Uncovering potential Drug Targets for Tuberculosis using Protein Networks

The emergence of HIV-TB co-infection and multi-drug resistant strains of Mycobacterium tuberculosis (Mtb) drive the need for new therapeutics against the infectious disease tuberculosis. Among the reported putative TB targets in the literature, the identification and characterization of the most probable therapeutic targets that influence the complex infectious disease, primarily through interactions with other influenced proteins, remains a statistical and computational challenge in proteomic epidemiology. Protein interaction network analysis provides an effective way to understand the relationships between protein products of genes by interconnecting networks of essential genes and its protein-protein interactions for 5 broad functional categories in Mtb. We also investigated the substructure of the protein interaction network and focused on highly connected nodes known as cliques by giving weight to the edges using data mining algorithms. Cliques containing Sulphate assimilation and Shikimate pathway enzymes appeared continuously inspite of increasing constraints applied by the K-Core algorithm during Network Decomposition. The potential target narrowed down through Systems approaches was Prephanate Dehydratase present in the Shikimate pathway this gives an insight to develop novel potential inhibitors through Structure Based Drug Design with natural compounds.     

Structure prediction of Bestrophin for the induced - fit docking of anthocyanins

Bestrophin, an integral membrane protein existing in basolateral region of the retina is a propitious target for drug discovery. Mutations in the Bestrophin protein cause Best Vitelliform Macular Dystrophy (BVMD) leading to retinal damages and loss of visual acuity. Owing to the lack of three dimensional structure and related structural homologs in the protein data bank, we modeled the bestrophin protein using Robetta ab initio method. Further, no treatment is available for the disease. In this situation, anthocyanins from natural sources are reported to combat retinal damages. Hence, we identified anthocyanins from Syzygium cumini fruit skin using Electrospray Ionization tandem mass spectrometry. These compounds were docked into the predicted bestrophin model to study the interactions within the active site. The results may provide a valuable insight into the structure of bestrophin and efficacy of anthocyanins in molecular docking studies.

Abbreviations

PTP - Putative transmembrane proteins, VMD - Vitelliform macular dystrophy, BVMD - Best''s vitelliform macular dystrophy, RPE - Retinal pigment epithelium, ESI-MS/MS - Electrospray Ionization Tandem Mass Spectrometry, UNIPROT - Universal Protein Resource, PSIPRED - Protein secondary structure prediction, TMH - Transmembrane Helices, SCFS - Syzygium cumini fruit skin DP - Declustering Potential IFD - Induced Fit Docking.     

Controlling cancer through the autotaxin-lysophosphatidic acid receptor axis

LPA (lysophosphatidic acid, 1-acyl-2-hydroxy-sn-glycero-3-phosphate), is a growth factor-like lipid mediator that regulates many cellular functions, many of which are unique to malignantly transformed cells. The simple chemical structure of LPA and its profound effects in cancer cells has attracted the attention of the cancer therapeutics field and drives the development of therapeutics based on the LPA scaffold. In biological fluids, LPA is generated by ATX (autotaxin), a lysophospholipase D that cleaves the choline/serine headgroup from lysophosphatidylcholine and lysophosphatidylserine to generate LPA. In the present article, we review some of the key findings that make the ATX-LPA signalling axis an emerging target for cancer therapy.     

Geriatric dentistry--meet the need

Geriatric dentistry or gerodontics is the delivery of dental care to older adults involving the diagnosis, prevention, and treatment of problems associated with normal ageing and age-related diseases as part of an inter-disciplinary team with other health care professionals. Geriatric health is an ignored and under-explored area worldwide. Oral health reflects overall well being for the elderly population. Conversely, elderly patients are more predisposed to oral conditions due to age-related systemic diseases and functional changes. The major barriers to practising geriatric dentistry are the lack of trained faculty members, a crowded curriculum and monetary concerns. For successful treatment, the practitioner must adopt a humanitarian approach and develop a better understanding of the feelings and attitudes of the elderly. Prevention and early intervention strategies must be formulated to reduce the risk of oral diseases in this population. In future, dental professionals must have a proper understanding of the magnitude of the services to be provided to the elderly. This could only be realised through an education programme in geriatric dentistry, which should be started without further delay. This article hence sets out the objectives, needs, present scenario, strategies and types of dental treatment required by the elderly population.     

Identification of QTL affecting seed mineral concentrations and content in the model legume <Emphasis Type="Italic">Medicago truncatula</Emphasis>

Increasing the amount of bioavailable micronutrients such as iron and zinc in plant foods for human consumption is an international goal, intended especially for developing countries where micronutrient deficiencies are an ongoing health risk. Legume seeds have the potential to provide the essential nutrients required by humans, but concentrations of several minerals are low when compared to other foods. In order to increase seed mineral concentrations, it is important to understand the genes and processes involved in mineral distribution within the plant. The main objectives of this study were to use a Medicago truncatula recombinant inbred population (Jemalong-6 × DZA 315.16) to determine loci governing seed mineral concentrations, seed mineral content, and average seed weight, and to use these loci to propose candidate genes whose expression might contribute to these traits. Ninety-three lines in 2004 and 169 lines in 2006 were grown for seed harvest and subsequent analysis of seed Ca, Cu, Fe, K, Mg, Mn, P, and Zn concentrations and content. Quantitative trait loci (QTL) cartographer was used to identify QTL using composite interval mapping (CIM). CIM identified 46 QTL for seed mineral concentration, 26 for seed mineral content, and 3 for average seed weight. At least one QTL was detected for each mineral trait, and colocation of QTL for several minerals was found in both years. Results comparing seed weight with seed mineral concentration and content QTL demonstrate that seed size can be an important determinant of seed mineral concentration. The identification, in this model legume, of transgressive segregation for nearly all the minerals suggests that allelic recombination of relevant mineral-related genes in agronomic legumes could be a successful strategy to increase seed mineral concentrations above current levels. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Regional Activities of Phospholipase C after Experimental Brain Injury in the Rat

Regional activities of phosphoinositide-specific phospholipase C (PLC) were measured after lateral fluid percussion (FP) brain injury in rats. The activity of PLC on phosphatidylinositol 4,5-bisphosphate (PIP₂) in the rat cortex required calcium, and at 45 M concentration it increased PLC activity by about ten-fold. The activity of PLC was significantly increased in the cytosol fraction in the injured (left) cortex (IC) at 5 min, 30 min and 120 min after brain injury. However, in the same site, increases were observed in the membrane fraction only at 5 min after brain injury. In both the contralateral (right) cortex (CC) and ipsilateral hippocampus (IH), the activity of PLC was increased in the cytosol only at 5 min after brain injury. These results suggest that increased activity of PLC may contribute to increases in levels of cellular diacylglycerol and inositol trisphosphate in the IC (the greatest site of injury), and to a smaller extent in the IH and CC, after lateral FP brain injury. It is likely that this increased PLC activity is caused by alteration in either the levels or activities of one or more of its isozymes (PLC, PLC, and PLC) after FP brain injury.     

The spatial and temporal distribution of young-of-the-year Osmerus mordax in the Great Bay Estuary

Juvenile smelt, Osmerus mordax, were collected from four eelgrass, Zostera marina, beds in the Great Bay Estuary, two within Great Bay and two located nearer the coast. Lapillar otoliths were used to estimate the ages of the smelt and to calculate daily somatic growth based on the widths of otolith increments. Smelt collected from the Bay sites were consistently younger and shorter in total length than smelt collected from the coastal sites. A repeated measures analysis of variance found significant differences among growth trajectories of smelt grouped by their dates of birth.     

La protein binding at the GCAC site near the initiator AUG facilitates the ribosomal assembly on the hepatitis C virus RNA to influence internal ribosome entry site-mediated translation

Human La autoantigen has been shown to influence internal initiation of translation of hepatitis C virus (HCV) RNA. Previously, we have demonstrated that, among the three RRMs of La protein, the RRM2 interacts with HCV internal ribosome entry site (IRES) around the GCAC motif near the initiator AUG present in the stem region of stem-loop IV (SL IV) (Pudi, R., Abhiman, S., Srinivasan, N., and Das S. (2003) J. Biol. Chem. 278, 12231-12240). Here, we have demonstrated that the mutations in the GCAC motif, which altered the binding to RRM2, had drastic effect on HCV IRES-mediated translation, both in vitro and in vivo. The results indicated that the primary sequence of the stem region of SL IV plays an important role in mediating internal initiation. Furthermore, we have shown that the mutations also altered the ability to bind to ribosomal protein S5 (p25), through which 40 S ribosomal subunit is known to contact the HCV IRES RNA. Interestingly, binding of La protein to SL IV region induced significant changes in the circular dichroism spectra of the HCV RNA indicating conformational alterations that might assist correct positioning of the initiation complex. Finally, the ribosome assembly analysis using sucrose gradient centrifugation implied that the mutations within SL IV of HCV IRES impair the formation of functional ribosomal complexes. These observations strongly support the hypothesis that La protein binding near the initiator AUG facilitates the interactions with ribosomal protein S5 and 48 S ribosomal assembly and influences the formation of functional initiation complex on the HCV IRES RNA to mediate efficient internal initiation of translation.     

Negative inotropic response to cerium in ventricular papillary muscle is mediated by reactive oxygen species

This study was performed with the objective of assessing the mechanical response of the myocardium to different levels of cerium and delineation of the mechanism underlying the mediation of the functional changes. Rat ventricular papillary muscle was used as the experimental model. Isolated papillary muscles were exposed to different concentrations of CeCl₃ and the force of contraction was measured using a force transducer. Experiments have revealed that the negative inotropic response to CeCl₃ was proportional to its concentration. The inotropic changes were found to be completely reversible at concentrations ≤5μM, and partially reversible at higher concentrations. Neutralization of cerium-induced inotropic changes by the superoxide anion scavenger superoxide dismutase (SOD) at concentrations ≤5 μM indicates that the mechanical changes are mediated by reactive oxygen species. At higher concentrations of Ce³⁺, SOD partially reversed the contractile changes. The beneficial effect of SOD was seen only if the muscles were pretreated with the scavenger prior to the addition of cerium chloride.