bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hippocampal volume across age: Nomograms derived from over 19,700 people in UK Biobank
Authors: Nobis Lisa , Manohar Sanjay G. , Smith Stephen M. , Alfaro-Almagro Fidel , Jenkinson Mark , Mackay Clare E. , Husain Masud 
Published: March 2019

AbstractMeasurement of hippocampal volume has proven useful to diagnose and track progression in several brain disorders, most notably in Alzheimer’s disease (AD). For example, an objective evaluation of a patient’s hippocampal volume status may provide important information that can assist diagnosis or risk stratification of AD. However, clinicians and researchers require access to age-related normative percentiles to reliably categorise a patient’s hippocampal volume as being pathologically small. Here we analysed effects of age, sex, and hemisphere on the hippocampus and neighbouring temporal lobe volumes, in 19,793 generally healthy participants in the UK Biobank. A key finding of the current study is a significant acceleration in the rate of hippocampal volume loss in middle age, more pronounced in females than in males. In this report, we provide normative values for hippocampal and total grey matter volume as a function of age for reference in clinical and research settings. These normative values may be used in combination with our online, automated percentile estimation tool to provide a rapid, objective evaluation of an individual’s hippocampal volume status. The data provide a large-scale normative database to facilitate easy age-adjusted determination of where an individual hippocampal and temporal lobe volume lies within the normal distribution.
A Cryo-EM Grid Preparation Device for Time-Resolved Structural Studies
Authors: Kontziampasis Dimitrios , Klebl David P. , Iadanza Matthew G. , Scarff Charlotte A. , Kopf Florian , Sobott Frank , Monteiro Diana C.F. , Trebbin Martin , Muench Stephen P. , White Howard D. 
Published: March 2019

AbstractStructural biology generally provides static snapshots of protein conformations that can inform on the functional mechanisms of biological systems. Time-resolved structural biology provides a means to visualise, at near-atomic resolution, the dynamic conformational changes that macromolecules undergo as they function. Recent advances in the resolution obtainable by electron microscopy (EM) and the broad range of samples that can be studied makes it ideally suited to time-resolved studies. Here we describe a cryo-electron microscopy grid preparation device that permits rapid mixing, voltage assisted spraying, and vitrification of samples. We show that the device produces grids of sufficient ice quality to enable data collection from single grids that results in a sub 4 Å reconstruction. Rapid mixing can be achieved by blot and spray or mix and spray approaches with a delay of ~10 ms, providing greater temporal resolution than previously reported approaches.
Optogenetic control of cell morphogenesis on protein micropatterns
Authors: Zieske Katja , Dyche Mullins R 
Published: March 2019

AbstractCell morphogenesis is critical for embryonic development, tissue formation, and wound healing. Our ability to manipulate endogenous mechanisms to control cell shape, however, remains limited. Here we combined surface micropatterning of adhesion molecules with optogenetic activation of intracellular signaling pathways to control the nature and morphology of cellular protrusions. We employed geometry-dependent pre-organization of cytoskeletal structures together with acute activation of signaling pathways that control actin assembly to create a tool capable of generating membrane protrusions at defined cellular locations. Further, we find that the size of microfabricated patterns of adhesion molecules influences the molecular mechanism of cell protrusion: larger patterns enable cells to create actin-filled lamellipodia while smaller patterns promote formation of spherical blebs. Optogenetic perturbation of signaling pathways in these cells changes the size of blebs and convert them into lamellipodia. Our results demonstrate how the coordinated manipulation of adhesion geometry and cytoskeletal dynamics can be used to control membrane protrusion and cell morphogenesis.
Functional RNA Structures in the 3’UTR of Tick-Borne, Insect-Specific and No-Known-Vector Flaviviruses
Authors: Ochsenreiter Roman , Hofacker Ivo L. , Wolfinger Michael T. 
Published: March 2019

AbstractUntranslated regions (UTRs) of flaviviruses contain a large number of RNA structural elements involved in mediating the viral life cycle, including cyclisation, replication, and encapsidation. Here we report on a comparative genomics approach to characterize evolutionarily conserved RNAs in the 3’UTR of tick-borne, insect-specific and no-known-vector flavivirusesin silico. Our data support the wide distribution of previously experimentally characterized exoribonuclease resistant RNAs (xrRNAs) within tick-borne and no-known-vector flaviviruses and provide evidence for the existence of a cascade of duplicated RNA structures within insect-specific flaviviruses. On a broader scale, our findings indicate that viral 3’UTRs represent a flexible scaffold for evolution to come up with novel xrRNAs.
Systems biology of cold adaptation in the polyextremophilic red algaGaldieria sulphuraria
Authors: Rossoni Alessandro W. , Weber Andreas P.M. 
Published: March 2019

AbstractRapid fluctuation of environmental conditions can impose severe stress upon living organisms. Surviving such episodes of stress requires a rapid acclimation response, e.g., by transcriptional and post-transcriptional mechanisms. Persistent change of the environmental context, however, requires longer-term adaptation at the genetic level. Fast-growing unicellular aquatic eukaryotes enable analysis of adaptive responses at the genetic level in a laboratory setting. In this study, we applied continuous cold stress (28°C) to the thermoacidophile red algaG. sulphuraria,which is 14°C below its optimal growth temperature of 42°C. Cold stress was applied for more than 100 generations to identify components that are critical for conferring thermal adaptation. After cold exposure for more than 100 generations, the cold-adapted samples grew ~30% faster than the starting population. Whole-genome sequencing revealed 757 variants located on 429 genes (6.1% of the transcriptome) encoding molecular functions involved in cell cycle regulation, gene regulation, signaling, morphogenesis, microtubule nucleation, and transmembrane transport. CpG islands located in the intergenic region accumulated a significant number of variants, which is likely a sign of epigenetic remodeling. We present 20 candidate genes and three putative cis-regulatory elements with various functions most affected by temperature. Our work shows that natural selection towards temperature tolerance is a complex systems biology problem that involves gradual reprogramming of an intricate gene network and deeply nested regulators.
Multiple elements of addiction vulnerability are independently heritable in rats
Authors: Eid Maya , Pullmann Dominika , Li Hao , Thomas Alen , Jhou Thomas C. 
Published: March 2019

ABSTRACTBackgroundAlthough cocaine is powerfully rewarding, only a fraction of drug-exposed individuals actually transition to become drug-dependent users, possibly due in part to genetic influences, as addictions are among the most heritable of human neuropsychiatric disorders. Consistent with addiction being a complex disorder, prior studies have noted many factors that predict addiction vulnerability, such as drug-induced aversive effects, behavioral responses to novelty, and sensitivity to punishment.MethodsWe tested different inbred strains of rats, as well as selectively bred Sprague-Dawley (SD) or Heterogeneous Stock (HS) rats, on cocaine avoidance, sensitivity to punishment, and locomotor responses to novelty, and calculated heritability estimates of these behaviors. We tested animals on additional control tasks (progressive ratio, shock avoidance) to control for alternate interpretations of addiction-like behaviors.ResultsConditioned avoidance to cocaine varied greatly between individual rats as measured using either the runway operant task or conditioned place aversion (CPA). Cocaine avoidance responded rapidly to selective breeding, yielding heritability estimates of 0.70 and 0.58 in SD and HS rats. Resistance to punishment was also highly heritable in inbred rats (estimated h2= 0.62), and varied independently of cocaine avoidance despite both behaviors being mediated by the RMTg. Furthermore, cocaine avoidance correlated positively with cocaine-induced c-Fos induction in the RMTg, negatively with initial rates of acquisition of intravenous cocaine self-administration, and positively with both cued and cocaine-primed reinstatement.ConclusionsCocaine avoidance and resistance to punishment are strongly and independently heritable behaviors that may both control different aspects of individual propensity to acquire and maintain drug-seeking.
Disentangling presentation and processing times in the brain
Authors: Caplette Laurent , Ince Robin A. A. , Jerbi Karim , Gosselin Frédéric 
Published: March 2019

AbstractVisual object recognition seems to occur almost instantaneously. However, not only does it require hundreds of milliseconds of processing, but our eyes also typically fixate the object for hundreds of milliseconds. Consequently, information reaching our eyes at different moments is processed in the brain together. Moreover, information received at different moments during fixation is likely to be processed differently, notably because different features might be selectively attended at different moments. Here, we introduce a novel reverse correlation paradigm that allows us to uncover with millisecond precision the processing time course of specific information received on the retina at specific moments. Using faces as stimuli, we observed that processing at several electrodes and latencies was different depending on the moment at which information was received. Some of these variations were caused by a disruption occurring 160-200 ms after the face onset, suggesting a role of the N170 ERP component in gating information processing; others hinted at temporal compression and integration mechanisms. Importantly, the observed differences were not explained by simple adaptation or repetition priming, they were modulated by the task, and they were correlated with differences in behavior. These results suggest that top-down routines of information sampling are applied to the continuous visual input, even within a single eye fixation.
NMDA receptors enhance the fidelity of synaptic integration
Authors: Li Chenguang , Gulledge Allan T. 
Published: March 2019

AbstractExcitatory synaptic transmission in many neurons is mediated by two co-expressed ionotropic glutamate receptor subtypes, AMPA and NMDA receptors, that differ in their kinetics, ion-selectivity, and voltage-sensitivity. AMPA receptors have fast kinetics and are voltage-insensitive, while NMDA receptors have slower kinetics and increased conductance at depolarized membrane potentials. Here we report that the voltage-dependency and kinetics of NMDA receptors act synergistically to stabilize synaptic integration of excitatory postsynaptic potentials (EPSPs) across spatial and voltage domains. Simulations of synaptic integration in simplified and morphologically realistic dendritic trees revealed that the combined presence of AMPA and NMDA conductances reduces the variability of somatic responses to spatiotemporal patterns of excitatory synaptic input presented at different initial membrane potentials and/or in different dendritic domains. This moderating effect of the NMDA conductance on synaptic integration was robust across a wide range of AMPA-to-NMDA ratios, and results from synergistic interaction of NMDA kinetics (which reduces variability across membrane potential) and voltage-dependence (which favors stabilization across dendritic location). When combined with AMPA conductance, the NMDA conductance balances voltage- and impedance-dependent changes in synaptic driving force, and distance-dependent attenuation of synaptic potentials arriving at the axon, to increase the fidelity of synaptic integration and EPSP-spike coupling across neuron state (i.e., initial membrane potential) and dendritic location of synaptic input. Thus, synaptic NMDA receptors convey advantages for synaptic integration that are independent of, but fully compatible with, their importance for coincidence detection and synaptic plasticity.Significance StatementGlutamate is an excitatory neurotransmitter that, at many synapses, gates two coexpressed receptor subtypes (AMPA and NMDA receptors). Computational simulations reveal that the combined synaptic presence of AMPA and NMDA receptors reduces variability in synaptic integration in response to identical patterns of synaptic input delivered to different dendritic locations and/or at different initial membrane potentials. This results from synergistic interaction of the slower kinetics and voltage-dependence of NMDA receptors, which combine to enhance synaptic currents when synaptic driving forces are otherwise reduced (e.g., at depolarized membrane potentials or in distal, high-impedance dendrites). By stabilizing synaptic integration across dendritic location and initial membrane potential, NMDA receptors provide advantages independent of, but fully compatible with, their well-known contribution to synaptic plasticity.
Uncovering hypergraphs of cell-cell interaction from single cell RNA-sequencing data
Authors: Tsuyuzaki Koki , Ishii Manabu , Nikaido Itoshi 
Published: March 2019

AbstractComplex biological systems can be described as a multitude of cell-cell interactions (CCIs). Recent single-cell RNA-sequencing technologies have enabled the detection of CCIs and related ligand-receptor (L-R) gene expression simultaneously. However, previous data analysis methods have focused on only one-to-one CCIs between two cell types. To also detect many-to-many CCIs, we proposescTensor, a novel method for extracting representative triadic relationships (hypergraphs), which include (i) ligand-expression, (ii) receptor-expression, and (iii) L-R pairs. When applied to simulated and empirical datasets,scTensorwas able to detect some hypergraphs including paracrine/autocrine CCI patterns, which cannot be detected by previous methods.
Non-responder phenotype reveals microbiome-wide antibiotic resistance in the murine gut
Authors: Diener Christian , Hoge Anna C. H. , Kearney Sean M. , Erdman Susan E. , Gibbons Sean M. 
Published: March 2019

AbstractBroad spectrum antibiotics can cause both transient and lasting damage to the ecology of the gut microbiome. Loss of gut bacterial diversity has been linked to immune dysregulation and disease susceptibility. Antibiotic-resistant populations of cells are known to arise spontaneously in single-strain systems. Furthermore, prior work on subtherapeutic antibiotic treatment in humans and therapeutic treatments in non-human animals have suggested that entire gut communities may exhibit spontaneous resistance phenotypes. In this study, we validate the existence of these community resistance phenotypes in the murine gut and explore how antibiotic duration or diet influence the frequency of this phenotype. We find that almost a third of mice exhibit whole-community resistance to a therapeutic concentration of theβ-lactam antibiotic cefoperazone, independent of antibiotic treatment duration or xenobiotic dietary amendment. These non-responder (i.e. resistant) microbiota were protected from biomass depletion, transient ecological community collapse, and lasting diversity loss seen in the susceptible microbiota. There were no major differences between non-responder microbiota and untreated control microbiota at the community structure level. However, gene expression was vastly different between non-responder microbiota and controls during antibiotic treatment, with non-responder communities showing an upregulation of antimicrobial resistance genes and a down-regulation of central metabolism. Thus, non-responder phenotypes appear to combat antibiotic assault through a combination of efflux transporter upregulation and a reduced growth rate across the entire gut community. Future work should focus on what factors are responsible for tipping entire communities from susceptible to resistant phenotypes so that we might harness this phenomenon to protect our microbiota from exposure to therapeutic antibiotic treatment regimes.
Deconvolving the contributions of cell-type heterogeneity on cortical gene expression
Authors: Patrick Ellis , Taga Mariko , Ergun Ayla , Ng Bernard , Casazza William , Cimpean Maria , Yung Christina , Schneider Julie A , Bennett David A , Gaiteri Chris , Jager Philip L De , Bradshaw Elizabeth M , Mostafavi Sara 
Published: March 2019

AbstractComplexity of cell-type composition has created much skepticism surrounding the interpretation of brain bulk-tissue transcriptomic studies. We generated paired tissue genome-wide gene expression data and immunohistochemistry data, enabling us to assess statistical methods for modeling and estimating cellular heterogeneity in the brain. We demonstrate that several algorithms that rely on single-cell and cell-sorted data to define cell marker gene sets yield accuraterelativeandabsoluteestimates of constituent cell-type proportions.
Testing for correlation between traits under directional evolution
Authors: Royer-Carenzi Manuela , Didier Gilles 
Published: March 2019

AbstractBeing confounding factors, directional trends are likely to make two quantitative traits appear as spuriously correlated. By determining the probability distributions of independent contrasts when traits evolve following Brownian motions with linear trends, we show that the standard independent contrasts can not be used to test for correlation in this situation. We propose a multiple regression approach which corrects the bias caused by directional evolution.We show that our approach is equivalent to performing a Phylogenetic Generalized Least Squares (PGLS) analysis with tip times as covariables by providing a new and more general proof of the equivalence between PGLS and independent contrasts methods.Our approach is assessed and compared with three previous correlation tests on data simulated in various situations and overall outperforms all the other methods. The approach is next illustrated on a real dataset to test for correlation between hominin cranial capacity and body mass.
Nebula: Ultra-efficient mapping-free structural variant genotyper
Authors: Khorsand Parsoa , Hormozdiari Fereydoun 
Published: March 2019

AbstractMotivationLarge scale catalogs of common genetic variants (including indels and structural variants) are being created using data from second and third generation whole-genome sequencing technologies. However, the genotyping of these variants in newly sequenced samples is a nontrivial task that requires extensive computational resources. Furthermore, current approaches are mostly limited to only specific types of variants and are generally prone to various errors and ambiguities when genotyping events in repeat regions. Thus we are proposing an ultra-efficient approach for genotyping any type of structural variation that is not limited by the shortcomings and complexities of current mapping-based approaches.ResultsOur method Nebula utilizes the changes in the count of k-mers to predict the genotype of common structural variations. We have shown that not only Nebula is an order of magnitude faster than mapping based approaches for genotyping deletions and mobile-element insertions, but also has comparable accuracy to state-of-the-art approaches. Furthermore, Nebula is a generic framework not limited to any specific type of event.AvailabilityNebula is publicly available at https://github.com/Parsoa/NebulousSerendipity
Chromatin arranges in chains of mesoscale domains with nanoscale functional topography independent of cohesin
Authors: Miron Ezequiel , Oldenkamp Roel , Brown Jill M. , Pinto David M. S. , Xu C. Shan , Faria Ana R. , Shaban Haitham A. , Rhodes James D. P. , Innocent Cassandravictoria , de Ornellas Sara , Hess Harald F. , Buckle Veronica , Schermelleh Lothar 
Published: March 2019

ABSTRACTThree-dimensional (3D) chromatin organization plays a key role in regulating mammalian genome function, however many of its physical features at the single-cell level remain underexplored. Here we use 3D super-resolution and scanning electron microscopy to analyze structural and functional nuclear organization in somatic cells. We identify linked chromatin domains (CDs) composed of irregular ∼200-300-nm-wide aggregates of nucleosomes that can overlap with individual topologically associating domains and are distinct from a surrounding RNA-populated interchromatin region. High-content mapping uncovers confinement of cohesin and active histone modifications to surfaces and enrichment of repressive modifications towards the core of CDs in both hetero- and euchromatic regions. This nanoscale functional topography is temporarily relaxed in post-replicative chromatin, but remarkably persists after ablation of cohesin. Our findings establish CDs as physical and functional modules of mesoscale genome organization.
Inter-Individual and Inter-Strain Differences in Cognitive and Social Abilities of Dark Agouti and Wistar Han Rats
Authors: Alonso Lucille , Peeva Polina , Ramos-Prats Arnau , Alenina Natalia , Winter York , Rivalan Marion 
Published: March 2019

AbstractBackgroundHealthy animals showing extreme behaviours spontaneously that resemble human psychiatric symptoms are relevant models to study the natural psychobiological processes of maladapted behaviours. Healthy poor decision makers (PDMs) identified using a Rat Gambling Task, co-express a combination of cognitive and reward-based characteristics similar to symptoms observed in human patients with impulse-control disorders. The main goals of this study were to 1) confirm the existence of PDMs and their unique behavioural phenotypes in the Dark Agouti (DA) and Wistar Han (WH), 2) to extend the behavioural profile of the PDMs to probability-based decision-making and social behaviours and 3) to discuss how the key traits of each strain could be relevant for biomedical research.MethodsWe compared cognitive abilities, natural behaviours and physiological responses in DA and WH rats using several tests. We analysed the results at the strain and the individual level.ResultsPrevious findings in WH rats were reproduced and could be generalized to DA. Each PDM of either strain displayed a similar, naturally occurring, combination of behavioural traits, including possibly higher social rank, but no deficits in probability-based decision-making. A Random forest analysis revealed interesting discriminating traits between WH and DA.ConclusionThe reproducibility and conservation of the socio-cognitive and behavioural phenotypes of GDM (good decision maker) and PDM individuals in the two genetically different strains of WH and DA support a good translational validity of these phenotypes. Both DA and WH rat strains present large phenotypic variations in behaviour pertinent for the study of the underlying mechanisms of poor decision making and associated disorders.