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OBJECTIVES: Children with congenital tracheal stenosis born in the developing world face a high risk of mortality due to limited access to proper treatment. Patients who required preoperative respiratory support were suspected to have poor survival after slide tracheoplasty; however, this was not clearly demonstrated in the previous studies. This study aims to investigate the impact of preoperative respiratory conditions on outcomes of slide tracheoplasty. METHODS: From 2016 to 2022, children who underwent slide tracheoplasty were retrospectively reviewed. Patients with respiratory distress requiring emergency operations (group A) were compared with patients in stable condition who were scheduled for surgery (group B). RESULTS: Perioperative results revealed that group A (n = 43) had a longer bypass time (P < 0.001), operation time (P = 0.01), postoperative ventilation time (P < 0.001) and length of intensive care unit stay (P = 0.00125) than group B (n = 60). The early mortality rate was 7.8%, and the actuarial 5-year survival rate was 85.3%. The cumulative incidence test revealed that group A was highly significant for overall mortality [sudistribution (SHR) 4.5; 95% confidence interval (CI) 1.23-16.4; P = 0.023]. Risk factors for overall mortality were prolonged postoperative ventilation time (hazard ratio 3.86; 95% CI 1.20-12.48; P = 0.024), bronchial stenosis (hazard ratio 5.77; 95% CI 1.72-19.31; P = 0.004), and preoperative tracheal mucositis (hazard ratio 5.67; 95% CI 1.51-21.31; P = 0.01). Four patients needed reintervention during a follow-up of 28.4 months (interquartile range 15.3-47.3). CONCLUSIONS: Preoperative respiratory distress negatively affected the outcomes of patients who required slide tracheoplasty. Therefore, early detection of congenital tracheal stenosis and aggressive slide tracheoplasty are crucial and obligatory to enhance long-term survival in this lethal congenital airway disease.
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Traqueia , Estenose Traqueal , Humanos , Estudos Retrospectivos , Feminino , Masculino , Estenose Traqueal/cirurgia , Estenose Traqueal/congênito , Estenose Traqueal/mortalidade , Traqueia/cirurgia , Traqueia/anormalidades , Recém-Nascido , Lactente , Resultado do Tratamento , Procedimentos de Cirurgia Plástica/métodos , Fatores de Risco , Pré-EscolarRESUMO
Tembusu virus (TMUV) is an important infectious disease, causing economic losses in duck production. Since the first report of TMUV infection in Vietnam in 2020, the disease has persisted and affected poultry production in the country. This study conducted epidemiological and genetic characterization of the viral strains circulating in north Vietnam based on 130 pooled tissue samples collected in six provinces/cities during 2021. The TMUV genome was examined using conventional PCR. The results indicated that 21 (16.15%) samples and 9 (23.68%) farms were positive for the viral genome. The positive rate was 59.26% for ducks at ages 2-4 weeks, which was significantly higher than for ducks at ages >4 weeks and < 2 weeks. Genetic analysis of the partial envelope gene (891 bp) sequences indicated that the five Vietnamese TMUVs shared 99.55-100% nucleotide identity, while the rates were in the range 99.59-100% based on the pre-membrane gene sequences (498 bp). The five Vietnamese TMUV strains obtained formed a novel single subcluster. These strains were closely related to Chinese strains and differed from the vaccine strain, suggesting that Vietnamese TMUV strains were field viruses. It needs to be further studied on vaccine development to prevent effects of TMUV infection on poultry production across Vietnam.
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Hypervirulent Klebsiella pneumoniae (hvKp) is a significant cause of severe invasive infections in Vietnam, yet data on its epidemiology, population structure and dynamics are scarce. We screened hvKp isolates from patients with bloodstream infections (BSIs) at a tertiary infectious diseases hospital in Vietnam and healthy individuals, followed by whole genome sequencing and plasmid analysis. Among 700 BSI-causing Kp strains, 100 (14.3%) were hvKp. Thirteen hvKp isolates were identified from 350 rectal swabs of healthy adults; none from 500 rectal swabs of healthy children. The hvKp isolates were genetically diverse, encompassing 17 sequence types (STs), predominantly ST23, ST86 and ST65. Among the 113 hvKp isolates, 14 (12.6%) carried at least one antimicrobial resistance (AMR) gene, largely mediated by IncFII, IncR, and IncA/C plasmids. Notably, the acquisition of AMR conjugative plasmids facilitated horizontal transfer of the non-conjugative virulence plasmid between K. pneumoniae strains. Phylogenetic analysis demonstrated hvKp isolates from BSIs and human carriage clustered together, suggesting a significant role of intestinal carriage in hvKp transmission. Enhanced surveillance is crucial to understand the factors driving intestinal carriage and hvKp transmission dynamics for informing preventive measures. Furthermore, we advocate the clinical use of our molecular assay for diagnosing hvKp infections to guide effective management.
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Infecções por Klebsiella , Klebsiella pneumoniae , Filogenia , Plasmídeos , Sequenciamento Completo do Genoma , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/patogenicidade , Klebsiella pneumoniae/isolamento & purificação , Vietnã/epidemiologia , Humanos , Plasmídeos/genética , Infecções por Klebsiella/epidemiologia , Infecções por Klebsiella/microbiologia , Virulência/genética , Adulto , Feminino , Transferência Genética Horizontal , Masculino , Genoma Bacteriano , Pessoa de Meia-Idade , Antibacterianos/farmacologia , Criança , Genômica , Farmacorresistência Bacteriana/genéticaRESUMO
Snakebite envenoming is a major global public health concern for which improved therapies are urgently needed. The antigenic diversity present in snake venom toxins from various species presents a considerable challenge to the development of a universal antivenom. Here, we used a synthetic human antibody library to find and develop an antibody that neutralizes long-chain three-finger α-neurotoxins produced by numerous medically relevant snakes. Our antibody bound diverse toxin variants with high affinity, blocked toxin binding to the nicotinic acetylcholine receptor in vitro, and protected mice from lethal venom challenge. Structural analysis of the antibody-toxin complex revealed a binding mode that mimics the receptor-toxin interaction. The overall workflow presented is generalizable for the development of antibodies that target conserved epitopes among antigenically diverse targets, and it offers a promising framework for the creation of a monoclonal antibody-based universal antivenom to treat snakebite envenoming.
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Antivenenos , Mordeduras de Serpentes , Humanos , Animais , Camundongos , Antivenenos/química , Mordeduras de Serpentes/tratamento farmacológico , Neurotoxinas/toxicidade , Anticorpos Amplamente Neutralizantes , Venenos de SerpentesRESUMO
Cats normally play a role of the definitive host in which the plerocercoid (sparganum), the second larval form of Spirometra spp., develops into an adult in the intestines. However, some cases of cats with visceral or subcutaneous sparganosis were sporadically reported worldwide. We herein documented the discovery of a sparganum in abdominal cavity of a domestic cat during a surgery of dystocia. The larva was molecularly identified as Spirometra mansoni, belonging to Type I, that was recently misidentified to be S. erinaceieuropaei in several Asian countries. This is the first report for sparganum of S. mansoni in the cat. The future study is necessary to provide further insights into the species of Spirometra causing sparganosis and spirometrosis in humans and other animals.
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Cavidade Abdominal , Doenças do Gato , Esparganose , Spirometra , Humanos , Animais , Gatos , Spirometra/genética , Plerocercoide/genética , Esparganose/diagnóstico , Esparganose/epidemiologia , Esparganose/veterinária , Vietnã , Larva , Doenças do Gato/diagnósticoRESUMO
Fat-soluble vitamins (vitamin A, D, E, and K) assume a pivotal role in maintaining human homeostasis by virtue of their enzymatic functions. The daily inclusion of these vitamins is imperative to the upkeep of various physiological processes including vision, bone health, immunity, and protection against oxidative stress. Current research highlights fat-soluble vitamins as potential therapeutics for human diseases, especially cancer. Fat-soluble vitamins exert their therapeutic effects through multiple pathways, including regulation of matrix metalloproteinases' (MMPs) expression and enzymatic activity. As MMPs have been reported to be involved in the pathology of various diseases, such as cancers, cardiovascular diseases, and neurological disorders, regulating the expression and/or activity of MMPs could be considered as a potent therapeutic strategy. Here, we summarize the properties of fat-soluble vitamins and their potential as promising candidates capable of effectively modulating MMPs through multiple pathways to treat human diseases.
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Doenças Cardiovasculares , Vitamina A , Humanos , Vitamina A/farmacologia , Metaloproteinase 2 da Matriz , Vitaminas/uso terapêutico , Vitamina K , Doenças Cardiovasculares/tratamento farmacológico , Vitamina D/uso terapêutico , Vitamina ERESUMO
African swine fever (ASF) is a lethal and highly contagious transboundary animal disease with the potential for rapid international spread. Currently, there is no ASF vaccine commercially available. All infected animals must be isolated and culled immediately upon the confirmation of the presence of the virus. Studies leading to the rational development of protective ASF vaccines are urgently needed. Here, we generated a safe and efficacious live-attenuated vaccine (LAV) VNUA-ASFV-LAVL2 by serially passaging a field isolate (VNUA-ASFV-05L1, genotype II) in porcine alveolar macrophages (PAMs, 65 passages) and an immortalized porcine alveolar macrophage cell line (3D4/21, 55 passages). VNUA-ASFV-LAVL2 can efficiently replicate in both PAMs and 3D4/21 cells. It provides 100% protection, even with the low dose of 102 HAD50, to the vaccinated pigs against the challenge of contemporary pandemic ASFV field isolate. Pigs vaccinated with this LAV in a dose range of 102 to 105 HAD50 remained clinically healthy during both the 28-day observation period of immunization and the 28-day observation period of challenge. VNUA-ASFV-LAVL2 was eliminated from blood by 28 days post-inoculation (DPI), and from feces or oral fluids by 17 DPI. Although the vaccine strain in serum remained a safe and attenuated phenotype after five passages in swine, a reversion-to-virulence study using blood or tissue homogenates at peak viremia will be conducted in the future. ASFV-specific IgG antibodies and significant cellular immunity were detected in vaccinated pigs before the ASFV challenge. These results indicate that the VNUA-ASFV-LAVL2 strain is a safe and efficacious LAV against the genotype II ASFV strain responsible for current ASF outbreaks in Asia.
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Vírus da Febre Suína Africana , Febre Suína Africana , Vacinas Virais , Suínos , Animais , Vacinas Atenuadas , PandemiasRESUMO
Three new minor steroidal glycosides were isolated from the whole plants of Hoya parasitica (Wall. ex Hornem.) Wight. Their structures were further elucidated as 3ß,4α-dihydroxy-5ß-spirost-(25)27-en-1ß-yl O-α-L-arabinopyranoside (1), 3ß-hydroxy-5ß-spirost-25(27)-en-1ß-yl O-α-L-rhamnopyranosyl-(1â2)-ß-D-xylopyranoside (2), and (23S,24S,25S)-3ß,4α,23,24-tetrahydroxy-5ß-spirostan-1ß-yl O-α-L-rhamnopyranosyl-(1â2)-ß-D-fucopyranoside (3) through interpretation of the spectroscopic data (one-dimensional and two-dimensional) and mass spectrometry (HR-ESI-MS). To the best of our knowledge, this is the first report of the isolation of spirostane-type steroidal saponins from the Hoya genus.
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Indoleamine 2,3-dioxygenase (IDO1) is a heme-containing enzyme mainly responsible for the metabolism of tryptophan to kynurenine. To date, the IDO1 inhibitors have been developed intensively for the re-activation of the anticancer immune response. In this report, we designed, and synthesized novel 1,3-dimethyl-6-amino indazole derivatives as IDO1 inhibitors based on the structure of IDO1 active site. We further examined their anticancer activity on hypopharyngeal carcinoma cells (FaDu), squamous cell carcinoma of the oral tongue (YD-15), breast cancer cells (MCF7), and human dental pulp stem cells (HDPSC). Of them, compound N-(4-bromobenzyl)-1,3-dimethyl-1H-indazol-6-amine (7) remarkably suppressed IDO1 expression in a concentration - dependent manner. In addition, 7 was the most potential anticancer compound with inducing apoptosis activity as well as selectively activated extracellular signal-regulated kinases (ERK) in mitogen-activated protein kinase (MAPK) pathways on FaDu cells. Finally, compound 7 suppressed cell mobility in wound healing assay with the reduced expression of matrix metalloproteinase MMP9. Taken together, we believe that 7 is the most promising compound, which may be applied to treatment of hypopharyngeal carcinoma.
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Antineoplásicos , Carcinoma , Humanos , Indazóis/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Triptofano , Indolamina-Pirrol 2,3,-Dioxigenase , Inibidores Enzimáticos/químicaRESUMO
OBJECTIVE: Alcohol abuse can cause developing cirrhosis, even liver cancer. Several single nucleotide polymorphisms (SNPs) of ADH1B, ADH1C, and ALDH2 genes have been reported to be associated with alcohol abuse and alcoholic cirrhosis (ALC). This study investigated the association between three SNPs of ADH1B rs1229984, ADH1C rs698, and ALDH2 rs671 with alcohol abuse and ALC in people living in the Northeast region of Vietnam. METHODS: 306 male participants were recruited including 206 alcoholics (106 ALC, 100 without ALC) and 100 healthy non-alcoholics. Clinical characteristics were collected by clinicians. Genotypes were identified by Sanger sequencing. Chi-Square (χ2) and Fisher-exact tests were used to assess the differences in age and clinical characteristics, Child-Pugh score, frequencies of alleles and genotypes. RESULT: Our data showed that the frequency of ALDH2*1 was significantly higher in alcoholics (88.59%) and ALC groups (93.40%) than that of healthy non-alcoholics (78.50%) with p=0.0009 and non-ALC group (83.50%) with p=0.002, respectively. We detected opposite results when examined ALDH2*2. Frequency of combined genotypes with high acetaldehyde accumulation were significantly lower in alcoholics and ALC group than those of control groups with p=0.005 and p=0.008, respectively. Meanwhile, the proportion of combined genotypes with non-acetaldehyde accumulation were significantly two times higher in the ALC group (19.98%) than those of the non-ALC group (8%) with p=0.035. These combined genotypes showed a decreasing trend in the Child-Pugh score from likely phenotype causing risk for non-acetaldehyde accumulation to high acetaldehyde accumulation. CONCLUSION: The ALDH2*1 allele was found as a risk factor for alcohol abuse and ALC, and combined genotypes of ADH1B rs1229984, ADH1C rs698, and ALDH2 rs671 with non-acetaldehyde accumulation increase ALC risk. In contrast, ALDH2*2 and the genotype combinations related to high acetaldehyde accumulation were protective factors against alcohol abuse and ALC.
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Alcoolismo , Masculino , Humanos , Alcoolismo/genética , Cirrose Hepática Alcoólica/epidemiologia , Cirrose Hepática Alcoólica/genética , Vietnã/epidemiologia , Aldeído-Desidrogenase Mitocondrial/genética , Álcool Desidrogenase/genética , Polimorfismo de Nucleotídeo Único , Genótipo , Acetaldeído , Aldeído Desidrogenase/genética , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/genéticaRESUMO
Family and intergenerational relationships are becoming increasingly important as sources of support and care for the elderly population in rapidly ageing Asian societies. However, this has also raised concerns over reinforcement of cultural preference for sons as a source of old-age security. This paper therefore revisits the question-what determines happiness in old age-by investigating the role of adult children's gender in the context of Thailand, an ageing Asian country with no legacy of sex-preference in fertility. We employ nationally representative data to examine the association between old-age happiness and presence of a co-residing child. Compared to living alone, living with at least one child is found to positively associate with older persons' happiness. However, this result is specific to daughters. Moreover, compared to older men, women systematically benefit from a "daughter effect". Co-residing daughters with university education and those who maintain a good relationship with their parents help explain the positive happiness effect on older persons. Co-residing daughters are also positively linked to reduced loneliness; improved self-rated health; and improved economic conditions of older parents. Our findings suggest that policies that increase human capital of the girl child and enhance family solidarity are likely to have long term intergenerational wellbeing benefits.
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The aim of this study was to determine the accuracy of two-dimensional and three-dimensional transesophageal echocardiography (TEE) in the detection of pannus and thrombus in left mechanical valve obstruction (LMVO) compared with surgical and histopathology findings. Materials and methods: Patients with suspected LMVO on transthoracic echocardiography were enrolled consecutively. All patients underwent two-dimensional and three-dimensional TEE, and open-heart surgery to replace obstructed valves. Macroscopic and microscopic analysis of the excised masses was used as the gold standard for the diagnosis of thrombus and/or pannus. Results: Forty-eight patients [34 women (70.8%), age 49±13 years, New York Heart Association II: 68.8%, New York Heart Association III: 31.2%] were enrolled. In the diagnostic of thrombus, the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of three-dimensional TEE were 89.2, 72.7, 85.4, 91.7, and 66.7%, respectively, compared with those of two-dimensional TEE (42.2, 66.7, 43.8, 95, and 7.1%, respectively). In the diagnosis of pannus, the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of three-dimensional TEE were 53.3, 100, 85.4, 100, and 82.5%, respectively; compared with those of two-dimensional TEE (7.4, 90.5, 43.8, 50, and 43.2%, respectively). Receiver operating characteristic curves depict that the area under the curves of three-dimensional TEE was higher than the area under the curves of two-dimensional TEE in both diagnoses of thrombus and pannus (0.8560 vs. 0.7330, P=0.0427 and 0.8077 vs. 0.5484, P=0.005, respectively). Conclusions: This study indicated that three-dimensional TEE had a higher diagnostic value than two-dimensional TEE in the detection of thrombus and pannus in patients with LMVO, and can be a reliable imaging modality to identify the causes of LMVO.
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The thermo-mechanical response of shock-initiated energetic materials (EMs) is highly influenced by their microstructures, presenting an opportunity to engineer EM microstructures in a "materials-by-design" framework. However, the current design practice is limited, as a large ensemble of simulations is required to construct the complex EM structure-property-performance linkages. We present the physics-aware recurrent convolutional (PARC) neural network, a deep learning algorithm capable of learning the mesoscale thermo-mechanics of EM from a modest number of high-resolution direct numerical simulations (DNS). Validation results demonstrated that PARC could predict the themo-mechanical response of shocked EMs with comparable accuracy to DNS but with notably less computation time. The physics-awareness of PARC enhances its modeling capabilities and generalizability, especially when challenged in unseen prediction scenarios. We also demonstrate that visualizing the artificial neurons at PARC can shed light on important aspects of EM thermos-mechanics and provide an additional lens for conceptualizing EM.
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Nowadays, cancers and dementia, such as Alzheimer's disease, are the most fatal causes of death. Many studies tried to understand the pathogenesis of those diseases clearly and develop a promising way to treat the diseases. Matrix metalloproteinases (MMPs) have been reported to be involved in the pathology of cancers and AD through tumor cell movement and amyloid degradation. Therefore, control of the levels and actions of MMPs, especially MMP-2 and MMP-9, is necessary to care for and/or cure cancer and AD. Various molecules have been examined for their potential application as regulators of MMPs expression and activity. Among the molecules, multiple metal complexes have shown advantages, including simple synthesis, less toxicity and specificity toward MMPs in cancer cells or in the brain. In this review, we summarize the recent studies and knowledge of metal complexes (e.g., Pt-, Ru-, Au-, Fe-, Cu-, Ni-, Zn-, and Sn-complexes) targeting MMPs and their potentials for treating and/or caring the most fatal human diseases, cancers and AD.
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Doença de Alzheimer , Complexos de Coordenação , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Metaloproteinases da Matriz/metabolismo , Encéfalo/metabolismoRESUMO
Scrub typhus is a mite-borne disease caused by the obligately intracellular bacterium Orientia tsutsugamushi. We previously demonstrated that ScaA, an autotransporter membrane protein of O. tsutsugamushi, is commonly shared in various genotypes and involved in adherence to host cells. Here, we identified a mixed-lineage leukemia 5 (MLL5) mammalian trithorax group protein as a host receptor that interacts with ScaA. MLL5, identified by yeast two-hybrid screening, is an alternative splicing variant of MLL5 (vMLL5) which contains 13 exons with additional intron sequences encoding a tentative transmembrane domain. Indeed, vMLL5 is expressed on the plasma membrane as well as in intracellular compartments in eukaryotic cells and colocalized with adherent O. tsutsugamushi. In addition, ScaA-expressing Escherichia coli showed significantly increased adherence to vMLL5-overexpressing cells compared with vector control cells. We mapped the C-terminal region of the passenger domain of ScaA as a ligand for vMLL5 and determined that the Su(var)3-9, Enhancer of zeste, Trithorax (SET) domain of MLL5 is an essential and sufficient motif for ScaA binding. We observed significant and specific inhibition of bacterial adhesion to host cells in competitive inhibition assays using the C-terminal fragment of ScaA or the SET domain of vMLL5. Moreover, immunization with the C-terminal fragment of ScaA provided neutralizing activity and protective immunity against lethal challenge with O. tsutsugamushi as efficiently as vaccination with the whole passenger domain of ScaA. These results indicate that vMLL5 is a novel cellular receptor for ScaA-mediated adhesion of O. tsutsugamushi and facilitates bacterial adhesion to host cells, thereby enhancing bacterial infection. IMPORTANCE O. tsutsugamushi is a mite-borne pathogen that causes scrub typhus. As an obligately intracellular pathogen, its adhesion to and invasion of host cells are critical steps for bacterial growth. However, the molecular basis of the bacterial ligand and host receptor interaction is poorly defined. Here, we identified a splicing variant of MLL5 (vMLL5) as a cellular adhesion receptor of ScaA, an outer membrane autotransporter protein of O. tsutsugamushi. We mapped the interacting domains in the bacterial ligand and host receptor and confirmed their functional interaction. In addition, immunization with the C-terminal region of ScaA, which involves an interaction with the SET domain of vMLL5, not only induces enhanced neutralizing antibodies but also provides protective immunity against lethal challenge with O. tsutsugamushi.
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Orientia tsutsugamushi , Tifo por Ácaros , Animais , Humanos , Processamento Alternativo , Ligantes , Mamíferos/metabolismo , Proteínas de Membrana/metabolismo , Proteína de Leucina Linfoide-Mieloide/genética , Proteína de Leucina Linfoide-Mieloide/metabolismo , Orientia tsutsugamushi/genética , Orientia tsutsugamushi/metabolismo , Tifo por Ácaros/microbiologia , Tifo por Ácaros/prevenção & controle , Sistemas de Secreção Tipo V/metabolismo , Proteínas de Bactérias/metabolismoRESUMO
OBJECTIVE: ADH1B, ADH1C and ALDH2 genes are mainly responsible for alcohol metabolism in the body. Several single nucleotide polymorphisms (SNPs) of these genes have been reported to be associated with alcohol dependence and are considered risk factors for various human diseases. This study aims to identify the prevalence of three SNPs of ADH1B (rs1229984), ADH1C (rs698) and ALDH2 (rs671) in 235 unrelated individuals living in Thai Nguyen province, the northeast region of Vietnam. METHODS: The target genotypes were identified by using PCR direct sequencing, and their frequencies were compared to previous reports. RESULT: Our data showed that allele frequencies of ADH1B*2, ADH1C*2 and ALDH2*2 were 68.8%, 8.3% and 20.4%, respectively. The ADH1B*2 and ADH1C*2 frequencies were similar to those of the Kinh ethnic individuals living in the south region of Vietnam, while the ALDH2*2 frequency was higher. Compared to data from other countries, ADH1B*2 frequency is similar to the Philippines (60.5%) and Mongolia (62.9%) but significantly different from the other populations. The ADH1C*2 frequency is not so different compared to Japanese (5.7%) and Chinese (7.1%) but is quite different in other populations. ALDH2*2 frequency was lower than Japanese (29.3%), Indonesian (30%) and higher than other countries. Regarding the risk of alcoholism, the percentage of Vietnamese people in this study with genotypes related to alcohol dependence is 8.1%. In contrast, the carrier has genotypes protecting against alcoholism with high frequency, 91.9%. Among them, the individuals can cause high acetaldehyde accumulation accounting for 33.2%. CONCLUSION: This study helps to understand the genetic polymorphisms of alcohol metabolism genes in the community living in Thai Nguyen province, northeast of Vietnam, and provides valuable scientific data relating to alcohol consumption behavior as well as public health protection.
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Alcoolismo , Polimorfismo de Nucleotídeo Único , Humanos , Vietnã/epidemiologia , População do Sudeste Asiático , Aldeído-Desidrogenase Mitocondrial/genética , Álcool Desidrogenase/genética , Genótipo , Aldeído Desidrogenase/genéticaRESUMO
The replication of Ebola virus (EBOV) is dependent upon actin functionality, especially at cell entry through macropinocytosis and at release of virus from cells. Previously, major actin-regulatory factors involved in actin nucleation, such as Rac1 and Arp2/3, were shown important in both steps. However, downstream of nucleation, many other cell factors are needed to control actin dynamics. How these regulate EBOV infection remains largely unclear. Here, we identified the actin-regulating protein, CAPG, as important for EBOV replication. Notably, knockdown of CAPG specifically inhibited viral infectivity and yield of infectious particles. Cell-based mechanistic analysis revealed a requirement of CAPG for virus production from infected cells. Proximity ligation and split-green fluorescent protein reconstitution assays revealed strong association of CAPG with VP40 that was mediated through the S1 domain of CAPG. Overall, CAPG is a novel host factor regulating EBOV infection through connecting actin filament stabilization to viral egress from cells.
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Ebolavirus , Doença pelo Vírus Ebola , Actinas/metabolismo , Ebolavirus/fisiologia , Proteínas de Fluorescência Verde/metabolismo , Humanos , Proteínas dos Microfilamentos/metabolismo , Proteínas Nucleares/metabolismo , Proteínas da Matriz Viral/metabolismo , Liberação de Vírus/fisiologiaRESUMO
Due to the overuse of antibiotics in treatment and regional variation in disease factors, community-acquired pneumonia (CAP) has a relatively high morbidity and mortality rate. This study determined the prevalence of bacteria that cause CAP and the rate of antibiotic resistance. From April 2018 to May 2019, a cross-sectional study was conducted on 254 CAP patients at hospitals and medical centers in the province of Vinh Long. Based on interviews and medical records, SPSS 18.0 was used to analyze the data. CAP-causing bacteria, antibiotic susceptibility, and extended-spectrum ß-lactamase production of bacteria were determined by performing Identification and Antibiotic Susceptibility Testing on sputum specimens using the VITEK 2 Automated instrument. With a total of 254 patients, the age of 60s accounted for the highest prevalence. Streptococcus pneumonia was the leading factor, accounting for 12.6%, followed by Klebsiella pneumonia and Pseudomonas aeruginosa at 12.2% and 8.3%, respectively. The Enterobacteriaceae group was the highest at 36.5%, followed by other gram-negative bacteria (34%) and gram-positive bacteria (29.5%). Amoxicillin/clavulanic acid ranked the highest in antibiotic resistance, accounting for 31.4% of Enterobacteriaceae and 91.7% of non-Enterobacteriaceae. S. pneumonia resisted erythromycin at a high prevalence (84.4%), followed by clindamycin (71.9%) and tetracycline (78.1%). The age of 60s was the leading group in community pneumonia and had increased resistance to amoxicillin/clavulanic acid and cefuroxime.
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Infecções Comunitárias Adquiridas , Pneumonia Pneumocócica , Amoxicilina , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Povo Asiático , Bactérias , Ácido Clavulânico , Infecções Comunitárias Adquiridas/tratamento farmacológico , Infecções Comunitárias Adquiridas/epidemiologia , Infecções Comunitárias Adquiridas/microbiologia , Estudos Transversais , Resistência Microbiana a Medicamentos , Bactérias Gram-Negativas , HumanosRESUMO
The heterodimer of human ubiquitin fusion degradation 1 (hUfd1) and human nuclear protein localization 4 (hNpl4) is a major cofactor of human p97 adenosine triphosphatase (ATPase). The p97-Ufd1-Npl4 complex translocates the ubiquitin-conjugated proteins from the endoplasmic reticulum membrane to the cytoplasm. Ubiquitinated proteins are then degraded by the proteasome. The structures of Npl4 and Ufd1-Npl4 (UN) complex in Saccharomyces cerevisiae have been recently reported; however, the structures of hNpl4 and the human UN complex remain unknown. Here, we report the crystal structures of the human UN complex at a resolution of 2.7 Å and hNpl4 at a resolution of 3.0 Å. We also present atomic details and characterization of the human UN complex. Crystallographic studies and site-directed mutagenesis of the hUfd1 residues involved in the interaction with hNpl4 revealed the atomic details of the two proteins.
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Adenosina Trifosfatases , Proteínas de Saccharomyces cerevisiae , Humanos , Ligação Proteica , Adenosina Trifosfatases/química , Proteínas Nucleares/metabolismo , Ubiquitina/metabolismo , Retículo Endoplasmático/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteína com Valosina/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismoRESUMO
Sphingosine-1-phosphate (S1P) is a potent lipid mediator that is secreted by several cell types. We recently showed that Mfsd2b is an S1P transporter from hematopoietic cells that contributes approximately 50% plasma S1P. Here we report the characterization of compound deletion of Mfsd2b and Spns2, another S1P transporter active primarily in endothelial cells. Global deletion of Mfsd2b and Spns2 (global double knockout [gDKO]) results in embryonic lethality beyond embryonic day 14.5 (E14.5), with severe hemorrhage accompanied by defects of tight junction proteins, indicating that Mfsd2b and Spns2 provide S1P for signaling, which is essential for blood vessel integrity. Compound postnatal deletion of Mfsd2b and Spns2 using Mx1Cre (ctDKO-Mx1Cre) results in maximal 80% reduction of plasma S1P. ctDKO-Mx1Cre mice exhibit severe susceptibility to anaphylaxis, indicating that S1P from Mfsd2b and Spns2 is indispensable for vascular homeostasis. Our results show that S1P export from Mfsd2b and Spns2 is essential for developing and mature vasculature.