The dazzling array of basal branches in the mtDNA macrohaplogroup M from India as inferred from complete genomes

Many efforts based on complete mitochondrial DNA (mtDNA) genomeshave been made to depict the global mtDNA landscape, but thephylogeny of Indian macrohaplogroup M has not yet been resolvedin detail. To fill this lacuna, we took the same strategy asin our recent analysis of Indian mtDNA macrohaplogroup N andselected 56 mtDNAs from over 1,200 samples across India forcomplete sequencing, with the intention to cover all Indianautochthonous M lineages. As a result, the phylogenetic statusof previously identified haplogroups based on control-regionand/or partial coding-region information, such as M2, M3, M4,M5, M6, M30, and M33, was solidified or redefined here. Moreover,seven novel basal M haplogroups (viz., M34–M40) were identified,and yet another five singular branches of the M phylogeny werediscovered in the present study. The comparison of matrilinealcomponents among India, East Asia, Southeast Asia, and Oceaniaat the deepest level yielded a star-like and nonoverlappingpattern, reflecting a rapid mode of modern human dispersal alongthe Asian coast after the initial "out-of-Africa" event.     

Differential effects of insulin-like growth factor-1 and atheroma-associated cytokines on cell proliferation and apoptosis in plaque smooth muscle cells of symptomatic and asymptomatic patients with carotid stenosis

Morbidity and mortality from atherosclerosis are associated with complicated atherosclerotic lesions due to plaque rupture, which is regulated by a balance between proliferation and apoptosis of vascular smooth muscle cells (VSMC). We examined insulin-like growth factor-1 (IGF-1)-induced survival of plaque VSMC from carotid endarterectomy specimens and investigated the underlying cellular mechanisms in the presence and absence of IL-12 and IFN-gamma. Both IL-12 and IFN-gamma were strongly expressed in symptomatic atherosclerotic plaques as compared with asymptomatic plaques. In asymptomatic plaque VSMC, IGF-1 induced the survival and proliferation of VSMC and accelerated VSMC into S-phase. IL-12 or IFN-gamma inhibited proliferation and VSMC were arrested in the G0-G1 phase. IGF-1 markedly inhibited the expression of p27(kip) and p21(cip) and significantly induced cyclin E and cyclin D. Both cytokines by themselves increased the expression of p27(kip) and p21(cip) and inhibited cyclin E and cyclin D. On the contrary, in symptomatic VSMC there was already increased apoptosis of VSMC and there was no significant effect of IGF-1 or inflammatory cytokines on proliferation, apoptosis or the expression of p27(kip) and p21(cip) and cyclin D and E. These data suggest that IGF-1 is more potent in inducing the survival of VSMC from the endarterectomy specimens of asymptomatic patients as compared to that of symptomatic subjects and cytokines associated with atheroma lesions decrease the activity of IGF-1-induced survival in the VSMC of asymptomatic plaques. The different expression and activity of cell cycle regulatory proteins could be responsible for apoptosis of VSMC and destabilization of atherosclerotic plaques.     

Immunobiology of Toll-like receptors: emerging trends

Toll-like receptors (TLR), a family of evolutionarily conserved pathogen recognition receptors, play pivotal role as primary sensors of invading pathogens. TLR identify molecular motifs of infectious agents (pathogen associated molecular patterns) and elicit an effective defensive response against them. Mammalian TLR derive their name from the Drosophila Toll protein, with which they share sequence similarity. So far, expression of 10 TLR is known in humans. The adaptor proteins, myeloid differentiation factor 88 and Toll IL-1 receptor (TIR) domain containing adaptor inducing IFN-beta (TRIF) are the key players in the TLR signalling cascade leading to the activation of nuclear factor (NF)-kappaB and interferon regulatory factor-3, respectively. Targeted manipulation of the TLR signalling pathway has immense therapeutic potential and may eventually prove to be a boon in the development of innovative treatments for diverse disease conditions. There is accumulating evidence that TLR agonists have tremendous potential as novel therapeutic targets. In this review, we have discussed the immunobiology of TLR and emphasize significant advances made within the ever-expanding field of TLR that provide intriguing insights efficacious in unravelling the complexities associated with TLR.     

Functional dichotomy in CD40 reciprocally regulates effector T cell functions

Activation of T cells requires signals through Ag-specific TCR and costimulatory molecules such as CD40L. Although the use of defined tumor Ags for the induction of protective T cells met with limited success, the CD40-CD40L interaction that was proposed to induce antitumor T cells did not prevent tumor growth completely. Using a model for prostate tumor, a leading cause of tumor-induced mortality in men, we show that the failure is due to a novel functional dichotomy of CD40 whereby it self-limits its antitumor functions by inducing IL-10. IL-10 prevents the CD40-induced CTL and TNF-alpha and IL-12 production, Th1 skewing, and tumor regression. Priming mice with tumor lysate-pulsed IL-10-deficient dendritic cells (DCs) or wild-type DC plus anti-IL-10 Ab establishes antitumor memory T cells that can transfer the protection into syngenic nude mice. Infusion of Ag-pulsed IL-10-deficient but not wild-type DCs back into syngenic mice results in successful therapeutic autovaccination. Thus, we demonstrate the IL-10-sensitive antitumor T cell memory formulating a novel prophylactic and therapeutic principle.     

CREMOFAC--a database of chromatin remodeling factors

MOTIVATION: Chromatin-remodeling is an important event in the eukaryotic nucleus rendering nucleosomal DNA accessible for various transaction processes. Remodeling Factors facilitate the dynamic nature of chromatin through participation of the collective action of (i) ATP and (ii) Non-ATP dependent factors. Considering the importance of these factors in eukaryotes, we have developed, CREMOFAC, a dedicated and frequently updated web-database for chromatin-remodeling factors. RESULTS: The database harbors factors from 49 different organisms reported in literature and facilitates a comprehensive search for them. In addition, it also provides in-depth information for the factors reported in the three widely studied mammals namely, human, mouse and rat. Further, information on literature, pathways and phylogenetic relationships has also been covered. The development of CREMOFAC as a central repository for chromatin-remodeling factors and the absence of such a pre-existing database heighten its utility thus making its presence indispensable. AVAILABILITY: http://www.jncasr.ac.in/cremofac/     

Monogeneans from the gills of glassfishes (Teleostei: Perciformes: Ambassidae) in India, with the proposal of Chandacleidus n. g. (Monogenea: Dactylogyridae)

Chandacleidus n. g. (Monogenea, Dactylogyridae) is proposed to include three species collected from the gills of Indian glassfishes (Ambassidae): Chandacleidus recurvatus (Jain, 1961) n. comb. (syn. Urocleidus recurvatus Jain, 1961) from Chanda nama and C. ranga (new host record) is redescribed; and Chandacleidus saiensis n. sp. and C. lucknowensis n. sp., both from Chanda nama and C. baculis, are described. Chandacleidus n. g. is characterised by species possessing: posteriorly united intestinal caeca; overlapping gonads (testis dorsal to ovary); a counterclockwise male copulatory organ; a grooved accessory piece; a dextro-marginal vaginal pore; a haptor with two lateral flaps and armed with dissimilar dorsal and ventral anchor/bar complexes and 14 similar hooks (dissimilar in size); and hook shanks comprised of two subunits.     

Bhageerath: an energy based web enabled computer software suite for limiting the search space of tertiary structures of small globular proteins

We describe here an energy based computer software suite for narrowing down the search space of tertiary structures of small globular proteins. The protocol comprises eight different computational modules that form an automated pipeline. It combines physics based potentials with biophysical filters to arrive at 10 plausible candidate structures starting from sequence and secondary structure information. The methodology has been validated here on 50 small globular proteins consisting of 2-3 helices and strands with known tertiary structures. For each of these proteins, a structure within 3-6 A RMSD (root mean square deviation) of the native has been obtained in the 10 lowest energy structures. The protocol has been web enabled and is accessible at http://www.scfbio-iitd.res.in/bhageerath.