cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.28740080
title: Ponatinib and other clinically approved inhibitors of Src and Rho-A kinases abrogate dengue virus serotype 2- induced endothelial permeability

description: Severe dengue often presents as shock syndrome with enhanced vascular permeability and plasma leakage into tissue spaces. <i>In vitro</i> studies have documented the role of Src family kinases (SFKs) and RhoA-kinases (ROCK) in dengue virus serotype 2 (DENV2)-induced endothelial permeability. Here, we show that the FDA-approved SFK inhibitors Bosutinib, Vandetanib and Ponatinib, as well as the ROCK inhibitors, Netarsudil and Ripasudil significantly inhibit DENV2-induced endothelial permeability. In cultured telomerase immortalized human microvascular endothelial cells (HMEC-1), treatment with these inhibitors reduced the phosphorylation of VE-Cadherin, Src and myosin light chain 2 (MLC2) proteins that were upregulated during DENV2 infection. It also prevented the loss of VE-Cadherin from the inter-endothelial cell junctions induced by viral infection. In <i>in-vivo</i> studies using DENV2-infected AG129 IFN receptor-α/β/γ deficient mice, ponatinib, when administered 24 h post-infection onwards, demonstrated significant benefits in improving body weight, clinical outcomes, and survival rates. While all virus-infected, untreated mice died by day-10 post-infection, 80% of the ponatinib-treated mice survived, and approximately 60% were still alive at the end of the 15-day observation period. The treatment also significantly reduced disease severity factors such as vascular leakage, thrombocytopenia; mRNA transcript levels of proinflammatory cytokines such as IL-1β and TNF-α; and restored liver function. Comparable effects were observed even when ponatinib treatment was initiated after symptom onset. The results highlight ponatinib as an effective therapeutic option in severe dengue; and also a similar potential for other FDA- approved SFK and ROCK inhibitors.
DOI: 10.6084/m9.figshare.28740080.v1
title: Ponatinib and other clinically approved inhibitors of Src and Rho-A kinases abrogate dengue virus serotype 2- induced endothelial permeability

description: Severe dengue often presents as shock syndrome with enhanced vascular permeability and plasma leakage into tissue spaces. <i>In vitro</i> studies have documented the role of Src family kinases (SFKs) and RhoA-kinases (ROCK) in dengue virus serotype 2 (DENV2)-induced endothelial permeability. Here, we show that the FDA-approved SFK inhibitors Bosutinib, Vandetanib and Ponatinib, as well as the ROCK inhibitors, Netarsudil and Ripasudil significantly inhibit DENV2-induced endothelial permeability. In cultured telomerase immortalized human microvascular endothelial cells (HMEC-1), treatment with these inhibitors reduced the phosphorylation of VE-Cadherin, Src and myosin light chain 2 (MLC2) proteins that were upregulated during DENV2 infection. It also prevented the loss of VE-Cadherin from the inter-endothelial cell junctions induced by viral infection. In <i>in-vivo</i> studies using DENV2-infected AG129 IFN receptor-α/β/γ deficient mice, ponatinib, when administered 24 h post-infection onwards, demonstrated significant benefits in improving body weight, clinical outcomes, and survival rates. While all virus-infected, untreated mice died by day-10 post-infection, 80% of the ponatinib-treated mice survived, and approximately 60% were still alive at the end of the 15-day observation period. The treatment also significantly reduced disease severity factors such as vascular leakage, thrombocytopenia; mRNA transcript levels of proinflammatory cytokines such as IL-1β and TNF-α; and restored liver function. Comparable effects were observed even when ponatinib treatment was initiated after symptom onset. The results highlight ponatinib as an effective therapeutic option in severe dengue; and also a similar potential for other FDA- approved SFK and ROCK inhibitors.
DOI: 10.6084/m9.figshare.30007337
title: Genetic insights into the interaction between chronic hepatitis B virus infection and metabolic syndrome

description: The association between chronic hepatitis B virus (HBV) infection and metabolic syndrome (MetS) remains controversial. We aimed to analyze the causal effects of chronic HBV infection on MetS components and vice versa. Mendelian randomization (MR) was applied to explore the genetic association of chronic HBV infection with both metabolic risk factors and metabolic diseases using summary-level data from GWAS. Further colocalization and mediation analyses were performed for traits with significant causal relationships. The effect of HBV on lipid metabolism was validated by <i>in vitro</i> assays. In European populations, the MR analyses did not support causal relationships between chronic HBV infection and metabolic traits. In East Asian populations, chronic HBV infection was associated with decreased low-density lipoprotein (LDL) and reduced risk of coronary artery disease (CAD). Reversely, CAD showed negative causal effects on chronic HBV infection risk. Colocalization analysis revealed that the association between chronic HBV infection and CAD was most likely driven by distinct rather than shared causal variants. Mediation analysis identified LDL as a major mediator in the causal effect of chronic HBV infection on CAD and aspirin use as the primary mediator in the causal effect of CAD on chronic HBV infection. <i>In vitro</i> experiments suggested that HBV may inhibit glucose plus insulin-induced lipogenesis in hepatocytes. Our results provide genetic evidence of chronic HBV infection as a protective factor against dyslipidemia and CAD and reveal the potential causal effect of CAD on genetically proxied chronic HBV infection via aspirin treatment in East Asian populations.
DOI: 10.6084/m9.figshare.30007337.v1
title: Genetic insights into the interaction between chronic hepatitis B virus infection and metabolic syndrome

description: The association between chronic hepatitis B virus (HBV) infection and metabolic syndrome (MetS) remains controversial. We aimed to analyze the causal effects of chronic HBV infection on MetS components and vice versa. Mendelian randomization (MR) was applied to explore the genetic association of chronic HBV infection with both metabolic risk factors and metabolic diseases using summary-level data from GWAS. Further colocalization and mediation analyses were performed for traits with significant causal relationships. The effect of HBV on lipid metabolism was validated by <i>in vitro</i> assays. In European populations, the MR analyses did not support causal relationships between chronic HBV infection and metabolic traits. In East Asian populations, chronic HBV infection was associated with decreased low-density lipoprotein (LDL) and reduced risk of coronary artery disease (CAD). Reversely, CAD showed negative causal effects on chronic HBV infection risk. Colocalization analysis revealed that the association between chronic HBV infection and CAD was most likely driven by distinct rather than shared causal variants. Mediation analysis identified LDL as a major mediator in the causal effect of chronic HBV infection on CAD and aspirin use as the primary mediator in the causal effect of CAD on chronic HBV infection. <i>In vitro</i> experiments suggested that HBV may inhibit glucose plus insulin-induced lipogenesis in hepatocytes. Our results provide genetic evidence of chronic HBV infection as a protective factor against dyslipidemia and CAD and reveal the potential causal effect of CAD on genetically proxied chronic HBV infection via aspirin treatment in East Asian populations.
DOI: 10.6084/m9.figshare.28099124
title: Are <i>Escherichia coli</i> causing recurrent cystitis just ordinary uropathogenic <i>E. coli</i> (UPEC) strains?

description: Specific determinants associated with Uropathogenic <i>Escherichia coli</i> (UPEC) causing recurrent cystitis are still poorly characterized. Using strains from a previous clinical study (Vitale study, clinicaltrials.gov, identifier NCT02292160) the aims of this study were (i) to describe genomic and phenotypic traits associated with recurrence using a large collection of recurrent and paired sporadic UPEC isolates and (ii) to explore within-host genomic adaptation associated with recurrence using series of 2 to 5 sequential UPEC isolates. Whole genome comparative analyses between 24 recurrent cystitis isolates (RCIs) and 24 phylogenetically paired sporadic cystitis isolates (SCIs) suggested a lower prevalence of putative mobile genetic elements (MGE) in RCIs, such as plasmids and prophages. The intra-patient evolution of the 24 RCI series over time was characterized by SNP occurrence in genes involved in metabolism or membrane transport and by plasmid loss in 5 out of the 24 RCI series. Genomic evolution occurred early in the course of recurrence, suggesting rapid adaptation to strong selection pressure in the urinary tract. However, RCIs did not exhibit specific virulence factor determinants and could not be distinguished from SCIs by their fitness, biofilm formation, or ability to invade HTB-9 bladder epithelial cells. Taken together, these results suggest a rapid but not convergent adaptation of RCIs that involves both strain- and host-specific characteristics.
DOI: 10.6084/m9.figshare.28099124.v1
title: Are <i>Escherichia coli</i> causing recurrent cystitis just ordinary uropathogenic <i>E. coli</i> (UPEC) strains?

description: Specific determinants associated with Uropathogenic <i>Escherichia coli</i> (UPEC) causing recurrent cystitis are still poorly characterized. Using strains from a previous clinical study (Vitale study, clinicaltrials.gov, identifier NCT02292160) the aims of this study were (i) to describe genomic and phenotypic traits associated with recurrence using a large collection of recurrent and paired sporadic UPEC isolates and (ii) to explore within-host genomic adaptation associated with recurrence using series of 2 to 5 sequential UPEC isolates. Whole genome comparative analyses between 24 recurrent cystitis isolates (RCIs) and 24 phylogenetically paired sporadic cystitis isolates (SCIs) suggested a lower prevalence of putative mobile genetic elements (MGE) in RCIs, such as plasmids and prophages. The intra-patient evolution of the 24 RCI series over time was characterized by SNP occurrence in genes involved in metabolism or membrane transport and by plasmid loss in 5 out of the 24 RCI series. Genomic evolution occurred early in the course of recurrence, suggesting rapid adaptation to strong selection pressure in the urinary tract. However, RCIs did not exhibit specific virulence factor determinants and could not be distinguished from SCIs by their fitness, biofilm formation, or ability to invade HTB-9 bladder epithelial cells. Taken together, these results suggest a rapid but not convergent adaptation of RCIs that involves both strain- and host-specific characteristics.
DOI: 10.6084/m9.figshare.29856128
title: Emergence and molecular evolution of carbapenem-resistant hypervirulent ST23 <i>Klebsiella pneumoniae</i>: The superbug phenomenon in China

description: This study aimed to investigate the molecular epidemiology of carbapenem-resistant hypervirulent <i>Klebsiella pneumoniae</i> (CR-hvKP) ST23 in China. We conducted comprehensive searches across five databases (PubMed, Web of Science, MEDLINE, CNKI, and Wanfang) spanning 1980–2024, identifying 30 eligible studies through rigorous screening. Our synthesis documents 120 ST23 CR-hvKP clinical isolates, including the earliest known case from Zhejiang in 2013 which harbored <i>bla</i><sub>KPC-2</sub> alongside hallmark virulence loci (<i>rmpA</i>, <i>rmpA2</i>, <i>iroN</i>, <i>iucA</i>, and <i>pagO</i>). Epidemiological analysis of 119 isolates reveals geographic disparities: Hebei (25.2%) and Jiangxi (22.7%) are hotspots, while carbapenemase distribution exhibits a north–south divide (<i>bla</i><sub>NDM</sub> predominating in northern China versus <i>bla</i><sub>KPC</sub> in the south). Phylogenetic analysis of 584 global ST23 genomes suggests independent plasmid-mediated acquisition of carbapenemase genes, with evidence of clonal transmission both among humans and between humans and environmental niches. This review highlights the urgent need for surveillance to track CR-hvKP’s evolving epidemiology, alongside interventions targeting plasmid-driven resistance spread.
DOI: 10.6084/m9.figshare.29856128.v2
title: Emergence and molecular evolution of carbapenem-resistant hypervirulent ST23 <i>Klebsiella pneumoniae</i>: The superbug phenomenon in China

description: This study aimed to investigate the molecular epidemiology of carbapenem-resistant hypervirulent <i>Klebsiella pneumoniae</i> (CR-hvKP) ST23 in China. We conducted comprehensive searches across five databases (PubMed, Web of Science, MEDLINE, CNKI, and Wanfang) spanning 1980–2024, identifying 30 eligible studies through rigorous screening. Our synthesis documents 120 ST23 CR-hvKP clinical isolates, including the earliest known case from Zhejiang in 2013 which harbored <i>bla</i><sub>KPC-2</sub> alongside hallmark virulence loci (<i>rmpA</i>, <i>rmpA2</i>, <i>iroN</i>, <i>iucA</i>, and <i>pagO</i>). Epidemiological analysis of 119 isolates reveals geographic disparities: Hebei (25.2%) and Jiangxi (22.7%) are hotspots, while carbapenemase distribution exhibits a north–south divide (<i>bla</i><sub>NDM</sub> predominating in northern China versus <i>bla</i><sub>KPC</sub> in the south). Phylogenetic analysis of 584 global ST23 genomes suggests independent plasmid-mediated acquisition of carbapenemase genes, with evidence of clonal transmission both among humans and between humans and environmental niches. This review highlights the urgent need for surveillance to track CR-hvKP’s evolving epidemiology, alongside interventions targeting plasmid-driven resistance spread.
DOI: 10.6084/m9.figshare.28928359
title: Genomic insights into the rapid rise of <i>Pseudomonas aeruginosa</i> ST463: A high-risk lineage’s adaptive strategy in China

description: High-risk lineages of <i>Pseudomonas aeruginosa</i> pose a serious threat to public health, causing severe infections with high mortality rates and limited treatment options. The emergence and rapid spread of the high-risk lineage ST463 in China have further exacerbated this issue. However, the basis of its success in China remains unidentified. In this study, we analyzed a comprehensive dataset of ST463 strains from 2000 to 2023 using whole genome sequencing to unravel the epidemiological characteristics, evolutionary trajectory, and antibiotic resistance profiles. Our findings suggest that ST463 likely originated from a single introduction from North America in 2007, followed by widespread domestic dissemination. Since its introduction, the lineage has undergone significant genomic changes, including the acquisition of three unique regions that enhanced its metabolism and adaptability. Frequent recombination events, along with the burden of bacteriophages, antibiotic resistance genes, and the spread of c1-type (<i>bla</i><sub>KPC-2</sub>) plasmid-carrying strains, have played crucial roles in its expansion in China. Mutation analysis reveals adaptive responses to antibiotics and selective pressures on key virulence factors, indicating that ST463 is evolving toward a more pathogenic lifestyle.
DOI: 10.6084/m9.figshare.28928359.v1
title: Genomic insights into the rapid rise of <i>Pseudomonas aeruginosa</i> ST463: A high-risk lineage’s adaptive strategy in China

description: High-risk lineages of <i>Pseudomonas aeruginosa</i> pose a serious threat to public health, causing severe infections with high mortality rates and limited treatment options. The emergence and rapid spread of the high-risk lineage ST463 in China have further exacerbated this issue. However, the basis of its success in China remains unidentified. In this study, we analyzed a comprehensive dataset of ST463 strains from 2000 to 2023 using whole genome sequencing to unravel the epidemiological characteristics, evolutionary trajectory, and antibiotic resistance profiles. Our findings suggest that ST463 likely originated from a single introduction from North America in 2007, followed by widespread domestic dissemination. Since its introduction, the lineage has undergone significant genomic changes, including the acquisition of three unique regions that enhanced its metabolism and adaptability. Frequent recombination events, along with the burden of bacteriophages, antibiotic resistance genes, and the spread of c1-type (<i>bla</i><sub>KPC-2</sub>) plasmid-carrying strains, have played crucial roles in its expansion in China. Mutation analysis reveals adaptive responses to antibiotics and selective pressures on key virulence factors, indicating that ST463 is evolving toward a more pathogenic lifestyle.
DOI: 10.6084/m9.figshare.30286991.v1
title: Rad53 orchestrates divergent pathways governing genotoxic resistance, morphogenesis, and virulence in <i>Candida albicans</i>: Mechanistic decoupling through overexpression analysis

description: The DNA damage response (DDR), an evolutionarily conserved surveillance mechanism enabling cells to detect genomic lesions and cell cycle arrest for repair, coordinates genomic stability through key effector kinases. In <i>Candida albicans</i>, our prior work characterized Rad53-mediated transcriptional reprogramming based on the <i>RAD53</i> deletion strain, establishing its canonical DDR functions. However, Rad53 activation dynamically orchestrates cell cycle synchronization and repair coordination during genotoxic challenge. Investigating cellular modifications resulting from increased Rad53 functionality is essential for a deeper understanding of its regulatory response. To this end, we overexpressed Rad53 revealing its dual regulatory capacity in stress adaptation and developmental plasticity. Global transcriptomic profiling demonstrated that <i>RAD53</i> overexpression enhances methyl methanesulfonate (MMS) resistance while paradoxically stimulating filamentous growth, accompanied by upregulation of DNA repair/replication genes (<i>RFA3</i>, <i>POL30</i>) and non-canonical DDR targets including cell wall remodeling factors. Comparative analysis of <i>RAD53</i> deletion and overexpression transcriptomes identified enriched transcription factors, notably Sfl1, Yox1, and Rfx1. In particular, Rfx1 mediated the resistance to genotoxic stress resulting from <i>RAD53</i> overexpression or deletion. Surprisingly, Rad53 overexpression substantially hindered hyphal formation and virulence, whereas its kinase-dead mutation restored these deficiencies. Notably, Rad53’s role in mediating morphogenesis was independent of Rfx1. This multi-modal functionality positions Rad53 as a critical node interfacing genomic stability, developmental plasticity, and pathogenicity in <i>C. albicans</i>. Our study enhances the understanding of the DDR pathway in <i>C. albicans</i>, providing a potential target for treating this fungal pathogen.
DOI: 10.6084/m9.figshare.30286991
title: Rad53 orchestrates divergent pathways governing genotoxic resistance, morphogenesis, and virulence in <i>Candida albicans</i>: Mechanistic decoupling through overexpression analysis

description: The DNA damage response (DDR), an evolutionarily conserved surveillance mechanism enabling cells to detect genomic lesions and cell cycle arrest for repair, coordinates genomic stability through key effector kinases. In <i>Candida albicans</i>, our prior work characterized Rad53-mediated transcriptional reprogramming based on the <i>RAD53</i> deletion strain, establishing its canonical DDR functions. However, Rad53 activation dynamically orchestrates cell cycle synchronization and repair coordination during genotoxic challenge. Investigating cellular modifications resulting from increased Rad53 functionality is essential for a deeper understanding of its regulatory response. To this end, we overexpressed Rad53 revealing its dual regulatory capacity in stress adaptation and developmental plasticity. Global transcriptomic profiling demonstrated that <i>RAD53</i> overexpression enhances methyl methanesulfonate (MMS) resistance while paradoxically stimulating filamentous growth, accompanied by upregulation of DNA repair/replication genes (<i>RFA3</i>, <i>POL30</i>) and non-canonical DDR targets including cell wall remodeling factors. Comparative analysis of <i>RAD53</i> deletion and overexpression transcriptomes identified enriched transcription factors, notably Sfl1, Yox1, and Rfx1. In particular, Rfx1 mediated the resistance to genotoxic stress resulting from <i>RAD53</i> overexpression or deletion. Surprisingly, Rad53 overexpression substantially hindered hyphal formation and virulence, whereas its kinase-dead mutation restored these deficiencies. Notably, Rad53’s role in mediating morphogenesis was independent of Rfx1. This multi-modal functionality positions Rad53 as a critical node interfacing genomic stability, developmental plasticity, and pathogenicity in <i>C. albicans</i>. Our study enhances the understanding of the DDR pathway in <i>C. albicans</i>, providing a potential target for treating this fungal pathogen.
DOI: 10.6084/m9.figshare.29856128.v1
title: Emergence and molecular evolution of carbapenem-resistant hypervirulent ST23 <i>klebsiella pneumoniae</i>: The superbug phenomenon in China

description: This study aimed to investigate the molecular epidemiology of carbapenem-resistant hypervirulent <i>Klebsiella pneumoniae</i> (CR-hvKP) ST23 in China. We conducted comprehensive searches across five databases (PubMed, Web of Science, MEDLINE, CNKI, and Wanfang) spanning 1980-2024, identifying 30 eligible studies through rigorous screening. Our synthesis documents 120 ST23 CR-hvKP clinical isolates, including the earliest known case from Zhejiang in 2013 which harboured <i>bla</i><sub>KPC-2</sub> alongside hallmark virulence loci (<i>rmpA</i>, <i>rmpA2</i>, <i>iroN</i>, <i>iucA</i>, and <i>pagO</i>). Epidemiological analysis of 119 isolates reveals geographic disparities: Hebei (25.2%) and Jiangxi (22.7%) are hotspots, while carbapenemase distribution exhibits a north-south divide (<i>bla</i><sub>NDM</sub> predominating in northern China versus <i>bla</i><sub>KPC</sub> in the south). Phylogenetic analysis of 584 global ST23 genomes suggests independent plasmid-mediated acquisition of carbapenemase genes, with evidence of clonal transmission both among humans and between humans and environmental niches. This review highlights the urgent need for surveillance to track CR-hvKP’s evolving epidemiology, alongside interventions targeting plasmid-driven resistance spread.