Identification of Inhibitors against Mycobacterium tuberculosis Thiamin Phosphate Synthase, an Important Target for the Development of Anti-TB Drugs

Tuberculosis (TB) continues to pose a serious challenge to human health afflicting a large number of people throughout the world. In spite of the availability of drugs for the treatment of TB, the non-compliance to 6–9 months long chemotherapeutic regimens often results in the emergence of multidrug resistant strains of Mycobacterium tuberculosis adding to the precariousness of the situation. This has necessitated the development of more effective drugs. Thiamin biosynthesis, an important metabolic pathway of M.tuberculosis, is shown to be essential for the intracellular growth of this pathogen and hence, it is believed that inhibition of this pathway would severely affect the growth of M.tuberculosis. In this study, a comparative homology model of M.tuberculosis thiamin phosphate synthase (MtTPS) was generated and employed for virtual screening of NCI diversity set II to select potential inhibitors. The best 39 compounds based on the docking results were evaluated for their potential to inhibit the MtTPS activity. Seven compounds inhibited MtTPS activity with IC50 values ranging from 20 – 100 µg/ml and two of these exhibited weak inhibition of M.tuberculosis growth with MIC99 values being 125 µg/ml and 162.5 µg/ml while one compound was identified as a very potent inhibitor of M.tuberculosis growth with an MIC99 value of 6 µg/ml. This study establishes MtTPS as a novel drug target against M.tuberculosis leading to the identification of new lead molecules for the development of antitubercular drugs. Further optimization of these lead compounds could result in more potent therapeutic molecules against Tuberculosis

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.</p

A Bluetooth Low Energy Based Beacon System for Smart Short Range Surveillance

The aim of this paper is to propose a fault-tolerant smart system which can render, track and monitor the process of attendance of students. A smart attendance system is refined in a systematic manner where the students enter the lecture hall with an android device which possesses a beacon compatible mobile app. The main purpose of this system is to minimize the power consumption of Bluetooth using Bluetooth Low Energy (BLE) technology, which prevents fraud and favors in an attendance system by using a Bluetooth smart beacon

How much demand for New HIV prevention technologies can we really expect? Results from a discrete choice experiment in South Africa.

BACKGROUND: For the first time in the history of HIV, new bio-medical interventions have been shown to be effective in preventing HIV transmission. For these new HIV prevention technologies (NPTs) to have an impact on the epidemic, they must be widely used. This study uses a discrete choice experiment (DCE) to: understand the relative strength of women's preferences for product characteristics, understand the implications for substitution away from male condoms, and inform realistic modelling of their potential impact and cost-effectiveness. METHODS: A DCE was conducted among 1017 women in urban South Africa. Women were presented with choices between potential women's NPTs (microbicides, diaphragm, female condom) and 'what I did last time' (use or not use a condom) with different HIV and pregnancy prevention effectiveness' and prices. Choice probabilities are estimated using the nested logit model and used to predict uptake. RESULTS: In this high HIV prevalence setting, HIV prevention effectiveness is the main driver of uptake followed by pregnancy prevention effectiveness. For example a microbicide with poor effectiveness would have niche appeal at just 11% predicted uptake, while a highly effective microbicide (95% effective against HIV and pregnancy) would have far wider appeal (56% predicted uptake). Though women who reported not using condoms were more likely to choose the NPTs, at current very high rates of male condom use in South Africa (60%), about half of microbicide uptake is projected to be among those currently not using condoms. CONCLUSIONS: Women are very interested in NPTs, especially if highly effective in preventing HIV and pregnancy. Women in greatest need were also most likely to switch to the new products. Where products are not yet available for distribution, proxy data, such as that generated by DCEs, can bring realism to overly optimistic uptake scenarios found in many current impact models

Envisioning a Social-Health Information Exchange as a Platform to Support a Patient-Centered Medical Neighborhood: A Feasibility Study

BACKGROUND: Social determinants directly contribute to poorer health, and coordination between healthcare and community-based resources is pivotal to addressing these needs. However, our healthcare system remains poorly equipped to address social determinants of health. The potential of health information technology to bridge this gap across the delivery of healthcare and social services remains unrealized. OBJECTIVE, DESIGN, AND PARTICIPANTS: We conducted in-depth, in-person interviews with 50 healthcare and social service providers to determine the feasibility of a social-health information exchange (S-HIE) in an urban safety-net setting in Dallas County, Texas. After completion of interviews, we conducted a town hall meeting to identify desired functionalities for a S-HIE. APPROACH: We conducted thematic analysis of interview responses using the constant comparative method to explore perceptions about current communication and coordination across sectors, and barriers and enablers to S-HIE implementation. We sought participant confirmation of findings and conducted a forced-rank vote during the town hall to prioritize potential S-HIE functionalities. KEY RESULTS: We found that healthcare and social service providers perceived a need for improved information sharing, communication, and care coordination across sectors and were enthusiastic about the potential of a S-HIE, but shared many technical, legal, and ethical concerns around cross-sector information sharing. Desired technical S-HIE functionalities encompassed fairly simple transactional operations such as the ability to view basic demographic information, visit and referral data, and medical history from both healthcare and social service settings. CONCLUSIONS: A S-HIE is an innovative and feasible approach to enabling better linkages between healthcare and social service providers. However, to develop S-HIEs in communities across the country, policy interventions are needed to standardize regulatory requirements, to foster increased IT capability and uptake among social service agencies, and to align healthcare and social service priorities to enable dissemination and broader adoption of this and similar IT initiatives