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.

Optimal Guidance for Accurate Lunar Soft Landing with Minimum Fuel Consumption using Model Predictive Static Programming

In this paper the soft lunar landing with minimum fuel expenditure is formulated as a nonlinear optimal guidance problem. The realization of pinpoint soft landing with terminal velocity and position constraints is achieved using Model Predictive Static Programming (MPSP). The high accuracy of the terminal conditions is ensured as the formulation of the MPSP inherently poses final conditions as a set of hard constraints. The computational efficiency and fast convergence make the MPSP preferable for fixed final time onboard optimal guidance algorithm. It has also been observed that the minimum fuel requirement strongly depends on the choice of the final time (a critical point that is not given due importance in many literature). Hence, to optimally select the final time, a neural network is used to learn the mapping between various initial conditions in the domain of interest and the corresponding optimal flight time. To generate the training data set, the optimal final time is computed offline using a gradient based optimization technique. The effectiveness of the proposed method is demonstrated with rigorous simulation results.

Dual Drug Conjugate Loaded Nanoparticles for the Treatment of Cancer

Two antineoplastic agents, Imatinib (IM) and 5-Fluorouracil (FU) were conjugated by hydrolysable linkers through an amide bond and entrapped in polymeric Human Serum Albumin (HSA) nanoparticles. The presence of dual drugs in a common carrier has the advantage of reaching the site of action simultaneously and acting at different phases of the cell cycle to arrest the growth of cancer cells before they develop chemoresistance. The study has demonstrated an enhanced anticancer activity of the conjugate, and conjugate loaded stealth HSA nanoparticles (NPs) in comparison to the free drug in A-549 human lung carcinoma cell line and Zebra fish embryos (Danio rerio). Hydrolysability of the conjugate has also been demonstrated with complete hydrolysis being observed after 12 h. In vivo pharmacodynamics study in terms of tumor volume and pharmacokinetics in mice for conjugate (IM-SC-FU) and conjugate loaded nanoparticles showed significant anti-cancer activity. The other parameters evaluated were particle size (86nm), Poly Dispersive Index (PDI) (0.209), zeta potential (-49mV), drug entrapment efficiency (96.73%) and drug loading efficiency (89%). Being in stealth mode gives the potential for the NPs to evade Reticulo-Endothelial system (RES), achieve passive targeting by Enhanced Permeation Retention (EPR) effect with controlled release of the therapeutic agent. As the conjugate cleaves into individual drugs in the tumor environment, this promises better suppression of cancer chemoresistance by delivering dual drugs with different modes of action at the same site, thereby synergistically inhibiting the growth of cancerous tissue.

Low power consumption and high sensitivity carbon monoxide gas sensor using indium oxide nanowire.

In this paper, micro gas sensor was fabricated using indium oxide nanowire for effective gas detection and monitoring system. Indium oxide nanowire was grown using thermal CVD, and their structural properties were examined by the SEM, XRD and TEM. The electric properties for microdropped indium oxide nanowire device were measured, and gas response characteristics were examined for CO gas. Sensors showed high sensitivity and stability for CO gas. And with below 20 mw power consumption, 5 ppm CO could be detected.

Population age structure and private consumption in Spain

In this paper we study the effect of population age distribution upon private consumption expenditure in Spain from 1964 to 1997 using aggregate data. We obtain four main results. First, changes in the population pyramid have substantial effects upon the behaviour of private consumption. Second, the pattern of the coefficients of the demographic variables is not consistent with the simplest version of the life cycle hypothesis. Third, we estimate the impact of the demographic transition upon consumption and find positive values associated with episodes in which the shares of groups of individuals with expenditure levels higher (lower) than the mean increased (decreased). Fourth, the results are robust to alternative specifications for the population age distribution.

Using forecasts to protect Federal facilities in the path of Hurricane Isabel

Hurricane Isabel made landfall as a Category 2 Hurricane on 18 September 2003, on the North Carolina Outer Banks between Cape Lookout and Cape Hatteras, then coursed northwestward through Pamlico Sound and west of Chesapeake Bay where it downgraded to a tropical storm. Wind damage on the west and southwest shores of Pamlico Sound and the western shore of Chesapeake Bay was moderate, but major damage resulted from the storm tide. The NOAA, National Ocean Service, National Centers for Coastal Ocean Sciences, Center for Coastal Fisheries and Habitat Research at Beaufort, North Carolina and the Center for Coastal Environmental Health and Biomedical Research Branch at Oxford, Maryland have hurricane preparedness plans in place. These plans call for tropical storms and hurricanes to be tracked carefully through NOAA National Weather Service (NWS) watches, warnings, and advisories. When a hurricane watch changes to a hurricane warning for the areas of Beaufort or Oxford, documented hurricane preparation plans are activated. Isabel exacted some wind damage at both Beaufort and Oxford. Storm tide caused damage at Oxford, where area-wide flooding isolated the laboratory for many hours. Storm tide also caused damage at Beaufort. Because of their geographic locations on or near the open ocean (Beaufort) or on or near large estuaries (Beaufort and Oxford), storm tide poses a major threat to these NOAA facilities and the safety of federal employees. Damage from storm surge and windblown water depends on the track and intensity of a storm. One tool used to predict storm surge is the Sea, Lake, and Overland Surges from Hurricanes (SLOSH) model of the NWS, which provides valuable surge forecasts that aid in hurricane preparation.

Guidelines for the Provision of Garbage Reception Facilities at Ports Under MARPOL Annex V

This report offers guidelines for the provision of adequate port reception facilities for vessel-generated garbage under the requirements of Annex V of the International Convention for the Prevention of Pollution From Ships, 1973 (MARPOL 73/78), Regulations for the Prevention of Pollution by Garbage from Ships. MARPOL Annex V prohibits at-sea disposal of plastic materials from vessels, and specifies the distance from shore at which other materials may be dumped. Annex V also requires the provision of port reception facilities for garbage, but it does not specify these facilities or how they are to be provided. Since the at-sea dumping restrictions apply to all vessels, the reception facility requirement applies to all ports, terminals, and marinas that serve vessels. These guidelines were prepared to assist port owners and operators in meeting their obligation to provide adequate reception facilities for garbage. The report synthesizes available information and draws upon experience from the first years ofimplementation of MARPOL Annex V. (PDF file contains 55 pages.)

Consumption and portfolio rules whit stochastic hyperbolic discounting

We extend the classic Merton (1969, 1971) problem that investigates the joint consumption-savings and portfolio-selection problem under capital risk by assuming sophisticated but time-inconsistent agents. We introduce stochastic hyperbolic preferences as in Harris and Laibson (2013) and find closed-form solutions for Merton's optimal consumption and portfolio selection problem in continuous time. We find that the portfolio rule remains identical to the time-consistent solution with power utility and no borrowing constraints. However,the marginal propensity to consume out of wealth is unambiguously greater than the time-consistent, exponential case and,importantly, it is also more responsive to changes in risk. These results suggest that hyperbolic discounting with sophisticated agents offers promise for contributing to explaining important aspects of asset market data.

Survey of fish protective facilities at water withdrawal sites on the Snake and Columbia Rivers

Proliferation of water withdrawals and new pump intake and screen designs has occurred with the growth of irrigated agriculture along the Columbia and Snake Rivers. Concern for the protection of anadromous and resident fish populations resulted in formulation of a survey of the water withdrawal systems. The survey included distribution studies of juvenile fish near pump sites and field inspection of those sites to determine adequacy of screening for protection of fish. A total of 225 sites were inspected in 1979 and 1980, with a follow-up inspection of 95 sites in 1982. Results indicated a definite trend toward lack of concern for the condition of fish protective facilities. Only 4 out of 22 sites not meeting criteria in 1979 had been upgraded to acceptable conditions. Of more concern, 13 of the sites meeting criteria in 1979 were below criteria when reinspected in 1982. Some of the discrepancies included lack of protective screens, poorly maintained screens, and screens permitting excessive velocity that could result in impingement of larvae or small fish. A conclusion from these surveys is that if adequate protection for fish is to exist, screens for water withdrawals need to be properly installed, inspected, and maintained. (PDF file contains 40 pages.)

Multi-drug resistance profiles and the genetic features of Acinetobacter baumannii isolates from Bolivia

Introduction: Acinetobacter baumannii is opportunistic in debilitated hospitalised patients. Because information from some South American countries was previously lacking, this study examined the emergence of multi-resistant A. baumannii in three hospitals in Cochabamba, Bolivia, from 2008 to 2009. Methodology: Multiplex PCR was used to identify the main resistance genes in 15 multi-resistant A. baumannii isolates. RT-PCR was used to measure gene expression. The genetic environment of these genes was also analysed by PCR amplification and sequencing. Minimum inhibitory concentrations were determined for key antibiotics and some were determined in the presence of an efflux pump inhibitor, 1-(1-napthylmethyl) piperazine. Results: Fourteen strains were found to be multi-resistant. Each strain was found to have the bla(OXA-58) gene with the ISAba3-like element upstream, responsible for over-expression of the latter and subsequent carbapenem resistance. Similarly, ISAba1, upstream of the bla(ADC) gene caused over-expression of the latter and cephalosporin resistance; mutations in the gyrA(Ser83 to Leu) and parC (Ser-80 to Phe) genes were commensurate with fluoroquinolone resistance. In addition, the adeA, adeB efflux genes were over-expressed. All 15 isolates were positive for at least two aminoglycoside resistance genes. Conclusion: This is one of the first reports analyzing the multi-drug resistance profile of A. baumannii strains isolated in Bolivia and shows that the over-expression of thebla(OXA-58), bla(ADC) and efflux genes together with aminoglycoside modifying enzymes and mutations in DNA topoisomerases are responsible for the multi-resistance of the bacteria and the subsequent difficulty in treating infections caused by them.

The effect of the drug colchicine on the early life of fish

The alkaloid drug colchicine is a mitotic inhibitor. The results of this study show that colchicine influence the normal functioning of the mitotic process in Sarotherodon galilaeus, S. melanotheron and the hybrid S. galilaeus, X S. melanotheron leading to the production of unusual chromosomal events such as anaphase bridges, laggards and polyploid cells. These unusual events could have serious genetic implications in the area of variability of the chromosome number. The use of colchicine also produces results with consistent karyotypes and better morphology as well as providing detailed information on the behaviour of the chromosome of the early life of fish. The knowledge of such information will be of great use in cytotaxonomy, fish breeding and in studying the effects of sub-lethal levels of water pollutants on fish