bluuebunny/crossref_metadata_2025_split huggingface dataset:
In vitroassessment of the virucidal activity of four mouthwashes containing Cetylpyridinium Chloride, ethanol, zinc and a mix of enzyme and proteins against a human coronavirus
Authors: Green A. , Roberts G. , Tobery T. , Vincent C. , Barili M. , Jones C. 
Published: October 2020

AbstractBackgroundsaliva is established to contain high counts SARS-CoV-2 virus and contact with saliva droplets, contaminated surfaces or airborne particles are sources of viral transmission. The generation of infective aerosols during clinical procedures is of particular concern. Therefore, a fuller understanding of the potential of mouthwash to reduce viral counts and modulate the risk of transmission in medical professional and public context is an important research topic.Methodwe determined the virucidal activity of four anti-bacterial mouthwashes against a surrogate for SARS-CoV-2, Human CoV-SARS 229E, using a standard ASTM suspension test, with dilution and contact times applicable to recommended mouthwash use.Resultsthe mouthwash formulated with 0.07% Cetylpyridinium Chloride exhibited virucidal effects providing a ≥3.0 log reduction HCoV-229E viral count. Mouthwashes containing 15.7% ethanol, 0.2% zinc sulphate heptahydrate and a mix of enzymes and proteins did not demonstrate substantive virucidal activity in this test.Conclusionmouthwash containing 0.07% Cetylpyridinium Chloride warrants further laboratory and clinical assessment to determine their potential benefit in reducing the risk of SARS-CoV-2.HighlightsSARS-CoV-2 can be transmitted through contact with infective saliva.Studies are needed to understand if mouthwash can lower SARS-CoV-2 transmission risk.0.07% Cetylpyridinium Chloride (CPC) mouthwash exhibited virucidal effects against HCoV-SARS 229E.Further studies on potential of 0.07% CPC mouthwash against SARS-CoV-2 are warranted.
Gene replacement of α-globin with β-globin restores hemoglobin balance in β-thalassemia-derived hematopoietic stem and progenitor cells
Authors: Cromer M. Kyle , Camarena Joab , Martin Renata M. , Lesch Benjamin J. , Vakulskas Christopher A. , Lemgart Viktor T. , Zhang Yankai , Goyal Ankush , Zhao Feifei , Ponce Ezequiel , Srifa Wai , Bak Rasmus O. , Uchida Naoya , Majeti Ravindra , Sheehan Vivien A. , Tisdale John F. , Dever Daniel P. , Porteus Matthew H. 
Published: October 2020

ABSTRACTβ-thalassemia pathology is not only due to loss of β-globin (HBB), but also erythrotoxic accumulation and aggregation of the β-globin binding partner, α-globin (HBA1/2). Here we describe a Cas9/AAV6-mediated genome editing strategy that can replace the entireHBA1gene with a full-lengthHBBtransgene in β-thalassemia-derived hematopoietic stem and progenitor cells (HSPCs), which is sufficient to normalize β-globin:α-globin mRNA and protein ratios and restore functional adult hemoglobin tetramers in patient-derived red blood cells. Edited HSPCs were capable of long-term and bi-lineage hematopoietic reconstitution in mice, establishing proof-of-concept for replacement ofHBA1withHBBas a novel therapeutic strategy for curing β-thalassemia.
The DEAD box RNA helicase DDX42 is an intrinsic inhibitor of positive-strand RNA viruses
Authors: Bonaventure Boris , Rebendenne Antoine , de Gracia Francisco Garcia , McKellar Joe , Gracias Ségolène , Labaronne Emmanuel , Tauziet Marine , Valadão Ana Luiza Chaves , Bernard Eric , Briant Laurence , Gros Nathalie , Djilli Wassila , Arnaud-Arnould Mary , Courgnaud Valérie , Parrinello Hugues , Rialle Stéphanie , Ricci Emiliano , Jouvenet Nolwenn , Schulz Reiner , Moncorgé Olivier , Goujon Caroline 
Published: October 2020

AbstractGenome-wide screens are powerful approaches to unravel new regulators of viral infections. Here, we used a CRISPR/Cas9 screen to reveal new HIV-1 inhibitors. This approach led us to identify the RNA helicase DDX42 as an intrinsic antiviral inhibitor. DDX42 was previously described as a non-processive helicase, able to bind RNA secondary structures such as G-quadruplexes, with no clearly defined function ascribed. Our data show that depletion of endogenous DDX42 significantly increased HIV-1 DNA accumulation and infection in cell lines and primary cells. DDX42 overexpression inhibited HIV-1, whereas a dominant-negative mutant increased infection. Importantly, DDX42 also restricted retrotransposition of LINE-1, infection with other retroviruses and positive-strand RNA viruses, including CHIKV and SARS-CoV-2. However, DDX42 did not inhibit infection with three negative-strand RNA viruses, arguing against a general, unspecific effect on target cells, which was confirmed by RNA-seq analysis. DDX42 was found in the vicinity of viral elements by proximity ligation assays, and cross-linking RNA immunoprecipitation confirmed a specific interaction of DDX42 with RNAs from sensitive viruses. This strongly suggested a direct mode of action of DDX42 on viral ribonucleoprotein complexes. Taken together, our results show for the first time a new and important role of DDX42 in intrinsic antiviral immunity.
Multistate Ornstein-Uhlenbeck approach for practical estimation of movement and resource selection around central places
Authors: Eisaguirre Joseph M. , Booms Travis L. , Barger Christopher P. , Goddard Scott D. , Breed Greg A. 
Published: October 2020

AbstractHome range dynamics and movement are central to a species’ ecology and strongly mediate both intra- and interspecific interactions. Numerous methods have been introduced to describe animal home ranges, but most lack predictive ability and cannot capture effects of dynamic environmental patterns, such as the impacts of air and water flow on movement.Here, we develop a practical, multi-stage approach for statistical inference into the behavioral mechanisms underlying how habitat and dynamic energy landscapes—in this case how airflow increases or decreases the energetic efficiency of flight—shape animal home ranges based around central places. We validated the new approach using simulations, then applied it to a sample of 12 adult golden eaglesAquila chrysaetostracked with satellite telemetry.The application to golden eagles revealed effects of habitat variables that align with predicted behavioral ecology. Further, we found that males and females partition their home ranges dynamically based on uplift. Specifically, changes in wind and sun angle drove differential space use between sexes, especially later in the breeding season when energetic demands of growing nestlings require both parents to forage more widely.This method is easily implemented using widely available programming languages and is based on a hierarchical multistate Ornstein-Uhlenbeck space use process that incorporates habitat and energy landscapes. The underlying mathematical properties of the model allow straightforward computation of predicted utilization distributions, permitting estimation of home range size and visualization of space use patterns under varying conditions.
GWAS in Africans identifies novel lipids loci and demonstrates heterogenous association within Africa
Authors: Bentley Amy R. , Chen Guanjie , Doumatey Ayo P. , Shriner Daniel , Meeks Karlijn , Gouveia Mateus H. , Ekoru Kenneth , Zhou Jie ,   the Africa America Diabetes Mellitus Investigators, Adeyemo Adebowale , Rotimi Charles N. 
Published: October 2020

AbstractBackgroundSerum lipids are biomarkers of cardiometabolic disease risk, and understanding the genomic factors contributing to their distribution has been of considerable interest. Large genome-wide association studies (GWAS) have identified over 150 lipids loci; however, GWAS of Africans (AF) are rare. Given the genomic diversity among those of African ancestry, it is expected that a GWAS in Africans could identify novel lipids loci. While GWAS have been conducted in African Americans (AA), such studies are not proxies for studies in continental Africans due to the drastically different environmental context. Therefore, we conducted a GWAS of 4,317 Africans enrolled in the Africa America Diabetes Mellitus study.Methods and ResultsWe used linear mixed models of the inverse normal transformations of covariate-djusted residuals of high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol (LDLC), total cholesterol (CHOL), triglycerides (TG), and TG/HDLC, with adjustment for three principal components and the random effect of relatedness. Replication of loci associated at p<5×10−8was attempted in 9,542 AA. Meta-analysis of AF and AA was also conducted. We also conducted analyses that excluded the relatively small number of East Africans. We evaluated known lipids loci in Africans using both exact replication and “local” replication, which accounts for interethnic differences in linkage disequilibrium.In our main analysis, we identified 23 novel associations in Africans. Of the 14 of these that were able to be tested in AA, two associations replicated (GPNMB-TG andENPP1-TG). Two additional novel loci were discovered upon meta-analysis with AA (rs138282551-TG andTLL2-CHOL). Analyses considering only those with predominantly West African ancestry (Nigeria, Ghana, and AA) yielded new insights:ORC5-LDLC and chr20:60973327-CHOL.ConclusionsWhile functional work will be useful to confirm and understand the biological mechanisms underlying these associations, this study demonstrates the utility of conducting large-scale genomic analyses in Africans for discovering novel loci. The functional significance of some of these loci in relation to lipids remains to be elucidated, yet some have known connections to lipids pathways. For instance, rs147706369 (intronic,TLL2) alters a regulatory motif for sterol regulatory element-binding proteins (SREBPs), which are a family of transcription factors that control the expression of a range of enzymes involved in cholesterol, fatty acid, and triglyceride synthesis.
A systematic analysis of the beta hairpin motif in the Protein Data Bank
Authors: DuPai Cory D. , Davies Bryan W. , Wilke Claus O. 
Published: October 2020

AbstractThe beta hairpin motif is a ubiquitous protein structural motif that can be found in molecules across the tree of life. This motif, which is also popular in synthetically designed proteins and peptides, is known for its stability and adaptability to broad functions. Here we systematically probe all 49,000 unique beta hairpin substructures contained within the Protein Data Bank (PDB) to uncover key characteristics correlated with stable beta hairpin structure, including amino acid biases and enriched inter-strand contacts. We also establish a set of broad design principles that can be applied to the generation of libraries encoding proteins or peptides containing beta hairpin structures.ImportanceThe beta hairpin motif is a common protein structural motif that is known for its stability and varied activity in diverse proteins. Here we use nearly fifty thousand beta hairpin substructures from the Protein Data Bank to systematically analyze and identify key characteristics of the beta hairpin motif. Ultimately, we provide a set of design principles for the generation of synthetic libraries encoding proteins containing beta hairpin structures.
The effect of activity, energy use, and species identity on environmental DNA shedding of freshwater fish
Authors: Thalinger Bettina , Rieder Andreas , Teuffenbach Anna , Pütz Yannick , Schwerte Thorsten , Wanzenböck Josef , Traugott Michael 
Published: October 2020

AbstractThe quantitative measurement of environmental DNA (eDNA) from field-collected water samples is gaining importance for the monitoring of fish communities and populations. The interpretation of these signal strengths depends, among other factors, on the amount of target eDNA shed into the water. However, shedding rates are presumably associated with species-specific traits such as physiology and behavior. Although such differences between juvenile and adult fish have been previously detected, the general impact of movement and energy use in a resting state on eDNA release into the surrounding water remains hardly addressed.In an aquarium experiment, we compared eDNA shedding between seven fish species occurring in European freshwaters. The investigated salmonids, cyprinids, and sculpin exhibit distinct adaptions to microhabitats, diets, and either solitary or schooling behavior. The fish were housed in aquaria with constant water flow and their activity was measured by snapshots taken every 30 s. Water samples for eDNA analysis were taken every 3 h and energy use was determined in an intermittent flow respirometer. After controlling for the effect of fish mass, our results demonstrate a positive correlation between target eDNA quantities as measured with digital PCR, fish activity, and energy use, as well as species-specific differences. For cyprinids, the model based on data from individual fish was only partly transferable to groups, which exhibited lower activity and higher energy use.Our findings highlight the importance of fish physiology and behavior for the comparative interpretation of taxon-specific eDNA quantities. Species traits should therefore be incorporated into eDNA-based monitoring and conservation efforts.
Developing Commotio Cordis Injury Metrics by Correlating Chest Force and Rib Deformation to Left Ventricle Strain and Pressure
Authors: Dickey Grant J. , Bian Kewei , Khan Habib R. , Mao Haojie 
Published: October 2020

AbstractCommotio cordis is a sudden death mechanism that occurs when the heart is impacted during the repolarization phase of the cardiac cycle. This study aimed to investigate commotio cordis injury metrics by correlating chest force and rib deformation to left ventricle (LV) strain and pressure. We simulated 128 chest impacts using a simulation matrix which included two initial velocities, 16 impact locations spread across the transverse and sagittal plane, and four baseball stiffness levels. Results showed that an initial velocity of 17.88 m/s and an impact location over the LV was the most damaging setting across all possible settings, causing the most considerable LV strain and pressure increases. The impact force metric did not correlate with LV strain and pressure, while rib deformations located over the LV were strongly correlated to LV strain. This leads us to the recommendation of exploring new injury metrics such as the rib deformations we have highlighted for future commotio cordis safety regulations.
Oleic acid triggers hippocampal neurogenesis by binding to TLX/NR2E1
Authors: Kandel Prasanna , Semerci Fatih , Bajic Aleksandar , Baluya Dodge , Ma LiHua , Chen Kevin , Cao Austin , Phongmekhin Tipwarin , Matinyan Nick , Choi William , Jiménez-Panizo Alba , Chamakuri Srinivas , Raji Idris O. , Chang Lyra , Fuentes-Prior Pablo , MacKenzie Kevin R. , Benn Caroline L. , Estébanez-Perpiñá Eva , Venken Koen , Moore David D. , Young Damian W. , Maletic-Savatic Mirjana 
Published: October 2020

AbstractAdult hippocampal neurogenesis underpins learning, memory, and mood, but diminishes with age and illness. The orphan nuclear receptor TLX/NR2E1 is known to regulate neural stem and progenitor cell self-renewal and proliferation, but the precise mechanism by which it accomplishes this is unknown. We found that neural stem and progenitor cells require monounsaturated fatty acids to survive and proliferate. Specifically, oleic acid (18:1ω9) binds to TLX to convert it from a transcriptional repressor to a transcriptional activator of cell cycle and neurogenesis genes. We propose a model in which sufficient quantities of this endogenous ligand must bind to TLX to trigger the switch to proliferation. These findings pave the way for future therapeutic manipulations to counteract pathogenic impairments of neurogenesis.
Aberrant Ca2+homeostasis in adipocytes links inflammation to metabolic dysregulation in obesity
Authors: Guney Ekin , Arruda Ana Paula , Parlakgul Gunes , Cagampan Erika , Min Nina , Lee Yankun , Greene Lily , Tsaousidou Eva , Inouye Karen , Han Myoung Sook , Davis Roger J. , Hotamisligil Gökhan S. 
Published: October 2020

SummaryChronic metabolic inflammation is a key feature of obesity, insulin resistance and diabetes, although the initiation and propagation mechanisms of metaflammation are not fully established, particularly in the adipose tissue. Here we show that in adipocytes, altered regulation of the Ca2+channel inositol triphosphate receptor (IP3Rs) is a key, adipocyte-intrinsic, event involved in the emergence and propagation of inflammatory signaling and the resulting insulin resistance. Inflammation, either induced by cytokine exposurein vitroor by obesityin vivolead to increased expression and activity of IP3Rs in adipocytes in a JNK-dependent manner. This results in increased cytosolic Ca2+and impaired insulin action. In mice, adipocyte-specific loss of IP3R1/2 protected against adipose tissue inflammation and insulin resistance despite significant diet-induced weight gain. Thus, this work reveals that IP3R over-activation and the resulting increase in cytosolic Ca2+is a key link between obesity, inflammation and insulin resistance, and suggests that approaches to target adipocyte Ca2+homeostasis may offer new therapeutic opportunities against metabolic diseases, especially since GWAS studies also implicate this locus in human obesity.
Structural basis for a natural circular permutation in proteins
Authors: Nonis Samuel G. , Haywood Joel , Schmidberger Jason W. , Bond Charles S. , Mylne Joshua S. 
Published: October 2020

AbstractOver 30 years ago, an intriguing post-translational modification was discovered to be responsible for creating concanavalin A (conA), a carbohydrate-binding protein found in the seeds of jack bean (Canavalia ensiformis) and commercially used for carbohydrate chromatography. Biosynthesis of conA involves what was then an unprecedented rearrangement in amino acid sequence, whereby the N-terminal half of the gene-encoded conA precursor is swapped to become the C-terminal half of conA. The cysteine protease, asparaginyl endopeptidase (AEP), was shown to be involved, but its mechanism was not fully elucidated. To understand the structural basis and consequences of conA circular permutation, we generated a recombinant jack bean conA precursor (pro-conA) plus jack bean AEP (CeAEP1) and solved crystal structures for each to 2.1 Å and 2.7 Å respectively. By reconstituting the biosynthesis of conAin vitro, we prove CeAEP1 alone can perform both the cleavage and cleavage-coupled transpeptidation to form conA. CeAEP1 structural analysis reveals how it is capable of carrying out both these reactions. Biophysical assays illustrated that conA is more thermally and pH stable than pro-conA, consistent with fewer intermolecular interactions between subunits in the pro-conA crystal structure. These findings elucidate the consequences of circular permutation in the only post-translation example known to occur in nature.
The fusion peptide proximal region of the HIV-1 envelope glycoproteins regulates exposure of immunogenic epitopes at the trimer base
Authors: Rojas Chávez Roberth Anthony , Boyt Devlin , Han Changze , Wu Li , Haim Hillel 
Published: October 2020

ABSTRACTThe error-prone replication machinery of HIV-1 continuously generates new variants of the envelope glycoproteins (Envs). Antibody selection pressures applied in the host can limit their persistence. The target specificity of antibodies elicited in different hosts varies considerably. Whether some specificities are shared and have affected the population-level evolution of Env structure is still unclear. We examined the historical changes in amino acid sequence of the gp41 fusion peptide proximal region (FPPR), which is not exposed on the Env trimer. For three FPPR positions, the residue found in the clade B ancestor was mainly replaced by alanine. However, the changes in alanine frequency at these positions between 1979 and 2016 followed different patterns; two positions maintained a historically-constant frequency whereas the third showed a gradual increase. To understand these patterns, we introduced alanine substitutions in the FPPR of primary HIV-1 strains and examined their fitness and antigenicity relative to the clade-ancestral form. The evolutionary patterns could not be explained by effects on Env fitness. Instead, the FPPR variants with a historically-constant alanine frequency exhibited a unique open-at-the-base conformation of the trimer that exposes partially-cryptic epitopes. These Envs were modestly but significantly more sensitive to poorly-neutralizing sera from HIV-infected individuals than the clade-ancestral form. Our findings suggest that weakly-neutralizing antibodies targeting the base of the trimer are commonly elicited. Such low-level antibody pressures do not exert catastrophic effects on the emerging variants but rather determine their set-point frequency in the population and historical patterns of change.IMPORTANCEHIV-1 infection elicits antibodies that target the Env proteins of the virus. The specific targets of these antibodies vary between infected individuals. It is unclear whether some target specificities are shared between the antibody responses of different individuals. Our data suggest that antibodies against the base of the Env protein are commonly elicited during infection and are contained in sera with low neutralization efficacy. Such antibody pressures are weak. As a result, they do not completely eliminate the sensitive Env forms from the population, but rather maintain their frequency at a low level that has not increased during the past 40 years.
Perceptual Degradation Affects Stop-Signal Performance in Normal Healthy Adults
Authors: Soloveva Maria V. , Jamadar Sharna D. , Hughes Matthew , Velakoulis Dennis , Poudel Govinda , Georgiou-Karistianis Nellie 
Published: October 2020

AbstractDuring stop-signal task performance, little is known how the quality of visual information of the ‘go’ stimuli may indirectly affect the interplay between the ‘go’ and ‘stop’ processes. In this study, we assessed how perceptual degradation of the visual ‘go’ stimuli affect response inhibition. Twenty-six healthy individuals (mean age 33.34 ± 9.61) completed a modified 12-minute stop-signal task, where ‘V’ and ‘Y’ letters were used as visual ‘go’ stimuli. The stimuli were subjected to four levels of perceptual degradation using Gaussian smoothing, to parametrically manipulate stop difficulty across low, intermediate-1, intermediate-2 and high difficulty conditions. On 33% of trials, the stop-signal (50ms audio tone) followed a ‘go’ stimulus after a stop-signal delay, which was individually adjusted for each participant. As predicted, we found that with increased level of stop difficulty (little perceptual degradation), reaction times on ‘go’ trials and the proportion of successful behavioural inhibitions on ‘stop’ trials (P(i)) decreased in normal healthy adults. Contrary to our predictions, there was no effect of increased stop difficulty on the number of correct responses on ‘go’ trials and reaction times on ‘stop’ trials. Overall, manipulation of the completion time of the ‘go’ process via perceptual degradation has been partially successful, whereby increased stop difficulty differentially affectedP(i) and SSRT. These findings have implications for the relationship between the ‘go’ and ‘stop’ processes and the horse-race model, which may be limited in explaining the role of various cortico-basal ganglia loops in modulation of response inhibition.HighlightsManipulation of the completion time of the ‘go’ process is partially successfulPerceptual degradation differentially affects stop-signal performanceIncreased stop difficulty (easy ‘go’) results in lowerP(i)Increased stop difficulty (easy ‘go’) has no effect on SSRTHorse-race model does not fully explain basal ganglia involvement in inhibition