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Shiv Nadar University

(SoNS) School of Natural Sciences

Adenoviruses are linear double-stranded DNA viruses that infect human and rodent cell lines, occasionally transform them and cause tumors in animal models. The host cell challenges the virus in multifaceted ways to restrain viral gene expression and DNA replication, and sometimes even eliminates the infected cells by programmed cell death. To combat these challenges, adenoviruses abrogate the cellular DNA damage response pathway. Tip60 is a lysine acetyltransferase that acetylates histones and other proteins to regulate gene expression, DNA damage response, apoptosis and cell cycle regulation. Tip60 is a bona fide tumor suppressor as mice that are haploid for Tip60 are predisposed to tumors. We have discovered that Tip60 is degraded by adenovirus oncoproteins EIB55K and E4orf6 by a proteasome-mediated pathway. Tip60 binds to the immediate early adenovirus promoter and suppresses adenovirus EIA gene expression, which is a master regulator of adenovirus transcription, at least partly through retention of the virally encoded repressor pVII on this promoter. Thus, degradation of Tip60 by the adenoviral early proteins is important for efficient viral early gene transcription and for changes in expression of cellular genes. © 2013 Macmillan Publishers Limited.

Life Sciences

World University root node

Fulltext

Oncogene

Tip60 degradation by adenovirus relieves transcriptional repression of viral transcriptional activator EIA

Vascular endothelium is a dynamic cellular interface that displays a unique phenotypic plasticity. This plasticity is critical for vascular function and when dysregulated is pathogenic in several diseases. Human genotype-phenotype studies of endothelium are limited by the unavailability of patient-specific endothelial cells. To establish a cellular platform for studying endothelial biology, we have generated vascular endothelium from human induced pluripotent stem cells (iPSCs) exhibiting the rich functional phenotypic plasticity of mature primary vascular endothelium. These endothelial cells respond to diverse proinflammatory stimuli, adopting an activated phenotype including leukocyte adhesion molecule expression, cytokine production, and support for leukocyte transmigration. They maintain dynamic barrier properties responsive to multiple vascular permeability factors. Importantly, biomechanical or pharmacological stimuli can induce pathophysiologically relevant atheroprotective or atheroprone phenotypes. Our results demonstrate that iPSC-derived endothelium possesses a repertoire of functional phenotypic plasticity and is amenable to cell-based assays probing endothelial contributions to inflammatory and cardiovascular diseases. © 2013 The Authors.

Stem Cell Reports

Functional vascular endothelium derived from human induced pluripotent stem cells

Sequencing of mRNA using next-generation sequencing (NGS) technologies (RNA-seq) has the potential to reveal unprecedented complexity of the transcriptomes. The transcriptome sequencing of an organism provides quick insights into the gene space, opportunity to isolate genes of interest, development of functional markers, quantitation of gene expression, and comparative genomic studies. Although becoming cheaper, transcriptome sequencing still remains an expensive endeavor. Further, the assembly of millions and billions of RNA-seq reads to construct the complete transcriptome poses great informatics challenges. Here, first we outline various important issues from experimental design to data analysis, including various strategies of transcriptome assembly, which need substantial consideration for a successful RNA-seq experiment. Further, we describe a method for using RNA-seq to characterize the transcriptome of a plant species, taking the example of a legume crop plant chickpea. Our aim is to provide a quick start guide to the nonexpert researchers for NGS-based transcriptome analysis. © 2013 Springer Science+Business Media, LLC.

Methods in Molecular Biology

RNA-Seq for transcriptome analysis in non-model plants

Imidazoleglycerol-phosphate dehydratase (IGPD; HisB), which catalyses the conversion of imidazoleglycerol-phosphate (IGP) to imidazoleacetol-phosphate in the histidine biosynthesis pathway, is absent in mammals. This feature makes it an attractive target for herbicide discovery. Here, the crystal structure of Mycobacterium tuberculosis (Mtb) IGPD is reported together with the first crystal structures of substrate-bound and inhibited (by 3-amino-1,2,4-triazole; ATZ) forms of IGPD from any organism. The overall tertiary structure of Mtb IGPD, a four-helix-bundle sandwiched between two four-stranded mixed $\beta$-sheets, resembles the three-dimensional structures of IPGD from other organisms; however, Mtb IGPD possesses a unique structural feature: the insertion of a one-turn 310-helix followed by a loop ten residues in length. The functional form of IGPD is 24-meric, exhibiting 432 point-group symmetry. The structure of the IGPD-IGP complex revealed that the imidazole ring of the IGP is firmly anchored between the two Mn atoms, that the rest of the substrate interacts through hydrogen bonds mainly with residues Glu21, Arg99, Glu180, Arg121 and Lys184 which protrude from three separate protomers and that the 24-mer assembly contains 24 catalytic centres. Both the structural and the kinetic data demonstrate that the inhibitor 3-amino-1,2,4-triazole inhibits IGPD competitively. {\textcopyright} 2013 International Union of Crystallography.

Acta Crystallographica Section D: Biological Crystallography

Structures of native, substrate-bound and inhibited forms of Mycobacterium tuberculosis imidazoleglycerol-phosphate dehydratase

Legumes represent an important family of flowering plants in terms of providing human nutrition and capacity to fix atmospheric N for agricultural sustainability. The recent availability of genome sequence of several legume plants has helped boosting genomics research. Study of the transcriptome at a global level can provide insights into the gene space, gene function, transcriptional programs, and molecular basis of various cellular processes in legumes, even in the absence of genome sequence. Transcriptome analysis has been realized as an essential step for basic and applied research in any organism. Considering the importance of transcriptome analyses, a few studies have been performed in legumes, such as soybean [Glycine max (L.) Merr.], Medicago truncatula Gaertn., Lotus corniculatus L. var. japonicus Regel [syn. Lotus japonicus (Regel) K. Larsen], and chickpea (Cicer arietinum L.), to uncover the overall and specific transcriptional activity of genes across various tissues and/or organs and developmental stages. Several candidate genes putatively involved in important agronomic traits, such as nodule, flower, and seed development, have been identified. The availability of these transcriptome data and future investigations will enable a variety of functional genomic studies to characterize these genes and define their function in legumes. © Crop Science Society of America.

Plant Genome

Transcriptome analyses in legumes: A resource for functional genomics

The role of bacterial DnaJ protein as a cochaperone of DnaK is strongly appreciated. Although DnaJ unaccompanied by DnaK can bind unfolded as well as native substrate proteins, its role as an individual chaperone remains elusive. In this study, we demonstrate that DnaJ binds a model non-native substrate with a low nanomolar dissociation constant and, more importantly, modulates the structure of its non-native state. The structural modulation achieved by DnaJ is different compared to that achieved by the DnaK-DnaJ complex. The nature of structural modulation exerted by DnaJ is suggestive of a unique unfolding activity on the non-native substrate by the chaperone. Furthermore, we demonstrate that the zinc binding motif along with the C-terminal substrate binding domain of DnaJ is necessary and sufficient for binding and the subsequent binding-induced structural alterations of the non-native substrate. We hypothesize that this hitherto unknown structural alteration of non-native states by DnaJ might be important for its chaperoning activity by removing kinetic traps of the folding intermediates. © 2013 American Chemical Society.

Biochemistry

Unique structural modulation of a non-native substrate by cochaperone DnaJ

Donor-Acceptor-Donor (D-A-D) based conjugated molecules 4,7-bis(5-(4-butoxyphenyl)thiophen-2-yl)benzo[c][1,2,5]thiadiazole (BOP-TBT) and 4,7-bis(5-(4-trifluoromethyl)phenyl)thiophen-2-yl)benzo[c][1,2,5]thiadiazole (TFP-TBT) using thiophene-benzothiadiazole-thiophene central core with trifluoromethyl phenyl and butoxyphenyl end capping groups were designed and synthesised via Suzuki coupling. Optical, electrochemical, thermal, and organic field effect transistor (OFET) device properties of BOP-TBT and TFP-TBT were investigated. Both small molecules possess two absorption bands. Optical band gaps were calculated from the absorption cut off to be in the range of 2.06-2.25eV. Cyclic voltammetry indicated reversible oxidation and reduction processes and the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) energy levels were calculated to be in the range of 5.15-5.40eV and 3.25-3.62eV, respectively. Upon testing both materials for OFET, trifluoromethylphenyl end capped material (TFP-TBT) shows n-channel behaviour whereas butoxyphenyl end capped material (BOP-TBT) shows p-channel behaviour. Density functional theory calculations correlated with shifting of HOMO-LUMO energy levels with respect to end capping groups. Vacuum processed OFET of these materials have shown highest hole carrier mobility of 0.02cm 2/Vs and electron carrier mobility of 0.004cm2/Vs, respectively using Si/SiO2 substrate. By keeping the central D-A-D segment and just by tuning end capping groups gives both p- and n-channel organic semiconductors which can be prepared in a single step using straightforward synthesis.

Physics

Australian Journal of Chemistry

Dithienylbenzothiadiazole-based donor-acceptor organic semiconductors and effect of end capping groups on organic field effect transistor performance

For a fixed positive integer n, let Wn be the permutation matrix corresponding to permutation. In this article, it is shown that a symmetric matrix with rational entries is circulant if, and only if, it lies in the subalgebra of Q[x]/ (xn-1) generated by Wn+Wn -1. On the basis of this, the singularity of graphs on n-vertices is characterized algebraically. This characterization is then extended to characterize the singularity of directed circulant graphs. The kth power matrix Wnk+Wn -k defines a circulant graph Cnk. The results above are then applied to characterize its singularity, and that of its complement graph. The digraph Cr,s,t is defined as that whose adjacency matrix is circulant circ(a), where a is a vector with the first r-components equal to 1, and the next s, t and n - (r + s + t) components equal to zero, one, and zero respectively. The singularity of this digraph (graph), under certain conditions, is also shown to depend algebraically upon these parameters. A slight generalization of these graphs are also studied.

Mathematics

Electronic Journal of Linear Algebra

Non-singular circulant graphs and digraphs

The Birkhoff-James orthogonality is a generalization of Hilbert space orthogonality to Banach spaces. We investigate this notion of orthogonality when the Banach space has more structures. We start by doing so for the Banach space of square matrices moving gradually to all bounded operators on any Hilbert space, then to an arbitrary C*-algebra and finally a Hilbert C*-module. © 2013 Elsevier Ltd.

Journal of Mathematical Analysis and Applications

Characterization of Birkhoff-James orthogonality

We propose a method based on the Wang-Landau algorithm to numerically generate the spectral densities of random matrix ensembles. The method employs Dyson's log-gas formalism for random matrix eigenvalues and also enables one to simultaneously investigate the thermodynamic properties. This approach is a powerful alternative to the conventionally used Monte Carlo simulations based on the Boltzmann sampling, and is ideally suited for investigating β-ensembles. Copyright © EPLA, 2013.