Discerning Drivers of Cancer: Computational Approaches to Somatic Exome Sequencing Data

Paired tumor-normal sequencing of thousands of patient’s exomes has revealed millions of somatic mutations, but functional characterization and clinical decision making are stymied because biologically neutral ‘passenger’ mutations greatly outnumber pathogenic ‘driver’ mutations. Since most mutations will return negative results if tested, conventional resource-intensive experiments are reserved for mutations which are observed in multiple patients or rarer mutations found in well-established cancer genes. Most mutations are therefore never tested, diminishing the potential to discover new mechanisms of cancer development and treatment opportunities. Computational methods that reliably prioritize mutations for testing would greatly increase the translation of sequencing results to clinical care. The goal of this thesis is to develop new approaches that use datasets of protein-coding somatic mutations to identify putative cancer-causing genes and mutations, and to validate these predictions in silico and experimentally. This effort will be split among several inter-related efforts, which taken together will help experimental biologists and clinicians focus on hypotheses that can yield novel insights into cancer biology, development, and treatment

Clinico-radiological evaluation of oligohydramnios with special reference to pregnancy outcome

Background: Oligohydramnios is defined as amniotic fluid index of less than 5cm. It is thought to be associated with increased fetal and maternal morbidity. Studies are not clear whether the adverse perinatal outcome merely reflects the sequel of other conditions or if, reduced amniotic fluid volume itself contributes to adverse outcomes.Methods: A total of 150 pregnant women with gestational age >34 weeks having clinically diagnosed oligohydramnios were enrolled in this observational prospective clinical study, during the study period of 12 months,1June 2020 to 31May 2021. Patients were first subjected to ultrasonographic AFI estimation, divided into two groups (oligohydramnios and borderline AFI) and then followed up for maternal and fetal outcome. Data was statistically analyzed.Results: A total 72.66% had AFI less than 5 cm. 97 (64.66%) were primigravida. 68% were prepared for Caesarean section irrespective of gestational period, the most common indication being fetal distress. 66.66% babies had good APGAR score at 1 minute after birth.41.06% delivered babies who required NICU admission, although only 2% neonatal deaths were recorded.Conclusions: Our study shows that isolated decreased AFI after 34 weeks of gestation is associated with satisfactory perinatal outcome. Both groups in the study, when compared statistically, were relatively similar in their pregnancy outcome. Significant association was found between oligohydramnios and increased rate of caesarean section, NICU admission and abnormal fetal heart rate tracing.

PoxA, YjeK and Elongation Factor P Coordinately Modulate Virulence and Drug Resistance in \u3cem\u3eSalmonella enterica\u3c/em\u3e

We report an interaction between poxA, encoding a paralog of lysyl tRNA-synthetase, and the closely linked yjeK gene, encoding a putative 2,3-β-lysine aminomutase, that is critical for virulence and stress resistance in Salmonella enterica. Salmonella poxA and yjeK mutants share extensive phenotypic pleiotropy, including attenuated virulence in mice, an increased ability to respire under nutrient-limiting conditions, hypersusceptibility to a variety of diverse growth inhibitors, and altered expression of multiple proteins, including several encoded on the SPI-1 pathogenicity island. PoxA mediates posttranslational modification of bacterial elongation factor P (EF-P), analogous to the modification of the eukaryotic EF-P homolog, eIF5A, with hypusine. The modification of EF-P is a mechanism of regulation whereby PoxA acts as an aminoacyl-tRNA synthetase that attaches an amino acid to a protein resembling tRNA rather than to a tRNA

Cross-talk between phosphorylation and lysine acetylation in a genome-reduced bacterium

The effect of kinase, phosphatase and N-acetyltransferase deletions on proteome phosphorylation and acetylation was investigated in Mycoplasma pneumoniae. Bi-directional cross-talk between post-transcriptional modifications suggests an underlying regulatory molecular code in prokaryotes

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD

Studies directed toward the exploitation of vicinal diols in the synthesis of (+)-nebivolol intermediates

While the exploitation of the Sharpless asymmetric dihydroxylation as the source of chirality in the synthesis of acyclic molecules and saturated heterocycles has been tremendous, its synthetic utility toward chiral benzo-annulated heterocycles is relatively limited. Thus, in the search for wider applications of Sharpless asymmetric dihydroxylation-derived diols for the synthesis of benzo-annulated heterocycles, we report herein our studies in the asymmetric synthesis of (R)-1-((R)-6-fluorochroman-2-yl)ethane-1,2-diol, (R)-1-((S)-6-fluorochroman-2-yl)ethane-1,2-diol and (S)-6-fluoro-2-((R)-oxiran-2-yl)chroman, which have been used as late-stage intermediates for the asymmetric synthesis of the antihypertensive drug (S,R,R,R)-nebivolol. Noteworthy is that a large number of racemic and asymmetric syntheses of nebivolol and their intermediates have been described in the literature, however, the Sharpless asymmetric dihydroxylation has never been employed as the sole source of chirality for this purpose

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Not AvailableTicks are important ectoparasites which results in economic loss in livestock industry. Therefore, the present study was undertaken with aim to study the comparative efficacy of some herbal extracts i.e. oil of Lemon grass (Cymbopogon citratus) and Litsea grass (Litsea cubeba) and three synthetic acaricides viz. Deltamethrin, Fipronil, and Amritraz against the Rhipicephalus microplus tick infestation in mithun. Among the chemical drugs, Fipronil showed 100% efficacy followed by Amitraz (98.38%) and Deltamithrin (93.28%). The lemon grass oil on 12 days of application resulted in very high efficacy (98.00 %) comparable to synthetic acaricides (Fipronil, Amitraz and Deltamithrin), however, Litsea grass oil did not showed significant efficacy on day 12 post application. However, the Adult Immersion Test (AIT) showed dose dependent acaricidal efficacy for Deltamethrin, Fipronil and Amritraz at final concentration of undiluted, 0.40%, 0.20 %, 0.10 % and 0.05% while among the herbal acaricides in 100 % concentration, lemon grass oil showed comparable efficacy with deltamethrin (12.5 W/V) while Listea grass oil did not showed better effects. Author concludes that lemon grass oil has potential acaricidal activity and may be recommended for holistic management of nymphal stages of tick infestation and can be proved as an alternative to synthetic acaricides without adversely affecting health and environment.Not Availabl

Prioritizing Potentially Druggable Mutations with dGene: An Annotation Tool for Cancer Genome Sequencing Data.

A major goal of cancer genome sequencing is to identify mutations or other somatic alterations that can be targeted by selective and specific drugs. dGene is an annotation tool designed to rapidly identify genes belonging to one of ten druggable classes that are frequently targeted in cancer drug development. These classes were comprehensively populated by combining and manually curating data from multiple specialized and general databases. dGene was used by The Cancer Genome Atlas squamous cell lung cancer project, and here we further demonstrate its utility using recently released breast cancer genome sequencing data. dGene is designed to be usable by any cancer researcher without the need for support from a bioinformatics specialist. A full description of dGene and options for its implementation are provided here

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Not AvailableTicks are important ectoparasites which results in economic loss in livestock industry. Therefore, the present study was undertaken with aim to study the comparative efficacy of some herbal extracts i.e. oil of Lemon grass (Cymbopogon citratus) and Litsea grass (Litsea cubeba) and three synthetic acaricides viz. Deltamethrin, Fipronil, and Amritraz against the Rhipicephalus microplus tick infestation in mithun. Among the chemical drugs, Fipronil showed 100% efficacy followed by Amitraz (98.38%) and Deltamithrin (93.28%). The lemon grass oil on 12 days of application resulted in very high efficacy (98.00 %) comparable to synthetic acaricides (Fipronil, Amitraz and Deltamithrin), however, Litsea grass oil did not showed significant efficacy on day 12 post application. However, the Adult Immersion Test (AIT) showed dose dependent acaricidal efficacy for Deltamethrin, Fipronil and Amritraz at final concentration of undiluted, 0.40%, 0.20 %, 0.10 % and 0.05% while among the herbal acaricides in 100 % concentration, lemon grass oil showed comparable efficacy with deltamethrin (12.5 W/V) while Listea grass oil did not showed better effects. Author concludes that lemon grass oil has potential acaricidal activity and may be recommended for holistic management of nymphal stages of tick infestation and can be proved as an alternative to synthetic acaricides without adversely affecting health and environment.Not Availabl