Combined inhalation and oral supplementation of Vitamin A and Vitamin D: A possible prevention and therapy for tuberculosis

Tuberculosis is continuing as a problem of mankind. With evolution, MDR and XDR forms of tuberculosis have emerged from drug sensitive strain. MDR and XDR strains are resistant to most of the antibiotics, making the management more difficult. BCG vaccine is not providing complete protection against tuberculosis. Therefore new infections are spreading at a tremendous rate. At the present moment there is experimental evidence to believe that Vitamin A and Vitamin D has anti-mycobacterial property. It is in this context, we have hypothesized a host based approach using the above vitamins that can cause possible prevention and cure of tuberculosis with minimal chance of resistance or toxicity. (C) 2015 Elsevier Ltd. All rights reserved.

Operand Isolation Circuits with Reduced Overhead for Low Power Data-Path Design

Dynamic power dissipation due to redundant switching is an important metric in data-path design. This paper focuses on the use of ingenious operand isolation circuits for low power design. Operand isolation attempts to reduce switching by clamping or latching the output of a first level of combinational circuit. This paper presents a novel method using power supply switching wherein both PMOS and NMOS stacks of a circuit are connected to the same power supply. Thus, the output gets clamped or latched to the power supply value with minimal leakage. The proposed circuits make use of only two transistors to clamp the entire Multiple Input Multiple Output (MIMO) block. Also, the latch-based designs have higher drive strength in comparison to the existing methods. Simulation results have shown considerable area reduction in comparison to the existing techniques without increasing timing overhead.

Equilibrium and equivariant triangulations of some small covers with minimum number of vertices

Small covers were introduced by Davis and Januszkiewicz in 1991. We introduce the notion of equilibrium triangulations for small covers. We study equilibrium and vertex minimal 4-equivariant triangulations of 2-dimensional small covers. We discuss vertex minimal equilibrium triangulations of RP3#RP3, S-1 x RP2 and a nontrivial S-1 bundle over RP2. We construct some nice equilibrium triangulations of the real projective space RPn with 2(n) + n 1 vertices. The main tool is the theory of small covers.

A CONVENIENT MODIFICATION OF THE FISCHER INDOLE SYNTHESIS WITH A SOLID ACID

A new one-pot version of the titled reaction involves heating a mixture of a carbonyl compound, a phenylhydrazine, and the cation exchange resin Amberlite IR 120 in refluxing ethanol. A variety of enolizable aldehydes, and ketones and several substituted phenylhydrazines could thus be converted to the corresponding indoles in excellent yields (70-88%). Reaction times were typically 6-10 h, with the resin being then filtered off and the product isolated after minimal workup.

An Implementation of Partitioned Scheduling Scheme for Hard Real-Time Tasks in Multicore Linux with Fair Share for Linux Tasks

The correctness of a hard real-time system depends its ability to meet all its deadlines. Existing real-time systems use either a pure real-time scheduler or a real-time scheduler embedded as a real-time scheduling class in the scheduler of an operating system (OS). Existing implementations of schedulers in multicore systems that support real-time and non-real-time tasks, permit the execution of non-real-time tasks in all the cores with priorities lower than those of real-time tasks, but interrupts and softirqs associated with these non-real-time tasks can execute in any core with priorities higher than those of real-time tasks. As a result, the execution overhead of real-time tasks is quite large in these systems, which, in turn, affects their runtime. In order that the hard real-time tasks can be executed in such systems with minimal interference from other Linux tasks, we propose, in this paper, an integrated scheduler architecture, called SchedISA, which aims to considerably reduce the execution overhead of real-time tasks in these systems. In order to test the efficacy of the proposed scheduler, we implemented partitioned earliest deadline first (P-EDF) scheduling algorithm in SchedISA on Linux kernel, version 3.8, and conducted experiments on Intel core i7 processor with eight logical cores. We compared the execution overhead of real-time tasks in the above implementation of SchedISA with that in SCHED_DEADLINE's P-EDF implementation, which concurrently executes real-time and non-real-time tasks in Linux OS in all the cores. The experimental results show that the execution overhead of real-time tasks in the above implementation of SchedISA is considerably less than that in SCHED_DEADLINE. We believe that, with further refinement of SchedISA, the execution overhead of real-time tasks in SchedISA can be reduced to a predictable maximum, making it suitable for scheduling hard real-time tasks without affecting the CPU share of Linux tasks.

Role of supersymmetric heavy Higgs boson production in the self-coupling measurement of 125 GeV Higgs boson at the LHC

Measurement of the self-coupling of the 125 GeV Higgs boson is one of the most crucial tasks for a high luminosity run of the LHC, and it can only be measured in the di-Higgs final state. In the minimal supersymmetric standard model, heavy CP even Higgs (H) can decay into a lighter 125 GeV Higgs boson (h) and, therefore, can influence the rate of di-Higgs production. We investigate the role of single H production in the context of measuring the self-coupling of h. We have found that the H -> hh decay can change the value of Higgs (h) self-coupling substantially, in a low tan beta regime where the mass of the heavy Higgs boson lies between 250 and 600 GeV and, depending on the parameter space, it may be seen as an enhancement of the self-coupling of the 125 GeV Higgs boson.

Protamine-carboxymethyl cellulose magnetic nanocapsules for enhanced delivery of anticancer drugs against drug resistant cancers

Multidrug resistance is a major therapeutic challenge faced in the conventional chemotherapy. Nanocarriers are beneficial in the transport of chemotherapeutics by their ability to bypass the P-gp efflux in cancers. Most of the P-gp inhibitors under phase II clinical trial are facing failures and hence there is a need to develop a suitable carrier to address P-gp efflux in cancer therapy. Herein, we prepared novel protamine and carboxymethyl cellulose polyelectrolyte multi-layered nanocapsules modified with Fe3O4 nanoparticles for the delivery of doxorubicin against highly drug resistant HeLa cells. The experimental results revealed that improved cellular uptake, enhanced drug intensity profile with greater percentage of apoptotic cells was attained when doxorubicin loaded magnetic nanocapsules were used in the presence of external magnetic field. Hence, we conclude that this magnetic field assisted nanocapsule system can be used for delivery of chemotherapeutics for potential therapeutic efficacy at minimal dose in multidrug resistant cancers. From the Clinical Editor: Many cancer drugs fail when cancer cells become drug resistant. Indeed, multidrug resistance (MDR) is a major therapeutic challenge. One way that tumor cells attain MDR is by over expression of molecular pumps comprising of P-glycoprotein (P-gp) and multidrug resistant proteins (MRP), which can expel chemotherapeutic drugs out of the cells. In this study, the authors prepared novel protamine and carboxymethyl cellulose polyelectrolyte multi-layered nanocapsules modified with Fe3O4 nanoparticles for the delivery of doxorubicin. The results show that there was better drug delivery and efficacy even against MDR tumor cells. (C) 2015 Elsevier Inc. All rights reserved.

Exploring CP violation in the MSSM

We explore the prospects for observing CP violation in the minimal supersymmetric extension of the Standard Model (MSSM) with six CP-violating parameters, three gaugino mass phases and three phases in trilinear soft supersymmetry-breaking parameters, using the CPsuperH code combined with a geometric approach to maximise CP-violating observables subject to the experimental upper bounds on electric dipole moments. We also implement CP-conserving constraints from Higgs physics, flavour physics and the upper limits on the cosmological dark matter density and spin-independent scattering. We study possible values of observables within the constrained MSSM (CMSSM), the non-universal Higgs model (NUHM), the CPX scenario and a variant of the phenomenological MSSM (pMSSM). We find values of the CP-violating asymmetry A(CP) in b -> s gamma decay that may be as large as 3 %, so future measurements of ACP may provide independent information about CP violation in the MSSM. We find that CP-violating MSSM contributions to the B-s meson mass mixing term Delta M-Bs are in general below the present upper limit, which is dominated by theoretical uncertainties. If these could be reduced, Delta M-Bs could also provide an interesting and complementary constraint on the six CP-violating MSSM phases, enabling them all to be determined experimentally, in principle. We also find that CP violation in the h(2,3)tau(+)tau(-) and h(2,3) (t) over bart couplings can be quite large, and so may offer interesting prospects for future pp, e(+) e(-), mu(+) mu(-) and gamma gamma colliders.

Dendron conjugation to graphene oxide using click chemistry for efficient gene delivery

Owing to its large surface area and rapid cellular uptake, graphene oxide (GO) is emerging as an attractive candidate material for delivery of drugs and genes. The inherent sp(2) pi-pi interaction of GO helps to carry drugs and single stranded RNA (ssRNA) but there is no such interaction with double stranded DNA (dsDNA). In this work, a polyamidoamine (PAMAM) dendron was conjugated with nano GO (nGO) through ``click'' chemistry to improve the DNA complexation capability of GO as well as its transfection efficiency. The DNA complexation capability of GO was significantly enhanced after dendronization of GO yielding spherical nanosized (250-350 nm) particles of the dendronized GO (DGO)/pDNA complex with a positive zeta potential. The transfection efficiency of GO dramatically increased after conjugation of the PAMAM dendron. Transfection efficiency of 51% in HeLa cells with cell viability of 80% was observed. The transfection efficiency was significantly higher than that of polyethyleneimine 25 kDa (27% efficiency) and also surpassed that of lipofectamine 2000 (47% efficiency). The uptake of the DGO/pDNA complex by the caveolae mediated endocytosis pathway may significantly contribute to the high transfection efficiency. Thus, dendronized GO is shown to be an efficient gene carrier with minimal toxicity and is a promising candidate for use as a nonviral carrier for gene therapy.

Biofunctionalized surface-modified silver nanoparticles for gene delivery

Silver nanoparticles (AgNPs) find use in different biomedical applications including wound healing and cancer. We propose that the efficacy of the nanoparticles can be further augmented by using these particles for gene delivery applications. The objective of this work was to engineer biofunctionalized stable AgNPs with good DNA binding ability for efficient transfection and minimal toxicity. Herein, we report on the one-pot facile green synthesis of polyethylene glycol (PEG) stabilized chitosan-g-polyacrylamide modified AgNPs. The size of the PEG stabilized AgNPs was 38 +/- 4 nm with a tighter size distribution compared to the unstabilized nanoparticles which showed bimodal distribution of particle sizes of 68 +/- 5 nm and 7 +/- 4 nm. To enhance the efficiency of gene transfection, the Arg-Gly-Asp-Ser (RGDS) peptide was immobilized on the silver nanoparticles. The transfection efficiency of AgNPs increased significantly after immobilization of the RGDS peptide reaching up to 42 +/- 4% and 30 +/- 3% in HeLa and A549 cells, respectively, and significantly higher than 34 +/- 3% and 23 +/- 2%, respectively, with the use of polyethyleneimine (25 kDa). These nanoparticles were found to induce minimal cellular toxicity. Differences in cellular uptake mechanisms with RGDS immobilization resulting in improved efficiency are elucidated. This study presents biofunctionalized AgNPs for potential use as efficient nonviral carriers for gene delivery with minimal cytotoxicity toward augmenting the therapeutic efficacy of AgNPs used in different biomedical products.

Catalytic pathway, substrate binding and stability in SAICAR synthetase: A structure and molecular dynamics study

The de novo purine biosynthesis is one of the highly conserved pathways among all organisms and is essential for the cell viability. A clear understanding of the enzymes in this pathway would pave way for the development of antimicrobial and anticancer drugs. Phosphoribosylaminoimidazole-succinocar boxamide (SAICAR) synthetase is one of the enzymes in this pathway that catalyzes ATP dependent ligation of carboxyaminoimidazole ribotide (CAIR) with L-aspartate (ASP). Here, we describe eight crystal structures of this enzyme, in C222(1) and H3 space groups, bound to various substrates and substrate mimics from a hyperthermophilic archaea Pyrococcus horikoshii along with molecular dynamics simulations of the structures with substrates. Complexes exhibit minimal deviation from its apo structure. The CAIR binding site displays a preference for pyrimidine nucleotides. In the ADP.TMP-ASP complex, the ASP binds at a position equivalent to that found in Saccharomyces cerevisiae structure (PDB: 2CNU) and thus, clears the ambiguity regarding ASP's position. A possible mode for the inhibition of the enzyme by CTP and UTP, observed earlier in the yeast enzyme, is clearly illustrated in the structures bound to CMP and UMP. The ADP.Mg2+.PO4.CD/MP complex having a phosphate ion between the ATP and CAIR sites strengthens one of the two probable pathways (proposed in Escherichia coli study) of catalytic mechanism and suggests the possibility of a phosphorylation taking place before the ASP's attack on CAIR. Molecular dynamic simulations of this enzyme along with its substrates at 90 degrees C reveal the relative strengths of substrate binding, possible antagonism and the role of Mg2+ ions. (C) 2015 Elsevier Inc. All rights reserved.

Lead selection and characterization of antitubercular compounds using the Nested Chemical Library

Discovering new drugs to treat tuberculosis more efficiently and to overcome multidrug resistance is a world health priority. To find novel antitubercular agents several approaches have been used in various institutions worldwide, including target-based approaches against several validated mycobacterial enzymes and phenotypic screens. We screened more than 17,000 compounds from Vichem's Nested Chemical Library(TM) using an integrated strategy involving whole cell-based assays with Corynebacterium glutamicum and Mycobacterium tuberculosis, and target-based assays with protein kinases PknA, PknB and PknG as well as other targets such as PimA and bacterial topoisomerases simultaneously. With the help of the target-based approach we have found very potent hits inhibiting the selected target enzymes, but good minimal inhibitory concentrations (MIC) against M. tuberculosis were not achieved. Focussing on the whole cell-based approach several potent hits were found which displayed minimal inhibitory concentrations (MIC) against M. tuberculosis below 10 mu M and were non-mutagenic, non-cytotoxic and the targets of some of the hits were also identified. The most active hits represented various scaffolds. Medicinal chemistry-based lead optimization was performed applying various strategies and, as a consequence, a series of novel potent compounds were synthesized. These efforts resulted in some effective potential antitubercular lead compounds which were confirmed in phenotypic assays. (C) 2015 Elsevier Ltd. All rights reserved.

Homing abilities of the tropical primitively eusocial paper wasp Ropalidia marginata

Compared to our extensive knowledge about the navigation and homing abilities of ants and bees, we know rather little about these phenomena in social wasps. Here, we report the homing abilities of the tropical primitively eusocial wasp Ropalidia marginata and the factors that affect their homing success. To determine from how far these wasps can return to their nests, we transported foragers blindfold and released them at gradually increasing distances from their nests in four cardinal directions. Their homing success was determined by checking their presence on their nests on three consecutive nights. All foragers (56 individuals, 115 releases) returned back from an area of 0.73 +/- A 0.25 km(2) on the day of release (minimal homing area), whereas 83.8 % of the foragers (217 individuals, 420 releases) returned when we enlarged the area of release to 6.22 +/- A 0.66 km(2) around their nests (maximal homing area). Of 66 releases, no wasps returned from beyond the maximal homing area. The minimal homing area might be familiar to the foragers because they probably routinely forage in this area and the maximal homing area represents the maximum distances from which the wasps are capable of returning to their nests, with or without familiarity.

Experimentally validated Raman Monte Carlo simulation for a cuboid object to obtain Raman spectroscopic signatures for hidden material

In conventional Raman spectroscopic measurements of liquids or surfaces the preferred geometry for detection of the Raman signal is the backscattering (or reflection) mode. For non-transparent layered materials, sub-surface Raman signals have been retrieved using spatially offset Raman spectroscopy (SORS), usually with light collection in the same plane as the point of excitation. However, as a result of multiple scattering in a turbid medium, Raman photons will be emitted in all directions. In this study, Monte Carlo simulations for a three-dimensional layered sample with finite geometry have been performed to confirm the detectability of Raman signals at all angles and at all sides of the object. We considered a non-transparent cuboid container (high density polyethylene) with explosive material (ammonium nitrate) inside. The simulation results were validated with experimental Raman intensities. Monte Carlo simulation results reveal that the ratio of sub-surface to surface signals improves at geometries other than backscattering. In addition, we demonstrate through simulations the effects of the absorption and scattering coefficients of the layers, and that of the diameter of the excitation beam. The advantage of collecting light from all possible 4 angles, over other collection modes, is that this technique is not geometry specific and molecular identification of layers underneath non-transparent surfaces can be obtained with minimal interference from the surface layer. To what extent all sides of the object will contribute to the total signal will depend on the absorption and scattering coefficients and the physical dimensions. Copyright (c) 2015 John Wiley & Sons, Ltd.

Direct Measurement of Three-Dimensional Forces in Atomic Force Microscopy

Direct measurement of three-dimensional (3-D) forces between an atomic force microscope (AFM) probe and the sample benefits diverse applications of AFM, including force spectroscopy, nanometrology, and manipulation. This paper presents the design and evaluation of a measurement system, wherein the deflection of the AFM probe is obtained at two points to enable direct measurement of all the three components of 3-D tip-sample forces in real time. The optimal locations for measurement of deflection on the probe are derived for a conventional AFM probe. Further, a new optimal geometry is proposed for the probe that enables measurement of 3-D forces with identical sensitivity and nearly identical resolution along all three axes. Subsequently, the designed measurement system and the optimized AFM probe are both fabricated and evaluated. The evaluation demonstrates accurate measurement of tip-sample forces with minimal cross-sensitivities. Finally, the real-time measurement system is employed as part of a feedback control system to regulate the normal component of the interaction force, and to perform force-controlled scribing of a groove on the surface of polymethyl methacrylate.