallopian tubes, convey egg cells from the ovaries to the uterus. Signalling between the ovary and oviduct, and secretory products produced throughout the reproductive tract, help to increase the likelihood of conception, minimise the loss of egg cells, and reduce the risk of ectopic pregnancy (in which an embryo implants outside the uterus). These processes may also influence the development of ovarian cancer, since Fallopian tube secretory cells were recently identified as the source of the most common and lethal subtype of epithelial ovarian cancer, high grade serous ovarian cancer.Oviduct to ovary signalling is poorly understood in mammals. However, experiments using model organisms such as the fruit fly (Drosophila melanogaster) provide a potentially powerful approach to the problem, since many mechanisms in gametogenesis are conserved between species. In particular, secretions within the Drosophila female reproductive tract appear to boost reproductive success by interacting with sperm cells and seminal proteins, as in mammals. But whether these secretions reach the ovary and influence ovulation, or simply act on other aspects of reproduction such as mating, sperm storage, fertilisation or egg laying, remained unknown.In this study, Sun and Spradling identified new genes controlling reproductive gland development and used this knowledge to elucidate secretory cell function. By mutating these genes, or the nuclear hormone receptor Hr39, they were able to reduce the total number of secretory cells that developed in the female reproductive tract, or to alter their function in adults. The ovaries of flies with abnormal secretory cell function contained as many egg cells as those of normal flies, but the mutant females laid fewer eggs. This indicates that secretory cells are required for at least one stage of reproduction.By comparing ovulation rates in mutant and normal flies, Sun and Spradling showed that the secretory cells generate a product that is specifically required for ovulation, and that production depends on Hr39 activity. This Hr39-dependent secretion is a good candidate for a conserved signal between the reproductive tract and ovary because mouse Lrh-1, a mammalian gene closely related to Hr39, is expressed in oviduct secretory cells and is itself required for ovulation. The secretory cells were also found to produce protein secretions that are necessary for female flies to store sperm in the reproductive tract after mating.By elucidating the roles played by female reproductive tract secretions, and demonstrating that they include a signal to the ovary that stimulates ovulation, the work of Sun and Spradling may lead to an increased understanding of ovarian cancer in humans.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00415.002",
"content_html": "<p hwp:id=\"p-4\">Mammalian oviducts, or Fallopian tubes, convey egg cells from the ovaries to the uterus. Signalling between the ovary and oviduct, and secretory products produced throughout the reproductive tract, help to increase the likelihood of conception, minimise the loss of egg cells, and reduce the risk of ectopic pregnancy (in which an embryo implants outside the uterus). These processes may also influence the development of ovarian cancer, since Fallopian tube secretory cells were recently identified as the source of the most common and lethal subtype of epithelial ovarian cancer, high grade serous ovarian cancer.<\/p>\n<p hwp:id=\"p-5\">Oviduct to ovary signalling is poorly understood in mammals. However, experiments using model organisms such as the fruit fly (<italic>Drosophila melanogaster<\/italic>) provide a potentially powerful approach to the problem, since many mechanisms in gametogenesis are conserved between species. In particular, secretions within the <italic>Drosophila<\/italic> female reproductive tract appear to boost reproductive success by interacting with sperm cells and seminal proteins, as in mammals. But whether these secretions reach the ovary and influence ovulation, or simply act on other aspects of reproduction such as mating, sperm storage, fertilisation or egg laying, remained unknown.<\/p>\n<p hwp:id=\"p-6\">In this study, Sun and Spradling identified new genes controlling reproductive gland development and used this knowledge to elucidate secretory cell function. By mutating these genes, or the nuclear hormone receptor <italic>Hr39<\/italic>, they were able to reduce the total number of secretory cells that developed in the female reproductive tract, or to alter their function in adults. The ovaries of flies with abnormal secretory cell function contained as many egg cells as those of normal flies, but the mutant females laid fewer eggs. This indicates that secretory cells are required for at least one stage of reproduction.<\/p>\n<p hwp:id=\"p-7\">By comparing ovulation rates in mutant and normal flies, Sun and Spradling showed that the secretory cells generate a product that is specifically required for ovulation, and that production depends on Hr39 activity. This Hr39-dependent secretion is a good candidate for a conserved signal between the reproductive tract and ovary because mouse <italic>Lrh-1<\/italic>, a mammalian gene closely related to <italic>Hr39<\/italic>, is expressed in oviduct secretory cells and is itself required for ovulation. The secretory cells were also found to produce protein secretions that are necessary for female flies to store sperm in the reproductive tract after mating.<\/p>\n<p hwp:id=\"p-8\">By elucidating the roles played by female reproductive tract secretions, and demonstrating that they include a signal to the ovary that stimulates ovulation, the work of Sun and Spradling may lead to an increased understanding of ovarian cancer in humans.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00415.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00415.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00415.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00415",
"title": "Ovulation in Drosophila is controlled by secretory cells of the female reproductive tract",
"metadata": {
"authors": "J. Sun, A. C. Spradling",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:32:08Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:32:08Z",
"updated_at": "2013-07-25T09:32:08Z"
},
{
"id": 95,
"content": "Epithelial tissue is one of the four major types of tissue found in animals, and is the only type of tissue that is able to form and maintain layers of cells that are just one cell thick. These layers provide inner linings to various cavities and hollow organs throughout the body\u2014including the lungs and glandular organs such as mammary glands. A single-cell layer of epithelium is separated from the tissues beneath it by a supporting substance called the extracellular matrix. The individual cells within a single-cell layer are physically attached to the matrix, and when displaced from it, they promptly undergo programmed cell death. This mechanism preserves the single-cell layer pattern throughout the body and prevents epithelial cells from growing in inappropriate locations.It is estimated that up to 90% of cancers in humans originate in epithelial tissue, and the cells within such tumors are known to survive and divide even when they are no longer attached to the extracellular matrix. Understanding how cancerous cells gain this ability may lead to new approaches to stopping tumor cells from dividing and colonizing tissues around the body.To address this problem, Pavlova et al. explored which genes enable epithelial cells from the human mammary gland to grow without being attached to the extracellular matrix. They found that the gene that codes for a protein called poliovirus receptor-like 4 (PVRL4) allows attachment-free cell growth and also makes cells cluster together once detached from the matrix.Normally, the PVRL4 gene is not active in breast epithelial cells, but its activity is detected in many breast, lung, and ovarian tumors. Moreover, cancerous cells tend to cluster together when they are detached from the extracellular matrix. This behavior is particularly evident in the cells that divide aggressively to form tumors that subsequently migrate and colonize other tissues around the body. When Pavlova et al. used genetic techniques to silence PVRL4 in cells from breast tumors, they found that it reduced the formation of clusters by the cancer cells and also reduced their ability to grow in the absence of attachment.Pavlova et al. also showed that interactions between the PVRL4 in one cell and a related protein called PVRL1 in a neighboring cell were responsible for holding the cells together in clusters. Moreover, PVRL4 triggers a form of signaling between the cells called integrin \u03b24 signaling that allows them to survive without being anchored to the extracellular matrix.Finally, Pavlova et al. found that injecting anti-PVRL4 antibodies (mouse proteins that attach to PVRL4 and prevent the formation of clusters) slows down the growth of breast tumors in mice. These findings suggest that inhibiting PVRL4 action with antibodies can be used as a new approach to the treatment of breast, lung, and ovarian cancers in humans.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00358.002",
"content_html": "<p hwp:id=\"p-5\">Epithelial tissue is one of the four major types of tissue found in animals, and is the only type of tissue that is able to form and maintain layers of cells that are just one cell thick. These layers provide inner linings to various cavities and hollow organs throughout the body&#x2014;including the lungs and glandular organs such as mammary glands. A single-cell layer of epithelium is separated from the tissues beneath it by a supporting substance called the extracellular matrix. The individual cells within a single-cell layer are physically attached to the matrix, and when displaced from it, they promptly undergo programmed cell death. This mechanism preserves the single-cell layer pattern throughout the body and prevents epithelial cells from growing in inappropriate locations.<\/p>\n<p hwp:id=\"p-6\">It is estimated that up to 90% of cancers in humans originate in epithelial tissue, and the cells within such tumors are known to survive and divide even when they are no longer attached to the extracellular matrix. Understanding how cancerous cells gain this ability may lead to new approaches to stopping tumor cells from dividing and colonizing tissues around the body.<\/p>\n<p hwp:id=\"p-7\">To address this problem, Pavlova et al. explored which genes enable epithelial cells from the human mammary gland to grow without being attached to the extracellular matrix. They found that the gene that codes for a protein called poliovirus receptor-like 4 (PVRL4) allows attachment-free cell growth and also makes cells cluster together once detached from the matrix.<\/p>\n<p hwp:id=\"p-8\">Normally, the <italic>PVRL4<\/italic> gene is not active in breast epithelial cells, but its activity is detected in many breast, lung, and ovarian tumors. Moreover, cancerous cells tend to cluster together when they are detached from the extracellular matrix. This behavior is particularly evident in the cells that divide aggressively to form tumors that subsequently migrate and colonize other tissues around the body. When Pavlova et al. used genetic techniques to silence PVRL4 in cells from breast tumors, they found that it reduced the formation of clusters by the cancer cells and also reduced their ability to grow in the absence of attachment.<\/p>\n<p hwp:id=\"p-9\">Pavlova et al. also showed that interactions between the PVRL4 in one cell and a related protein called PVRL1 in a neighboring cell were responsible for holding the cells together in clusters. Moreover, PVRL4 triggers a form of signaling between the cells called integrin &#x3B2;4 signaling that allows them to survive without being anchored to the extracellular matrix.<\/p>\n<p hwp:id=\"p-10\">Finally, Pavlova et al. found that injecting anti-PVRL4 antibodies (mouse proteins that attach to PVRL4 and prevent the formation of clusters) slows down the growth of breast tumors in mice. These findings suggest that inhibiting PVRL4 action with antibodies can be used as a new approach to the treatment of breast, lung, and ovarian cancers in humans.<\/p>\n<p hwp:id=\"p-11\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00358.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00358.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00358.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00358",
"title": "A role for PVRL4-driven cell-cell interactions in tumorigenesis",
"metadata": {
"authors": "N. N. Pavlova, C. Pallasch, A. E. Elia, C. J. Braun, T. F. Westbrook, M. Hemann, S. J. Elledge",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:32:16Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:32:16Z",
"updated_at": "2013-07-25T09:32:16Z"
},
{
"id": 271,
"content": "Cells must be able to rapidly repair damage to their outer membranes. This is particularly important in the case of muscle cells, which are vulnerable to damage, and the failure of these cells to repair their outer membranes leads to the muscle wastage seen in muscular dystrophy. Researchers do not fully understand how cells repair membrane, but one popular theory is that they use the membranes of specialized vesicles to \u2018patch\u2019 areas that have been damaged.A group of proteins called caveolins have also been implicated in membrane repair but, again, the details have not been worked out. These proteins are best known for their role in the formation of caveolae \u2014 small pouches formed by invaginated sections of the plasma membrane. Now, Corrotte et al. have obtained evidence that membrane repair relies not on patching, but on endocytosis (the process by which substances are taken into the cell in small vesicles that \u2018pinch\u2019 from the plasma membrane) of these caveolae pouches.Corrotte et al. treated cells with streptolysin O, a toxin that forms pores in the membrane that cannot be repaired using patches, and found that this led to the formation of small membrane-derived vesicles that looked just like caveolae. Further tests confirmed that these vesicles contained caveolar proteins, and that they removed the toxin from the plasma membrane by endocytosis. Similar effects were seen in response to mechanical damage caused by tiny glass beads. Moreover, blocking the expression of caveolar genes prevented cells from repairing membrane damage.Based on their findings, Corrotte et al. propose an alternative model for the repair process; namely that cellular damage triggers an influx of calcium ions, which causes vesicles called lysosomes to release chemicals that promote the formation of caveolae. These then remove the damaged area through endocytosis, restoring the integrity of the membrane. The results offer new insights into why mutations in caveolar proteins are associated with muscle disorders, including muscular dystrophy and cardiac dysfunction.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00926.002",
"content_html": "<p hwp:id=\"p-5\">Cells must be able to rapidly repair damage to their outer membranes. This is particularly important in the case of muscle cells, which are vulnerable to damage, and the failure of these cells to repair their outer membranes leads to the muscle wastage seen in muscular dystrophy. Researchers do not fully understand how cells repair membrane, but one popular theory is that they use the membranes of specialized vesicles to &#x2018;patch&#x2019; areas that have been damaged.<\/p>\n<p hwp:id=\"p-6\">A group of proteins called caveolins have also been implicated in membrane repair but, again, the details have not been worked out. These proteins are best known for their role in the formation of caveolae &#x2014; small pouches formed by invaginated sections of the plasma membrane. Now, Corrotte et al. have obtained evidence that membrane repair relies not on patching, but on endocytosis (the process by which substances are taken into the cell in small vesicles that &#x2018;pinch&#x2019; from the plasma membrane) of these caveolae pouches.<\/p>\n<p hwp:id=\"p-7\">Corrotte et al. treated cells with streptolysin O, a toxin that forms pores in the membrane that cannot be repaired using patches, and found that this led to the formation of small membrane-derived vesicles that looked just like caveolae. Further tests confirmed that these vesicles contained caveolar proteins, and that they removed the toxin from the plasma membrane by endocytosis. Similar effects were seen in response to mechanical damage caused by tiny glass beads. Moreover, blocking the expression of caveolar genes prevented cells from repairing membrane damage.<\/p>\n<p hwp:id=\"p-8\">Based on their findings, Corrotte et al. propose an alternative model for the repair process; namely that cellular damage triggers an influx of calcium ions, which causes vesicles called lysosomes to release chemicals that promote the formation of caveolae. These then remove the damaged area through endocytosis, restoring the integrity of the membrane. The results offer new insights into why mutations in caveolar proteins are associated with muscle disorders, including muscular dystrophy and cardiac dysfunction.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00926.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00926.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00926.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00926",
"title": "Caveolae internalization repairs wounded cells and muscle fibers",
"metadata": {
"authors": "M. Corrotte, P. E. Almeida, C. Tam, T. Castro-Gomes, M. C. Fernandes, B. A. Millis, M. Cortez, H. Miller, W. Song, T. K. Maugel, N. W. Andrews",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2014-01-13T00:40:16Z",
"updated_at": "2014-01-13T00:40:16Z"
},
"created_at": "2014-01-13T00:40:16Z",
"updated_at": "2014-01-13T00:40:16Z"
},
{
"id": 96,
"content": "We live in a world with a 24-hr cycle in which day follows night follows day with complete predictability. Life on earth has evolved to take advantage of this predictability by using circadian clocks to prepare for the coming of night (or day), and plants are no exception. Even in constant darkness, characteristics such as leaf movements show a constant cycle of around 24 hr.Most circadian clocks rely on negative feedback loops involving various genes and proteins to keep track of time. In one of these feedback loops, certain genes\u2014called morning-phased genes\u2014are expressed as proteins during the day, and these proteins prevent other genes\u2014called evening-phased genes\u2014from producing proteins. As night approaches, however, a second feedback loop acts to stop the morning-phased genes being expressed, thus allowing the evening-phased genes to produce proteins. And as day approaches, expression of these genes is stopped and the whole cycle starts again.Many of the genes and proteins involved in the circadian system of Arabidopsis thaliana, a small flowering plant that is widely used as a model organism, have been identified, and its circadian clock was thought to rely almost entirely on proteins called repressors that block the transcription of genes. Now, Hsu et al. have shown that the Arabidopsis clock also involves proteins that increase the expression of certain genes at specific times of the day.Hsu et al. focused on the promoter regions of evening-phased genes: these regions are stretches of DNA that proteins called transcription factors bind to and either encourage the expression of a gene (if the protein is a transcriptional activator) or block its expression (as a transcriptional repressor). In particular, they focused on a protein called RVE8 that is most strongly expressed in the afternoon and, based on previous research, is thought to activate the transcription of genes. Using genetically modified plants in which the gene for RVE8 can be turned on and off, they found that this protein led to increases in the expression of some genes, and reductions in the expression of others.Further analysis showed that RVE8 was able to activate the expression of evening-phased genes directly, without requiring that new proteins be made first. By contrast, morning-expressed genes were likely to be suppressed by RVE8 via an indirect mechanism that involved other proteins that had previously been activated by RVE8. The expression of RVE8 itself is regulated by other clock genes and also by an undefined post-transcriptional process. Therefore rather than consisting of a morning feedback loop coupled to an evening feedback loop, with both loops being based on repressors, the plant clock is instead better viewed as a highly connected network of activators and repressors. Further research is clearly necessary to understand this unexpected complexity in the circadian clock of Arabidopsis.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00473.002",
"content_html": "<p hwp:id=\"p-4\">We live in a world with a 24-hr cycle in which day follows night follows day with complete predictability. Life on earth has evolved to take advantage of this predictability by using circadian clocks to prepare for the coming of night (or day), and plants are no exception. Even in constant darkness, characteristics such as leaf movements show a constant cycle of around 24 hr.<\/p>\n<p hwp:id=\"p-5\">Most circadian clocks rely on negative feedback loops involving various genes and proteins to keep track of time. In one of these feedback loops, certain genes&#x2014;called morning-phased genes&#x2014;are expressed as proteins during the day, and these proteins prevent other genes&#x2014;called evening-phased genes&#x2014;from producing proteins. As night approaches, however, a second feedback loop acts to stop the morning-phased genes being expressed, thus allowing the evening-phased genes to produce proteins. And as day approaches, expression of these genes is stopped and the whole cycle starts again.<\/p>\n<p hwp:id=\"p-6\">Many of the genes and proteins involved in the circadian system of <italic>Arabidopsis thaliana<\/italic>, a small flowering plant that is widely used as a model organism, have been identified, and its circadian clock was thought to rely almost entirely on proteins called repressors that block the transcription of genes. Now, Hsu et al. have shown that the Arabidopsis clock also involves proteins that increase the expression of certain genes at specific times of the day.<\/p>\n<p hwp:id=\"p-7\">Hsu et al. focused on the promoter regions of evening-phased genes: these regions are stretches of DNA that proteins called transcription factors bind to and either encourage the expression of a gene (if the protein is a transcriptional activator) or block its expression (as a transcriptional repressor). In particular, they focused on a protein called RVE8 that is most strongly expressed in the afternoon and, based on previous research, is thought to activate the transcription of genes. Using genetically modified plants in which the gene for RVE8 can be turned on and off, they found that this protein led to increases in the expression of some genes, and reductions in the expression of others.<\/p>\n<p hwp:id=\"p-8\">Further analysis showed that RVE8 was able to activate the expression of evening-phased genes directly, without requiring that new proteins be made first. By contrast, morning-expressed genes were likely to be suppressed by RVE8 via an indirect mechanism that involved other proteins that had previously been activated by RVE8. The expression of RVE8 itself is regulated by other clock genes and also by an undefined post-transcriptional process. Therefore rather than consisting of a morning feedback loop coupled to an evening feedback loop, with both loops being based on repressors, the plant clock is instead better viewed as a highly connected network of activators and repressors. Further research is clearly necessary to understand this unexpected complexity in the circadian clock of Arabidopsis.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00473.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00473.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00473.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00473",
"title": "Accurate timekeeping is controlled by a cycling activator in Arabidopsis",
"metadata": {
"authors": "P. Y. Hsu, U. K. Devisetty, S. L. Harmer",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:32:23Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:32:23Z",
"updated_at": "2013-07-25T09:32:23Z"
},
{
"id": 97,
"content": "Dengue fever is an infectious tropical disease that is transmitted by mosquitoes carrying dengue virus. Almost half of the world\u2019s population lives in dengue-plagued regions and it is estimated that between 50 and 100 million people are infected annually. However, there is no effective vaccine and researchers have only a limited understanding of the mechanisms behind the disease.While most infected individuals experience fever, headache, muscle and joint pain, and a skin rash, a small percentage go on to develop a life-threatening condition known as dengue hemorrhagic fever (DHF). This is marked by internal bleeding, and by the leakage of water and salts from blood vessels (vascular leakage). At present, it is difficult to tell which patients will develop this complication, making it hard to tailor treatment appropriately.Here, St John et al. reveal that the vascular leakage that occurs in DHF is triggered by mast cells, which line blood vessels and regulate their permeability through the release of molecules such as histamines and leukotrienes. They also found that mice deficient in mast cells did not show dengue-induced vascular leakage, and that wild-type animals treated with drugs that block the actions of proteins produced by these cells, showed less vascular leakage than controls. Moreover, levels of an enzyme called chymase, another mast cell product, are higher in human patients with DHF than in those with dengue fever. Since chymase release occurs early in infection, tests for the presence of this enzyme could be used to predict which patients are likely to develop DHF.The work of St John et al. suggests new lines of inquiry into the mechanisms that lead some individuals infected with dengue fever to develop DHF, and indicates that drugs that target mast cells could offer an effective treatment.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00481.002",
"content_html": "<p hwp:id=\"p-4\">Dengue fever is an infectious tropical disease that is transmitted by mosquitoes carrying dengue virus. Almost half of the world&#x2019;s population lives in dengue-plagued regions and it is estimated that between 50 and 100 million people are infected annually. However, there is no effective vaccine and researchers have only a limited understanding of the mechanisms behind the disease.<\/p>\n<p hwp:id=\"p-5\">While most infected individuals experience fever, headache, muscle and joint pain, and a skin rash, a small percentage go on to develop a life-threatening condition known as dengue hemorrhagic fever (DHF). This is marked by internal bleeding, and by the leakage of water and salts from blood vessels (vascular leakage). At present, it is difficult to tell which patients will develop this complication, making it hard to tailor treatment appropriately.<\/p>\n<p hwp:id=\"p-6\">Here, St John et al. reveal that the vascular leakage that occurs in DHF is triggered by mast cells, which line blood vessels and regulate their permeability through the release of molecules such as histamines and leukotrienes. They also found that mice deficient in mast cells did not show dengue-induced vascular leakage, and that wild-type animals treated with drugs that block the actions of proteins produced by these cells, showed less vascular leakage than controls. Moreover, levels of an enzyme called chymase, another mast cell product, are higher in human patients with DHF than in those with dengue fever. Since chymase release occurs early in infection, tests for the presence of this enzyme could be used to predict which patients are likely to develop DHF.<\/p>\n<p hwp:id=\"p-7\">The work of St John et al. suggests new lines of inquiry into the mechanisms that lead some individuals infected with dengue fever to develop DHF, and indicates that drugs that target mast cells could offer an effective treatment.<\/p>\n<p hwp:id=\"p-8\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00481.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00481.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00481.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00481",
"title": "Contributions of mast cells and vasoactive products, leukotrienes and chymase, to dengue virus-induced vascular leakage",
"metadata": {
"authors": "A. L. St John, A. P. Rathore, B. Raghavan, M.-L. Ng, S. N. Abraham",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:32:25Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:32:25Z",
"updated_at": "2013-07-25T09:32:25Z"
},
{
"id": 98,
"content": "To process the sights and sounds around us, our senses must be attuned to a huge range of signals: from barely audible whispers to deafening rock concerts, and from dim glimmers of light to bright spotlights. Sensory neurons face the challenge of encoding this huge range of inputs within their much more restricted response range. Thus, neurons in our eyes and ears must continually adjust their gain or sensitivity to match changes in the light and sound inputs. These gain control processes must operate rapidly to keep up with the ever-changing input signals, but must also operate accurately so as not to distort the inputs.The trade-off between rapid and accurate gain control can be illustrated by considering how the retina processes information at low light levels. There are two main types of light-sensitive cells in the retina: rods and cones. Vision at night relies on the ability of the rods to detect single photons\u2014the smallest unit of light. In starlight, an individual rod will register photons only rarely, and most of the time, the majority of the rods will not register any photons. Neurons in the retinal circuits that read out the rod signals receive input from hundreds or thousands of rods, and those rod inputs are highly amplified to allow detection of the responses produced when a tiny fraction of the rods absorbs a photon. But this amplification is dangerous, as it could easily saturate retinal signals when light levels increase. Gain control mechanisms are needed to avoid such saturation.Schwartz and Rieke now add to our understanding of this process by examining how the retinas of non-human primates behave in low light. They reveal that levels of background light that can only just be detected behaviorally trigger retinal gain controls; these gain controls operate when less than 1% of rods absorb a photon. Under these conditions, the physics of light itself will cause considerable variability in the stream of photons arriving at the retina, leading to high variability in the gain of retinal responses. Nonetheless, changes in gain occurred rapidly following changes in background, indicating that the underlying mechanisms spend little time averaging incident photons. Taken together, these findings will require revisiting our ideas about how adaptational mechanisms balance the competing demands of speed and reliability to help us see the world around us.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00467.002",
"content_html": "<p hwp:id=\"p-4\">To process the sights and sounds around us, our senses must be attuned to a huge range of signals: from barely audible whispers to deafening rock concerts, and from dim glimmers of light to bright spotlights. Sensory neurons face the challenge of encoding this huge range of inputs within their much more restricted response range. Thus, neurons in our eyes and ears must continually adjust their gain or sensitivity to match changes in the light and sound inputs. These gain control processes must operate rapidly to keep up with the ever-changing input signals, but must also operate accurately so as not to distort the inputs.<\/p>\n<p hwp:id=\"p-5\">The trade-off between rapid and accurate gain control can be illustrated by considering how the retina processes information at low light levels. There are two main types of light-sensitive cells in the retina: rods and cones. Vision at night relies on the ability of the rods to detect single photons&#x2014;the smallest unit of light. In starlight, an individual rod will register photons only rarely, and most of the time, the majority of the rods will not register any photons. Neurons in the retinal circuits that read out the rod signals receive input from hundreds or thousands of rods, and those rod inputs are highly amplified to allow detection of the responses produced when a tiny fraction of the rods absorbs a photon. But this amplification is dangerous, as it could easily saturate retinal signals when light levels increase. Gain control mechanisms are needed to avoid such saturation.<\/p>\n<p hwp:id=\"p-6\">Schwartz and Rieke now add to our understanding of this process by examining how the retinas of non-human primates behave in low light. They reveal that levels of background light that can only just be detected behaviorally trigger retinal gain controls; these gain controls operate when less than 1% of rods absorb a photon. Under these conditions, the physics of light itself will cause considerable variability in the stream of photons arriving at the retina, leading to high variability in the gain of retinal responses. Nonetheless, changes in gain occurred rapidly following changes in background, indicating that the underlying mechanisms spend little time averaging incident photons. Taken together, these findings will require revisiting our ideas about how adaptational mechanisms balance the competing demands of speed and reliability to help us see the world around us.<\/p>\n<p hwp:id=\"p-7\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00467.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00467.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00467.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00467",
"title": "Controlling gain one photon at a time",
"metadata": {
"authors": "G. W. Schwartz, F. Rieke",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:32:28Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:32:28Z",
"updated_at": "2013-07-25T09:32:28Z"
},
{
"id": 99,
"content": "Plants have developed a variety of strategies to defend themselves against herbivorous animals, particularly insects. In addition to mechanical defences such as thorns and spines, plants also produce compounds known as secondary metabolites that keep insects and other herbivores at bay by acting as repellents or toxins. Some of these metabolites are produced on a continuous basis by plants, whereas others\u2014notably compounds called green-leaf volatiles\u2014are only produced once the plant has been attacked. Green-leaf volatiles\u2014which are also responsible for the smell of freshly cut grass\u2014have been observed to provide plants with both direct protection, by inhibiting or repelling herbivores, and indirect protection, by attracting predators of the herbivores themselves.The hawkmoth Manduca sexta lays its eggs on various plants, including tobacco plants and sacred Datura plants. Once the eggs have hatched into caterpillars, they start eating the leaves of their host plant, and if present in large numbers, these caterpillars can quickly defoliate and destroy it. In an effort to defend itself, the host plant releases green-leaf volatiles to attract various species of Geocoris, and these bugs eat the eggs.One of the green-leaf volatiles released by tobacco plants is known as (Z)-3-hexenal, but enzymes released by M. sexta caterpillars change some of these molecules into (E)-2-hexenal, which has the same chemical formula but a different structure. The resulting changes in the \u2018volatile profile\u2019 alerts Geocoris bugs to the presence of M. sexta eggs and caterpillars on the plant.Now Allmann et al. show that adult female M. sexta moths can also detect similar changes in the volatile profile emitted by sacred Datura plants that have been damaged by M. sexta caterpillars. This alerts the moths to the fact that Geocoris bugs are likely to be attacking eggs and caterpillars on the plant, or on their way to the plant, so they lay their eggs on other plants. This reduces competition for resources and also reduces the risk of newly laid eggs being eaten by predators. Allmann et al. also identified the neural mechanism that allows moths to detect changes in the volatile profile of plants\u2014the E- and Z- odours lead to different activation patterns in the moth brain.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00421.002",
"content_html": "<p hwp:id=\"p-7\">Plants have developed a variety of strategies to defend themselves against herbivorous animals, particularly insects. In addition to mechanical defences such as thorns and spines, plants also produce compounds known as secondary metabolites that keep insects and other herbivores at bay by acting as repellents or toxins. Some of these metabolites are produced on a continuous basis by plants, whereas others&#x2014;notably compounds called green-leaf volatiles&#x2014;are only produced once the plant has been attacked. Green-leaf volatiles&#x2014;which are also responsible for the smell of freshly cut grass&#x2014;have been observed to provide plants with both direct protection, by inhibiting or repelling herbivores, and indirect protection, by attracting predators of the herbivores themselves.<\/p>\n<p hwp:id=\"p-8\">The hawkmoth <italic>Manduca sexta<\/italic> lays its eggs on various plants, including tobacco plants and sacred Datura plants. Once the eggs have hatched into caterpillars, they start eating the leaves of their host plant, and if present in large numbers, these caterpillars can quickly defoliate and destroy it. In an effort to defend itself, the host plant releases green-leaf volatiles to attract various species of <italic>Geocoris<\/italic>, and these bugs eat the eggs.<\/p>\n<p hwp:id=\"p-9\">One of the green-leaf volatiles released by tobacco plants is known as (<italic>Z<\/italic>)-3-hexenal, but enzymes released by <italic>M. sexta<\/italic> caterpillars change some of these molecules into (<italic>E<\/italic>)-2-hexenal, which has the same chemical formula but a different structure. The resulting changes in the &#x2018;volatile profile&#x2019; alerts <italic>Geocoris<\/italic> bugs to the presence of <italic>M. sexta<\/italic> eggs and caterpillars on the plant.<\/p>\n<p hwp:id=\"p-10\">Now Allmann et al. show that adult female <italic>M. sexta<\/italic> moths can also detect similar changes in the volatile profile emitted by sacred Datura plants that have been damaged by <italic>M. sexta<\/italic> caterpillars. This alerts the moths to the fact that <italic>Geocoris<\/italic> bugs are likely to be attacking eggs and caterpillars on the plant, or on their way to the plant, so they lay their eggs on other plants. This reduces competition for resources and also reduces the risk of newly laid eggs being eaten by predators. Allmann et al. also identified the neural mechanism that allows moths to detect changes in the volatile profile of plants&#x2014;the <italic>E<\/italic>- and <italic>Z<\/italic>- odours lead to different activation patterns in the moth brain.<\/p>\n<p hwp:id=\"p-11\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00421.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00421.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00421.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00421",
"title": "Feeding-induced rearrangement of green leaf volatiles reduces moth oviposition",
"metadata": {
"authors": "S. Allmann, A. Spathe, S. Bisch-Knaden, M. Kallenbach, A. Reinecke, S. Sachse, I. T. Baldwin, B. S. Hansson",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:32:31Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:32:31Z",
"updated_at": "2013-07-25T09:32:31Z"
},
{
"id": 100,
"content": "One of the main roles of the spleen is to make the antibodies that protect the body against viruses, bacteria and other microorganisms. Antibodies are made by B cells, which are a type of white blood cell, after they have been exposed to antigens. For most antibody responses, it is also necessary for the B cells to get help from other white blood cells called T cells that have been exposed to antigens. Specialized cells called dendritic cells have a central role in bringing the antigens\u2014which are usually fragments of the infectious agents that have invaded the body\u2014to the T cells.One subset of dendritic cells, called CD4+ dendritic cells, are found in large numbers in a part of the spleen called the bridging channel, but the process by which these cells become localized in this channel has not been fully understood. Now, Yi and Cyster show that a receptor called EBI2, which is found on the surface of CD4+ dendritic cells, binds to a type of organic molecule called an oxysterol that is produced in the bridging channel.In mice that had been genetically engineered to lack EBI2 or the enzymes needed to make this particular oxysterol\u2014which is known as 7\u03b1,25-dihydroxycholesterol, or 7\u03b1,25-OHC for short\u2014the CD4+ dendritic cells were no longer clustered in the bridging channel and their number was markedly decreased. This showed that the interaction between EBI2 and the oxysterol was essential for ensuring that the CD4+ dendritic cells were in the right place. The correct positioning of the CD4+ dendritic cells was, in turn, necessary for maintaining cell numbers. Moreover, these mice had a weakened immune response because of the very low number of antigens that were being presented to the T cells.A number of autoimmune diseases, such as lupus, are caused by the body developing an immune response to its own cells and tissues. One implication of the work of Yi and Cyster is that if small molecule inhibitors of EBI2 could be designed, they might be able to suppress the onset of such autoimmune responses.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00757.002",
"content_html": "<p hwp:id=\"p-4\">One of the main roles of the spleen is to make the antibodies that protect the body against viruses, bacteria and other microorganisms. Antibodies are made by B cells, which are a type of white blood cell, after they have been exposed to antigens. For most antibody responses, it is also necessary for the B cells to get help from other white blood cells called T cells that have been exposed to antigens. Specialized cells called dendritic cells have a central role in bringing the antigens&#x2014;which are usually fragments of the infectious agents that have invaded the body&#x2014;to the T cells.<\/p>\n<p hwp:id=\"p-5\">One subset of dendritic cells, called CD4<sup>+<\/sup> dendritic cells, are found in large numbers in a part of the spleen called the bridging channel, but the process by which these cells become localized in this channel has not been fully understood. Now, Yi and Cyster show that a receptor called EBI2, which is found on the surface of CD4<sup>+<\/sup> dendritic cells, binds to a type of organic molecule called an oxysterol that is produced in the bridging channel.<\/p>\n<p hwp:id=\"p-6\">In mice that had been genetically engineered to lack EBI2 or the enzymes needed to make this particular oxysterol&#x2014;which is known as 7&#x3B1;,25-dihydroxycholesterol, or 7&#x3B1;,25-OHC for short&#x2014;the CD4<sup>+<\/sup> dendritic cells were no longer clustered in the bridging channel and their number was markedly decreased. This showed that the interaction between EBI2 and the oxysterol was essential for ensuring that the CD4<sup>+<\/sup> dendritic cells were in the right place. The correct positioning of the CD4<sup>+<\/sup> dendritic cells was, in turn, necessary for maintaining cell numbers. Moreover, these mice had a weakened immune response because of the very low number of antigens that were being presented to the T cells.<\/p>\n<p hwp:id=\"p-7\">A number of autoimmune diseases, such as lupus, are caused by the body developing an immune response to its own cells and tissues. One implication of the work of Yi and Cyster is that if small molecule inhibitors of EBI2 could be designed, they might be able to suppress the onset of such autoimmune responses.<\/p>\n<p hwp:id=\"p-8\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00757.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00757.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00757.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00757",
"title": "EBI2-mediated bridging channel positioning supports splenic dendritic cell homeostasis and particulate antigen capture",
"metadata": {
"authors": "T. Yi, J. G. Cyster",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:32:41Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:32:41Z",
"updated_at": "2013-07-25T09:32:41Z"
},
{
"id": 102,
"content": "During evolution, the effect of one mutation on a protein can depend on whether another mutation is also present. This phenomenon is similar to the game in which one word is converted to another word, one letter at a time, subject to the rule that all the intermediate steps are also valid words: for example, the word WORD can be converted to the word GENE as follows: WORD\u2192WORE\u2192GORE\u2192GONE\u2192GENE. In this example, the D must be changed to an E before the W is changed to a G, because GORD is not a valid word.Similarly, during the evolution of a virus, a mutation that helps the virus evade the human immune system might only be tolerated if the virus has acquired another mutation beforehand. This type of mutational interaction would constrain the evolution of the virus, since its capacity to take advantage of the second mutation depends on the first mutation having already occurred.Gong et al. examined whether such interactions have indeed constrained evolution of the influenza virus. Between 1968 and 2007, the nucleoprotein\u2014which acts as a scaffold for the replication of genetic material\u2014in the human H3N2 influenza virus underwent a series of 39 mutations. To test whether all of these mutations could have been tolerated by the 1968 virus, Gong et al. introduced each one individually into the 1968 nucleoprotein. They found that several mutations greatly reduced the fitness of the 1968 virus when introduced on their own, which strongly suggests that these \u2018constrained mutations\u2019 became part of the virus\u2019s genetic makeup as a result of interactions with \u2018enabling\u2019 mutations.The constrained mutations decreased the stability of the nucleoprotein at high temperatures, while the enabling mutations counteracted this effect. It may, therefore, be possible to identify enabling mutations based on their effects on thermal stability. Intriguingly, the constrained mutations helped the virus overcome one form of human immunity to influenza, suggesting that interactions between mutations might limit the rate at which viruses evolve to evade the immune system.Overall, these results show that interactions among mutations constrain the evolution of the influenza nucleoprotein in a fashion that can be largely understood in terms of protein stability. If the same is true for other proteins and viruses, this work could lead to a deeper understanding of the constraints that govern evolution at the molecular level.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00631.002",
"content_html": "<p hwp:id=\"p-4\">During evolution, the effect of one mutation on a protein can depend on whether another mutation is also present. This phenomenon is similar to the game in which one word is converted to another word, one letter at a time, subject to the rule that all the intermediate steps are also valid words: for example, the word WORD can be converted to the word GENE as follows: WORD&#x2192;WORE&#x2192;GORE&#x2192;GONE&#x2192;GENE. In this example, the D must be changed to an E before the W is changed to a G, because GORD is not a valid word.<\/p>\n<p hwp:id=\"p-5\">Similarly, during the evolution of a virus, a mutation that helps the virus evade the human immune system might only be tolerated if the virus has acquired another mutation beforehand. This type of mutational interaction would constrain the evolution of the virus, since its capacity to take advantage of the second mutation depends on the first mutation having already occurred.<\/p>\n<p hwp:id=\"p-6\">Gong et al. examined whether such interactions have indeed constrained evolution of the influenza virus. Between 1968 and 2007, the nucleoprotein&#x2014;which acts as a scaffold for the replication of genetic material&#x2014;in the human H3N2 influenza virus underwent a series of 39 mutations. To test whether all of these mutations could have been tolerated by the 1968 virus, Gong et al. introduced each one individually into the 1968 nucleoprotein. They found that several mutations greatly reduced the fitness of the 1968 virus when introduced on their own, which strongly suggests that these &#x2018;constrained mutations&#x2019; became part of the virus&#x2019;s genetic makeup as a result of interactions with &#x2018;enabling&#x2019; mutations.<\/p>\n<p hwp:id=\"p-7\">The constrained mutations decreased the stability of the nucleoprotein at high temperatures, while the enabling mutations counteracted this effect. It may, therefore, be possible to identify enabling mutations based on their effects on thermal stability. Intriguingly, the constrained mutations helped the virus overcome one form of human immunity to influenza, suggesting that interactions between mutations might limit the rate at which viruses evolve to evade the immune system.<\/p>\n<p hwp:id=\"p-8\">Overall, these results show that interactions among mutations constrain the evolution of the influenza nucleoprotein in a fashion that can be largely understood in terms of protein stability. If the same is true for other proteins and viruses, this work could lead to a deeper understanding of the constraints that govern evolution at the molecular level.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00631.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00631.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00631.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00631",
"title": "Stability-mediated epistasis constrains the evolution of an influenza protein",
"metadata": {
"authors": "L. I. Gong, M. A. Suchard, J. D. Bloom",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:32:47Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:32:47Z",
"updated_at": "2013-07-25T09:32:47Z"
},
{
"id": 103,
"content": "Malaria is one of the world\u2019s most deadly infectious diseases. The most severe form is caused by the parasite Plasmodium falciparum, which can reside within red blood cells and thus evade the human immune system.Plasmodium is transmitted between humans by mosquitoes. When a mosquito takes a blood meal from an individual infected with the parasite, the insect ingests Plasmodium gametocytes (i.e., eggs and sperm), and these go on to reproduce in the gut of the mosquito. These parasites then move to the mosquito\u2019s salivary glands, to be injected into the next person whom the mosquito bites.Although malaria is both preventable and curable, the mortality rates in many African countries remain high, especially among children. Reducing the transmission of malaria to mosquitoes is one of the primary goals in the global effort to control and eliminate the disease. While a range of drugs and vaccines that specifically try to reduce transmission are in development, non-medical interventions such as mosquito nets and insecticide spraying can quickly and effectively reduce infection rates.Here, Churcher et al. examine the dynamics of human to mosquito transmission of P. falciparum, and report that the ease with which mosquitoes become infected is not directly proportional to the density of parasite gametocytes in human blood. They found that the transmission occurs readily at very low gametocyte densities. Moreover, the transmission rate remains relatively stable as the density increases, before increasing significantly when the density reaches around 200 cells per microlitre.Churcher et al. also challenge the assumption that children are mostly responsible for transmitting the malaria parasite by suggesting that, in certain locations, there is a more significant role for adults than previously assumed. By identifying the groups that contribute most to transmission, and targeting resources to reduce gametocyte density in those individuals, it could be possible to greatly reduce the number of infected mosquitoes and, therefore, the number of infected humans.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00626.002",
"content_html": "<p hwp:id=\"p-4\">Malaria is one of the world&#x2019;s most deadly infectious diseases. The most severe form is caused by the parasite <italic>Plasmodium falciparum<\/italic>, which can reside within red blood cells and thus evade the human immune system.<\/p>\n<p hwp:id=\"p-5\"><italic>Plasmodium<\/italic> is transmitted between humans by mosquitoes. When a mosquito takes a blood meal from an individual infected with the parasite, the insect ingests <italic>Plasmodium<\/italic> gametocytes (i.e., eggs and sperm), and these go on to reproduce in the gut of the mosquito. These parasites then move to the mosquito&#x2019;s salivary glands, to be injected into the next person whom the mosquito bites.<\/p>\n<p hwp:id=\"p-6\">Although malaria is both preventable and curable, the mortality rates in many African countries remain high, especially among children. Reducing the transmission of malaria to mosquitoes is one of the primary goals in the global effort to control and eliminate the disease. While a range of drugs and vaccines that specifically try to reduce transmission are in development, non-medical interventions such as mosquito nets and insecticide spraying can quickly and effectively reduce infection rates.<\/p>\n<p hwp:id=\"p-7\">Here, Churcher et al. examine the dynamics of human to mosquito transmission of <italic>P. falciparum<\/italic>, and report that the ease with which mosquitoes become infected is not directly proportional to the density of parasite gametocytes in human blood. They found that the transmission occurs readily at very low gametocyte densities. Moreover, the transmission rate remains relatively stable as the density increases, before increasing significantly when the density reaches around 200 cells per microlitre.<\/p>\n<p hwp:id=\"p-8\">Churcher et al. also challenge the assumption that children are mostly responsible for transmitting the malaria parasite by suggesting that, in certain locations, there is a more significant role for adults than previously assumed. By identifying the groups that contribute most to transmission, and targeting resources to reduce gametocyte density in those individuals, it could be possible to greatly reduce the number of infected mosquitoes and, therefore, the number of infected humans.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00626.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00626.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00626.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00626",
"title": "Predicting mosquito infection from Plasmodium falciparum gametocyte density and estimating the reservoir of infection",
"metadata": {
"authors": "T. S. Churcher, T. Bousema, M. Walker, C. Drakeley, P. Schneider, A. L. Ouedraogo, M.-G. Basanez",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:32:51Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:32:51Z",
"updated_at": "2013-07-25T09:32:51Z"
},
{
"id": 104,
"content": "Hematopoietic stem cells are cells that both renew themselves and develop into any type of blood cell, including red blood cells and the several classes of immune cells. When an injury or infection occurs, it is vital that hematopoietic stem cells replenish themselves in addition to developing into the new blood cells that are needed to help the body recover. Injury and infection also lead to the inflammatory response: tissue becomes inflamed as cytokines and other molecules are released at the site of the damage to help maintain the body\u2019s immunity. It is thought that inflammatory molecules directly affect the rate at which stem cells become immune cells, with the protein NF-\u03baB having an important role, but the details of this process are not fully understood.To explore the connections between hematopoietic stem cells and the inflammatory response, Zhao et al. bred mice that do not produce a type of RNA called microRNA-146a. In wild-type mice, this RNA would inhibit the production of NF-\u03baB, so the mutant mice have abnormally high levels of NF-\u03baB. They found that the rate at which stem cells were being converted into immune cells in the mutant mice was so high that the stores of stems cells became exhausted, which was very detrimental to the health of the mice. They also went on to identify the signaling pathways that microRNA-146a influences in order to maintain supplies of stem cells and an adequate inflammatory response in healthy mice.Zhao et al. also studied individuals with human myelodysplastic syndrome, a severe blood disorder that is associated with faulty hematopoietic stem cells, and found that these individuals produce relatively little microRNA-146a. The establishment of a link between microRNA-146a and having an adequate level of hematopoietic stem cells could have implications for human health, given the importance of these cells in both the aging process and the immune response.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00537.002",
"content_html": "<p hwp:id=\"p-4\">Hematopoietic stem cells are cells that both renew themselves and develop into any type of blood cell, including red blood cells and the several classes of immune cells. When an injury or infection occurs, it is vital that hematopoietic stem cells replenish themselves in addition to developing into the new blood cells that are needed to help the body recover. Injury and infection also lead to the inflammatory response: tissue becomes inflamed as cytokines and other molecules are released at the site of the damage to help maintain the body&#x2019;s immunity. It is thought that inflammatory molecules directly affect the rate at which stem cells become immune cells, with the protein NF-&#x3BA;B having an important role, but the details of this process are not fully understood.<\/p>\n<p hwp:id=\"p-5\">To explore the connections between hematopoietic stem cells and the inflammatory response, Zhao et al. bred mice that do not produce a type of RNA called microRNA-146a. In wild-type mice, this RNA would inhibit the production of NF-&#x3BA;B, so the mutant mice have abnormally high levels of NF-&#x3BA;B. They found that the rate at which stem cells were being converted into immune cells in the mutant mice was so high that the stores of stems cells became exhausted, which was very detrimental to the health of the mice. They also went on to identify the signaling pathways that microRNA-146a influences in order to maintain supplies of stem cells and an adequate inflammatory response in healthy mice.<\/p>\n<p hwp:id=\"p-6\">Zhao et al. also studied individuals with human myelodysplastic syndrome, a severe blood disorder that is associated with faulty hematopoietic stem cells, and found that these individuals produce relatively little microRNA-146a. The establishment of a link between microRNA-146a and having an adequate level of hematopoietic stem cells could have implications for human health, given the importance of these cells in both the aging process and the immune response.<\/p>\n<p hwp:id=\"p-7\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00537.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00537.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00537.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00537",
"title": "MicroRNA-146a acts as a guardian of the quality and longevity of hematopoietic stem cells in mice",
"metadata": {
"authors": "J. L. Zhao, D. S. Rao, R. M. O'Connell, Y. Garcia-Flores, D. Baltimore",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:32:54Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:32:54Z",
"updated_at": "2013-07-25T09:32:54Z"
},
{
"id": 105,
"content": "Animals require nutrients, including carbohydrates, lipids, and amino acids, for development and growth, and to maintain the normal functioning of cells. However, in most natural environments, the availability of food tends to fluctuate. Some animals have therefore acquired the ability to dramatically reduce their metabolic activity, and thus their energy and nutrient needs to survive fasting conditions.Caenorhabditis elegans is a transparent nematode worm that is used extensively as a model organism. When C. elegans larvae hatch in a food-free environment, they enter a quiescent state in which they suspend growth and cell division to conserve energy. However, the mechanisms that underlie this ability are not fully understood.Here, Zhu et al. reveal that a type of lipid called a sphingolipid is required for C. elegans larvae to begin postembryonic development. When this lipid is absent in the environment and not synthesized internally, the larvae remain in a state of arrested development, which can be overcome by resupplying the lipid. Zhu et al. show that the lipid acts through a signaling pathway involving an enzyme complex called TORC1 and that the effect of the lipid can be blocked by another protein complex called NPRL-2\/3. TORC1 is well known for its role in sensing amino acids and growth factors, but this is the first time that it has been shown to be involved in detecting lipids. Strikingly, Zhu et al. also show that, in the absence of the lipid, postembryonic growth and development can be initiated by activating TORC1 or inhibiting NPRL-2\/3.The work of Zhu et al. thus reveals a novel regulatory function of a specific fatty acid and sphingolipid variant that is used by C. elegans to coordinate its growth and development with its metabolic status or the availability of nutrients. Since all components of the pathway are conserved in mammals, the results could help to improve our understanding of how caloric restriction influences human health and aging.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00429.002",
"content_html": "<p hwp:id=\"p-4\">Animals require nutrients, including carbohydrates, lipids, and amino acids, for development and growth, and to maintain the normal functioning of cells. However, in most natural environments, the availability of food tends to fluctuate. Some animals have therefore acquired the ability to dramatically reduce their metabolic activity, and thus their energy and nutrient needs to survive fasting conditions.<\/p>\n<p hwp:id=\"p-5\"><italic>Caenorhabditis elegans<\/italic> is a transparent nematode worm that is used extensively as a model organism. When <italic>C. elegans<\/italic> larvae hatch in a food-free environment, they enter a quiescent state in which they suspend growth and cell division to conserve energy. However, the mechanisms that underlie this ability are not fully understood.<\/p>\n<p hwp:id=\"p-6\">Here, Zhu et al. reveal that a type of lipid called a sphingolipid is required for <italic>C. elegans<\/italic> larvae to begin postembryonic development. When this lipid is absent in the environment and not synthesized internally, the larvae remain in a state of arrested development, which can be overcome by resupplying the lipid. Zhu et al. show that the lipid acts through a signaling pathway involving an enzyme complex called TORC1 and that the effect of the lipid can be blocked by another protein complex called NPRL-2\/3. TORC1 is well known for its role in sensing amino acids and growth factors, but this is the first time that it has been shown to be involved in detecting lipids. Strikingly, Zhu et al. also show that, in the absence of the lipid, postembryonic growth and development can be initiated by activating TORC1 or inhibiting NPRL-2\/3.<\/p>\n<p hwp:id=\"p-7\">The work of Zhu et al. thus reveals a novel regulatory function of a specific fatty acid and sphingolipid variant that is used by <italic>C. elegans<\/italic> to coordinate its growth and development with its metabolic status or the availability of nutrients. Since all components of the pathway are conserved in mammals, the results could help to improve our understanding of how caloric restriction influences human health and aging.<\/p>\n<p hwp:id=\"p-8\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00429.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00429.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00429.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00429",
"title": "A novel sphingolipid-TORC1 pathway critically promotes postembryonic development in Caenorhabditis elegans",
"metadata": {
"authors": "H. Zhu, H. Shen, A. K. Sewell, M. Kniazeva, M. Han",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:32:59Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:32:59Z",
"updated_at": "2013-07-25T09:32:59Z"
},
{
"id": 106,
"content": "The deadly toxins produced by many creatures, including spiders, snakes, and scorpions, work by blocking the ion channels that are essential for the normal operation of many different types of cells. Ion channels are proteins and, as their name suggests, they allow ions\u2014usually sodium, potassium, or calcium ions\u2014to move in and out of cells. They are especially important for cells that generate or respond to electrical signals, such as neurons and the cells in heart muscle.Ion channels are located in the lipid membranes that surround all cells, and the ions enter or leave the cell via a pore that runs through the channel protein. They can be opened and closed (or \u2018gated\u2019) in different ways: some ion channels open and close in response to voltages, whereas others are gated by biomolecules, such as neurotransmitters, that bind to them.Now, Banerjee et al. have used x-ray crystallography to study the structure of the complex that is formed when charybdotoxin (CTX), a toxin that is found in scorpion venom, blocks a voltage-gated potassium channel. Previous studies have shown that CTX binds to the channel on the extracellular side of the pore. Banerjee et al. show that the toxin fits into the entrance to the channel like a key into a lock, which means the toxin is preformed to fit the shape of the channel.The potassium ion channel is made up of four subunits, and the pore contains four ion-binding sites that form a \u2018selectivity filter\u2019: it is this filter that ensures that only potassium ions can pass through the channel when it is open. When CTX binds to the channel, a lysine residue poised at a critical position on the toxin is so close to the outermost ion-binding site that it prevents potassium ions binding to the site. The structure determined by Banerjee et al. explains many previous findings, including the fact that ions entering the pore from inside the cell can disrupt the binding between the toxin and the ion channel protein. It remains to be seen if the toxins that target the pore of other types of ion channels work in the same way.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00594.002",
"content_html": "<p hwp:id=\"p-5\">The deadly toxins produced by many creatures, including spiders, snakes, and scorpions, work by blocking the ion channels that are essential for the normal operation of many different types of cells. Ion channels are proteins and, as their name suggests, they allow ions&#x2014;usually sodium, potassium, or calcium ions&#x2014;to move in and out of cells. They are especially important for cells that generate or respond to electrical signals, such as neurons and the cells in heart muscle.<\/p>\n<p hwp:id=\"p-6\">Ion channels are located in the lipid membranes that surround all cells, and the ions enter or leave the cell via a pore that runs through the channel protein. They can be opened and closed (or &#x2018;gated&#x2019;) in different ways: some ion channels open and close in response to voltages, whereas others are gated by biomolecules, such as neurotransmitters, that bind to them.<\/p>\n<p hwp:id=\"p-7\">Now, Banerjee et al. have used x-ray crystallography to study the structure of the complex that is formed when charybdotoxin (CTX), a toxin that is found in scorpion venom, blocks a voltage-gated potassium channel. Previous studies have shown that CTX binds to the channel on the extracellular side of the pore. Banerjee et al. show that the toxin fits into the entrance to the channel like a key into a lock, which means the toxin is preformed to fit the shape of the channel.<\/p>\n<p hwp:id=\"p-8\">The potassium ion channel is made up of four subunits, and the pore contains four ion-binding sites that form a &#x2018;selectivity filter&#x2019;: it is this filter that ensures that only potassium ions can pass through the channel when it is open. When CTX binds to the channel, a lysine residue poised at a critical position on the toxin is so close to the outermost ion-binding site that it prevents potassium ions binding to the site. The structure determined by Banerjee et al. explains many previous findings, including the fact that ions entering the pore from inside the cell can disrupt the binding between the toxin and the ion channel protein. It remains to be seen if the toxins that target the pore of other types of ion channels work in the same way.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00594.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00594.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00594.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00594",
"title": "Structure of a pore-blocking toxin in complex with a eukaryotic voltage-dependent K+ channel",
"metadata": {
"authors": "A. Banerjee, A. Lee, E. Campbell, R. MacKinnon",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:33:01Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:33:01Z",
"updated_at": "2013-07-25T09:33:01Z"
},
{
"id": 107,
"content": "Goblet cells are specialized cells that produce proteins called mucins, which combine with water, salt and other proteins to form mucus, the slippery fluid that protects the respiratory and digestive tracts from bacteria, viruses and other pathogens. However, a defect in the production of one particular type of mucin\u2014Mucin 5AC\u2014can result in diseases such as cystic fibrosis, chronic obstructive pulmonary disease and Crohn\u2019s disease, so there is a clear need to understand the production of mucus in detail.Before they are secreted, the mucins are packaged inside granules in the goblet cells. When a certain extracellular signal arrives at a goblet cell, these granules move through the cell, fuse with the cell membrane and release the mucins, which then expand their volume by a factor of up to a 1000. Calcium ions (Ca2+) have a critical role in the signal that leads to the secretion of mucins, but many details about the signalling and secretion processes are poorly understood.Now, Mitrovic et al. have used genetic methods to study 7343 gene products in goblet cells derived from a human colon. They identified 16 new proteins that are involved in the secretion of Mucin 5AC, including a channel protein called TRPM5. This protein is activated when the concentration of Ca2+ inside the cell increases, and its activation allows sodium (Na+) ions to enter the cells. These intracellular Na+ ions are then exchanged for Ca2+ ions from outside the cell, and these Ca2+ ions then couple to the molecular machinery that is responsible for the secretion of the mucins.By using electrophysiological and Ca2+ imaging approaches, Mitrovic et al. were able to visualize and measure TRPM5-mediated Na+ currents and the subsequent Ca2+ uptake by the cells, and confirmed that extracellular Ca2+ ions were responsible for stimulating the secretion of mucins. The next step is to determine how the other 15 genes are involved in mucin secretion and, in the longer term, explore how these insights might be translated into treatments for cystic fibrosis and other conditions associated with defective mucus secretion.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00658.002",
"content_html": "<p hwp:id=\"p-6\">Goblet cells are specialized cells that produce proteins called mucins, which combine with water, salt and other proteins to form mucus, the slippery fluid that protects the respiratory and digestive tracts from bacteria, viruses and other pathogens. However, a defect in the production of one particular type of mucin&#x2014;Mucin 5AC&#x2014;can result in diseases such as cystic fibrosis, chronic obstructive pulmonary disease and Crohn&#x2019;s disease, so there is a clear need to understand the production of mucus in detail.<\/p>\n<p hwp:id=\"p-7\">Before they are secreted, the mucins are packaged inside granules in the goblet cells. When a certain extracellular signal arrives at a goblet cell, these granules move through the cell, fuse with the cell membrane and release the mucins, which then expand their volume by a factor of up to a 1000. Calcium ions (Ca<sup>2+<\/sup>) have a critical role in the signal that leads to the secretion of mucins, but many details about the signalling and secretion processes are poorly understood.<\/p>\n<p hwp:id=\"p-8\">Now, Mitrovic et al. have used genetic methods to study 7343 gene products in goblet cells derived from a human colon. They identified 16 new proteins that are involved in the secretion of Mucin 5AC, including a channel protein called TRPM5. This protein is activated when the concentration of Ca<sup>2+<\/sup> inside the cell increases, and its activation allows sodium (Na<sup>+<\/sup>) ions to enter the cells. These intracellular Na<sup>+<\/sup> ions are then exchanged for Ca<sup>2+<\/sup> ions from outside the cell, and these Ca<sup>2+<\/sup> ions then couple to the molecular machinery that is responsible for the secretion of the mucins.<\/p>\n<p hwp:id=\"p-9\">By using electrophysiological and Ca<sup>2+<\/sup> imaging approaches, Mitrovic et al. were able to visualize and measure TRPM5-mediated Na<sup>+<\/sup> currents and the subsequent Ca<sup>2+<\/sup> uptake by the cells, and confirmed that extracellular Ca<sup>2+<\/sup> ions were responsible for stimulating the secretion of mucins. The next step is to determine how the other 15 genes are involved in mucin secretion and, in the longer term, explore how these insights might be translated into treatments for cystic fibrosis and other conditions associated with defective mucus secretion.<\/p>\n<p hwp:id=\"p-10\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00658.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00658.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00658.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00658",
"title": "TRPM5-mediated calcium uptake regulates mucin secretion from human colon goblet cells",
"metadata": {
"authors": "S. Mitrovic, C. Nogueira, G. Cantero-Recasens, K. Kiefer, J. M. Fernandez-Fernandez, J.-F. Popoff, L. Casano, F. A. Bard, R. Gomez, M. A. Valverde, V. Malhotra",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:33:04Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:33:04Z",
"updated_at": "2013-07-25T09:33:04Z"
},
{
"id": 108,
"content": "During many cellular processes, the double helix must be transiently unwound so that the enzymes responsible for maintaining the genome can access the two strands. During DNA synthesis, for instance, the two strands of DNA are first separated and then used as templates for the production of new strands. The role of destabilizing, separating and unwinding the double helix falls to enzymes known as DNA helicases.Helicases are also involved in separating strands of nucleic acids during myriad other cellular processes, including DNA repair, transcription and translation. While the functions of helicases are clear, the precise mechanisms by which they unwind DNA are not.Here, Qi et al. have investigated the mechanism of a helicase called XPD, which is involved in DNA repair and the initiation of transcription of DNA into RNA. Using optical tweezers\u2014in which a laser beam is used to exert extremely small forces on a single DNA molecule\u2014they followed the activity of individual molecules of XPD as they unwound DNA with base pair resolution.Qi et al. observed that the helicase unwinds DNA strands 1 base pair at a time, but that it sometimes moves backwards by 1 base pair and at other times makes 5 base pair backward and forward steps. The frequency of these backwards steps depends on the availability of ATP, and the sequence of the DNA. Due to the high resolution of the data, Qi et al. were able to correlate these stepping dynamics with the DNA sequence with base pair level accuracy. While some helicases actively separate the strands, using energy derived from ATP to break the hydrogen bonds between pairs of bases, Qi et al. showed that XPD appears to take advantage of momentary separations that arise spontaneously between base pairs.As well as providing insights into the role of XPD in DNA repair and transcription, the work of Qi et al. presents a method that could be used to explore the mechanisms of other helicases. Given that the unwinding mechanism described here is likely to be a universal feature of enzymes related to XPD, the current work could shed light on a number of other cellular processes involving XPD-like helicases, such as homologous DNA recombination, inter-strand cross-link repair, and accurate chromosome segregation.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00334.002",
"content_html": "<p hwp:id=\"p-4\">During many cellular processes, the double helix must be transiently unwound so that the enzymes responsible for maintaining the genome can access the two strands. During DNA synthesis, for instance, the two strands of DNA are first separated and then used as templates for the production of new strands. The role of destabilizing, separating and unwinding the double helix falls to enzymes known as DNA helicases.<\/p>\n<p hwp:id=\"p-5\">Helicases are also involved in separating strands of nucleic acids during myriad other cellular processes, including DNA repair, transcription and translation. While the functions of helicases are clear, the precise mechanisms by which they unwind DNA are not.<\/p>\n<p hwp:id=\"p-6\">Here, Qi et al. have investigated the mechanism of a helicase called XPD, which is involved in DNA repair and the initiation of transcription of DNA into RNA. Using optical tweezers&#x2014;in which a laser beam is used to exert extremely small forces on a single DNA molecule&#x2014;they followed the activity of individual molecules of XPD as they unwound DNA with base pair resolution.<\/p>\n<p hwp:id=\"p-7\">Qi et al. observed that the helicase unwinds DNA strands 1 base pair at a time, but that it sometimes moves backwards by 1 base pair and at other times makes 5 base pair backward and forward steps. The frequency of these backwards steps depends on the availability of ATP, and the sequence of the DNA. Due to the high resolution of the data, Qi et al. were able to correlate these stepping dynamics with the DNA sequence with base pair level accuracy. While some helicases actively separate the strands, using energy derived from ATP to break the hydrogen bonds between pairs of bases, Qi et al. showed that XPD appears to take advantage of momentary separations that arise spontaneously between base pairs.<\/p>\n<p hwp:id=\"p-8\">As well as providing insights into the role of XPD in DNA repair and transcription, the work of Qi et al. presents a method that could be used to explore the mechanisms of other helicases. Given that the unwinding mechanism described here is likely to be a universal feature of enzymes related to XPD, the current work could shed light on a number of other cellular processes involving XPD-like helicases, such as homologous DNA recombination, inter-strand cross-link repair, and accurate chromosome segregation.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00334.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00334.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00334.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00334",
"title": "Sequence-dependent base pair stepping dynamics in XPD helicase unwinding",
"metadata": {
"authors": "Z. Qi, R. A. Pugh, M. Spies, Y. R. Chemla",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:33:09Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:33:09Z",
"updated_at": "2013-07-25T09:33:09Z"
},
{
"id": 109,
"content": "The synthesis of proteins is an essential step in many biological processes, including memory, and drugs that inhibit protein synthesis are known to impair memory in rodents. It is thought that the brain needs these proteins to convert short-term memories into long-term memories through a process known as consolidation.A protein called EIF2\u03b1 has a key role in the regulation of protein synthesis, and has also been implicated in memory. EIF2\u03b1 can be activated as a result of being phosphorylated by any of four protein kinases: these are in turn activated by processes that subject cells to stress, such as viral infection, UV light or\u2014in the case of a kinase known as PERK\u2014the accumulation of unfolded proteins in a cellular organelle called the endoplasmic reticulum. Activation of EIF2\u03b1 downregulates most protein synthesis inside the cell, but upregulates the production of a small number of key regulatory molecules: these changes help cells to cope with whatever stressful event they have just experienced.To obtain further insight into the cellular stress response, Sidrauski et al. screened a large library of compounds in search of one that inhibits PERK. They identified a molecule\u2014known as ISRIB\u2014which acts downstream of all four protein kinases by reversing the effects of EIF2\u03b1 phosphorylation. ISRIB is the first molecule shown to have this effect, and thus represents an important tool for investigating the stress response inside cells.When Sidrauski et al. injected ISRIB into mice, the animals showed improved memory: for example, they learnt to locate a hidden platform in a water maze more rapidly than controls. This suggests that ISRIB could be used to explore the mechanisms that underlie memory consolidation, and possibly even as a memory enhancer. Moreover, given that many tumor cells exploit the cellular stress response to aid their own growth, ISRIB may have potential as a novel chemotherapeutic agent.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00498.002",
"content_html": "<p hwp:id=\"p-4\">The synthesis of proteins is an essential step in many biological processes, including memory, and drugs that inhibit protein synthesis are known to impair memory in rodents. It is thought that the brain needs these proteins to convert short-term memories into long-term memories through a process known as consolidation.<\/p>\n<p hwp:id=\"p-5\">A protein called EIF2&#x3B1; has a key role in the regulation of protein synthesis, and has also been implicated in memory. EIF2&#x3B1; can be activated as a result of being phosphorylated by any of four protein kinases: these are in turn activated by processes that subject cells to stress, such as viral infection, UV light or&#x2014;in the case of a kinase known as PERK&#x2014;the accumulation of unfolded proteins in a cellular organelle called the endoplasmic reticulum. Activation of EIF2&#x3B1; downregulates most protein synthesis inside the cell, but upregulates the production of a small number of key regulatory molecules: these changes help cells to cope with whatever stressful event they have just experienced.<\/p>\n<p hwp:id=\"p-6\">To obtain further insight into the cellular stress response, Sidrauski et al. screened a large library of compounds in search of one that inhibits PERK. They identified a molecule&#x2014;known as ISRIB&#x2014;which acts downstream of all four protein kinases by reversing the effects of EIF2&#x3B1; phosphorylation. ISRIB is the first molecule shown to have this effect, and thus represents an important tool for investigating the stress response inside cells.<\/p>\n<p hwp:id=\"p-7\">When Sidrauski et al. injected ISRIB into mice, the animals showed improved memory: for example, they learnt to locate a hidden platform in a water maze more rapidly than controls. This suggests that ISRIB could be used to explore the mechanisms that underlie memory consolidation, and possibly even as a memory enhancer. Moreover, given that many tumor cells exploit the cellular stress response to aid their own growth, ISRIB may have potential as a novel chemotherapeutic agent.<\/p>\n<p hwp:id=\"p-8\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00498.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00498.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00498.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00498",
"title": "Pharmacological brake-release of mRNA translation enhances cognitive memory",
"metadata": {
"authors": "C. Sidrauski, D. Acosta-Alvear, A. Khoutorsky, P. Vedantham, B. R. Hearn, H. Li, K. Gamache, C. M. Gallagher, K. K.-H. Ang, C. Wilson, V. Okreglak, A. Ashkenazi, B. Hann, K. Nader, M. R. Arkin, A. R. Renslo, N. Sonenberg, P. Walter",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:33:15Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:33:15Z",
"updated_at": "2013-07-25T09:33:15Z"
},
{
"id": 110,
"content": "The use of tools is a key characteristic of primates. Chimpanzees\u2014our closest living relatives\u2014use sticks to probe for termites as well as stones to crack open nuts, and have even been seen using specially sharpened sticks as spear-like tools for hunting. However, despite its importance in human evolution, relatively little is known about how tool use is supported by the brain.One possibility is that the brain areas involved in controlling hand movements may also begin to incorporate the use of tools. Another is that distinct brain areas evolved to enable tool use. To test these ideas, Gallivan et al. scanned the brains of human subjects as they reached towards and grasped an object using either their right hand or a set of tongs. The tongs had been designed so that they opened whenever the subjects closed their grip, thereby requiring subjects to perform a different set of movements to use the tongs as opposed to their hand alone.Three distinct patterns of brain activity were observed. First, areas previously linked to the processing of hand movements and the human body were found to represent actions of the hand alone (and not those of the tool), whereas areas previously linked to the processing of tools and tool-related actions represented actions of the tool alone (and not those of the hand). Second, areas of motor cortex implicated in the generation of movement represented actions performed with both the hand and the tool, but showed distinct activity patterns according to which of these was to be used.Lastly, areas associated with high-level cognitive and action-related processing showed similar patterns of activity regardless of whether the subjects were about to use the tongs or just their hand. Given that use of the hand and tool required distinct patterns of muscle contractions, this suggests that these higher-level brain regions must be encoding the action itself rather than the movements needed to achieve it.This study is one of the first to use functional neuroimaging to examine real as opposed to simulated tool use, and increases our understanding of the neural basis of tool use in humans. This knowledge could ultimately have applications for the development of brain-machine interfaces, in which electrodes implanted in motor regions of the brain are used to control prosthetic limbs.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00425.002",
"content_html": "<p hwp:id=\"p-4\">The use of tools is a key characteristic of primates. Chimpanzees&#x2014;our closest living relatives&#x2014;use sticks to probe for termites as well as stones to crack open nuts, and have even been seen using specially sharpened sticks as spear-like tools for hunting. However, despite its importance in human evolution, relatively little is known about how tool use is supported by the brain.<\/p>\n<p hwp:id=\"p-5\">One possibility is that the brain areas involved in controlling hand movements may also begin to incorporate the use of tools. Another is that distinct brain areas evolved to enable tool use. To test these ideas, Gallivan et al. scanned the brains of human subjects as they reached towards and grasped an object using either their right hand or a set of tongs. The tongs had been designed so that they opened whenever the subjects closed their grip, thereby requiring subjects to perform a different set of movements to use the tongs as opposed to their hand alone.<\/p>\n<p hwp:id=\"p-6\">Three distinct patterns of brain activity were observed. First, areas previously linked to the processing of hand movements and the human body were found to represent actions of the hand alone (and not those of the tool), whereas areas previously linked to the processing of tools and tool-related actions represented actions of the tool alone (and not those of the hand). Second, areas of motor cortex implicated in the generation of movement represented actions performed with both the hand and the tool, but showed distinct activity patterns according to which of these was to be used.<\/p>\n<p hwp:id=\"p-7\">Lastly, areas associated with high-level cognitive and action-related processing showed similar patterns of activity regardless of whether the subjects were about to use the tongs or just their hand. Given that use of the hand and tool required distinct patterns of muscle contractions, this suggests that these higher-level brain regions must be encoding the action itself rather than the movements needed to achieve it.<\/p>\n<p hwp:id=\"p-8\">This study is one of the first to use functional neuroimaging to examine real as opposed to simulated tool use, and increases our understanding of the neural basis of tool use in humans. This knowledge could ultimately have applications for the development of brain-machine interfaces, in which electrodes implanted in motor regions of the brain are used to control prosthetic limbs.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00425.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00425.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00425.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00425",
"title": "Decoding the neural mechanisms of human tool use",
"metadata": {
"authors": "J. P. Gallivan, D. A. McLean, K. F. Valyear, J. C. Culham",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:33:18Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:33:18Z",
"updated_at": "2013-07-25T09:33:18Z"
},
{
"id": 111,
"content": "Few crop failures have been as devastating as those caused by potato late blight in the 1840s. This disease is caused by a filamentous microbe called Phytophthora infestans, which spread from North America to Europe in 1845, leading to the Great Famine in Ireland and to severe crop losses in the rest of Europe. Phytophthora is thought to have originated in the Toluca valley of Mexico, where many different strains evolve alongside wild potato relatives, but the exact strain that caused the Great Famine, and how it is related to modern strains of the pathogen, has remained a mystery.Yoshida et al. have used a technique call \u2018shotgun\u2019 sequencing to map the genomes of 11 historical strains of P. infestans and 15 modern strains. The historical strains were extracted from the leaves of potato and tomato plants that were collected in North America and Europe, including Ireland and Great Britain, from 1845 onwards and stored in herbaria for future research. By comparing the genomes of the historical and modern samples, Yoshida et al. found that the historical strains all belonged to a single lineage that shows very little genetic diversity.Previously it has been proposed that this lineage was the same as US-1, which was the dominant strain of potato blight in the world until the end of the 1970s, or that it was more closely related to modern strains than to US-1. Yoshida et al. now rule out both of these possibilities and show that the lineage that caused the great famine, which they call HERB-1, is clearly distinct from US-1, although they are closely related, and they conclude that both HERB-1 and US-1 might have dispersed from a common ancestor that existed outside of Mexico in the early 1800s. Why US-1 later replaced HERB-1 as the dominant strain in the world is an important question for future studies.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00731.002",
"content_html": "<p hwp:id=\"p-6\">Few crop failures have been as devastating as those caused by potato late blight in the 1840s. This disease is caused by a filamentous microbe called <italic>Phytophthora infestans,<\/italic> which spread from North America to Europe in 1845, leading to the Great Famine in Ireland and to severe crop losses in the rest of Europe. <italic>Phytophthora<\/italic> is thought to have originated in the Toluca valley of Mexico, where many different strains evolve alongside wild potato relatives, but the exact strain that caused the Great Famine, and how it is related to modern strains of the pathogen, has remained a mystery.<\/p>\n<p hwp:id=\"p-7\">Yoshida et al. have used a technique call &#x2018;shotgun&#x2019; sequencing to map the genomes of 11 historical strains of <italic>P. infestans<\/italic> and 15 modern strains. The historical strains were extracted from the leaves of potato and tomato plants that were collected in North America and Europe, including Ireland and Great Britain, from 1845 onwards and stored in herbaria for future research. By comparing the genomes of the historical and modern samples, Yoshida et al. found that the historical strains all belonged to a single lineage that shows very little genetic diversity.<\/p>\n<p hwp:id=\"p-8\">Previously it has been proposed that this lineage was the same as US-1, which was the dominant strain of potato blight in the world until the end of the 1970s, or that it was more closely related to modern strains than to US-1. Yoshida et al. now rule out both of these possibilities and show that the lineage that caused the great famine, which they call HERB-1, is clearly distinct from US-1, although they are closely related, and they conclude that both HERB-1 and US-1 might have dispersed from a common ancestor that existed outside of Mexico in the early 1800s. Why US-1 later replaced HERB-1 as the dominant strain in the world is an important question for future studies.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00731.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00731.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00731.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00731",
"title": "The rise and fall of the Phytophthora infestans lineage that triggered the Irish potato famine",
"metadata": {
"authors": "K. Yoshida, V. J. Schuenemann, L. M. Cano, M. Pais, B. Mishra, R. Sharma, C. Lanz, F. N. Martin, S. Kamoun, J. Krause, M. Thines, D. Weigel, H. A. Burbano",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:33:21Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:33:21Z",
"updated_at": "2013-07-25T09:33:21Z"
},
{
"id": 112,
"content": "Mitochondria are tiny organelles, less than a micrometre across, found inside almost all eukaryotic cells. Their main function is to act as the \u2018power plant\u2019 of the cell, generating adenosine triphosphate or ATP, which is the source of chemical energy for cellular processes. Beyond generating ATP, mitochondria perform many other functions: they contribute to various signalling pathways; they influence cellular differentiation; and they are involved in processes related to cell death.Mitochondria are quite distinctive in appearance\u2014they are enclosed by two membranes, a porous outer one and a largely impermeable inner membrane. Most mitochondrial functions involve proteins that control the movement of various molecules and ions across the inner membrane. One particularly important ion that must pass through this membrane is calcium; once inside the mitochondria, these calcium ions regulate cell survival and the generation of ATP.Although several calcium import mechanisms exist, the best-studied pathway involves a pore-forming protein complex called the mitochondrial calcium uniporter. This ion channel has an exquisite selectivity, allowing only calcium into mitochondria even when other ions outnumber it a million-fold. Previously, researchers had identified several genes that are required for the formation of the uniporter, but it had not been established which of these encodes the central pore through which the calcium ions pass. Now, Chaudhuri et al. have shown that one of these\u2014a gene called mitochondrial calcium uniporter (MCU)\u2014codes for the protein subunit that creates the pore.Prior studies used optical methods or purified proteins to study genes encoding the uniporter complex, producing controversial results regarding pore identity. This study uses a much more direct assay, namely electrophysiology performed on mitochondrial inner membranes. To access the inner membrane, the authors stripped off the outer membrane from whole mitochondria, and made them expand. By using a technique called voltage-clamping, Chaudhuri et al. were able to precisely measure calcium ion movement through intact or mutated channels. This technique controls confounding factors and minimizes the effect of contaminants that can plague interpretation of data acquired by other methods. They showed that blocking the expression of the MCU gene reduced the flow of calcium ions through the uniporter, whereas increasing MCU expression increased calcium transport.One unique feature of the mitochondrial calcium uniporter is that it can be blocked by a dye called ruthenium red. Chaudhuri et al. used this property to confirm that the MCU gene encodes the pore-forming subunit of the channel complex\u2014they identified a single point mutation in MCU that did not affect the channel\u2019s ability to transport calcium ions, but did abolish its sensitivity to ruthenium red. Together, these results show that the MCU gene encodes the pore of the mitochondrial calcium uniporter, and should lead to further research into the physiology and structure of this channel.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00704.002",
"content_html": "<p hwp:id=\"p-4\">Mitochondria are tiny organelles, less than a micrometre across, found inside almost all eukaryotic cells. Their main function is to act as the &#x2018;power plant&#x2019; of the cell, generating adenosine triphosphate or ATP, which is the source of chemical energy for cellular processes. Beyond generating ATP, mitochondria perform many other functions: they contribute to various signalling pathways; they influence cellular differentiation; and they are involved in processes related to cell death.<\/p>\n<p hwp:id=\"p-5\">Mitochondria are quite distinctive in appearance&#x2014;they are enclosed by two membranes, a porous outer one and a largely impermeable inner membrane. Most mitochondrial functions involve proteins that control the movement of various molecules and ions across the inner membrane. One particularly important ion that must pass through this membrane is calcium; once inside the mitochondria, these calcium ions regulate cell survival and the generation of ATP.<\/p>\n<p hwp:id=\"p-6\">Although several calcium import mechanisms exist, the best-studied pathway involves a pore-forming protein complex called the mitochondrial calcium uniporter. This ion channel has an exquisite selectivity, allowing only calcium into mitochondria even when other ions outnumber it a million-fold. Previously, researchers had identified several genes that are required for the formation of the uniporter, but it had not been established which of these encodes the central pore through which the calcium ions pass. Now, Chaudhuri et al. have shown that one of these&#x2014;a gene called <italic>mitochondrial calcium uniporter<\/italic> (<italic>MCU<\/italic>)&#x2014;codes for the protein subunit that creates the pore.<\/p>\n<p hwp:id=\"p-7\">Prior studies used optical methods or purified proteins to study genes encoding the uniporter complex, producing controversial results regarding pore identity. This study uses a much more direct assay, namely electrophysiology performed on mitochondrial inner membranes. To access the inner membrane, the authors stripped off the outer membrane from whole mitochondria, and made them expand. By using a technique called voltage-clamping, Chaudhuri et al. were able to precisely measure calcium ion movement through intact or mutated channels. This technique controls confounding factors and minimizes the effect of contaminants that can plague interpretation of data acquired by other methods. They showed that blocking the expression of the <italic>MCU<\/italic> gene reduced the flow of calcium ions through the uniporter, whereas increasing <italic>MCU<\/italic> expression increased calcium transport.<\/p>\n<p hwp:id=\"p-8\">One unique feature of the mitochondrial calcium uniporter is that it can be blocked by a dye called ruthenium red. Chaudhuri et al. used this property to confirm that the <italic>MCU<\/italic> gene encodes the pore-forming subunit of the channel complex&#x2014;they identified a single point mutation in <italic>MCU<\/italic> that did not affect the channel&#x2019;s ability to transport calcium ions, but did abolish its sensitivity to ruthenium red. Together, these results show that the <italic>MCU<\/italic> gene encodes the pore of the mitochondrial calcium uniporter, and should lead to further research into the physiology and structure of this channel.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00704.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00704.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00704.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00704",
"title": "MCU encodes the pore conducting mitochondrial calcium currents",
"metadata": {
"authors": "D. Chaudhuri, Y. Sancak, V. K. Mootha, D. E. Clapham",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:33:24Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:33:24Z",
"updated_at": "2013-07-25T09:33:24Z"
},
{
"id": 113,
"content": "Ribosomes are complex molecular machines that join amino acids together to form proteins. The order of amino acids in the protein is specified by a strand of messenger RNA (mRNA), and the process of decoding the mRNA into a string of amino acids is called translation. A ribosome consists of two subunits\u2014one large, one small\u2014that come together at a particular site on the mRNA strand called the translation initiation site. The ribosome then moves along the mRNA\u2014joining together amino acids brought to it by transfer RNA (tRNA)\u2014until it reaches a termination site and releases the protein.The ribosome has three sites; the first amino acid to be delivered by a tRNA molecule to the ribosome occupies the site in the middle\u2014also called the P site\u2014and the second amino acid is delivered to the A site. Once the first two amino acids have been joined together, the ribosome moves along the mRNA so that the first amino acid now occupies the third site, called the E or exit site, and the second amino acid occupies the P site, leaving the A site vacant. The third amino acid is then delivered to the A site, and the whole process repeats itself until the ribosome reaches the termination site. Proteins called release factors are responsible for terminating the translation process and releasing the translated string of amino acids, which folds to form a protein. In bacteria this task can by performed by two releases factors, known as RF1 and RF2. However, the release factor must itself be released to leave the ribosome free to translate another strand of mRNA.Pallesen et al. have used cryo-electron microscopy (cryo-EM) to study how a third release factor, RF3, helps to release RF1 from the ribosome in bacteria. In cells, RF3 usually forms a complex with a molecule called GDP, and the cryo-EM studies show that this molecule is released shortly after the RF3\u2022GDP complex enters the ribosome. Once inside the ribosome, RF3 comes into contact with RF1 and with a protein called L12 that is part of the ribosome. A molecule called GTP\u2014which is well known as a source of energy within cells\u2014then binds to RF3, and this causes the shape of the ribosome to change. This change of shape results in the release of RF1 and the formation of a new RF3\u2022GDP complex, which then leaves the ribosome.Further work is needed to fully understand the role of L12 in these events, but a detailed understanding of the mechanism for terminating the translation of mRNA by the ribosome is coming into view.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00411.002",
"content_html": "<p hwp:id=\"p-4\">Ribosomes are complex molecular machines that join amino acids together to form proteins. The order of amino acids in the protein is specified by a strand of messenger RNA (mRNA), and the process of decoding the mRNA into a string of amino acids is called translation. A ribosome consists of two subunits&#x2014;one large, one small&#x2014;that come together at a particular site on the mRNA strand called the translation initiation site. The ribosome then moves along the mRNA&#x2014;joining together amino acids brought to it by transfer RNA (tRNA)&#x2014;until it reaches a termination site and releases the protein.<\/p>\n<p hwp:id=\"p-5\">The ribosome has three sites; the first amino acid to be delivered by a tRNA molecule to the ribosome occupies the site in the middle&#x2014;also called the P site&#x2014;and the second amino acid is delivered to the A site. Once the first two amino acids have been joined together, the ribosome moves along the mRNA so that the first amino acid now occupies the third site, called the E or exit site, and the second amino acid occupies the P site, leaving the A site vacant. The third amino acid is then delivered to the A site, and the whole process repeats itself until the ribosome reaches the termination site. Proteins called release factors are responsible for terminating the translation process and releasing the translated string of amino acids, which folds to form a protein. In bacteria this task can by performed by two releases factors, known as RF1 and RF2. However, the release factor must itself be released to leave the ribosome free to translate another strand of mRNA.<\/p>\n<p hwp:id=\"p-6\">Pallesen et al. have used cryo-electron microscopy (cryo-EM) to study how a third release factor, RF3, helps to release RF1 from the ribosome in bacteria. In cells, RF3 usually forms a complex with a molecule called GDP, and the cryo-EM studies show that this molecule is released shortly after the RF3&#x2022;GDP complex enters the ribosome. Once inside the ribosome, RF3 comes into contact with RF1 and with a protein called L12 that is part of the ribosome. A molecule called GTP&#x2014;which is well known as a source of energy within cells&#x2014;then binds to RF3, and this causes the shape of the ribosome to change. This change of shape results in the release of RF1 and the formation of a new RF3&#x2022;GDP complex, which then leaves the ribosome.<\/p>\n<p hwp:id=\"p-7\">Further work is needed to fully understand the role of L12 in these events, but a detailed understanding of the mechanism for terminating the translation of mRNA by the ribosome is coming into view.<\/p>\n<p hwp:id=\"p-8\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00411.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00411.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00411.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00411",
"title": "Cryo-EM visualization of the ribosome in termination complex with apo-RF3 and RF1",
"metadata": {
"authors": "J. Pallesen, Y. Hashem, G. Korkmaz, R. K. Koripella, C. Huang, M. Ehrenberg, S. Sanyal, J. Frank",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:33:26Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:33:26Z",
"updated_at": "2013-07-25T09:33:26Z"
},
{
"id": 114,
"content": "Variations occur throughout our genome. These variations can cause genes to be expressed (switched on) in slightly different ways among individuals. Moreover, the same gene can also be expressed in different ways in different cells within an individual. A third level of variation is supplied by epigenetic markers: these are molecules that bind to the DNA at specific points and can have profound effects on the expression of nearby genes. One such epigenetic marker is the addition of a methyl group to a cytosine base, a process that is known as DNA methylation.DNA methylation usually happens when a cytosine base is next to a guanine base, forming a CpG site. In mammals, most CpG sites have methyl groups attached, although regions with a lot of CpG sites (called CpG islands) are mostly unmethylated. Initial studies suggested that methylation prevented particular genes from being expressed, but more recent work has indicated that methylation can be associated with both reduced and increased expression of genes. Moreover, it is not clear if this association is active (i.e., changes in methylation drive changes in gene expression) or passive (DNA methylation is the result of gene regulation).Now, Gutierrez-Arcelus et al. have carried out a large-scale study to clarify the relationships between three different types of gene-related variations among individuals. They extracted fibroblasts, T-cells and lymphoblastoid cells from the umbilical cords of 204 babies, and analysed them for variations in DNA sequence, gene expression and DNA methylation. Their results show that the associations between the three are more complex than was previously thought.Gutierrez-Arcelus et al. show that the mechanisms that control the association between the variations in DNA methylation and gene expression in individuals are likely to be different to those that are responsible for the establishment of methylation patterns during the process of cell differentiation. They also find that the association between DNA methylation and gene expression can be either active or passive, and can depend on the context in which they occur in our genome. Finally, where the two copies or alleles of a gene are not equally expressed in a given cell, the difference in expression is primarily regulated by DNA sequence variation, with DNA methylation having little or no role on its own. Equally complex interactions and effects are expected in further studies of genetic and epigenetic variation.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00523.002",
"content_html": "<p hwp:id=\"p-4\">Variations occur throughout our genome. These variations can cause genes to be expressed (switched on) in slightly different ways among individuals. Moreover, the same gene can also be expressed in different ways in different cells within an individual. A third level of variation is supplied by epigenetic markers: these are molecules that bind to the DNA at specific points and can have profound effects on the expression of nearby genes. One such epigenetic marker is the addition of a methyl group to a cytosine base, a process that is known as DNA methylation.<\/p>\n<p hwp:id=\"p-5\">DNA methylation usually happens when a cytosine base is next to a guanine base, forming a CpG site. In mammals, most CpG sites have methyl groups attached, although regions with a lot of CpG sites (called CpG islands) are mostly unmethylated. Initial studies suggested that methylation prevented particular genes from being expressed, but more recent work has indicated that methylation can be associated with both reduced and increased expression of genes. Moreover, it is not clear if this association is active (i.e., changes in methylation drive changes in gene expression) or passive (DNA methylation is the result of gene regulation).<\/p>\n<p hwp:id=\"p-6\">Now, Gutierrez-Arcelus et al. have carried out a large-scale study to clarify the relationships between three different types of gene-related variations among individuals. They extracted fibroblasts, T-cells and lymphoblastoid cells from the umbilical cords of 204 babies, and analysed them for variations in DNA sequence, gene expression and DNA methylation. Their results show that the associations between the three are more complex than was previously thought.<\/p>\n<p hwp:id=\"p-7\">Gutierrez-Arcelus et al. show that the mechanisms that control the association between the variations in DNA methylation and gene expression in individuals are likely to be different to those that are responsible for the establishment of methylation patterns during the process of cell differentiation. They also find that the association between DNA methylation and gene expression can be either active or passive, and can depend on the context in which they occur in our genome. Finally, where the two copies or alleles of a gene are not equally expressed in a given cell, the difference in expression is primarily regulated by DNA sequence variation, with DNA methylation having little or no role on its own. Equally complex interactions and effects are expected in further studies of genetic and epigenetic variation.<\/p>\n<p hwp:id=\"p-8\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00523.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00523.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00523.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00523",
"title": "Passive and active DNA methylation and the interplay with genetic variation in gene regulation",
"metadata": {
"authors": "M. Gutierrez-Arcelus, T. Lappalainen, S. B. Montgomery, A. Buil, H. Ongen, A. Yurovsky, J. Bryois, T. Giger, L. Romano, A. Planchon, E. Falconnet, D. Bielser, M. Gagnebin, I. Padioleau, C. Borel, A. Letourneau, P. Makrythanasis, M. Guipponi, C. Gehrig, S. E. Antonarakis, E. T. Dermitzakis",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:33:29Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:33:29Z",
"updated_at": "2013-07-25T09:33:29Z"
},
{
"id": 115,
"content": "Most plant and animal cells contain an organelle known as the Golgi apparatus, which consists of a series of four to six stacked cisternae. Almost all the proteins that are secreted from the cell, or targeted to its plasma membrane, transit through the Golgi. This process takes roughly 5\u201320 min.Although transport of proteins through the Golgi was first observed more than 50 years ago, it is still unclear exactly how this process occurs. One possibility is that proteins to be packaged move through the cisternae enclosed in vesicles, as if on a conveyor belt. Alternatively, the proteins themselves may remain stationary while the Golgi cisternae move over them.Now, Lavieu et al. provide evidence that the Golgi shows both mobile and static behaviour depending on the type and size of the cargo being processed. To distinguish between these two mechanisms, they created a new type of protein cargo\u2014which they called a \u2018staple\u2019\u2014that became fixed to the walls on each side of the cisternae and could not, therefore, move freely through the Golgi. They compared the processing of this protein to that of a more typical soluble protein cargo, which could move freely through the Golgi stack.Surprisingly, the Golgi processed these two types of cargo in very different ways. The staples remained embedded in the walls in the center of the cisternae, whereas the conventional soluble cargo was transported past the staples and collected at the edges of the cisternae, which are known as rims. These are wider than the center of the cisternae, and the staples are too narrow to span them. Lavieu et al. suggest that the Golgi cisternae can be divided into two functionally distinct domains: the centers of cisternae, which remain stationary, and the edges or rims, which can move.In addition to increasing our understanding of how proteins are prepared for transport inside cells, this new mechanism reconciles seemingly conflicting data by revealing that the Golgi can be both mobile and static.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00558.002",
"content_html": "<p hwp:id=\"p-4\">Most plant and animal cells contain an organelle known as the Golgi apparatus, which consists of a series of four to six stacked cisternae. Almost all the proteins that are secreted from the cell, or targeted to its plasma membrane, transit through the Golgi. This process takes roughly 5&#x2013;20 min.<\/p>\n<p hwp:id=\"p-5\">Although transport of proteins through the Golgi was first observed more than 50 years ago, it is still unclear exactly how this process occurs. One possibility is that proteins to be packaged move through the cisternae enclosed in vesicles, as if on a conveyor belt. Alternatively, the proteins themselves may remain stationary while the Golgi cisternae move over them.<\/p>\n<p hwp:id=\"p-6\">Now, Lavieu et al. provide evidence that the Golgi shows both mobile and static behaviour depending on the type and size of the cargo being processed. To distinguish between these two mechanisms, they created a new type of protein cargo&#x2014;which they called a &#x2018;staple&#x2019;&#x2014;that became fixed to the walls on each side of the cisternae and could not, therefore, move freely through the Golgi. They compared the processing of this protein to that of a more typical soluble protein cargo, which could move freely through the Golgi stack.<\/p>\n<p hwp:id=\"p-7\">Surprisingly, the Golgi processed these two types of cargo in very different ways. The staples remained embedded in the walls in the center of the cisternae, whereas the conventional soluble cargo was transported past the staples and collected at the edges of the cisternae, which are known as rims. These are wider than the center of the cisternae, and the staples are too narrow to span them. Lavieu et al. suggest that the Golgi cisternae can be divided into two functionally distinct domains: the centers of cisternae, which remain stationary, and the edges or rims, which can move.<\/p>\n<p hwp:id=\"p-8\">In addition to increasing our understanding of how proteins are prepared for transport inside cells, this new mechanism reconciles seemingly conflicting data by revealing that the Golgi can be both mobile and static.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00558.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00558.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00558.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00558",
"title": "Stapled Golgi cisternae remain in place as cargo passes through the stack",
"metadata": {
"authors": "G. Lavieu, H. Zheng, J. E. Rothman",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:33:31Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:33:31Z",
"updated_at": "2013-07-25T09:33:31Z"
},
{
"id": 116,
"content": "Cilia and flagella protrude like bristles from the cell surface. They share the same basic \u20189+2\u2019 axoneme structure, being made up of nine microtubule doublets that surround a central pair of singlet microtubules. Flagella are generally involved in cell propulsion, whereas motile cilia help to move fluids over cell surfaces.Maintaining cilia and flagella is a challenge for cells, which must find a way to send new proteins all the way along the axoneme to the site of assembly at the flagellar tip. Cells achieve this via a process called intraflagellar transport, in which proteins are carried back and forth by kinesin and dynein motors along the axonemal doublet microtubules. Intraflagellar transport has been proposed to influence other functions of cilia and flagella, including the propulsion of cells over surfaces. However, the details of these interactions are unclear.Through a combination of biophysical and microscopy approaches, Shih et al. describe the mechanism that the green alga Chalmydomonas uses to power flagellar gliding over surfaces. By tracking single fluorescently tagged molecules, Shih et al. observed that flagellar membrane glycoproteins are carried along the axoneme by the intraflagellar transport machinery. During transport, flagellar membrane glycoproteins transiently adhere to the surface, and dynein motors that were previously engaged in carrying these glycoproteins now transmit force that moves the axonemal microtubules. This process, which is dependent on the concentration of calcium ions in the extracellular environment, generates the force that propels the alga's flagella along the surface.Gliding motility is thought to have been one of the initial driving forces for the evolution of cilia and flagella. How the intricate mechanism of flagellar beat motility could have evolved has been the subject of much discussion, as it would require the flagellum to have evolved first. In demonstrating that gliding motility is powered by the same intraflagellar transport mechanism that is required for flagellar assembly, Shih et al. provide strong evidence for the evolution of primitive flagella before the evolution of flagellar beating. Furthermore, since algal flagella have essentially the same structure as the cilia of human cells, these findings could ultimately aid in the development of treatments for diseases that result from defects in intraflagellar transport, including polycystic kidney disease and retinal degeneration.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00744.002",
"content_html": "<p hwp:id=\"p-5\">Cilia and flagella protrude like bristles from the cell surface. They share the same basic &#x2018;9+2&#x2019; axoneme structure, being made up of nine microtubule doublets that surround a central pair of singlet microtubules. Flagella are generally involved in cell propulsion, whereas motile cilia help to move fluids over cell surfaces.<\/p>\n<p hwp:id=\"p-6\">Maintaining cilia and flagella is a challenge for cells, which must find a way to send new proteins all the way along the axoneme to the site of assembly at the flagellar tip. Cells achieve this via a process called intraflagellar transport, in which proteins are carried back and forth by kinesin and dynein motors along the axonemal doublet microtubules. Intraflagellar transport has been proposed to influence other functions of cilia and flagella, including the propulsion of cells over surfaces. However, the details of these interactions are unclear.<\/p>\n<p hwp:id=\"p-7\">Through a combination of biophysical and microscopy approaches, Shih et al. describe the mechanism that the green alga <italic>Chalmydomonas<\/italic> uses to power flagellar gliding over surfaces. By tracking single fluorescently tagged molecules, Shih et al. observed that flagellar membrane glycoproteins are carried along the axoneme by the intraflagellar transport machinery. During transport, flagellar membrane glycoproteins transiently adhere to the surface, and dynein motors that were previously engaged in carrying these glycoproteins now transmit force that moves the axonemal microtubules. This process, which is dependent on the concentration of calcium ions in the extracellular environment, generates the force that propels the alga's flagella along the surface.<\/p>\n<p hwp:id=\"p-8\">Gliding motility is thought to have been one of the initial driving forces for the evolution of cilia and flagella. How the intricate mechanism of flagellar beat motility could have evolved has been the subject of much discussion, as it would require the flagellum to have evolved first. In demonstrating that gliding motility is powered by the same intraflagellar transport mechanism that is required for flagellar assembly, Shih et al. provide strong evidence for the evolution of primitive flagella before the evolution of flagellar beating. Furthermore, since algal flagella have essentially the same structure as the cilia of human cells, these findings could ultimately aid in the development of treatments for diseases that result from defects in intraflagellar transport, including polycystic kidney disease and retinal degeneration.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00744.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00744.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00744.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00744",
"title": "Intraflagellar transport drives flagellar surface motility",
"metadata": {
"authors": "S. M. Shih, B. D. Engel, F. Kocabas, T. Bilyard, A. Gennerich, W. F. Marshall, A. Yildiz",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:33:34Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:33:34Z",
"updated_at": "2013-07-25T09:33:34Z"
},
{
"id": 117,
"content": "Like many animals, the fruit fly Drosophila uses pheromones to influence sexual behaviour, with males and females producing different versions of these chemicals. One of the pheromones produced by male flies, for example, is a chemical called 11-cis-vaccenyl-acetate (cVA), which is an aphrodisiac for female flies and an anti-aphrodisiac for males.The production of the correct pheromones in each sex is genetically controlled using a process called splicing that allows a single gene to be expressed as two or more different proteins. A variety of proteins called splicing factors ensures that splicing results in the production of the correct pheromones for each sex. Sometimes, however, the process by which sex genes are expressed as proteins can be \u2018leaky\u2019, which results in the wrong proteins being produced for one or both sexes.Small RNA molecules called microRNAs act in some genetic pathways to limit the leaky expression of genes, and a microRNA called miR-124 carries out this function in the developing brain Drosophila. Now, Weng et al. show that miR-124 also helps to regulate sex-specific splicing and thereby to control pheromone production and sexual behaviour.Mutant male flies lacking miR-124 were less successful than wild-type males at mating with female flies, and were almost always rejected if a female fly was given a choice between a mutant male and a wild-type male. Moreover, both wild-type and mutant male flies were more likely to initiate courtship behaviour towards another male if it lacked miR-124 than if it did not.The mutant male flies produced less cVA than wild-type males, but more of other pheromones called pentacosenes, which is consistent with the observed behaviour because cVA attracts females and repels males, whereas pentacosenes act as aphrodisiacs for male flies in large amounts. Weng et al. showed that these changes in the production of pheromones were caused by an increased expression of the female version of a splicing factor called transformer in the mutant males, but further work is needed to understand this process in detail.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00640.002",
"content_html": "<p hwp:id=\"p-4\">Like many animals, the fruit fly <italic>Drosophila<\/italic> uses pheromones to influence sexual behaviour, with males and females producing different versions of these chemicals. One of the pheromones produced by male flies, for example, is a chemical called 11-cis-vaccenyl-acetate (cVA), which is an aphrodisiac for female flies and an anti-aphrodisiac for males.<\/p>\n<p hwp:id=\"p-5\">The production of the correct pheromones in each sex is genetically controlled using a process called splicing that allows a single gene to be expressed as two or more different proteins. A variety of proteins called splicing factors ensures that splicing results in the production of the correct pheromones for each sex. Sometimes, however, the process by which sex genes are expressed as proteins can be &#x2018;leaky&#x2019;, which results in the wrong proteins being produced for one or both sexes.<\/p>\n<p hwp:id=\"p-6\">Small RNA molecules called microRNAs act in some genetic pathways to limit the leaky expression of genes, and a microRNA called <italic>miR-124<\/italic> carries out this function in the developing brain <italic>Drosophila<\/italic>. Now, Weng et al. show that <italic>miR-124<\/italic> also helps to regulate sex-specific splicing and thereby to control pheromone production and sexual behaviour.<\/p>\n<p hwp:id=\"p-7\">Mutant male flies lacking <italic>miR-124<\/italic> were less successful than wild-type males at mating with female flies, and were almost always rejected if a female fly was given a choice between a mutant male and a wild-type male. Moreover, both wild-type and mutant male flies were more likely to initiate courtship behaviour towards another male if it lacked <italic>miR-124<\/italic> than if it did not.<\/p>\n<p hwp:id=\"p-8\">The mutant male flies produced less cVA than wild-type males, but more of other pheromones called pentacosenes, which is consistent with the observed behaviour because cVA attracts females and repels males, whereas pentacosenes act as aphrodisiacs for male flies in large amounts. Weng et al. showed that these changes in the production of pheromones were caused by an increased expression of the female version of a splicing factor called <italic>transformer<\/italic> in the mutant males, but further work is needed to understand this process in detail.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00640.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00640.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00640.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00640",
"title": "miR-124 controls male reproductive success in Drosophila",
"metadata": {
"authors": "R. Weng, J. S. Chin, J. Y. Yew, N. Bushati, S. M. Cohen",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:33:36Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:33:36Z",
"updated_at": "2013-07-25T09:33:36Z"
},
{
"id": 118,
"content": "The nucleus of a cell is surrounded by a two-layered membrane that controls the flow of molecules from the cytoplasm into the nucleus and vice versa. The molecular traffic between the cytoplasm and nucleus is essentially controlled by nuclear pore complexes\u2014large, multi-protein structures that are embedded in the membrane. Each nuclear pore complex contains about 30 different proteins called nucleoporins or nups, which combine to form a structure with a central pore that allows the molecules to enter and leave the nucleus.The centre of the nuclear pore complex is thought to be filled with protein filaments that contain a large number of so-called FG repeats (where F and G are the amino acids phenylalanine and glycine). Specialized molecules called soluble nuclear transport receptors, which carry various cargoes between the cytoplasm and nucleus, can bind to these FG repeats, and the interaction between the receptors and the FG repeats is crucial for the selective transport of molecules between the cytoplasm and the nucleus.The large size of the nuclear pore complex has hindered efforts to work out its structure, but in recent years researchers have been able to obtain structures for many individual nups and their subcomplexes. Now, Andersen et al. have determined the structure of one of the largest nups, Nup188. This has led to the discovery that it and a related nup, Nup192, share unexpected features with soluble nuclear transport receptors.In general the first step when attempting to determine the structure of a biomolecule is to form a crystal. Since full-length Nup188 did not crystallize, Andersen et al. instead crystallized two large fragments of Nup188, determined the structures of these fragments, and then combined these to produce the likely structure of the full-length protein. They found that Nup188 has a structure that consists of stacked helices and is more flexible than other nups. Moreover, its structure was very similar to those of soluble nuclear transport receptors, and this led Andersen et al. to investigate whether Nup188 also had similar functional features.Surprisingly, they discovered that both Nup188 and Nup192 could bind FG repeats, just like nuclear transport receptors. What is more, this binding allowed both nups to travel through nuclear pore complexes in in vitro transport reactions. These findings have implications for the understanding of the organization and function of FG-repeats and suggest that the stationary elements of the nuclear pore complex and soluble nuclear transport receptors are evolutionarily related.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00745.002",
"content_html": "<p hwp:id=\"p-5\">The nucleus of a cell is surrounded by a two-layered membrane that controls the flow of molecules from the cytoplasm into the nucleus and vice versa. The molecular traffic between the cytoplasm and nucleus is essentially controlled by nuclear pore complexes&#x2014;large, multi-protein structures that are embedded in the membrane. Each nuclear pore complex contains about 30 different proteins called nucleoporins or nups, which combine to form a structure with a central pore that allows the molecules to enter and leave the nucleus.<\/p>\n<p hwp:id=\"p-6\">The centre of the nuclear pore complex is thought to be filled with protein filaments that contain a large number of so-called FG repeats (where F and G are the amino acids phenylalanine and glycine). Specialized molecules called soluble nuclear transport receptors, which carry various cargoes between the cytoplasm and nucleus, can bind to these FG repeats, and the interaction between the receptors and the FG repeats is crucial for the selective transport of molecules between the cytoplasm and the nucleus.<\/p>\n<p hwp:id=\"p-7\">The large size of the nuclear pore complex has hindered efforts to work out its structure, but in recent years researchers have been able to obtain structures for many individual nups and their subcomplexes. Now, Andersen et al. have determined the structure of one of the largest nups, Nup188. This has led to the discovery that it and a related nup, Nup192, share unexpected features with soluble nuclear transport receptors.<\/p>\n<p hwp:id=\"p-8\">In general the first step when attempting to determine the structure of a biomolecule is to form a crystal. Since full-length Nup188 did not crystallize, Andersen et al. instead crystallized two large fragments of Nup188, determined the structures of these fragments, and then combined these to produce the likely structure of the full-length protein. They found that Nup188 has a structure that consists of stacked helices and is more flexible than other nups. Moreover, its structure was very similar to those of soluble nuclear transport receptors, and this led Andersen et al. to investigate whether Nup188 also had similar functional features.<\/p>\n<p hwp:id=\"p-9\">Surprisingly, they discovered that both Nup188 and Nup192 could bind FG repeats, just like nuclear transport receptors. What is more, this binding allowed both nups to travel through nuclear pore complexes in <italic>in vitro<\/italic> transport reactions. These findings have implications for the understanding of the organization and function of FG-repeats and suggest that the stationary elements of the nuclear pore complex and soluble nuclear transport receptors are evolutionarily related.<\/p>\n<p hwp:id=\"p-10\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00745.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00745.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00745.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00745",
"title": "Scaffold nucleoporins Nup188 and Nup192 share structural and functional properties with nuclear transport receptors",
"metadata": {
"authors": "K. R. Andersen, E. Onischenko, J. H. Tang, P. Kumar, J. Z. Chen, A. Ulrich, J. T. Liphardt, K. Weis, T. U. Schwartz",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:33:41Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:33:41Z",
"updated_at": "2013-07-25T09:33:41Z"
},
{
"id": 119,
"content": "Cells with an unusually large number of mutations\u2014either in the form of changes to the DNA sequence or changes in the number or structure of chromosomes\u2014are said to show genome instability. Although these mutations sometimes boost an organism's chances of survival and reproduction, they more often have detrimental effects, which can include cancer.Genome instability can arise as a result of mistakes occurring during the repair of damaged DNA, or due to inappropriate hybridization of RNA to its DNA template. These RNA\u2013DNA hybrids had been thought to occur strictly during the transcription of DNA into RNA. During this process, the two strands of the DNA molecule separate behind the moving RNA polymerase, and this provides an opportunity for the newly formed RNA to hybridize back to its DNA template. When these RNA\u2013DNA hybrids persist, they give rise to DNA damage that leads to genome instability.Although much is known about the factors that prevent the formation of hybrids, or promote their removal, little is known about how hybrids form in the first place. Now, Wahba et al. have identified one such mechanism in the model yeast, Saccharomyces cerevisiae. It involves a protein called Rad51p, which helps to join stretches of nucleic acids together to repair breaks in DNA. However, Wahba et al. showed that if Rad51p is not properly regulated, it can also trigger the formation of RNA\u2013DNA hybrids; yeast cells that lack the gene for Rad51p showed significantly reduced levels of hybrid formation. Moreover, dysfunctional Rad51p causes RNA sequences to anneal to DNA throughout the genome, rather than just at the site in which the RNA was originally produced. This means that RNA sequences produced during transcription are much more of a threat to genomic stability than previously thought.The work of Wahba et al. presents a paradox in which a protein that is normally involved in repairing DNA can itself cause damage if it is not carefully regulated. It also raises the possibility that the elevated levels of Rad51p expression observed in cancer cells could be a cause, rather than a consequence, of mutations.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00505.002",
"content_html": "<p hwp:id=\"p-5\">Cells with an unusually large number of mutations&#x2014;either in the form of changes to the DNA sequence or changes in the number or structure of chromosomes&#x2014;are said to show genome instability. Although these mutations sometimes boost an organism's chances of survival and reproduction, they more often have detrimental effects, which can include cancer.<\/p>\n<p hwp:id=\"p-6\">Genome instability can arise as a result of mistakes occurring during the repair of damaged DNA, or due to inappropriate hybridization of RNA to its DNA template. These RNA&#x2013;DNA hybrids had been thought to occur strictly during the transcription of DNA into RNA. During this process, the two strands of the DNA molecule separate behind the moving RNA polymerase, and this provides an opportunity for the newly formed RNA to hybridize back to its DNA template. When these RNA&#x2013;DNA hybrids persist, they give rise to DNA damage that leads to genome instability.<\/p>\n<p hwp:id=\"p-7\">Although much is known about the factors that prevent the formation of hybrids, or promote their removal, little is known about how hybrids form in the first place. Now, Wahba et al. have identified one such mechanism in the model yeast, <italic>Saccharomyces cerevisiae<\/italic>. It involves a protein called Rad51p, which helps to join stretches of nucleic acids together to repair breaks in DNA. However, Wahba et al. showed that if Rad51p is not properly regulated, it can also trigger the formation of RNA&#x2013;DNA hybrids; yeast cells that lack the gene for Rad51p showed significantly reduced levels of hybrid formation. Moreover, dysfunctional Rad51p causes RNA sequences to anneal to DNA throughout the genome, rather than just at the site in which the RNA was originally produced. This means that RNA sequences produced during transcription are much more of a threat to genomic stability than previously thought.<\/p>\n<p hwp:id=\"p-8\">The work of Wahba et al. presents a paradox in which a protein that is normally involved in repairing DNA can itself cause damage if it is not carefully regulated. It also raises the possibility that the elevated levels of Rad51p expression observed in cancer cells could be a cause, rather than a consequence, of mutations.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00505.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00505.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00505.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00505",
"title": "The homologous recombination machinery modulates the formation of RNA-DNA hybrids and associated chromosome instability",
"metadata": {
"authors": "L. Wahba, S. K. Gore, D. Koshland",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:33:48Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:33:48Z",
"updated_at": "2013-07-25T09:33:48Z"
},
{
"id": 120,
"content": "All multicellular organisms, including plants, produce hormones\u2014chemical messengers that are released in one part of an organism but act in another. The binding of hormones to receptor proteins on the surface of target cells activates signal transduction cascades, leading ultimately to changes in the transcription and translation of genes.Ethylene is a gaseous plant hormone that acts at trace levels to stimulate or regulate a variety of processes, including the regulation of plant growth, the ripening of fruit and the shedding of leaves. Plants also produce ethylene in response to wounding, pathogen attack or exposure to environmental stresses, such as extreme temperatures or drought. Although the effects of ethylene on plants are well documented, much less is known about how its functions are controlled and coordinated at the molecular level.Here, Chang et al. reveal how ethylene alters the transcription of DNA into messenger DNA (mRNA) in the plant model organism, Arabidopsis thaliana. Ethylene is known to exert some of its effects via a protein called EIN3, which is a transcription factor that acts as the master regulator of the ethylene signaling pathway. To identify the targets of EIN3, Chang et al. exposed plants to ethylene and then used a technique called ChIP-Seq to identify those regions of the DNA that EIN3 binds to. At the same time, they used genome-wide mRNA sequencing to determine which genes showed altered transcription.Over the course of 24 hr, ethylene induced four distinct waves of transcription, suggesting that discrete layers of transcriptional control are present. EIN3 binding also controlled a multitude of downstream transcriptional cascades, including a major negative feedback loop. Surprisingly, many of the genes that showed altered expression in response to EIN3 binding were also influenced by hormones other than ethylene.In addition to extending our knowledge of the role of EIN3 in coordinating the effects of ethylene, the work of Chang et al. reveals the extensive connectivity between pathways regulated by distinct hormones in plants. The results may also make it easier to identify key players involved in hormone signaling pathways in other plant species.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00675.002",
"content_html": "<p hwp:id=\"p-5\">All multicellular organisms, including plants, produce hormones&#x2014;chemical messengers that are released in one part of an organism but act in another. The binding of hormones to receptor proteins on the surface of target cells activates signal transduction cascades, leading ultimately to changes in the transcription and translation of genes.<\/p>\n<p hwp:id=\"p-6\">Ethylene is a gaseous plant hormone that acts at trace levels to stimulate or regulate a variety of processes, including the regulation of plant growth, the ripening of fruit and the shedding of leaves. Plants also produce ethylene in response to wounding, pathogen attack or exposure to environmental stresses, such as extreme temperatures or drought. Although the effects of ethylene on plants are well documented, much less is known about how its functions are controlled and coordinated at the molecular level.<\/p>\n<p hwp:id=\"p-7\">Here, Chang et al. reveal how ethylene alters the transcription of DNA into messenger DNA (mRNA) in the plant model organism, <italic>Arabidopsis thaliana<\/italic>. Ethylene is known to exert some of its effects via a protein called EIN3, which is a transcription factor that acts as the master regulator of the ethylene signaling pathway. To identify the targets of EIN3, Chang et al. exposed plants to ethylene and then used a technique called ChIP-Seq to identify those regions of the DNA that EIN3 binds to. At the same time, they used genome-wide mRNA sequencing to determine which genes showed altered transcription.<\/p>\n<p hwp:id=\"p-8\">Over the course of 24 hr, ethylene induced four distinct waves of transcription, suggesting that discrete layers of transcriptional control are present. EIN3 binding also controlled a multitude of downstream transcriptional cascades, including a major negative feedback loop. Surprisingly, many of the genes that showed altered expression in response to EIN3 binding were also influenced by hormones other than ethylene.<\/p>\n<p hwp:id=\"p-9\">In addition to extending our knowledge of the role of EIN3 in coordinating the effects of ethylene, the work of Chang et al. reveals the extensive connectivity between pathways regulated by distinct hormones in plants. The results may also make it easier to identify key players involved in hormone signaling pathways in other plant species.<\/p>\n<p hwp:id=\"p-10\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00675.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00675.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00675.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00675",
"title": "Temporal transcriptional response to ethylene gas drives growth hormone cross-regulation in Arabidopsis",
"metadata": {
"authors": "K. N. Chang, S. Zhong, M. T. Weirauch, G. Hon, M. Pelizzola, H. Li, S.-s. C. Huang, R. J. Schmitz, M. A. Urich, D. Kuo, J. R. Nery, H. Qiao, A. Yang, A. Jamali, H. Chen, T. Ideker, B. Ren, Z. Bar-Joseph, T. R. Hughes, J. R. Ecker",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:33:51Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:33:51Z",
"updated_at": "2013-07-25T09:33:51Z"
},
{
"id": 121,
"content": "Viruses are infectious agents made up of proteins and a genome made of DNA or RNA. Upon infecting a host cell, viruses hijack the cell\u2019s gene expression machinery and force it to produce copies of the viral genome and proteins, which then assemble into new viruses that can eventually infect other host cells. Because assembly is an essential step in the viral life cycle, understanding how this process occurs could significantly advance the fight against viral diseases.In many viral families, a protein shell called a capsid forms around the viral genome during the assembly process. However, capsids can also assemble around nucleic acids in solution, indicating that a host cell is not required for their formation. Since capsid proteins are positively charged, and nucleic acids are negatively charged, electrostatic interactions between the two are thought to have an important role in capsid assembly. However, it is unclear how structural features of the viral genome affect assembly, and why the negative charge on viral genomes is actually far greater than the positive charge on capsids. These questions are difficult to address experimentally because most of the intermediates that form during virus assembly are too short-lived to be imaged.Here, Perlmutter et al. have used state of the art computational methods and advances in graphical processing units (GPUs) to produce the most realistic model of capsid assembly to date. They showed that the stability of the complex formed between the nucleic acid and the capsid depends on the length of the viral genome. Yield was highest for genomes within a certain range of lengths, and capsids that assembled around longer or shorter genomes tended to be malformed.Perlmutter et al. also explored how structural features of the virus\u2014including base-pairing between viral nucleic acids, and the size and charge of the capsid\u2014determine the optimal length of the viral genome. When they included structural data from real viruses in their simulations and predicted the optimal lengths for the viral genome, the results were very similar to those seen in existing viruses. This indicates that the structure of the viral genome has been optimized to promote packaging into capsids. Understanding this relationship between structure and packaging will make it easier to develop antiviral agents that thwart or misdirect virus assembly, and could aid the redesign of viruses for use in gene therapy and drug delivery.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00632.002",
"content_html": "<p hwp:id=\"p-4\">Viruses are infectious agents made up of proteins and a genome made of DNA or RNA. Upon infecting a host cell, viruses hijack the cell&#x2019;s gene expression machinery and force it to produce copies of the viral genome and proteins, which then assemble into new viruses that can eventually infect other host cells. Because assembly is an essential step in the viral life cycle, understanding how this process occurs could significantly advance the fight against viral diseases.<\/p>\n<p hwp:id=\"p-5\">In many viral families, a protein shell called a capsid forms around the viral genome during the assembly process. However, capsids can also assemble around nucleic acids in solution, indicating that a host cell is not required for their formation. Since capsid proteins are positively charged, and nucleic acids are negatively charged, electrostatic interactions between the two are thought to have an important role in capsid assembly. However, it is unclear how structural features of the viral genome affect assembly, and why the negative charge on viral genomes is actually far greater than the positive charge on capsids. These questions are difficult to address experimentally because most of the intermediates that form during virus assembly are too short-lived to be imaged.<\/p>\n<p hwp:id=\"p-6\">Here, Perlmutter et al. have used state of the art computational methods and advances in graphical processing units (GPUs) to produce the most realistic model of capsid assembly to date. They showed that the stability of the complex formed between the nucleic acid and the capsid depends on the length of the viral genome. Yield was highest for genomes within a certain range of lengths, and capsids that assembled around longer or shorter genomes tended to be malformed.<\/p>\n<p hwp:id=\"p-7\">Perlmutter et al. also explored how structural features of the virus&#x2014;including base-pairing between viral nucleic acids, and the size and charge of the capsid&#x2014;determine the optimal length of the viral genome. When they included structural data from real viruses in their simulations and predicted the optimal lengths for the viral genome, the results were very similar to those seen in existing viruses. This indicates that the structure of the viral genome has been optimized to promote packaging into capsids. Understanding this relationship between structure and packaging will make it easier to develop antiviral agents that thwart or misdirect virus assembly, and could aid the redesign of viruses for use in gene therapy and drug delivery.<\/p>\n<p hwp:id=\"p-8\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00632.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00632.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00632.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00632",
"title": "Viral genome structures are optimal for capsid assembly",
"metadata": {
"authors": "J. D. Perlmutter, C. Qiao, M. F. Hagan",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:33:53Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:33:53Z",
"updated_at": "2013-07-25T09:33:53Z"
},
{
"id": 122,
"content": "Our blood contains many different types of cells. Red blood cells carry oxygen around the body, whereas white blood cells are a key part of our immune system. All these different types of blood cells are derived from special cells in our bone marrow called hematopoietic stem cells. The type of blood cell that the stem cell becomes depends on the genes that are expressed as proteins in that stem cell.Gene expression can be controlled in a number of ways, including epigenetic process that influence the expression of genes without altering the underlying sequence of bases in the DNA. For example, DNA is wrapped around histone proteins and the addition of a methyl group to these proteins, a process known as histone methylation, can increase the expression of a gene, whereas the removal of a methyl group (demethylation) can repress gene expression. Lysine-specific demethylase 1 (Lsd1) is an enzyme that is known to mediate the demethylation of lysine amino acids on histone proteins. The role of Lsd1 in embryonic stem cells has been widely studied, and deletion of the gene that codes for Lsd1 is known to result in the death of mice embryos. However, very little is known about its roles in the later stages of mammalian development.Here, Kerenyi et al. use new genetic tools to knock out the gene for Lsd1 at different stages of development in order to examine its impact on the formation of new blood cells. They find that Lsd1 is required for the successful differentiation of hematopoietic stem cells into different types of blood cells, and that knocking out Lsd1 results in a severe loss of white and red blood cells. Moreover, they show that the lack of Lsd1 causes problems during both the early and later stages of development.Kerenyi et al. go on to demonstrate that Lsd1 regulates the activity of promoters and enhancers of various genes associated with hematopoietic stem cells. They also show that knocking out the Lsd1 gene results in impaired silencing of these genes, and that the incomplete expression of these genes is not compatible with the maturation of blood cells.Lsd1 has recently been proposed as the potential target for the treatment of leukemia and other blood disorders. However, the fact that a loss of Lsd1 function has adverse effects during both the early and later stages of blood cell development suggests that research into drugs that target Lsd1 should not begin until a suitable time window for the administration of such drugs can be identified.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00633.002",
"content_html": "<p hwp:id=\"p-4\">Our blood contains many different types of cells. Red blood cells carry oxygen around the body, whereas white blood cells are a key part of our immune system. All these different types of blood cells are derived from special cells in our bone marrow called hematopoietic stem cells. The type of blood cell that the stem cell becomes depends on the genes that are expressed as proteins in that stem cell.<\/p>\n<p hwp:id=\"p-5\">Gene expression can be controlled in a number of ways, including epigenetic process that influence the expression of genes without altering the underlying sequence of bases in the DNA. For example, DNA is wrapped around histone proteins and the addition of a methyl group to these proteins, a process known as histone methylation, can increase the expression of a gene, whereas the removal of a methyl group (demethylation) can repress gene expression. Lysine-specific demethylase 1 (Lsd1) is an enzyme that is known to mediate the demethylation of lysine amino acids on histone proteins. The role of Lsd1 in embryonic stem cells has been widely studied, and deletion of the gene that codes for Lsd1 is known to result in the death of mice embryos. However, very little is known about its roles in the later stages of mammalian development.<\/p>\n<p hwp:id=\"p-6\">Here, Kerenyi et al. use new genetic tools to knock out the gene for Lsd1 at different stages of development in order to examine its impact on the formation of new blood cells. They find that Lsd1 is required for the successful differentiation of hematopoietic stem cells into different types of blood cells, and that knocking out <italic>Lsd1<\/italic> results in a severe loss of white and red blood cells. Moreover, they show that the lack of Lsd1 causes problems during both the early and later stages of development.<\/p>\n<p hwp:id=\"p-7\">Kerenyi et al. go on to demonstrate that Lsd1 regulates the activity of promoters and enhancers of various genes associated with hematopoietic stem cells. They also show that knocking out the <italic>Lsd1<\/italic> gene results in impaired silencing of these genes, and that the incomplete expression of these genes is not compatible with the maturation of blood cells.<\/p>\n<p hwp:id=\"p-8\">Lsd1 has recently been proposed as the potential target for the treatment of leukemia and other blood disorders. However, the fact that a loss of Lsd1 function has adverse effects during both the early and later stages of blood cell development suggests that research into drugs that target Lsd1 should not begin until a suitable time window for the administration of such drugs can be identified.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00633.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00633.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00633.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00633",
"title": "Histone demethylase Lsd1 represses hematopoietic stem and progenitor cell signatures during blood cell maturation",
"metadata": {
"authors": "M. A. Kerenyi, Z. Shao, Y.-J. Hsu, G. Guo, S. Luc, K. O'Brien, Y. Fujiwara, C. Peng, M. Nguyen, S. H. Orkin",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:33:58Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:33:58Z",
"updated_at": "2013-07-25T09:33:58Z"
},
{
"id": 123,
"content": "In many species, including humans, females have two X chromosomes whereas males have only one. To ensure that females do not end up with a double dose of the proteins encoded by genes on the X chromosome, animals employ a strategy called dosage compensation to control the expression of X-linked genes.The mechanisms underlying dosage compensation vary between species, but they typically involve a regulatory complex that binds to the X chromosomes of one sex to modify gene expression. In the nematode worm Caenorhabditis elegans\u2014which consists of hermaphrodites (XX) and males (XO)\u2014this regulatory complex, called the dosage compensation complex (DCC), binds to both X chromosomes of XX individuals, reducing gene expression from each by 50%. DCC shares many subunits with a protein complex called condensin, which regulates the structure of chromosomes to achieve proper chromosome segregation. However, it is unclear exactly how the DCC controls the expression of X-linked genes.For a gene to be expressed, an enzyme called RNA polymerase II must bind to the gene\u2019s promoter\u2014a stretch of DNA upstream of the protein-coding part of the gene\u2014so that it can begin transcribing the DNA into RNA. Promoters have been difficult to define in C. elegans, but Kruesi et al. devised a strategy to map transcription start sites, and hence promoters, throughout the worm genome. The strategy integrates the results of two methods: One measures the extent and orientation of each gene\u2019s transcribed region, and the other locates the distinctive cap structures that mark the true 5\u2032 ends of newly made RNAs.Using this new promoter information, coupled with genome-wide measurements of the levels of newly synthesized transcripts from wild-type and dosage-compensation-defective animals, they showed that C. elegans achieves dosage compensation by reducing the recruitment of RNA polymerase II to the promoters of X-linked genes in XX individuals.Kruesi et al. also identified a second regulatory mechanism that acts in both sexes to increase the level of transcription of genes on the X chromosome. This ensures that after dosage compensation, genes on the X chromosome are expressed at a similar level to those on the autosomes (all chromosomes other than X and Y).As well as shedding light on the mechanism by which dosage compensation occurs in C. elegans, the study by Kruesi et al. provides a valuable data set on transcription start sites in the worm, and puts forward a general strategy that could be used to map these sites in other species.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00808.002",
"content_html": "<p hwp:id=\"p-5\">In many species, including humans, females have two X chromosomes whereas males have only one. To ensure that females do not end up with a double dose of the proteins encoded by genes on the X chromosome, animals employ a strategy called dosage compensation to control the expression of X-linked genes.<\/p>\n<p hwp:id=\"p-6\">The mechanisms underlying dosage compensation vary between species, but they typically involve a regulatory complex that binds to the X chromosomes of one sex to modify gene expression. In the nematode worm <italic>Caenorhabditis elegans<\/italic>&#x2014;which consists of hermaphrodites (XX) and males (XO)&#x2014;this regulatory complex, called the dosage compensation complex (DCC), binds to both X chromosomes of XX individuals, reducing gene expression from each by 50%. DCC shares many subunits with a protein complex called condensin, which regulates the structure of chromosomes to achieve proper chromosome segregation. However, it is unclear exactly how the DCC controls the expression of X-linked genes.<\/p>\n<p hwp:id=\"p-7\">For a gene to be expressed, an enzyme called RNA polymerase II must bind to the gene&#x2019;s promoter&#x2014;a stretch of DNA upstream of the protein-coding part of the gene&#x2014;so that it can begin transcribing the DNA into RNA. Promoters have been difficult to define in <italic>C. elegans<\/italic>, but Kruesi et al. devised a strategy to map transcription start sites, and hence promoters, throughout the worm genome. The strategy integrates the results of two methods: One measures the extent and orientation of each gene&#x2019;s transcribed region, and the other locates the distinctive cap structures that mark the true 5&#x2032; ends of newly made RNAs.<\/p>\n<p hwp:id=\"p-8\">Using this new promoter information, coupled with genome-wide measurements of the levels of newly synthesized transcripts from wild-type and dosage-compensation-defective animals, they showed that <italic>C. elegans<\/italic> achieves dosage compensation by reducing the recruitment of RNA polymerase II to the promoters of X-linked genes in XX individuals.<\/p>\n<p hwp:id=\"p-9\">Kruesi et al. also identified a second regulatory mechanism that acts in both sexes to increase the level of transcription of genes on the X chromosome. This ensures that after dosage compensation, genes on the X chromosome are expressed at a similar level to those on the autosomes (all chromosomes other than X and Y).<\/p>\n<p hwp:id=\"p-10\">As well as shedding light on the mechanism by which dosage compensation occurs in <italic>C. elegans<\/italic>, the study by Kruesi et al. provides a valuable data set on transcription start sites in the worm, and puts forward a general strategy that could be used to map these sites in other species.<\/p>\n<p hwp:id=\"p-11\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00808.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00808.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00808.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00808",
"title": "Condensin controls recruitment of RNA polymerase II to achieve nematode X-chromosome dosage compensation",
"metadata": {
"authors": "W. S. Kruesi, L. J. Core, C. T. Waters, J. T. Lis, B. J. Meyer",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:34:01Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:34:01Z",
"updated_at": "2013-07-25T09:34:01Z"
},
{
"id": 124,
"content": "Transposons are regions of mobile DNA that can jump from one location in the genome to another. This represents a genetic burden to the host because there is always the risk that the transposon will inactivate a cellular gene. However, a greater problem is that transposition is accompanied by an increase in the number of copies of the transposon. Since each new copy will be a source of further new copies, amplification of transposons is necessarily exponential. The fact that eukaryotic cells are able to tolerate DNA transposons suggests the existence of regulatory mechanisms to defuse the inevitable genomic melt-down. Host-mediated epigenetic modifications and RNA interference will provide some level of protection. However, they are by no means completely effective and a well-adapted genomic parasite, such as a transposon, might be expected to have its own mechanism of regulation.Now, Claeys Bouuaert, Lipkow and colleagues have used a computer model in combination with in vivo and in vitro experiments to search for this mechanism. Their experiments reveal how a DNA transposon is down-regulated by its own transposase. The transposase is the enzyme that catalyzes the \u2018jump\u2019 or transposition. It binds to specific sites at either end of the transposon and brings these together to make up a nucleoprotein complex called the transpososome. It is within this complex that the chemical steps of the reaction take place. When the number of transposons increases, so does the concentration of transposase. Claeys Bouuaert et al. show that the binding sites become saturated at a relatively low transposase concentration and that negative regulation arises from the resulting competition. Thus, the rate of transposition decreases as the number of transposons increases. They further use the computer model to explore how the amplification of the transposon is affected by transposon-specific and cellular-specific factors.Claeys Bouuaert, Lipkow and colleagues based their study predominantly on a resurrected copy of the Hsmar1 transposon, which was active in the human genome 50 million years ago. However, they also tested two distantly related eukaryotic transposons and observed that their behavior was similar, which suggests that this could be a general mechanism that controls the activity of jumping genes. They also note that their competition mechanism is conceptually similar to the immunological \u2018prozone effect\u2019. This is a recurrent theme in protein chemistry and demonstrates once again that less is in fact sometimes more.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00668.002",
"content_html": "<p hwp:id=\"p-6\">Transposons are regions of mobile DNA that can jump from one location in the genome to another. This represents a genetic burden to the host because there is always the risk that the transposon will inactivate a cellular gene. However, a greater problem is that transposition is accompanied by an increase in the number of copies of the transposon. Since each new copy will be a source of further new copies, amplification of transposons is necessarily exponential. The fact that eukaryotic cells are able to tolerate DNA transposons suggests the existence of regulatory mechanisms to defuse the inevitable genomic melt-down. Host-mediated epigenetic modifications and RNA interference will provide some level of protection. However, they are by no means completely effective and a well-adapted genomic parasite, such as a transposon, might be expected to have its own mechanism of regulation.<\/p>\n<p hwp:id=\"p-7\">Now, Claeys Bouuaert, Lipkow and colleagues have used a computer model in combination with in vivo and in vitro experiments to search for this mechanism. Their experiments reveal how a DNA transposon is down-regulated by its own transposase. The transposase is the enzyme that catalyzes the &#x2018;jump&#x2019; or transposition. It binds to specific sites at either end of the transposon and brings these together to make up a nucleoprotein complex called the transpososome. It is within this complex that the chemical steps of the reaction take place. When the number of transposons increases, so does the concentration of transposase. Claeys Bouuaert et al. show that the binding sites become saturated at a relatively low transposase concentration and that negative regulation arises from the resulting competition. Thus, the rate of transposition decreases as the number of transposons increases. They further use the computer model to explore how the amplification of the transposon is affected by transposon-specific and cellular-specific factors.<\/p>\n<p hwp:id=\"p-8\">Claeys Bouuaert, Lipkow and colleagues based their study predominantly on a resurrected copy of the Hsmar1 transposon, which was active in the human genome 50 million years ago. However, they also tested two distantly related eukaryotic transposons and observed that their behavior was similar, which suggests that this could be a general mechanism that controls the activity of jumping genes. They also note that their competition mechanism is conceptually similar to the immunological &#x2018;prozone effect&#x2019;. This is a recurrent theme in protein chemistry and demonstrates once again that less is in fact sometimes more.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00668.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00668.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00668.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00668",
"title": "The autoregulation of a eukaryotic DNA transposon",
"metadata": {
"authors": "C. Claeys Bouuaert, K. Lipkow, S. S. Andrews, D. Liu, R. Chalmers",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:34:04Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:34:04Z",
"updated_at": "2013-07-25T09:34:04Z"
},
{
"id": 125,
"content": "The inner surface of the vertebrate eye is lined with a multilayered structure known as the retina. The bottom layer of the retina is composed of rods and cones\u2014neurons that are directly sensitive to light\u2014and is called the photoreceptor layer. Rods function primarily in dim light and provide black-and-white vision, while cones support daytime vision and are responsible for colour perception. Unlike the upper layers of the retina, the photoreceptor layer does not contain blood vessels: oxygen and nutrients are instead provided by a structure just underneath the retina called the choroid.The eye relies on the rods and cones converting light into electrical signals, and the photoreceptor layer must remain free of blood vessels for this process to work properly. If blood vessels extend into the photoreceptor layer from rest of the retina (which is above it) or the choroid (below), they can disrupt the retina and give rise to a condition called age-related macular degeneration, which is a leading cause of irreversible blindness in adults.Within the eye, the development of new blood vessels from pre-existing vessels is stimulated by a protein known as vascular endothelial growth factor A (VEGF-A), while an inhibitor protein called sFLT-1 prevents the growth of new blood vessels in the other tissues of the eye like the cornea. However, it has not been clear what keeps the photoreceptor layer (and also the cells that support the photoreceptor layer) free of blood vessels, and what happens to disrupt this process of vascular demarcation in age-related macular degeneration.Now, Luo et al. reveal that cells in the photoreceptor layer produce sFLT-1, and that the levels of this protein are indeed reduced in people with age-related macular degeneration. Using genetic and pharmacological methods, they show that a reduction in sFLT-1 triggers blood vessels to grow into the photoreceptor layer from above or below. Luo et al. also report two new genetic mouse models in which blood vessels form spontaneously in the photoreceptor layer at an early age, which should prove useful for further research into age-related macular degeneration.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00324.002",
"content_html": "<p hwp:id=\"p-5\">The inner surface of the vertebrate eye is lined with a multilayered structure known as the retina. The bottom layer of the retina is composed of rods and cones&#x2014;neurons that are directly sensitive to light&#x2014;and is called the photoreceptor layer. Rods function primarily in dim light and provide black-and-white vision, while cones support daytime vision and are responsible for colour perception. Unlike the upper layers of the retina, the photoreceptor layer does not contain blood vessels: oxygen and nutrients are instead provided by a structure just underneath the retina called the choroid.<\/p>\n<p hwp:id=\"p-6\">The eye relies on the rods and cones converting light into electrical signals, and the photoreceptor layer must remain free of blood vessels for this process to work properly. If blood vessels extend into the photoreceptor layer from rest of the retina (which is above it) or the choroid (below), they can disrupt the retina and give rise to a condition called age-related macular degeneration, which is a leading cause of irreversible blindness in adults.<\/p>\n<p hwp:id=\"p-7\">Within the eye, the development of new blood vessels from pre-existing vessels is stimulated by a protein known as vascular endothelial growth factor A (VEGF-A), while an inhibitor protein called sFLT-1 prevents the growth of new blood vessels in the other tissues of the eye like the cornea. However, it has not been clear what keeps the photoreceptor layer (and also the cells that support the photoreceptor layer) free of blood vessels, and what happens to disrupt this process of vascular demarcation in age-related macular degeneration.<\/p>\n<p hwp:id=\"p-8\">Now, Luo et al. reveal that cells in the photoreceptor layer produce sFLT-1, and that the levels of this protein are indeed reduced in people with age-related macular degeneration. Using genetic and pharmacological methods, they show that a reduction in sFLT-1 triggers blood vessels to grow into the photoreceptor layer from above or below. Luo et al. also report two new genetic mouse models in which blood vessels form spontaneously in the photoreceptor layer at an early age, which should prove useful for further research into age-related macular degeneration.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00324.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00324.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00324.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00324",
"title": "Photoreceptor avascular privilege is shielded by soluble VEGF receptor-1",
"metadata": {
"authors": "L. Luo, H. Uehara, X. Zhang, S. K. Das, T. Olsen, D. Holt, J. M. Simonis, K. Jackman, N. Singh, T. R. Miya, W. Huang, F. Ahmed, A. Bastos-Carvalho, Y. Z. Le, C. Mamalis, V. A. Chiodo, W. W. Hauswirth, J. Baffi, P. M. Lacal, A. Orecchia, N. Ferrara, G. Gao, K. Young-hee, Y. Fu, L. Owen, R. Albuquerque, W. Baehr, K. Thomas, D. Y. Li, K. V. Chalam, M. Shibuya, S. Grisanti, D. J. Wilson, J. Ambati, B. K. Ambati",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:34:09Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:34:09Z",
"updated_at": "2013-07-25T09:34:09Z"
},
{
"id": 126,
"content": "The incredible diversity of living creatures belies the fact that their genes are quite similar. In the 1970s Mary-Claire King and Allan Wilson proposed that a process called gene regulation\u2014which determines when, where and how genes are expressed as proteins\u2014is responsible for this diversity. Four decades later, the central role of gene regulation in evolution has been confirmed in a wide range of species including bacteria, fungi, flies and mammals, although the details remain poorly understood. In recent years it has been suggested that the duplication of genes\u2014and sometimes the duplication of whole genomes\u2014has had a crucial influence on the part played by gene regulation in the evolution of many different species.Ascomycota fungi are uniquely suited to the study of genetics and evolution because of their diversity\u2014they include C. albicans, a fungus that is found in the human mouth and gut, and various species of yeast\u2014and because many of their genomes have already been sequenced. Moreover, their genomes are relatively small, which simplifies the task of working out how it has changed over the course of evolution. It is also known that species in this branch of the tree of life diverged before and after an event in which a whole genome was duplicated.Ascomycota fungi use glucose as a source of carbon in different ways during aerobic growth. Most, including C. albicans, are respiratory and rely on oxidative phosphorylation processes to produce energy. However, a small number\u2014including S. cerevisiae and S. pombe, two types of yeast that are widely used as model organisms\u2014prefer to ferment glucose, even when oxygen is available. Species that favor the latter respiro-fermentative lifestyle have evolved independently at least twice: once after the whole genome duplication event that lead to S. cerevisiae, and once when S. pombe and the other fission yeasts evolved.Thompson et al. have measured mRNA profiles in 15 different species of yeast and reconstructed how the regulation of groups of genes (modules) have evolved over a period of more than 300 million years. They found that modules have diverged proportionally to evolutionary time, with prominent changes in gene regulation being associated with changes in lifestyle (especially changes in carbon metabolism) and a whole genome duplication event.Gene duplication events result in gene paralogs\u2014identical genes at different places in the genome\u2014and these have made significant contributions to the evolution of different forms of gene regulation, especially just after the duplication event. Moreover, the paralogs produced in whole genome duplication events have resulted in bigger changes over longer periods of time. Similar patterns were observed in the regulation of the genes involved in the response to heat shock in eight of the species, which suggests that these are general evolutionary principles.The changes in gene expression associated with the respiro-fermentative lifestyle may also have implications for our understanding of cancer: healthy cells rely on oxidative phosphorylation to produce energy whereas, similar to yeast cells, most cancerous cells rely on respiro-fermentation. Furthermore, yeast cells and cancer cells both support their rapid growth and proliferation by using glucose for biosynthesis to support cell division, although this process is not fully understood. Normal cells, on the other hand, use glucose primarily for energy and tend not to divide rapidly.Thompson et al. found that the genes encoding enzymes in two biosynthetic pathways\u2014one that produces the nucleotides necessary for DNA replication, and one that synthesizes glycine\u2014are induced in respiro-fermentative yeasts but repressed in respiratory yeast cells. The fact that similar changes are observed in the same two pathways when normal cells become cancer cells suggests that these pathways have an important role in the development of cancer. The framework developed by Thompson et al. could also be used to explore the evolution of gene regulation in other species and biological processes.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00603.002",
"content_html": "<p hwp:id=\"p-8\">The incredible diversity of living creatures belies the fact that their genes are quite similar. In the 1970s Mary-Claire King and Allan Wilson proposed that a process called gene regulation&#x2014;which determines when, where and how genes are expressed as proteins&#x2014;is responsible for this diversity. Four decades later, the central role of gene regulation in evolution has been confirmed in a wide range of species including bacteria, fungi, flies and mammals, although the details remain poorly understood. In recent years it has been suggested that the duplication of genes&#x2014;and sometimes the duplication of whole genomes&#x2014;has had a crucial influence on the part played by gene regulation in the evolution of many different species.<\/p>\n<p hwp:id=\"p-9\">Ascomycota fungi are uniquely suited to the study of genetics and evolution because of their diversity&#x2014;they include <italic>C. albicans<\/italic>, a fungus that is found in the human mouth and gut, and various species of yeast&#x2014;and because many of their genomes have already been sequenced. Moreover, their genomes are relatively small, which simplifies the task of working out how it has changed over the course of evolution. It is also known that species in this branch of the tree of life diverged before and after an event in which a whole genome was duplicated.<\/p>\n<p hwp:id=\"p-10\">Ascomycota fungi use glucose as a source of carbon in different ways during aerobic growth. Most, including <italic>C<\/italic>. <italic>albicans<\/italic>, are respiratory and rely on oxidative phosphorylation processes to produce energy. However, a small number&#x2014;including <italic>S<\/italic>. <italic>cerevisiae<\/italic> and <italic>S<\/italic>. <italic>pombe<\/italic>, two types of yeast that are widely used as model organisms&#x2014;prefer to ferment glucose, even when oxygen is available. Species that favor the latter respiro-fermentative lifestyle have evolved independently at least twice: once after the whole genome duplication event that lead to <italic>S<\/italic>. <italic>cerevisiae<\/italic>, and once when <italic>S<\/italic>. <italic>pombe<\/italic> and the other fission yeasts evolved.<\/p>\n<p hwp:id=\"p-11\">Thompson et al. have measured mRNA profiles in 15 different species of yeast and reconstructed how the regulation of groups of genes (modules) have evolved over a period of more than 300 million years. They found that modules have diverged proportionally to evolutionary time, with prominent changes in gene regulation being associated with changes in lifestyle (especially changes in carbon metabolism) and a whole genome duplication event.<\/p>\n<p hwp:id=\"p-12\">Gene duplication events result in gene paralogs&#x2014;identical genes at different places in the genome&#x2014;and these have made significant contributions to the evolution of different forms of gene regulation, especially just after the duplication event. Moreover, the paralogs produced in whole genome duplication events have resulted in bigger changes over longer periods of time. Similar patterns were observed in the regulation of the genes involved in the response to heat shock in eight of the species, which suggests that these are general evolutionary principles.<\/p>\n<p hwp:id=\"p-13\">The changes in gene expression associated with the respiro-fermentative lifestyle may also have implications for our understanding of cancer: healthy cells rely on oxidative phosphorylation to produce energy whereas, similar to yeast cells, most cancerous cells rely on respiro-fermentation. Furthermore, yeast cells and cancer cells both support their rapid growth and proliferation by using glucose for biosynthesis to support cell division, although this process is not fully understood. Normal cells, on the other hand, use glucose primarily for energy and tend not to divide rapidly.<\/p>\n<p hwp:id=\"p-14\">Thompson et al. found that the genes encoding enzymes in two biosynthetic pathways&#x2014;one that produces the nucleotides necessary for DNA replication, and one that synthesizes glycine&#x2014;are induced in respiro-fermentative yeasts but repressed in respiratory yeast cells. The fact that similar changes are observed in the same two pathways when normal cells become cancer cells suggests that these pathways have an important role in the development of cancer. The framework developed by Thompson et al. could also be used to explore the evolution of gene regulation in other species and biological processes.<\/p>\n<p hwp:id=\"p-15\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00603.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00603.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00603.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00603",
"title": "Evolutionary principles of modular gene regulation in yeasts",
"metadata": {
"authors": "D. A. Thompson, S. Roy, M. Chan, M. P. Styczynsky, J. Pfiffner, C. French, A. Socha, A. Thielke, S. Napolitano, P. Muller, M. Kellis, J. H. Konieczka, I. Wapinski, A. Regev",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:34:14Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:34:14Z",
"updated_at": "2013-07-25T09:34:14Z"
},
{
"id": 127,
"content": "Although aging might seem to be a passive process\u2014resulting simply from wear and tear over a lifetime\u2014it can actually be accelerated or slowed down by genetic mutations. This phenomenon has been most thoroughly studied in the nematode worm, Caenorhabditis elegans. Normally, this worm lives for just two or three weeks, but genetic mutations that reduce the activity of certain enzymes in a series of biochemical reactions known as the insulin\/IGF-1 signalling pathway can extend its lifespan by up to a factor of ten, and similar effects have been seen in flies and mice. Lifespans can also be increased by blocking other signalling pathways or restricting the intake of calories.This increase in lifespan associated with the insulin\/IGF-1 signalling pathway is known to involve a protein called DAF-16 and two kinases called AKT-1 and AKT-2. Under normal conditions the AKT kinases add several phosphate groups to the DAF-16, which prevents it from travelling to the nucleus of the cell. However, when genetic techniques are used to block the insulin\/IGF-1 signalling pathway, the AKT kinases are unable to add the phosphate groups; this leaves the DAF-16 free to enter the nucleus, where it activates a network of genes that promotes longevity.In addition to kinases, the insulin\/IGF-1 signalling pathway also involves enzymes called phosphatases that remove the phosphate groups from other proteins. In particular, a phosphatase called calcineurin is known to be involved in the regulation of lifespan, but the details of this process are not fully understood.Now, Tao et al. have carried out a series of genetic and biochemical experiments to determine how phosphatases exert their influence on aging. The results show that calcineurin targets DAF-16, the same protein that is targeted by the AKT kinases. Moreover, another kinase also targets DAF-16 when the worm is exposed to heat, starvation or some other form of stress: this kinase, which is not involved in the insulin\/IGF-1 signalling pathway, is called CAMKII.Tao et al. show that these kinases act on DAF-16 in different ways: CAMKII activates it by adding the phosphate group at a specific site known as S286, whereas the AKT kinases deactivate DAF-16 because they add phosphate groups at different sites, thereby preventing it from entering the nucleus. Calcineurin neutralizes the effect of CAMKII by removing the phosphate group at S286 to deactivate the DAF-16.In addition to shedding new light on the regulation of lifespan in C. elegans, the new results could improve our understanding of aging in humans, and also the development of diabetes and other age-related diseases, because the equivalent molecules in mammalian cells are regulated in similar ways.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00518.002",
"content_html": "<p hwp:id=\"p-4\">Although aging might seem to be a passive process&#x2014;resulting simply from wear and tear over a lifetime&#x2014;it can actually be accelerated or slowed down by genetic mutations. This phenomenon has been most thoroughly studied in the nematode worm, <italic>Caenorhabditis elegans<\/italic>. Normally, this worm lives for just two or three weeks, but genetic mutations that reduce the activity of certain enzymes in a series of biochemical reactions known as the insulin\/IGF-1 signalling pathway can extend its lifespan by up to a factor of ten, and similar effects have been seen in flies and mice. Lifespans can also be increased by blocking other signalling pathways or restricting the intake of calories.<\/p>\n<p hwp:id=\"p-5\">This increase in lifespan associated with the insulin\/IGF-1 signalling pathway is known to involve a protein called DAF-16 and two kinases called AKT-1 and AKT-2. Under normal conditions the AKT kinases add several phosphate groups to the DAF-16, which prevents it from travelling to the nucleus of the cell. However, when genetic techniques are used to block the insulin\/IGF-1 signalling pathway, the AKT kinases are unable to add the phosphate groups; this leaves the DAF-16 free to enter the nucleus, where it activates a network of genes that promotes longevity.<\/p>\n<p hwp:id=\"p-6\">In addition to kinases, the insulin\/IGF-1 signalling pathway also involves enzymes called phosphatases that remove the phosphate groups from other proteins. In particular, a phosphatase called calcineurin is known to be involved in the regulation of lifespan, but the details of this process are not fully understood.<\/p>\n<p hwp:id=\"p-7\">Now, Tao et al. have carried out a series of genetic and biochemical experiments to determine how phosphatases exert their influence on aging. The results show that calcineurin targets DAF-16, the same protein that is targeted by the AKT kinases. Moreover, another kinase also targets DAF-16 when the worm is exposed to heat, starvation or some other form of stress: this kinase, which is not involved in the insulin\/IGF-1 signalling pathway, is called CAMKII.<\/p>\n<p hwp:id=\"p-8\">Tao et al. show that these kinases act on DAF-16 in different ways: CAMKII activates it by adding the phosphate group at a specific site known as S286, whereas the AKT kinases deactivate DAF-16 because they add phosphate groups at different sites, thereby preventing it from entering the nucleus<bold>.<\/bold> Calcineurin neutralizes the effect of CAMKII by removing the phosphate group at S286 to deactivate the DAF-16.<\/p>\n<p hwp:id=\"p-9\">In addition to shedding new light on the regulation of lifespan in <italic>C. elegans<\/italic>, the new results could improve our understanding of aging in humans, and also the development of diabetes and other age-related diseases, because the equivalent molecules in mammalian cells are regulated in similar ways.<\/p>\n<p hwp:id=\"p-10\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00518.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00518.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00518.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00518",
"title": "CAMKII and Calcineurin regulate the lifespan of Caenorhabditis elegans through the FOXO transcription factor DAF-16",
"metadata": {
"authors": "L. Tao, Q. Xie, Y.-H. Ding, S.-T. Li, S. Peng, Y.-P. Zhang, D. Tan, Z. Yuan, M.-Q. Dong",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:34:22Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:34:22Z",
"updated_at": "2013-07-25T09:34:22Z"
},
{
"id": 128,
"content": "The hippocampus is a seahorse-shaped structure in the brain and its role in memory has been recognized since the 1950s. However, much less is known about two small structures called the mammillary bodies that are found near the hippocampus. These bodies are part of the limbic system\u2014a network of brain regions that also includes the hippocampus and the amygdala\u2014and this system is known to be involved in the regulation of emotion and the formation of long-term memories.In 1937, James Papez injected rabies virus into the hippocampus and, by tracing its movement through the brain, identified a distinct circuit within the limbic system. This circuit, which is today known as Papez\u2019 circuit, consists of projections from the hippocampal formation to the mammillary bodies, and from the mammillary bodies on to another region called the anterior thalamus. From here, projections form a loop via several other regions back to the hippocampus.It is widely thought that the mammillary bodies are required for memory formation due to their role in relaying projections from the hippocampus. However, the mammillary bodies also receive projections from other regions, including Gudden's ventral tegmental nucleus, and it is possible that these could contribute to the role of the mammillary bodies in memory.To distinguish between these possibilities, Seralynne Vann compared the performance of three groups of lesioned rats in tests of spatial short-term memory. The first group had lesions of the hippocampal inputs to the mammillary bodies; the second had lesions of the ventral tegmental inputs to the mammillary bodies; and the third group had lesions of the mammillary body outputs to the thalamus. Vann found that the third group was impaired in the memory tasks, consistent with the idea that outputs sent from the mammillary bodies to the thalamus are required for memory formation. Surprisingly, however, blocking signals sent from the hippocampal formation to the mammillary bodies had little impact on the formation of memories, whereas blocking inputs from Gudden's ventral tegmental nucleus led to significant impairments in memory.By revealing that limbic midbrain inputs to the mammillary bodies have an essential role in the formation of memories, these new results challenge dogma in the field, and highlight the importance of looking beyond the hippocampus when considering memory.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00736.002",
"content_html": "<p hwp:id=\"p-4\">The hippocampus is a seahorse-shaped structure in the brain and its role in memory has been recognized since the 1950s. However, much less is known about two small structures called the mammillary bodies that are found near the hippocampus. These bodies are part of the limbic system&#x2014;a network of brain regions that also includes the hippocampus and the amygdala&#x2014;and this system is known to be involved in the regulation of emotion and the formation of long-term memories.<\/p>\n<p hwp:id=\"p-5\">In 1937, James Papez injected rabies virus into the hippocampus and, by tracing its movement through the brain, identified a distinct circuit within the limbic system. This circuit, which is today known as Papez&#x2019; circuit, consists of projections from the hippocampal formation to the mammillary bodies, and from the mammillary bodies on to another region called the anterior thalamus. From here, projections form a loop via several other regions back to the hippocampus.<\/p>\n<p hwp:id=\"p-6\">It is widely thought that the mammillary bodies are required for memory formation due to their role in relaying projections from the hippocampus. However, the mammillary bodies also receive projections from other regions, including Gudden's ventral tegmental nucleus, and it is possible that these could contribute to the role of the mammillary bodies in memory.<\/p>\n<p hwp:id=\"p-7\">To distinguish between these possibilities, Seralynne Vann compared the performance of three groups of lesioned rats in tests of spatial short-term memory. The first group had lesions of the hippocampal inputs to the mammillary bodies; the second had lesions of the ventral tegmental inputs to the mammillary bodies; and the third group had lesions of the mammillary body outputs to the thalamus. Vann found that the third group was impaired in the memory tasks, consistent with the idea that outputs sent from the mammillary bodies to the thalamus are required for memory formation. Surprisingly, however, blocking signals sent from the hippocampal formation to the mammillary bodies had little impact on the formation of memories, whereas blocking inputs from Gudden's ventral tegmental nucleus led to significant impairments in memory.<\/p>\n<p hwp:id=\"p-8\">By revealing that limbic midbrain inputs to the mammillary bodies have an essential role in the formation of memories, these new results challenge dogma in the field, and highlight the importance of looking beyond the hippocampus when considering memory.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00736.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00736.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00736.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00736",
"title": "Dismantling the Papez circuit for memory in rats",
"metadata": {
"authors": "S. D. Vann",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:34:24Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:34:24Z",
"updated_at": "2013-07-25T09:34:24Z"
},
{
"id": 129,
"content": "Patients with Alzheimer's disease often forget where they have been or who they have just met. This happens because the neurons in those areas of the brain where memories are processed are dying. Indeed, by the time Alzheimer's disease has been diagnosed, many of the neurons in these regions have already died. The symptoms of Alzheimer's disease are then produced by the remaining neurons. However, the reasons why the remaining neurons cannot make new memories are unknown.In normal mice the neurons in the hippocampus, a part of the brain that is important for memory, are called \u2018place cells\u2019 because they are turned on when the mouse is in a specific place. As a consequence, when the mice moves around, different neurons are turned on one by one, and this sequence of activation is believed to be a memory code that represents the places the animal has travelled.Cheng and Ji have explored this phenomenon in mice that have been genetically engineered so that their neurons contain structures called \u2018tau tangles\u2019 that are thought to be involved in the death of neurons. More importantly, these transgenic mice suffer age-dependent neuron loss in a way that is similarly to people with Alzheimer's disease.Cheng and Ji implanted tiny sensors into the hippocampus of these mice, and used these sensors to monitor the activity of the remaining hippocampal neurons as the mice moved around while searching for food. They found that the neurons were activated almost everywhere, which indicates that the hippocampal neurons in transgenic mice are no longer working as place cells. However, these neurons were still activated one by one in robust sequences. Moreover, the sequences generated by the transgenic mice were the same in many different surroundings, which suggests that these sequences are not memory codes of the animal's current surroundings. Cheng and Ji propose that the sequences reflect existing memories already stored in the brain, which would suggest that Alzheimer's patients cannot form new memories because the brain is preoccupied by old memories, and thus fails to store the new information that is coming in from the outside world.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00647.002",
"content_html": "<p hwp:id=\"p-4\">Patients with Alzheimer's disease often forget where they have been or who they have just met. This happens because the neurons in those areas of the brain where memories are processed are dying. Indeed, by the time Alzheimer's disease has been diagnosed, many of the neurons in these regions have already died. The symptoms of Alzheimer's disease are then produced by the remaining neurons. However, the reasons why the remaining neurons cannot make new memories are unknown.<\/p>\n<p hwp:id=\"p-5\">In normal mice the neurons in the hippocampus, a part of the brain that is important for memory, are called &#x2018;place cells&#x2019; because they are turned on when the mouse is in a specific place. As a consequence, when the mice moves around, different neurons are turned on one by one, and this sequence of activation is believed to be a memory code that represents the places the animal has travelled.<\/p>\n<p hwp:id=\"p-6\">Cheng and Ji have explored this phenomenon in mice that have been genetically engineered so that their neurons contain structures called &#x2018;tau tangles&#x2019; that are thought to be involved in the death of neurons. More importantly, these transgenic mice suffer age-dependent neuron loss in a way that is similarly to people with Alzheimer's disease.<\/p>\n<p hwp:id=\"p-7\">Cheng and Ji implanted tiny sensors into the hippocampus of these mice, and used these sensors to monitor the activity of the remaining hippocampal neurons as the mice moved around while searching for food. They found that the neurons were activated almost everywhere, which indicates that the hippocampal neurons in transgenic mice are no longer working as place cells. However, these neurons were still activated one by one in robust sequences. Moreover, the sequences generated by the transgenic mice were the same in many different surroundings, which suggests that these sequences are not memory codes of the animal's current surroundings. Cheng and Ji propose that the sequences reflect existing memories already stored in the brain, which would suggest that Alzheimer's patients cannot form new memories because the brain is preoccupied by old memories, and thus fails to store the new information that is coming in from the outside world.<\/p>\n<p hwp:id=\"p-8\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00647.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00647.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00647.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00647",
"title": "Rigid firing sequences undermine spatial memory codes in a neurodegenerative mouse model",
"metadata": {
"authors": "J. Cheng, D. Ji",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:34:27Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:34:27Z",
"updated_at": "2013-07-25T09:34:27Z"
},
{
"id": 130,
"content": "As medicine becomes increasingly personalized, more and more emphasis is being placed on the development of therapies that target specific cancer-causing mutations. But while many of these drugs are effective in the short term, and do extend patient lives, tumors tend to evolve resistance to them within a few months.The key problem is that large tumors are genetically diverse. This means that for any given treatment, there is likely to be a small population of cells within the tumor that is resistant to the effects of the drug. When the drug is given to a patient, these cells will survive and multiply and this will lead ultimately to treatment failure. Given that a single drug is therefore highly unlikely to eradicate a tumor, combinations of two or more drugs may offer a higher chance of cure. This approach has been effective in the treatment of HIV as well as certain forms of leukemia.Here, Bozic et al. present a mathematical model designed to predict the effects of combination targeted therapies on tumors, based on the data obtained from 20 melanoma (skin cancer) patients. Their model revealed that if even 1 of the 6.6 billion base pairs of DNA present in a human diploid cell has undergone a mutation that confers resistance to each of two drugs, treatment with those drugs will not lead to sustained improvement for the majority of patients. This confirms the need to develop drugs that target distinct pathways.The model also reveals that combination therapy with two drugs given simultaneously is far more effective than sequential therapy where the drugs are used one after the other. Indeed, the model of Bozic et al. indicates that sequential treatment offers no chance of a cure, even when there are no cross-resistance mutations present, whereas combination therapy offers some hope of a cure, even in the presence of cross-resistance mutations.By emphasizing the need to develop drugs that target distinct pathways, and to administer them in combination rather than sequentially, the study by Bozic et al. offers valuable advice for drug development and the design of clinical trials, as well as for clinical practice.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00747.002",
"content_html": "<p hwp:id=\"p-5\">As medicine becomes increasingly personalized, more and more emphasis is being placed on the development of therapies that target specific cancer-causing mutations. But while many of these drugs are effective in the short term, and do extend patient lives, tumors tend to evolve resistance to them within a few months.<\/p>\n<p hwp:id=\"p-6\">The key problem is that large tumors are genetically diverse. This means that for any given treatment, there is likely to be a small population of cells within the tumor that is resistant to the effects of the drug. When the drug is given to a patient, these cells will survive and multiply and this will lead ultimately to treatment failure. Given that a single drug is therefore highly unlikely to eradicate a tumor, combinations of two or more drugs may offer a higher chance of cure. This approach has been effective in the treatment of HIV as well as certain forms of leukemia.<\/p>\n<p hwp:id=\"p-7\">Here, Bozic et al. present a mathematical model designed to predict the effects of combination targeted therapies on tumors, based on the data obtained from 20 melanoma (skin cancer) patients. Their model revealed that if even 1 of the 6.6 billion base pairs of DNA present in a human diploid cell has undergone a mutation that confers resistance to each of two drugs, treatment with those drugs will not lead to sustained improvement for the majority of patients. This confirms the need to develop drugs that target distinct pathways.<\/p>\n<p hwp:id=\"p-8\">The model also reveals that combination therapy with two drugs given simultaneously is far more effective than sequential therapy where the drugs are used one after the other. Indeed, the model of Bozic et al. indicates that sequential treatment offers no chance of a cure, even when there are no cross-resistance mutations present, whereas combination therapy offers some hope of a cure, even in the presence of cross-resistance mutations.<\/p>\n<p hwp:id=\"p-9\">By emphasizing the need to develop drugs that target distinct pathways, and to administer them in combination rather than sequentially, the study by Bozic et al. offers valuable advice for drug development and the design of clinical trials, as well as for clinical practice.<\/p>\n<p hwp:id=\"p-10\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00747.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00747.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00747.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00747",
"title": "Evolutionary dynamics of cancer in response to targeted combination therapy",
"metadata": {
"authors": "I. Bozic, J. G. Reiter, B. Allen, T. Antal, K. Chatterjee, P. Shah, Y. S. Moon, A. Yaqubie, N. Kelly, D. T. Le, E. J. Lipson, P. B. Chapman, L. A. Diaz, B. Vogelstein, M. A. Nowak",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:34:29Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:34:29Z",
"updated_at": "2013-07-25T09:34:29Z"
},
{
"id": 131,
"content": "Many organisms build up reserves of food when it is available so that metabolism and growth can continue when food is no longer available. Plants, for example, use energy from the sun to produce starch during the day, which is then used as a source of energy during the night. In some plants the amount of starch increases linearly with time during the day, and declines linearly with time during the night, so that the plant contains very little starch when the sun rises the following day. Although a plant is likely to starve if it cannot store or consume starch effectively, very little is known about the mechanisms that plants use to ensure that they store enough starch and do not use it up too quickly.Plants are able to track the time to dawn using their internal circadian clock so, as Scialdone et al. point out, if they can also track how much starch they have stored, they might somehow be dividing the amount of starch by the time to dawn to work out the rate at which starch can be consumed so that it lasts until sunrise. But could plants actually perform such calculations?To gain some insight into this puzzle, Scialdone et al. constructed mathematical models in which information about the size of the starch store and the time until dawn was encoded in the concentrations of two kinds of molecules (called S for starch and T for time). In one model, they propose that the S molecules stimulate starch consumption, and the T molecules prevent this from happening, with the rate of starch consumption being equal to the concentration of S molecules divided by the concentration of T molecules. These models were able to reproduce the results of previous experiments, including experiments in which dawn arrived unexpectedly early or unexpectedly late.Scialdone et al. then performed experiments which confirmed predictions of the models for the pattern of starch consumption in plants lacking relevant enzymes. These experiments also revealed that an enzyme called PWD may be the point at which results of the division computation are integrated into the starch consumption pathway. More generally, this work shows that sophisticated arithmetic computations can be important in biology. Moreover, whereas computers rely on digital logic, Scialdone et al. show that arithmetic computations can also be performed by exploiting the analogue dynamics that take place between molecules.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00669.002",
"content_html": "<p hwp:id=\"p-6\">Many organisms build up reserves of food when it is available so that metabolism and growth can continue when food is no longer available. Plants, for example, use energy from the sun to produce starch during the day, which is then used as a source of energy during the night. In some plants the amount of starch increases linearly with time during the day, and declines linearly with time during the night, so that the plant contains very little starch when the sun rises the following day. Although a plant is likely to starve if it cannot store or consume starch effectively, very little is known about the mechanisms that plants use to ensure that they store enough starch and do not use it up too quickly.<\/p>\n<p hwp:id=\"p-7\">Plants are able to track the time to dawn using their internal circadian clock so, as Scialdone et al. point out, if they can also track how much starch they have stored, they might somehow be dividing the amount of starch by the time to dawn to work out the rate at which starch can be consumed so that it lasts until sunrise. But could plants actually perform such calculations?<\/p>\n<p hwp:id=\"p-8\">To gain some insight into this puzzle, Scialdone et al. constructed mathematical models in which information about the size of the starch store and the time until dawn was encoded in the concentrations of two kinds of molecules (called <italic>S<\/italic> for starch and <italic>T<\/italic> for time). In one model, they propose that the <italic>S<\/italic> molecules stimulate starch consumption, and the <italic>T<\/italic> molecules prevent this from happening, with the rate of starch consumption being equal to the concentration of <italic>S<\/italic> molecules divided by the concentration of <italic>T<\/italic> molecules. These models were able to reproduce the results of previous experiments, including experiments in which dawn arrived unexpectedly early or unexpectedly late.<\/p>\n<p hwp:id=\"p-9\">Scialdone et al. then performed experiments which confirmed predictions of the models for the pattern of starch consumption in plants lacking relevant enzymes. These experiments also revealed that an enzyme called PWD may be the point at which results of the division computation are integrated into the starch consumption pathway. More generally, this work shows that sophisticated arithmetic computations can be important in biology. Moreover, whereas computers rely on digital logic, Scialdone et al. show that arithmetic computations can also be performed by exploiting the analogue dynamics that take place between molecules.<\/p>\n<p hwp:id=\"p-10\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00669.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00669.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00669.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00669",
"title": "Arabidopsis plants perform arithmetic division to prevent starvation at night",
"metadata": {
"authors": "A. Scialdone, S. T. Mugford, D. Feike, A. Skeffington, P. Borrill, A. Graf, A. M. Smith, M. Howard",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:34:32Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:34:32Z",
"updated_at": "2013-07-25T09:34:32Z"
},
{
"id": 132,
"content": "Ammonium provides a vital source of nitrogen for bacteria, fungi and plants, and is produced by animals as a waste product of metabolism. High levels of ammonium can be toxic, so all organisms need to control their uptake or excretion of this substance. Ammonium transporters, which are highly conserved from bacteria to plants to humans, are essential for this process but, along with transporters in general, they are hard to study. Their activity can be examined in vitro by expressing them in heterologous systems\u2014that is, in cells other than those in which they are naturally found. But in vivo studies must rely on indirect techniques such as monitoring radioactive isotopes or membrane potentials, and these cannot distinguish between the activity of ammonium transporters and uptake of ammonium through other routes.One approach that has been successful in other fields is the use of fluorescent proteins that can signal conformational changes\u2014such as those that occur when a transporter is activated\u2014by a shift in fluorescence. Green fluorescent protein (GFP) is a commonly used fluorescent indicator, and a particularly useful variant is \u2018circularly permutated GFP\u2019. This is GFP in which parts of the amino acid sequence have been rearranged without fundamentally changing the overall structure or function of the protein. Circularly permutated GFP can be fused to another protein in such a way that a conformational change in the second protein triggers a change in fluorescence that can be detected by fluorescence spectroscopy or microscopy.Now, De Michele et al. have applied this approach to the study of both plant and yeast ammonium transporters. They constructed a library of fusion proteins made up of circularly permutated GFP and an ammonium transporter from the plant Arabidopsis thaliana\u2014and found one version that functioned normally as a transporter but also produced a detectable change in fluorescence that correlated precisely with transporter activity.De Michele et al. then used the same method to produce fluorescent indicator fusion proteins of two more ammonium transporters\u2014a second isoform from Arabidopsis and one from yeast. These fluorescent sensors should be a great boon to researchers studying the ammonium transport system. Moreover, this approach could in theory be applied to other transporter proteins that are currently difficult to study, and so could help to open up research into a variety of transport processes.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00800.002",
"content_html": "<p hwp:id=\"p-5\">Ammonium provides a vital source of nitrogen for bacteria, fungi and plants, and is produced by animals as a waste product of metabolism. High levels of ammonium can be toxic, so all organisms need to control their uptake or excretion of this substance. Ammonium transporters, which are highly conserved from bacteria to plants to humans, are essential for this process but, along with transporters in general, they are hard to study. Their activity can be examined in vitro by expressing them in heterologous systems&#x2014;that is, in cells other than those in which they are naturally found. But in vivo studies must rely on indirect techniques such as monitoring radioactive isotopes or membrane potentials, and these cannot distinguish between the activity of ammonium transporters and uptake of ammonium through other routes.<\/p>\n<p hwp:id=\"p-6\">One approach that has been successful in other fields is the use of fluorescent proteins that can signal conformational changes&#x2014;such as those that occur when a transporter is activated&#x2014;by a shift in fluorescence. Green fluorescent protein (GFP) is a commonly used fluorescent indicator, and a particularly useful variant is &#x2018;circularly permutated GFP&#x2019;. This is GFP in which parts of the amino acid sequence have been rearranged without fundamentally changing the overall structure or function of the protein. Circularly permutated GFP can be fused to another protein in such a way that a conformational change in the second protein triggers a change in fluorescence that can be detected by fluorescence spectroscopy or microscopy.<\/p>\n<p hwp:id=\"p-7\">Now, De Michele et al. have applied this approach to the study of both plant and yeast ammonium transporters. They constructed a library of fusion proteins made up of circularly permutated GFP and an ammonium transporter from the plant <italic>Arabidopsis thaliana<\/italic>&#x2014;and found one version that functioned normally as a transporter but also produced a detectable change in fluorescence that correlated precisely with transporter activity.<\/p>\n<p hwp:id=\"p-8\">De Michele et al. then used the same method to produce fluorescent indicator fusion proteins of two more ammonium transporters&#x2014;a second isoform from <italic>Arabidopsis<\/italic> and one from yeast. These fluorescent sensors should be a great boon to researchers studying the ammonium transport system. Moreover, this approach could in theory be applied to other transporter proteins that are currently difficult to study, and so could help to open up research into a variety of transport processes.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00800.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00800.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00800.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00800",
"title": "Fluorescent sensors reporting the activity of ammonium transceptors in live cells",
"metadata": {
"authors": "R. De Michele, C. Ast, D. Loque, C.-H. Ho, S. L. Andrade, V. Lanquar, G. Grossmann, S. Gehne, M. U. Kumke, W. B. Frommer",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:34:36Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:34:36Z",
"updated_at": "2013-07-25T09:34:36Z"
},
{
"id": 133,
"content": "The roundworm C. elegans is a key model organism in neuroscience. It has a simple nervous system, made up of just 302 neurons, and was the first multicellular organism to have its genome fully sequenced. The lifecycle of C. elegans begins with an embryonic stage, followed by four larval stages and then adulthood, and worms can progress through this cycle in only three days. However, relatively little is known about how the behaviour of the worms varies across these distinct developmental phases.The body wall of C. elegans contains pairs of muscles that extend along its length, and when waves of muscle contraction travel along its body, the worm undergoes a sinusoidal pattern of movement. A signalling cascade involving a molecule called protein kinase A is thought to help control these movements, and upregulation of this cascade has been shown to increase locomotion.Now, Nagy et al. have analysed the movement of C. elegans during these different stages of development. This involved developing an image processing tool that can analyze the position and posture of a worm\u2019s body in each of three million (or more) images per day. Using this tool, which is called PyCelegans, Nagy et al. identified two behavioral macro-states in one of the larval forms of C. elegans: these states, which can persist for hours, are referred to as active wakefulness and quiet wakefulness. During periods of active wakefulness, the worms spent most (but not all) of their time moving forwards; during quiet wakefulness, they remained largely still.The worms switched abruptly between these two states, and the transition seemed to be regulated by PKA signaling. By using PyCelegans to compare locomotion in worms with mutations in genes encoding various components of this pathway, Nagy et al. showed that mutants with increased PKA activity spent more time in a state of active wakefulness, while the opposite was true for worms with mutations that reduced PKA activity.In addition to providing new insights into the control of locomotion in C. elegans, this study has provided a new open-source PyCelegans suite of tools, which are available to be extended and adapted by other researchers for new uses.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00782.002",
"content_html": "<p hwp:id=\"p-4\">The roundworm <italic>C. elegans<\/italic> is a key model organism in neuroscience. It has a simple nervous system, made up of just 302 neurons, and was the first multicellular organism to have its genome fully sequenced. The lifecycle of <italic>C. elegans<\/italic> begins with an embryonic stage, followed by four larval stages and then adulthood, and worms can progress through this cycle in only three days. However, relatively little is known about how the behaviour of the worms varies across these distinct developmental phases.<\/p>\n<p hwp:id=\"p-5\">The body wall of <italic>C. elegans<\/italic> contains pairs of muscles that extend along its length, and when waves of muscle contraction travel along its body, the worm undergoes a sinusoidal pattern of movement. A signalling cascade involving a molecule called protein kinase A is thought to help control these movements, and upregulation of this cascade has been shown to increase locomotion.<\/p>\n<p hwp:id=\"p-6\">Now, Nagy et al. have analysed the movement of <italic>C. elegans<\/italic> during these different stages of development. This involved developing an image processing tool that can analyze the position and posture of a worm&#x2019;s body in each of three million (or more) images per day. Using this tool, which is called PyCelegans, Nagy et al. identified two behavioral macro-states in one of the larval forms of <italic>C. elegans<\/italic>: these states, which can persist for hours, are referred to as active wakefulness and quiet wakefulness. During periods of active wakefulness, the worms spent most (but not all) of their time moving forwards; during quiet wakefulness, they remained largely still.<\/p>\n<p hwp:id=\"p-7\">The worms switched abruptly between these two states, and the transition seemed to be regulated by PKA signaling. By using PyCelegans to compare locomotion in worms with mutations in genes encoding various components of this pathway, Nagy et al. showed that mutants with increased PKA activity spent more time in a state of active wakefulness, while the opposite was true for worms with mutations that reduced PKA activity.<\/p>\n<p hwp:id=\"p-8\">In addition to providing new insights into the control of locomotion in <italic>C. elegans<\/italic>, this study has provided a new open-source PyCelegans suite of tools, which are available to be extended and adapted by other researchers for new uses.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00782.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00782.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00782.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00782",
"title": "A longitudinal study of Caenorhabditis elegans larvae reveals a novel locomotion switch, regulated by G&#xA0;s signaling",
"metadata": {
"authors": "S. Nagy, C. Wright, N. Tramm, N. Labello, S. Burov, D. Biron",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:34:39Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:34:39Z",
"updated_at": "2013-07-25T09:34:39Z"
},
{
"id": 134,
"content": "The tunicates are an evolutionary group that includes species such as sea squirts and sea tulips. Their name comes from the structure known as a \u2018tunic\u2019 that surrounds their sac-like bodies. As marine filter feeders, tunicates obtain nutrients by straining food particles from water, and they can live either alone or in colonies depending on the species. Charles Darwin suggested that tunicates may be the key to understanding the evolution of vertebrates, and indeed today they are regarded as the closest living relatives of this group.Colonial tunicates can reproduce either sexually, or asexually by budding. Compatible colonies have the ability to recognize one another and to fuse their blood vessels to form a single organism, whereas incompatible colonies reject one another and remain separate. This recognition process bears some resemblance to the rejection of foreign organ transplants in mammals.Here, Voskoboynik and co-workers present the first genome sequence of a colonial tunicate, Botryllus schlosseri. They used a novel sequencing approach that significantly increased the length of a DNA molecule that can be determined by next-generation sequencing, and allowed large DNA repeat regions to be easily resolved. In total, they sequenced 580 million base pairs of DNA, which they estimate contains roughly 27,000 genes.By comparing the B. schlosseri genome with those of a number of vertebrates, Voskoboynik et al. identified multiple B. schlosseri genes that also participate in the development and functioning of the vertebrate eye, heart, and auditory system, as well as others that may have contributed to the evolution of the immune system and of blood cells. The genome of B. schlosseri thus provides an important new tool for studying the genetic basis of the evolution of vertebrates.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00569.002",
"content_html": "<p hwp:id=\"p-5\">The tunicates are an evolutionary group that includes species such as sea squirts and sea tulips. Their name comes from the structure known as a &#x2018;tunic&#x2019; that surrounds their sac-like bodies. As marine filter feeders, tunicates obtain nutrients by straining food particles from water, and they can live either alone or in colonies depending on the species. Charles Darwin suggested that tunicates may be the key to understanding the evolution of vertebrates, and indeed today they are regarded as the closest living relatives of this group.<\/p>\n<p hwp:id=\"p-6\">Colonial tunicates can reproduce either sexually, or asexually by budding. Compatible colonies have the ability to recognize one another and to fuse their blood vessels to form a single organism, whereas incompatible colonies reject one another and remain separate. This recognition process bears some resemblance to the rejection of foreign organ transplants in mammals.<\/p>\n<p hwp:id=\"p-7\">Here, Voskoboynik and co-workers present the first genome sequence of a colonial tunicate, <italic>Botryllus schlosseri.<\/italic> They used a novel sequencing approach that significantly increased the length of a DNA molecule that can be determined by next-generation sequencing, and allowed large DNA repeat regions to be easily resolved. In total, they sequenced 580 million base pairs of DNA, which they estimate contains roughly 27,000 genes.<\/p>\n<p hwp:id=\"p-8\">By comparing the <italic>B. schlosseri<\/italic> genome with those of a number of vertebrates, Voskoboynik et al. identified multiple <italic>B. schlosseri<\/italic> genes that also participate in the development and functioning of the vertebrate eye, heart, and auditory system, as well as others that may have contributed to the evolution of the immune system and of blood cells. The genome of <italic>B. schlosseri<\/italic> thus provides an important new tool for studying the genetic basis of the evolution of vertebrates.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00569.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00569.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00569.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00569",
"title": "The genome sequence of the colonial chordate, Botryllus schlosseri",
"metadata": {
"authors": "A. Voskoboynik, N. F. Neff, D. Sahoo, A. M. Newman, D. Pushkarev, W. Koh, B. Passarelli, H. C. Fan, G. L. Mantalas, K. J. Palmeri, K. J. Ishizuka, C. Gissi, F. Griggio, R. Ben-Shlomo, D. M. Corey, L. Penland, R. A. White, I. L. Weissman, S. R. Quake",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:34:44Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:34:44Z",
"updated_at": "2013-07-25T09:34:44Z"
},
{
"id": 135,
"content": "The ability to launch an immune response is not unique to animals. Plants have also evolved the ability to detect molecules present on the surface of pathogens such as fungi. These molecular signatures are known as pathogen-associated molecular patterns (PAMPs), and they are detected by specialized receptors on the surface of plant cells.Chitin, the main structural component of the cell wall in fungi, is one example of a PAMP. Many species of plants are able to detect chitin using receptors that contain sequences of amino acids called lysin motifs. Previous work in the model plant Arabidopsis has shown that chitin binds to a single lysin motif within each plant receptor.However, just as plants have evolved the ability to recognize PAMPs, so fungi have evolved ways to outwit plants. They have developed small molecules called effector proteins that bind to PAMPs, in effect hiding them from the plant receptors. The tomato fungus Cladosporium fulvum, for example, secretes an effector protein called Ecp6, which contains lysin motifs just like those in the plant receptors. By binding chitin fragments, Ecp6 helps the fungus to avoid detection by its host plant.Now, S\u00e1nchez-Vallet et al. present the high resolution crystal structure of Ecp6 and reveal the mechanism by which it outcompetes the plant\u2019s own chitin receptors. In the presence of chitin, two lysin binding motifs within the Ecp6 protein combine to produce a binding site with ultrahigh affinity for chitin. This can outcompete the plant receptors, which use only a single lysin domain to bind the fungal protein.As well as providing a molecular explanation for how certain fungi manage to evade the immune response in plants, the work of S\u00e1nchez-Vallet et al. offers an unusual example of convergent evolution, in which two evolutionarily distant organisms have evolved the ability to recognize the same molecule through structurally diverse proteins.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00790.002",
"content_html": "<p hwp:id=\"p-6\">The ability to launch an immune response is not unique to animals. Plants have also evolved the ability to detect molecules present on the surface of pathogens such as fungi. These molecular signatures are known as pathogen-associated molecular patterns (PAMPs), and they are detected by specialized receptors on the surface of plant cells.<\/p>\n<p hwp:id=\"p-7\">Chitin, the main structural component of the cell wall in fungi, is one example of a PAMP. Many species of plants are able to detect chitin using receptors that contain sequences of amino acids called lysin motifs. Previous work in the model plant Arabidopsis has shown that chitin binds to a single lysin motif within each plant receptor.<\/p>\n<p hwp:id=\"p-8\">However, just as plants have evolved the ability to recognize PAMPs, so fungi have evolved ways to outwit plants. They have developed small molecules called effector proteins that bind to PAMPs, in effect hiding them from the plant receptors. The tomato fungus <italic>Cladosporium fulvum<\/italic>, for example, secretes an effector protein called Ecp6, which contains lysin motifs just like those in the plant receptors. By binding chitin fragments, Ecp6 helps the fungus to avoid detection by its host plant.<\/p>\n<p hwp:id=\"p-9\">Now, S&#xE1;nchez-Vallet et al. present the high resolution crystal structure of Ecp6 and reveal the mechanism by which it outcompetes the plant&#x2019;s own chitin receptors. In the presence of chitin, two lysin binding motifs within the Ecp6 protein combine to produce a binding site with ultrahigh affinity for chitin. This can outcompete the plant receptors, which use only a single lysin domain to bind the fungal protein.<\/p>\n<p hwp:id=\"p-10\">As well as providing a molecular explanation for how certain fungi manage to evade the immune response in plants, the work of S&#xE1;nchez-Vallet et al. offers an unusual example of convergent evolution, in which two evolutionarily distant organisms have evolved the ability to recognize the same molecule through structurally diverse proteins.<\/p>\n<p hwp:id=\"p-11\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00790.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00790.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00790.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00790",
"title": "Fungal effector Ecp6 outcompetes host immune receptor for chitin binding through intrachain LysM dimerization",
"metadata": {
"authors": "A. Sanchez-Vallet, R. Saleem-Batcha, A. Kombrink, G. Hansen, D.-J. Valkenburg, B. P. Thomma, J. R. Mesters",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:34:46Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:34:46Z",
"updated_at": "2013-07-25T09:34:46Z"
},
{
"id": 136,
"content": "The immune system identifies and combats foreign objects, including pathogens, in the body. T cells are key components of the immune system, and each has a unique variant of a signalling complex known as the T cell receptor on its surface. T cells scan the surfaces of other cells in search of antigens, which are peptides (fragments of proteins) that derive from foreign pathogens such as viruses. Successful recognition of a foreign peptide leads to an immune response that, in most cases, ultimately rids the body of the pathogen. Most importantly, however, the immune system must be able to discriminate between peptides that are produced naturally in the body (\u2018self\u2019 peptides) and foreign or \u2018non-self\u2019 peptides. This is challenging because self peptides may have similar structures to non-self peptides and are often much more abundant.Many models have been proposed to explain how T cells are able to detect just a few molecules of foreign peptide. According to some hypotheses the T cell receptors get together in clusters to function cooperatively; alternatively, it has been suggested that rapid binding of a foreign peptide to multiple T cell receptors sequentially can build up a strong signal. However, none of these phenomena have been directly observed.O'Donoghue et al. now image the interactions between T cell receptors and peptides bound to molecules called major histocompatibility complexes (MHCs), and show that T cell activation can occur when a single foreign peptide binds to a single receptor. These interactions are long-lived and ultimately result in the recruitment of ZAP70, which has an important role in the activation of T cells, to the complex formed by the T cell, the peptide and the MHC molecule. Therefore, any amplification of the activating signal transmitted by non-self peptides occurs following receptor binding, in contrast to previous models.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00778.002",
"content_html": "<p hwp:id=\"p-5\">The immune system identifies and combats foreign objects, including pathogens, in the body. T cells are key components of the immune system, and each has a unique variant of a signalling complex known as the T cell receptor on its surface. T cells scan the surfaces of other cells in search of antigens, which are peptides (fragments of proteins) that derive from foreign pathogens such as viruses. Successful recognition of a foreign peptide leads to an immune response that, in most cases, ultimately rids the body of the pathogen. Most importantly, however, the immune system must be able to discriminate between peptides that are produced naturally in the body (&#x2018;self&#x2019; peptides) and foreign or &#x2018;non-self&#x2019; peptides. This is challenging because self peptides may have similar structures to non-self peptides and are often much more abundant.<\/p>\n<p hwp:id=\"p-6\">Many models have been proposed to explain how T cells are able to detect just a few molecules of foreign peptide. According to some hypotheses the T cell receptors get together in clusters to function cooperatively; alternatively, it has been suggested that rapid binding of a foreign peptide to multiple T cell receptors sequentially can build up a strong signal. However, none of these phenomena have been directly observed.<\/p>\n<p hwp:id=\"p-7\">O'Donoghue et al. now image the interactions between T cell receptors and peptides bound to molecules called major histocompatibility complexes (MHCs), and show that T cell activation can occur when a single foreign peptide binds to a single receptor. These interactions are long-lived and ultimately result in the recruitment of ZAP70, which has an important role in the activation of T cells, to the complex formed by the T cell, the peptide and the MHC molecule. Therefore, any amplification of the activating signal transmitted by non-self peptides occurs following receptor binding, in contrast to previous models.<\/p>\n<p hwp:id=\"p-8\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00778.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00778.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00778.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00778",
"title": "Direct single molecule measurement of TCR triggering by agonist pMHC in living primary T cells",
"metadata": {
"authors": "G. P. O'Donoghue, R. M. Pielak, A. A. Smoligovets, J. J. Lin, J. T. Groves",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:34:55Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:34:55Z",
"updated_at": "2013-07-25T09:34:55Z"
},
{
"id": 137,
"content": "Many physiological processes are directional, which means that tissues and organs often need a sense of spatial orientation in order to function properly. In most tissues, this sense of direction relies on certain proteins and infrastructure components of the cell being located in specific subcellular regions, rather than being distributed in a more symmetrical fashion throughout the cell: the latter phenomenon is known as cell polarity.Exocrine tissues (that is, glands) are composed of tubular epithelial cells organized around a central lumen: the cells in the gland secrete various products (such as enzymes) into the lumen, so that they can be carried to the target organ elsewhere in the body. Epithelial cells in these tissues are therefore polarized to enable directional transport to the lumen. An example of cell polarity is a network of actin filaments that lines the apical surface of these cells (the surface nearest the common lumen). This actin network helps to shuttle cargo to the lumen by assisting with directional, coordinated secretion, among other processes.In fruitflies, the construction of the apical actin network depends on the presence of a protein called Diaphanous. However, the signals that lead to the localization of this protein near the apical membrane of the cells are not well understood. Now Rousso et al. report that a modified lipid, called PI(4,5)P2, is involved in this localization. However, they also show that this lipid does not govern the apical localization of Diaphanous on its own: rather, an enzyme called Rho1 must also be present to assist with the localization of Diaphanous and to ensure that actin is deposited in the correct place. Rousso et al. also demonstrate that PI(4,5)P2-mediated localization of Drosophila Diaphanous occurs in mammalian cells. Lipid-protein collaboration also targets other proteins to the apical membrane. A common mechanism may therefore underlie cell polarity in tubular organ tissues in flies and mammals.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00666.002",
"content_html": "<p hwp:id=\"p-5\">Many physiological processes are directional, which means that tissues and organs often need a sense of spatial orientation in order to function properly. In most tissues, this sense of direction relies on certain proteins and infrastructure components of the cell being located in specific subcellular regions, rather than being distributed in a more symmetrical fashion throughout the cell: the latter phenomenon is known as cell polarity.<\/p>\n<p hwp:id=\"p-6\">Exocrine tissues (that is, glands) are composed of tubular epithelial cells organized around a central lumen: the cells in the gland secrete various products (such as enzymes) into the lumen, so that they can be carried to the target organ elsewhere in the body. Epithelial cells in these tissues are therefore polarized to enable directional transport to the lumen. An example of cell polarity is a network of actin filaments that lines the apical surface of these cells (the surface nearest the common lumen). This actin network helps to shuttle cargo to the lumen by assisting with directional, coordinated secretion, among other processes.<\/p>\n<p hwp:id=\"p-7\">In fruitflies, the construction of the apical actin network depends on the presence of a protein called Diaphanous. However, the signals that lead to the localization of this protein near the apical membrane of the cells are not well understood. Now Rousso et al. report that a modified lipid, called PI(4,5)P<sub>2<\/sub>, is involved in this localization. However, they also show that this lipid does not govern the apical localization of Diaphanous on its own: rather, an enzyme called Rho1 must also be present to assist with the localization of Diaphanous and to ensure that actin is deposited in the correct place. Rousso et al. also demonstrate that PI(4,5)P<sub>2<\/sub>-mediated localization of <italic>Drosophila<\/italic> Diaphanous occurs in mammalian cells. Lipid-protein collaboration also targets other proteins to the apical membrane. A common mechanism may therefore underlie cell polarity in tubular organ tissues in flies and mammals.<\/p>\n<p hwp:id=\"p-8\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00666.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00666.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00666.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00666",
"title": "Apical targeting of the formin Diaphanous in Drosophila tubular epithelia",
"metadata": {
"authors": "T. Rousso, A. M. Shewan, K. E. Mostov, E. D. Schejter, B.-Z. Shilo",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:34:58Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:34:58Z",
"updated_at": "2013-07-25T09:34:58Z"
},
{
"id": 138,
"content": "PTEN is an enzyme that is found in almost every tissue in the body, and its job is to stop cells dividing. If it fails to perform this job, the uncontrolled proliferation of cells can lead to the growth of tumors. PTEN stops cells dividing by localizing at the plasma membrane of a cell and removing a phosphate group from a lipid called PIP3: this sends a signal, via the PI3K pathway, that suppresses the replication and survival of cells.Three regions of PTEN are thought to be central to its biological functions: one of these regions, the phosphatase domain, is directly responsible for removing a phosphate group from the lipid PIP3; a second region, called the C2 domain, is known to be critical for PTEN binding to the cell membrane; however, the role of third region, called the C-terminal domain, is poorly understood.Many proteins are regulated by the addition and removal of phosphate groups, and PTEN is no exception. In particular, it seems as if the addition of phosphate groups to four amino acid residues in the C-terminal domain can switch off the activity of PTEN, but the details of this process have been elusive.Now, Bolduc et al. have employed a variety of biochemical and biophysical techniques to explore this process, finding that the addition of the phosphate groups reduced PTEN\u2019s affinity for the plasma membrane. At the same time, interactions between the C-terminal and C2 domains of the PTEN cause the shape of the enzyme to change in a way that \u2018buries\u2019 the residues to which the phosphate groups have been added.In addition to offering new insights into PTEN, the work of Bolduc et al. could help efforts to identify compounds with clinical anti-cancer potential.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00691.002",
"content_html": "<p hwp:id=\"p-4\">PTEN is an enzyme that is found in almost every tissue in the body, and its job is to stop cells dividing. If it fails to perform this job, the uncontrolled proliferation of cells can lead to the growth of tumors. PTEN stops cells dividing by localizing at the plasma membrane of a cell and removing a phosphate group from a lipid called PIP<sub>3<\/sub>: this sends a signal, via the PI3K pathway, that suppresses the replication and survival of cells.<\/p>\n<p hwp:id=\"p-5\">Three regions of PTEN are thought to be central to its biological functions: one of these regions, the phosphatase domain, is directly responsible for removing a phosphate group from the lipid PIP<sub>3<\/sub>; a second region, called the C2 domain, is known to be critical for PTEN binding to the cell membrane; however, the role of third region, called the C-terminal domain, is poorly understood.<\/p>\n<p hwp:id=\"p-6\">Many proteins are regulated by the addition and removal of phosphate groups, and PTEN is no exception. In particular, it seems as if the addition of phosphate groups to four amino acid residues in the C-terminal domain can switch off the activity of PTEN, but the details of this process have been elusive.<\/p>\n<p hwp:id=\"p-7\">Now, Bolduc et al. have employed a variety of biochemical and biophysical techniques to explore this process, finding that the addition of the phosphate groups reduced PTEN&#x2019;s affinity for the plasma membrane. At the same time, interactions between the C-terminal and C2 domains of the PTEN cause the shape of the enzyme to change in a way that &#x2018;buries&#x2019; the residues to which the phosphate groups have been added.<\/p>\n<p hwp:id=\"p-8\">In addition to offering new insights into PTEN, the work of Bolduc et al. could help efforts to identify compounds with clinical anti-cancer potential.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00691.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00691.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00691.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00691",
"title": "Phosphorylation-mediated PTEN conformational closure and deactivation revealed with protein semisynthesis",
"metadata": {
"authors": "D. Bolduc, M. Rahdar, B. Tu-Sekine, S. C. Sivakumaren, D. Raben, L. M. Amzel, P. Devreotes, S. B. Gabelli, P. Cole",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:35:00Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:35:01Z",
"updated_at": "2013-07-25T09:35:01Z"
},
{
"id": 139,
"content": "Functional magnetic resonance imaging (fMRI) is a widely used technique that makes it possible to observe changes in a person\u2019s brain activity as they perform specific tasks while lying in a scanner. These could range from listening to music or looking at images, to recalling words or imagining a scene, and each will produce a distinct pattern of neural activity.However, fMRI data can be difficult to interpret. Say a particular area of the brain is very active when a subject is trying to perform a new task, but becomes less active as the subject becomes better at the task and performs it more easily. Does this mean that the brain region is used for learning the task, but not for performing once it has been learned? Or alternatively, does it show that the brain area is involved in carrying out the task, but that it becomes more efficient with practice, and so shows less activity in later scans?Now, Wiestler and Diedrichsen have obtained data that help to distinguish between these alternatives. Subjects were trained to carry out four specific sequences of finger movements and then asked either to reproduce these \u2018trained\u2019 sequences or to perform four \u2018untrained\u2019 sequences while in the fMRI scanner. All eight sequences produced high levels of activity in the areas of motor cortex that control finger movements.However, closer analysis showed marked differences between the patterns of activity produced during the \u2018trained\u2019 sequences and those seen during \u2018untrained\u2019 sequences that involved moving the same fingers.Wiestler and Diedrichsen proposed that when subjects train to perform specific movement sequences, this should lead to the development of neural circuits that are specialized to carry out those specific movements\u2014and that detailed analysis of the fMRI data would allow them to identify patterns of activity that correspond to these circuits. Sure enough, when they analysed the fMRI scans, Wiestler and Diedrichsen found that the activation patterns associated with \u2018trained\u2019 movement sequences were more readily distinguishable from each other than those associated with the \u2018untrained\u2019 movement sequences, even in areas where training led to an overall reduction in activity.As well as showing that movement sequences become associated with specific spatial patterns of activation as they are learned, this study provides a new way to study learning in fMRI that should be useful for many future studies.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00801.002",
"content_html": "<p hwp:id=\"p-4\">Functional magnetic resonance imaging (fMRI) is a widely used technique that makes it possible to observe changes in a person&#x2019;s brain activity as they perform specific tasks while lying in a scanner. These could range from listening to music or looking at images, to recalling words or imagining a scene, and each will produce a distinct pattern of neural activity.<\/p>\n<p hwp:id=\"p-5\">However, fMRI data can be difficult to interpret. Say a particular area of the brain is very active when a subject is trying to perform a new task, but becomes less active as the subject becomes better at the task and performs it more easily. Does this mean that the brain region is used for learning the task, but not for performing once it has been learned? Or alternatively, does it show that the brain area is involved in carrying out the task, but that it becomes more efficient with practice, and so shows less activity in later scans?<\/p>\n<p hwp:id=\"p-6\">Now, Wiestler and Diedrichsen have obtained data that help to distinguish between these alternatives. Subjects were trained to carry out four specific sequences of finger movements and then asked either to reproduce these &#x2018;trained&#x2019; sequences or to perform four &#x2018;untrained&#x2019; sequences while in the fMRI scanner. All eight sequences produced high levels of activity in the areas of motor cortex that control finger movements.<\/p>\n<p hwp:id=\"p-7\">However, closer analysis showed marked differences between the patterns of activity produced during the &#x2018;trained&#x2019; sequences and those seen during &#x2018;untrained&#x2019; sequences that involved moving the same fingers.<\/p>\n<p hwp:id=\"p-8\">Wiestler and Diedrichsen proposed that when subjects train to perform specific movement sequences, this should lead to the development of neural circuits that are specialized to carry out those specific movements&#x2014;and that detailed analysis of the fMRI data would allow them to identify patterns of activity that correspond to these circuits. Sure enough, when they analysed the fMRI scans, Wiestler and Diedrichsen found that the activation patterns associated with &#x2018;trained&#x2019; movement sequences were more readily distinguishable from each other than those associated with the &#x2018;untrained&#x2019; movement sequences, even in areas where training led to an overall reduction in activity.<\/p>\n<p hwp:id=\"p-9\">As well as showing that movement sequences become associated with specific spatial patterns of activation as they are learned, this study provides a new way to study learning in fMRI that should be useful for many future studies.<\/p>\n<p hwp:id=\"p-10\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00801.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00801.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00801.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00801",
"title": "Skill learning strengthens cortical representations of motor sequences",
"metadata": {
"authors": "T. Wiestler, J. Diedrichsen",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:35:03Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:35:03Z",
"updated_at": "2013-07-25T09:35:03Z"
},
{
"id": 140,
"content": "Mutations are permanent changes to a cell\u2019s genome. If one or more mutations result in a cell proliferating in an unregulated manner, it is referred to as a cancer cell. The generation of cancer cells is a relatively common occurrence within organisms, but these rogue cells are generally recognized and destroyed by the organism\u2019s immune system. However, when the immune system fails to identify and eliminate cancer cells, they can proliferate to form malignant, life-threatening tumors.Mutations in a gene called PTEN are often found within cells that develop into cancerous tumors. This gene is normally expressed as a protein that is involved in the regulation of cell division, preventing cells from growing and dividing too quickly. However, when the protein PTEN is absent or non-functional, cells experience enhanced growth, proliferation, and survival. Such cells are also thought to be resistant to nutrient restriction, but the mechanism responsible for this resistance is not well understood.Here, Nowak et al. investigate the behavior of cells lacking PTEN in a fly model under a variety of nutritional conditions. When the supply of nutrients is limited, cells lacking PTEN shift resources from cell growth to cell multiplication. This appears to allow PTEN-deficient cells to outcompete neighboring wild-type cells; Nowak et al. suggest these rapidly proliferating cells are capable of effectively hoarding nutrient stores, both in their immediate vicinity and organism-wide. Further studies that focus on changes in gene expression may be able to uncover the mechanism that allows PTEN-deficient cells to proliferate when nutrients are restricted. Moreover, by shedding light on a factor that has an important influence on tumor development, these results may have implications for cancer treatment strategies.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00380.002",
"content_html": "<p hwp:id=\"p-6\">Mutations are permanent changes to a cell&#x2019;s genome. If one or more mutations result in a cell proliferating in an unregulated manner, it is referred to as a cancer cell. The generation of cancer cells is a relatively common occurrence within organisms, but these rogue cells are generally recognized and destroyed by the organism&#x2019;s immune system. However, when the immune system fails to identify and eliminate cancer cells, they can proliferate to form malignant, life-threatening tumors.<\/p>\n<p hwp:id=\"p-7\">Mutations in a gene called <italic>PTEN<\/italic> are often found within cells that develop into cancerous tumors. This gene is normally expressed as a protein that is involved in the regulation of cell division, preventing cells from growing and dividing too quickly. However, when the protein PTEN is absent or non-functional, cells experience enhanced growth, proliferation, and survival. Such cells are also thought to be resistant to nutrient restriction, but the mechanism responsible for this resistance is not well understood.<\/p>\n<p hwp:id=\"p-8\">Here, Nowak et al. investigate the behavior of cells lacking PTEN in a fly model under a variety of nutritional conditions. When the supply of nutrients is limited, cells lacking PTEN shift resources from cell growth to cell multiplication. This appears to allow PTEN-deficient cells to outcompete neighboring wild-type cells; Nowak et al. suggest these rapidly proliferating cells are capable of effectively hoarding nutrient stores, both in their immediate vicinity and organism-wide. Further studies that focus on changes in gene expression may be able to uncover the mechanism that allows PTEN-deficient cells to proliferate when nutrients are restricted. Moreover, by shedding light on a factor that has an important influence on tumor development, these results may have implications for cancer treatment strategies.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00380.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00380.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00380.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00380",
"title": "Nutrient restriction enhances the proliferative potential of cells lacking the tumor suppressor PTEN in mitotic tissues",
"metadata": {
"authors": "K. Nowak, G. Seisenbacher, E. Hafen, H. Stocker",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:35:06Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:35:06Z",
"updated_at": "2013-07-25T09:35:06Z"
},
{
"id": 141,
"content": "Huntington\u2019s disease is an inheritable neurodegenerative disorder that typically begins in mid-adulthood. It initially affects muscle coordination and progresses to include psychiatric symptoms and cognitive decline, leading to premature death. The disease is caused by a mutation in the huntingtin gene, which codes for the huntingtin protein, and all individuals who inherit a pathogenic form of the mutant gene will eventually develop the condition.The huntingtin gene contains a series of repeats of the tri-nucleotide sequence CAG, which encodes for the amino acid glutamine. The number of repeats varies between individuals but if it exceeds 36, the huntingtin protein starts to form aggregates in the brain. Aggregation occurs when soluble protein precursors, known as oligomers, combine to form structures called fibrils, which in turn assemble into larger clusters. This phenomenon also occurs in several other tri-nucleotide diseases, each of which involves a mutated gene with an excess of tri-nucleotide repeats.Inside cells, proteins called chaperones regulate the folding of other proteins and help to prevent aggregate formation. A chaperone protein known as TRiC, which interacts with approximately 10% of proteins in the cytosol, has been shown to inhibit the aggregation of mutant huntingtin proteins. However, it has not been possible to map the structural interactions between TRiC and huntingtin to date.Now, Shahmoradian and Galaz-Montoya et al. have used cryo-electron tomography, combined with 3-D mapping and computer-aided reconstruction, to reveal the structure of a molecular complex consisting of TRiC and a pathogenic mutant huntingtin protein containing 51 CAG repeats. By imaging this system at different time points during the aggregation of mutant huntingtin, it was possible to characterize how the aggregates changed over time. They found that their shape differs in the presence and absence of TRiC, and that the chaperone interacts both with soluble huntingtin molecules\u2014sequestering them so that they cannot join together\u2014and with the tips of fibrils, preventing them from growing longer.By providing the first direct demonstration of how TRiC inhibits the aggregation of mutant huntingtin, the results of Shahmoradian and Galaz-Montoya et al. could aid in the design of TRiC-based drugs to be used in the treatment of Huntington\u2019s disease.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00710.002",
"content_html": "<p hwp:id=\"p-8\">Huntington&#x2019;s disease is an inheritable neurodegenerative disorder that typically begins in mid-adulthood. It initially affects muscle coordination and progresses to include psychiatric symptoms and cognitive decline, leading to premature death. The disease is caused by a mutation in the huntingtin gene, which codes for the huntingtin protein, and all individuals who inherit a pathogenic form of the mutant gene will eventually develop the condition.<\/p>\n<p hwp:id=\"p-9\">The huntingtin gene contains a series of repeats of the tri-nucleotide sequence CAG, which encodes for the amino acid glutamine. The number of repeats varies between individuals but if it exceeds 36, the huntingtin protein starts to form aggregates in the brain. Aggregation occurs when soluble protein precursors, known as oligomers, combine to form structures called fibrils, which in turn assemble into larger clusters. This phenomenon also occurs in several other tri-nucleotide diseases, each of which involves a mutated gene with an excess of tri-nucleotide repeats.<\/p>\n<p hwp:id=\"p-10\">Inside cells, proteins called chaperones regulate the folding of other proteins and help to prevent aggregate formation. A chaperone protein known as TRiC, which interacts with approximately 10% of proteins in the cytosol, has been shown to inhibit the aggregation of mutant huntingtin proteins. However, it has not been possible to map the structural interactions between TRiC and huntingtin to date.<\/p>\n<p hwp:id=\"p-11\">Now, Shahmoradian and Galaz-Montoya et al. have used cryo-electron tomography, combined with 3-D mapping and computer-aided reconstruction, to reveal the structure of a molecular complex consisting of TRiC and a pathogenic mutant huntingtin protein containing 51 CAG repeats. By imaging this system at different time points during the aggregation of mutant huntingtin, it was possible to characterize how the aggregates changed over time. They found that their shape differs in the presence and absence of TRiC, and that the chaperone interacts both with soluble huntingtin molecules&#x2014;sequestering them so that they cannot join together&#x2014;and with the tips of fibrils, preventing them from growing longer.<\/p>\n<p hwp:id=\"p-12\">By providing the first direct demonstration of how TRiC inhibits the aggregation of mutant huntingtin, the results of Shahmoradian and Galaz-Montoya et al. could aid in the design of TRiC-based drugs to be used in the treatment of Huntington&#x2019;s disease.<\/p>\n<p hwp:id=\"p-13\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00710.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00710.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00710.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00710",
"title": "TRiC's tricks inhibit huntingtin aggregation",
"metadata": {
"authors": "S. H. Shahmoradian, J. G. Galaz-Montoya, M. F. Schmid, Y. Cong, B. Ma, C. Spiess, J. Frydman, S. J. Ludtke, W. Chiu",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:35:08Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:35:08Z",
"updated_at": "2013-07-25T09:35:08Z"
},
{
"id": 142,
"content": "Human African trypanosomiasis\u2014commonly known as sleeping sickness\u2014is a debilitating and potentially fatal tropical disease that is widespread in sub-Saharan Africa. It is caused by the single-celled parasite Trypanosoma brucei, which is transmitted to humans by the bite of the tsetse fly. The infection takes its name from the disruption of the circadian clock that occurs early on in the disorder and leads to sleep disturbances. If left untreated, T. brucei infection leads to coma, organ failure and death.Most of the existing pharmaceutical treatments for sleeping sickness were developed more than 50 years ago. However, they are only weakly absorbed into the bloodstream\u2014meaning that high doses must be used\u2014and they lead to unpleasant side effects. Moreover, the T. brucei parasite is developing resistance to existing drugs, so further research is needed to identify new therapeutic targets.One promising option could be the parasite\u2019s protein kinases. These enzymes, which add phosphate-based chemical groups to proteins, have a key role in regulating protein function and many of them are already being investigated as therapeutic targets for cancers and autoimmune diseases. T. brucei has 182 different kinases, suggesting a wealth of potential new targets. However, many of these are similar to human enzymes, and inhibiting the latter could lead to harmful side effects.Now, Nishino et al. have produced a synthetic version of a microbially derived kinase inhibitor, called hypothemycin, and have shown that it kills T. brucei cells grown in culture. Hypothemycin also killed T. brucei in infected mice, completely curing the infection in one third of animals, although high doses of the drug led to side effects. Using a chemical biology approach and quantitative mass spectrometry, Nishino et al. found that the main target of hypothemycin was a previously unknown kinase that is essential for T. brucei survival. Although hypothemycin itself is probably unsuitable as a treatment due to its lack of specificity, the work of Nishino et al. suggests that its kinase targets deserve further investigation.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00712.002",
"content_html": "<p hwp:id=\"p-5\">Human African trypanosomiasis&#x2014;commonly known as sleeping sickness&#x2014;is a debilitating and potentially fatal tropical disease that is widespread in sub-Saharan Africa. It is caused by the single-celled parasite <italic>Trypanosoma brucei<\/italic>, which is transmitted to humans by the bite of the tsetse fly. The infection takes its name from the disruption of the circadian clock that occurs early on in the disorder and leads to sleep disturbances. If left untreated, <italic>T. brucei<\/italic> infection leads to coma, organ failure and death.<\/p>\n<p hwp:id=\"p-6\">Most of the existing pharmaceutical treatments for sleeping sickness were developed more than 50 years ago. However, they are only weakly absorbed into the bloodstream&#x2014;meaning that high doses must be used&#x2014;and they lead to unpleasant side effects. Moreover, the <italic>T. brucei<\/italic> parasite is developing resistance to existing drugs, so further research is needed to identify new therapeutic targets.<\/p>\n<p hwp:id=\"p-7\">One promising option could be the parasite&#x2019;s protein kinases. These enzymes, which add phosphate-based chemical groups to proteins, have a key role in regulating protein function and many of them are already being investigated as therapeutic targets for cancers and autoimmune diseases. <italic>T. brucei<\/italic> has 182 different kinases, suggesting a wealth of potential new targets. However, many of these are similar to human enzymes, and inhibiting the latter could lead to harmful side effects.<\/p>\n<p hwp:id=\"p-8\">Now, Nishino et al. have produced a synthetic version of a microbially derived kinase inhibitor, called hypothemycin, and have shown that it kills <italic>T. brucei<\/italic> cells grown in culture. Hypothemycin also killed <italic>T. brucei<\/italic> in infected mice, completely curing the infection in one third of animals, although high doses of the drug led to side effects. Using a chemical biology approach and quantitative mass spectrometry, Nishino et al. found that the main target of hypothemycin was a previously unknown kinase that is essential for <italic>T. brucei<\/italic> survival. Although hypothemycin itself is probably unsuitable as a treatment due to its lack of specificity, the work of Nishino et al. suggests that its kinase targets deserve further investigation.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00712.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00712.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00712.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00712",
"title": "Hypothemicin, a fungal natural product, identifies therapeutic targets in Trypanosoma brucei",
"metadata": {
"authors": "M. Nishino, J. W. Choy, N. N. Gushwa, J. A. Oses-Prieto, K. Koupparis, A. L. Burlingame, A. R. Renslo, J. H. McKerrow, J. Taunton",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:35:10Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:35:10Z",
"updated_at": "2013-07-25T09:35:10Z"
},
{
"id": 143,
"content": "Calcium is an essential element for many biological functions. In particular, the movement of calcium ions through the cell membrane has a central role in many of the signalling pathways that cells use to communicate with other cells. Signals are produced by calcium ions both entering and leaving the cell, with information being contained in the rate, location, and duration of the flow of ions.Calcium is stored inside cells in a structure called the endoplasmic reticulum, and when stores of calcium are low, special channels in the cell membrane called CRAC (calcium release activated calcium) channels are used to ferry more calcium ions into the cell. This process, known as store-operated calcium entry, relies on two important groups of proteins: the Stim proteins that sense when calcium stores are low; and, the Orai structural proteins that form the actual channel.Previous work has shown that when the calcium stores are low, the Stim proteins\u2014which reside in the endoplasmic reticulum\u2014form clusters and these clusters then move to a part of the endoplasmic reticulum that is next to the cell membrane, where they join the Orai1 proteins to form larger clusters. However, to date it has been unclear whether Stim-Orai clustering at the cell membrane is sufficient for CRAC channels to open, or if additional steps are involved.Miao et al. now show that another protein is involved in the formation of functional CRAC channels. Working with fruit fly cells, Miao et al. used genetic techniques to prevent the expression of various proteins that were thought to have a role in the movement of calcium ions through the cell membrane. One of these candidates, a protein called \u03b1-SNAP that is found in the internal fluid of the cell, was identified as having a central role in the import of calcium ions into the cell. Further work showed that \u03b1-SNAP re-organizes the Stim and Orai proteins to produce working CRAC channels.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00802.002",
"content_html": "<p hwp:id=\"p-4\">Calcium is an essential element for many biological functions. In particular, the movement of calcium ions through the cell membrane has a central role in many of the signalling pathways that cells use to communicate with other cells. Signals are produced by calcium ions both entering and leaving the cell, with information being contained in the rate, location, and duration of the flow of ions.<\/p>\n<p hwp:id=\"p-5\">Calcium is stored inside cells in a structure called the endoplasmic reticulum, and when stores of calcium are low, special channels in the cell membrane called CRAC (calcium release activated calcium) channels are used to ferry more calcium ions into the cell. This process, known as store-operated calcium entry, relies on two important groups of proteins: the Stim proteins that sense when calcium stores are low; and, the Orai structural proteins that form the actual channel.<\/p>\n<p hwp:id=\"p-6\">Previous work has shown that when the calcium stores are low, the Stim proteins&#x2014;which reside in the endoplasmic reticulum&#x2014;form clusters and these clusters then move to a part of the endoplasmic reticulum that is next to the cell membrane, where they join the Orai1 proteins to form larger clusters. However, to date it has been unclear whether Stim-Orai clustering at the cell membrane is sufficient for CRAC channels to open, or if additional steps are involved.<\/p>\n<p hwp:id=\"p-7\">Miao et al. now show that another protein is involved in the formation of functional CRAC channels. Working with fruit fly cells, Miao et al. used genetic techniques to prevent the expression of various proteins that were thought to have a role in the movement of calcium ions through the cell membrane. One of these candidates, a protein called &#x3B1;-SNAP that is found in the internal fluid of the cell, was identified as having a central role in the import of calcium ions into the cell. Further work showed that &#x3B1;-SNAP re-organizes the Stim and Orai proteins to produce working CRAC channels.<\/p>\n<p hwp:id=\"p-8\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00802.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00802.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00802.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00802",
"title": "An essential and NSF independent role for &#xA0;-SNAP in store-operated calcium entry",
"metadata": {
"authors": "Y. Miao, C. Miner, L. Zhang, P. I. Hanson, A. Dani, M. Vig",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:35:15Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:35:15Z",
"updated_at": "2013-07-25T09:35:15Z"
},
{
"id": 144,
"content": "Protein synthesis in eukaryotes occurs in two stages: transcription of DNA into messenger RNA (mRNA) in the nucleus, and then translation of that mRNA into a protein by ribosomes in the cytoplasm. These processes are regulated by a complex network of signaling pathways that enables cells to tailor protein synthesis to match current conditions. This involves regulating the expression of the genes that code for these proteins.When cells experience stressful events, such as a shortage of oxygen or nutrients, they reduce the synthesis of most proteins. This response is regulated, in part, by a signaling pathway known as the insulin and insulin-like receptor pathway. In particular, stressful events inhibit a protein complex called eIF4F, which normally initiates the translation of mRNA molecules by binding to a structure on one end of the mRNA called the 5\u2032 cap. Despite this general inhibition, the production of certain other proteins\u2014including the insulin receptor itself\u2014is actually increased in response to stress.Olson et al. have carried out a series of experiments to explore how inhibition of the eIF4F protein complex influences the translation of the mRNA for the insulin receptor. The eIF4F complex is made up of three proteins, including one that binds to the 5\u2032 cap and a helicase that unwinds the RNA. Previous work in the fruit fly Drosophila showed that translation of this mRNA can continue even if formation of the eIF4F complex is inhibited by targeting the cap binding protein. Olsen et al. now show that translation of this mRNA is also independent of the helicase. Instead, translation is maintained under these conditions because the insulin receptor mRNA contains a sequence called an internal ribosome entry site, which allows ribosomes to bind to the mRNA without the influence of the 5\u2032 cap.Olson et al. reveal the details of this regulatory pathway in Drosophila and show that similar mechanisms are at work in mammalian cells, suggesting this pathway represents a crucial regulatory process that has been conserved during evolution. A key question for future research is whether other genes within the insulin and insulin-receptor like signaling pathway use this same trick to evade translational inhibitors.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00542.002",
"content_html": "<p hwp:id=\"p-4\">Protein synthesis in eukaryotes occurs in two stages: transcription of DNA into messenger RNA (mRNA) in the nucleus, and then translation of that mRNA into a protein by ribosomes in the cytoplasm. These processes are regulated by a complex network of signaling pathways that enables cells to tailor protein synthesis to match current conditions. This involves regulating the expression of the genes that code for these proteins.<\/p>\n<p hwp:id=\"p-5\">When cells experience stressful events, such as a shortage of oxygen or nutrients, they reduce the synthesis of most proteins. This response is regulated, in part, by a signaling pathway known as the insulin and insulin-like receptor pathway. In particular, stressful events inhibit a protein complex called eIF4F, which normally initiates the translation of mRNA molecules by binding to a structure on one end of the mRNA called the 5&#x2032; cap. Despite this general inhibition, the production of certain other proteins&#x2014;including the insulin receptor itself&#x2014;is actually increased in response to stress.<\/p>\n<p hwp:id=\"p-6\">Olson et al. have carried out a series of experiments to explore how inhibition of the eIF4F protein complex influences the translation of the mRNA for the insulin receptor. The eIF4F complex is made up of three proteins, including one that binds to the 5&#x2032; cap and a helicase that unwinds the RNA. Previous work in the fruit fly <italic>Drosophila<\/italic> showed that translation of this mRNA can continue even if formation of the eIF4F complex is inhibited by targeting the cap binding protein. Olsen et al. now show that translation of this mRNA is also independent of the helicase. Instead, translation is maintained under these conditions because the insulin receptor mRNA contains a sequence called an internal ribosome entry site, which allows ribosomes to bind to the mRNA without the influence of the 5&#x2032; cap.<\/p>\n<p hwp:id=\"p-7\">Olson et al. reveal the details of this regulatory pathway in <italic>Drosophila<\/italic> and show that similar mechanisms are at work in mammalian cells, suggesting this pathway represents a crucial regulatory process that has been conserved during evolution. A key question for future research is whether other genes within the insulin and insulin-receptor like signaling pathway use this same trick to evade translational inhibitors.<\/p>\n<p hwp:id=\"p-8\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00542.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00542.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00542.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00542",
"title": "The insulin receptor cellular IRES confers resistance to eIF4A inhibition",
"metadata": {
"authors": "C. M. Olson, M. R. Donovan, M. J. Spellberg, M. T. Marr",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:35:17Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:35:17Z",
"updated_at": "2013-07-25T09:35:17Z"
},
{
"id": 145,
"content": "Vaccines increase resistance to disease by priming the immune system to respond to specific viruses or microorganisms. By presenting a weakened (or dead) form of a pathogen, or its toxins or surface proteins, to the immune system, vaccines trigger the production of antibodies against the virus or microorganism. If a vaccinated individual then encounters the pathogen, their immune system should be able to recognize and destroy it. Many vaccines also include a secondary agent, known as an adjuvant, to further stimulate the immune response.Influenza, an RNA virus commonly referred to as the \u2018flu\u2019, is an infectious disease that affects both birds and mammals. Seasonal epidemics occur each year affecting 2\u20137% of the population. According to the World Health Organization, influenza leads to nearly 5 million hospitalizations each year and causes up to half a million deaths. Vaccination is a primary strategy for the prevention of seasonal influenza, but responses to the vaccine vary markedly, partly because of variation in the genetic makeup or genotype of individuals. However, the details of how genes influence response to vaccination, and indeed susceptibility to influenza, remain unclear.To investigate the genetic basis of variation in the immune response of healthy adults to the seasonal influenza vaccine, Franco et al. combined information about the genotypes of individuals with measurements of their gene transcription and antibody response to vaccination. They identified 20 genes that contributed to differential immune responses to the vaccine. Almost half of these encode proteins that are not specifically associated with the immune system, but have more general roles in processes such as membrane trafficking and intracellular transport.Focusing on these genes may enable researchers to spot those individuals who are less likely to respond to a vaccine. It could also open up new avenues of research for vaccine development: rather than designing adjuvants that target known immune mechanisms, researchers should develop adjuvants that target the proteins encoded by these 20 genes.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00299.002",
"content_html": "<p hwp:id=\"p-6\">Vaccines increase resistance to disease by priming the immune system to respond to specific viruses or microorganisms. By presenting a weakened (or dead) form of a pathogen, or its toxins or surface proteins, to the immune system, vaccines trigger the production of antibodies against the virus or microorganism. If a vaccinated individual then encounters the pathogen, their immune system should be able to recognize and destroy it. Many vaccines also include a secondary agent, known as an adjuvant, to further stimulate the immune response.<\/p>\n<p hwp:id=\"p-7\">Influenza, an RNA virus commonly referred to as the &#x2018;flu&#x2019;, is an infectious disease that affects both birds and mammals. Seasonal epidemics occur each year affecting 2&#x2013;7% of the population. According to the World Health Organization, influenza leads to nearly 5 million hospitalizations each year and causes up to half a million deaths. Vaccination is a primary strategy for the prevention of seasonal influenza, but responses to the vaccine vary markedly, partly because of variation in the genetic makeup or genotype of individuals. However, the details of how genes influence response to vaccination, and indeed susceptibility to influenza, remain unclear.<\/p>\n<p hwp:id=\"p-8\">To investigate the genetic basis of variation in the immune response of healthy adults to the seasonal influenza vaccine, Franco et al. combined information about the genotypes of individuals with measurements of their gene transcription and antibody response to vaccination. They identified 20 genes that contributed to differential immune responses to the vaccine. Almost half of these encode proteins that are not specifically associated with the immune system, but have more general roles in processes such as membrane trafficking and intracellular transport.<\/p>\n<p hwp:id=\"p-9\">Focusing on these genes may enable researchers to spot those individuals who are less likely to respond to a vaccine. It could also open up new avenues of research for vaccine development: rather than designing adjuvants that target known immune mechanisms, researchers should develop adjuvants that target the proteins encoded by these 20 genes.<\/p>\n<p hwp:id=\"p-10\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00299.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00299.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00299.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00299",
"title": "Integrative genomic analysis of the human immune response to influenza vaccination",
"metadata": {
"authors": "L. M. Franco, K. L. Bucasas, J. M. Wells, D. Nino, X. Wang, G. E. Zapata, N. Arden, A. Renwick, P. Yu, J. M. Quarles, M. S. Bray, R. B. Couch, J. W. Belmont, C. A. Shaw",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:35:20Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:35:20Z",
"updated_at": "2013-07-25T09:35:20Z"
},
{
"id": 146,
"content": "ErbB proteins are found in most multi-cellular organisms, and are involved in the regulation of a number of important cellular processes, including proliferation, migration, and differentiation. Humans have four ErbB proteins, which span the plasma membrane of cells. These proteins respond to interactions with molecules outside the cell\u2014such as growth factors and hormones\u2014by sending signals along the appropriate signaling pathway within the cell.ErbB proteins have three portions: an ectodomain that extends outside the cell; a single helix that spans the membrane; and a cytoplasmic domain inside the cell. When a signaling ligand molecule outside the cell binds to the ectodomain of an ErbB protein, this protein must then combine with another ErbB protein to form a dimer before a signal can be sent within the cell. These dimers can include two copies of the same ErbB protein or two different ErbB proteins. However, one of the ErbB proteins\u2014Her2\u2014works in a different way. It cannot bind ligands outside the cell, and it can only send a signal within the cell if it first forms a dimer with an ErbB protein of another type, which itself must be bound to an external ligand.The four ErbB proteins diverged from a common ancestor relatively recently, yet they are now diverse enough to play key roles in a variety of complex signaling networks. In particular, the fact that Her2 cannot bind external ligands, and that it must form a dimer with a different ErbB protein before it can send a signal, has led to suggestions that the role of Her2 is to amplify the signals from other ErbB proteins. Since high levels of Her2 are associated with aggressive forms of breast and ovarian cancer, understanding how it is activated could improve our understanding of these cancers.Arkhipov et al. have now used computer simulations to model how Her2 forms dimers with other ErbB proteins in human cells. They based these simulations on crystal structures of human ErbB proteins and dEGFR, a growth-factor receptor found in fruit flies that closely resembles the ErbB proteins found in humans. They found that the dimers were stable as long as one protein within the dimer was bound to a ligand. Removing this ligand, however, distorted the ectodomain of the host protein, creating a gap that weakened the dimer and prevented Her2 from sending a signal within the cell. Similar results were obtained with the fruit fly dEGFR proteins. These simulations suggest that ErbB proteins form dimers and send signals through a mechanism conserved in evolution. Research in this field might help ongoing efforts to develop new treatments for human tumors characterized by high levels of Her2 expression.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00708.002",
"content_html": "<p hwp:id=\"p-4\">ErbB proteins are found in most multi-cellular organisms, and are involved in the regulation of a number of important cellular processes, including proliferation, migration, and differentiation. Humans have four ErbB proteins, which span the plasma membrane of cells. These proteins respond to interactions with molecules outside the cell&#x2014;such as growth factors and hormones&#x2014;by sending signals along the appropriate signaling pathway within the cell.<\/p>\n<p hwp:id=\"p-5\">ErbB proteins have three portions: an ectodomain that extends outside the cell; a single helix that spans the membrane; and a cytoplasmic domain inside the cell. When a signaling ligand molecule outside the cell binds to the ectodomain of an ErbB protein, this protein must then combine with another ErbB protein to form a dimer before a signal can be sent within the cell. These dimers can include two copies of the same ErbB protein or two different ErbB proteins. However, one of the ErbB proteins&#x2014;Her2&#x2014;works in a different way. It cannot bind ligands outside the cell, and it can only send a signal within the cell if it first forms a dimer with an ErbB protein of another type, which itself must be bound to an external ligand.<\/p>\n<p hwp:id=\"p-6\">The four ErbB proteins diverged from a common ancestor relatively recently, yet they are now diverse enough to play key roles in a variety of complex signaling networks. In particular, the fact that Her2 cannot bind external ligands, and that it must form a dimer with a different ErbB protein before it can send a signal, has led to suggestions that the role of Her2 is to amplify the signals from other ErbB proteins. Since high levels of Her2 are associated with aggressive forms of breast and ovarian cancer, understanding how it is activated could improve our understanding of these cancers.<\/p>\n<p hwp:id=\"p-7\">Arkhipov et al. have now used computer simulations to model how Her2 forms dimers with other ErbB proteins in human cells. They based these simulations on crystal structures of human ErbB proteins and dEGFR, a growth-factor receptor found in fruit flies that closely resembles the ErbB proteins found in humans. They found that the dimers were stable as long as one protein within the dimer was bound to a ligand. Removing this ligand, however, distorted the ectodomain of the host protein, creating a gap that weakened the dimer and prevented Her2 from sending a signal within the cell. Similar results were obtained with the fruit fly dEGFR proteins. These simulations suggest that ErbB proteins form dimers and send signals through a mechanism conserved in evolution. Research in this field might help ongoing efforts to develop new treatments for human tumors characterized by high levels of Her2 expression.<\/p>\n<p hwp:id=\"p-8\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00708.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00708.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00708.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00708",
"title": "Her2 activation mechanism reflects evolutionary preservation of asymmetric ectodomain dimers in the human EGFR family",
"metadata": {
"authors": "A. Arkhipov, Y. Shan, E. T. Kim, R. O. Dror, D. E. Shaw",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:35:22Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:35:22Z",
"updated_at": "2013-07-25T09:35:22Z"
},
{
"id": 147,
"content": "Blood cells are produced within bone marrow by specialized stem cells and progenitor cells. Abnormalities in this process lead to a group of diseases known as myeloid malignancies, which include acute myeloid leukaemia\u2014in which the bone marrow produces abnormal white blood cells\u2014and myelodysplastic syndromes, which are caused by too few mature blood cells being produced.Many individuals affected by these disorders possess a shortened form of chromosome 20 that lacks a number of genes. This deletion is only ever seen in one of their two copies of the chromosome\u2014suggesting that at least some of these genes are essential for survival\u2014but the identity of the gene(s) that are associated with the increased risk of myeloid malignancies is unknown.Now, Heinrichs et al. have uncovered a key tumor suppressor among those genes frequently lost on chromosome 20. The gene, which is called MYBL2, encodes a transcription factor that helps to control the cell division cycle. Myeloid malignancy patients lacking one copy of this gene showed levels of MYBL2 expression that were less than 50% of those in healthy individuals. This suggests that additional mechanisms must be acting to reduce expression of their remaining copy of the gene. Surprisingly, MYBL2 levels were also reduced in myeloid malignancy patients who possessed two intact copies of chromosome 20, indicating that loss of a single copy represents only one mechanism to reduce MYBL2 expression, i.e., the \u2018tip-of-the-iceberg\u2019. Hence, this finding reveals a more general role for MYBL2 as it indicates that more patients are likely to be affected by altered expression of this gene.To confirm their findings from studies in patients, Heinrichs et al. used gene silencing techniques to reduce the expression of MYBL2 in mice and showed that this induced symptoms of myeloid malignancies in the animals. Moreover, injection of modified cells from these animals into healthy mice also induced symptoms in the recipients. The modified cells are able to expand more robustly than normal cells, and this dominance induced by downregulation of the tumor suppressor increases the risk of malignancy.In addition to revealing a new tumor suppressor gene and its contribution to myeloid malignancies, the study by Heinrichs et al. highlights the importance of gene dosage in mediating the effects of tumor suppressors.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00825.002",
"content_html": "<p hwp:id=\"p-4\">Blood cells are produced within bone marrow by specialized stem cells and progenitor cells. Abnormalities in this process lead to a group of diseases known as myeloid malignancies, which include acute myeloid leukaemia&#x2014;in which the bone marrow produces abnormal white blood cells&#x2014;and myelodysplastic syndromes, which are caused by too few mature blood cells being produced.<\/p>\n<p hwp:id=\"p-5\">Many individuals affected by these disorders possess a shortened form of chromosome 20 that lacks a number of genes. This deletion is only ever seen in one of their two copies of the chromosome&#x2014;suggesting that at least some of these genes are essential for survival&#x2014;but the identity of the gene(s) that are associated with the increased risk of myeloid malignancies is unknown.<\/p>\n<p hwp:id=\"p-6\">Now, Heinrichs et al. have uncovered a key tumor suppressor among those genes frequently lost on chromosome 20. The gene, which is called <italic>MYBL2<\/italic>, encodes a transcription factor that helps to control the cell division cycle. Myeloid malignancy patients lacking one copy of this gene showed levels of <italic>MYBL2<\/italic> expression that were less than 50% of those in healthy individuals. This suggests that additional mechanisms must be acting to reduce expression of their remaining copy of the gene. Surprisingly, <italic>MYBL2<\/italic> levels were also reduced in myeloid malignancy patients who possessed two intact copies of chromosome 20, indicating that loss of a single copy represents only one mechanism to reduce <italic>MYBL2<\/italic> expression, i.e., the &#x2018;tip-of-the-iceberg&#x2019;. Hence, this finding reveals a more general role for <italic>MYBL2<\/italic> as it indicates that more patients are likely to be affected by altered expression of this gene.<\/p>\n<p hwp:id=\"p-7\">To confirm their findings from studies in patients, Heinrichs et al. used gene silencing techniques to reduce the expression of <italic>MYBL2<\/italic> in mice and showed that this induced symptoms of myeloid malignancies in the animals. Moreover, injection of modified cells from these animals into healthy mice also induced symptoms in the recipients. The modified cells are able to expand more robustly than normal cells, and this dominance induced by downregulation of the tumor suppressor increases the risk of malignancy.<\/p>\n<p hwp:id=\"p-8\">In addition to revealing a new tumor suppressor gene and its contribution to myeloid malignancies, the study by Heinrichs et al. highlights the importance of gene dosage in mediating the effects of tumor suppressors.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00825.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00825.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00825.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00825",
"title": "MYBL2 is a sub-haploinsufficient tumor suppressor gene in myeloid malignancy",
"metadata": {
"authors": "S. Heinrichs, L. F. Conover, C. E. Bueso-Ramos, O. Kilpivaara, K. Stevenson, D. Neuberg, M. L. Loh, W.-S. Wu, S. J. Rodig, G. Garcia-Manero, H. M. Kantarjian, A. T. Look",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:35:29Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:35:29Z",
"updated_at": "2013-07-25T09:35:29Z"
},
{
"id": 148,
"content": "Alzheimer\u2019s disease is the most common form of dementia, estimated to affect roughly five million people in the United States, and its incidence is steadily increasing as the population ages. A pathological hallmark of Alzheimer\u2019s disease is the presence in the brain of aggregates of two proteins: tangles of a protein called tau; and fibers and smaller units (oligomers) of a peptide called amyloid beta.Many attempts have been made to screen libraries of natural and synthetic compounds to identify substances that might prevent the aggregation and toxicity of amyloid. Such studies revealed that polyphenols found in green tea and in the spice turmeric can inhibit the formation of amyloid fibrils. Moreover, a number of dyes reduce the toxic effects of amyloid on cells, although significant side effects prevent these from being used as drugs.Structure-based drug design, in which the structure of a target protein is used to help identify compounds that will interact with it, has been used to generate therapeutic agents for a number of diseases. Here, Jiang et al. report the first application of this technique in the hunt for compounds that inhibit the cytotoxicity of amyloid beta. Using the known atomic structure of the protein in complex with a dye, Jiang et al. performed a computational screen of 18,000 compounds in search of those that are likely to bind effectively.The compounds that showed the strongest predicted binding were then tested for their ability to interfere with the aggregation of amyloid beta and to protect cells grown in culture from its toxic effects. Compounds that reduced toxicity did not reduce the abundance of protein aggregates, but they appear to increase the stability of fibrils. This is consistent with other evidence suggesting that small, soluble forms (oligomers) of amyloid beta that break free from the fibrils may be the toxic agent in Alzheimer\u2019s disease, rather than the fibrils themselves.In addition to uncovering compounds with therapeutic potential in Alzheimer\u2019s disease, this work presents a new approach for identifying proteins that bind to amyloid fibrils. Given that amyloid accumulation is a feature of many other diseases, including Parkinson\u2019s disease, Huntington\u2019s disease and type 2 diabetes, the approach could have broad therapeutic applications.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00857.002",
"content_html": "<p hwp:id=\"p-7\">Alzheimer&#x2019;s disease is the most common form of dementia, estimated to affect roughly five million people in the United States, and its incidence is steadily increasing as the population ages. A pathological hallmark of Alzheimer&#x2019;s disease is the presence in the brain of aggregates of two proteins: tangles of a protein called tau; and fibers and smaller units (oligomers) of a peptide called amyloid beta.<\/p>\n<p hwp:id=\"p-8\">Many attempts have been made to screen libraries of natural and synthetic compounds to identify substances that might prevent the aggregation and toxicity of amyloid. Such studies revealed that polyphenols found in green tea and in the spice turmeric can inhibit the formation of amyloid fibrils. Moreover, a number of dyes reduce the toxic effects of amyloid on cells, although significant side effects prevent these from being used as drugs.<\/p>\n<p hwp:id=\"p-9\">Structure-based drug design, in which the structure of a target protein is used to help identify compounds that will interact with it, has been used to generate therapeutic agents for a number of diseases. Here, Jiang et al. report the first application of this technique in the hunt for compounds that inhibit the cytotoxicity of amyloid beta. Using the known atomic structure of the protein in complex with a dye, Jiang et al. performed a computational screen of 18,000 compounds in search of those that are likely to bind effectively.<\/p>\n<p hwp:id=\"p-10\">The compounds that showed the strongest predicted binding were then tested for their ability to interfere with the aggregation of amyloid beta and to protect cells grown in culture from its toxic effects. Compounds that reduced toxicity did not reduce the abundance of protein aggregates, but they appear to increase the stability of fibrils. This is consistent with other evidence suggesting that small, soluble forms (oligomers) of amyloid beta that break free from the fibrils may be the toxic agent in Alzheimer&#x2019;s disease, rather than the fibrils themselves.<\/p>\n<p hwp:id=\"p-11\">In addition to uncovering compounds with therapeutic potential in Alzheimer&#x2019;s disease, this work presents a new approach for identifying proteins that bind to amyloid fibrils. Given that amyloid accumulation is a feature of many other diseases, including Parkinson&#x2019;s disease, Huntington&#x2019;s disease and type 2 diabetes, the approach could have broad therapeutic applications.<\/p>\n<p hwp:id=\"p-12\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00857.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00857.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00857.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00857",
"title": "Structure-based discovery of fiber-binding compounds that reduce the cytotoxicity of amyloid beta",
"metadata": {
"authors": "L. Jiang, C. Liu, D. Leibly, M. Landau, M. Zhao, M. P. Hughes, D. S. Eisenberg",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:35:32Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:35:32Z",
"updated_at": "2013-07-25T09:35:32Z"
},
{
"id": 149,
"content": "Even when seated in the middle of a crowded restaurant, we are still able to distinguish the speech of the person sitting opposite us from the conversations of fellow diners and a host of other background noise. While we generally perform this task almost effortlessly, it is unclear how the brain solves what is in reality a complex information processing problem.In the 1970s, researchers began to address this question using stimuli consisting of simple tones. When subjects are played a sequence of alternating high and low frequency tones, they perceive them as two independent streams of sound. Similar experiments in macaque monkeys reveal that each stream activates a different area of auditory cortex, suggesting that the brain may distinguish acoustic stimuli on the basis of their frequency.However, the simple tones that are used in laboratory experiments bear little resemblance to the complex sounds we encounter in everyday life. These are often made up of multiple frequencies, and overlap\u2014both in frequency and in time\u2014with other sounds in the environment. Moreover, recent experiments have shown that if a subject hears two tones simultaneously, he or she perceives them as belonging to a single stream of sound even if they have different frequencies: models that assume that we distinguish stimuli from noise on the basis of frequency alone struggle to explain this observation.Now, Teki, Chait, et al. have used more complex sounds, in which frequency components of the target stimuli overlap with those of background signals, to obtain new insights into how the brain solves this problem. Subjects were extremely good at discriminating these complex target stimuli from background noise, and computational modelling confirmed that they did so via integration of both frequency and temporal information. The work of Teki, Chait, et al. thus offers the first explanation for our ability to home in on speech and other pertinent sounds, even amidst a sea of background noise.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00699.002",
"content_html": "<p hwp:id=\"p-5\">Even when seated in the middle of a crowded restaurant, we are still able to distinguish the speech of the person sitting opposite us from the conversations of fellow diners and a host of other background noise. While we generally perform this task almost effortlessly, it is unclear how the brain solves what is in reality a complex information processing problem.<\/p>\n<p hwp:id=\"p-6\">In the 1970s, researchers began to address this question using stimuli consisting of simple tones. When subjects are played a sequence of alternating high and low frequency tones, they perceive them as two independent streams of sound. Similar experiments in macaque monkeys reveal that each stream activates a different area of auditory cortex, suggesting that the brain may distinguish acoustic stimuli on the basis of their frequency.<\/p>\n<p hwp:id=\"p-7\">However, the simple tones that are used in laboratory experiments bear little resemblance to the complex sounds we encounter in everyday life. These are often made up of multiple frequencies, and overlap&#x2014;both in frequency and in time&#x2014;with other sounds in the environment. Moreover, recent experiments have shown that if a subject hears two tones simultaneously, he or she perceives them as belonging to a single stream of sound even if they have different frequencies: models that assume that we distinguish stimuli from noise on the basis of frequency alone struggle to explain this observation.<\/p>\n<p hwp:id=\"p-8\">Now, Teki, Chait, et al. have used more complex sounds, in which frequency components of the target stimuli overlap with those of background signals, to obtain new insights into how the brain solves this problem. Subjects were extremely good at discriminating these complex target stimuli from background noise, and computational modelling confirmed that they did so via integration of both frequency and temporal information. The work of Teki, Chait, et al. thus offers the first explanation for our ability to home in on speech and other pertinent sounds, even amidst a sea of background noise.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00699.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00699.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00699.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00699",
"title": "Segregation of complex acoustic scenes based on temporal coherence",
"metadata": {
"authors": "S. Teki, M. Chait, S. Kumar, S. Shamma, T. D. Griffiths",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:35:36Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:35:36Z",
"updated_at": "2013-07-25T09:35:36Z"
},
{
"id": 272,
"content": "Proteins often need to move between different compartments within cells. To do this they are packaged into transport pods called vesicles. Many trafficked proteins are synthesized in an organelle called the endoplasmic reticulum, or ER; these proteins are transported away from the ER in \u2018COPII\u2019 vesicles, which are formed when the COPII proteins assemble on the ER membrane and force it to bulge outward. The bulge pinches off from the ER membrane, forming the vesicle, which can then move to, and fuse with, a different compartment in the cell.The COPII proteins assemble in a particular order to form the vesicle\u2014Sar1 inserts into the membrane of the ER; Sec23 and Sec24 form an inner coat and capture the proteins that the vesicle will transport; and Sec13 and Sec31 form an outer coat. Although the structures of the coat proteins are known, how they bind to each other\u2014and to the ER membrane\u2014to form vesicles of many shapes and sizes is less well understood. Now, Zanetti et al. show how the inner and outer coat proteins can interact flexibly to accommodate a variety of cargoes.Zanetti et al. mixed purified Sar1 and COPII coat proteins with artificial membranes in vitro. As in cells, the proteins assembled a coat on the membranes, creating bulges and vesicles of different shapes. These coats were imaged using an electron microscope, and the images were analysed using computational image-analysis methods. In this way, Zanetti et al. produced a detailed 3D view of the assembled coat.It was found that the inner and outer proteins each arranged to form lattice structures\u2014like fishing nets\u2014which showed flexibility and variability in the way the individual proteins interact, as well as imperfections in the arrangement. Both coats may help to reshape the membrane, and the inner-coat and outer-coat lattices were also found to move with respect to each other. These flexible properties could allow the coat to assemble on membranes with different shapes and curvatures, forming COPII vesicles with distinct sizes and shapes that can carry a range of cargoes.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00951.002",
"content_html": "<p hwp:id=\"p-5\">Proteins often need to move between different compartments within cells. To do this they are packaged into transport pods called vesicles. Many trafficked proteins are synthesized in an organelle called the endoplasmic reticulum, or ER; these proteins are transported away from the ER in &#x2018;COPII&#x2019; vesicles, which are formed when the COPII proteins assemble on the ER membrane and force it to bulge outward. The bulge pinches off from the ER membrane, forming the vesicle, which can then move to, and fuse with, a different compartment in the cell.<\/p>\n<p hwp:id=\"p-6\">The COPII proteins assemble in a particular order to form the vesicle&#x2014;Sar1 inserts into the membrane of the ER; Sec23 and Sec24 form an inner coat and capture the proteins that the vesicle will transport; and Sec13 and Sec31 form an outer coat. Although the structures of the coat proteins are known, how they bind to each other&#x2014;and to the ER membrane&#x2014;to form vesicles of many shapes and sizes is less well understood. Now, Zanetti et al. show how the inner and outer coat proteins can interact flexibly to accommodate a variety of cargoes.<\/p>\n<p hwp:id=\"p-7\">Zanetti et al. mixed purified Sar1 and COPII coat proteins with artificial membranes in vitro. As in cells, the proteins assembled a coat on the membranes, creating bulges and vesicles of different shapes. These coats were imaged using an electron microscope, and the images were analysed using computational image-analysis methods. In this way, Zanetti et al. produced a detailed 3D view of the assembled coat.<\/p>\n<p hwp:id=\"p-8\">It was found that the inner and outer proteins each arranged to form lattice structures&#x2014;like fishing nets&#x2014;which showed flexibility and variability in the way the individual proteins interact, as well as imperfections in the arrangement. Both coats may help to reshape the membrane, and the inner-coat and outer-coat lattices were also found to move with respect to each other. These flexible properties could allow the coat to assemble on membranes with different shapes and curvatures, forming COPII vesicles with distinct sizes and shapes that can carry a range of cargoes.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00951.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00951.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00951.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00951",
"title": "The structure of the COPII transport-vesicle coat assembled on membranes",
"metadata": {
"authors": "G. Zanetti, S. Prinz, S. Daum, A. Meister, R. Schekman, K. Bacia, J. A. Briggs",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2014-01-13T00:40:19Z",
"updated_at": "2014-01-13T00:40:19Z"
},
"created_at": "2014-01-13T00:40:19Z",
"updated_at": "2014-01-13T00:40:19Z"
},
{
"id": 150,
"content": "Bacteria studied in the laboratory are, in general, readily amenable to culture, and they easily form colonies when grown on agar plates. In the wild, however, many bacteria exhibit a range of more complex behaviors, including the growth of super-organisms that contain many cells.The bacterium Myxococcus xanthus can exist either as single cells or as a super-organism. Each cell has an inner and outer plasma membrane separated by a periplasmic space. Previous work has found that individual cells communicate with each other by exchanging the contents of their outer membranes, and that these swaps can govern multicellular behavior.Membrane exchange is known to depend on both donor and recipient cells having the proteins TraA and TraB. TraA proteins are similar to the adhesion factors that hold cells together, and they are found in many species: this suggests that TraA therefore might help the outer membranes of cells to fuse so that they can swap materials. The role of TraB is not known at present.To investigate membrane exchange more closely, Ducret et al. measured the transfer of fluorescent proteins from the periplasm and the inner and outer membranes of the donor cell to the recipient cell, as well as the transfer of fluorescent lipids from the donor\u2019s outer membrane. Both proteins and lipids from the outer membrane were transferred rapidly (within minutes); although a small amount of protein transfer from the periplasmic space was observed after 36 hr, there was no transfer from the inner membrane. As in previous studies, exchange depended on the presence of TraA.Ducret et al. observed that contact between two cells was sufficient to stimulate transfer of proteins and lipids from the outer membrane. But not all contacts led to a transfer. Importantly, when cells that had swapped fluorescent membrane components moved apart, they appeared to remain connected by tubular structures, suggesting that an inter-membrane junction must form to allow proteins and lipids to be transferred between the cells. This junction is referred to as an outer-membrane synapse.Ducret et al. also noted another phenomenon: cells shed pieces of membrane as they moved across surfaces or separated after outer membrane exchange. This suggests that both synapse formation after direct cell-to-cell contact and the shedding of membrane components can help to propagate bacterial signals, enabling population-wide behavioral changes, including the formation or collapse of super-organisms.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00868.002",
"content_html": "<p hwp:id=\"p-6\">Bacteria studied in the laboratory are, in general, readily amenable to culture, and they easily form colonies when grown on agar plates. In the wild, however, many bacteria exhibit a range of more complex behaviors, including the growth of super-organisms that contain many cells.<\/p>\n<p hwp:id=\"p-7\">The bacterium <italic>Myxococcus xanthus<\/italic> can exist either as single cells or as a super-organism. Each cell has an inner and outer plasma membrane separated by a periplasmic space. Previous work has found that individual cells communicate with each other by exchanging the contents of their outer membranes, and that these swaps can govern multicellular behavior.<\/p>\n<p hwp:id=\"p-8\">Membrane exchange is known to depend on both donor and recipient cells having the proteins TraA and TraB. TraA proteins are similar to the adhesion factors that hold cells together, and they are found in many species: this suggests that TraA therefore might help the outer membranes of cells to fuse so that they can swap materials. The role of TraB is not known at present.<\/p>\n<p hwp:id=\"p-9\">To investigate membrane exchange more closely, Ducret et al. measured the transfer of fluorescent proteins from the periplasm and the inner and outer membranes of the donor cell to the recipient cell, as well as the transfer of fluorescent lipids from the donor&#x2019;s outer membrane. Both proteins and lipids from the outer membrane were transferred rapidly (within minutes); although a small amount of protein transfer from the periplasmic space was observed after 36 hr, there was no transfer from the inner membrane. As in previous studies, exchange depended on the presence of TraA.<\/p>\n<p hwp:id=\"p-10\">Ducret et al. observed that contact between two cells was sufficient to stimulate transfer of proteins and lipids from the outer membrane. But not all contacts led to a transfer. Importantly, when cells that had swapped fluorescent membrane components moved apart, they appeared to remain connected by tubular structures, suggesting that an inter-membrane junction must form to allow proteins and lipids to be transferred between the cells. This junction is referred to as an outer-membrane synapse.<\/p>\n<p hwp:id=\"p-11\">Ducret et al. also noted another phenomenon: cells shed pieces of membrane as they moved across surfaces or separated after outer membrane exchange. This suggests that both synapse formation after direct cell-to-cell contact and the shedding of membrane components can help to propagate bacterial signals, enabling population-wide behavioral changes, including the formation or collapse of super-organisms.<\/p>\n<p hwp:id=\"p-12\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00868.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00868.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00868.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00868",
"title": "Direct live imaging of cell-cell protein transfer by transient outer membrane fusion in Myxococcus xanthus",
"metadata": {
"authors": "A. Ducret, B. Fleuchot, P. Bergam, T. Mignot",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:35:39Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:35:39Z",
"updated_at": "2013-07-25T09:35:39Z"
},
{
"id": 151,
"content": "All cells are enclosed by a membrane that is made up of fatty molecules called lipids and is studded with proteins. This membrane allows cells to detect and react to outside events. Since external conditions, such as temperature, can vary dramatically, membranes need to be able to adjust their properties. For example, lipids become more fluid as the temperature rises, so membranes respond to heat stress by incorporating molecules called sterols to increase their rigidity. In fact, sterols have profound effects on membrane properties and are essential to regulate a number of cellular processes. But high levels of sterols can become toxic, so it is essential that they are carefully controlled.Sterols, such as ergosterol in yeast or cholesterol in mammals, are synthesized in a tightly regulated multi-step process; some of the early steps in sterol production also make common building blocks for other key molecules in the cell. A mechanism to control sterol levels is the regulated destruction of an enzyme that carries out an early step of their synthesis. This occurs via one branch of the ER-associated degradation (ERAD) pathway, which also destroys non-functional proteins. Now, Foresti et al. have found that sterol synthesis is also regulated by another branch of the ERAD pathway. This second control point, which occurs later in the biosynthetic process, allows cells to regulate sterol levels independent of the other products of the pathway that are derived from the same preliminary compounds.In yeast, the two ERAD branches are directed by Hrd1 and Doa10. These are both ubiquitin ligases\u2014proteins that attach a tag called ubiquitin to other proteins, thus labeling them for recycling by the proteasome (essentially a waste-disposal complex in the cell). To identify the proteins that are tagged by Doa10, Foresti et al. compared protein levels in strains lacking Doa10 with those in wild type yeast. Unexpectedly, the enzyme Erg1, which helps to synthesize ergosterol, was more abundant in cells lacking Doa10.Foresti et al. found that Doa10 tagged Erg1 for destruction when levels of the building blocks of ergosterol rose inside the cell. These ergosterol intermediates are toxic to yeast, which converts them into less harmful molecules known as sterol esters using the proteins Are1\/2. When the DOA10 or ARE1\/2 genes were deleted, these intermediates were more abundant; strikingly, they became even more prevalent when all three genes were knocked out in the same strain. In contrast, blocking the other ERAD branch by deleting HRD1 did not cause ergosterol intermediates to accumulate, nor did it exacerbate the effects of ARE1\/2 knockout.When combined with previous findings, these results provide evidence that the different branches of the ERAD pathway regulate ergosterol synthesis at distinct steps. The same mechanism is observed in human cells when high levels of cholesterol are detected. By identifying parallel routes to control sterol levels, this work reinforces the importance of membrane integrity to life.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00953.002",
"content_html": "<p hwp:id=\"p-4\">All cells are enclosed by a membrane that is made up of fatty molecules called lipids and is studded with proteins. This membrane allows cells to detect and react to outside events. Since external conditions, such as temperature, can vary dramatically, membranes need to be able to adjust their properties. For example, lipids become more fluid as the temperature rises, so membranes respond to heat stress by incorporating molecules called sterols to increase their rigidity. In fact, sterols have profound effects on membrane properties and are essential to regulate a number of cellular processes. But high levels of sterols can become toxic, so it is essential that they are carefully controlled.<\/p>\n<p hwp:id=\"p-5\">Sterols, such as ergosterol in yeast or cholesterol in mammals, are synthesized in a tightly regulated multi-step process; some of the early steps in sterol production also make common building blocks for other key molecules in the cell. A mechanism to control sterol levels is the regulated destruction of an enzyme that carries out an early step of their synthesis. This occurs via one branch of the ER-associated degradation (ERAD) pathway, which also destroys non-functional proteins. Now, Foresti et al. have found that sterol synthesis is also regulated by another branch of the ERAD pathway. This second control point, which occurs later in the biosynthetic process, allows cells to regulate sterol levels independent of the other products of the pathway that are derived from the same preliminary compounds.<\/p>\n<p hwp:id=\"p-6\">In yeast, the two ERAD branches are directed by Hrd1 and Doa10. These are both ubiquitin ligases&#x2014;proteins that attach a tag called ubiquitin to other proteins, thus labeling them for recycling by the proteasome (essentially a waste-disposal complex in the cell). To identify the proteins that are tagged by Doa10, Foresti et al. compared protein levels in strains lacking Doa10 with those in wild type yeast. Unexpectedly, the enzyme Erg1, which helps to synthesize ergosterol, was more abundant in cells lacking Doa10.<\/p>\n<p hwp:id=\"p-7\">Foresti et al. found that Doa10 tagged Erg1 for destruction when levels of the building blocks of ergosterol rose inside the cell. These ergosterol intermediates are toxic to yeast, which converts them into less harmful molecules known as sterol esters using the proteins Are1\/2. When the <italic>DOA10<\/italic> or <italic>ARE1\/2<\/italic> genes were deleted, these intermediates were more abundant; strikingly, they became even more prevalent when all three genes were knocked out in the same strain. In contrast, blocking the other ERAD branch by deleting <italic>HRD1<\/italic> did not cause ergosterol intermediates to accumulate, nor did it exacerbate the effects of <italic>ARE1\/2<\/italic> knockout.<\/p>\n<p hwp:id=\"p-8\">When combined with previous findings, these results provide evidence that the different branches of the ERAD pathway regulate ergosterol synthesis at distinct steps. The same mechanism is observed in human cells when high levels of cholesterol are detected. By identifying parallel routes to control sterol levels, this work reinforces the importance of membrane integrity to life.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00953.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00953.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00953.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00953",
"title": "Sterol homeostasis requires regulated degradation of squalene monooxygenase by the ubiquitin ligase Doa10\/Teb4",
"metadata": {
"authors": "O. Foresti, A. Ruggiano, H. K. Hannibal-Bach, C. S. Ejsing, P. Carvalho",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:35:48Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:35:48Z",
"updated_at": "2013-07-25T09:35:48Z"
},
{
"id": 152,
"content": "The simplest account of gene expression is that DNA is transcribed into messenger RNA, which is then translated into a protein. However, not all genes encode proteins; for some it is the RNA molecule itself that is the end product. Many of these \u2018non-coding RNAs\u2019 are thought to be involved in regulating the expression of other genes, but their exact functions are unknown.Pseudogenes are genes that have lost their protein-coding abilities as a result of mutations they have accumulated mutations over the course of evolution. They were previously referred to as \u2018junk DNA\u2019 or \u2018dead genes\u2019 because they were thought to be completely non-functional, lacking even the ability to encode RNA. However, recent work has shown that pseudogenes are in fact transcribed into long non-coding RNAs, and these are now the focus of much research.Here, Rapicavoli et al. report that certain pseudogenes and long non-coding RNAs are involved in regulating the immune response. Specific and distinct pseudogene-derived long RNAs are made when cells are exposed to different kinds of infections. Immune cells such as macrophages and lymphocytes produce a protein called tumor necrosis factor alpha (TNF\u03b1), which is involved in triggering fever and inflammation. TNF\u03b1 exerts these effects by binding to and activating a transcription factor called NF-\u03baB, which then moves to the nucleus and binds to DNA, regulating the expression of genes that encode immune proteins.Rapicavoli et al. found that the production of a long non-coding RNA called Lethe (after the \u2018river of forgetfulness\u2019 in Greek mythology) increases when TNF\u03b1 activates NF-\u03baB. Surprisingly, however, Lethe then binds to NF-\u03baB and prevents it from interacting with DNA, thereby reducing the production of various inflammatory proteins.This is the first time that a pseudogene has been shown to have an active role in regulating signaling pathways involved in inflammation, and raises the possibility that other pseudogenes may also influence distinct feedback loops and signaling networks. It suggests that many novel functions for pseudogenes and long non-coding RNAs remain to be discovered.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00762.002",
"content_html": "<p hwp:id=\"p-4\">The simplest account of gene expression is that DNA is transcribed into messenger RNA, which is then translated into a protein. However, not all genes encode proteins; for some it is the RNA molecule itself that is the end product. Many of these &#x2018;non-coding RNAs&#x2019; are thought to be involved in regulating the expression of other genes, but their exact functions are unknown.<\/p>\n<p hwp:id=\"p-5\">Pseudogenes are genes that have lost their protein-coding abilities as a result of mutations they have accumulated mutations over the course of evolution. They were previously referred to as &#x2018;junk DNA&#x2019; or &#x2018;dead genes&#x2019; because they were thought to be completely non-functional, lacking even the ability to encode RNA. However, recent work has shown that pseudogenes are in fact transcribed into long non-coding RNAs, and these are now the focus of much research.<\/p>\n<p hwp:id=\"p-6\">Here, Rapicavoli et al. report that certain pseudogenes and long non-coding RNAs are involved in regulating the immune response. Specific and distinct pseudogene-derived long RNAs are made when cells are exposed to different kinds of infections. Immune cells such as macrophages and lymphocytes produce a protein called tumor necrosis factor alpha (TNF&#x3B1;), which is involved in triggering fever and inflammation. TNF&#x3B1; exerts these effects by binding to and activating a transcription factor called NF-&#x3BA;B, which then moves to the nucleus and binds to DNA, regulating the expression of genes that encode immune proteins.<\/p>\n<p hwp:id=\"p-7\">Rapicavoli et al. found that the production of a long non-coding RNA called Lethe (after the &#x2018;river of forgetfulness&#x2019; in Greek mythology) increases when TNF&#x3B1; activates NF-&#x3BA;B. Surprisingly, however, Lethe then binds to NF-&#x3BA;B and prevents it from interacting with DNA, thereby reducing the production of various inflammatory proteins.<\/p>\n<p hwp:id=\"p-8\">This is the first time that a pseudogene has been shown to have an active role in regulating signaling pathways involved in inflammation, and raises the possibility that other pseudogenes may also influence distinct feedback loops and signaling networks. It suggests that many novel functions for pseudogenes and long non-coding RNAs remain to be discovered.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00762.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00762.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00762.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00762",
"title": "A mammalian pseudogene lncRNA at the interface of inflammation and anti-inflammatory therapeutics",
"metadata": {
"authors": "N. A. Rapicavoli, K. Qu, J. Zhang, M. Mikhail, R.-M. Laberge, H. Y. Chang",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:35:53Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:35:53Z",
"updated_at": "2013-07-25T09:35:53Z"
},
{
"id": 254,
"content": "One of the hallmarks of Alzheimer\u2019s disease is the formation of plaques in the brain by a protein called \u03b2-amyloid. This protein is generated by the cleavage of a precursor protein, and mutations in the gene that encodes amyloid precursor protein greatly increase the risk of developing a familial, early-onset form of Alzheimer\u2019s disease in middle age. Individuals with a particular variant of a lipoprotein called ApoE (ApoE4) are also more likely to develop Alzheimer\u2019s disease at a younger age than the rest of the population. Due to its prevalence\u2014approximately 20% of the world\u2019s population are carriers of at least one allele\u2014ApoE4 is the single-most important risk factor for the late-onset form of Alzheimer\u2019s disease.Amyloid precursor protein and the receptors for ApoE\u2014in particular one called LRP4\u2014are also essential for the development of the specialized synapse that forms between motor neurons and muscles. However, the mechanisms by which they, individually or together, contribute to the formation of these neuromuscular junctions are incompletely understood.Now, Choi et al. have shown that amyloid precursor protein and LRP4 interact at the developing neuromuscular junction. A protein called agrin, which is produced by motor neurons and which must bind to LRP4 to induce neuromuscular junction formation, also binds directly to amyloid precursor protein. This latter interaction leads to the formation of a complex between LRP4 and amyloid precursor protein that robustly promotes the formation of the neuromuscular junction. Mutations that remove the part of LRP4 that anchors it to the cell membrane weaken this complex and thus reduce the development of neuromuscular junctions in mice, especially if the animals also lack amyloid precursor protein.These three proteins thus seem to influence the development and maintenance of neuromuscular junctions by regulating the activity of a fourth protein, called MuSK, which is present on the surface of muscle cells. Activation of MuSK by agrin bound to LRP4 promotes the clustering of acetylcholine receptors in the membrane, which is a crucial step in the formation of the neuromuscular junction. Intriguingly, Choi et al. have now shown that amyloid precursor protein can, by interacting directly with LRP4, also activate MuSK even in the absence of agrin, albeit only to a small extent.The work of Choi et al. suggests that the complex formed between agrin, amyloid precursor protein and LRP4 helps to focus the activation of MuSK, and thus the clustering of acetylcholine receptors, to the site of the developing neuromuscular junction. Since all four proteins are also found in the central nervous system, similar processes might well be at work during the development and maintenance of synapses in the brain. Further studies of these interactions, both at the neuromuscular junction and in the brain, should shed new light on both normal synapse formation and the synaptic dysfunction that is seen in Alzheimer\u2019s disease.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00220.002",
"content_html": "<p hwp:id=\"p-6\">One of the hallmarks of Alzheimer&#x2019;s disease is the formation of plaques in the brain by a protein called &#x3B2;-amyloid. This protein is generated by the cleavage of a precursor protein, and mutations in the gene that encodes amyloid precursor protein greatly increase the risk of developing a familial, early-onset form of Alzheimer&#x2019;s disease in middle age. Individuals with a particular variant of a lipoprotein called ApoE (ApoE4) are also more likely to develop Alzheimer&#x2019;s disease at a younger age than the rest of the population. Due to its prevalence&#x2014;approximately 20% of the world&#x2019;s population are carriers of at least one allele&#x2014;ApoE4 is the single-most important risk factor for the late-onset form of Alzheimer&#x2019;s disease.<\/p>\n<p hwp:id=\"p-7\">Amyloid precursor protein and the receptors for ApoE&#x2014;in particular one called LRP4&#x2014;are also essential for the development of the specialized synapse that forms between motor neurons and muscles. However, the mechanisms by which they, individually or together, contribute to the formation of these neuromuscular junctions are incompletely understood.<\/p>\n<p hwp:id=\"p-8\">Now, Choi et al. have shown that amyloid precursor protein and LRP4 interact at the developing neuromuscular junction. A protein called agrin, which is produced by motor neurons and which must bind to LRP4 to induce neuromuscular junction formation, also binds directly to amyloid precursor protein. This latter interaction leads to the formation of a complex between LRP4 and amyloid precursor protein that robustly promotes the formation of the neuromuscular junction. Mutations that remove the part of LRP4 that anchors it to the cell membrane weaken this complex and thus reduce the development of neuromuscular junctions in mice, especially if the animals also lack amyloid precursor protein.<\/p>\n<p hwp:id=\"p-9\">These three proteins thus seem to influence the development and maintenance of neuromuscular junctions by regulating the activity of a fourth protein, called MuSK, which is present on the surface of muscle cells. Activation of MuSK by agrin bound to LRP4 promotes the clustering of acetylcholine receptors in the membrane, which is a crucial step in the formation of the neuromuscular junction. Intriguingly, Choi et al. have now shown that amyloid precursor protein can, by interacting directly with LRP4, also activate MuSK even in the absence of agrin, albeit only to a small extent.<\/p>\n<p hwp:id=\"p-10\">The work of Choi et al. suggests that the complex formed between agrin, amyloid precursor protein and LRP4 helps to focus the activation of MuSK, and thus the clustering of acetylcholine receptors, to the site of the developing neuromuscular junction. Since all four proteins are also found in the central nervous system, similar processes might well be at work during the development and maintenance of synapses in the brain. Further studies of these interactions, both at the neuromuscular junction and in the brain, should shed new light on both normal synapse formation and the synaptic dysfunction that is seen in Alzheimer&#x2019;s disease.<\/p>\n<p hwp:id=\"p-11\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00220.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00220.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00220.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00220",
"title": "APP interacts with LRP4 and agrin to coordinate the development of the neuromuscular junction in mice",
"metadata": {
"authors": "H. Y. Choi, Y. Liu, C. Tennert, Y. Sugiura, A. Karakatsani, S. Kroger, E. B. Johnson, R. E. Hammer, W. Lin, J. Herz",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2014-01-13T00:39:16Z",
"updated_at": "2014-01-13T00:39:16Z"
},
"created_at": "2014-01-13T00:39:16Z",
"updated_at": "2014-01-13T00:39:16Z"
},
{
"id": 43,
"content": "It has been clear since the early days of structural biology in the late 1950s that proteins and other biomolecules are continually changing shape, and that these changes have an important influence on both the structure and function of the molecules. X-ray diffraction can provide detailed information about the structure of a protein, but only limited information about how its structure fluctuates over time. Detailed information about the dynamic behaviour of proteins is essential for a proper understanding of a variety of processes, including catalysis, ligand binding and protein\u2013protein interactions, and could also prove useful in drug design.Currently most of the X-ray crystal structures in the Protein Data Bank are \u2018snap-shots\u2019 with limited or no information about protein dynamics. However, X-ray diffraction patterns are affected by the dynamics of the protein, and also by distortions of the crystal lattice, so three-dimensional (3D) models of proteins ought to take these phenomena into account. Molecular-dynamics (MD) computer simulations transform 3D structures into 4D \u2018molecular movies\u2019 by predicting the movement of individual atoms.Combining MD simulations with crystallographic data has the potential to produce more realistic ensemble models of proteins in which the atomic fluctuations are represented by multiple structures within the ensemble. Moreover, in addition to improved structural information, this process\u2014which is called ensemble refinement\u2014can provide dynamical information about the protein. Earlier attempts to do this ran into problems because the number of model parameters needed was greater than the number of observed data points. Burnley et al. now overcome this problem by modelling local molecular vibrations with MD simulations and, at the same time, using a course-grain model to describe global disorder of longer length scales.Ensemble refinement of high-resolution X-ray diffraction datasets for 20 different proteins from the Protein Data Bank produced a better fit to the data than single structures for all 20 proteins. Ensemble refinement also revealed that 3 of the 20 proteins had a \u2018molten core\u2019, rather than the well-ordered residues core found in most proteins: this is likely to be important in various biological functions including ligand binding, filament formation and enzymatic function. Burnley et al. also showed that a HIV enzyme underwent an order\u2013disorder transition that is likely to influence how this enzyme works, and that similar transitions might influence the interactions between the small-molecule drug Imatinib (also known as Gleevec) and the enzymes it targets. Ensemble refinement could be applied to the majority of crystallography data currently being collected, or collected in the past, so further insights into the properties and interactions of a variety of proteins and other biomolecules can be expected.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00311.002",
"content_html": "<p>It has been clear since the early days of structural biology in the late 1950s that proteins and other biomolecules are continually changing shape, and that these changes have an important influence on both the structure and function of the molecules. X-ray diffraction can provide detailed information about the structure of a protein, but only limited information about how its structure fluctuates over time. Detailed information about the dynamic behaviour of proteins is essential for a proper understanding of a variety of processes, including catalysis, ligand binding and protein\u2013protein interactions, and could also prove useful in drug design.Currently most of the X-ray crystal structures in the Protein Data Bank are \u2018snap-shots\u2019 with limited or no information about protein dynamics. However, X-ray diffraction patterns are affected by the dynamics of the protein, and also by distortions of the crystal lattice, so three-dimensional (3D) models of proteins ought to take these phenomena into account. Molecular-dynamics (MD) computer simulations transform 3D structures into 4D \u2018molecular movies\u2019 by predicting the movement of individual atoms.Combining MD simulations with crystallographic data has the potential to produce more realistic ensemble models of proteins in which the atomic fluctuations are represented by multiple structures within the ensemble. Moreover, in addition to improved structural information, this process\u2014which is called ensemble refinement\u2014can provide dynamical information about the protein. Earlier attempts to do this ran into problems because the number of model parameters needed was greater than the number of observed data points. Burnley et al. now overcome this problem by modelling local molecular vibrations with MD simulations and, at the same time, using a course-grain model to describe global disorder of longer length scales.Ensemble refinement of high-resolution X-ray diffraction datasets for 20 different proteins from the Protein Data Bank produced a better fit to the data than single structures for all 20 proteins. Ensemble refinement also revealed that 3 of the 20 proteins had a \u2018molten core\u2019, rather than the well-ordered residues core found in most proteins: this is likely to be important in various biological functions including ligand binding, filament formation and enzymatic function. Burnley et al. also showed that a HIV enzyme underwent an order\u2013disorder transition that is likely to influence how this enzyme works, and that similar transitions might influence the interactions between the small-molecule drug Imatinib (also known as Gleevec) and the enzymes it targets. Ensemble refinement could be applied to the majority of crystallography data currently being collected, or collected in the past, so further insights into the properties and interactions of a variety of proteins and other biomolecules can be expected.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00311.002<\/p>\n",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00311",
"title": "Modelling dynamics in protein crystal structures by ensemble refinement",
"metadata": {
"authors": "B. T. Burnley, P. V. Afonine, P. D. Adams, P. Gros",
"journal": "eLife 2012"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:28:45Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:28:45Z",
"updated_at": "2013-07-25T16:43:30Z"
},
{
"id": 159,
"content": "Stress-induced [hypermutation](https:\/\/en.wikipedia.org\/wiki\/Somatic_hypermutation) in the phenomena is which individuals who are under stress or are [maladapted](https:\/\/en.wikipedia.org\/wiki\/Maladaptation) to their environments increase their mutation rates by, for example, reducing the effectiveness of the [DNA proof-reading system](https:\/\/en.wikipedia.org\/wiki\/Proofreading_(biology)). The phenomena has been demonstrated in bacteria and yeast.\r\nIn this paper we use mathematical models and computer simulations to study the evolution of stress-induced hypermutation. We show that a gene that increases the mutation rate in stressed individuals is: 1) more fit than genes that cause a constant mutation rate, both in changing and constant environments, and 2) can invade populations in which the mutation rate is constant, regardless if the mutation rate of these populations is high or low.\r\n\r\nOur results show that natural selection favors stress-induced mutation rates and therefore it is likely that many organisms induce elevated mutation rates under stress. Because mutation is a fundamental process in evolution, this has implications across the life sciences and medicine, including [epidemiology](https:\/\/en.wikipedia.org\/wiki\/Epidemiology), [ecology](https:\/\/en.wikipedia.org\/wiki\/Ecology) and most importantly, our basic understanding of evolution.",
"content_html": "<p>Stress-induced <a href=\"https:\/\/en.wikipedia.org\/wiki\/Somatic_hypermutation\">hypermutation<\/a> in the phenomena is which individuals who are under stress or are <a href=\"https:\/\/en.wikipedia.org\/wiki\/Maladaptation\">maladapted<\/a> to their environments increase their mutation rates by, for example, reducing the effectiveness of the <a href=\"https:\/\/en.wikipedia.org\/wiki\/Proofreading_(biology)\">DNA proof-reading system<\/a>. The phenomena has been demonstrated in bacteria and yeast.\nIn this paper we use mathematical models and computer simulations to study the evolution of stress-induced hypermutation. We show that a gene that increases the mutation rate in stressed individuals is: 1) more fit than genes that cause a constant mutation rate, both in changing and constant environments, and 2) can invade populations in which the mutation rate is constant, regardless if the mutation rate of these populations is high or low.<\/p>\n\n<p>Our results show that natural selection favors stress-induced mutation rates and therefore it is likely that many organisms induce elevated mutation rates under stress. Because mutation is a fundamental process in evolution, this has implications across the life sciences and medicine, including <a href=\"https:\/\/en.wikipedia.org\/wiki\/Epidemiology\">epidemiology<\/a>, <a href=\"https:\/\/en.wikipedia.org\/wiki\/Ecology\">ecology<\/a> and most importantly, our basic understanding of evolution.<\/p>\n",
"user": {
"email": "yoavram@twitter.oauth"
},
"paper": {
"identifier": "doi: 10.1111\/j.1558-5646.2012.01576.x",
"title": "THE EVOLUTION OF STRESS-INDUCED HYPERMUTATION IN ASEXUAL POPULATIONS",
"metadata": {
"authors": "Yoav Ram, Lilach Hadany",
"journal": " 2012"
},
"abstract": null,
"abstract_html": null,
"created_at": "2014-05-10T07:10:53Z",
"updated_at": "2014-05-10T07:10:53Z"
},
"created_at": "2013-08-11T08:53:44Z",
"updated_at": "2014-05-10T07:11:25Z"
},
{
"id": 241,
"content": "Neurons communicate with each other at specialized junctions called synapses. When signals travelling along a neuron reach the presynaptic cell, this triggers small packages (vesicles) containing neurotransmitter molecules to release their contents into the synapse, and these molecules then cross the gap and bind to receptors on the postsynaptic neuron.To release their cargo, individual vesicles fuse with the plasma membrane of the presynaptic neuron and form a \u2018pore\u2019 through which neurotransmitter molecules can leave the cell. However, to avoid running out of vesicles, the neuron must recycle and rebuild them through a process known as endocytosis. This involves recapturing the proteins that make up the synaptic vesicle and internalizing them back into the presynaptic terminal.Exactly how endocytosis is regulated has been the subject of much debate in recent years. Now, Armbruster et al. have used fluorescent markers to study the timing of endocytosis in unprecedented detail. Observations of individual synapses reveal that when a series of action potentials (spikes of electrical activity) occurs in a neuron, endocytosis accelerates during the first few action potentials, and then slows. However, this acceleration was only detectable at a physiological temperature of 37\u00b0C\u2014markedly higher than the 30\u00b0C at which synaptic endocytosis is typically studied.The new study showed that acceleration of endocytosis depends on the phosphorylation status of dynamin, a mechano-chemical enzyme long known to be crucial for endocytosis, which helps to sever the connection between the endocytosing membrane and the surface of the cell. Phosphorylation is a common mechanism for controlling enzyme activity, and involves the addition of phosphate groups to specific amino acids by enzymes called kinases. Phosphatase enzymes reverse the process by removing the phosphate groups. Dynamin is usually phosphorylated at two specific amino acids, but when levels of calcium in the cell increase (as occurs during action potentials), a phosphatase called calcineurin dephosphorylates these sites. Using versions of dynamin that were either permanently phosphorylated or never phosphorylated, Armbruster et al. showed that a decrease in dynamin phosphorylation was required for the initial acceleration of endocytosis.This type of regulation seems to optimize the recycling of vesicles to enable neurons to respond effectively to brief bursts of stimulation. Given that dynamin phosphorylation is conserved in evolution, it is likely that regulation of synaptic endocytosis is a key mechanism for ensuring the efficient functioning of the nervous system. Future research will investigate how calcium influx mediates the later slowing of endocytosis, and help to further unravel this previously unknown regulatory process.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00845.002",
"content_html": "<p hwp:id=\"p-4\">Neurons communicate with each other at specialized junctions called synapses. When signals travelling along a neuron reach the presynaptic cell, this triggers small packages (vesicles) containing neurotransmitter molecules to release their contents into the synapse, and these molecules then cross the gap and bind to receptors on the postsynaptic neuron.<\/p>\n<p hwp:id=\"p-5\">To release their cargo, individual vesicles fuse with the plasma membrane of the presynaptic neuron and form a &#x2018;pore&#x2019; through which neurotransmitter molecules can leave the cell. However, to avoid running out of vesicles, the neuron must recycle and rebuild them through a process known as endocytosis. This involves recapturing the proteins that make up the synaptic vesicle and internalizing them back into the presynaptic terminal.<\/p>\n<p hwp:id=\"p-6\">Exactly how endocytosis is regulated has been the subject of much debate in recent years. Now, Armbruster et al. have used fluorescent markers to study the timing of endocytosis in unprecedented detail. Observations of individual synapses reveal that when a series of action potentials (spikes of electrical activity) occurs in a neuron, endocytosis accelerates during the first few action potentials, and then slows. However, this acceleration was only detectable at a physiological temperature of 37&#xB0;C&#x2014;markedly higher than the 30&#xB0;C at which synaptic endocytosis is typically studied.<\/p>\n<p hwp:id=\"p-7\">The new study showed that acceleration of endocytosis depends on the phosphorylation status of dynamin, a mechano-chemical enzyme long known to be crucial for endocytosis, which helps to sever the connection between the endocytosing membrane and the surface of the cell. Phosphorylation is a common mechanism for controlling enzyme activity, and involves the addition of phosphate groups to specific amino acids by enzymes called kinases. Phosphatase enzymes reverse the process by removing the phosphate groups. Dynamin is usually phosphorylated at two specific amino acids, but when levels of calcium in the cell increase (as occurs during action potentials), a phosphatase called calcineurin dephosphorylates these sites. Using versions of dynamin that were either permanently phosphorylated or never phosphorylated, Armbruster et al. showed that a decrease in dynamin phosphorylation was required for the initial acceleration of endocytosis.<\/p>\n<p hwp:id=\"p-8\">This type of regulation seems to optimize the recycling of vesicles to enable neurons to respond effectively to brief bursts of stimulation. Given that dynamin phosphorylation is conserved in evolution, it is likely that regulation of synaptic endocytosis is a key mechanism for ensuring the efficient functioning of the nervous system. Future research will investigate how calcium influx mediates the later slowing of endocytosis, and help to further unravel this previously unknown regulatory process.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00845.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00845.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00845.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00845",
"title": "Dynamin phosphorylation controls optimization of endocytosis for brief action potential bursts",
"metadata": {
"authors": "M. Armbruster, M. Messa, S. M. Ferguson, P. De Camilli, T. A. Ryan",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2014-01-13T00:38:32Z",
"updated_at": "2014-01-13T00:38:32Z"
},
"created_at": "2014-01-13T00:38:32Z",
"updated_at": "2014-01-13T00:38:32Z"
},
{
"id": 242,
"content": "Schistosomiasis\u2014a disease caused by parasitic flatworms known as schistosomes\u2014affects more than 200 million people worldwide, mainly in tropical regions, and in public health importance is second only to malaria (according to the World Health Organization). Chronic infection leads to damage to internal organs, and the disease is responsible for roughly 250,000 deaths each year.The schistosome parasite has a complex life cycle, and the worms are capable of infecting mammals during just one stage of this cycle. Infection occurs through contact with contaminated freshwater, with the infectious form of the parasite burrowing through skin. Once inside the body, the parasites mature into adults, before reproducing sexually and laying eggs that are excreted by their host back into the water supply.However, to generate the form of the parasite that can infect mammals, schistosomes must first infect an intermediate host, namely a freshwater snail. When the larval form of the parasite\u2014which cannot infect mammals\u2014enters the snail, the larvae undergo an unusual type of asexual embryogenesis. This results in thousands of parasites that are capable of infecting mammals. Studies suggest that a population of cells known as germinal cells are responsible for this transformation and replication process, but little is known about these cells at the molecular level.Here, Wang et al. report the gene expression profile of these cells in a species of schistosome, and use RNA-mediated silencing techniques to explore the functions of the genes. This analysis revealed that the germinal cells have a molecular signature similar to that of neoblasts\u2014adult pluripotent stem cells found in free-living flatworms such as planarians. Neoblasts can develop into any cell type in the body, enabling planarians to repair or even replace damaged body parts.The similarity between neoblasts and germinal cells led Wang et al. to suggest that schistosomes may have evolved their parasitic life cycle partly by adapting a program of development based on stem cells in non-parasitic worms.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00768.002",
"content_html": "<p hwp:id=\"p-4\">Schistosomiasis&#x2014;a disease caused by parasitic flatworms known as schistosomes&#x2014;affects more than 200 million people worldwide, mainly in tropical regions, and in public health importance is second only to malaria (according to the World Health Organization). Chronic infection leads to damage to internal organs, and the disease is responsible for roughly 250,000 deaths each year.<\/p>\n<p hwp:id=\"p-5\">The schistosome parasite has a complex life cycle, and the worms are capable of infecting mammals during just one stage of this cycle. Infection occurs through contact with contaminated freshwater, with the infectious form of the parasite burrowing through skin. Once inside the body, the parasites mature into adults, before reproducing sexually and laying eggs that are excreted by their host back into the water supply.<\/p>\n<p hwp:id=\"p-6\">However, to generate the form of the parasite that can infect mammals, schistosomes must first infect an intermediate host, namely a freshwater snail. When the larval form of the parasite&#x2014;which cannot infect mammals&#x2014;enters the snail, the larvae undergo an unusual type of asexual embryogenesis. This results in thousands of parasites that are capable of infecting mammals. Studies suggest that a population of cells known as germinal cells are responsible for this transformation and replication process, but little is known about these cells at the molecular level.<\/p>\n<p hwp:id=\"p-7\">Here, Wang et al. report the gene expression profile of these cells in a species of schistosome, and use RNA-mediated silencing techniques to explore the functions of the genes. This analysis revealed that the germinal cells have a molecular signature similar to that of neoblasts&#x2014;adult pluripotent stem cells found in free-living flatworms such as planarians. Neoblasts can develop into any cell type in the body, enabling planarians to repair or even replace damaged body parts.<\/p>\n<p hwp:id=\"p-8\">The similarity between neoblasts and germinal cells led Wang et al. to suggest that schistosomes may have evolved their parasitic life cycle partly by adapting a program of development based on stem cells in non-parasitic worms.<\/p>\n<p hwp:id=\"p-9\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00768.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00768.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00768.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00768",
"title": "Functional genomic characterization of neoblast-like stem cells in larval Schistosoma mansoni",
"metadata": {
"authors": "B. Wang, J. J. Collins, P. A. Newmark",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2014-01-13T00:38:34Z",
"updated_at": "2014-01-13T00:38:34Z"
},
"created_at": "2014-01-13T00:38:35Z",
"updated_at": "2014-01-13T00:38:35Z"
},
{
"id": 243,
"content": "Humans and other animals can use the five senses\u2014touch, taste, sight, smell, and hearing\u2014to interpret the world around them. Single-celled organisms, however, must rely on molecular cues to understand their immediate surroundings. In particular, bacteria gather information about external conditions, including potential hosts nearby, by secreting protein sensors that can relay messages back to the cell.Bacteria export these sensors via secretion systems that enable the organism both to receive information about the environment and to invade a host cell. A total of seven separate secretion systems, known as types I\u2013VII, have been identified. These different secretion systems handle distinct cargoes, allowing the bacterial cell to respond to a range of feedback from the external milieu.The type III secretion system, also known as the \u2018injectisome\u2019, is found in bacterial species that are enclosed by two membranes separated by a periplasmic space. The injectisome comprises different components that combine to form the basal body, which spans the inner and outer membranes, and a projection from the basal body, called the hollow needle, that mediates the export of cargo from a bacterium to its host or the local environment.The distance between the inner and outer membranes may vary across species or according to environmental conditions, so the basal body must be able to accommodate these changes. However, no mechanism has yet been established that might introduce such elasticity into the injectisome. Now, Kudryashev et al. have generated three-dimensional structures for the injectisomes of two species of bacteria, Shigella flexneri and Yersinia enterocolitica, and shown that the size of the basal body can fluctuate by up to 20%.Kudryashev et al. imaged whole injectisomes in these two species and found that the height of the basal body was proportional to the distance between the inner and outer membranes. To probe how this could occur, the properties of two proteins that are important components of the basal body were studied in greater detail. YscD, a protein that extends across the periplasmic space, was crystallized and its structure was then determined and used to develop a computer model to assess its compressibility: this model indicated that YscD could stretch or contract by up to 50% of its total length. The outer membrane component YscC also appeared elastic: when the protein was isolated and introduced into synthetic membranes, its length was reduced 30\u201340% relative to that observed in intact bacterial membranes.A further experiment confirmed the adaptability of the basal body: when the separation of the membranes was deliberately increased by placing bacteria in a high-salt medium, the basal body extended approximately 10% in length. Cumulatively, therefore, these experiments suggest that the in-built flexibility of the basal body of the injectisome allows bacteria to adjust to environmental changes while maintaining their sensory abilities and host-invasion potential.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00792.002",
"content_html": "<p hwp:id=\"p-6\">Humans and other animals can use the five senses&#x2014;touch, taste, sight, smell, and hearing&#x2014;to interpret the world around them. Single-celled organisms, however, must rely on molecular cues to understand their immediate surroundings. In particular, bacteria gather information about external conditions, including potential hosts nearby, by secreting protein sensors that can relay messages back to the cell.<\/p>\n<p hwp:id=\"p-7\">Bacteria export these sensors via secretion systems that enable the organism both to receive information about the environment and to invade a host cell. A total of seven separate secretion systems, known as types I&#x2013;VII, have been identified. These different secretion systems handle distinct cargoes, allowing the bacterial cell to respond to a range of feedback from the external milieu.<\/p>\n<p hwp:id=\"p-8\">The type III secretion system, also known as the &#x2018;injectisome&#x2019;, is found in bacterial species that are enclosed by two membranes separated by a periplasmic space. The injectisome comprises different components that combine to form the basal body, which spans the inner and outer membranes, and a projection from the basal body, called the hollow needle, that mediates the export of cargo from a bacterium to its host or the local environment.<\/p>\n<p hwp:id=\"p-9\">The distance between the inner and outer membranes may vary across species or according to environmental conditions, so the basal body must be able to accommodate these changes. However, no mechanism has yet been established that might introduce such elasticity into the injectisome. Now, Kudryashev et al. have generated three-dimensional structures for the injectisomes of two species of bacteria, <italic>Shigella flexneri<\/italic> and <italic>Yersinia enterocolitica<\/italic>, and shown that the size of the basal body can fluctuate by up to 20%.<\/p>\n<p hwp:id=\"p-10\">Kudryashev et al. imaged whole injectisomes in these two species and found that the height of the basal body was proportional to the distance between the inner and outer membranes. To probe how this could occur, the properties of two proteins that are important components of the basal body were studied in greater detail. YscD, a protein that extends across the periplasmic space, was crystallized and its structure was then determined and used to develop a computer model to assess its compressibility: this model indicated that YscD could stretch or contract by up to 50% of its total length. The outer membrane component YscC also appeared elastic: when the protein was isolated and introduced into synthetic membranes, its length was reduced 30&#x2013;40% relative to that observed in intact bacterial membranes.<\/p>\n<p hwp:id=\"p-11\">A further experiment confirmed the adaptability of the basal body: when the separation of the membranes was deliberately increased by placing bacteria in a high-salt medium, the basal body extended approximately 10% in length. Cumulatively, therefore, these experiments suggest that the in-built flexibility of the basal body of the injectisome allows bacteria to adjust to environmental changes while maintaining their sensory abilities and host-invasion potential.<\/p>\n<p hwp:id=\"p-12\"><bold>DOI:<\/bold> <ext-link l:rel=\"related\" l:ref-type=\"doi\" l:ref=\"10.7554\/eLife.00792.002\" ext-link-type=\"doi\" xlink:href=\"10.7554\/eLife.00792.002\" xlink:type=\"simple\" hwp:id=\"ext-link-3\">http:\/\/dx.doi.org\/10.7554\/eLife.00792.002<\/ext-link><\/p>",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00792",
"title": "In situ structural analysis of the Yersinia enterocolitica injectisome",
"metadata": {
"authors": "M. Kudryashev, M. Stenta, S. Schmelz, M. Amstutz, U. Wiesand, D. Castano-Diez, M. T. Degiacomi, S. Munnich, C. K. Bleck, J. Kowal, A. Diepold, D. W. Heinz, M. Dal Peraro, G. R. Cornelis, H. Stahlberg",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2014-01-13T00:38:37Z",
"updated_at": "2014-01-13T00:38:37Z"
},
"created_at": "2014-01-13T00:38:37Z",
"updated_at": "2014-01-13T00:38:37Z"
},
{
"id": 70,
"content": "The brains of all members of a species are similar, but not identical, and these differences are partly responsible for the range of behaviors displayed by individuals. The development of the nervous system is known to depend on the Notch signaling pathway, but the mechanisms that regulate the balance between fixed patterns of neuronal connectivity vs individual variability are largely unknown.Notch proteins are transmembrane proteins, which means that they have one part inside the cell membrane and another outside the cell. When a ligand protein\u2014such as a Delta ligand\u2014binds to the part that is outside the cell, the Notch protein breaks in two and the part inside the cell travels to the nucleus, where it can influence the expression of genes.Cells are selected to become neurons through a process known as mutual, or lateral, inhibition. When a Delta ligand belonging to one cell binds to the Notch receptor on a neighboring cell, the production of Delta ligands in the second cell is reduced. This amplifies any initial differences in the amount of Delta produced by each cell, and leads ultimately to them becoming distinct cell types.Now, Langen et al. show that this same mechanism is reactivated at a later stage of development during wiring up of the visual system. They used the fruit fly (Drosophila)\u2014a model organism with a fully sequenced genome and short intergeneration time\u2014to study a group of brain cells known as dorsal cluster neurons. At the end of the fruit fly larval stage, these neurons extend long axons across the brain to the opposite hemisphere: however, it is unclear how the neurons decide which cells to form connections with.Using genetically modified flies, Langen et al. showed that inhibiting Notch in a single dorsal cluster neuron caused that neuron to target a different cell: however, other neurons adjusted their choices accordingly so that the overall pattern of connections remained unchanged. Inhibiting Notch in a cluster of dorsal cluster neurons, on the other hand, disrupted the entire network, suggesting that Notch-mediated communication between neurons (via mutual inhibition) is needed to establish a robust wiring map.Langen et al. suggest that evolution has favored a mechanism that ensures that the overall pattern of connections within a circuit is preserved, while individual connections differ from one species member to the next.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00337.002",
"content_html": "<p>The brains of all members of a species are similar, but not identical, and these differences are partly responsible for the range of behaviors displayed by individuals. The development of the nervous system is known to depend on the Notch signaling pathway, but the mechanisms that regulate the balance between fixed patterns of neuronal connectivity vs individual variability are largely unknown.Notch proteins are transmembrane proteins, which means that they have one part inside the cell membrane and another outside the cell. When a ligand protein\u2014such as a Delta ligand\u2014binds to the part that is outside the cell, the Notch protein breaks in two and the part inside the cell travels to the nucleus, where it can influence the expression of genes.Cells are selected to become neurons through a process known as mutual, or lateral, inhibition. When a Delta ligand belonging to one cell binds to the Notch receptor on a neighboring cell, the production of Delta ligands in the second cell is reduced. This amplifies any initial differences in the amount of Delta produced by each cell, and leads ultimately to them becoming distinct cell types.Now, Langen et al. show that this same mechanism is reactivated at a later stage of development during wiring up of the visual system. They used the fruit fly (Drosophila)\u2014a model organism with a fully sequenced genome and short intergeneration time\u2014to study a group of brain cells known as dorsal cluster neurons. At the end of the fruit fly larval stage, these neurons extend long axons across the brain to the opposite hemisphere: however, it is unclear how the neurons decide which cells to form connections with.Using genetically modified flies, Langen et al. showed that inhibiting Notch in a single dorsal cluster neuron caused that neuron to target a different cell: however, other neurons adjusted their choices accordingly so that the overall pattern of connections remained unchanged. Inhibiting Notch in a cluster of dorsal cluster neurons, on the other hand, disrupted the entire network, suggesting that Notch-mediated communication between neurons (via mutual inhibition) is needed to establish a robust wiring map.Langen et al. suggest that evolution has favored a mechanism that ensures that the overall pattern of connections within a circuit is preserved, while individual connections differ from one species member to the next.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00337.002<\/p>\n",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00337",
"title": "Mutual inhibition among postmitotic neurons regulates robustness of brain wiring in Drosophila",
"metadata": {
"authors": "M. Langen, M. Koch, J. Yan, N. De Geest, M.-L. Erfurth, B. D. Pfeiffer, D. Schmucker, Y. Moreau, B. A. Hassan",
"journal": "eLife 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:30:33Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:30:33Z",
"updated_at": "2013-07-25T16:48:45Z"
},
{
"id": 154,
"content": "This study is a [longitudinal](http:\/\/en.wikipedia.org\/wiki\/Longitudinal_study) [meta-analysis](http:\/\/en.wikipedia.org\/wiki\/Meta-analysis) of associations between increases in temperature and [macro](http:\/\/en.wiktionary.org\/wiki\/macro) level human conflict, in example war or violent crime. Studies went as far back as 10,000BC, and were spread over various areas of the world. There is found to be a clear and consistent correlation between as little as approximately 5 degrees Fahrenheit increase in temperature and increase in human conflict. While not finding true [causality](https:\/\/en.wikipedia.org\/wiki\/Causality) for conflict by way of the temperature alone, it is hypothesized that these temperature changes can bring about cultural events most conducive to conflict. This 5 degree increase can indicate the beginning warring seasons, increase unemployment of farmers due to drought, promote migrations of groups of people, or create climate that has a tendency to increase social encounters. These events, among others, are known for increasing the chances of conflict from things like cultural conflict from migration and invasion, an irritable working class from unemployed farmers, and increased probability of violence simply by having people be around each other more.\r\n\r\nWhile it has been studied that increased temperatures can make people more irritable, in this analysis the temperature is more of an indicator of violent social events being more likely, as opposed to the cause of violence in and of itself.",
"content_html": "<p>This study is a <a href=\"http:\/\/en.wikipedia.org\/wiki\/Longitudinal_study\">longitudinal<\/a> <a href=\"http:\/\/en.wikipedia.org\/wiki\/Meta-analysis\">meta-analysis<\/a> of associations between increases in temperature and <a href=\"http:\/\/en.wiktionary.org\/wiki\/macro\">macro<\/a> level human conflict, in example war or violent crime. Studies went as far back as 10,000BC, and were spread over various areas of the world. There is found to be a clear and consistent correlation between as little as approximately 5 degrees Fahrenheit increase in temperature and increase in human conflict. While not finding true <a href=\"https:\/\/en.wikipedia.org\/wiki\/Causality\">causality<\/a> for conflict by way of the temperature alone, it is hypothesized that these temperature changes can bring about cultural events most conducive to conflict. This 5 degree increase can indicate the beginning warring seasons, increase unemployment of farmers due to drought, promote migrations of groups of people, or create climate that has a tendency to increase social encounters. These events, among others, are known for increasing the chances of conflict from things like cultural conflict from migration and invasion, an irritable working class from unemployed farmers, and increased probability of violence simply by having people be around each other more.<\/p>\n\n<p>While it has been studied that increased temperatures can make people more irritable, in this analysis the temperature is more of an indicator of violent social events being more likely, as opposed to the cause of violence in and of itself.<\/p>\n",
"user": {
"email": "rdreiley1@aol.com"
},
"paper": {
"identifier": "doi: 10.1126\/science.1235367",
"title": "Quantifying the Influence of Climate on Human Conflict",
"metadata": {
"authors": "Solomon M. Hsiang, Marshall Burke, Edward Miguel",
"journal": "Science 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-08-03T21:29:39Z",
"updated_at": "2013-08-05T20:11:53Z"
},
"created_at": "2013-08-04T20:49:16Z",
"updated_at": "2014-02-14T14:06:46Z"
},
{
"id": 29,
"content": "The ways people respond to conditions of reduced visibility is a central topic in vision research. Notably, it has been shown that people tend to underestimate speeds when visibility is reduced equally at all distances, as for example, when driving with a fogged up windshield. But what happens when the visibility decreases as you look further into the distance, as happens when driving in fog? Fortunately, as new research reveals, people tend to overestimate their speed when driving in fog-like conditions, and show a natural tendency to drive at a slower pace.Pretto et al. performed a series of experiments involving experienced drivers and high-quality virtual reality simulations. In one experiment, drivers were presented with two driving scenes and asked to guess which scene was moving faster. In the reference scene, the car was driving at a fixed speed through a landscape under conditions of clear visibility; in the test scene, it was moving through the same landscape, again at a fixed speed, but with the visibility reduced in different ways. The experiments showed that drivers overestimated speeds in fog-like conditions, and they underestimated speeds when the reduction in visibility did not depend on distance. Further experiments confirmed that these perceptions had an influence on driving behaviour: drivers recorded an average speed of 85.1 km\/hr when the visibility was good, and this dropped to 70.9 km\/hr in severe fog. However, when visibility was reduced equally at all distances, as happens with a fogged up windshield, the average driving speed increased to 101.3 km\/hr.Based on previous work, Pretto et al. developed the theory that the perception of speed is influenced by the relative speeds of the visible regions in the scene. When looking directly into the fog, visibility is strongly reduced in the distant regions, where the relative motion is slow, and is preserved in the near regions, where the motion is fast. This visibility gradient would lead to speed overestimation. To test this theory, the experiments were repeated with new drivers under three different conditions: good visibility, fog, and an artificial situation called \u2018anti-fog\u2019 in which visibility is poor in the near regions and improves as the driver looks further into the distance. As predicted, the estimated speed was lower in anti-fog than in clear visibility and fog. Conversely, the driving speed was 104.4 km\/hr in anti-fog compared with 67.9 km\/hr in good visibility and 51.3 km\/hr in fog.Overall, the results show that the perception of speed is influenced by spatial variations in visibility, and they strongly suggest that this is due to the relative speed contrast between the visible and covert areas within the scene.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00031.002",
"content_html": "<p>The ways people respond to conditions of reduced visibility is a central topic in vision research. Notably, it has been shown that people tend to underestimate speeds when visibility is reduced equally at all distances, as for example, when driving with a fogged up windshield. But what happens when the visibility decreases as you look further into the distance, as happens when driving in fog? Fortunately, as new research reveals, people tend to overestimate their speed when driving in fog-like conditions, and show a natural tendency to drive at a slower pace.Pretto et al. performed a series of experiments involving experienced drivers and high-quality virtual reality simulations. In one experiment, drivers were presented with two driving scenes and asked to guess which scene was moving faster. In the reference scene, the car was driving at a fixed speed through a landscape under conditions of clear visibility; in the test scene, it was moving through the same landscape, again at a fixed speed, but with the visibility reduced in different ways. The experiments showed that drivers overestimated speeds in fog-like conditions, and they underestimated speeds when the reduction in visibility did not depend on distance. Further experiments confirmed that these perceptions had an influence on driving behaviour: drivers recorded an average speed of 85.1 km\/hr when the visibility was good, and this dropped to 70.9 km\/hr in severe fog. However, when visibility was reduced equally at all distances, as happens with a fogged up windshield, the average driving speed increased to 101.3 km\/hr.Based on previous work, Pretto et al. developed the theory that the perception of speed is influenced by the relative speeds of the visible regions in the scene. When looking directly into the fog, visibility is strongly reduced in the distant regions, where the relative motion is slow, and is preserved in the near regions, where the motion is fast. This visibility gradient would lead to speed overestimation. To test this theory, the experiments were repeated with new drivers under three different conditions: good visibility, fog, and an artificial situation called \u2018anti-fog\u2019 in which visibility is poor in the near regions and improves as the driver looks further into the distance. As predicted, the estimated speed was lower in anti-fog than in clear visibility and fog. Conversely, the driving speed was 104.4 km\/hr in anti-fog compared with 67.9 km\/hr in good visibility and 51.3 km\/hr in fog.Overall, the results show that the perception of speed is influenced by spatial variations in visibility, and they strongly suggest that this is due to the relative speed contrast between the visible and covert areas within the scene.DOI: http:\/\/dx.doi.org\/10.7554\/eLife.00031.002<\/p>\n",
"user": {
"email": "staff@elifesciences.org"
},
"paper": {
"identifier": "doi: 10.7554\/eLife.00031",
"title": "Foggy perception slows us down",
"metadata": {
"authors": "P. Pretto, J.-P. Bresciani, G. Rainer, H. H. Bulthoff",
"journal": "eLife 2012"
},
"abstract": null,
"abstract_html": null,
"created_at": "2013-07-25T09:27:49Z",
"updated_at": "2013-08-06T20:57:32Z"
},
"created_at": "2013-07-25T09:27:49Z",
"updated_at": "2013-10-10T03:34:54Z"
},
{
"id": 157,
"content": "Almost all of the cells in a complex organism contain the same set of [genes](http:\/\/en.wikipedia.org\/wiki\/Gene). Yet these cells can be very different (for example, brain cells and muscle cells). One of the main reasons for this difference is that cells turn their genes on or off. This means that the set of genes which is 'on' in a brain cell is very different from the set of genes which is 'on' in a muscle cell. The process of turning a gene 'on' is complicated, but one crucial step is for the gene to be [transcribed](http:\/\/en.wikipedia.org\/wiki\/Transcription_%28genetics%29). When a gene is transcribed, a copy is made of the DNA sequence in a slightly different molecule called [RNA](http:\/\/en.wikipedia.org\/wiki\/Transcription_%28genetics%29). One of the ways cells control transcription is to produce proteins called [transcription factors](http:\/\/en.wikipedia.org\/wiki\/Transcription_factor), which bind to a specific DNA sequences near the start of genes and bring other proteins to the gene which will start to copy the DNA into RNA.\r\n\r\nIn this paper, the authors use [chromatin immunoprecipitation](http:\/\/en.wikipedia.org\/wiki\/Chromatin_immunoprecipitation) to identify the regions of the genome bound by two of these transcription factors, which are called Rev-Erb-a and Rev-Erb-b. They find that these proteins actually mostly bind to regions outside of genes, which they think might be enhancers. [Enhancers](http:\/\/en.wikipedia.org\/wiki\/Enhancer_%28genetics%29) are regions of DNA which direct which genes should be turned on in any given cell type. Enhancers can be very far away from genes in the linear DNA sequence but often seem to physically touch the DNA sequence of the gene they are activating by forming a DNA loop.\r\n\r\nLike genes themselves, enhancers can also be in an 'active' state, where they produce RNA. Using a technique called [GRO-seq](http:\/\/en.wikipedia.org\/wiki\/Nuclear_run-on), the authors show that the enhancers which are bound by the Rev-Erbs proteins are mostly active. They go on to show that when the Rev-Erbs proteins bind to an enhancer, the activity of the enhancer (i.e. the amount of RNA it produces) is reduced. At the same time, the activity of nearby genes which are controlled by the enhancer is also decreased. Many people think that enhancers produce RNA because they grab the transcription machinery responsible for creating RNA and physically deliver it to a gene. This would explain why enhancers have frequently been observed to physically contact genes. If this hypothesis was true, the RNA which is produced by the enhancer would be a by-product of the enhancer binding the transcription machinery, so it should not be required for the enhancer to activate a nearby gene.\r\n\r\nThrough a series of experiments, the authors show that if you remove the RNA produced by the enhancer, you impair the ability of the enhancer to activate nearby genes. This indicates that the RNA is not simply a by-product of the enhancer binding to activation proteins. Instead this paper suggests that RNAs produced by enhancers may play a more active role in activating genes.",
"content_html": "<p>Almost all of the cells in a complex organism contain the same set of <a href=\"http:\/\/en.wikipedia.org\/wiki\/Gene\">genes<\/a>. Yet these cells can be very different (for example, brain cells and muscle cells). One of the main reasons for this difference is that cells turn their genes on or off. This means that the set of genes which is \u2018on\u2019 in a brain cell is very different from the set of genes which is \u2018on\u2019 in a muscle cell. The process of turning a gene \u2018on\u2019 is complicated, but one crucial step is for the gene to be <a href=\"http:\/\/en.wikipedia.org\/wiki\/Transcription_%28genetics%29\">transcribed<\/a>. When a gene is transcribed, a copy is made of the DNA sequence in a slightly different molecule called <a href=\"http:\/\/en.wikipedia.org\/wiki\/Transcription_%28genetics%29\">RNA<\/a>. One of the ways cells control transcription is to produce proteins called <a href=\"http:\/\/en.wikipedia.org\/wiki\/Transcription_factor\">transcription factors<\/a>, which bind to a specific DNA sequences near the start of genes and bring other proteins to the gene which will start to copy the DNA into RNA.<\/p>\n\n<p>In this paper, the authors use <a href=\"http:\/\/en.wikipedia.org\/wiki\/Chromatin_immunoprecipitation\">chromatin immunoprecipitation<\/a> to identify the regions of the genome bound by two of these transcription factors, which are called Rev-Erb-a and Rev-Erb-b. They find that these proteins actually mostly bind to regions outside of genes, which they think might be enhancers. <a href=\"http:\/\/en.wikipedia.org\/wiki\/Enhancer_%28genetics%29\">Enhancers<\/a> are regions of DNA which direct which genes should be turned on in any given cell type. Enhancers can be very far away from genes in the linear DNA sequence but often seem to physically touch the DNA sequence of the gene they are activating by forming a DNA loop.<\/p>\n\n<p>Like genes themselves, enhancers can also be in an \u2018active\u2019 state, where they produce RNA. Using a technique called <a href=\"http:\/\/en.wikipedia.org\/wiki\/Nuclear_run-on\">GRO-seq<\/a>, the authors show that the enhancers which are bound by the Rev-Erbs proteins are mostly active. They go on to show that when the Rev-Erbs proteins bind to an enhancer, the activity of the enhancer (i.e. the amount of RNA it produces) is reduced. At the same time, the activity of nearby genes which are controlled by the enhancer is also decreased. Many people think that enhancers produce RNA because they grab the transcription machinery responsible for creating RNA and physically deliver it to a gene. This would explain why enhancers have frequently been observed to physically contact genes. If this hypothesis was true, the RNA which is produced by the enhancer would be a by-product of the enhancer binding the transcription machinery, so it should not be required for the enhancer to activate a nearby gene.<\/p>\n\n<p>Through a series of experiments, the authors show that if you remove the RNA produced by the enhancer, you impair the ability of the enhancer to activate nearby genes. This indicates that the RNA is not simply a by-product of the enhancer binding to activation proteins. Instead this paper suggests that RNAs produced by enhancers may play a more active role in activating genes.<\/p>\n",
"user": {
"email": "robbeagrie@twitter.oauth"
},
"paper": {
"identifier": "doi:10.1038\/nature12209",
"title": "Rev-Erbs repress macrophage gene expression by inhibiting enhancer-directed transcription",
"metadata": {
"authors": "Michael T. Y. Lam, Han Cho, Hanna P. Lesch, David Gosselin, Sven Heinz, Yumiko Tanaka-Oishi, Christopher Benner, Minna U. Kaikkonen, Aneeza S. Kim, Mika Kosaka, Cindy Y. Lee, Andy Watt, Tamar R. Grossman, Michael G. Rosenfeld, Ronald M. Evans, Christopher K. Glass",
"journal": "Nature 2013"
},
"abstract": null,
"abstract_html": null,
"created_at": "2014-05-10T07:04:53Z",
"updated_at": "2014-05-10T07:04:53Z"
},
"created_at": "2013-08-08T13:48:41Z",
"updated_at": "2014-05-10T07:06:14Z"
},
{
"id": 160,
"content": "Almost all of the cells in a complex organism contain the same set of [genes](http:\/\/en.wikipedia.org\/wiki\/Gene). Yet these cells can be very different (for example, brain cells and muscle cells). One of the main reasons for this difference is that cells turn their genes on or off. This means that the set of genes which is 'on' in a brain cell is very different from the set of genes which is 'on' in a muscle cell. The process of turning a gene 'on' is complicated, but one crucial step is for the gene to be [transcribed](http:\/\/en.wikipedia.org\/wiki\/Transcription_%28genetics%29). When a gene is transcribed, a copy is made of the DNA sequence in a slightly different molecule called [RNA](http:\/\/en.wikipedia.org\/wiki\/Transcription_%28genetics%29). In many cases, the process of turning a gene on or off can involve small chemicals binding to a protein called a [transcription factor](http:\/\/en.wikipedia.org\/wiki\/Transcription_factor). Acting together, the complex formed by the protein and the chemical can either help to bring the machinery for making RNA to the gene, or it can disrupt it.\r\n\r\nIn this paper, the authors use [chromatin immunoprecipitation](http:\/\/en.wikipedia.org\/wiki\/Chromatin_immunoprecipitation) to identify the regions of the genome bound by a transcription factor called ER-a. By measuring ER-a binding in the presence and absence of a small molecule called [17b-oestradiol](http:\/\/en.wikipedia.org\/wiki\/Estradiol) (also known as E2), they can determine how the chemical changes the binding of the ER-a protein. They find that the E2 molecule causes ER-a to bind to regions outside of genes, which they think might be enhancers. [Enhancers](http:\/\/en.wikipedia.org\/wiki\/Enhancer_%28genetics%29) are regions of DNA that direct which genes should be turned on in any given cell type. They can be very far away from genes, but often appear to control specific groups of genes by physically touching their DNA sequence.\r\n\r\nLike genes themselves, enhancers can also be in an 'active' state, where they produce RNA. Using a technique called [GRO-seq](http:\/\/en.wikipedia.org\/wiki\/Nuclear_run-on), the authors show that the enhancers produce more RNA when they are bound by the ER-a protein, and that the genes near to these enhancers also produce more RNA. Many people think that enhancers are active because they grab the machinery that activates genes and physically delivers it to the gene. This would also explain why enhancers have been observed to physically contact genes quite frequently. If this hypothesis was the case, the RNA which is produced by the enhancer is simply a by-product and should not itself be required for the enhancer to activate a nearby gene.\r\n\r\nThrough a series of experiments, the authors show that if you remove the RNA produced by the enhancer, you impair the ability of the enhancer to activate nearby genes. This indicates that the RNA is not simply a by-product of the enhancer binding to proteins that stimulate RNA production. They also show that when E2 (the chemical activator) is present, the enhancers touch the genes that they activate more frequently. Surprisingly, this effect is reduced when the enhancer RNA is removed at the same time as treating the cells with E2. This indicates that the enhancer RNA may be directly involved with bringing the gene and the enhancer together in some way. Finally, they show that the some of the RNAs can directly bind to a protein called cohesin, which is thought to be involved in forming gene\/enhancer loops. Removing cohesin, just like removing the enhancer RNA, reduces the frequency that an enhancer touches nearby genes as well as preventing the enhancer from fully activating the gene.",
"content_html": "<p>Almost all of the cells in a complex organism contain the same set of <a href=\"http:\/\/en.wikipedia.org\/wiki\/Gene\">genes<\/a>. Yet these cells can be very different (for example, brain cells and muscle cells). One of the main reasons for this difference is that cells turn their genes on or off. This means that the set of genes which is \u2018on\u2019 in a brain cell is very different from the set of genes which is \u2018on\u2019 in a muscle cell. The process of turning a gene \u2018on\u2019 is complicated, but one crucial step is for the gene to be <a href=\"http:\/\/en.wikipedia.org\/wiki\/Transcription_%28genetics%29\">transcribed<\/a>. When a gene is transcribed, a copy is made of the DNA sequence in a slightly different molecule called <a href=\"http:\/\/en.wikipedia.org\/wiki\/Transcription_%28genetics%29\">RNA<\/a>. In many cases, the process of turning a gene on or off can involve small chemicals binding to a protein called a <a href=\"http:\/\/en.wikipedia.org\/wiki\/Transcription_factor\">transcription factor<\/a>. Acting together, the complex formed by the protein and the chemical can either help to bring the machinery for making RNA to the gene, or it can disrupt it.<\/p>\n\n<p>In this paper, the authors use <a href=\"http:\/\/en.wikipedia.org\/wiki\/Chromatin_immunoprecipitation\">chromatin immunoprecipitation<\/a> to identify the regions of the genome bound by a transcription factor called ER-a. By measuring ER-a binding in the presence and absence of a small molecule called <a href=\"http:\/\/en.wikipedia.org\/wiki\/Estradiol\">17b-oestradiol<\/a> (also known as E2), they can determine how the chemical changes the binding of the ER-a protein. They find that the E2 molecule causes ER-a to bind to regions outside of genes, which they think might be enhancers. <a href=\"http:\/\/en.wikipedia.org\/wiki\/Enhancer_%28genetics%29\">Enhancers<\/a> are regions of DNA that direct which genes should be turned on in any given cell type. They can be very far away from genes, but often appear to control specific groups of genes by physically touching their DNA sequence.<\/p>\n\n<p>Like genes themselves, enhancers can also be in an \u2018acti
Sign up for free to join this conversation on GitHub. Already have an account? Sign in to comment