bluuebunny/crossref_metadata_2025_split huggingface dataset:
EnteropathogenicEscherichia coli(EPEC) Infection Induces Diarrhea, Intestinal Damage, Metabolic Alterations and Increased Intestinal Permeability in a Murine Model
Authors: Ledwaba Solanka E. , Costa Deiziane V.S. , Bolick David T. , Giallourou Natasa , Medeiros Pedro H.Q.S. , Swann J Jonathan R. , Traore-Hoffman Afsatou N. , Potgieter Natasha , Nataro James P. , Guerrant Richard L. 
Published: June 2020

ABSTRACTEnteropathogenicE. coli(EPEC) are recognized as one of the leading bacterial causes of infantile diarrhea worldwide. Weaned C57BL/6 mice pretreated with antibiotics were challenged orally with wild-type EPEC orescNmutant (lacking type 3 secretion system) to determine colonization, inflammatory responses and clinical outcomes during infection. Antibiotic disruption of intestinal microbiota enabled efficient colonization by wild-type EPEC resulting in growth impairment and diarrhea. Increase in inflammatory biomarkers, chemokines, cellular recruitment and pro-inflammatory cytokines were observed in intestinal tissues. Metabolomic changes were also observed in EPEC infected mice with changes in TCA cycle intermediates, increased creatine excretion and shifts in gut microbial metabolite levels. In addition, by 7 days after infection, although weights were recovering, EPEC-infected mice had increased intestinal permeability and decreased colonic claudin-1 levels. TheescNmutant colonized the mice, but had no weight changes or increased inflammatory biomarkers, showing the importance of the T3SS in EPEC virulence in this model. In conclusion, a murine infection model treated with antibiotics has been developed to mimic many clinical outcomes seen in children with EPEC infection and to examine potential roles of selected virulence traits. This model can help in further understanding mechanisms involved in the pathogenesis of EPEC infections and potential outcomes and thus assist in the development of potential preventive or therapeutic interventions.
Convergence of cortical types and functional motifs in the mesiotemporal lobe
Authors: Paquola Casey , Benkarim Oualid , DeKraker Jordan , Lariviere Sara , Frässle Stefan , Royer Jessica , Tavakol Shahin , Valk Sofie , Bernasconi Andrea , Bernasconi Neda , Khan Ali , Evans Alan , Razi Adeel , Smallwood Jonathan , Bernhardt Boris 
Published: June 2020

AbstractThe parahippocampus-hippocampus complex in the mesiotemporal lobe (MTL) is implicated in many different cognitive processes, is compromised in numerous disorders, and exhibits a unique cytoarchitectural transition from six-layered isocortex to three-layered allocortex. Our study leveraged an ultra-high-resolution histological reconstruction of a human brain to (i) develop a continuous surface model of the MTL iso-to-allocortex transition and (ii) quantitatively characterise the region’s cytoarchitecture. We projected the model into the native space ofin vivofunctional magnetic resonance imaging of healthy adults to (iii) construct a generative model of its intrinsic circuitry and (iv) determine its relationship with distributed functional dynamics of macroscale isocortical fluctuations. We provide evidence that the most prominent axis of cytoarchitectural differentiation of the MTL follows infolding from iso-to-allocortex and is defined by depth-specific variations in neuron density. Intrinsic effective connectivity exhibited a more complex relationship to MTL geometry, varying across both iso-to-allocortical and anterior-posterior axes. Variation along the long axis of the MTL was associated with differentiation between transmodal and unimodal systems, with anterior regions linked to transmodal cortex. In contrast, the iso-to-allocortical gradient was associated with the multiple demand system, with isocortex linked to regions activated when task demands prohibit the use of prior knowledge. Our findings establish a novel model of the MTL, in which its broad influence on neural function emerges through the combination micro- and macro-scale structural features.
A predictive coarse-grained model for position-specific effects of post-translational modifications on disordered protein phase separation
Authors: Perdikari T. M. , Jovic N. , Dignon G. L. , Kim Y. C. , Fawzi N. L. , Mittal J. 
Published: June 2020

AbstractBiomolecules undergo liquid-liquid phase separation (LLPS) resulting in the formation of multicomponent protein-RNA membraneless organelles in cells. However, the physiological and pathological role of post translational modifications (PTMs) on the biophysics of phase behavior is only beginning to be probed. To study the effect of PTMs on LLPSin silico, we extend our transferable coarse-grained model of intrinsically disordered proteins to include phosphorylated and acetylated amino acids. Using the parameters for modified amino acids available for fixed charge atomistic forcefields, we parameterize the size and atomistic hydropathy of the coarse-grained modified amino acid beads, and hence the interactions between the modified and natural amino acids. We then elucidate how the number and position of phosphorylated and acetylated residues alter the protein’s single chain compactness and its propensity to phase separate. We show that both the number and the position of phosphorylated threonines/serines or acetylated lysines can serve as a molecular on/off switch for phase separation in the well-studied disordered regions of FUS and DDX3X, respectively. We also compare modified residues to their commonly used PTM mimics for their impact on chain properties. Importantly, we show that the model can predict and capture experimentally measured differences in the phase behavior for position-specific modifications, showing that the position of modifications can dictate phase separation. In sum, this model will be useful for studying LLPS of post-translationally modified intrinsically disordered proteins and predicting how modifications control phase behavior with position-specific resolution.Statement of SignificancePost-translational modifications are important regulators of liquid-liquid phase separation (LLPS) which drives the formation of biomolecular condensates. Theoretical methods can be used to characterize the biophysical properties of intrinsically disordered proteins (IDPs). Our recent framework for molecular simulations using a Cα-centered coarse-grained model can predict the effect of various perturbations such as mutations (Dignon et al.PloS Comput. Biol, 2018) and temperature (Dignon et al,ACS Cent. Sci., 2019) on LLPS. Here, we expand this framework to incorporate modified residues like phosphothreonine, phosphoserine and acetylysine. This model will prove useful for simulating the phase separation of post-translationally modified IDPs and predicting how position-specific modifications can control phase behavior across the large family of proteins known to be phosphorylated and acetylated.
Structural basis for potent neutralization of SARS-CoV-2 and role of antibody affinity maturation
Authors: Hurlburt Nicholas K. , Wan Yu-Hsin , Stuart Andrew B. , Feng Junli , McGuire Andrew T. , Stamatatos Leonidas , Pancera Marie 
Published: June 2020

AbstractSARS-CoV-2 is a betacoronavirus virus responsible for the COVID-19 pandemic. Here, we determined the X-ray crystal structure of a potent neutralizing monoclonal antibody, CV30, isolated from a patient infected with SARS-CoV-2, in complex with the receptor binding domain (RBD). The structure reveals CV30’s epitope overlaps with the human ACE2 receptor binding site thus providing the structural basis for its neutralization by preventing ACE2 binding.
Ordered dephosphorylation initiated by the selective proteolysis of cyclin B drives mitotic exit
Authors: Holder James , Mohammed Shabaz , Barr Francis A. 
Published: June 2020

ABSTRACTAPC/C-mediated proteolysis of cyclin B and securin promotes entry into anaphase, inactivating CDK1 and permitting chromosome segregation, respectively. Reduction of CDK1 activity relieves inhibition of the CDK1-opposing phosphatases PP1 and PP2A-B55 leading to dephosphorylation of substrates crucial for mitotic exit. Meanwhile, continued APC/C activity is required to target various proteins, including Aurora and Polo kinases, for degradation. Together, these activities orchestrate a complex series of events during mitotic exit. However, the relative importance of regulated proteolysis and dephosphorylation in dictating the order and timing of these events remains unclear. Using high temporal-resolution mass spectrometry, we compare the relative extent of proteolysis and protein dephosphorylation. This reveals highly-selective rapid (∼5min half-life) proteolysis of cyclin B, securin and geminin at the metaphase to anaphase transition, followed by slow proteolysis (>60 min half-life) of other mitotic regulators. Protein dephosphorylation requires APC/C-dependent destruction of cyclin B and was resolved into PP1-dependent fast, intermediate and slow categories with unique sequence motifs. We conclude that dephosphorylation initiated by the selective proteolysis of cyclin B drives the bulk of changes observed during mitotic exit.
Pandora: 4-D white matter bundle population-based atlases derived from diffusion MRI fiber tractography
Authors: Hansen Colin B , Yang Qi , Lyu Ilwoo , Rheault Francois , Kerley Cailey , Chandio Bramsh Qamar , Fadnavis Shreyas , Williams Owen , Shafer Andrea T. , Resnick Susan M. , Zald David H. , Cutting Laurie , Taylor Warren D , Boyd Brian , Garyfallidis Eleftherios , Anderson Adam W , Descoteaux Maxime , Landman Bennett A , Schilling Kurt G 
Published: June 2020

AbstractBrain atlases have proven to be valuable neuroscience tools for localizing regions of interest and performing statistical inferences on populations. Although many human brain atlases exist, most do not contain information about white matter structures, often neglecting them completely or labelling all white matter as a single homogenous substrate. While few white matter atlases do exist based on diffusion MRI fiber tractography, they are often limited to descriptions of white matter as spatially separate “regions” rather than as white matter “bundles” or fascicles, which are well-known to overlap throughout the brain. Additional limitations include small sample sizes, few white matter pathways, and the use of outdated diffusion models and techniques. Here, we present a new population-based collection of white matter atlases represented in both volumetric and surface coordinates in a standard space. These atlases are based on 2443 subjects, and include 216 white matter bundles derived from 6 different state-of-the-art tractography techniques. This atlas is freely available and will be a useful resource for parcellation and segmentation.
Methionine synthase is essential for cancer cell proliferation in physiological folate environments
Authors: Sullivan Mark R. , Darnell Alicia M. , Reilly Montana F. , Lewis Caroline A. , Vander Heiden Matthew G. 
Published: June 2020

ABSTRACTTargeting folate metabolism can be an effective way to treat cancer. The enzyme methionine synthase catalyzes a key reaction in both folate and methionine metabolism. Early work suggested that inhibiting methionine synthase might restrain tumor growth, though the mechanism remains unclear. We find that due to its specific role in processing folates, methionine synthase is required for cancer proliferation. However, widely used cell culture conditions obscure the proliferative and metabolic consequences of methionine synthase inhibition. Complete dependence on methionine synthase only arises when 5-methyl tetrahydrofolate, the major folate found in circulation, is the predominant folate source provided to cells. In these physiological folate conditions, methionine synthase activity is necessary to maintain intracellular levels of nucleotides, but not methionine. These data reveal that the extracellular environment can alter the essentiality of methionine synthase and suggest that this enzyme plays a crucial cell-autonomous role in supporting nucleotide synthesis and cell proliferation in physiological contexts.
MonitoringS. pombegenome stress by visualizing end-binding protein Ku
Authors: Jones Chance , Forsburg Susan L 
Published: June 2020

AbstractStudies of genome stability have exploited visualization of fluorescently tagged proteins in live cells to characterize DNA damage, checkpoint, and repair responses. In this report, we describe a new tool for fission yeast, a tagged version of the end-binding protein Pku70 which is part of the KU protein complex. We compare Pku70 localization to other markers upon treatment to various genotoxins, and identify a unique pattern of distribution. Pku70 provides a new tool to define and characterize DNA lesions and the repair response.
Self-fertilization, but not mating strategy, predicts the evolution of sex allocation plasticity in a hermaphroditic flatworm genus
Authors: Singh Pragya , Schärer Lukas 
Published: June 2020

AbstractSex allocation (SA) theory in simultaneous hermaphrodites predicts that optimal SA is influenced by local sperm competition (LSC), which occurs when related sperm compete to fertilize a given set of eggs. Different factors, including the mating strategy and the ability to self-fertilize, are predicted to affect LSC and hence the optimal SA. Moreover, since the LSC experienced by an individual can vary temporally and spatially, this can favour the evolution of SA plasticity. Here, using seven species of the free-living flatworm genus Macrostomum, we document sizable interspecific variation in SA, but neither their mating strategy nor their ability to self-fertilize significantly predicted SA among these species. Since we also found considerable interspecific variation in SA plasticity, we further estimated standardized effect sizes for plasticity in response to i) the presence of mating partners (i.e. in isolation vs. with partners) and ii) the strength of LSC (i.e. in small vs. large groups). We found that self-fertilization predicted SA plasticity with respect to the presence of mating partners, with plasticity being lower for self-fertilizing species. Finally, we showed that interspecific variation in SA is higher than intraspecific variation due to SA plasticity. Our study suggests that both SA and SA plasticity are evolutionarily labile, with self-fertilization predicting the latter in Macrostomum.
ZZ Top: faster and more adaptive Z chromosome evolution in two Lepidoptera
Authors: Mongue Andrew J. , Hansen Megan E. , Walters James R. 
Published: June 2020

AbstractThe rate of divergence for Z or X chromosomes is theoretically predicted to be greater than autosomes, but the possible explanations for this pattern vary, as do empirical results from diverse taxa. Even among moths and butterflies (Lepidoptera), which generally share a single-origin Z chromosome, the handful of available studies give mixed support for faster or more adaptive evolution of the Z chromosome, depending on the species assayed. Here, we examine the molecular evolution of Z chromosomes in two additional lepidopteran species: the Carolina sphinx moth and the monarch butterfly, the latter of which possesses a recent chromosomal fusion yielding a segment of newly Z-linked DNA. We find evidence for both faster and more adaptive Z chromosome evolution in both species, though this effect is strongest in the neo-Z portion of the monarch sex chromosome. The neo-Z is less male-biased than expected of a Z chromosome, and unbiased and female-biased genes drive the signal for adaptive evolution here. Together these results suggest that male-biased gene accumulation and haploid selection have opposing effects on long-term rates of adaptation and may help explain the discrepancies in previous findings as well as the repeated evolution of neo-sex chromosomes in Lepidoptera.
Deep multitask learning of gene risk for comorbid neurodevelopmental disorders
Authors: Beyreli Ilayda , Karakahya Oguzhan , Cicek A. Ercument 
Published: June 2020

AbstractAutism Spectrum Disorder (ASD) and Intellectual Disability (ID) are comorbid neurodevelopmental disorders with complex genetic architectures. Despite large-scale sequencing studies only a fraction of the risk genes were identified for both. Here, we present a novel network-based gene risk prioritization algorithm named DeepND that performs cross-disorder analysis to improve prediction power by exploiting the comorbidity of ASD and ID via multitask learning. Our model leverages information from gene coexpression networks that model human brain development using graph convolutional neural networks and learns which spatio-temporal neurovelopmental windows are important for disorder etiologies. We show that our approach substantially improves the state-of-the-art prediction power in both single-disorder and cross-disorder settings. DeepND identifies prefrontal and primary motor-somatosensory cortex brain region, and periods from early fetal to mid fetal periods and from early childhood to young adulthood as the highest neurodevelopmental risk windows for both ASD and ID. Finally, we investigate frequent ASD and ID associated copy number variation regions and report our findings for several susceptibility gene candidates. DeepND can be generalized to analyze any combinations of comorbid disorders and is released athttp://github.com/ciceklab/deepnd.
A temporal map of maternal immune activation-induced changes reveals a shift in neurodevelopmental timing and perturbed cortical development in mice
Authors: Canales Cesar P. , Estes Myka L. , Cichewicz Karol , Angara Kartik , Aboubechara John Paul , Cameron Scott , Prendergast Kathryn , Su-Feher Linda , Zdilar Iva , Kreun Ellie J. , Connolly Emma C. , Seo Jin M. , Goon Jack B. , Farrelly Kathleen , Stradleigh Tyler , van der List Deborah , Haapanen Lori , Van de Water Judy , Vogt Daniel , McAllister A. Kimberley , Nord Alex S. 
Published: June 2020

AbstractBackgroundEnvironmental insults that activate the maternal immune system are potent primers of developmental neuropathology and maternal immune activation (MIA) has emerged as a risk factor for neurodevelopmental and psychiatric disorders. Animal models of MIA provide an opportunity to identify molecular pathways that initiate disease processes and lead to neuropathology and behavioral deficits in offspring. MIA-induced behaviors are accompanied by anatomical and neurochemical alterations in adult offspring that parallel those seen in affected human populations.MethodsWe performed transcriptional profiling and neuroanatomical characterization in a time course across mouse embryonic cortical development, following MIA via single injection of the viral mimic polyinosinic:polycytidylic acid (polyI:C) at E12.5. Transcriptional changes identified in the cortex of MIA offspring at E17.5 were validated and mapped to cortical neuroanatomy and cell types via protein analysis and immunohistochemistry.ResultsMIA induced strong transcriptomic signatures, including induction of genes associated with hypoxia, immune signaling, and angiogenesis. The acute response identified 6h after the MIA insult was followed by changes in proliferation, neuronal and glial differentiation, and cortical lamination that emerged at E14.5 and peaked at E17.5. Decreased numbers of proliferative cell types in germinal zones and alterations in neuronal and glial cell types across cortical lamina were identified in the MIA-exposed cortex.ConclusionsMIA-induced transcriptomic signatures in fetal offspring overlap significantly with perturbations identified in neurodevelopmental disorders (NDDs), and provide novel insights into alterations in molecular and developmental timing processes linking MIA and neuropathology, potentially revealing new targets for development of novel approaches for earlier diagnosis and treatment of these disorders.
Calreticulin co-expression supports high level production of a recombinant SARS-CoV-2 spike mimetic inNicotiana benthamiana
Authors: Margolin Emmanuel , Verbeek Matthew , Meyers Ann , Chapman Ros , Williamson Anna-Lise , Rybicki Edward P 
Published: June 2020

AbstractAn effective prophylactic vaccine is urgently needed to protect against SARS-CoV-2 infection. The viral spike, which mediates entry into cells by interacting with the host angiotensin-converting enzyme 2, is the primary target of most vaccines in development. These vaccines aim to elicit protective immunity against the glycoprotein by use of inactivated virus, vector-mediated delivery of the antigenin vivo, or by direct immunization with the purified antigen following expression in a heterologous system. These approaches are mostly dependent on the growth of mammalian or insect cells, which requires a sophisticated infrastructure that is not generally available in developing countries due to the incumbent costs which are prohibitive. Plant-based subunit vaccine production has long been considered as a cheaper alternative, although low expression yields and differences along the secretory pathway to mammalian cells have posed a challenge to producing certain viral glycoproteins. Recent advances that have enabled many of these constraints to be addressed include expressing the requisite human proteins in plants to support the maturation of the protein of interest. In this study we investigated these approaches to support the production of a soluble and putatively trimeric SARS-CoV-2 spike mimetic inNicotiana benthamianavia transientAgrobacterium-mediatedexpression. The co-expression of human calreticulin dramatically improved the accumulation of the viral spike, which was barely detectable in the absence of the co-expressed accessory protein. The viral antigen was efficiently processed even in the absence of co-expressed furin, suggesting that processing may have occurred at the secondary cleavage site and was mediated by an endogenous plant protease. In contrast, the spike was not efficiently processed when expressed in mammalian cells as a control, although the co-expression of furin improved processing considerably. This study demonstrates the feasibility of molecular engineering to improve the production of viral glycoproteins in plants, and supports plant-based production of SARS-CoV-2 spike-based vaccines and reagents for serological assays.
The Human Telomeric Proteome During Telomere Replication
Authors: Lin Chih-Yi Gabriela , Näger Anna Christina , Lunardi Thomas , Vančevska Aleksandra , Lossaint Gérald , Lingner Joachim 
Published: June 2020

SummaryTelomere shortening can cause detrimental diseases and contribute to aging. It occurs due to the end replication problem in cells lacking telomerase. Furthermore, recent studies revealed that telomere shortening can be attributed to difficulties of the semi-conservative DNA replication machinery to replicate through the bulk of telomeric DNA repeats. To investigate telomere replication in a comprehensive manner, we develop QTIP-iPOND, which enables purification of proteins that associate with telomeres specifically during replication. We identify in addition to the core replisome a large number of proteins that associate with telomere replication forks and validate their importance. We find that POT1 is depleted, whereas histone H1 is specifically enriched, at telomere replication forks. Our work reveals the dynamic changes of the telomeric proteome during replication, providing a valuable resource of telomere replication proteins. To our knowledge, this is the first study that examines the replisome at a specific region of the genome.