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Basu S.,Council of Scientific and Industrial Research Institute of Genomics and Integrative Biology | Sachidanandan C.,Council of Scientific and Industrial Research Institute of Genomics and Integrative Biology
Chemical Reviews | Year: 2013

Multicellular life forms rely heavily on intercellular and interorgan communication to survive, maintain homeostasis, and reproduce. It is not possible to capture these complex interactions in the in vitro systems such as purified preparations or even cultured cells. Model organisms allow the study of biological processes in their natural context. Zebrafish, a small pet-shop fish, has been serving as an informative model for understanding human biology. The females spawn in the dawn hours and only in the presence of the males, laying unfertilized eggs into the water, which are externally fertilized by the males. In the laboratory, the timing of the egg-laying can be controlled using a regulated light-dark cycle. For optimum breeding and collection of eggs, males and females are maintained in a tank with shallow water overnight, and the newly laid eggs are separated from the adults by a mesh to prevent them from eating the eggs. Source


Chadha A.,University of Delhi | Mehto S.,University of Delhi | Selvakumar A.,University of Delhi | Vashishta M.,University of Delhi | And 5 more authors.
Tuberculosis | Year: 2015

Summary Multiple strategies evolved by Mycobacterium tuberculosis (M. tb) have contributed to its successful prevalence. We previously identified specific genes in the cysteine protease and calcium-calmodulin pathways that regulated immune responses from dendritic cells (DCs). In this study we have characterized the role of neddylation in regulating various defense responses from DCs during mycobacterial infection. Neddylation is a process that is similar to ubiquitination. It however has its own enzyme machinery. It is coupled to ubiquitination and is important for maintaining cellular homeostasis. Here we show that stimulation of DCs with M. tb antigens Rv2463 and Rv3416 as well as infection with live M. tb modulates the expression levels of key proteins in the neddylation pathway. Further, stimulation with the two antigens promoted the association of NEDD8 with its target Cullin-1. The modulation in the expression levels of NEDD8 and SENtrin specific Protein 8 (SENP8) by the two antigens was in a calcium, MAPK and TLR dependent mechanism. Further, knockdown of specific genes of neddylation promoted the generation of oxidative burst, promoted phagolysosome fusion in mycobacteria infected DCs and induced higher expression of autophagy and apoptosis associated proteins in DCs. These results point toward a unique strategy employed by mycobacteria and its antigens towards immune suppression via modulating neddylation in DCs. © 2015 Elsevier Ltd. Source


Bhatt S.P.,Diabetic Foundation India and National Diabetes Obesity and Cholesterol Foundation N DOC | Bhatt S.P.,All India Institute of Medical Sciences | Bhatt S.P.,Council of Scientific and Industrial Research Institute of Genomics and Integrative Biology | Nigam P.,Diabetic Foundation India and National Diabetes Obesity and Cholesterol Foundation N DOC | And 3 more authors.
Atherosclerosis | Year: 2013

Objective: We analysed the associations of 25 hydroxy vitamin D [25(OH) D] and parathyroid hormone (PTH) levels with clinical, anthropometric, biochemical and body composition parameters in Asian Indians with nonalcoholic fatty liver disease (NAFLD). Methods: In this case-control study, 162 cases and 173 age and sex matched controls were recruited. Clinical, anthropometric, biochemical parameters and liver ultrasound were done. Percentage body fat (%BF), lean body mass and bone mineral density (BMD) were assessed by dual energy X-ray absorptiometry (DXA). Fasting insulin levels, value of homeostasis model assessment of insulin resistance (HOMA-IR), serum 25(OH) D, calcium and PTH levels were measured. Results: Subjects with NAFLD had lower serum 25(OH) D (19.4±8.5 vs. 27.8±9.4ng/ml, p=0.0001) and higher serum PTH (54.9±19.5 vs.41.5±18.3pg/ml, p=0.0001) levels as compared to controls. We observed significantly high values of systolic blood pressure (p=0.002), waist circumference (p=0.05), serum triglycerides (p=0.002), total cholesterol (p=0.002), alanine transaminase (p=0.05), fasting insulin (p=0.02) and HOMA-IR (p=0.03) in the lowest 25(OH) D quartile. Multivariable-logistic regression showed that low serum 25(OH) D [OR (95%CI): 4.46 (2.58-7.72), p=0.0001] and high PTH [OR (95%CI): 2.21 (1.50-3.30), p=0.0001] level were independently associated with NAFLD. Conclusion: Low serum 25(OH) D and high PTH levels were independently associated with the presence of NAFLD in Asian Indians residing in north India. © 2013. Source


Manikandan K.,Institute of Molecular Medicine | Sabareesh V.,Council of Scientific and Industrial Research Institute of Genomics and Integrative Biology | Sabareesh V.,Vellore Institute of Technology | Singh N.,University of Delhi | And 3 more authors.
PLoS ONE | Year: 2014

Cyclic di-AMP is a recently discovered signaling molecule which regulates various aspects of bacterial physiology and virulence. Here we report the characterization of c-di-AMP synthesizing and hydrolyzing proteins from Mycobacterium tuberculosis. Recombinant Rv3586 (MtbDisA) can synthesize c-di-AMP from ATP through the diadenylate cyclase activity. Detailed biochemical characterization of the protein revealed that the diadenylate cyclase (DAC) activity is allosterically regulated by ATP. We have identified the intermediates of the DAC reaction and propose a two-step synthesis of c-di-AMP from ATP/ADP. MtbDisA also possesses ATPase activity which is suppressed in the presence of the DAC activity. Investigations by liquid chromatography -electrospray ionization mass spectrometry have detected multimeric forms of c-di-AMP which have implications for the regulation of c-di-AMP cellular concentration and various pathways regulated by the dinucleotide. We have identified Rv2837c (MtbPDE) to have c-di-AMP specific phosphodiesterase activity. It hydrolyzes c-di- AMP to 59-AMP in two steps. First, it linearizes c-di-AMP into pApA which is further hydrolyzed to 5′-AMP. MtbPDE is novel compared to c-di-AMP specific phosphodiesterase, YybT (or GdpP) in being a soluble protein and hydrolyzing c-di-AMP to 5′-AMP. Our results suggest that the cellular concentration of c-di-AMP can be regulated by ATP concentration as well as the hydrolysis by MtbPDE. © 2014 Manikandan et al. Source


Arora G.,Council of Scientific and Industrial Research Institute of Genomics and Integrative Biology | Sajid A.,Council of Scientific and Industrial Research Institute of Genomics and Integrative Biology | Arulanandh M.D.,Council of Scientific and Industrial Research Institute of Genomics and Integrative Biology | Singhal A.,Council of Scientific and Industrial Research Institute of Genomics and Integrative Biology | And 5 more authors.
Journal of Biological Chemistry | Year: 2012

Dual specificity protein kinases (DSPKs) are unique enzymes that can execute multiple functions in the cell, which are otherwise performed exclusively by serine/threonine and tyrosine protein kinases. In this study, we have characterized the protein kinases Bas2152 (PrkD) and Bas2037 (PrkG) from Bacillus anthracis. Transcriptional analyses of these kinases showed that they are expressed in all phases of growth. In a serendipitous discovery, both kinases were found to be DSPKs. PrkD was found to be similar to the eukaryotic dual specificity Tyr phosphorylation-regulated kinase class of dual specificity kinases, which autophosphorylates on Ser, Thr, and Tyr residues and phosphorylates Ser and Thr residues on substrates. PrkG was found to be a bona fide dual specificity protein kinase that mediates autophosphorylation and substrate phosphorylation on Ser, Thr, and Tyr residues. The sites of phosphorylation in both of the kinases were identified through mass spectrometry. Phosphorylation on Tyr residues regulates the kinase activity of PrkD and PrkG. PrpC, the only known Ser/Thr protein phosphatase, was also found to possess dual specificity. Genistein, a known Tyr kinase inhibitor, was found to inhibit the activities of PrkD and PrkG and affect the growth of B. anthracis cells, indicating a possible role of these kinases in cell growth and development. In addition, the glycolytic enzyme pyruvate kinase was found to be phosphorylated by PrkD on Ser and Thr residues but not by PrkG. Thus, this study provides the first evidence of DSPKs in B. anthracis that belong to different classes and have different modes of regulation. Source

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