bluuebunny/crossref_metadata_2025_split huggingface dataset:
Atypical genomic patterning of the cerebral cortex in autism with poor early language outcome
Authors: Lombardo Michael V. , Eyler Lisa , Pramparo Tiziano , Gazestani Vahid H. , Hagler Donald J. , Chen Chi-Hua , Dale Anders M. , Seidlitz Jakob , Bethlehem Richard A. I. , Bertelsen Natasha , Barnes Cynthia Carter , Lopez Linda , Campbell Kathleen , Lewis Nathan E. , Pierce Karen , Courchesne Eric 
Published: August 2020

AbstractCortical regional identities develop through anterior-posterior (A-P) and dorsal-ventral (D-V) prenatal genomic patterning gradients. Here we find that A-P and D-V genomic patterning of cortical surface area (SA) and thickness (CT) is intact in typically developing and autistic toddlers with good language outcome, but is absent in autistic toddlers with poor early language outcome. Genes driving this effect are prominent in midgestational A-P and D-V gene expression gradients and prenatal cell types driving SA and CT variation (e.g., progenitor cells versus excitatory neurons). These genes are also important for vocal learning, human-specific evolution, and prenatal co-expression networks enriched for high-penetrance autism risk genes. Autism with poor early language outcome may be linked to atypical genomic cortical patterning starting in prenatal periods and which impacts later development of regional functional specialization and circuit formation.One Sentence SummaryGenomic patterning of the cortex is atypical in autistic toddlers with poor early language outcome.
Reactive or transgenic increase in microglial TYROBP reveals a TREM2-independent TYROBP-APOE link in wild-type and Alzheimer’s-related mice
Authors: Audrain Mickael , Haure-Mirande Jean-Vianney , Mleczko Justyna , Wang Minghui , Griffin Jennifer K. , Fraser Paul , Zhang Bin , Gandy Sam , Ehrlich Michelle E. 
Published: August 2020

ABSTRACTMicroglial TYROBP (also known as DAP12) has been identified by computational transcriptomics as a network hub and driver in late-onset sporadic Alzheimer’s disease (AD) and as an important regulator of the microglial environmental sensing function. TYROBP is the transmembrane adaptor of AD-related receptors TREM2 and CR3, but importantly, TYROBP interacts with many other receptors, and little is known about its roles in microglial action and/or in the pathogenesis of AD. Herein, using dual RNAin situhybridization and immunohistochemistry, we demonstrate that endogenousTyrobptranscription is increased specifically in recruited microglia in the brains of wild-type and AD-related mouse models. To determine whether chronically elevated TYROBP might modify microglial phenotype and/or progression of AD pathogenesis, we generated a novel transgenic mouse overexpressing TYROBP in microglia. TYROBP-overexpressing mice were crossed with eitherAPP/PSEN1orMAPTP301Smice, resulting in a decrease of the amyloid burden in the former and an increase of TAU phosphorylation in the latter. Apolipoprotein E (Apoe) transcription was upregulated inMAPTP301Smice overexpressing TYROBP and transcription of genes previously associated withApoe, includingAxl,Ccl2,TgfβandIl6, was altered in bothAPP/PSEN1andMAPTP301Smice overexpressing TYROBP. Lastly,TyrobpandApoemRNAs were clearly increased inTrem2-null mice in microglia recruited around a cortical stab injury or amyloid-β (Aβ) deposits. Conversely, microglialApoetranscription was dramatically diminished whenTyrobpwas absent. Our results provide compelling evidence that TYROBP-APOE signaling in the microglial sensome does not require TREM2. We propose that activation of a TREM2-independent TYROBP-APOE signaling could be an early or even initiating step in the transformation of microglia from the homeostatic phenotype to the Disease-Associated Microglia (DAM) phenotype.
Agonist and antagonist diverted twisting motions of single TRPV1 channel
Authors: Fujimura Shoko , Mio Kazuhiro , Kuramochi Masahiro , Sekiguchi Hiroshi , Ikezaki Keigo , Mio Muneyo , Hengphasatporn Kowit , Shigeta Yasuteru , Kubo Tai , Sasaki Yuji C. 
Published: August 2020

AbstractTransient receptor potential vanilloid type 1 (TRPV1) channels are activated by heat, vanilloids, and extracellular protons. Cryo-EM has revealed various conformations of TRPV1, and these structures suggest an intramolecular twisting motion in response to ligand binding. However, limited experimental data support this observation. Here we analyzed the intramolecular motion of TRPV1 using diffracted X-ray tracking (DXT). DXT analyzes trajectories of Laue spots generated from attached gold nanocrystals, and provides picometer spatial and microsecond time scale information about intramolecular motion. We observed that both an agonist and a competitive antagonist evoked rotating bias in TRPV1, though these biases were in opposing directions. Furthermore, the rotational bias generated by capsaicin was reversed between the wild type and the capsaicin-insensitive Y511A mutant. Our findings bolster the understanding of the mechanisms used activation and modulation of TRP channels, and this knowledge can be exploited for pharmacological usage such as inhibitor design.
Intracellular accumulation and secretion of hydrophobin-enriched vesicles aid the rapid sporulation of molds
Authors: Cai Feng , Zhao Zheng , Gao Renwei , Ding Mingyue , Jiang Siqi , Gao Qi , Chenthamara Komal , Grujic Marica , Fu Zhifei , Zhang Jian , Przylucka Agnes , Xu Pingyong , Akcapinar Günseli Bayram , Shen Qirong , Druzhinina Irina S. 
Published: August 2020

AbstractFungi can rapidly produce large amounts of spores suitable for aerial dispersal. The hydrophobicity of spores is provided by the unique amphiphilic and superior surface-active proteins – hydrophobins (HFBs) – that self-assemble at hydrophobic/hydrophilic interfaces and thus change surface properties. Using the HFB-enriched moldTrichodermaand the HFB-free yeastPichia pastoris, we revealed a distinctive HFB secretory pathway that includes an intracellular accumulation of HFBs in lipid bodies (LBs) that can internalize in vacuoles. The resulting vacuolar multicisternal structures (VMS) are stabilized by HFB layers that line up on their surfaces. These HFB-enriched VMSs can move to the periplasm for secretion or become fused in large tonoplast-like organelles. The latter contributes to the maintenance of turgor pressure required for the erection of sporogenic structures and rapid HFB secretion by squeezing out periplasmic VMSs through the cell wall. Thus, HFBs are essential accessory proteins for the development of aerial hyphae and colony architecture.
Genetic ablation of serotonin receptor 2B improves aortic valve hemodynamics in a high-cholesterol diet mouse model
Authors: Joll J. Ethan , Clark Cynthia R. , Peters Christine S. , Raddatz Michael A. , Bersi Matthew R. , Merryman W. David 
Published: August 2020

ABSTRACTCalcific aortic valve disease (CAVD) is a deadly disease that is rising in prevalence due to population aging. While the disease is complex and poorly understood, one well-documented driver of valvulopathy is serotonin agonism. Both serotonin overexpression, as seen with carcinoid tumors and drug-related agonism, such as with Fenfluramine use, are linked with various diseases of the valves. Thus, the objective of this study was to determine if genetic ablation or pharmacological antagonism of the 5-HT2Bserotonin receptor (gene:Htr2b) could improve the hemodynamic and histological progression of calcific aortic valve disease.Htr2bmutant mice were crossed withNotch1+/-mice, an established small animal model of CAVD, to determine if genetic ablation affects CAVD progression. To assess the effect of pharmacological inhibition on CAVD progression,Notch1+/-mice were treated with the 5-HT2Breceptor antagonist SB204741. Mice were analyzed using echocardiography, histology, immunofluorescence, and real-time quantitative polymerase chain reaction.Htr2bmutant mice showed lower aortic valve peak velocity and mean pressure gradient – classical hemodynamic indicators of aortic valve stenosis – without concurrent left ventricle change. 5-HT2Breceptor antagonism, however, did not affect hemodynamic progression. Leaflet thickness, collagen density, and CAVD-associated transcriptional markers were not significantly different in any group. This study reveals that genetic ablation ofHtr2battenuates hemodynamic development of CAVD in theNotch1+/-mice, but pharmacological antagonism may require high doses or long-term treatment to slow progression.
Bacterial behavior in human blood reveals complement evaders with persister-like features
Authors: Pont Stéphane , Fraikin Nathan , Caspar Yvan , Van Melderen Laurence , Attrée Ina , Cretin François 
Published: August 2020

AbstractsBacterial bloodstream infections (BSI) are a major health concern and can cause up to 40% mortality.Pseudomonas aeruginosaBSI is often of nosocomial origin and is associated with a particularly poor prognosis. The mechanism of bacterial persistence in blood is still largely unknown. Here, we analyzed the behavior of a cohort of clinical and laboratoryPseudomonas aeruginosastrains in human blood. In this specific environment, complement was the main defensive mechanism, acting either by direct bacterial lysis or by opsonophagocytosis, which required recognition by immune cells. We found highly variable survival rates for different strains in blood, whatever their origin, serotype, or the nature of their secreted toxins and despite their detection by immune cells. We identified and characterized a complement-tolerant subpopulation of bacterial cells that we named “evaders”. Evaders represented 0.1-0.001% of the initial bacterial load and displayed transient tolerance. Although evaders shared some features with bacterial persisters, which tolerate antibiotic treatment, they appear to have evolved distinct strategies to escape complement. We detected the evaders for five other major human pathogens:Acinetobacter baumannii, Burkholderia multivorans, enteroaggregativeEscherichia coli, Klebsiella pneumoniae, andYersinia enterocolitica. Thus, the evaders could allow the pathogen to persist within the bloodstream, and may be the cause of fatal bacteremia or dissemination, notably in the absence of effective antibiotic treatments.Author summary for “Complement evaders”Blood infections by antibiotic resistant bacteria, notablyPseudomonas aeruginosa, are major concerns in hospital settings. The complex interplay betweenP.aeruginosaand the innate immune system in the context of human blood is still poorly understood. By studying the behavior of variousP.aeruginosastrains in human whole blood and plasma, we showed that bacterial strains display different rate of tolerance to the complement system. Despite the complement microbicide activity, most bacteria withstand elimination through phenotypic heterogeneity creating a tiny (<0.1%) subpopulation of transiently tolerant evaders. While genetically identical to the rest of the complement-sensitive population, evaders allow the bacteria to persist in plasma. This phenotypic heterogeneity thus prevents total elimination of the pathogen from the circulation, and represent a new strategy to disseminate within the organism.
Spike protein mutational landscape in India: Could Muller’s ratchet be a future game-changer for COVID-19?
Authors: Banerjee Rachana , Basak Kausik , Ghosh Anamika , Rajachandran Vyshakh , Sureka Kamakshi , Ganguly Debabani , Chattopadhyay Sujay 
Published: August 2020

AbstractThe dire need of effective preventive measures and treatment approaches against SARS-CoV-2 virus, causing COVID-19 pandemic, calls for an in-depth understanding of its evolutionary dynamics with attention to specific geographic locations, since lockdown and social distancing to prevent the virus spread could lead to distinct localized dynamics of virus evolution within and between countries owing to different environmental and host-specific selection pressures. To decipher any correlation between SARS-CoV-2 evolution and its epidemiology in India, we studied the mutational diversity of spike glycoprotein, the key player for the attachment, fusion and entry of virus to the host cell. For this, we analyzed the sequences of 630 Indian isolates as available in GISAID database till June 07, 2020, and detected the spike protein variants to emerge from two major ancestors – Wuhan-Hu-1/2019 and its D614G variant. Average stability of the docked spike protein – host receptor (S-R) complexes for these variants correlated strongly (R2=0.96) with the fatality rates across Indian states. However, while more than half of the variants were found unique to India, 67% of all variants showed lower stability of S-R complex than the respective ancestral variants, indicating a possible fitness loss in recently emerged variants, despite a continuous increase in mutation rate. These results conform to the sharply declining fatality rate countrywide (>7-fold during April 11 – June 28, 2020). Altogether, while we propose the potential of S-R complex stability to track disease severity, we urge an immediate need to explore if SARS-CoV-2 is approaching mutational meltdown in India.Author summaryEpidemiological features are intricately linked to evolutionary diversity of rapidly evolving pathogens, and SARS-CoV-2 is no exception. Our work suggests the potential of average stability of complexes formed by the circulating spike mutational variants and the human host receptor to track the severity of SARS-CoV-2 infection in a given region. In India, the stability of these complexes for recent variants tend to decrease relative to their ancestral ones, following countrywide declining fatality rate, in contrast to an increasing mutation rate. We hypothesize such a scenario as nascent footprints of Muller’s ratchet, proposing large-scale population genomics study for its validation, since this understanding could lead to therapeutic approaches for facilitating mutational meltdown of SARS-CoV-2, as experienced earlier for influenza A virus.
First report of antiviral activity of carbon nanofibers: Enhancement of the viral inhibition capacity of calcium alginate films
Authors: Sanmartín-Santos Isaías , Gandía-Llop Sofía , Serrano-Aroca Ángel 
Published: August 2020

AbstractThe World Health Organization has called for new effective and affordable alternative antiviral materials for the prevention and treatment of viral infections. In this regard, calcium alginate has previously shown to possesses antiviral activity against the enveloped double-stranded DNA herpes simplex virus type 1. However, non-enveloped viruses are more resistant to inactivation than enveloped ones. Thus, the viral inhibition capacity of calcium alginate and the effect of adding a minuscule amount of carbon nanomaterials (0.1%w/w) have been explored here against a non-enveloped double-stranded DNA virus model for the first time. The results of this study showed that neat calcium alginate films are able to inactivate this type of non-enveloped virus and that including that extremely low percentage of carbon nanofibers significantly enhanced its viral inhibition from ~55.6% to 96.33%. This is the first published study to demonstrate CNFs’ antiviral activity. However, adding this small percentage of graphene oxide did not improve the antiviral activity of calcium alginate, although both composite biomaterials possess antiviral and other outstanding properties very promising for biomedical applications.
Infection and transmission of SARS-CoV-2 depends on heparan sulfate proteoglycans
Authors: Bermejo-Jambrina Marta , Eder Julia , Kaptein Tanja M. , van Hamme John L. , Helgers Leanne C. , Vlaming Killian E. , Brouwer Philip J.M. , Vlaar Alexander P.J. , van Baarle Frank E.H.P. , Spaargaren Marcel , de Bree Godelieve J. , Nijmeijer Bernadien M. , Kootstra Neeltje A. , van Gils Marit J. , Sanders Rogier W. , Geijtenbeek Teunis B. H. 
Published: August 2020

AbstractThe current pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and outbreaks of new variants highlight the need for preventive treatments. Here we identified heparan sulfate proteoglycans as attachment receptors for SARS-CoV-2. Notably, neutralizing antibodies against SARS-CoV-2 isolated from COVID-19 patients interfered with SARS-CoV-2 binding to heparan sulfate proteoglycans, which might be an additional mechanism of antibodies to neutralize infection. SARS-CoV-2 binding to and infection of epithelial cells was blocked by low molecular weight heparins (LMWH). Although dendritic cells (DCs) and mucosal Langerhans cells (LCs) were not infected by SARS-CoV-2, both DC subsets efficiently captured SARS-CoV-2 via heparan sulfate proteoglycans, and transmitted the virus to ACE2-positive cells. Moreover, human primary nasal cells were infected by SARS-CoV-2 and infection was blocked by pre-treatment with LMWH. These data strongly suggest that heparan sulfate proteoglycans are important attachment receptors facilitating infection and transmission, and support the use of LMWH as prophylaxis against SARS-CoV-2 infection.
Drug Repurposing Screen for Compounds Inhibiting the Cytopathic Effect of SARS-CoV-2
Authors: Chen Catherine Z. , Shinn Paul , Itkin Zina , Eastman Richard T. , Bostwick Robert , Rasmussen Lynn , Huang Ruili , Shen Min , Hu Xin , Wilson Kelli M. , Brooks Brianna , Guo Hui , Zhao Tongan , Klump-Thomas Carleen , Simeonov Anton , Michael Samuel G. , Lo Donald C. , Hall Matthew D. , Zheng Wei 
Published: August 2020

AbstractDrug repurposing is a rapid approach to identifying therapeutics for the treatment of emerging infectious diseases such as COVID-19. To address the urgent need for treatment options, we carried out a quantitative high-throughput screen using a SARS-CoV-2 cytopathic assay with a compound collection of 8,810 approved and investigational drugs, mechanism-based bioactive compounds, and natural products. Three hundred and nineteen compounds with anti-SARS-CoV-2 activities were identified and confirmed, including 91 approved drug and 49 investigational drugs. Among these confirmed compounds, the anti-SARS-CoV-2 activities of 230 compounds, including 38 approved drugs, have not been previously reported. Chlorprothixene, methotrimeprazine, and piperacetazine were the three most potent FDA approved drugs with anti-SARS-CoV-2 activities. These three compounds have not been previously reported to have anti-SARS-CoV-2 activities, although their antiviral activities against SARS-CoV and Ebola virus have been reported. These results demonstrate that this comprehensive data set of drug repurposing screen for SARS-CoV-2 is useful for drug repurposing efforts including design of new drug combinations for clinical trials.
Enhanced reinstatement of naturalistic event memories due to hippocampal-network-targeted stimulation
Authors: Hebscher Melissa , Kragel James E. , Kahnt Thorsten , Voss Joel L. 
Published: August 2020

AbstractEpisodic memory involves the reinstatement of distributed patterns of brain activity present when events were initially experienced. The hippocampus is thought to coordinate reinstatement via its interactions with a network of brain regions, but this hypothesis has not been causally tested in humans. The current study directly tested the involvement of the hippocampal network in reinstatement using network-targeted noninvasive stimulation. We measured reinstatement of multi-voxel patterns of fMRI activity during encoding and retrieval of naturalistic video clips depicting everyday activities. Reinstatement of video-specific activity patterns was robust in posterior-parietal and occipital areas previously implicated in event reinstatement. Theta-burst stimulation targeting the hippocampal network increased videospecific reinstatement of fMRI activity patterns in occipital cortex and improved memory accuracy relative to stimulation of a control out-of-network location. Furthermore, stimulation targeting the hippocampal network influenced the trial-by-trial relationship between hippocampal activity during encoding and later reinstatement in occipital cortex. These findings implicate the hippocampal network in the reinstatement of spatially distributed patterns of event-specific activity, and identify a role for the hippocampus in encoding complex naturalistic events that later undergo cortical reinstatement.
Fitting side-chain NMR relaxation data using molecular simulations
Authors: Kümmerer Felix , Orioli Simone , Harding-Larsen David , Hoffmann Falk , Gavrilov Yulian , Teilum Kaare , Lindorff-Larsen Kresten 
Published: August 2020

AbstractProteins display a wealth of dynamical motions that can be probed using both experiments and simulations. We present an approach to integrate side chain NMR relaxation measurements with molecular dynamics simulations to study the structure and dynamics of these motions. The approach, which we term ABSURDer (Average Block Selection Using Relaxation Data with Entropy Restraints) can be used to find a set of trajectories that are in agreement with relaxation measurements. We apply the method to deuterium relaxation measurements in T4 lysozyme, and show how it can be used to integrate the accuracy of the NMR measurements with the molecular models of protein dynamics afforded by the simulations. We show how fitting of dynamic quantities leads to improved agreement with static properties, and highlight areas needed for further improvements of the approach.
Activation of VTA GABA Neurons Disrupts Reward Seeking by Altering Temporal Processing
Authors: Shields Andrea K. , Suarez Mauricio , Wakabayashi Ken T. , Bass Caroline E. 
Published: August 2020

AbstractThe role of ventral tegmental area (VTA) dopamine in reward, cue processing, and interval timing is well characterized. Using a combinatorial viral approach to target activating DREADDs (DesignerReceptorsExclusivelyActivated byDesignerDrugs, hM3D) to GABAergic neurons in the VTA of male rats, we previously showed that activation disrupts responding to reward-predictive cues. Here we explored how VTA GABA neurons influence the perception of time in two fixed interval (FI) tasks, one where the reward or interval is not paired with predictive cues (Non-Cued FI), and another where the start of the FI is signaled by a constant tone that continues until the rewarded response is emitted (Cued FI). Under vehicle conditions in both tasks, responding was characterized by “scalloping” over the 30s FI, in which responding increased towards the end of the FI. However, when VTA GABA neurons were activated in the Non-Cued FI, the time between the end of the 30s interval and when the rats made a reinforced response increased. Additionally, post-reinforcement pauses and overall session length increased. In the Cued FI task, VTA GABA activation produced erratic responding, with a decrease in earned rewards. Thus, while both tasks were disrupted by VTA GABA activation, responding that is constrained by a cue was more sensitive to this manipulation, possibly due to convergent effects on timing and cue processing. Together these results demonstrate that VTA GABA activity disrupts the perception of interval timing, particularly when the timing is set by cues.
Machine learning optimization of peptides for presentation by class II MHCs
Authors: Dai Zheng , Huisman Brooke D. , Zeng Haoyang , Carter Brandon , Jain Siddhartha , Birnbaum Michael E. , Gifford David K. 
Published: August 2020

AbstractT cells play a critical role in normal immune responses to pathogens and cancer and can be targeted to MHC-presented antigens via interventions such as peptide vaccines. Here, we present a machine learning method to optimize the presentation of peptides by class II MHCs by modifying the peptide’s anchor residues. Our method first learns a model of peptide affinity for a class II MHC using an ensemble of deep residual networks, and then uses the model to propose anchor residue changes to improve peptide affinity. We use a high throughput yeast display assay to show that anchor residue optimization successfully improved peptide binding.