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   ISSN (Print) 1544-9173 - ISSN (Online) 1545-7885
   Published by PLoS Homepage  [13 journals]
  • Receptors of intermediates of carbohydrate metabolism, GPR91 and GPR99,
           mediate axon growth

    • Authors: Hosni Cherif , François Duhamel , Bruno Cécyre , Alex Bouchard , Ariane Quintal , Sylvain Chemtob , Jean-François Bouchard
      PubDate: 2018-05-17T21:00:00Z
  • Do plants have a segregated germline'

    • Authors: Robert Lanfear
      PubDate: 2018-05-16T21:00:00Z
  • High-dimensional single-cell phenotyping reveals extensive

    • Authors: Shinsuke Ohnuki , Yoshikazu Ohya
      PubDate: 2018-05-16T21:00:00Z
  • Tissue-specific activities of the Fat1 cadherin cooperate to control
           neuromuscular morphogenesis

    • Authors: Françoise Helmbacher
      PubDate: 2018-05-16T21:00:00Z
  • Death and population dynamics affect mutation rate estimates and
           evolvability under stress in bacteria

    • Authors: Antoine Frenoy Sebastian Bonhoeffer
      Abstract: by Antoine Frenoy, Sebastian BonhoefferThe stress-induced mutagenesis hypothesis postulates that in response to stress, bacteria increase their genome-wide mutation rate, in turn increasing the chances that a descendant is able to better withstand the stress. This has implications for antibiotic treatment: exposure to subinhibitory doses of antibiotics has been reported to increase bacterial mutation rates and thus probably the rate at which resistance mutations appear and lead to treatment failure. More generally, the hypothesis posits that stress increases evolvability (the ability of a population to generate adaptive genetic diversity) and thus accelerates evolution. Measuring mutation rates under stress, however, is problematic, because existing methods assume there is no death. Yet subinhibitory stress levels may induce a substantial death rate. Death events need to be compensated by extra replication to reach a given population size, thus providing more opportunities to acquire mutations. We show that ignoring death leads to a systematic overestimation of mutation rates under stress. We developed a system based on plasmid segregation that allows us to measure death and division rates simultaneously in bacterial populations. Using this system, we found that a substantial death rate occurs at the tested subinhibitory concentrations previously reported to increase mutation rate. Taking this death rate into account lowers and sometimes removes the signal for stress-induced mutagenesis. Moreover, even when antibiotics increase mutation rate, we show that subinhibitory treatments do not increase genetic diversity and evolvability, again because of effects of the antibiotics on population dynamics. We conclude that antibiotic-induced mutagenesis is overestimated because of death and that understanding evolvability under stress requires accounting for the effects of stress on population dynamics as much as on mutation rate. Our goal here is dual: we show that population dynamics and, in particular, the numbers of cell division are crucial but neglected parameters in the evolvability of a population, and we provide experimental and computational tools and methods to study evolvability under stress, leading to a reassessment of the magnitude and significance of the stress-induced mutagenesis paradigm.
      PubDate: 2018-05-11T21:00:00Z
      DOI: 10.1371/journal.pbio.2005056
  • Tumor-associated neutrophils suppress pro-tumoral IL-17+ γδ T cells
           through induction of oxidative stress

    • Authors: Sofia Mensurado Margarida Rei Telma Lança Marianna Ioannou Natacha Gonçalves-Sousa Hiroshi Kubo Marie Malissen Venizelos Papayannopoulos Karine Serre Bruno Silva-Santos
      Abstract: by Sofia Mensurado, Margarida Rei, Telma Lança, Marianna Ioannou, Natacha Gonçalves-Sousa, Hiroshi Kubo, Marie Malissen, Venizelos Papayannopoulos, Karine Serre, Bruno Silva-SantosInterleukin 17 (IL-17)–producing γδ T cells (γδ17 T cells) have been recently found to promote tumor growth and metastasis formation. How such γδ17 T-cell responses may be regulated in the tumor microenvironment remains, however, largely unknown. Here, we report that tumor-associated neutrophils can display an overt antitumor role by strongly suppressing γδ17 T cells. Tumor-associated neutrophils inhibited the proliferation of murine CD27− Vγ6+ γδ17 T cells via induction of oxidative stress, thereby preventing them from constituting the major source of pro-tumoral IL-17 in the tumor microenvironment. Mechanistically, we found that low expression of the antioxidant glutathione in CD27− γδ17 T cells renders them particularly susceptible to neutrophil-derived reactive oxygen species (ROS). Consistently, superoxide deficiency, or the administration of a glutathione precursor, rescued CD27− Vγ6+ γδ17 T-cell proliferation in vivo. Moreover, human Vδ1+ γδ T cells, which contain most γδ17 T cells found in cancer patients, also displayed low glutathione levels and were potently inhibited by ROS. This work thus identifies an unanticipated, immunosuppressive yet antitumoral, neutrophil/ROS/γδ17 T-cell axis in the tumor microenvironment.
      PubDate: 2018-05-11T21:00:00Z
      DOI: 10.1371/journal.pbio.2004990
  • Metabolic benefits of inhibition of p38α in white adipose tissue in

    • Authors: Shengjie Zhang Hongchao Cao Yan Li Yanyan Jing Shengnan Liu Cheng Ye Hui Wang Shuxian Yu Chengyuan Peng Lijian Hui Yu-cheng Wang Haibing Zhang Feifan Guo Qiwei Zhai Hui Wang Ruimin Huang Ling Zhang Jingjing Jiang Wei Liu Hao Ying
      Abstract: by Shengjie Zhang, Hongchao Cao, Yan Li, Yanyan Jing, Shengnan Liu, Cheng Ye, Hui Wang, Shuxian Yu, Chengyuan Peng, Lijian Hui, Yu-cheng Wang, Haibing Zhang, Feifan Guo, Qiwei Zhai, Hui Wang, Ruimin Huang, Ling Zhang, Jingjing Jiang, Wei Liu, Hao Yingp38 has long been known as a central mediator of protein kinase A (PKA) signaling in brown adipocytes, which positively regulate the transcription of uncoupling protein 1 (UCP-1). However, the physiological role of p38 in adipose tissues, especially the white adipose tissue (WAT), is largely unknown. Here, we show that mice lacking p38α in adipose tissues display a lean phenotype, improved metabolism, and resistance to diet-induced obesity. Surprisingly, ablation of p38α causes minimal effects on brown adipose tissue (BAT) in adult mice, as evident from undetectable changes in UCP-1 expression, mitochondrial function, body temperature (BT), and energy expenditure. In contrast, genetic ablation of p38α in adipose tissues not only markedly facilitates the browning in WAT upon cold stress but also prevents diet-induced obesity. Consistently, pharmaceutical inhibition of p38α remarkably enhances the browning of WAT and has metabolic benefits. Furthermore, our data suggest that p38α deficiency promotes white-to-beige adipocyte reprogramming in a cell-autonomous manner. Mechanistically, inhibition of p38α stimulates the UCP-1 transcription through PKA and its downstream cAMP-response element binding protein (CREB), which form a positive feedback loop that functions to reinforce the white-to-beige phenotypic switch during cold exposure. Together, our study reveals that inhibition of p38α is able to promote WAT browning and confer metabolic benefits. Our study also indicates that p38α in WAT represents an exciting pharmacological target to combat obesity and metabolic diseases.
      PubDate: 2018-05-11T21:00:00Z
      DOI: 10.1371/journal.pbio.2004225
  • Hey1- and p53-dependent TrkC proapoptotic activity controls neuroblastoma

    • Authors: Marie Ménard Clélia Costechareyre Gabriel Ichim Jonathan Blachier David Neves Loraine Jarrosson-Wuilleme Reinhard Depping Jan Koster Pierre Saintigny Patrick Mehlen Servane Tauszig-Delamasure
      Abstract: by Marie Ménard, Clélia Costechareyre, Gabriel Ichim, Jonathan Blachier, David Neves, Loraine Jarrosson-Wuilleme, Reinhard Depping, Jan Koster, Pierre Saintigny, Patrick Mehlen, Servane Tauszig-DelamasureThe neurotrophin-3 (NT-3) receptor tropomyosin receptor kinase C (TrkC/NTRK3) has been described as a dependence receptor and, as such, triggers apoptosis in the absence of its ligand NT-3. This proapoptotic activity has been proposed to confer a tumor suppressor activity to this classic tyrosine kinase receptor (RTK). By investigating interacting partners that might facilitate TrkC-induced cell death, we have identified the basic helix-loop-helix (bHLH) transcription factor Hey1 and importin-α3 (karyopherin alpha 4 [KPNA4]) as direct interactors of TrkC intracellular domain, and we show that Hey1 is required for TrkC-induced apoptosis. We propose here that the cleaved proapoptotic portion of TrkC intracellular domain (called TrkC killer-fragment [TrkC-KF]) is translocated to the nucleus by importins and interacts there with Hey1. We also demonstrate that Hey1 and TrkC-KF transcriptionally silence mouse double minute 2 homolog (MDM2), thus contributing to p53 stabilization. p53 transcriptionally regulates the expression of TrkC-KF cytoplasmic and mitochondrial interactors cofactor of breast cancer 1 (COBRA1) and B cell lymphoma 2–associated X (BAX), which will subsequently trigger the intrinsic pathway of apoptosis. Of interest, TrkC was proposed to constrain tumor progression in neuroblastoma (NB), and we demonstrate in an avian model that TrkC tumor suppressor activity requires Hey1 and p53.
      PubDate: 2018-05-11T21:00:00Z
      DOI: 10.1371/journal.pbio.2002912
  • Rif1 prolongs the embryonic S phase at the Drosophila mid-blastula

    • Authors: Charles A. Seller , Patrick H. O’Farrell
      PubDate: 2018-05-10T21:00:00Z
  • The Cybathlon BCI race: Successful longitudinal mutual learning with two
           tetraplegic users

    • Authors: Serafeim Perdikis Luca Tonin Sareh Saeedi Christoph Schneider José del R. Millán
      Abstract: by Serafeim Perdikis, Luca Tonin, Sareh Saeedi, Christoph Schneider, José del R. MillánThis work aims at corroborating the importance and efficacy of mutual learning in motor imagery (MI) brain–computer interface (BCI) by leveraging the insights obtained through our participation in the BCI race of the Cybathlon event. We hypothesized that, contrary to the popular trend of focusing mostly on the machine learning aspects of MI BCI training, a comprehensive mutual learning methodology that reinstates the three learning pillars (at the machine, subject, and application level) as equally significant could lead to a BCI–user symbiotic system able to succeed in real-world scenarios such as the Cybathlon event. Two severely impaired participants with chronic spinal cord injury (SCI), were trained following our mutual learning approach to control their avatar in a virtual BCI race game. The competition outcomes substantiate the effectiveness of this type of training. Most importantly, the present study is one among very few to provide multifaceted evidence on the efficacy of subject learning during BCI training. Learning correlates could be derived at all levels of the interface—application, BCI output, and electroencephalography (EEG) neuroimaging—with two end-users, sufficiently longitudinal evaluation, and, importantly, under real-world and even adverse conditions.
      PubDate: 2018-05-10T21:00:00Z
      DOI: 10.1371/journal.pbio.2003787
  • Identifying novel strategies for treating human hair loss disorders:
           Cyclosporine A suppresses the Wnt inhibitor, SFRP1, in the dermal papilla
           of human scalp hair follicles

    • Authors: Nathan J. Hawkshaw Jonathan A. Hardman Iain S. Haslam Asim Shahmalak Amos Gilhar Xinhong Lim Ralf Paus
      Abstract: by Nathan J. Hawkshaw, Jonathan A. Hardman, Iain S. Haslam, Asim Shahmalak, Amos Gilhar, Xinhong Lim, Ralf PausHair growth disorders often carry a major psychological burden. Therefore, more effective human hair growth–modulatory agents urgently need to be developed. Here, we used the hypertrichosis-inducing immunosuppressant, Cyclosporine A (CsA), as a lead compound to identify new hair growth–promoting molecular targets. Through microarray analysis we identified the Wnt inhibitor, secreted frizzled related protein 1 (SFRP1), as being down-regulated in the dermal papilla (DP) of CsA-treated human scalp hair follicles (HFs) ex vivo. Therefore, we further investigated the function of SFRP1 using a pharmacological approach and found that SFRP1 regulates intrafollicular canonical Wnt/β-catenin activity through inhibition of Wnt ligands in the human hair bulb. Conversely, inhibiting SFRP1 activity through the SFRP1 antagonist, WAY-316606, enhanced hair shaft production, hair shaft keratin expression, and inhibited spontaneous HF regression (catagen) ex vivo. Collectively, these data (a) identify Wnt signalling as a novel, non–immune-inhibitory CsA target; (b) introduce SFRP1 as a physiologically important regulator of canonical β-catenin activity in a human (mini-)organ; and (c) demonstrate WAY-316606 to be a promising new promoter of human hair growth. Since inhibiting SFRP1 only facilitates Wnt signalling through ligands that are already present, this ‘ligand-limited’ therapeutic strategy for promoting human hair growth may circumvent potential oncological risks associated with chronic Wnt over-activation.
      PubDate: 2018-05-08T21:00:00Z
      DOI: 10.1371/journal.pbio.2003705
  • POMC neurons in heat: A link between warm temperatures and appetite

    • Authors: Maria A. Vicent Conor L. Mook Matthew E. Carter
      Abstract: by Maria A. Vicent, Conor L. Mook, Matthew E. CarterWhen core body temperature increases, appetite and food consumption decline. A higher core body temperature can occur during exercise, during exposure to warm environmental temperatures, or during a fever, yet the mechanisms that link relatively warm temperatures to appetite suppression are unknown. A recent study in PLOS Biology demonstrates that neurons in the mouse hypothalamus that express pro-opiomelanocortin (POMC), a neural population well known to suppress food intake, also express a temperature-sensitive ion channel, transient receptor potential vanilloid 1 (TRPV1). Slight increases in body temperature cause a TRPV1-dependent increase in activity in POMC neurons, which suppresses feeding in mice. Taken together, this study suggests a novel mechanism linking body temperature and food-seeking behavior.
      PubDate: 2018-05-07T21:00:00Z
      DOI: 10.1371/journal.pbio.2006188
  • Structural basis for overhang excision and terminal unwinding of DNA
           duplexes by TREX1

    • Authors: Kuan-Wei Huang Tung-Chang Liu Ruei-Yue Liang Lee-Ya Chu Hiu-Lo Cheng Jhih-Wei Chu Yu-Yuan Hsiao
      Abstract: by Kuan-Wei Huang, Tung-Chang Liu, Ruei-Yue Liang, Lee-Ya Chu, Hiu-Lo Cheng, Jhih-Wei Chu, Yu-Yuan HsiaoThree prime repair exonuclease 1 (TREX1) is an essential exonuclease in mammalian cells, and numerous in vivo and in vitro data evidenced its participation in immunity regulation and in genotoxicity remediation. In these very complicated cellular functions, the molecular mechanisms by which duplex DNA substrates are processed are mostly elusive because of the lack of structure information. Here, we report multiple crystal structures of TREX1 complexed with various substrates to provide the structure basis for overhang excision and terminal unwinding of DNA duplexes. The substrates were designed to mimic the intermediate structural DNAs involved in various repair pathways. The results showed that the Leu24-Pro25-Ser26 cluster of TREX1 served to cap the nonscissile 5′-end of the DNA for precise removal of the short 3′-overhang in L- and Y-structural DNA or to wedge into the double-stranded region for further digestion along the duplex. Biochemical assays were also conducted to demonstrate that TREX1 can indeed degrade double-stranded DNA (dsDNA) to a full extent. Overall, this study provided unprecedented knowledge at the molecular level on the enzymatic substrate processing involved in prevention of immune activation and in responses to genotoxic stresses. For example, Arg128, whose mutation in TREX1 was linked to a disease state, were shown to exhibit consistent interaction patterns with the nonscissile strand in all of the structures we solved. Such structure basis is expected to play an indispensable role in elucidating the functional activities of TREX1 at the cellular level and in vivo.
      PubDate: 2018-05-07T21:00:00Z
      DOI: 10.1371/journal.pbio.2005653
  • Correction: Nucleic acid purification from plants, animals and microbes in
           under 30 seconds

    • Authors: Yiping Zou Michael Glenn Mason Yuling Wang Eugene Wee Conny Turni Patrick J. Blackall Matt Trau Jose Ramon Botella
      Abstract: by Yiping Zou, Michael Glenn Mason, Yuling Wang, Eugene Wee, Conny Turni, Patrick J. Blackall, Matt Trau, Jose Ramon Botella
      PubDate: 2018-05-07T21:00:00Z
      DOI: 10.1371/journal.pbio.1002630
  • Robust stochastic Turing patterns in the development of a one-dimensional
           cyanobacterial organism

    • Authors: Francesca Di Patti Laura Lavacchi Rinat Arbel-Goren Leora Schein-Lubomirsky Duccio Fanelli Joel Stavans
      Abstract: by Francesca Di Patti, Laura Lavacchi, Rinat Arbel-Goren, Leora Schein-Lubomirsky, Duccio Fanelli, Joel StavansUnder nitrogen deprivation, the one-dimensional cyanobacterial organism Anabaena sp. PCC 7120 develops patterns of single, nitrogen-fixing cells separated by nearly regular intervals of photosynthetic vegetative cells. We study a minimal, stochastic model of developmental patterns in Anabaena that includes a nondiffusing activator, two diffusing inhibitor morphogens, demographic fluctuations in the number of morphogen molecules, and filament growth. By tracking developing filaments, we provide experimental evidence for different spatiotemporal roles of the two inhibitors during pattern maintenance and for small molecular copy numbers, justifying a stochastic approach. In the deterministic limit, the model yields Turing patterns within a region of parameter space that shrinks markedly as the inhibitor diffusivities become equal. Transient, noise-driven, stochastic Turing patterns are produced outside this region, which can then be fixed by downstream genetic commitment pathways, dramatically enhancing the robustness of pattern formation, also in the biologically relevant situation in which the inhibitors' diffusivities may be comparable.
      PubDate: 2018-05-04T21:00:00Z
      DOI: 10.1371/journal.pbio.2004877
  • Morphological changes of plasma membrane and protein assembly during
           clathrin-mediated endocytosis

    • Authors: Aiko Yoshida Nobuaki Sakai Yoshitsugu Uekusa Yuka Imaoka Yoshitsuna Itagaki Yuki Suzuki Shige H. Yoshimura
      Abstract: by Aiko Yoshida, Nobuaki Sakai, Yoshitsugu Uekusa, Yuka Imaoka, Yoshitsuna Itagaki, Yuki Suzuki, Shige H. YoshimuraClathrin-mediated endocytosis (CME) proceeds through a series of morphological changes of the plasma membrane induced by a number of protein components. Although the spatiotemporal assembly of these proteins has been elucidated by fluorescence-based techniques, the protein-induced morphological changes of the plasma membrane have not been fully clarified in living cells. Here, we visualize membrane morphology together with protein localizations during CME by utilizing high-speed atomic force microscopy (HS-AFM) combined with a confocal laser scanning unit. The plasma membrane starts to invaginate approximately 30 s after clathrin starts to assemble, and the aperture diameter increases as clathrin accumulates. Actin rapidly accumulates around the pit and induces a small membrane swelling, which, within 30 s, rapidly covers the pit irreversibly. Inhibition of actin turnover abolishes the swelling and induces a reversible open–close motion of the pit, indicating that actin dynamics are necessary for efficient and irreversible pit closure at the end of CME.
      PubDate: 2018-05-03T21:00:00Z
      DOI: 10.1371/journal.pbio.2004786
  • Active photosynthetic inhibition mediated by MPK3/MPK6 is critical to
           effector-triggered immunity

    • Authors: Jianbin Su Liuyi Yang Qiankun Zhu Hongjiao Wu Yi He Yidong Liu Juan Xu Dean Jiang Shuqun Zhang
      Abstract: by Jianbin Su, Liuyi Yang, Qiankun Zhu, Hongjiao Wu, Yi He, Yidong Liu, Juan Xu, Dean Jiang, Shuqun ZhangExtensive research revealed tremendous details about how plants sense pathogen effectors during effector-triggered immunity (ETI). However, less is known about downstream signaling events. In this report, we demonstrate that prolonged activation of MPK3 and MPK6, two Arabidopsis pathogen-responsive mitogen-activated protein kinases (MPKs), is essential to ETI mediated by both coiled coil-nucleotide binding site-leucine rich repeats (CNLs) and toll/interleukin-1 receptor nucleotide binding site-leucine rich repeats (TNLs) types of R proteins. MPK3/MK6 activation rapidly alters the expression of photosynthesis-related genes and inhibits photosynthesis, which promotes the accumulation of superoxide and hydrogen peroxide (H2O2), two major reactive oxygen species (ROS), in chloroplasts under light. In the chemical-genetically rescued mpk3 mpk6 double mutants, ETI-induced photosynthetic inhibition and chloroplastic ROS accumulation are compromised, which correlates with delayed hypersensitive response (HR) cell death and compromised resistance. Furthermore, protection of chloroplasts by expressing a plastid-targeted cyanobacterial flavodoxin (pFLD) delays photosynthetic inhibition and compromises ETI. Collectively, this study highlights a critical role of MPK3/MPK6 in manipulating plant photosynthetic activities to promote ROS accumulation in chloroplasts and HR cell death, which contributes to the robustness of ETI. Furthermore, the dual functionality of MPK3/MPK6 cascade in promoting defense and inhibiting photosynthesis potentially allow it to orchestrate the trade-off between plant growth and defense in plant immunity.
      PubDate: 2018-05-03T21:00:00Z
      DOI: 10.1371/journal.pbio.2004122
  • A direct link between MITF, innate immunity, and hair graying

    • Authors: Melissa L. Harris Temesgen D. Fufa Joseph W. Palmer Sandeep S. Joshi Denise M. Larson Arturo Incao Derek E. Gildea Niraj S. Trivedi Autumne N. Lee Chi-Ping Day Helen T. Michael Thomas J. Hornyak Glenn Merlino NISC Comparative Sequencing Program William J. Pavan
      Abstract: by Melissa L. Harris, Temesgen D. Fufa, Joseph W. Palmer, Sandeep S. Joshi, Denise M. Larson, Arturo Incao, Derek E. Gildea, Niraj S. Trivedi, Autumne N. Lee, Chi-Ping Day, Helen T. Michael, Thomas J. Hornyak, Glenn Merlino, NISC Comparative Sequencing Program , William J. PavanMelanocyte stem cells (McSCs) and mouse models of hair graying serve as useful systems to uncover mechanisms involved in stem cell self-renewal and the maintenance of regenerating tissues. Interested in assessing genetic variants that influence McSC maintenance, we found previously that heterozygosity for the melanogenesis associated transcription factor, Mitf, exacerbates McSC differentiation and hair graying in mice that are predisposed for this phenotype. Based on transcriptome and molecular analyses of Mitfmi-vga9/+ mice, we report a novel role for MITF in the regulation of systemic innate immune gene expression. We also demonstrate that the viral mimic poly(I:C) is sufficient to expose genetic susceptibility to hair graying. These observations point to a critical suppressor of innate immunity, the consequences of innate immune dysregulation on pigmentation, both of which may have implications in the autoimmune, depigmenting disease, vitiligo.
      PubDate: 2018-05-03T21:00:00Z
      DOI: 10.1371/journal.pbio.2003648
  • Antibiotic combination efficacy (ACE) networks for a Pseudomonas

    • Authors: Camilo Barbosa , Robert Beardmore , Hinrich Schulenburg , Gunther Jansen
      PubDate: 2018-04-30T21:00:00Z
  • Mib1 prevents Notch Cis-inhibition to defer differentiation and preserve
           neuroepithelial integrity during neural delamination

    • Authors: Chooyoung Baek , Lucy Freem , Rosette Goïame , Helen Sang , Xavier Morin , Samuel Tozer
      PubDate: 2018-04-30T21:00:00Z
  • Dependence of innate lymphoid cell 1 development on NKp46

    • Authors: Yufeng Wang Wenjuan Dong Yibo Zhang Michael A. Caligiuri Jianhua Yu
      Abstract: by Yufeng Wang, Wenjuan Dong, Yibo Zhang, Michael A. Caligiuri, Jianhua YuNKp46, a natural killer (NK) cell–activating receptor, is involved in NK cell cytotoxicity against virus-infected cells or tumor cells. However, the role of NKp46 in other NKp46+ non-NK innate lymphoid cell (ILC) populations has not yet been characterized. Here, an NKp46 deficiency model of natural cytotoxicity receptor 1 (Ncr1)gfp/gfp and Ncr1gfp/+ mice, i.e., homozygous and heterozygous knockout (KO), was used to explore the role of NKp46 in regulating the development of the NKp46+ ILCs. Surprisingly, our studies demonstrated that homozygous NKp46 deficiency resulted in a nearly complete depletion of the ILC1 subset (ILC1) of group 1 ILCs, and heterozygote KO decreased the number of cells in the ILC1 subset. Moreover, transplantation studies confirmed that ILC1 development depends on NKp46 and that the dependency is cell intrinsic. Interestingly, however, the cell depletion specifically occurred in the ILC1 subset but not in the other ILCs, including ILC2s, ILC3s, and NK cells. Thus, our studies reveal that NKp46 selectively participates in the regulation of ILC1 development.
      PubDate: 2018-04-27T21:00:00Z
      DOI: 10.1371/journal.pbio.2004867
  • Polarization-resolved microscopy reveals a muscle myosin motor-independent
           mechanism of molecular actin ordering during sarcomere maturation

    • Authors: Olivier Loison Manuela Weitkunat Aynur Kaya-Çopur Camila Nascimento Alves Till Matzat Maria L. Spletter Stefan Luschnig Sophie Brasselet Pierre-François Lenne Frank Schnorrer
      Abstract: by Olivier Loison, Manuela Weitkunat, Aynur Kaya-Çopur, Camila Nascimento Alves, Till Matzat, Maria L. Spletter, Stefan Luschnig, Sophie Brasselet, Pierre-François Lenne, Frank SchnorrerSarcomeres are stereotyped force-producing mini-machines of striated muscles. Each sarcomere contains a pseudocrystalline order of bipolar actin and myosin filaments, which are linked by titin filaments. During muscle development, these three filament types need to assemble into long periodic chains of sarcomeres called myofibrils. Initially, myofibrils contain immature sarcomeres, which gradually mature into their pseudocrystalline order. Despite the general importance, our understanding of myofibril assembly and sarcomere maturation in vivo is limited, in large part because determining the molecular order of protein components during muscle development remains challenging. Here, we applied polarization-resolved microscopy to determine the molecular order of actin during myofibrillogenesis in vivo. This method revealed that, concomitantly with mechanical tension buildup in the myotube, molecular actin order increases, preceding the formation of immature sarcomeres. Mechanistically, both muscle and nonmuscle myosin contribute to this actin order gain during early stages of myofibril assembly. Actin order continues to increase while myofibrils and sarcomeres mature. Muscle myosin motor activity is required for the regular and coordinated assembly of long myofibrils but not for the high actin order buildup during sarcomere maturation. This suggests that, in muscle, other actin-binding proteins are sufficient to locally bundle or cross-link actin into highly regular arrays.
      PubDate: 2018-04-27T21:00:00Z
      DOI: 10.1371/journal.pbio.2004718
  • Assessing the stability of polio eradication after the withdrawal of oral
           polio vaccine

    • Authors: Michael Famulare Christian Selinger Kevin A. McCarthy Philip A. Eckhoff Guillaume Chabot-Couture
      Abstract: by Michael Famulare, Christian Selinger, Kevin A. McCarthy, Philip A. Eckhoff, Guillaume Chabot-CoutureThe oral polio vaccine (OPV) contains live-attenuated polioviruses that induce immunity by causing low virulence infections in vaccine recipients and their close contacts. Widespread immunization with OPV has reduced the annual global burden of paralytic poliomyelitis by a factor of 10,000 or more and has driven wild poliovirus (WPV) to the brink of eradication. However, in instances that have so far been rare, OPV can paralyze vaccine recipients and generate vaccine-derived polio outbreaks. To complete polio eradication, OPV use should eventually cease, but doing so will leave a growing population fully susceptible to infection. If poliovirus is reintroduced after OPV cessation, under what conditions will OPV vaccination be required to interrupt transmission' Can conditions exist in which OPV and WPV reintroduction present similar risks of transmission' To answer these questions, we built a multi-scale mathematical model of infection and transmission calibrated to data from clinical trials and field epidemiology studies. At the within-host level, the model describes the effects of vaccination and waning immunity on shedding and oral susceptibility to infection. At the between-host level, the model emulates the interaction of shedding and oral susceptibility with sanitation and person-to-person contact patterns to determine the transmission rate in communities. Our results show that inactivated polio vaccine (IPV) is sufficient to prevent outbreaks in low transmission rate settings and that OPV can be reintroduced and withdrawn as needed in moderate transmission rate settings. However, in high transmission rate settings, the conditions that support vaccine-derived outbreaks have only been rare because population immunity has been high. Absent population immunity, the Sabin strains from OPV will be nearly as capable of causing outbreaks as WPV. If post-cessation outbreak responses are followed by new vaccine-derived outbreaks, strategies to restore population immunity will be required to ensure the stability of polio eradication.
      PubDate: 2018-04-27T21:00:00Z
      DOI: 10.1371/journal.pbio.2002468
  • Human white matter and knowledge representation

    • Authors: Franco Pestilli
      Abstract: by Franco PestilliUnderstanding how knowledge is represented in the human brain is a fundamental challenge in neuroscience. To date, most of the work on this topic has focused on knowledge representation in cortical areas and debated whether knowledge is represented in a distributed or localized fashion. Fang and colleagues provide evidence that brain connections and the white matter supporting such connections might play a significant role. The work opens new avenues of investigation, breaking through disciplinary boundaries across network neuroscience, computational neuroscience, cognitive science, and classical lesion studies.
      PubDate: 2018-04-26T21:00:00Z
      DOI: 10.1371/journal.pbio.2005758
  • Correction: Brain–Computer Interface–Based Communication in the
           Completely Locked-In State

    • Authors: The PLOS Biology Staff
      Abstract: by The PLOS Biology Staff
      PubDate: 2018-04-25T21:00:00Z
      DOI: 10.1371/journal.pbio.1002629
  • Full disclosure: Genome assembly is still hard

    • Authors: Stephen Richards
      Abstract: by Stephen RichardsTwo recent papers highlight the fascinating comparative genomics of anhydrobiosis, the ability to withstand complete desiccation, in bdelloid rotifers and tardigrades. However, both groups had to openly deal with the significant difficulties of generating and interpreting short-read draft assemblies—especially challenging in microscopic species with high sequence polymorphism. These exemplars demonstrate the need to go beyond single draft-quality reference genomes to high-quality multiple species comparative genomics if we are to fully capture the value of genomics.
      PubDate: 2018-04-24T21:00:00Z
      DOI: 10.1371/journal.pbio.2005894
  • Evolutionary novelty in gravity sensing through horizontal gene transfer
           and high-order protein assembly

    • Authors: Tu Anh Nguyen Jamie Greig Asif Khan Cara Goh Gregory Jedd
      Abstract: by Tu Anh Nguyen, Jamie Greig, Asif Khan, Cara Goh, Gregory JeddHorizontal gene transfer (HGT) can promote evolutionary adaptation by transforming a species’ relationship to the environment. In most well-understood cases of HGT, acquired and donor functions appear to remain closely related. Thus, the degree to which HGT can lead to evolutionary novelties remains unclear. Mucorales fungi sense gravity through the sedimentation of vacuolar protein crystals. Here, we identify the octahedral crystal matrix protein (OCTIN). Phylogenetic analysis strongly supports acquisition of octin by HGT from bacteria. A bacterial OCTIN forms high-order periplasmic oligomers, and inter-molecular disulphide bonds are formed by both fungal and bacterial OCTINs, suggesting that they share elements of a conserved assembly mechanism. However, estimated sedimentation velocities preclude a gravity-sensing function for the bacterial structures. Together, our data suggest that HGT from bacteria into the Mucorales allowed a dramatic increase in assembly scale and emergence of the gravity-sensing function. We conclude that HGT can lead to evolutionary novelties that emerge depending on the physiological and cellular context of protein assembly.
      PubDate: 2018-04-24T21:00:00Z
      DOI: 10.1371/journal.pbio.2004920
  • Comparative genomics of bdelloid rotifers: Insights from desiccating and
           nondesiccating species

    • Authors: Reuben W. Nowell Pedro Almeida Christopher G. Wilson Thomas P. Smith Diego Fontaneto Alastair Crisp Gos Micklem Alan Tunnacliffe Chiara Boschetti Timothy G. Barraclough
      Abstract: by Reuben W. Nowell, Pedro Almeida, Christopher G. Wilson, Thomas P. Smith, Diego Fontaneto, Alastair Crisp, Gos Micklem, Alan Tunnacliffe, Chiara Boschetti, Timothy G. BarracloughBdelloid rotifers are a class of microscopic invertebrates that have existed for millions of years apparently without sex or meiosis. They inhabit a variety of temporary and permanent freshwater habitats globally, and many species are remarkably tolerant of desiccation. Bdelloids offer an opportunity to better understand the evolution of sex and recombination, but previous work has emphasised desiccation as the cause of several unusual genomic features in this group. Here, we present high-quality whole-genome sequences of 3 bdelloid species: Rotaria macrura and R. magnacalcarata, which are both desiccation intolerant, and Adineta ricciae, which is desiccation tolerant. In combination with the published assembly of A. vaga, which is also desiccation tolerant, we apply a comparative genomics approach to evaluate the potential effects of desiccation tolerance and asexuality on genome evolution in bdelloids. We find that ancestral tetraploidy is conserved among all 4 bdelloid species, but homologous divergence in obligately aquatic Rotaria genomes is unexpectedly low. This finding is contrary to current models regarding the role of desiccation in shaping bdelloid genomes. In addition, we find that homologous regions in A. ricciae are largely collinear and do not form palindromic repeats as observed in the published A. vaga assembly. Consequently, several features interpreted as genomic evidence for long-term ameiotic evolution are not general to all bdelloid species, even within the same genus. Finally, we substantiate previous findings of high levels of horizontally transferred nonmetazoan genes in both desiccating and nondesiccating bdelloid species and show that this unusual feature is not shared by other animal phyla, even those with desiccation-tolerant representatives. These comparisons call into question the proposed role of desiccation in mediating horizontal genetic transfer.
      PubDate: 2018-04-24T21:00:00Z
      DOI: 10.1371/journal.pbio.2004830
  • Agent-specific learning signals for self–other distinction during

    • Authors: Sam Ereira Raymond J. Dolan Zeb Kurth-Nelson
      Abstract: by Sam Ereira, Raymond J. Dolan, Zeb Kurth-NelsonHumans have a remarkable ability to simulate the minds of others. How the brain distinguishes between mental states attributed to self and mental states attributed to someone else is unknown. Here, we investigated how fundamental neural learning signals are selectively attributed to different agents. Specifically, we asked whether learning signals are encoded in agent-specific neural patterns or whether a self–other distinction depends on encoding agent identity separately from this learning signal. To examine this, we tasked subjects to learn continuously 2 models of the same environment, such that one was selectively attributed to self and the other was selectively attributed to another agent. Combining computational modelling with magnetoencephalography (MEG) enabled us to track neural representations of prediction errors (PEs) and beliefs attributed to self, and of simulated PEs and beliefs attributed to another agent. We found that the representational pattern of a PE reliably predicts the identity of the agent to whom the signal is attributed, consistent with a neural self–other distinction implemented via agent-specific learning signals. Strikingly, subjects exhibiting a weaker neural self–other distinction also had a reduced behavioural capacity for self–other distinction and displayed more marked subclinical psychopathological traits. The neural self–other distinction was also modulated by social context, evidenced in a significantly reduced decoding of agent identity in a nonsocial control task. Thus, we show that self–other distinction is realised through an encoding of agent identity intrinsic to fundamental learning signals. The observation that the fidelity of this encoding predicts psychopathological traits is of interest as a potential neurocomputational psychiatric biomarker.
      PubDate: 2018-04-24T21:00:00Z
      DOI: 10.1371/journal.pbio.2004752
  • Activation of temperature-sensitive TRPV1-like receptors in ARC POMC
           neurons reduces food intake

    • Authors: Jae Hoon Jeong Dong Kun Lee Shun-Mei Liu Streamson C. Chua Jr. Gary J. Schwartz Young-Hwan Jo
      Abstract: by Jae Hoon Jeong, Dong Kun Lee, Shun-Mei Liu, Streamson C. Chua Jr., Gary J. Schwartz, Young-Hwan JoProopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARC) respond to numerous hormonal and neural signals, resulting in changes in food intake. Here, we demonstrate that ARC POMC neurons express capsaicin-sensitive transient receptor potential vanilloid 1 receptor (TRPV1)-like receptors. To show expression of TRPV1-like receptors in ARC POMC neurons, we use single-cell reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry, electrophysiology, TRPV1 knock-out (KO), and TRPV1-Cre knock-in mice. A small elevation of temperature in the physiological range is enough to depolarize ARC POMC neurons. This depolarization is blocked by the TRPV1 receptor antagonist and by Trpv1 gene knockdown. Capsaicin-induced activation reduces food intake that is abolished by a melanocortin receptor antagonist. To selectively stimulate TRPV1-like receptor-expressing ARC POMC neurons in the ARC, we generate an adeno-associated virus serotype 5 (AAV5) carrying a Cre-dependent channelrhodopsin-2 (ChR2)–enhanced yellow fluorescent protein (eYFP) expression cassette under the control of the two neuronal POMC enhancers (nPEs). Optogenetic stimulation of TRPV1-like receptor-expressing POMC neurons decreases food intake. Hypothalamic temperature is rapidly elevated and reaches to approximately 39 °C during treadmill running. This elevation is associated with a reduction in food intake. Knockdown of the Trpv1 gene exclusively in ARC POMC neurons blocks the feeding inhibition produced by increased hypothalamic temperature. Taken together, our findings identify a melanocortinergic circuit that links acute elevations in hypothalamic temperature with acute reductions in food intake.
      PubDate: 2018-04-24T21:00:00Z
      DOI: 10.1371/journal.pbio.2004399
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