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https://www.readbyqxmd.com/read/29161093/b-cells-producing-type-i-interferon-modulate-macrophage-polarization-in-tuberculosis
#1
Alan Bénard, Imme Sakwa, Pablo Schierloh, André Colom, Ingrid Mercier, Ludovic Tailleux, Luc Jouneau, Pierre Boudinot, Talal Al-Saati, Roland Lang, Jan Rehwinkel, Andre G Loxton, Stefan He Kaufmann, Véronique Anton-Leberre, Anne O'Garra, Maria Del Carmen Sasiain, Brigitte Gicquel, Simon Fillatreau, Olivier Neyrolles, Denis Hudrisier
RATIONALE: In addition to their well-known function as antibody-producing cells, B lymphocytes can markedly influence the course of infectious or non-infectious diseases via antibody-independent mechanisms. In tuberculosis, B cells accumulate in lungs, yet their functional contribution to the host response remains poorly understood. OBJECTIVES: To document the role of B cells in tuberculosis in an unbiased manner. METHODS: We generated the transcriptome of B cells isolated from Mycobacterium tuberculosis (Mtb)-infected mice, and validated the identified key pathways using in vitro and in vivo assays...
November 21, 2017: American Journal of Respiratory and Critical Care Medicine
https://www.readbyqxmd.com/read/29158372/enhancing-next-generation-sequencing-guided-cancer-care-through-cognitive-computing
#2
Nirali M Patel, Vanessa V Michelini, Jeff M Snell, Saianand Balu, Alan P Hoyle, Joel S Parker, Michele C Hayward, David A Eberhard, Ashley H Salazar, Patrick McNeillie, Jia Xu, Claudia S Huettner, Takahiko Koyama, Filippo Utro, Kahn Rhrissorrakrai, Raquel Norel, Erhan Bilal, Ajay Royyuru, Laxmi Parida, H Shelton Earp, Juneko E Grilley-Olson, D Neil Hayes, Stephen J Harvey, Norman E Sharpless, William Y Kim
BACKGROUND: Using next-generation sequencing (NGS) to guide cancer therapy has created challenges in analyzing and reporting large volumes of genomic data to patients and caregivers. Specifically, providing current, accurate information on newly approved therapies and open clinical trials requires considerable manual curation performed mainly by human "molecular tumor boards" (MTBs). The purpose of this study was to determine the utility of cognitive computing as performed by Watson for Genomics (WfG) compared with a human MTB...
November 20, 2017: Oncologist
https://www.readbyqxmd.com/read/29158203/p2x7-receptor-in-spinal-tuberculosis-gene-polymorphisms-and-protein-levels-in-chinese-han-population
#3
Ying Zhou, Chun-Yan Tan, Zhi-Jiang Mo, Qi-le Gao, Dan He, Jiong Li, Rong-Fu Huang, Yan-Bing Li, Chao-Feng Guo, Qiang Guo, Long-Jie Wang, Guan-Teng Yang, Hong-Qi Zhang
Spinal tuberculosis (TB) accounts for 1%-5% of all TB infections. Host genetic variation influences susceptibility to Mycobacterium tuberculosis (MTB). P2X7 receptor (P2X7R) expressed on cells has been identified as a regulatory molecule in cell death/apoptosis, killing of intercellular pathogens, and bone turnover. This study investigated the P2X7 gene polymorphisms and protein levels in spinal TB. P2X7 gene -762C>T and 489C>T polymorphisms were genotyped. The expression of P2X7R in bone or intervertebral disc (ID) tissues was analyzed by Western blot assay...
November 17, 2017: Infection, Genetics and Evolution
https://www.readbyqxmd.com/read/29157227/metabolic-adaptation-of-two-in-silico-mutants-of-mycobacterium-tuberculosis-during-infection
#4
Víctor A López-Agudelo, Andres Baena, Howard Ramirez-Malule, Silvia Ochoa, Luis F Barrera, Rigoberto Ríos-Estepa
BACKGROUND: Up to date, Mycobacterium tuberculosis (Mtb) remains as the worst intracellular killer pathogen. To establish infection, inside the granuloma, Mtb reprograms its metabolism to support both growth and survival, keeping a balance between catabolism, anabolism and energy supply. Mtb knockouts with the faculty of being essential on a wide range of nutritional conditions are deemed as target candidates for tuberculosis (TB) treatment. Constraint-based genome-scale modeling is considered as a promising tool for evaluating genetic and nutritional perturbations on Mtb metabolic reprogramming...
November 21, 2017: BMC Systems Biology
https://www.readbyqxmd.com/read/29154831/detection-of-mycobacterium-tuberculosis-derived-dna-in-circulating-cell-free-dna-from-a-patient-with-disseminated-infection-with-digital-pcr
#5
Masaki Yamamoto, Ryota Ushio, Hiroki Watanabe, Takayoshi Tachibana, Masatsugu Tanaka, Tomoyuki Yokose, Jun Tsukiji, Hideaki Nakajima, Takeshi Kaneko
Mycobacterium tuberculosis (MTB) can disseminate to extra-pulmonary organs, particularly in severely immunosuppressed patients. Confirmation of active MTB infection is often difficult in subjects with contraindication for invasive procedures. We herein report a case of disseminated MTB infection after hematopoietic stem cell transplantation. Circulating cell free DNA of the patient showed positive amplification for a MTB complex specific sequence using digital PCR technique. MTB infection could be confirmed with positive acid fast stain and approved quantitative PCR assay using the liver tissue obtained at an autopsy...
November 14, 2017: International Journal of Infectious Diseases: IJID
https://www.readbyqxmd.com/read/29151636/bedaquiline-fallible-hope-against-drug-resistant-tuberculosis
#6
REVIEW
Priya Singh, Rashmi Kumari, Rup Lal
Tuberculosis (TB) is a deadly bacterial infectious disease caused by intra-cellular pathogen Mycobacterium tuberculosis (Mtb). There were an estimated 1.4 million TB deaths in 2015 and an additional 0.4 million deaths resulting from TB among individuals with HIV. Drug-discovery for its cure is very slow in comparison with the causative organism's fast pace of mutations conferring drug resistance. Moreover, the field of drug-discovery of anti-TB drugs is constantly being challenged by the drug resistant strains of Mtb...
December 2017: Indian Journal of Microbiology
https://www.readbyqxmd.com/read/29148755/novel-anti-tubercular-6-dialkylaminopyrimidine-carboxamides-from-phenotypic-whole-cell-high-throughput-screening-of-a-softfocus-library-structure-activity-relationship-and-target-identification-studies
#7
Colin R Wilson, Richard K Gessner, Atica Moosa, Ronnett Seldon, Digby F Warner, Valerie Mizrahi, Candice Soares de Melo, Sandile B Simelane, Aloysius T Nchinda, Efrem Abay, Dale Taylor, Mathew Njoroge, Christel Brunschwig, Nina Lawrence, Helena I M Boshoff, Clifton E Barry, Frederick A Sirgel, Paul van Helden, C John Harris, Richard Gordon, Sonja Ghidelli-Disse, Hannah Pflaumer, Markus Boesche, Gerard Drewes, Olalla Sanz, Gracia Santos, Maria José Rebollo-Lopez, Beatriz Urones, Carolyn Selenski, Maria Jose Lafuente-Monasterio, Matthew Axtman, Joël Lelièvre, Lluis Ballell, Rudolf Mueller, Leslie J Street, Sandeep R Ghorpade, Kelly Chibale
A BioFocus DPI SoftFocus library of ~35,000 compounds was screened against Mycobacterium tuberculosis (Mtb) in order to identify novel hits with anti-tubercular activity. The hits were evaluated in biology triage assays to exclude compounds suggested to function via frequently encountered promiscuous mechanisms of action including inhibition of the QcrB subunit of the cytochrome bc1 complex, disruption of cell-wall homeostasis, and DNA damage. Among the hits which passed this screening cascade, a 6-dialkylaminopyrimidine carboxamide series was prioritized for hit to lead optimization...
November 17, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29142046/quantitative-analysis-of-interferon-%C3%AE-release-assay-response-in-children-with-latent-and-active-tuberculosis
#8
Giulia Lombardi, Roberta Petrucci, Ilaria Corsini, Maria Letizia Bacchi Reggiani, Francesca Visciotti, Filippo Bernardi, Maria Paola Landini, Salvatore Cazzato, Paola Dal Monte
The use of interferon-γ (IFN-γ) release assays (IGRAs) for the diagnosis of tuberculosis (TB) infection in children is still under debate because of concerns about their immature immune response.The aim of this study was to investigate quantitative values of QuantiFERON®-TB Gold In-Tube (QFT-IT), a commercially available IGRA, in a large cohort of children screened for TB infection.A retrospective analysis was conducted on samples from 517 children aged 0-14 years old at the Pediatric Unit of S. Orsola-Malpighi University Hospital of Bologna (Italy); quantitative responses to QFT-IT stimuli were analyzed according to diagnosis and age...
November 15, 2017: Journal of Clinical Microbiology
https://www.readbyqxmd.com/read/29141986/arfgap1-restricts-mycobacterium-tuberculosis-entry-by-controlling-the-actin-cytoskeleton
#9
Ok-Ryul Song, Christophe J Queval, Raffaella Iantomasi, Vincent Delorme, Sabrina Marion, Romain Veyron-Churlet, Elisabeth Werkmeister, Michka Popoff, Isabelle Ricard, Samuel Jouny, Nathalie Deboosere, Frank Lafont, Alain Baulard, Edouard Yeramian, Laurent Marsollier, Eik Hoffmann, Priscille Brodin
The interaction of Mycobacterium tuberculosis (Mtb) with pulmonary epithelial cells is critical for early stages of bacillus colonization and during the progression of tuberculosis. Entry of Mtb into epithelial cells has been shown to depend on F-actin polymerization, though the molecular mechanisms are still unclear. Here, we demonstrate that mycobacterial uptake into epithelial cells requires rearrangements of the actin cytoskeleton, which are regulated by ADP-ribosylation factor 1 (Arf1) and phospholipase D1 (PLD1), and is dependent on the M3 muscarinic receptor (M3R)...
November 15, 2017: EMBO Reports
https://www.readbyqxmd.com/read/29138284/rapid-diagnosis-of-pulmonary-tuberculosis-and-detection-of-drug-resistance-by-combined-simultaneous-amplification-testing-and-reverse-dot-blot
#10
Yiwen Chen, Lahong Zhang, Liquan Hong, Xian Luo, Juping Chen, Leiming Tang, Jiahuan Chen, Xia Liu, Zhaojun Chen
AIMS: Making a correct and rapid diagnosis is essential for managing pulmonary tuberculosis (PTB), particularly multidrug-resistant tuberculosis. We aimed to evaluate the efficacy of the combination of simultaneous amplification testing (SAT) and reverse dot blot (RDB) for the rapid detection of Mycobacterium tuberculosis (MTB) and drug-resistant mutants in respiratory samples. METHODS: 225 suspected PTB and 32 non-TB pulmonary disease samples were collected. All sputum samples were sent for acid-fast bacilli smear, SAT, culture and drug susceptibility testing (DST) by the BACTEC(TM) MGIT(TM) 960 system...
November 14, 2017: Journal of Clinical Pathology
https://www.readbyqxmd.com/read/29133554/what-is-resistance-impact-of-phenotypic-versus-molecular-drug-resistance-testing-on-multi-and-extensively-drug-resistant-tuberculosis-therapy
#11
Jan Heyckendorf, Sönke Andres, Claudio U Köser, Ioana D Olaru, Thomas Schön, Erik Sturegård, Patrick Beckert, Viola Schleusener, Thomas A Kohl, Doris Hillemann, Danesh Moradigaravand, Julian Parkhill, Sharon J Peacock, Stefan Niemann, Christoph Lange, Matthias Merker
Rapid and accurate drug-susceptibility testing (DST) is essential for the treatment of multi- and extensively drug-resistant tuberculosis (M/XDR-TB). We compared the utility of genotypic DST assays with phenotypic DST (pDST) using BACTEC 960 MGIT or Löwenstein-Jensen to construct M/XDR-TB treatment regimens for a cohort of 25 consecutive M/XDR-TB patients and 15 possible anti-TB drugs.Genotypic DST results from Cepheid GeneXpert MTB/RIF (Xpert) and line probe assays (LPAs: Hain GenoType MTBDRplus 2.0 and MTBDRsl 2...
November 13, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29133346/mycobacterium-tuberculosis-groel2-modulates-dendritic-cell-responses
#12
Maria Georgieva, Jonathan Kevin Sia, Erica Bizzell, Ranjna Madan-Lala, Jyothi Rengarajan
Mycobacterium tuberculosis (Mtb) successfully subverts the host immune response to promote disease progression. In addition to its known intracellular niche in macrophages, Mtb interferes with the functions of dendritic cells (DCs), which are the primary antigen presenting cells in the immune system. We previously showed that Mtb dampens proinflammatory responses and impairs DC functions through the cell envelope-associated serine protease, Hip1. Here we present data showing that Mtb GroEL2, a substrate of Hip1, modulates DC functions...
November 13, 2017: Infection and Immunity
https://www.readbyqxmd.com/read/29130630/a-structure-based-strategy-toward-the-development-of-novel-candidates-for-antimycobacterial-activity-synthesis-biological-evaluation-and-docking-study
#13
Linhu Li, Yuanyuan Jin, Bin Wang, Zhaoyong Yang, Mingliang Liu, Huiyuan Guo, Jun Zhang, Yu Lu
Bacterial resistance to most of the available antibiotics has stimulated the discovery of novel efficacious antibacterial agents. Bedaquiline is first of its type that has been specifically introduced for the management of MDR-TB in combination with other drugs. In the current study, a series of isoniazid/ethambutol/pyrazinamide -quinoline conjugates based on the structures of Bedaquiline were designed and synthesized. Biological activity tests revealed that some of isoniazid/ethambutol-quinoline conjugates have useful antibiotic activity against MTB H37Rv (MIC: 2...
November 11, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29126226/optimizing-tuberculosis-diagnosis-in-hiv-infected-inpatients-meeting-the-criteria-of-seriously-ill-in-the-who-algorithm
#14
Rulan Griesel, Annemie Stewart, Helen van der Plas, Welile Sikhondze, Molebogeng X Rangaka, Mark P Nicol, Andre P Kengne, Marc Mendelson, Gary Maartens
BACKGROUND: The WHO algorithm for the diagnosis of tuberculosis in seriously ill HIV-infected patients lacks a firm evidence base. We aimed to develop a clinical prediction rule for the diagnosis of tuberculosis and to determine the diagnostic utility of the Xpert MTB/RIF assay in seriously ill HIV-infected patients. METHODS: We conducted a prospective study among HIV-infected inpatients with any cough duration and WHO-defined danger signs. Culture-positive tuberculosis from any site was the reference standard...
November 6, 2017: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
https://www.readbyqxmd.com/read/29125874/pulmonary-immune-responses-to-mycobacterium-tuberculosis-in-exposed-individuals
#15
Christian Herzmann, Martin Ernst, Christoph Lange, Steffen Stenger, Stefan H E Kaufmann, Norbert Reiling, Tom Schaberg, Lize van der Merwe, Jeroen Maertzdorf
BACKGROUND: Blood based Interferon-(IFN)-γ release assays (IGRAs) have a poor predictive value for the development of tuberculosis. This study aimed to investigate the correlation between IGRAs and pulmonary immune responses in tuberculosis contacts in Germany. METHODS: IGRAs were performed on bronchoalveolar lavage (BAL) cells and peripheral blood from close healthy contacts of patients with culturally confirmed tuberculosis. Cellular BAL composition was determined by flow cytometry...
2017: PloS One
https://www.readbyqxmd.com/read/29125705/m-tuberculosis-mce3c-promotes-mycobacteria-entry-into-macrophages-through-activation-of-%C3%AE-2-integrin-mediated-signaling-pathway
#16
Yong Zhang, Jie Li, Bingxi Li, Jing Wang, Cui Hua Liu
Establishment of infection by facultative intracellular pathogen Mycobacterium tuberculosis (Mtb) requires adherence to and internalization by macrophages. However, the effector molecules exploited by Mtb for entry into macrophages remain to be fully understood. The mammalian cell entry (Mce) proteins play an essential role in facilitating the internalization of mycobacteria into mammalian cells. Here we characterized Mtb Mce3C as a new mycobacterial surface protein that could promote mycobacterial adhesion to and invasion of macrophages in an RGD motif-dependent manner...
November 10, 2017: Cellular Microbiology
https://www.readbyqxmd.com/read/29124751/detailed-characterization-of-human-mycobacterium-tuberculosis-specific-hla-e-restricted-cd8-t-cells
#17
Teresa Prezzemolo, Krista E van Meijgaarden, Kees Lmc Franken, Nadia Caccamo, Francesco Dieli, Tom Hm Ottenhoff, Simone A Joosten
HLA-E presented antigens are interesting targets for vaccination given HLA-Es' essentially monomorphic nature. We have shown previously that Mycobacterium tuberculosis (Mtb) peptides are presented by HLA-E to CD8(+) effector T-cells, but the precise phenotype and functional capacity of these cells remains poorly characterized. We have developed and utilized in this study a new protocol combining HLA-E tetramer with intracellular staining for cytokines, transcription factors and cytotoxic molecules to characterize these cells in depth...
November 9, 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/29124568/pkng-supports-mycobacterial-adaptation-in-acidic-environment
#18
Ruchi Paroha, Rashmi Chourasia, Rajesh Mondal, Shivendra K Chaurasiya
Mycobacterium tuberculosis (Mtb), causative agent of human tuberculosis (TB), has the remarkable ability to adapt to the hostile environment inside host cells. Eleven eukaryotic like serine-threonine protein kinases (STPKs) are present in Mtb. Protein kinase G (PknG) has been shown to promote mycobacterial survival inside host cells. A homolog of PknG is also present in Mycobacterium smegmatis (MS), a fast grower, non-pathogenic mycobacterium. In the present study, we have analyzed the role of PknG in mycobacteria during exposure to acidic environment...
November 9, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/29123253/the-gene-fmt-encoding-trna-fmet-formyl-transferase-is-essential-for-normal-growth-of-m-bovis-but-not-for-viability
#19
Miriam Vanunu, Ziv Lang, Daniel Barkan
Mycobacterium tuberculosis is a major health threat, necessitating novel drug targets. Protein synthesis in bacteria uses initiator tRNAi charged with formylated methionine residue. Deletion of the formylase gene, tRNA(fMet)-formyl transferase (fmt), causes severe growth-retardation in E. coli and in S. pneumoniae, but not in P. aeruginosa or S. aureus. fmt was predicted to be essential in M. tuberculosis by transposon library analysis, but this was never formally tested in any mycobacteria. We performed a targeted deletion of fmt in M...
November 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29119630/mycobacterium-tuberculosis-rv3651-is-a-triple-sensor-domain-protein
#20
Jan Abendroth, Andrew Frando, Isabelle Q Phan, Bart L Staker, Peter J Myler, Thomas E Edwards, Christoph Grundner
The genome of the human pathogen Mycobacterium tuberculosis (Mtb) encodes ∼4,400 proteins, but one third of them have unknown functions. We solved the crystal structure of Rv3651, a hypothetical protein with no discernible similarity to proteins with known function. Rv3651 has a three-domain architecture that combines one cGMP-specific phosphodiesterases, adenylyl cyclases and FhlA (GAF) domain and two Per-ARNT-Sim (PAS) domains. GAF and PAS domains are typically sensor domains that are linked to signaling effector molecules...
November 9, 2017: Protein Science: a Publication of the Protein Society
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