Recognizing drug targets using evolutionary information: implications for repurposing FDA-approved drugs against Mycobacterium tuberculosis H37Rv

Drug repurposing to explore target space has been gaining pace over the past decade with the upsurge in the use of systematic approaches for computational drug discovery. Such a cost and time-saving approach gains immense importance for pathogens of special interest, such as Mycobacterium tuberculosis H37Rv. We report a comprehensive approach to repurpose drugs, based on the exploration of evolutionary relationships inferred from the comparative sequence and structural analyses between targets of FDA-approved drugs and the proteins of M. tuberculosis. This approach has facilitated the identification of several polypharmacological drugs that could potentially target unexploited M. tuberculosis proteins. A total of 130 FDA-approved drugs, originally intended against other diseases, could be repurposed against 78 potential targets in M. tuberculosis. Additionally, we have also made an attempt to augment the chemical space by recognizing compounds structurally similar to FDA-approved drugs. For three of the attractive cases we have investigated the probable binding modes of the drugs in their corresponding M. tuberculosis targets by means of structural modelling. Such prospective targets and small molecules could be prioritized for experimental endeavours, and could significantly influence drug-discovery and drug-development programmes for tuberculosis.

Comparative sequence analyses of genome and transcriptome reveal novel transcripts and variants in the Asian elephant Elephas maximus

The Asian elephant Elephas maximus and the African elephant Loxodonta africana that diverged 5-7 million years ago exhibit differences in their physiology, behaviour and morphology. A comparative genomics approach would be useful and necessary for evolutionary and functional genetic studies of elephants. We performed sequencing of E. maximus and map to L. africana at similar to 15X coverage. Through comparative sequence analyses, we have identified Asian elephant specific homozygous, non-synonymous single nucleotide variants (SNVs) that map to 1514 protein coding genes, many of which are involved in olfaction. We also present the first report of a high-coverage transcriptome sequence in E. maximus from peripheral blood lymphocytes. We have identified 103 novel protein coding transcripts and 66-long non-coding (lnc)RNAs. We also report the presence of 181 protein domains unique to elephants when compared to other Afrotheria species. Each of these findings can be further investigated to gain a better understanding of functional differences unique to elephant species, as well as those unique to elephantids in comparison with other mammals. This work therefore provides a valuable resource to explore the immense research potential of comparative analyses of transcriptome and genome sequences in the Asian elephant.

Molecular profiling of sepsis in mice using Fourier Transform Infrared Microspectroscopy

Sepsis is a life threatening condition resulting from a high burden of infection. It is a major health care problem and associated with inflammation, organ dysfunction and significant mortality. However, proper understanding and delineating the changes that occur during this complex condition remains a challenge. A comparative study involving intra-peritoneal injection of BALB/c mice with Salmonella Typhimurium (infection), lipopolysaccharide (endotoxic shock) or thioglycollate (sterile peritonitis) was performed. The changes in organs and sera were profiled using immunological assays and Fourier Transform Infrared (FTIR) micro-spectroscopy. There is a rapid rise in inflammatory cytokines accompanied with lowering of temperature, respiratory rate and glucose amounts in mice injected with S. Typhimurium or lipopolysaccharide. FTIR identifies distinct changes in liver and sera: decrease in glycogen and protein/lipid ratio and increase in DNA and cholesteryl esters. These changes were distinct from the pattern observed in mice treated with thioglycollate and the differences in the data obtained between the three models are discussed. The combination of FTIR spectroscopy and other biomarkers will be valuable in monitoring molecular changes during sepsis. GRAPHICS] Intra-peritoneal infection with high dose of Salmonella Typhimurium leads to rapid increase in inflammatory cytokines, e.g. Tnf alpha (A). FTIR analysis of liver (B) and sera (C) identifies several metabolic changes: glycogen, protein/lipid, cholesteryl esters and DNA.

A comparative phase 1 clinical trial to identify anti-infective mechanisms of vitamin D in people with HIV infection

Objectives:To determine if there is a biological mechanism that explains the association between HIV disease progression and increased mortality with low circulating vitamin D levels; specifically, to determine if restoring vitamin D levels induced T-cell functional changes important for antiviral immunity.Design:This was a pilot, open-label, three-arm prospective phase 1 study.Methods:We recruited 28 patients with low plasma vitamin D (<50nmol/l 25-hydroxyvitamin D3), comprising 17 HIV+ patients (11 on HAART, six treatment-naive) and 11 healthy controls, who received a single dose of 200000IU oral cholecalciferol. Advanced T-cell flow cytometry methods measured CD4(+) T-cell function associated with viral control in blood samples at baseline and 1-month after vitamin D supplementation.Results:One month of vitamin D supplementation restored plasma levels to sufficiency (>75nmol/l) in 27 of 28 patients, with no safety issues. The most striking change was in HIV+ HAART+ patients, where increased frequencies of antigen-specific T cells expressing macrophage inflammatory protein (MIP)-1 - an important anti-HIV blocking chemokine - were observed, with a concomitant increase in plasma MIP-1, both of which correlated significantly with vitamin D levels. In addition, plasma cathelicidin - a vitamin D response gene with broad antimicrobial activity - was enhanced.Conclusion:Vitamin D supplementation modulates disease-relevant T-cell functions in HIV-infected patients, and may represent a useful adjunct to HAART therapy. Copyright (C) 2015 Wolters Kluwer Health, Inc. All rights reserved.

Disaggregation of LST over India: comparative analysis of different vegetation indices

The non-availability of high-spatial-resolution thermal data from satellites on a consistent basis led to the development of different models for sharpening coarse-spatial-resolution thermal data. Thermal sharpening models that are based on the relationship between land-surface temperature (LST) and a vegetation index (VI) such as the normalized difference vegetation index (NDVI) or fraction vegetation cover (FVC) have gained much attention due to their simplicity, physical basis, and operational capability. However, there are hardly any studies in the literature examining comprehensively various VIs apart from NDVI and FVC, which may be better suited for thermal sharpening over agricultural and natural landscapes. The aim of this study is to compare the relative performance of five different VIs, namely NDVI, FVC, the normalized difference water index (NDWI), soil adjusted vegetation index (SAVI), and modified soil adjusted vegetation index (MSAVI), for thermal sharpening using the DisTrad thermal sharpening model over agricultural and natural landscapes in India. Multi-temporal LST data from Landsat-7 Enhanced Thematic Mapper Plus (ETM+) and Moderate Resolution Imaging Spectroradiometer (MODIS) sensors obtained over two different agro-climatic grids in India were disaggregated from 960 m to 120 m spatial resolution. The sharpened LST was compared with the reference LST estimated from the Landsat data at 120 m spatial resolution. In addition to this, MODIS LST was disaggregated from 960 m to 480 m and compared with ground measurements at five sites in India. It was found that NDVI and FVC performed better only under wet conditions, whereas under drier conditions, the performance of NDWI was superior to other indices and produced accurate results. SAVI and MSAVI always produced poorer results compared with NDVI/FVC and NDWI for wet and dry cases, respectively.

Comparative studies of AOT and NaDEHP by fluorescence technique and z-potential (ζ) measurements

The aggregation behaviors of two surfactants with the same hydrophobic tail, sodium bis(2-ethylhexyl)sulfosuccinate (AOT) and sodium bis(2-ethylhexyl)phosphate (NaDEHP), have been investigated by the fluorescence technique and z-potential (ζ) measurements. Five fine peaks of the pyrene molecule fluorescence spectroscopy appear in the surfactant solution, and the micropolarity at which pyrene locates is monitored from the intensity ratio of the first (I1) and the third peak (I3). A wide peak around 475 nm, the emission spectra of the excimer of pyrene molecules, is observed in the NaDEHP solution, while this is not found for the AOT system. The value of I1/I3 decreases in a more limited concentration range for the AOT system than for NaDEHP, indicating that small aggregates can be more easily formed by NaDEHP molecules. The z-potential results for the aggregates formed by the two surfactants show that the interaction between AOT and PVP is stronger than that between NaDEHP and PVP.

A comparative study of plasma-enhanced chemical vapor gate dielectrics for solution-processed polymer thin-film transistor circuit integration

This paper considers plasma-enhanced chemical vapor deposited (PECVD) silicon nitride (SiNx) and silicon oxide (SiOx) as gate dielectrics for organic thin-film transistors (OTFTs), with solution-processed poly[5, 5′ -bis(3-dodecyl-2-thienyl)-2, 2′ -bithiophene] (PQT-12) as the active semiconductor layer. We examine transistors with SiNx films of varying composition deposited at 300 °C as well as 150 °C for plastic compatibility. The transistors show over 100% (two times) improvement in field-effect mobility as the silicon content in SiNx increases, with mobility (μFE) up to 0.14 cm2 /V s and on/off current ratio (ION / IOFF) of 108. With PECVD SiOx gate dielectric, preliminary devices exhibit a μFE of 0.4 cm2 /V s and ION / IOFF of 108. PQT-12 OTFTs with PECVD SiNx and SiOx gate dielectrics on flexible plastic substrates are also presented. These results demonstrate the viability of using PECVD SiN x and SiOx as gate dielectrics for OTFT circuit integration, where the low temperature and large area deposition capabilities of PECVD films are highly amenable to integration of OTFT circuits targeted for flexible and lightweight applications. © 2008 American Institute of Physics.

Comparative study of the slurry erosion and free-fall particle erosion of aluminum

A study has been performed of the erosion of aluminium by silica sand particles at a velocity of 4.5 m s-1, both air-borne and in the form of a water-borne slurry. Measurements made under similar experimental conditions show that slurry erosion proceeds at a rate several times that of air-borne erosion, the ratio of the two rates depending strongly on the angle of impact. Sand particles become embedded into the metal surface during air-borne particle erosion, forming a composite layer of metal and silica, and provide the major cause of the difference in wear rate. The embedded particles giving rise to surface hardening and a significant reduction in the erosion rate. Embedment of erodent particles was not observed during slurry erosion. Lubrication of the impacting interfaces by water appears to have minimal effect on the wear of aluminium by slurry erosion.

Comparative Study Of The Influence Of Natural Convection On Directional Solidification Of Al-3.5 Wt% Ni And Al-7 Wt% Si Alloys

We present numerical simulations of thermosolutal convection for directional solidification of Al-3.5 wt% Ni and Al-7 wt% Si. Numerical results predict that fragmentation of dendrite arms resulting from dissolution could be favored in Al-7 wt% Si, but not in Al-3.5 wt% Ni. Corresponding experiments are in qualitative agreement with the numerical predictions. Distinguishing the two fragmentation mechanisms, namely dissolution and remelting, is critical during experiments on earth, when fluid flow is dominant. (C) 2007 COSPAR. Published by Elsevier Ltd. All rights reserved.

Comparative observation of Ar, Ar-H-2 and Ar-N-2 DC arc plasma jets and their arc root behaviour at reduced pressure

Results observed experimentally are presented, about the DC arc plasma jets and their arc-root behaviour generated at reduced gas pressure without or with an applied magnetic field. Pure argon, argon-hydrogen or argon- nitrogen mixture was used as the plasma-forming gas. A specially designed copper mirror was used for a better observation of the arc-root behaviour on the anode surface of the DC non-transferred arc plasma torch. It was found that in the cases without an applied magnetic field, the laminar plasma jets were stable and approximately axisymmetrical. The arc-root attachment on the anode surface was completely diffusive when argon was used as the plasma-forming gas, while the arc-root attachment often became constrictive when hydrogen or nitrogen was added into the argon. As an external magnetic field was applied, the arc root tended to rotate along the anode surface of the non-transferred arc plasma torch.

The effect of flexibility in working hours on fertility: A comparative analysis of selected european countries

The main aim of this paper is to measure the extent to which part-time work enhances fertility for married or cohabiting women of fertile age. The study covers eleven European countries. The data used are a pool sample of five waves of the European Community Household Panel. Given that we believe that the decisions concerning fertility and labor market status are taken jointly, we carry out a simultaneous estimation approach. Results suggest that policy makers wishing to implement adequate part-time schedules so as to enhance fertility should look at the part-time schedules available in Belgium, Ireland and The Netherlands, which enhance fertility for women who take advantage of this flexibility measure so as to reconcile family and work.