Biology subjects

Haque, M. R.

Publications and source records attributed to Haque, M. R..

6 recordsLinked to original sources

bioRxiv2023

TGF-β blockade drives a transitional effector phenotype in T cells reversing SIV latency and decreasing SIV reservoirs in vivo

HIV-1 persistence during ART is due to the establishment of long-lived viral reservoirs in resting immune cells. Using an NHP model of barcoded SIVmac239 intravenous infection and therapeutic dosing of the anti-TGFBR1 inhibitor galunisertib (LY2157299), we confirmed the latency reversal properties of in vivo TGF-{beta} blockade, decreased viral reservoirs and stimulated immune responses. Eight SIV-infected macaques on ART were treated with four 2-week cycles of galunisertib. ART was discontinued 3 weeks after the last dose, and macaques euthanized 6 weeks after ART-interruption (ATI). 7 out of 8 macaques rebounded between week 2 and 6 post-ATI. Galunisertib led to viral reactivation as indicated by plasma viral load and immunoPET/CT with 64Cu-DOTA-F(ab)2-p7D3-probe. A decrease in cell-associated (CA-)SIV DNA was detected in lymph nodes, gut and PBMC, while intact pro-virus in PBMC decreased by 3-fold. No systemic increase in inflammatory cytokines was observed. High-dimensions cytometry, bulk, and single-cell (sc)RNAseq revealed a shift toward an effector phenotype in T and NK cells characterized by a progressive downregulation in TCF1. In summary, we demonstrated that galunisertib, a clinical stage TGF-{beta} inhibitor, reverses SIV latency and decreases SIV reservoirs by driving T cells toward an effector phenotype, enhancing immune responses in vivo in absence of toxicity. One-sentence summaryTGF-{beta} blockade drives an effector phenotype in immune cells leading to SIV latency reversal and enhanced immune responses in vivo.

immunology↗

bioRxiv2023

A Robust Combination Test Using the Normal Distribution, with Application to Phylogenetic Inference

Combination tests are used to combine P-values from individual studies to test a global null hypothesis. These types of tests can also be applied to combine P-values from testing separate null hypotheses within the same study in cases for which the procedure for testing a global null hypothesis is unavailable. One such application of a combination test is to detect the presence of hybrid species within a set of species. Although many combination tests have been proposed in the literature, there is no uniformly most powerful test applicable for all conditions. For instance, in the hybrid detection application, it is expected that only a few of the species within a set species might have truly arisen via hybridization, and thus when tested, only a few of the individual P-values are expected to be significant. Thus, a desirable property of a combination test for this situation is to be able to reject the global null hypothesis even if only a small fraction of the individual P-values are significant. In this paper, we propose a new combination test based on the normal distribution that assigns weight to each test adaptively, thereby providing powerful results even when only a small fraction of the individual null hypotheses are false. A comprehensive simulation study, as well as real data applications, demonstrate that the proposed test is powerful in detecting false global null hypotheses under several situations for which existing tests have low power.

genetics↗

bioRxiv2023

A global test of hybrid ancestry fromgenome-scale data

Methods based on the multi-species coalescence have been widely used in phylogenetic tree estimation using genome-scale DNA sequence data to understand the underlying evolutionary relationship between the sampled species. Evolutionary processes such as hybridization, which creates new species through interbreeding between two different species, necessitate inferring a species network instead of a species tree. A species tree is strictly bifurcating and thus fails to incorporate hybridization events which require an internal node of degree three. Hence, it is crucial to decide whether a tree or network analysis should be performed given a DNA sequence data set, a decision that is based on the presence of hybrid species in the sampled species. Although many methods have been proposed for hybridization detection, it is rare to find a technique that does so globally while considering a data generation mechanism that allows both hybridization and incomplete lineage sorting. In this paper, we consider hybridization and coalescence in a unified framework and propose a new test that can detect whether there are any hybrid species in a given set of species. We propose that based on this global test of hybridization, one can decide whether a tree or network analysis is appropriate for a given data set.

bioinformatics↗

bioRxiv2023

Effects of phylogenetic variation on prioritization of species for conservation

Many questions in evolutionary biology require the specification of a phylogeny for downstream phylogenetic analyses. However, with the increasingly widespread availability of genomic data, phylogenetic studies are often confronted with conflicting signal in the form of genomic heterogeneity and incongruence between gene trees and the species tree. This raises the question of determining what data and phylogeny should be used in downstream analyses, and to what extent the choice of phylogeny (e.g., gene trees versus species trees) impacts the analyses and their outcomes. In this paper, we study this question in the realm of phylogenetic diversity indices, which provide ways to prioritize species for conservation based on their relative evolutionary isolation on a phylogeny, and are thus one example of downstream phylogenetic analyses. We use the Fair Proportion (FP) index, also known as the evolutionary distinctiveness score, and explore the variability in species rankings based on gene trees as compared to the species tree for several empirical data sets. Our results indicate that prioritization rankings among species vary greatly depending on the underlying phylogeny, suggesting that the choice of phylogeny is a major influence in assessing phylogenetic diversity in a conservation setting. While we use phylogenetic diversity conservation as an example, we suspect that other types of downstream phylogenetic analyses such as ancestral state reconstruction are similarly affected by genomic heterogeneity and incongruence. Our aim is thus to raise awareness of this issue and inspire new research on which evolutionary information (species trees, gene trees, or a combination of both) should form the basis for analyses in these settings.

evolutionary biology↗

bioRxiv2022

Epstein-Barr virus nuclear antigen proteins deploy diverse mechanisms to bind the human genome

Viral transcription factors (vTFs) are known to bind the human genome and impact critical biological processes. However, a vTF can infect multiple cell-types, and the extent to which they deploy the same mechanisms for DNA binding across different cell-types is poorly understood. We used the Epstein-Barr virus Nuclear Antigen Proteins 2 and 3 (EBNA2 and EBNA3) to address this gap, the two widely studied vTFs associated with cancers, as case studies. We analyze multiple ChIP-seq datasets of these vTFs from different human cell-lines using a state-of-the-art convolutional neural network model. We show that each vTF uses both cell-type specific and cell-type independent cofactors to bind the human genome. Interestingly, each vTF requires [~]10 cofactors consistently across all binding peaks. Such dependency on a large number of cofactors is in contrast to human TFs since human TFs typically co-bind with 2-3 cofactors. Our de novo motif finding approach also reveals novel sequence motifs at the ChIP peaks of these vTFs. These critical signals were missed by previous studies doing enrichment analysis using known human TFs. Finally, we find that although a vTF impacts similar biological processes across cell-types, it also impacts distinct biological processes in a cell-type specific manner. Our study provides a roadmap for integrative analysis of vTF binding and pinpointing their diverse mechanisms of targeting the human genome across different human cell-types.

genomics↗

bioRxiv2020

Phytochemical screening of Colocasia gigantea and Colocasia affinis (Family: Araceae) using 1H-NMR and 13C-NMR techniques

Colocasia affinis and Colocasia gigantea are two of commonly found species under Colocasia genus. Folkloric use of these plants ascertains their ethnopharmacological importance and these plants are eaten as vegetables in several regions all around the world while Colocasia gigantea has planted as an ornamental plant too. Phytochemical screening of dichloromethane fractions of these plants using several separation techniques along followed by 1H-NMR and 13C-NMR techniques provide flavonoids and some other phyto compounds. However, in total 7 compounds were isolated from these plants i.e. penduletin (1), 7,8 -(3",3"-dimethyl-pyrano)-4-hydroxy flavonol (2), mixture of 7,8 -(3,3-dimethyl-pyrano)-4-hydroxy flavonol from C. affinis and mixture of -amyrin and {beta}-amyrin (3), penduletin (5), monoglyceride of stearic acid (6) from C. gigantea.

plant biology↗