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Mycobacterium tuberculosis Transcriptional Adaptation, Growth Arrest and Dormancy Phenotype Development Is Triggered by Vitamin C  [PDF]
Neetu Kumra Taneja,Sakshi Dhingra,Aditya Mittal,Mohit Naresh,Jaya Sivaswami Tyagi
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0010860
Abstract: Tubercle bacilli are thought to persist in a dormant state during latent tuberculosis (TB) infection. Although little is known about the host factors that induce and maintain Mycobacterium tuberculosis (M. tb) within latent lesions, O2 depletion, nutrient limitation and acidification are some of the stresses implicated in bacterial dormancy development/growth arrest. Adaptation to hypoxia and exposure to NO/CO is implemented through the DevRS/DosT two-component system which induces the dormancy regulon.
Mycobacterium tuberculosis Uses Host Triacylglycerol to Accumulate Lipid Droplets and Acquires a Dormancy-Like Phenotype in Lipid-Loaded Macrophages  [PDF]
Jaiyanth Daniel ,Hédia Maamar equal contributor,Chirajyoti Deb equal contributor,Tatiana D. Sirakova,Pappachan E. Kolattukudy
PLOS Pathogens , 2011, DOI: 10.1371/journal.ppat.1002093
Abstract: Two billion people are latently infected with Mycobacterium tuberculosis (Mtb). Mtb-infected macrophages are likely to be sequestered inside the hypoxic environments of the granuloma and differentiate into lipid-loaded macrophages that contain triacylglycerol (TAG)-filled lipid droplets which may provide a fatty acid-rich host environment for Mtb. We report here that human peripheral blood monocyte-derived macrophages and THP-1 derived macrophages incubated under hypoxia accumulate Oil Red O-staining lipid droplets containing TAG. Inside such hypoxic, lipid-loaded macrophages, nearly half the Mtb population developed phenotypic tolerance to isoniazid, lost acid-fast staining and accumulated intracellular lipid droplets. Dual-isotope labeling of macrophage TAG revealed that Mtb inside the lipid-loaded macrophages imports fatty acids derived from host TAG and incorporates them intact into Mtb TAG. The fatty acid composition of host and Mtb TAG were nearly identical suggesting that Mtb utilizes host TAG to accumulate intracellular TAG. Utilization of host TAG by Mtb for lipid droplet synthesis was confirmed when fluorescent fatty acid-labeled host TAG was utilized to accumulate fluorescent lipid droplets inside the pathogen. Deletion of the Mtb triacylglycerol synthase 1 (tgs1) gene resulted in a drastic decrease but not a complete loss in both radiolabeled and fluorescent TAG accumulation by Mtb suggesting that the TAG that accumulates within Mtb is generated mainly by the incorporation of fatty acids released from host TAG. We show direct evidence for the utilization of the fatty acids from host TAG for lipid metabolism inside Mtb. Taqman real-time PCR measurements revealed that the mycobacterial genes dosR, hspX, icl1, tgs1 and lipY were up-regulated in Mtb within hypoxic lipid loaded macrophages along with other Mtb genes known to be associated with dormancy and lipid metabolism.
Human Granuloma In Vitro Model, for TB Dormancy and Resuscitation  [PDF]
Nidhi Kapoor, Santosh Pawar, Tatiana D. Sirakova, Chirajyoti Deb, William L. Warren, Pappachan E. Kolattukudy
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0053657
Abstract: Tuberculosis (TB) is responsible for death of nearly two million people in the world annually. Upon infection, Mycobacterium tuberculosis (Mtb) causes formation of granuloma where the pathogen goes into dormant state and can live for decades before resuscitation to develop active disease when the immune system of the host is weakened and/or suppressed. In an attempt to better understand host-pathogen interactions, several groups have been developing in vitro models of human tuberculosis granuloma. However, to date, an in vitro granuloma model in which Mtb goes into dormancy and can subsequently resuscitate under conditions that mimic weakening of the immune system has not been reported. We describe the development of a biomimetic in vitro model of human tuberculosis granuloma using human primary leukocytes, in which the Mtb exhibited characteristics of dormant mycobacteria as demonstrated by (1) loss of acid-fastness, (2) accumulation of lipid bodies (3) development of rifampicin-tolerance and (4) gene expression changes. Further, when these micro granulomas were treated with immunosuppressant anti-tumor necrosis factor-alpha monoclonal antibodies (anti-TNFα mAbs), resuscitation of Mtb was observed as has been found in humans. In this human in vitro granuloma model triacylglycerol synthase 1deletion mutant (Δtgs1) with impaired ability to accumulate triacylglycerides (TG), but not the complemented mutant, could not go into dormancy. Deletion mutant of lipY, with compromised ability to mobilize the stored TG, but not the complemented mutant, was unable to come out of dormancy upon treatment with anti-TNFα mAbs. In conclusion, we have developed an in vitro human tuberculosis granuloma model that largely exhibits functional features of dormancy and resuscitation observed in human tuberculosis.
Effects of dormant faults on reliability of fault-tolerant real-time computer system

ZHOU Jing,SHEN Yuan-long,

重庆邮电大学学报(自然科学版) , 2007,
Abstract: As most of the fault-tolerant systems are based on single-fault assumption, the dormant fault is a potential threat to its reliability. Using the example of an automotive control system, the effects of dormant faults on the reliability of the system were studied. Moreover, based on the analysis of the effects of ancient parameters on mean time to the system failure, a new parameter of the time required for emergence handling was introduced. This parameter is important for permanent faults, and its effects on the reliability of the system were analyzed.
Mycobacterium tuberculosis DosR Regulon Gene Rv0079 Encodes a Putative, ‘Dormancy Associated Translation Inhibitor (DATIN)’  [PDF]
Ashutosh Kumar, Mohammad Majid, Ralph Kunisch, Pittu Sandhya Rani, Insaf A. Qureshi, Astrid Lewin, Seyed E. Hasnain, Niyaz Ahmed
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0038709
Abstract: Mycobacterium tuberculosis is a major human pathogen that has evolved survival mechanisms to persist in an immune-competent host under a dormant condition. The regulation of M. tuberculosis metabolism during latent infection is not clearly known. The dormancy survival regulon (DosR regulon) is chiefly responsible for encoding dormancy related functions of M. tuberculosis. We describe functional characterization of an important gene of DosR regulon, Rv0079, which appears to be involved in the regulation of translation through the interaction of its product with bacterial ribosomal subunits. The protein encoded by Rv0079, possibly, has an inhibitory role with respect to protein synthesis, as revealed by our experiments. We performed computational modelling and docking simulation studies involving the protein encoded by Rv0079 followed by in vitro translation and growth curve analysis experiments, involving recombinant E. coli and Bacille Calmette Guérin (BCG) strains that overexpressed Rv0079. Our observations concerning the interaction of the protein with the ribosomes are supportive of its role in regulation/inhibition of translation. We propose that the protein encoded by locus Rv0079 is a ‘dormancy associated translation inhibitor’ or DATIN.
Inheritance of fresh seed dormancy in groundnut
AJ Yaw, A Richard, O Safo-Kantanka, HK Adu-Dapaah, S Ohemeng-Dapaah, A Agyeman
African Journal of Biotechnology , 2008,
Abstract: Pre-harvest sprouting in groundnut (Arachis hypogaea L) seeds belonging to sub species fastigiata is undesirable since it leads to substantial loss of seeds, both in quantity and quality. A short period of dormancy is therefore desirable in this sub-species to reduce such losses. This study was conducted to determine the heritability of fresh seed dormancy in groundnut and to transfer this trait from exotic lines (ICGV 86158 and ICGV 87378) known to posses dormancy, into the genetic background of two groundnut varieties (Shitaochi and Aprewa) widely grown in Ghana but lack dormancy. Freshly harvested seeds of mature pods from parents, F1, F2 and the backcross populations were assessed for their dormancy by incubating in petri dishes in the laboratory. The F1 progenies from crosses between dormant and non-dormant parents were dormant. The F2 progenies fitted the expected 3 dormant to 1 non-dormant ratio. The study showed that seed dormancy is controlled by monogenic inheritance with dormancy dominant over non-dormant.
Wax Ester Synthesis is Required for Mycobacterium tuberculosis to Enter In Vitro Dormancy  [PDF]
Tatiana D. Sirakova, Chirajyoti Deb, Jaiyanth Daniel, Harminder D. Singh, Hedia Maamar, Vinod S. Dubey, Pappachan E. Kolattukudy
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0051641
Abstract: Mycobacterium tuberculosis (Mtb) is known to produce wax esters (WE) when subjected to stress. However, nothing is known about the enzymes involved in biosynthesis of WE and their role in mycobacterial dormancy. We report that two putative Mtb fatty acyl-CoA reductase genes (fcr) expressed in E. coli display catalytic reduction of fatty acyl-CoA to fatty aldehyde and fatty alcohol. Both enzymes (FCR1/Rv3391) and FCR2/Rv1543) showed a requirement for NADPH as the reductant, a preference for oleoyl-CoA over saturated fatty acyl-CoA and were inhibited by thiol-directed reagents. We generated Mtb gene-knockout mutants for each reductase. Metabolic incorporation of 14C-oleate into fatty alcohols and WE was severely diminished in the mutants under dormancy-inducing stress conditions that are thought to be encountered by the pathogen in the host. The fatty acyl-CoA reductase activity in cell lysates of the mutants under nitric oxide stress was significantly reduced when compared with the wild type. Complementation restored the lost activity completely in the Δfcr1 mutant and partially in the Δfcr2 mutant. WE synthesis was inhibited in both Δfcr mutants. The Δfcr mutants exhibited faster growth rates, an increased uptake of 14C-glycerol suggesting increased permeability of the cell wall, increased metabolic activity levels and impaired phenotypic antibiotic tolerance under dormancy-inducing combined multiple stress conditions. Complementation of the mutants did not restore the development of antibiotic tolerance to wild-type levels. Transcript analysis of Δfcr mutants showed upregulation of genes involved in energy generation and transcription, indicating the inability of the mutants to become dormant. Our results indicate that the fcr1 and fcr2 gene products are involved in WE synthesis under in vitro dormancy-inducing conditions and that WE play a critical role in reaching a dormant state. Drugs targeted against the Mtb reductases may inhibit its ability to go into dormancy and therefore increase susceptibility of Mtb to currently used antibiotics thereby enhancing clearance of the pathogen from patients.
Mechanisms of Metastatic Tumor Dormancy  [PDF]
Mary Osisami,Evan T. Keller
Journal of Clinical Medicine , 2013, DOI: 10.3390/jcm2030136
Abstract: Tumor metastasis can occur years after an apparent cure due to a phenomenon known as metastatic tumor dormancy; in which tumor masses or individual tumor cells are growth restricted for extended periods of time. This period of dormancy is induced and maintained by several mechanisms, including: (1) Tumor microenvironment factors such as cytokine expression, immunosurveillance and angiogenesis; (2) Metastasis suppressor gene activity; and (3) Cancer therapeutics. Disseminated tumor cells (DTC) are the key cells that result in dormant tumors. However, many challenges exist towards isolating DTCs for mechanistic studies. The main DTC that may represent the dormant cell is the cancer stem cells (CSC) as they have a slow proliferation rate. In addition to limited knowledge regarding induction of tumor dormancy, there are large gaps in knowledge regarding how tumors escape from dormancy. Emerging research into cancer stem cells, immunotherapy, and metastasis suppressor genes, may lead to new approaches for targeted anti-metastatic therapy to prevent dormancy escape. Overall, an enhanced understanding of tumor dormancy is critical for better targeting and treatment of patients to prevent cancer recurrence.
Insights into Seasonal Dormancy of Perennial Herbaceous Forages  [PDF]
Laxman Adhikari, Rasyidah M. Razar, Dev Paudel, Ruyue Ding, Ali M. Missaoui
American Journal of Plant Sciences (AJPS) , 2017, DOI: 10.4236/ajps.2017.811179
Abstract: Seasonal dormancy is an adaptive mechanism where plants suspend growth and become physiologically inactive to avoid extreme environmental conditions. Environmental factors like temperature, photoperiod, nutrients, and soil moisture control plant growth and development through various complex molecular mechanisms. Crown and seed dormancy of plants are mostly influenced by day length and temperature. Genes and physiological pathways triggered by these two factors along with genotype variability are some targets to manipulate seasonal dormancy. There is genetic variation in the depth and duration of seasonal dormancy. Therefore, their genetic manipulation is possible. Manipulations of summer and fall dormancy are relatively easier compared to winter dormancy because plants require protection of their apical meristem from freezing temperatures and limited water supply. Genetic factors that regulate seed dormancy may also have regulatory role for seasonal dormancy of the maternal plants. Limited genetic and genomic information are available for seasonal dormancy in herbaceous perennial species. Knowledge of genes controlling seasonal dormancy of eudicots, forest trees, and horticultural crops could be interpolated to explore possible dormancy mechanisms in perennial forages. This study reviews current knowledge of seasonal dormancy of herbaceous forages emphasizing the genetic and physiological context that would be valuable to breeders and plant biologists to expand the production season of perennial species by developing non-dormant and semi-dormant cultivars.
Dormancy in breast cancer  [cached]
Banys M,Hartkopf AD,Krawczyk N,Kaiser T
Breast Cancer: Targets and Therapy , 2012,
Abstract: Malgorzata Banys,1,2 Andreas D Hartkopf,1 Natalia Krawczyk,1 Tatjana Kaiser,1 Franziska Meier-Stiegen,1 Tanja Fehm,1 Hans Neubauer11Department of Obstetrics and Gynecology, University of Tuebingen, Tuebingen, Germany; 2Department of Obstetrics and Gynecology, Marienkrankenhaus Hamburg, Hamburg, GermanyAbstract: Tumor dormancy describes a prolonged quiescent state in which tumor cells are present, but disease progression is not yet clinically apparent. Breast cancer is especially known for long asymptomatic periods, up to 25 years, with no evidence of the disease, followed by a relapse. Factors that determine the cell's decision to enter a dormant state and that control its duration remain unclear. In recent years, considerable progress has been made in understanding how tumor cells circulating in the blood interact and extravasate into secondary sites and which factors might determine whether these cells survive, remain dormant, or become macrometastases. The mechanisms of tumor cell dormancy are still not clear. Two different hypotheses are currently discussed: tumor cells persist either by completely withdrawing from the cell cycle or by continuing to proliferate at a slow rate that is counterbalanced by cell death. Because dormant disseminated tumor cells may be the founders of metastasis, one hypothesis is that dormant tumor cells, or at least a fraction of them, share stem cell-like characteristics that may be responsible for their long half-lives and their suggested resistance to standard chemotherapy. Therefore, knowledge of the biology of tumor cell dormancy may be the basis from which to develop innovative targeted therapies to control or eliminate this tumor cell fraction. In this review, we discuss biological mechanisms and clinical implications of tumor dormancy in breast cancer patients.Keywords: tumor dormancy, disseminated tumor cell, circulating tumor cell, targeted therapy
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