The complementation of yeast with human or Plasmodium falciparum Hsp90 confers differential inhibitor sensitivities

Developing novel drugs against the unicellular parasite Plasmodium is complicated by the paucity of simple screening systems. Heat-shock proteins are an essential class of proteins for the parasite's cyclical life style between different cellular milieus and temperatures. The molecular chaperone Hsp90 assists a large variety of proteins, but its supporting functions for many proteins that are important for cancer have made it into a well-studied drug target. With a better understanding of the differences between Hsp90 of the malarial parasite and Hsp90 of its human host, new therapeutic options might become available. We have generated a set of isogenic strains of the budding yeast Saccharomyces cerevisiae where the essential yeast Hsp90 proteins have been replaced with either of the two human cytosolic isoforms Hsp90 alpha or Hsp90 beta, or with Hsp90 from Plasmodium falciparum (Pf). All strains express large amounts of the Flag-tagged Hsp90 proteins and are viable. Even though the strain with Pf Hsp90 grows more poorly, it provides a tool to reconstitute additional aspects of the parasite Hsp90 complex and its interactions with substrates in yeast as a living test tube. Upon exposure of the set of Hsp90 test strains to the two Hsp90 inhibitors radicicol (Rd) and geldanamycin (GA), we found that the strain with Pf Hsp90 is relatively more sensitive to GA than to Rd compared to the strains with human Hsp90's. This indicates that this set of yeast strains could be used to screen for new Pf Hsp90 inhibitors with a wider therapeutic window.

Salmonella pathogenicity island 2 mediates protection of intracellular Salmonella from reactive nitrogen intermediates.

Salmonella typhimurium causes an invasive disease in mice that has similarities to human typhoid. A type III protein secretion system encoded by Salmonella pathogenicity island 2 (SPI2) is essential for virulence in mice, as well as survival and multiplication within macrophages. Reactive nitrogen intermediates (RNI) synthesized by inducible nitric oxide synthase (iNOS) are involved in the control of intracellular pathogens, including S. typhimurium. We studied the effect of Salmonella infection on iNOS activity in macrophages. Immunofluorescence microscopy demonstrated efficient colocalization of iNOS with bacteria deficient in SPI2 but not wild-type Salmonella, and suggests that the SPI2 system interferes with the localization of iNOS and Salmonella. Furthermore, localization of nitrotyrosine residues in the proximity was observed for SPI2 mutant strains but not wild-type Salmonella, indicating that peroxynitrite, a potent antimicrobial compound, is excluded from Salmonella-containing vacuoles by action of SPI2. Altered colocalization of iNOS with intracellular Salmonella required the function of the SPI2-encoded type III secretion system, but not of an individual "Salmonella translocated effector." Inhibition of iNOS increased intracellular proliferation of SPI2 mutant bacteria and, to a lesser extent, of wild-type Salmonella. The defect in systemic infection of a SPI2 mutant strain was partially restored in iNOS(-/-) mice. In addition to various strategies to detoxify RNI or repair damage due to RNI, avoidance of colocalization with RNI is important in adaptation of a pathogen to an intracellular life style.

Vaccination for pregnant women: Need to address

Pregnancy is a critically important state for any women in her life time. Administration of a vaccine to a pregnant woman is not a routine event and it is generally preferred to administer vaccines either prior to conception or in the postpartum period. Currently vaccination with inactivated vaccines are recommended due to potential risk to mother and fetus with live vaccines. Multiple factors determine the administration of the vaccines for example age, life style, medical conditions (e.g., asthma, diabetes etc.), type and location of travel and status of previous vaccination. If pregnant woman is exposed to these vaccines or if pregnancy occurs soon after vaccination, the women should be counselled regarding the risks to the fetus and vaccination should not be a reason to consider termination of pregnancy. Further research in vaccination among pregnancy is warranted for the safety of the pregnant women and their newborn for a healthy living and better life.

Enhancement of fatigue life of Ni-Ti-Fe shape memory alloys by thermal cycling

The effect of thermal cycling on the load-controlled tension-tension fatigue behavior of a Ni-Ti-Fe shape memory alloy (SMA) at room temperature was studied. Considerable strain accumulation was observed to occur in this alloy under both quasi-static and cyclic loading conditions. Though, in all cases, steady-state is reached within the first 50-100 cycles, the accumulated steady-state strain, epsilon(p.ss), is much smaller in thermally cycled alloy. As a result, the fatigue performance of them was found to be significantly enhanced vis-a-vis the as-solutionized alloy. Furthermore, under load-controlled conditions, the fatigue life of Ni-Ti-Fe alloys was found to be exclusively dependent on epsilon(p.ss). Observations made by profilometry and differential scanning calorimetry (DSC) indicate that the 200-500% enhancement in fatigue life of thermally cycled alloy is due to the homogeneous distribution of the accumulated fatigue strain. (C) 2010 Elsevier B.V. All rights reserved.

WLS method for parameter estimation in water distribution networks

The weighted-least-squares method based on the Gauss-Newton minimization technique is used for parameter estimation in water distribution networks. The parameters considered are: element resistances (single and/or group resistances, Hazen-Williams coefficients, pump specifications) and consumptions (for single or multiple loading conditions). The measurements considered are: nodal pressure heads, pipe flows, head loss in pipes, and consumptions/inflows. An important feature of the study is a detailed consideration of the influence of different choice of weights on parameter estimation, for error-free data, noisy data, and noisy data which include bad data. The method is applied to three different networks including a real-life problem.

Influence of land use changes in river basins on diversity and distribution of amphibians

Land-use changes influence local biodiversity directly, and also cumulatively, contribute to regional and global changes in natural systems and quality of life. Consequent to these, direct impacts on the natural resources that support the health and integrity of living beings are evident in recent times. The Western Ghats being one of the global biodiversity hotspots, is reeling under a tremendous pressure from human induced changes in terms of developmental projects like hydel or thermal power plants, big dams, mining activities, unplanned agricultural practices,monoculture plantations, illegal timber logging, etc. This has led to the once contiguous forest habitats to be fragmented in patches, which in turn has led to the shrinkage of original habitat for the wildlife, change in the hydrological regime of the catchment, decreased inflow in streams,human-animal conflicts, etc. Under such circumstances, a proper management practice is called for requiring suitable biological indicators to show the impact of these changes, set priority regions and in developing models for conservation planning. Amphibians are regarded as one of the best biological indicators due to their sensitivity to even the slightest changes in the environment and hence they could be used as surrogates in conservation and management practices. They are the predominating vertebrates with a high degree of endemism (78%) in Western Ghats. The present study is an attempt to bring in the impacts of various land-uses on anuran distribution in three river basins. Sampling was carried out for amphibians during all seasons of 2003-2006 in basins of Sharavathi, Aghanashini and Bedthi. There are as many as 46 species in the region, one of which is new to science and nearly 59% of them are endemic to the Western Ghats. They belong to nine families, Dicroglossidae being represented by 14 species,followed by Rhacophoridae (9 species) and Ranidae (5 species). Species richness is high in Sharavathi river basin, with 36 species, followed by Bedthi 33 and Aghanashini 27. The impact of land-use changes, was investigated in the upper catchment of Sharavathi river basin. Species diversity indices, relative abundance values, percentage endemics gave clear indication of differences in each sub-catchment. Karl Pearson’s correlation coefficient (r) was calculated between species richness, endemics, environmental descriptors, land-use classes and fragmentation metrics. Principal component analysis was performed to depict the influence of these variables. Results show that sub-catchments with lesser percentage of forest, low canopy cover, higher amount of agricultural area, low rainfall have low species richness, less endemic species and abundant non-endemic species, whereas endemism, species richness and abundance of endemic species are more in the sub-catchments with high tree density, endemic trees, canopy cover, rainfall and lower amount of agriculture fields. This analysis aided in prioritising regions in the Sharavathi river basin for further conservation measures.

Inference for the Component and System Lifetime Distribution of a k-unit Parallel System Based on System Data

In this paper, we consider the inference for the component and system lifetime distribution of a k-unit parallel system with independent components based on system data. The components are assumed to have identical Weibull distribution. We obtain the maximum likelihood estimates of the unknown parameters based on system data. The Fisher information matrix has been derived. We propose -expectation tolerance interval and -content -level tolerance interval for the life distribution of the system. Performance of the estimators and tolerance intervals is investigated via simulation study. A simulated dataset is analyzed for illustration.

Bayesian Accelerated Life Testing under Competing Weibull Causes of Failure

Consider a J-component series system which is put on Accelerated Life Test (ALT) involving K stress variables. First, a general formulation of ALT is provided for log-location-scale family of distributions. A general stress translation function of location parameter of the component log-lifetime distribution is proposed which can accommodate standard ones like Arrhenius, power-rule, log-linear model, etc., as special cases. Later, the component lives are assumed to be independent Weibull random variables with a common shape parameter. A full Bayesian methodology is then developed by letting only the scale parameters of the Weibull component lives depend on the stress variables through the general stress translation function. Priors on all the parameters, namely the stress coefficients and the Weibull shape parameter, are assumed to be log-concave and independent of each other. This assumption is to facilitate Gibbs sampling from the joint posterior. The samples thus generated from the joint posterior is then used to obtain the Bayesian point and interval estimates of the system reliability at usage condition.

Bayesian Accelerated Life Testing under Competing Weibull Causes of Failure

Consider a J-component series system which is put on Accelerated Life Test (ALT) involving K stress variables. First, a general formulation of ALT is provided for log-location-scale family of distributions. A general stress translation function of location parameter of the component log-lifetime distribution is proposed which can accommodate standard ones like Arrhenius, power-rule, log-linear model, etc., as special cases. Later, the component lives are assumed to be independent Weibull random variables with a common shape parameter. A full Bayesian methodology is then developed by letting only the scale parameters of the Weibull component lives depend on the stress variables through the general stress translation function. Priors on all the parameters, namely the stress coefficients and the Weibull shape parameter, are assumed to be log-concave and independent of each other. This assumption is to facilitate Gibbs sampling from the joint posterior. The samples thus generated from the joint posterior is then used to obtain the Bayesian point and interval estimates of the system reliability at usage condition.

Life-cycle analysis of energy and greenhouse gas emissions of automotive fuels in India: Part 2-Well-to-wheels analysis

In this second of the two-part study, the results of the Tank-to-Wheels study reported in the first part are combined with Well-to-Tank results in this paper to provide a comprehensive Well-to-Wheels energy consumption and greenhouse gas emissions evaluation of automotive fuels in India. The results indicate that liquid fuels derived from petroleum have Well-to-Tank efficiencies in the range of 75-85% with liquefied petroleum gas being the most efficient fuel in the Well-to-Tank stage with 85% efficiency. Electricity has the lowest efficiency of 20% which is mainly attributed due to its dependence on coal and 25.4% losses during transmission and distribution. The complete Well-to-Wheels results show diesel vehicles to be the most efficient among all configurations, specifically the diesel-powered split hybrid electric vehicle. Hydrogen engine configurations are the least efficient due to low efficiency of production of hydrogen from natural gas. Hybridizing electric vehicles reduces the Well-to-Wheels greenhouse gas emissions substantially with split hybrid configuration being the most efficient. Electric vehicles do not offer any significant improvement over gasoline-powered configurations; however a shift towards renewable sources for power generation and reduction in losses during transmission and distribution can make it a feasible option in the future. (C) 2015 Elsevier Ltd. All rights reserved.