bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutagenesis Mapping of RNA Structures within the Foot-and-Mouth Disease Virus Genome Reveals Functional Elements Localised in the Polymerase (3Dpol) Encoding Region
Authors: Lasecka-Dykes Lidia , Tulloch Fiona , Simmonds Peter , Luke Garry A. , Ribeca Paolo , Gold Sarah , Knowles Nick J. , Wright Caroline F. , Wadsworth Jemma , Azhar Mehreen , King Donald P. , Tuthill Tobias J. , Jackson Terry , Ryan Martin D. 
Published: January 2021

ABSTRACTAbstractRNA structure plays a crucial role in the replication of positive sense RNA viruses and can form functional elements within the untranslated regions (UTRs) and the protein coding sequences (or open reading frames (ORFs)). While RNA structures in the UTRs of several picornaviruses have been functionally characterised, the roles of putative RNA structures predicted for the ORF remain largely undefined. Here we have undertaken a bioinformatic analysis of the foot-and-mouth disease virus (FMDV) genome and predicted the existence of 53 evolutionarily conserved RNA structures within the ORF. Forty-five (45) of these structures were located in the regions encoding the non-structural proteins (nsps). To investigate if the structures in the regions encoding the nsps are required for FMDV replication we used a mutagenesis method, CDLR mapping, where sequential coding segments were shuffled to minimise RNA secondary structures while preserving protein coding, native dinucleotide frequencies and codon usage. To examine the impact of these changes on replicative fitness, mutated sequences were inserted into an FMDV sub-genomic replicon. We found that three of the RNA structures, all at the 3’ termini of the FMDV ORF, were critical for replicon replication. Contrastingly, disruption of the other 42 conserved RNA structures that lie within the regions encoding the nsps had no effect on replicon replication, suggesting that these structures are not required for initiating translation or replication of viral RNA. Conserved RNA structures that are not essential for virus replication could provide ideal targets for the rational attenuation of a wide range of FMDV strains.ImportanceSome RNA structures formed by the genomes of RNA viruses are critical for viral replication. Our study shows that of 45 conserved RNA structures located within the regions of the foot-and-mouth disease virus (FMDV) genome that encode the non-structural proteins, only three are essential for replication of an FMDV sub-genomic replicon. Replicons replication is dependent on RNA translation and synthesis; thus, our results suggest that the three RNA structures are critical for either initiation of viral RNA translation and/or viral RNA synthesis. Although further studies are required to identify if the remaining 42 RNA structures have other roles in virus replication, they may provide targets for the rational large-scale attenuation of a wide range of FMDV strains. FMDV causes a highly contagious disease posing a constant threat to global livestock industries. Such weakened FMDV strains could be investigated as live-attenuated vaccines or could enhance biosecurity of conventional inactivated vaccine production.
Molecular epidemiology of Escherichia coli and Klebsiella species bloodstream infections in Oxfordshire (UK) 2008-2018
Authors: Lipworth Samuel , Vihta Karina-Doris , Chau Kevin , Barker Leanne , George Sophie , Kavanagh James , Davies Timothy , Vaughan Alison , Andersson Monique , Jeffery Katie , Oakley Sarah , Morgan Marcus , Hopkins Susan , Peto Timothy E. A. , Crook Derrick W. , Walker Ann Sarah , Stoesser Nicole 
Published: January 2021

AbstractThe incidence of Gram-negative bloodstream infections (BSIs), predominantly caused by Escherichia coli and Klebsiella species, continues to increase; however the causes of this are unclear and effective interventions are therefore hard to design. In this study we sequenced 3468 sequential, unselected isolates over a decade in Oxfordshire, UK. We demonstrate that the observed increases in E. coli incidence were not driven by clonal expansion; instead, four major sequence types (STs) continue to dominate a stable population structure, with no evidence of adaptation to hospital/community settings. Conversely in Klebsiella spp. most infections are caused by sporadic STs with the exception of a local drug-resistant outbreak strain (ST490). Virulence elements are highly structured by ST in E. coli but not Klebsiella spp. where they occur in a diverse spectrum of STs and equally across healthcare and community settings. Most clinically hypervirulent (i.e. community-onset) Klebsiella BSIs have no known acquired virulence loci. Finally we demonstrate a diverse but largely genus-restricted mobilome with close associations between antimicrobial resistance (AMR) genes and insertion sequences but not typically specific plasmid replicon types; consistent with the dissemination of AMR genes being highly contingent on smaller mobile genetic elements (MGEs). Our large genomic study highlights distinct differences in the molecular epidemiology of E. coli and Klebsiella BSIs, and suggests that no single specific pathogen genetic factors are likely contributing to the increasing incidence of BSI overall, that association with AMR genes in E. coli is a contributor to the increasing number of E. coli BSIs, and that more attention should be given to AMR gene associations with non-plasmid MGEs to try and understand horizontal gene transfer networks.
Prevalence of RT-qPCR-detected SARS-CoV-2 infection at schools: First results from the Austrian School-SARS-CoV-2 prospective cohort study
Authors: Willeit Peter , Krause Robert , Lamprecht Bernd , Berghold Andrea , Hanson Buck , Stelzl Evelyn , Stoiber Heribert , Zuber Johannes , Heinen Robert , Köhler Alwin , Bernhard David , Borena Wegene , Doppler Christian , von Laer Dorothee , Schmidt Hannes , Pröll Johannes , Steinmetz Ivo , Wagner Michael 
Published: January 2021

AbstractBackgroundThe role of schools in the SARS-CoV-2 pandemic is much debated. We aimed to quantify reliably the prevalence of SARS-CoV-2 infections at schools detected with reverse-transcription quantitative polymerase-chain-reaction (RT-qPCR).MethodsThis nationwide prospective cohort study monitors a representative sample of pupils (grade 1-8) and teachers at Austrian schools throughout the school year 2020/2021. We repeatedly test participants for SARS-CoV-2 infection using a gargling solution and RT-qPCR. We herein report on the first two rounds of examinations. We used mixed-effect logistic regression to estimate odds ratios and robust 95% confidence intervals (95% CI).FindingsWe analysed data on 10734 participants from 245 schools (9465 pupils, 1269 teachers). Prevalence of SARS-CoV-2 infection increased from 0.39% at round 1 (95% CI 0.28-0·55%, 29 September-22 October 2020) to 1·39% at round 2 (95% CI 1·04-1·85%, 10-16 November). Odds ratios for SARS-CoV-2 infection were 2·26 (95% CI 1·25-4·12, P=0·007) in regions with >500 vs. ≤500 inhabitants/km2, 1·67 (95% CI 1·42-1·97, P<0·001) per two-fold higher regional 7-day incidence, and 2·78 (95% CI 1·73-4·48, P<0·001) in pupils at schools with high/very high vs. low/moderate social deprivation. Associations of community incidence and social deprivation persisted in a multivariable adjusted model. Prevalence did not differ by average number of pupils per class nor between age groups, sexes, pupils vs. teachers, or primary (grade 1-4) vs. secondary schools (grade 5-8).InterpretationThis monitoring study in Austrian schools revealed SARS-CoV-2 infection in 0·39%-1·39% of participants and identified associations of regional community incidence and social deprivation with higher prevalence.FundingBMBWF Austria.
Ivermectin shows clinical benefits in mild to moderate COVID19: A randomised controlled double blind dose response study in Lagos
Authors: Babalola OE , Bode CO , Ajayi AA , Alakaloko FM , Akase IE , Otrofanowei E , Salu OB , Adeyemo WL , Ademuyiwa AO , Omilabu S 
Published: January 2021

ABSTRACTIntroductionIn vitro studies have shown the efficacy of Ivermectin (IV) to inhibit the SARS - CoV-2 viral replication, but questions remained as to In-vivo applications. We set out to explore the efficacy and safety of Ivermectin in persons infected with COVID19.MethodsWe conducted a translational proof of concept (PoC) randomized, double blind placebo controlled, dose response, parallel group study of IV efficacy in RT - PCR proven COVID 19 positive patients. 62 patients were randomized to 3 treatment groups. (A) IV 6mg regime, (B)IV 12 mg regime (given Q84hrs for 2weeks) (C, control) Lopinavir/Ritonavir. All groups plus standard of Care.ResultsThe Days to COVID negativity [DTN] was significantly and dose dependently reduced by IV (p = 0.0066). The DTN for Control were, = 9.1+/−5.2, for A 6.0 +/− 2.9, and for B 4.6 +/−3.2. 2 Way repeated measures ANOVA of ranked COVID 19 + / − scores at 0, 84, 168, 232 hours showed a significant IV treatment effect (p=0.035) and time effect (p <0.0001). IV also tended to increase SPO2 % compared to controls, p = 0.073, 95% CI - 0.39 to 2.59 and increased platelet count compared to C (p = 0.037) 95%CI 5.55 - 162.55 × 103/ml. The platelet count increase was inversely correlated to DTN (r = −0.52, p = 0.005). No SAE was reported.Conclusions12 mg IV regime may have superior efficacy. IV should be considered for use in clinical management of SARS-Cov-2, and may find applications in community prophylaxis in high-risk areas.
In Vivo Assessment of the Safety of Standard Fractionation Temporally Feathered Radiation Therapy (TFRT) for Head and Neck Squamous Cell Carcinoma: An R-IDEAL Stage 1/2a First-in-Humans/Feasibility Demonstration of New Technology Implementation
Authors: Parsai Shireen , Qiu Richard Lei J. , Qi Peng , Sedor Geoffrey , Fuller Clifton D. , Murray Eric , Majkszak David , Dorio Nicole , Koyfman Shlomo , Woody Neil , Joshi Nikhil , Scott Jacob G. 
Published: January 2021

AbstractIntroductionPrior in silico simulations of studies of Temporally Feathered Radiation Therapy (TFRT) have demonstrated potential reduction in normal tissue toxicity. This R-IDEAL Stage 1/2A study seeks to demonstrate the first-in-human implementation of TFRT in treating patients with head and neck squamous cell carcinoma (HNSCC).Materials and MethodsPatients with HNSCC treated with definitive radiation therapy were eligible (70 Gy in 35 fractions) were eligible. The primary endpoint was feasibility of TFRT planning as defined by radiation start within 15 days of CT simulation. Secondary endpoints included estimates of acute grade 3-5 toxicity.ResultsThe study met its accrual goal of 5 patients. TFRT plans were generated in four of the five patients within 15 business days of CT simulation, therefore meeting the primary endpoint. One patient was not treated with TFRT at physician’s discretion, though the TFRT plan had been generated within sufficient time from the CT simulation. For patients who received TFRT, the median time from CT simulation to radiation start was 10 business days (range 8-15). The average time required for radiation planning was 6 days. In all patients receiving TFRT, each subplan and every daily fraction was delivered in the correct sequence without error. The OARs feathered included: oral cavity, each submandibular gland, each parotid gland, supraglottis, and posterior pharyngeal wall (OAR pharynx). Prescription dose PTV coverage (>95%) was ensured in each TFRT subplan and the composite TFRT plan. One of five patients developed an acute grade 3 toxicity.ConclusionsThis study demonstrates the first-in-human implementation of TFRT (R-IDEAL Stage 1), proving its feasibility in the modern clinical workflow. Additionally, assessments of acute toxicities and dosimetric comparisons to a standard radiotherapy plan were described (R-IDEAL Stage 2a).HighlightsThis prospective study is the first-in-human application for Temporally Feathered Radiation Therapy (TFRT).In theory, TFRT may reduce radiation-induced toxicities by optimizing the time through which radiation is delivered and consequently improve normal tissue recovery.In this study, patients with head and neck squamous cell carcinoma were treated with TFRT.The primary endpoint of technical feasibility was met when patients were successfully treated with TFRT techniques without introducing delays in radiation commencement.
Representative Estimates of COVID-19 Infection Fatality Rates from Three Locations in India
Authors: Cai R. , Novosad P. , Tandel V. , Asher S. , Malani A. 
Published: January 2021

AbstractThere are very few estimates of the age-specific infection fatality rate (IFR) of SARS-CoV-2 in low- and middle-income countries. India reports the second highest number of SARS-CoV-2 infections in the world. We estimate age-specific IFR using data from seroprevalence surveys in Mumbai (population 12 million) and Karnataka (population 61 million), and a random sample of economically distressed migrants in Bihar with mortality followup. Among men aged 50–89, IFR is 0.12% in Karnataka (95% C.I. 0.09%–0.15%), 0.53% in Mumbai (0.52%–0.54%), and 5.64% among migrants in Bihar (0–11.16%). IFR in India is approximately twice as high for men as for women, is heterogeneous across contexts, and rises much less at older ages than in comparable studies from high income countries.
A novel age-informed approach for genetic association analysis in Alzheimer’s disease
Authors: Guen Yann Le , Belloy Michael E. , Napolioni Valerio , Eger Sarah J. , Kennedy Gabriel , Tao Ran , He Zihuai , Greicius Michael D. ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: January 2021

ABSTRACTIntroductionMany Alzheimer’s disease (AD) genetic association studies disregard age or incorrectly account for it, hampering variant discovery.MethodUsing simulated data, we compared the statistical power of several models: logistic regression on AD diagnosis adjusted and not adjusted for age; linear regression on a score integrating case-control status and age; and multivariate Cox regression on age-at-onset. We applied these models to real exome-wide data of 11,127 sequenced individuals (54% cases) and replicated suggestive associations in 21,631 genotype-imputed individuals (51% cases).ResultsModelling variable AD risk across age results in 10-20% statistical power gain compared to logistic regression without age adjustment, while incorrect age adjustment leads to critical power loss. Applying our novel AD-age score and/or Cox regression, we discovered and replicated novel variants associated with AD on KIF21B, USH2A, RAB10, RIN3 and TAOK2 genes.DiscussionOur AD-age score provides a simple means for statistical power gain and is recommended for future AD studies.
Dopamine transporter in obesity: a meta-analysis
Authors: Pak Kyoungjune , Kim Keunyoung , Kim In Joo 
Published: January 2021

ABSTRACTThe brain plays a major role in controlling the desire to eat. This meta-analysis aimed to assess the association between dopamine transporter (DAT) availability, and obesity. We performed a systematic search of MEDLINE (from inception to November 2020) and EMBASE (from inception to November 2020) for articles published in English using the keywords “dopamine transporter,” “obesity,” and “neuroimaging”. Data were plotted for each radiopharmaceutical, and linear regression was used to describe the relationship between DAT ratio, and body mass index (BMI), spline curves were adopted to fit data between DAT ratio and BMI. Five studies including 421 subjects were eligible for inclusion in this study. Two studies with 123I-FP-CIT, one with 99mTc-TRODAT, one with 123I-PE21, and one with 18F-FP-CIT were included. DAT availabilities from ENC-DAT project were higher than those from PPMI database both for caudate nucleus, and putamen. As there might be the inter-study variability, we calculated DAT ratio, after dividing DAT availabilities of subjects with overweight/obese BMI with mean DAT availabilities of subjects with normal BMI. In conclusion, we have shown that DAT availability of subjects with overweight/obesity was not different from those with normal BMI.
Plastid phylogenomics of theSansevieriaclade (Dracaena; Asparagaceae) resolves a rapid evolutionary radiation
Authors: van Kleinwee Iris , Larridon Isabel , Shah Toral , Bauters Kenneth , Asselman Pieter , Goetghebeur Paul , Leliaert Frederik , Veltjen Emily 
Published: January 2021

ABSTRACTSansevierias are a diverse group of flowering plants native to Africa, Madagascar, the Arabian Peninsula and the Indian subcontinent, popular outside their native range as low maintenance houseplants. Traditionally recognized as a distinct genus,Sansevieriawas recently merged with the larger genusDracaenabased on molecular phylogenetic data. Within theSansevieriaclade, taxonomic uncertainties remain despite numerous attempts to classify the species. We aim to arrive at a robust phylogeny using a plastid phylogenomic approach, and estimate a time-frame of diversification to infer the evolutionary history of the group, including geographical and morphological evolution. Molecular data was obtained using genome skimming for 50Sansevieria, representing all informal groups previously instated based on morphology, and twoDracaena sensu strictospecies. The resulting Maximum Likelihood phylogenetic hypotheses are generally well supported, except for some very short branches along the backbone of the tree. The time-calibrated phylogeny indicates a recent rapid radiation with the main clades emerging in the Pliocene. Two well-supported clades align with previously defined informal groups, i.e.,SansevieriasectionDracomima, characterised by the Dracomima-type inflorescence, and theZeylanicagroup, native to the Indian subcontinent. Other morphologically defined informal groups are shown to be polyphyletic: a pattern due to convergent evolution of the identifying characters. Cylindrical leaves arose multiple times independently in the evolution of theSansevieriaclade and similarly, the Cephalantha-type inflorescence has originated multiple times from an ancestor with a Sansevieria-type inflorescence. To provide a more accessible tool for species identification and delimitation, genes and spacer regions were screened for variability and phylogenetic informativeness to investigate their potential as chloroplast DNA barcodes. Candidate chloroplast DNA barcodes include thetrnH-rpl12, ndhH-rps15, psbE-petL, psbT-psbN, rps18-rpl20intergenic spacers, the chloroplast generps8and the first intron ofycf3.
Genome Wide Association Study in the New Haven Lexinome Project IdentifiesGARRE1as a Novel Gene for Reading Performance
Authors: Adams Andrew K. , Guertin Emily L. , Truong Dongnhu T. , Atkinson Elizabeth G. , DeMille Mellissa M.C. , Bosson-Heenan Joan M. , Frijters Jan C. , Gruen Jeffrey R. 
Published: January 2021

AbstractDespite high prevalence and high heritability, few candidate genes have been identified for reading disability. To identify novel genetic variants we performed a genome-wide association study (GWAS) using high-depth whole genome sequencing and predicated on reading performance in 407 subjects enrolled in a longitudinal study of response-to-intervention, called the New Haven Lexinome Project. The primary GWAS identified a single peak of 31 SNPs on chromosome 19 that achieved the threshold for genome-wide significance (rs2599553P=3.13×10−8) located over an expression quantitative trait locus (eQTL) forGARRE1(Granule Associated Rac And RHOG Effector 1). Little is known about the function ofGARRE1, except that it is highly and developmentally expressed in human cerebellum relative to cortex. Local ancestry regression showed the strongest association for the lead variant in African or Admixed American populations, who have been under-represented in previous genetic studies of reading. We replicated our chromosome 19 results in the Genes, Reading, and Dyslexia (GRaD) cohort and found a moderating effect of age with implications for the consideration of developmental effects in the design of future analyses. Growth curve modeling demonstrated that minor alleles of the lead SNP are related to reading longitudinally from Grade 1 to Grade 5, and that children with at least 1 minor allele of rs2599553 persistently underperformed relative to their peers by 0.33 to 0.5 standard deviations on standardized assessments of non-word decoding and reading fluency.Significance StatementTo the best of our knowledge, this work represents the only GWAS predicated on longitudinal reading performance data. Starting with initial discovery, we replicate our association in a second cohort, address common causes of type I error, localize the signal to a single gene, implicate a region of the brain most likely to be affected by variation in our candidate, show a gene-by-age effect with implications for study design in this field, and demonstrate that minor alleles of our lead SNP are associated with significant and persistent clinical effects on reading development in children.
Respiratory and intestinal epithelial cells exhibit differential susceptibility and innate immune responses to contemporary EV-D68 isolates
Authors: Freeman Megan Culler , Wells Alexandra I. , Ciomperlik-Patton Jessica , Myerburg Michael M. , Anstadt Jennifer , Coyne Carolyn B. 
Published: January 2021

AbstractEnterovirus D68 (EV-D68) has been implicated in outbreaks of severe respiratory illness and acute flaccid myelitis (AFM) and is detected in patient respiratory samples and from stool and wastewater, suggesting both respiratory and enteric routes of transmission. Here, we used a panel of EV-D68 isolates, including a historical isolate and multiple contemporary isolates from AFM outbreak years, to define the dynamics of viral replication and the host response to infection in primary human airway cells and stem cell-derived enteroids. We show that some recent EV-D68 isolates have decreased sensitivity to acid and temperature compared with an earlier isolate and that the respiratory, but not intestinal, epithelium induces a robust type III interferon (IFN) response that restricts infection. Our findings define the differential responses of the respiratory and intestinal epithelium to contemporary EV-D68 isolates and suggest that some isolates have the potential to target both the human airway and gastrointestinal tracts.
Inferring the basis of binaural detection with a modified autoencoder
Authors: Smith Samuel S. , Sollini Joseph , Akeroyd Michael A. 
Published: January 2021

AbstractThe binaural system utilizes interaural timing cues to improve the detection of auditory signals presented in noise. In humans, the binaural mechanisms underlying this phenomenon cannot be directly measured - and hence remain contentious. As an alternative, we trained modified autoencoder networks to mimic human-like behavior in a binaural detection task. The autoencoder architecture emphasizes interpretability and, hence, we “opened it up” to see if it could infer latent mechanisms underlying binaural detection. We found that the optimal network automatically developed artificial neurons with sensitivity to timing cues and with dynamics consistent with a cross-correlation mechanism. These computations were similar to neural dynamics reported in animal models. That these computations emerged to account for human hearing attests to their generality as a solution for binaural signal detection. Methodologically, the study examines the utility of explanatory-driven neural networks and how they may be used to infer mechanisms of audition.