cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.9034100.v4
title: Intra-host emergence of an enterovirus A71 variant with enhanced PSGL1 usage and neurovirulence

description: Enterovirus A71 (EV-A71) is one of the main causative agents of hand-foot-and-mouth disease and is occasionally associated with severe neurological complications. EV-A71 pathophysiology is poorly understood due to the lack of small animal models that robustly support viral replication in relevant organs/tissues. Here, we show that adult severe combined immune-deficient (SCID) mice can serve as an EV-A71 infection model to study neurotropic determinants and viral tropism. Mice inoculated intraperitoneally with an EV-A71 clinical isolate had an initial infection of the lung compartment, followed by neuroinvasion and infection of (motor)neurons, resulting in slowly progressing paralysis of the limbs. We identified a substitution (V135I) in the capsid protein VP2 as a key requirement for neurotropism. This substitution was also present in a mouse-adapted variant, obtained by passaging the clinical isolate in the brain of one-day-old mice, and induced exclusive neuropathology and rapid paralysis, confirming its role in neurotropism. Finally, we showed that this residue enhances the capacity of EV-A71 to use mouse PSGL1 for viral entry. Our data reveal that EV-A71 initially disseminates to the lung and identify viral and host determinants that define the neurotropic character of EV-A71, pointing to a hitherto understudied role of PSGL1 in EV-A71 tropism and neuropathology.
DOI: 10.6084/m9.figshare.9841370.v2
title: CRISPR-based rapid and ultra-sensitive diagnostic test for <i>Mycobacterium tuberculosis</i>

description: Rapid and simple-to-use diagnostic methods for tuberculosis are urgently needed. Recent development has unveiled the diagnostic power of the CRISPR system in the detection of viral infections. However, its potential use in detecting the <i>Mycobacterium tuberculosis</i> complex (MTB) remained unexplored. We developed a rapid CRISPR-based assay for TB detection and conducted a retrospective cohort study of 179 patients to evaluate the CRISPR-MTB test for identifying MTB in various forms of direct clinical samples. Its diagnostic performance was compared, in parallel with culture and the GeneXpert MTB/RIF assay (Xpert). The CRISPR-MTB test is highly sensitive with a near single-copy sensitivity, demands less sample input and offers shorter turnaround time than Xpert. When evaluated in the clinical cohort of both pulmonary and extra-pulmonary tuberculosis, the CRISPR-MTB test exhibited an overall improved sensitivity over both culture (79% vs 33%) and Xpert (79% vs 66%), without comprise in specificity (62/63, 98%). The CRISPR-MTB test exhibits an improved overall diagnostic performance over culture and Xpert across a variety of sample types, and offers great potential as a new diagnostic technique for both pulmonary and extra-pulmonary tuberculosis.
DOI: 10.6084/m9.figshare.8798144
title: Zika virus differentially infects human neural progenitor cells according to their state of differentiation and dysregulates neurogenesis through the Notch pathway

description: Zika virus (ZIKV) is a mosquito-borne Flavivirus that causes Zika disease with particular neurological complications, including Guillain-Barré Syndrome and congenital microcephaly. Although ZIKV has been shown to directly infect human neural progenitor cells (hNPCs), thereby decreasing their viability and growth, it is as yet unknown which of the cellular pathways involved in the disruption of neurogenesis are affected following ZIKV infection. By comparing the effect of two ZIKV strains <i>in vitro</i> on hNPCs, the differentiation process of the latter cells was found to lead to a decreased susceptibility to infection and cell death induced by each of the ZIKV strains, which was associated with an earlier and stronger antiviral innate immune response in infected, differentiated hNPCs, as compared to undifferentiated cells. Moreover, ZIKV modulated, both in hNPCs and <i>in vivo</i> in fetal brain in an experimental mouse model, the expression of the Notch pathway which is involved in cellular proliferation, apoptosis and differentiation during neurogenesis. These results show that the differentiation state of hNPCs is a significant factor contributing to the outcome of ZIKV infection and furthermore suggest that ZIKV infection might initiate early activation of the Notch pathway resulting in an abnormal differentiation process, implicated in ZIKV-induced brain injury.
DOI: 10.6084/m9.figshare.8798144.v3
title: Zika virus differentially infects human neural progenitor cells according to their state of differentiation and dysregulates neurogenesis through the Notch pathway

description: Zika virus (ZIKV) is a mosquito-borne Flavivirus that causes Zika disease with particular neurological complications, including Guillain-Barré Syndrome and congenital microcephaly. Although ZIKV has been shown to directly infect human neural progenitor cells (hNPCs), thereby decreasing their viability and growth, it is as yet unknown which of the cellular pathways involved in the disruption of neurogenesis are affected following ZIKV infection. By comparing the effect of two ZIKV strains <i>in vitro</i> on hNPCs, the differentiation process of the latter cells was found to lead to a decreased susceptibility to infection and cell death induced by each of the ZIKV strains, which was associated with an earlier and stronger antiviral innate immune response in infected, differentiated hNPCs, as compared to undifferentiated cells. Moreover, ZIKV modulated, both in hNPCs and <i>in vivo</i> in fetal brain in an experimental mouse model, the expression of the Notch pathway which is involved in cellular proliferation, apoptosis and differentiation during neurogenesis. These results show that the differentiation state of hNPCs is a significant factor contributing to the outcome of ZIKV infection and furthermore suggest that ZIKV infection might initiate early activation of the Notch pathway resulting in an abnormal differentiation process, implicated in ZIKV-induced brain injury.
DOI: 10.6084/m9.figshare.8798144.v2
title: Zika virus differentially infects human neural progenitor cells according to their state of differentiation and dysregulates neurogenesis through the Notch pathway

description: Zika virus (ZIKV) is a mosquito-borne Flavivirus that causes Zika disease with particular neurological complications, including Guillain-Barré Syndrome and congenital microcephaly. Although ZIKV has been shown to directly infect human neural progenitor cells (hNPCs), thereby decreasing their viability and growth, it is as yet unknown which of the cellular pathways involved in the disruption of neurogenesis are affected following ZIKV infection. By comparing the effect of two ZIKV strains <i>in vitro</i> on hNPCs, the differentiation process of the latter cells was found to lead to a decreased susceptibility to infection and cell death induced by each of the ZIKV strains, which was associated with an earlier and stronger antiviral innate immune response in infected, differentiated hNPCs, as compared to undifferentiated cells. Moreover, ZIKV modulated, both in hNPCs and <i>in vivo</i> in fetal brain in an experimental mouse model, the expression of the Notch pathway which is involved in cellular proliferation, apoptosis and differentiation during neurogenesis. These results show that the differentiation state of hNPCs is a significant factor contributing to the outcome of ZIKV infection and furthermore suggest that ZIKV infection might initiate early activation of the Notch pathway resulting in an abnormal differentiation process, implicated in ZIKV-induced brain injury.
DOI: 10.6084/m9.figshare.9735443
title: Metabonomics on <i>Candida albicans</i> indicate the excessive H3K56ac is involved in the antifungal activity of Shikonin

description: Development of antifungal agents with novel mechanism and low toxicity are essential due to the prevalence of the infectious diseases caused by <i>Candida albicans</i>. The current study employed a new research method, which combined the ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry and gas chromatography-mass spectrometry, to investigate the intrinsic mechanism of Shikonin (SK) against <i>C. albicans</i>. The levels of 27 metabolites, which mainly involved in histone deacetylation, amino acid synthesis, lipid synthesis, nitrogen metabolism, tricarboxylic acid cycle, oxidative stress and glycolysis, were remarkably changed upon SK treatment. Specially, the down-regulation of nicotinamide (NAM) upon SK treatment indicated the suppression of the deacetylation of the histone H3 on lysine 56 residue (H3K56). Further experiment confirmed that the level of H3K56 acetylation (H3K56ac) was dramatically increased upon SK treatment which was mediated by <i>HST3</i>, the gene encoding the H3K56 deacetylase (Hst3p). Our results demonstrated that SK is the first natural compound reported to execute antifungal activity directly via boosting H3K56ac mediated by <i>HST3</i>. Importantly, this finding shed new light on the mechanisms to relieve the side effects or reverse the drug tolerance, as well as the development of agents for antifungal therapies.
DOI: 10.6084/m9.figshare.9735443.v2
title: Metabonomics on <i>Candida albicans</i> indicate the excessive H3K56ac is involved in the antifungal activity of Shikonin

description: Development of antifungal agents with novel mechanism and low toxicity are essential due to the prevalence of the infectious diseases caused by <i>Candida albicans</i>. The current study employed a new research method, which combined the ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry and gas chromatography-mass spectrometry, to investigate the intrinsic mechanism of Shikonin (SK) against <i>C. albicans</i>. The levels of 27 metabolites, which mainly involved in histone deacetylation, amino acid synthesis, lipid synthesis, nitrogen metabolism, tricarboxylic acid cycle, oxidative stress and glycolysis, were remarkably changed upon SK treatment. Specially, the down-regulation of nicotinamide (NAM) upon SK treatment indicated the suppression of the deacetylation of the histone H3 on lysine 56 residue (H3K56). Further experiment confirmed that the level of H3K56 acetylation (H3K56ac) was dramatically increased upon SK treatment which was mediated by <i>HST3</i>, the gene encoding the H3K56 deacetylase (Hst3p). Our results demonstrated that SK is the first natural compound reported to execute antifungal activity directly via boosting H3K56ac mediated by <i>HST3</i>. Importantly, this finding shed new light on the mechanisms to relieve the side effects or reverse the drug tolerance, as well as the development of agents for antifungal therapies.
DOI: 10.6084/m9.figshare.9735443.v3
title: Metabonomics on <i>Candida albicans</i> indicate the excessive H3K56ac is involved in the antifungal activity of Shikonin

description: Development of antifungal agents with novel mechanism and low toxicity are essential due to the prevalence of the infectious diseases caused by <i>Candida albicans</i>. The current study employed a new research method, which combined the ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry and gas chromatography-mass spectrometry, to investigate the intrinsic mechanism of Shikonin (SK) against <i>C. albicans</i>. The levels of 27 metabolites, which mainly involved in histone deacetylation, amino acid synthesis, lipid synthesis, nitrogen metabolism, tricarboxylic acid cycle, oxidative stress and glycolysis, were remarkably changed upon SK treatment. Specially, the down-regulation of nicotinamide (NAM) upon SK treatment indicated the suppression of the deacetylation of the histone H3 on lysine 56 residue (H3K56). Further experiment confirmed that the level of H3K56 acetylation (H3K56ac) was dramatically increased upon SK treatment which was mediated by <i>HST3</i>, the gene encoding the H3K56 deacetylase (Hst3p). Our results demonstrated that SK is the first natural compound reported to execute antifungal activity directly via boosting H3K56ac mediated by <i>HST3</i>. Importantly, this finding shed new light on the mechanisms to relieve the side effects or reverse the drug tolerance, as well as the development of agents for antifungal therapies.
DOI: 10.6084/m9.figshare.7937375
title: Genomic epidemiology of erythromycin-resistant <i>Bordetella pertussis</i> in China

description: Macrolides such as erythromycin are the empirical treatment of <i>Bordetella pertussis</i> infections. China has experienced an increase in erythromycin-resistant <i>B. pertussis</i> isolates since they were first reported in 2013. Here, we undertook a genomic study on Chinese <i>B. pertussis</i> isolates from 2012 to 2015 to elucidate the origins and phylogenetic relationships of erythromycin-resistant <i>B. pertussis</i> isolates in China. A total of 167 Chinese <i>B. pertussis</i> isolates were used for antibiotic sensitivity testing and multiple locus variable-number tandem repeat (VNTR) analysis (MLVA). All except four isolates were erythromycin-resistant and of the four erythromycin-sensitive isolates, three were <i>non-ptxP1</i>. MLVA types (MT), MT55, MT104 and MT195 were the predominant types. Fifty of those isolates were used for whole genome sequencing and phylogenetic analysis. Genome sequencing and phylogenetic analysis revealed three independent erythromycin-resistant lineages and all resistant isolates carried a mutation in the 23S rRNA gene. A novel <i>fhaB3</i> allele was found uniquely in Chinese <i>ptxP1</i> isolates and these Chinese <i>ptxP1-ptxA1-fhaB3</i> had a 5-fold higher mutation rate than the global <i>ptxP1-ptxA1 B. pertussis</i> population. Our results suggest that the evolution of Chinese <i>B. pertussis</i> is likely to be driven by selection pressure from both vaccination and antibiotics. The emergence of the new non-vaccine <i>fhaB3</i> allele in Chinese <i>B. pertussis</i> population may be a result of selection from vaccination, whereas the expansion of <i>ptxP1-fhaB3</i> lineages was most likely to be the result of selection pressure from antibiotics. Further monitoring of <i>B. pertussis</i> in China is required to better understand the evolution of the pathogen.
DOI: 10.6084/m9.figshare.7937375.v3
title: Genomic epidemiology of erythromycin-resistant <i>Bordetella pertussis</i> in China

description: Macrolides such as erythromycin are the empirical treatment of <i>Bordetella pertussis</i> infections. China has experienced an increase in erythromycin-resistant <i>B. pertussis</i> isolates since they were first reported in 2013. Here, we undertook a genomic study on Chinese <i>B. pertussis</i> isolates from 2012 to 2015 to elucidate the origins and phylogenetic relationships of erythromycin-resistant <i>B. pertussis</i> isolates in China. A total of 167 Chinese <i>B. pertussis</i> isolates were used for antibiotic sensitivity testing and multiple locus variable-number tandem repeat (VNTR) analysis (MLVA). All except four isolates were erythromycin-resistant and of the four erythromycin-sensitive isolates, three were <i>non-ptxP1</i>. MLVA types (MT), MT55, MT104 and MT195 were the predominant types. Fifty of those isolates were used for whole genome sequencing and phylogenetic analysis. Genome sequencing and phylogenetic analysis revealed three independent erythromycin-resistant lineages and all resistant isolates carried a mutation in the 23S rRNA gene. A novel <i>fhaB3</i> allele was found uniquely in Chinese <i>ptxP1</i> isolates and these Chinese <i>ptxP1-ptxA1-fhaB3</i> had a 5-fold higher mutation rate than the global <i>ptxP1-ptxA1 B. pertussis</i> population. Our results suggest that the evolution of Chinese <i>B. pertussis</i> is likely to be driven by selection pressure from both vaccination and antibiotics. The emergence of the new non-vaccine <i>fhaB3</i> allele in Chinese <i>B. pertussis</i> population may be a result of selection from vaccination, whereas the expansion of <i>ptxP1-fhaB3</i> lineages was most likely to be the result of selection pressure from antibiotics. Further monitoring of <i>B. pertussis</i> in China is required to better understand the evolution of the pathogen.
DOI: 10.6084/m9.figshare.8019968
title: Evaluation of rodent control to fight Lassa fever based on field data and mathematical modelling

description: The Natal multimammate mouse (<i>Mastomys natalensis</i>) is the reservoir host of Lassa virus, an arenavirus that causes Lassa haemorrhagic fever in humans in West Africa. Because no vaccine exists and therapeutic options are limited, preventing infection through rodent control and human behavioural measures is currently considered to be the only option. In order to assess the efficacy of rodent control, we performed a 4-year field experiment in rural Upper Guinea and developed a mathematical model to simulate different control strategies (annual density control, continuous density control, and rodent vaccination). For the field study, rodenticide baits were placed each year in three rural villages, while three other villages were used as controls. Rodents were trapped before and after every treatment and their antibody status and age were determined. Data from the field study were used to parameterize the mathematical model. In the field study, we found a significant negative effect of rodent control on seroprevalence, but this effect was small especially given the effort. Furthermore, the rodent populations recovered rapidly after rodenticide application, leading us to conclude that an annual control strategy is unlikely to significantly reduce Lassa virus spillover to humans. In agreement with this finding, the mathematical model suggests that the use of continuous control or rodent vaccination is the only strategy that could lead to Lassa virus elimination. These field and model results can serve as a guide for determining how long and frequent rodent control should be done in order to eliminate Lassa virus in rural villages.
DOI: 10.6084/m9.figshare.8019968.v2
title: Evaluation of rodent control to fight Lassa fever based on field data and mathematical modelling

description: The Natal multimammate mouse (<i>Mastomys natalensis</i>) is the reservoir host of Lassa virus, an arenavirus that causes Lassa haemorrhagic fever in humans in West Africa. Because no vaccine exists and therapeutic options are limited, preventing infection through rodent control and human behavioural measures is currently considered to be the only option. In order to assess the efficacy of rodent control, we performed a 4-year field experiment in rural Upper Guinea and developed a mathematical model to simulate different control strategies (annual density control, continuous density control, and rodent vaccination). For the field study, rodenticide baits were placed each year in three rural villages, while three other villages were used as controls. Rodents were trapped before and after every treatment and their antibody status and age were determined. Data from the field study were used to parameterize the mathematical model. In the field study, we found a significant negative effect of rodent control on seroprevalence, but this effect was small especially given the effort. Furthermore, the rodent populations recovered rapidly after rodenticide application, leading us to conclude that an annual control strategy is unlikely to significantly reduce Lassa virus spillover to humans. In agreement with this finding, the mathematical model suggests that the use of continuous control or rodent vaccination is the only strategy that could lead to Lassa virus elimination. These field and model results can serve as a guide for determining how long and frequent rodent control should be done in order to eliminate Lassa virus in rural villages.
DOI: 10.6084/m9.figshare.8019968.v3
title: Evaluation of rodent control to fight Lassa fever based on field data and mathematical modelling

description: The Natal multimammate mouse (<i>Mastomys natalensis</i>) is the reservoir host of Lassa virus, an arenavirus that causes Lassa haemorrhagic fever in humans in West Africa. Because no vaccine exists and therapeutic options are limited, preventing infection through rodent control and human behavioural measures is currently considered to be the only option. In order to assess the efficacy of rodent control, we performed a 4-year field experiment in rural Upper Guinea and developed a mathematical model to simulate different control strategies (annual density control, continuous density control, and rodent vaccination). For the field study, rodenticide baits were placed each year in three rural villages, while three other villages were used as controls. Rodents were trapped before and after every treatment and their antibody status and age were determined. Data from the field study were used to parameterize the mathematical model. In the field study, we found a significant negative effect of rodent control on seroprevalence, but this effect was small especially given the effort. Furthermore, the rodent populations recovered rapidly after rodenticide application, leading us to conclude that an annual control strategy is unlikely to significantly reduce Lassa virus spillover to humans. In agreement with this finding, the mathematical model suggests that the use of continuous control or rodent vaccination is the only strategy that could lead to Lassa virus elimination. These field and model results can serve as a guide for determining how long and frequent rodent control should be done in order to eliminate Lassa virus in rural villages.
DOI: 10.6084/m9.figshare.7937375.v2
title: Genomic epidemiology of erythromycin-resistant <i>Bordetella pertussis</i> in China

description: Macrolides such as erythromycin are the empirical treatment of <i>Bordetella pertussis</i> infections. China has experienced an increase in erythromycin-resistant <i>B. pertussis</i> isolates since they were first reported in 2013. Here, we undertook a genomic study on Chinese <i>B. pertussis</i> isolates from 2012 to 2015 to elucidate the origins and phylogenetic relationships of erythromycin-resistant <i>B. pertussis</i> isolates in China. A total of 167 Chinese <i>B. pertussis</i> isolates were used for antibiotic sensitivity testing and multiple locus variable-number tandem repeat (VNTR) analysis (MLVA). All except four isolates were erythromycin-resistant and of the four erythromycin-sensitive isolates, three were <i>non-ptxP1</i>. MLVA types (MT), MT55, MT104 and MT195 were the predominant types. Fifty of those isolates were used for whole genome sequencing and phylogenetic analysis. Genome sequencing and phylogenetic analysis revealed three independent erythromycin-resistant lineages and all resistant isolates carried a mutation in the 23S rRNA gene. A novel <i>fhaB3</i> allele was found uniquely in Chinese <i>ptxP1</i> isolates and these Chinese <i>ptxP1-ptxA1-fhaB3</i> had a 5-fold higher mutation rate than the global <i>ptxP1-ptxA1 B. pertussis</i> population. Our results suggest that the evolution of Chinese <i>B. pertussis</i> is likely to be driven by selection pressure from both vaccination and antibiotics. The emergence of the new non-vaccine <i>fhaB3</i> allele in Chinese <i>B. pertussis</i> population may be a result of selection from vaccination, whereas the expansion of <i>ptxP1-fhaB3</i> lineages was most likely to be the result of selection pressure from antibiotics. Further monitoring of <i>B. pertussis</i> in China is required to better understand the evolution of the pathogen.