bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural basis to design multi-epitope vaccines against Novel Coronavirus 19 (COVID19) infection, the ongoing pandemic emergency: an in silico approach
Authors: Srivastava Sukrit , Verma Sonia , Kamthania Mohit , Kaur Rupinder , Badyal Ruchi Kiran , Saxena Ajay Kumar , Shin Ho-Joon , Kolbe Michael , Pandey Kailash C 
Published: April 2020

AbstractThe 2019 novel coronavirus (COVID19 / Wuhan coronavirus), officially named as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is a positive-sense single-stranded RNA coronavirus. SARS-CoV-2 causes the contagious COVID19 disease also known as 2019-nCoV acute respiratory disease and has led to the ongoing 2019–20 pandemic COVID19 outbreak. The effective counter measures against SARS-CoV-2 infection require the design and development of specific and effective vaccine candidate. In the present study, we have screened and shortlisted 38 CTL, 33 HTL and 12 B cell epitopes from the eleven Protein sequences of SARS-CoV-2 by utilizing different in silico tools. The screened epitopes were further validated for their binding with their respective HLA allele binders and TAP (Transporter associated with antigen processing) molecule by molecular docking. The shortlisted screened epitopes were further utilized to design novel two multi-epitope vaccines (MEVs) composed of CTL, HTL and B cell epitopes overlaps with potential to elicit humoral as well as cellular immune response against SARS-CoV-2. To enhance the immune response for our vaccine design, truncated (residues 10-153) Onchocerca volvulus activation-associated secreted protein-1 (Ov-ASP-1) has been utilized as an adjuvant at N terminal of both the MEVs. Further molecular models for both the MEVs were prepared and validated for their stable molecular interactions with Toll-Like Receptor 3 (TLR 3). The codon-optimized cDNA of both the MEVs were further analyzed for their potential of high level of expression in a human cell line. The present study is very significant in terms of molecular designing of prospective CTL and HTL vaccine against SARS-CoV-2 infection with the potential to elicit cellular as well as humoral immune response. (SARS-CoV-2), Coronavirus, Human Transporter associated with antigen processing (TAP), Toll-Like Receptor (TLR), Epitope, Immunoinformatics, Molecular Docking, Molecular dynamics simulation, Multi-epitope VaccineGraphical abstractThe designed CTL (Cytotoxic T lymphocyte) and HTL (Helper T lymphocyte) multi-epitope vaccines (MEV) against COVID19 infection. Both the CTL and HTL MEV models show a very stable and well fit conformational complex formation tendency with the Toll like receptor 3. CTL and HTL MEVs:ribbon; Toll like receptor 3:gray cartoon; Adjuvant [truncated (residues 10-153) Onchocerca volvulus activation-associated secreted protein-1]:orange ribbon regions; Epitopes:cyan ribbons regions; 6xHis Tag:magenta ribbon regions.
Homeostatic scaling is driven by a translation-dependent degradation axis that recruits miRISC remodeling
Authors: Srinivasan Balakumar , Samaddar Sarbani , Mylavarapu Sivaram V.S. , Clement James P. , Banerjee Sourav 
Published: April 2020

AbstractHomeostatic scaling in neurons has been attributed to the individual contribution of either translation or degradation; however there remains limited insight towards understanding how the interplay between the two processes effectuates synaptic homeostasis. Here, we report that a co-dependence between protein synthesis and degradation mechanisms drives synaptic homeostasis whereas abrogation of either prevents it. Coordination between the two processes is achieved through the formation of a tripartite complex between translation regulators, the 26S proteasome and the miRNA-induced-silencing-complex (miRISC) components such as Argonaute, MOV10 and Trim32 on actively translating transcripts or polysomes. The components of this ternary complex directly interact with each other in an RNA-dependent manner. Disruption of polysomes abolishes this ternary interaction, suggesting that translating RNAs facilitate the combinatorial action of the proteasome and the translational apparatus. We identify that synaptic downscaling involves miRISC remodeling which entails the mTORC1-dependent translation of Trim32, an E3 ligase and the subsequent degradation of its target, MOV10viathe phosphorylation of p70 S6 kinase. We find that the E3 ligase Trim32 specifically polyubiquitinates MOV10 for its degradation during synaptic downscaling. MOV10 degradation alone is sufficient to invoke downscaling by enhancing Arc translation through its 3’ UTR and causing the subsequent removal of post-synaptic AMPA receptors. Synaptic scaling was occluded when we depleted Trim32 and overexpressed MOV10 in neurons, suggesting that the Trim32-MOV10 axis is necessary for synaptic downscaling. We propose a mechanism that exploits a translation-driven protein degradation paradigm to invoke miRISC remodeling and induce homeostatic scaling during chronic network activity.
Defining the Neural Kinome: Strategies and Opportunities for Small Molecule Drug Discovery to Target Neurodegenerative Diseases
Authors: Krahn Andrea I. , Wells Carrow , Drewry David H. , Beitel Lenore K. , Durcan Thomas M. , Axtman Alison D. 
Published: April 2020

ABSTRACTKinases are highly tractable drug targets that have reached unparalleled success in fields such as cancer but whose potential has not yet been realized in neuroscience. There are currently 55 approved small molecule kinase-targeting drugs, 48 of which have an anti-cancer indication. The intrinsic complexity linked to central nervous system (CNS) drug development and a lack of validated targets has hindered progress in developing kinase inhibitors for CNS disorders when compared to other therapeutic areas such as oncology. Identification and/or characterization of new kinases as potential drug targets for neurodegenerative diseases will create opportunities for development of CNS drugs in the future. The track record of kinase inhibitors in other disease indications supports the idea that with the best targets identified small molecule kinase modulators will become impactful therapeutics for neurodegenerative diseases.KEY CONCEPTSChemical probe: a high-quality small molecule that is potent, selective, and cell-active that meets the following criteria: (1)in vitrobiochemical IC50< 50 nM, (2) ≥ 30-fold selectivity relative to other kinases in a large assay panel such as DiscoverXscanMAX, and (3) cellular activity or target engagement with an IC50< 1 μMNarrow spectrum: a selectivity threshold that can be defined as potently inhibiting ∼10% or less of all kinases screenedKinome: all human kinasesKinase chemogenomic set (KCGS): publicly-available curated physical library of narrow spectrum and potent kinase inhibitors for which the SGC-UNC has received permission to share the compounds; subsequent releases will increase kinome-wide coverageIlluminating the Druggable Genome (IDG) program: several interconnected projects currently funded by the National Institutes of Health to provide information on historically understudied members within protein families that have provided drug targets; the three main focus areas are kinases, G-protein coupled receptors, and ion channelsIDG kinase: a kinase that was nominated as dark (understudied) by the National Institutes of Health IDG program (curated list found here:https://druggablegenome.net/IDGProteinList); IDG consortium members generate data and resources to aid in the illumination of the function of these kinasesDK tool: a narrow spectrum inhibitor that exhibits a defined selectivity score (S10(1 μM) < 0.05) and cellular target engagement with an IC50< 1 μM; S10(1 μM) is a measure of selectivity equal to the percentage of screened kinases biochemically inhibited by >90% at 1 μM
Disconnection somewhere down the line: Multivariate lesion-symptom mapping of the line bisection error
Authors: Wiesen Daniel , Karnath Hans-Otto , Sperber Christoph 
Published: April 2020

AbstractLine Bisection is a simple task frequently used in stroke patients to diagnose disorders of spatial perception characterized by a directional bisection bias to the ipsilesional side. However, previous anatomical and behavioural findings are contradictory, and the diagnostic validity of the line bisection task has been challenged. We hereby aimed to re-analyse the anatomical basis of pathological line bisection by using multivariate lesion-symptom mapping and disconnection-symptom mapping based on support vector regression in a sample of 163 right hemispheric acute stroke patients. In line with some previous studies, we observed that pathological line bisection was related to more than a single focal lesion location. Cortical damage primarily to right parietal areas, particularly the inferior parietal lobe, including the angular gyrus, as well as damage to the right basal ganglia contributed to the pathology. In contrast to some previous studies, an involvement of frontal cortical brain areas in the line bisection task was not observed. Subcortically, damage to the right superior longitudinal fasciculus (I, II and III) and arcuate fasciculus as well as the internal capsule was associated with line bisection errors. Moreover, white matter damage of interhemispheric fibre bundles, such as the anterior commissure and posterior parts of the corpus callosum projecting into the left hemisphere, was predictive of pathological deviation in the line bisection task.
The Parkinson’s Disease GWAS Locus Browser
Authors: Grenn Francis P. , Kim Jonggeol J. , Makarious Mary B. , Iwaki Hirotaka , Illarionova Anastasia , Brolin Kajsa , Kluss Jillian H. , Schumacher-Schuh Artur F. , Leonard Hampton , Faghri Faraz , Billingsley Kimberley , Krohn Lynne , Hall Ashley , Diez-Fairen Monica , Periñán Maria Teresa , Sandor Cynthia , Webber Caleb , Gibbs J. Raphael , Nalls Mike A. , Singleton Andrew B. , Bandres-Ciga Sara , Reed Xylena , Blauwendraat Cornelis ,   on behalf of the International Parkinson’s Disease Genomics Consortium (IPDGC)
Published: April 2020

AbstractParkinson’s disease (PD) is a neurodegenerative disease with an often complex genetic component identifiable by genome-wide association studies (GWAS). The most recent large scale PD GWASes have identified more than 90 independent risk variants for PD risk and progression across 80 loci. One major challenge in current genomics is identifying the causal gene(s) and variant(s) from each GWAS locus. Here we present a GWAS locus browser application that combines data from multiple databases to aid in the prioritization of genes associated with PD GWAS loci. We included 92 independent genome-wide significant signals from multiple recent PD GWAS studies including the PD risk GWAS, age-at-onset GWAS and progression GWAS. We gathered data for all 2336 genes within 1Mb up and downstream of each variant to allow users to assess which gene(s) are most associated with the variant of interest based on a set of self-ranked criteria. Our aim is that the information contained in this browser (https://pdgenetics.shinyapps.io/GWASBrowser/) will assist the PD research community with the prioritization of genes for follow-up functional studies and as potential therapeutic targets.
Voluntary modification of rapid tactile-motor responses during reaching differs from its visuo-motor counterpart
Authors: Reschechtko Sasha , Pruszynski J. Andrew 
Published: April 2020

AbstractPeople commonly hold and manipulate a variety of objects in everyday life, and these objects have different physical properties. In order to successfully control this wide range of objects, people must associate new patterns of tactile stimuli with appropriate motor outputs. We performed a series of experiments investigating the extent to which people can voluntarily modify tactile-motor associations in the context of a rapid tactile-motor response guiding the hand to a moving target (previously described in Pruszynski et al. 2016) by using an anti-reach paradigm in which participants were instructed to move their hands in the opposite direction of a target jump. We compared performance to that observed when people make visually guided reaches to a moving target (cf. Day & Lyon 2000, Pisella et al. 2000). When participants had visual feedback, motor responses during the anti-reach task showed early automatic responses toward the moving target before voluntary modification to move in the instructed direction. When the same participants had only tactile feedback, however, they were able to suppress this early phase of the motor response, which occurs less than 100 ms after the target jump. Our results indicate that, while the tactile motor and visual motor systems both support rapid responses that appear similar under some conditions, these responses show sharp distinctions in terms of their malleability.
Making sense of virus size and the tradeoffs shaping viral fitness
Authors: Edwards Kyle F. , Steward Grieg F. , Schvarcz Christopher R. 
Published: April 2020

AbstractViruses span an impressive size range, with genome length varying more than a thousandfold and capsid volume nearly a millionfold. Physical constraints suggest that smaller viruses may have multiple fitness advantages, because a greater number of viral offspring can be created from limited host resources, and because smaller particles diffuse to encounter new hosts more rapidly. At the same time, a larger genome size allows for numerous additional functions that may increase fitness, such as better control of replication, transcription, translation, and host metabolism, and neutralization of host defenses. However, it is unclear whether important viral traits correlate with size, and whether this causes size to vary among host types or environmental contexts. Here we focus on viruses of aquatic unicellular organisms, which exhibit the greatest known range of virus size. We develop and synthesize theory, and analyze data where available, to consider how size affects the primary components of viral fitness. We suggest that the costs of larger size (lower burst size and diffusivity) are mitigated by the role of a larger genome in increasing infection efficiency, broadening host range, and potentially increasing attachment success and decreasing decay rate. These countervailing selective pressures may explain why such a breadth of sizes exist and can even coexist when infecting the same host populations. We argue that oligotrophic environments may be particularly enriched in unusually large or “giant” viruses, because environments with diverse, resource-limited phagotrophic eukaryotes at persistently low concentrations may select for broader host range, better control of host metabolism, lower decay rate, and a physical size that mimics bacterial prey. Finally, we describe areas where further research is needed to understand the ecology and evolution of viral size diversity.
Visualization of spatial gene expression in plants by modified RNAscope fluorescentin situhybridization
Authors: Solanki Shyam , Ameen Gazala , Zhao Jin , Flaten Jordan , Borowicz Pawel , Brueggeman Robert 
Published: April 2020

AbstractIn situanalysis of biomarkers such as DNA, RNA and proteins are important for research and diagnostic purposes. At the RNA level, plant gene expression studies rely on qPCR, RNAseq and probe-basedinsituhybridization (ISH). However, for ISH experiments poor stability of RNA and RNA based probes commonly results in poor detection or poor reproducibility. Recently, the development and availability of the RNAscope RNA-ISH method addressed these problems by novel signal amplification and background suppression. This method is capable of simultaneous detection of multiple target RNAs down to the single molecule level in individual cells, allowing researchers to study spatio-temporal patterning of gene expression. However, this method has not been optimized thus poorly utilized for plant specific gene expression studies which would allow for fluorescent multiplex detection. Here we provide a step-by-step method for sample collection and pretreatment optimization to perform the RNAscope assay in the leaf tissues of model monocot plant barley. We have shown the ubiquitousHvGAPHand predominantly stomatal guard cell expressedRpg1expression pattern in barley leaf sections and described the improve RNAcope methodology suitable for plant tissues using confocal laser microscope. By addressing the problems in the sample collection and incorporating additional sample backing steps we have significantly reduced the section detachment and experiment failure problems. Further, by reducing the time of protease treatment, we minimized the sample disintegration due to over digestion of barley tissues. Thus, we optimized the RNAscope detection method in plants to visualize the spatial expression and semi-quantification of target RNAs which can be employed in other plants such as the widely utilized model dicot plant Arabidopsis.
Modeling the Degradation Effects of Autophagosome Tethering Compounds (ATTEC)
Authors: Zhang Hang , An Ping , Fei Yiyan , Lu Boxun 
Published: April 2020

AbstractAutophagy is a powerful protein degradation pathway with limited specificity. Our recent study proposed and demonstrated a potential strategy to harness autophagy to selectively degrade a specific pathogenic protein using autophagosome tethering compounds (ATTEC). ATTEC interact with both the target protein and the autophagosome protein LC3, and thus tether the target protein to the autophagosomes for subsequent degradation. The concentration-dependent curve of the target protein is U-shaped, but there has been lack of both kinetic and steady-state modeling of the degradation effects of ATTEC. Here we established a simplified model describing the kinetics and steady-state level of target protein, and characterized how compounds’ properties, especially binding affinities to LC3 and to the target protein, may influence their degradation effects.
Hyperactive end joining repair mediates resistance to DNA damaging therapy in p53-deficient cells
Authors: Kumar Rashmi J. , Chao Hui Xiao , Roberts Victoria R. , Sullivan Aurora R. , Shah Sonam J. , Simpson Dennis A. , Feng Wanjuan , Wozny Anne-Sophie , Kumar Sunil , Purvis Jeremy E. , Gupta Gaorav P. 
Published: April 2020

AbstractTP53mutations in cancer are associated with poor patient outcomes and resistance to DNA damaging therapies1–3. However, the mechanisms underlying treatment resistance in p53-deficient cells remain poorly characterized. Here, we show that p53-deficient cells exhibit hyperactive repair of therapy-induced DNA double strand breaks (DSBs), which is suppressed by inhibition of DNA-dependent protein kinase (DNA-PK). Single-cell analyses of DSB repair kinetics and cell cycle state transitions reveal an essential role for DNA-PK in suppressing S phase DNA damage and mitotic catastrophe in p53-deficient cells. Yet, a subset of p53-deficient cells exhibit intrinsic resistance to therapeutic DSBs due to a repair pathway that is not sensitive to DNA-PK inhibition. We show that p53 deficiency induces overexpression of DNA Polymerase Theta (Pol θ), which mediates an alternative end-joining repair pathway that becomes hyperactivated by DNA-PK inhibition4. Combined inhibition of DNA-PK and Pol θ restores therapeutic DNA damage sensitivity in p53-deficient cells. Thus, our study identifies two targetable DSB end joining pathways that can be suppressed as a strategy to overcome resistance to DNA-damaging therapies in p53-deficient cancers.
The Effectiveness of Targeted Quarantine for Minimising Impact of COVID-19
Authors: Jamieson-Lane Alastair , Cytrnbaum Eric 
Published: April 2020

AbstractWe model the extent to which age targeted quarantine can be used to reduce ICU admissions caused by novel coronavirus COVID-19. Using demographic data from New Zealand, we demonstrate that lowering the age threshold for quarantine to 50 years of age reduces ICU admissions drastically, and show that for sufficiently strict isolation protocols, isolating one third of the countries population for a total of 6 months is sufficient to avoid overwhelming ICU capacity throughout the entire course of the epidemic. Similar results are expected to hold for other countries, though some minor adaption will be required based on local age demographics and hospital facilities.
A Deep Learning Algorithm for Automated Cardiac Murmur Detection Via a Digital Stethoscope Platform
Authors: Chorba John S. , Shapiro Avi M. , Le Le , Maidens John , Prince John , Pham Steve , Kanzawa Mia M. , Barbosa Daniel N. , White Brent E. , Paek Jason , Fuller Sophie G. , Stalker Grant W. , Bravo Sara A. , Jean Dina , Venkatraman Subramaniam , McCarthy Patrick M. , Thomas James D. 
Published: April 2020

AbstractBackgroundThere is variability among clinicians in their ability to detect murmurs during cardiac auscultation and identify the underlying pathology. Deep learning approaches have shown promise in medicine by transforming collected data into clinically significant information.ObjectiveThe objective of this research is to assess the performance of a deep learning algorithm to detect murmurs and clinically significant valvular heart disease using recordings from a commercial digital stethoscope platform.MethodsUsing over 34 hours of previously acquired and annotated heart sound recordings, we trained a deep neural network to detect murmurs. To test the algorithm, we enrolled 373 patients in a clinical study and collected recordings at the four primary auscultation locations. Ground truth was established using patient echocardiograms and annotations by three expert cardiologists.ResultsAlgorithm performance for detecting murmurs has sensitivity and specificity of 76.3% and 91.4%, respectively. By omitting softer murmurs, those with grade 1, sensitivity increases to 90.0%. The algorithm detects moderate-to-severe or greater aortic stenosis with sensitivity of 97.5% and specificity of 77.7% and detects moderate-to-severe or greater mitral regurgitation with sensitivity of 64.0% and specificity of 90.5%.ConclusionThe deep learning algorithm’s ability to detect murmurs and clinically significant aortic stenosis and mitral regurgitation is comparable to expert cardiologists. The research findings attest to the reliability and utility of such algorithms as front-line clinical support tools to aid clinicians in screening for cardiac murmurs caused by valvular heart disease.
Screening for dementia: Q* index as a global measure of test accuracy revisited
Authors: Larner Andrew J 
Published: April 2020

AbstractReceiver operating characteristic (ROC) curves intersect the downward diagonal through ROC space at a point, the Q* index, where by definition sensitivity and specificity are equal. Aside from its use in meta-analysis, Q* index has also been suggested as a possible global parameter summarising test accuracy of cognitive screening instruments and as a definition for optimal test cut-off. Area under the ROC curve (AUC ROC) is a recognised measure of test accuracy. This study compared different methods for determining Q* index (both graphical and calculation from diagnostic odds ratio) and AUC ROC (integration and calculation from diagnostic odds ratio) using the dataset of a prospective screening test accuracy study of the Mini-Addenbrooke’s Cognitive Examination. The different methods did not agree. DOR-based calculations gave a very sensitive cut-off but with poorer global metrics than the graphical method. DOR-based calculations are not recommended for defining optimal test cut-off or test accuracy.