bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dynamic measurement of cytosolic pH and [NO3-] uncovers the role of the vacuolar transporter AtCLCa in the control of cytosolic pH
Authors: Demes Elsa , Besse Laetitia , Satiat-Jeunemaitre Béatrice , Thomine Sébastien , De Angeli Alexis 
Published: July 2019

AbstractIon transporters are key players of cellular processes. The mechanistic properties of ion transporters have been well elucidated by biophysical methods. Meanwhile the understanding of their exact functions in the whole cell homeostasis is limited by the difficulty to monitor their activity in vivo. The development of biosensors to track subtle changes in intracellular parameters provides an invaluable key to tackle this challenging issue. Here, we adapted the use of a dual biosensor using guard cells as experimental model to visualize the impact on the cytosol of anion transport from intracellular compartments. To image the activity of AtCLCa, a vacuolar NO3-/H+ exchanger regulating stomata aperture in Arabidopsis thaliana, we expressed a genetically encoded biosensor, ClopHensor allowing monitoring the dynamics of cytosolic anion concentration and pH. We first show that ClopHensor is not only a Cl- but also a NO3- sensor. We were then able to unravel and quantify the variations of NO3- and pH in the cytosol. Our data show that AtCLCa activity modifies cytosolic pH and NO3-, demonstrating that the transport activity of a vacuolar exchanger has a profound impact on cytosolic homeostasis. We propose that a major function of this endomembrane transporter is to adjust cytosolic conditions to cellular needs. This opens a novel perspective on the function of intracellular transporters of the CLC family in eukaryotes: not only controlling the intra organelle lumen but also actively modifying cytosolic conditions.SignificanceIntracellular transporters are key actors in cell biological processes. Their disruption causes major physiological defects. The role of intracellular ion transporters is usually seen through an “intra organelle” lens, meanwhile their potential action on cytosolic ion homeostasis is still a black box. The case of a plant CLC is used as a model to uncover the missing link between the regulation of conditions inside the vacuole and inside the cytosol. The development of an original live imaging workflow to simultaneously measure pH and anion dynamics in the cytosol reveals the role of an Arabidopsis thaliana CLC, AtCLCa, in the modification of cytosolic pH. Our data highlight an unsuspected function of endomembrane transporters in the regulation of cytosolic pH.
Meta-analysis of longitudinal epigenome-wide association studies of military cohorts reveals multiple CpG sites associated with post-traumatic stress disorder
Authors: Snijders Clara , Maihofer Adam X. , Ratanatharathorn Andrew , Baker Dewleen G. , Boks Marco P. , Geuze Elbert , Jain Sonia , Kessler Ronald C. , Pishva Ehsan , Risbrough Victoria B. , Stein Murray B. , Ursano Robert J. , Vermetten Eric , Vinkers Christiaan H. ,   PGC PTDS EWAS Consortium, Smith Alicia K. , Uddin Monica , Rutten Bart P. F. , Nievergelt Caroline M. 
Published: July 2019

AbstractBackgroundEpigenetic mechanisms have been suggested to play a role in the development of post-traumatic stress disorder (PTSD). Here, blood-derived DNA methylation data (HumanMethylation450 BeadChip) collected prior to and following combat exposure in three cohorts composed of male military members were combined to assess whether DNA methylation profiles are associated with the development of PTSD.MethodsA total of 123 cases and 143 trauma-exposed controls were included. The Psychiatric Genomics Consortium (PGC) PTSD EWAS QC pipeline was used on all cohorts, and results were combined using a sample size weighted meta-analysis. We first combined two cohorts in a discovery stage (N=126 and 78), sought targeted replication in the third cohort (N=62) and then performed a meta-analysis of all three datasets.ResultsThe discovery stage identified four CpG sites in which, conditional on pre-deployment DNA methylation, post-deployment DNA methylation was associated with PTSD status after adjustment for multiple comparisons. The most significant CpG (p = 1.0 × 10−08) was located on 5q31 and replicated in the third cohort. When combining all cohorts, this intergenic site remained most significant along with two CpGs located in MAD1L1 and HEXDC. Interestingly, the CpG site of MAD1L1 had an underlying single nucleotide polymorphism (SNP) which was located within the same LD block as a recently identified PTSD-associated SNP. Twelve differential methylated regions (DMRs) were also identified, one of which was located in MAD1L1 and four were situated in the human leukocyte antigen (HLA) region.ConclusionThis study suggests that the development of PTSD is associated with distinct methylation patterns in several genomic positions and regions. Our most prominent finding points to the involvement of MAD1L1 which was previously associated with PTSD.
Integrating memories: Congruency and reactivation aid memory integration through reinstatement of prior knowledge
Authors: van Kesteren Marlieke T.R. , Rignanese Paul , Gianferrara Pierre G. , Krabbendam Lydia , Meeter Martijn 
Published: July 2019

AbstractBuilding consistent knowledge schemas that organize information and guide future learning is of great importance in everyday life. Such knowledge building is suggested to occur through reinstatement of prior knowledge during new learning in stimulus-specific brain regions. This process is proposed to yield integration of new with old memories, supported by the medial prefrontal cortex (mPFC) and medial temporal lobe (MTL). Possibly as a consequence, congruency of new information with prior knowledge is known to enhance subsequent memory. Yet, it is unknown how reactivation and congruency interact to optimize memory integration processes that lead to knowledge schemas. To investigate this question, we here used an adapted AB-AC inference paradigm in combination with functional Magnetic Resonance Imaging (fMRI). Participants first studied an AB-association followed by an AC-association, so B (a scene) and C (an object) were indirectly linked through their common association with A (an unknown pseudoword). BC-associations were either congruent or incongruent with prior knowledge (e.g. a bathduck or a hammer in a bathroom), and participants were asked to report subjective reactivation strength for B while learning AC. Behaviorally, both the congruency and reactivation measures enhanced memory integration. In the brain, these behavioral effects related to univariate and multivariate parametric effects of congruency and reactivation on activity patterns in the MTL, mPFC, and Parahippocampal Place Area (PPA). Moreover, mPFC exhibited larger connectivity with the PPA for more congruent associations. These outcomes provide insights into the neural mechanisms underlying memory integration enhancement, which can be important for educational learning.Significance statementHow does our brain build knowledge through integrating information that is learned at different periods in time? This question is important in everyday learning situations such as educational settings. Using an inference paradigm, we here set out to investigate how congruency with, and active reactivation of previously learned information affects memory integration processes in the brain. Both these factors were found to relate to activity in memory-related regions such as the medial prefrontal cortex (mPFC) and the hippocampus. Moreover, activity in the parahippocampal place area (PPA), assumed to reflect reinstatement of the previously learned associate, was found to predict subjective reactivation strength. These results show how we can moderate memory integration processes to enhance subsequent knowledge building.
The neural bases of resilient cognitive systems: Evidence of variable neuro-displacement in the semantic system
Authors: Jung JeYoung , Rice Grace E. , Lambon Ralph Matthew A. 
Published: July 2019

AbstractThe purpose of this study was to initiate exploration of an equally-important research goal: what are the neurocomputational mechanisms that make these cognitive systems “well engineered” and thus resilient across a range of performance demands and to mild levels of perturbation or even damage? We achieved this aim by investigating the neural dynamics of the semantic network with two task difficulty manipulations. We found that intrinsic resilience-related mechanisms were observed in both the domain-specific semantic representational system and the parallel executive control networks. Functional connectivity between these regions was also increased and these increases were related to better semantic task performance. Our results suggest that higher cognitive functions are made resilient by flexible, dynamic changes (variable neuro-displacement) across both domain-specific and multi-demand networks. Our findings provide strong evidence that the compensatory functional alterations in the impaired brain might reflect intrinsic mechanisms of a well-engineered neural system.
The Embodied Nature of Well-Timed Behavior
Authors: Safaie Mostafa , Jurado-Parras Maria-Teresa , Sarno Stefania , Louis Jordane , Karoutchi Corane , Petit Ludovic F. , Pasquet Matthieu O. , Eloy Christophe , Robbe David 
Published: July 2019

AbstractHow animals adapt their movements to take advantage of behaviorally-relevant time intervals is not well understood, especially in the supra-second timescale. It has been proposed that motor timing depends on the emergence of self-sustained dynamics across ensembles of neurons. Alternatively, evidence from operant conditioning suggests that animals can develop motor routines to adapt their behavior to fixed temporal constraints. But it is unclear whether animals can accurately time their behavior without the help of motor routines. To address this issue, we used a task in which rats, freely moving on a motorized treadmill, could obtain a reward if they approached it after a fixed interval. Most animals took advantage of the treadmill length and its moving direction to develop, by trial-and-error, a unique motor routine whose execution resulted in the precise timing of their reward approaches. Noticeably, when proficient animals occasionally failed to follow this routine, the timing of their reward approaches was systematically poor. In a second step, we trained naive animals in modified versions of the task specifically designed to prevent the development of this motor strategy. Compared to rats trained in the first protocol, these animals never reached a comparable level of timing accuracy. We conclude that motor timing critically depends on the ability of animals to develop motor routines adapted to the structure of their environment. Our work also suggests that self-sustained neuronal activity alone may not be sufficient to support motor timing, at least in the supra-second timescale.
Post-learning replay of hippocampal-striatal activity is biased by reward-prediction errors
Authors: Roscow Emma L. , Howe Timothy , Lepora Nathan F. , Jones Matthew W. 
Published: July 2019

AbstractNeural activity encoding recent experiences is replayed during sleep and rest to promote consolidation of memories. However, precisely which features of experience influence replay prioritisation to optimise adaptive behaviour remains unclear. Here, we trained adult male rats on a novel maze-based reinforcement learning task designed to dissociate reward outcomes from reward-prediction errors. Four variations of a reinforcement learning model were fitted to the rats’ behaviour over multiple days. Behaviour was best predicted by a model incorporating replay biased by reward-prediction error, compared to the same model with no replay, random replay or reward-biased replay. Neural population recordings from the hippocampus and ventral striatum of rats trained in the task evidenced preferential reactivation of reward-prediction signals during post-task rest. These insights disentangle the influences of salience on replay, suggesting that reinforcement learning is tuned by post-learning replay biased by reward-prediction error, not by reward per se. This work therefore provides a behavioural and theoretical toolkit with which to measure and interpret the neural mechanisms linking replay and reinforcement learning.
Anisotropic ESCRT-III architecture governs helical membrane tube formation
Authors: von Filseck Joachim Moser , Barberi Luca , Talledge Nathaniel , Johnson Isabel , Frost Adam , Lenz Martin , Roux Aurélien 
Published: July 2019

AbstractESCRT-III proteins assemble into ubiquitous membrane-remodeling polymers during many cellular processes. Here we describe the structure of helical membrane tubes that are scaffolded by bundled ESCRT-III filaments. Cryo-ET reveals how the shape of the helical membrane tube arises from the assembly of distinct bundles of protein filaments that bind the membrane with different mean curvatures. Cryo-EM reveals how one of these ESCRT-III filaments engages the membrane tube through a novel interface. Mathematical modeling of the helical membrane tube suggests how its shape emerges from differences in membrane binding energy, positional rigidity, and membrane tension. Altogether, our findings support a model in which increasing the rigidity of ESCRT-III filaments through the assembly of multi-strands triggers buckling of the membrane.One Sentence SummaryESCRT-III heteropolymers deform membranes into helical tubes.
Distinct roles for innexin gap junctions and hemichannels in mechanosensation
Authors: Walker Denise S. , Schafer William R. 
Published: July 2019

AbstractMechanosensation is central to a wide range of functions, including tactile and pain perception, hearing, proprioception, and control of blood pressure, but identifying the molecules underlying mechanotransduction has proved challenging. In Caenorhabditis elegans, the avoidance response to gentle body touch is mediated by 6 touch receptor neurons (TRNs), and is dependent on MEC-4, a DEG/ENaC channel. We show that hemichannels containing the innexin protein UNC-7 are also essential for gentle touch in the TRNs, as well as harsh touch in both the TRNs and the PVD nociceptors. UNC-7 and MEC-4 do not colocalize, suggesting that their roles in mechanosensory transduction are independent. Heterologous expression of unc-7 in touch-insensitive chemosensory neurons confers ectopic touch sensitivity, indicating a direct role for UNC-7 hemichannels in mechanosensation. The unc-7 touch defect can be rescued by the homologous mouse gene Panx1 gene, thus, innexin/pannexin proteins may play broadly conserved roles in neuronal mechanotransduction.
The 20S proteasome activator PA28γ controls the compaction of chromatin
Authors: Fesquet Didier , Llères David , Grimaud Charlotte , Viganò Cristina , Méchali Francisca , Boulon Séverine , Coux Olivier , Bonne-Andrea Catherine , Baldin Véronique 
Published: July 2019

AbstractPA28γ, a nuclear activator of the 20S proteasome, is involved in the degradation of several proteins regulating cell growth and proliferation and in the dynamics of various nuclear bodies, but its precise cellular functions remain unclear. Here, using a quantitative FLIM-FRET based microscopy assay monitoring close proximity between nucleosomes in living human cells, we show that PA28γ controls chromatin compaction. We find that its depletion induces a decompaction of pericentromeric heterochromatin, similarly to that observed upon the knockdown of HP1β, a key factor in heterochromatin structure. We show that PA28γ is present at HP1β-containing repetitive-DNA sequences abundant in heterochromatin and importantly, that HP1β on its own is unable to drive chromatin compaction without the presence of PA28γ. At the molecular level, we show that this novel function of PA28γ is independent of its stable interaction with the 20S proteasome, and most likely depends on its ability to maintain appropriate levels of H3K9me3 and H4K20me3, histone modifications that are both involved in heterochromatin formation. Overall, our results implicate PA28γ as a key factor involved in the higher order structuration of chromatin.
Balanced polymorphism at the Pgm-1 locus of the Pompeii worm Alvinella pompejana and its variant adaptability is only governed by two QE mutations at linked sites
Authors: Alexis Bioy , Anne-Sophie Le Port , Emeline Sabourin , Marie Verheye , Patrice Piccino , Baptiste Faure , Stéphane Hourdez , Jean Mary , Didier Jollivet 
Published: July 2019

AbstractThe polychaete Alvinella pompejana lives exclusively on the walls of deep-sea hydrothermal chimneys along the East Pacific Rise and, display specific adaptations to withstand high temperature and hypoxia associated with this highly variable habitat. Previous studies revealed the existence of a balanced polymorphism on the enzyme phosphoglucomutase associated with thermal variations where allozymes 90 and 100 exhibited different optimal activities and thermostabilities. The exploration of the mutational landscape of the phosphoglucomutase1 revealed the maintenance of four highly divergent allelic lineages encoding the three most frequent electromorphs over the worm’s geographic range. This polymorphism is only governed by two linked amino-acid replacements located in exon 3 (E155Q and E190Q). A two-niches model of selection with ‘cold’ and ‘hot’ conditions represents the most likely way for the long-term persistence of these isoforms. Using directed mutagenesis, overexpression of the three recombinant variants allowed us to test the additive effect of these two mutations on the biochemical properties of this enzyme. Results are coherent with those previously obtained from native proteins and reveal a thermodynamic trade-off between the protein thermostability and catalysis, which is likely to have maintained these functional phenotypes prior to the geographic separation of populations across the Equator, about 1.2 Mya.
Leveraging biobank-scale rare and common variant analyses to identify ASPHD1 as the main driver of reproductive traits in the 16p11.2 locus
Authors: Männik Katrin , Arbogast Thomas , Lepamets Maarja , Lepik Kaido , Pellaz Anna , Ademi Herta , Kupchinsky Zachary A , Ellegood Jacob , Attanasio Catia , Messina Andrea , Rotman Samuel , Martin-Brevet Sandra , Dubruc Estelle , Chrast Jacqueline , Lerch Jason P , Qiu Lily R , Laisk Triin ,   The 16p11.2 European Consortium,   The Simons VIP Consortium,   The eQTLGen Consortium, Henkelman R Mark , Jacquemont Sébastien , Herault Yann , Lindgren Cecilia M , Peterson Hedi , Stehle Jean Christophe , Katsanis Nicholas , Kutalik Zoltan , Nef Serge , Draganski Bogdan , Davis Erica E , Mägi Reedik , Reymond Alexandre 
Published: July 2019

AbstractWhereas genome-wide association studies (GWAS) allowed identifying thousands of associations between variants and traits, their success rate in pinpointing causal genes has been disproportionately low. Here, we integrate biobank-scale phenotype data from carriers of a rare copy-number variant (CNV), Mendelian randomization and animal modeling to identify causative genes in a GWAS locus for age at menarche (AaM). We show that the dosage of the 16p11.2 BP4-BP5 interval is correlated positively with AaM in the UK and Estonian biobanks and 16p11.2 clinical cohorts, with a directionally consistent trend for pubertal onset in males. These correlations parallel an increase in reproductive tract disorders in both sexes. In support of these observations, 16p11.2 mouse models display perturbed pubertal onset and structurally altered reproductive organs that track with CNV dose. Further, we report a negative correlation between the 16p11.2 dosage and relative hypothalamic volume in both humans and mice, intimating a perturbation in the gonadotropin-releasing hormone (GnRH) axis. Two independent lines of evidence identified candidate causal genes for AaM; Mendelian randomization and agnostic dosage modulation of each 16p11.2 gene in zebrafish gnrh3:egfp models. ASPHD1, expressed predominantly in brain and pituitary gland, emerged as a major phenotype driver; and it is subject to modulation by KCTD13 to exacerbate GnRH neuron phenotype. Together, our data highlight the power of an interdisciplinary approach to elucidate disease etiologies underlying complex traits.
Extracellular adenosine enhances the ability of PMNs to killStreptococcus pneumoniaeby inhibiting IL-10 production
Authors: Siwapornchai Nalat , Lee James N. , Tchalla Essi Y. I. , Bhalla Manmeet , Yeoh Jun Hui , Roggensack Sara E. , Leong John M. , Bou Ghanem Elsa N. 
Published: July 2019

AbstractPMNs are crucial for initial control ofStreptococcus pneumoniae(pneumococcus) lung infection; however, as the infection progresses their persistence in the lungs becomes detrimental. Here we explored why the anti-microbial efficacy of PMNs declines over the course of infection. We found that the progressive inability of PMNs to control infection correlated with phenotypic differences characterized by a decrease in CD73 expression, an enzyme required for production of extracellular adenosine (EAD). EAD production by CD73 was crucial for the ability of both murine and human PMNs to killS. pneumoniae.In exploring the mechanisms by which CD73 controlled PMN function, we found that CD73 mediated its anti-microbial activity by inhibiting IL-10 production. PMNs from wild type mice did not increase IL-10 production in response toS. pneumoniae,however, CD73-/-PMNs up-regulated IL-10 production upon pneumococcal infectionin vitroand during lung challenge. IL-10 inhibited the ability of wild type PMNs to kill pneumococci. Conversely, blocking IL-10 boosted the bactericidal activity of CD73-/-PMNs as well as host resistance of CD73-/-mice to pneumococcal pneumonia. CD73/IL-10 did not affect apoptosis, bacterial uptake and intracellular killing or production of anti-microbial Neutrophil Elastase and Myeloperoxidase. Rather, inhibition of IL-10 production by CD73 was important for optimal ROS production by PMNs. ROS contributed to PMN anti-microbial function as their removal or detoxification impaired the ability of PMNs to efficiently killS. pneumoniae. This study demonstrates that CD73 controls PMN anti-microbial phenotype duringS. pneumoniaeinfection.