cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.28112041.v1
title: Tanshinone I as a novel therapeutic agent targeting von Willebrand factor-binding protein to mitigate <i>Staphylococcus aureus</i> pathogenicity

description: <i>Staphylococcus aureus</i> (<i>S. aureus</i>) is a prevalent pathogen responsible for a wide range of diseases in humans, contributing to both hospital-acquired and community-acquired infections. The von Willebrand factor-binding protein (vWbp) is pivotal for <i>S. aureus</i> pathogenicity because it induces blood coagulation, thereby facilitating bacterial survival and dissemination within the host. Notably, the absence of vWbp does not hinder <i>S. aureus</i> growth, indicating that vWbp is an attractive target for combating <i>S. aureus</i> infections while mitigating the risk of antibiotic resistance. Our findings revealed that tanshinone I significantly inhibited vWbp-induced coagulation without affecting the proliferation of <i>S. aureus</i>. Hemolysis assays confirmed the biocompatibility of tanshinone I, while Western blot analysis, fluorescence quenching, and thermal shift assays (TSAs) demonstrated that tanshinone I does not alter vWbp expression but directly binds to the protein. Molecular docking studies elucidated the interaction mechanism, identifying ARG-479 and GLN-484 as critical residues for tanshinone I binding. Furthermore, <i>in vivo</i> studies demonstrated that tanshinone I reduces lung tissue damage in mice infected with <i>S. aureus</i>, thereby increasing survival rates. Additionally, tanshinone I was tested in greater wax moth larvae and showed similar protective effects. In conclusion, tanshinone I effectively inhibits vWbp, reducing the virulence of <i>S. aureus</i>. This study underscores the potential of tanshinone I as a therapeutic agent against <i>S. aureus</i> infections, offering a novel strategy to combat bacterial infections while decreasing the critical issue of antibiotic resistance.
DOI: 10.6084/m9.figshare.30784844
title: YTHDC2 promotes sepsis-induced cardiomyopathy by activating apoptosis and NF-κB pathway

description: Sepsis-induced cardiomyopathy (SICM) is a severe complication of sepsis, especially in children, and identification of novel therapeutic targets remains essential for improving patient outcomes. Recent studies have implicated N6-methyladenosine (m<sup>6</sup>A), an RNA epigenetic modification, in SICM pathogenesis. However, the role of YTH domain-containing 2 (YTHDC2), an m<sup>6</sup>A reader protein, in SICM remains unclear. This study used lipopolysaccharide (LPS)-treated adolescent rats, primary cardiomyocytes and H9c2 cardiomyocytes to mimic SICM <i>in</i> <i>vivo</i> and <i>in</i> <i>vitro</i>. We observed a significant upregulation of YTHDC2 <i>in</i> <i>vivo</i> and <i>in</i> <i>vitro</i>. Through comprehensive analyses including RNA sequencing (RNA-seq), Western blotting, and flow cytometry, we demonstrated that YTHDC2 promotes LPS-induced cardiomyocyte apoptosis. RNA immunoprecipitation sequencing (RIP-seq) and Western blotting further showed that YTHDC2 activates the LPS-induced NF-κB pathway. Mechanistic investigations using RIP-qPCR confirmed direct binding of YTHDC2 to mRNAs encoding the pro-apoptotic proteins BAX and BAK1, as well as the NF-κB subunit p65, with subsequent regulation of NF-κB transcriptional activity. Importantly, adeno-associated virus 9 (AAV9)-mediated cardiac-specific inhibition of YTHDC2 in adolescent rats effectively attenuated LPS-induced cardiomyocyte apoptosis and NF-κB pathway activation. Collectively, our findings establish YTHDC2 as a key regulator in SICM pathogenesis, promoting cardiomyocyte apoptosis and NF-κB signaling activation. These results highlight YTHDC2 as a promising therapeutic target for SICM.
DOI: 10.6084/m9.figshare.30784844.v1
title: YTHDC2 promotes sepsis-induced cardiomyopathy by activating apoptosis and NF-κB pathway

description: Sepsis-induced cardiomyopathy (SICM) is a severe complication of sepsis, especially in children, and identification of novel therapeutic targets remains essential for improving patient outcomes. Recent studies have implicated N6-methyladenosine (m<sup>6</sup>A), an RNA epigenetic modification, in SICM pathogenesis. However, the role of YTH domain-containing 2 (YTHDC2), an m<sup>6</sup>A reader protein, in SICM remains unclear. This study used lipopolysaccharide (LPS)-treated adolescent rats, primary cardiomyocytes and H9c2 cardiomyocytes to mimic SICM <i>in</i> <i>vivo</i> and <i>in</i> <i>vitro</i>. We observed a significant upregulation of YTHDC2 <i>in</i> <i>vivo</i> and <i>in</i> <i>vitro</i>. Through comprehensive analyses including RNA sequencing (RNA-seq), Western blotting, and flow cytometry, we demonstrated that YTHDC2 promotes LPS-induced cardiomyocyte apoptosis. RNA immunoprecipitation sequencing (RIP-seq) and Western blotting further showed that YTHDC2 activates the LPS-induced NF-κB pathway. Mechanistic investigations using RIP-qPCR confirmed direct binding of YTHDC2 to mRNAs encoding the pro-apoptotic proteins BAX and BAK1, as well as the NF-κB subunit p65, with subsequent regulation of NF-κB transcriptional activity. Importantly, adeno-associated virus 9 (AAV9)-mediated cardiac-specific inhibition of YTHDC2 in adolescent rats effectively attenuated LPS-induced cardiomyocyte apoptosis and NF-κB pathway activation. Collectively, our findings establish YTHDC2 as a key regulator in SICM pathogenesis, promoting cardiomyocyte apoptosis and NF-κB signaling activation. These results highlight YTHDC2 as a promising therapeutic target for SICM.
DOI: 10.6084/m9.figshare.28643140
title: Assessment for antibiotic resistance in <i>Helicobacter pylori</i>: A practical and interpretable machine learning model based on genome-wide genetic variation

description: <i>Helicobacter pylori</i> (<i>H. pylori</i>) antibiotic resistance poses a global health threat. Accurate identification of antibiotic resistant strains is essential for the control of infection. In the present study, our goal is to leverage the whole-genome data of <i>H. pylori</i> to develop practical and interpretable machine learning (ML) models for comprehensive antibiotic resistance assessment. A total of 296 <i>H. pylori</i> isolates with genome-wide data were downloaded from the Bacterial and Viral Bioinformatics Resource Center (BV-BRC) and the National Center for Biotechnology Information (NCBI) databases. By training ML models on feature sets of single nucleotide polymorphisms from SNP calling (SNPs-1), antibiotic-resistance SNP annotated by the Comprehensive Antibiotic Resistance Database (SNPs-2), gene presence or absence (GPA), we generated predictive models for four antibiotics and multidrug-resistance (MDR). Among them, the models that combined SNPs-1, SNPs-2, and GPA data demonstrated the best performance, with the eXtreme Gradient Boosting (XGBoost) consistently outperforming others. And then we utilized the SHapley Additive exPlanations (SHAP) method to interpret the ML models. Furthermore, a free web application for the MDR model was deployed to the GitHub repository (https://H.pylori/MDR/App/). Our study demonstrated the promise of employing whole-genome data in conjunction with ML algorithms to forecast <i>H. pylori</i> antibiotic resistance. In the future, the application of this approach for predicting <i>H. pylori</i> antibiotic resistance would hold the potential to mitigate the empiric administration.
DOI: 10.6084/m9.figshare.28643140.v1
title: Assessment for antibiotic resistance in <i>Helicobacter pylori</i>: A practical and interpretable machine learning model based on genome-wide genetic variation

description: <i>Helicobacter pylori</i> (<i>H. pylori</i>) antibiotic resistance poses a global health threat. Accurate identification of antibiotic resistant strains is essential for the control of infection. In the present study, our goal is to leverage the whole-genome data of <i>H. pylori</i> to develop practical and interpretable machine learning (ML) models for comprehensive antibiotic resistance assessment. A total of 296 <i>H. pylori</i> isolates with genome-wide data were downloaded from the Bacterial and Viral Bioinformatics Resource Center (BV-BRC) and the National Center for Biotechnology Information (NCBI) databases. By training ML models on feature sets of single nucleotide polymorphisms from SNP calling (SNPs-1), antibiotic-resistance SNP annotated by the Comprehensive Antibiotic Resistance Database (SNPs-2), gene presence or absence (GPA), we generated predictive models for four antibiotics and multidrug-resistance (MDR). Among them, the models that combined SNPs-1, SNPs-2, and GPA data demonstrated the best performance, with the eXtreme Gradient Boosting (XGBoost) consistently outperforming others. And then we utilized the SHapley Additive exPlanations (SHAP) method to interpret the ML models. Furthermore, a free web application for the MDR model was deployed to the GitHub repository (https://H.pylori/MDR/App/). Our study demonstrated the promise of employing whole-genome data in conjunction with ML algorithms to forecast <i>H. pylori</i> antibiotic resistance. In the future, the application of this approach for predicting <i>H. pylori</i> antibiotic resistance would hold the potential to mitigate the empiric administration.
DOI: 10.6084/m9.figshare.29527958
title: Identification of fecal microbes as potential biomarkers for early diagnosis of fatty liver disease in cattle

description: Fatty liver disease is prevalent during parturition in dairy cattle. Therefore, there is an urgent need to develop novel, sensitive biomarkers for the early diagnosis of the metabolic disorders. Macroproteomics revealed that the faecal microbial community changes significantly when animal develops fatty liver disease. The microbial changes in cows with severe fatty liver (SFL) were greater than cows with moderate fatty liver (MFL) and normal condition (Norm). This suggests that microorganisms play an important role in the pathogenesis of metabolic disorders. In this study, faeces-sourced microorganisms and microbial proteins were identified and testified as novel biomarkers for the early diagnosis of fatty liver disease in cattle. For example, the AUC (area under curve) values, based on Receiver Operating Characteristics analysis, of using the combination of <i>Lachnoanaerobaculum</i> and <i>Bifidobacterium</i> (at the <i>genus</i> level) to discriminate MFL and SFL animals reached 0.944 and 0.867, respectively, and 0.922 and 0.985, respectively, for the combination of <i>Bifidobacterium pseudolongum</i> and <i>Lachnospiraceae bacterium</i> (at the <i>species</i> level). Interestingly, the differentially expressed microbial proteins are closely related to the identified microorganisms. For example, the majority of the top 20 microbial proteins with significant expression differences were derived from <i>Bifidobacterium pseudolongum</i>. <i>Bifidobacterium pseudolongum</i> was considered a prominent potential biomarker for the diagnosis of metabolic disorders, especially in fatty liver cattle. The results of this study confirm that faecal microbial dysbiosis signatures can serve as a diagnosis biomarker for non-alcoholic fatty liver disease (NAFLD), but also shed light on faecal microbiota transfer (FMT) experiments in treating NAFLD.
DOI: 10.6084/m9.figshare.29527958.v1
title: Identification of fecal microbes as potential biomarkers for early diagnosis of fatty liver disease in cattle

description: Fatty liver disease is prevalent during parturition in dairy cattle. Therefore, there is an urgent need to develop novel, sensitive biomarkers for the early diagnosis of the metabolic disorders. Macroproteomics revealed that the faecal microbial community changes significantly when animal develops fatty liver disease. The microbial changes in cows with severe fatty liver (SFL) were greater than cows with moderate fatty liver (MFL) and normal condition (Norm). This suggests that microorganisms play an important role in the pathogenesis of metabolic disorders. In this study, faeces-sourced microorganisms and microbial proteins were identified and testified as novel biomarkers for the early diagnosis of fatty liver disease in cattle. For example, the AUC (area under curve) values, based on Receiver Operating Characteristics analysis, of using the combination of <i>Lachnoanaerobaculum</i> and <i>Bifidobacterium</i> (at the <i>genus</i> level) to discriminate MFL and SFL animals reached 0.944 and 0.867, respectively, and 0.922 and 0.985, respectively, for the combination of <i>Bifidobacterium pseudolongum</i> and <i>Lachnospiraceae bacterium</i> (at the <i>species</i> level). Interestingly, the differentially expressed microbial proteins are closely related to the identified microorganisms. For example, the majority of the top 20 microbial proteins with significant expression differences were derived from <i>Bifidobacterium pseudolongum</i>. <i>Bifidobacterium pseudolongum</i> was considered a prominent potential biomarker for the diagnosis of metabolic disorders, especially in fatty liver cattle. The results of this study confirm that faecal microbial dysbiosis signatures can serve as a diagnosis biomarker for non-alcoholic fatty liver disease (NAFLD), but also shed light on faecal microbiota transfer (FMT) experiments in treating NAFLD.
DOI: 10.6084/m9.figshare.28375977
title: Protection acquired upon intraperitoneal group a <i>Streptococcus</i> immunization is independent of concurrent adaptive immune responses but relies on macrophages and IFN-γ

description: Group A <i>Streptococcus</i> (GAS; <i>Streptococcus pyogenes</i>) is an important bacterial pathogen causing over 700 million superficial infections and around 500.000 deaths due to invasive disease or severe post-infection sequelae yearly. In spite of this major impact on society, there is currently no vaccine available against this bacterium. GAS strains can be separated into &gt;250 distinct <i>emm</i> (M)-types, and protective immunity against GAS is believed to in part be dependent on type-specific antibodies. Here, we analyse the nature of protective immunity generated against GAS in a model of intraperitoneal immunization in mice. We demonstrate that multiple immunizations are required for the ability to survive a subsequent lethal challenge, and although significant levels of GAS-specific antibodies are produced, these are redundant for protection. Instead, our data show that the immunization-dependent protection in this model is induced in the absence of B and T cells and is accompanied by the induction of an altered acute cytokine profile upon subsequent infection, noticeable e.g. by the absence of classical pro-inflammatory cytokines and increased IFN-γ production. Further, the ability of immunized mice to survive a lethal infection is dependent on macrophages and the macrophage-activating cytokine IFN-γ. To our knowledge these findings are the first to suggest that GAS may have the ability to induce forms of trained innate immunity. Taken together, the current study proposes a novel role for the innate immune system in response to GAS infections that potentially could be leveraged for future development of effective vaccines.
DOI: 10.6084/m9.figshare.28375977.v1
title: Protection acquired upon intraperitoneal group a <i>Streptococcus</i> immunization is independent of concurrent adaptive immune responses but relies on macrophages and IFN-γ

description: Group A <i>Streptococcus</i> (GAS; <i>Streptococcus pyogenes</i>) is an important bacterial pathogen causing over 700 million superficial infections and around 500.000 deaths due to invasive disease or severe post-infection sequelae yearly. In spite of this major impact on society, there is currently no vaccine available against this bacterium. GAS strains can be separated into &gt;250 distinct <i>emm</i> (M)-types, and protective immunity against GAS is believed to in part be dependent on type-specific antibodies. Here, we analyse the nature of protective immunity generated against GAS in a model of intraperitoneal immunization in mice. We demonstrate that multiple immunizations are required for the ability to survive a subsequent lethal challenge, and although significant levels of GAS-specific antibodies are produced, these are redundant for protection. Instead, our data show that the immunization-dependent protection in this model is induced in the absence of B and T cells and is accompanied by the induction of an altered acute cytokine profile upon subsequent infection, noticeable e.g. by the absence of classical pro-inflammatory cytokines and increased IFN-γ production. Further, the ability of immunized mice to survive a lethal infection is dependent on macrophages and the macrophage-activating cytokine IFN-γ. To our knowledge these findings are the first to suggest that GAS may have the ability to induce forms of trained innate immunity. Taken together, the current study proposes a novel role for the innate immune system in response to GAS infections that potentially could be leveraged for future development of effective vaccines.
DOI: 10.6084/m9.figshare.28103602
title: Arginine depletion-induced autophagy and metabolic dysregulation are involved in the disease severity of hand, foot, and mouth disease

description: Amino acid metabolism provides significant insight into the development and prevention of many viral diseases. Therefore, the present study aimed to compare the amino acid profiles of hand, foot, and mouth disease (HFMD) patients with those of healthy individuals and to further reveal the molecular mechanisms of HFMD severity. Using UPLC-MS/MS, we determined the plasma amino acid expression profiles of pediatric patients with HFMD (mild, <i>n</i> = 42; severe, <i>n</i> = 43) and healthy controls (<i>n</i> = 25). Brain tissues from CVA6-infected mice were examined using untargeted metabolomics. Several amino acids were significantly different between the three groups. Pathway analysis revealed that arginine, proline, and tryptophan metabolism are implicated in the pathogenesis of HFMD. A similar arginine depletion was observed in the brain tissues of CVA6-infected mice. Importantly, L-arginine supplementation improved the survival rate of CVA6-infected mice, inhibited virus multiplication, and reduced pathological autophagy associated with mTOR-autophagy pathway in the brain. Collectively, arginine, as the hub amino acid metabolite of the mammalian target of rapamycin (mTOR) signaling pathway affecting autophagy, plays an important role in the pathogenesis of severe HFMD. L-arginine supplementation may serve as a potential therapeutic option for critical patients with HFMD.
DOI: 10.6084/m9.figshare.28103602.v1
title: Arginine depletion-induced autophagy and metabolic dysregulation are involved in the disease severity of hand, foot, and mouth disease

description: Amino acid metabolism provides significant insight into the development and prevention of many viral diseases. Therefore, the present study aimed to compare the amino acid profiles of hand, foot, and mouth disease (HFMD) patients with those of healthy individuals and to further reveal the molecular mechanisms of HFMD severity. Using UPLC-MS/MS, we determined the plasma amino acid expression profiles of pediatric patients with HFMD (mild, <i>n</i> = 42; severe, <i>n</i> = 43) and healthy controls (<i>n</i> = 25). Brain tissues from CVA6-infected mice were examined using untargeted metabolomics. Several amino acids were significantly different between the three groups. Pathway analysis revealed that arginine, proline, and tryptophan metabolism are implicated in the pathogenesis of HFMD. A similar arginine depletion was observed in the brain tissues of CVA6-infected mice. Importantly, L-arginine supplementation improved the survival rate of CVA6-infected mice, inhibited virus multiplication, and reduced pathological autophagy associated with mTOR-autophagy pathway in the brain. Collectively, arginine, as the hub amino acid metabolite of the mammalian target of rapamycin (mTOR) signaling pathway affecting autophagy, plays an important role in the pathogenesis of severe HFMD. L-arginine supplementation may serve as a potential therapeutic option for critical patients with HFMD.
DOI: 10.6084/m9.figshare.30790557
title: Mapping evolutionary paradigm of Oropouche virus driven by dinucleotide bias and context-dependent codon bias

description: Arthropod-borne viruses (arboviruses) pose significant public health threats, and understanding their evolutionary mechanisms can inform molecular diagnostics and vaccine design. Oropouche virus (OROV), a relatively understudied arbovirus, exhibits unique evolutionary dynamics in nucleotide composition. We analyzed 45 OROV strains across genotypes to assess selective pressures shaping nucleoprotein, glycoprotein, and RNA-dependent RNA polymerase (RdRp) evolution. We utilized information entropy, dinucleotide odds ratios, relative synonymous codon usage values, and context-dependent codon bias (CDCB) to elucidate the genetic characteristics associated with mono-, di-, tri-, and tetranucleotide compositions. The extent of overall nucleotide usage bias, dinucleotide bias, and synonymous codon usage bias did not correlate with genotype-specific patterns, but rather exhibited a protein function-dependent pattern across the three proteins. Although dinucleotide bias and synonymous codon usage bias varied within a relatively broad range, the dinucleotide CpG, the over- and under-represented synonymous codons, and CDCB remained strongly influenced by natural selective pressures from both the host and the viral life cycle. Furthermore, the codon usage patterns, as indicated by the effective number of codons, suggest that the OROV nucleoprotein has been subject to stronger selective pressures in its evolutionary paradigm compared to the glycoprotein and RdRp, which appear to be primarily influenced by natural selection and mutation pressure. Additionally, analysis of relative codon deoptimization index (RCDI) and tRNA adaptation index (tAI) revealed suboptimal translational efficiency of OROV coding sequences in human hosts, suggesting limited codon usage adaptation.
DOI: 10.6084/m9.figshare.30790557.v2
title: Mapping evolutionary paradigm of Oropouche virus driven by dinucleotide bias and context-dependent codon bias

description: Arthropod-borne viruses (arboviruses) pose significant public health threats, and understanding their evolutionary mechanisms can inform molecular diagnostics and vaccine design. Oropouche virus (OROV), a relatively understudied arbovirus, exhibits unique evolutionary dynamics in nucleotide composition. We analyzed 45 OROV strains across genotypes to assess selective pressures shaping nucleoprotein, glycoprotein, and RNA-dependent RNA polymerase (RdRp) evolution. We utilized information entropy, dinucleotide odds ratios, relative synonymous codon usage values, and context-dependent codon bias (CDCB) to elucidate the genetic characteristics associated with mono-, di-, tri-, and tetranucleotide compositions. The extent of overall nucleotide usage bias, dinucleotide bias, and synonymous codon usage bias did not correlate with genotype-specific patterns, but rather exhibited a protein function-dependent pattern across the three proteins. Although dinucleotide bias and synonymous codon usage bias varied within a relatively broad range, the dinucleotide CpG, the over- and under-represented synonymous codons, and CDCB remained strongly influenced by natural selective pressures from both the host and the viral life cycle. Furthermore, the codon usage patterns, as indicated by the effective number of codons, suggest that the OROV nucleoprotein has been subject to stronger selective pressures in its evolutionary paradigm compared to the glycoprotein and RdRp, which appear to be primarily influenced by natural selection and mutation pressure. Additionally, analysis of relative codon deoptimization index (RCDI) and tRNA adaptation index (tAI) revealed suboptimal translational efficiency of OROV coding sequences in human hosts, suggesting limited codon usage adaptation.