cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.18743686.v2
title: B cell receptor signatures associated with strong and poor SARS-CoV-2 vaccine responses

description: Breakthrough infection of SARS-CoV-2 is a serious challenge, as increased infections were documented in fully-vaccinated individuals. Recipients with poor antibody response are highly vulnerable to reinfection, whereas those with strong antibody responses achieve sterilizing immunity. Thus far, biomarkers associated with levels of vaccine-elicited antibody response are still lacking. Here, we studied the antibody response of age- and gender-controlled healthy cohort, who received inactivated SARS-CoV-2 vaccines and profiled the B cell receptor repertoires in longitudinally consecutive samples. Upon vaccination, all vaccinated individuals displayed a convergent antibody response with shared common antibody clones and public neutralizing antibodies. Strikingly, poor vaccine-responders are distinguishable from strong vaccine-responders by a biased V-usage before vaccination and IgG to IgM mRNA ratio. These findings reveal molecular signatures associated with the different levels of vaccine-induced antibody response, which could be further developed into biomarkers for the design of vaccination strategies.
DOI: 10.6084/m9.figshare.19063918.v2
title: H<sub>2</sub>O<sub>2</sub> concentration-dependent kinetics of gene expression: linking the intensity of oxidative stress and mycobacterial physiological adaptation

description: Defence against oxidative stress is crucial for <i>Mycobacterium tuberculosis</i> to survive and replicate within macrophages. Mycobacteria have evolved multilayer antioxidant systems, including scavenging enzymes, iron homeostasis, repair pathways, and metabolic adaptation, for coping with oxidative stress. How these systems are coordinated to enable the physiological adaptation to different intensities of oxidative stress, however, remains unclear. To address this, we investigated the expression kinetics of the well-characterized antioxidant genes at bacteriostatic H<sub>2</sub>O<sub>2</sub> concentrations ranging from 1 mM to 10 mM employing <i>Mycolicibacterium smegmatis</i> as a model. Our results showed that most of the selected genes were expressed in a H<sub>2</sub>O<sub>2</sub> concentration-dependent manner, whereas a subset exhibited sustained induction or repression without dose–effect, reflecting H<sub>2</sub>O<sub>2</sub> concentration-dependent physiological adaptations. Through analyzing the dynamics of the coordinated gene expression, we demonstrated that the expressions of the H<sub>2</sub>O<sub>2</sub> scavenging enzymes, DNA damage response, and Fe–S cluster repair function were strikingly correlated to the intensity of oxidative stress. The sustained induction of <i>mbtB</i>, <i>irtA</i>, and <i>dnaE2</i> indicated that mycobacteria might deploy increased iron acquisition and error-prone lesion bypass function as fundamental strategies to counteract oxidative damages, which are distinct from the defence tactics of <i>Escherichia coli</i> characterized by shrinking the iron pool and delaying the DNA repair. Moreover, the distinct gene expression kinetics among the tricarboxylic acid cycle, glyoxylate shunt, and methylcitrate cycle suggested that mycobacteria could dynamically redirect its metabolic fluxes according to the intensity of oxidative stress. This work defines the H<sub>2</sub>O<sub>2</sub> concentration-dependent gene expression kinetics and provides unique insights into mycobacterial antioxidant defence strategies.
DOI: 10.6084/m9.figshare.19063918
title: H<sub>2</sub>O<sub>2</sub> concentration-dependent kinetics of gene expression: linking the intensity of oxidative stress and mycobacterial physiological adaptation

description: Defence against oxidative stress is crucial for <i>Mycobacterium tuberculosis</i> to survive and replicate within macrophages. Mycobacteria have evolved multilayer antioxidant systems, including scavenging enzymes, iron homeostasis, repair pathways, and metabolic adaptation, for coping with oxidative stress. How these systems are coordinated to enable the physiological adaptation to different intensities of oxidative stress, however, remains unclear. To address this, we investigated the expression kinetics of the well-characterized antioxidant genes at bacteriostatic H<sub>2</sub>O<sub>2</sub> concentrations ranging from 1 mM to 10 mM employing <i>Mycolicibacterium smegmatis</i> as a model. Our results showed that most of the selected genes were expressed in a H<sub>2</sub>O<sub>2</sub> concentration-dependent manner, whereas a subset exhibited sustained induction or repression without dose–effect, reflecting H<sub>2</sub>O<sub>2</sub> concentration-dependent physiological adaptations. Through analyzing the dynamics of the coordinated gene expression, we demonstrated that the expressions of the H<sub>2</sub>O<sub>2</sub> scavenging enzymes, DNA damage response, and Fe–S cluster repair function were strikingly correlated to the intensity of oxidative stress. The sustained induction of <i>mbtB</i>, <i>irtA</i>, and <i>dnaE2</i> indicated that mycobacteria might deploy increased iron acquisition and error-prone lesion bypass function as fundamental strategies to counteract oxidative damages, which are distinct from the defence tactics of <i>Escherichia coli</i> characterized by shrinking the iron pool and delaying the DNA repair. Moreover, the distinct gene expression kinetics among the tricarboxylic acid cycle, glyoxylate shunt, and methylcitrate cycle suggested that mycobacteria could dynamically redirect its metabolic fluxes according to the intensity of oxidative stress. This work defines the H<sub>2</sub>O<sub>2</sub> concentration-dependent gene expression kinetics and provides unique insights into mycobacterial antioxidant defence strategies.
DOI: 10.6084/m9.figshare.17263133
title: Pharmacologically induced endolysosomal cholesterol imbalance through clinically licensed drugs itraconazole and fluoxetine impairs Ebola virus infection <i>in vitro</i>

description: Ebola virus disease (EVD) is a severe and frequently lethal disease caused by Ebola virus (EBOV). The latest occasional EVD outbreak (2013–2016) in Western African, which was accompanied by a high fatality rate, showed the great potential of epidemic and pandemic spread. Antiviral therapies against EBOV are very limited, strain-dependent (only antibody therapies are available) and mostly restricted to symptomatic treatment, illustrating the urgent need for novel antiviral strategies. Thus, we evaluated the effect of the clinically widely used antifungal itraconazole and the antidepressant fluoxetine for a repurposing against EBOV infection. While itraconazole, similar to U18666A, directly binds to and inhibits the endosomal membrane protein Niemann-Pick C1 (NPC1), fluoxetine, which belongs to the structurally unrelated group of weakly basic, amphiphile so-called “functional inhibitors of acid sphingomyelinase” (FIASMA) indirectly acts on the lysosome-residing acid sphingomyelinase via enzyme detachment leading to subsequent lysosomal degradation. Both, the drug-induced endolysosomal cholesterol accumulation and the altered endolysosomal pH, might interfere with the fusion of viral and endolysosomal membrane, preventing infection with EBOV. We further provide evidence that cholesterol imbalance is a conserved cross-species mechanism to hamper EBOV infection. Thus, exploring the endolysosomal host–pathogen interface as a suitable antiviral treatment may offer a general strategy to combat EBOV infection.
DOI: 10.6084/m9.figshare.17263133.v2
title: Pharmacologically induced endolysosomal cholesterol imbalance through clinically licensed drugs itraconazole and fluoxetine impairs Ebola virus infection <i>in vitro</i>

description: Ebola virus disease (EVD) is a severe and frequently lethal disease caused by Ebola virus (EBOV). The latest occasional EVD outbreak (2013–2016) in Western African, which was accompanied by a high fatality rate, showed the great potential of epidemic and pandemic spread. Antiviral therapies against EBOV are very limited, strain-dependent (only antibody therapies are available) and mostly restricted to symptomatic treatment, illustrating the urgent need for novel antiviral strategies. Thus, we evaluated the effect of the clinically widely used antifungal itraconazole and the antidepressant fluoxetine for a repurposing against EBOV infection. While itraconazole, similar to U18666A, directly binds to and inhibits the endosomal membrane protein Niemann-Pick C1 (NPC1), fluoxetine, which belongs to the structurally unrelated group of weakly basic, amphiphile so-called “functional inhibitors of acid sphingomyelinase” (FIASMA) indirectly acts on the lysosome-residing acid sphingomyelinase via enzyme detachment leading to subsequent lysosomal degradation. Both, the drug-induced endolysosomal cholesterol accumulation and the altered endolysosomal pH, might interfere with the fusion of viral and endolysosomal membrane, preventing infection with EBOV. We further provide evidence that cholesterol imbalance is a conserved cross-species mechanism to hamper EBOV infection. Thus, exploring the endolysosomal host–pathogen interface as a suitable antiviral treatment may offer a general strategy to combat EBOV infection.
DOI: 10.6084/m9.figshare.19130297
title: Modern Beijing sublineage of <i>Mycobacterium tuberculosis</i> shift macrophage into a hyperinflammatory status

description: The high prevalence of the modern Beijing sublineage of <i>Mycobacterium tuberculosis</i> may be related to increased virulence, although the responsible mechanisms remain poorly understood. We previously described enhanced triacylglycerol accumulation in modern Beijing strains. Here we show that modern Beijing strains grow faster <i>in vitro</i> and trigger a vigorous immune response and pronounced macrophage infiltration. Transcriptomic analysis of bone marrow derived macrophages infected with modern Beijing lineage strains revealed a significant enrichment of infection, cholesterol homeostasis and amino acid metabolic pathways. The upregulation of proinflammatory / bactericidal cytokines was confirmed by RT–PCR analysis, which is also in consistent with the reduced bacterial burden in modern strains infected macrophages. These results suggest that modern Beijing strains elicit a hyperinflammatory response which might indicate a stronger virulence and contribute to their extensive global prevalence.
DOI: 10.6084/m9.figshare.19130297.v2
title: Modern Beijing sublineage of <i>Mycobacterium tuberculosis</i> shift macrophage into a hyperinflammatory status

description: The high prevalence of the modern Beijing sublineage of <i>Mycobacterium tuberculosis</i> may be related to increased virulence, although the responsible mechanisms remain poorly understood. We previously described enhanced triacylglycerol accumulation in modern Beijing strains. Here we show that modern Beijing strains grow faster <i>in vitro</i> and trigger a vigorous immune response and pronounced macrophage infiltration. Transcriptomic analysis of bone marrow derived macrophages infected with modern Beijing lineage strains revealed a significant enrichment of infection, cholesterol homeostasis and amino acid metabolic pathways. The upregulation of proinflammatory / bactericidal cytokines was confirmed by RT–PCR analysis, which is also in consistent with the reduced bacterial burden in modern strains infected macrophages. These results suggest that modern Beijing strains elicit a hyperinflammatory response which might indicate a stronger virulence and contribute to their extensive global prevalence.
DOI: 10.6084/m9.figshare.17086337
title: Emergence, prevalence, and evolution of H5N8 avian influenza viruses in central China, 2020

description: Highly pathogenic influenza A(H5N8) viruses have caused several worldwide outbreaks in birds and are able cross the species barrier to infect humans, posing a substantial threat to public health. After the first detection of H5N8 viruses in deceased swans in Inner Mongolia, we performed early warning and active monitoring along swan migration routes in central China. We isolated and sequenced 42 avian influenza viruses, including 40 H5N8 viruses, 1 H5N2 virus, and 1 H9N2 virus, in central China. Our H5N8 viruses isolated in swan stopover sites and wintering grounds showed high nucleotide homologies in the whole genome, revealing a common evolutionary source. Phylogenetic analysis revealed that the H5 viruses of clade 2.3.4.4b prevalent in 2020 have further diverged into two sub-clades: b1 and b2. The phylogeographic analysis also showed that the viruses of sub-clade b2 most likely originated from poultry in Russia. Notably, whooper swans were found to be responsible for the introduction of sub-clade b2 viruses in central China; whooper and tundra swans play a role in viral spread in the Yellow River Basin and the Yangtze River Basin, respectively. Our findings highlight swans as an indicator species for transborder spreading and monitoring of the H5N8 virus.
DOI: 10.6084/m9.figshare.17086337.v2
title: Emergence, prevalence, and evolution of H5N8 avian influenza viruses in central China, 2020

description: Highly pathogenic influenza A(H5N8) viruses have caused several worldwide outbreaks in birds and are able cross the species barrier to infect humans, posing a substantial threat to public health. After the first detection of H5N8 viruses in deceased swans in Inner Mongolia, we performed early warning and active monitoring along swan migration routes in central China. We isolated and sequenced 42 avian influenza viruses, including 40 H5N8 viruses, 1 H5N2 virus, and 1 H9N2 virus, in central China. Our H5N8 viruses isolated in swan stopover sites and wintering grounds showed high nucleotide homologies in the whole genome, revealing a common evolutionary source. Phylogenetic analysis revealed that the H5 viruses of clade 2.3.4.4b prevalent in 2020 have further diverged into two sub-clades: b1 and b2. The phylogeographic analysis also showed that the viruses of sub-clade b2 most likely originated from poultry in Russia. Notably, whooper swans were found to be responsible for the introduction of sub-clade b2 viruses in central China; whooper and tundra swans play a role in viral spread in the Yellow River Basin and the Yangtze River Basin, respectively. Our findings highlight swans as an indicator species for transborder spreading and monitoring of the H5N8 virus.
DOI: 10.6084/m9.figshare.18478789.v2
title: Antibiotic resistance in hospital-acquired ESKAPE-E infections in low- and lower-middle-income countries: a systematic review and meta-analysis

description: Antimicrobial resistance (AMR) and hospital-acquired infections (HAIs) are global health challenges. The burden of antibiotic resistance in HAIs is still unclear in low- and lower-middle-income countries (L-LMICs). This study summarizes recent data on antibiotic resistance in priority HAIs (ESKAPE-E) in L-LMICs and compares them with data from high-income countries (HICs). EMBASE, Web of Science, and Global Index Medicus were searched for studies on AMR patterns in HAIs published from 01/2010 to 10/2020. Random-effects meta-analyses were performed to obtain pooled estimates. In total, 163 eligible studies were included in the review and meta-analysis. The pooled methicillin resistance proportion in <i>Staphylococcus aureus</i> was 48.4% (95% confidence interval [95%CI] 41·7-55·2, n = 80). Pooled carbapenem resistance proportions were high in Gram-negative pathogens: <i>Escherichia coli</i>: 16·6% (95%CI 10·7-23·4, n = 60); <i>Klebsiella pneumoniae</i>: 34·9% (95%CI 24·6-45·9, n = 50); <i>Pseudomonas aeruginosa</i>: 37.1% (95%CI 24·6-45·9, n = 56); <i>Enterobacter</i> spp.: 51·2% (95%CI 27·5-74·7, n = 7); and <i>Acinetobacter baumannii (complex):</i> 72·4% (95%CI 62·1-81·7%, n = 36). A higher resistance proportions were observed for third-generation cephalosporins: <i>Klebsiella pneumoniae</i>: 78·7% (95%CI 71·5-85·2, n = 46); <i>Escherichia coli:</i> 78·5% (95%CI 72·1-84·2%, n = 58); and <i>Enterobacter</i> spp.: 83·5% (95%CI 71·9-92·8, n = 8). We observed a high between-study heterogeneity (I<sup>2</sup>  &gt;  80%), which could not be explained by our set of moderators. Pooled resistance proportions for Gram-negative pathogens were higher in L-LMICs than regional and national estimates from HICs. Patients in resource-constrained regions are particularly affected by AMR. To combat the high resistance to critical antibiotics in L-LMICs, and bridge disparities in health, it is crucial to strengthen local surveillance and the health systems in general.
DOI: 10.6084/m9.figshare.18478789
title: Antibiotic resistance in hospital-acquired ESKAPE-E infections in low- and lower-middle-income countries: a systematic review and meta-analysis

description: Antimicrobial resistance (AMR) and hospital-acquired infections (HAIs) are global health challenges. The burden of antibiotic resistance in HAIs is still unclear in low- and lower-middle-income countries (L-LMICs). This study summarizes recent data on antibiotic resistance in priority HAIs (ESKAPE-E) in L-LMICs and compares them with data from high-income countries (HICs). EMBASE, Web of Science, and Global Index Medicus were searched for studies on AMR patterns in HAIs published from 01/2010 to 10/2020. Random-effects meta-analyses were performed to obtain pooled estimates. In total, 163 eligible studies were included in the review and meta-analysis. The pooled methicillin resistance proportion in <i>Staphylococcus aureus</i> was 48.4% (95% confidence interval [95%CI] 41·7-55·2, n = 80). Pooled carbapenem resistance proportions were high in Gram-negative pathogens: <i>Escherichia coli</i>: 16·6% (95%CI 10·7-23·4, n = 60); <i>Klebsiella pneumoniae</i>: 34·9% (95%CI 24·6-45·9, n = 50); <i>Pseudomonas aeruginosa</i>: 37.1% (95%CI 24·6-45·9, n = 56); <i>Enterobacter</i> spp.: 51·2% (95%CI 27·5-74·7, n = 7); and <i>Acinetobacter baumannii (complex):</i> 72·4% (95%CI 62·1-81·7%, n = 36). A higher resistance proportions were observed for third-generation cephalosporins: <i>Klebsiella pneumoniae</i>: 78·7% (95%CI 71·5-85·2, n = 46); <i>Escherichia coli:</i> 78·5% (95%CI 72·1-84·2%, n = 58); and <i>Enterobacter</i> spp.: 83·5% (95%CI 71·9-92·8, n = 8). We observed a high between-study heterogeneity (I<sup>2</sup>  &gt;  80%), which could not be explained by our set of moderators. Pooled resistance proportions for Gram-negative pathogens were higher in L-LMICs than regional and national estimates from HICs. Patients in resource-constrained regions are particularly affected by AMR. To combat the high resistance to critical antibiotics in L-LMICs, and bridge disparities in health, it is crucial to strengthen local surveillance and the health systems in general.
DOI: 10.6084/m9.figshare.18858163
title: Etesevimab in combination with JS026 neutralizing SARS-CoV-2 and its variants

description: The neutralizing antibody is a potential therapeutic for the ongoing COVID-19 pandemic. As an antiviral agent, numerous mAbs recognize the epitopes that overlap with ACE2-binding sites in the SARS-CoV-2-RBD. Some studies have shown that residual changes on the spike protein can significantly decrease the efficiency of neutralizing antibodies. To address this issue, a therapeutic cocktail could be an effective countermeasure. In the present study, we isolated a fully human neutralizing antibody, JS026, from a convalescent patient. The comparative analysis revealed that JS026 binding to SARS-CoV-2-RBD mainly located between epitopes for class 2 and class 3 mAbs as opposed to that of class 1 (etesevimab) antibodies. A cocktail of etesevimab and JS026 increased neutralizing efficacy against both wild-type SARS-CoV-2 and the recent emergence of Alpha, Beta, Gamma, and Delta variants. JS026 and the cocktail reduced virus titers in the infected lungs of hACE2 transgenic mice and relieved pathological changes. These findings would benefit antibody-based therapeutic countermeasures in the treatment of COVID-19.
DOI: 10.6084/m9.figshare.18858632
title: Establishing and applying an adaptive strategy and approach to eliminating malaria: practice and lessons learnt from China from 2011 to 2020

description: On 30 June 2021, China was certified malaria-free by the World Health Organization. In this study, the evolution, performance, outcomes, and impact of China’s adaptive strategy and approach for malaria elimination from 2011 to 2020 were analysed using 10-year data. The strategy and approach focused on timely detection and rapid responses to individual cases and foci. Indigenous cases declined from 1,308 in 2011 to 36 in 2015, and the last one was reported from Yunnan Province in April 2016, although thousands of imported cases still occur annually. The “1–3–7” approach was implemented successfully between 2013 and 2020, with 100% of cases reported within 24 h, 94.5% of cases investigated within three days of case reporting, and 93.4% of foci responses performed within seven days. Additionally, 81.6% of patients attended the first healthcare visit within 1–3 days of onset and 58.4% were diagnosed as malaria within three days of onset, in 2017–2020. The adaptive strategy and approach, along with their universal implementation, are most critical in malaria elimination. In addition to strengthening surveillance on drug resistance and vectors and border malaria collaboration, a further adapted three-step strategy and the corresponding “3–3–7” model are recommended to address the risks of re-transmission and death by imported cases after elimination. China’s successful practice and lessons learnt through long-term efforts provide a reference for countries moving towards elimination.
DOI: 10.6084/m9.figshare.18858632.v1
title: Establishing and applying an adaptive strategy and approach to eliminating malaria: practice and lessons learnt from China from 2011 to 2020

description: On 30 June 2021, China was certified malaria-free by the World Health Organization. In this study, the evolution, performance, outcomes, and impact of China’s adaptive strategy and approach for malaria elimination from 2011 to 2020 were analysed using 10-year data. The strategy and approach focused on timely detection and rapid responses to individual cases and foci. Indigenous cases declined from 1,308 in 2011 to 36 in 2015, and the last one was reported from Yunnan Province in April 2016, although thousands of imported cases still occur annually. The “1–3–7” approach was implemented successfully between 2013 and 2020, with 100% of cases reported within 24 h, 94.5% of cases investigated within three days of case reporting, and 93.4% of foci responses performed within seven days. Additionally, 81.6% of patients attended the first healthcare visit within 1–3 days of onset and 58.4% were diagnosed as malaria within three days of onset, in 2017–2020. The adaptive strategy and approach, along with their universal implementation, are most critical in malaria elimination. In addition to strengthening surveillance on drug resistance and vectors and border malaria collaboration, a further adapted three-step strategy and the corresponding “3–3–7” model are recommended to address the risks of re-transmission and death by imported cases after elimination. China’s successful practice and lessons learnt through long-term efforts provide a reference for countries moving towards elimination.