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1.
Methods Mol Biol ; 2314: 481-512, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34235667

RESUMO

RNA sequencing (RNAseq) in bacteria has become a transformative tool for many applications, including the identification of mechanisms that contribute to pathogenesis, environmental adaptation, and drug response. The kinds of analysis outputs achievable from RNA-seq depend heavily on several key technical parameters during the sample preparation, sequencing, and data processing steps. In this chapter, we will describe the process of preparing Mycobacterium tuberculosis samples into sequencing libraries, selecting the appropriate sequencing platform, and performing data processing compatible with gene expression quantification. We will also discuss how each parameter could affect outcomes. The protocols described below produce consistently high yields. This chapter should inform on the technical considerations that impact sequencing output and enable the reader to decide on the best parameters to implement based on their own experimental goals.


Assuntos
Proteínas de Bactérias/genética , Biologia Computacional/métodos , Perfilação da Expressão Gênica/métodos , Mycobacterium tuberculosis/genética , RNA Bacteriano/genética , Análise de Sequência de RNA/métodos , Humanos , RNA Bacteriano/análise , Fluxo de Trabalho
2.
Microbiol Resour Announc ; 10(20)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34016671

RESUMO

This report describes the isolation, sequencing, and annotation of Ws20160810, which was isolated from a blood sample from a brucellosis patient suffering from swelling of the right testicle in the Inner Mongolia Autonomous Region, China. The genome size was 3,244,234 bp with a 57.23% GC content, 3,294 coding DNA sequences (CDSs), 55 tRNAs, 5 rRNAs (5S [n = 2], 16S [n = 1], and 23S [n = 2]), and 3 small RNAs (sRNAs).

3.
J Hazard Mater ; 415: 125662, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-33761420

RESUMO

Recently, tremendous research interest was stimulated to obtain advanced function materials with hierarchical structure and tailored chemical composition from metal-organic frameworks (MOFs) based precursors. Herein, Bimetal-organic frameworks of Ni-Co-BTC solid microspheres synthesized through hydrothermal method were acted as template to induce multishelled NiO/NiCo2O4 hollow microspheres by annealing treatment. When evaluated as gas sensing material, the optimal hybrid of NiO/NiCo2O4 (the molar ration of NiCo=1.5) multishelled hollow microspheres endowed a high sensitivity (17.86) to 100 ppm acetone with rapid response/recovery time (11/13 s) under low working temperature (160 °C) and the low detection limit reached 25 ppb. The enhanced mechanism was originated from the following aspects: the multishelled hollow architecture provided efficient diffusion path for gas molecules and sufficient active site for gas sensing reaction; the nanoscale p-p heterojunction created at NiO and NiCo2O4 nanoparticles interface amplified the resistance variation by tuning the potential barrier; the potent combination of the "chemical catalytic" effect of NiO and the "electrical catalytic" effect of NiCo2O4 improved the selective acetone detection.

4.
Nat Microbiol ; 6(1): 44-50, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33199862

RESUMO

Transposon-based strategies provide a powerful and unbiased way to study the bacterial stress response1-8, but these approaches cannot fully capture the complexities of network-based behaviour. Here, we present a network-based genetic screening approach: the transcriptional regulator-induced phenotype (TRIP) screen, which we used to identify previously uncharacterized network adaptations of Mycobacterium tuberculosis to the first-line anti-tuberculosis drug isoniazid (INH). We found regulators that alter INH susceptibility when induced, several of which could not be identified by standard gene disruption approaches. We then focused on a specific regulator, mce3R, which potentiated INH activity when induced. We compared mce3R-regulated genes with baseline INH transcriptional responses and implicated the gene ctpD (Rv1469) as a putative INH effector. Evaluating a ctpD disruption mutant demonstrated a previously unknown role for this gene in INH susceptibility. Integrating TRIP screening with network information can uncover sophisticated molecular response programs.


Assuntos
Antituberculosos/farmacologia , Redes Reguladoras de Genes/genética , Isoniazida/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Transcrição Genética/genética , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Estresse Fisiológico/fisiologia
5.
Prev Vet Med ; 183: 105080, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32919319

RESUMO

Although the prevalence of brucellosis in Inner Mongolia Autonomous Region currently remains high, data available on the epidemiological of circulating Brucella abortus strains were limited. A total of 75 isolates obtained from cattle, sheep, and humans were analysed using both the classical method and multiple locus variable-number tandem repeat analysis (MLVA). There are at least three B. abortus biovars (1, 3 and 6) in this region, and B. abortus biovar 3 is the predominant one. Ten known MLVA-11 genotypes were identified, of which five genotypes (72, 75, 78, 82 and 210) were shared among strains from this study and others previously collected in two to seven different nations, suggesting that this population has multiple geographic origins. An MLVA-16 assay sorted the 75 B. abortus strains into two groups (I and II), 5 clusters (A-E) and 44 genotypes (GT1-44), with 26 unique genotypes represented by single isolates, indicating that these B. abortus brucellosis cases were not directly epidemiologically related. The remaining 18 shared genotypes (among a total of 47 isolates) were represented by two to eight isolates, suggesting that there were epidemiologically related pathogens from each shared genotype among the cases. Importantly, the cluster B1 branch including 22 cluster isolates with identical or similar genotypes confirmed the occurrence of a concentrated outbreak epidemic in the eastern region during 1988-1995. This work will contribute to better understanding of B. abortus brucellosis epidemiology in Inner Mongolia.


Assuntos
Brucella abortus/genética , Brucelose Bovina/epidemiologia , Brucelose/epidemiologia , Brucelose/veterinária , Genótipo , Doenças das Cabras/epidemiologia , Repetições Minissatélites , Doenças dos Ovinos/epidemiologia , Animais , Bovinos , China/epidemiologia , Feminino , Cabras , Humanos , Epidemiologia Molecular , Tipagem de Sequências Multilocus/veterinária , Filogenia , Ovinos , Carneiro Doméstico
6.
Annu Rev Genet ; 54: 511-537, 2020 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-32926793

RESUMO

Tuberculosis claims more human lives than any other bacterial infectious disease and represents a clear and present danger to global health as new tools for vaccination, treatment, and interruption of transmission have been slow to emerge. Additionally, tuberculosis presents with notable clinical heterogeneity, which complicates diagnosis, treatment, and the establishment of nonrelapsing cure. How this heterogeneity is driven by the diversity ofclinical isolates of the causative agent, Mycobacterium tuberculosis, has recently garnered attention. Herein, we review advances in the understanding of how naturally occurring variation in clinical isolates affects transmissibility, pathogenesis, immune modulation, and drug resistance. We also summarize how specific changes in transcriptional responses can modulate infection or disease outcome, together with strain-specific effects on gene essentiality. Further understanding of how this diversity of M. tuberculosis isolates affects disease and treatment outcomes will enable the development of more effective therapeutic options and vaccines for this dreaded disease.


Assuntos
Variação Genética/genética , Mycobacterium tuberculosis/genética , Animais , Genótipo , Humanos , Transcrição Genética/genética , Tuberculose/microbiologia
7.
Sci Total Environ ; 744: 140935, 2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-32688005

RESUMO

The novel coronavirus disease 2019 (COVID-19) has spread globally and the meteorological factors vary greatly across the world. Understanding the effect of meteorological factors and control strategies on COVID-19 transmission is critical to contain the epidemic. Using individual-level data in mainland China, Hong Kong, and Singapore, and the number of confirmed cases in other regions, we explore the effect of temperature, relative humidity, and control measures on the spread of COVID-19. We find that high temperature mitigates the transmission of the disease. High relative humidity promotes COVID-19 transmission when temperature is low, but tends to reduce transmission when temperature is high. Implementing classical control measures can dramatically slow the spread of the disease. However, due to the occurrence of pre-symptomatic infections, the effect of the measures to shorten treatment time is markedly reduced and the importance of contact quarantine and social distancing increases.


Assuntos
Infecções por Coronavirus , Coronavirus , Pandemias , Pneumonia Viral , Betacoronavirus , COVID-19 , China , Hong Kong , Humanos , Conceitos Meteorológicos , SARS-CoV-2 , Singapura
8.
Artigo em Inglês | MEDLINE | ID: mdl-32571828

RESUMO

We have identified a previously unknown mechanism of reversible high-level ethambutol (EMB) resistance in Mycobacterium tuberculosis that is caused by a reversible frameshift mutation in the M. tuberculosis orn gene. A frameshift mutation in orn produces the small-colony-variant (SCV) phenotype, but this mutation does not change the MICs of any drug for wild-type M. tuberculosis However, the same orn mutation in a low-level EMB-resistant double embB-aftA mutant (MIC = 8 µg/ml) produces an SCV with an EMB MIC of 32 µg/ml. Reversible resistance is indistinguishable from a drug-persistent phenotype, because further culture of these orn-embB-aftA SCV mutants results in rapid reversion of the orn frameshifts, reestablishing the correct orn open reading frame, returning the culture to normal colony size, and reversing the EMB MIC back to that (8 µg/ml) of the parental strain. Transcriptomic analysis of orn-embB-aftA mutants compared to wild-type M. tuberculosis identified a 27-fold relative increase in the expression of embC, which is a cellular target for EMB. Expression of embC in orn-embB-aftA mutants was also increased 5-fold compared to that in the parental embB-aftA mutant, whereas large-colony orn frameshift revertants of the orn-embB-aftA mutant had levels of embC expression similar to that of the parental embB-aftA strain. Reversible frameshift mutants may contribute to a reversible form of microbiological drug resistance in human tuberculosis.


Assuntos
Farmacorresistência Bacteriana , Etambutol , Mutação da Fase de Leitura , Mycobacterium tuberculosis , Antituberculosos/farmacologia , Farmacorresistência Bacteriana/genética , Etambutol/farmacologia , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Pentosiltransferases/genética
9.
Emerg Microbes Infect ; 9(1): 1618-1627, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32594852

RESUMO

Brucellosis caused by Brucella melitensis is considered to be one of the most important zoonotic diseases in China. In this study, Conventional bio-typing, MLVA (multiple locus variable-number tandem repeat analysis), and WGS (whole-genome sequencing)-SNP (single nucleotide polymorphism) were used to study the genetic similarity of B. melitensis in northern and southern China and analyze its relationship with worldwide lineages. Currently, the distribution of species/biovars of B. melitensis has obviously changed, and B. melitensis has become the dominant species in southern regions of China. Strains from the southern had a common geographic origin with strains from the northern. Many MLVA-16 events were shared in the genotypes of the southern and northern strains, suggest that genotypic movement occurred from north to south. Based on WGS-SNP analysis, strains from different provinces were closely related and may have descended from one common ancestor, suggests that the southern strains originated from northern China. These data indicate that B. melitensis is a latent "travel bacterium" that spread and expanded from North China to South China. Moreover, B. melitensis strains from China are also genetically related to strains from other Asian regions (Kazakhstan, Russia, Mongolia, and India). The movement of infected sheep and their products requires control.


Assuntos
Brucella melitensis/classificação , Brucelose/microbiologia , Tipagem de Sequências Multilocus/métodos , Doenças dos Ovinos/microbiologia , Sequenciamento Completo do Genoma/métodos , Animais , Brucella melitensis/genética , Brucella melitensis/isolamento & purificação , Brucelose/veterinária , China , Genoma Bacteriano , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Repetições Minissatélites , Filogenia , Polimorfismo de Nucleotídeo Único , Ovinos , Zoonoses/microbiologia
10.
Ultrasonics ; 106: 106141, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32325302

RESUMO

Guided waves are sensitive to variations in propagation environments. Many recent studies have focused on the uniform thermal effect on Lamb waves. However, there is little research on the thermal effect in a more complex situation, such as a nonuniform thermal effect and wave propagation in an arbitrary cross-section. In this study, a thermo-acoustoelastic theory combined with the semi-analytical finite element (TAE-SAFE) method is proposed to investigate both uniform and nonuniform thermal effects on acoustoelastic guided wave propagation. In the TAE-SAFE method, effective thermo-acoustoelastic constants including third-order elastic constants are employed. Then, an acoustoelastic wave equation of the thermal effect is formulated by Hamilton's principle and computed by the semi-analytical finite element (SAFE) method. The phase velocity, group velocity, velocity thermal sensitivity, and displacement mode shape shift can be extracted by the proposed method. To validate this method, numerical results of Lamb waves in an aluminum plate subjected to a uniform thermal effect are compared with the results of a previous theoretical analysis. The results show computational veracity and validity. Two typical cases are investigated: (1) an isotropic aluminum plate under a linear temperature gradient condition; (2) a uniform temperature case in a rail track with a constant irregular cross-section. This study provides an effective numerical method to analyze thermo-acoustoelastic guided wave propagation.

11.
Sci Rep ; 10(1): 3490, 2020 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-32103057

RESUMO

Spatial heterogeneity is a fundamental feature of the tumor microenvironment (TME), and tackling spatial heterogeneity in neoplastic metabolic aberrations is critical for tumor treatment. Genome-scale metabolic network models have been used successfully to simulate cancer metabolic networks. However, most models use bulk gene expression data of entire tumor biopsies, ignoring spatial heterogeneity in the TME. To account for spatial heterogeneity, we performed spatially-resolved metabolic network modeling of the prostate cancer microenvironment. We discovered novel malignant-cell-specific metabolic vulnerabilities targetable by small molecule compounds. We predicted that inhibiting the fatty acid desaturase SCD1 may selectively kill cancer cells based on our discovery of spatial separation of fatty acid synthesis and desaturation. We also uncovered higher prostaglandin metabolic gene expression in the tumor, relative to the surrounding tissue. Therefore, we predicted that inhibiting the prostaglandin transporter SLCO2A1 may selectively kill cancer cells. Importantly, SCD1 and SLCO2A1 have been previously shown to be potently and selectively inhibited by compounds such as CAY10566 and suramin, respectively. We also uncovered cancer-selective metabolic liabilities in central carbon, amino acid, and lipid metabolism. Our novel cancer-specific predictions provide new opportunities to develop selective drug targets for prostate cancer and other cancers where spatial transcriptomics datasets are available.


Assuntos
Redes e Vias Metabólicas/genética , Neoplasias da Próstata/patologia , Ácido Araquidônico/metabolismo , Cisteína/metabolismo , Bases de Dados Factuais , Humanos , Masculino , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Transportadores de Ânions Orgânicos/metabolismo , Neoplasias da Próstata/metabolismo , Estearoil-CoA Dessaturase/antagonistas & inibidores , Estearoil-CoA Dessaturase/metabolismo , Ácido Succínico/metabolismo , Suramina/química , Suramina/metabolismo , Microambiente Tumoral
12.
mBio ; 10(6)2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31719182

RESUMO

The rapid spread of multidrug-resistant strains has created a pressing need for new drug regimens to treat tuberculosis (TB), which kills 1.8 million people each year. Identifying new regimens has been challenging due to the slow growth of the pathogen Mycobacterium tuberculosis (MTB), coupled with the large number of possible drug combinations. Here we present a computational model (INDIGO-MTB) that identified synergistic regimens featuring existing and emerging anti-TB drugs after screening in silico more than 1 million potential drug combinations using MTB drug transcriptomic profiles. INDIGO-MTB further predicted the gene Rv1353c as a key transcriptional regulator of multiple drug interactions, and we confirmed experimentally that Rv1353c upregulation reduces the antagonism of the bedaquiline-streptomycin combination. A retrospective analysis of 57 clinical trials of TB regimens using INDIGO-MTB revealed that synergistic combinations were significantly more efficacious than antagonistic combinations (P value = 1 × 10-4) based on the percentage of patients with negative sputum cultures after 8 weeks of treatment. Our study establishes a framework for rapid assessment of TB drug combinations and is also applicable to other bacterial pathogens.IMPORTANCE Multidrug combination therapy is an important strategy for treating tuberculosis, the world's deadliest bacterial infection. Long treatment durations and growing rates of drug resistance have created an urgent need for new approaches to prioritize effective drug regimens. Hence, we developed a computational model called INDIGO-MTB that identifies synergistic drug regimens from an immense set of possible drug combinations using the pathogen response transcriptome elicited by individual drugs. Although the underlying input data for INDIGO-MTB was generated under in vitro broth culture conditions, the predictions from INDIGO-MTB correlated significantly with in vivo drug regimen efficacy from clinical trials. INDIGO-MTB also identified the transcription factor Rv1353c as a regulator of multiple drug interaction outcomes, which could be targeted for rationally enhancing drug synergy.


Assuntos
Antituberculosos/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Transcriptoma , Tuberculose/microbiologia , Antituberculosos/uso terapêutico , Biomarcadores , Sinergismo Farmacológico , Quimioterapia Combinada , Perfilação da Expressão Gênica , Humanos , Resultado do Tratamento , Tuberculose/tratamento farmacológico
13.
Proc Natl Acad Sci U S A ; 116(39): 19665-19674, 2019 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-31488707

RESUMO

The length and complexity of tuberculosis (TB) therapy, as well as the propensity of Mycobacterium tuberculosis to develop drug resistance, are major barriers to global TB control efforts. M. tuberculosis is known to have the ability to enter into a drug-tolerant state, which may explain many of these impediments to TB treatment. We have identified a mechanism of genetically encoded but rapidly reversible drug tolerance in M. tuberculosis caused by transient frameshift mutations in a homopolymeric tract (HT) of 7 cytosines (7C) in the glpK gene. Inactivating frameshift mutations associated with the 7C HT in glpK produce small colonies that exhibit heritable multidrug increases in minimal inhibitory concentrations and decreases in drug-dependent killing; however, reversion back to a fully drug-susceptible large-colony phenotype occurs rapidly through the introduction of additional insertions or deletions in the same glpK HT region. These reversible frameshift mutations in the 7C HT of M. tuberculosis glpK occur in clinical isolates, accumulate in M. tuberculosis-infected mice with further accumulation during drug treatment, and exhibit a reversible transcriptional profile including induction of dosR and sigH and repression of kstR regulons, similar to that observed in other in vitro models of M. tuberculosis tolerance. These results suggest that GlpK phase variation may contribute to drug tolerance, treatment failure, and relapse in human TB. Drugs effective against phase-variant M. tuberculosis may hasten TB treatment and improve cure rates.


Assuntos
Tolerância a Medicamentos/genética , Glicerol Quinase/genética , Mycobacterium tuberculosis/genética , Animais , Antituberculosos/farmacologia , Proteínas de Bactérias/genética , Farmacorresistência Bacteriana Múltipla/genética , Feminino , Glicerol Quinase/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/metabolismo , Regiões Promotoras Genéticas/genética , Tuberculose/microbiologia
14.
Mikrochim Acta ; 186(5): 271, 2019 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-30963315

RESUMO

A method is described for the preparation of copper(II)-modified keratin-capped gold nanoclusters (AuNCs) with adjustable Au/Cu molar ratio through a two-step synthetic route. The introduction of Cu(II) is known to cause quenching of the fluorescence of such AuNCs. It is found, however, that the Cu(II) loaded AuNC (AuNC-Cu2+) display strongly enhanced peroxidase-like activity and improved chemical stability. This is assumed to be due to the synergistic effect of the gold and copper atoms and in contrast to the single components (pure AuNCs and copper ions). The kinetic parameters of the new peroxidase mimic show a higher Kcat value (12.1 × 10-4 s-1) and a lower Km value (53 µM) for H2O2 (compared to those of conventional AuNCs). The catalytic activity is stable and remains essentially unchanged after two months. The interactions of AuNCs with Cu(II) were characterized by fluorescence spectroscopy, UV-vis spectroscopy and X-ray photoelectron spectroscopy. Based on these findings, a glucose colorimetric assay at 452 nm was developed that has a detection range from 1.6 to 800 µM and a 0.26 µM detection limit. Graphical abstract Copper ion-modified keratin-capped gold nanoclusters (AuNC-Cu2+) exhibit enhanced peroxidase-like activity owing to the synergistic effect of the gold and copper atoms which is in contrast to pure AuNCs.


Assuntos
Materiais Biomiméticos/química , Colorimetria/métodos , Cobre/química , Glucose/análise , Ouro/química , Queratinas/química , Peroxidase/metabolismo , Humanos , Cinética , Limite de Detecção , Nanopartículas Metálicas/química
15.
J Colloid Interface Sci ; 543: 285-299, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30822660

RESUMO

Nobel metal modification could be a valuable method for the fabrication of advanced chemiresistive gas sensor. Herein, a series of Au loaded In-doped ZnSnO3 nanofibers were prepared via electrospinning technique. The crystal structure, morphology and chemical composition of the synthesized materials were characterized by field-emission X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), elemental mapping, X-ray photoelectron spectroscopy (XPS) and Brunauere-Emmette-Teller (BET) analyses. The optimal sensor, which was based on 0.25 mol% Au loaded In-doped ZnSnO3 nanofibers, could detect 50 ppm acetone effectively, it possessed a high response (19.3) and fast response/recovery time (10/13 s) at low operating temperature (200 °C). The enhanced gas sensing performance was mainly derived from proper introduction of Au. Since the electronic catalysis of Au nanoparticles created Schottky barrier-type junctions at Au and ZnSnO3 interfaces which could cause tremendous change of resistance and induce to high sensitivity, meanwhile the chemical catalysis of Au nanoparticles promoted the chemisorption and dissociation of gas molecules which could accelerate the reaction with gas sensing material. Moreover, the Au loaded In-doped ZnSnO3 sensors displayed certain stability under different humidity condition, it meant that the negative influence of water vapor on gas sensing performance could be inhibited by loading Au nanoparticles.

16.
Ultrasonics ; 92: 13-20, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30216781

RESUMO

Lamb waves and electro-mechanical impedance (EMI) based methods are increasingly used in damage detection owing to their high sensitivity to small structural defects. Lamb wave based methods are effective in detecting damages in a large area and electro-impedance based methods are suitable for characterizing the identified damage. Based on these two methods, a novel combined damage detection method is presented in this research. To achieve this, first, a mobile transducer set is developed, which can be used for both the Lamb waves and EMI based methods. Then, a baseline-free damage detection strategy that combines the Lamb waves and EMI methods is presented. Finally, a laboratory-sized test piece is used to validate the effectiveness of the proposed approach. The results achieved with the application of the presented combined method for characterizing an L-shape crack in an aluminum plate show better location accuracy and detection efficiency than those obtained by applying only one method.

17.
Mar Drugs ; 16(9)2018 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-30205616

RESUMO

The importance of fucoidan as a functional ingredient in food, health products, and pharmaceutics is well-recognized due to its beneficial biological effects. Fucoidan is usually extracted from brown seaweeds, including Undaria pinnatifida. Fucoidan exhibits beneficial bio-activity and has antioxidant, anticancer, and anticoagulant properties. This review focuses on the biological activity of U. pinnatifida-derived fucoidan and investigates its structure⁻activity or fraction⁻activity relationship. It also describes several fucoidan extracts, along with their claimed anticancer effects. It aims to provide information and thoughts for future research such as the development of fucoidan into functional foods or nutraceuticals.


Assuntos
Suplementos Nutricionais , Alimento Funcional , Polissacarídeos/farmacologia , Undaria/química , Anticoagulantes/química , Anticoagulantes/isolamento & purificação , Anticoagulantes/farmacologia , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Antioxidantes/química , Antioxidantes/isolamento & purificação , Antioxidantes/farmacologia , Estrutura Molecular , Polissacarídeos/química , Polissacarídeos/isolamento & purificação , Relação Estrutura-Atividade
18.
N Engl J Med ; 379(9): 823-833, 2018 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-30157391

RESUMO

BACKGROUND: Approximately 5% of patients with drug-susceptible tuberculosis have a relapse after 6 months of first-line therapy, as do approximately 20% of patients after 4 months of short-course therapy. We postulated that by analyzing pretreatment isolates of Mycobacterium tuberculosis obtained from patients who subsequently had a relapse or were cured, we could determine any correlations between the minimum inhibitory concentration (MIC) of a drug below the standard resistance breakpoint and the relapse risk after treatment. METHODS: Using data from the Tuberculosis Trials Consortium Study 22 (development cohort), we assessed relapse and cure isolates to determine the MIC values of isoniazid and rifampin that were below the standard resistance breakpoint (0.1 µg per milliliter for isoniazid and 1.0 µg per milliliter for rifampin). We combined this analysis with clinical, radiologic, and laboratory data to generate predictive relapse models, which we validated by analyzing data from the DMID 01-009 study (validation cohort). RESULTS: In the development cohort, the mean (±SD) MIC of isoniazid below the breakpoint was 0.0334±0.0085 µg per milliliter in the relapse group and 0.0286±0.0092 µg per milliliter in the cure group, which represented a higher value in the relapse group by a factor of 1.17 (P=0.02). The corresponding MIC values of rifampin were 0.0695±0.0276 and 0.0453±0.0223 µg per milliliter, respectively, which represented a higher value in the relapse group by a factor of 1.53 (P<0.001). Higher MIC values remained associated with relapse in a multivariable analysis that included other significant between-group differences. In an analysis of receiver-operating-characteristic curves of relapse based on these MIC values, the area under the curve (AUC) was 0.779. In the development cohort, the AUC in a multivariable model that included MIC values was 0.875. In the validation cohort, the MIC values either alone or combined with other patient characteristics were also predictive of relapse, with AUC values of 0.964 and 0.929, respectively. The use of a model score for the MIC values of isoniazid and rifampin to achieve 75.0% sensitivity in cross-validation analysis predicted relapse with a specificity of 76.5% in the development cohort and a sensitivity of 70.0% and a specificity of 100% in the validation cohort. CONCLUSIONS: In pretreatment isolates of M. tuberculosis with decrements of MIC values of isoniazid or rifampin below standard resistance breakpoints, higher MIC values were associated with a greater risk of relapse than lower MIC values. (Funded by the National Institute of Allergy and Infectious Diseases.).


Assuntos
Antituberculosos/farmacologia , Farmacorresistência Bacteriana , Isoniazida/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Rifampina/farmacologia , Tuberculose/tratamento farmacológico , Adulto , Antituberculosos/uso terapêutico , Área Sob a Curva , Feminino , Humanos , Isoniazida/uso terapêutico , Masculino , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/isolamento & purificação , Curva ROC , Recidiva , Rifampina/uso terapêutico , Falha de Tratamento , Tuberculose/microbiologia
19.
Clin Microbiol Rev ; 31(4)2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30021818

RESUMO

Tuberculosis (TB) is the leading infectious cause of mortality worldwide, due in part to a limited understanding of its clinical pathogenic spectrum of infection and disease. Historically, scientific research, diagnostic testing, and drug treatment have focused on addressing one of two disease states: latent TB infection or active TB disease. Recent research has clearly demonstrated that human TB infection, from latent infection to active disease, exists within a continuous spectrum of metabolic bacterial activity and antagonistic immunological responses. This revised understanding leads us to propose two additional clinical states: incipient and subclinical TB. The recognition of incipient and subclinical TB, which helps divide latent and active TB along the clinical disease spectrum, provides opportunities for the development of diagnostic and therapeutic interventions to prevent progression to active TB disease and transmission of TB bacilli. In this report, we review the current understanding of the pathogenesis, immunology, clinical epidemiology, diagnosis, treatment, and prevention of both incipient and subclinical TB, two emerging clinical states of an ancient bacterium.


Assuntos
Tuberculose Latente/patologia , Tuberculose/patologia , Antituberculosos/uso terapêutico , Humanos , Tuberculose Latente/tratamento farmacológico , Tuberculose Latente/imunologia , Tuberculose Latente/prevenção & controle , Mycobacterium tuberculosis , Tuberculose/tratamento farmacológico , Tuberculose/imunologia , Tuberculose/prevenção & controle
20.
Respir Physiol Neurobiol ; 251: 8-15, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29438808

RESUMO

This substudy of a large, randomized, controlled trial (NCT01072396) examined tiotropium (18 µg qd) effects on dynamic hyperinflation during constant work rate treadmill exercise. Areas-under-the-spontaneous expiratory flow-volume (SEFV)-curves were compared in 20 COPD patients and 16 age-matched untreated controls, using rectangular area ratio (RAR) between peak intrabreath and end-expiratory flow. Seven patients exhibited SEFV curve concavity with RAR ≤ 0.5 (RARlow) in ≥1 test without tiotropium; (mean ±â€¯SD FEV1: 1.60 ±â€¯0.59 L; 63.4 ±â€¯14.0%predicted). In RARlow patients, tiotropium increased end-exercise inspiratory capacity (IC, 2.10 ±â€¯0.05 vs. 1.89 ±â€¯0.05 L, tiotropium vs. placebo; p = 0.045) and RAR (0.57 ±â€¯0.02 vs. 0.53 ±â€¯0.02; p < 0.001). Patients without SEFV curve concavity with RAR > 0.5 (n = 13; RARhigh), had higher screening FEV1 (2.15 ±â€¯0.47 L; 79.6 ±â€¯10.1%predicted) versus RARlow patients and no difference in end-exercise IC and RAR between tiotropium and placebo (IC: 2.24 ±â€¯0.03 vs. 2.17 ±â€¯0.03 L; RAR: 0.63 ±â€¯0.005 vs. 0.62 ±â€¯0.005). RAR and%predicted IC at peak exercise were positively correlated in RARlow patients (R2 = 0.43, p = 0.0002). Tiotropium increased exercise RAR in GOLD 1-2 patients with SEFV curve concavity.


Assuntos
Broncodilatadores/uso terapêutico , Exercício Físico/fisiologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Ventilação Pulmonar/efeitos dos fármacos , Brometo de Tiotrópio/uso terapêutico , Idoso , Análise de Variância , Estudos Cross-Over , Método Duplo-Cego , Feminino , Seguimentos , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Cooperação Internacional , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/psicologia , Ventilação Pulmonar/fisiologia , Espirometria , Capacidade Vital/efeitos dos fármacos , Capacidade Vital/fisiologia
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