targetTB: A target identification pipeline for Mycobacterium tuberculosis through an interactome, reactome and genome-scale structural analysis

Background: Tuberculosis still remains one of the largest killer infectious diseases, warranting the identification of newer targets and drugs. Identification and validation of appropriate targets for designing drugs are critical steps in drug discovery, which are at present major bottle-necks. A majority of drugs in current clinical use for many diseases have been designed without the knowledge of the targets, perhaps because standard methodologies to identify such targets in a high-throughput fashion do not really exist. With different kinds of 'omics' data that are now available, computational approaches can be powerful means of obtaining short-lists of possible targets for further experimental validation. Results: We report a comprehensive in silico target identification pipeline, targetTB, for Mycobacterium tuberculosis. The pipeline incorporates a network analysis of the protein-protein interactome, a flux balance analysis of the reactome, experimentally derived phenotype essentiality data, sequence analyses and a structural assessment of targetability, using novel algorithms recently developed by us. Using flux balance analysis and network analysis, proteins critical for survival of M. tuberculosis are first identified, followed by comparative genomics with the host, finally incorporating a novel structural analysis of the binding sites to assess the feasibility of a protein as a target. Further analyses include correlation with expression data and non-similarity to gut flora proteins as well as 'anti-targets' in the host, leading to the identification of 451 high-confidence targets. Through phylogenetic profiling against 228 pathogen genomes, shortlisted targets have been further explored to identify broad-spectrum antibiotic targets, while also identifying those specific to tuberculosis. Targets that address mycobacterial persistence and drug resistance mechanisms are also analysed. Conclusion: The pipeline developed provides rational schema for drug target identification that are likely to have high rates of success, which is expected to save enormous amounts of money, resources and time in the drug discovery process. A thorough comparison with previously suggested targets in the literature demonstrates the usefulness of the integrated approach used in our study, highlighting the importance of systems-level analyses in particular. The method has the potential to be used as a general strategy for target identification and validation and hence significantly impact most drug discovery programmes.

Spatial Analysis and Characterisation of Lentic Ecosystems: A Case Study of Varthur Lake, Bangalore

Lentic ecosystems vital functions such as recycling of nutrients, purification of water, recharge of groundwater,augmenting and maintenance of stream flow and habitat provision for a wide variety of flora and fauna along with their recreation values necessitates their sustainable management through appropriate conservation mechanisms. Failure to restore these ecosystems will result in extinction of species or ecosystem types and cause permanent ecological damage. In Bangalore, lentic ecosystems (for example lakes) have played a prominent role serving the needs of agriculture and drinking water. But the burgeoning population accompanied by unplanned developmental activities has led to the drastic reduction in their numbers (from 262 in 1976 to 81). The existing water bodies are contaminated by residential, agricultural, commercial and industrial wastes/effluents. In order to restore the ecosystem, assessment of the level of contamination is crucial. This paper focuses on characterisation and restoration aspects of Varthur lake based on hydrological, morphometric, physical-chemical and socio-economic investigations for a period of six months covering post monsoon seasons. The results of the water quality analysis show that the lake is eutrophic with high concentrations of phosphorous and organic matter. The morphometric analysis indicates that the lake is shallow in relation to its surface area. Socio-economic analyses show dependence of local residents for irrigation, fodder, etc. These analyses highlight the need and urgency to restore the physical, chemical and biological integrity through viable restoration and sustainable watershed management strategies, which include pollution abatement, catchment treatment, desilting of the lake and educating all stakeholders on the conservation and restoration of lake ecosystems.

Urban Growth Analysis Using Spatial and Temporal Data

Urban growth identification, quantification, knowledge of rate and the trends of growth would help in regional planning for better infrastructure provision in environmentally sound way. This requires analysis of spatial and temporal data, which help in quantifying the trends of growth on spatial scale. Emerging technologies such as Remote Sensing, Geographic Information System (GIS) along with Global Positioning System (GPS) help in this regard. Remote sensing aids in the collection of temporal data and GIS helps in spatial analysis. This paper focuses on the analysis of urban growth pattern in the form of either radial or linear sprawl along the Bangalore - Mysore highway. Various GIS base layers such as builtup areas along the highway, road network, village boundary etc. were generated using collateral data such as the Survey of India toposheet, etc. Further, this analysis was complemented with the computation of Shannon's entropy, which helped in identifying prevalent sprawl zone, rate of growth and in delineating potential sprawl locations. The computation Shannon's entropy helped in delineating regions with dispersed and compact growth. This study reveals that the Bangalore North and South taluks contributed mainly to the sprawl with 559% increase in built-up area over a period of 28 years and high degree of dispersion. The Mysore and Srirangapatna region showed 128% change in built-up area and a high potential for sprawl with slightly high dispersion. The degree of sprawl was found to be directly proportional to the distances from the cities.

Spatial variations of effective elastic thickness over the Ninetyeast Ridge and implications for its structure and tectonic evolution

We present new data on the strength of oceanic lithosphere along the Ninetyeast Ridge (NER) from two independent methods: spectral analysis (Bouguer coherence) using the fan wavelet transform technique, and spatial analysis (flexure inversion) with the convolution method. The two methods provide effective elastic thickness (T-e) patterns that broadly complement each other, and correlate well with known surface structures and regional-scale features. Furthermore, our study presents a new high resolution database on the Moho configuration, which obeys flexural isostasy, and exhibit regional correlations with the T-e variations. A continuous ridge structure with a much lower T-e value than that of normal oceanic lithosphere provides strong support for the hotspot theory. The derived T-e values vary over the northern (higher T-e similar to 10-20 km), central (anomalously low T-e similar to 0-5 km), and southern (low T-e similar to 5 km) segments of the NER. The lack of correlation of the T-e value with the progressive aging of the lithosphere implies differences in thermo-mechanical setting of the crust and underlying mantle in different parts of the NER, again indicating diversity in their evolution. The anomalously low T-e and deeper Moho (similar to 22 km) estimates of the central NER (between 0.5 degrees N and 17 degrees S) are attributed to the interaction of a hotspot with the Wharton spreading ridge that caused significant thermal rejuvenation and hence weakening of the lithosphere. The higher mechanical strength values in the northern NER (north of 0.5 degrees N) may support the idea of off-ridge emplacement and a relatively large plate motion at the time of volcanism. The low T-e and deeper Moho (similar to 22 km) estimates in the southern part (south of 17 degrees S) suggest that the lithosphere was weak and therefore younger at the time of volcanism, and this supports the idea that the southern NER was emplaced on the edge of the Indian plate. (C) 2013 Elsevier B.V. All rights reserved.

Diagnosis of dominant forcing factors for large-scale vertical velocities during active and break phases of the monsoon

An attempt to diagnose the dominant forcings which drive the large-scale vertical velocities over the monsoon region has been made by computing the forcings like diabatic heating fields,etc. and the large-scale vertical velocities driven by these forcings for the contrasting periods of active and break monsoon situations; in order to understand the rainfall variability associated with them. Computation of diabatic heating fields show us that among different components of diabatic heating it is the convective heating that dominates at mid-tropospheric levels during an active monsoon period; whereas it is the sensible heating at the surface that is important during a break period. From vertical velocity calculations we infer that the prime differences in the large-scale vertical velocities seen throughout the depth of the atmosphere are due to the differences in the orders of convective heating; the maximum rate of latent heating being more than 10 degrees Kelvin per day during an active monsoon period; whereas during a break monsoon period it is of the order of 2 degrees Kelvin per day at mid-tropospheric levels. At low levels of the atmosphere, computations show that there is large-scale ascent occurring over a large spatial region, driven only by the dynamic forcing associated with vorticity and temperature advection during an active monsoon period. However, during a break monsoon period such large-scale spatial organization in rising motion is not seen. It is speculated that these differences in the low-level large-scale ascent might be causing differences in convective heating because the weaker the low level ascent, the lesser the convective instability which produces deep cumulus clouds and hence lesser the associated latent heat release. The forcings due to other components of diabatic heating, namely, the sensible heating and long wave radiative cooling do not influence the large-scale vertical velocities significantly.

WEPA: Wind energy potential assessment-spatial decision support system

Spatial Decision Support System (SDSS) assist in strategic decision-making activities considering spatial and temporal variables, which help in Regional planning. WEPA is a SDSS designed for assessment of wind potential spatially. A wind energy system transforms the kinetic energy of the wind into mechanical or electrical energy that can be harnessed for practical use. Wind energy can diversify the economies of rural communities, adding to the tax base and providing new types of income. Wind turbines can add a new source of property value in rural areas that have a hard time attracting new industry. Wind speed is extremely important parameter for assessing the amount of energy a wind turbine can convert to electricity: The energy content of the wind varies with the cube (the third power) of the average wind speed. Estimation of the wind power potential for a site is the most important requirement for selecting a site for the installation of a wind electric generator and evaluating projects in economic terms. It is based on data of the wind frequency distribution at the site, which are collected from a meteorological mast consisting of wind anemometer and a wind vane and spatial parameters (like area available for setting up wind farm, landscape, etc.). The wind resource is governed by the climatology of the region concerned and has large variability with reference to space (spatial expanse) and time (season) at any fixed location. Hence the need to conduct wind resource surveys and spatial analysis constitute vital components in programs for exploiting wind energy. SDSS for assessing wind potential of a region / location is designed with user friendly GUI’s (Graphic User Interface) using VB as front end with MS Access database (backend). Validation and pilot testing of WEPA SDSS has been done with the data collected for 45 locations in Karnataka based on primary data at selected locations and data collected from the meteorological observatories of the India Meteorological Department (IMD). Wind energy and its characteristics have been analysed for these locations to generate user-friendly reports and spatial maps. Energy Pattern Factor (EPF) and Power Densities are computed for sites with hourly wind data. With the knowledge of EPF and mean wind speed, mean power density is computed for the locations with only monthly data. Wind energy conversion systems would be most effective in these locations during May to August. The analyses show that coastal and dry arid zones in Karnataka have good wind potential, which if exploited would help local industries, coconut and areca plantations, and agriculture. Pre-monsoon availability of wind energy would help in irrigating these orchards, making wind energy a desirable alternative.

Atomic Scale Fluctuations Govern Brittle Fracture and Cavitation Behavior in Metallic Glasses

We perform atomistic simulations on the fracture behavior of two typical metallic glasses, one brittle (FeP) and the other ductile (CuZr), and show that brittle fracture in the FeP glass is governed by an intrinsic cavitation mechanism near crack tips in contrast to extensive shear banding in the ductile CuZr glass. We show that a high degree of atomic scale spatial fluctuations in the local properties is the main reason for the observed cavitation behavior in the brittle metallic glass. Our study corroborates with recent experimental observations of nanoscale cavity nucleation found on the brittle fracture surfaces of metallic glasses and provides important insights into the root cause of the ductile versus brittle behavior in such materials.

A simple model for spatial disaggregation of evaporative fraction: Comparative study with thermal sharpened land surface temperature data over India

[1] Evaporative fraction (EF) is a measure of the amount of available energy at the earth surface that is partitioned into latent heat flux. The currently operational thermal sensors like the Moderate Resolution Imaging Spectroradiometer (MODIS) on satellite platforms provide data only at 1000 m, which constraints the spatial resolution of EF estimates. A simple model (disaggregation of evaporative fraction (DEFrac)) based on the observed relationship between EF and the normalized difference vegetation index is proposed to spatially disaggregate EF. The DEFrac model was tested with EF estimated from the triangle method using 113 clear sky data sets from the MODIS sensor aboard Terra and Aqua satellites. Validation was done using the data at four micrometeorological tower sites across varied agro-climatic zones possessing different land cover conditions in India using Bowen ratio energy balance method. The root-mean-square error (RMSE) of EF estimated at 1000 m resolution using the triangle method was 0.09 for all the four sites put together. The RMSE of DEFrac disaggregated EF was 0.09 for 250 m resolution. Two models of input disaggregation were also tried with thermal data sharpened using two thermal sharpening models DisTrad and TsHARP. The RMSE of disaggregated EF was 0.14 for both the input disaggregation models for 250 m resolution. Moreover, spatial analysis of disaggregation was performed using Landsat-7 (Enhanced Thematic Mapper) ETM+ data over four grids in India for contrasted seasons. It was observed that the DEFrac model performed better than the input disaggregation models under cropped conditions while they were marginally similar under non-cropped conditions.

Characterization of an Evolutionarily Conserved Metallophosphoesterase That Is Expressed in the Fetal Brain and Associated with the WAGR Syndrome

Among the human diseases that result from chromosomal aberrations, a de novo deletion in chromosome 11p13 is clinically associated with a syndrome characterized by Wilms' tumor, aniridia, genitourinary anomalies, and mental retardation (WAGR). Not all genes in the deleted region have been characterized biochemically or functionally. We have recently identified the first Class III cyclic nucleotide phosphodiesterase, Rv0805, from Mycobacterium tuberculosis, which biochemically and structurally belongs to the superfamily of metallophosphoesterases. We performed a large scale bioinformatic analysis to identify orthologs of the Rv0805 protein and identified many eukaryotic genes that included the human 239FB gene present in the region deleted in the WAGR syndrome. We report here the first detailed biochemical characterization of the rat 239FB protein and show that it possesses metallophosphodiesterase activity. Extensive mutational analysis identified residues that are involved in metal interaction at the binuclear metal center. Generation of a rat 239FB protein with a mutation corresponding to a single nucleotide polymorphism seen in human 239FB led to complete inactivation of the protein. A close ortholog of 239FB is found in adult tissues, and biochemical characterization of the 239AB protein demonstrated significant hydrolytic activity against 2',3'-cAMP, thus representing the first evidence for a Class III cyclic nucleotide phosphodiesterase in mammals. Highly conserved orthologs of the 239FB protein are found in Caenorhabditis elegans and Drosophila and, coupled with available evidence suggesting that 239FB is a tumor suppressor, indicate the important role this protein must play in diverse cellular events.

Satellite-derived direct radiative effect of aerosols dependent on cloud cover

Aerosols from biomass burning can alter the radiative balance of the Earth by reflecting and absorbing solar radiation(1). Whether aerosols exert a net cooling or a net warming effect will depend on the aerosol type and the albedo of the underlying surface(2). Here, we use a satellite-based approach to quantify the direct, top-of-atmosphere radiative effect of aerosol layers advected over the partly cloudy boundary layer of the southeastern Atlantic Ocean during July-October of 2006 and 2007. We show that the warming effect of aerosols increases with underlying cloud coverage. This relationship is nearly linear, making it possible to define a critical cloud fraction at which the aerosols switch from exerting a net cooling to a net warming effect. For this region and time period, the critical cloud fraction is about 0.4, and is strongly sensitive to the amount of solar radiation the aerosols absorb and the albedo of the underlying clouds. We estimate that the regional-mean warming effect of aerosols is three times higher when large-scale spatial covariation between cloud cover and aerosols is taken into account. These results demonstrate the importance of cloud prediction for the accurate quantification of aerosol direct effects.

The Evolution of Guanylyl Cyclases as Multidomain Proteins: Conserved Features of Kinase-Cyclase Domain Fusions

Guanylyl cyclases (GCs) are enzymes that generate cyclic GMP and regulate different physiologic and developmental processes in a number of organisms. GCs possess sequence similarity to class III adenylyl cyclases (ACs) and are present as either membrane-bound receptor GCs or cytosolic soluble GCs. We sought to determine the evolution of GCs using a large-scale bioinformatic analysis and found multiple lineage-specific expansions of GC genes in the genomes of many eukaryotes. Moreover, a few GC-like proteins were identified in prokaryotes, which come fused to a number of different domains, suggesting allosteric regulation of nucleotide cyclase activity Eukaryotic receptor GCs are associated with a kinase homology domain (KHD), and phylogenetic analysis of these proteins suggest coevolution of the KHD and the associated cyclase domain as well as a conservation of the sequence and the size of the linker region between the KHD and the associated cyclase domain. Finally, we also report the existence of mimiviral proteins that contain putative active kinase domains associated with a cyclase domain, which could suggest early evolution of the fusion of these two important domains involved in signa transduction.

High contrast imaging and thickness determination of graphene with in-column secondary electron microscopy

We report a new method for quantitative estimation of graphene layer thicknesses using high contrast imaging of graphene films on insulating substrates with a scanning electron microscope. By detecting the attenuation of secondary electrons emitted from the substrate with an in-column low-energy electron detector, we have achieved very high thickness-dependent contrast that allows quantitative estimation of thickness up to several graphene layers. The nanometer scale spatial resolution of the electron micrographs also allows a simple structural characterization scheme for graphene, which has been applied to identify faults, wrinkles, voids, and patches of multilayer growth in large-area chemical vapor deposited graphene. We have discussed the factors, such as differential surface charging and electron beam induced current, that affect the contrast of graphene images in detail. (C) 2011 American Institute of Physics. doi:10.1063/1.3608062]

Cannibalism can drive the evolution of behavioural phase polyphenism in locusts

During outbreaks, locust swarms can contain millions of insects travelling thousands of kilometers while devastating vegetation and crops. Such large-scale spatial organization is preceded locally by a dramatic density-dependent phenotypic transition in multiple traits. Behaviourally, low-density solitarious individuals avoid contact with one another; above a critical local density, they undergo a rapid behavioural transition to the gregarious phase whereby they exhibit mutual attraction. Although proximate causes of this phase polyphenism have been widely studied, the ultimate driving factors remain unclear. Using an individual-based evolutionary model, we reveal that cannibalism, a striking feature of locust ecology, could lead to the evolution of density-dependent behavioural phase-change in juvenile locusts. We show that this behavioural strategy minimizes risk associated with cannibalistic interactions and may account for the empirically observed persistence of locust groups during outbreaks. Our results provide a parsimonious explanation for the evolution of behavioural plasticity in locusts.

Lineage delimitation and description of nine new species of bush frogs (Anura: Raorchestes, Rhacophoridae) from the Western Ghats Escarpment

Bush frogs of the genus Raorchestes are distributed mainly in the Western Ghats Escarpment of Peninsular India. The inventory of species in this genus is incomplete and there is ambiguity in the systematic status of species recognized by morphological criteria. To address the dual problem of taxon sampling and systematic uncertainty in bush frogs, we used a large-scale spatial sampling design, explicitly incorporating the geographic and ecological heterogeneity of the Western Ghats. We then used a hierarchical multi-criteria approach by combining mitochondrial phylogeny, genetic distance, geographic range, morphology and advertisement call to delimit bush frog lineages. Our analyses revealed the existence of a large number of new lineages with varying levels of genetic divergence. Here, we provide diagnoses and descriptions for nine lineages that exhibit divergence across multiple axes. The discovery of new lineages that exhibit high divergence across wide ranges of elevation and across the major massifs highlights the large gaps in historical sampling. These discoveries underscore the significance of addressing inadequate knowledge of species distribution, namely the ``Wallacean shortfall'', in addressing the problem of taxon sampling and unknown diversity in tropical hotspots. A biogeographically informed sampling and analytical approach was critical in detecting and delineating lineages in a consistent manner across the genus. Through increased taxon sampling, we were also able to discern a number of well-supported sub-clades that were either unresolved or absent in earlier phylogenetic reconstructions and identify a number of shallow divergent lineages which require further examination for assessment of their taxonomic status.

Systematic status of Fejervarya ((Amphibia, Anura, Dicroglossidae) from South and SE Asia with the description of a new species from the Western Ghats of Peninsular India

We carried out a large-scale phylogenetic analysis of fejervaryan (dicroglossid frogs with `Fejervaryan lines' on the ventral side of the body) frogs, distributed in South and SE Asia, using published and newly generated sequences of unidentified individuals from the northern Western Ghats. The results corroborate the presence of a larger fejervaryan clade with a sister relationship to a clade composed of Sphaerotheca. Two sister clades could be discerned within the lager fejervaryan clade. The unidentified individuals formed a monophyletic group and showed a strong support for a sister relationship with Minervarya sahyadris. The species was found to be highly divergent (16S rRNA-4% and tyr-1%) from its sister lineage Minervarya sahyadris, and the clade composed of these two lineages were found to be deeply nested within the larger clade of Fejervarya. Based on this, the genus Minervarya Dubois, Ohler and Biju, 2001 is synonymized under the genus Fejervarya Bolkay, 1915. The unidentified lineage is recognized, based on phylogenetic position, genetic divergence and morphological divergence, as a distinct species and named here as Fejervarya gomantaki sp. nov. The presence of rictal glands was observed to be a synapomorphic character shared by the nested clade members, Fejervarya sahyadris and Fejervarya gomantaki sp. nov. Based on the presence of rictal gland and small size, Minervarya chilapata, a species from a lowland region in the Eastern Himalayas, is synonymized under Fejervarya and evidence for morphological separation from the new species, Fejervarya gomantaki sp. nov. is provided. For the fejervaryan frogs, currently three generic names (Frost, 2015) are available for the two phylogenetic subclades; the genus Fejervarya Bolkay, 1915 for the species of fejervaryan frogs having distribution in the South East Asia; the genus Zakerana Howlader, 2011 for the species of fejervaryan frogs having distribution in the South Asia and the genus Minervarya Dubois, Ohler and Biju, 2001 nested within the `Zakerana clade'. In the phylogenetic analysis Minervarya sahyadris, the new species described herein as Fejervarya gomantaki sp. nov. are nested within the `Zakerana clade', if the `Zakerana clade' for the fejervaryan frogs having distribution in the South Asia is provided a generic status the nomen `Minervarya' should be considered as per the principle of priority of the ICZN Code. Taking into consideration the overlapping distribution ranges of members of the sister clades within the larger fejervaryan clade and the absence of distinct morphological characteristics, we also synonymize the genus Zakerana Howlader, 2011, a name assigned to one of the sister clades with members predominantly distributed in South Asia, under the genus Fejervarya Bolkay, 1915. We discuss the need for additional sampling to identify additional taxa and determine the geographical ranges of the members of the sister clades within Fejervarya to resolve taxonomy within this group.