Biology subjects

Kaur, B.

Publications and source records attributed to Kaur, B..

27 records · Page 2Linked to original sources

bioRxiv2024

The genomic trajectory of ovarian high grade serous carcinoma is determined in STIC lesions

Ovarian high-grade serous carcinoma (HGSC) originates in the fallopian tube, with secretory cells carrying a TP53 mutation, known as p53 signatures, identified as potential precursors. p53 signatures evolve into serous tubal intraepithelial carcinomas (STIC) lesions, which, in turn, progress into invasive HGSC that readily spread to the ovary and disseminate around the peritoneal cavity. We recently investigated the genomic landscape of early- and late-stage HGSC and found higher ploidy in late-stage (median 3.1) than early-stage (median 2.0) samples. Here, to explore whether the high ploidy and possible whole genome duplication observed in late-stage disease are determined early in the evolution of HGSC, we analysed archival formalin-fixed paraffin-embedded samples (FFPE) from five HGSC patients. p53 signatures and STIC lesions were laser-capture microdissected and sequenced using shallow whole genome sequencing (sWGS), while invasive ovarian/fallopian tube and metastatic carcinoma samples underwent macrodissection and were profiled using both sWGS and targeted next generation sequencing. Results showed highly similar patterns of global copy number change between STIC lesions and invasive carcinoma samples within each patient. Ploidy changes were evident in STIC lesions, but not p53 signatures, and there was strong correlation between ploidy in STIC lesions and invasive ovarian/fallopian tube and metastatic samples in each patient. The reconstruction of sample phylogeny for each patient from relative copy number indicated that high ploidy, when present, occurred early in the evolution of HGSC, which was further validated by copy number signatures in ovarian and metastatic tumours. These findings suggest that aberrant ploidy, suggestive of whole genome duplication, arises early in HGSC, and is detected in STIC lesions, implying that the trajectory of HGSC may be determined at the earliest stages of tumour development.

cancer biology↗

bioRxiv2023

Curcumin alleviates Arsenic trioxide-induced behavioural impairment, oxidative damage & morphological alterations in striatal region of mice brain

Arsenic-induced neurotoxicity is well-documented in literature and reported to have dose-dependent damaging effects in the mice brain. Curcumin, a cost-effective plant polyphenol, safely demonstrates protective effects against arsenic-induced neurotoxicity by modifying oxidative stress, apoptosis, and neurochemistry in rodents brain. The present study determined the neuroprotective potential of curcumin (CUR) on adverse effects induced by arsenic trioxide (As2O3) in mice striatal region. Healthy adult male mice were chronically administered with varying concentrations of As2O3 (2, 4 & 8 mg/kg bw) alone and along with CUR (100 mg/kg bw) via oral route for 45 days. Towards the end of experimental period, the animals were subjected to behavioural paradigm including open field task, novel object recognition, rota-rod and morris water maze. Fresh striatal tissues were collected from the animals on day 46 for biochemical analysis such as MDA, GPx and GSH. While perfusion fixed brains were processed for morphological observations. Behavioural study showed an apparent decrease in certain cognitive functions (learning and memory) and locomotor activity in mice exposed to As2O3 compared to controls. Simultaneous treatment of As2O3 (2, 4 & 8 mg/kg bw) and curcumin (100 mg/kg bw) alleviated the As-induced locomotor and cognitive deficits. As2O3 alone exposure also exhibited a significant increase in oxidative stress marker (MDA) and decrease in antioxidant enzyme levels (GPx, GSH). Morphological alterations were noted in mice subjected to elevated doses of As2O3 (4 & 8 mg/kg bw). However, these changes were reversed in mice who received As2O3 + CUR co-treatment. Together, our findings provide preliminary evidence that curcumin protects mice striatal region from As2O3-induced behavioral, biochemical and morphological alterations.

pharmacology and toxicology↗

bioRxiv2022

The lupus susceptibility allele DRB1*03:01 encodes a disease-driving epitope

The HLA-DRB1*03:01 allele is a major genetic risk factor in systemic lupus erythematosus (SLE), but the mechanistic basis of the association is unclear. Here we show that in the presence of interferon gamma (IFN-{gamma}), a short DRB1*03:01-encoded allelic epitope activates a characteristic lupus transcriptome in mouse and human macrophages. It also triggers a cascade of SLE-associated cellular aberrations, including endoplasmic reticulum stress, unfolded protein response, mitochondrial dysfunction, necroptotic cell death, and production of pro-inflammatory cytokines. Parenteral administration of IFN-{gamma} to naive DRB1*03:01 transgenic mice causes increased serum levels of anti-double stranded DNA antibodies, glomerular immune complex deposition and histopathological renal changes that resemble human lupus nephritis. This study provides evidence for a noncanonical, antigen presentation-independent mechanism of HLA-disease association in SLE and could lay new foundations for our understanding of key molecular mechanisms that trigger and propagate this devastating autoimmune disease.

immunology↗

bioRxiv2022

Time series analysis of SARS-CoV-2 genomes and correlations among highly prevalent mutations

The efforts of the scientific community to tame the recent SARS-CoV-2 pandemic seems to have been diluted by the emergence of new viral strains. Therefore, it becomes imperative to study and understand the effect of mutations on viral evolution, fitness and pathogenesis. In this regard, we performed a time-series analysis on 59541 SARS-CoV-2 genomic sequences from around the world. These 59541 genomes were grouped according to the months (January 2020-March 2021) based on the collection date. Meta-analysis of this data led us to identify highly significant mutations in viral genomes. Correlation and Hierarchical Clustering of the highly significant mutations led us to the identification of sixteen mutation pairs that were correlated with each other and were present in >30% of the genomes under study. Among these mutation pairs, some of the mutations have been shown to contribute towards the viral replication and fitness suggesting the possible role of other unexplored mutations in viral evolution and pathogenesis. Additionally, we employed various computational tools to investigate the effects of T85I, P323L, and Q57H mutations in Non-structural protein 2 (Nsp2), RNA-dependent RNA polymerase (RdRp) and Open reading frame 3a (ORF3a) respectively. Results show that T85I in Nsp2 and Q57H in ORF3a mutations are deleterious and destabilize the parent protein whereas P323L in RdRp is neutral and has a stabilizing effect. The normalized linear mutual information (nLMI) calculations revealed the significant residue correlation in Nsp2 and ORF3a in contrast to reduce correlation in RdRp protein.

bioinformatics↗

bioRxiv2022

Modeling of Aryl Hydrocarbon Receptor Pathway Intrinsic Immunometabolic Role using Glioblastoma Stem Cells and Patient-Derived Organoids

The intrinsic genetic program of glioblastoma (GBM) stem cells is critical for tumor evolution and recurrence. We recently identified intrinsic phenotypes and immune-like genetic programs of GBM organoids (GBMO)1 from patient derived glioblastoma stem cells (GSCs), replicating genomic, metabolic, and cellular aspects of GBM in vivo. Aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, is a key regulator of infiltrating immune cells in gliomas2, 3 and associated with poor prognosis, but its role in GSC biology is unknown2. Here, we show that AHR is a patient-specific regulator of the glioma intrinsic gene program in GSCs and GSC-derived GBMO that are enriched for AHR. We find that AHR is required for GSC self-renewal, GBMO expansion, radial glia-like cell proliferation, and expression of immune mediators seen in the mesenchymal subtype. CRISPR-Cas9 genetic ablation and pharmacological inhibition revealed that AHR regulates genes linked to intrinsic immunity, proliferation, and migration in GBMO. Genomic analysis of GBMO treated with AHR inhibitors identified expression signatures and candidate markers associated with survival of gliomas. Our work defines the glioma intrinsic function of AHR in a model of early GBM formation, offering a rationale for clinical exploration of a potential two-hit target of both GBM cells and infiltrating immune cells in patients with GBM expressing high levels of AHR.

cancer biology↗

bioRxiv2021

Homogeneity of antibody-drug conjugates critically impacts the therapeutic efficacy in brain tumors

Glioblastoma multiforme (GBM) is characterized by aggressive growth and the poorest prognosis of all brain tumor types. Most therapies rarely provide clinically meaningful improvements in outcomes of patients with GBM. Antibody-drug conjugates (ADCs) are emerging chemotherapeutics with stunning success in cancer management. Although promising, clinical studies of three ADCs for treating GBM, including Depatux-M, have been discontinued because of safety concerns and limited therapeutic benefits. Here, we report that ADC homogeneity is a critical parameter to maximize the therapeutic potential in GBM therapy. We demonstrate that homogeneous conjugates generated using our linker show enhanced drug delivery to intracranial brain tumors. Notably, compared to heterogeneous ADCs, including a Depatux-M analog, our ADCs provide greatly improved antitumor effects and survival benefits in orthotopic brain tumor models, including a patient-derived xenograft model of GBM. Our findings warrant the future development of homogeneous ADCs as promising molecular entities toward cures for intractable brain tumors.

bioengineering↗

bioRxiv2021

A novel binary k-mer approach for classification of coding and non-coding RNAs across diverse species

Classification among coding (CDS) and non-coding RNA (ncRNA) sequences is a challenge and several machine learning models have been developed for the same. Since the frequency of curated coding sequences is many-folds as compared to that of the ncRNAs, we devised a novel approach to work with the complete datasets from fifteen diverse species. In our proposed novel binary approach, we replaced all the As and Ts with 0s and Gs and Cs with 1s to obtain a binary form of coding and ncRNAs. The k-mer analysis of these binary sequences revealed that the frequency of binary patterns among the coding and ncRNAs can be used as features to distinguish among them. Using insights from these distinguishing frequencies, we used k-nearest neighbour classifier to classify among them. Our strategy is not only time-efficient but leads to significantly increased performance metrics including Matthews correlation coefficient (MCC) for some species like P. paniscus, M. mulatta, M. lucifugus, G. gallus, C. japonica, C. abingdonii, A. carolinensis, D. melanogaster and C. elegans when compared with the conventional ATGC approach. Additionally, we also show that the values of MCC obtained for diverse species tested on the model based on H. sapiens correlated with the geological evolutionary timeline thereby further strengthening our approach. Therefore, we propose that CDS and ncRNAs can be efficiently classified using "2-character" frequency as compared to "4-character" frequency of ATGC approach. Thus, our highly efficient binary approach can replace the more complex ATGC approach successfully.

genomics↗

bioRxiv2021

The genomic landscape of early stage ovarian high grade serous carcinoma

PurposeHigh grade serous carcinoma (HGSC) is the commonest type of ovarian cancer. Nearly all HGSC cases are diagnosed at late stage and it is not clear whether early stage HGSC has unique characteristics compared to late stage tumours. Experimental DesignWe analysed samples from 45 patients with FIGO stage I - IIA HGSC - 40 from the pathology archives of three large UK cancer centres and 5 from the BriTROC-1 study. We performed shallow whole genome sequencing (sWGS) and targeted next generation sequencing to investigate somatic mutations and copy number alterations. We compared results to 51 stage IIIC/IV HGSC patients from the BriTROC-1 study. ResultsThere was no difference in median age between the early stage (median 61.3 years, range 40-84) and late stage (median 62.3 years, range 34-76) patients at diagnosis. TP53 mutations were near-universal (92% early stage, 100% late stage samples) and there were no significant differences in the rates of other somatic mutations, including BRCA1 and BRCA2, or focal copy number alterations between early- and late-stage cohorts. There were also no unique amplifications or deletions in either cohort. However, median ploidy was greater in late stage (median 3.1) than early stage (median 2.0) samples. In addition, there were higher numbers of breakpoints per 10MB and per chromosome arm and higher absolute copy number in late stage than early stage cohorts; early stage samples had longer segment length. Overall copy number signature exposures were significantly different between early and late stage samples with greater signature 3 exposure in early stage and greater signature 4 in late stage. Both simplex plot and unsupervised hierarchical clustering suggested that a subset of late stage samples retain early stage appearances with high signature 3 and co-clustering with the early stage samples ConclusionsThese data suggest that there are no unique mutations or focal copy number alterations in early stage HGSC. However, whole genome duplication is significantly more common in late-stage disease, suggesting evolution during disease progression. However, a subset of late stage HGSC retains early-stage features, which are associated with improved overall survival.

cancer biology↗

bioRxiv2017

Persistent homology demarcates a leaf morphospace

Current morphometric methods that comprehensively measure shape cannot compare the disparate leaf shapes found in seed plants and are sensitive to processing artifacts. We explore the use of persistent homology, a topological method applied across the scales of a function, to overcome these limitations. The described method isolates subsets of shape features and measures the spatial relationship of neighboring pixel densities in a shape. We apply the method to the analysis of 182,707 leaves, both published and unpublished, representing 141 plant families collected from 75 sites throughout the world. By measuring leaves from throughout the seed plants using persistent homology, a defined morphospace comparing all leaves is demarcated. Clear differences in shape between major phylogenetic groups are detected and estimates of leaf shape diversity within plant families are made. This approach does not only predict plant family, but also the collection site, confirming phylogenetically invariant morphological features that characterize leaves from specific locations. The application of a persistent homology method to measure leaf shape allows for a unified morphometric framework to measure plant form, including shape and branching architectures.

plant biology↗