Identification of genes associated with tumorigenesis of meibomian cell carcinoma by microarray analysis

Meibomian cell carcinoma (MCC) is a malignant tumor of the meibomian glands located in the eyelids. No information exists on the cytogenctic and genetic aspects of MCC. There is no report on the gene expression profile of MCC. Thus there is a need, for both scientific and clinical reasons, to identify genes and pathways that are involved in the development and progression of MCC. We analyzed the gene expression profile of MCC by the microarray technique. Forty-four genes were upregulated and 149 genes were downregulated in MCC. Differential expression data were confirmed for 5 genes by semiquantitative RT-PCR in MCC tumors: GTF2H4, RBM12, UBE2D3, DDX17, and LZTS1. We found dysregulation of two major pathways in MCC: MAPK and JAK/STAT. Clusters of genes on chromosomes 1, 12, and 19 were dysregUlated in MCC. The data presented here will facilitate the identification of specific markers and therapeutic targets for the treatment of MCC patients. (c) 2007 Elsevier Inc. All rights reserved.

Variation at Diabetes- and Obesity-Associated Loci May Mirror Neutral Patterns of Human Population Diversity and Diabetes Prevalence in India

South Asian populations harbor a high degree of genetic diversity, due in part to demographic history. Two studies on genome-wide variation in Indian populations have shown that most Indian populations show varying degrees of admixture between ancestral north Indian and ancestral south Indian components. As a result of this structure, genetic variation in India appears to follow a geographic cline. Similarly, Indian populations seem to show detectable differences in diabetes and obesity prevalence between different geographic regions of the country. We tested the hypothesis that genetic variation at diabetes-and obesity-associated loci may be potentially related to different genetic ancestries. We genotyped 2977 individuals from 61 populations across India for 18 SNPs in genes implicated in T2D and obesity. We examined patterns of variation in allele frequency across different geographical gradients and considered state of origin and language affiliation. Our results show that most of the 18 SNPs show no significant correlation with latitude, the geographic cline reported in previous studies, or by language family. Exceptions include KCNQ1 with latitude and THADA and JAK1 with language, which suggests that genetic variation at previously ascertained diabetes-associated loci may only partly mirror geographic patterns of genome-wide diversity in Indian populations.

A novel gene THSD7A is associated with obesity

Body mass index (BMI) is a non-invasive measurement of obesity. It is commonly used for assessing adiposity and obesity-related risk prediction. Genetic differences between ethnic groups are important factors, which contribute to the variation in phenotypic effects. India inhabited by the first out-of-Africa human population and the contemporary Indian populations are admixture of two ancestral populations; ancestral north Indians (ANI) and ancestral south Indians (ASI). Although ANI are related to Europeans, ASI are not related to any group outside Indian-subcontinent. Hence, we expect novel genetic loci associated with BMI. In association analysis, we found eight genic SNPs in extreme of distribution (P <= 3.75 x 10(-5)), of which WWOX has already been reported to be associated with obesity-related traits hence excluded from further study. Interestingly, we observed rs1526538, an intronic SNP of THSD7A; a novel gene significantly associated with obesity (P = 2.88 x 10(-5), 8.922 x 10(-6) and 2.504 x 10(-9) in discovery, replication and combined stages, respectively). THSD7A is neural N-glycoprotein, which promotes angiogenesis and it is well known that angiogenesis modulates obesity, adipose metabolism and insulin sensitivity, hence our result find a correlation. This information can be used for drug target, early diagnosis of obesity and treatment.

Certain Aspects Related To Computation By Modified Crack Closure Integral(MCCI)

This paper presents the proper computational approach for the estimation of strain energy release rates by modified crack closure integral (MCCI). In particular, in the estimation of consistent nodal force vectors used in the MCCI expressions for quarter-point singular elements (wherein all the nodal force vectors participate in computation of strain energy release rates by MCCI). The numerical example of a centre crack tension specimen under uniform loading is presented to illustrate the approach.

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.

Some aspects of multilevel load-frequency control of a power system

The application of multilevel control strategies for load-frequency control of interconnected power systems is assuming importance. A large multiarea power system may be viewed as an interconnection of several lower-order subsystems, with possible change of interconnection pattern during operation. The solution of the control problem involves the design of a set of local optimal controllers for the individual areas, in a completely decentralised environment, plus a global controller to provide the corrective signal to account for interconnection effects. A global controller, based on the least-square-error principle suggested by Siljak and Sundareshan, has been applied for the LFC problem. A more recent work utilises certain possible beneficial aspects of interconnection to permit more desirable system performances. The paper reports the application of the latter strategy to LFC of a two-area power system. The power-system model studied includes the effects of excitation system and governor controls. A comparison of the two strategies is also made.

Monoblock cylinder internally pressurised under asymmetric end constraints Some aspects of design

The finite element method is used to analyse stresses and displacements in a monoblock cylinder open at one end only. The cylinder is internally pressurised. The analysis shows that the minimum pressure required to cause yield in the cylinder decreases rapidly with increasing cylinder height until the height is about the same as the outer radius of the cylinder, beyond which the decrease is marginal. Introduction of a fillet at the internal corner enhances the design pressure substantially while a fillet at the outer corner affects this pressure only marginally.

Timing the Emergence of Resistance to Anti-HIV Drugs with Large Genetic Barriers

New antiretroviral drugs that offer large genetic barriers to resistance, such as the recently approved inhibitors of HIV-1 protease, tipranavir and darunavir, present promising weapons to avert the failure of current therapies for HIV infection. Optimal treatment strategies with the new drugs, however, are yet to be established. A key limitation is the poor understanding of the process by which HIV surmounts large genetic barriers to resistance. Extant models of HIV dynamics are predicated on the predominance of deterministic forces underlying the emergence of resistant genomes. In contrast, stochastic forces may dominate, especially when the genetic barrier is large, and delay the emergence of resistant genomes. We develop a mathematical model of HIV dynamics under the influence of an antiretroviral drug to predict the waiting time for the emergence of genomes that carry the requisite mutations to overcome the genetic barrier of the drug. We apply our model to describe the development of resistance to tipranavir in in vitro serial passage experiments. Model predictions of the times of emergence of different mutant genomes with increasing resistance to tipranavir are in quantitative agreement with experiments, indicating that our model captures the dynamics of the development of resistance to antiretroviral drugs accurately. Further, model predictions provide insights into the influence of underlying evolutionary processes such as recombination on the development of resistance, and suggest guidelines for drug design: drugs that offer large genetic barriers to resistance with resistance sites tightly localized on the viral genome and exhibiting positive epistatic interactions maximally inhibit the emergence of resistant genomes.

Structural Basis of Drug Resistance by Genetic Variants of HIV Type 1 Clade C Protease from India

Using computer modeling of three-dimensional structures and structural information available on the crystal structures of HIV-1 protease, we investigated the structural effects of mutations, in treatment-naive and treatment-exposed individuals from India and postulated mechanisms of resistance in clade C variants. A large number of models (14) have been generated by computational mutation of the available crystal structures of drug bound proteases. Localized energy minimization was carried out in and around the sites of mutation in order to optimize the geometry of interactions present. Most of the mutations result in structural differences at the flap that favors the semiopen state of the enzyme. Some of the mutations were also found to confer resistance by affecting the geometry of the active site. The E35D mutation affects the flap structure in clade B strains and E35N and E35K mutation, seen in our modeled strains, have a more profound effect. Common polymorphisms at positions 36 and 63 in clade C also affected flap structure. Apart from a few other residues Gln-58, Asn-83, Asn-88, and Gln-92 and their interactions are important for the transition from the closed to the open state. Development of protease inhibitors by structure-based design requires investigation of mechanisms operative for clade C to improve the efficacy of therapy.

Bismuth tungsten-oxide bronzes - a study of intergrowth phases and related aspects

Reaction of bismuth metal with WO$_3$ in the absence of oxygen yields interesting bronze-like phases. From analytical electron microscopy and X-ray photoelectron spectroscopy, the product phases are found to have the general composition Bi$_x$ WO$_3$ with bismuth in the 3+ state. Structural investigations made with high resolution electron micrscopy and cognate techniques reveal that when x < 0.02, a perovskite bronze is formed. When x $\geqslant$ 0.02, however, intergrowth tungsten bronzes (i.t.b.) containing varying widths of the WO$_3$ slab are formed, the lattice periodicity being in the range 2.3-5.1 nm in a direction perpendicular to the WO$_3$ slabs. Image-matching studies indicate that the bismuth atoms are in the tunnels of the hexagonal tungsten bronze (h.t.b.) strips and the h.t.b. strips always remain one-tunnel wide. Annealed samples show a satellite structure around the superlattice spots in the electron diffraction patterns, possibly owing to ordering of the bismuth atoms in the tunnels. The i.t.b. phases show recurrent intergrowths extending up to 100 nm in several crystals. The periodicity varies considerably within the same crystal wherever there is disordered intergrowth, but unit cell dimensions can be assigned from X-ray and electron diffraction patterns. The maximum value of x in the i.t.b. phases is ca. 0.07 and there is no evidence for the i.t.b. phase progressively giving way to the h.t.b. phase with increase in x. Hexagonal tungsten bronzes that contain bismuth with x up to 0.02 can be formed by starting from hexagonal WO$_3$, but the h.t.b. phase seems to be metastable. Optical, magnetic and electron transport properties of the i.t.b. phases have been measured and it appears that the electrons become itinerant when x > 0.05.

Genetic analysis of foot-and-mouth disease virus serotype A of Indian origin and detection of positive selection and recombination in leader protease- and capsid-coding regions

The leader protease (L-pro) and capsid-coding sequences (P1) constitute approximately 3 kb of the foot-and-mouth disease virus (FMDV). We studied the phylogenetic relationship of 46 FMDV serotype A isolates of Indian origin collected during the period 1968-2005 and also eight vaccine strains using the neighbour-joining tree and Bayesian tree methods. The viruses were categorized under three major groups - Asian, Euro-South American and European. The Indian isolates formed a distinct genetic group among the Asian isolates. The Indian isolates were further classified into different genetic subgroups (<5% divergence). Post-1995 isolates were divided into two subgroups while a few isolates which originated in the year 2005 from Andhra Pradesh formed a separate group. These isolates were closely related to the isolates of the 1970s. The FMDV isolates seem to undergo reverse mutation or onvergent evolution wherein sequences identical to the ancestors are present in the isolates in circulation. The eight vaccine strains included in the study were not related to each other and belonged to different genetic groups. Recombination was detected in the L-pro region in one isolate (A IND 20/82) and in the VP1 coding 1D region in another isolate (A RAJ 21/96). Positive selection was identified at aa positions 23 in the L-pro (P<0.05; 0.046*) and at aa 171 in the capsid protein VP1 (P<0.01; 0.003**).

Photochemical Oxidation of Thioketones: Steric and Electronic Aspects

Oxidation of diaryl, aryl alkyl, and dialkyl thioketones by singlet oxygen generated via self-sensitization and other independent methods yielded the corresponding ketone and sulfine in varying amounts. A zwitterionic/ diradical intermediate arising out of the primary interaction of singlet oxygen with the thiocarbonyl chromophore is believed to be the common intermediate for the ketone and sulfine. While closure of the zwitterion/diradical to give 1,2,3-dioxathietane would lead to the ketone, competing oxygen elimination is believed to lead to the sulfine. This partitioning is governed by steric and electronic factors operating on the zwitterionic/diradical intermediate.

Inbreeding and the incidence of childhood genetic disorders in Karnataka, South India

Consanguineous marriages are strongly favoured among the populations of South India. In a study conducted on 407 infants and children, a total of 35 genetic diseases was diagnosed in 63 persons: 44 with single gene defects, 12 with polygenic disorders, and seven with Down's syndrome. The coefficient of inbreeding of the total study group, F = 0.0414, was significantly higher than that previously calculated for the general population, F = 0.0271, and autosomal recessive disorders formed the largest single disease category diagnosed. The results suggest that long term inbreeding may not have resulted in appreciable elimination of recessive lethals and sub-lethals from the gene pool.

Photochemical oxidation of thio ketones: steric and electronic aspects

Oxidation of diaryl, aryl alkyl, and dialkyl thioketones by singlet oxygen generated via self-sensitization and other independent methods yielded the corresponding ketone and sulfine in varying amounts. A zwitterionic/ diradical intermediate arising out of the primary interaction of singlet oxygen with the thiocarbonyl chromophore is believed to be the common intermediate for the ketone and sulfine. While closure of the zwitterion/diradical to give 1,2,3-dioxathietane would lead to the ketone, competing oxygen elimination is believed to lead to the sulfine. This partitioning is governed by steric and electronic factors operating on the zwitterionic/diradical intermediate.

Chemical aspects of the hypergolic preignition reactions of some hybrid hypergols

A new class of solid compounds, viz., bisthiocarbonohydrazones and thiosemicarbazones, have been found to be hypergolic with fuming nitric acid. The observed ignition delays of these hypergols have been compared with those of the monothiocarbonohydrazones-nitric acid systems and explained in terms of the chemical reactions-neutralization, oxidation, and nitration-occurring in the preignition stage. p-Nitrobenzoic acid, benzoic acid, benzaldehyde, sulfur trioxide, nitrogen dioxide, and nitrogen have been isolated as preignition reaction intermediates in the mono- and bisbenzaldehydethiocarbonohydrazone-nitric acid systems. A scheme of reactions occurring in the preignition stage is proposed based on the formation of these products.