Life Sciences

<p>Shiv Nadar University is a comprehensive, multidisciplinary, research-focused, and student-centric University offering a full range of academic programs at the undergraduate, postgraduate and doctoral level. With state-of-the-art infrastructure, the University comprises of academic wings, sophisticated labs, international standard sports facilities, amphitheaters, auditorium, conference rooms and smart classrooms. The University&rsquo;s goal is to become internationally recognized for the quality of its research and creative endeavors and their applicability to improving quality of life, generating new insights and expanding the boundaries of human knowledge creativity. Committed to excellence in teaching, research and service, the University aims to serve the higher education needs of India and the world beyond.</p>

Shiv Nadar University

Microbial load of nurses’ white coats in a hospital was determined on polyester cotton blend and polyester fabric after the first and second work shift. Contamination on the blend fabric was significantly higher (P < .05) than on polyester. After the second shift, bacterial colonies on polyester and blend fabrics increased by ~98\% and ~70\%, respectively. Among the isolates detected on polyester after the second shift, Escherichia coli was the most abundant (47.8\%), followed by staphylococci (19.1\%). © 2017 Association for Professionals in Infection Control and Epidemiology, Inc.

World University root node

(SoNS) School of Natural Sciences

American Journal of Infection Control

Bacterial contamination of nurses’ white coats after first and second shift

Unraveling transcriptional heterogeneity and the labyrinthine nature of neurodevelopment can probe insights into neuropsychiatric disorders. It is noteworthy that adult neurogenesis is restricted to the subventricular and subgranular zones of the brain. Recent studies suggest long non-coding RNAs (lncRNAs) as an avant-garde class of regulators implicated in neurodevelopment. But, paucity exists in the knowledge regarding lncRNAs in neurogenesis and their associations with neurodevelopmental defects. To address this, we extensively reviewed the existing literature databases as well as performed relevant in-silico analysis. We utilized Allen Brain Atlas (ABA) differential search module and generated a catalogue of ∼30,000 transcripts specific to the neurogenic zones, including coding and non-coding transcripts. To explore the existing lncRNAs reported in neurogenesis, we performed extensive literature mining and identified 392 lncRNAs. These degenerate lncRNAs were mapped onto the ABA transcript list leading to detection of 20 lncRNAs specific to neurogenic zones (Dentate gyrus/Lateral ventricle), among which 10 showed associations to several neurodevelopmental disorders following in-silico mapping onto brain disease databases like Simons Foundation Autism Research Initiative, AutDB, and lncRNADisease. Notably, using ABA correlation module, we could establish lncRNA-to-mRNA coexpression networks for the above 10 candidate lncRNAs. Finally, pathway prediction revealed physical, biochemical, or regulatory interactions for nine lncRNAs. In addition, ABA differential search also revealed 54 novel significant lncRNAs from the null set (∼30,000). Conclusively, this review represents an updated catalogue of lncRNAs in neurogenesis and neurological diseases, and overviews the field of OMICs-based data analysis for understanding lncRNome-based regulation in neurodevelopment. © 2017, Mary Ann Liebert, Inc.

Stem Cells and Development

Decoding Crucial LncRNAs Implicated in Neurogenesis and Neurological Disorders

Visceral Leishmaniasis is a deadly parasitic disease caused by Leishmania donovani. Paucity exists in the discovery of novel chemotherapeutics against Leishmaniasis. In this study, we synthesized a natural product inspired Diversity Oriented Synthesis library of L. donovani Trypanothione reductase (LdTR) inhibitor β-carboline-quinazolinone hybrids, which are different in stereochemical architecture and diverse in the bioactive chemical space. It is noteworthy that chirality affects drug-to-protein binding affinity since proteins in any living system are present only in one of the chiral forms. Upon evaluation of the hybrids, one of the chiral forms i.e. Compound 1 showed profound cytotoxic effect in micromolar range as compared to its other chiral form i.e. Compound 2. In-silico docking studies confirmed high binding efficiency of Compound 1 with the catalytic pocket of LdTR. Treatment of L. donovani parasites with Compound 1 inhibits LdTR activity, induces imbalance in redox homeostasis by enhancing ROS, disrupts the mitochondrial membrane potential, modifies actin polymerization and alters the surface topology and architecture. All these cellular modifications eventually led to apoptosis-like death of promastigotes. Furthermore, we synthesized the analogues of Compound 1 and found that these compounds show profound antileishmanial activity in the nanomolar range both in promastigotes and intracellular amastigotes. The enhanced inhibitory potential of these compounds was further supported by in-silico analysis of protein-ligand interactions which revealed high binding efficiency towards the catalytic pocket of LdTR. Taken together, this study reports the serendipitous discovery of β-carboline-quinazolinone hybrids with enhanced antileishmanial activity along with the in-depth structure-activity relationships and mechanism of action of these analogues. © 2016 Elsevier Inc.

Chemistry

Biochemical Pharmacology

Novel β-carboline-quinazolinone hybrids disrupt Leishmania donovani redox homeostasis and show promising antileishmanial activity

PXR is a member of nuclear receptor superfamily and a well-characterized mediator of xenobiotic metabolism. The classical mode of PXR activation involves its binding to appropriate ligand and subsequent heterodimerization with its partner RXR. However, various factors such as post-translational modifications and crosstalk with different cellular factors may also regulate the functional dynamics and behavior of PXR. In the present study, we have identified that TIP60, an essential lysine acetyltransferase protein interacts with unliganded PXR and together this complex promotes cell migration & adhesion. TIP60 utilizes its NR Box to interact with LBD region of PXR and acetylates PXR at lysine 170 to induce its intranuclear reorganization. Also, RXR is not required for TIP60-PXR complex formation and this complex does not induce ligand-dependent PXR target gene transactivation. Interestingly, we observed that PXR augments the catalytic activity of TIP60 for histones. This is the first report demonstrating the exclusive interaction of TIP60 with PXR and uncovers a potential role for the TIP60-PXR complex in cell migration and adhesion. © 2017 The Author(s).

Fulltext

Scientific Reports

Novel complex of HAT protein TIP60 and nuclear receptor PXR promotes cell migration and adhesion

Thalidomide [α-(N-phthalimido)glutarimide] (1) is a sedative and antiemetic drug originally introduced into the clinic in the 1950s for the treatment of morning sickness. Although marketed as entirely safe, more than 10000 babies were born with severe birth defects. Thalidomide was banned and subsequently approved for the treatment of multiple myeloma and complications associated with leprosy. Although known for more than 5 decades, the mechanism of teratogenicity remains to be conclusively understood. Various theories have been proposed in the literature including DNA damage and ROS and inhibition of angiogenesis and cereblon. All of the theories have their merits and limitations. Although the recently proposed cereblon theory has gained wide acceptance, it fails to explain the metabolism and low-dose requirement reported by a number of groups. Recently, we have provided convincing structural evidence in support of the presence of arene oxide and the quinone-reactive intermediates. However, the ability of these reactive intermediates to impart toxicity/teratogenicity needs investigation. Herein we report that the oxidative metabolite of thalidomide, dihydroxythalidomide, is responsible for generating ROS and causing DNA damage. We show, using cell lines, the formation of comet (DNA damage) and ROS. Using DNA-cleavage assays, we also show that catalase, radical scavengers, and desferal are capable of inhibiting DNA damage. A mechanism of teratogenicity is proposed that not only explains the DNA-damaging property but also the metabolism, low concentration, and species-specificity requirements of thalidomide. © 2017 American Chemical Society.

Chemical Research in Toxicology

The Dihydroxy Metabolite of the Teratogen Thalidomide Causes Oxidative DNA Damage

Long non-coding RNAs (lncRNAs) make up a significant portion of non-coding RNAs and are involved in a variety of biological processes. Accurate identification/annotation of lncRNAs is the primary step for gaining deeper insights into their functions. In this study, we report a novel tool, PLncPRO, for prediction of lncRNAs in plants using transcriptome data. PLncPRO is based on machine learning and uses random forest algorithm to classify coding and long non-coding transcripts. PLncPRO has better prediction accuracy as compared to other existing tools and is particularly well-suited for plants. We developed consensus models for dicots and monocots to facilitate prediction of lncRNAs in non-model/orphan plants. The performance of PLncPRO was quite better with vertebrate transcriptome data as well. Using PLncPRO, we discovered 3714 and 3457 high-confidence lncRNAs in rice and chickpea, respectively, under drought or salinity stress conditions. We investigated different characteristics and differential expression under drought/salinity stress conditions, and validated lncRNAs via RT-qPCR. Overall, we developed a new tool for the prediction of lncRNAs in plants and showed its utility via identification of lncRNAs in rice and chickpea. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Nucleic Acids Research

PLncPRO for prediction of long non-coding RNAs (lncRNAs) in plants and its application for discovery of abiotic stress-responsive lncRNAs in rice and chickpea

Auxin response factors (ARFs) are the transcription factors that regulate auxin responses in various aspects of plant growth and development. Although genome-wide analysis of ARF gene family has been done in some species, no information is available regarding ARF genes in chickpea. In this study, we identified 28 ARF genes (CaARF) in the chickpea genome. Phylogenetic analysis revealed that CaARFs can be divided into four different groups. Duplication analysis revealed that 50\% of CaARF genes arose from duplication events. We analyzed expression pattern of CaARFs in various developmental stages. CaARF16.3, CaARF17.1 and CaARF17.2 showed highest expression at initial stages of flower bud development, while CaARF6.2 had higher expression at later stages of flower development. Further, CaARF4.2, CaARF9.2, CaARF16.2 and CaARF7.1 exhibited differential expression under different abiotic stress conditions, suggesting their role in abiotic stress responses. Co-expression network analysis among CaARF, CaIAA and CaGH3 genes enabled us to recognize components involved in the regulatory network associated with CaARFs. Further, we identified microRNAs that target CaARFs and TAS3 locus that trigger production of trans-acting siRNAs targeting CaARFs. The analyses presented here provide comprehensive information on ARF family members and will help in elucidating their exact function in chickpea. © 2017 The Author(s).

Genome-wide identification and co-expression network analysis provide insights into the roles of auxin response factor gene family in chickpea

Seed development is an intricate process regulated via a complex transcriptional regulatory network. To understand the molecular mechanisms governing seed development and seed size/weight in chickpea, we performed a comprehensive analysis of transcriptome dynamics during seed development in two cultivars with contrasting seed size/weight (small-seeded, Himchana 1 and large-seeded, JGK 3). Our analysis identified stage-specific expression for a significant proportion (>13\%) of the genes in each cultivar. About one half of the total genes exhibited significant differential expression in JGK 3 as compared with Himchana 1. We found that different seed development stages can be delineated by modules of coexpressed genes. A comparative analysis revealed differential developmental stage specificity of some modules between the two cultivars. Furthermore, we constructed transcriptional regulatory networks and identified key components determining seed size/weight. The results suggested that extended period of cell division during embryogenesis and higher level of endoreduplication along with more accumulation of storage compounds during maturation determine large seed size/weight. Further, we identified quantitative trait loci-associated candidate genes harboring single nucleotide polymorphisms in the promoter sequences that differentiate small- and large-seeded chickpea cultivars. The results provide a valuable resource to dissect the role of candidate genes governing seed development and seed size/weight in chickpea. © 2017 The Authors The Plant Journal © 2017 John Wiley & Sons Ltd

Plant Journal

Global transcriptome and coexpression network analyses reveal cultivar-specific molecular signatures associated with seed development and seed size/weight determination in chickpea

Nucleoside reverse transcriptase inhibitors (NRTIs) with L-stereochemistry have long been an effective treatment for viral infections because of the strong D-stereoselectivity exhibited by human DNA polymerases relative to viral reverse transcriptases. The D-stereoselectivity of DNA polymerases has only recently been explored structurally and all three DNA polymerases studied to date have demonstrated unique stereochemical selection mechanisms. Here, we have solved structures of human DNA polymerase $\beta$ (hPol$\beta$), in complex with single-nucleotide gapped DNA and L-nucleotides and performed presteady-state kinetic analysis to determine the Dstereoselectivity mechanism of hPol$\beta$. Beyond a similar 180° rotation of the L-nucleotide ribose ring seen in other studies, the pre-catalytic ternary crystal structures of hPol$\beta$, DNA and L-dCTP or the triphosphate forms of antiviral drugs lamivudine ((-)3TC-TP) and emtricitabine ((-)FTC-TP) provide little structural evidence to suggest that hPol$\beta$ follows the previously characterized mechanisms of D-stereoselectivity. Instead, hPol$\beta$ discriminates against L-stereochemistry through accumulation of several active site rearrangements that lead to a decreased nucleotide binding affinity and incorporation rate. The two NRTIs escape some of the active site selection through the base and sugar modifications but are selected against through the inability of hPol$\beta$ to complete thumb domain closure.

Structural basis for the D-stereoselectivity of human DNA polymerase $\beta$

Membrane proteins plays significant role in living cells. Transmembrane proteins are estimated to constitute approximately 30\% of proteins at genomic scale. It has been a difficult task to develop specific alignment tools for transmembrane proteins due to limited number of experimentally validated protein structures. Alignment tools based on homology modeling provide fairly good result by recapitulating 70-80\% residues in reference alignment provided all input sequences should have known template structures. However, homology modeling tools took substantial amount of time, thus aligning large numbers of sequences becomes computationally demanding. Here we present TM-Aligner, a new tool for transmembrane protein sequence alignment. TM-Aligner is based on Wu-Manber and dynamic string matching algorithm which has significantly improved its accuracy and speed of multiple sequence alignment. We compared TM-Aligner with prevailing other popular tools and performed benchmarking using three separate reference sets, BaliBASE3.0 reference set7 of alpha-helical transmembrane proteins, structure based alignment of transmembrane proteins from Pfam database and structure alignment from GPCRDB. Benchmarking against reference datasets indicated that TM-Aligner is more advanced method having least turnaround time with significant improvements over the most accurate methods such as PROMALS, MAFFT, TM-Coffee, Kalign, ClustalW, Muscle and PRALINE. TM-Aligner is freely available through http://lms.snu.edu.in/TM-Aligner/. © 2017 The Author(s).