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1.
Nucleic Acids Res ; 51(17): 9356-9368, 2023 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-37486777

RESUMO

RIG-I (retinoic acid inducible gene-I) can sense subtle differences between endogenous and viral RNA in the cytoplasm, triggering an anti-viral immune response through induction of type I interferons (IFN) and other inflammatory mediators. Multiple crystal and cryo-EM structures of RIG-I suggested a mechanism in which the C-terminal domain (CTD) is responsible for the recognition of viral RNA with a 5'-triphoshate modification, while the CARD domains serve as a trigger for downstream signaling, leading to the induction of type I IFN. However, to date contradicting conclusions have been reached around the role of ATP in the mechanism of the CARD domains ejection from RIG-I's autoinhibited state. Here we present an application of NMR spectroscopy to investigate changes induced by the binding of 5'-triphosphate and 5'-OH dsRNA, both in the presence and absence of nucleotides, to full length RIG-I with all its methionine residues selectively labeled (Met-[ϵ-13CH3]). With this approach we were able to identify residues on the CTD, helicase domain, and CARDs that served as probes to sense RNA-induced conformational changes in those respective regions. Our results were analyzed in the context of either agonistic or antagonistic RNAs, by and large supporting a mechanism proposed by the Pyle Lab in which CARD release is primarily dependent on the RNA binding event.


Assuntos
Transativadores , Proteína DEAD-box 58/genética , Proteína DEAD-box 58/metabolismo , Interferon Tipo I/genética , Estrutura Terciária de Proteína , RNA de Cadeia Dupla , RNA Viral/genética , RNA Viral/metabolismo , Transdução de Sinais , Transativadores/metabolismo
2.
Thorac Cardiovasc Surg ; 72(1): 63-69, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-36780925

RESUMO

AIM: The aim of this study was to define determinants of length of hospital stay (LOS) longer than mean and recurrence of infection (ROI) after complete healing of patients with deep sternal wound infections (DSWI). PATIENTS AND METHODS: In this observational study, we included 303 patients (155 females and 148 males, with mean age of 68 years) treated from 2016 to 2020 at the Department of Plastic Surgery of the HELIOS Klinik Krefeld, Germany. All patients received extensive necrosectomy, repetitive negative pressure therapy periods, and final transplantation of a pectoral musculocutaneous flap. In the German diagnosis-related group (DRG)-system, the mean inpatient LOS depends on the number of surgical procedures and is longer in those with four or more surgical procedures (DRG IO2B) and shorter in those with fewer procedures (DRGs I02C and I02D). The determinants which have a significant effect on LOS longer than mean and ROI after complete healing were identified by estimating a logistic regression model. The effect of the different calculated determinants was quantified as odds ratio. To measure the discriminant ability of the model between patients, we determined a receiver operating characteristic curve. The fit of the model was quantified by comparing predicted probabilities of the model with empirical probabilities of the data. The goodness of fit was then measured by applying the Hosmer-Lemeshow test. RESULTS: Among patients in DRG IO2B (n = 246), the variable clopidogrel and therapeutic anticoagulation was the most important determinant for a longer LOS, with an odds ratio of 5.83 (95% CI = 0.83/40.80). Female sex and renal insufficiency also prolonged LOS. Applying this analysis to the patients with group DRG groups I02C and I02D (n = 57), none of these parameters were predictive. The variable immunosuppression was the most important determinant for ROI (n = 49) (OR = 4.67; 95% CI = 1.01/21.52). Body mass index also played a role, but with a much smaller influence. CONCLUSION: There are specific risk factors for LOS longer than mean and ROI in patients with DSWI that can be identified on admission. Addressing these risk factors, if possible, could reduce the rate of patients with LOS longer than mean and ROI.


Assuntos
Procedimentos Cirúrgicos Cardíacos , Masculino , Humanos , Feminino , Idoso , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Infecção da Ferida Cirúrgica/diagnóstico , Infecção da Ferida Cirúrgica/cirurgia , Infecção da Ferida Cirúrgica/etiologia , Tempo de Internação , Estudos Retrospectivos , Resultado do Tratamento , Esterno/cirurgia , Fatores de Risco , Músculos
3.
Cancer Invest ; : 1-17, 2023 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-36719061

RESUMO

The SPOT-MAS assay "Screening for the Presence Of Tumor by Methylation And Size" detects the five most common cancers in Vietnam by evaluating circulating tumor DNA in the blood. Here, we validated its performance in a prospective multi-center clinical trial, K-DETEK. Our analysis of 2795 participants from 14 sites across Vietnam demonstrates its ability to detect cancers in asymptomatic individuals with a positive predictive value of 60%, with 83.3% accuracy in detecting tumor location. We present a case report to support further using SPOT-MAS as a complementary method to achieve early cancer detection and provide the opportunity for early treatment.

4.
J Environ Manage ; 335: 117537, 2023 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-36842358

RESUMO

The length of global coastline is about 356 thousand kilometers with various dynamic natural and anthropogenic. Although the number of studies on coastal landscape categorization has been increasing, it is still difficult to distinguish precisely them because the used methods commonly are traditional qualitative ones. With the leverage of remote sensing data and GIS tools, it helps categorize and identify a variety of features on land and water based on multi-source data. The aim of study is using different natural - social profile data obtained from ALOS, NOAA, and multi-temporal Landsat satellite images as input data of the convolutional-neural-network (CvNet) models for coastal landscape classification. Studies used 900 cut-line samples which represent coastal landscapes in Vietnam for training and optimizing CvNet models. As a result, nine coastal landscapes were identified including: deltas, alluvial, mature and young sand dunes, cliff, lagoon, tectonic, karst, and transitional landscapes. Three CvNet models using three different optimizer types classified the landscapes of other 1150 cut-lines in Vietnam with the accuracies about 98% and low loss function value. Excepting dalmatian, karst and delta coastal landscapes, five others distribute heterogeneous along the coasts in Vietnam. Therefore, the evaluation of additional natural components is necessary and CvNet model have ability to update new landscape types in variety of tropical nation as a step toward coastal landscape classification at both national and global scales.


Assuntos
Monitoramento Ambiental , Tecnologia de Sensoriamento Remoto , Vietnã , Monitoramento Ambiental/métodos , Redes Neurais de Computação , Meio Ambiente
5.
NMR Biomed ; 35(11): e4792, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35767281

RESUMO

In 2016, the World Health Organization (WHO) updated the glioma classification by incorporating molecular biology parameters, including low-grade glioma (LGG). In the new scheme, LGGs have three molecular subtypes: isocitrate dehydrogenase (IDH)-mutated 1p/19q-codeleted, IDH-mutated 1p/19q-noncodeleted, and IDH-wild type 1p/19q-noncodeleted entities. This work proposes a model prediction of LGG molecular subtypes using magnetic resonance imaging (MRI). MR images were segmented and converted into radiomics features, thereby providing predictive information about the brain tumor classification. With 726 raw features obtained from the feature extraction procedure, we developed a hybrid machine learning-based radiomics by incorporating a genetic algorithm and eXtreme Gradient Boosting (XGBoost) classifier, to ascertain 12 optimal features for tumor classification. To resolve imbalanced data, the synthetic minority oversampling technique (SMOTE) was applied in our study. The XGBoost algorithm outperformed the other algorithms on the training dataset by an accuracy value of 0.885. We continued evaluating the XGBoost model, then achieved an overall accuracy of 0.6905 for the three-subtype classification of LGGs on an external validation dataset. Our model is among just a few to have resolved the three-subtype LGG classification challenge with high accuracy compared with previous studies performing similar work.


Assuntos
Neoplasias Encefálicas , Glioma , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Glioma/patologia , Humanos , Isocitrato Desidrogenase/genética , Aprendizado de Máquina , Imageamento por Ressonância Magnética/métodos , Mutação/genética , Estudos Retrospectivos
6.
J Reprod Infant Psychol ; : 1-12, 2022 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-35852090

RESUMO

OBJECTIVES: The present study aims to investigate whether each coping style used by Vietnamese people living with infertility diagnosis is associated with specific types of infertility-related stress (IRS). METHODS: In this cross-sectional design study, 997 patients with primary infertility diagnosis from three hospitals and two clinics in three regions of Vietnam completed questionnaire that consisted of Fertility Problem Inventory, the Copenhagen Multi-Centre Psychosocial Infertility and other questions. Four different linear regression analyses were performed on four coping styles. The five types of IRS and covariates were included in these models. FINDINGS: The results show that participants who experience all five types of IRS reported the dominant use of active-avoidance coping, while having four types of IRS, except for social concern, was associated with higher use of meaning-based coping. Utilising active-confronting coping was reported to be the outcome of experiencing increasing need for parenthood and decreasing rejection of child-free lifestyle. Choice of passive-avoidance coping was more common among those with increasing social concern and need for parenthood. Age and educational level impacted infertile people's choice of avoidance coping strategies. CONCLUSIONS: The results provide evidence to understand the direct impact of each type of IRS on infertile people's choice of coping styles to better support them during their individual and family therapy.

7.
BMC Pregnancy Childbirth ; 21(1): 546, 2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34364368

RESUMO

BACKGROUND: Respiratory distress syndrome (RDS) is one of the leading causes of early neonatal morbidity and mortality in late preterm infants (LPIs) worldwide. This matched cohort study aimed to assess how the antenatal dexamethasone use affect the respiratory distress (RD) proportion in preterm newborns between 34 0/7 weeks and 36 6/7 weeks of gestation. METHODS: This was a prospective cohort study on 78 women with singleton pregnancy who were in threatened preterm birth and had not received prior dexamethasone, who were admitted between 34 0/7 weeks and 36 6/7 weeks at Hue University of Medicine and Pharmacy Hospital from June 2018 to May 2020. The matched control group without dexamethasone use included 78 pregnant women diagnosed with threatened late preterm births who were at similar gestational ages and estimated fetal weights as the treatment group. The treatment group received 6 mg intramuscular dexamethasone every 12 h for a total of 4 doses or until delivery. Primary outcome was the rate of neonatal RD. Secondary neonatal outcomes included the need for respiratory support, neonatal intensive care unit (NICU) admission, hypoglycemia, necrotizing enterocolitis, intraventricular hemorrhage, and neonatal death. Statistical analyses were performed by using SPSS software, version 26.0. RESULTS: The proportion of RD in LPI was significantly lower in the treatment group than in the matched control group (10.3% vs. 23.1%, respectively), adjusted Odds Ratio [aOR] 0.29; 95% confidence interval [CI] 0.10 - 0.83 and p = 0.021. Neonatal hypoglycemia was more common in the dexamethasone group than in the matched group (25.6% vs. 12.8%, respectively; aOR, 2.59; 95% CI, 1.06 - 6.33; p = 0.037). There were no significant between-groups differences in the incidence of respiratory support, NICU admission or length of hospital stay. CONCLUSIONS: Administration of antenatal dexamethasone to women at risk for late preterm birth could help to lower the proportion of respiratory distress in late preterm infants.


Assuntos
Dexametasona/administração & dosagem , Glucocorticoides/administração & dosagem , Nascimento Prematuro , Síndrome do Desconforto Respiratório do Recém-Nascido/prevenção & controle , Insuficiência Respiratória/prevenção & controle , Adulto , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Recém-Nascido , Doenças do Recém-Nascido/prevenção & controle , Recém-Nascido Prematuro , Gravidez , Cuidado Pré-Natal , Vietnã/epidemiologia
8.
Biol Conserv ; 255: 108973, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35125500

RESUMO

Emerging infectious diseases are on the rise in many different taxa, including, among others, the amphibian batrachochytrids, the snake fungal disease and the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) virus, responsible for Coronavirus disease 2019 (COVID-19) in mammals. Following the onset of the pandemic linked to COVID-19, eastern Asia has shown strong leadership, taking actions to regulate the trade of potential vector species in several regions. These actions were taken in response to an increase in public awareness, and the need for a quick reaction to mitigate against further pandemics. However, trade restrictions rarely affect amphibians, despite the risk of pathogen transmission, directly, or indirectly through habitat destruction and the loss of vector consumption. Thus, species that help alleviate the risk of zoonoses or provide biological control are not protected. Hence, in view of the global amphibian decline and the risk of zoonoses, we support the current wildlife trade regulations and support measures to safeguard wildlife from overexploitation. The current period of regulation overhaul should be used as a springboard for amphibian conservation. To mitigate risks, we suggest the following stipulations specifically for amphibians. I) Restrictions to amphibian farming in eastern Asia, in relation to pathogen transmission and the establishment of invasive species. II) Regulation of the amphibian pet trade, with a focus on potential vector species. III) Expansion of the wildlife trade ban, to limit the wildlife-human-pet interface. The resulting actions will benefit both human and wildlife populations, as they will lead to a decrease in the risk of zoonoses and better protection of the environment. SIGNIFICANCE STATEMENT: There is an increasing number of emerging infectious diseases impacting all species, including amphibians, reptiles and mammals. The latest threat to humans is the virus responsible for COVID-19, and the resulting pandemic. Countries in eastern Asia have taken steps to regulate wildlife trade and prevent further zoonoses thereby decreasing the risk of pathogens arising from wild species. However, as amphibians are generally excluded from regulations we support specific trade restrictions: I) Restrictions to amphibian farming; II) regulation of the amphibian pet trade; III) expansion of the wildlife trade ban. These restrictions will benefit both human and wildlife populations by decreasing the risks of zoonoses and better protecting the environment.

9.
J Community Health ; 45(6): 1263-1269, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32894387

RESUMO

This study aimed to describe knowledge, attitudes, and practices (KAP) in controlling COVID-19 and some related factors among the Vietnamese population in 2020. A cross-sectional study was conducted involving 1999 participants aged 18-59 years old, through an online questionnaire. The results showed that 92.2% of the participants had a high knowledge level regarding COVID-19 prevention measures, 68.6% had a positive attitude toward COVID-19 prevention measures, and 75.8% practiced all six measures for preventing the spread of the virus. Age, sex, marital status, knowledge, and fear were significantly associated with the practices aimed at COVID-19 prevention. Married people and participants with high levels of knowledge were more likely to practice all preventive measures. In contrast, young people, men, and those who fear COVID-19 were less likely to practice all preventative measures. Good KAP among Vietnamese people could be an important factor in helping authorities gain initial success in containing the coronavirus and COVID-19. In addition to continuously raising and maintaining the community's awareness, attitude, and practices in disease prevention, the introduction and strict implementation of sanctions and regulations were also important in ensuring good practices were implemented and sustained over time. Groups with lower KAP levels should be provided with more information and support to promote appropriate disease prevention practices.


Assuntos
Controle de Doenças Transmissíveis , Infecções por Coronavirus/prevenção & controle , Conhecimentos, Atitudes e Prática em Saúde , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Adolescente , Adulto , Betacoronavirus , COVID-19 , Estudos Transversais , Feminino , Humanos , Masculino , Estado Civil , Pessoa de Meia-Idade , SARS-CoV-2 , Inquéritos e Questionários , Vietnã , Adulto Jovem
10.
Int J Equity Health ; 18(1): 128, 2019 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-31420044

RESUMO

BACKGROUND: The newborn and child death associated with inadequate post-natal health checks continued to be a significant issue across the world. This study aimed to assess the socioeconomic inequalities in post-natal health checks for the newborn in Vietnam in 2014. METHODS: We used the secondary data from the Multiple Indicator Cluster Survey in 2014. We included women aged 15-49 years who had a live birth within two years of the time of the interview. We estimated the concentration index to measure socioeconomic inequalities post-natal health checks for the newborn. We conducted multiple logistic regression analysis to identify factors associated with post-natal health checks for the newborn. RESULTS: Overall, the proportion of post-natal health checks for the newborn in Vietnam was 89.1%. The concentration index of post-natal health checks for the newborn was positive at 0.06. It indicated that the newborns in the rich households were more likely to get post-natal health checks as compared to in the poor households. The common factors significantly associated with the higher percentage of post-natal health checks for the newborn were women belonging to the Kinh and Hoa ethnic, higher education, and wealthier groups. CONCLUSION: Socioeconomic inequalities in post-natal health checks for the newborn in Vietnam were not strong, but it still existed. Thus, we recommended that policy efforts to increase access to post-natal health services for poor women. In addition, there is a need to improve access to post-natal health services for women belonging to minor ethnic group and low education.


Assuntos
Acessibilidade aos Serviços de Saúde , Disparidades em Assistência à Saúde , Cuidado Pós-Natal , Pobreza , Classe Social , Adolescente , Adulto , Etnicidade/estatística & dados numéricos , Características da Família , Feminino , Humanos , Recém-Nascido , Modelos Logísticos , Pessoa de Meia-Idade , Fatores Socioeconômicos , Inquéritos e Questionários , Vietnã , Adulto Jovem
11.
Surgeon ; 17(3): 127-132, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31003870

RESUMO

BACKGROUND: Patients undergoing non-cardiac surgery are at risk for peri-operative major cardiac events (PMCEs). The most common risk assessment tool is Revised Cardiac Risk Index (RCRI). N-terminal pro-brain natriuretic peptide (NT-proBNP) measured peri-operatively has prognostic information but the implication is uncertain. This study aimed to determine the accuracy of combining NT-proBNP and RCRI in predicting the PMCE in major non-cardiac surgery. METHODS: We performed a prospective cohort study to include non-cardiac surgical patients with moderate or high risk. PMCE included myocardial infarction, pulmonary edema, severe cardiac arrhythmias, and cardiac death occurring within 30 days post-operatively. Logistic regression models and the receiver operating characteristic (ROC) curves were used to determine the discriminative ability of NT-proBNP alone or incorporation with RCRI or its components in predicting PMCE. RESULTS: A total of 366 patients was included in the study with 48 PMCEs. When predicting PMCE, the area under the ROC curve (AUC) (95%-CI) of NT-proBNP alone and NT-proBNP incorporated with RCRI were 0.875 (0.819-0.932) and 0.882 (0.827-0.937), respectively. When incorporating NT-proBNP with the RCRI's components, the best four chosen models had the AUCs between 0.879 and 0.891. All these AUCs were not significantly different with the AUC of NT-proBNP alone. CONCLUSIONS: Higher preoperative NT-proBNP level leads to the increased risk of PMCE in patients undergoing non-cardiac surgery. Compared to NT-proBNP alone, the combination of NT-proBNP with the RCRI and other factors does not improve the accuracy in predicting PMCE. Future large studies are required to build a more accurate risk score.


Assuntos
Regras de Decisão Clínica , Cardiopatias/diagnóstico , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Complicações Pós-Operatórias/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Feminino , Cardiopatias/sangue , Cardiopatias/etiologia , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/etiologia , Período Pré-Operatório , Prognóstico , Estudos Prospectivos , Curva ROC , Medição de Risco , Fatores de Risco , Adulto Jovem
12.
Mol Phylogenet Evol ; 124: 162-171, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29530499

RESUMO

Southeast Asia and southern China (SEA-SC) harbor a highly diverse and endemic flora and fauna that is under increasing threat. An understanding of the biogeographical history and drivers of this diversity is lacking, especially in some of the most diverse and threatened groups. The Asian leaf-litter frog genus Leptolalax Dubois 1980 is a forest-dependent genus distributed throughout SEA-SC, making it an ideal study group to examine specific biogeographic hypotheses. In addition, the diversity of this genus remains poorly understood, and the phylogenetic relationships among species of Leptolalax and closely related Leptobrachella Smith 1928 remain unclear. Herein, we evaluate species-level diversity based on 48 of the 53 described species from throughout the distribution of Leptolalax. Molecular analyses reveal many undescribed species, mostly in southern China and Indochina. Our well-resolved phylogeny based on multiple nuclear DNA markers shows that Leptolalax is not monophyletic with respect to Leptobrachella and, thus, we assign the former to being a junior synonym of the latter. Similarly, analyses reject monophyly of the two subgenera of Leptolalax. The diversification pattern of the group is complex, involving a high degree of sympatry and prevalence of microendemic species. Northern Sundaland (Borneo) and eastern Indochina (Vietnam) appear to have played pivotal roles as geographical centers of diversification, and paleoclimatic changes and tectonic movements seem to have driven the major divergence of clades. Analyses fail to reject an "upstream" colonization hypothesis, and, thus, the genus appears to have originated in Sundaland and then colonized mainland Asia. Our results reveal that both vicariance and dispersal are responsible for current distribution patterns in the genus.


Assuntos
Anuros/classificação , Biodiversidade , Filogenia , Animais , Ásia , Sequência de Bases , Teorema de Bayes , Filogeografia , Especificidade da Espécie , Fatores de Tempo
13.
Nat Mater ; 15(6): 640-6, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26974410

RESUMO

Molybdenum sulfides are very attractive noble-metal-free electrocatalysts for the hydrogen evolution reaction (HER) from water. The atomic structure and identity of the catalytically active sites have been well established for crystalline molybdenum disulfide (c-MoS2) but not for amorphous molybdenum sulfide (a-MoSx), which exhibits significantly higher HER activity compared to its crystalline counterpart. Here we show that HER-active a-MoSx, prepared either as nanoparticles or as films, is a molecular-based coordination polymer consisting of discrete [Mo3S13](2-) building blocks. Of the three terminal disulfide (S2(2-)) ligands within these clusters, two are shared to form the polymer chain. The third one remains free and generates molybdenum hydride moieties as the active site under H2 evolution conditions. Such a molecular structure therefore provides a basis for revisiting the mechanism of a-MoSx catalytic activity, as well as explaining some of its special properties such as reductive activation and corrosion. Our findings open up new avenues for the rational optimization of this HER electrocatalyst as an alternative to platinum.

14.
Bioorg Med Chem Lett ; 27(23): 5349-5352, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29056248

RESUMO

(2'R)-Ethynyl uridine 3, and its (2'S)-diastereomer 10, are synthesised in a divergent fashion from the inexpensive parent nucleoside. Both nucleoside analogues are obtained from a total of 5 simple synthetic steps and 3 trivial column chromatography purifications. To evaluate their effectiveness against HCV NS5B polymerase, the nucleosides were converted to their respective 5'-O-triphosphates. Subsequently, this lead to the discovery of the 2'-ß-ethynyl 18 and -propynyl 20 nucleotides having significantly improved potency over Sofosbuvir triphosphate 24.


Assuntos
Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Nucleosídeos/farmacologia , Uridina/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/síntese química , Antivirais/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Conformação Molecular , Nucleosídeos/síntese química , Nucleosídeos/química , Relação Estrutura-Atividade , Uridina/análogos & derivados , Uridina/química
15.
Nano Lett ; 16(9): 5829-35, 2016 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-27479582

RESUMO

Exploring novel electrode materials is critical for the development of a next-generation rechargeable magnesium battery with high volumetric capacity. Here, we showed that a distinct amorphous molybdenum sulfide, being a coordination polymer of disulfide-bridged (Mo3S11) clusters, has great potential as a rechargeable magnesium battery cathode. This material provided good reversible capacity, attributed to its unique structure with high flexibility and capability of deformation upon Mg insertion. Free-terminal disulfide moiety may act as the active site for reversible insertion and extraction of magnesium.

16.
Microb Pathog ; 95: 175-185, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27057678

RESUMO

Brucella abortus RB51 is an attenuated vaccine strain that has been most frequently used for bovine brucellosis. Although it is known to provide good protection in cattle, it still has some drawbacks including resistance to rifampicin, residual virulence and pathogenicity in humans. Thus, there has been a continuous interest on new safe and effective bovine vaccine candidates. In the present study, we have constructed unmarked mutants by deleting singly cydD and cydC genes, which encode ATP-binding cassette transporter proteins, from the chromosome of the virulent Brucella abortus isolate from Korean cow (referred to as IVK15). Both IVK15ΔcydD and ΔcydC mutants showed increased sensitivity to metal ions, hydrogen peroxide and acidic pH, which are mimic to intracellular environment during host infection. Additionally, the mutants exhibited a significant growth defect in RAW264.7 cells and greatly attenuated in mice. Vaccination of mice with either IVK15ΔcydC or IVK15ΔcydD mutant could elicit an anti-Brucella specific immunoglobulin G (IgG) and IgG subclass responses as well as enhance the secretion of interferon-gamma, and provided better protection against challenge with B. abortus strain 2308 than with the commercial B. abortus strain RB51 vaccine. Collectively, these results suggest that both IVK15ΔcydC and IVK15ΔcydD mutants could be an attenuated vaccine candidate against B. abortus.


Assuntos
Transportadores de Cassetes de Ligação de ATP/deficiência , Vacinas Bacterianas/imunologia , Brucella abortus/imunologia , Brucella abortus/patogenicidade , Brucelose Bovina/prevenção & controle , Fatores de Virulência/deficiência , Animais , Anticorpos Antibacterianos/sangue , Carga Bacteriana , Vacinas Bacterianas/administração & dosagem , Vacinas Bacterianas/genética , Brucella abortus/genética , Brucella abortus/isolamento & purificação , Brucelose Bovina/imunologia , Bovinos , Modelos Animais de Doenças , Deleção de Genes , Imunoglobulina G/sangue , Interferon gama/metabolismo , Leucócitos Mononucleares/imunologia , Macrófagos/imunologia , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Células RAW 264.7 , Baço/microbiologia , Baço/patologia , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/genética , Vacinas Atenuadas/imunologia , Virulência
17.
Bioorg Med Chem Lett ; 26(6): 1529-1535, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26898814

RESUMO

MK-4256, a tetrahydro-ß-carboline sstr3 antagonist, was discontinued due to a cardiovascular (CV) adverse effect observed in dogs. Additional investigations revealed that the CV liability (QTc prolongation) was caused by the hERG off-target activity of MK-4256 and was not due to sstr3 antagonism. In this Letter, we describe our extensive SAR effort at the C3 position of the tetrahydro-ß-carboline structure. This effort resulted in identification of 5-fluoro-pyridin-2-yl as the optimal substituent on the imidazole ring to balance sstr3 activity and the hERG off-target liability.


Assuntos
Carbolinas/química , Carbolinas/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Animais , Carbolinas/síntese química , Cães , Relação Dose-Resposta a Droga , Humanos , Camundongos , Estrutura Molecular , Ratos , Relação Estrutura-Atividade
18.
Microbiology (Reading) ; 161(11): 2137-48, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26341622

RESUMO

Brucella abortus attenuated strain RB51 vaccine (RB51) is widely used in prevention of bovine brucellosis. Although vaccination with this strain has been shown to be effective in conferring protection against bovine brucellosis, RB51 has several drawbacks, including residual virulence for animals and humans. Therefore, a safe and efficacious vaccine is needed to overcome these disadvantages. In this study, we constructed several gene deletion mutants (ΔcydC, ΔcydD and ΔpurD single mutants, and ΔcydCΔcydD and ΔcydCΔpurD double mutants) of RB51 with the aim of increasing the safety of the possible use of these mutants as vaccine candidates. The RB51ΔcydC, RB51ΔcydD, RB51ΔpurD, RB51ΔcydCΔcydD and RB51ΔcydCΔpurD mutants exhibited significant attenuation of virulence when assayed in murine macrophages in vitro or in BALB/c mice. A single intraperitoneal immunization with RB51ΔcydC, RB51ΔcydD, RB51ΔcydCΔcydD or RB51ΔcydCΔpurD mutants was rapidly cleared from mice within 3 weeks, whereas the RB51ΔpurD mutant and RB51 were detectable in spleens until 4 and 7 weeks, respectively. Vaccination with a single dose of RB51 mutants induced lower protective immunity in mice than did parental RB51. However, a booster dose of these mutants provided significant levels of protection in mice against challenge with either the virulent homologous B. abortus strain 2308 or the heterologous Brucella canis strain 26. In addition, these mutants were found to induce a mixed but T-helper-1-biased humoral and cellular immune response in immunized mice. These data suggest that immunization with a booster dose of attenuated RB51 mutants provides an attractive strategy to protect against either bovine or canine brucellosis.


Assuntos
Vacina contra Brucelose/imunologia , Brucella abortus/imunologia , Brucella canis/imunologia , Brucelose/prevenção & controle , Imunização Secundária/métodos , Animais , Vacina contra Brucelose/administração & dosagem , Vacina contra Brucelose/efeitos adversos , Vacina contra Brucelose/isolamento & purificação , Brucella abortus/genética , Brucelose/imunologia , Brucelose/microbiologia , Modelos Animais de Doenças , Deleção de Genes , Imunidade Celular , Imunidade Humoral , Injeções Intraperitoneais , Macrófagos/imunologia , Macrófagos/microbiologia , Camundongos Endogâmicos BALB C , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/efeitos adversos , Vacinas Atenuadas/imunologia , Vacinas Atenuadas/isolamento & purificação , Virulência , Fatores de Virulência/genética
19.
Microb Pathog ; 79: 1-7, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25546140

RESUMO

In the present study, transposon mutagenesis was used to further attenuate Brucella abortus RB51 vaccine strain. Two purD and purF mutants were constructed, characterized and evaluated for attenuation via intracellular survival in murine macrophage-like RAW264.7 and HeLa cells, and by clearance in BALB/c mice. The purD and purF mutants showed significantly decreased intracellular survival, and complementation of these mutants with intact copies of purD or purF genes of RB51 strain was able to restore these defects. In addition, the pur mutants presented significantly lowered persistence in mice. Immunization with purD and purF mutants protected mice against a challenge with the virulent B. abortus strain 544 at a level similar to that of the parent RB51. These data suggest that genes encoding the early stages of purine biosynthesis (purD and purF) are required for intracellular survival and virulence of B. abortus.


Assuntos
Brucella abortus/crescimento & desenvolvimento , Brucelose/microbiologia , Células Epiteliais/microbiologia , Macrófagos/microbiologia , Mutação , Fatores de Virulência/metabolismo , Animais , Vias Biossintéticas/genética , Brucella abortus/genética , Brucella abortus/metabolismo , Brucelose/patologia , Linhagem Celular , Elementos de DNA Transponíveis , Modelos Animais de Doenças , Teste de Complementação Genética , Camundongos Endogâmicos BALB C , Mutagênese Insercional , Purinas/biossíntese , Virulência , Fatores de Virulência/genética
20.
Microbiol Immunol ; 59(5): 262-7, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25683557

RESUMO

Vibrio cholerae non-O1, non-O139 (VC_NAG) organisms are universally present in the aquatic environment and regarded as non-pathogenic bacteria. However, considering that they do occasionally induce gastroenteritis, a study of their virulence and antibiotic resistance genes is important. The presence of enteropathogenic genes, including ctxA, VC_NAG-specific heat-stable toxin gene (st), hemolysin (hly), and zona occludens toxin (zot) was determined by PCR in 100 VC_NAG strains isolated in southern Vietnam in 2010-2013 from 94 environmental and six human origins. These 100 VC_NAG strains were also tested phenotypically and genotypically for the presence of the New Delhi metallo-ß-lactamase (NDM-1). Of the 100 VC_NAG strains tested, six were positive for ctxA; five from the environment and one of human origin. The st gene was detected in 17 isolates, 15 and two of which were of environmental and human origins, respectively. Gene hly was detected in 19 VC_NAG strains examined, two of which were isolated from humans and 17 from environments. The zot gene was not detected in any of the strains tested. Three VC_NAG strains of environmental origin were confirmed to produce NDM-1 and the blaNDM-1 gene was detected in those strains by PCR. Of note, one of the three NDM-1-producing VC_NAG strains was confirmed to carry ctxA, st and hly genes concurrently. This is the first report of isolation of NDM-1-producing VC_NAG strains in Vietnam.


Assuntos
Proteínas de Bactérias/genética , Toxina da Cólera/genética , Enterotoxinas/genética , Proteínas Hemolisinas/genética , Vibrio cholerae não O1/enzimologia , Vibrio cholerae não O1/isolamento & purificação , beta-Lactamases/metabolismo , Cólera/microbiologia , DNA Bacteriano/genética , Endotoxinas , Microbiologia Ambiental , Genótipo , Humanos , Testes de Sensibilidade Microbiana , Reação em Cadeia da Polimerase , Vibrio cholerae não O1/genética , Vietnã , beta-Lactamases/genética
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