bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase 2 Randomized Trial of an AS03 Adjuvanted Plant-Based Virus-Like Particle Vaccine for Covid-19 in Healthy Adults, Older Adults and Adults with Comorbidities
Authors: Gobeil Philipe , Pillet Stéphane , Boulay Iohann , Séguin Annie , Makarkov Alexander , Heizer Gretchen , Bhutada Kapil , Mahmood Asif , Charland Nathalie , Trépanier Sonia , Hager Karen , Jiang-Wright Julia , Atkins Judith , Cheng Matthew P. , Vinh Donald C. , Boutet Philippe , Roman François , Van Der Most Robbert , Ceregido Maria Angeles , Dionne Marc , Tellier Guy , Gauthier Jean-Sébastien , Essink Brandon , Libman Michael , Haffizulla Jason , Fréchette André , D’Aoust Marc-André , Landry Nathalie , Ward Brian J. 
Published: May 2021

AbstractThe rapid spread of SARS-CoV-2 continues to impact humanity on a global scale with rising total morbidity and mortality. Despite the development of several effective vaccines, new products are needed to supply ongoing demand and the needs of specific populations. We report herein a pre-specified interim analysis of the phase 2 portion of an ongoing Phase 2/3, randomized, placebo-controlled trial of a coronavirus virus-like particle (CoVLP) vaccine candidate produced in plants that displays the SARS-CoV-2 spike glycoprotein adjuvanted with AS03 (NCT04636697). A total of 753 subjects were recruited between 25 November 2020 and 24 March 2021 into three groups: Healthy Adults (18-64 years: N=306), Older Adults (≥ 65 years: N=282) and Adults with Comorbidities (≥18 years: N=165) and randomized 5:1 to receive two intramuscular doses of either vaccine CoVLP (3.75 μg/dose + AS03) or placebo 21 days apart. This report presents safety, tolerability and immunogenicity data collected up to 21 days after the second dose. The immune outcomes presented include neutralizing antibody (NAb) titres and cellular (IFN-γ and IL-4 ELISpot) responses. In this study, CoVLP+AS03 was well-tolerated and adverse events (AE) after each dose were generally mild to moderate and transient. Solicited AEs in Older Adults and Adults with Comorbidities were generally less frequent than in Healthy Adults. CoVLP+AS03 induced seroconversion in >35% of subjects in each group after the first dose and in ∼98% of subjects 21 days after the second dose. In all treatment groups, NAb levels were ∼10-fold higher than those in a panel of convalescent sera. A significant minority (∼20%) of subjects had evidence of a pre-existing IFN-γ response to the S protein and almost all subjects in all groups (>88%) had detectable cellular responses (IFN-γ, IL-4 or both) at 21 days after the second dose. A Th1-biased response was most evident after the first dose and was still present after dose two. These data demonstrated that CoVLP+AS03 will likely be well-tolerated and highly immunogenic in adults ≥18 years of age with and without comorbidities.
Single cell analysis of RA synovial B cells reveals a dynamic spectrum of ectopic lymphoid B cell activation and hypermutation characterized by NR4A nuclear receptor expression
Authors: Meednu Nida , Rangel-Moreno Javier , Zhang Fan , Escalera-Rivera Katherine , Corsiero Elisa , Prediletto Edoardo , DiCarlo Edward , Goodman Susan , Donlin Laura T , Raychauduri Soumya , Bombardieri Michele , Pitzalis Costantino , Orange Dana E ,   Accelerating Medicines Partnership Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Network, McDavid Andrew , Anolik Jennifer H 
Published: May 2021

ABSTRACTEctopic lymphoid structures (ELS) can develop in rheumatoid arthritis (RA) synovial tissue, but the precise pathways of B cell activation and selection are not well understood. Here, we identified a unique B cell population in the synovium characterized by co-expression of a family of orphan nuclear receptors, NR4A1 (also known as NUR77), NR4A2 (NURR1) and NR4A3 (NOR1), that is highly enriched at both early and late stages of RA. NR4A B cells are rare in healthy peripheral blood, RA blood, and SLE kidney, but share markers with blood transcriptomic signatures that peak during RA disease flare. Using combined single cell transcriptomics and B cell receptor (BCR) sequencing, we demonstrate that NR4A synovial B cells have an activated transcriptomic profile that significantly overlaps with germinal center (GC) light zone (LZ) B cells and an accrual of somatic hypermutation that correlates with loss of naïve B cell status. NR4A B cells uniquely co-express lymphotoxinβand IL6, supporting important functions in ELS promotion and pro-inflammatory cytokine production. Further, the presence of shared clones in this activated B cell state and NR4A expressing synovial plasma cells (PC) and the rapid up-regulation with BCR stimulation points toin situdifferentiation. Taken together, we identified a dynamic progression of B cell activation in RA synovial ELS, with NR4A transcription factors having an important role in antigen activation and local adaptive immune responses.One sentence summaryB cells in the rheumatoid arthritis synovium undergo a spectrum of in situ activation, with the NR4A family of transcription factors having an important role in antigen stimulation, local adaptive immunity, and pathological B cell responses.
riboviz 2: A flexible and robust ribosome profiling data analysis and visualization workflow
Authors: Cope Alexander L. , Anderson Felicity , Favate John , Jackson Michael , Mok Amanda , Kurowska Anna , MacKenzie Emma , Shivakumar Vikram , Tilton Peter , Winterbourne Sophie M. , Xue Siyin , Kavoussanakis Kostas , Lareau Liana F. , Shah Premal , Wallace Edward W.J. 
Published: May 2021

AbstractMotivationRibosome profiling, or Ribo-seq, is the state of the art method for quantifying protein synthesis in living cells. Computational analysis of Ribo-seq data remains challenging due to the complexity of the procedure, as well as variations introduced for specific organisms or specialized analyses. Many bioinformatic pipelines have been developed, but these pipelines have key limitations in terms of functionality or usability.ResultsWe present riboviz 2, an updated riboviz package, for the comprehensive transcript-centric analysis and visualization of Ribo-seq data. riboviz 2 includes an analysis workflow built on the Nextflow workflow management system, combining freely available software with custom code. The package is extensively documented and provides example configuration files for organisms spanning the domains of life. riboviz 2 is distinguished by clear separation of concerns between annotation and analysis: prior to a run, the user chooses a transcriptome in FASTA format, paired with annotation for the CDS locations in GFF3 format. The user is empowered to choose the relevant transcriptome for their biological question, or to run alternative analyses that address distinct questions. riboviz 2 has been extensively tested on various library preparation strategies, including multiplexed samples. riboviz 2 is flexible and uses open, documented file formats, allowing users to integrate new analyses with the pipeline.Availabilityriboviz 2 is freely available at github.com/riboviz/riboviz.Supplementary information
Ranking Reprogramming Factors for Directed Differentiation
Authors: Hammelman Jennifer , Patel Tulsi , Closser Michael , Wichterle Hynek , Gifford David 
Published: May 2021

AbstractTranscription factor over-expression is a proven method for reprogramming cells to a desired cell type for regenerative medicine and therapeutic discovery. However, a general method for the identification of reprogramming factors to create an arbitrary cell type is an open problem. We examine the success rate of methods and data for directed differentiation by testing the ability of nine computational methods (CellNet, GarNet, EBSeq, AME, DREME, HOMER, KMAC, diffTF, and DeepAccess) to correctly discover and rank candidate factors for eight target cell types with known reprogramming solutions. We compare methods that utilize gene expression, biological networks, and chromatin accessibility data to identify eight sets of known reprogramming factors and comprehensively test parameter and pre-processing of input data to optimize performance of these methods. We find the best factor identification methods can identify an average of 50-60% of reprogramming factors within the top 10 candidates, and methods that use chromatin accessibility perform the best. Among the chromatin accessibility methods, complex methods DeepAccess and diffTF are more likely to consistently correctly rank the significance of transcription factor candidates within reprogramming protocols for differentiation. We provide evidence that AME and DeepAccess are optimal methods for transcription factor recovery and ranking which will allow for systematic prioritization of transcription factor candidates to aid in the design of novel reprogramming protocols.
SENIES: DNA Shape Enhanced Two-layer Deep Learning Predictor for the Identification of Enhancers and Their Strength
Authors: Li Ye , Kong Fanhui , Cui Hui , Li Chunquan , Ma Jiquan 
Published: May 2021

AbstractThe identification of enhancers has always been an important task in bioinformatics owing to their major role in regulating gene expression. For this reason, many computational algorithms devoted to enhancer identification have been put forward over the years. To boost the performance of their methods, more features are extracted from the single DNA sequences and integrated to develop an ensemble classifier. Nevertheless, the sequence-derived features used in previous studies can hardly provide the 3D structure information of DNA sequences, which is regarded as an important factor affecting the binding preferences of transcription factors to regulatory elements like enhancers. Given that, we here propose SENIES, a DNA shape enhanced deep learning predictor, for the identification of enhancers and their strength. The predictor consists of two layers where the first layer is for enhancer and non-enhancer identification, and the second layer is for predicting the strength of enhancers. Besides utilizing two common sequence-derived features (i.e. one-hot and k-mer) as input, it introduces DNA shape for describing the 3D structures of DNA sequences. Performance comparison with state-of-the-art methods conducted on the same datasets demonstrates the effectiveness and robustness of our method. The code implementation of our predictor is publicly available at https://github.com/hlju-liye/SENIES.
A contraction-reaction-diffusion model for circular pattern formation in embryogenesis
Authors: Zhao Tiankai , Sun Yubing , Li Xin , Baghaee Mehdi , Wang Yuenan , Yuan Hongyan 
Published: May 2021

AbstractReaction-diffusion models have been widely used to elucidate pattern formation in developmental biology. More recently, they have also been applied in modeling cell fate patterning that mimic early-stage human development events utilizing geometrically confined pluripotent stem cells. However, the traditional reaction-diffusion equations could not satisfactorily explain the concentric ring distributions of various cell types, as they do not yield circular patterns even for circular domains. In previous mathematical models that yield ring patterns, certain conditions that lack biophysical understandings had been considered in the reaction-diffusion models. Here we hypothesize that the circular patterns are the results of the coupling of the mechanobiological factors with the traditional reaction-diffusion model. We propose two types of coupling scenarios: tissue tension-dependent diffusion flux and traction stress-dependent activation of signaling molecules. By coupling reaction-diffusion equations with the elasticity equations, we demonstrate computationally that the contraction-reaction-diffusion model can naturally yield the circular patterns.
Large-scale digital traces of university students show that morning classes are bad for attendance, sleep, and academic performance
Authors: Yeo Sing Chen , Lai Clin K.Y. , Tan Jacinda , Lim Samantha , Chandramoghan Yuvan , Gooley Joshua J. 
Published: May 2021

AbstractAttending classes and sleeping well are important for students’ academic success. However, early classes might impede learning by contributing to absenteeism and insufficient sleep. We used big datasets collected passively from university students to test the hypothesis that morning classes are associated with poorer attendance, shorter sleep, and lower grades. Wi-Fi connection data were used to estimate attendance rates of 24,678 students enrolled in lecture courses with start times ranging from 08:00 to 16:00. Students’ interactions with the university’s Learning Management System (LMS) were used to estimate nocturnal sleep opportunities by compiling 17.4 million logins from 39,458 students with data sorted by students’ first class of the day. Objective sleep behavior was assessed in 181 students who took part in a 6-week actigraphy study. We found that Wi-Fi confirmed attendance was about 15 percentage points lower in students taking classes at 08:00 compared with later start times. Actigraphy data revealed that students frequently slept past the start of morning classes. LMS and actigraphy data showed that nocturnal sleep opportunities and total sleep time decreased with earlier class start times due to students waking up earlier. Analyses of grades in 27,281 students showed that having morning classes on more days of the week resulted in a lower grade point average. These findings suggest cumulative negative effects of morning classes on learning. Early morning classes force many students to decide to either sleep more and skip class, or sleep less to attend class. Therefore, universities should avoid scheduling early morning classes.Significance StatementWe show that morning classes are associated with lower attendance, shorter nocturnal sleep, and lower grade point average in university students. Scalable methods for measuring attendance and sleep were developed using students’ Wi-Fi connection data and interactions with the Learning Management System. Students had lower attendance rates and frequently slept past the start of early morning classes. However, students still lost about an hour of sleep on average when they had early morning classes due to waking up earlier than usual. Students who had morning classes on more days of the week had a lower grade point average. Our results suggest cumulative negative effects of morning classes on students’ academic performance. Universities should avoid scheduling early morning classes.
A multiple-causal-gene-cluster model underlying GWAS signals of Alzheimer’s disease
Authors: Xu Min , Liu Qianjin , Bi Rui , Li Yu , Zeng Chunhua , Yan Zhongjiang , Zheng Quanzhen , Li Xiao , Sun Chunli , Ye Maosen , Luo Xiong-Jian , Li Ming , Zhang Deng-Feng , Yao Yong-Gang 
Published: May 2021

AbstractGenome-wide association studies (GWASs) have identified dozens of genetic susceptibility loci for Alzheimer’s disease (AD). Nevertheless, the underlying causal variants and biological mechanisms remain elusive. Here, we systematically integrated AD GWAS with comprehensive multi-omics data, and distilled 304 potentially functional variants and 166 causal genes from 49 loci. Intriguingly, we found that most of AD GWAS loci contain multiple functional variants and causal genes. In vitro assays showed that one functional variant regulated multiple genes in the 11p11.2 locus (the CELF1/SPI1 locus) and alteration of these target genes contributed to AD-related molecular processes, supporting the co-existence of multiple functional variants and AD-relevant causal genes within a single locus. We thus proposed a multiple-causal-gene-cluster model that co-dysregulation of a cluster of genes within a single GWAS loci individually or synergistically contribute to AD development. This model provides a novel insight into the biological mechanisms underlying the GWAS loci of complex traits.
The quality of dissolved organic matter shapes the biogeography of the active bathypelagic microbiome
Authors: Sebastián Marta , Sánchez Pablo , Salazar Guillem , Álvarez-Salgado Xosé A. , Reche Isabel , Morán Xosé Anxelu G , Sala M Montserrat , Duarte Carlos M. , Acinas Silvia G. , Gasol Josep M. 
Published: May 2021

AbstractThe bathypelagic ocean (1000-4000 m depth) is the largest aquatic biome on Earth but it is still largely unexplored. Due to its prevalent low dissolved organic carbon concentrations, most of the prokaryotic metabolic activity is assumed to be associated to particles. The role of free-living prokaryotes has thus been mostly ignored, except that of some chemolithoautotrophic lineages. Here we used a global bathypelagic survey of size-fractionated metagenomic and 16S (genes and transcripts) data and performed a differential abundance analysis to explore the functional traits of the different prokaryotic life-strategies, their contribution to the active microbiome, and the role that the quality of the dissolved organic matter (DOM) plays in driving this contribution. We found that free-living prokaryotes have limited capacity to uplift their metabolism in response to environmental changes and display comparatively lower growth rates than particle associated prokaryotes, but are responsible for the synthesis of vitamins in the bathypelagic. Furthermore, their contribution to the active prokaryotic microbiome increased towards waters depleted of labile DOM, which represented a large fraction of the tropical and subtropical ocean sampled stations. This points to a relevant yet overlooked role of free-living prokaryotes in DOM cycling in the vast bathypelagic desert.
OnTheFly2.0: a text-mining web application for automated biomedical entity recognition, document annotation, network and functional enrichment analysis
Authors: Baltoumas Fotis A. , Zafeiropoulou Sofia , Karatzas Evangelos , Paragkamian Savvas , Thanati Foteini , Iliopoulos Ioannis , Eliopoulos Aristides G. , Schneider Reinhard , Jensen Lars Juhl , Pafilis Evangelos , Pavlopoulos Georgios A. 
Published: May 2021

ABSTRACTExtracting and processing information from documents is of great importance as lots of experimental results and findings are stored in local files. Therefore, extracting and analysing biomedical terms from such files in an automated way is absolutely necessary. In this article, we present OnTheFly2.0, a web application for extracting biomedical entities from individual files such as plain texts, Office documents, PDF files or images. OnTheFly2.0can generate informative summaries in popup windows containing knowledge related to the identified terms along with links to various databases. It uses the EXTRACT tagging service to perform Named Entity Recognition (NER) for genes/proteins, chemical compounds, organisms, tissues, environments, diseases, phenotypes and Gene Ontology terms. Multiple files can be analysed, whereas identified terms such as proteins or genes can be explored through functional enrichment analysis or be associated with diseases and PubMed entries. Finally, protein-protein and protein-chemical networks can be generated with the use of STRING and STITCH services. To demonstrate its capacity for knowledge discovery, we interrogated published meta-analyses of clinical biomarkers of severe COVID-19 and uncovered inflammatory and senescence pathways that impact disease pathogenesis. OnTheFly2.0currently supports 197 species and is available athttp://onthefly.pavlopouloslab.info.
Nitric oxide signalling underlies salicylate-induced increases in neuronal firing in the inferior colliculus: a central mechanism of tinnitus?
Authors: Olthof Bas MJ , Lyzwa Dominika , Gartside Sarah E , Rees Adrian 
Published: May 2021

AbstractThe tinnitus-inducing agent salicylate reduces cochlear output but causes hyperactivity in higher auditory centres, including the inferior colliculus (the auditory midbrain). Using multi-electrode recording in anaesthetised guinea pigs (Cavia porcellus), we addressed the hypothesis that salicylate-induced hyperactivity in the inferior colliculus involves nitric oxide signalling secondary to increased ascending excitatory input.In the inferior colliculus, systemic salicylate (200 mg/kg i.p., 0 h) markedly increased spontaneous and sound-driven neuronal firing (3-6 h post drug) with both onset and sustained responses to pure tones being massively increased. Reverse microdialysis of increasing concentrations of salicylate directly into the inferior colliculus (100 µM-10 mM, from 0 h) failed to mimic systemic salicylate. In contrast, it caused a small, transient, increase in sound-driven firing (1 h), followed by a larger sustained decrease in both spontaneous and sound-driven firing (2-5 h). When salicylate was given systemically, reverse microdialysis of the neuronal nitric oxide synthase inhibitor L-methyl arginine into the inferior colliculus (500 mM, 2-6 h) completely blocked the salicylate-induced increase in spontaneous and sound-driven neuronal firing.Our data indicate that systemic salicylate induces neuronal hyperactivity in the auditory midbrain via a mechanism outside the inferior colliculus, presumably upstream in the auditory pathway; and that the mechanism is ultimately dependent on nitric oxide signalling within the inferior colliculus.Given that nitric oxide is known to mediate NMDA receptor signalling in the inferior colliculus, we propose that salicylate activates an ascending glutamatergic input to the inferior colliculus and that this is an important mechanism underlying salicylate-induced tinnitus.Graphical abstractTinnitus is associated with increased activity in the central auditory pathway, an effect replicated by high dose sodium salicylate. Here we show that salicylate-induced increases in neuronal activity in the auditory midbrain are mediated by nitric oxide signalling within this region. Nitric oxide is a key mediator of neuronal responses to NMDA receptor stimulation in this region. Our data support the hypothesis that tinnitus is mediated by increased ascending glutamatergic input to the auditory midbrain.
Effect of charge on protein preferred orientation at the air–water interface in cryo-electron microscopy
Authors: Li Bufan , Zhu Dongjie , Shi Huigang , Zhang Xinzheng 
Published: May 2021

AbstractThe air–water interface (AWI) tends to absorb proteins and frequently causes preferred orientation problems in cryo-electron microscopy (cryo-EM). Here, we examined cryo-EM data from protein samples frozen with different detergents and found that both anionic and cationic detergents promoted binding of proteins to the AWI. By contrast, nonionic and zwitterionic detergents tended to prevent proteins from attaching to the AWI. This ability was positively associated with the critical micelle concentration of the detergent. The protein orientation distributions with different anionic detergents were similar and resembled that obtained without detergent. By contrast, cationic detergents gave distinct orientation distributions. The AWI is negatively charged and the absorption of cationic detergents to the AWI alters its charge. Our results indicates that proteins absorb to charged interface and the negative charge of the AWI plays an important role in absorbing proteins in the conventional cryo-EM sample preparation. According to these findings, a new method was developed to modify the charge distribution of the AWI by adding a very low concentration of anionic detergent. Using this method, the protein particles exhibited a more evenly distributed orientations and still absorbed to the AWI enabling them embedding in a thin layer of ice, which will benefit the cryo-EM structural determination.