Department of Bioscience & Bioengineering

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Aspirin and other nonsteroidal anti-inflammatory drugs inhibit cell proliferation and induce apoptosis in various cancer cell lines, which is considered to be an important mechanism for their anti-tumor activity and prevention of carcinogenesis. However, the molecular mechanisms through which these compounds induce apoptosis are not well understood. Here we have found that aspirin treatment of the mouse Neuro 2a cells impaired the proteasome function and caused severe mitochondrial abnormalities. Treatment with aspirin lead to a dose- and time-dependent decrease in proteasome activity and an increase in the accumulation of ubiquitylated proteins in the cells, which correlated with its effect on cell death. Aspirin exposure also resulted in an increase in the half-life of pd1EGFP, a model substrate of proteasome, as well as various intracellular substrates like Bax, IκB-α, p53, and p27kip1. Aspirin-induced proteasomal malfunction might be responsible, at least in part, for the downregulation of NF-κB activity and neurite outgrowth. Finally, we have shown that aspirin treatment caused changes in the mitochondrial membrane potential, release of cytochrome c from mitochondria, and activation of caspase-9 and -3, which could be because of the proteasomal dysfunction. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.

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Fulltext

Journal of Biological Chemistry

Aspirin induces apoptosis through the inhibition of proteasome function

It has been seen that inertial mismatches in 1D granular chains lead to remarkable energy absorption which increases with the number of spheres, N, and tapering, q. Short chains, however, are limited in that regard, and we therefore present one solution which greatly improves performance for any size chain. These strongly nonlinear and scalable systems feature surprisingly complicated dynamics and are inadequately represented by a hard-sphere approximation. Additionally, such systems have shock absorption capacities that vary as a function of position along the chain. In this Letter, we present results in the form of normalized kinetic energy diagrams to illustrate the impressive mitigation capability of both original and improved tapered chains. © 2006 The American Physical Society.

Physical Review Letters

Decorated, tapered, and highly nonlinear granular chain

Indian population, comprising of more than a billion people, consists of 4693 communities with several thousands of endogamous groups, 325 functioning languages and 25 scripts. To address the questions related to ethnic diversity, migrations, founder populations, predisposition to complex disorders or pharmacogenomics, one needs to understand the diversity and relatedness at the genetic level in such a diverse population. In this backdrop, six constituent laboratories of the Council of Scientific and Industrial Research (CSIR), with funding from the Government of India, initiated a network program on predictive medicine using repeats and single nucleotide polymorphisms. The Indian Genome Variation (IGV) consortium aims to provide data on validated SNPs and repeats, both novel and reported, along with gene duplications, in over a thousand genes, in 15,000 individuals drawn from Indian subpopulations. These genes have been selected on the basis of their relevance as functional and positional candidates in many common diseases including genes relevant to pharmacogenomics. This is the first large-scale comprehensive study of the structure of the Indian population with wide-reaching implications. A comprehensive platform for Indian Genome Variation (IGV) data management, analysis and creation of IGVdb portal has also been developed. The samples are being collected following ethical guidelines of Indian Council of Medical Research (ICMR) and Department of Biotechnology (DBT), India. This paper reveals the structure of the IGV project highlighting its various aspects like genesis, objectives, strategies for selection of genes, identification of the Indian subpopulations, collection of samples and discovery and validation of genetic markers, data analysis and monitoring as well as the project's data release policy. © Springer-Verlag 2005.

Human Genetics

The Indian Genome Variation database (IGVdb): A project overview

Spinocerebellar ataxia type 12 (SCA12) is an autosomal dominant cerebellar ataxia associated with the expansion of an unstable CAG repeat in the 5′ region of the PPP2R2B gene on chromosome 5q31-5q32. We found that it accounts for ∼16% (20/124) of all the autosomal dominant ataxia cases diagnosed in AIIMS, a major tertiary referral centre in North India. The length of the expanded allele in this population ranges from 51-69 CAG triplets. Interestingly, all the affected families belong to an endogamous population, which originated in the state of Haryana, India. We identified four novel SNPs and a dinucleotide marker spanning ∼137 kb downstream of CAG repeat in the PPP2R2B gene. Analysis of 20 Indian SCA12 families and ethnically matched normal unrelated individuals revealed one haplotype to be significantly associated with the affected alleles (P = 0.000), clearly indicating the presence of a common founder for SCA12 in the Indian population. This haplotype was not shared by the American pedigree with SCA12. Therefore, the SCA12 expansion appears to have originated at least twice. © University College London 2005.

Annals of Human Genetics

Evidence of a common founder for SCA12 in the Indian population

Background: Chromosome 22q13 has shown linkage with schizophrenia (SCZ) and bipolar affective disorder (BPAD). A missense mutation in MLC1 (putative cation-channel gene on 22q13) co-segregating with periodic catatonic schizophrenia has been reported. We have investigated the relationship of MLC1 with SCZ and BPAD in Southern India. Methods: All exons and flanking intronic sequences of MLC1 were screened for novel variations. Case-control (216 BPAD, 193 SCZ, 116 control subjects) and family-based analyses (113 BPAD, 107 SCZ families) were performed to evaluate association of MLC1 with these disorders. Results: We found 33 MLC1 sequence variations, including three novel mutations: Val210Ile, Leu308Gln, and Arg328His in six BPAD cases and Val210Ile in one control individual. Minor allele of a common variation, ss16339182 (in ∼6 Kb Linkage-Disequilibrium [LD]-block) was associated with BPAD in case-control (p = .03) and family-based analyses (transmitted/nontransmitted [T/NT]-44/20; p = .003). Association was observed for rs2235349 and rs2076137 with SCZ and ss16339163 with BPAD in case-control study. Using Block 2 haplotype tagging single nucleotide polymorphisms (htSNPs), GC haplotype revealed association (p = .02) and excess transmission (p = .002) with BPAD. Conclusions: Association of MLC1 with SCZ and BPAD suggests involvement of a common pathway. Rare missense mutations and common variants associated with BPAD favors hypothesis about likely involvement of both rare and common polymorphisms in etiology of this complex disorder. © 2005 Society of Biological Psychiatry.

Biological Psychiatry

MLC1 gene is associated with schizophrenia and bipolar disorder in Southern India

Background: The ACA haplotype is associated with 72% of the expanded repeats in Machado-Joseph disease (MJD) worldwide and has been traced to a Portuguese ancestry. It is present in only 5% of the normal chromosomes in the Portuguese population. Objective: To trace the origin of expanded alleles of MJD in the Indian population. Methods: We performed CAG repeat size determination and haplotype analysis for 9 families with MJD and 263 unrelated chromosomes with unexpanded CAG sequences from the Indian population. Results: All the expanded alleles were exclusively associated with the ACA haplotype in the Indian population. Interestingly, this haplotype was very common in normal alleles (40%) as compared with the Portuguese population (5%) and was significantly associated with large normal alleles (Pearson χ 12=87.1, P&lt;.001) in the Indian population. We also observed a rare intermediate allele of MJD with the ACA haplotype but with a CAG variant instead of CAA at the sixth position in the repeat tract. Conclusions: Overrepresentation of the ACA haplotype in large normal alleles in India as compared with the Portuguese population suggests that the expansion-prone large normal alleles with the ACA haplotype may have been introduced in the Portuguese population through admixture with South Asian populations. Detailed haplotype analysis of a CAG variant within the repeat tract in an intermediate allele of MJD suggests a mechanism of gene conversion in the expansion.

Archives of Neurology

Founder haplotype for Machado-Joseph disease in the Indian population: Novel insights from history and polymorphism studies

Elucidation of complete nucleotide sequence of the human has revealed that coding sequences that store the information needed to synthesize functional proteins, occupy only 2% of the genomic region. The remaining 98%, barring few regulatory sequences, has been referred to as non-functional or junk DNA and consists of many kinds of repeat elements. In fact, human genome is the most repeat rich genome sequenced so far, in which more than half of the region is occupied by such sequences. Determination of significance of these repeats in the human genome has become the focus of many studies all over the world, especially after genome sequencing did not reveal any significant difference in coding regions between lower eukaryotes and human. In this article, we have focused on Alu repeats that are primate specific elements with many interesting biological properties. Moreover, these are the repeats with highest copy number in the human genome. We have highlighted different facets of their interaction with the genome and changing paradigms regarding their role in genome organization. © Springer 2005.

Genetica

ALU-ring elements in the primate genomes

We present an analytical and numerical study of the problem of mechanical impulse propagation through a horizontal alignment of progressively shrinking (tapered) elastic spheres that are placed between two rigid end walls. The studies are confined to cases where initial loading between the spheres is zero (i.e., in the "sonic vacuum" region). The spheres are assumed to interact via the Hertz potential. Force and energy as a function of time for selected grains that comprise the solitary wave are provided and shed light on the system's behavior. Propagation of energy is analytically studied in the hard-sphere approximation and phase diagrams plotting normalized kinetic energy of the smallest grain at the tapered end are developed for various chain lengths and tapering factors. These details are then compared to kinetic energy phase diagrams obtained via extensive dynamical simulations. Our figures indicate that the ratios of the kinetic energies of the smallest to largest grains possess a Gaussian dependence on tapering and an exponential decay when the number of grains increases. The conclusions are independent of system size, thus being applicable to tapered alignments of micron-sized spheres as well as those that are macroscopic and more easily realizable in the laboratory. Results demonstrate the capabililty of these chains to thermalize propagating impulses and thereby act as potential shock absorbing devices. © 2005 The American Physical Society.

Physical Review E - Statistical, Nonlinear, and Soft Matter Physics

Impulse absorption by tapered horizontal alignments of elastic spheres

We show that time evolution initiated via kinetic energy perturbations in conservative, discrete, spring-mass chains with purely nonlinear, non-integrable, algebraic potentials of the form V(x1 - x i+1) ∼ (xi - xi+1)2n, n ≥ 2 and an integer, occurs via discrete solitary waves (DSWs) and discrete antisolitary waves (DASWs). Presence of reflecting and periodic boundaries in the system leads to collisions between the DSWs and DASWs. Such collisions lead to the breakage and subsequent reformation of (different) DSWs and DASWs. Our calculations show that the system eventually reaches a stable 'quasi-equilibrium' phase that appears to be independent of initial conditions, possesses Gaussian velocity distribution, and has a higher mean kinetic energy and larger range of kinetic energy fluctuations as compared to the pure harmonic system with n = 1; the latter indicates possible violation of equipartition. © Indian Academy of Sciences.

Pramana - Journal of Physics

The quasi-equilibrium phase of nonlinear chains

We present the preliminary results towards a useful detection method effective for distinguishing buried objects in granular media. A non-linear particle dynamics based simulational study of the propagation of δ function mechanical impulses in idealized three-dimensional hexagonal close packed lattices of monosized Hertz spheres is considered. Our first step towards this goal involves characterizing the impulse backscattering of the granular bed with (i) restitution, (ii) effect of different impulse areas and (iii) effect of random-massed particles. After the granular bed has been characterized, the obstacle (landmine) is introduced into the granular bed. Initial results indicate that the size of the obstacle to be detected is dependent on the ratio of the area of the impulse to the area of the obstacle. This avenue is explored to determine the ratio mentioned above. The characterization of the backscattered impulse is done for the bed (without the obstacle) to form a reference when an obstacle is present. The change in the behavior of the backscattered impulse contains critical information (size and shape of the object) to be reflected off buried objects, such as land mines. This leads to the most important question: How small an obstacle can be detected for how small an impulse? In this work, these questions are answered.