bluuebunny/crossref_metadata_2025_split huggingface dataset:
Healthy cells functionally present TAP-independent SSR1 peptides: implications for selection of clinically relevant antigens
Authors: de Waard Antonius A. , Verkerk Tamara , Hoefakker Kelly , van der Steen Dirk M. , Jongsma Marlieke L.M. , Bliss Sophie , de Ru Arnoud H. , van Veelen Peter A. , Griffioen Marieke , Heemskerk Mirjam H.M. , Spaapen Robbert M. 
Published: June 2020

AbstractTumors with an impaired transporter associated with antigen processing (TAP) present several ER-derived self-antigens on HLA class I (HLA-I) which are absent on healthy cells. Selection of such TAP-independent antigens for T cell-based immunotherapy should include analysis of their expression on healthy cells to prevent therapy-induced adverse toxicities. However, it is unknown how the absence of clinically relevant antigens on healthy cells needs to be validated. Here we monitored TAP-independent antigen presentation on various healthy cells using a new toolbox consisting of a T cell clone recognizing a TAP-independent SSR1-derived antigen. We found that most but not all healthy cells present this antigen under normal and inflammatory conditions, indicating that TAP-independent antigen presentation is a variable phenomenon. Our data emphasize the necessity of extensive testing of a wide variety of healthy cell types to define clinically relevant TAP-independent antigens that can be safely targeted by immunotherapy.
Bacterial H-NS contacts DNA at the same irregularly spaced sites in both bridged and hemi-sequestered linear filaments
Authors: Shen Beth A. , Hustmyer Christine M. , Roston Daniel , Wolfe Michael B. , Landick Robert 
Published: June 2020

SUMMARYGene silencing in bacteria is mediated by chromatin proteins, of whichEscherichia coliH-NS is a paradigmatic example. H-NS forms nucleoprotein filaments with either one or two DNA duplexes. However, the structures, arrangements of DNA-binding domains (DBDs), and positions of DBD–DNA contacts in linear and bridged filaments are uncertain. To characterize the contacts that silence transcription by RNA polymerase, we combined ·OH footprinting, molecular dynamics, statistical modeling, and DBD mapping using a chemical nuclease (Fe2+-EDTA) tethered to the DBDs (TEN-map). We find that H-NS DBDs contact DNA at indistinguishable locations in bridged or linear filaments and that the DBDs vary in orientation and position with ~10-bp average spacing. Our results support a hemi-sequestration model of linear-to-bridged H-NS switching in which linear filaments able to inhibit only transcription initiation switch to bridged filaments able to inhibit both initiation and elongation using the same irregularly spaced DNA contact sites.HighlightsTethered-nuclease mapping (TEN-map) of H-NS DNA-binding domains detects DNA contactsBridged and linear H-NS filaments use the same DNA contact sitesH-NS–DNA contacts are unevenly spaced with ~10 bp average separationAT-steps, minor groove width, and electrostatic potential best predict contact sites
A strain-specific inhibitor of receptor-bound HIV-1 targets a pocket near the fusion peptide and offers a template for drug design
Authors: Ozorowski Gabriel , Torres Jonathan L. , Santos-Martins Diogo , Forli Stefano , Ward Andrew B. 
Published: June 2020

AbstractDisruption of viral fusion represents a viable, albeit under-explored, target for HIV therapeutics. While studying the receptor-bound envelope glycoprotein conformation by cryo-EM, we identified a pocket near the base of the trimer containing a bound detergent molecule and performedin silicodrug screening using a library of drug-like and commercially available molecules. After down-selection, we solved cryo-EM structures that validated binding of two small molecule hits in very similar manners to the predicted binding poses, including interactions with aromatic residues within the fusion peptide. One of the molecules demonstrated low micromolar inhibition of the autologous virus by utilizing a very rare phenylalanine in the fusion peptide and stabilizing the surrounding region. This work demonstrates that small molecules can target the fusion process, providing a new target for anti-HIV therapeutics, and highlights the need to explore how fusion peptide sequence variations affect receptor-mediated conformational states across diverse HIV strains.
Neuroscience Cloud Analysis As a Service
Authors: Abe Taiga , Kinsella Ian , Saxena Shreya , Buchanan E. Kelly , Couto Joao , Briggs John , Kitt Sian Lee , Glassman Ryan , Zhou John , Paninski Liam , Cunningham John P. 
Published: June 2020

AbstractA major goal of computational neuroscience is the development of powerful data analyses that operate on large datasets. These analyses form an essential toolset to derive scientific insights from new experiments. Unfortunately, a major obstacle currently impedes progress: novel data analyses have a hidden dependence upon complex computing infrastructure (e.g. software dependencies, hardware), acting as an unaddressed deterrent to potential analysis users. While existing analyses are increasingly shared as open source software, the infrastructure needed to deploy these analyses – at scale, reproducibly, cheaply, and quickly – remains totally inaccessible to all but a minority of expert users. In this work we develop Neuroscience Cloud Analysis As a Service (NeuroCAAS): a fully automated analysis platform that makes state-of-the-art data analysis tools accessible to the neuroscience community. Based on modern large-scale computing advances, NeuroCAAS is an open source platform with a drag-and-drop interface, entirely removing the burden of infrastructure purchase, configuration, deployment, and maintenance from analysis users and developers alike. NeuroCAAS offers two major scientific benefits to any data analysis. First, NeuroCAAS provides automatic reproducibility of analyses at no extra effort to the analysis developer or user. Second, NeuroCAAS cleanly separates tool implementation from usage, allowing for immediate use of arbitrarily complex analyses, at scale. We show how these benefits drive the design of simpler, more powerful data analyses. Furthermore, we show that many popular data analysis tools offered through NeuroCAAS outperform typical analysis solutions (in terms of speed and cost) while improving ease of use, dispelling the myth that cloud compute is prohibitively expensive and technically inaccessible. By removing barriers to fast, efficient cloud computation, NeuroCAAS can dramatically accelerate both the dissemination and the effective use of cutting-edge analysis tools for neuroscientific discovery.
Cohesin residency determines chromatin loop patterns
Authors: Costantino Lorenzo , Hsieh Tsung-Han S. , Lamothe Rebecca , Darzacq Xavier , Koshland Douglas 
Published: June 2020

ABSTRACTThe organization of chromatin into higher-order structures is essential for chromosome segregation, the repair of DNA-damage, and the regulation of gene expression. Using Micro-C XL to detect chromosomal interactions, we observed the pervasive presence of cohesin-dependent loops with defined positions throughout the genome of budding yeast, as seen in mammalian cells. In early S phase, cohesin stably binds to cohesin associated regions (CARs) genome-wide. Subsequently, positioned loops accumulate with CARs at the bases of the loops. Cohesin regulators Wpl1 and Pds5 alter the levels and distribution of cohesin at CARs, changing the pattern of positioned loops. From these observations, we propose that cohesin with loop extrusion activity is stopped by preexisting CAR-bound cohesins, generating positioned loops. The patterns of loops observed in a population of wild-type and mutant cells can be explained by this mechanism, coupled with a heterogeneous residency of cohesin at CARs in individual cells.
Activity Dependent Stimulation Increases Synaptic Efficacy In Spared Pathways In An Anesthetized Rat Model Of Spinal Cord Contusion Injury
Authors: Borrell Jordan A. , Krizsan-Agbas Dora , Nudo Randolph J. , Frost Shawn B. 
Published: June 2020

AbstractThe purpose of this study was to assess the ability of intraspinal microstimulation (ISMS), triggered by action potentials (spikes) recorded in motor cortex, to alter synaptic efficacy in descending motor pathways in an anesthetized rat model of spinal cord injury (SCI). Experiments were carried out in adult, male, Sprague Dawley rats with a moderate contusion injury at T8. For activity-dependent stimulation (ADS) sessions, a recording microelectrode was used to detect neuronal spikes in motor cortex that triggered ISMS in the spinal cord grey matter. SCI rats were randomly assigned to one of four experimental groups differing by: a) cortical spike-ISMS stimulus delay (10 or 25 ms) and b) number of ISMS pulses (1 or 3). Four weeks after SCI, ADS sessions were conducted in three consecutive 1-hour conditioning bouts for a total of 3 hours. At the end of each conditioning bout, changes in synaptic efficacy were assessed using intracortical microstimulation (ICMS) to examine the number of spikes evoked in spinal cord neurons during 5-minute test bouts. A multichannel microelectrode recording array was used to record cortically-evoked spike activity from multiple layers of the spinal cord. The results showed that ADS resulted in an increase in cortically-evoked spikes in spinal cord neurons at specific combinations of spike-ISMS delays and numbers of pulses. Efficacy in descending motor pathways was increased throughout all dorsoventral depths of the hindlimb spinal cord. These results show that after an SCI, ADS can increase synaptic efficacy in spared pathways between motor cortex and spinal cord. This study provides further support for ADS as an effective therapeutic approach for enhancing descending motor control after SCI.
Capturing brain dynamics: latent spatiotemporal patterns predict stimuli and individual differences
Authors: Venkatesh Manasij , JaJa Joseph , Pessoa Luiz 
Published: June 2020

AbstractInsights from functional Magnetic Resonance Imaging (fMRI), and more recently from recordings of large numbers of neurons through calcium imaging, reveal that many cognitive, emotional, and motor functions depend on the multivariate interactions of neuronal populations. To capture and characterize spatiotemporal properties of brain events, we propose an architecture based on long short-term memory (LSTM) networks to uncover distributed spatiotemporal signatures during dynamic experimental conditions1. We demonstrate the potential of the approach using naturalistic movie-watching fMRI data. We show that movie clips result in complex but distinct spatiotemporal patterns in brain data that can be classified using LSTMs (≈ 90% for 15-way classification), demonstrating that learned representations generalized to unseen participants. LSTMs were also superior to existing methods in predicting behavior and personality traits of individuals. We propose a dimensionality reduction approach that uncovers low-dimensional trajectories and captures essential informational properties of brain dynamics. Finally, we employed saliency maps to characterize spatiotemporally-varying brain-region importance. The spatiotemporal saliency maps revealed dynamic but consistent changes in fMRI activation data. We believe our approach provides a powerful framework for visualizing, analyzing, and discovering dynamic spatially distributed brain representations during naturalistic conditions.
Specific viral RNA drives the SARS CoV-2 nucleocapsid to phase separate
Authors: Iserman Christiane , Roden Christine , Boerneke Mark , Sealfon Rachel , McLaughlin Grace , Jungreis Irwin , Park Chris , Boppana Avinash , Fritch Ethan , Hou Yixuan J. , Theesfeld Chandra , Troyanskaya Olga G , Baric Ralph S. , Sheahan Timothy P. , Weeks Kevin , Gladfelter Amy S. 
Published: June 2020

AbstractA mechanistic understanding of the SARS-CoV-2 viral replication cycle is essential to develop new therapies for the COVID-19 global health crisis. In this study, we show that the SARS-CoV-2 nucleocapsid protein (N-protein) undergoes liquid-liquid phase separation (LLPS) with the viral genome, and propose a model of viral packaging through LLPS. N-protein condenses with specific RNA sequences in the first 1000 nts (5’-End) under physiological conditions and is enhanced at human upper airway temperatures. N-protein condensates exclude non-packaged RNA sequences. We comprehensively map sites bound by N-protein in the 5’-End and find preferences for single-stranded RNA flanked by stable structured elements. Liquid-like N-protein condensates form in mammalian cells in a concentration-dependent manner and can be altered by small molecules. Condensation of N-protein is sequence and structure specific, sensitive to human body temperature, and manipulatable with small molecules thus presenting screenable processes for identifying antiviral compounds effective against SARS-CoV-2.
Responsiveness to perturbations is a hallmark of transcription factors that maintain cell identity
Authors: Mellis Ian A. , Edelstein Hailey I. , Truitt Rachel , Beck Lauren E. , Symmons Orsolya , Goyal Yogesh , Dunagin Margaret C. , Saldana Ricardo A. Linares , Shah Parisha P. , Yang Wenli , Jain Rajan , Raj Arjun 
Published: June 2020

AbstractOur ability to identify the particular transcription factors that maintain cell type is limited. Identification of factors by their cell type-specific expression or their participation in developmental regulation has been only modestly successful. We hypothesized that because cell type is often resilient to perturbations, the transcriptional response to perturbations would identify identity-maintaining factors. We developed Perturbation Panel Profiling (P3) as a framework for perturbing cells in dozens of conditions and measuring gene expression responsiveness transcriptome-wide. Applying P3to human iPSC-derived cardiac myocytes showed that transcription factors known to function in cardiac differentiation and maintenance were among the most frequently up-regulated (most responsive). We reasoned that one potential function of responsive genes may be to maintain cellular identity. We identified responsive transcription factors in fibroblasts using P3and found that suppressing their expression led to enhanced reprogramming efficiency. We propose that responsiveness to perturbations is a property of factors that help maintain cellular identity.
Right lateralized posterior parietal theta-gamma coupling during sustained attention in mice
Authors: Yang Ryan , Dunbar Corrinne , Sonesra Alina , Park Suhyeorn , Pham Timothy , Samaco Rodney C. , Foster Brett L. , Maheshwari Atul 
Published: June 2020

AbstractSustained attention is supported by circuits in the frontoparietal attention network. In human and primate studies, the right posterior parietal cortex (PPC) shows dominance for sustained attention, and phase-amplitude coupling (PAC) throughout the frontoparietal network correlates with performance on attention tasks. Here we evaluate oscillatory dynamics of bilateral PPC in mice during the 5-Choice Serial Reaction Time Task (5-CSRTT). Right PPC theta-gamma PAC (TG-PAC) and gamma power were independently elevated to a greater degree than the left PPC during the period prior to a correct response and were significantly correlated with accuracy in both simple and difficult tasks. Greater task difficulty was also associated with greater hemispheric asymmetry in TG-PAC, favoring the right PPC. These findings highlight the engagement of PPC with sustained attention in mice, reflected by increases in TG-PAC and gamma power, with maximal expression in the right hemisphere.
A Platform Incorporating Trimeric Antigens into Self-Assembling Nanoparticles Reveals SARS-CoV-2-Spike Nanoparticles to Elicit Substantially Higher Neutralizing Responses than Spike Alone
Authors: Zhang Baoshan , Chao Cara W. , Tsybovsky Yaroslav , Abiona Olubukola M. , Hutchinson Geoffrey B. , Moliva Juan I. , Olia Adam S. , Pegu Amarendra , Phung Emily , Stewart-Jones Guillaume , Verardi Raffaello , Wang Lingshu , Wang Shuishu , Werner Anne , Yang Eun Sung , Yap Christina , Zhou Tongqing , Mascola John R. , Sullivan Nancy J. , Graham Barney S. , Corbett Kizzmekia S. , Kwong Peter D. 
Published: June 2020

AbstractAntigens displayed on self-assembling nanoparticles can stimulate strong immune responses and have been playing an increasingly prominent role in structure-based vaccines. However, the development of such immunogens is often complicated by inefficiencies in their production. To alleviate this issue, we developed a plug-and-play platform using the spontaneous isopeptide-bond formation of the SpyTag:SpyCatcher system to display trimeric antigens on self-assembling nanoparticles, including the 60-subunitAquifex aeolicuslumazine synthase (LuS) and the 24-subunitHelicobacter pyloriferritin. LuS and ferritin coupled to SpyTag expressed well in a mammalian expression system when anN-linked glycan was added to the nanoparticle surface. The respiratory syncytial virus fusion (F) glycoprotein trimer – stabilized in the prefusion conformation and fused with SpyCatcher – could be efficiently conjugated to LuS-SpyTag or ferritin-SpyTag, enabling multivalent display of F trimers with prefusion antigenicity. Similarly, F-glycoprotein trimers from human parainfluenza virus-type 3 and spike-glycoprotein trimers from SARS-CoV-2 could be displayed on LuS nanoparticles with decent yield and antigenicity. Notably, murine vaccination with the SARS-CoV-2 spike-LuS nanoparticles elicited ~25-fold higher neutralizing responses, weight-per-weight relative to spike alone. The versatile platform described here thus allows for multivalent plug-and-play presentation on self-assembling nanoparticles of trimeric viral antigens, with SARS-CoV-2 spike-LuS nanoparticles inducing particularly potent neutralizing responses.
How far Covid19 virus spread can be curbed by relaxing lockdown in different stages? -A study in Indian scenario
Authors: Chakraborty Arindom , Das Kalyan 
Published: June 2020

ABSTRACTAfter the emergence of the first cases in Wuhan, China, the novel coronavirus (2019-nCoV) infection has rapidly spread out to other provinces, neighboring countries and finally has become a global terror. It is indeed a matter of serious concern to study the transmission dynamics of this virus. The potential and severity of an outbreak and providing critical information for identifying the type of disease interventions and intensity can be well understood by the unknown basic reproduction number. A stochastic model can be used to estimate this number with possible safeguard on uncertainties. It is essential to assess how the expensive, resource-intensive measures can contribute to the prevention and control of the 2019-nCoV infection and how long they should be maintained. A short-term forecast of incidences are often of high priority. The challenge is to forecast unseen “future” simulated data for three different scenarios at some time points. We estimate current levels of transmissibility, over variable time points under different levels of interventions and use that to forecast near-future incidence. The forecasted values of incidence can be used for determining the near future mortality also.
Room Temperature Isothermal Colorimetric Padlock Probe Rolling Circle Amplification for Viral DNA and RNA Detection
Authors: Huang Wilson , Ting Joyce , Fang Matthew , Hsu Hannah , Su Jimmy , Misaki Tsuyoshi , Chan Derek , Yang Justin , Yeh Ting-Yu , Yang Kelly , Chien Vera , Huang Tiffany , Chen Andrew , Wei Claire , Hsu Jonathan , Clapper Jude C. 
Published: June 2020

AbstractSeasonal flu and pandemics, which account for millions of infections and hundreds of thousands of deaths, require rapid and reliable detection mechanisms to implement preventive and therapeutic measures. Current detection methods of viral infections have limitations in speed, accuracy, accessibility, and usability. This project presents a novel, widely applicable viral diagnostic test that uses a modified version of rolling circle amplification (RCA) to be sensitive, specific, direct RNA targeted, colorimetric and operable at room temperature. We are specifically detecting the following high-impact viruses: SARS-CoV-2, Influenza A (H1N1pdm09), and Influenza B (Victoria Lineage), although our test can be adapted to any viral infection. Results using synthetic viral DNA and RNA sequences show that our diagnostic test takes approximately one hour, detects femtomolar concentrations of RNA strands, and differentiates between virus strains. We believe implementing our diagnostic test will provide faster responses to future viral-related outbreaks for quicker societal recovery.
Systematic analysis of protein targets associated with adverse events of drugs from clinical trials and post-marketing reports
Authors: Smit Ines A. , Afzal Avid M. , Allen Chad H. G. , Svensson Fredrik , Hanser Thierry , Bender Andreas 
Published: June 2020

AbstractAdverse drug reactions (ADRs) are undesired effects of medicines that can harm patients and are a significant source of attrition in drug development. ADRs are anticipated by routinely screening drugs against secondary pharmacology protein panels. However, there is still a lack of quantitative information on the links between these off-target proteins and the risk of ADRs in humans. Here, we present a systematic analysis of associations between measured and predictedin vitrobioactivities of drugs, and adverse events (AEs) in humans from two sources of data: the Side Effect Resource (SIDER), derived from clinical trials, and the Food and Drug Administration Adverse Event Reporting System (FAERS), derived from post-marketing surveillance. The ratio of a drug’sin vitropotency against a given protein relative to its therapeutic unbound drug plasma concentration was used to select proteins most likely to be relevant toin vivoeffects. In examining individual target bioactivities as predictors of AEs, we found a trade-off between the Positive Predictive Value and the fraction of drugs with AEs that can be detected, however considering sets of multiple targets for the same AE can help identify a greater fraction of AE-associated drugs. Of the 45 targets with statistically significant associations to AEs, 30 are included on existing safety target panels. The remaining 15 targets include 8 carbonic anhydrases, of which CA5B was significantly associated with cholestatic jaundice. We include the full quantitative data on associations betweenin vitrobioactivities and AEs in humans in this work, which can be used to make a more informed selection of safety profiling targets.