bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gut microbiota diversity and C-Reactive Protein are predictors of disease severity in COVID-19 patients
Authors: Moreira-Rosário André , Marques Cláudia , Pinheiro Hélder , Araújo João Ricardo , Ribeiro Pedro , Rocha Rita , Mota Inês , Pestana Diogo , Ribeiro Rita , Pereira Ana , de Sousa Maria José , Pereira-Leal José , de Sousa José , Morais Juliana , Teixeira Diana , Rocha Júlio César , Silvestre Marta , Príncipe Nuno , Gatta Nuno , Amado José , Santos Lurdes , Maltez Fernando , Boquinhas Ana , de Sousa Germano , Germano Nuno , Sarmento Gonçalo , Granja Cristina , Póvoa Pedro , Faria Ana , Calhau Conceição 
Published: April 2021

AbstractRisk factors for COVID-19 disease severity are still poorly understood. Considering the pivotal role of gut microbiota on host immune and inflammatory functions, we investigated the association between changes in gut microbiota composition and the clinical severity of COVID-19. We conducted a multicentre cross-sectional study prospectively enrolling 115 COVID-19 patients categorized according to: 1) WHO Clinical Progression Scale - mild 19 (16.5%), moderate 37 (32.2%) or severe 59 (51.3%); and 2) location of recovery from COVID-19 - ambulatory 14 (household isolation; 12.2%), hospitalized in ward 40 (34.8%) or intensive care unit 61 (53.0%). Gut microbiota analysis was performed through 16S rRNA gene sequencing and data obtained was further related with clinical parameters of COVID-19 patients. Risk factors for COVID-19 severity were identified by univariate and multivariable logistic regression models.In comparison with mild COVID-19 patients, the gut microbiota of moderate and severe patients has: a) lower Firmicutes/Bacteroidetes ratio, b) higher abundance of Proteobacteria; and c) lower abundance of beneficial butyrate-producing bacteria such asRoseburiaandLachnospiragenera. Multivariable regression analysis showed that Shannon index diversity (odds ratio [OR] 2.85 [95% CI 1.09-7.41]; p=0.032) and C-Reactive Protein (OR 3.45 [95% CI 1.33-8.91]; p=0.011) were risk factors for COVID-19 severe disease (a score of 6 or higher in WHO clinical progression scale).In conclusion, our results demonstrated that hospitalised moderate and severe COVID-19 patients have microbial signatures of gut dysbiosis and for the first time, the gut microbiota diversity is pointed out as a prognostic biomarker for COVID-19 disease severity.
WRKY33-mediated indole glucosinolate metabolic pathway confers host resistance againstAlternaria brassicicola
Authors: Tao Han , Miao Huiying , Chen Lili , Wang Mengyu , Xia Chuchu , Zeng Wei , Li Yubo , Zhang Shuqun , Li Chuanyou , Wang Qiaomei 
Published: April 2021

AbstractThe tryptophan (Trp)-derived plant secondary metabolites, including camalexin, 4-hydroxy-indole-3-carbonylnitrile (4OH-ICN), and indole glucosinolate (IGS), show broad-spectrum antifungal activity. However, the upstream regulators of these metabolic pathways among different plant species in response to fungus infection are rarely studied. In this study, our results revealed a positive role of WRKY33 in host resistance toAlternaria brassicicolaby directly regulating the transcription of genes involved in the biosynthesis and atypical hydrolysis of IGS both inArabidopsisand Chinese kale. Indole-3-yl-methylglucosinolate (I3G) and 4-methoxyindole-3-yl-methylglucosinolate (4MI3G) are the main components of IGS. WRKY33 induces the expression ofMYB51andCYP83B1which promotes the biosynthesis of I3G, the precursor of 4MI3G. Moreover, it also directly activates the expression ofCYP81F2,IGMT1, andIGMT2to drive side chain modification of I3G to produce 4MI3G, which is in turn hydrolyzed byPEN2.However, Chinese kale showed a more severe symptom thanArabidopsiswhen infected byAlternaria brassicicola. Comparative analyses of the origin and evolution of Trp-metabolism indicate that the loss of camalexin biosynthesis in Brassica crops during evolution might attenuate the resistance of crops toAlternaria brassicicola. As a result, IGS metabolic pathway mediated by WRKY33 becomes essential for Chinese kale to deterAlternaria brassicicola. Our results highlight the differential regulation of Trp-derived camalexin and IGS biosynthetic pathways in plant immunity betweenArabidopsisand Brassica crops.One-sentence SummaryPathogen-responsive WRKY33 directly regulates indole glucosinolates biosynthesis and atypical hydrolysis, conferring to host resistance toAlternaria brassicicolainArabidopsisand Brassica crops.
Inactivation of SARS-CoV-2 by β-propiolactone Causes Aggregation of Viral Particles and Loss of Antigenic Potential
Authors: Gupta Divya , Parthasarathy Haripriya , Sah Vishal , Tandel Dixit , Vedagiri Dhiviya , Reddy Shashikala , Harshan Krishnan H 
Published: April 2021

ABSTRACTInactivated viral preparations are important resources in vaccine and antisera industry. Of the many vaccines that are being developed against COVID-19, inactivated whole-virus vaccines are also considered effective. β-propiolactone (BPL) is a widely used chemical inactivator of several viruses. Here, we analyze various concentrations of BPL to effectively inactivate SARS-CoV-2 and their effects on the biochemical properties of the virion particles. BPL at 1:2000 (v/v) concentrations effectively inactivated SARS-CoV-2. However, higher BPL concentrations resulted in the loss of both protein content as well as the antigenic integrity of the structural proteins. Higher concentrations also caused substantial aggregation of the virion particles possibly causing undesirable outcomes including a potential immune escape by infectious virions, and a loss in antigenic potential. We also identify that the viral RNA content in the culture supernatants can be a direct indicator of their antigenic content. Our findings may have important implications in the vaccine and antisera industry during COVID-19 pandemic.
A two-level, dynamic fitness landscape of hepatitis C virus revealed by self-organized haplotype maps
Authors: Delgado Soledad , Perales Celia , García-Crespo Carlos , Soria María Eugenia , Gallego Isabel , de Ávila Ana Isabel , Martínez-González Brenda , Vázquez-Sirvent Lucía , López-Galíndez Cecilio , Morán Federico , Domingo Esteban 
Published: April 2021

ABSTRACTFitness landscapes reflect the adaptive potential of viruses. There is no information on how fitness peaks evolve when a virus replicates extensively in a controlled cell culture environment. Here we report the construction of Self-Organized Maps (SOMs), based on deep sequencing reads of three amplicons of the NS5A-NS5B-coding region of hepatitis C virus (HCV). A two-dimensional neural network was constructed and organized according to sequence relatedness. The third dimension of the fitness profile was given by the haplotype frequencies at each neuron. Fitness maps were derived for 44 HCV populations that share a common ancestor that was passaged up to 210 times in human hepatoma Huh-7.5 cells. As the virus increased its adaptation to the cells, the number of fitness peaks expanded, and their distribution shifted in sequence space. The landscape consisted of an extended basal platform, and a lower number of protruding higher fitness peaks. The function that relates fitness level and peak abundance corresponds a power law, a relationship observed with other complex natural phenomena. The dense basal platform may serve as spring-board to attain high fitness peaks. The study documents a highly dynamic, double-layer fitness landscape of HCV when evolving in a monotonous cell culture environment. This information may help interpreting HCV fitness landscapes in complex in vivo environments.IMPORTANCEThe study provides for the first time the fitness landscape of a virus in the course of its adaptation to a cell culture environment, in absence of external selective constraints. The deep sequencing-based self-organized maps document a two-layer fitness distribution with an ample basal platform, and a lower number of protruding, high fitness peaks. This landscape structure offers potential benefits for virus resilience to mutational inputs.
COV-ID: A LAMP sequencing approach for high-throughput co-detection of SARS-CoV-2 and influenza virus in human saliva
Authors: Warneford-Thomson Robert , Shah Parisha P. , Lundgren Patrick , Lerner Jonathan , Abella Benjamin S. , Zaret Kenneth S. , Schug Jonathan , Jain Rajan , Thaiss Christoph A. , Bonasio Roberto 
Published: April 2021

ABSTRACTThe COVID-19 pandemic has created an urgent need for rapid, effective, and low-cost SARS-CoV-2 diagnostic testing. Here, we describe COV-ID, an approach that combines RT-LAMP with deep sequencing to detect SARS-CoV-2 in unprocessed human saliva with high sensitivity (5–10 virions). Based on a multi-dimensional barcoding strategy, COV-ID can be used to test thousands of samples overnight in a single sequencing run with limited labor and laboratory equipment. The sequencing-based readout allows COV-ID to detect multiple amplicons simultaneously, including key controls such as host transcripts and artificial spike-ins, as well as multiple pathogens. Here we demonstrate this flexibility by simultaneous detection of 4 amplicons in contrived saliva samples: SARS-CoV-2, influenza A, humanSTATHERIN, and an artificial SARS spike-in. The approach was validated on clinical saliva samples, where it showed 100% agreement with RT-qPCR. COV-ID can also be performed directly on saliva adsorbed on filter paper, simplifying collection logistics and sample handling.
A trade-off between stress resistance and tolerance underlies the adaptive response to hydrogen peroxide
Authors: Jacquel Basile , Kavčič Bor , Aspert Théo , Matifas Audrey , Kuehn Antoine , Zhuralev Andrei , Byckov Elena , Morgan Bruce , Julou Thomas , Charvin Gilles 
Published: April 2021

SummaryThe physiological adaptation to environmental stress involves complex molecular responses leading to separate cellular fates aimed at maximizing fitness: either cells can maintain proliferation by degrading the effects of the stressor (i.e. resistance), or they focus on ensuring cell survival (i.e. tolerance), even at the expense of proliferation. These strategies are complementary, yet whether they are coordinated to ensure an optimal physiological stress response remains unknown. Here, we used microfluidics and live cell imaging to explore the genetic basis of the interplay between resistance and tolerance during the response to hydrogen peroxide (H2O2) in budding yeast. Our analysis unraveled that the deletion ofzwf1Δ, which is responsible for NADPH synthesis via the PPP pathway, led to a decrease in resistance that was counterbalanced by an unexpected exacerbation of tolerance to H2O2. This trade-off between stress resistance and stress tolerance was further characterized using both genetic and environmental interventions, and we confirmed that it was conserved in bacteria. Our results support a model in which redox signaling triggers the switch to a nutrients-dependent non-proliferative tolerant state via inhibition of protein kinase A when the H2O2homeostatic response is overwhelmed. Our framework could help develop synergistic therapies that target mechanisms driving both resistance and tolerance to prevent drug escape mechanisms and disease relapse.
Diffusion and distal linkages govern interchromosomal dynamics during meiotic prophase
Authors: Newman Trent A. C. , Beltran Bruno , McGehee James M. , Elnatan Daniel , Cahoon Cori K. , Paddy Michael R. , Chu Daniel B. , Spakowitz Andrew J. , Burgess Sean M. 
Published: April 2021

AbstractThe pairing of homologous chromosomes (homologs) in meiosis is essential for distributing the correct numbers of chromosomes into haploid gametes. In budding yeast, pairing depends on the formation of 150-200 Spo11-mediated double-strand breaks (DSBs) that are distributed among 16 homolog pairs, but it is not known if all, or only a subset of these DSBs, contribute to the close juxtaposition of homologs. Having established a system to measure the position of fluorescently tagged chromosomal loci in 3D space over time, we analyzed locus trajectories to determine how frequently, and how long, loci spend colocalized or apart. Continuous imaging revealed highly heterogeneous cell-to-cell behavior of foci, with the majority of cells exhibiting a “mixed” phenotype where foci move into and out of proximity, even at late stages of prophase, suggesting that the axial structures of the synaptonemal complex may be more dynamic than anticipated. The observed plateaus of the mean-squared change in distance (MSCD) between foci informed the development of a biophysical model of two diffusing polymers that captures the loss of centromere linkages as cells enter meiosis, nuclear confinement, and the formation of Spo11-dependent linkages. The predicted number of linkages per chromosome in our theoretical model closely approximates the small number (~2-4) of estimated synapsis-initiation sites, suggesting that excess DSBs have negligible effects on the overall juxtaposition of homologs. These insights into the dynamic in-terchromosomal behavior displayed during homolog pairing demonstrate the power of combining time-resolvedin vivoanalysis with modeling at the granular level.Significance StatementEssential for sexual reproduction, meiosis is a specialized cell division required for the production of haploid gametes. Critical to this process is the pairing, recombination, and segregation of homologous chromosomes (homologs). While pairing and recombination are linked, it is not known how many linkages are sufficient to hold homologs in proximity. Here, we reveal that random diffusion and the placement of a small number of linkages are sufficient to establish the apparent “pairing” of homologs. We also show that colocalization between any two loci is more dynamic than anticipated. Our study is the first to provide observations of live interchromosomal dynamics during meiosis and illustrates the power of combining single-cell measurements with theoretical polymer modeling.
Dravet variantSCN1AA1783Vimpairs interneuron firing predominantly by altered channel activation
Authors: Layer N. , Sonnenberg L. , Pardo González E. , Benda J. , Lerche H. , Koch H. , Wuttke TV. 
Published: April 2021

AbstractDravet syndrome (DS) is a developmental epileptic encephalopathy mainly caused by functional NaV1.1 haploinsufficiency in interneurons (IN). Recently, a new conditional mouse model expressing the recurrent human p.A1783V missense variant has become available. Here we provide an electrophysiological characterization of this variant in tsA201 cells, revealing both altered voltage-dependence of activation and slow inactivation without reduced sodium peak current density. Simulating IN excitability in a Hodgkin-Huxley one-compartment model suggested surprisingly similar firing deficits forScn1aA1783Vand full haploinsufficiency as caused by heterozygous truncation variants. Impaired NaVA1783Vchannel activation was predicted to have a significantly larger impact on channel function than altered slow inactivation and is therefore proposed as the main mechanism underlying IN dysfunction. The computational model was validated in cortical organotypic slice cultures derived from conditionalScn1aA1783Vmice. Pan-neuronal activation of the p.A1783V variantin vitroconfirmed the predicted IN firing deficit while demonstrating normal excitability of pyramidal neurons. Taken together these data demonstrate that despite maintained physiological peak currents density LOF gating properties may match effects of full haploinsufficiency on neuronal level, thereby causing DS.HighlightsNaV1.1A1783Valters voltage-dependence of activation and slow inactivation while not affecting fast inactivation.Depolarizing and hyperpolarizing shifts of activation and slow inactivation curves result in combined channel loss of function (LOF).Simulations of NaV1.1A1783Vinterneuronal properties indicate reduced action potential firing rates comparable to fullSCN1Ahaploinsufficiency, which is often found in Dravet syndrome.In silicomodelling identifies impaired channel activation as the predominant mechanism of channel LOF.Panneuronal induction ofScn1a+/A1783Vin a cortical slice culture model confirms restriction of loss of function and its restriction to interneurons.
Cyclin F drives proliferation through SCF-dependent degradation of the retinoblastoma-like tumor suppressor p130/RBL2
Authors: Enrico Taylor P. , Stallaert Wayne , Wick Elizaveta T. , Ngoi Peter , Rubin Seth M. , Brown Nicholas G. , Purvis Jeremy E. , Emanuele Michael J. 
Published: April 2021

AbstractCell cycle gene expression programs fuel proliferation and are dysregulated in many cancers. The retinoblastoma-family proteins, RB, p130/RBL2 and p107/RBL1, coordinately repress cell cycle gene expression, inhibiting proliferation and suppressing tumorigenesis. Ubiquitin-dependent protein degradation is essential to cell cycle control, and numerous proliferative regulators, tumor suppressors, and oncoproteins are ubiquitinated. However, little is known about the role of ubiquitin signaling in controlling RB-family proteins. A systems genetics analysis of several hundred CRISPR/Cas9 loss-of-function screens suggested the potential regulation of the RB-network by cyclin F, a substrate recognition receptor for the SCF family of E3 ligases. We demonstrate that RBL2/p130 is a direct substrate of SCFcyclin F. We map a cyclin F regulatory site to a flexible linker in the p130 pocket domain, and show that this site mediates binding, stability, and ubiquitination. Expression of a non-degradable p130 represses cell cycle gene expression and strongly reduces proliferation. These data suggest that SCFcyclin Fplays a key role in the CDK-RB network and raises the possibility that aberrant p130 degradation could dysregulate the cell cycle in human cancers.
Updates to data versions and analytic methods influence the reproducibility of results from epigenome-wide association studies
Authors: Lussier Alexandre A. , Zhu Yiwen , Smith Brooke J. , Simpkin Andrew J. , Smith Andrew D.A.C. , Suderman Matthew J. , Walton Esther , Ressler Kerry J. , Dunn Erin C. 
Published: April 2021

ABSTRACTIntroductionBiomedical research has grown increasingly cooperative, with several large consortia compiling and sharing epigenomic data. Since data are typically preprocessed by consortia prior to distribution, the implementation of new pipelines can lead to different versions of the same dataset. Analytic frameworks also constantly evolve to incorporate cutting-edge methods and shifting best practices. However, it remains unknown how differences in data and analytic versions alter the results of epigenome-wide analyses, which has broad implications for the replicability of epigenetic associations. Thus, we assessed the impact of these changes using a subsample of the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort.MethodsWe analyzed two versions of DNA methylation data, processed using separate preprocessing and analytic pipelines, to examine associations between childhood adversity and prenatal smoking exposure on DNA methylation at age 7. We performed two sets of analyses: (1) epigenome-wide association studies (EWAS); (2) Structured Life Course Modeling Approach (SLCMA), a two-stage method that models time-dependent effects. We also compared results from the SLCMA using more recent methodological recommendations.ResultsDifferences between ALSPAC data versions impacted both EWAS and SLCMA analyses, yielding different sets of associations at conventional p-value thresholds. However, the magnitude and direction of associations was generally consistent between data versions, regardless of significance thresholds. Updating the SLCMA analytic version similarly altered top associations, but time-dependent effects remained concordant.ConclusionsChanges to data and analytic versions influenced the results of epigenome-wide studies, particularly when using p-value thresholds as reference points for successful replication and stability.
The Great Deceiver: miR-2392’s Hidden Role in Driving SARS-CoV-2 Infection
Authors: McDonald J. Tyson , Enguita Francisco Javier , Taylor Deanne , Griffin Robert J. , Priebe Waldemar , Emmett Mark R. , Sajadi Mohammad M. , Harris Anthony D. , Clement Jean , Dybas Joseph M. , Aykin-Burns Nukhet , Guarnieri Joseph W. , Singh Larry N. , Grabham Peter , Baylin Stephen B. , Yousey Aliza , Pearson Andrea N. , Corry Peter M. , Saravia-Butler Amanda , Aunins Thomas R. , Sharma Sadhana , Nagpal Prashant , Meydan Cem , Foox Jonathan , Mozsary Christopher , Cerqueira Bianca , Zaksas Viktorija , Singh Urminder , Wurtele Eve Syrkin , Costes Sylvain V. , Davanzo Gustavo Gastão , Galeano Diego , Paccanaro Alberto , Meinig Suzanne L. , Hagan Robert S. , Bowman Natalie M ,   UNC COVID-19 Pathobiology Consortium, Wolfgang Matthew C. , Altinok Selin , Sapoval Nicolae , Treangen Todd J. , Moraes-Vieira Pedro M. , Vanderburg Charles , Wallace Douglas C. , Schisler Jonathan , Mason Christopher E. , Chatterjee Anushree , Meller Robert , Beheshti Afshin 
Published: April 2021

SummaryMicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene regulation that have a major impact on many diseases and provides an exciting avenue towards antiviral therapeutics. From patient transcriptomic data, we have discovered a circulating miRNA, miR-2392, that is directly involved with SARS-CoV-2 machinery during host infection. Specifically, we show that miR-2392 is key in driving downstream suppression of mitochondrial gene expression, increasing inflammation, glycolysis, and hypoxia as well as promoting many symptoms associated with COVID-19 infection. We demonstrate miR-2392 is present in the blood and urine of COVID-19 positive patients, but not detected in COVID-19 negative patients. These findings indicate the potential for developing a novel, minimally invasive, COVID-19 detection method. Lastly, usingin vitrohuman andin vivohamster models, we have developed a novel miRNA-based antiviral therapeutic that targets miR-2392, significantly reduces SARS-CoV-2 viability in hamsters and may potentially inhibit a COVID-19 disease state in humans.
Limiting factors for queen conch (Lobatus gigas) reproduction: A simulation-based evaluation
Authors: Farmer Nicholas A. , Doerr Jennifer C. 
Published: April 2021

AbstractQueen conch are among the most economically, socially, and culturally important fishery resources in the Caribbean. Despite a multitude of fisheries management measures enacted across the region, populations are depleted and failing to recover. It is believed that queen conch are highly susceptible to depensatory processes, impacting reproductive success and contributing to the lack of recovery. We developed a model of reproductive dynamics to evaluate how variations in biological factors such as population density, movement speeds, movement restrictions, rest periods between mating events, sexual facilitation, and perception of conspecifics affect reproductive success and overall reproductive output. We compared simulation results to empirical observations of mating and spawning frequencies from conch populations in the central Bahamas and Florida Keys. Our results confirm that low probability of mate finding associated with decreased population density is the primary driver behind observed breeding behavior in the field, although additional factors also play important roles. In particular, sexual facilitation and perception of conspecifics may explain observed lack of mating at low densities and differences between mating frequencies in the central Bahamas and Florida Keys, respectively. Our simulations suggest densities greater than 200 adults/ha are needed for high levels of spawning output, supporting the suggestion that effective management strategies for queen conch should aim to protect high-density reproductive aggregations and critical breeding habitats.