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1.
Hum Vaccin Immunother ; : 1-9, 2020 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-32429793

RESUMO

Debate continues regarding the need for a booster vaccination in children who received a universal infant hepatitis B virus (HBV) vaccination. The aim was to explore the need and the strategies for the booster HBV vaccination. 8-year prospective cohort study was conducted among children aged 5-15 years in 2009-2010 in Zhejiang Province. The participants were divided into groups A (<0.1 mIU/mL), B (0.1 to < 1 mIU/mL) and C (1 to <10 mIU/mL) according to the pre-booster anti-HBs antibody levels. 5 µg (group I), 10 µg (group II), 20 µg hepatitis B vaccines (group III) or 5 µg hepatitis A and B (HAB) vaccines (group IV) with 0-1-6-month schedule were randomly administered to children negative for all markers. Blood samples were collected at baseline HBV marker testing, 1 month after the first dose, 1 month, 1 year, 5 years and 8 years after the third dose. Among 4170 children, 2326 (55.8%) were negative for all HBV markers. Group II showed the highest seropositive rates of 92.8%, 99.7%, 97.6%, 90.3% and 83.4% with GMTs of 4194.5 mIU/ml, 4163.9 mIU/ml, 466.9 mIU/ml, 190.6 mIU/ml, 122.6 mIU/ml from 1 month after dose 1 to 8 years after dose 3, respectively (P < .01). Participants in group C showed seropositive rates of 98.9%, 99.9%, 99.5%, 95.5%, 92.8% after the revaccination with GMTs of 6519.6 mIU/ml, 5267.4 mIU/ml, 547.1 mIU/ml, 249.5 mIU/ml, 155.3 mIU/ml, respectively, higher than group A and B (P < .001), except 1 month after the third dose. The 10 µg of HBV vaccine with a 0-1-6-month booster regimen may elicit robust responses and persist for 8 years or longer. Additionally, 1-dose revaccination maybe suitable for children with 1 to < 10 mIU/ml anti-HBs titers.

2.
Circulation ; 2020 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-32441115

RESUMO

Background: Stroke is a leading cause of adult disability that can severely compromise patients' quality of life, yet no effective medication currently exists to accelerate rehabilitation. A variety of circular RNA (circRNAs) molecules are known to function in ischemic brain injury. Lentivirus-based expression systems have been widely used in basic studies of circRNAs, but safety issues with such delivery systems have limited exploration of potential therapeutic roles for circRNAs. Methods: Circular RNA SCMH1 (circSCMH1) was screened from the plasma of acute ischemic stroke (AIS) patients using circRNA microarrays. Engineered RVG-circSCMH1-extracellular vesicles (RVG-circSCMH1-EVs) were generated to selectively deliver circSCMH1 to the brain. Nissl staining was used to examine infarct size. Behavioral tasks were performed to evaluate motor functions in both rodent and nonhuman primate ischemic stroke models. Golgi staining and immunostaining were used to examine neuroplasticity and glial activation. Proteomic assays and RNA-seq data combined with transcriptional profiling were used to identify downstream targets of circSCMH1. Results: CircSCMH1 levels were significantly decreased in plasma of AIS patients, offering significant power in predicting stroke outcomes. The decreased levels of circSCMH1 were further confirmed in the plasma and peri-infarct cortex of photothrombotic (PT) stroke mice. Beyond demonstrating proof-of-concept for an RNA drug delivery technology, we observed that circSCMH1 treatment improved functional recovery post stroke in both mice and monkeys, and discovered that circSCMH1 enhanced the neuronal plasticity and also inhibited glial activation and peripheral immune cell infiltration. Mechanistically, circSCMH1 binds to the transcription factor MeCP2, thereby releasing repression of MeCP2 target gene transcription. Conclusions: RVG-circSCMH1-EVs afford protection by promoting functional recovery in the rodent and the nonhuman primate ischemic stroke models. Our study presents a potentially widely applicable nucleotide drug delivery technology and demonstrates the basic mechanism of how circRNAs can be therapeutically exploited to improve post-stroke outcomes.

4.
Front Immunol ; 11: 518, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32296431

RESUMO

Little is known about how tuberculosis (TB) impairs dendritic cell (DC) function and anti-TB immune responses. We previously showed that the B and T lymphocyte attenuator (BTLA), an immune inhibitory receptor, is involved in TB pathogenesis. Here, we examined whether BTLA expression in TB affects phenotypic and functional aspects of DCs. Active TB patients exhibited higher expression of BTLA in myeloid dendritic cells (mDCs) and plasmacytoid DCs (pDCs) subsets compared with healthy controls (HCs). BTLA expression was similarly high in untreated TB, TB relapse, and sputum-bacillus positive TB, but anti-TB therapy reduced TB-driven increases in frequencies of BTLA+ DCs. BTLA+ DCs in active TB showed decreased expression of the DC maturation marker CD83, with an increased expression of CCR7 in mDCs. BTLA+ DCs in active TB displayed a decreased ability to express HLA-DR and to uptake foreign antigen, with a reduced expression of the co-stimulatory molecule CD80, but not CD86. Functionally, BTLA+ DCs in active TB showed a decreased production of IL-12 and IFN-α as well as a reduced ability to stimulate allogeneic T-cell proliferative responses. BTLA+ mDCs produced larger amounts of IL-4 and TGF-ß than BTLA- mDCs in both HCs and APT patients. BTLA+ DCs from active TB patients showed a reduced ability to stimulate Mtb antigen-driven Th17 and Th22 polarizations as compared to those from HCs. Conversely, these BTLA+ DCs more readily promoted the differentiation of T regulatory cells (Treg) and Th2 than those from HCs. These findings suggest that TB-driven BTLA expression in DCs impairs the expression of functional DC surrogate markers and suppress the ability of DCs to induce anti-TB Th17 and Th22 response while promoting Th2 and Foxp3+ Tregs.

5.
Sci Rep ; 10(1): 6626, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32296079

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

6.
EBioMedicine ; 52: 102660, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32062357

RESUMO

BACKGROUND: Circular RNAs (circRNAs) have been reported to be involved in central nervous system (CNS) diseases and to have a close connection with neuronal development. However, the role of circRNAs in neural stem cell (NSC) differentiation and the treatment of ischaemic stroke remains unknown. METHODS: Ischaemic stroke was induced in mice using transient middle cerebral artery occlusion (tMCAO). NSCs were transducted with circHIPK2 siRNA (si-circHIPK2-NSCs) or vehicle control (si-circCon-NSCs) and microinjected into lateral ventricle of brain at 7 d post-tMCAO. Magnetic resonance imaging (MRI) was used to detect brain damage, and functional deficits were evaluated with sensorimotor behavioural tests. The distribution of the transplanted NSCs was investigated by near-infrared fluorescence imaging (NIF) and immunofluorescence. The neural plasticity of si-circHIPK2-NSCs was verified by western blot and immunofluorescence in vivo and in vitro. FINDINGS: We investigated the role of circHIPK2 in NCS differentiation. In vitro, silencing of circHIPK2 facilitated NSCs directionally differentiated to neurons but had no effect on the differentiation to astrocytes. In vivo, microinjected NSCs could migrate to the ischaemic hemisphere after stroke induction. Si-circHIPK2-NSCs increased neuronal plasticity in the ischaemic brain, conferred long-lasting neuroprotection, and significantly reduced functional deficits. INTERPRETATIONS: Si-circHIPK2 regulates NSC differentiation, and microinjection of si-circHIPK2-NSCs exhibits a promising therapeutic strategy to neuroprotection and functional recovery after stroke. FUNDING: The National Key Research and Development Program of China; the International Cooperation and Exchange of the National Natural Science Foundation of China; the National Natural Science Foundation of China; the Jiangsu Innovation & Entrepreneurship Team Program.

7.
Cell ; 180(4): 655-665.e18, 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32004463

RESUMO

Human endocannabinoid systems modulate multiple physiological processes mainly through the activation of cannabinoid receptors CB1 and CB2. Their high sequence similarity, low agonist selectivity, and lack of activation and G protein-coupling knowledge have hindered the development of therapeutic applications. Importantly, missing structural information has significantly held back the development of promising CB2-selective agonist drugs for treating inflammatory and neuropathic pain without the psychoactivity of CB1. Here, we report the cryoelectron microscopy structures of synthetic cannabinoid-bound CB2 and CB1 in complex with Gi, as well as agonist-bound CB2 crystal structure. Of important scientific and therapeutic benefit, our results reveal a diverse activation and signaling mechanism, the structural basis of CB2-selective agonists design, and the unexpected interaction of cholesterol with CB1, suggestive of its endogenous allosteric modulating role.

8.
Angew Chem Int Ed Engl ; 59(8): 3226-3234, 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-31756258

RESUMO

Pathogenesis hallmarks for tuberculosis (TB) are the Mycobacterium tuberculosis (Mtb) escape from phagolysosomal destruction and limited drug delivery into infected cells. Several nanomaterials can be entrapped in lysosomes, but the development of functional nanomaterials to promote phagolysosomal Mtb clearance remains a big challenge. Here, we report on the bactericidal effects of selenium nanoparticles (Se NPs) against Mtb and further introduce a novel nanomaterial-assisted anti-TB strategy manipulating Ison@Man-Se NPs for synergistic drug-induced and phagolysosomal destruction of Mtb. Ison@Man-Se NPs preferentially entered macrophages and accumulated in lysosomes releasing Isoniazid. Surprisingly, Ison@Man-Se/Man-Se NPs further promoted the fusion of Mtb into lysosomes for synergistic lysosomal and Isoniazid destruction of Mtb. Concurrently, Ison@Man-Se/Man-Se NPs also induced autophagy sequestration of Mtb, evolving into lysosome-associated autophagosomal Mtb degradation linked to ROS-mitochondrial and PI3K/Akt/mTOR signaling pathways. This novel nanomaterial-assisted anti-TB strategy manipulating antimicrobial immunity and Mtb clearance may potentially serve in more effective therapeutics against TB and drug-resistant TB.

9.
Chin J Nat Med ; 17(12): 935-944, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31882049

RESUMO

Bipolarins A-H (1-8), eight new tetracyclic ophiobolin-type sesterterpenes featuring a rare oxaspiro[4.4]nonane moiety, were isolated from cultures of fungus Bipolaris sp. TJ403-B1. Their structures and absolute configurations were elucidated by comprehensive spectroscopic analyses, single-crystal X-ray diffraction experiments, electronic circular dichroism and 13C NMR calculations. Additionally, compound 5 exhibited significant selective antimicrobial activity against Enterococcus faecalis with an MIC value 8 µg·mL-1.


Assuntos
Anti-Infecciosos/química , Ascomicetos/efeitos dos fármacos , Sesterterpenos/química , Anti-Infecciosos/isolamento & purificação , China , Cristalografia por Raios X , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Sesterterpenos/isolamento & purificação , Triticum/microbiologia
10.
Adv Exp Med Biol ; 1206: 199-220, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31776987

RESUMO

Autophagy is an important metabolic pathway of cells. Cells degrade harmful intracellular components with the aid of autophagy to maintain a healthy state. In recent decades, the study of non-coding RNA in the regulation of autophagy has been a hot area. Mounting evidence indicates that many ncRNAs are involved in the dynamic process of autophagy, and further studies were undertaken to dissect the detailed cellular and molecular mechanisms underlying this process. In this chapter, we mainly summarized the regulation of different non-coding RNAs in autophagy as well as the detailed mechanisms. Based on these findings, we also discussed the roles of non-coding RNAs in the diagnosis, treatment, and prognosis of diseases with an emphasis on their use as potential biomarkers and therapeutic targets for different diseases.


Assuntos
Autofagia , RNA Longo não Codificante , Animais , Regulação da Expressão Gênica , Humanos , MicroRNAs , Prognóstico , RNA não Traduzido/genética
11.
Artigo em Inglês | MEDLINE | ID: mdl-31736052

RESUMO

BACKGROUND: Dexmedetomidine is widely used for non-invasive pediatric procedural sedation. However, the hemodynamic effects of intravenous dexmedetomidine are a concern. There has been a growing interest in the application of intranasal dexmedetomidine as a sedative in children. OBJECTIVE: To investigate the incidence of bradycardia in children undergoing intranasal dexmedetomidine sedation and to identify the associated risk factors. METHODS: Data pertaining to pediatric patients who underwent intranasal dexmedetomidine sedation for non-invasive investigations at the Kunming Children's Hospital between October 2017 and August 2018 were retrospectively analyzed. RESULTS: Out of 9984 children who qualified for inclusion, 228 children (2.3%) developed bradycardia. The incidence of bradycardia in the group that received additional dose of dexmedetomidine was higher than that in the group that did not receive additional dose (9.2% vs 16.7%; P = .003). The incidence of bradycardia in males was higher than that in females (2.6% vs 1.8%; P = .007). On multivariate logistic regression, only male gender showed an independent association with the occurrence of bradycardia (odds ratio 1.48; 95% confidence interval 1.11-1.97; P = .008). CONCLUSIONS: The overall incidence of bradycardia in children after sole use of intranasal dexmedetomidine sedation was 2.3%. Male children showed a 1.48-fold higher risk of bradycardia. However, the blood pressure of the children who developed bradycardia was within the normal range. Simple wake-up can effectively manage bradycardia induced by intranasal dexmedetomidine sedation.

12.
Nat Med ; 25(12): 1928-1937, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31768066

RESUMO

Accurate identification of tumor-derived somatic variants in plasma circulating cell-free DNA (cfDNA) requires understanding of the various biological compartments contributing to the cfDNA pool. We sought to define the technical feasibility of a high-intensity sequencing assay of cfDNA and matched white blood cell DNA covering a large genomic region (508 genes; 2 megabases; >60,000× raw depth) in a prospective study of 124 patients with metastatic cancer, with contemporaneous matched tumor tissue biopsies, and 47 controls without cancer. The assay displayed high sensitivity and specificity, allowing for de novo detection of tumor-derived mutations and inference of tumor mutational burden, microsatellite instability, mutational signatures and sources of somatic mutations identified in cfDNA. The vast majority of cfDNA mutations (81.6% in controls and 53.2% in patients with cancer) had features consistent with clonal hematopoiesis. This cfDNA sequencing approach revealed that clonal hematopoiesis constitutes a pervasive biological phenomenon, emphasizing the importance of matched cfDNA-white blood cell sequencing for accurate variant interpretation.


Assuntos
Ácidos Nucleicos Livres/sangue , DNA Tumoral Circulante/sangue , Genômica , Neoplasias/sangue , Adulto , Biomarcadores Tumorais/sangue , DNA Tumoral Circulante/genética , Análise Mutacional de DNA , DNA de Neoplasias/sangue , Feminino , Regulação Neoplásica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Mutação , Neoplasias/genética , Neoplasias/patologia
14.
J Nat Prod ; 82(10): 2897-2906, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31573805

RESUMO

A preliminary phytochemical investigation on the EtOAc extracts of the fungus Bipolaris sp. TJ403-B1 resulted in the identification of 12 ophiobolin-type phytotoxins (1-12), including nine new ones, termed bipolaricins A-I (1-9). The structures of 1-9 were elucidated via spectroscopic data (including HRESIMS and 1D and 2D NMR) and single-crystal X-ray diffraction (Cu Kα) analyses. All of the isolated compounds were tested in terms of HMG-CoA reductase inhibitory, anti-inflammatory, and cytotoxic activities. Compound 10 showed HMG-CoA reductase inhibitory activity (IC50 = 8.4 ± 0.4 µM), and 2, 3, and 10-12 showed significant inhibitory potency against lipopolysaccharide (LPS)-induced nitric oxide production, with IC50 values in the range of 5.1 ± 0.3 to 20 ± 1 µM. Further experiments showed that 10 could significantly inhibit the production of IL-1ß, RANTES, MIP-1ß, and TNF-α as well as enhance the release of IL-13 in macrophages through the inhibition of HO-1 induction as well as the NF-κB pathway. These findings provide a scientific rationale for an anti-inflammatory therapeutic and a template for a new HMG-CoA reductase inhibitor to produce a potential anti-hyperlipidemia agent.

15.
J Grad Med Educ ; 11(5): 521-526, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31636820

RESUMO

Background: The Comprehensive Osteopathic Medical Licensure Examination (COMLEX-USA) Level 2-Cognitive Examination (CE) and the Comprehensive Osteopathic Medical Achievement Test (COMAT) are administered to similar populations (third- and fourth-year osteopathic students) at similar points in time. Examining the relationship between scores on the 2 assessments that measure similar constructs ultimately supports the validity of both. Objective: The purpose of this study is to provide empirical evidence of the concurrent and predictive validity of COMAT and COMLEX-USA Level 2-CE. Methods: In 2018, first-attempt scores on Level 2-CE were aggregated from June 2015 to May 2018 and matched with first-attempt scores on each COMAT clinical subject. We conducted correlational analyses between performance on COMAT and Level 2-CE, and COMAT scores and Level 2-CE discipline subscores. Additionally, we used multivariate regression to analyze the predictive relationship between performance on all COMAT clinical subjects and Level 2-CE. Results: The results from correlational analyses indicated statistically significant, positive associations between COMAT and Level 2-CE scores (r = 0.49-0.68, P < .0001), and statistically significant, but slightly weaker relationships between COMAT scores and Level 2-CE discipline subscores (r = 0.31-0.60, P < .0001). Furthermore, results from the multiple regression indicated that scores on COMAT explained 68% of the variance in Level 2-CE scores, and that COMAT internal medicine and emergency medicine were weighted more heavily than other specialties. Conclusions: The findings from this study can inform assessment practices by supporting the use of COMAT for osteopathic medical schools that do not administer COMAT.

19.
Artigo em Inglês | MEDLINE | ID: mdl-31430997

RESUMO

In order to solve the optimization problem of emergency logistics system, this paper provides an environmental protection point of view and combines with the overall optimization idea of emergency logistics system, where a fuzzy low-carbon open location-routing problem (FLCOLRP) model in emergency logistics is constructed with the multi-objective function, which includes the minimum delivery time, total costs and carbon emissions. Taking into account the uncertainty of the needs of the disaster area, this article illustrates a triangular fuzzy function to gain fuzzy requirements. This model is tackled by a hybrid two-stage algorithm: Particle swarm optimization is adopted to obtain the initial optimal solution, which is further optimized by tabu search, due to its global optimization capability. The effectiveness of the proposed algorithm is verified by the classic database in LRP. What's more, an example of a post-earthquake rescue is used in the model for acquiring reliable conclusions, and the application of the model is tested by setting different target weight values. According to these results, some constructive proposals are propounded for the government to manage emergency logistics and for the public to aware and measure environmental emergency after disasters.


Assuntos
Poluentes Atmosféricos , Poluição do Ar/prevenção & controle , Carbono , Conservação dos Recursos Naturais/métodos , Planejamento em Desastres/métodos , Modelos Teóricos , Poluentes Atmosféricos/economia , Algoritmos , Carbono/economia , China , Conservação dos Recursos Naturais/economia , Custos e Análise de Custo , Planejamento em Desastres/economia , Planejamento em Desastres/organização & administração , Emergências
20.
Stroke Vasc Neurol ; 4(2): 96-98, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31338219

RESUMO

Stroke is the major leading cause of death and serious, long-term disability with major economic consequences. At present, the lack of rapid diagnostic, prognostic biomarkers and effective treatment methods are two major challenges facing stroke. Circular RNAs (circRNAs) are potential clinical biomarkers in central nervous system diseases. However, the potential role of circRNAs in neuroinflammation and neuron functional recovery in acute ischaemic stroke (AIS) remains largely unknown. This review aimed to give an overview of the function of circRNAs in AIS and summarise the latest achievements in this field.

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