Biology subjects

Choudhary, S.

Publications and source records attributed to Choudhary, S..

42 records · Page 3Linked to original sources

bioRxiv2019

Integrated analyses of early responses to radiation in glioblastoma identify new alterations in RNA processing and candidate target genes to improve treatment outcomes

BackgroundHigh-dose radiation is the main component of glioblastoma therapy. Unfortunately, radio-resistance is a common problem and a major contributor to tumor relapse. Understanding the molecular mechanisms driving response to radiation is critical for identifying regulatory routes that could be targeted to improve treatment response. MethodsWe conducted an integrated analysis in the U251 and U343 glioblastoma cell lines to map early alterations in the expression of genes at three levels: transcription, splicing, and translation in response to ionizing radiation. ResultsChanges at the transcriptional level were the most prevalent response. Downregulated genes are strongly associated with cell cycle and DNA replication and linked to a coordinated module of expression. Alterations in this group are likely driven by decreased expression of the transcription factor FOXM1 and members of the E2F family. Genes involved in RNA regulatory mechanisms were affected at the mRNA, splicing, and translation levels, highlighting their importance in radiation-response. We identified a number of oncogenic factors, with an increased expression upon radiation exposure, including BCL6, RRM2B, IDO1, FTH1, APIP, and LRIG2 and lncRNAs NEAT1 and FTX. Several of these targets have been previously implicated in radio-resistance. Therefore, antagonizing their effects post-radiation could increase therapeutic efficacy. ConclusionsOur integrated analysis provides a comprehensive view of early response to radiation in glioblastoma. We identify new biological processes involved in altered expression of various oncogenic factors and suggest new target options to increase radiation sensitivity and prevent relapse.

cancer biology↗

bioRxiv2019

Deciphering the multi-scale mechanisms of Tephrosia purpurea against polycystic ovarian syndrome (PCOS) and its major psychiatric comorbidities: studies from network-pharmacological perspective

Tephrosia purpurea (T. purpurea), a plant belonging to Fabaceae (pea) family, is a well-known Ayurvedic herb and is commonly known as Sarapunkha in traditional Indian medicinal system. Described as \"Sarwa wranvishapaka\", i.e. having capability to heal all types of wounds, it is particularly recognized for its usage in splenomegaly. Towards exploring the comprehensive effects of T. purpurea against polycystic ovarian syndrome (PCOS), its phytochemicals were extensively reviewed and their network pharmacology evaluation is carried out in this study. The complex regulatory potential of its 76 phytochemicals (PCs) against PCOS are enquired by developing and analyzing high confidence tripartite networks of protein targets of each phytochemical at both pathway and disease association scales. We also developed a high-confidence human PPI sub-network specific to PCOS, explored its modular architecture and probed the drug-like phytochemicals (DPCs) having multi-module regulatory potential. The proteins belonging to endocrine system were identified as major targets of the PCs. The study reports 30 DPCs based on ADMET and drug-like properties. Multi-targeting and synergistic capacities of the 12 DPCs against 10 protein targets were identified and evaluated using molecular docking and interaction analyses. The study concludes by highlighting a couple of DPCs as potential sources of PCOS regulators.

systems biology↗

bioRxiv2019

Mapping person-to-person variation in viral mutations that escape polyclonal serum targeting influenza hemagglutinin

A longstanding question is how influenza evolves to escape human immunity, which is polyclonal and can target many distinct epitopes on the virus. Here we map how all amino-acid mutations to influenzas major surface protein affect viral neutralization by polyclonal human sera. The serum of some individuals is so focused that it selects single mutations that reduce viral neutralization by over an order of magnitude. However, different viral mutations escape the sera of different individuals. This individual-to-individual variation in viral escape mutations is not present among ferrets, which are frequently used as a model in influenza studies. Our results show how different single mutations help influenza escape the immunity of different members of the human population, a phenomenon that could shape viral evolution and disease susceptibility.

microbiology↗

bioRxiv2019

pysradb: A Python package to query next-generation sequencing metadata and data from NCBI Sequence Read Archive

NCBIs Sequence Read Archive (SRA) is the primary archive of next-generation sequencing datasets. SRA makes metadata and raw sequencing data available to the research community to encourage reproducibility, and to provide avenues for testing novel hypotheses on publicly available data. However, existing methods to programmatically access these data are limited. We introduce a Python package pysradb that provides a collection of command line methods to query and download metadata and data from SRA utilizing the curated metadata database available through the SRAdb project. We demonstrate the utility of pysradb on multiple use cases for searching and downloading SRA datasets. It is available freely at https://github.com/saketkc/pysradb.

bioinformatics↗

bioRxiv2018

Determining the link between alpha-gal-containing antigens in North American ticks and red meat allergy

Development of specific IgE antibodies to the oligosaccharide galactose--1, 3-galactose (-gal) following tick bites has been shown to be the source of red meat allergy. In this study, we investigated the presence of -gal in four tick species: the lone-star tick (Amblyomma americanum), the Gulf-Coast tick (Amblyomma maculatum), the American dog tick (Dermacentor variabilis), and the black-legged tick (Ixodes scapularis) by using a combination of immunoproteome, carbohydrate analysis, and basophil activation approaches. Using anti--gal antibodies, -gal was identified in the salivary glands of both Am. americanum and Ix. scapularis, while Am. maculatum and De. variabilis appeared to lack the sugar. PNGase F treatment confirmed the deglycosylation of N-linked -gal-containing proteins in tick salivary glands. Immunolocalization of -gal moieties to the salivary secretory vesicles of the salivary acini also confirmed the secretory nature of -gal-containing antigens in ticks. Am. americanum ticks were fed human blood (lacks -gal) using an artificial membrane feeding system to determine the source of -gal. N-linked glycan analysis revealed that Am. americanum and Ix. scapularis have -gal in their saliva and salivary glands, but Am. maculatum contains no detectable quantity. Salivary samples from Am. americanum and Ix. scapularis stimulated activation of basophils primed with plasma from -gal allergic subjects. Together, our data support the idea that bites from certain tick species may specifically create a risk for the development of -gal-specific IgE and hypersensitivity reactions in humans. Alpha-Gal syndrome challenges the current food allergy paradigm and broadens opportunities for future research.

immunology↗

bioRxiv2017

Expanding primary cells from mucoepidermoid and other salivary gland neoplasms for genetic and chemosensitivity testing

Restricted availability of cell and animal models is a rate-limiting step for investigation of salivary gland neoplasm pathophysiology and therapeutic response. Conditionally reprogrammed cell (CRC) technology enables establishment of primary epithelial cell cultures from patient material. This study tested a translational workflow for acquisition, expansion and testing of CRC-derived primary cultures of salivary gland neoplasms from patients presenting to an academic surgical practice. Results showed cultured cells were sufficient for epithelial cell-specific transcriptome characterization to detect candidate therapeutic pathways and fusion genes in addition to screening for cancer-risk-associated single nucleotide polymorphisms (SNPs) and driver gene mutations through exome sequencing. Focused study of primary cultures of a low-grade mucoepidermoid carcinoma demonstrated Amphiregulin-Mechanistic Target of Rapamycin-AKT/Protein kinase B (AKT) pathway activation, identified through bioinformatics and subsequently confirmed as present in primary tissue and preserved through different secondary 2D and 3D culture media and xenografts. Candidate therapeutic testing showed that the allosteric AKT inhibitor MK2206 reproducibly inhibited cell survival across different culture formats. In contrast, the cells appeared resistant to the adenosine triphosphate competitive AKT inhibitor GSK690693. Procedures employed here illustrate an approach for reproducibly obtaining material for pathophysiological studies of salivary gland neoplasms, and other less common epithelial cancer types, that can be executed without compromising pathological examination of patient specimens. The approach permits combined genetic and cell-based physiological and therapeutic investigations in addition to more traditional pathologic studies and can be used to build sustainable bio-banks for future inquiries.

cancer biology↗