Biology subjects

Sharma, T.

Publications and source records attributed to Sharma, T..

41 records · Page 3Linked to original sources

bioRxiv2020

A Combined Evidence Approach to Prioritize Nipah Virus Inhibitors

Nipah Virus (NiV) came into limelight due to an outbreak in Kerala, India. NiV causes severe disease and death in people with over 75% case fatality rate. It is a public health concern and has the potential to become a global pandemic. Lack of treatment has forced the containment methods to be restricted to isolation and surveillance. WHOs R&D Blueprint list of priority diseases (2018) indicates that there is an urgent need for accelerated research & development for addressing NiV. In the quest for druglike NiV inhibitors (NVIs) a thorough literature search followed by systematic data curation was conducted. Rigorous data analysis was done with curated NVIs for prioritizing druglike compounds. For the same, more than 1800 descriptors of NVIs were computed and comparative analysis was performed with the FDA approved small molecules and antivirals. These compounds were further evaluated through PAINS filter to study their toxicity profile. Simultaneously, compounds were also prioritized based on the robustness of the assays through which they were identified. Our efforts lead to the creation of a well-curated structured knowledgebase of 182 NVIs with 98 small molecule inhibitors. The reported IC50/EC50 values for some of these inhibitors are in the nanomolar range - as low as 0.47 nM. In order to prioritize these inhibitors, we performed several tests and applied filters to identify drug-like non-toxic compounds. Of 98, a few compounds passed DruLito & PAINS filters exhibiting drug-like properties and were also prioritized in an independent screen based only the assay robustness. The NVIs have diverse structural features and offer a wide spectrum of ways in which they can be developed further as druglike molecules. We report a knowledgebase for furthering the development of NVIs. The platform has a diverse set of 98 NVIs of which a few have been prioritized based on a combined evidence strategy. The platform has the provision to submit new inhibitors as and when reported by the community for further enhancement of NiV inhibitor landscape.

bioinformatics↗

bioRxiv2019

Proteome-wide characterization and biomarker identification of intracranial aneurysm

The scientific basis of intracranial aneurysm (IA) formation, its rupture and further development of cerebral vasospasm remains incompletely understood. Deciphering the molecular mechanisms underlying these events will lead to identification of early detection biomarkers and in turn, improved treatment outcomes. Aberrant protein expression may drive structural alterations of vasculature found in IA. To unravel these aberrations, we performed untargeted, global, quantitative proteomic analysis of aneurysm tissue and serum from patients with IA. Samples were derived from patients of three clinical sub groups- 1) unruptured aneurysm 2) ruptured aneurysm without vasospasm 3) ruptured aneurysm who developed vasospasm. A total of 937 and 294 proteins were identified in aneurysm tissue and serum samples respectively. Several proteins that are known to maintain the structural integrity of vasculature were found to be dysregulated. ORM1, a glycoprotein, was significantly upregulated in both the aneurysm tissue and serum samples of unruptured IA patients. We employed a larger cohort of patients and validated ORM1 as a potential biomarker for screening of unruptured aneurysm using ELISA. Samples from ruptured aneurysm with vasospasm showed significant upregulation of MMP9 as compared to ruptured aneurysm without vasospasm. Using a cohort of ruptured aneurysm patients with and without vasospasm, we validated MMP9 as a potential biomarker for vasospasm. This study reveals pathophysiology underlying different clinical sub groups of IA and also suggests potential biomarkers.

neuroscience↗

bioRxiv2018

Regulation of ATM and ATR by SMARCAL1 and BRG1

The G2/M checkpoint is activated on DNA damage by the ATM and ATR kinases that are regulated by post-translational modifications. In this paper, the transcriptional co-regulation of ATM and ATR by SMARCAL1 and BRG1, both members of the ATP-dependent chromatin remodeling protein family, is described. SMARCAL1 and BRG1 co-localize on the promoters of ATM and ATR; downregulation of SMARCAL1/BRG1 results in transcriptional repression of ATM/ATR and therefore, overriding of the G2/M checkpoint leading to mitotic abnormalities. On doxorubicin-induced DNA damage, SMARCAL1 and BRG1 are upregulated and in turn, upregulate the expression of ATM/ATR.\n\nPhosphorylation of ATM/ATR is needed for the transcriptional upregulation of SMARCAL1 and BRG1, and therefore, of ATM and ATR on DNA damage. The regulation of ATM/ATR is rendered non-functional if SMARCAL1 and/or BRG1 are absent or if the two proteins are mutated such that they are unable to hydrolyze ATP, as in for example in Schimke Immuno-Osseous Dysplasia and Coffin-Siris Syndrome. Thus, an intricate transcriptional regulation of DNA damage response genes mediated by SMARCAL1 and BRG1 is present in mammalian cells.

molecular biology↗

bioRxiv2017

Identification and analysis of mobile genetic elements in Gibbon genome

Recent sequencing of genome of northern white-cheeked gibbon (Nomascus leucogenys) has provided important insight into fast evolution of gibbons and signatures relevant to gibbon biology. It was revealed that mobile genetic elements (MGE) seems to play major role in gibbon evolution. Here we report that most of the gibbon genome is occupied by the MGEs such as ALUs, MIRs, LINE1, LINE 2, LINE 3, ERVL, ERV-class1, ERV-class II and other DNA elements which include hAT Charlie and TcMar tigger. We provide detailed description and genome wide distribution of all the MGEs present in gibbon genome. Previously, it was reported that gibbon-specific retrotransposon (LAVA) tend to insert into chromosome segregation genes and alter transcription by providing a premature termination site, suggesting a possible molecular mechanism for the genome plasticity of the gibbon lineage. We show that insertion sites of LAVA elements present atypical signals/patterns which are different from typical signals present at insertion sites of Alu elements. This suggests possibility of distinct insertion mechanism used by LAVA elements for their insertions. We also find similarity in signals of LAVA elements insertion sites with atypical signals present at Alus /L1s insertion sites disrupting the genes leading to diseases such as cancer and Duchenne muscular dystrophy. This suggest role of LAVA in premature transcription termination.

bioinformatics↗

bioRxiv2017

Parallel loss of symbiosis genes in relatives of nitrogen-fixing non-legume Parasponia

Rhizobium nitrogen-fixing nodules are a well-known trait of legumes, but nodules also occur in other plant lineages either with rhizobium or the actinomycete Frankia as microsymbiont. The widely accepted hypothesis is that nodulation evolved independently multiple times, with only a few losses. However, insight in the evolutionary trajectory of nodulation is lacking. We conducted comparative studies using Parasponia (Cannabaceae), the only non-legume able to establish nitrogen fixing nodules with rhizobium. This revealed that Parasponia and legumes utilize a large set of orthologous symbiosis genes. Comparing genomes of Parasponia and its non-nodulating relative Trema did not reveal specific gene duplications that could explain a recent gain of nodulation in Parasponia. Rather, Trema and other non-nodulating species in the Order Rosales show evidence of pseudogenization or loss of key symbiosis genes. This demonstrates that these species have lost the potential to nodulate. This finding challenges a long-standing hypothesis on evolution of nitrogen-fixing symbioses, and has profound implications for translational approaches aimed at engineering nitrogen-fixing nodules in crop plants.

plant biology↗