Constraints on axino warm dark matter from X-ray observation at the Chandra telescope and SPI

A sufficiently long lived warm dark matter could be a source of X-rays observed by satellite based X-ray telescopes. We consider axinos and gravitinos with masses between 1 keV and 100 keV in supersymmetric models with sin all R-parity violation. We show that axino dark matter receives significant constraints from X-ray observations of Chandra and SPI, especially for the lower end of the allowed range of the axino decay constant f(a), while the gravitino dark matter remains unconstrained.

Remote sensing study of snowline altitude at the end of melting season, Chandra-Bhaga basin, Himachal Pradesh, 1980-2007

Glaciers have a direct relation with climate change. The equilibrium line altitude (ELA) is the most useful parameter to study the effect of climate change on glaciers. The ELA is a theoretical snowline at which the glacier mass balance is zero. Snowline altitude (SLA) at the end of melting season is generally regarded as the ELA. Glaciers of Chandra-Bhaga basin in Lahaul-Spiti district of Himachal Pradesh were chosen to study the ELA, using satellite images from 1980 to 2007. A total of 19 glaciers from the Chandra-Bhaga basin were identified and selected to carry out the study of ELA variation over 27 years. This study reveals that the mean SLA of the sub-basin has increased from 5009 +/- 61m to 5401 +/- 21m from 1980 to 2007. The study is in agreement with the reported increase in the temperature and decrease in winter snowfall of North-West Himalaya in the last century.

Asymptotics of Harish-Chandra expansions, bounded hypergeometric functions associated with root systems, and applications

A series expansion for Heckman-Opdam hypergeometric functions phi(lambda) is obtained for all lambda is an element of alpha(C)*. As a consequence, estimates for phi(lambda) away from the walls of a Weyl chamber are established. We also characterize the bounded hypergeometric functions and thus prove an analogue of the celebrated theorem of Helgason and Johnson on the bounded spherical functions on a Riemannian symmetric space of the noncompact type. The L-P-theory for the hypergeometric Fourier transform is developed for 0 < p < 2. In particular, an inversion formula is proved when 1 <= p < 2. (C) 2013 Elsevier Inc. All rights reserved.

X-ray studies on crystalline complexes involving amino acids and peptides. XXXIII. Crystal structures of L- and DL-arginine complexed with oxalic acid and a comparative study of amino acid oxalic acid complexes

The DL- and L-arginine complexes of oxalic acid are made up of zwitterionic positively charged amino acid molecules and semi-oxalate ions. The dissimilar molecules aggregate into separate alternating layers in the former. The basic unit in the arginine layer is a centrosymmetric dimer, while the semi-oxalate ions form hydrogen-bonded strings in their layer. In the L-arginine complex each semi-oxalate ion is surrounded by arginine molecules and the complex can be described as an inclusion compound. The oxalic acid complexes of basic amino acids exhibit a variety of ionization states and stoichiometry. They illustrate the effect of aggregation and chirality on ionization state and stoichiometry, and that of molecular properties on aggregation. The semi-oxalate/oxalate ions tend to be planar, but large departures from planarity are possible. The amino acid aggregation in the different oxalic acid complexes do not resemble one another significantly, but the aggregation of a particular amino acid in its oxalic acid complex tends to have similarities with its aggregation in other structures. Also, semi-oxalate ions aggregate into similar strings in four of the six oxalic acid complexes. Thus, the intrinsic aggregation propensities of individual molecules tend to be retained in the complexes.

First donor-acceptor interaction promoted gelation of organic fluids

In recent years there has been considerable interest in developing new types of gelators of organic solvents.1 Despite the recent advances, a priori design of a gelator for gelling a given solvent has remained a challenging task. Various noncovalent interactions like hydrogen-bonding,2 metal coordination3 etc. have been used as the driving force for the gelation process. A special class of cholesterol-based gelators were reported by Weiss,4 and by Shinkai.5 Gels derived from these molecules have been used for chiral recognition/sensing,6 for studying photo- and metal-responsive functions,7 and as templates to make hollow fiber silica.8 Other types of organogels have been used for designing polymerized 9 and reverse aerogels,10 and in molecular imprinting.11 Hanabusa’s group has recently reported organogels with a bile acid derivative.12 This has prompted us to disclose our results on a novel electron donor–acceptor (EDA) interaction mediated two-component13 gelator system based on the bile acid14 backbone.

Measurement of Partition Coefficients of Substituted Benzoic Acids between Two Immiscible Solvents by Hyper-Rayleigh Scattering

We demonstrate that the hyper-Rayleigh scattering technique can be employed to measure the partition coefficient (k(p)) of a solute in a mixture of two immiscible solvents. Specifically, partition coefficients of six substituted benzoic acids in water/toluene (1:1 v/v) and water/chloroform (1:1 v/v) systems have been measured. Our values compare well with the k(p) values measured earlier by other techniques, The advantages offered by this technique are also discussed.

PocketMatch: A new algorithm to compare binding sites in protein structures

Recognizing similarities and deriving relationships among protein molecules is a fundamental requirement in present-day biology. Similarities can be present at various levels which can be detected through comparison of protein sequences or their structural folds. In some cases similarities obscure at these levels could be present merely in the substructures at their binding sites. Inferring functional similarities between protein molecules by comparing their binding sites is still largely exploratory and not as yet a routine protocol. One of the main reasons for this is the limitation in the choice of appropriate analytical tools that can compare binding sites with high sensitivity. To benefit from the enormous amount of structural data that is being rapidly accumulated, it is essential to have high throughput tools that enable large scale binding site comparison. Results: Here we present a new algorithm PocketMatch for comparison of binding sites in a frame invariant manner. Each binding site is represented by 90 lists of sorted distances capturing shape and chemical nature of the site. The sorted arrays are then aligned using an incremental alignment method and scored to obtain PMScores for pairs of sites. A comprehensive sensitivity analysis and an extensive validation of the algorithm have been carried out. A comparison with other site matching algorithms is also presented. Perturbation studies where the geometry of a given site was retained but the residue types were changed randomly, indicated that chance similarities were virtually non-existent. Our analysis also demonstrates that shape information alone is insufficient to discriminate between diverse binding sites, unless combined with chemical nature of amino acids. Conclusion: A new algorithm has been developed to compare binding sites in accurate, efficient and high-throughput manner. Though the representation used is conceptually simplistic, we demonstrate that along with the new alignment strategy used, it is sufficient to enable binding comparison with high sensitivity. Novel methodology has also been presented for validating the algorithm for accuracy and sensitivity with respect to geometry and chemical nature of the site. The method is also fast and takes about 1/250(th) second for one comparison on a single processor. A parallel version on BlueGene has also been implemented.

Heat shock protein 70 on Neuro2a cells is a putative receptor for Japanese encephalitis virus

Japanese encephalitis virus (JEV) envelope (E) protein has been shown to play a critical role in attachment to cells. However, the receptor interacting with envelope protein has not been conclusively identified. Using mouse neuroblastoma (Neuro2a) cells and purified JEV-E protein in `Virus Overlay Protein Binding Assay' followed by MALDI-TOF analysis, we identified `heat shock protein 70' (Hsp70) as a possible receptor for JEV. Indirect immunofluorescence and flow-cytometry analysis demonstrated localization of Hsp70 on Neuro2a cell surface. Co-immunoprecipitation followed by Western blot analysis reconfirmed the interaction between Hsp70 and JEV-E protein. Further, anti-Hsp70 polyclonal-antibodies were able to block JEV entry into Neuro2a cells. Additionally, using the bioinformatic tool - FTDOCK, clocking between the proteins was performed. Amongst six interacting structural poses studied one pose involving RGD motif on JEV-E and leucine(539) on Hsp70 displayed stable interaction. These observations indicate that Hsp70 serves as putative receptor for JEV in Neuro2A cells.

Localisation of Plasmodium falciparum uroporphyrinogen III decarboxylase of the heme-biosynthetic pathway in the apicoplast and characterisation of its catalytic properties

Uroporphyrinogen decarboxylase (UROD) is a key enzyme in the heme-biosynthetic pathway and in Plasmodium falciparum it occupies a strategic position in the proposed hybrid pathway for heme biosynthesis involving shuttling of intermediates between different subcellular compartments in the parasite. In the present study, we demonstrate that an N-terminally truncated recombinant P. falciparum UROD (r(Δ)PfUROD) over-expressed and purified from Escherichia coli cells, as well as the native enzyme from the parasite were catalytically less efficient compared with the host enzyme, although they were similar in other enzyme parameters. Molecular modeling of PfUROD based on the known crystal structure of the human enzyme indicated that the protein manifests a distorted triose phosphate isomerase (TIM) barrel fold which is conserved in all the known structures of UROD. The parasite enzyme shares all the conserved or invariant amino acid residues at the active and substrate binding sites, but is rich in lysine residues compared with the host enzyme. Mutation of specific lysine residues corresponding to residues at the dimer interface in human UROD enhanced the catalytic efficiency of the enzyme and dimer stability indicating that the lysine rich nature and weak dimer interface of the wild-type PfUROD could be responsible for its low catalytic efficiency. PfUROD was localised to the apicoplast, indicating the requirement of additional mechanisms for transport of the product coproporphyrinogen to other subcellular sites for its further conversion and ultimate heme formation.

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.

Structural basis for the function of anti-idiotypic antibody in immune memory

We had earlier proposed a hypothesis to explain the mechanism of perpetuation of immunological memory based on the operation of idiotypic network in the complete absence of antigen. Experimental evidences were provided for memory maintenance through anti-idiotypic antibody (Ab2) carrying the internal image of the antigen. In the present work, we describe a structural basis for such memory perpetuation by molecular modeling and structural analysis studies. A three-dimensional model of Ab2 was generated and the structure of the antigenic site on the hemagglutinin protein H of Rinderpest virus was modeled using the structural template of hemagglutinin protein of Measles virus. Our results show that a large portion of heavy chain containing the CDR regions of Ab2 resembles the domain of the hemagglutinin housing the epitope regions. The similarity demonstrates that an internal image of the H antigen is formed in Ab2, which provides a structural basis for functional mimicry demonstrated earlier. This work brings out the importance of the structural similarity between a domain of hemagglutinin protein to that of its corresponding Ab2. It provides evidence that Ab2 is indeed capable of functioning as surrogate antigen and provides support to earlier proposed relay hypothesis which has provided a mechanism for the maintenance of immunological memory.

A linear programming approach for estimating the structure of a sparse linear genetic network from transcript profiling data

Background: A genetic network can be represented as a directed graph in which a node corresponds to a gene and a directed edge specifies the direction of influence of one gene on another. The reconstruction of such networks from transcript profiling data remains an important yet challenging endeavor. A transcript profile specifies the abundances of many genes in a biological sample of interest. Prevailing strategies for learning the structure of a genetic network from high-dimensional transcript profiling data assume sparsity and linearity. Many methods consider relatively small directed graphs, inferring graphs with up to a few hundred nodes. This work examines large undirected graphs representations of genetic networks, graphs with many thousands of nodes where an undirected edge between two nodes does not indicate the direction of influence, and the problem of estimating the structure of such a sparse linear genetic network (SLGN) from transcript profiling data. Results: The structure learning task is cast as a sparse linear regression problem which is then posed as a LASSO (l1-constrained fitting) problem and solved finally by formulating a Linear Program (LP). A bound on the Generalization Error of this approach is given in terms of the Leave-One-Out Error. The accuracy and utility of LP-SLGNs is assessed quantitatively and qualitatively using simulated and real data. The Dialogue for Reverse Engineering Assessments and Methods (DREAM) initiative provides gold standard data sets and evaluation metrics that enable and facilitate the comparison of algorithms for deducing the structure of networks. The structures of LP-SLGNs estimated from the INSILICO1, INSILICO2 and INSILICO3 simulated DREAM2 data sets are comparable to those proposed by the first and/or second ranked teams in the DREAM2 competition. The structures of LP-SLGNs estimated from two published Saccharomyces cerevisae cell cycle transcript profiling data sets capture known regulatory associations. In each S. cerevisiae LP-SLGN, the number of nodes with a particular degree follows an approximate power law suggesting that its degree distributions is similar to that observed in real-world networks. Inspection of these LP-SLGNs suggests biological hypotheses amenable to experimental verification. Conclusion: A statistically robust and computationally efficient LP-based method for estimating the topology of a large sparse undirected graph from high-dimensional data yields representations of genetic networks that are biologically plausible and useful abstractions of the structures of real genetic networks. Analysis of the statistical and topological properties of learned LP-SLGNs may have practical value; for example, genes with high random walk betweenness, a measure of the centrality of a node in a graph, are good candidates for intervention studies and hence integrated computational – experimental investigations designed to infer more realistic and sophisticated probabilistic directed graphical model representations of genetic networks. The LP-based solutions of the sparse linear regression problem described here may provide a method for learning the structure of transcription factor networks from transcript profiling and transcription factor binding motif data.

Ion conductance in electrolyte solutions

We develop a new theoretical formulation to study ion conductance in electrolyte solutions, based on a mode coupling theory treatment of the electrolyte friction. The new theory provides expressions for both the ion atmosphere relaxation and electrophoretic contributions to the total electrolyte friction that acts on a moving ion. While the ion atmosphere relaxation term arises from the time-dependent microscopic interaction of the moving ion with the surrounding ions in the solution, the electrophoretic term originates from the coupling of the ion's velocity to the collective current mode of the ion atmosphere. Mode coupling theory, combined with time-dependent density functional theory of ion atmosphere fluctuations, leads to self-consistent expressions for these two terms which also include the effects of self-motion of the ion under consideration. These expressions have been solved for the concentration dependence of electrolyte friction and ion conductance. It is shown that in the limit of very low ion concentration, the present theory correctly reduces to the well-known Debye-Huckel-Onsager limiting law which predicts a linear dependence of conductance on the square root of ion concentration (c). At moderate and high concentrations, the present theory predicts a significant nonlinear and weaker dependence on root c which is in very good agreement with experimental results. The present theory is self-contained and does not involve any adjustable parameter.

A comparative study of the energetics, structures, and mechanisms of the HCN H HNC and LiCN <-> LiNC isomerizations

The potential energy surfaces of the HCN<->HNC and LiCN<->LiNC isomerization processes were determined by ab initio theory using fully optimized triple-zeta double polarization types of basis sets. Both the MP2 corrections and the QCISD level of calculations were performed to correct for the electron correlation. Results show that electron correlation has a considerable influence on the energetics and structures. Analysis of the intramolecular bond rearrangement processes reveals that, in both cases, H (or Li+) migrates in an almost elliptic path in the plane of the molecule. In HCN<->HNC, the migrating hydrogen interacts with the in-plane pi,pi* orbitals of CN, leading to a decrease in the C-N bond order. In LiCN<->LiNC, Li+ does not interact with the corresponding pi,pi* orbitals of CN.

Nimbolide a limonoid from Azadirachta indica inhibits proliferation and induces apoptosis of human choriocarcinoma (BeWo) cells

We investigated the cytotoxic effects of nimbolide, a limonoid present in leaves and flowers of the neem tree (Azadirachta indica) on human choriocarcinoma (BeWo) cells. Treatment with nimbolide resulted in dose- and time-dependent inhibition of growth of BeWo cells with IC50 values of 2.01 and 1.19 μM for 7 and 24 h respectively, accompanied by downregulation of proliferating cell nuclear antigen. Examination of nuclear morphology revealed fragmentation and condensation indicating apoptosis. Increase in the generation of reactive oxygen species (ROS) that was reversed by addition of reduced glutathione suggested ROS involvement in the cytotoxicity of nimbolide. A decrease in Bcl-2/Bax ratio with increased expression of Apaf-1 and caspase-3, and cleavage of poly(ADP-ribose) polymerase provide compelling evidence that nimbolide-induced apoptosis is mediated by the mitochondrial pathway. The results of the present study suggest that nimbolide has immense potential in cancer prevention and therapy based on its antiproliferative and apoptosis inducing effects.