Molecular insight into the genesis of ranked caste populations of western India based upon polymorphisms across non-recombinant and recombinant regions in genome

Background  

Large-scale trade and cultural contacts between coastal populations of western India and Western-Eurasians paved for extensive immigration and genesis of wide spectrum of admixed gene pool. To trace admixture and genesis of caste populations of western India, we have examined polymorphisms across non-recombining 20 Y-SNPs, 20 Y-STRs, 18 mtDNA diagnostic sites, HVS-1 plus HVS-2 regions; and recombining 15 highly polymorphic autosomal STRs in four predominant caste populations- upper-ranking Desasth-brahmin and Chitpavan-brahmin; a middle-ranking Kshtriya Maratha; and a lower-rank peasant Dhangar.     

Lower levels of F2-isoprostanes in serum and livers of long-lived Ames dwarf mice

F₂-isoprostanes (IsoPs), lipid peroxidation products, are markers that quantitatively measure levels of oxidative stress. IsoP levels increase in tissues and serum of aging animals suggesting an increase in oxidative stress. This supports the Free Radical Theory of Aging, which proposes that elevated levels of reactive oxygen species (ROS) cause macromolecular damage, and is a factor in the age-associated decline in tissue function. Numerous studies have shown that the longevity of long-lived mutant mice correlates with their resistance to oxidative stress. However, although the Ames dwarf (DW) mice show resistance to oxidative stress, it has not been shown that these mice have inherently lower levels of ROS. Our results show that the serum and liver IsoP levels in DW mice are lower at all ages suggesting that the lower levels of endogenous ROS production in DW mice may be a factor in their resistance to oxidative stress and longevity.     

Pharmacophore modeling and molecular dynamics approach to identify putative DNA Gyrase B inhibitors for resistant tuberculosis

One of the major mechanisms followed by the therapeutic agents to target the causative organism of TB, mycobacterium tuberculosis (Mtb), involves disruption of the replication cycle of the pathogen DNA. The process involves two steps that occur simultaneously, ie, breakage and reunion of DNA at gyrase A (GyrA) domain and ATP hydrolysis at gyrase B (GyrB) domain. Current therapy for multi-drug resistant TB involves FDA approved, Fluoroquinolone-based antibiotics, which act by targeting the replication process at GyrA domain. However, resistance against fluoroquinolones due to mutations in the GyrA domain has limited the use of this therapy and shifted the focus of the research community on the GyrB domain. Thus, this study involves in silico designing of chemotherapeutic agents for resistant TB by targeting GyrB domain. In the current study, a pharmacophore model for GyrB domain was generated using reported inhibitors. It was utilized as a query search against three commercial databases to identify GyrB domain inhibitors. Additionally, a qualitative Hip-Hop pharmacophore model for GyrA was also developed on the basis of some marketed fluoroquinolone-based GyrA inhibitors, to remove non-selective gyrase inhibitors obtained in virtual screening. Further, molecular dynamic simulations were carried out to determine the stability of the obtained molecules in complex with both the domains. Finally, Molecular mechanics with generalized Born and surface area solvation score was calculated to determine the binding affinity of obtained molecule with both domains to determine the selectivity of the obtained molecules that resulted in seven putative specific inhibitors of GyrB domain.     

Novel Small Molecule XPO1/CRM1 Inhibitors Induce Nuclear Accumulation of TP53, Phosphorylated MAPK and Apoptosis in Human Melanoma Cells

XPO1/CRM1 is a key nuclear exporter protein that mediates translocation of numerous cellular regulatory proteins. We investigated whether XPO1 is a potential therapeutic target in melanoma using novel selective inhibitors of nuclear export (SINE). In vitro effects of SINE on cell growth and apoptosis were measured by MTS assay and flow cytometry [Annexin V/propidium iodide (PI)], respectively in human metastatic melanoma cell lines. Immunoblot analysis was used to measure nuclear localization of key cellular proteins. The in vivo activity of oral SINE was evaluated in NOD/SCID mice bearing A375 or CHL-1 human melanoma xenografts. SINE compounds induced cytostatic and pro-apoptotic effects in both BRAF wild type and mutant (V600E) cell lines at nanomolar concentrations. The cytostatic and pro-apoptotic effects of XPO1 inhibition were associated with nuclear accumulation of TP53, and CDKN1A induction in the A375 cell line with wild type TP53, while pMAPK accumulated in the nucleus regardless of TP53 status. The orally bioavailable KPT-276 and KPT-330 compounds significantly inhibited growth of A375 (p<0.0001) and CHL-1 (p = 0.0087) human melanoma cell lines in vivo at well tolerated doses. Inhibition of XPO1 using SINE represents a potential therapeutic approach for melanoma across cells with diverse molecular phenotypes by promoting growth inhibition and apoptosis.     

Hidden reservoirs of pathogens in dental settings

Nosocomial infections are a major concern to both clinicians and health care seekers. Investigations have suggested that laptops & mobile phones may contribute to cross-contamination and can serve as vehicles for infection transmission. Therefore, it is of interest to document the data on hidden reservoirs such as mobile phones and laptops of pathogens in dental settings at the Hazaribag College of dental sciences and Hospital, Jharkhand. The samples were collected from 25 laptops and 25 mobile phones from dentists working in a dental college in Hazaribag city. The samples were collected aseptically using sterile cotton swabs dipped in sterile saline by rotating the swabs on the keyboard surfaces of laptops and mobile phones, inoculated into Brain Heart Infusion broth, vortexed for 1 minute in Fischer Vortex Genie 2 on highest setting & streaked immediately on 5% sheep blood agar plates and were incubated at 37°C for 24 hours aerobically. The isolates were identified based on the colony morphology, colony characteristics and biochemical reactions. The bacterial species isolated were Staphylococcus aureus, Coagulase negative Staphylococcus, Bacillus species, Enterococci, Micrococci, and Pseudomonas etc. Predominant species isolated was Staphylococcus aureus and least was Micrococci. Higher percentage of organisms was found at the Department of Periodontics, Endodontics and least was found in Department of Public Health Dentistry. The percentage and type of organism isolated from keyboards of laptops and mobile phones were similar. Thus, laptops and mobile phones act as vehicles for transfer of potential pathogens associated with dental hospitals. Disinfecting the hands prior to examination of patients and disinfection of laptops and mobiles with alcohol wipes should be done to prevent nosocomial infections.     

The Phylogeography of Y-Chromosome Haplogroup H1a1a-M82 Reveals the Likely Indian Origin of the European Romani Populations

Linguistic and genetic studies on Roma populations inhabited in Europe have unequivocally traced these populations to the Indian subcontinent. However, the exact parental population group and time of the out-of-India dispersal have remained disputed. In the absence of archaeological records and with only scanty historical documentation of the Roma, comparative linguistic studies were the first to identify their Indian origin. Recently, molecular studies on the basis of disease-causing mutations and haploid DNA markers (i.e. mtDNA and Y-chromosome) supported the linguistic view. The presence of Indian-specific Y-chromosome haplogroup H1a1a-M82 and mtDNA haplogroups M5a1, M18 and M35b among Roma has corroborated that their South Asian origins and later admixture with Near Eastern and European populations. However, previous studies have left unanswered questions about the exact parental population groups in South Asia. Here we present a detailed phylogeographical study of Y-chromosomal haplogroup H1a1a-M82 in a data set of more than 10,000 global samples to discern a more precise ancestral source of European Romani populations. The phylogeographical patterns and diversity estimates indicate an early origin of this haplogroup in the Indian subcontinent and its further expansion to other regions. Tellingly, the short tandem repeat (STR) based network of H1a1a-M82 lineages displayed the closest connection of Romani haplotypes with the traditional scheduled caste and scheduled tribe population groups of northwestern India.     

A novel device for long bone osteodistraction: description of device and case series

The purpose of this study was to present a novel intramedullary device (M-Bone; Phenix, Paris, France) that contains a mechanism for internal osteodistraction and bone transport in patients with segmental bone defects or limb length discrepancy after limb salvage operations. A total of five patients with primary bone tumors were enrolled in the study. After implantation, daily lengthening was performed in an outpatient setting either by the patient or with the help of a therapist, without the use of anesthesia. This unique device offers a totally new approach for the treatment of segmental bone defects or limb length discrepancy. It is designed to expand the remaining native bone by a magnetically activated drive system and induces new bone formation using osteodistraction and bone transport.