Modification of Rifamycin Polyketide Backbone Leads to Improved Drug Activity Against Rifampicin-Resistant Mycobacterium tuberculosis

Rifamycin B, a product of Amycolatopsis mediterranei S699, is the precursor of clinically used antibiotics that are effective against tuberculosis, leprosy and AIDS related mycobacterial infections. However, prolonged usage of these antibiotics has resulted in the emergence of rifamycin resistant strains of Mycobacterium tuberculosis. As part of our effort to generate better analogs of rifamycin, we substituted the acyltransferase (AT) domain of module 6 of rifamycin polyketide synthase (rifPKS) with that of module 2 of rapamycin PKS. The resulting mutants (rifAT6::rapAT2) of A. mediterranei S699 produced new rifamycin analogs, 24-desmethylrifamycin B and 24-desmethylrifamycin SV, which contained modification in the polyketide backbone. 24-desmethylrifamycin B was then converted to 24-desmethylrifamycin S, whose structure was confirmed by MS, NMR, and X-ray crystallography. Subsequently, 24-desmethylrifamycin S was converted to 24-desmethylrifampicin, which showed excellent antibacterial activity against several rifampicin-resistant M. tuberculosis strains.This research was originally published in the Journal of Biological Chemistry. Nigam, A., Almabruk, K. H., Saxena, A., Yang, J., Mukherjee, U., Kaur, H., ... & Lal, R. Modification of Rifamycin Polyketide Backbone Leads to Improved Drug Activity against Rifampicin-resistant Mycobacterium tuberculosis. Journal of Biological Chemistry. 2014. 289:21142-21152. © the American Society for Biochemistry and Molecular Biology. This is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by The American Society for Biochemistry and Molecular Biology, Inc., and can be found at: http://www.jbc.org/Keywords: Domain Swapping, Polyketide Synthase, Rifamycin analogs, Multiple Drug Resistant, 24-desmethylrifamyci

Classification of early tuberculosis states to guide research for improved care and prevention: an international Delphi consensus exercise

The current active–latent paradigm of tuberculosis largely neglects the documented spectrum of disease. Inconsistency with regard to definitions, terminology, and diagnostic criteria for different tuberculosis states has limited the progress in research and product development that are needed to achieve tuberculosis elimination. We aimed to develop a new framework of classification for tuberculosis that accommodates key disease states but is sufficiently simple to support pragmatic research and implementation. Through an international Delphi exercise that involved 71 participants representing a wide range of disciplines, sectors, income settings, and geographies, consensus was reached on a set of conceptual states, related terminology, and research gaps. The International Consensus for Early TB (ICE-TB) framework distinguishes disease from infection by the presence of macroscopic pathology and defines two subclinical and two clinical tuberculosis states on the basis of reported symptoms or signs of tuberculosis, further differentiated by likely infectiousness. The presence of viable Mycobacterium tuberculosis and an associated host response are prerequisites for all states of infection and disease. Our framework provides a clear direction for tuberculosis research, which will, in time, improve tuberculosis clinical care and elimination policies

Effects of supplemented isoenergetic diets varying in cereal fiber and protein content on the bile acid metabolic signature and relation to insulin resistance

Bile acids (BA) are potent metabolic regulators influenced by diet. We studied effects of isoenergetic increases in the dietary protein and cereal-fiber contents on circulating BA and insulin resistance (IR) in overweight and obese adults. Randomized controlled nutritional intervention (18 weeks) in 72 non-diabetic participants (overweight/obese: 29/43) with at least one further metabolic risk factor. Participants were group-matched and allocated to four isoenergetic supplemented diets: control; high cereal fiber (HCF); high-protein (HP); or moderately increased cereal fiber and protein (MIX). Whole-body IR and insulin-mediated suppression of hepatic endogenous glucose production were measured using euglycaemic–hyperinsulinemic clamps with [6-62H2] glucose infusion. Circulating BA, metabolic biomarkers, and IR were measured at 0, 6, and 18 weeks. Under isoenergetic conditions, HP-intake worsened IR in obese participants after 6 weeks (M-value: 3.77 ± 0.58 vs. 3.07 ± 0.44 mg/kg/min, p = 0.038), with partial improvement back to baseline levels after 18 weeks (3.25 ± 0.45 mg/kg/min, p = 0.089). No deleterious effects of HP-intake on IR were observed in overweight participants. HCF-diet improved IR in overweight participants after 6 weeks (M-value 4.25 ± 0.35 vs. 4.81 ± 0.31 mg/kg/min, p = 0.016), but did not influence IR in obese participants. Control and MIX diets did not influence IR. HP-induced, but not HCF-induced changes in IR strongly correlated with changes of BA profiles. MIX-diet significantly increased most BA at 18 weeks in obese, but not in overweight participants. BA remained unchanged in controls. Pooled BA concentrations correlated with fasting fibroblast growth factor-19 (FGF-19) plasma levels (r = 0.37; p = 0.003). Higher milk protein intake was the only significant dietary predictor for raised total and primary BA in regression analyses (total BA, p = 0.017; primary BA, p = 0.011). Combined increased intake of dietary protein and cereal fibers markedly increased serum BA concentrations in obese, but not in overweight participants. Possible mechanisms explaining this effect may include compensatory increases of the BA pool in the insulin resistant, obese state; or defective BA transport

Gamification and Mobile Marketing Effectiveness

A variety of business sectors have been buffeted by the diffusion of mobile technology, a trend that presents a variety of difficult challenges but interesting opportunities to marketers. One such opportunity is gamification, which, one hopes, will enhance appeal to mobile consumers. Our sense from both personal experience and the literature is that the gamified mobile apps currently offered by firms mostly miss the mark. We provide a systematic overview of game design and note how principles derived from that field are highly applicable to gamification in mobile marketing settings. We are aided by the work of Schell (2008), whose Elemental Game Tetrad Model allows us to offer a coherent look at how gamification should affect mobile marketing outcomes

Fundamental understanding of the physics and modeling of boron source/drain extension evolution during CMOS device fabrication

textImprovements in the integrated circuit performance over the past three decades have been mainly possible by the downward scaling of device dimensions. Device scaling requires that all lateral and vertical dimensions of the transistor be scaled. In the last decade, in order to continue conventional scaling of the source/drain junctions, the semiconductor industry has relied heavily on decreasing the implant energy, and also on minimizing the thermal budget of the activation anneal. With Transient Enhanced Diffusion less pronounced for low implant energies and sharper anneal temperature profiles, interactions of dopant atoms and point defects with surface films and interfaces are becoming of paramount importance in determining the concentrations of dopants and point defects, and therefore the resulting device structures. A nitride spacer with an underlying deposited TEOS oxide, that behaves as a convenient etch stop layer, is a popular choice for sidewall spacer in modern CMOS process flows. In this work the effect of the silicon nitride spacer process on the B profile in silicon and the related dose loss of B from the Si into the silicon dioxide has been investigated. This is reflected as a dramatic decrease in the junction depth. The influence of the nitride spacer chemistry on B dose loss from the Si has also been investigated. The different nitride chemistries result in different B dose loss. A new model that predicts B junction depths and dose loss during fabrication of ultra-shallow junctions has been developed. A study of the interactions of dopant atoms and silicon point defects with silicon oxide films during annealing for ultra-shallow junction formation has been included. A new method for activation of source/drain junctions by microwave annealing has been proposed.Electrical and Computer Engineerin