bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and immunogenicity of inactivated whole virion vaccine CoviVac against COVID-19: a multicenter, randomized, double-blind, placebo-controlled phase I/II clinical trial
Authors: Ishmukhametov Aydar A , Siniugina Aleksandra A , Yagovkina Nadezhda V , Kuzubov Vladimir I , Zakharov Konstantin A , Volok Viktor P , Dodina Maria S , Gmyl Larissa V , Korotina Natalya A , Theodorovich Rostislav D , Ulitina Yulia I , Tsaan Andrey A , Pomaskina Tatiana V , Kalenskaya Anna V , Solovjeva Irina V , Tivanova Elena V , Kondrasheva Larissa Y , Ploskireva Antonina A , Akimkin Vasiliy G , Subbotina Ksenia A , Ignatyev Georgy M , Korduban Anastasia K , Shustova Elena Y , Bayurova Ekaterina O , Kondrashova Alla S , Avdoshina Darya V , Piniaeva Anastasia N , Kovpak Anastasia A , Antonova Liliya P , Rogova Yulia V , Shishova Anna A , Ivin Yury Y , Sotskova Svetlana E , Chernov Konstantin A , Ipatova Elena G , Korduban Ekaterina A , Kozlovskaya Liubov I , Gordeychuk Ilya V 
Published: February 2022

ABSTRACTWe present the results of a randomized, double-blind, placebo-controlled, multi-center clinical trial of the tolerability, safety, and immunogenicity of the inactivated whole virion concentrated purified coronavirus vaccine CoviVac in adult volunteers aged 18-60.Safety of the vaccine was assessed in 398 volunteers who received two doses of the vaccine (n=298) or placebo (n=100). The studied vaccine has shown good tolerability and safety. No deaths, serious adverse events (AE), or other significant AE related to vaccination have been detected. The most common AE in vaccinated participants was pain at the injection site (p<0.05).Immunogenicity assessment was performed in 167 volunteers (122 vaccinated and 45 in Placebo Group) separately for the participants who were anti-SARS-CoV-2 nAB negative (69/122 in Vaccine Group and 28/45 in Placebo Group) or positive (53/122 in Vaccine Group and 17/45 in Placebo Group) at screening.At Day 42 after the first immunization the seroconversion rate in participants who were seronegative at screening was 86.9% with average the geometric mean neutralizing antibody (nAB) titer of 1:20. Statistically significant (p<0.05) increase of IFN-γ production by peptide-stimulated T-cells was observed at Days 14 and 21 after the first immunization.In participants who were seropositive at screening but had nAB titers below 1:256 the rate of 4-fold increase in nAB levels was 85.2%, while in the participants with nAB titers >1:256 the rate of 4-fold increase in nAB levels was below 45%. For the participants who were seropositive at screening the second immunization did not lead to a significant increase in nAB titers.In conclusion, inactivated vaccine CoviVac has shown good tolerability and safety, with 86.9% seroconversion rates in participants, who were seronegative at screening. In participants who were seropositive at screening and had nAB titers below 1:256, a single immunization lead to a 4-fold increase in nAB levels in 85.2% cases.
Genome-wide Analysis of Bromodomain Gene Family in Arabidopsis and Rice
Authors: Abiraami T.V. , Sanyal Ravi Prakash , Misra Hari Sharan , Saini Ajay 
Published: February 2022

AbstractThe bromodomain containing proteins (Brd-proteins) belongs to family of ‘epigenetic mark readers’, integral to epigenetic regulation. The Brd-members contain a conserved ‘bromodomain’ (BRD/BRD-fold: interacts with acetylated-lysine in histones), and several additional domains, making them structurally/functionally diverse. Like animals, plants also contain multiple Brd-homologs, however the extent of their diversity and impact of molecular events (genomic duplications, alternative splicing, AS) therein, is relatively less explored. The present genome-wide analysis of Brd-families of Arabidopsis thaliana and Oryza sativa showed extensive diversity in structure of genes/proteins, regulatory elements, expression pattern, domains/motifs, and the bromodomain (length/sequence, location) among Brd-members. Orthology analysis identified 13 ortholog groups, three paralog groups and four singleton members. While more than 40% Brd-genes were affected by genomic duplication events in both plants, AS-events affected 60% A. thaliana and 40% O. sativa genes. These molecular events affected various regions (promoters, untranslated regions, exons) of different Brd-members with potential impact on expression/structure-function characteristics. RNA-Seq data analysis of Brd-members, and RT-qPCR of duplicate Brd-genes showed differences in tissue-specificity and response to salinity. Phylogenetic analysis based on conserved BRD-region placed the A. thaliana and O. sativa homologs into clusters/sub-clusters, consistent with ortholog/paralog groups. The bromodomain-region displayed conserved signatures in key BRD-fold elements (α-helices, loops), and variations (1-20 sites) including indels among the Brd-duplicates. Homology modeling and superposition identified structural variations in BRD-folds of divergent and duplicate Brd-members, which might affect their interaction with chromatin and associated functions. The study also showed contribution of various duplication events in Brd-family expansion among diverse plants, including monocots and dicots.
A bacterial pan-genome makes gene essentiality strain-dependent and evolvable
Authors: Rosconi Federico , Rudmann Emily , Li Jien , Surujon Defne , Anthony Jon , Frank Matthew , Jones Dakota S. , Rock Charles , Rosch Jason W. , Johnston Christopher D. , van Opijnen Tim 
Published: February 2022

AbstractMany bacterial species are represented by a pan-genome, whose genetic repertoire far outstrips that of any single bacterial genome. Here we investigate how a bacterial pan-genome might influence gene essentiality, and whether essential genes that are initially critical for the survival of an organism can evolve to become non-essential. By using Tn-Seq, whole-genome sequencing, and RNA-Seq on a set of 36 clinicalStreptococcus pneumoniaestrains representative of >68% of the species’ pan-genome, we identify a species-wide ‘essentialome’ that can be subdivided into universal, strain-specific and accessory essential genes. By employing ‘forced-evolution experiments’ we show that specific genetic changes allow bacteria to bypass essentiality. Moreover, by untangling several genetic mechanisms we show that gene-essentiality can be highly influenced and/or dependent on: 1) the composition of the accessory genome; 2) the accumulation of toxic intermediates; 3) functional redundancy; 4) efficient recycling of critical metabolites; and 5) pathway rewiring. While this functional characterization underscores the evolvability-potential of many essential genes, we also show that genes with differential essentiality remain important antimicrobial drug target candidates, as their inactivation almost always has a severe fitness costin vivo.
Functionally competent CD4+ T cells express high levels of T-bet in Plasmodium chabaudi infected young mice
Authors: Smith Margaret R. , Gbedande Komi , Johnson Corey M. , Campbell Logan A. , Richard Lyndsay B. , Onjiko Robert S. , Domingos Nadia , Opata Michael M. 
Published: February 2022

ABSTRACTThe immune system plays an important role in the elimination of Plasmodium parasites that cause malaria, which affect children the most worldwide. Immunity to malaria, especially in young children is poorly understood due to the absence of a developmentally-equivalent rodent model to study the pathogenesis of disease. We have developed a mouse model using 15-day old mice (pups) of malaria infection in neonatal mice. Using C57BL/6 pups, we determined that P. chabaudi infection decreases the growth rate of young mice compared to controls, and results in 60% mortality, and neurological damage not present in adults, as indicated by a battery of behavioral assays. When all splenic cells were stimulated in vitro stimulation, cells from pups proliferated faster than adult cells, but purified CD4 T cells were slower. Upon infection with Plasmodium parasites, both adult and pup CD4+ T cells were activated and differentiated to an effector T cell (Teff) phenotype; however, pup CD4+ Teff were less differentiated than adult Teff. Pup CD4+ T cells also produced more IL-2 than cells from adult B6 mice, and TNF-α was increased in parasite-specific BALB/c pup T cells. Interestingly, there were more pup CD4+T-bethi Teff after infection suggestive of increased Th1 commitment, potentially contributing to cerebral symptoms.
Worldwide antibiotic resistance dynamics: how different is it from one drug-bug pair to another?
Authors: Rahbe Eve , Watier Laurence , Guillemot Didier , Glaser Philippe , Opatowski Lulla 
Published: February 2022

SummaryBackgroundAntibiotic resistance (ABR) is a major concern for global health. However, factors driving its emergence and dissemination are not fully understood. Identification of such factors is crucial to explain heterogeneity in ABR rates observed across space, time and species and antibiotics.MethodsWe analyzed count data of clinical isolates from 51 countries over 2006-2019 for thirteen drug-bug pairs from the ATLAS surveillance system. We characterized ABR spatial and temporal patterns and used a mixed-effect negative binomial model, accounting for country-year dependences with random effects (RE), to investigate associations with potential drivers including antibiotic sales, economic and health indicators, meteorological data, population density and tourism.FindingsABR patterns were strongly country and drug-bug pair dependent. In 2019, median ABR rates ranged from 6×3% (interquartile range (IQR): 19×7%) for carbapenem-resistant (CR)Klebsiella pneumoniaeto 80×7% (IQR: 41×8%) for fluoroquinolone-resistant (FR)Acinetobacter baumannii, with heterogeneity across countries. Over 2006-2019, carbapenem resistance was on the rise in >60% of investigated countries, while no global trend was observed for other resistances. Multivariable analyses identified significant associations of ABR with country-level selecting antibiotic sales, but only in FR-Escherichia coli, FR-Pseudomonas aeruginosaand CR-A. baumannii;with temperature in investigated Enterobacterales but not in other drug-bug pairs; and with the health system quality for all drug-bug pairs exceptEnterococciandStreptococcus pneumoniaepairs. Despite wide consideration of possible explanatory variables, drug-bug pairs ABR rates still showed unexplained spatial RE variance.InterpretationOur findings reflect the diversity of mechanisms driving global antibiotic resistance across pathogens and stress the need for tailored interventions to tackle bacterial resistance.FundingIndependent research Pfizer Global Medical Grant; ANR Labex IBEID (ANR-10-LABX-62)
Characterization of the gene expression profile in younger and older low-grade glioma patients
Authors: Dong Cathryn , Fei Xiang , Guo Youtang , Jiang Minde , Mao Yifan , Wang Zhaoying , Wei Yutong , Yu Tianyi , Shi Yong , Yang Yi , Qing Tao , Zhu Sibo 
Published: February 2022

AbstractLow-grade gliomas (LGG) are the slowest growing type of brain cancer that often affects young adults. Of all LGG cases, older patients were associated with the poor prognosis compared to younger patients. However, the molecular mechanism underlying this association remains unclear. Here, we compared genes expression profiles between younger (age≤50) and older (age > 50) patients from The Cancer Genome Atlas (TCGA) and demonstrate the age-related gene expressions. Pathway and gene set enrichment analysis reveal that differentially expressed genes (DEGs) between tumors of older and younger patients have been involved in cancer-related biological procedures, such as, transcriptional misregulation in cancer, nucleotide synthesis, mTOR, and DNA damage repair signaling. We also demonstrated that older patients have higher expression of Mitosis Kinase Score (MKS) and Tumor Inflammation Signature (TIS) which reflects high cell proliferation and high immune cell activity; respectively. The comprehensive characterization of gene-expression profiles in younger versus older LGG may explain the age-related prognosis and facilitate the development of potential therapeutic biomarkers for LGG.
A regulatory network of Sox and Six transcription factors initiate a cell fate transformation during hearing regeneration in adult zebrafish
Authors: Jimenez Erin , Slevin Claire C. , Song Wei , Chen Zelin , Frederickson Stephen C. , Gildea Derek , Wu Weiwei , Elkahloun Abdel G. , Ovcharenko Ivan , Burgess Shawn M. 
Published: February 2022

ABSTRACTUsing adult zebrafish inner ears as a model for sensorineural regeneration, we performed a targeted ablation of the mechanosensory receptors in the utricle and saccule and characterized the single-cell epigenome and transcriptome at consecutive time-points following hair cell ablation. Using deep learning on the regeneration-induced open chromatin sequences, we were able to identify unique, cell-specific transcription factor (TF) motif patterns enriched in the raw data. We correlated enhancer activity with gene expression to identify gene regulatory networks. A clear pattern of overlapping Sox- and Six-family transcription factor gene expression and binding motifs was detected, suggesting a combinatorial program of TFs driving regeneration and cell identity. Pseudo-time analysis of single-cell transcriptomic data demonstrated that the support cells within the sensory epithelium changed cell identity to a more pluripotent “progenitor” cell population that could either differentiate into hair cells or return to a support cell identity. We showed thatsox2becomes enriched in the progenitor cells and is reduced again when the cells differentiate in either direction. Analysis of the scATAC-seq data identified a 2.6 kb DNA sequence element upstream of thesox2promoter that dynamically changed in accessibility during hair cell regeneration. When deleted, the upstream regulator ofsox2showed a dominant phenotype that resulted in a hair cell regeneration-specific deficit in both the lateral line and adult inner ear.HIGHLIGHTSIntegrated scRNA-seq and scATAC-seq of the adult zebrafish inner ear during hair cell regeneration.Support cells transition to an intermediate cell type that can differentiate to hair cells. Coordinated expression of Sox and Six transcription factors are key to hearing regeneration.Sox transcription factors trigger the regeneration response in the support cells while Sox and Six factors cooperate during hair cell differentiation.Deletion of an upstream enhancer that controls the timing ofsox2expression causes regeneration-specific defects in hearing regeneration.
Adipose cells and tissues soften with lipid accumulation while in diabetes adipose tissue stiffens
Authors: Abuhattum Shada , Kotzbeck Petra , Schlüßler Raimund , Harger Alexandra , Schellenberger Angela Ariza , Kim Kyoohyun , Escolano Joan-Carles , Müller Torsten , Braun Jürgen , Wabitsch Martin , Tschöp Matthias , Sack Ingolf , Brankatschk Marko , Guck Jochen , Stemmer Kerstin , Taubenberger Anna V. 
Published: February 2022

AbstractAdipose tissue expansion involves both differentiation of new precursors and size increase of mature adipocytes. While the two processes are well balanced in healthy tissues, obesity and diabetes type II are associated with abnormally enlarged adipocytes and excess lipid accumulation. We hypothesised that adipocyte shape and size changes with differentiation and lipid accumulation would be accompanied by changes in the mechanical phenotype at both the cell and tissue level. We quantified by optical diffraction tomography (ODT) that differentiating preadipocytes increased their volumes drastically. Atomic force microscopy (AFM)-indentation and -microrheology revealed that during the early phase of differentiation, human preadipocytes became more compliant and more fluid-like, concomitant with ROCK-mediated F-actin remodelling. Adipocytes that had accumulated large lipid droplets were more compliant, and further promoting lipid accumulation led to an even more compliant phenotype. In line with that, high fat diet-induced obesity was associated with more compliant adipose tissue compared to lean animals, both for drosophila fat bodies and murine gonadal adipose tissue. In contrast, adipose tissue of diabetic mice became significantly stiffer as shown not only by AFM but also magnetic resonance elastography (MRE). Altogether, we dissect relative contributions of the cytoskeleton and lipid droplets to cell and tissue mechanical changes across different functional states, such as differentiation, nutritional state and disease. Since preadipocytes are mechanosensitive, tissue stiffening in diabetes might be critical to the balance between hyperplasia and hypertrophy and moreover present a potential target in the prevention of metabolic disorders.
Anti-inflammatory effects of WFS1 in pancreatic β-cells
Authors: Morikawa Shuntaro , Blacher Lindsey , Onwumere Chinyere , Urano Fumihiko 
Published: February 2022

AbstractWolfram syndrome is a rare genetic disorder characterized by juvenile-onset diabetes mellitus, optic nerve atrophy, hearing loss, diabetes insipidus, and progressive neurodegeneration. Pathogenic variants in the WFS1 gene are the main causes of Wolfram syndrome. WFS1 encodes a transmembrane protein localized to the endoplasmic reticulum (ER) and regulates the unfolded protein response (UPR). Loss of function of WFS1 leads to dysregulation of insulin production and secretion, ER calcium depletion, and cytosolic calpains activation, resulting in activation of apoptotic cascades. Although the terminal UPR has been shown to induce inflammation that accelerates β-cell dysfunction and death in diabetes, the contribution of β-cell inflammation to the development of diabetes in Wolfram syndrome has not been fully understood. Here we show that WFS1-deficiency enhances the gene expression of inflammatory cytokines and chemokines, leading to cytokine-induced ER-stress and cell death in pancreatic β-cells. PERK and IRE1α pathways mediate high glucose-induced inflammation in a β-cell model of Wolfram syndrome. M1-macrophage infiltration and hypervascularization are seen in the pancreatic islets of Wfs1 whole-body knockout mice, demonstrating that WFS1 regulates anti-inflammatory responses in β-cells. Our results demonstrate that inflammation plays an essential role in the progression of β-cell death and diabetes in Wolfram syndrome and reveal that the pathways involved in ER stress-mediated inflammation provide potential therapeutic targets for the treatment of Wolfram syndrome.
The Role of Notch Signaling in Endometrial Mesenchymal Stromal/Stem-like Cells Maintenance
Authors: Zhang Sisi , Chan Rachel W.S. , Ng Ernest H.Y. , Yeung William S.B. 
Published: February 2022

AbstractHuman endometrium undergoes cycles of regeneration in reproductive women. The endometrial mesenchymal stromal/stem cells (eMSC) contribute to this process. Notch signaling is essential for the homeostasis of somatic stem cells. However, its role in eMSC remains unclear. The gain and loss function shows that activation of Notch signaling promotes eMSC maintenance, while inhibition displays opposite effect. Activation of Notch pathway better maintains eMSC in a quiescent state. However, these quiescent eMSC can re-enter into the cell cycle depending on Notch and Wnt activity in the microenvironment, suggesting a crosstalk between two signaling pathways. In a mouse menstrual-like model, we observe that Notch signaling is highly involved in the dynamic endometrial remodeling event. Suppression of Notch signaling significantly reduces the proliferation of Notch1+ label-retaining stromal cells and consequently delays the endometrial repair. Our data demonstrate the importance of Notch signaling in regulating the endometrial stem/progenitor cells in vitro and in vivo.
The Composition of Diesel Fuel Influences the Structure of Microbiological Assemblages in Contaminated Storage Tanks
Authors: Floyd James G. , Stamps Blake W. , Bojanowski Caitlin L. , Goodson Wendy J. , Stevenson Bradley S. 
Published: February 2022

AbstractMicrobiological contamination in diesel storage tanks is widespread and under-reported. The contaminating microorganisms can degrade components of the fuel, which contributes to fouling and corrosion. To better understand the connection between the microorganisms that are responsible for this contamination, the composition of affected fuels, and the resulting impact on fuel quality, we conducted a survey of 106 fuel tanks at 17 military bases across the continental United States. Fuel was sampled from each tank and the resident microbial communities were characterized using high throughput sequencing of small subunit ribosomal RNA gene libraries. Fatty acid methyl esters (FAME) and n-alkanes were characterized and quantified using GC-MS to determine their correlation with the presence of microbial taxa. Redundancy Analyses identified which microbial taxa were more prominent in contaminated fuels. Members of the fungal family Trichomaceae were found to be prominent in fuels containing more FAME. Members of the yeast family Debaryomycetaceae were found to be prominent in fuels containing more pentadecanoic and oleic acid methyl esters. These relationships between fungal taxa and fuel components were directly tested in growth experiments with representative isolates of the Trichocomaceae (Paecilomyces AF001) and Debaryomycetaceae (Wickerhamomyces SE3) families. Paecilomyces was capable of growth on linoleic acid methyl ester but unable to grow on pentadecanoic acid methyl ester, while Wickerhamomyces was able to grow on both substrates. Fuel composition may provide some insight into which microorganisms can proliferate but other factors like competition and symbiosis may also drive microbial proliferation, fouling, degradation, and corrosion in diesel fuels.ImportanceBiodiesel, widely used as an additive or extender of ultra-low sulfur diesel, can increase the potential for microorganisms to proliferate in storage tanks. It is important to know how the composition of diesel fuels can influence the growth of organisms linked to fuel degradation and microbiologically influenced corrosion. This research describes how certain populations of fungi and bacteria can prevail in fuels of different composition, which can be helpful in predicting biodegradation and biocorrosion, and formulating fuels less susceptible to the growth of problematic organisms.