bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rad53 controls DNA unwinding after helicase-polymerase uncoupling at DNA replication forks
Authors: Devbhandari Sujan , Remus Dirk 
Published: October 2019

ABSTRACTThe coordination of DNA unwinding and synthesis at replication forks promotes efficient and faithful replication of chromosomal DNA. Using the reconstituted budding yeast DNA replication system, we demonstrate that Pol ε variants harboring catalytic point mutations in the Pol2 polymerase domain, contrary to Pol2 polymerase domain deletions, inhibit DNA synthesis at replication forks by displacing Pol δ from PCNA/primer-template junctions, causing excessive DNA unwinding by the replicative DNA helicase, CMG, uncoupled from DNA synthesis. Mutations that suppress the inhibition of Pol δ by Pol ε restore viability in Pol2 polymerase point mutant cells. We also observe uninterrupted DNA unwinding at replication forks upon dNTP depletion or chemical inhibition of DNA polymerases, demonstrating that leading strand synthesis is not tightly coupled to DNA unwinding by CMG. Importantly, the Rad53 kinase controls excessive DNA unwinding at replication forks by limiting CMG helicase activity, suggesting a mechanism for fork-stabilization by the replication checkpoint.
Orexin signaling in GABAergic lateral habenula neurons modulates aggressive behavior
Authors: Flanigan Meghan E. , Aleyasin Hossein , Li Long , Burnett C. Joseph , Chan Kenny L. , LeClair Katherine B. , Lucas Elizabeth K. , Matikainen-Ankney Bridget , Janssen William , Takahashi Aki , Menard Caroline , Pfau Madeline L. , Golden Sam A. , Bouchard Sylvain , Calipari Erin S. , Nestler Eric J. , DiLeone Ralph J. , Yamanaka Akihiro , Huntley George W. , Clem Roger L. , Russo Scott J. 
Published: October 2019

AbstractHeightened aggression is characteristic of multiple neuropsychiatric disorders and can have a wide variety of negative effects on patients, their families, and the public. Recent studies in humans and animals have implicated brain reward circuits in aggression and suggest that, in subsets of aggressive individuals, repeated domination of subordinate social targets is reinforcing. Here, we show that orexin neurons originating from the lateral hypothalamus activate a small population of GABAergic interneurons in the lateral habenula (LHb) via orexin receptor 2 (OxR2) to promote aggression and conditioned place preference (CPP) for aggression-paired contexts. Our study suggests that the orexin system is a potential target for the development of novel therapies aimed at reducing aggressive behaviors and provides the first functional evidence of a local inhibitory circuit within the LHb.
Perception and memory have distinct spatial tuning properties in human visual cortex
Authors: Favila Serra E. , Kuhl Brice A. , Winawer Jonathan 
Published: October 2019

AbstractReactivation of earlier perceptual activity is thought to underlie long-term memory recall. Despite evidence for this view, it is unknown whether mnemonic activity exhibits the same tuning properties as feedforward perceptual activity. Here, we leveraged population receptive field models to parameterize fMRI activity in human visual cortex during spatial memory retrieval. Though retinotopic organization was present during both perception and memory, large systematic differences in tuning were also evident. Notably, whereas there was a three-fold decline in spatial precision from early to late visual areas during perception, this property was entirely abolished during memory retrieval. This difference could not be explained by reduced signal-to-noise or poor performance on memory trials. Instead, by simulating top-down activity in a network model of cortex, we demonstrate that this property is well-explained by the hierarchical structure of the visual system. Our results provide insight into the computational constraints governing memory reactivation in sensory cortex.
Hitching a Ride: Mechanics of Organelle Transport Through Linker-Mediated Hitchhiking
Authors: Mogre Saurabh S. , Christensen Jenna R. , Reck-Peterson Samara L. , Koslover Elena F. 
Published: October 2019

ABSTRACTIn contrast to the canonical picture of transport by direct attachment to motor proteins, recent evidence shows that a number of intracellular ‘cargos’ navigate the cytoplasm by hitchhiking on motor-driven ‘carrier’ organelles. We describe a quantitative model of intracellular cargo transport via hitchhiking, examining the efficiency of hitchhiking initiation as a function of geometric and mechanical parameters. We focus specifically on the parameter regime relevant to the hitchhiking motion of peroxisome organelles in fungal hyphae. Our work predicts the dependence of transport initiation rates on the distribution of cytoskeletal tracks and carrier organelles, as well as the number, length and flexibility of the linker proteins that mediate contact between the carrier and the hitchhiking cargo. Furthermore, we demonstrate that attaching organelles to microtubules can result in a substantial enhancement of the hitchhiking initiation rate in tubular geometries such as those found in fungal hyphae. This enhancement is expected to increase the overall transport rate of hitchhiking organelles, and lead to greater efficiency in organelle dispersion. Our results leverage a quantitative physical model to highlight the importance of organelle encounter dynamics in non-canonical intracellular transport.SIGNIFICANCEA variety of cellular components are transported via hitchhiking by attaching to other motile organelles. Defects in the molecular machinery responsible for organelle hitchhiking may be linked with neurodegenerative disorders. To date, no comprehensive physical models of this non-canonical mode of transport have been developed. In particular, the connection between molecular- and organelle-scale properties of hitchhiking components and their effect on cellular-scale transport has remained unclear. Here, we investigate the mechanics of hitchhiking initiation and explore organelle interactions that can modulate the efficiency of this process.
Wnt signaling activates gene expression in the absence of theC. elegansDREAM repressor complex in somatic cells
Authors: Cherian Jerrin R. , Petrella Lisa N. 
Published: October 2019

ABSTRACTEstablishment and maintenance of proper gene expression is a requirement for normal growth and development. The DREAM complex inCaenorhabditis elegansfunctions as a transcriptional repressor of germline genes in somatic cells. At 26°C, DREAM complex mutants show temperature associated increase in misexpression of germline genes in somatic cells and High Temperature Arrest (HTA) of worms at the first larval stage. To identify transcription factors required for the ectopic expression of germline genes in DREAM complex mutants, we conducted an RNA interference screen against 123 transcription factors capable of binding DREAM target promoter loci for suppression of the HTA phenotype inlin-54mutants. We found 15 embryonically expressed transcription factors that suppress the HTA phenotype inlin-54mutants. Five of the transcription factors found in the initial screen interact with the Wnt signaling pathways. In a subsequent RNAi suppression screen of Wnt signaling factors we found that knock-down of the non-canonical Wnt/PCP pathway factorsvang-1,prkl-1andfmi-1inlin-54mutant background resulted in strong suppression of the HTA phenotype. Animals mutant for bothlin-54andvang-1showed almost complete suppression of the HTA phenotype,pgl-1misexpression, and fertility defects associated withlin-54single mutants at 26°C. We propose a model whereby a set of embryonically expressed transcription factors, and the Wnt/PCP pathway, act opportunistically to activate DREAM complex target genes in somatic cells of DREAM complex mutants at 26°C.
Contrasting dates of rainforest fragmentation in Africa inferred from trees with different dispersal abilities
Authors: Piñeiro Rosalía , Hardy Olivier J. , Tovar Carolina , Gopalakrishnan Shyam , Vieira Filipe Garrett , Gilbert M Thomas P 
Published: October 2019

ABSTRACTThe rainforests of Tropical Africa have fluctuated over time. Although today the forest cover is continuous in Central Africa this may have not always been the case, as the scarce fossil record in this region suggests that more arid conditions might have significantly reduced the density of trees during the Ice Ages. Our aim was to investigate whether the dry ice-age periods left a genetic signature on tree species that can be used to date the past fragmentation of the rainforest. We sequenced reduced representation libraries of 182 samples representing five Legume tree species that are widespread in African rainforests and seven outgroups. Phylogenetic analyses identified an early divergent lineage for all species in West Africa (Upper Guinea), and two clades in Central Africa: Lower Guinea-North and Lower Guinea-South. As the structure separating the Northern and Southern clades cannot be explained by geographic barriers, we tested other hypotheses using demographic model testing. The best estimates recovered using ∂a∂I indicate that the two clades split between the Upper Pliocene and the Pleistocene, a date compatible with forest fragmentation driven by ice-age climatic oscillations. Furthermore, we found remarkably older split dates for the shade-tolerant tree species with non-assisted seed dispersal than for light-demanding long-distance wind-dispersed trees. We also show that the genetic diversity significantly declines with the distance from ice-age refugia in the two long-distance dispersed species only. Different recolonisation abilities after recurrent cycles of forest fragmentation seem to explain why we observe congruent genetic spatial structures across species with contrasted timescales.SIGNIFICANCE STATEMENTAlthough today the rainforest cover is continuous in Central Africa, the scarce fossil record suggests that arid conditions during the Ice Ages might have reduced the density of trees during the Ice Ages. However, the vast majority of the fossil pollen records preserved in Tropical Africa is too young to inform about this period. Investigating whether the past climate change left a genetic signature on trees can thus be useful to date past forest fragmentation. However, most genetic studies available to date lack resolution as they use limited numbers of loci. In this study we use modern DNA technology to study five Legume trees. Our results show significant differentiation of the populations of each species at a date compatible with forest fragmentation driven by ice-age climatic oscillations. Contrasted timescales were obtained for each species, which probably reflects their different recolonisation abilities after forest fragmentation.
Nonlinear convergence boosts information coding in circuits with parallel outputs
Authors: Gutierrez Gabrielle J. , Rieke Fred , Shea-Brown Eric T. 
Published: October 2019

Neural circuits are structured with layers of converging and diverging connectivity, and selectivity-inducing nonlinearities at neurons and synapses. These components have the potential to hamper an accurate encoding of the circuit inputs. Past computational studies have optimized the nonlinearities of single neurons, or connection weights in networks, to maximize encoded information, but have not grappled with the simultaneous impact of convergent circuit structure and nonlinear response functions for efficient coding. Our approach is to compare model circuits with different combinations of convergence, divergence, and nonlinear neurons to discover how interactions between these components affect coding efficiency. We find that a convergent circuit with divergent parallel pathways can encode more information with nonlinear subunits than with linear subunits, despite the compressive loss induced by the convergence and the nonlinearities when considered individually. These results show that the combination of selective nonlinearities and a convergent architecture - both elements that reduce information when acting separately - can promote efficient coding.Significance StatementComputation in neural circuits relies on a common set of motifs, including divergence of common inputs to parallel pathways, convergence of multiple inputs to a single neuron, and nonlinearities that select some signals over others. Convergence and circuit nonlinearities, considered individually, can lead to a loss of information about inputs. Past work has detailed how optimized nonlinearities and circuit weights can maximize information, but here, we show that incorporating non-invertible nonlinearities into a circuit with divergence and convergence, can enhance encoded information despite the suboptimality of these components individually. This study extends a broad literature on efficient coding to convergent circuits. Our results suggest that neural circuits may preserve more information using suboptimal components than one might expect.
Identifying Sialylation Linkages at the Glycopeptide Level by Glycosyltransferase Labeling Assisted Mass Spectrometry (GLAMS)
Authors: Zhu He , Wang Shuaishuai , Liu Ding , Ding Lang , Chen Congcong , Liu Yunpeng , Wu Zhigang , Bollag Roni , Liu Kebin , Yin Jun , Ma Cheng , Li Lei , Wang Peng George 
Published: October 2019

ABSTRACTPrecise assignment of sialylation linkages at the glycopeptide level is of importance in bottom-up glycoproteomics, and is also an indispensable step to understand the function of glycoproteins in pathogen-host interactions and cancer progression. Even though some efforts have been dedicated to the discrimination of α2,3/α2,6-sialylated isomers, unambiguous identification of sialoglycopeptide isomers is still needed. Herein, an innovative strategy of glycosyltransferase labeling assisted mass spectrometry (GLAMS) was developed. After specific enzymatic labeling, oxonium ions from higher-energy C-trap dissociation (HCD) fragmentation of α2,3-sailoglycopeptides generate unique reporters to distinctly differentiate those of α2,6-sailoglycopeptide isomers. Using this strategy, a total of 1,236 linkage-specific sialoglycopeptides were successfully identified from 161 glycoproteins in human serum.Abstract Figure
A Chromatin Accessibility Atlas of the Developing Human Telencephalon
Authors: Markenscoff-Papadimitriou Eirene , Whalen Sean , Przytycki Pawel , Thomas Reuben , Binyameen Fadya , Nowakowski Tomasz J. , Sanders Stephan J. , State Matthew W. , Pollard Katherine S. , Rubenstein John L. 
Published: October 2019

AbstractGene expression differs between cell types and regions within complex tissues such as the developing brain. To discover regulatory elements underlying this specificity, we generated genome-wide maps of chromatin accessibility in eleven anatomically-defined regions of the developing human telencephalon, including upper and deep layers of the prefrontal cortex. We predicted a subset of open chromatin regions (18%) that are most likely to be active enhancers, many of which are dynamic with 26% differing between early and late mid-gestation and 28% present in only one brain region. These region-specific predicted regulatory elements (pREs) are enriched proximal to genes with expression differences across regions and developmental stages and harbor distinct sequence motifs that suggest potential upstream regulators of regional and temporal transcription. We leverage this atlas to identify regulators of genes associated with autism spectrum disorder (ASD) including an enhancer of BCL11A, validated in mouse, and two functional de novo mutations in individuals with ASD in an enhancer of SLC6A1, validated in neuroblastoma cells. These applications demonstrate the utility of this atlas for decoding neurodevelopmental gene regulation in health and disease.SummaryTo discover regulatory elements driving the specificity of gene expression in different cell types and regions of the developing human brain, we generated an atlas of open chromatin from eleven dissected regions of the mid-gestation human telencephalon, including upper and deep layers of the prefrontal cortex. We identified a subset of open chromatin regions (OCRs), termed predicted regulatory elements (pREs), that are likely to function as developmental brain enhancers. pREs showed regional differences in chromatin accessibility, including many specific to one brain region, and were correlated with gene expression differences across the same regions and gestational ages. pREs allowed us to map neurodevelopmental disorder risk genes to developing telencephalic regions, and we identified three functional de novo noncoding variants in pREs that alter enhancer function. In addition, transgenic experiments in mouse validated enhancer activity for a pRE proximal to BCL11A, showing how this atlas serves as a resource for decoding neurodevelopmental gene regulation in health and disease.
Genome-wide association study of gastrointestinal disorders reinforces the link between the digestive tract and the nervous system
Authors: Wu Yeda , Murray Graham K. , Byrne Enda M. , Sidorenko Julia , Visscher Peter M. , Wray Naomi R. 
Published: October 2019

AbstractGenetic factors are recognized to contribute to common gastrointestinal (GI) diseases such as gastro-oesophageal reflux disease (GORD), peptic ulcer disease (PUD), irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). We conducted genome-wide association analyses based on 456,414 individuals and identified 27 independent and significant loci for GORD, PUD and IBS, including SNPs associated with PUD at or near genesMUC1, FUT2, PSCAandCCKBR, for which there are previously established roles inHelicobacter pyloriinfection, response to counteract infection-related damage, gastric acid secretion and gastrointestinal motility. Post-GWAS analyses implicate putative functional links between the nervous system and gastrointestinal tract for GORD, PUD and IBS, including the central nervous system, the enteric nervous system and their connection. Mendelian Randomisation analyses imply potentially bi-directional causality (the risk of GORD in liability to major depression and the risk of major depression in liability to GORD) or pleiotropic effect between them. A stronger genetic similarity among GORD, PUD and IBS than between these disorders and IBD is reported. These findings advance understanding the role of genetic variants in the etiology of GORD, PUD and IBS and add biological insights into the link between the nervous system and the gastrointestinal tract.
Voltage-sensitive dye imaging reveals inhibitory modulation of ongoing cortical activity
Authors: Newton Taylor H. , Abdellah Marwan , Chevtchenko Grigori , Muller Eilif B. , Markram Henry 
Published: October 2019

AbstractVoltage-sensitive dye imaging (VSDI) is a powerful technique for interrogating membrane potential dynamics in assemblies of cortical neurons, but with effective resolution limits that confound interpretation. In particular, it is unclear how VSDI signals relate to population firing rates. To address this limitation, we developed an in silico model of VSDI in a biologically faithful digital reconstruction of rodent neocortical microcircuitry. Using this model, we extend previous experimental observations regarding the cellular origins of VSDI, finding that the signal is driven primarily by neurons in layers 2/3 and 5. We proceed by exploring experimentally inaccessible circuit properties to show that during periods of spontaneous activity, membrane potential fluctuations are anticorrelated with population firing rates. Furthermore, we manipulate network connections to show that this effect depends on recurrent connectivity and is modulated by external input. We conclude that VSDI primarily reflects inhibitory responses to ongoing excitatory dynamics.
Errors associated with compound specific δ15N analysis of amino acids in preserved fish samples purified by high pressure liquid chromatography
Authors: Swalethorp Rasmus , Aluwihare Lihini , Thompson Andrew R. , Ohman Mark D. , Landry Michael R. 
Published: October 2019

AbstractCompound specific isotopic analysis of amino acids (CSIA-AA) is increasingly used in ecological and biogeochemical studies tracking the origin and fate of nitrogen (N). Its advantages include the potential for resolving finer-scale trophic dynamics than possible with standard bulk SIA and for reconstructing historical changes in the food webs of consumers from analyses of specimens in preserved sample archives. For the latter, assessing the effects of chemical preservatives on δ15NAA has been inconclusive because the conventional CSIA approach for derivatized AAs by gas chromatography – combustion – isotope ratio mass spectrometry (GC-C-IRMS) has analytical errors (0.4 - 1.0 ‰) in the range expected from chemical preservation. Here, we show improved analytical precision (0.15 ± 0.08 ‰) for 11 underivatized AA standards analyzed by high pressure liquid chromatography followed by offline elemental analysis – IRMS (HPLC/EA-IRMS), an approach originally developed by Broek and McCarthy (2014). Using this method, we report the first high-precision tests of preservation effects on δ15NAA in Northern Anchovy (Engraulis mordax) kept 1½-year in ethanol and up to 27-years in formaldehyde. We found minimal methodological induced fractionation for 8 AAs, and preservation effects on δ15N were similar regardless of duration and preservative used. Although some of the AAs differed significantly from frozen control samples (average +1.0 ± 0.8 ‰), changes in δ15N in the source AA Phenylalanine and trophic position estimates were statistically insignificant. Our results are encouraging for resolving fine-scale natural variability using HPLC/EA-IRMS on chemically preserved specimens and for ultimately reconstructing biogeochemical records and trophic dynamics over long time scales.
Molecular species delimitation in the primitively segmented spider genusHeptathelaendemic to Japanese islands
Authors: Xu Xin , Kuntner Matjaž , Bond Jason E. , Ono Hirotsugu , Ho Simon Y. W. , Liu Fengxiang , Yu Long , Li Daiqin 
Published: October 2019

ABSTRACTDetermining species boundaries forms an important foundation for biological research. However, the results of molecular species delimitation can vary with the data sets and methods that are used. Here we use a two-step approach to delimit species in the genusHeptathela, a group of primitively segmented trapdoor spiders that are endemic to Japanese islands. Morphological evidence suggests the existence of 19 species in the genus. We tested this initial species hypothesis by using six molecular species-delimitation methods to analyse 180 mitochondrialCOIsequences ofHeptathelasampled from across the known range of the genus. We then conducted a set of more focused analyses by sampling additional genetic markers from the subset of taxa that were inconsistently delimited by the single-locus analyses of mitochondrial DNA. Multilocus species delimitation was performed using two Bayesian approaches based on the multispecies coalescent. Our approach identified 20 putative species among the 180 sampled individuals ofHeptathela. We suggest that our two-step approach provides an efficient strategy for delimiting species while minimizing costs and computational time.