bluuebunny/crossref_metadata_2025_split huggingface dataset:
Presynaptic NMDA receptors cooperate with local action potentials to implement activity-dependent GABA release from the reciprocal olfactory bulb granule cell spine
Authors: Lage-Rupprecht Vanessa , Zhou Li , Bianchini Gaia , Aghvami S. Sara , Mueller Max , Rózsa Balázs , Sassoé-Pognetto Marco , Egger Veronica 
Published: October 2018

AbstractIn the rodent olfactory bulb the smooth dendrites of the principal glutamatergic mitral cells (MCs) form reciprocal dendrodendritic synapses with large spines on GABAergic granule cells (GC), where unitary release of glutamate can trigger postsynaptic local activation of voltage-gated Na+-channels (Navs), i.e. a spine spike. Can such single MC input evoke reciprocal release? We find that unitary-like activation via two-photon uncaging of glutamate causes GC spines to release GABA both synchronously and asynchronously onto MC dendrites. This release indeed requires activation of Navs and high-voltage-activated Ca2+-channels (HVACCs), but also of NMDA receptors (NMDAR). Simulations show temporally overlapping HVACC- and NMDAR-mediated Ca2+-currents during the spine spike, and ultrastructural data prove NMDAR presence within the GABAergic presynapse. This cooperative action of presynaptic NMDARs allows to implement synapse-specific, activity-dependent lateral inhibition and thus could provide an efficient solution to combinatorial percept synthesis in a sensory system with many receptor channels.
Human iPSC-derived retinal pigment epithelium: a model system for identifying and functionally characterizing causal variants at AMD risk loci
Authors: Smith Erin N. , D’Antonio-Chronowska Agnieszka , Greenwald William W. , Borja Victor , Aguiar Lana R. , Pogue Robert , Matsui Hiroko , Borooah Shyamanga , D’Antonio Matteo , Ayyagari Radha , Frazer Kelly A. 
Published: October 2018

SummaryWe evaluate whether human induced pluripotent stem cell-derived retinal pigment epithelium (iPSC-RPE) cells can be used to prioritize and functionally characterize causal variants at age-related macular degeneration (AMD) risk loci. We generated iPSC-RPE from six subjects and show that they have morphological and molecular characteristics similar to native RPE. We generated RNA-seq, ATAC-seq, and H3K27ac ChIP-seq data and observe high similarity in gene expression and enriched transcription factor motif profiles between iPSC-RPE and human fetal-RPE. We performed fine-mapping of AMD risk loci by integrating molecular data from the iPSC-RPE, adult retina, and adult RPE, which identified rs943080 as the probable causal variant at VEGFA. We show that rs943080 is associated with altered chromatin accessibility of a distal ATAC-seq peak, decreased overall gene expression of VEGFA, and allele specific expression of a non-coding transcript. These results provide insight into the mechanism underlying the association of the VEGFA locus with AMD.
The microRNA, miR-18a, regulates NeuroD and photoreceptor differentiation in the retina of the zebrafish
Authors: Taylor Scott M. , Giuffre Emily , Moseley Patience , Hitchcock Peter F. 
Published: October 2018

ABSTRACTDuring embryonic retinal development, six types of retinal neurons are generated from a pool of multipotent progenitors in a strict spatiotemporal pattern. This pattern requires cell cycle exit (i.e. neurogenesis) and differentiation to be precisely regulated in a lineage-specific manner. In zebrafish, the bHLH transcription factor NeuroD governs photoreceptor genesis through Notch signaling but also governs photoreceptor differentiation though distinct mechanisms that are currently unknown. Also unknown are the mechanisms that regulate NeuroD and the spatiotemporal pattern of photoreceptor development. Members of the miR-17-92 microRNA cluster regulate CNS neurogenesis, and a member of this cluster, miR-18a, is predicted to target neuroD mRNA. The purpose of this study was to determine if miR-18a regulates NeuroD in the retina and if it plays a role in photoreceptor development. Quantitative RT-PCR showed that, of the three miR-18 family members (miR-18a, b and c), miR-18a expression most closely parallels neuroD expression. Morpholino oligonucleotides and CRISPR/Cas9 gene editing were used for miR-18a loss-of-function (LOF) and both approaches resulted in larvae with more mature photoreceptors at 70 hpf without affecting cell proliferation. Western blot showed that miR-18a LOF increases NeuroD protein levels and in vitro dual luciferase assay showed that miR-18a directly interacts with the 32UTR of neuroD. Finally, tgif1 mutants have increased miR-18a expression, less NeuroD protein and fewer mature photoreceptors, and the photoreceptor deficiency is rescued by miR-18a knockdown. Together these results show that, independent of neurogenesis, miR-18a regulates the timing of photoreceptor differentiation and indicate that this occurs through post-transcriptional regulation of NeuroD.
Dropout-Enabled Ensemble Learning for Multi-Scale Biomedical Data
Authors: Momeni Alexandre , Thibault Marc , Gevaert Olivier 
Published: October 2018

AbstractLeveraging information from multiple scales is crucial to understanding complex diseases such as cancer where this could have a significant impact in improving diagnoses, patient management and treatment decisions. Recent advances in Convolutional Neural Networks (CNNs) have enabled major breakthroughs in biomedical image analysis, in particular for histopathology and radiology images. Our main contribution is a methodology to combine independent CNN models built for these two types of images in order to improve diagnostic accuracy. We train separate CNN models and combine them using a Dropout-Enabled meta-classifier. Our framework achieved second place in the MICCAI 2018 Computational Precision Medicine Challenge.
Functional clustering of dendritic activity during decision-making
Authors: Kerlin A , Mohar B , Flickinger D , MacLennan BJ , Davis C , Spruston N , Svoboda K 
Published: October 2018

SummaryThe active properties of dendrites support local nonlinear operations, but previous imaging and electrophysiological measurements have produced conflicting views regarding the prevalence of local nonlinearities in vivo. We imaged calcium signals in pyramidal cell dendrites in the motor cortex of mice performing a tactile decision task. A custom microscope allowed us to image the soma and up to 300 μm of contiguous dendrite at 15 Hz, while resolving individual spines. New analysis methods were used to estimate the frequency and spatial scales of activity in dendritic branches and spines. The majority of dendritic calcium transients were coincident with global events. However, task-associated calcium signals in dendrites and spines were compartmentalized by dendritic branching and clustered within branches over approximately 10 μm. Diverse behavior-related signals were intermingled and distributed throughout the dendritic arbor, potentially supporting a large computational repertoire and learning capacity in individual neurons.
Cross-Sectional and Longitudinal Brain Scans Reveal Accelerated Brain Aging in Multiple Sclerosis
Authors: Høgestøl Einar A. , Kaufmann Tobias , Nygaard Gro O. , Beyer Mona K. , Sowa Piotr , Nordvik Jan E. , Kolskår Knut , Richard Geneviève , Andreassen Ole A. , Harbo Hanne F. , Westlye Lars T. 
Published: October 2018

ABSTRACTMultiple sclerosis (MS) is an inflammatory disorder of the central nervous system. By combining longitudinal MRI-based brain morphometry and brain age estimation using machine learning, we tested the hypothesis that MS patients have higher brain age relative to chronological age than healthy controls (HC) and that longitudinal rate of brain aging in MS patients is associated with clinical course.Seventy-six MS patients, 71 % females and mean age 34.8 years (range 21-49) at inclusion, were examined with brain MRI at three time points with a mean total follow up period of 4.4 years. A machine learning model was applied on an independent training set of 3208 HC, estimating individual brain age and calculating the difference between estimated brain age and chronological age, termed brain age gap (BAG). We also assessed the longitudinal change rate in BAG in MS individuals. We used additional cross-sectional MRI data from 235 HC for case-control comparison.MS patients showed increased BAG (4.4 ±6.6 years) compared to HC (Cohen’s D = 0.69, p = 4.0 × 10−6). Longitudinal estimates of BAG in MS patients suggested an accelerated rate of brain aging corresponding to an annual increase of 0.41 (±1.23) years compared to chronological aging for the MS patients (p = 0.008).On average, patients with MS have significantly higher BAG compared to HC and accelerated rate of brain aging compared to chronological aging. Brain age estimation represents a promising method for evaluation of brain changes in MS, with potential for predicting future outcome and guide treatment.
The impact of short- and long-range perception on population movements
Authors: Johnston S. T. , Painter K. J. 
Published: October 2018

AbstractNavigation of cells and organisms is typically achieved by detecting and processing orienteering cues. Occasionally, a cue may be assessed over a much larger range than the individual’s body size, as in visual scanning for landmarks. In this paper we formulate models that account for orientation in response to short- or long-range cue evaluation. Starting from an underlying random walk movement model, where a generic cue is evaluated locally or nonlocally to determine a preferred direction, we state corresponding macroscopic partial differential equations to describe population movements. Under certain approximations, these models reduce to well-known local and nonlocal biological transport equations, including those of Keller-Segel type. We consider a case-study application: “hilltopping” in Lepidoptera and other insects, a phenomenon in which populations accumulate at summits to improve encounter/mating rates. Nonlocal responses are shown to efficiently filter out the natural noisiness (or roughness) of typical landscapes and allow the population to preferentially accumulate at a subset of hilltopping locations, in line with field studies. Moreover, according to the timescale of movement, optimal responses may occur for different perceptual ranges.
Gradient in cytoplasmic pressure in the germline cells controls overlying epithelial cell morphogenesis
Authors: Lamiré Laurie-Anne , Milani Pascale , Runel Gaël , Kiss Annamaria , Arias Leticia , Vergier Blandine , Das Pradeep , Cluet David , Boudaoud Arezki , Grammont Muriel 
Published: October 2018

AbstractIt is unknown how growth in one tissue impacts morphogenesis in a neighboring tissue. To address this, we used theDrosophilaovarian follicle, where a cluster of 15 nurse cells and a posteriorly located oocyte are surrounded by a layer of epithelial cells. It is known that as the nurse cells grow, the overlying epithelial cells flatten in a wave that begins in the anterior. Here, we demonstrate that an anterior to posterior gradient of decreasing cytoplasmic pressure is present across the nurse cells and that this gradient acts through TGFß to control both the triggering and the progression of the wave of epithelial cell flattening. Our data indicate that intrinsic nurse cell growth is important to control proper nurse cell pressure. Finally, we reveal that nurse cell pressure and subsequent TGFß activity in the StC combine to increase follicle elongation in the anterior, which is crucial for allowing nurse cell growth and pressure control. More generally, our results reveal that during development, inner cytoplasmic pressure in individual cells has an important role in shaping their neighbors.Impact StatementCell shape change depends on extrinsic forces exerted by cytoplasmic pressure in neighbouring cells.
Intra-individual methylomics detects the impact of early-life adversity
Authors: Jiang Shan , Kamei Noriko , Bolton Jessica L. , Ma Xinyi , Stern Hal S. , Baram Tallie Z. , Mortazavi Ali 
Published: October 2018

AbstractGenetic and environmental factors interact during sensitive periods early in life to influence mental health and disease via epigenetic processes such as DNA methylation. However, it is not known if DNA methylation changes outside the brain provide an ‘epigenetic signature’ of early-life experiences. Here, we employed a novel intra-individual approach by testing DNA methylation from buccal cells of individual rats before and immediately after exposure to one week of typical or adverse life experience. We find that whereas inter-individual changes in DNA methylation reflect the effect of age, DNA methylation changes within paired DNA samples from the same individual reflect the impact of diverse neonatal experiences. Genes coding for critical cellular–metabolic enzymes, ion channels and receptors were more methylated in pups exposed to the adverse environment, predictive of their repression. In contrast, the adverse experience was associated with less methylation on genes involved in pathways of death and inflammation as well as cell-fate related transcription factors, indicating their potential upregulation. Thus, intra-individual methylome signatures indicate large-scale transcription-driven alterations of cellular fate, growth and function.
Genomic signatures of extensive inbreeding in Isle Royale wolves, a population on the threshold of extinction
Authors: Robinson Jacqueline A. , Räikkönen Jannikke , Vucetich Leah M. , Vucetich John A. , Peterson Rolf O. , Lohmueller Kirk E. , Wayne Robert K. 
Published: October 2018

AbstractThe observation that small, isolated populations often suffer reduced fitness as a result of inbreeding depression has guided conservation theory and practice for decades. However, investigating the genome-wide dynamics associated with inbreeding depression in natural populations is only now feasible with relatively inexpensive sequencing technology and annotated reference genomes. To characterize the genome-wide effects of intense inbreeding and isolation, we sequenced complete genomes from an iconic inbred population, the gray wolves (Canis lupus) of Isle Royale. Through comparison with other wolf genomes from a variety of demographic histories, we found that Isle Royale wolf genomes contain extensive runs of homozygosity, but neither the overall level of heterozygosity nor the number of deleterious variants per genome were reliable predictors of inbreeding depression. These findings are consistent with the hypothesis that severe inbreeding depression results from increased homozygosity of strongly deleterious recessive mutations, which are more prevalent in historically large source populations. Our results have particular relevance in light of the recently proposed reintroduction of wolves to Isle Royale, as well as broader implications for management of genetic variation in the fragmented landscape of the modern world.
Molecular phylogeny and diversification timing of the Nemouridae family (Insecta, Plecoptera) in the Japanese Archipelago
Authors: Gamboa Maribet , Muranyi David , Kanmori Shota , Watanabe Kozo 
Published: October 2018

AbstractThe generation of the high species diversity of insects in Japan was profoundly influenced by the formation of the Japanese Archipelago. We explored the species diversification and biogeographical history of the Nemouridae family in the Japanese Archipelago using mitochondrial DNA and nuclear DNA markers. We collected 49 species among four genera:Indonemoura,Protonemura,AmphinemuraandNemourain Japan, China, South Korea and North America. We estimated their divergence times—based on three molecular clock node calibrations—using Bayesian phylogeography approaches. Our results suggested that Japanese Archipelago formation events resulted in diversification events in the middle of the Cretaceous (<120 Ma), speciation in the Paleogene (<50 Ma) and intra-species diversification segregated into eastern and western Japan of the Fossa Magna region at late Neogene (20 Ma). TheIndonemourasamples were genetically separated into two clades—that of Mainland China and that of Japan. The Japanese clade clustered with the Nemouridae species from North America, suggesting the possibility of a colonisation event prior to the formation of the Japanese Archipelago. We believe that our results enhanced the understanding both of the origin of the species and of local species distribution in the Japanese Archipelago.
Minimal phenotyping yields GWAS hits of reduced specificity for major depression
Authors: Cai Na , Revez Joana A. , Adams Mark J , Andlauer Till F. M. , Breen Gerome , Byrne Edna M. , Clarke Toni-Kim , Forstner Andreas J. , Grabe Hans J. , Hamilton Steven P. , Levinson Douglas F. , Lewis Cathryn M. , Lewis Glyn , Martin Nicholas G. , Milaneschi Yuri , Mors Ole , Müller-Myhsok Bertram , Pennix Brenda W. J. H. , Perlis Roy H. , Pistis Giorgio , Potash James B. , Preisig Martin , Shi Jianxin , Smoller Jordan W. , Streit Fabien , Tiemeier Henning , Uher Rudolf , Van der Auwera Sandra , Viktorin Alexander , Weissman Myrna M. ,   MDD Working Group of the Psychiatric Genomics Consortium, Kendler Kenneth S. , Flint Jonathan 
Published: October 2018

AbstractMinimal phenotyping refers to the reliance on the use of a small number of self-report items for disease case identification. This strategy has been applied to genome-wide association studies (GWAS) of major depressive disorder (MDD). Here we report that the genotype derived heritability (h2SNP) of depression defined by minimal phenotyping (14%, SE = 0.8%) is lower than strictly defined MDD (26%, SE = 2.2%). This cannot be explained by differences in prevalence between definitions or including cases of lower liability to MDD in minimal phenotyping definitions of depression, but can be explained by misdiagnosis of those without depression or with related conditions as cases of depression. Depression defined by minimal phenotyping is as genetically correlated with strictly defined MDD (rG = 0.81, SE = 0.03) as it is with the personality trait neuroticism (rG = 0.84, SE = 0.05), a trait not defined by the cardinal symptoms of depression. While they both show similar shared genetic liability with neuroticism, a greater proportion of the genome contributes to the minimal phenotyping definitions of depression (80.2%, SE = 0.6%) than to strictly defined MDD (65.8%, SE = 0.6%). We find that GWAS loci identified in minimal phenotyping definitions of depression are not specific to MDD: they also predispose to other psychiatric conditions. Finally, while highly predictive polygenic risk scores can be generated from minimal phenotyping definitions of MDD, the predictive power can be explained entirely by the sample size used to generate the polygenic risk score, rather than specificity for MDD. Our results reveal that genetic analysis of minimal phenotyping definitions of depression identifies non-specific genetic factors shared between MDD and other psychiatric conditions. Reliance on results from minimal phenotyping for MDD may thus bias views of the genetic architecture of MDD and may impede our ability to identify pathways specific to MDD.
Decreased kinesin-1 mitigates NMDA-induced exicitotoxicity and ischemia-evoked neurodegeneration
Authors: Lin Raozhou , Duan Zhigang , Sun Haitao , Fung Man-Lung , Chen Hansen , Wang Jing , Lau Chi-Fai , Yang Di , Liu Yu , Ni Yanxiang , Wang Zai , Cui Ju , Wu Wutian , Yung Wing-Ho , Chan Ying-Shing , Lo Amy C. Y. , Xia Jun , Shen Jiangang , Huang Jian-Dong 
Published: October 2018

AbstractN-methyl-D-aspartate receptor (NMDAR) is highly compartmentalized in neurons and the dysfunction has been implicated in various neuropsychiatric and neurodegenerative disorders. Recent failure to exploit NMDAR antagonization as a potential therapeutic target has driven the need to identify molecular mechanisms that regulate NMDAR compartmentalization. Here, we report that neural activity-dependent reduction of Kif5b, the heavy chain of kinesin-1, protected neurons against NMDA-induced excitotoxicity and ischemia-provoked neurodegeneration. Direct binding of Kinesin-1 to the GluN2B cytoplasmic tails regulated levels of NMDAR at extrasynaptic sites and the subsequent influx of calcium mediated by extrasynaptic NMDAR via regulating the insertion of NMDARs into neuronal surface. Transient increase of Kif5b restored the surface levels of NMDAR and the decreased neuronal susceptibility to NMDA-induced excitotoxicity. Our findings reveal that kinesin-1 regulates extrasynaptic NMDAR targeting and signaling, and the reduction of kinesin-1 could be regulated by neural activity and could be exploited to postpone or halt neurodegeneration.
Aminoacyl tRNA Synthetases as Malarial Drug Targets: A Comparative Bioinformatics Study
Authors: Wavinya Nyamai Dorothy , Tastan Bishop Özlem 
Published: October 2018

AbstractTreatment of parasitic diseases has been challenging due to the development of drug resistance by parasites, and thus there is need to identify new class of drugs and drug targets. Protein translation is important for survival of plasmodium and the pathway is present in all the life cycle stages of the plasmodium parasite. Aminoacyl tRNA synthetases are primary enzymes in protein translation as they catalyse the first reaction where an amino acid is added to the cognate tRNA. Currently, there is limited research on comparative studies of aminoacyl tRNA synthetases as potential drug targets. The aim of this study is to understand differences between plasmodium and human aminoacyl tRNA synthetases through bioinformatics analysis.Plasmodium falciparum,P. fragile,P. vivax,P. ovale,P. knowlesi,P. bergei,P. malariaeand human aminoacyl tRNA synthetase sequences were retrieved from UniProt database and grouped into 20 families based on amino acid specificity. Despite functional and structural conservation, multiple sequence analysis, motif discovery, pairwise sequence identity calculations and molecular phylogenetic analysis showed striking differences between parasite and human proteins. Prediction of alternate binding sites revealed potential druggable sites in PfArgRS, PfMetRS and PfProRS at regions that were weakly conserved when compared to the human homologues. These differences provide a basis for further exploration of plasmodium aminoacyl tRNA synthetases as potential drug targets.