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reduced phagocytic capacity of blood monocyte/macrophages in tuberculosis patients is further reduced by smoking.tuberculosis (tb) and tobacco use are two major alarming global health issues posing immense threats to human populations. mycobacterium tuberculosis (mtb) by activation of macrophages could induce the sequences of cells activation and releases of inflammatory cytokines such as cxcl-8, il-12 and tnf-α which in turn induces the immune system network. however no information is available on other activity of cells by mtb and smoking. in the current study we aimed to investigate the serum levels tnf ...201627424132
in vitro evaluation of novel inhalable dry powders consisting of thioridazine and rifapentine for rapid tuberculosis treatment.thioridazine is an orally administered antipsychotic drug with potential for treatment of drug-resistant tuberculosis (tb). however, drug-induced adverse cardiac effects have been reported when thioridazine was used at an efficacious oral dose of 200mg/day to treat tb. pulmonary delivery of thioridazine could be a rational approach to reduce dose-related side effects while enabling high drug concentrations at the primary site of infection. the present study compares in vitro aerosol performance, ...201627422209
a multilaboratory, multicountry study to determine mic quality control ranges for phenotypic drug susceptibility testing of selected first-line antituberculosis drugs, second-line injectables, fluoroquinolones, clofazimine, and linezolid.our objective was to establish reference mic quality control (qc) ranges for drug susceptibility testing of antimycobacterials, including first-line agents, second-line injectables, fluoroquinolones, and world health organization category 5 drugs for multidrug-resistant tuberculosis using a 7h9 broth microdilution mic method. a tier-2 reproducibility study was conducted in eight participating laboratories using clinical laboratory and standards institute (clsi) guidelines. three lots of custom-m ...201627654338
a multilaboratory, multicountry study to determine bedaquiline mic quality control ranges for phenotypic drug susceptibility testing.the aim of this study was to establish standardized drug susceptibility testing (dst) methodologies and reference mic quality control (qc) ranges for bedaquiline, a diarylquinoline antimycobacterial, used in the treatment of adults with multidrug-resistant tuberculosis. two tier-2 qc reproducibility studies of bedaquiline dst were conducted in eight laboratories using clinical laboratory and standards institute (clsi) guidelines. agar dilution and broth microdilution methods were evaluated. myco ...201627654337
metabolic network for the biosynthesis of intra- and extracellular α-glucans required for virulence of mycobacterium tuberculosis.mycobacterium tuberculosis synthesizes intra- and extracellular α-glucans that were believed to originate from separate pathways. the extracellular glucose polymer is the main constituent of the mycobacterial capsule that is thought to be involved in immune evasion and virulence. however, the role of the α-glucan capsule in pathogenesis has remained enigmatic due to an incomplete understanding of α-glucan biosynthetic pathways preventing the generation of capsule-deficient mutants. three separat ...201627513637
controlled fire use in early humans might have triggered the evolutionary emergence of tuberculosis.tuberculosis (tb) is caused by the mycobacterium tuberculosis complex (mtbc), a wildly successful group of organisms and the leading cause of death resulting from a single bacterial pathogen worldwide. it is generally accepted that mtbc established itself in human populations in africa and that animal-infecting strains diverged from human strains. however, the precise causal factors of tb emergence remain unknown. here, we propose that the advent of controlled fire use in early humans created th ...201627457933
convergence of a diabetes mellitus, protein energy malnutrition, and tb epidemic: the neglected elderly population.on a global scale, nearly two billion persons are infected with mycobacterium tuberculosis. from this vast reservoir of latent tuberculosis (tb) infection, a substantial number will develop active tb during their lifetime, with some being able to transmit tb or multi-drug- resistant (mdr) tb to others. there is clinical evidence pointing to a higher prevalence of infectious diseases including tb among individuals with diabetes mellitus (dm). furthermore, ageing and diabetes mellitus may further ...201627456231
[the screening of diagnostic potential of native protein fractions of mycobacterium tuberculosis using technique of immune blotting].the technique of immune blotting was used to analyze surface proteins obtained from cells m tuberculosis exposed to partialmode of delipidization. at that, there were applied serums of patients with tuberculosis of lungs; hiv agents and patients with concomitant infection tuberculosis-aids and also hiv-negative patients without clinical signs of disease of lungs and with chronic diseases of lungs of other etiology the fractions oflow-molecular antigens with molecular mass 6.5-30 kilodaltons beca ...201627455562
induction of transcription factors, mirnas and cytokines involved in t lymphocyte differentiation in bcg-vaccinated subjects.the bcg vaccine induces a th1 phenotype, which is essential for protection against mycobacterium tuberculosis. however, the effects of bcg vaccination over time on the t helper subpopulation and the micrornas involved in adulthood have not been studied. in the present study, we explored the involvement of micrornas, transcription factors and multifunctional cytokines in bcg vaccination by examining their levels both before and after vaccination of healthy adults. peripheral blood mononuclear cel ...201627454344
global efforts in the development of vaccines for tuberculosis: requirements for improved vaccines against mycobacterium tuberculosis.currently, more than 9.0 million people develop acute pulmonary tuberculosis (tb) each year and about 1.5 million people worldwide die from this infection. thus, developing vaccines to prevent active tb disease remains a priority. this article discusses recent progress in the development of new vaccines against tb and focusses on the main requirements for development of improved vaccines against mycobacterium tuberculosis (m. tb). over the last two decades, significant progress has been made in ...201627454335
comparison of a real-time polymerase chain reaction-based system and erlich-ziehl-neelsen method with culture in the identification of mycobacterium tuberculosis.mycobacterium tuberculosis is still a major health problem throughout the world, especially in developing countries. disease control heavily depends on the establishment of early diagnosis. the aim of this study is to compare the efficacy of culture, genexpert mtb/rif device, and erlich-ziehl-neelsen direct microscopic method.201627511355
[cost-effectiveness study of the microbiological diagnosis of tuberculosis using genexpert mtb/rif(®)].to perform a cost-effectiveness analysis of a molecular biology technique for the diagnosis of tuberculosis compared to the classical diagnostic alternative.201627445177
mean platelet volume in mycobacterium tuberculosis infection.introduction. mean platelet volume (mpv) has been thought as a useful index of platelet activation. it is supposed that mpv is also associated with several inflammatory and infectious diseases. korea still has a high incidence of tuberculosis (tb). the aim of this study was to investigate mpv as an inflammatory marker in tb patients. materials and methods. mpv were determined in 221 patients with tb and 143 individuals for control group. mpv was estimated by an advia 2120 (siemens healthcare dia ...201627419136
molecular epidemiology of mycobacterium tuberculosis in baja california, mexico: a result of human migration?the state of baja california (bc) exhibits the highest incidence and prevalence rates of tuberculosis (tb), and multidrug-resistant tb (mdr-tb) in mexico. however information about the circulation of m. tuberculosis lineages in bc and mexico as a whole is limited. here, we describe the genetic relationship and genetic diversity among m. tuberculosis clinical isolates (n=140) collected in bc between october 2009 and april 2011 with other regions of mexico, the united states, and latin america. al ...201627418234
redox chemistry of mycobacterium tuberculosis alkylhydroperoxide reductase e (ahpe): structural and mechanistic insight into a mycoredoxin-1 independent reductive pathway of ahpe via mycothiol.mycobacterium tuberculosis (mtb) has the ability to persist within the human host for a long time in a dormant stage and re-merges when the immune system is compromised. the pathogenic bacterium employs an elaborate antioxidant defence machinery composed of the mycothiol- and thioredoxin system in addition to a superoxide dismutase, a catalase, and peroxiredoxins (prxs). among the family of peroxiredoxins, mtb expresses a 1-cysteine peroxiredoxin, known as alkylhydroperoxide reductase e (mtahpe) ...201627417938
assembling of the mycobacterium tuberculosis cell wall core.the unique cell wall of mycobacteria is essential to their viability and the target of many clinically used anti-tuberculosis drugs and inhibitors under development. despite intensive efforts to identify the ligase(s) responsible for the covalent attachment of the two major heteropolysaccharides of the mycobacterial cell wall, arabinogalactan (ag) and peptidoglycan (pg), the enzyme or enzymes responsible have remained elusive. we here report on the identification of the two enzymes of mycobacter ...201627417139
disseminated tuberculosis with prostatic abscesses in an immunocompromised patient-a case report and review of literature.we describe a case of disseminated mycobacterium tuberculosis (mtb) with prostatic abscess in a newly diagnosed hiv patient in the united states. the patient is a 34 year-old male who presented with respiratory symptoms and was diagnosed with hiv/aids complicated by disseminated mtb infection of the lungs, liver, and prostate. his prostate showed abscess formation on imaging that required drainage however he did not present with any genitourinary complaints. our literature review revealed that p ...201627413691
safety of recombinant fusion protein esat6-cfp10 as a skin test reagent for tuberculosis diagnosis: an open-label, randomized, single-center phase i clinical trial.this trial was conducted to explore the safety of recombinant fusion protein esat6-cfp10 as a skin test reagent for the diagnosis of mycobacterium tuberculosis infection. twenty-four healthy adult volunteers were recruited and randomized into four groups (groups a to d) to study four increasing doses of esat6-cfp10. all subjects in each dose group received an intradermal injection of reagent (0.1 ml) via the mantoux technique. then, the vital signs of all subjects were monitored, and skin reacti ...201627413070
(1)h, (15)n, (13)c resonance assignments for pyrazinoic acid binding domain of ribosomal protein s1 from mycobacterium tuberculosis.ribosomal protein s1 of mycobacterium tuberculosis (mtrpsa) binds to ribosome and mrna, and plays significant role in the regulation of translation initiation, conventional protein synthesis and transfer-messenger rna (tmrna) mediated trans-translation. it has been identified as the target of pyrazinoic acid (poa), a bactericidal moiety from hydrolysis of pyrazinamide, which is a mainstay of combination therapy for tuberculosis. poa prevented the interactions between the c-terminal s1 domain of ...201627412769
bacillus calmette-guérin (bcg) revaccination of adults with latent mycobacterium tuberculosis infection induces long-lived bcg-reactive nk cell responses.one third of the global population is estimated to be latently infected with mycobacterium tuberculosis we performed a phase i randomized controlled trial of isoniazid preventive therapy (ipt) before revaccination with bacillus calmette-guérin (bcg) in healthy, tuberculin skin test-positive (≥15-mm induration), hiv-negative south african adults. we hypothesized that preclearance of latent bacilli with ipt modulates bcg immunogenicity following revaccination. frequencies and coexpression of ifn-γ ...201627412415
homology modeling, substrate docking, and molecular simulation studies of mycobacteriophage che12 lysin a.mycobacteriophages produce lysins that break down the host cell wall at the end of lytic cycle to release their progenies. the ability to lyse mycobacterial cells makes the lysins significant. mycobacteriophage che12 is the first reported temperate phage capable of infecting and lysogenising mycobacterium tuberculosis. gp11 of che12 was found to have chitinase domain that serves as endolysin (lysin a) for che12. structure of gp11 was modeled and evaluated using ramachandran plot in which 98 % of ...201627411553
investigating essential gene function in mycobacterium tuberculosis using an efficient crispr interference system.despite many methodological advances that have facilitated investigation of mycobacterium tuberculosis pathogenesis, analysis of essential gene function in this slow-growing pathogen remains difficult. here, we describe an optimized crispr-based method to inhibit expression of essential genes based on the inducible expression of an enzymatically inactive cas9 protein together with gene-specific guide rnas (crispr interference). using this system to target several essential genes of m. tuberculos ...201627407107
synthesis and antibacterial evaluation of macrocyclic diarylheptanoid derivatives.bacterial infections, caused by mycobacterium tuberculosis and other problematic bacterial pathogens, continue to pose a significant threat to global public health. as such, new chemotype antibacterial agents are desperately needed to fuel and strengthen the antibacterial drug discovery and development pipeline. as part of our antibacterial research program to develop natural product-inspired new antibacterial agents, here we report synthesis, antibacterial evaluation, and structure-activity rel ...201627406794
tackling threats and future problems of multidrug-resistant bacteria.with the advent of the antibiotic era, the overuse and inappropriate consumption and application of antibiotics have driven the rapid emergence of multidrug-resistant pathogens. antimicrobial resistance increases the morbidity, mortality, length of hospitalization and healthcare costs. among gram-positive bacteria, staphylococcus aureus (mrsa) and multidrug-resistant (mdr) mycobacterium tuberculosis, and among the gram-negative bacteria, extended-spectrum beta-lactamase (esbls)-producing bacteri ...201627406189
benzothiazinethione is a potent preclinical candidate for the treatment of drug-resistant tuberculosis.new chemotherapeutic compounds are needed to combat multidrug-resistant mycobacterium tuberculosis (mtb), which remains a serious public-health challenge. decaprenylphosphoryl-β-d-ribose 2'-epimerase (dpre1 enzyme) has been characterized as an attractive therapeutic target to address this urgent demand. herein, we have identified a new class of dpre1 inhibitors benzothiazinethiones as antitubercular agents. benzothiazinethione analogue sklb-tb1001 exhibited excellent activity against mtb in the ...201627405961
diagnostic test of sputum genexpert mtb/rif for smear negative pulmonary tuberculosis.the objective of this study was to evaluate the performance of the gene-xpert mtb/rif sputum test for diagnosing pulmonary tuberculosis (tb) among patients sputum acid-fast bacillus (afb) smear negative results in thailand, a country with a high prevalence of pulmonary tuberculosis. we studied 151 patients who presented to srinagarind hospital, khon kaen, thailand with a 2 week or more history of fever and/or cough and an abnormal chest radiograph between 2010 and 2014; these patients had at lea ...201627405129
molecular typing of mycobacterium tuberculosis strains: a fundamental tool for tuberculosis control and elimination.tuberculosis (tb) is still an important cause of morbidity and mortality worldwide. an improvement of the strategies for disease control is necessary in both low- and high-incidence tb countries. clinicians, epidemiologists, laboratory specialists, and public health players should work together in order to achieve a significant reduction in tb transmission and spread of drug-resistant strains. effective tb surveillance relies on early diagnosis of new cases, appropriate therapy, and accurate det ...201627403266
negative screening does not rule out the risk of tuberculosis in patients with inflammatory bowel disease undergoing anti-tnf treatment: a descriptive study on the getaid cohort.to describe the characteristics of incident cases of tuberculosis [tb] despite negative tb screening tests, in patients with inflammatory bowel disease [ibd] undergoing anti-tnf treatment, and to identify the risk factors involved.201627402916
iron homeostasis in mycobacterium tuberculosis: mechanistic insights into siderophore-mediated iron uptake.mycobacterium tuberculosis requires iron for normal growth but faces a limitation of the metal ion due to its low solubility at biological ph and the withholding of iron by the mammalian host. the pathogen expresses the fe(3+)-specific siderophores mycobactin and carboxymycobactin to chelate the metal ion from insoluble iron and the host proteins transferrin, lactoferrin, and ferritin. siderophore-mediated iron uptake is essential for the survival of m. tuberculosis, as knockout mutants, which w ...201627402628
[pulmonary actinomycosis and tuberculosis. a comorbidity pediatric case].actinomycosis is a chronic suppurative infection, produced by anaerobic gram-positive bacteria or microaerobic actinomyces species. it is rare in children and adolescents and it is more common in immunocompromised. mycobacterium tuberculosis collaborates on the development of the disease. pulmonary involvement appears as a picture of chronic condensation that does not improve with conventional antibiotic treatment. classic complications affecting the thoracic wall with drainage in «sulfur granul ...201627399023
stereoselective synthesis of 1-tuberculosinyl adenosine; a virulence factor of mycobacterium tuberculosis.despite its status as one of the world's most prevalent and deadly bacterial pathogens, mycobacterium tuberculosis (mtb) infection is not routinely diagnosed by rapid and highly reliable tests. a program to discover mtb-specific biomarkers recently identified two natural compounds, 1-tuberculosinyl adenosine (1-tbad) and n(6)-tuberculosinyl adenosine (n(6)-tbad). based on their association with virulence, the lack of similar compounds in nature, the presence of multiple stereocenters, and the ne ...201627398789
population-based resistance of mycobacterium tuberculosis isolates to pyrazinamide and fluoroquinolones: results from a multicountry surveillance project.pyrazinamide and fluoroquinolones are essential antituberculosis drugs in new rifampicin-sparing regimens. however, little information about the extent of resistance to these drugs at the population level is available.201627397590
preparation, biological evaluation and molecular docking study of imidazolyl dihydropyrimidines as potential mycobacterium tuberculosis dihydrofolate reductase inhibitors.a series of novel dihydropyrimidine derivatives bearing an imidazole nucleus at c-4 position were synthesized in excellent yields via biginelli multi-component reaction. the newly synthesized compounds were characterized by ir, (1)h nmr, (13)c nmr and mass spectroscopy. in vitro antitubercular evaluation of all the newly synthesized compounds 4a-p against mycobacterium tuberculosis (mtb) h37rv showed, 4j (mic: 0.39μg/ml; si: >25.64), 4m (mic: 0.78μg/ml; si: >12.82) and 4p (mic: 0.39μg/ml; si: 24 ...201627397497
limited value of whole blood xpert(®) mtb/rif for diagnosing tuberculosis in children.we evaluated the ability of the xpert(®) mtb/rif assay to detect mycobacterium tuberculosis in whole blood of children with tuberculosis in tuberculosis endemic settings with high rates of hiv infection.201627394403
tuberculosis in older adults.tuberculosis (tb) remains one of the world's most lethal infectious diseases. preventive and control strategies among other high-risk groups, such as the elderly population, continues to be a challenge. clinical features of tb in older adults may be atypical and confused with age-related diseases. diagnosis and management of tb in the elderly person can be difficult; treatment can be associated with adverse drug reactions. this article reviews the current global epidemiology, pathogenesis, clini ...201627394018
a serine/threonine kinase pknl, is involved in the adaptive response of mycobacterium tuberculosis.mycobacterium tuberculosis adapts itself to various environmental stress conditions to thrive inside the phagosome for establishing a chronic infection. serine/threonine protein kinases (stpks) play a major role in the physiology and pathogenesis of mycobacterium tuberculosis. some of these stpks are involved in regulating the growth of the mycobacterium under nutrient stress and starvation conditions. in this study, we have investigated the role of pknl, a stpk in the adaptive responses of m. t ...201627393993
xpert(®) mtb/rif detection of mycobacterium tuberculosis from sputum collected in molecular transport medium.the xpert(®) mtb/rif assay is widely used for mycobacterium tuberculosis detection. however, specimen transport remains a challenge. primestore molecular transport medium(®) (ps-mtm) inactivates specimens and stabilizes dna/rna at ambient temperature for subsequent molecular detection.201627393549
xpert(®) mtb/rif for detection of mycobacterium tuberculosis from frozen string and induced sputum sediments.although it is now widely used for tuberculosis (tb) diagnosis, xpert(®) mtb/rif availability remains inadequate in low-resource settings. moreover, its accuracy in testing stored samples from non-expectorating patients has not been evaluated.201627393548
comparison of taqman(®) array card and mycotb(tm) with conventional phenotypic susceptibility testing in mdr-tb.although phenotypic drug susceptibility testing (dst) is endorsed as the standard for second-line drug testing of mycobacterium tuberculosis, it is slow and laborious.201627393547
detection of katg and inha mutations to guide isoniazid and ethionamide use for drug-resistant tuberculosis.depending on the presence of mutations that determine isoniazid (inh) susceptibility (katg and inha), mycobacterium tuberculosis may be susceptible to high doses of inh or ethionamide (eth).201627393546
interferon-gamma reduces the proliferation of m. tuberculosis within macrophages from a patient with a novel hypomorphic nemo mutation.x-linked ectodermal dysplasia with immunodeficiency (xl-eda-id) is caused by mutations in the nuclear factor-kappa b essential modulator (nemo) gene. here, we report the clinical and genetic features of a xl-eda-id patient who developed bacillus calmette-guérin infection. patient lymphocytes failed to degrade iκb-α, and sequencing of nemo identified the novel mutation c.1238a>c/p.h413p. furthermore, patient monocyte-derived macrophages ingested mycobacterium tuberculosis normally, but failed to ...201627391872
detection and quantification of mycobacterium tuberculosis in the sputum of culture-negative hiv-infected pulmonary tuberculosis suspects: a proof-of-concept study.rapid diagnosis of pulmonary tuberculosis (tb) is critical for timely initiation of treatment and interruption of transmission. yet, despite recent advances, many patients remain undiagnosed. culture, usually considered the most sensitive diagnostic method, is sub-optimal for paucibacillary disease.201627391604
deep whole-genome sequencing to detect mixed infection of mycobacterium tuberculosis.mixed infection by multiple mycobacterium tuberculosis (mtb) strains is associated with poor treatment outcome of tuberculosis (tb). traditional genotyping methods have been used to detect mixed infections of mtb, however, their sensitivity and resolution are limited. deep whole-genome sequencing (wgs) has been proved highly sensitive and discriminative for studying population heterogeneity of mtb. here, we developed a phylogenetic-based method to detect mtb mixed infections using wgs data. we c ...201627391214
preliminary evaluation of a new kit for differentiation of mycobacterium tuberculosis complex species using speed-oligo mtbc.we present the first evaluation of a novel molecular assay, the speed-oligo mycobacterium tuberculosis complex (so-mtbc), which is based on pcr combined with a dipstick for the differentiation of m. tuberculosis complex (mtbc) members. the results of this assay were compared with findings obtained using the genotype mtbc assay. in this study, 189 strains of mtbc isolates from 2011 to 2014 were evaluated to determine the mtbc species. most (174, 92 %) of the strains were identified as m. tubercul ...201627389862
predicting promiscuous antigenic t cell epitopes of mycobacterium tuberculosis myma operon proteins binding to mhc class i and class ii molecules.limited efficacy of bacillus calmette-guérin vaccine has raised the need to explore other immunogenic candidates to develop an effective vaccine against mycobacterium tuberculosis (mtb). both cd4+ and cd8+ t cells play a critical role in host immunity to mtb. infection of macrophages with mtb results in upregulation of myma operon genes thereby suggesting their importance as immune targets. in the present study, after exclusion of self-peptides myma operon proteins of mtb were analyzed in silico ...201627389362
schistosome soluble egg antigen decreases mycobacterium tuberculosis-specific cd4+ t-cell effector function with concomitant arrest of macrophage phago-lysosome maturation.helminth-infected individuals possess a higher risk of developing tuberculosis, but the precise immunologic mechanism of mycobacterium tuberculosis control remains unclear. we hypothesized that a perturbation of the m. tuberculosis-specific cd4(+) t-cell response weakens the ability of macrophages to contain m. tuberculosis we exposed peripheral blood mononuclear cells from m. tuberculosis-infected humans to schistosome soluble egg antigen (sea) and then profiled m. tuberculosis-specific cd4(+) ...201627389351
role of interleukin 36γ in host defense against tuberculosis.tuberculosis remains a major killer worldwide, not the least because of our incomplete knowledge of protective and pathogenic immune mechanism. the roles of the interleukin 1 (il-1) and interleukin 18 pathways in host defense are well established, as are their regulation through the inflammasome complex. in contrast, the regulation of interleukin 36γ (il-36γ), a recently described member of the il-1 family, and its immunological relevance in host defense remain largely unknown. here we show that ...201627389350
draft genome sequence of a new zealand rangipo strain of mycobacterium tuberculosis.the rangipo genotype of the mycobacterium tuberculosis complex has been associated with a number of tuberculosis (tb) outbreaks in new zealand. we report here the draft whole-genome sequence of a representative isolate of this strain.201627389273
evidence to support the hypothesis of tuberculosis as a cause of extreme osteonecrosis and osteomyelitis of the mandible in a west african population.maxillofacial tuberculosis (tb) is rare. the cases of 19 patients showing extreme bony destruction in the mandible, collected over a 3-month period in west africa, are presented. clinical, radiographic, and histological evidence indicated mycobacterium tuberculosis as a possible cause. further studies are in progress.201627388429
antibacterial and anticancer activity of a series of novel peptides incorporating cyclic tetra-substituted c(α) amino acids.eleven antimicrobial peptides (amp) based on the incorporation of cyclic tetra substituted c(α) amino acids, as well as other unnatural amino acids were designed, synthesized and screened for in vitro activity against 18 strains of bacteria as well as 12 cancer cell lines. the amps discussed herein are derived from the following peptide sequence: ac-gf(x)g(x)b(x)g(x)f(x)g(x)gb(x)bbbb-amide, x=any one of the following residues, a5c, a6c, tic or oic and b=any one of the following residues, arg, ly ...201627387357
sustained activation of mtorc1 in macrophages increases ampkα-dependent autophagy to maintain cellular homeostasis.the mechanistic target of rapamycin complex 1 (mtorc1) is a well-conserved serine/threonine protein kinase that controls autophagy as well as many other processes such as protein synthesis, cell growth, and metabolism. the activity of mtorc1 is stringently and negatively controlled by the tuberous sclerosis proteins 1 and 2 complex (tsc1/2).201627387347
the emerging role of gasotransmitters in the pathogenesis of tuberculosis.mycobacterium tuberculosis (mtb) is a facultative intracellular pathogen and the second largest contributor to global mortality caused by an infectious agent after hiv. in infected host cells, mtb is faced with a harsh intracellular environment including hypoxia and the release of nitric oxide (no) and carbon monoxide (co) by immune cells. hypoxia, no and co induce a state of in vitro dormancy where mtb senses these gases via the doss and dost heme sensor kinase proteins, which in turn induce a ...201627387335
adjunctive role of mmp-9 inhibition along with conventional anti-tubercular drugs against experimental tuberculous meningitis.tuberculous meningitis (tbm) is an outcome of neuroinflammatory degeneration caused due to mycobacterium tuberculosis infection and leads to death or neurological disabilities in the affected individuals. it causes the highest morbidity and mortality amongst all forms of tuberculosis. matrix metalloproteinase-9 levels increase and cause inflammatory destruction during progression of the disease. although corticosteroids are usually given as an adjuvant therapy to overcome these complications, tr ...201627385155
stat3 represses nitric oxide synthesis in human macrophages upon mycobacterium tuberculosis infection.mycobacterium tuberculosis is a successful intracellular pathogen. numerous host innate immune responses signaling pathways are induced upon mycobacterium invasion, however their impact on m. tuberculosis replication is not fully understood. here we reinvestigate the role of stat3 specifically inside human macrophages shortly after m. tuberculosis uptake. we first show that stat3 activation is mediated by il-10 and occurs in m. tuberculosis infected cells as well as in bystander non-colonized ce ...201627384401
pet ct identifies reactivation risk in cynomolgus macaques with latent m. tuberculosis.mycobacterium tuberculosis infection presents across a spectrum in humans, from latent infection to active tuberculosis. among those with latent tuberculosis, it is now recognized that there is also a spectrum of infection and this likely contributes to the variable risk of reactivation tuberculosis. here, functional imaging with 18f-fluorodeoxygluose positron emission tomography and computed tomography (pet ct) of cynomolgus macaques with latent m. tuberculosis infection was used to characteriz ...201627379816
severe early-onset combined immunodeficiency due to heterozygous gain-of-function mutations in stat1.loss and gain-of-function (gof) mutations in human signal transducer and activator of transcription 1 (stat1) lead to distinct phenotypes. although recurrent infections are common to both types of stat1 mutations, gof mutations are distinguished by chronic mucocutaneous candidiasis and autoimmunity. however, the clinical spectra of stat1 gof mutations continue to expand. we here describe two patients with stat1 gof mutations presenting early in life with combined immunodeficiency (cid).201627379765
inhibitors of the cysteine synthase cysm with antibacterial potency against dormant mycobacterium tuberculosis.cysteine is an important amino acid in the redox defense of mycobacterium tuberculosis, primarily as a building block of mycothiol. genetic studies have implicated de novo cysteine biosynthesis in pathogen survival in infected macrophages, in particular for persistent m. tuberculosis. here, we report on the identification and characterization of potent inhibitors of cysm, a critical enzyme in cysteine biosynthesis during dormancy. a screening campaign of 17 312 compounds identified ligands that ...201627379713
diagnosis of ocular tuberculosis.ocular tuberculosis remains a presumptive clinical diagnosis, as the gold standard tests for diagnosing ocular tuberculosis are often not useful: mycobacterium tuberculosis cultures require weeks to process on lowenstein-jenson media and have low yield from ocular samples; while acid-fast bacilli smears or polymerase chain reaction detection of m. tuberculosis dna have low sensitivities. thus, diagnosis is often based on suggestive clinical signs, which are supported by positive investigations: ...201627379384
combined expression of ifn-γ, il-17, and il-4 mrna by recall pbmcs moderately discriminates active tuberculosis from latent mycobacterium tuberculosis infection in patients with miscellaneous inflammatory underlying conditions.new biomarkers are needed for discriminating active tuberculosis (tb) from latent tb infection (ltbi), especially in vulnerable groups representing the major diagnostic challenge. this pilot study was carried out to explore the diagnostic potential of selected genes, ifn-γ, il-17, il-4, and foxp3, associated with tb immunity and immunopathology. ifn-γ, il-17, il-4, and foxp3 mrna expression levels were measured by quantitative reverse transcription pcr (rt-qpcr) from antigen-stimulated periphera ...201627379100
pharmacologic inhibition of host phosphodiesterase-4 improves isoniazid-mediated clearance of mycobacterium tuberculosis.the lengthy duration of multidrug therapy needed to cure tuberculosis (tb) poses significant challenges for global control of the disease. moreover, chronic inflammation associated with tb leads to pulmonary damage that can remain even after successful cure. thus, there is a great need for the development of effective shorter drug regimens to improve clinical outcome and strengthen tb control. host-directed therapy (hdt) is emerging as a novel adjunctive strategy to enhance the efficacy and shor ...201627379099
evaluation of a high-intensity green fluorescent protein fluorophage method for drug- resistance diagnosis in tuberculosis for isoniazid, rifampin, and streptomycin.a novel method for detecting drug resistance in mycobacterium tuberculosis using mycobacteriophage φ (2) gfp10 was evaluated with clinical isolates. the phage facilitates microscopic fluorescence detection due to the high expression of green fluorescence protein which also simplifies the operative protocol as well. a total of 128 clinical isolates were tested by the phage assay for isoniazid (inh), rifampin (rif), and streptomycin (str) resistance while conventional drug susceptibility test, by ...201627379052
quantifying limits on replication, death, and quiescence of mycobacterium tuberculosis in mice.when an individual is exposed to mycobacterium tuberculosis (mtb) three outcomes are possible: bacterial clearance, active disease, or latent infection. it is generally believed that most individuals exposed to mtb become latently infected and carry the mycobacteria for life. how mtb is maintained during this latent infection remains largely unknown. during an mtb infection in mice, there is a phase of rapid increase in bacterial numbers in the murine lungs within the first 3 weeks, and then bac ...201627379030
analysis of expression profile of mce operon genes (mce1, mce2, mce3 operon) in different mycobacterium tuberculosis isolates at different growth phases.mycobacterium tuberculosis (m. tuberculosis) has four homologous mammalian cell entry (mce) operons (mce1-4) that encode exported proteins and have a possible role in the virulence mechanism of this pathogen. the expression of mce operon is considered to be complex and not completely understood. although expression of mce operon at different in vitro growth phases has been studied earlier, its expression in different m. tuberculosis isolates under different growth phases is not yet studied. the ...201627377506
genetic diversity of mycobacterium tuberculosis isolates from central india.there is a paucity of data available on genetic biodiversity of mycobacterium tuberculosis isolates from central india. the present study was carried out on isolates of m. tuberculosis cultured from diagnostic clinical samples of patients from bhopal, central india, using spoligotyping as a method of molecular typing.201627377505
molecular and growth-based drug susceptibility testing of mycobacterium tuberculosis complex for ethambutol resistance in the united states.ethambutol (emb) is used as a part of drug regimens for treatment of tuberculosis (tb). susceptibility of mycobacterium tuberculosis complex (mtbc) isolates to emb can be discerned by dna sequencing to detect mutations in the embb gene associated with resistance. us public health laboratories (phl) primarily use growth-based drug susceptibility test (dst) methods to determine emb resistance. the centers for disease control and prevention (cdc) provides a service for molecular detection of drug r ...201627375902
functional, structural and epitopic prediction of hypothetical proteins of mycobacterium tuberculosis h37rv: an in silico approach for prioritizing the targets.the global control of tuberculosis (tb) remains a great challenge from the standpoint of diagnosis, detection of drug resistance, and treatment. major serodiagnostic limitations include low sensitivity and high cost in detecting tb. on the other hand, treatment measures are often hindered by low efficacies of commonly used drugs and resistance developed by the bacteria. hence, there is a need to look into newer diagnostic and therapeutic targets. the proteome information available suggests that ...201627374154
monitoring antigenic protein integrity during glycoconjugate vaccine synthesis using capillary electrophoresis-mass spectrometry.a capillary electrophoresis-mass spectrometry (ce-ms) method was developed for the characterization and integrity assessment of the mycobacterium tuberculosis (mtb) antigens tb10.4 and ag85b and their chemically produced glycoconjugates, which are glycovaccine candidates against tuberculosis (tb). in order to prevent protein adsorption to the inner capillary wall and to achieve efficient separation of the antigen proteoforms, a polyionic multilayer coating of polybrene-dextran sulfate-polybrene ...201627372716
engineering another class of anti-tubercular lead: hit to lead optimization of an intriguing class of gyrase atpase inhibitors.a structure based medium throughput virtual screening campaign of bits-pilani in house chemical library to identify novel binders of mycobacterium tuberculosis gyrase atpase domain led to the discovery of a quinoline scaffold. further medicinal chemistry explorations on the right hand core of the early hit, engendered a potent lead demonstrating superior efficacy both in the enzyme and whole cell screening assay. the binding affinity shown at the enzyme level was further corroborated by biophysi ...201627371925
[ag85b and bcg enhance immune activity of dendritic cells in patients with initially treated tuberculosis].objective to investigate the regulatory effects of mycobacterium tuberculosis major secreted protein ag85b and bacillus calmette-guerin (bcg) on the immune function of dendritic cells (dcs) in the patients with tuberculosis who have received an initial treatment. methods the peripheral blood mononuclear cells were collected and separated in 26 healthy subjects and 31 patients with tuberculosis who had been treated initially. every specimen was divided into 4 groups and dcs were induced and cultu ...201627371851
[secretory acid phosphatase of mycobacterium tuberculosis inhibits the autophagy of murine macrophages].objective to investigate the effect of secretory acid phosphatase as a virulence factor of mycobacterium tuberculosis (sapm) on the autophagy of murine macrophages. methods gfp-lc3-raw264.7 cells were treated with sapm, wortmannin, or starvation. then the formation of autophagosomes was observed under a fluorescence microscope. the level of microtubule-associated protein 1 light chain 3 (lc3) ii was detected using western blotting. after chloroquine was added in the sapm-treated cells, lc3ii lev ...201627371835
structural and biochemical insight into the mechanism of rv2837c from mycobacterium tuberculosis as a c-di-nmp phosphodiesterase. 201627371563
dynamic igg antibody response to immunodominant antigens of m. tuberculosis for active tb diagnosis in high endemic settings.even though various techniques have been developed for rapid diagnosis of tuberculosis (tb), still there is an immense need for a simple, cost effective, highly sensitive and specific test. hence, one of the possibilities is identification of mycobacterium tuberculosis specific antibodies in infected serum by using specific antigens.201627370403
tuberculosis therapy modifies the cytokine profile, maturation state, and expression of inhibitory molecules on mycobacterium tuberculosis-specific cd4+ t-cells.little is known about the expression of inhibitory molecules cytotoxic t-lymphocyte antigen-4 (ctla-4) and programmed-death-1 (pd-1) on mycobacterium tuberculosis (mtb)-specific cd4 t-cells and how their expression is impacted by tb treatment.201627367521
nlrp3 activation was regulated by dna methylation modification during mycobacterium tuberculosis infection.mycobacterium tuberculosis (mtb) infection activates the nlrp3 inflammasome in macrophages and dendritic cells. much attention has been paid to the mechanisms for regulation of nlrp3 against mtb. however, whether epigenetic mechanisms participated in nlrp3 activation is still little known. here we showed that nlrp3 activation was regulated by dna methylation modification. mtb infection promoted nlrp3 activation and inflammatory cytokines expression. nlrp3 promoter was cloned and subsequently ide ...201627366746
macrophage immune response suppression by recombinant mycobacterium tuberculosis antigens, the esat-6, cfp-10, and esat-6/cfp-10 fusion proteins.macrophage immune responses are affected by the secretory proteins of mycobacterium tuberculosis (mtb). this study aimed to examine the immune responses of macrophages to mtb secretory antigens, namely esat-6, cfp-10, and esat-6/cfp-10.201627365551
whole-genome shotgun sequencing and annotation of mycobacterium tuberculosis mtb221/11 isolated from a cerebrospinal fluid sample in malaysia.here, we report of the annotated genome sequence of mycobacterium tuberculosis mtb221/11. the organism was isolated from the cerebrospinal fluid of a patient in malaysia.201627365342
mefloquine and its oxazolidine derivative compound are active against drug-resistant mycobacterium tuberculosis strains and in a murine model of tuberculosis infection.repurposing of drugs to treat tuberculosis (tb) has been considered an alternative to overcome the global tb epidemic, especially to combat drug-resistant forms of the disease. mefloquine has been reported as a potent drug to kill drug-resistant strains of mycobacterium tuberculosis. in addition, mefloquine-derived molecules have been synthesised and their effectiveness against mycobacteria has been assessed. in this work, we demonstrate for the first time the activities of mefloquine and its ox ...201627364701
rv2074 is a novel f420 h2 -dependent biliverdin reductase in mycobacterium tuberculosis.bilirubin is a potent antioxidant that is produced from the reduction of the heme degradation product biliverdin. in mammalian cells and cyanobacteria, nadh/nadph-dependent biliverdin reductases (bvrs) of the rossmann-fold have been shown to catalyze this reaction. here, we describe the characterization of rv2074 from mycobacterium tuberculosis, which belongs to a structurally and mechanistically distinct family of f420 h2 -dependent bvrs (f-bvrs) that are exclusively found in actinobacteria. we ...201627364382
polymorphisms in the pattern recognition receptor mincle gene (clec4e) and association with tuberculosis.the mechanisms involved in interactions between mycobacterium tuberculosis and host innate immune cells determine outcome. antigen-presenting cells, including macrophages and dendritic cells, express many pattern recognition receptors to identify pathogen-associated molecular patterns, thereby initiating an immune response. a major mycobacterial virulence factor, trehalose-6',6-dimycolate, is recognised by the macrophage-inducible c-type lectin, mincle, which leads to the activation of the syk-c ...201627363694
burden of respiratory tract infections at post mortem in zambian children.autopsy studies are the gold standard for determining cause-of-death and can inform on improved diagnostic strategies and algorithms to improve patient care. we conducted a cross-sectional observational autopsy study to describe the burden of respiratory tract infections in inpatient children who died at the university teaching hospital in lusaka, zambia.201627363601
deciphering the recent phylogenetic expansion of the originally deeply rooted mycobacterium tuberculosis lineage 7.a deeply rooted phylogenetic lineage of mycobacterium tuberculosis (m. tuberculosis) termed lineage 7 was discovered in ethiopia. whole genome sequencing of 30 lineage 7 strains from patients in ethiopia was performed. intra-lineage genome variation was defined and unique characteristics identified with a focus on genes involved in dna repair, recombination and replication (3r genes).201627363525
forensic analysis reveals acute decompensation of chronic heart failure in a 3500-year-old egyptian dignitary.naturally preserved and embalmed bodies from archeological contexts represent a powerful source of information for forensic investigators. they allow one to ascertain pathology, cause of death, to enhance diagnostic methodology, and to improve the analysis of altered remains. we investigated the complete head and lung remnants of a 3,500-year-old egyptian dignitary by radiological, microscopic, and genetic approaches. the individual, a middle-aged male, suffered from severe periodontitis, mild a ...201627362779
diagnosis and treatment of tb patients with rifampicin resistance detected using xpert(®) mtb/rif in zimbabwe.in zimbabwe, there are concerns about the management of tuberculosis (tb) patients with rifampicin (rmp) resistance diagnosed using xpert(®) mtb/rif.201627358806
pre-multidrug-resistant mycobacterium tuberculosis infection causing fatal enteric disease in a dog from a family with history of human tuberculosis.this report describes a fatal case of a pet dog with major enteric signs owned by a family that has experienced cases of pulmonary tuberculosis (tb) in the household. clinical and epidemiological aspects, imaging data, microbiological, haematological and histopathological examinations were assessed to diagnosis of disease. gyrb-rflp, spoligotyping and miru-vntr allowed molecular detection of m. tuberculosis strain from s family. the resazurin microtiter assay indicated that all isolates were res ...201627357532
proteome analysis of the mycobacterium tuberculosis beijing b0/w148 cluster.beijing b0/w148, a "successful" clone of mycobacterium tuberculosis, is widespread in the russian federation and some countries of the former soviet union. here, we used label-free gel-lc-ms/ms shotgun proteomics to discover features of beijing b0/w148 strains that could explain their success. qualitative and quantitative proteome analyses of beijing b0/w148 strains allowed us to identify 1,868 proteins, including 266 that were differentially abundant compared with the control strain h37rv. to p ...201627356881
mra_1571 is required for isoleucine biosynthesis and improves mycobacterium tuberculosis h37ra survival under stress.threonine dehydratase is a pyridoxal 5-phosphate dependent enzyme required for isoleucine biosynthesis. threonine dehydratase (ilva) participates in conversion of threonine to 2-oxobutanoate and ammonia is released as a by-product. mra_1571 is annotated to be coding for ilva in mycobacterium tuberculosis h37ra (mtb-ra). we developed a recombinant (kd) mtb-ra strain by down-regulating ilva. the growth studies on different carbon sources suggested reduced growth of kd compared to wild-type (wt), a ...201627353854
biochemical evidence for relaxed substrate specificity of nα-acetyltransferase (rv3420c/rimi) of mycobacterium tuberculosis.nα-acetylation is a naturally occurring irreversible modification of n-termini of proteins catalyzed by nα-acetyltransferases (nats). although present in all three domains of life, it is little understood in bacteria. the functional grouping of nats into six types nata - natf, in eukaryotes is based on subunit requirements and stringent substrate specificities. bacterial orthologs are phylogenetically divergent from eukaryotic nats, and only a couple of them are characterized biochemically. acco ...201627353550
characterization of a putative arsr transcriptional regulator encoded by rv2642 from mycobacterium tuberculosis. 201627353442
inhaled pyrazinoic acid esters for the treatment of tuberculosis.analog development of existing drugs and direct drug delivery to the lungs by inhalation as treatments for multiple and extensively drug resistant (mdr and xdr) tuberculosis (tb) represent new therapeutic strategies. pyrazinamide (pza) is critical to drug sensitive tb therapy and is included in regimens for mdr tb. however, pza-resistant mycobacterium tuberculosis (mtb) strains threaten its use. pyrazinoic acid esters (paes) are pza analogs effective against mtb in vitro, including against the m ...201627351427
mycobacterium tuberculosis lipoproteins in virulence and immunity - fighting with a double-edged sword.bacterial lipoproteins are secreted membrane-anchored proteins characterized by a lipobox motif. this lipobox motif directs post-translational modifications at the conserved cysteine through the consecutive action of three enzymes: lgt, lspa and lnt, which results in di- or triacylated forms. lipoproteins are abundant in all bacteria including mycobacterium tuberculosis and often involved in virulence and immunoregulatory processes. on the one hand, disruption of the biosynthesis pathway of lipo ...201627350117
mycobacterium tuberculosis-associated synthetic mycolates differentially exert immune stimulatory adjuvant activity.mycolic acids (mas) are highly hydrophobic long-chain α-alkyl β-hydroxy fatty acids present in the cell wall of mycobacterium tuberculosis (mtb) as a complex mixture of molecules with a common general structure but with variable functional groups in the meromycolate chain. in this study, we addressed the relationship between the ma molecular structure and their contribution to the development of t-cell immune responses. hereto, we used the model antigen ovalbumin and single synthetic mas, differ ...201627349218
searching for new leads for tuberculosis: design, synthesis, and biological evaluation of novel 2-quinolin-4-yloxyacetamides.in this study, a new series of more than 60 quinoline derivatives has been synthesized and evaluated against mycobacterium tuberculosis (h37rv). apart from the sar exploration around the initial hits, the optimization process focused on the improvement of the physicochemical properties, cytotoxicity, and metabolic stability of the series. the best compounds obtained exhibited mic values in the low micromolar range, excellent intracellular antimycobacterial activity, and an improved physicochemic ...201627348630
induction of a stable sigma factor sigr by translation-inhibiting antibiotics confers resistance to antibiotics.antibiotic-producing streptomycetes are rich sources of resistance mechanisms against endogenous and exogenous antibiotics. an ecf sigma factor σ(r) (sigr) is known to govern the thiol-oxidative stress response in streptomyces coelicolor. amplification of this response is achieved by producing an unstable isoform of σ(r) called σ(r'). in this work, we present evidence that antibiotics induce the sigr regulon via a redox-independent pathway, leading to antibiotic resistance. the translation-inhib ...201627346454
mycobacterium tuberculosis ruvx is a holliday junction resolvase formed by dimerisation of the monomeric yqgf nuclease domain. 201627345943
correction for chen et al., rolling circle amplification for direct detection of rpob gene mutations in mycobacterium tuberculosis isolates from clinical specimens. 201627343297
global burden of drug-resistant tuberculosis in children: a mathematical modelling study.after infection with mycobacterium tuberculosis, children are at an increased risk of progression to tuberculosis disease; a condition that can be challenging to diagnose. new estimation approaches for children have highlighted the gap between incidence and notifications of m tuberculosis, and suggest there are more cases of isoniazid-resistant and multidrug-resistant (mdr) disease than are identified. no work has yet quantified the burden of drug-resistant infection, or accounted for other type ...201627342768
[latent-disseminated tuberculosis revealed by atypical skin ulcerations].cutaneous tuberculosis (ct) is rare in industrialized countries. given the clinicopathological polymorphism and the difficulty of isolating the pathogen, diagnosis can be difficult. the condition may be associated with other known locations of the disease or in rare cases, it may be a tell-tale sign, as in our case, in which leg ulcers revealed paucisymptomatic disseminated tuberculosis.201627342431
[tuberculous prosthetic knee joint infection: a case report and literature review].prosthetic late infection occurs in the second month after surgery in the context of haematogenous spread from another source. prosthetic mycobacterial infection is a rare complication whose clinical management is not standardized.201627341025
multiple subcutaneous granulomas and severe rhinitis after intradermal deposition of epoxy: a case report.we present an unusual case of subcutaneous granulomas that also highlights the importance of assessing possible associations between exposure and symptoms early in the diagnostic approach to prevent further adverse health effects. granulomas of the skin are seen in association with several diseases and after foreign body penetration of soft tissue, but have not been described after contact with epoxy. epoxy resins are commonly used in paints and other protective coatings, including flooring mate ...201627340424
annotated sequence of mycobacterium tuberculosis mtbr3/09 isolated from a sputum sample in malaysia.this is a report of the annotated genome sequence of mycobacterium tuberculosis mtbr3/09. the organism was isolated from a sputum sample in malaysia.201627340055
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