bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhanced RhoA signaling stabilizes E-cadherin in migrating epithelial monolayers
Authors: Gupta Shafali , Duszyc Kinga , Verma Suzie , Budnar Srikanth , Liang Xuan , Gomez Guillermo A. , Marcq Philippe , Noordstra Ivar , Yap Alpha S. 
Published: April 2021

AbstractEpithelia migrate as physically coherent populations of cells. Earlier studies revealed that mechanical stress accumulates in these cellular layers as they move. These stresses are characteristically tensile in nature and have often been inferred to arise when moving cells pull upon the cell-cell adhesions that hold them together. We now report that epithelial tension at adherens junctions between migrating cells also reflects an increase in RhoA-mediated junctional contractility. We find that active RhoA levels were stimulated by p114 RhoGEF at the junctions between migrating MCF-7 monolayers, and this is accompanied by increased levels of actomyosin and mechanical tension. By applying a strategy to restore active RhoA specifically at adherens junctions by manipulating its scaffold, anillin, we found that this junctional RhoA signal was necessary to stabilize junctional E-cadherin during epithelial migration. We suggest that stabilization of E-cadherin by RhoA serves to increase cell-cell adhesion against the mechanical stresses of migration.
Role of Anthropogenic drivers in altering the forest community structure in a prime tiger habitat in central India
Authors: Dasgupta Soumya , Bhattacharya Tapajit , Bhamburkar Prafulla , Kaul Rahul 
Published: April 2021

AbstractTropical forests are complex systems with heterogenous community assemblages often threatened under conservation conflicts. Herbivory and disturbances affect the diversity and species assemblages within forest patches having different disturbance regimes. We studied the change in plant community composition and structure under a disturbance gradient in the tropical dry deciduous forest of the corridor area between Nagzira-Navegaon Tiger reserve of central India. We tested the hypothesis that the plant community will change along the proximity gradient from the human settlement depending on the anthropogenic stress. We sampled 183 nested quadrat plots to collect data on species abundance and various disturbance parameters. Density, diversity, and Importance Value Index were calculated from the collected data on species abundance and girth at breast height (GBH) of individual tree species. We did multivariate analysis to assess the changes in species assemblage along the disturbance gradients. We found 76% dissimilarity between the plant communities in the three disturbance gradients from near to far from the villages perpetrated by the difference in mean abundance of species likeTectona grandis, Terminalia sp, andLargerstroemia parviflora. The anthropogenic factors significantly influence the density and diversity of tree species and regeneration classes. We found the abundance of regeneration class increased along the distance from the villages. The study intensifies the need for proper management and conservative approach to preserve the minimum diversity of the forest patches for its structural and functional contiguity as a corridor in the central India’s highly susceptible and intricate corridor framework.
Intrinsic Mechanisms in the Gating of Resurgent Na+Currents
Authors: Ransdell Joseph L. , Moreno Jonathan D. , Bhagavan Druv , Silva Jonathan R. , Nerbonne Jeanne M. 
Published: April 2021

ABSTRACTThe resurgent component of the voltage-gated sodium current (INaR) is a depolarizing conductance, revealed on membrane hyperpolarizations following brief depolarizing voltage steps, which has been shown to contribute to regulating the firing properties of numerous neuronal cell types throughout the central and peripheral nervous systems. Although mediated by the same voltage-gated sodium (Nav) channels that underlie the transient and persistent Nav current components, the gating mechanisms that contribute to the generation of INaRremain unclear. Here, we characterized Nav currents in mouse cerebellar Purkinje neurons, and used tailored voltage-clamp protocols to define how the voltage and the duration of the initial membrane depolarization affect the amplitudes and kinetics of INaR. Using the acquired voltage-clamp data, we developed a novel Markov kinetic state model with parallel (fast and slow) inactivation pathways and, we show that this model reproduces the properties of the resurgent, as well as the transient and persistent, Nav currents recorded in (mouse) cerebellar Purkinje neurons. Based on the acquired experimental data and the simulations, we propose that resurgent Na+influx occurs as a result of fast inactivating Nav channels transitioning into an open/conducting state on membrane hyperpolarization, and that the decay of INaRreflects the slow accumulation of recovered/opened Nav channels into a second, alternative and more slowly populated, inactivated state. Additional simulations reveal that extrinsic factors that affect the kinetics of fast or slow Nav channel inactivation and/or impact the relative distribution of Nav channels in the fast- and slow-inactivated states, such as the accessory Navβ4 channel subunit, can modulate the amplitude of INaR.SUMMARYThe resurgent component of the voltage-gated sodium current (INaR) is revealed on membranehyperpolarizationsfollowing brief depolarizing voltage steps that activate the rapidly activating and inactivating, transient Nav current (INaT). To probe the mechanisms contributing to the generation and properties of INaR, we combined whole-cell voltage-clamp recordings from mouse cerebellar Purkinje neurons with computational modeling to develop a novel, blocking particle-independent, model for the gating of INaRthat involves two parallel inactivation pathways, and we show that this model recapitulates the detailed biophysical properties of INaRmeasured in mouse cerebellar Purkinje neurons.
Comprehensive-immunopeptidomics analysis reveals presentation of potential neoantigens carrying cancer driver mutations
Authors: Minegishi Yuriko , Kiyotani Kazuma , Nemoto Kensaku , Inoue Yoshikage , Haga Yoshimi , Fujii Risa , Saichi Naomi , Nagayama Satoshi , Ueda Koji 
Published: April 2021

AbstractUnderstanding the properties of human leukocyte antigen (HLA) peptides (HLAp) is essential for cancer precision medicine, while the direct identification of HLAp from a tiny piece of clinical tissues by mass spectrometry (MS) is still confronted with technical challenges. Here, to overcome that hindrances, high-field asymmetric waveform ion mobility spectrometry (FAIMS) is introduced to conduct differential ion mobility (DIM)-MS by seamless gas-phase fractionation optimal for scarce samples. The global-immunopeptidomics analysis enables in-depth identification of 44,785 HLAp, including 2 neoantigens with KRAS-G12V and CPPED1-R228Q from stage IV colorectal cancer (CRC) tissues obtained from 17 subjects. Comparison of tissue-based personal immunopeptidome disclosed cancer-specific processing of HLAp. Since the direct identification of neoantigens from CRC tissues suggests more potential neoantigens have yet to been identified, the targeted-immunopeptidomics by screening-oriented parallel reaction monitoring (PRM) has been established and identified two more neoantigens with oncogenic KRAS. The targeted-immunopeptidomics analysis clarifies the presentation of aimed neoantigens, including neoantigens that are unpredictable by computational algorithms. The comprehensive-immunopeptidomics approach combining the FAIMS-assisted DIM-MS and the screening-oriented PRM contributes the direct and effective identification of HLAp and emerging neoantigens from clinical tissue samples, as an advanced strategy to identify the authentic and recurrent neoantigens for cancer immunotherapy.
Eosinophils are dispensable for development of MOG35-55-induced experimental autoimmune encephalomyelitis in mice
Authors: Ruppova Klara , Lim Jong-Hyung , Fodelianaki Georgia , August Avery , Neuwirth Ales 
Published: April 2021

AbstractExperimental autoimmune encephalomyelitis (EAE) represents the mouse model of multiple sclerosis, a devastating neurological disorder. EAE development and progression involves the infiltration of different immune cells into the brain and spinal cord. However, less is known about a potential role of eosinophil granulocytes for EAE disease pathogenesis. In the present study, we found enhanced eosinophil abundance accompanied by increased concentration of the eosinophil chemoattractant eotaxin-1 in the spinal cord in the course of EAE induced in C57BL/6 mice by immunization with MOG35-55peptide. However, the absence of eosinophils did not affect neuroinflammation, demyelination and clinical development or severity of EAE, as assessed in ΔdblGATA1 eosinophil-deficient mice. Taken together, despite their enhanced abundance in the inflamed spinal cord during disease progression, eosinophils were dispensable for EAE development.
What is a supercoiling-sensitive gene? Insights from topoisomerase I inhibition in the Gram-negative bacteriumDickeya dadantii
Authors: Pineau Maïwenn , Shiny Martis B. , Forquet Raphaël , Baude Jessica , Villard Camille , Grand Lucie , Popowycz Florence , Soulère Laurent , Hommais Florence , Nasser William , Reverchon Sylvie , Meyer Sam 
Published: April 2021

AbstractDNA supercoiling is an essential mechanism of bacterial chromosome compaction, whose level is mainly regulated by topoisomerase I and DNA gyrase. Inhibiting either of these enzymes with antibiotics leads to global supercoiling modifications and subsequent changes in global gene expression. In previous studies, genes responding to DNA relaxation induced by gyrase inhibition were categorised as “supercoiling-sensitive”. Here, we studied the opposite variation of DNA supercoiling in the phytopathogenDickeya dadantiiusing the non-marketed antibiotic seconeolitsine. We showed that the drug is active against topoisomerase I from this species, and analysed the first transcriptomic response of a Gram-negative bacterium to topoisomerase I inhibition. We find that the responding genes essentially differ from those observed after DNA relaxation, and further depend on the growth phase. We characterised these genes at the functional level, and also detected distinct patterns in terms of expression level, spatial and orientational organisation along the chromosome. Altogether, these results highlight that the supercoiling-sensitivity is a complex feature, which depends on the action of specific topoisomerases, on the physiological conditions, and on their genomic context. Based on previousin vitroexpression data of several promoters, we propose a qualitative model of SC-dependent regulation that accounts for many of the contrasting transcriptomic features observed after gyrase or topoisomerase I inhibition.
Overcoming Attenuation Bias in Regressions using Polygenic Indices: A Comparison of Approaches
Authors: van Kippersluis Hans , Biroli Pietro , Pereira Rita Dias , Galama Titus J. , Hinke Stephanie von , Meddens S. Fleur W. , Muslimova Dilnoza , Slob Eric A.W. , de Vlaming Ronald , Rietveld Cornelius A. 
Published: April 2021

ABSTRACTMeasurement error in polygenic indices (PGIs) attenuates the estimation of their effects in regression models. While this measurement error shrinks with growing Genome-wide Association Study (GWAS) sample sizes, the marginal returns to bigger sample sizes are rapidly decreasing. We analyze and compare two alternative approaches to reduce measurement error: Obviously Related Instrumental Variables (ORIV) and the PGI Repository Correction (PGI-RC). Through simulations, we show that both approaches outperform the typical (meta-analysis based) PGI in terms of bias and root mean squared error. Between families, the PGI-RC performs slightly better than ORIV, unless the prediction sample is very small (N <1, 000), or when there is considerable assortative mating. Within families, ORIV is the default choice since the PGI-RC is not available in this setting. We verify the empirical validity of the simulations by predicting educational attainment (EA) and height in a sample of siblings from the UK Biobank. We show that applying ORIV between families increases the standardized effect of the PGI by 12% (height) and by 22% (EA) compared to a meta-analysis-based PGI, yet remains slightly below the PGI-RC estimates. Furthermore, within-family ORIV regression provides the tightest lower bound for the direct genetic effect, increasing the lower bound for the direct genetic effect on EA from 0.14 to 0.18, and for height from 0.54 to 0.61 compared to a meta-analysis-based PGI.
In-depth phylogenomic analysis of arbuscular mycorrhizal fungi based on a comprehensive set of de novo genome assemblies
Authors: Montoliu-Nerin Merce , Sánchez-García Marisol , Bergin Claudia , Kutschera Verena Esther , Johannesson Hanna , Bever James D. , Rosling Anna 
Published: April 2021

SummaryMorphological characters and nuclear ribosomal DNA (rDNA) phylogenies have so far been the basis of the current classifications of arbuscular mycorrhizal (AM) fungi. Improved understanding of the phylogeny and evolutionary history of AM fungi requires extensive ortholog sampling and analyses of genome and transcriptome data from a wide range of taxa.To circumvent the need for axenic culturing of AM fungi we gathered and combined genomic data from single nuclei to generatede novogenome assemblies covering seven families of AM fungi. Comparative analysis of the previously publishedRhizophagus irregularisDAOM197198 assembly confirm that our novel workflow generates high-quality genome assemblies suitable for phylogenomic analysis. Predicted genes of our assemblies, together with published protein sequences of AM fungi and their sister clades, were used for phylogenomic analyses.Based on analyses of sets of orthologous genes, we highlight three alternative topologies among families of AM fungi. In the main topology, Glomerales is polyphyletic and Claroideoglomeraceae, is the basal sister group to Glomeraceae and Diversisporales.Our results support family level classification from previous phylogenetic studies. New evolutionary relationships among families where highlighted with phylogenomic analysis using the hitherto most extensive taxon sampling for AM fungi.
Motor usage imprints microtubule stability in the shaft
Authors: Andreu-Carbó Mireia , Fernandes Simon , Velluz Marie-Claire , Kruse Karsten , Aumeier Charlotte 
Published: April 2021

SUMMARYTubulin dimers assemble into dynamic microtubules which are used by molecular motors as tracks for intracellular transport. Organization and dynamics of the microtubule network is commonly thought to be regulated at the polymer ends, where tubulin-dimers can be added or removed. Here we show that molecular motors running on microtubules cause exchange of dimers along the shaft. These sites of dimer exchange act as rescue sites where depolymerising microtubules stop shrinking and start re-growing. Consequently, the average length of microtubules increases depending on how frequently they are used as motor tracks. An increase of motor activity densifies the cellular microtubule network and enhances cell polarity. Running motors leave marks in the shaft serving as traces of microtubule usage to organize the polarity landscape of the cell.
Persistence and expansion of cryptic endangered red wolf genomic ancestry along the American Gulf coast
Authors: vonHoldt Bridgett M. , Brzeski Kristin E. , Aardema Matthew L. , Schell Christopher , Rutledge Linda Y. , Fain Steven R. , Shutt Amy , Linderholm Anna , Murphy William J. 
Published: April 2021

AbstractAdmixture and introgression play a critical role in adaptation and genetic rescue that has only recently gained a deeper appreciation. Here, we explored the geographic and genomic landscape of cryptic ancestry of the endangered red wolf that persists within the genome of a ubiquitous sister taxon, the coyote, all the while the red wolf has been extinct in the wild since the early 1980s. We assessed admixture across 102,621 SNP loci genotyped in 293 canid genomes. We found support for increased red wolf ancestry along an east-to-west gradient across the southern United States that was associated with historical admixture in the past 100 years. Southwestern Louisiana and southeastern Texas, the geographic zone where the last red wolves were known prior to their extinction in the wild, contained the highest and oldest levels of red wolf ancestry. X-linked regions of low recombination rates were depleted of introgression, relative to the autosomes, suggestive of the large X effect and enrichment with loci involved in maintaining reproductive isolation. Recombination rate was positively correlated with red wolf ancestry across coyote genomes, consistent with theoretical predictions. The geographic and genomic extent of cryptic red wolf ancestry can provide novel and variable genomic resources for the survival of the endangered red wolf.
Faster-haplodiploid evolution under divergence-with-gene-flow: simulations and empirical data from pine-feeding hymenopterans
Authors: Bendall Emily E. , Bagley Robin K. , Sousa Vitor C. , Linnen Catherine R. 
Published: April 2021

AbstractAlthough haplodiploidy is widespread in nature, the evolutionary consequences of this sex determination mechanism are not well characterized. Here, we examine how genome-wide hemizygosity and a lack of recombination in haploid males affects genomic differentiation in populations that diverge via natural selection while experiencing gene flow. First, we simulated diploid and haplodiploid “genomes” (500-kb loci) evolving under an isolation-with-migration model with mutation, drift, selection, migration, and recombination; and examined differentiation at neutral sites both tightly and loosely linked to a divergently selected site. So long as there is divergent selection and migration, sex-limited hemizygosity and recombination cause elevated differentiation (i.e., produce a “faster-haplodiploid effect”) in haplodiploid populations relative to otherwise equivalent diploid populations, for both recessive and codominant mutations. Second, we used genome-wide SNP data to model divergence history and describe patterns of genomic differentiation between sympatric populations of Neodiprion lecontei and N. pinetum, a pair of pine sawfly species (order: Hymenoptera; family: Diprionidae) that are specialized on different pine hosts. These analyses support a history of continuous gene exchange throughout divergence and reveal a pattern of heterogeneous genomic differentiation that is consistent with divergent selection on many unlinked loci. Third, using simulations of haplodiploid and diploid populations evolving according to the estimated divergence history of N. lecontei and N. pinetum, we found that divergent selection would lead to higher differentiation in haplodiploids. Based on these results, we hypothesize that haplodiploids undergo divergence-with-gene-flow and sympatric speciation more readily than diploids.
Loss of TDP-43 function and rimmed vacuoles persist after T cell depletion in a xenograft model of sporadic inclusion body myositis
Authors: Britson Kyla A. , Ling Jonathan P. , Braunstein Kerstin E. , Montagne Janelle M. , Kastenschmidt Jenna M. , Wilson Andrew , Ikenaga Chiseko , Tsao William , Pinal-Fernandez Iago , Russel Katelyn A. , Reed Nicole , Wagner Kathryn R. , Ostrow Lyle W. , Corse Andrea M. , Mammen Andrew L. , Villalta S. Armando , Larman H. Benjamin , Wong Philip C. , Lloyd Thomas E. 
Published: April 2021

AbstractSporadic inclusion body myositis (IBM) is the most common acquired muscle disease in adults over age 50, yet it remains unclear whether the disease is primarily driven by T cell-mediated autoimmunity. IBM muscle biopsies exhibit nuclear clearance and cytoplasmic aggregation of TDP-43 in muscle cells, a pathologic finding observed initially in neurodegenerative disease, and nuclear loss of TDP-43 in neurons causes aberrant RNA splicing. Here, we show that loss of TDP-43 splicing repression, as determined by inclusion of cryptic exons, occurs in skeletal muscle of IBM patients. Out of 119 muscle biopsies tested, RT-PCR-mediated detection of cryptic exon expression is 84% sensitive and 99% specific for diagnosing IBM, indicating utility as a functional and diagnostic biomarker. To determine the role of T cells in pathogenesis, we generated a novel xenograft model by transplanting human IBM muscle into the hindlimb of immunodeficient mice. Xenografts from IBM patients display robust regeneration of human myofibers and recapitulate both inflammatory and degenerative features of the disease. Myofibers in IBM xenografts are invaded by human, oligoclonal CD8+ T cells and exhibit MHC-I upregulation, rimmed vacuoles, mitochondrial pathology, p62-positive inclusions, and nuclear clearance and cytoplasmic aggregation of TDP-43, resulting in expression of cryptic exons. Depletion of human T cells within IBM xenografts by treating mice intraperitoneally with anti-CD3 (OKT3) suppresses MHC-I upregulation, but rimmed vacuoles and loss of TDP-43 function persist. These data suggest that myofiber degeneration occurs independent of T cells, and muscle cell-intrinsic mechanisms, such as loss of TDP-43 splicing repression, drive IBM pathogenesis.One Sentence SummaryDepletion of T cells in a xenograft model of sporadic inclusion body myositis suppresses inflammation but not TDP-43 pathology or muscle degeneration.
Integrating Rigidity Analysis into the Exploration of Protein Conformational Pathways using RRT* and MC
Authors: Afrasiabi Fatemeh , Dehghanpoor Ramin , Haspel Nurit 
Published: April 2021

AbstractTo understand how proteins function on a cellular level, it is of paramount importance to understand their structures and dynamics, including the conformational changes they undergo to carry out their function. For the aforementioned reasons, the study of large conformational changes in proteins has been an interest to researchers for years. However, since some proteins experience rapid and transient conformational changes, it is hard to experimentally capture the intermediate structures. Additionally, computational brute force methods are computationally intractable, which makes it impossible to find these pathways which require a search in a high-dimensional, complex space. In our previous work, we implemented a hybrid algorithm that combines Monte-Carlo (MC) sampling and RRT*, a version of the Rapidly Exploring Random Trees (RRT) robotics-based method, to make the conformational exploration more accurate and efficient, and produce smooth conformational pathways. In this work, we integrated the rigidity analysis of proteins into our algorithm to guide the search to explore flexible regions. We demonstrate that rigidity analysis dramatically reduces the run time and accelerates convergence.