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Journal Cover PLoS Biology
  [SJR: 5.293]   [H-I: 185]   [311 followers]  Follow
  This is an Open Access Journal Open Access journal
   ISSN (Print) 1544-9173 - ISSN (Online) 1545-7885
   Published by PLoS Homepage  [13 journals]
  • 60 years ago, Francis Crick changed the logic of biology

    • Authors: Matthew Cobb
      Abstract: by Matthew CobbIn September 1957, Francis Crick gave a lecture in which he outlined key ideas about gene function, in particular what he called the central dogma. These ideas still frame how we understand life. This essay explores the concepts he developed in this influential lecture, including his prediction that we would study evolution by comparing sequences.
      PubDate: 2017-09-18T21:00:00Z
      DOI: 10.1371/journal.pbio.2003243
  • Reduced insulin signaling maintains electrical transmission in a
           neural circuit in aging flies

    • Authors: Hrvoje Augustin Kieran McGourty Marcus J. Allen Sirisha Kudumala Madem Jennifer Adcott Fiona Kerr Chi Tung Wong Alec Vincent Tanja Godenschwege Emmanuel Boucrot Linda Partridge
      Abstract: by Hrvoje Augustin, Kieran McGourty, Marcus J. Allen, Sirisha Kudumala Madem, Jennifer Adcott, Fiona Kerr, Chi Tung Wong, Alec Vincent, Tanja Godenschwege, Emmanuel Boucrot, Linda PartridgeLowered insulin/insulin-like growth factor (IGF) signaling (IIS) can extend healthy lifespan in worms, flies, and mice, but it can also have adverse effects (the “insulin paradox”). Chronic, moderately lowered IIS rescues age-related decline in neurotransmission through the Drosophila giant fiber system (GFS), a simple escape response neuronal circuit, by increasing targeting of the gap junctional protein innexin shaking-B to gap junctions (GJs). Endosomal recycling of GJs was also stimulated in cultured human cells when IIS was reduced. Furthermore, increasing the activity of the recycling small guanosine triphosphatases (GTPases) Rab4 or Rab11 was sufficient to maintain GJs upon elevated IIS in cultured human cells and in flies, and to rescue age-related loss of GJs and of GFS function. Lowered IIS thus elevates endosomal recycling of GJs in neurons and other cell types, pointing to a cellular mechanism for therapeutic intervention into aging-related neuronal disorders.
      PubDate: 2017-09-13T21:00:00Z
      DOI: 10.1371/journal.pbio.2001655
  • Place field assembly distribution encodes preferred locations

    • Authors: Omar Mamad Lars Stumpp Harold M. McNamara Charu Ramakrishnan Karl Deisseroth Richard B. Reilly Marian Tsanov
      Abstract: by Omar Mamad, Lars Stumpp, Harold M. McNamara, Charu Ramakrishnan, Karl Deisseroth, Richard B. Reilly, Marian TsanovThe hippocampus is the main locus of episodic memory formation and the neurons there encode the spatial map of the environment. Hippocampal place cells represent location, but their role in the learning of preferential location remains unclear. The hippocampus may encode locations independently from the stimuli and events that are associated with these locations. We have discovered a unique population code for the experience-dependent value of the context. The degree of reward-driven navigation preference highly correlates with the spatial distribution of the place fields recorded in the CA1 region of the hippocampus. We show place field clustering towards rewarded locations. Optogenetic manipulation of the ventral tegmental area demonstrates that the experience-dependent place field assembly distribution is directed by tegmental dopaminergic activity. The ability of the place cells to remap parallels the acquisition of reward context. Our findings present key evidence that the hippocampal neurons are not merely mapping the static environment but also store the concurrent context reward value, enabling episodic memory for past experience to support future adaptive behavior.
      PubDate: 2017-09-12T21:00:00Z
      DOI: 10.1371/journal.pbio.2002365
  • Extreme genome diversity in the hyper-prevalent parasitic eukaryote

    • Authors: Eleni Gentekaki Bruce A. Curtis Courtney W. Stairs Vladimír Klimeš Marek Eliáš Dayana E. Salas-Leiva Emily K. Herman Laura Eme Maria C. Arias Bernard Henrissat Frédérique Hilliou Mary J. Klute Hiroshi Suga Shehre-Banoo Malik Arthur W. Pightling Martin Kolisko Richard A. Rachubinski Alexander Schlacht Darren M. Soanes Anastasios D. Tsaousis John M. Archibald Steven G. Ball Joel B. Dacks C. Graham Clark Mark van der Giezen Andrew J. Roger
      Abstract: by Eleni Gentekaki, Bruce A. Curtis, Courtney W. Stairs, Vladimír Klimeš, Marek Eliáš, Dayana E. Salas-Leiva, Emily K. Herman, Laura Eme, Maria C. Arias, Bernard Henrissat, Frédérique Hilliou, Mary J. Klute, Hiroshi Suga, Shehre-Banoo Malik, Arthur W. Pightling, Martin Kolisko, Richard A. Rachubinski, Alexander Schlacht, Darren M. Soanes, Anastasios D. Tsaousis, John M. Archibald, Steven G. Ball, Joel B. Dacks, C. Graham Clark, Mark van der Giezen, Andrew J. RogerBlastocystis is the most prevalent eukaryotic microbe colonizing the human gut, infecting approximately 1 billion individuals worldwide. Although Blastocystis has been linked to intestinal disorders, its pathogenicity remains controversial because most carriers are asymptomatic. Here, the genome sequence of Blastocystis subtype (ST) 1 is presented and compared to previously published sequences for ST4 and ST7. Despite a conserved core of genes, there is unexpected diversity between these STs in terms of their genome sizes, guanine-cytosine (GC) content, intron numbers, and gene content. ST1 has 6,544 protein-coding genes, which is several hundred more than reported for ST4 and ST7. The percentage of proteins unique to each ST ranges from 6.2% to 20.5%, greatly exceeding the differences observed within parasite genera. Orthologous proteins also display extreme divergence in amino acid sequence identity between STs (i.e., 59%–61% median identity), on par with observations of the most distantly related species pairs of parasite genera. The STs also display substantial variation in gene family distributions and sizes, especially for protein kinase and protease gene families, which could reflect differences in virulence. It remains to be seen to what extent these inter-ST differences persist at the intra-ST level. A full 26% of genes in ST1 have stop codons that are created on the mRNA level by a novel polyadenylation mechanism found only in Blastocystis. Reconstructions of pathways and organellar systems revealed that ST1 has a relatively complete membrane-trafficking system and a near-complete meiotic toolkit, possibly indicating a sexual cycle. Unlike some intestinal protistan parasites, Blastocystis ST1 has near-complete de novo pyrimidine, purine, and thiamine biosynthesis pathways and is unique amongst studied stramenopiles in being able to metabolize α-glucans rather than β-glucans. It lacks all genes encoding heme-containing cytochrome P450 proteins. Predictions of the mitochondrion-related organelle (MRO) proteome reveal an expanded repertoire of functions, including lipid, cofactor, and vitamin biosynthesis, as well as proteins that may be involved in regulating mitochondrial morphology and MRO/endoplasmic reticulum (ER) interactions. In sharp contrast, genes for peroxisome-associated functions are absent, suggesting Blastocystis STs lack this organelle. Overall, this study provides an important window into the biology of Blastocystis, showcasing significant differences between STs that can guide future experimental investigations into differences in their virulence and clarifying the roles of these organisms in gut health and disease.
      PubDate: 2017-09-11T21:00:00Z
      DOI: 10.1371/journal.pbio.2003769
  • A map of protein dynamics during cell-cycle progression and cell-cycle

    • Authors: Sara Gookin Mingwei Min Harsha Phadke Mingyu Chung Justin Moser Iain Miller Dylan Carter Sabrina L. Spencer
      Abstract: by Sara Gookin, Mingwei Min, Harsha Phadke, Mingyu Chung, Justin Moser, Iain Miller, Dylan Carter, Sabrina L. SpencerThe cell-cycle field has identified the core regulators that drive the cell cycle, but we do not have a clear map of the dynamics of these regulators during cell-cycle progression versus cell-cycle exit. Here we use single-cell time-lapse microscopy of Cyclin-Dependent Kinase 2 (CDK2) activity followed by endpoint immunofluorescence and computational cell synchronization to determine the temporal dynamics of key cell-cycle proteins in asynchronously cycling human cells. We identify several unexpected patterns for core cell-cycle proteins in actively proliferating (CDK2-increasing) versus spontaneously quiescent (CDK2-low) cells, including Cyclin D1, the levels of which we find to be higher in spontaneously quiescent versus proliferating cells. We also identify proteins with concentrations that steadily increase or decrease the longer cells are in quiescence, suggesting the existence of a continuum of quiescence depths. Our single-cell measurements thus provide a rich resource for the field by characterizing protein dynamics during proliferation versus quiescence.
      PubDate: 2017-09-11T21:00:00Z
      DOI: 10.1371/journal.pbio.2003268
  • ‘Spin’ in published biomedical literature: A methodological
           systematic review

    • Authors: Kellia Chiu Quinn Grundy Lisa Bero
      Abstract: by Kellia Chiu, Quinn Grundy, Lisa BeroIn the scientific literature, spin refers to reporting practices that distort the interpretation of results and mislead readers so that results are viewed in a more favourable light. The presence of spin in biomedical research can negatively impact the development of further studies, clinical practice, and health policies. This systematic review aims to explore the nature and prevalence of spin in the biomedical literature. We searched MEDLINE, PreMEDLINE, Embase, Scopus, and hand searched reference lists for all reports that included the measurement of spin in the biomedical literature for at least 1 outcome. Two independent coders extracted data on the characteristics of reports and their included studies and all spin-related outcomes. Results were grouped inductively into themes by spin-related outcome and are presented as a narrative synthesis. We used meta-analyses to analyse the association of spin with industry sponsorship of research. We included 35 reports, which investigated spin in clinical trials, observational studies, diagnostic accuracy studies, systematic reviews, and meta-analyses. The nature of spin varied according to study design. The highest (but also greatest) variability in the prevalence of spin was present in trials. Some of the common practices used to spin results included detracting from statistically nonsignificant results and inappropriately using causal language. Source of funding was hypothesised by a few authors to be a factor associated with spin; however, results were inconclusive, possibly due to the heterogeneity of the included papers. Further research is needed to assess the impact of spin on readers’ decision-making. Editors and peer reviewers should be familiar with the prevalence and manifestations of spin in their area of research in order to ensure accurate interpretation and dissemination of research.
      PubDate: 2017-09-11T21:00:00Z
      DOI: 10.1371/journal.pbio.2002173
  • Simple rules can guide whether land- or ocean-based conservation will best
           benefit marine ecosystems

    • Authors: Megan I. Saunders Michael Bode Scott Atkinson Carissa J. Klein Anna Metaxas Jutta Beher Maria Beger Morena Mills Sylvaine Giakoumi Vivitskaia Tulloch Hugh P. Possingham
      Abstract: by Megan I. Saunders, Michael Bode, Scott Atkinson, Carissa J. Klein, Anna Metaxas, Jutta Beher, Maria Beger, Morena Mills, Sylvaine Giakoumi, Vivitskaia Tulloch, Hugh P. PossinghamCoastal marine ecosystems can be managed by actions undertaken both on the land and in the ocean. Quantifying and comparing the costs and benefits of actions in both realms is therefore necessary for efficient management. Here, we quantify the link between terrestrial sediment runoff and a downstream coastal marine ecosystem and contrast the cost-effectiveness of marine- and land-based conservation actions. We use a dynamic land- and sea-scape model to determine whether limited funds should be directed to 1 of 4 alternative conservation actions—protection on land, protection in the ocean, restoration on land, or restoration in the ocean—to maximise the extent of light-dependent marine benthic habitats across decadal timescales. We apply the model to a case study for a seagrass meadow in Australia. We find that marine restoration is the most cost-effective action over decadal timescales in this system, based on a conservative estimate of the rate at which seagrass can expand into a new habitat. The optimal decision will vary in different social–ecological contexts, but some basic information can guide optimal investments to counteract land- and ocean-based stressors: (1) marine restoration should be prioritised if the rates of marine ecosystem decline and expansion are similar and low; (2) marine protection should take precedence if the rate of marine ecosystem decline is high or if the adjacent catchment is relatively intact and has a low rate of vegetation decline; (3) land-based actions are optimal when the ratio of marine ecosystem expansion to decline is greater than 1:1.4, with terrestrial restoration typically the most cost-effective action; and (4) land protection should be prioritised if the catchment is relatively intact but the rate of vegetation decline is high. These rules of thumb illustrate how cost-effective conservation outcomes for connected land–ocean systems can proceed without complex modelling.
      PubDate: 2017-09-06T21:00:00Z
      DOI: 10.1371/journal.pbio.2001886
  • Correction: Dramatic and concerted conformational changes enable
           rhodocetin to block α2β1 integrin selectively

    • Authors: Johannes A. Eble Matthew McDougall George L. Orriss Stephan Niland Benjamin Johanningmeier Gottfried Pohlentz Markus Meier Simone Karrasch Maria Inacia Estevão-Costa Augusto Martins Lima Jörg Stetefeld
      Abstract: by Johannes A. Eble, Matthew McDougall, George L. Orriss, Stephan Niland, Benjamin Johanningmeier, Gottfried Pohlentz, Markus Meier, Simone Karrasch, Maria Inacia Estevão-Costa, Augusto Martins Lima, Jörg Stetefeld
      PubDate: 2017-09-06T21:00:00Z
      DOI: 10.1371/journal.pbio.1002613
  • Systematic analysis of transcription start sites in avian development

    • Authors: Marina Lizio Ruslan Deviatiiarov Hiroki Nagai Laura Galan Erik Arner Masayoshi Itoh Timo Lassmann Takeya Kasukawa Akira Hasegawa Marian A. Ros Yoshihide Hayashizaki Piero Carninci Alistair R. R. Forrest Hideya Kawaji Oleg Gusev Guojun Sheng
      Abstract: by Marina Lizio, Ruslan Deviatiiarov, Hiroki Nagai, Laura Galan, Erik Arner, Masayoshi Itoh, Timo Lassmann, Takeya Kasukawa, Akira Hasegawa, Marian A. Ros, Yoshihide Hayashizaki, Piero Carninci, Alistair R. R. Forrest, Hideya Kawaji, Oleg Gusev, Guojun ShengCap Analysis of Gene Expression (CAGE) in combination with single-molecule sequencing technology allows precision mapping of transcription start sites (TSSs) and genome-wide capture of promoter activities in differentiated and steady state cell populations. Much less is known about whether TSS profiling can characterize diverse and non-steady state cell populations, such as the approximately 400 transitory and heterogeneous cell types that arise during ontogeny of vertebrate animals. To gain such insight, we used the chick model and performed CAGE-based TSS analysis on embryonic samples covering the full 3-week developmental period. In total, 31,863 robust TSS peaks (>1 tag per million [TPM]) were mapped to the latest chicken genome assembly, of which 34% to 46% were active in any given developmental stage. ZENBU, a web-based, open-source platform, was used for interactive data exploration. TSSs of genes critical for lineage differentiation could be precisely mapped and their activities tracked throughout development, suggesting that non-steady state and heterogeneous cell populations are amenable to CAGE-based transcriptional analysis. Our study also uncovered a large set of extremely stable housekeeping TSSs and many novel stage-specific ones. We furthermore demonstrated that TSS mapping could expedite motif-based promoter analysis for regulatory modules associated with stage-specific and housekeeping genes. Finally, using Brachyury as an example, we provide evidence that precise TSS mapping in combination with Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-on technology enables us, for the first time, to efficiently target endogenous avian genes for transcriptional activation. Taken together, our results represent the first report of genome-wide TSS mapping in birds and the first systematic developmental TSS analysis in any amniote species (birds and mammals). By facilitating promoter-based molecular analysis and genetic manipulation, our work also underscores the value of avian models in unravelling the complex regulatory mechanism of cell lineage specification during amniote development.
      PubDate: 2017-09-05T21:00:00Z
      DOI: 10.1371/journal.pbio.2002887
  • Identifying genetic variants that affect viability in large cohorts

    • Authors: Hakhamanesh Mostafavi Tomaz Berisa Felix R. Day John R. B. Perry Molly Przeworski Joseph K. Pickrell
      Abstract: by Hakhamanesh Mostafavi, Tomaz Berisa, Felix R. Day, John R. B. Perry, Molly Przeworski, Joseph K. PickrellA number of open questions in human evolutionary genetics would become tractable if we were able to directly measure evolutionary fitness. As a step towards this goal, we developed a method to examine whether individual genetic variants, or sets of genetic variants, currently influence viability. The approach consists in testing whether the frequency of an allele varies across ages, accounting for variation in ancestry. We applied it to the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort and to the parents of participants in the UK Biobank. Across the genome, we found only a few common variants with large effects on age-specific mortality: tagging the APOE ε4 allele and near CHRNA3. These results suggest that when large, even late-onset effects are kept at low frequency by purifying selection. Testing viability effects of sets of genetic variants that jointly influence 1 of 42 traits, we detected a number of strong signals. In participants of the UK Biobank of British ancestry, we found that variants that delay puberty timing are associated with a longer parental life span (P~6.2 × 10−6 for fathers and P~2.0 × 10−3 for mothers), consistent with epidemiological studies. Similarly, variants associated with later age at first birth are associated with a longer maternal life span (P~1.4 × 10−3). Signals are also observed for variants influencing cholesterol levels, risk of coronary artery disease (CAD), body mass index, as well as risk of asthma. These signals exhibit consistent effects in the GERA cohort and among participants of the UK Biobank of non-British ancestry. We also found marked differences between males and females, most notably at the CHRNA3 locus, and variants associated with risk of CAD and cholesterol levels. Beyond our findings, the analysis serves as a proof of principle for how upcoming biomedical data sets can be used to learn about selection effects in contemporary humans.
      PubDate: 2017-09-05T21:00:00Z
      DOI: 10.1371/journal.pbio.2002458
  • Genomic dissection of conserved transcriptional regulation in intestinal
           epithelial cells

    • Authors: Colin R. Lickwar J. Gray Camp Matthew Weiser Jordan L. Cocchiaro David M. Kingsley Terrence S. Furey Shehzad Z. Sheikh John F. Rawls
      Abstract: by Colin R. Lickwar, J. Gray Camp, Matthew Weiser, Jordan L. Cocchiaro, David M. Kingsley, Terrence S. Furey, Shehzad Z. Sheikh, John F. RawlsThe intestinal epithelium serves critical physiologic functions that are shared among all vertebrates. However, it is unknown how the transcriptional regulatory mechanisms underlying these functions have changed over the course of vertebrate evolution. We generated genome-wide mRNA and accessible chromatin data from adult intestinal epithelial cells (IECs) in zebrafish, stickleback, mouse, and human species to determine if conserved IEC functions are achieved through common transcriptional regulation. We found evidence for substantial common regulation and conservation of gene expression regionally along the length of the intestine from fish to mammals and identified a core set of genes comprising a vertebrate IEC signature. We also identified transcriptional start sites and other putative regulatory regions that are differentially accessible in IECs in all 4 species. Although these sites rarely showed sequence conservation from fish to mammals, surprisingly, they drove highly conserved IEC expression in a zebrafish reporter assay. Common putative transcription factor binding sites (TFBS) found at these sites in multiple species indicate that sequence conservation alone is insufficient to identify much of the functionally conserved IEC regulatory information. Among the rare, highly sequence-conserved, IEC-specific regulatory regions, we discovered an ancient enhancer upstream from her6/HES1 that is active in a distinct population of Notch-positive cells in the intestinal epithelium. Together, these results show how combining accessible chromatin and mRNA datasets with TFBS prediction and in vivo reporter assays can reveal tissue-specific regulatory information conserved across 420 million years of vertebrate evolution. We define an IEC transcriptional regulatory network that is shared between fish and mammals and establish an experimental platform for studying how evolutionarily distilled regulatory information commonly controls IEC development and physiology.
      PubDate: 2017-08-29T21:00:00Z
      DOI: 10.1371/journal.pbio.2002054
  • Spontaneous mutation rate is a plastic trait associated with population
           density across domains of life

    • Authors: Rok Krašovec Huw Richards Danna R. Gifford Charlie Hatcher Katy J. Faulkner Roman V. Belavkin Alastair Channon Elizabeth Aston Andrew J. McBain Christopher G. Knight
      Abstract: by Rok Krašovec, Huw Richards, Danna R. Gifford, Charlie Hatcher, Katy J. Faulkner, Roman V. Belavkin, Alastair Channon, Elizabeth Aston, Andrew J. McBain, Christopher G. KnightRates of random, spontaneous mutation can vary plastically, dependent upon the environment. Such plasticity affects evolutionary trajectories and may be adaptive. We recently identified an inverse plastic association between mutation rate and population density at 1 locus in 1 species of bacterium. It is unknown how widespread this association is, whether it varies among organisms, and what molecular mechanisms of mutagenesis or repair are required for this mutation-rate plasticity. Here, we address all 3 questions. We identify a strong negative association between mutation rate and population density across 70 years of published literature, comprising hundreds of mutation rates estimated using phenotypic markers of mutation (fluctuation tests) from all domains of life and viruses. We test this relationship experimentally, determining that there is indeed density-associated mutation-rate plasticity (DAMP) at multiple loci in both eukaryotes and bacteria, with up to 23-fold lower mutation rates at higher population densities. We find that the degree of plasticity varies, even among closely related organisms. Nonetheless, in each domain tested, DAMP requires proteins scavenging the mutagenic oxidised nucleotide 8-oxo-dGTP. This implies that phenotypic markers give a more precise view of mutation rate than previously believed: having accounted for other known factors affecting mutation rate, controlling for population density can reduce variation in mutation-rate estimates by 93%. Widespread DAMP, which we manipulate genetically in disparate organisms, also provides a novel trait to use in the fight against the evolution of antimicrobial resistance. Such a prevalent environmental association and conserved mechanism suggest that mutation has varied plastically with population density since the early origins of life.
      PubDate: 2017-08-24T21:00:00Z
      DOI: 10.1371/journal.pbio.2002731
  • Lef1-dependent hypothalamic neurogenesis inhibits anxiety

    • Authors: Yuanyuan Xie Dan Kaufmann Matthew J. Moulton Samin Panahi John A. Gaynes Harrison N. Watters Dingxi Zhou Hai-Hui Xue Camille M. Fung Edward M. Levine Anthea Letsou K. C. Brennan Richard I. Dorsky
      Abstract: by Yuanyuan Xie, Dan Kaufmann, Matthew J. Moulton, Samin Panahi, John A. Gaynes, Harrison N. Watters, Dingxi Zhou, Hai-Hui Xue, Camille M. Fung, Edward M. Levine, Anthea Letsou, K. C. Brennan, Richard I. DorskyWhile innate behaviors are conserved throughout the animal kingdom, it is unknown whether common signaling pathways regulate the development of neuronal populations mediating these behaviors in diverse organisms. Here, we demonstrate that the Wnt/ß-catenin effector Lef1 is required for the differentiation of anxiolytic hypothalamic neurons in zebrafish and mice, although the identity of Lef1-dependent genes and neurons differ between these 2 species. We further show that zebrafish and Drosophila have common Lef1-dependent gene expression in their respective neuroendocrine organs, consistent with a conserved pathway that has diverged in the mouse. Finally, orthologs of Lef1-dependent genes from both zebrafish and mouse show highly correlated hypothalamic expression in marmosets and humans, suggesting co-regulation of 2 parallel anxiolytic pathways in primates. These findings demonstrate that during evolution, a transcription factor can act through multiple mechanisms to generate a common behavioral output, and that Lef1 regulates circuit development that is fundamentally important for mediating anxiety in a wide variety of animal species.
      PubDate: 2017-08-24T21:00:00Z
      DOI: 10.1371/journal.pbio.2002257
  • Understanding and overcoming antibiotic resistance

    • Authors: Lauren A. Richardson
      Abstract: by Lauren A. Richardson
      PubDate: 2017-08-23T21:00:00Z
      DOI: 10.1371/journal.pbio.2003775
  • Different patterns of neuronal activity trigger distinct responses of
           oligodendrocyte precursor cells in the corpus callosum

    • Authors: Balint Nagy Anahit Hovhannisyan Ruxandra Barzan Ting-Jiun Chen Maria Kukley
      Abstract: by Balint Nagy, Anahit Hovhannisyan, Ruxandra Barzan, Ting-Jiun Chen, Maria KukleyIn the developing and adult brain, oligodendrocyte precursor cells (OPCs) are influenced by neuronal activity: they are involved in synaptic signaling with neurons, and their proliferation and differentiation into myelinating glia can be altered by transient changes in neuronal firing. An important question that has been unanswered is whether OPCs can discriminate different patterns of neuronal activity and respond to them in a distinct way. Here, we demonstrate in brain slices that the pattern of neuronal activity determines the functional changes triggered at synapses between axons and OPCs. Furthermore, we show that stimulation of the corpus callosum at different frequencies in vivo affects proliferation and differentiation of OPCs in a dissimilar way. Our findings suggest that neurons do not influence OPCs in “all-or-none” fashion but use their firing pattern to tune the response and behavior of these nonneuronal cells.
      PubDate: 2017-08-22T21:00:00Z
      DOI: 10.1371/journal.pbio.2001993
  • Object segmentation controls image reconstruction from natural scenes

    • Authors: Peter Neri
      Abstract: by Peter NeriThe structure of the physical world projects images onto our eyes. However, those images are often poorly representative of environmental structure: well-defined boundaries within the eye may correspond to irrelevant features of the physical world, while critical features of the physical world may be nearly invisible at the retinal projection. The challenge for the visual cortex is to sort these two types of features according to their utility in ultimately reconstructing percepts and interpreting the constituents of the scene. We describe a novel paradigm that enabled us to selectively evaluate the relative role played by these two feature classes in signal reconstruction from corrupted images. Our measurements demonstrate that this process is quickly dominated by the inferred structure of the environment, and only minimally controlled by variations of raw image content. The inferential mechanism is spatially global and its impact on early visual cortex is fast. Furthermore, it retunes local visual processing for more efficient feature extraction without altering the intrinsic transduction noise. The basic properties of this process can be partially captured by a combination of small-scale circuit models and large-scale network architectures. Taken together, our results challenge compartmentalized notions of bottom-up/top-down perception and suggest instead that these two modes are best viewed as an integrated perceptual mechanism.
      PubDate: 2017-08-21T21:00:00Z
      DOI: 10.1371/journal.pbio.1002611
  • Perceived effort for motor control and decision-making

    • Authors: Ignasi Cos
      Abstract: by Ignasi CosHow effort is internally quantified and how it influences both movement generation and decisions between potential movements are 2 difficult questions to answer. Physical costs are known to influence motor control and decision-making, yet we lack a general, principled characterization of how the perception of effort operates across tasks and conditions. Morel and colleagues introduce an insightful approach to that end, assessing effort indifference points and presenting a quadratic law between perceived effort and force production.
      PubDate: 2017-08-18T21:00:00Z
      DOI: 10.1371/journal.pbio.2002885
  • Let’s rise up to unite taxonomy and technology

    • Authors: Holly M. Bik
      Abstract: by Holly M. BikWhat do you think of when you think of taxonomy' An 18th century gentlemen in breeches' Or perhaps botany drawings hung on the walls of a boutique hotel' Such old-fashioned conceptions to the contrary, taxonomy is alive today although constantly struggling for survival and recognition. The scientific community is losing valuable resources as taxonomy experts age and retire, and funding for morphological studies and species descriptions remains stagnant. At the same time, organismal knowledge (morphology, ecology, physiology) has never been more important: genomic studies are becoming more taxon focused, the scientific community is recognizing the limitations of traditional “model” organisms, and taxonomic expertise is desperately needed to fight against global biodiversity declines resulting from human impacts. There has never been a better time for a taxonomic renaissance.
      PubDate: 2017-08-18T21:00:00Z
      DOI: 10.1371/journal.pbio.2002231
  • Rictor positively regulates B cell receptor signaling by modulating actin
           reorganization via ezrin

    • Authors: Lu Huang Yongjie Zhang Chenguang Xu Xiaomei Gu Linlin Niu Jinzhi Wang Xiaoyu Sun Xiaoming Bai Xingtian Xuan Qubei Li Chunwei Shi Bing Yu Heather Miller Gangyi Yang Lisa S. Westerberg Wanli Liu Wenxia Song Xiaodong Zhao Chaohong Liu
      Abstract: by Lu Huang, Yongjie Zhang, Chenguang Xu, Xiaomei Gu, Linlin Niu, Jinzhi Wang, Xiaoyu Sun, Xiaoming Bai, Xingtian Xuan, Qubei Li, Chunwei Shi, Bing Yu, Heather Miller, Gangyi Yang, Lisa S. Westerberg, Wanli Liu, Wenxia Song, Xiaodong Zhao, Chaohong LiuAs the central hub of the metabolism machinery, the mammalian target of rapamycin complex 2 (mTORC2) has been well studied in lymphocytes. As an obligatory component of mTORC2, the role of Rictor in T cells is well established. However, the role of Rictor in B cells still remains elusive. Rictor is involved in B cell development, especially the peripheral development. However, the role of Rictor on B cell receptor (BCR) signaling as well as the underlying cellular and molecular mechanism is still unknown. This study used B cell–specfic Rictor knockout (KO) mice to investigate how Rictor regulates BCR signaling. We found that the key positive and negative BCR signaling molecules, phosphorylated Brutons tyrosine kinase (pBtk) and phosphorylated SH2-containing inositol phosphatase (pSHIP), are reduced and enhanced, respectively, in Rictor KO B cells. This suggests that Rictor positively regulates the early events of BCR signaling. We found that the cellular filamentous actin (F-actin) is drastically increased in Rictor KO B cells after BCR stimulation through dysregulating the dephosphorylation of ezrin. The high actin-ezrin intensity area restricts the lateral movement of BCRs upon stimulation, consequently reducing BCR clustering and BCR signaling. The reduction in the initiation of BCR signaling caused by actin alteration is associated with a decreased humoral immune response in Rictor KO mice. The inhibition of actin polymerization with latrunculin in Rictor KO B cells rescues the defects of BCR signaling and B cell differentiation. Overall, our study provides a new pathway linking cell metablism to BCR activation, in which Rictor regulates BCR signaling via actin reorganization.
      PubDate: 2017-08-18T21:00:00Z
      DOI: 10.1371/journal.pbio.2001750
  • The ESCRT-III pathway facilitates cardiomyocyte release of
           cBIN1-containing microparticles

    • Authors: Bing Xu Ying Fu Yan Liu Sosse Agvanian Robert C. Wirka Rachel Baum Kang Zhou Robin M. Shaw TingTing Hong
      Abstract: by Bing Xu, Ying Fu, Yan Liu, Sosse Agvanian, Robert C. Wirka, Rachel Baum, Kang Zhou, Robin M. Shaw, TingTing HongMicroparticles (MPs) are cell–cell communication vesicles derived from the cell surface plasma membrane, although they are not known to originate from cardiac ventricular muscle. In ventricular cardiomyocytes, the membrane deformation protein cardiac bridging integrator 1 (cBIN1 or BIN1+13+17) creates transverse-tubule (t-tubule) membrane microfolds, which facilitate ion channel trafficking and modulate local ionic concentrations. The microfold- generated microdomains continuously reorganize, adapting in response to stress to modulate the calcium signaling apparatus. We explored the possibility that cBIN1-microfolds are externally released from cardiomyocytes. Using electron microscopy imaging with immunogold labeling, we found in mouse plasma that cBIN1 exists in membrane vesicles about 200 nm in size, which is consistent with the size of MPs. In mice with cardiac-specific heterozygous Bin1 deletion, flow cytometry identified 47% less cBIN1-MPs in plasma, supporting cardiac origin. Cardiac release was also evidenced by the detection of cBIN1-MPs in medium bathing a pure population of isolated adult mouse cardiomyocytes. In human plasma, osmotic shock increased cBIN1 detection by enzyme-linked immunosorbent assay (ELISA), and cBIN1 level decreased in humans with heart failure, a condition with reduced cardiac muscle cBIN1, both of which support cBIN1 release in MPs from human hearts. Exploring putative mechanisms of MP release, we found that the membrane fission complex endosomal sorting complexes required for transport (ESCRT)-III subunit charged multivesicular body protein 4B (CHMP4B) colocalizes and coimmunoprecipitates with cBIN1, an interaction enhanced by actin stabilization. In HeLa cells with cBIN1 overexpression, knockdown of CHMP4B reduced the release of cBIN1-MPs. Using truncation mutants, we identified that the N-terminal BAR (N-BAR) domain in cBIN1 is required for CHMP4B binding and MP release. This study links the BAR protein superfamily to the ESCRT pathway for MP biogenesis in mammalian cardiac ventricular cells, identifying elements of a pathway by which cytoplasmic cBIN1 is released into blood.
      PubDate: 2017-08-14T21:00:00Z
      DOI: 10.1371/journal.pbio.2002354
  • Fungal genome and mating system transitions facilitated by chromosomal
           translocations involving intercentromeric recombination

    • Authors: Sheng Sun Vikas Yadav R. Blake Billmyre Christina A. Cuomo Minou Nowrousian Liuyang Wang Jean-Luc Souciet Teun Boekhout Betina Porcel Patrick Wincker Joshua A. Granek Kaustuv Sanyal Joseph Heitman
      Abstract: by Sheng Sun, Vikas Yadav, R. Blake Billmyre, Christina A. Cuomo, Minou Nowrousian, Liuyang Wang, Jean-Luc Souciet, Teun Boekhout, Betina Porcel, Patrick Wincker, Joshua A. Granek, Kaustuv Sanyal, Joseph HeitmanSpecies within the human pathogenic Cryptococcus species complex are major threats to public health, causing approximately 1 million infections globally annually. Cryptococcus amylolentus is the most closely known related species of the pathogenic Cryptococcus species complex, and it is non-pathogenic. Additionally, while pathogenic Cryptococcus species have bipolar mating systems with a single large mating type (MAT) locus that represents a derived state in Basidiomycetes, C. amylolentus has a tetrapolar mating system with 2 MAT loci (P/R and HD) located on different chromosomes. Thus, studying C. amylolentus will shed light on the transition from tetrapolar to bipolar mating systems in the pathogenic Cryptococcus species, as well as its possible link with the origin and evolution of pathogenesis. In this study, we sequenced, assembled, and annotated the genomes of 2 C. amylolentus isolates, CBS6039 and CBS6273, which are sexual and interfertile. Genome comparison between the 2 C. amylolentus isolates identified the boundaries and the complete gene contents of the P/R and HD MAT loci. Bioinformatic and chromatin immunoprecipitation sequencing (ChIP-seq) analyses revealed that, similar to those of the pathogenic Cryptococcus species, C. amylolentus has regional centromeres (CENs) that are enriched with species-specific transposable and repetitive DNA elements. Additionally, we found that while neither the P/R nor the HD locus is physically closely linked to its centromere in C. amylolentus, and the regions between the MAT loci and their respective centromeres show overall synteny between the 2 genomes, both MAT loci exhibit genetic linkage to their respective centromere during meiosis, suggesting the presence of recombinational suppressors and/or epistatic gene interactions in the MAT-CEN intervening regions. Furthermore, genomic comparisons between C. amylolentus and related pathogenic Cryptococcus species provide evidence that multiple chromosomal rearrangements mediated by intercentromeric recombination have occurred during descent of the 2 lineages from their common ancestor. Taken together, our findings support a model in which the evolution of the bipolar mating system was initiated by an ectopic recombination event mediated by similar repetitive centromeric DNA elements shared between chromosomes. This translocation brought the P/R and HD loci onto the same chromosome, and further chromosomal rearrangements then resulted in the 2 MAT loci becoming physically linked and eventually fusing to form the single contiguous MAT locus that is now extant in the pathogenic Cryptococcus species.
      PubDate: 2017-08-11T21:00:00Z
      DOI: 10.1371/journal.pbio.2002527
  • History of antibiotic adaptation influences microbial evolutionary
           dynamics during subsequent treatment

    • Authors: Phillip Yen Jason A. Papin
      Abstract: by Phillip Yen, Jason A. PapinAntibiotic regimens often include the sequential changing of drugs to limit the development and evolution of resistance of bacterial pathogens. It remains unclear how history of adaptation to one antibiotic can influence the resistance profiles when bacteria subsequently adapt to a different antibiotic. Here, we experimentally evolved Pseudomonas aeruginosa to six 2-drug sequences. We observed drug order–specific effects, whereby adaptation to the first drug can limit the rate of subsequent adaptation to the second drug, adaptation to the second drug can restore susceptibility to the first drug, or final resistance levels depend on the order of the 2-drug sequence. These findings demonstrate how resistance not only depends on the current drug regimen but also the history of past regimens. These order-specific effects may allow for rational forecasting of the evolutionary dynamics of bacteria given knowledge of past adaptations and provide support for the need to consider the history of past drug exposure when designing strategies to mitigate resistance and combat bacterial infections.
      PubDate: 2017-08-08T21:00:00Z
      DOI: 10.1371/journal.pbio.2001586
  • Regulation of Gli ciliary localization and Hedgehog signaling by the
           PY-NLS/karyopherin-β2 nuclear import system

    • Authors: Yuhong Han Yue Xiong Xuanming Shi Jiang Wu Yun Zhao Jin Jiang
      Abstract: by Yuhong Han, Yue Xiong, Xuanming Shi, Jiang Wu, Yun Zhao, Jin JiangHedgehog (Hh) signaling in vertebrates depends on primary cilia. Upon stimulation, Hh pathway components, including Gli transcription factors, accumulate at primary cilia to transduce the Hh signal, but the mechanisms underlying their ciliary targeting remains largely unknown. Here, we show that the PY-type nuclear localization signal (PY-NLS)/karyopherinβ2 (Kapβ2) nuclear import system regulates Gli ciliary localization and Hh pathway activation. Mutating the PY-NLS in Gli or knockdown of Kapβ2 diminished Gli ciliary localization. Kapβ2 is required for the formation of Gli activator (GliA) in wild-type but not in Sufu mutant cells. Knockdown of Kapβ2 affected Hh signaling in zebrafish embryos, as well as in vitro cultured cerebellum granule neuron progenitors (CGNPs) and SmoM2-driven medulloblastoma cells. Furthermore, Kapβ2 depletion impaired the growth of cultured medulloblastoma cells, which was rescued by Gli overexpression. Interestingly, Kapβ2 is a transcriptional target of the Hh pathway, thus forming a positive feedback loop for Gli activation. Our study unravels the molecular mechanism and cellular machinery regulating Gli ciliary localization and identifies Kapβ2 as a critical regulator of the Hh pathway and a potential drug target for Hh-driven cancers.
      PubDate: 2017-08-04T21:00:00Z
      DOI: 10.1371/journal.pbio.2002063
  • The Genomic Observatories Metadatabase (GeOMe): A new repository for field
           and sampling event metadata associated with genetic samples

    • Authors: John Deck Michelle R. Gaither Rodney Ewing Christopher E. Bird Neil Davies Christopher Meyer Cynthia Riginos Robert J. Toonen Eric D. Crandall
      Abstract: by John Deck, Michelle R. Gaither, Rodney Ewing, Christopher E. Bird, Neil Davies, Christopher Meyer, Cynthia Riginos, Robert J. Toonen, Eric D. CrandallThe Genomic Observatories Metadatabase (GeOMe, is an open access repository for geographic and ecological metadata associated with biosamples and genetic data. Whereas public databases have served as vital repositories for nucleotide sequences, they do not accession all the metadata required for ecological or evolutionary analyses. GeOMe fills this need, providing a user-friendly, web-based interface for both data contributors and data recipients. The interface allows data contributors to create a customized yet standard-compliant spreadsheet that captures the temporal and geospatial context of each biosample. These metadata are then validated and permanently linked to archived genetic data stored in the National Center for Biotechnology Information’s (NCBI’s) Sequence Read Archive (SRA) via unique persistent identifiers. By linking ecologically and evolutionarily relevant metadata with publicly archived sequence data in a structured manner, GeOMe sets a gold standard for data management in biodiversity science.
      PubDate: 2017-08-03T21:00:00Z
      DOI: 10.1371/journal.pbio.2002925
  • Assembly and stoichiometry of the core structure of the bacterial
           flagellar type III export gate complex

    • Authors: Takuma Fukumura Fumiaki Makino Tobias Dietsche Miki Kinoshita Takayuki Kato Samuel Wagner Keiichi Namba Katsumi Imada Tohru Minamino
      Abstract: by Takuma Fukumura, Fumiaki Makino, Tobias Dietsche, Miki Kinoshita, Takayuki Kato, Samuel Wagner, Keiichi Namba, Katsumi Imada, Tohru MinaminoThe bacterial flagellar type III export apparatus, which is required for flagellar assembly beyond the cell membranes, consists of a transmembrane export gate complex and a cytoplasmic ATPase complex. FlhA, FlhB, FliP, FliQ, and FliR form the gate complex inside the basal body MS ring, although FliO is required for efficient export gate formation in Salmonella enterica. However, it remains unknown how they form the gate complex. Here we report that FliP forms a homohexameric ring with a diameter of 10 nm. Alanine substitutions of conserved Phe-137, Phe-150, and Glu-178 residues in the periplasmic domain of FliP (FliPP) inhibited FliP6 ring formation, suppressing flagellar protein export. FliO formed a 5-nm ring structure with 3 clamp-like structures that bind to the FliP6 ring. The crystal structure of FliPP derived from Thermotoga maritia, and structure-based photo-crosslinking experiments revealed that Phe-150 and Ser-156 of FliPP are involved in the FliP–FliP interactions and that Phe-150, Arg-152, Ser-156, and Pro-158 are responsible for the FliP–FliO interactions. Overexpression of FliP restored motility of a ∆fliO mutant to the wild-type level, suggesting that the FliP6 ring is a functional unit in the export gate complex and that FliO is not part of the final gate structure. Copurification assays revealed that FlhA, FlhB, FliQ, and FliR are associated with the FliO/FliP complex. We propose that the assembly of the export gate complex begins with FliP6 ring formation with the help of the FliO scaffold, followed by FliQ, FliR, and FlhB and finally FlhA during MS ring formation.
      PubDate: 2017-08-03T21:00:00Z
      DOI: 10.1371/journal.pbio.2002281
  • A flagellum-specific chaperone facilitates assembly of the core type III
           export apparatus of the bacterial flagellum

    • Authors: Florian D. Fabiani Thibaud T. Renault Britta Peters Tobias Dietsche Eric J. C. Gálvez Alina Guse Karen Freier Emmanuelle Charpentier Till Strowig Mirita Franz-Wachtel Boris Macek Samuel Wagner Michael Hensel Marc Erhardt
      Abstract: by Florian D. Fabiani, Thibaud T. Renault, Britta Peters, Tobias Dietsche, Eric J. C. Gálvez, Alina Guse, Karen Freier, Emmanuelle Charpentier, Till Strowig, Mirita Franz-Wachtel, Boris Macek, Samuel Wagner, Michael Hensel, Marc ErhardtMany bacteria move using a complex, self-assembling nanomachine, the bacterial flagellum. Biosynthesis of the flagellum depends on a flagellar-specific type III secretion system (T3SS), a protein export machine homologous to the export machinery of the virulence-associated injectisome. Six cytoplasmic (FliH/I/J/G/M/N) and seven integral-membrane proteins (FlhA/B FliF/O/P/Q/R) form the flagellar basal body and are involved in the transport of flagellar building blocks across the inner membrane in a proton motive force-dependent manner. However, how the large, multi-component transmembrane export gate complex assembles in a coordinated manner remains enigmatic. Specific for most flagellar T3SSs is the presence of FliO, a small bitopic membrane protein with a large cytoplasmic domain. The function of FliO is unknown, but homologs of FliO are found in >80% of all flagellated bacteria. Here, we demonstrate that FliO protects FliP from proteolytic degradation and promotes the formation of a stable FliP–FliR complex required for the assembly of a functional core export apparatus. We further reveal the subcellular localization of FliO by super-resolution microscopy and show that FliO is not part of the assembled flagellar basal body. In summary, our results suggest that FliO functions as a novel, flagellar T3SS-specific chaperone, which facilitates quality control and productive assembly of the core T3SS export machinery.
      PubDate: 2017-08-03T21:00:00Z
      DOI: 10.1371/journal.pbio.2002267
  • EBV epigenetically suppresses the B cell-to-plasma cell differentiation
           pathway while establishing long-term latency

    • Authors: Christine T. Styles Quentin Bazot Gillian A. Parker Robert E. White Kostas Paschos Martin J. Allday
      Abstract: by Christine T. Styles, Quentin Bazot, Gillian A. Parker, Robert E. White, Kostas Paschos, Martin J. AlldayMature human B cells infected by Epstein-Barr virus (EBV) become activated, grow, and proliferate. If the cells are infected ex vivo, they are transformed into continuously proliferating lymphoblastoid cell lines (LCLs) that carry EBV DNA as extra-chromosomal episomes, express 9 latency-associated EBV proteins, and phenotypically resemble antigen-activated B-blasts. In vivo similar B-blasts can differentiate to become memory B cells (MBC), in which EBV persistence is established. Three related latency-associated viral proteins EBNA3A, EBNA3B, and EBNA3C are transcription factors that regulate a multitude of cellular genes. EBNA3B is not necessary to establish LCLs, but EBNA3A and EBNA3C are required to sustain proliferation, in part, by repressing the expression of tumour suppressor genes. Here we show, using EBV-recombinants in which both EBNA3A and EBNA3C can be conditionally inactivated or using virus completely lacking the EBNA3 gene locus, that—after a phase of rapid proliferation—infected primary B cells express elevated levels of factors associated with plasma cell (PC) differentiation. These include the cyclin-dependent kinase inhibitor (CDKI) p18INK4c, the master transcriptional regulator of PC differentiation B lymphocyte-induced maturation protein-1 (BLIMP-1), and the cell surface antigens CD38 and CD138/Syndecan-1. Chromatin immunoprecipitation sequencing (ChIP-seq) and chromatin immunoprecipitation quantitative PCR (ChIP-qPCR) indicate that in LCLs inhibition of CDKN2C (p18INK4c) and PRDM1 (BLIMP-1) transcription results from direct binding of EBNA3A and EBNA3C to regulatory elements at these loci, producing stable reprogramming. Consistent with the binding of EBNA3A and/or EBNA3C leading to irreversible epigenetic changes, cells become committed to a B-blast fate
      PubDate: 2017-08-03T21:00:00Z
      DOI: 10.1371/journal.pbio.2001992
  • Developing international open science collaborations: Funder reflections
           on the Open Science Prize

    • Authors: Elizabeth Kittrie Audie A. Atienza Robert Kiley David Carr Aki MacFarlane Vinay Pai Jennifer Couch Jared Bajkowski Joseph F. Bonner Daniel Mietchen Philip E. Bourne
      Abstract: by Elizabeth Kittrie, Audie A. Atienza, Robert Kiley, David Carr, Aki MacFarlane, Vinay Pai, Jennifer Couch, Jared Bajkowski, Joseph F. Bonner, Daniel Mietchen, Philip E. BourneThe Open Science Prize was established with the following objectives: first, to encourage the crowdsourcing of open data to make breakthroughs that are of biomedical significance; second, to illustrate that funders can indeed work together when scientific interests are aligned; and finally, to encourage international collaboration between investigators with the intent of achieving important innovations that would not be possible otherwise. The process for running the competition and the successes and challenges that arose are presented.
      PubDate: 2017-08-01T21:00:00Z
      DOI: 10.1371/journal.pbio.2002617
  • Dynamic transcriptome changes during adipose tissue energy expenditure
           reveal critical roles for long noncoding RNA regulators

    • Authors: Zhiqiang Bai Xiao-ran Chai Myeong Jin Yoon Hye-Jin Kim Kinyui Alice LO Zhi-chun Zhang Dan Xu Diana Teh Chee Siang Arcinas Camille Esther Walet Shao-hai Xu Sook-Yoong Chia Peng Chen Hongyuan Yang Sujoy Ghosh Lei Sun
      Abstract: by Zhiqiang Bai, Xiao-ran Chai, Myeong Jin Yoon, Hye-Jin Kim, Kinyui Alice LO, Zhi-chun Zhang, Dan Xu, Diana Teh Chee Siang, Arcinas Camille Esther Walet, Shao-hai Xu, Sook-Yoong Chia, Peng Chen, Hongyuan Yang, Sujoy Ghosh, Lei SunEnhancing brown fat activity and promoting white fat browning are attractive therapeutic strategies for treating obesity and associated metabolic disorders. To provide a comprehensive picture of the gene regulatory network in these processes, we conducted a series of transcriptome studies by RNA sequencing (RNA-seq) and quantified the mRNA and long noncoding RNA (lncRNA) changes during white fat browning (chronic cold exposure, beta-adrenergic agonist treatment, and intense exercise) and brown fat activation or inactivation (acute cold exposure or thermoneutrality, respectively). mRNA–lncRNA coexpression networks revealed dynamically regulated lncRNAs to be largely embedded in nutrient and energy metabolism pathways. We identified a brown adipose tissue–enriched lncRNA, lncBATE10, that was governed by the cAMP-cAMP response element-binding protein (Creb) axis and required for a full brown fat differentiation and white fat browning program. Mechanistically, lncBATE10 can decoy Celf1 from Pgc1α, thereby protecting Pgc1α mRNA from repression by Celf1. Together, these studies provide a comprehensive data framework to interrogate the transcriptomic changes accompanying energy homeostasis transition in adipose tissue.
      PubDate: 2017-08-01T21:00:00Z
      DOI: 10.1371/journal.pbio.2002176
  • The beneficial effects of dietary restriction on learning are distinct
           from its effects on longevity and mediated by depletion of a
           neuroinhibitory metabolite

    • Authors: Mihir Vohra George A. Lemieux Lin Lin Kaveh Ashrafi
      Abstract: by Mihir Vohra, George A. Lemieux, Lin Lin, Kaveh AshrafiIn species ranging from humans to Caenorhabditis elegans, dietary restriction (DR) grants numerous benefits, including enhanced learning. The precise mechanisms by which DR engenders benefits on processes related to learning remain poorly understood. As a result, it is unclear whether the learning benefits of DR are due to myriad improvements in mechanisms that collectively confer improved cellular health and extension of organismal lifespan or due to specific neural mechanisms. Using an associative learning paradigm in C. elegans, we investigated the effects of DR as well as manipulations of insulin, mechanistic target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and autophagy pathways—processes implicated in longevity—on learning. Despite their effects on a vast number of molecular effectors, we found that the beneficial effects on learning elicited by each of these manipulations are fully dependent on depletion of kynurenic acid (KYNA), a neuroinhibitory metabolite. KYNA depletion then leads, in an N-methyl D-aspartate receptor (NMDAR)-dependent manner, to activation of a specific pair of interneurons with a critical role in learning. Thus, fluctuations in KYNA levels emerge as a previously unidentified molecular mechanism linking longevity and metabolic pathways to neural mechanisms of learning. Importantly, KYNA levels did not alter lifespan in any of the conditions tested. As such, the beneficial effects of DR on learning can be attributed to changes in a nutritionally sensitive metabolite with neuromodulatory activity rather than indirect or secondary consequences of improved health and extended longevity.
      PubDate: 2017-08-01T21:00:00Z
      DOI: 10.1371/journal.pbio.2002032
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