ALBERT

Description: by Yaniv Erlich, James B. Williams, David Glazer, Kenneth Yocum, Nita Farahany, Maynard Olson, Arvind Narayanan, Lincoln D. Stein, Jan A. Witkowski, Robert C. Kain Fulfilling the promise of the genetic revolution requires the analysis of large datasets containing information from thousands to millions of participants. However, sharing human genomic data requires protecting subjects from potential harm. Current models rely on de-identification techniques in which privacy versus data utility becomes a zero-sum game. Instead, we propose the use of trust-enabling techniques to create a solution in which researchers and participants both win. To do so we introduce three principles that facilitate trust in genetic research and outline one possible framework built upon those principles. Our hope is that such trust-centric frameworks provide a sustainable solution that reconciles genetic privacy with data sharing and facilitates genetic research.

Description: by Kalie Sacco, John H. Falk, James Bell

Description: by Lars Råberg How do we defend ourselves against pathogenic microbes and other parasites infecting us? Research on defence against parasites has traditionally focused on resistance—the ability to prevent infection or limit parasite replication. The genetics, physiology, and evolutionary ecology of such traits are now relatively well understood. During the last few years it has been realized that another, conceptually different type of defence also plays an important role in animal host–parasite interactions. This type of defence is called tolerance, and can be defined as the ability to limit the health effects of parasites without preventing infection or controlling parasite replication. Our understanding of the causes and consequences of variation in tolerance is, however, still rudimentary. Three recent studies shed light on these questions. In a study of HIV in humans, Regoes et al. show that an MHC class I gene affects not only resistance (as previously known) but also tolerance. In a study of voles, Jackson et al. identify a transcription factor mediating age differences in tolerance to macroparasites. Finally, Hayward et al. demonstrate that tolerance to intestinal parasites in sheep is under positive directional selection, but that most of the variation is environmentally induced rather than heritable. These studies increase our knowledge of the genetic and physiological sources of variation in tolerance, and how this variation affects Darwinian fitness. In addition, they illustrate different approaches to untangle tolerance from other factors determining the health effects of infectious disease.

Description: by Gerlinde Reim, Martina Hruzova, Sandra Goetze, Konrad Basler The Wingless (Wg/Wnt) signaling pathway is essential for metazoan development, where it is central to tissue growth and cellular differentiation. Deregulated Wg pathway activation underlies severe developmental abnormalities, as well as carcinogenesis. Armadillo/β-Catenin plays a key role in the Wg transduction cascade; its cytoplasmic and nuclear levels directly determine the output activity of Wg signaling and are thus tightly controlled. In all current models, once Arm is targeted for degradation by the Arm/β-Catenin destruction complex, its fate is viewed as set. We identified a novel Wg/Wnt pathway component, Armless (Als), which is required for Wg target gene expression in a cell-autonomous manner. We found by genetic and biochemical analyses that Als functions downstream of the destruction complex, at the level of the SCF/Slimb/βTRCP E3 Ub ligase. In the absence of Als, Arm levels are severely reduced. We show by biochemical and in vivo studies that Als interacts directly with Ter94, an AAA ATPase known to associate with E3 ligases and to drive protein turnover. We suggest that Als antagonizes Ter94's positive effect on E3 ligase function and propose that Als promotes Wg signaling by rescuing Arm from proteolytic degradation, spotlighting an unexpected step where the Wg pathway signal is modulated.

Description: by Brian M. Donovan, David Moreno Mateos, Jonathan F. Osborne, Daniel J. Bisaccio

Description: by Klaus Heger, Kaat Fierens, J. Christoph Vahl, Attila Aszodi, Katrin Peschke, Dominik Schenten, Hamida Hammad, Rudi Beyaert, Dieter Saur, Geert van Loo, Axel Roers, Bart N. Lambrecht, Mirjam Kool, Marc Schmidt-Supprian Mast cells are implicated in the pathogenesis of inflammatory and autoimmune diseases. However, this notion based on studies in mast cell-deficient mice is controversial. We therefore established an in vivo model for hyperactive mast cells by specifically ablating the NF-κB negative feedback regulator A20. While A20 deficiency did not affect mast cell degranulation, it resulted in amplified pro-inflammatory responses downstream of IgE/FcεRI, TLRs, IL-1R, and IL-33R. As a consequence house dust mite- and IL-33-driven lung inflammation, late phase cutaneous anaphylaxis, and collagen-induced arthritis were aggravated, in contrast to experimental autoimmune encephalomyelitis and immediate anaphylaxis. Our results provide in vivo evidence that hyperactive mast cells can exacerbate inflammatory disorders and define diseases that might benefit from therapeutic intervention with mast cell function.

Description: by Anissa Kempf, Bjoern Tews, Michael E. Arzt, Oliver Weinmann, Franz J. Obermair, Vincent Pernet, Marta Zagrebelsky, Andrea Delekate, Cristina Iobbi, Ajmal Zemmar, Zorica Ristic, Miriam Gullo, Peter Spies, Dana Dodd, Daniel Gygax, Martin Korte, Martin E. Schwab Nogo-A is a membrane protein of the central nervous system (CNS) restricting neurite growth and synaptic plasticity via two extracellular domains: Nogo-66 and Nogo-A-Δ20. Receptors transducing Nogo-A-Δ20 signaling remained elusive so far. Here we identify the G protein-coupled receptor (GPCR) sphingosine 1-phosphate receptor 2 (S1PR2) as a Nogo-A-Δ20-specific receptor. Nogo-A-Δ20 binds S1PR2 on sites distinct from the pocket of the sphingolipid sphingosine 1-phosphate (S1P) and signals via the G protein G 13 , the Rho GEF LARG, and RhoA. Deleting or blocking S1PR2 counteracts Nogo-A-Δ20- and myelin-mediated inhibition of neurite outgrowth and cell spreading. Blockade of S1PR2 strongly enhances long-term potentiation (LTP) in the hippocampus of wild-type but not Nogo-A −/− mice, indicating a repressor function of the Nogo-A/S1PR2 axis in synaptic plasticity. A similar increase in LTP was also observed in the motor cortex after S1PR2 blockade. We propose a novel signaling model in which a GPCR functions as a receptor for two structurally unrelated ligands, a membrane protein and a sphingolipid. Elucidating Nogo-A/S1PR2 signaling platforms will provide new insights into regulation of synaptic plasticity.

Description: by Péter Poczai, Neil Bell, Jaakko Hyvönen

Description: by Joost M. Woltering, Daan Noordermeer, Marion Leleu, Denis Duboule The evolution of tetrapod limbs from fish fins enabled the conquest of land by vertebrates and thus represents a key step in evolution. Despite the use of comparative gene expression analyses, critical aspects of this transformation remain controversial, in particular the origin of digits. Hoxa and Hoxd genes are essential for the specification of the different limb segments and their functional abrogation leads to large truncations of the appendages. Here we show that the selective transcription of mouse Hoxa genes in proximal and distal limbs is related to a bimodal higher order chromatin structure, similar to that reported for Hoxd genes, thus revealing a generic regulatory strategy implemented by both gene clusters during limb development. We found the same bimodal chromatin architecture in fish embryos, indicating that the regulatory mechanism used to pattern tetrapod limbs may predate the divergence between fish and tetrapods. However, when assessed in mice, both fish regulatory landscapes triggered transcription in proximal rather than distal limb territories, supporting an evolutionary scenario whereby digits arose as tetrapod novelties through genetic retrofitting of preexisting regulatory landscapes. We discuss the possibility to consider regulatory circuitries, rather than expression patterns, as essential parameters to define evolutionary synapomorphies.

Description: by Michael C. Corballis Summary Handedness and brain asymmetry are widely regarded as unique to humans, and associated with complementary functions such as a left-brain specialization for language and logic and a right-brain specialization for creativity and intuition. In fact, asymmetries are widespread among animals, and support the gradual evolution of asymmetrical functions such as language and tool use. Handedness and brain asymmetry are inborn and under partial genetic control, although the gene or genes responsible are not well established. Cognitive and emotional difficulties are sometimes associated with departures from the “norm” of right-handedness and left-brain language dominance, more often with the absence of these asymmetries than their reversal.

Description: by Pedro F. Vale, Andy Fenton, Sam P. Brown

Description: by Jan Mueller, Julia Pfanzelter, Christoph Winkler, Akihiro Narita, Christophe Le Clainche, Maria Nemethova, Marie-France Carlier, Yuichiro Maeda, Matthew D. Welch, Taro Ohkawa, Christian Schmeiser, Guenter P. Resch, J. Victor Small Several pathogens induce propulsive actin comet tails in cells they invade to disseminate their infection. They achieve this by recruiting factors for actin nucleation, the Arp2/3 complex, and polymerization regulators from the host cytoplasm. Owing to limited information on the structural organization of actin comets and in particular the spatial arrangement of filaments engaged in propulsion, the underlying mechanism of pathogen movement is currently speculative and controversial. Using electron tomography we have resolved the three-dimensional architecture of actin comet tails propelling baculovirus, the smallest pathogen yet known to hijack the actin motile machinery. Comet tail geometry was also mimicked in mixtures of virus capsids with purified actin and a minimal inventory of actin regulators. We demonstrate that propulsion is based on the assembly of a fishbone-like array of actin filaments organized in subsets linked by branch junctions, with an average of four filaments pushing the virus at any one time. Using an energy-minimizing function we have simulated the structure of actin comet tails as well as the tracks adopted by baculovirus in infected cells in vivo . The results from the simulations rule out gel squeezing models of propulsion and support those in which actin filaments are continuously tethered during branch nucleation and polymerization. Since Listeria monocytogenes , Shigella flexneri , and Vaccinia virus among other pathogens use the same common toolbox of components as baculovirus to move, we suggest they share the same principles of actin organization and mode of propulsion.

Description: by Ian M. Devonshire, Gareth J. Hathway

Description: by Aaron M. New, Bram Cerulus, Sander K. Govers, Gemma Perez-Samper, Bo Zhu, Sarah Boogmans, Joao B. Xavier, Kevin J. Verstrepen Organisms respond to environmental changes by adapting the expression of key genes. However, such transcriptional reprogramming requires time and energy, and may also leave the organism ill-adapted when the original environment returns. Here, we study the dynamics of transcriptional reprogramming and fitness in the model eukaryote Saccharomyces cerevisiae in response to changing carbon environments. Population and single-cell analyses reveal that some wild yeast strains rapidly and uniformly adapt gene expression and growth to changing carbon sources, whereas other strains respond more slowly, resulting in long periods of slow growth (the so-called “lag phase”) and large differences between individual cells within the population. We exploit this natural heterogeneity to evolve a set of mutants that demonstrate how the frequency and duration of changes in carbon source can favor different carbon catabolite repression strategies. At one end of this spectrum are “specialist” strategies that display high rates of growth in stable environments, with more stringent catabolite repression and slower transcriptional reprogramming. The other mutants display less stringent catabolite repression, resulting in leaky expression of genes that are not required for growth in glucose. This “generalist” strategy reduces fitness in glucose, but allows faster transcriptional reprogramming and shorter lag phases when the cells need to shift to alternative carbon sources. Whole-genome sequencing of these mutants reveals that mutations in key regulatory genes such as HXK2 and STD1 adjust the regulation and transcriptional noise of metabolic genes, with some mutations leading to alternative gene regulatory strategies that allow “stochastic sensing” of the environment. Together, our study unmasks how variable and stable environments favor distinct strategies of transcriptional reprogramming and growth.

Description: by Caitlin Sedwick

Description: by Pierre Montaville, Antoine Jégou, Julien Pernier, Christel Compper, Bérengère Guichard, Binyam Mogessie, Melina Schuh, Guillaume Romet-Lemonne, Marie-France Carlier In mammalian oocytes, three actin binding proteins, Formin 2 (Fmn2), Spire, and profilin, synergistically organize a dynamic cytoplasmic actin meshwork that mediates translocation of the spindle toward the cortex and is required for successful fertilization. Here we characterize Fmn2 and elucidate the molecular mechanism for this synergy, using bulk solution and individual filament kinetic measurements of actin assembly dynamics. We show that by capping filament barbed ends, Spire recruits Fmn2 and facilitates its association with barbed ends, followed by rapid processive assembly and release of Spire. In the presence of actin, profilin, Spire, and Fmn2, filaments display alternating phases of rapid processive assembly and arrested growth, driven by a “ping-pong” mechanism, in which Spire and Fmn2 alternately kick off each other from the barbed ends. The results are validated by the effects of injection of Spire, Fmn2, and their interacting moieties in mouse oocytes. This original mechanism of regulation of a Rho-GTPase–independent formin, recruited by Spire at Rab11a-positive vesicles, supports a model for modulation of a dynamic actin-vesicle meshwork in the oocyte at the origin of asymmetric positioning of the meiotic spindle.

Description: by Theodora Bloom, Emma Ganley, Margaret Winker

Description: by Mary Hoff

Description: by The PLOS Biology Staff

Description: by The PLOS Biology Staff

Description: by Erica White-Grindley, Liying Li, Repon Mohammad Khan, Fengzhen Ren, Anita Saraf, Laurence Florens, Kausik Si How learned experiences persist as memory for a long time is an important question. In Drosophila the persistence of memory is dependent upon amyloid-like oligomers of the Orb2 protein. However, it is not clear how the conversion of Orb2 to the amyloid-like oligomeric state is regulated. The Orb2 has two protein isoforms, and the rare Orb2A isoform is critical for oligomerization of the ubiquitous Orb2B isoform. Here, we report the discovery of a protein network comprised of protein phosphatase 2A (PP2A), Transducer of Erb-B2 (Tob), and Lim Kinase (LimK) that controls the abundance of Orb2A. PP2A maintains Orb2A in an unphosphorylated and unstable state, whereas Tob-LimK phosphorylates and stabilizes Orb2A. Mutation of LimK abolishes activity-dependent Orb2 oligomerization in the adult brain. Moreover, Tob-Orb2 association is modulated by neuronal activity and Tob activity in the mushroom body is required for stable memory formation. These observations suggest that the interplay between PP2A and Tob-LimK activity may dynamically regulate Orb2 amyloid-like oligomer formation and the stabilization of memories.

Description: by Tony Y.-C. Tsai, Julie A. Theriot, James E. Ferrell During the early development of Xenopus laevis embryos, the first mitotic cell cycle is long (∼85 min) and the subsequent 11 cycles are short (∼30 min) and clock-like. Here we address the question of how the Cdk1 cell cycle oscillator changes between these two modes of operation. We found that the change can be attributed to an alteration in the balance between Wee1/Myt1 and Cdc25. The change in balance converts a circuit that acts like a positive-plus-negative feedback oscillator, with spikes of Cdk1 activation, to one that acts like a negative-feedback-only oscillator, with a shorter period and smoothly varying Cdk1 activity. Shortening the first cycle, by treating embryos with the Wee1A/Myt1 inhibitor PD0166285, resulted in a dramatic reduction in embryo viability, and restoring the length of the first cycle in inhibitor-treated embryos with low doses of cycloheximide partially rescued viability. Computations with an experimentally parameterized mathematical model show that modest changes in the Wee1/Cdc25 ratio can account for the observed qualitative changes in the cell cycle. The high ratio in the first cycle allows the period to be long and tunable, and decreasing the ratio in the subsequent cycles allows the oscillator to run at a maximal speed. Thus, the embryo rewires its feedback regulation to meet two different developmental requirements during early development.

Description: by Richard Robinson

Description: by Benjamin Petre, Sophien Kamoun Fungal and oomycete plant parasites are among the most devastating pathogens of food crops. These microbes secrete effector proteins inside plant cells to manipulate host processes and facilitate colonization. How these effectors reach the host cytoplasm remains an unclear and debated area of plant research. In this article, we examine recent conflicting findings that have generated discussion in the field. We also highlight promising approaches based on studies of both parasite and host during infection. Ultimately, this knowledge may inform future broad spectrum strategies for protecting crops from such pathogens.

Description: by Jon F. Wilkins Mammalian development involves significant interactions between offspring and mother. But is this interaction a carefully coordinated effort by two individuals with a common goal—offspring survival? Or is it an evolutionary battleground (a central idea in our understanding of reproduction). The conflict between parents and offspring extends to an offspring's genes, where paternally inherited genes favor demanding more from the mother, while maternally inherited genes favor restraint. This “intragenomic conflict” (among genes within a genome) is the dominant evolutionary explanation for “genomic imprinting.” But a new study in PLOS Biology provides support for a different perspective: that imprinting might facilitate coordination between mother and offspring. According to this “coadaptation theory,” paternally inherited genes might be inactivated because maternally inherited genes are adapted to function harmoniously with the mother. As discussed in this article, the growth effects associated with the imprinted gene Grb10 are consistent with this idea, but it remains to be seen just how general the pattern is.

Description: by Feng Wang, Lin He, Peiwei Huangyang, Jing Liang, Wenzhe Si, Ruorong Yan, Xiao Han, Shumeng Liu, Bin Gui, Wanjin Li, Di Miao, Chao Jing, Zhihua Liu, Fei Pei, Luyang Sun, Yongfeng Shang Jumonji domain-containing 6 (JMJD6) is a member of the Jumonji C domain-containing family of proteins. Compared to other members of the family, the cellular activity of JMJD6 is still not clearly defined and its biological function is still largely unexplored. Here we report that JMJD6 is physically associated with the tumor suppressor p53. We demonstrated that JMJD6 acts as an α-ketoglutarate– and Fe(II)-dependent lysyl hydroxylase to catalyze p53 hydroxylation. We found that p53 indeed exists as a hydroxylated protein in vivo and that the hydroxylation occurs mainly on lysine 382 of p53. We showed that JMJD6 antagonizes p53 acetylation, promotes the association of p53 with its negative regulator MDMX, and represses transcriptional activity of p53. Depletion of JMJD6 enhances p53 transcriptional activity, arrests cells in the G 1 phase, promotes cell apoptosis, and sensitizes cells to DNA damaging agent-induced cell death. Importantly, knockdown of JMJD6 represses p53-dependent colon cell proliferation and tumorigenesis in vivo , and significantly, the expression of JMJD6 is markedly up-regulated in various types of human cancer especially in colon cancer, and high nuclear JMJD6 protein is strongly correlated with aggressive clinical behaviors of colon adenocarcinomas. Our results reveal a novel posttranslational modification for p53 and support the pursuit of JMJD6 as a potential biomarker for colon cancer aggressiveness and a potential target for colon cancer intervention.

Description: by Aniruddh D. Patel In The Descent of Man , Darwin speculated that our capacity for musical rhythm reflects basic aspects of brain function broadly shared among animals. Although this remains an appealing idea, it is being challenged by modern cross-species research. This research hints that our capacity to synchronize to a beat, i.e., to move in time with a perceived pulse in a manner that is predictive and flexible across a broad range of tempi, may be shared by only a few other species. Is this really the case? If so, it would have important implications for our understanding of the evolution of human musicality.

Description: by Anders Hedenström Insights into how exactly a fly powers and controls flight have been hindered by the need to unpick the dynamic complexity of the muscles involved. The wingbeats of insects are driven by two antagonistic groups of power muscles and the force is funneled to the wing via a very complex hinge mechanism. The hinge consists of several hardened and articulated cuticle elements called sclerites. This articulation is controlled by a great number of small steering muscles, whose function has been studied by means of kinematics and muscle activity. The details and partly novel function of some of these steering muscles and their tendons have now been revealed in research published in this issue of PLOS Biology . The new study from Graham Taylor and colleagues applies time-resolved X-ray microtomography to obtain a three-dimensional view of the blowfly wingbeat. Asymmetric power output is achieved by differential wingbeat amplitude on the left and right wing, which is mediated by muscular control of the hinge elements to mechanically block the wing stroke and by absorption of work by steering muscles on one of the sides. This new approach permits visualization of the motion of the thorax, wing muscles, and the hinge mechanism. This very promising line of work will help to reveal the complete picture of the flight motor of a fly. It also holds great potential for novel bio-inspired designs of fly-like micro air vehicles.

Description: by Rajesh Jayachandran, Xiaolong Liu, Somdeb BoseDasgupta, Philipp Müller, Chun-Lei Zhang, Despina Moshous, Vera Studer, Jacques Schneider, Christel Genoud, Catherine Fossoud, Frédéric Gambino, Malik Khelfaoui, Christian Müller, Deborah Bartholdi, Helene Rossez, Michael Stiess, Xander Houbaert, Rolf Jaussi, Daniel Frey, Richard A. Kammerer, Xavier Deupi, Jean-Pierre de Villartay, Andreas Lüthi, Yann Humeau, Jean Pieters Cognitive and behavioral disorders are thought to be a result of neuronal dysfunction, but the underlying molecular defects remain largely unknown. An important signaling pathway involved in the regulation of neuronal function is the cyclic AMP/Protein kinase A pathway. We here show an essential role for coronin 1, which is encoded in a genomic region associated with neurobehavioral dysfunction, in the modulation of cyclic AMP/PKA signaling. We found that coronin 1 is specifically expressed in excitatory but not inhibitory neurons and that coronin 1 deficiency results in loss of excitatory synapses and severe neurobehavioral disabilities, including reduced anxiety, social deficits, increased aggression, and learning defects. Electrophysiological analysis of excitatory synaptic transmission in amygdala revealed that coronin 1 was essential for cyclic–AMP–protein kinase A–dependent presynaptic plasticity. We further show that upon cell surface stimulation, coronin 1 interacted with the G protein subtype Gαs to stimulate the cAMP/PKA pathway. The absence of coronin 1 or expression of coronin 1 mutants unable to interact with Gαs resulted in a marked reduction in cAMP signaling. Strikingly, synaptic plasticity and behavioral defects of coronin 1–deficient mice were restored by in vivo infusion of a membrane-permeable cAMP analogue. Together these results identify coronin 1 as being important for cognition and behavior through its activity in promoting cAMP/PKA-dependent synaptic plasticity and may open novel avenues for the dissection of signal transduction pathways involved in neurobehavioral processes.

Description: by Carrie Friese, Claire Marris

Description: by Simon M. Walker, Daniel A. Schwyn, Rajmund Mokso, Martina Wicklein, Tonya Müller, Michael Doube, Marco Stampanoni, Holger G. Krapp, Graham K. Taylor Dipteran flies are amongst the smallest and most agile of flying animals. Their wings are driven indirectly by large power muscles, which cause cyclical deformations of the thorax that are amplified through the intricate wing hinge. Asymmetric flight manoeuvres are controlled by 13 pairs of steering muscles acting directly on the wing articulations. Collectively the steering muscles account for

Description: by Crow White, Christopher Costello The world's oceans are governed as a system of over 150 sovereign exclusive economic zones (EEZs, ∼42% of the ocean) and one large high seas (HS) commons (∼58% of ocean) with essentially open access. Many high-valued fish species such as tuna, billfish, and shark migrate around these large oceanic regions, which as a consequence of competition across EEZs and a global race-to-fish on the HS, have been over-exploited and now return far less than their economic potential. We address this global challenge by analyzing with a spatial bioeconomic model the effects of completely closing the HS to fishing. This policy both induces cooperation among countries in the exploitation of migratory stocks and provides a refuge sufficiently large to recover and maintain these stocks at levels close to those that would maximize fisheries returns. We find that completely closing the HS to fishing would simultaneously give rise to large gains in fisheries profit (〉100%), fisheries yields (〉30%), and fish stock conservation (〉150%). We also find that changing EEZ size may benefit some fisheries; nonetheless, a complete closure of the HS still returns larger fishery and conservation outcomes than does a HS open to fishing.

Description: by Calistus N. Ngonghala, Mateusz M. Pluciński, Megan B. Murray, Paul E. Farmer, Christopher B. Barrett, Donald C. Keenan, Matthew H. Bonds Understanding why some human populations remain persistently poor remains a significant challenge for both the social and natural sciences. The extremely poor are generally reliant on their immediate natural resource base for subsistence and suffer high rates of mortality due to parasitic and infectious diseases. Economists have developed a range of models to explain persistent poverty, often characterized as poverty traps, but these rarely account for complex biophysical processes. In this Essay, we argue that by coupling insights from ecology and economics, we can begin to model and understand the complex dynamics that underlie the generation and maintenance of poverty traps, which can then be used to inform analyses and possible intervention policies. To illustrate the utility of this approach, we present a simple coupled model of infectious diseases and economic growth, where poverty traps emerge from nonlinear relationships determined by the number of pathogens in the system. These nonlinearities are comparable to those often incorporated into poverty trap models in the economics literature, but, importantly, here the mechanism is anchored in core ecological principles. Coupled models of this sort could be usefully developed in many economically important biophysical systems—such as agriculture, fisheries, nutrition, and land use change—to serve as foundations for deeper explorations of how fundamental ecological processes influence structural poverty and economic development.

Description: by Athanasios Metaxakis, Luke S. Tain, Sebastian Grönke, Oliver Hendrich, Yvonne Hinze, Ulrike Birras, Linda Partridge Sleep fragmentation, particularly reduced and interrupted night sleep, impairs the quality of life of older people. Strikingly similar declines in sleep quality are seen during ageing in laboratory animals, including the fruit fly Drosophila . We investigated whether reduced activity of the nutrient- and stress-sensing insulin/insulin-like growth factor (IIS)/TOR signalling network, which ameliorates ageing in diverse organisms, could rescue the sleep fragmentation of ageing Drosophila . Lowered IIS/TOR network activity improved sleep quality, with increased night sleep and day activity and reduced sleep fragmentation. Reduced TOR activity, even when started for the first time late in life, improved sleep quality. The effects of reduced IIS/TOR network activity on day and night phenotypes were mediated through distinct mechanisms: Day activity was induced by adipokinetic hormone, dFOXO, and enhanced octopaminergic signalling. In contrast, night sleep duration and consolidation were dependent on reduced S6K and dopaminergic signalling. Our findings highlight the importance of different IIS/TOR components as potential therapeutic targets for pharmacological treatment of age-related sleep fragmentation in humans.

Description: by Jonathan Chase

Description: by Jean-Marie Buerstedde, Jukka Alinikula, Hiroshi Arakawa, Jessica J. McDonald, David G. Schatz Somatic hypermutation (SH) generates point mutations within rearranged immunoglobulin ( Ig ) genes of activated B cells, providing genetic diversity for the affinity maturation of antibodies. SH requires the activation-induced cytidine deaminase (AID) protein and transcription of the mutation target sequence, but how the Ig gene specificity of mutations is achieved has remained elusive. We show here using a sensitive and carefully controlled assay that the Ig enhancers strongly activate SH in neighboring genes even though their stimulation of transcription is negligible. Mutations in certain E-box, NFκB, MEF2, or Ets family binding sites—known to be important for the transcriptional role of Ig enhancers—impair or abolish the activity. Full activation of SH typically requires a combination of multiple Ig enhancer and enhancer-like elements. The mechanism is evolutionarily conserved, as mammalian Ig lambda and Ig heavy chain intron enhancers efficiently stimulate hypermutation in chicken cells. Our results demonstrate a novel regulatory function for Ig enhancers, indicating that they either recruit AID or alter the accessibility of the nearby transcription units.

Description: by Floriane Plard, Jean-Michel Gaillard, Tim Coulson, A. J. Mark Hewison, Daniel Delorme, Claude Warnant, Christophe Bonenfant Marked impacts of climate change on biodiversity have frequently been demonstrated, including temperature-related shifts in phenology and life-history traits. One potential major impact of climate change is the modification of synchronization between the phenology of different trophic levels. High phenotypic plasticity in laying date has allowed many bird species to track the increasingly early springs resulting from recent environmental change, but although changes in the timing of reproduction have been well studied in birds, these questions have only recently been addressed in mammals. To track peak resource availability, large herbivores like roe deer, with a widespread distribution across Europe, should also modify their life-history schedule in response to changes in vegetation phenology over time. In this study, we analysed the influence of climate change on the timing of roe deer births and the consequences for population demography and individual fitness. Our study provides a rare quantification of the demographic costs associated with the failure of a species to modify its phenology in response to a changing world. Given these fitness costs, the lack of response of roe deer birth dates to match the increasingly earlier onset of spring is in stark contrast with the marked phenotypic responses to climate change reported in many other mammals. We suggest that the lack of phenotypic plasticity in birth timing in roe deer is linked to its inability to track environmental cues of variation in resource availability for the timing of parturition.

Description: by Li Tao, Han Du, Guobo Guan, Yu Dai, Clarissa J. Nobile, Weihong Liang, Chengjun Cao, Qiuyu Zhang, Jin Zhong, Guanghua Huang Non-genetic phenotypic variations play a critical role in the adaption to environmental changes in microbial organisms. Candida albicans , a major human fungal pathogen, can switch between several morphological phenotypes. This ability is critical for its commensal lifestyle and for its ability to cause infections. Here, we report the discovery of a novel morphological form in C. albicans , referred to as the “gray” phenotype, which forms a tristable phenotypic switching system with the previously reported white and opaque phenotypes. White, gray, and opaque cell types differ in a number of aspects including cellular and colony appearances, mating competency, secreted aspartyl proteinase (Sap) activities, and virulence. Of the three cell types, gray cells exhibit the highest Sap activity and the highest ability to cause cutaneous infections. The three phenotypes form a tristable phenotypic switching system, which is independent of the regulation of the mating type locus ( MTL ). Gray cells mate over 1,000 times more efficiently than do white cells, but less efficiently than do opaque cells. We further demonstrate that the master regulator of white-opaque switching, Wor1, is essential for opaque cell formation, but is not required for white-gray transitions. The Efg1 regulator is required for maintenance of the white phenotype, but is not required for gray-opaque transitions. Interestingly, the wor1/wor1 efg1/efg1 double mutant is locked in the gray phenotype, suggesting that Wor1 and Efg1 could function coordinately and play a central role in the regulation of gray cell formation. Global transcriptional analysis indicates that white, gray, and opaque cells exhibit distinct gene expression profiles, which partly explain their differences in causing infections, adaptation ability to diverse host niches, metabolic profiles, and stress responses. Therefore, the white-gray-opaque tristable phenotypic switching system in C. albicans may play a significant role in a wide range of biological aspects in this common commensal and pathogenic fungus.

Description: by Roland R. Regoes, Paul J. McLaren, Manuel Battegay, Enos Bernasconi, Alexandra Calmy, Huldrych F. Günthard, Matthias Hoffmann, Andri Rauch, Amalio Telenti, Jacques Fellay, the Swiss HIV Cohort Study In ecology, “disease tolerance” is defined as an evolutionary strategy of hosts against pathogens, characterized by reduced or absent pathogenesis despite high pathogen load. To our knowledge, tolerance has to date not been quantified and disentangled from host resistance to disease in any clinically relevant human infection. Using data from the Swiss HIV Cohort Study, we investigated if there is variation in tolerance to HIV in humans and if this variation is associated with polymorphisms in the human genome. In particular, we tested for associations between tolerance and alleles of the Human Leukocyte Antigen (HLA) genes, the CC chemokine receptor 5 (CCR5), the age at which individuals were infected, and their sex. We found that HLA-B alleles associated with better HIV control do not confer tolerance. The slower disease progression associated with these alleles can be fully attributed to the extent of viral load reduction in carriers. However, we observed that tolerance significantly varies across HLA-B genotypes with a relative standard deviation of 34%. Furthermore, we found that HLA-B homozygotes are less tolerant than heterozygotes. Lastly, tolerance was observed to decrease with age, resulting in a 1.7-fold difference in disease progression between 20 and 60-y-old individuals with the same viral load. Thus, disease tolerance is a feature of infection with HIV, and the identification of the mechanisms involved may pave the way to a better understanding of pathogenesis.

Description: by Caitlin Sedwick

Description: by Brooke Tata, Lukas Huijbregts, Sandrine Jacquier, Zsolt Csaba, Emmanuelle Genin, Vincent Meyer, Sofia Leka, Joelle Dupont, Perrine Charles, Didier Chevenne, Jean-Claude Carel, Juliane Léger, Nicolas de Roux Characterization of the genetic defects causing gonadotropic deficiency has made a major contribution to elucidation of the fundamental role of Kisspeptins and Neurokinin B in puberty onset and reproduction. The absence of puberty may also reveal neurodevelopmental disorders caused by molecular defects in various cellular pathways. Investigations of these neurodevelopmental disorders may provide information about the neuronal processes controlling puberty onset and reproductive capacity. We describe here a new syndrome observed in three brothers, which involves gonadotropic axis deficiency, central hypothyroidism, peripheral demyelinating sensorimotor polyneuropathy, mental retardation, and profound hypoglycemia, progressing to nonautoimmune insulin-dependent diabetes mellitus. High-throughput sequencing revealed a homozygous in-frame deletion of 15 nucleotides in DMXL2 in all three affected patients. This homozygous deletion was associated with lower DMXL2 mRNA levels in the blood lymphocytes of the patients. DMXL2 encodes the synaptic protein rabconnectin-3α, which has been identified as a putative scaffold protein for Rab3-GAP and Rab3-GEP, two regulators of the GTPase Rab3a. We found that rabconnectin-3α was expressed in exocytosis vesicles in gonadotropin-releasing hormone (GnRH) axonal extremities in the median eminence of the hypothalamus. It was also specifically expressed in cells expressing luteinizing hormone (LH) and follicle-stimulating hormone (FSH) within the pituitary. The conditional heterozygous deletion of Dmxl2 from mouse neurons delayed puberty and resulted in very low fertility. This reproductive phenotype was associated with a lower number of GnRH neurons in the hypothalamus of adult mice. Finally, Dmxl2 knockdown in an insulin-secreting cell line showed that rabconnectin-3α controlled the constitutive and glucose-induced secretion of insulin. In conclusion, this study shows that low levels of DMXL2 expression cause a complex neurological phenotype, with abnormal glucose metabolism and gonadotropic axis deficiency due to a loss of GnRH neurons. Our findings identify rabconectin-3α as a key controller of neuronal and endocrine homeostatic processes.

Description: by Richard Robinson

Description: by Nazanin Rohani, Andrea Parmeggiani, Rudolf Winklbauer, François Fagotto Ephrins and Eph receptors are involved in the establishment of vertebrate tissue boundaries. The complexity of the system is puzzling, however in many instances, tissues express multiple ephrins and Ephs on both sides of the boundary, a situation that should in principle cause repulsion between cells within each tissue. Although co-expression of ephrins and Eph receptors is widespread in embryonic tissues, neurons, and cancer cells, it is still unresolved how the respective signals are integrated into a coherent output. We present a simple explanation for the confinement of repulsion to the tissue interface: Using the dorsal ectoderm–mesoderm boundary of the Xenopus embryo as a model, we identify selective functional interactions between ephrin–Eph pairs that are expressed in partial complementary patterns. The combined repulsive signals add up to be strongest across the boundary, where they reach sufficient intensity to trigger cell detachments. The process can be largely explained using a simple model based exclusively on relative ephrin and Eph concentrations and binding affinities. We generalize these findings for the ventral ectoderm–mesoderm boundary and the notochord boundary, both of which appear to function on the same principles. These results provide a paradigm for how developmental systems may integrate multiple cues to generate discrete local outcomes.

Description: by Daniel Simberloff The earliest concept of a balance of nature in Western thought saw it as being provided by gods but requiring human aid or encouragement for its maintenance. With the rise of Greek natural philosophy, emphasis shifted to traits gods endowed species with at the outset, rather than human actions, as key to maintaining the balance. The dominance of a constantly intervening God in the Middle Ages lessened interest in the inherent features of nature that would contribute to balance, but the Reformation led to renewed focus on such features, particularly traits of species that would maintain all of them but permit none to dominate nature. Darwin conceived of nature in balance, and his emphasis on competition and frequent tales of felicitous species interactions supported the idea of a balance of nature. But Darwin radically changed its underlying basis, from God to natural selection. Wallace was perhaps the first to challenge the very notion of a balance of nature as an undefined entity whose accuracy could not be tested. His skepticism was taken up again in the 20th century, culminating in a widespread rejection of the idea of a balance of nature by academic ecologists, who focus rather on a dynamic, often chaotic nature buffeted by constant disturbances. The balance-of-nature metaphor, however, lives on in large segments of the public, representing a fragile aspect of nature and biodiversity that it is our duty to protect.

Description: by Raquel A. Oliveira, Shaila Kotadia, Alexandra Tavares, Mihailo Mirkovic, Katherine Bowlin, Christian S. Eichinger, Kim Nasmyth, William Sullivan Pericentric heterochromatin, while often considered as “junk” DNA, plays important functions in chromosome biology. It contributes to sister chromatid cohesion, a process mediated by the cohesin complex that ensures proper genome segregation during nuclear division. Long stretches of heterochromatin are almost exclusively placed at centromere-proximal regions but it remains unclear if there is functional (or mechanistic) importance in linking the sites of sister chromatid cohesion to the chromosomal regions that mediate spindle attachment (the centromere). Using engineered chromosomes in Drosophila melanogaster , we demonstrate that cohesin enrichment is dictated by the presence of heterochromatin rather than centromere proximity. This preferential accumulation is caused by an enrichment of the cohesin-loading factor (Nipped-B/NIPBL/Scc2) at dense heterochromatic regions. As a result, chromosome translocations containing ectopic pericentric heterochromatin embedded in euchromatin display additional cohesin-dependent constrictions. These ectopic cohesion sites, placed away from the centromere, disjoin abnormally during anaphase and chromosomes exhibit a significant increase in length during anaphase (termed chromatin stretching). These results provide evidence that long stretches of heterochromatin distant from the centromere, as often found in many cancers, are sufficient to induce abnormal accumulation of cohesin at these sites and thereby compromise the fidelity of chromosome segregation.

Description: by Joseph Moeller Schinaman, Rachel Lynn Giesey, Claudia Mieko Mizutani, Tamas Lukacsovich, Rui Sousa-Neves Courtship is a widespread behavior in which one gender conveys to the other a series of cues about their species identity, gender, and suitability as mates. In many species, females decode these male displays and either accept or reject them. Despite the fact that courtship has been investigated for a long time, the genes and circuits that allow females to generate these mutually exclusive responses remain largely unknown. Here, we provide evidence that the Krüppel-like transcription factor datilógrafo ( dati ) is required for proper locomotion and courtship acceptance in adult Drosophila females. dati mutant females are completely unable to decode male courtship and almost invariably reject males. Molecular analyses reveal that dati is broadly expressed in the brain and its specific removal in excitatory cholinergic neurons recapitulates the female courtship behavioral phenotype but not the locomotor deficits, indicating that these are two separable functions. Clonal analyses in female brains identified three discrete foci where dati is required to generate acceptance. These include neurons around the antennal lobe, the lateral horn, and the posterior superior lateral protocerebrum. Together, these results show that dati is required to organize and maintain a relatively simple excitatory circuit in the brain that allows females to either accept or reject courting males.

Description: by The PLOS Biology Staff

Description: by Costis Papanayotou, Ataaillah Benhaddou, Anne Camus, Aitana Perea-Gomez, Alice Jouneau, Valérie Mezger, Francina Langa, Sascha Ott, Délara Sabéran-Djoneidi, Jérôme Collignon During early development, modulations in the expression of Nodal, a TGFβ family member, determine the specification of embryonic and extra-embryonic cell identities. Nodal has been extensively studied in the mouse, but aspects of its early expression remain unaccounted for. We identified a conserved hotspot for the binding of pluripotency factors at the Nodal locus and called this sequence “highly bound element” (HBE). Luciferase-based assays, the analysis of fluorescent HBE reporter transgenes, and a conditional mutation of HBE allowed us to establish that HBE behaves as an enhancer, is activated ahead of other Nodal enhancers in the epiblast, and is essential to Nodal expression in embryonic stem cells (ESCs) and in the mouse embryo. We also showed that HBE enhancer activity is critically dependent on its interaction with the pluripotency factor Oct4 and on Activin/Nodal signaling. Use of an in vitro model of epiblast maturation, relying on the differentiation of ESCs into epiblast stem cells (EpiSCs), revealed that this process entails a shift in the regulation of Nodal expression from an HBE-driven phase to an ASE-driven phase, ASE being another autoregulatory Nodal enhancer. Deletion of HBE in ESCs or in EpiSCs allowed us to show that HBE, although not necessary for Nodal expression in EpiSCs, is required in differentiating ESCs to activate the differentiation-promoting ASE and therefore controls this regulatory shift. Our findings clarify how early Nodal expression is regulated and suggest how this regulation can promote the specification of extra-embryonic precusors without inducing premature differentiation of epiblast cells. More generally, they open new perspectives on how pluripotency factors achieve their function.

Description: by Andreas Schoofs, Sebastian Hückesfeld, Philipp Schlegel, Anton Miroschnikow, Marc Peters, Malou Zeymer, Roland Spieβ, Ann-Shyn Chiang, Michael J. Pankratz Central mechanisms by which specific motor programs are selected to achieve meaningful behaviors are not well understood. Using electrophysiological recordings from pharyngeal nerves upon central activation of neurotransmitter-expressing cells, we show that distinct neuronal ensembles can regulate different feeding motor programs. In behavioral and electrophysiological experiments, activation of 20 neurons in the brain expressing the neuropeptide hugin, a homolog of mammalian neuromedin U, simultaneously suppressed the motor program for food intake while inducing the motor program for locomotion. Decreasing hugin neuropeptide levels in the neurons by RNAi prevented this action. Reducing the level of hugin neuronal activity alone did not have any effect on feeding or locomotion motor programs. Furthermore, use of promoter-specific constructs that labeled subsets of hugin neurons demonstrated that initiation of locomotion can be separated from modulation of its motor pattern. These results provide insights into a neural mechanism of how opposing motor programs can be selected in order to coordinate feeding and locomotive behaviors.

Description: by Oscar Venter, Richard A. Fuller, Daniel B. Segan, Josie Carwardine, Thomas Brooks, Stuart H. M. Butchart, Moreno Di Marco, Takuya Iwamura, Liana Joseph, Damien O'Grady, Hugh P. Possingham, Carlo Rondinini, Robert J. Smith, Michelle Venter, James E. M. Watson Governments have agreed to expand the global protected area network from 13% to 17% of the world's land surface by 2020 (Aichi target 11) and to prevent the further loss of known threatened species (Aichi target 12). These targets are interdependent, as protected areas can stem biodiversity loss when strategically located and effectively managed. However, the global protected area estate is currently biased toward locations that are cheap to protect and away from important areas for biodiversity. Here we use data on the distribution of protected areas and threatened terrestrial birds, mammals, and amphibians to assess current and possible future coverage of these species under the convention. We discover that 17% of the 4,118 threatened vertebrates are not found in a single protected area and that fully 85% are not adequately covered (i.e., to a level consistent with their likely persistence). Using systematic conservation planning, we show that expanding protected areas to reach 17% coverage by protecting the cheapest land, even if ecoregionally representative, would increase the number of threatened vertebrates covered by only 6%. However, the nonlinear relationship between the cost of acquiring land and species coverage means that fivefold more threatened vertebrates could be adequately covered for only 1.5 times the cost of the cheapest solution, if cost efficiency and threatened vertebrates are both incorporated into protected area decision making. These results are robust to known errors in the vertebrate range maps. The Convention on Biological Diversity targets may stimulate major expansion of the global protected area estate. If this expansion is to secure a future for imperiled species, new protected areas must be sited more strategically than is presently the case.

Description: by Johanna M. Zumer, René Scheeringa, Jan-Mathijs Schoffelen, David G. Norris, Ole Jensen Given the limited processing capabilities of the sensory system, it is essential that attended information is gated to downstream areas, whereas unattended information is blocked. While it has been proposed that alpha band (8–13 Hz) activity serves to route information to downstream regions by inhibiting neuronal processing in task-irrelevant regions, this hypothesis remains untested. Here we investigate how neuronal oscillations detected by electroencephalography in visual areas during working memory encoding serve to gate information reflected in the simultaneously recorded blood-oxygenation-level-dependent (BOLD) signals recorded by functional magnetic resonance imaging in downstream ventral regions. We used a paradigm in which 16 participants were presented with faces and landscapes in the right and left hemifields; one hemifield was attended and the other unattended. We observed that decreased alpha power contralateral to the attended object predicted the BOLD signal representing the attended object in ventral object-selective regions. Furthermore, increased alpha power ipsilateral to the attended object predicted a decrease in the BOLD signal representing the unattended object. We also found that the BOLD signal in the dorsal attention network inversely correlated with visual alpha power. This is the first demonstration, to our knowledge, that oscillations in the alpha band are implicated in the gating of information from the visual cortex to the ventral stream, as reflected in the representationally specific BOLD signal. This link of sensory alpha to downstream activity provides a neurophysiological substrate for the mechanism of selective attention during stimulus processing, which not only boosts the attended information but also suppresses distraction. Although previous studies have shown a relation between the BOLD signal from the dorsal attention network and the alpha band at rest, we demonstrate such a relation during a visuospatial task, indicating that the dorsal attention network exercises top-down control of visual alpha activity.

Description: by Roos Eisma, Tracey Wilkinson For decades, embalmed cadavers have played an important role in teaching anatomy to the scientists and doctors of the future. Most anatomy departments use a traditional formaldehyde-based embalming method, but formalin embalming makes the bodies very rigid, which limits their usefulness for procedures other than dissection. A more recent embalming method developed by W. Thiel has allowed these “silent teachers” to take on a further role in applied anatomy research and teaching: to act as models for surgical training and medical research.

Description: by Katriona Shea, Michael J. Tildesley, Michael C. Runge, Christopher J. Fonnesbeck, Matthew J. Ferrari Optimal intervention for disease outbreaks is often impeded by severe scientific uncertainty. Adaptive management (AM), long-used in natural resource management, is a structured decision-making approach to solving dynamic problems that accounts for the value of resolving uncertainty via real-time evaluation of alternative models. We propose an AM approach to design and evaluate intervention strategies in epidemiology, using real-time surveillance to resolve model uncertainty as management proceeds, with foot-and-mouth disease (FMD) culling and measles vaccination as case studies. We use simulations of alternative intervention strategies under competing models to quantify the effect of model uncertainty on decision making, in terms of the value of information, and quantify the benefit of adaptive versus static intervention strategies. Culling decisions during the 2001 UK FMD outbreak were contentious due to uncertainty about the spatial scale of transmission. The expected benefit of resolving this uncertainty prior to a new outbreak on a UK-like landscape would be £45–£60 million relative to the strategy that minimizes livestock losses averaged over alternate transmission models. AM during the outbreak would be expected to recover up to £20.1 million of this expected benefit. AM would also recommend a more conservative initial approach (culling of infected premises and dangerous contact farms) than would a fixed strategy (which would additionally require culling of contiguous premises). For optimal targeting of measles vaccination, based on an outbreak in Malawi in 2010, AM allows better distribution of resources across the affected region; its utility depends on uncertainty about both the at-risk population and logistical capacity. When daily vaccination rates are highly constrained, the optimal initial strategy is to conduct a small, quick campaign; a reduction in expected burden of approximately 10,000 cases could result if campaign targets can be updated on the basis of the true susceptible population. Formal incorporation of a policy to update future management actions in response to information gained in the course of an outbreak can change the optimal initial response and result in significant cost savings. AM provides a framework for using multiple models to facilitate public-health decision making and an objective basis for updating management actions in response to improved scientific understanding.

Description: by Tom Baden, Anton Nikolaev, Federico Esposti, Elena Dreosti, Benjamin Odermatt, Leon Lagnado The visual system transmits information about fast and slow changes in light intensity through separate neural pathways. We used in vivo imaging to investigate how bipolar cells transmit these signals to the inner retina. We found that the volume of the synaptic terminal is an intrinsic property that contributes to different temporal filters. Individual cells transmit through multiple terminals varying in size, but smaller terminals generate faster and larger calcium transients to trigger vesicle release with higher initial gain, followed by more profound adaptation. Smaller terminals transmitted higher stimulus frequencies more effectively. Modeling global calcium dynamics triggering vesicle release indicated that variations in the volume of presynaptic compartments contribute directly to all these differences in response dynamics. These results indicate how one neuron can transmit different temporal components in the visual signal through synaptic terminals of varying geometries with different adaptational properties.

Description: by Yangkyun Oh, Sung-Eun Yoon, Qi Zhang, Hyo-Seok Chae, Ivana Daubnerová, Orie T. Shafer, Joonho Choe, Young-Joon Kim Sleep, a reversible quiescent state found in both invertebrate and vertebrate animals, disconnects animals from their environment and is highly regulated for coordination with wakeful activities, such as reproduction. The fruit fly, Drosophila melanogaster , has proven to be a valuable model for studying the regulation of sleep by circadian clock and homeostatic mechanisms. Here, we demonstrate that the sex peptide receptor (SPR) of Drosophila , known for its role in female reproduction, is also important in stabilizing sleep in both males and females. Mutants lacking either the SPR or its central ligand, myoinhibitory peptide (MIP), fall asleep normally, but have difficulty in maintaining a sleep-like state. Our analyses have mapped the SPR sleep function to pigment dispersing factor ( pdf ) neurons, an arousal center in the insect brain. MIP downregulates intracellular cAMP levels in pdf neurons through the SPR. MIP is released centrally before and during night-time sleep, when the sleep drive is elevated. Sleep deprivation during the night facilitates MIP secretion from specific brain neurons innervating pdf neurons. Moreover, flies lacking either SPR or MIP cannot recover sleep after the night-time sleep deprivation. These results delineate a central neuropeptide circuit that stabilizes the sleep state by feeding a slow-acting inhibitory input into the arousal system and plays an important role in sleep homeostasis.

Description: by Richard Robinson

Description: by Richard Robinson

Description: by Joshua W. Modell, Tracy K. Kambara, Barrett S. Perchuk, Michael T. Laub Cells must coordinate DNA replication with cell division, especially during episodes of DNA damage. The paradigm for cell division control following DNA damage in bacteria involves the SOS response where cleavage of the transcriptional repressor LexA induces a division inhibitor. However, in Caulobacter crescentus , cells lacking the primary SOS-regulated inhibitor, sidA , can often still delay division post-damage. Here we identify didA , a second cell division inhibitor that is induced by DNA damage, but in an SOS-independent manner. Together, DidA and SidA inhibit division, such that cells lacking both inhibitors divide prematurely following DNA damage, with lethal consequences. We show that DidA does not disrupt assembly of the division machinery and instead binds the essential division protein FtsN to block cytokinesis. Intriguingly, mutations in FtsW and FtsI, which drive the synthesis of septal cell wall material, can suppress the activity of both SidA and DidA, likely by causing the FtsW/I/N complex to hyperactively initiate cell division. Finally, we identify a transcription factor, DriD, that drives the SOS-independent transcription of didA following DNA damage.

Description: by W. Seth Childers, Qingping Xu, Thomas H. Mann, Irimpan I. Mathews, Jimmy A. Blair, Ashley M. Deacon, Lucy Shapiro One of the simplest organisms to divide asymmetrically is the bacterium Caulobacter crescentus . The DivL pseudo-histidine kinase, positioned at one cell pole, regulates cell-fate by controlling the activation of the global transcription factor CtrA via an interaction with the response regulator (RR) DivK. DivL uniquely contains a tyrosine at the histidine phosphorylation site, and can achieve these regulatory functions in vivo without kinase activity. Determination of the DivL crystal structure and biochemical analysis of wild-type and site-specific DivL mutants revealed that the DivL PAS domains regulate binding specificity for DivK∼P over DivK, which is modulated by an allosteric intramolecular interaction between adjacent domains. We discovered that DivL's catalytic domains have been repurposed as a phosphospecific RR input sensor, thereby reversing the flow of information observed in conventional histidine kinase (HK)-RR systems and coupling a complex network of signaling proteins for cell-fate regulation.

Description: by Richard Robinson

Description: by Cynthia Pan, Jeffrey P. Potratz, Brian Cannon, Zachary B. Simpson, Jessica L. Ziehr, Pilar Tijerina, Rick Russell DEAD-box helicase proteins accelerate folding and rearrangements of highly structured RNAs and RNA–protein complexes (RNPs) in many essential cellular processes. Although DEAD-box proteins have been shown to use ATP to unwind short RNA helices, it is not known how they disrupt RNA tertiary structure. Here, we use single molecule fluorescence to show that the DEAD-box protein CYT-19 disrupts tertiary structure in a group I intron using a helix capture mechanism. CYT-19 binds to a helix within the structured RNA only after the helix spontaneously loses its tertiary contacts, and then CYT-19 uses ATP to unwind the helix, liberating the product strands. Ded1, a multifunctional yeast DEAD-box protein, gives analogous results with small but reproducible differences that may reflect its in vivo roles. The requirement for spontaneous dynamics likely targets DEAD-box proteins toward less stable RNA structures, which are likely to experience greater dynamic fluctuations, and provides a satisfying explanation for previous correlations between RNA stability and CYT-19 unfolding efficiency. Biologically, the ability to sense RNA stability probably biases DEAD-box proteins to act preferentially on less stable misfolded structures and thereby to promote native folding while minimizing spurious interactions with stable, natively folded RNAs. In addition, this straightforward mechanism for RNA remodeling does not require any specific structural environment of the helicase core and is likely to be relevant for DEAD-box proteins that promote RNA rearrangements of RNP complexes including the spliceosome and ribosome.

Description: by Bongsoo Suh, Stephen A. Baccus Sensory systems must be able to extract features of a stimulus to detect and represent properties of the world. Because sensory signals are constantly changing, a critical aspect of this transformation relates to the timing of signals and the ability to filter those signals to select dynamic properties, such as visual motion. At first assessment, one might think that the primary biophysical properties that construct a temporal filter would be dynamic mechanisms such as molecular concentration or membrane electrical properties. However, in the current issue of PLOS Biology , Baden et al. identify a mechanism of temporal filtering in the zebrafish and goldfish retina that is not dynamic but is in fact a structural building block—the physical size of a synapse itself. The authors observe that small, bipolar cell synaptic terminals are fast and highly adaptive, whereas large ones are slower and adapt less. Using a computational model, they conclude that the volume of the synaptic terminal influences the calcium concentration and the number of available vesicles. These results indicate that the size of the presynaptic terminal is an independent control for the dynamics of a synapse and may reveal aspects of synaptic function that can be inferred from anatomical structure.

Description: by The PLOS Biology Staff

Description: by Jennifer Lin, Carly Strasser As appeals for public access of research data continue to proliferate, many scholarly publishers—alongside funders, institutions, and libraries—are expanding their role to address this need. Here we outline eight recommendations and a set of suggested action items for publishers to promote and contribute to increasing access to data. This call to action emerged from a summit that brought together data stewardship leaders across stakeholder groups. The recommendations were subsequently refined by the community as a result of public input gathered online and in meetings.

Description: by The PLOS Biology Staff

Description: by Caitlin Sedwick

Description: by Béla Szamecz, Gábor Boross, Dorottya Kalapis, Károly Kovács, Gergely Fekete, Zoltán Farkas, Viktória Lázár, Mónika Hrtyan, Patrick Kemmeren, Marian J. A. Groot Koerkamp, Edit Rutkai, Frank C. P. Holstege, Balázs Papp, Csaba Pál Adaptive evolution is generally assumed to progress through the accumulation of beneficial mutations. However, as deleterious mutations are common in natural populations, they generate a strong selection pressure to mitigate their detrimental effects through compensatory genetic changes. This process can potentially influence directions of adaptive evolution by enabling evolutionary routes that are otherwise inaccessible. Therefore, the extent to which compensatory mutations shape genomic evolution is of central importance. Here, we studied the capacity of the baker's yeast genome to compensate the complete loss of genes during evolution, and explored the long-term consequences of this process. We initiated laboratory evolutionary experiments with over 180 haploid baker's yeast genotypes, all of which initially displayed slow growth owing to the deletion of a single gene. Compensatory evolution following gene loss was rapid and pervasive: 68% of the genotypes reached near wild-type fitness through accumulation of adaptive mutations elsewhere in the genome. As compensatory mutations have associated fitness costs, genotypes with especially low fitnesses were more likely to be subjects of compensatory evolution. Genomic analysis revealed that as compensatory mutations were generally specific to the functional defect incurred, convergent evolution at the molecular level was extremely rare. Moreover, the majority of the gene expression changes due to gene deletion remained unrestored. Accordingly, compensatory evolution promoted genomic divergence of parallel evolving populations. However, these different evolutionary outcomes are not phenotypically equivalent, as they generated diverse growth phenotypes across environments. Taken together, these results indicate that gene loss initiates adaptive genomic changes that rapidly restores fitness, but this process has substantial pleiotropic effects on cellular physiology and evolvability upon environmental change. Our work also implies that gene content variation across species could be partly due to the action of compensatory evolution rather than the passive loss of genes.

Description: by Mina Gouti, Anestis Tsakiridis, Filip J. Wymeersch, Yali Huang, Jens Kleinjung, Valerie Wilson, James Briscoe Cells of the spinal cord and somites arise from shared, dual-fated precursors, located towards the posterior of the elongating embryo. Here we show that these neuromesodermal progenitors (NMPs) can readily be generated in vitro from mouse and human pluripotent stem cells by activating Wnt and Fgf signalling, timed to emulate in vivo development. Similar to NMPs in vivo , these cells co-express the neural factor Sox2 and the mesodermal factor Brachyury and differentiate into neural and paraxial mesoderm in vitro and in vivo . The neural cells produced by NMPs have spinal cord but not anterior neural identity and can differentiate into spinal cord motor neurons. This is consistent with the shared origin of spinal cord and somites and the distinct ontogeny of the anterior and posterior nervous system. Systematic analysis of the transcriptome during differentiation identifies the molecular correlates of each of the cell identities and the routes by which they are obtained. Moreover, we take advantage of the system to provide evidence that Brachyury represses neural differentiation and that signals from mesoderm are not necessary to induce the posterior identity of spinal cord cells. This indicates that the mesoderm inducing and posteriorising functions of Wnt signalling represent two molecularly separate activities. Together the data illustrate how reverse engineering normal developmental mechanisms allows the differentiation of specific cell types in vitro and the analysis of previous difficult to access aspects of embryo development.

Description: by Johan J. Bolhuis, Ian Tattersall, Noam Chomsky, Robert C. Berwick The evolution of the faculty of language largely remains an enigma. In this essay, we ask why. Language's evolutionary analysis is complicated because it has no equivalent in any nonhuman species. There is also no consensus regarding the essential nature of the language “phenotype.” According to the “Strong Minimalist Thesis,” the key distinguishing feature of language (and what evolutionary theory must explain) is hierarchical syntactic structure. The faculty of language is likely to have emerged quite recently in evolutionary terms, some 70,000–100,000 years ago, and does not seem to have undergone modification since then, though individual languages do of course change over time, operating within this basic framework. The recent emergence of language and its stability are both consistent with the Strong Minimalist Thesis, which has at its core a single repeatable operation that takes exactly two syntactic elements a and b and assembles them to form the set {a, b}.

Description: by Sara M. Szczepanski, Nathan E. Crone, Rachel A. Kuperman, Kurtis I. Auguste, Josef Parvizi, Robert T. Knight Attention is a core cognitive mechanism that allows the brain to allocate limited resources depending on current task demands. A number of frontal and posterior parietal cortical areas, referred to collectively as the fronto-parietal attentional control network, are engaged during attentional allocation in both humans and non-human primates. Numerous studies have examined this network in the human brain using various neuroimaging and scalp electrophysiological techniques. However, little is known about how these frontal and parietal areas interact dynamically to produce behavior on a fine temporal (sub-second) and spatial (sub-centimeter) scale. We addressed how human fronto-parietal regions control visuospatial attention on a fine spatiotemporal scale by recording electrocorticography (ECoG) signals measured directly from subdural electrode arrays that were implanted in patients undergoing intracranial monitoring for localization of epileptic foci. Subjects ( n  = 8) performed a spatial-cuing task, in which they allocated visuospatial attention to either the right or left visual field and detected the appearance of a target. We found increases in high gamma (HG) power (70–250 Hz) time-locked to trial onset that remained elevated throughout the attentional allocation period over frontal, parietal, and visual areas. These HG power increases were modulated by the phase of the ongoing delta/theta (2–5 Hz) oscillation during attentional allocation. Critically, we found that the strength of this delta/theta phase-HG amplitude coupling predicted reaction times to detected targets on a trial-by-trial basis. These results highlight the role of delta/theta phase-HG amplitude coupling as a mechanism for sub-second facilitation and coordination within human fronto-parietal cortex that is guided by momentary attentional demands.

Description: by The PLOS BIOLOGY Staff

Description: by Cody J. Smith, Angela D. Morris, Taylor G. Welsh, Sarah Kucenas Rapid conduction of action potentials along motor axons requires that oligodendrocytes and Schwann cells myelinate distinct central and peripheral nervous system (CNS and PNS) domains along the same axon. Despite the importance of this arrangement for nervous system function, the mechanisms that establish and maintain this precise glial segregation at the motor exit point (MEP) transition zone are unknown. Using in vivo time-lapse imaging in zebrafish, we observed that prior to myelination, oligodendrocyte progenitor cells (OPCs) extend processes into the periphery via the MEP and immediately upon contact with spinal motor root glia retract back into the spinal cord. Characterization of the peripheral cell responsible for repelling OPC processes revealed that it was a novel, CNS-derived population of glia we propose calling MEP glia. Ablation of MEP glia resulted in the absence of myelinating glia along spinal motor root axons and an immediate breach of the MEP by OPCs. Taken together, our results identify a novel population of CNS-derived peripheral glia located at the MEP that selectively restrict the migration of OPCs into the periphery via contact-mediated inhibition.

Description: by Adam Dinsmore, Liz Allen, Kevin Dolby

Description: by Manuel Gomez-Ramirez, Natalie K. Trzcinski, Stefan Mihalas, Ernst Niebur, Steven S. Hsiao Studies in vision show that attention enhances the firing rates of cells when it is directed towards their preferred stimulus feature. However, it is unknown whether other sensory systems employ this mechanism to mediate feature selection within their modalities. Moreover, whether feature-based attention modulates the correlated activity of a population is unclear. Indeed, temporal correlation codes such as spike-synchrony and spike-count correlations (r sc ) are believed to play a role in stimulus selection by increasing the signal and reducing the noise in a population, respectively. Here, we investigate (1) whether feature-based attention biases the correlated activity between neurons when attention is directed towards their common preferred feature, (2) the interplay between spike-synchrony and r sc during feature selection, and (3) whether feature attention effects are common across the visual and tactile systems. Single-unit recordings were made in secondary somatosensory cortex of three non-human primates while animals engaged in tactile feature (orientation and frequency) and visual discrimination tasks. We found that both firing rate and spike-synchrony between neurons with similar feature selectivity were enhanced when attention was directed towards their preferred feature. However, attention effects on spike-synchrony were twice as large as those on firing rate, and had a tighter relationship with behavioral performance. Further, we observed increased r sc when attention was directed towards the visual modality (i.e., away from touch). These data suggest that similar feature selection mechanisms are employed in vision and touch, and that temporal correlation codes such as spike-synchrony play a role in mediating feature selection. We posit that feature-based selection operates by implementing multiple mechanisms that reduce the overall noise levels in the neural population and synchronize activity across subpopulations that encode the relevant features of sensory stimuli.

Description: by Roland G. Roberts

Description: by Guilherme Testa-Silva, Matthijs B. Verhoog, Daniele Linaro, Christiaan P. J. de Kock, Johannes C. Baayen, Rhiannon M. Meredith, Chris I. De Zeeuw, Michele Giugliano, Huibert D. Mansvelder Neuronal firing, synaptic transmission, and its plasticity form the building blocks for processing and storage of information in the brain. It is unknown whether adult human synapses are more efficient in transferring information between neurons than rodent synapses. To test this, we recorded from connected pairs of pyramidal neurons in acute brain slices of adult human and mouse temporal cortex and probed the dynamical properties of use-dependent plasticity. We found that human synaptic connections were purely depressing and that they recovered three to four times more swiftly from depression than synapses in rodent neocortex. Thereby, during realistic spike trains, the temporal resolution of synaptic information exchange in human synapses substantially surpasses that in mice. Using information theory, we calculate that information transfer between human pyramidal neurons exceeds that of mouse pyramidal neurons by four to nine times, well into the beta and gamma frequency range. In addition, we found that human principal cells tracked fine temporal features, conveyed in received synaptic inputs, at a wider bandwidth than for rodents. Action potential firing probability was reliably phase-locked to input transients up to 1,000 cycles/s because of a steep onset of action potentials in human pyramidal neurons during spike trains, unlike in rodent neurons. Our data show that, in contrast to the widely held views of limited information transfer in rodent depressing synapses, fast recovering synapses of human neurons can actually transfer substantial amounts of information during spike trains. In addition, human pyramidal neurons are equipped to encode high synaptic information content. Thus, adult human cortical microcircuits relay information at a wider bandwidth than rodent microcircuits.

Description: by Johnna Doherty, Amy E. Sheehan, Rachel Bradshaw, A. Nicole Fox, Tsai-Yi Lu, Marc R. Freeman Glial cells are exquisitely sensitive to neuronal injury but mechanisms by which glia establish competence to respond to injury, continuously gauge neuronal health, and rapidly activate reactive responses remain poorly defined. Here, we show glial PI3K signaling in the uninjured brain regulates baseline levels of Draper, a receptor essential for Drosophila glia to sense and respond to axonal injury. After injury, Draper levels are up-regulated through a Stat92E-modulated, injury-responsive enhancer element within the draper gene. Surprisingly, canonical JAK/STAT signaling does not regulate draper expression. Rather, we find injury-induced draper activation is downstream of the Draper/Src42a/Shark/Rac1 engulfment signaling pathway. Thus, PI3K signaling and Stat92E are critical in vivo regulators of glial responsiveness to axonal injury. We provide evidence for a positive auto-regulatory mechanism whereby signaling through the injury-responsive Draper receptor leads to Stat92E-dependent, transcriptional activation of the draper gene. We propose that Drosophila glia use this auto-regulatory loop as a mechanism to adjust their reactive state following injury.

Description: by Benjamin A. Gilston, Suning Wang, Mason D. Marcus, Mónica A. Canalizo-Hernández, Elden P. Swindell, Yi Xue, Alfonso Mondragón, Thomas V. O'Halloran Commensal microbes, whether they are beneficial or pathogenic, are sensitive to host processes that starve or swamp the prokaryote with large fluctuations in local zinc concentration. To understand how microorganisms coordinate a dynamic response to changes in zinc availability at the molecular level, we evaluated the molecular mechanism of the zinc-sensing zinc uptake regulator (Zur) protein at each of the known Zur-regulated genes in Escherichia coli . We solved the structure of zinc-loaded Zur bound to the P znuABC promoter and show that this metalloregulatory protein represses gene expression by a highly cooperative binding of two adjacent dimers to essentially encircle the core element of each of the Zur-regulated promoters. Cooperativity in these protein-DNA interactions requires a pair of asymmetric salt bridges between Arg52 and Asp49′ that connect otherwise independent dimers. Analysis of the protein-DNA interface led to the discovery of a new member of the Zur-regulon: pliG . We demonstrate this gene is directly regulated by Zur in a zinc responsive manner. The pliG promoter forms stable complexes with either one or two Zur dimers with significantly less protein-DNA cooperativity than observed at other Zur regulon promoters. Comparison of the in vitro Zur-DNA binding affinity at each of four Zur-regulon promoters reveals ca. 10,000-fold variation Zur-DNA binding constants. The degree of Zur repression observed in vivo by comparison of transcript copy number in wild-type and Δ zur strains parallels this trend spanning a 100-fold difference. We conclude that the number of ferric uptake regulator (Fur)-family dimers that bind within any given promoter varies significantly and that the thermodynamic profile of the Zur-DNA interactions directly correlates with the physiological response at different promoters.

Description: by Ariel D. Chipman, David E. K. Ferrier, Carlo Brena, Jiaxin Qu, Daniel S. T. Hughes, Reinhard Schröder, Montserrat Torres-Oliva, Nadia Znassi, Huaiyang Jiang, Francisca C. Almeida, Claudio R. Alonso, Zivkos Apostolou, Peshtewani Aqrawi, Wallace Arthur, Jennifer C. J. Barna, Kerstin P. Blankenburg, Daniela Brites, Salvador Capella-Gutiérrez, Marcus Coyle, Peter K. Dearden, Louis Du Pasquier, Elizabeth J. Duncan, Dieter Ebert, Cornelius Eibner, Galina Erikson, Peter D. Evans, Cassandra G. Extavour, Liezl Francisco, Toni Gabaldón, William J. Gillis, Elizabeth A. Goodwin-Horn, Jack E. Green, Sam Griffiths-Jones, Cornelis J. P. Grimmelikhuijzen, Sai Gubbala, Roderic Guigó, Yi Han, Frank Hauser, Paul Havlak, Luke Hayden, Sophie Helbing, Michael Holder, Jerome H. L. Hui, Julia P. Hunn, Vera S. Hunnekuhl, LaRonda Jackson, Mehwish Javaid, Shalini N. Jhangiani, Francis M. Jiggins, Tamsin E. Jones, Tobias S. Kaiser, Divya Kalra, Nathan J. Kenny, Viktoriya Korchina, Christie L. Kovar, F. Bernhard Kraus, François Lapraz, Sandra L. Lee, Jie Lv, Christigale Mandapat, Gerard Manning, Marco Mariotti, Robert Mata, Tittu Mathew, Tobias Neumann, Irene Newsham, Dinh N. Ngo, Maria Ninova, Geoffrey Okwuonu, Fiona Ongeri, William J. Palmer, Shobha Patil, Pedro Patraquim, Christopher Pham, Ling-Ling Pu, Nicholas H. Putman, Catherine Rabouille, Olivia Mendivil Ramos, Adelaide C. Rhodes, Helen E. Robertson, Hugh M. Robertson, Matthew Ronshaugen, Julio Rozas, Nehad Saada, Alejandro Sánchez-Gracia, Steven E. Scherer, Andrew M. Schurko, Kenneth W. Siggens, DeNard Simmons, Anna Stief, Eckart Stolle, Maximilian J. Telford, Kristin Tessmar-Raible, Rebecca Thornton, Maurijn van der Zee, Arndt von Haeseler, James M. Williams, Judith H. Willis, Yuanqing Wu, Xiaoyan Zou, Daniel Lawson, Donna M. Muzny, Kim C. Worley, Richard A. Gibbs, Michael Akam, Stephen Richards Myriapods (e.g., centipedes and millipedes) display a simple homonomous body plan relative to other arthropods. All members of the class are terrestrial, but they attained terrestriality independently of insects. Myriapoda is the only arthropod class not represented by a sequenced genome. We present an analysis of the genome of the centipede Strigamia maritima . It retains a compact genome that has undergone less gene loss and shuffling than previously sequenced arthropods, and many orthologues of genes conserved from the bilaterian ancestor that have been lost in insects. Our analysis locates many genes in conserved macro-synteny contexts, and many small-scale examples of gene clustering. We describe several examples where S. maritima shows different solutions from insects to similar problems. The insect olfactory receptor gene family is absent from S. maritima , and olfaction in air is likely effected by expansion of other receptor gene families. For some genes S. maritima has evolved paralogues to generate coding sequence diversity, where insects use alternate splicing. This is most striking for the Dscam gene, which in Drosophila generates more than 100,000 alternate splice forms, but in S. maritima is encoded by over 100 paralogues. We see an intriguing linkage between the absence of any known photosensory proteins in a blind organism and the additional absence of canonical circadian clock genes. The phylogenetic position of myriapods allows us to identify where in arthropod phylogeny several particular molecular mechanisms and traits emerged. For example, we conclude that juvenile hormone signalling evolved with the emergence of the exoskeleton in the arthropods and that RR-1 containing cuticle proteins evolved in the lineage leading to Mandibulata. We also identify when various gene expansions and losses occurred. The genome of S. maritima offers us a unique glimpse into the ancestral arthropod genome, while also displaying many adaptations to its specific life history.

Description: by David Gurwitz, Elena Milanesi, Thomas Koenig

Description: by Dai-Yin Chao, Yi Chen, Jiugeng Chen, Shulin Shi, Ziru Chen, Chengcheng Wang, John M. Danku, Fang-Jie Zhao, David E. Salt Inorganic arsenic is a carcinogen, and its ingestion through foods such as rice presents a significant risk to human health. Plants chemically reduce arsenate to arsenite. Using genome-wide association (GWA) mapping of loci controlling natural variation in arsenic accumulation in Arabidopsis thaliana allowed us to identify the arsenate reductase required for this reduction, which we named High Arsenic Content 1 (HAC1). Complementation verified the identity of HAC1 , and expression in Escherichia coli lacking a functional arsenate reductase confirmed the arsenate reductase activity of HAC1. The HAC1 protein accumulates in the epidermis, the outer cell layer of the root, and also in the pericycle cells surrounding the central vascular tissue. Plants lacking HAC1 lose their ability to efflux arsenite from roots, leading to both increased transport of arsenic into the central vascular tissue and on into the shoot. HAC1 therefore functions to reduce arsenate to arsenite in the outer cell layer of the root, facilitating efflux of arsenic as arsenite back into the soil to limit both its accumulation in the root and transport to the shoot. Arsenate reduction by HAC1 in the pericycle may play a role in limiting arsenic loading into the xylem. Loss of HAC1 -encoded arsenic reduction leads to a significant increase in arsenic accumulation in shoots, causing an increased sensitivity to arsenate toxicity. We also confirmed the previous observation that the ACR2 arsenate reductase in A. thaliana plays no detectable role in arsenic metabolism. Furthermore, ACR2 does not interact epistatically with HAC1 , since arsenic metabolism in the acr2 hac1 double mutant is disrupted in an identical manner to that described for the hac1 single mutant. Our identification of HAC1 and its associated natural variation provides an important new resource for the development of low arsenic-containing food such as rice.

Description: by Aditya Saxena, Barry Denholm, Stephanie Bunt, Marcus Bischoff, Krishnaswamy VijayRaghavan, Helen Skaer Most epithelial tubes arise as small buds and elongate by regulated morphogenetic processes including oriented cell division, cell rearrangements, and changes in cell shape. Through live analysis of Drosophila renal tubule morphogenesis we show that tissue elongation results from polarised cell intercalations around the tubule circumference, producing convergent-extension tissue movements. Using genetic techniques, we demonstrate that the vector of cell movement is regulated by localised epidermal growth factor (EGF) signalling from the distally placed tip cell lineage, which sets up a distal-to-proximal gradient of pathway activation to planar polarise cells, without the involvement for PCP gene activity. Time-lapse imaging at subcellular resolution shows that the acquisition of planar polarity leads to asymmetric pulsatile Myosin II accumulation in the basal, proximal cortex of tubule cells, resulting in repeated, transient shortening of their circumferential length. This repeated bias in the polarity of cell contraction allows cells to move relative to each other, leading to a reduction in cell number around the lumen and an increase in tubule length. Physiological analysis demonstrates that animals whose tubules fail to elongate exhibit abnormal excretory function, defective osmoregulation, and lethality.

Description: by Kurt Vermeire, Thomas W. Bell, Victor Van Puyenbroeck, Anne Giraut, Sam Noppen, Sandra Liekens, Dominique Schols, Enno Hartmann, Kai-Uwe Kalies, Mark Marsh In eukaryotic cells, surface expression of most type I transmembrane proteins requires translation and simultaneous insertion of the precursor protein into the endoplasmic reticulum (ER) membrane for subsequent routing to the cell surface. This co-translational translocation pathway is initiated when a hydrophobic N-terminal signal peptide (SP) on the nascent protein emerges from the ribosome, binds the cytosolic signal recognition particle (SRP), and targets the ribosome-nascent chain complex to the Sec61 translocon, a universally conserved protein-conducting channel in the ER-membrane. Despite their common function in Sec61 targeting and ER translocation, SPs have diverse but unique primary sequences. Thus, drugs that recognise SPs could be exploited to inhibit translocation of specific proteins into the ER. Here, through flow cytometric analysis the small-molecule macrocycle cyclotriazadisulfonamide (CADA) is identified as a highly selective human CD4 (hCD4) down-modulator. We show that CADA inhibits CD4 biogenesis and that this is due to its ability to inhibit co-translational translocation of CD4 into the lumen of the ER, both in cells as in a cell-free in vitro translation/translocation system. The activity of CADA maps to the cleavable N-terminal SP of hCD4. Moreover, through surface plasmon resonance analysis we were able to show direct binding of CADA to the SP of hCD4 and identify this SP as the target of our drug. Furthermore, CADA locks the SP in the translocon during a post-targeting step, possibly in a folded state, and prevents the translocation of the associated protein into the ER lumen. Instead, the precursor protein is routed to the cytosol for degradation. These findings demonstrate that a synthetic, cell-permeable small-molecule can be developed as a SP-binding drug to selectively inhibit protein translocation and to reversibly regulate the expression of specific target proteins.

Description: by Robin Meadows

Description: by Amanda V. Utevsky, Michael L. Platt Social hierarchy is a fact of life for many animals. Navigating social hierarchy requires understanding one's own status relative to others and behaving accordingly, while achieving higher status may call upon cunning and strategic thinking. The neural mechanisms mediating social status have become increasingly well understood in invertebrates and model organisms like fish and mice but until recently have remained more opaque in humans and other primates. In a new study in this issue, Noonan and colleagues explore the neural correlates of social rank in macaques. Using both structural and functional brain imaging, they found neural changes associated with individual monkeys' social status, including alterations in the amygdala, hypothalamus, and brainstem—areas previously implicated in dominance-related behavior in other vertebrates. A separate but related network in the temporal and prefrontal cortex appears to mediate more cognitive aspects of strategic social behavior. These findings begin to delineate the neural circuits that enable us to navigate our own social worlds. A major remaining challenge is identifying how these networks contribute functionally to our social lives, which may open new avenues for developing innovative treatments for social disorders.

Description: by Bill Sugden

Description: by Roland G. Roberts

Description: by Philippe Remigi, Delphine Capela, Camille Clerissi, Léna Tasse, Rachel Torchet, Olivier Bouchez, Jacques Batut, Stéphane Cruveiller, Eduardo P. C. Rocha, Catherine Masson-Boivin Horizontal gene transfer (HGT) is an important mode of adaptation and diversification of prokaryotes and eukaryotes and a major event underlying the emergence of bacterial pathogens and mutualists. Yet it remains unclear how complex phenotypic traits such as the ability to fix nitrogen with legumes have successfully spread over large phylogenetic distances. Here we show, using experimental evolution coupled with whole genome sequencing, that co-transfer of imuABC error-prone DNA polymerase genes with key symbiotic genes accelerates the evolution of a soil bacterium into a legume symbiont. Following introduction of the symbiotic plasmid of Cupriavidus taiwanensis , the Mimosa symbiont, into pathogenic Ralstonia solanacearum we challenged transconjugants to become Mimosa symbionts through serial plant-bacteria co-cultures. We demonstrate that a mutagenesis imuABC cassette encoded on the C. taiwanensis symbiotic plasmid triggered a transient hypermutability stage in R. solanacearum transconjugants that occurred before the cells entered the plant. The generated burst in genetic diversity accelerated symbiotic adaptation of the recipient genome under plant selection pressure, presumably by improving the exploration of the fitness landscape. Finally, we show that plasmid imuABC cassettes are over-represented in rhizobial lineages harboring symbiotic plasmids. Our findings shed light on a mechanism that may have facilitated the dissemination of symbiotic competency among α- and β-proteobacteria in natura and provide evidence for the positive role of environment-induced mutagenesis in the acquisition of a complex lifestyle trait. We speculate that co-transfer of complex phenotypic traits with mutagenesis determinants might frequently enhance the ecological success of HGT.

Description: by MaryAnn P. Noonan, Jerome Sallet, Rogier B. Mars, Franz X. Neubert, Jill X. O'Reilly, Jesper L. Andersson, Anna S. Mitchell, Andrew H. Bell, Karla L. Miller, Matthew F. S. Rushworth Despite widespread interest in social dominance, little is known of its neural correlates in primates. We hypothesized that social status in primates might be related to individual variation in subcortical brain regions implicated in other aspects of social and emotional behavior in other mammals. To examine this possibility we used magnetic resonance imaging (MRI), which affords the taking of quantitative measurements noninvasively, both of brain structure and of brain function, across many regions simultaneously. We carried out a series of tests of structural and functional MRI (fMRI) data in 25 group-living macaques. First, a deformation-based morphometric (DBM) approach was used to show that gray matter in the amygdala, brainstem in the vicinity of the raphe nucleus, and reticular formation, hypothalamus, and septum/striatum of the left hemisphere was correlated with social status. Second, similar correlations were found in the same areas in the other hemisphere. Third, similar correlations were found in a second data set acquired several months later from a subset of the same animals. Fourth, the strength of coupling between fMRI-measured activity in the same areas was correlated with social status. The network of subcortical areas, however, had no relationship with the sizes of individuals' social networks, suggesting the areas had a simple and direct relationship with social status. By contrast a second circuit in cortex, comprising the midsuperior temporal sulcus and anterior and dorsal prefrontal cortex, covaried with both individuals' social statuses and the social network sizes they experienced. This cortical circuit may be linked to the social cognitive processes that are taxed by life in more complex social networks and that must also be used if an animal is to achieve a high social status.

Description: by Catherine A. Del Vecchio, Yuxiong Feng, Ethan S. Sokol, Erik J. Tillman, Sandhya Sanduja, Ferenc Reinhardt, Piyush B. Gupta Malignant carcinomas that recur following therapy are typically de-differentiated and multidrug resistant (MDR). De-differentiated cancer cells acquire MDR by up-regulating reactive oxygen species (ROS)–scavenging enzymes and drug efflux pumps, but how these genes are up-regulated in response to de-differentiation is not known. Here, we examine this question by using global transcriptional profiling to identify ROS-induced genes that are already up-regulated in de-differentiated cells, even in the absence of oxidative damage. Using this approach, we found that the Nrf2 transcription factor, which is the master regulator of cellular responses to oxidative stress, is preactivated in de-differentiated cells. In de-differentiated cells, Nrf2 is not activated by oxidation but rather through a noncanonical mechanism involving its phosphorylation by the ER membrane kinase PERK. In contrast, differentiated cells require oxidative damage to activate Nrf2. Constitutive PERK-Nrf2 signaling protects de-differentiated cells from chemotherapy by reducing ROS levels and increasing drug efflux. These findings are validated in therapy-resistant basal breast cancer cell lines and animal models, where inhibition of the PERK-Nrf2 signaling axis reversed the MDR of de-differentiated cancer cells. Additionally, analysis of patient tumor datasets showed that a PERK pathway signature correlates strongly with chemotherapy resistance, tumor grade, and overall survival. Collectively, these results indicate that de-differentiated cells up-regulate MDR genes via PERK-Nrf2 signaling and suggest that targeting this pathway could sensitize drug-resistant cells to chemotherapy.

Description: by Jia-Min Zhang, Xiao-Man Liu, Yue-He Ding, Liang-Yao Xiong, Jing-Yi Ren, Zhi-Xiong Zhou, Hai-Tao Wang, Mei-Jun Zhang, Yang Yu, Meng-Qiu Dong, Li-Lin Du Structure-specific nucleases play crucial roles in many DNA repair pathways. They must be precisely controlled to ensure optimal repair outcomes; however, mechanisms of their regulation are not fully understood. Here, we report a fission yeast protein, Pxd1, that binds to and regulates two structure-specific nucleases: Rad16 XPF -Swi10 ERCC1 and Dna2-Cdc24. Strikingly, Pxd1 influences the activities of these two nucleases in opposite ways: It activates the 3′ endonuclease activity of Rad16-Swi10 but inhibits the RPA-mediated activation of the 5′ endonuclease activity of Dna2. Pxd1 is required for Rad16-Swi10 to function in single-strand annealing, mating-type switching, and the removal of Top1-DNA adducts. Meanwhile, Pxd1 attenuates DNA end resection mediated by the Rqh1-Dna2 pathway. Disabling the Dna2-inhibitory activity of Pxd1 results in enhanced use of a break-distal repeat sequence in single-strand annealing and a greater loss of genetic information. We propose that Pxd1 promotes proper DNA repair by differentially regulating two structure-specific nucleases.

Description: by Federico M. Lauro, Svend Jacob Senstius, Jay Cullen, Russell Neches, Rachelle M. Jensen, Mark V. Brown, Aaron E. Darling, Michael Givskov, Diane McDougald, Ron Hoeke, Martin Ostrowski, Gayle K. Philip, Ian T. Paulsen, Joseph J. Grzymski

Description: by Tun Li, Cuiping Tian, Paolo Scalmani, Carolina Frassoni, Massimo Mantegazza, Yonghong Wang, Mingpo Yang, Si Wu, Yousheng Shu Action potential (AP) generation in inhibitory interneurons is critical for cortical excitation-inhibition balance and information processing. However, it remains unclear what determines AP initiation in different interneurons. We focused on two predominant interneuron types in neocortex: parvalbumin (PV)- and somatostatin (SST)-expressing neurons. Patch-clamp recording from mouse prefrontal cortical slices showed that axonal but not somatic Na + channels exhibit different voltage-dependent properties. The minimal activation voltage of axonal channels in SST was substantially higher (∼7 mV) than in PV cells, consistent with differences in AP thresholds. A more mixed distribution of high- and low-threshold channel subtypes at the axon initial segment (AIS) of SST cells may lead to these differences. Surprisingly, Na V 1.2 was found accumulated at AIS of SST but not PV cells; reducing Na V 1.2-mediated currents in interneurons promoted recurrent network activity. Together, our results reveal the molecular identity of axonal Na + channels in interneurons and their contribution to AP generation and regulation of network activity.

Description: by Richard Robinson

Description: by Paloma M. Sato, Kogulan Yoganathan, Jae H. Jung, Sergio G. Peisajovich The rearrangement of protein domains is known to have key roles in the evolution of signaling networks and, consequently, is a major tool used to synthetically rewire networks. However, natural mutational events leading to the creation of proteins with novel domain combinations, such as in frame fusions followed by domain loss, retrotranspositions, or translocations, to name a few, often simultaneously replace pre-existing genes. Thus, while proteins with new domain combinations may establish novel network connections, it is not clear how the concomitant deletions are tolerated. We investigated the mechanisms that enable signaling networks to tolerate domain rearrangement-mediated gene replacements. Using as a model system the yeast mitogen activated protein kinase (MAPK)-mediated mating pathway, we analyzed 92 domain-rearrangement events affecting 11 genes. Our results indicate that, while domain rearrangement events that result in the loss of catalytic activities within the signaling complex are not tolerated, domain rearrangements can drastically alter protein interactions without impairing function. This suggests that signaling complexes can maintain function even when some components are recruited to alternative sites within the complex. Furthermore, we also found that the ability of the complex to tolerate changes in interaction partners does not depend on long disordered linkers that often connect domains. Taken together, our results suggest that some signaling complexes are dynamic ensembles with loose spatial constraints that could be easily re-shaped by evolution and, therefore, are ideal targets for cellular engineering.

Description: by John M. Zaborske, Vanessa L. Bauer DuMont, Edward W. J. Wallace, Tao Pan, Charles F. Aquadro, D. Allan Drummond Natural selection favors efficient expression of encoded proteins, but the causes, mechanisms, and fitness consequences of evolved coding changes remain an area of aggressive inquiry. We report a large-scale reversal in the relative translational accuracy of codons across 12 fly species in the Drosophila / Sophophora genus. Because the reversal involves pairs of codons that are read by the same genomically encoded tRNAs, we hypothesize, and show by direct measurement, that a tRNA anticodon modification from guanosine to queuosine has coevolved with these genomic changes. Queuosine modification is present in most organisms but its function remains unclear. Modification levels vary across developmental stages in D. melanogaster , and, consistent with a causal effect, genes maximally expressed at each stage display selection for codons that are most accurate given stage-specific queuosine modification levels. In a kinetic model, the known increased affinity of queuosine-modified tRNA for ribosomes increases the accuracy of cognate codons while reducing the accuracy of near-cognate codons. Levels of queuosine modification in D. melanogaster reflect bioavailability of the precursor queuine, which eukaryotes scavenge from the tRNAs of bacteria and absorb in the gut. These results reveal a strikingly direct mechanism by which recoding of entire genomes results from changes in utilization of a nutrient.

Description: by Richard Robinson

Description: by Claire Tang, Diala Chehayeb, Kyle Srivastava, Ilya Nemenman, Samuel J. Sober Studies of motor control have almost universally examined firing rates to investigate how the brain shapes behavior. In principle, however, neurons could encode information through the precise temporal patterning of their spike trains as well as (or instead of) through their firing rates. Although the importance of spike timing has been demonstrated in sensory systems, it is largely unknown whether timing differences in motor areas could affect behavior. We tested the hypothesis that significant information about trial-by-trial variations in behavior is represented by spike timing in the songbird vocal motor system. We found that neurons in motor cortex convey information via spike timing far more often than via spike rate and that the amount of information conveyed at the millisecond timescale greatly exceeds the information available from spike counts. These results demonstrate that information can be represented by spike timing in motor circuits and suggest that timing variations evoke differences in behavior.

Description: by Maria R. Servedio, Yaniv Brandvain, Sumit Dhole, Courtney L. Fitzpatrick, Emma E. Goldberg, Caitlin A. Stern, Jeremy Van Cleve, D. Justin Yeh

Description: by Janelle Weaver