bluuebunny/crossref_metadata_2025_split huggingface dataset:
CRSIPR-A-I: a webtool for the efficacy prediction of CRISPR activation and interference
Authors: Zheng Xiao , Cui Jiajun , Wang Yixuan , Zhang Jing , Wang Chaochen 
Published: December 2021

AbstractCRISPR-based gene activation (CRISPRa) or interference (CRISPRi) are powerful and easy-to-use approaches to modify the transcription of endogenous genes in eukaryotes. Successful CRISPRa/i requires sgRNA binding and alteration of local chromatin structure, hence largely depends on the original epigenetic status of the target. Consequently, the efficacy of the CRISPRa/i varies in a wide range when applied to target different gene loci, while a reliable prediction tool is unavailable. To address this problem, we integrated published single cell RNA-Seq data involved CRISPRa/i and epigenomic profiles from K562 cells, identified the significant epigenetic features contributing to CRISPRa/i efficacy by ranking the weight of each feature. We further established a mathematic model and built a user-friendly webtool to predict the CRISPRa/i efficacy of customer-designed sgRNA in different cells. Moreover, we experimentally validated our model by employing CROP-Seq assays. Our work provides both the epigenetic insights into CRISPRa/i and an effective tool for the users.
Omicron and Delta Variant of SARS-CoV-2: A Comparative Computational Study of Spike protein
Authors: Kumar Suresh , Thambiraja Thiviya S. , Karuppanan Kalimuthu , Subramaniam Gunasekaran 
Published: December 2021

AbstractEmerging SARS-CoV-2 variants, especially those of concern, may have an impact on the virus’s transmissibility and pathogenicity, as well as diagnostic equipment performance and vaccine effectiveness. Even though the SARS-CoV-2 Delta variant (B.1.617.2) emerged during India’s second wave of infections, Delta variants have grown dominant internationally and are still evolving. On November 26, 2021, WHO identified the variant B.1.1.529 as a variant of concern, naming it Omicron, based on evidence that Omicron contains numerous mutations that may influence its behaviour. However, the mode of transmission and severity of the Omicron variant remains unknown. We used computational studies to examine the Delta and Omicron variants in this work and found that the Omicron variant had a higher affinity for human ACE2 than the Delta variant due to a significant number of mutations in the SARS-CoV-2 receptor binding domain, indicating a higher potential for transmission. Based on docking studies, the Q493R, N501Y, S371L, S373P, S375F, Q498R, and T478K mutations contribute significantly to high binding affinity with human ACE2. In comparison to the Delta variant, both the entire spike protein and the RBD in Omicron include a high proportion of hydrophobic amino acids such as leucine and phenylalanine. These amino acids are located within the protein’s core and are required for structural stability. Omicron has a higher percentage of alpha-helix structure than the Delta variant in both whole spike protein and RBD, indicating that it has a more stable structure. We observed a disorder-order transition in the Omicron variant between spike protein RBD regions 468-473, and it may be significant in the influence of disordered residues/regions on spike protein stability and binding to ACE2. A future study might investigate the epidemiological and biological consequences of the Omicron variant.
VExD: A curated resource for human gene expression alterations following viral infection
Authors: Dexheimer Phillip J , Pujato Mario , Roskin Krishna , Weirauch Matthew T 
Published: December 2021

AbstractMuch of the host antiviral response is mediated through changes to host gene expression levels. Likewise, viruses induce changes to host gene expression levels in order to promote the viral life cycle and evade the host immune system. However, there is no resource that specifically collects human gene expression levels pre- and post-virus infection. Further, public gene expression repositories do not contain enough specialized metadata to easily find relevant experiments. Here, we present the Virus Expression Database (VExD), a freely available web site and database that collects human gene expression datasets in response to viral infection. VExD contains ∼8,000 uniformly processed samples obtained from 289 studies examining 51 distinct human viruses. We show that the VExD processing pipeline preserves known antiviral responses in the form of interferon-stimulated genes. We further show that the datasets collected in VExD can be used to quickly identify supporting data for experiments performed in human cells or model organisms. VExD is freely available athttps://vexd.cchmc.org/.
Secreted ORF8 is a pathogenic cause of severe COVID-19 and is potentially targetable with select NLRP3 inhibitors
Authors: Wu Xiaosheng , Manske Michelle K. , Ruan Gordon J. , Witter Taylor L. , Nowakowski Kevin E. , Abeykoon Jithma P. , Tang Xinyi , Yu Yue , Gwin Kimberly A. , Wu Annie , Taupin Vanessa , Bhardwaj Vaishali , Paludo Jonas , Dasari Surendra , Dong Haidong , Ansell Stephen M. , Badley Andrew D. , Schellenberg Matthew J. , Witzig Thomas E. 
Published: December 2021

ABSTRACTCOVID-19 is a significant cause of morbidity and mortality in blood cancer patients, especially those on immunosuppressive therapy. Despite extensive research, the specific factor associated with SARS-CoV-2 infection that mediates the life-threatening inflammatory cytokine response in patients with severe COVID-19 remains unidentified. Herein we demonstrate that the virus-encoded Open Reading Frame 8 (ORF8) protein is abundantly secreted as a glycoprotein in vitro and in symptomatic patients with COVID-19. ORF8 specifically binds to the NOD-like receptor family pyrin domain-containing 3 (NLRP3) in CD14+ monocytes to induce a non-canonical inflammasomal response, and a canonical response when the second activation signal is present. Levels of ORF8 protein in the blood correlate with severity and disease-specific mortality in patients with acute SARS-CoV-2 infection. Furthermore, the ORF8-induced inflammasome response was readily inhibited by the NLRP3 inhibitor MCC950 in vitro. Our study identifies a dominant cause of pathogenesis, its underlying mechanism, and a potential new treatment for severe COVID-19.Key pointsSecreted glycoprotein ORF8 induces monocytic pro-inflammatory cytokines involving the activation of the NLPR3 inflammasome pathway.ORF8 is prognostically present in the blood of symptomatic patients with covid-19 and is targetable with NLRP3 inhibitor MCC-950.
ImaGene: A web-based software platform for tumor radiogenomic evaluation and reporting
Authors: Sukhadia Shrey S. , Tyagi Aayush , Venkataraman Vivek , Mukherjee Pritam , Prathosh AP , Divate Mayur D. , Gevaert Olivier , Nagaraj Shivashankar H. 
Published: December 2021

ABSTRACTThe field of radiomics has undergone several advancements in approaches to uncovering hidden quantitative features from tumor imaging data for use in guiding clinical decision-making for cancer patients. Radiographic imaging techniques provide insight into the imaging features of tumor regions of interest (ROIs), while immunohistochemistry and sequencing techniques performed on biopsy samples yield omics data. Potential associations between tumor genotype and phenotype can be identified from imaging and omics data via traditional correlation analysis, as well as through artificial intelligence (AI) models. However, at present the radiogenomics community lacks a unified software platform for which to conduct such analyses in a reproducible manner.To address this gap, we propose ImaGene, a web-based platform that takes tumor omics and imaging data sets as input, performs correlation analysis between them, and constructs AI models (optionally using only those features found to exhibit statistically significant correlation with some element of the opposing dataset). ImaGene has several modifiable configuration parameters, providing users complete control over their analysis. For each run, ImaGene produces a comprehensive report displaying a number of intuitive model diagnostics.To demonstrate the utility of ImaGene,exploratory studies surrounding Invasive Breast Carcinoma (IBC) and Head and Neck Squamous Cell Carcinoma (HNSCC) on datasets acquired from public databases are conducted. Potential associations are identified between several imaging features and 6 genes: CRABP1, SMTNL2, FABP1, HAS1, FAM163A and DSG1 for IBC, and 4 genes: CEACAM6, NANOG, ACSM2B, and UPK2 for HNSCC.In summary, the software provides researchers with a transparent tool for which to begin radiogenomic analysis and explore possible further directions in their research. We anticipate that ImaGenewill become the standard platform for tumor analyses in the field of radiogenomics due to its ease of use, flexibility, and reproducibility, and that it can serve as an enabling centrepoint for an emerging radiogenomic knowledge base.
High viral loads: what drives fatal cases of COVID-19 in vaccinees? – an autopsy study
Authors: Hirschbühl Klaus , Schaller Tina , Märkl Bruno , Claus Rainer , Sipos Eva , Rentschler Lukas , Maccagno Andrea , Grosser Bianca , Kling Elisabeth , Neidig Michael , Kröncke Thomas , Spring Oliver , Braun Georg , Bösmüller Hans , Seidl Maximilian , Esposito Irene , Pablik Jessica , Hilsenbeck Julia , Boor Peter , Beer Martin , Dintner Sebastian , Wylezich Claudia 
Published: December 2021

AbstractBackgroundThe rate of SARS-CoV-2 breakthrough infections in vaccinees is becoming an increasingly serious issue.ObjectiveTo determine the causes of death, histological organ alteration, and viral spread in relation to demographic, clinical-pathological, viral variants, and vaccine types.DesignComprehensive retrospective observational cohort study. Setting: Consecutive cases from four German academic medical centers.PatientsDeceased with proven SARS-CoV-2 infection after vaccination who died between January and November 2021. Collections of 29 vaccinees which were analyzed and compared to 141 nonvaccinated control cases.ResultsAutopsies were performed on 16 partially and 13 fully vaccinated individuals. Most patients were elderly and suffered from several relevant comorbidities. Real-time RT-PCR (RT-qPCR) identified a significantly increased rate of generalized viral dissemination within the organism in vaccinated cases versus nonvaccinated cases (45% vs. 16%, respectively; P = 0.008). Vaccinated cases also showed high viral loads, reaching Ct values below 10, especially in the upper airways and lungs. This was accompanied by high rates of pulmonal bacterial or mycotic superinfections and the occurrence of immunocompromising factors such as malignancies, immunosuppressive drug intake, or decreased immunoglobulin levels. All these findings were particularly accentuated in partially vaccinated patients compared to fully vaccinated individuals. A fatal course after vaccination occurred in only 14% of all COVID-19 deceased in Augsburg.LimitationsRestricted number of casesConclusionsFatal cases of COVID-19 in vaccinees were rare and often associated with severe comorbidities or other immunosuppressive conditions. Interestingly, we observed striking virus dissemination in our case study, which may indicate a decreased ability to eliminate the virus in patients with an impaired immune system. However, the potential role of antibody-dependent enhancement must also be ruled out in future studies.Funding sourceThis work was supported by the German Registry of COVID-19 Autopsies (www.DeRegCOVID.ukaachen.de) and funded by the Federal Ministry of Health (ZMVI1-2520COR201), the Federal Ministry of Education and Research within the framework of the network of university medicine (DEFEAT PANDEMICs, 01KX2021), and the German Federal Ministry of Food and Agriculture through the Federal Office for Agriculture and Food (project ZooSeq, grant number 2819114019).
A Syx-RhoA-Dia1 signaling axis regulates cell cycle progression, DNA damage, and therapy resistance in glioblastoma
Authors: Lin Wan-Hsin , Feathers Ryan W. , Cooper Lisa M. , Lewis-Tuffin Laura J. , Sarkaria Jann N. , Anastasiadis Panos Z. 
Published: December 2021

AbstractGlioblastomas (GBM) are aggressive tumors that lack effective treatments. Here, we show that the Rho family guanine nucleotide exchange factor Syx promotes GBM cell growth both in vitro and in orthotopic GBM patient-derived xenografts. Growth defects upon Syx depletion are attributed to prolonged mitosis, increased DNA damage, G2/M cell cycle arrest, and cell apoptosis, mediated by altered mRNA and protein expression of various cell cycle regulators. These effects are phenocopied by depletion of the Rho downstream effector Dia1 and are due at least in part to increased cytoplasmic retention and reduced activity of the YAP/TAZ transcriptional coactivators. Further, targeting Syx signaling cooperates with radiation treatment and temozolomide (TMZ) to decrease viability in GBM cells irrespective of their inherent response to TMZ. Taken together, the data indicate that a Syx-RhoA-Dia1-YAP/TAZ signaling axis regulates cell cycle progression, DNA damage, and therapy resistance in GBM and argue for its targeting for cancer treatment.One Sentence SummarySyx promotes growth and therapy resistance in glioblastoma.
RORA regulates neutrophil migration and activation in zebrafish
Authors: Hsu Alan Y. , Wang Tianqi , Syahirah Ramizah , Liu Sheng , Li Kailing , Zhang Weiwei , Wang Jiao , Cao Ziming , Tian Simon , Matosevic Sandro , Staiger Chris , Wan Jun , Deng Qing 
Published: December 2021

AbstractNeutrophil migration and activation are essential for defense against pathogens. However, this process may also lead to collateral tissue injury. We used microRNA overexpression as a platform and discovered protein-coding genes that regulate neutrophil migration. Here we show that miR-99 decreased the chemotaxis of zebrafish neutrophils and human neutrophil-like cells. In zebrafish neutrophils, miR-99 directly targets the transcriptional factorRAR-related orphan receptor alpha (roraa). Inhibiting RORα, but not the closely related RORγ, reduced chemotaxis of zebrafish and primary human neutrophils without causing cell death, and increased susceptibility of zebrafish to bacterial infection. Expressing a dominant-negative form of Rorα or disrupting theroraalocus specifically in zebrafish neutrophils reduced cell migration. At the transcriptional level, RORα regulates transmembrane signaling receptor activity and protein phosphorylation pathways. Our results, therefore, reveal previously unknown functions of miR- 99 and RORα in regulating neutrophil migration and anti-microbial defense.
Thermal asymmetries influence effects of warming on stage and size-dependent predator-prey interactions
Authors: Pepi Adam , Hayes Tracie , Lyberger Kelsey 
Published: December 2021

AbstractClimate warming directly influences the developmental and feeding rates of organisms. Changes in these rates are likely to have consequences for species interactions, particularly for organisms affected by stage- or size-dependent predation. However, because of differences in species-specific responses to warming, predicting the impact of warming on predator and prey densities can be difficult. We present a general model of stage-dependent predation with temperature-dependent vital rates to explore the effects of warming when predator and prey have different thermal optima. We found that warming generally favored the interactor with the higher thermal optimum. Part of this effect occurred due to the stage-dependent nature of the interaction, and part due to thermal asymmetries. Furthermore, large differences in thermal optima between predators and prey (i.e., a high degree of asymmetry) led to a weaker interaction. Interestingly, below the predator and prey thermal optima, warming caused prey densities to decline, even as increasing temperature improved prey performance. We also parameterize our model using values from a well-studied system,Arctia virginalisandFormica lasioides, in which the predator has a warmer optimum. Overall, our results provide a general framework for understanding stage- and temperature-dependent predator-prey interactions, and illustrate that the thermal niche of both predator and prey are important to consider when predicting the effects of climate warming.
Transcriptional shift and metabolic adaptations during Leishmania quiescence using stationary-phase and drug pressure as models
Authors: Jara Marlene , Barrett Michael , Maes Ilse , Regnault Clement , Imamura Hideo , Domagalska Malgorzata Anna , Dujardin Jean-Claude 
Published: December 2021

AbstractMicroorganisms can adopt a quiescent physiological condition which acts as a survival strategy under unfavourable conditions. Quiescent cells are characterized by slow or non-proliferation and deep down-regulation of processes related to biosynthesis. Although quiescence has been described mostly in bacteria, this survival skill is widespread, including in eukaryotic microorganisms. In Leishmania, a digenetic parasitic protozoan that causes a major infectious disease, quiescence has been demonstrated, but molecular and metabolic features enabling its maintenance are unknown. Here we quantified the transcriptome and metabolome of Leishmania promastigotes and amastigotes where quiescence was induced in vitro either through drug pressure or by stationary phase. Quiescent cells have a global and coordinated reduction in overall transcription, with levels dropping to as low as 0.4% of those in proliferating cells. However, a subset of transcripts did not follow this trend and were relatively upregulated in quiescent populations, including those encoding membrane components such as amastins and GP63 or processes like autophagy. The metabolome followed a similar trend of overall downregulation albeit to a lesser magnitude than the transcriptome. Noteworthy, among the commonly upregulated metabolites were those involved in carbon sources as an alternative to glucose. This first integrated two omics layers affords novel insights into cell regulation and shows commonly modulated features across stimuli and stages.
Protein length distribution is remarkably consistent across Life
Authors: Nevers Yannis , Glover Natasha , Dessimoz Christophe , Lecompte Odile 
Published: December 2021

AbstractIn every living species, the function of a protein depends on its organisation of structural domains, and the length of a protein is a direct reflection of this. Because every species evolved under different evolutionary pressures, the protein length distribution, much like other genomic features, is expected to vary across species. Here we evaluated this diversity by comparing protein length distribution across 2,326 species (1,688 bacteria, 153 archaea and 485 eukaryotes). We found that proteins tend to be on average slightly longer in eukaryotes than in bacteria or archaea, but that the variation of length distribution across species is low, especially compared to the variation of other genomic features (genome size, number of proteins, gene length, GC content, isoelectric points of proteins). Moreover, most cases of atypical protein length distribution appear to be due to artifactual gene annotation, suggesting the actual variation of protein length distribution across species is even smaller. These results open the way for developing a genome annotation quality metric based on protein length distribution to complement conventional quality measures. Overall, our findings show that protein length distribution between living species is more consistent than previously thought, and provide evidence for a universal purifying selection on protein length, whose mechanism and fitness effect remain intriguing open questions.
Anti-inflammatory compounds improve spiral ganglion neuron survival after aminoglycoside-induced hair cell loss in rats
Authors: Rahman Muhammad T. , Bailey Erin M. , Gansemer Benjamin M. , Pieper Andrew , Manak J. Robert , Green Steven H. 
Published: December 2021

AbstractSpiral ganglion neurons (SGNs) relay auditory information from cochlear hair cells to the central nervous system. After hair cells are destroyed by aminoglycoside antibiotics, SGNs gradually die. However, the reasons for this cochlear neurodegeneration are unclear. We used microarray gene expression profiling to assess transcriptomic changes in the spiral ganglia of kanamycin-deafened and age-matched control rats and found that many of the genes upregulated after deafening are associated with immune/inflammatory responses. In support of this, we observed increased numbers of macrophages in the spiral ganglion of deafened rats. We also found, via CD68 immunoreactivity, an increase in activated macrophages after deafening. An increase in CD68-associated nuclei was observed by postnatal day 23, a time before significant SGN degeneration is observed. Finally, we show that the immunosuppressive drugs dexamethasone and ibuprofen, as well as the NAD salvage pathway activator P7C3, provide at least some neuroprotection post-deafening. Ibuprofen and dexamethasone also decreased the degree of macrophage activation. These results suggest that activated macrophages specifically, and perhaps a more general neuroinflammatory response, are actively contributing to SGN degeneration after hair cell loss.
Role of glycine-N-methyl transferase in human and murine nonalcoholic steatohepatitis
Authors: Quinn Connor R. , Rico Mario C. , Merali Carmen , Merali Salim 
Published: December 2021

AbstractNon-alcoholic fatty liver disease (NAFLD) has become one of the most prominent forms of chronic liver disease worldwide, mirroring the obesity epidemic. NAFLD is the number one cause of chronic liver disease worldwide, with 25% of these patients developing nonalcoholic steatohepatitis (NASH). This significantly increases the risk of cirrhosis and decompensated liver failure. Past studies in rodent models have shown that the knockout of glycine-N-methyltransferase (GNMT) is associated with steatosis, fibrosis, and hepatocellular carcinoma. However, the attenuation of GNMT in subjects with NASH and the molecular basis for its impact on the disease process have yet to be elucidated. To address this knowledge gap, we show the reduction of GNMT protein levels in the liver of NASH subjects compared to healthy controls. To gain insight into the impact of decreased GNMT in the disease process, we performed global label-free proteome studies on the livers from a murine Western diet-based model of NASH. We identified the differential expression of essential proteins involved in hallmark NASH pathogenesis, including lipid metabolism, inflammation, and fibrosis. Significantly, the downregulation of GNMT, the prominent regulator of S-adenosylmethionine (AdoMet), was identified as a contributing factor to these networks, increasing fourfold in AdoMet levels. AdoMet is an essential metabolite for transmethylation reactions and a substrate for polyamine synthesis, and its levels can impact polyamine flux and generate oxidative stress. Therefore, we performed targeted proteome and metabolomics studies to show a decrease in GNMT transmethylation, an increase in flux through the polyamine pathway, and increased oxidative stress.Abstract Figure