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2.
Blood ; 135(1): 41-55, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31697823

RESUMO

To study the mechanisms of relapse in acute lymphoblastic leukemia (ALL), we performed whole-genome sequencing of 103 diagnosis-relapse-germline trios and ultra-deep sequencing of 208 serial samples in 16 patients. Relapse-specific somatic alterations were enriched in 12 genes (NR3C1, NR3C2, TP53, NT5C2, FPGS, CREBBP, MSH2, MSH6, PMS2, WHSC1, PRPS1, and PRPS2) involved in drug response. Their prevalence was 17% in very early relapse (<9 months from diagnosis), 65% in early relapse (9-36 months), and 32% in late relapse (>36 months) groups. Convergent evolution, in which multiple subclones harbor mutations in the same drug resistance gene, was observed in 6 relapses and confirmed by single-cell sequencing in 1 case. Mathematical modeling and mutational signature analysis indicated that early relapse resistance acquisition was frequently a 2-step process in which a persistent clone survived initial therapy and later acquired bona fide resistance mutations during therapy. In contrast, very early relapses arose from preexisting resistant clone(s). Two novel relapse-specific mutational signatures, one of which was caused by thiopurine treatment based on in vitro drug exposure experiments, were identified in early and late relapses but were absent from 2540 pan-cancer diagnosis samples and 129 non-ALL relapses. The novel signatures were detected in 27% of relapsed ALLs and were responsible for 46% of acquired resistance mutations in NT5C2, PRPS1, NR3C1, and TP53. These results suggest that chemotherapy-induced drug resistance mutations facilitate a subset of pediatric ALL relapses.

3.
Nat Metab ; 1(9): 912-926, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31572976

RESUMO

Atherosclerosis is a progressive vascular disease triggered by interplay between abnormal shear stress and endothelial lipid retention. A combination of these and, potentially, other factors leads to a chronic inflammatory response in the vessel wall, which is thought to be responsible for disease progression characterized by a buildup of atherosclerotic plaques. Yet molecular events responsible for maintenance of plaque inflammation and plaque growth have not been fully defined. Here we show that endothelial TGFß signaling is one of the primary drivers of atherosclerosis-associated vascular inflammation. Inhibition of endothelial TGFß signaling in hyperlipidemic mice reduces vessel wall inflammation and vascular permeability and leads to arrest of disease progression and regression of established lesions. These pro-inflammatory effects of endothelial TGFß signaling are in stark contrast with its effects in other cell types and identify it as an important driver of atherosclerotic plaque growth and show the potential of cell-type specific therapeutic intervention aimed at control of this disease.

4.
Ecotoxicol Environ Saf ; 183: 109601, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31509931

RESUMO

The Nanfei River, located in Hefei City, Anhui Province, subjected to increased nutrient loads from point and/or non-point source. Little is known about the indicators indicating heterogeneity of surface sediments. We aimed to identify the suitable indicators that can reflect the sediment heterogeneity by analyzing the sensitivity of sediment physicochemical properties group, microbial communities and diversity indices group and C, N, S-functional genes group to seasonal and regional changes. River sediments from different areas (urban area, urban-rural fringe and rural area) were collected in the level, dry and wet seasons, respectively. The chemical parameters had most significant regional heterogeneity, but no seasonal differences. Seasons had a greater impact on the overall microbial community structure than the areas. Specifically, the relative abundance of Firmicutes and Bacteroidetes were more sensitive to seasonal changes. Overall, seasonal changes showed the greatest impact on the functional genes group, with the S-functional genes (dsrB and aprA) group providing the clearest seasonal variation. Considering the seasonal distribution of functional genes and their sensitivity to environmental factors, we speculated that the sulfate-reducing gene (dsrB), the methanogenic gene (mcrA) and the anammox gene (hzo) could be identified as sensitive indicators to indicate the seasonal heterogeneity of surface sediments in different river sections of the same river in the short term. We also concluded that environmental variables were more conducive to indicating the regional heterogeneity of sediments. This study provided a valuable reference for assessing the heterogeneity or ecological stress of river sediments.


Assuntos
Monitoramento Ambiental/métodos , Sedimentos Geológicos/química , Microbiota/genética , Rios/química , China , Cidades , Atividades Humanas , Humanos , Estações do Ano
5.
J Dermatol ; 46(11): 1024-1026, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31435946

RESUMO

Hailey-Hailey disease (HHD) is a rare autosomal dominant inherited keratosis caused by mutations in ATP2C1. The aim of our study was to identify and analyze the features of the mutations in HHD. We examined 52 Chinese Han cases which were diagnosed as HHD based on their clinical and histological findings. Genomic DNA polymerase chain reaction and direct sequencing of ATP2C1 were performed from peripheral blood samples of the patients and 100 unrelated healthy controls. Twenty-five novel mutations and 14 recurrent mutations were identified, including 11 (28.2%) missense mutations, nine (23.1%) frame-shift deletion mutations, eight (20.5%) nonsense mutations, seven (17.9%) splicing mutations and four (10.3%) frame-shift insertion mutations. Together with ours, all 209 mutations showed a uniform distribution without hotspots or clusters. In addition, there is no specific genotype-phenotype correlation in HHD. Our findings update the spectrum of mutations in ATP2C1.

6.
J Environ Manage ; 248: 109293, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31386990

RESUMO

Studying the composition and structure of bacterial communities in sediments helps to understand the contribution of bacteria to environmental changes and the role of feedback in response to disturbances. However, seasonal changes in bacterial communities of river sediments with different pollution levels and sources have not been clear yet. In this study, we collected sediment samples during the dry season, wet season and level season from 40 sites with various pollution sources in three inflow rivers (Fengle-Hangbu River, Nanfei River and Zhegao River) of Chaohu Lake. Bacterial community compositions were determined based on high-throughput sequencing. The 'Bioenv' in the R package 'Vegan' and redundancy analysis was used to explore the influence of environmental factors on the bacterial community in the river sediments. Results showed that a significant deviation in bacterial communities was found among seasons and rivers. In addition, seasonal dynamics had a greater impact on shaping bacterial communities than rivers with different pollution sources. A higher diversity was found in the wet season as compared to the other seasons. The bacterial diversity was negatively correlated with nutrients (OM, TN, NH4+, IP, OP and TP) and metals (Cu and Zn). Bacterial communities were more sensitive to heavy metals pressure than nutrients. We also concluded that heavy metals (Cu and Cd) were the key contributing factors in explaining variations in bacterial communities. This study provided a valuable reference for assessing ecological stress.


Assuntos
Metais Pesados , Poluentes Químicos da Água , China , Monitoramento Ambiental , Sedimentos Geológicos , Rios , Estações do Ano
7.
BMC Infect Dis ; 19(1): 382, 2019 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-31060582

RESUMO

BACKGROUND: Herpes simplex virus type-2 (HSV-2) infection is the main cause of genital ulcer disease and increases the risk of HIV acquisition. Little information is available regards the epidemiological characteristics of HSV-2 among general population in China. The aim of this study was to explore seroprevalence and associated factors of HSV-2 and provide information for design of HSV-2 control strategy in Shandong, China. METHODS: In this cross-sectional study, a total of 8074 persons, 18-49 years of age, were selected using multi-stage probability sampling to represent the general population of Shandong in 2016. Demographic data were collected through face-to-face interviews. Other variables were obtained by self-administered questionnaire surveys. Blood was collected for HSV-2 IgG detection with ELISA. RESULTS: A total of 7256 sexually-active participants were included in the analysis. The weighted seroprevalence of HSV-2 infection was 4.2% (95% confidence interval [CI], 3.2-5.3) in females, which was significant higher than that in males (2.7%; 95% CI, 1.1-4.2) (P = 0.04). The seroprevalence of HSV-2 was higher in individuals from eastern region (6.4%; 95% CI, 5.9-6.9) and urban areas (4.3%; 95% CI, 2.6-6.0) of Shandong than those from other regions (P < 0.01). Associated factors for HSV-2 infection among men were being urban residents (adjusted odds ratio [AOR], 2.36; 95% CI, 1.14-4.88), having two or more sex partners in the past year (AOR, 3.22; 95% CI, 1.90-5.43) and having commercial sex (AOR, 1.51; 95% CI, 1.00-2.26). Among females, being divorced or widowed (AOR, 1.79; 95% CI, 1.08-2.97), having a tattoo (AOR, 2.89; 95% CI, 1.07-7.84), and being dissatisfied with the sex activity quality (AOR, 2.12; 95% CI, 1.24-3.63) was associated with HSV-2 infection. CONCLUSIONS: This study showed a relatively low burden of HSV-2 in Shandong province, China compared with the seroprevalence reported in many other provinces and countries. HSV-2 control programs in Shandong should focus on eastern, urban and female residents, and pay more attention to individuals with identified associated factors.


Assuntos
Herpes Simples/diagnóstico , Adolescente , Adulto , China/epidemiologia , Estudos Transversais , Feminino , Herpes Simples/epidemiologia , Herpes Simples/virologia , Herpesvirus Humano 2/isolamento & purificação , Humanos , Entrevistas como Assunto , Masculino , Pessoa de Meia-Idade , Razão de Chances , Estudos Soroepidemiológicos , Comportamento Sexual , Parceiros Sexuais , Inquéritos e Questionários , Adulto Jovem
8.
JAMA Dermatol ; 155(6): 666-672, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30916737

RESUMO

Importance: Dapsone hypersensitivity syndrome (DHS) is the most serious adverse reaction associated with dapsone administration and one of the major causes of death in patients with leprosy, whose standard treatment includes multidrug therapy (MDT) with dapsone, rifampicin, and clofazimine. Although the HLA-B*13:01 polymorphism has been identified as the genetic determinant of DHS in the Chinese population, no studies to date have been done to evaluate whether prospective HLA-B*13:01 screening could prevent DHS by identifying patients who should not receive dapsone. Objective: To evaluate the clinical use of prospective HLA-B*13:01 screening for reduction of the incidence of DHS by excluding dapsone from the treatment for patients with HLA-B*13:01-positive leprosy. Design, Setting, and Participants: A prospective cohort study was conducted from February 15, 2015, to April 30, 2018, in 21 provinces throughout China. A total of 1539 patients with newly diagnosed leprosy were enrolled who had not received dapsone previously. After excluding patients who had a history of allergy to sulfones or glucose-6-phosphate dehydrogenase deficiency, 1512 individuals underwent HLA-B*13:01 genotyping. All of the patients were followed up weekly for the first 8 weeks after treatment to monitor for adverse events. Exposures: Patients who were HLA-B*13:01 carriers were instructed to eliminate dapsone from their treatment regimens, and noncarrier patients received standard MDT. Main Outcomes and Measures: The primary outcome was the incidence of DHS. The historical incidence rate of DHS (1.0%) was used as a control. Results: Among 1512 patients (1026 [67.9%] men, 486 [32.1%] women; mean [SD] age, 43.1 [16.2] years), 261 (17.3%) were identified as carriers of the HLA-B*13:01 allele. A total of 714 adverse events in 384 patients were observed during the follow-up period. Dapsone hypersensitivity syndrome did not develop in any of the 1251 patients who were HLA-B*13:01-negative who received dapsone, while approximately 13 patients would be expected to experience DHS, based on the historical incidence rate of 1.0% per year (P = 2.05 × 10-5). No significant correlation was found between other adverse events, including dermatologic or other events, and HLA-B*13:01 status. Conclusions and Relevance: Prospective HLA-B*13:01 screening and subsequent elimination of dapsone from MDT for patients with HLA-B*13:01-positive leprosy may significantly reduce the incidence of DHS in the Chinese population.

9.
PLoS Negl Trop Dis ; 13(3): e0007284, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30883558

RESUMO

BACKGROUND: The reduced amounts of Mycobacterium leprae (M. leprae) among paucibacillary (PB) patients reflect the need to further optimize methods for leprosy diagnosis. An increasing number of reports have shown that droplet digital polymerase chain reaction (ddPCR) is a promising tool for diagnosis of infectious disease among samples with low copy number. To date, no publications have investigated the utility of ddPCR in the detection of M. leprae. The aim of this study was to develop and evaluate a ddPCR assay for the diagnosis of PB leprosy. METHODOLOGY: The two most sensitive DNA targets for detection of M. leprae were selected from electronic databases for assessment of sensitivity and specificity by quantitative polymerase chain reaction (qPCR) and ddPCR. Control patients (n = 59) suffering from other dermatological diseases were used to define the cut-off of the duplex ddPCR assay. For comparative evaluation, qPCR and ddPCR assays were performed in 44 PB patients and 68 multibacillary (MB) patients. PRINCIPAL FINDINGS: M. leprae-specific repetitive element (RLEP) and groEL (encoding the 65 kDa molecular chaperone GroEL) were used to develop the ddPCR assay by systematically analyzing specificity and sensitivity. Based on the defined cut-off value, the ddPCR assay showed greater sensitivity in detecting M. leprae DNA in PB patients compared with qPCR (79.5% vs 36.4%), while both assays have a 100% sensitivity in MB patients. CONCLUSIONS/SIGNIFICANCE: We developed and evaluated a duplex ddPCR assay for leprosy diagnosis in skin biopsy samples from leprosy patients. While still costly, ddPCR might be a promising diagnostic tool for detection of PB leprosy.


Assuntos
Hanseníase Paucibacilar/diagnóstico , Técnicas de Diagnóstico Molecular/métodos , Mycobacterium leprae/isolamento & purificação , Reação em Cadeia da Polimerase/métodos , Pele/microbiologia , Adolescente , Adulto , Idoso , Biópsia , Chaperonina 60/genética , Feminino , Humanos , Sequências Repetitivas Dispersas , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae/genética , Sensibilidade e Especificidade , Adulto Jovem
10.
Allergy ; 74(8): 1533-1548, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30844087

RESUMO

BACKGROUND: Research into drug hypersensitivity associated with the expression of specific HLA alleles has focussed on the interaction between parent drug and the HLA with no attention given to reactive metabolites. For this reason, we have studied HLA-B*13:01-linked dapsone hypersensitivity to (a) explore whether the parent drug and/or nitroso metabolite activate T cells and (b) determine whether HLA-B*13:01 is involved in the response. METHODS: Peripheral blood mononuclear cells (PBMC) from six patients were cultured with dapsone and nitroso dapsone, and proliferative responses and IFN-γ release were measured. Dapsone- and nitroso dapsone-specific T-cell clones were generated and phenotype, function, HLA allele restriction, and cross-reactivity assessed. Dapsone intermediates were characterized by mass spectrometry. RESULTS: Peripheral blood mononuclear cells from six patients and cloned T cells proliferated and secreted Th1/2/22 cytokines when stimulated with dapsone (clones: n = 395; 80% CD4+ CXCR3hi CCR4hi , 20% CD8+CXCR3hi CCR4hi CCR6hi CCR9hi CCR10hi ) and nitroso dapsone (clones: n = 399; 78% CD4+, 22% CD8+ with same chemokine receptor profile). CD4+ and CD8+ clones were HLA class II and class I restricted, respectively, and displayed three patterns of reactivity: compound specific, weakly cross-reactive, and strongly cross-reactive. Nitroso dapsone formed dimers in culture and was reduced to dapsone, providing a rationale for the cross-reactivity. T-cell responses to nitroso dapsone were dependent on the formation of a cysteine-modified protein adduct, while dapsone interacted in a labile manner with antigen-presenting cells. CD8+ clones displayed an HLA-B*13:01-restricted pattern of activation. CONCLUSION: These studies describe the phenotype and function of dapsone- and nitroso dapsone-responsive CD4+ and CD8+ T cells from hypersensitive patients. Discovery of HLA-B*13:01-restricted CD8+ T-cell responses indicates that drugs and their reactive metabolites participate in HLA allele-linked forms of hypersensitivity.

11.
J Phys Chem Lett ; 10(1): 82-89, 2019 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-30565943

RESUMO

Most proteins perform functions in intracellular milieu. The crowding, compartmentalized cytosol environment affects the protein structure, folding, conformational stability, substrate diffusion, and substrate-enzyme binding. Moreover, enzymes are available at single or very low copy numbers in a cell, and thus the conformation fluctuations of a single enzyme in a crowding environment could also greatly influence its kinetics. However, the crowding effect is poorly understood in the kinetical aspect of enzymatic reactions. In the present study, individual horseradish peroxidase (HRP) is encapsulated in a liposome containing crowding reagents as mimics of viscous cytosol. The confined crowding environment possesses a profound influence on both the catalytic activity and the product inhibition of enzymes. By analyzing the correlation between product generation and product inhibition, we find that the allosteric noncompetitive inhibition of HRP is alleviated in the crowded and confined milieu. Small-angle X-ray scattering experiments provide straightforward proofs of structural changes of enzymes in crowding environments, which are responsible for the reduced enzyme activity and increased enzyme-substrate affinity. We expect that this work may deepen the understanding of correlations between enzymatic conformations and activity performance in real cellular environments.


Assuntos
Inibidores Enzimáticos/farmacologia , Peroxidase do Rábano Silvestre/antagonistas & inibidores , Lipossomos/química , Biomimética , Citosol/metabolismo , Ativação Enzimática , Peroxidase do Rábano Silvestre/química , Peroxidase do Rábano Silvestre/metabolismo , Cinética , Modelos Moleculares , Conformação Proteica , Viscosidade
12.
J Phys Chem Lett ; 9(23): 6786-6794, 2018 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-30412409

RESUMO

Unraveling the conformational changes of enzymes together with inhibition kinetics during an enzymatic reaction has great potential in screening therapeutic candidates; however, it remains challenging due to the transient nature of each intermediate step. We report our study on the noncompetitive inhibition of horseradish peroxidase with single-turnover resolution using single-molecule fluorescence microscopy. By introducing DNA origami as an addressable nanoreactor, we observe the coexistence of nascent-formed fluorescent product on both catalytic and docking sites. We further propose a single-molecule kinetic model to reveal the interplay between product generation and noncompetitive inhibition and find three distinct inhibitor releasing pathways. Moreover, the kinetic isotope effect experiment indicates a strong correlation between catalytic and docking sites, suggesting an allosteric conformational change in noncompetitive inhibition. A memory effect is also observed. This work provides an in-depth understanding of the correlation between enzyme behavior and enzymatic conformational fluctuation, substrate conversion, and product releasing pathway and kinetics.


Assuntos
DNA/química , Corantes Fluorescentes/química , Peroxidase do Rábano Silvestre/antagonistas & inibidores , Regulação Alostérica , Sítios de Ligação , Cinética , Conformação Molecular , Simulação de Acoplamento Molecular , Imagem Individual de Molécula
13.
BMC Infect Dis ; 18(1): 534, 2018 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-30367605

RESUMO

BACKGROUND: A population-based study of Chlamydia trachomatis (CT) infections is essential in designing a specific control program; however, no large investigation of CT infections among the general population in mainland China has been conducted since 2000. We aimed to determine the prevalence, risk factors, and associated medical costs of CT among residents, 18-49 years of age, in Shandong, China. METHODS: From May to August 2016, a multistage probability sampling survey involving 8074 individuals was distributed. Data were collected via face-to-face interviews, followed by self-administered questionnaire surveys. First-void urines were collected and tested for CT and Neisseria gonorrhoeae (NG) using nucleic acid amplification. RESULTS: The weighted prevalence of CT infection was 2.3% (95% confidence interval [CI], 1.5-3.2) in females and 2.7% (1.6-3.8) in males. Women, 30-34 years of age, had the highest prevalence of CT infections (3.5%, 2.6-4.4), while the highest prevalence of CT infections in males was in those 18-24 years of age (4.3%, 0.0-8.8). Neisseria gonorrhoeae infection had a prevalence of 0.1% (0.0-0.3) in women and 0.03% (0.0-0.1) in men. Risk factors for CT infections among females included being unmarried, divorced, or widowed (odds ratio [OR], 95% CI 3.57, 1.54-8.24) and having two or more lifetime sex partners (3.72, 1.14-12.16). Among males, first intercourse before 20 years of age (1.83, 1.10-3.02) and having two or more lifetime sex partners (1.85, 1.14-3.02) were associated with CT infections. The estimated lifetime cost of CT infections in patients 18-49 years of age in Shandong was 273 million (range, 172-374 million) China Renminbi in 2016. CONCLUSIONS: This study demonstrated a high burden of CT infections among females < 35 years of age and males < 25 years of age in Shandong. Thus, a CT infection control program should focus on this population, as well as others with identified risk factors.


Assuntos
Infecções por Chlamydia/epidemiologia , Chlamydia trachomatis/isolamento & purificação , Gonorreia/epidemiologia , Neisseria gonorrhoeae/isolamento & purificação , Adolescente , Adulto , Fatores Etários , China/epidemiologia , Infecções por Chlamydia/economia , Infecções por Chlamydia/urina , Custos e Análise de Custo , Estudos Transversais , Feminino , Gonorreia/economia , Gonorreia/urina , Humanos , Masculino , Pessoa de Meia-Idade , Técnicas de Amplificação de Ácido Nucleico , Prevalência , Fatores de Risco , Fatores Sexuais , Parceiros Sexuais , Inquéritos e Questionários , Adulto Jovem
14.
Chem Sci ; 9(27): 5967-5975, 2018 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-30079211

RESUMO

Intracellular delivery of proteins provides a direct means to manipulate cell function and probe the intracellular environment. However, direct cytoplasmic delivery of proteins suffers from limited availability of efficient toolsets, and thus remains challenging in research and therapeutic applications. Natural biological cargo delivery processes, like SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complex mediated membrane fusion and other vesicle fusion in live cells, enable targeted delivery with high efficiency. A surrogate of SNARE machinery represents a new direction in intracellular protein delivery. Here, we report a DNA-programmed membrane fusion strategy for guiding the efficient intracellular delivery of proteins into live cells. The inherent programmability of DNA hybridization provides spatiotemporal control of the fusion between protein-encapsulated liposomes and cell membranes, enabling rapid release of proteins directly into the cytoplasm, while still remaining functional due to the bypassing of the endosomal trap. We further demonstrate that delivered exogenous Cytochrome c effectively regulates the cell fate. Hence, this DNA-mediated fusion strategy holds great potential for protein drug delivery, regenerative medicine and gene editing.

15.
Am J Trop Med Hyg ; 99(1): 124-126, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29785921

RESUMO

Chromoblastomycosis is a worldwide chronic subcutaneous infection caused by dematiaceous fungi and clinically characterized by verrucous lesions. Herein, we report a rare case of chromoblastomycosis caused by Fonsecaea monophora in a 60-year-old male carpenter with a 40-year history of psoriasis from Shandong in northern China. A fungal infection coexisting with psoriasis presents a management dilemma. Our patient responded well to combined itraconazole and acitretin therapy and the lesions resolved completely after 1 month of treatment.


Assuntos
Acitretina/uso terapêutico , Antifúngicos/uso terapêutico , Cromoblastomicose/tratamento farmacológico , Itraconazol/uso terapêutico , Saccharomycetales/efeitos dos fármacos , Corticosteroides/uso terapêutico , Cromoblastomicose/complicações , Cromoblastomicose/microbiologia , Cromoblastomicose/patologia , Quimioterapia Combinada , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Psoríase/complicações , Psoríase/tratamento farmacológico , Psoríase/microbiologia , Psoríase/patologia , Saccharomycetales/crescimento & desenvolvimento , Saccharomycetales/patogenicidade , Pele/efeitos dos fármacos , Pele/microbiologia , Pele/patologia , Resultado do Tratamento
17.
Exp Dermatol ; 27(3): 245-250, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29283461

RESUMO

The nuclear transcription factor-κB (NF-κB) plays a pivotal role in controlling both innate and adaptive immunity and regulates the expressions of many immunological mediators. Abundant evidences have showed the importance of NF-κB pathway in the host immune responses against Mycobacterium leprae in the development of leprosy. However, no particular association study between leprosy and NF-κB pathway-related gene polymorphisms was reported. Here, we performed a large-scale and two-stage candidate association study to investigate the association between 94 NF-κB pathway-related genes and leprosy. Our results showed that rs58744688 was significantly associated with leprosy (P = 7.57 × 10-7 , OR = 1.12) by combining the previous genomewide association data sets and four independent validation sample series, consisting of a total of 4631 leprosy cases and 6413 healthy controls. This founding implicated that MAP3K14 and FMNL1 were susceptibility genes for leprosy, which suggested the involvement of macrophage targeting and NF-κB pathway in the development of leprosy.


Assuntos
Proteínas do Citoesqueleto/genética , Predisposição Genética para Doença , Hanseníase/genética , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais/genética , Idoso , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Polimorfismo de Nucleotídeo Único
18.
Matern Child Nutr ; 14(1)2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28752645

RESUMO

Caesarean section is associated with weaker newborn suction pressure. This nonblinded, randomized trial explored the effect of suction pressures generating by a breast pump on mothers' onset of lactation and milk supply after caesarean section. A high pressure group (-150 mmHg), a low pressure group (-100 mmHg), and a control group (none) were generated under computer random assignment with concealed allocation in 2 tertiary hospitals. The breast pumping began within 2 hr after caesarean operation (6 times a day and 30 min per time) until onset of lactation. The primary outcomes were the timing of onset of lactation, milk supply, and mother's satisfaction in lactation, using both intention-to-treat and per-protocol analyses. The secondary endpoints were the pumping-related pain, nipple injury, and maternal fatigue. All 164 women randomized were included in analysis. The breast pumping at -150 mmHg optimally advanced the timing of the onset of lactation and increased daytime milk supply. The pumping also appeared to boost mothers' confidence in lactation. The results in the per-protocol population (n = 148) were consistent with those of intention-to-treat population (n = 164). However, the pumping aggravated maternal nipple pain and fatigue, though there was no statistical significance. The findings suggest that a higher pumping pressure within the range of normal vaginally born infant suction could promote onset of lactation and milk supply among mothers giving birth by caesarean section. The pumping could also enhance mothers' confidence in breastfeeding.


Assuntos
Extração de Leite/efeitos adversos , Cesárea/efeitos adversos , Lactação , Satisfação do Paciente , Autoimagem , Adulto , Grupo com Ancestrais do Continente Asiático , China , Fadiga/etiologia , Fadiga/fisiopatologia , Fadiga/prevenção & controle , Feminino , Humanos , Análise de Intenção de Tratamento , Mamilos/lesões , Medição da Dor , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/fisiopatologia , Dor Pós-Operatória/prevenção & controle , Pacientes Desistentes do Tratamento , Período Pós-Parto , Gravidez , Pressão/efeitos adversos , Índice de Gravidade de Doença , Centros de Atenção Terciária , Adulto Jovem
19.
Int J Equity Health ; 16(1): 206, 2017 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-29183335

RESUMO

BACKGROUND: Southwest China is home to more than 30 ethnic minority groups. Since most of these populations reside in mountainous areas, convenient access to medical services is an important metric of how well their livelihoods are being protected. METHODS: This paper proposes a medical convenience index (MCI) and computation model for mountain residents, taking into account various conditions including topography, geology, and climate. Data on road networks were used for comprehensive evaluation from three perspectives: vulnerability, complexity, and accessibility. The model is innovative for considering road network vulnerability in mountainous areas, and proposing a method of evaluating road network vulnerability by measuring the impacts of debris flows based on only links. The model was used to compute and rank the respective MCIs for settlements of each ethnic population in the Dehong Dai and Jingpo Autonomous Prefecture of Yunnan Province, in 2009 and 2015. Data on the settlements over the two periods were also used to analyze the spatial differentiation of medical convenience levels within the study area. RESULTS: The medical convenience levels of many settlements improved significantly. 80 settlements were greatly improved, while another 103 showed slight improvement.Areas with obvious improvement were distributed in clusters, and mainly located in the southwestern part of Yingjiang County, northern Longchuan County, eastern Lianghe County, and the region where Lianghe and Longchuan counties and Mang City intersect. CONCLUSIONS: Development of the road network was found to be a major contributor to improvements in MCI for mountain residents over the six-year period.


Assuntos
Planejamento Ambiental/estatística & dados numéricos , Grupos Étnicos , Acesso aos Serviços de Saúde , Grupos Minoritários , Características de Residência/estatística & dados numéricos , China , Humanos
20.
J Am Chem Soc ; 139(48): 17525-17532, 2017 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-29131610

RESUMO

The dynamics of enzymes are directly associated with their functions in various biological processes. Nevertheless, the ability to image motions of single enzymes in a highly parallel fashion remains a challenge. Here, we develop a DNA origami raft-based platform for in-situ real-time imaging of enzyme cascade at the single-molecule level. The motions of enzymes are rationally controlled via different tethering modes on a two-dimensional (2D) supported lipid bilayer (SLB). We construct an enzyme cascade by anchoring catalase on cholesterol-labeled double-stranded (ds) DNA and glucose oxidase on cholesterol-labeled origami rafts. DNA functionalized with cholesterol can be readily incorporated in SLB via the cholesterol-lipid interaction. By using a total internal reflection fluorescence microscope (TIRFM), we record the moving trajectory of fluorophore-labeled single enzymes on the 2D surface: the downstream catalase diffuses freely in SLB, whereas the upstream glucose oxidase is relatively immobile. By analyzing the trajectories of individual enzymes, we find that the lateral motion of enzymes increases in a substrate concentration-dependent manner and that the enhanced diffusion of enzymes can be transmitted via the cascade reaction. We expect that this platform sheds new light on studying dynamic interactions of proteins and even cellular interactions.


Assuntos
Catalase/metabolismo , DNA/química , Glucose Oxidase/metabolismo , Imagem Individual de Molécula/métodos , Colesterol/química , Difusão , Bicamadas Lipídicas/química
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