bluuebunny/crossref_metadata_2025_split huggingface dataset:
Barrett’s esophagus is the precursor of all esophageal adenocarcinomas
Authors: Curtius Kit , Rubenstein Joel H. , Chak Amitabh , Inadomi John M. 
Published: May 2020

AbstractObjectiveBarrett’s esophagus (BE) is a known precursor to esophageal adenocarcinoma (EAC) but current clinical data have not been consolidated to address whether BE is the origin of all incident EAC, which would reinforce evidence for BE screening efforts. We aimed to answer whether all expected prevalent BE, diagnosed and undiagnosed, could account for all incident EACs in the US cancer registry data.DesignWe used a multi-scale computational model of EAC that includes the evolutionary process from normal esophagus through BE in individuals from the US population. The model was previously calibrated to fit SEER cancer incidence curves. Here we also utilized age- and sex-specific US census data for numbers at-risk. The primary outcome for model validation was the expected number of EAC cases for a given calendar year. Secondary outcomes included the comparisons of resulting model-predicted prevalence of BE and BE-to-EAC progression to the observed prevalence and progression rates.ResultsThe model estimated the total number of EAC cases in 2010 was 9,970 (95% CI 9,140 – 11,980), which recapitulates all EAC cases from population data. The model simultaneously predicted 8-9% BE prevalence in high-risk males age 45-55, and 0.1-0.2% non-dysplastic BE-to-EAC annual progression in males, consistent with clinical studies.ConclusionThere are no additional EAC cases that plausibly arise in the US population outside the BE pathway. Effective screening of high-risk patients could capture the majority of population destined for EAC progression and decrease mortality through early detection and curative removal of small (pre)cancers during surveillance.Summary BoxWhat is already known about this subject?Barrett’s esophagus (BE) patients have a 40 to 50-fold higher risk of developing esophageal adenocarcinoma (EAC) than the general population yet many remain undiagnosed.Identified BE patients receiving surveillance can have early cancers discovered endoscopically, which decreases the high overall EAC-associated mortality.Currently around 90% of patients who develop EAC were never part of a BE surveillance program, and those BE patients on surveillance have a low annual progression rate of 0.1 - 0.3% to develop EAC.What are the new findings?By applying a model that incorporates the evolution from normal cells to BE to EAC in patients, we found that the numbers add up - the expected number of EAC cases in the US population are explained by the published rates of BE described above.We cohesively examined the published estimates to determine that all EAC likely arises from both identified BE and occult, undiagnosed BE in the population.How might it impact on clinical practice in the foreseeable future?Based on current best estimates, our findings suggest there is no public health need to seek cases of a non-BE alternative pathway to EAC.Increasing efforts for effective, sensitive screening and surveillance of the true BE population will decrease EAC mortality in the coming years.
Homology-guided identification of a conserved motif linking the antiviral functions of IFITM3 to its oligomeric state
Authors: Rahman Kazi , Coomer Charles A. , Majdoul Saliha , Ding Selena , Padilla-Parra Sergi , Compton Alex A. 
Published: May 2020

AbstractThe interferon-inducible transmembrane (IFITM) proteins belong to the Dispanin/CD225 family and inhibit diverse virus infections. IFITM3 reduces membrane fusion between cells and virions through a poorly characterized mechanism. We identified a GxxxG motif in many CD225 proteins, including IFITM3 and proline rich transmembrane protein 2 (PRRT2). Mutation of PRRT2, a regulator of neurotransmitter release, at glycine-305 was previously linked to paroxysmal neurological disorders in humans. Here, we show that glycine-305 and the homologous site in IFITM3, glycine-95, drive protein oligomerization from within a GxxxG motif. Mutation of glycine-95 in IFITM3 disrupted its oligomerization and reduced its antiviral activity against Influenza A and HIV-1. The oligomerization-defective variant was used to reveal that IFITM3 promotes membrane rigidity in a glycine-95-dependent manner. Furthermore, a compound which counteracts virus inhibition by IFITM3, amphotericin B, prevented the IFITM3-mediated rigidification of membranes. Overall, these data suggest that IFITM3 oligomers inhibit virus-cell fusion by promoting membrane rigidity.
Experience-dependent refinement of natural approach responses towards specific visual stimuli in mice
Authors: Procacci Nicole M. , Allen Kelsey M. , Robb Gael E. , Ijekah Rebecca , Hoy Jennifer L. 
Published: May 2020

AbstractSpecific features of visual objects innately draw orienting and approach responses in animals, and provide natural signals of potential reward. In addition, the rapid refinement of innate approach responses enhances the ability of an animal to effectively and conditionally forage, capture prey or initiate a rewarding social experience. However, the neural mechanisms underlying how the brain encodes naturally appetitive stimuli and conditionally transforms stimuli into approach behavior remain unclear. As a first step towards this goal, we have developed a behavioral assay to quantify innate, visually-evoked approach behaviors in freely moving mice presented with simple, computer generated stimuli of varying sizes and speeds in the lower visual field. We found that specific combinations of stimulus features selectively evoked innate approach versus freezing behavioral responses. Surprisingly, we also discovered that prey capture experience selectively modified a range of visually-guided appetitive behaviors, including increasing the probability of approach and pursuit of moving stimuli, as well as altering those visual features that evoked approach. These findings will enable the use of sophisticated genetic strategies to uncover novel neural mechanisms underlying predictive coding, innate behavioral choice, and flexible, state-dependent processing of stimuli in the mouse visual system.HighlightsNovel stimuli with specific visual features reliably elicit an approach in C57BL/6J mice.Introduction of motion to stimuli makes freezing the most probable behavioral response.Spontaneous behavioral responses are tuned to size, speed and visual field location.Prey capture experience selectively refines natural, visually-evoked approach behaviors.
Fractal Genomics ofSOD1Evolution
Authors: Saeed Mohammad 
Published: May 2020

AbstractTo understand the fundamental processes of gene evolution such as the impact of point mutations and segmental duplications on statistical topography, Superoxide Dismutase-1 (SOD1) orthologous sequences (n=50) were studied. These demonstrated scale invariant self-similarity patterns and long-range correlations (LRC) indicating fractal organization. Phylogenetic hierarchies changed whenSOD1orthologs were grouped according to fractal measures, indicating statistical topographies can be used to study gene evolution. Sliding window k-mer analysis showed that majority of k-mers across allSOD1orthologs were unique, with very few duplications. Orthologs from simpler species contributed minimally (<1% of k-mers) to more complex species. Both simple and complex random processes failed to produce significant matching k-mer sequences forSOD1orthologs. Point mutations causing amyotrophic lateral sclerosis did not impact the fractal organization of humanSOD1. Hence,SOD1did not evolve by a patchwork of repetitive sequences modified by point mutations. Instead, this study proposes thatSOD1gene sequences evolved by regulated interweaving of unique oligomer sequences that led to LRC, signifying convergent evolution.Summary StatementSOD1has long-range correlations which resulted not from point mutations, segmental duplications or patching together sequences from simpler organisms. Instead,SOD1underwent convergent evolution by repeated unique sequence assemblies.
SARS-CoV-2 transcriptome analysis and molecular cataloguing of immunodominant epitopes for multi-epitope based vaccine design
Authors: Kushwaha Sandeep Kumar , Kesarwani Veerbhan , Choudhury Samraggi , Gandhi Sonu , Sharma Shailesh 
Published: May 2020

AbstractSARS-CoV-2 is a single-stranded RNA virus that has caused more than 0.29 million deaths worldwide as of May 2020, and influence of COVID-19 pandemic is increasing continuously in the absence of approved vaccine and drug. Moreover, very limited information is available about SARS-CoV-2 expressed regions and immune responses. In this paper an effort has been made, to facilitate vaccine development by proposing multiple epitopes as potential vaccine candidates by utilising SARS-CoV-2 transcriptome data. Here, publicly available RNA-seq data of SARS-CoV-2 infection in NHBE and A549 human cell lines were used to construct SARS-CoV-2 transcriptome to understand disease pathogenesis and immune responses. In the first step, epitope prediction, MHC class I and II gene identification for epitopes, population coverage, antigenicity, immunogenicity, conservation and crossreactivity analysis with host antigens were performed by using SARS-CoV-2 transcriptome, and in the second step, structural compatibility of identified T-and B-cell epitopes were evaluated with MHC molecules and B-cell receptors through molecular docking studies. Quantification of MHC gene expression was also performed that indicated high variation in allele types and expression level of MHC genes with respect to cell lines. In A549 cell line, HLA-A*30:01:01:01 and HLA-B*44:03:01:01 were highly expressed, whereas 92 variants of HLA-A*24 genes such as HLA-A*24:02:01:01, HLA-A*24:286, HLA-A*24:479Q, HLA-A*24:02:134 and HLA-A*24:02:116 were highly expressed in NHBE cell lines. Prevalence of HLA-A*24 alleles was suggested as risk factors for H1N1 infection, and associated with type-1 diabetes. HLA-C*03:03, linked with male infertility factors was also highly expressed in SARS-CoV-2 infected NHBE cell lines. Finally, three potential T-cell and five B-cell epitopes were selected for molecular docking studies with twenty-two MHC molecules and two B-cell receptors respectively. The results ofin silicoanalysis indicated that proposed epitopes have high potential to recognize immune response of SARS-CoV-2 infection. This study will facilitatein vitroandin vivovaccine related research studies.
Recommendations for sample pooling on the Cepheid GeneXpert®system using the Cepheid Xpert®Xpress SARS-CoV-2 assay
Authors: Becker Michael G. , Taylor Tracy , Kiazyk Sandra , Cabiles Dana R. , Meyers Adrienne F.A. , Sandstrom Paul A. 
Published: May 2020

AbstractThe coronavirus disease 2019 (Covid-19) pandemic, caused by SARS-CoV-2, has resulted in a global testing supply shortage. In response, pooled testing has emerged as a promising strategy that can immediately increase testing capacity. Here, we provide support for the adoption of sample pooling with the point-of-care Cepheid Xpert®Xpress SARS-CoV-2 molecular assay. Corroborating previous findings, the Xpert®Xpress SARS-CoV-2 assay limit of detection was comparable to central laboratory reverse-transcription quantitative PCR tests with observed SARS-CoV-2 detection below 100 copies/mL. The Xpert®Xpress assay detected SARS-CoV-2 after samples with minimum viral loads of 461 copies/mL were diluted into six sample pools. Based on these data, we recommend the adoption of pooled testing with the Xpert®Xpress SARS-CoV-2 assay where warranted by population public health needs. The suggested number of samples per pool, or pooling depth, is unique for each point-of-care test site and should be determined by assessing positive test rates. To statistically determine appropriate pooling depth, we have calculated the pooling efficiency for numerous combinations of pool sizes and test rates. This information is included as a supplemental dataset that we encourage public health authorities to use as a guide to make recommendations that will maximize testing capacity and resource conservation.
Performance assessment of Respiratory Viral ELITe MGB® assay for the quantitative detection of influenza A/B and respiratory syncytial viruses
Authors: Piralla Antonio , Giardina Federica , Fratini Alice , Sapia Davide , Rovida Francesca , Baldanti Fausto 
Published: May 2020

AbstractInfluenza (Flu) and respiratory syncytial virus (RSV) are responsible for lower respiratory tract infections (LRTIs) associated with significant hospitalization among young children. In the present study, the performances of a triplex PCR assay detecting Flu A/B and RSV were compared with our in-house single-plex assays using 160 stored respiratory specimens previously tested using a panel of laboratory-developed real-time RT-PCR. Of them, 61 were positive for FluA, 41 for FluB, and 58 for RSV. All samples were retrospectively quantified with Respiratory Viral (RV) ELITe MGB® Panel (ELITechGroup Molecular Diagnostics, Puteaux, France) processed using ELITe InGenius® system. Overall, the total percentage agreement observed was 93.4% (57/61) for FluA, 92.7% (38/41) for FluB, and 86.2% (50/58) for RSV. A significant correlation of VL values was observed between the two methods for FluA and RSV (ρ= 0.91 and 0.84). This finding was supported by the strength of agreement between the two methods, as showed by the linear regression analysis (R2 =0.84 and 0.80). FluB viral load values measured by RV Panel were less significantly correlated (ρ= 0.77 and R2 =0.56). The bland-Altman analysis showed how 84.2% (48/57) of FluA and 86.0% of RSV (43/50) samples fell within ±1.0 Log10 variation from our laboratory results, while only 21.1% (8/38) of FluB results fell within this range. The great majority of FluB samples (29/30) outside range had values higher than +1.0 Log10 (median +2.1 Log10 range +1.0 to +3.5 Log10). In conclusion, RV ELITe MGB® Panel constitutes a valid and robust system for simultaneous detection and quantification of Flu A/B and RSV.
Analytical and Clinical Comparison of Three Nucleic Acid Amplification Tests for SARS-CoV-2 Detection
Authors: Smith Elizabeth , Zhen Wei , Manji Ryhana , Schron Deborah , Duong Scott , Berry Gregory J. 
Published: May 2020

AbstractSevere Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was first identified in December 2019 and has quickly become a worldwide pandemic. In response, many diagnostic manufacturers have developed molecular assays for SARS-CoV-2 under the Food and Drug Administration (FDA) Emergency Use Authorization (EUA) pathway. This study compared three of these assays: the Hologic Panther Fusion SARS-CoV-2 assay (Fusion), the Hologic Aptima SARS-CoV-2 assay (Aptima) and the BioFire Diagnostics COVID-19 test (BioFire), to determine analytical and clinical performance, as well as workflow. All three assays showed a similar limit of detection (LOD) using inactivated virus, with 100% detection ranging from 500-1,000 genome equivalents/ml, whereas use of a quantified RNA transcript standard showed the same trend, but had values ranging from 62.5 to 125 copies/ml, confirming variability in absolute quantification of reference standards. The clinical correlation found that the Fusion and BioFire assays had a positive percent agreement (PPA) of 98.7%, followed by the Aptima assay at 94.7% when compared to the consensus result. All three assays exhibited 100% negative percent agreement (NPA). Analysis of discordant results revealed that all four samples missed by the Aptima assay had Ct values >37 on the Fusion assay.In conclusion, while all three assays showed similar relative LODs, we showed differences in absolute LODs depending on which standard was employed. In addition, the Fusion and BioFire assays showed better clinical performance, while the Aptima assay showed a modest decrease in overall PPA. These findings should be kept in mind when making platform testing decisions.
Association of zinc-finger antiviral protein (ZAP) binding to viral genomic RNA with attenuation of replication of echovirus 7
Authors: Goonawardane Niluka , Nguyen Dung , Simmonds Peter 
Published: May 2020

AbstractPrevious studies have implicated both zinc finger antiviral protein (ZAP) and oligoadenylate synthetase 3 (OAS3)/RNASeL in the attenuation of RNA viruses with elevated CpG and UpA dinucleotides. Mechanisms and inter-relationships between these two pathways were investigated using an echovirus 7 (E7) replicon with compositionally modified sequences inserted into the 3’untranslated region. ZAP and OAS3 immunoprecipitation (IP) assays provided complementary data on dinucleotide composition effects on binding. Elevated frequencies of alternative pyrimidine/purine (CpA and UpG) and reversed (GpC and ApU) dinucleotides showed no attenuating effect nor specific binding to ZAP by IP. However, the bases 3’ and 5’ to CpG motifs influenced replication and ZAP binding; UCGU enhanced CpG-mediated attenuation and ZAP-binding while A residues shielded CpGs from ZAP recognition. Attenuating effects of elevated frequencies of UpA on replication occurred independently of CpG dinucleotides and bound non-competitively with CpG-enriched RNA consistent with a separate recognition site from CpG. Remarkably, immunoprecipitation with OAS3 antibody reproduced the specific binding to CpG- and UpA-enriched RNA sequences. However, OAS3 and ZAP were coimmunoprecipitated in both ZAP and OAS3 IP, and colocalised with E7 and stress granules (SGs) by confocal microscopy analysis of infected cells. ZAP’s association with larger cellular complexes may mediate the recruitment of OAS3/RNAseL, KHNYN and other RNA degradation pathways.ImportanceWe have recently discovered that the OAS3/RNAseL antiviral pathway is essential for restriction of CpG- and UpA-enriched viruses, in addition to the requirement for zinc finger antiviral protein (ZAP). The current study provides evidence for the specific dinucleotide and wider recognition contexts associated with virus recognition and attenuation. It further documents the association of ZAP and OAS3 and association with stress granules and a wider protein interactome that may mediate antiviral effects in different cellular compartments. The study provides a striking re-conceptualisation of the pathways associated with this aspect of antiviral defence.
Glucocorticoid signaling in pancreatic islets modulates gene regulatory programs and genetic risk of type 2 diabetes
Authors: Aylward Anthony , Okino Mei-Lin , Benaglio Paola , Chiou Joshua , Beebe Elisha , Padilla Jose Andres , Diep Sharlene , Gaulton Kyle J 
Published: May 2020

AbstractGlucocorticoids are key regulators of glucose homeostasis and pancreatic islet function, but the gene regulatory programs driving responses to glucocorticoid signaling in islets and the contribution of these programs to diabetes risk are unknown. In this study we used ATAC-seq and RNA-seq to map chromatin accessibility and gene expression from eight primary human islet samples culturedin vitrowith the glucocorticoid dexamethasone. We identified 2,838 accessible chromatin sites and 1,114 genes with significant changes in activity in response to glucocorticoids. Chromatin sites up-regulated in glucocorticoid signaling were prominently enriched for glucocorticoid receptor binding sites and up-regulated genes were enriched for ion transport and lipid metabolism, whereas down-regulated chromatin sites and genes were enriched for inflammatory, stress response and proliferative processes. Genetic variants associated with glucose levels and T2D risk were enriched in glucocorticoid-responsive chromatin sites, including fine-mapped risk variants at 54 known signals. Among fine-mapped variants in glucocorticoid-responsive chromatin, a likely casual variant at the 2p21 locus had glucocorticoid-dependent allelic effects on beta cell enhancer activity and affectedSIX2andSIX3expression. Our results provide a comprehensive map of islet regulatory programs in response to glucocorticoids through which we uncover a role for islet glucocorticoid signaling in mediating risk of type 2 diabetes.
Nutrient restriction, inducer of yeast meiosis, induces meiotic initiation in mammals
Authors: Zhang Xiaoyu , Gunewardena Sumedha , Wang Ning 
Published: May 2020

ABSTRACTFrom yeasts to mammals, the molecular machinery and chromosome structures carrying out meiosis are frequently conserved. However, the signal to initiate meiosis appears divergent: while nutrient restriction induces meiosis in the yeast system, retinoic acid (RA), a chordate morphogen, is necessary but not sufficient to induce meiotic initiation in mammalian germ cells via its target,Stra8. Here, using cultured mouse male germline stem cells without the support of gonadal somatic cells, we show that nutrient restriction in combination with RA robustly inducesSpo11-dependent meiotic DNA double strand breaks (DSBs) andStra8-dependent meiotic gene programs recapitulating those of early meiosisin vivo. Moreover, a distinct network of 11 nutrient restriction-upregulated transcription factor genes was identified, whose expression does not require RA and is associated with early meiosisin vivo. Thus, our study proposes a conserved model, in which nutrient restriction induces meiotic initiation by upregulating transcriptional factors for meiotic gene programs, and provides anin vitroplatform to derive haploid gametes in culture.One Sentence Summarynutrient restriction synergizes with retinoic acid to induce mammalian meiotic initiation
Sensing soluble uric acid by Naip1-Nlrp3 platform
Authors: Braga Tarcio Teodoro , Davanso Mariana Rodrigues , Mendes Davi , de Souza Tiago Antonio , de Brito Anderson Fernandes , Cruz Mario Costa , Hiyane Meire Ioshie , de Lima Dhemerson Souza , Nunes Vinicius , Giarola Juliana de Fátima , Souto Denio Emanuel Pires , Próchnicki Tomasz , Lauterbach Mario , Biscaia Stellee Marcela Petris , de Freitas Rilton Alves , Curi Rui , Pontillo Alessandra , Latz Eicke , Saraiva Camara Niels Olsen 
Published: May 2020

SummaryThe immune system can recognize microbes and sterile tissue damage. Among the damage-associated molecular patterns (DAMPs), uric acid is considered a major component which can trigger inflammation. It represents a breakpoint in the evolutionary history of humans as our ancestors lost the uricase gene, the enzyme responsible for its cleavage. High soluble uric acid (sUA) concentration is able to increase IL-1β in murine, but not human macrophages. We observed that sUA increased the mRNA expression ofNaip1in murine macrophages, and, therefore, we hypothesized that the recognition of sUA can be made by a Naip1-Nlrp3 inflammasome platform. Additionally, we used genome-wide transcriptome analysis, functional analyses and structural modeling predictions and observed that virus-transduction of murine Naip1 into human macrophages induced IL-1β after sUA stimulus, besides leading to fatty acid production and an inflammation-related response. Moreover, pharmacologic inhibition and genetic loss of Nlrp3 led to decreased IL-1β production upon sUA stimulus. Surface plasmon resonance and quartz crystal microbalance showed that sUA is able to interact with Naip1. Naip could be a lost receptor for sUA in the evolutionary process and a better understanding of the immune modulatory function of sUA could lead to design rational novel anti-hyperuricemic therapies.