Biology subjects

Hamid, R.

Publications and source records attributed to Hamid, R..

8 recordsLinked to original sources

bioRxiv2026

Inhibition of Stemness Pathways during Acute SIV Limits Infection of Central Memory CD4+ T Cells and Alters Viral Reservoir Activity in Macaques

The establishment of a reservoir of latently infected CD4+ T cells that persist on antiretroviral therapy (ART) through proliferation represents the main barrier to HIV cure. Here, we evaluated in macaques a therapeutic approach targeting Wnt and Notch pathways that regulate T cell proliferation and differentiation during acute SIV infection, when the viral reservoir is seeded. The combination of PRI-724 and LY3039478 led to reprogramming of central memory CD4+ T cells away from quiescence and stemness toward a metabolically active effector profile resulting in reduced infection of central memory CD4+ T cells. Following sustained ART, levels of SIV RNA in CD4+ T cells were higher in the PRI-724 + LY3039478-treated group compared to controls, although SIV DNA was similar. These findings suggest that stemness pathway inhibition promotes memory T cell differentiation leading to a more transcriptionally active reservoir and has potential to synergize with "shock-and-kill" approaches to reduce HIV persistence.

microbiology↗

bioRxiv2024

IspE Kinase as an Anti-infective Target: Role of a Hydrophobic Pocket in Inhibitor Binding

Enzymes of the methylerythritol phosphate (MEP) pathway are potential targets for antimicrobial drug discovery. Here we focus on 4-diphosphocytidyl-2-C-methyl-D-erythritol (IspE) kinase from the MEP pathway. We use biochemical and structural biology methods to investigate homologs from the pathogenic microorganisms; Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii. We determined the X-ray structures of IspE-inhibitor complexes and studied selected inhibitors binding modes targeting the substrate pocket. The experimental results indicate the need for distinct inhibitor strategies due to structural differences among IspE homologs, particularly for A. baumannii IspE, which displays unique inhibitory profile due to a tighter hydrophobic subpocket in the substrate binding site. This study enhances our understanding of the MEP enzymes and sets the stage for structure-based drug design of selective inhibitors to combat pathogenic microorganisms.

biophysics↗

bioRxiv2023

Multigenerational inheritance of parasitic stress memory in Drosophila melanogaster

Organisms sense harmful environmental conditions and employ strategies to safeguard themselves. Moreover, they can communicate this experience to the next generation or beyond via non-DNA sequence-based mechanisms, referred to as intergenerational or transgenerational epigenetic inheritance, respectively. Using a specialist larval parasitoid, Leptopilina boulardi, and its host, Drosophila melanogaster, we show that the parental experience of parasitic stress results in an increased survivability of the immediate offspring of the host. Furthermore, we observe that the increased survivability in response to the parasitic stress is transmitted transgenerationally where the grandparents have been exposed to the parasitoid but not the parents. The increased survivability is primarily inherited through male parents, and at least one of the forms of the memory is better immune priming at larval stage. Our study suggests that the stress exposure during the pre-adult stage of the host has lifetime benefits for its progeny to deal with the future parasitic attack.

genetics↗

bioRxiv2022

Structural analysis of 1-deoxy-D-xylulose 5-phosphate synthase from Pseudomonas aeruginosa and Klebsiella pneumoniae reveals conformational changes upon cofactor binding

Isoprenoid precursor biosynthesis is an essential part of primary metabolism in all living organisms. While eukaryotes utilize the mevalonate (MEV) pathway for isoprenoid-precursor biosynthesis, the most important bacterial pathogens rely on the methylerythritol-phosphate (MEP) pathway. Therefore, enzymes involved in the MEP pathway are potentially valuable targets for the development of novel antibacterials to tackle the current antimicrobial resistance crisis. Within the MEP pathway, the enzyme 1-deoxy-D-xylulose-5-phosphate synthase (DXPS) represents a crucial, rate-limiting first step and a branch point in the biosynthesis of the vitamins B1 and B6. Herein, we present two novel, high-resolution DXPS crystal structures of the important ESKAPE pathogens Pseudomonas aeruginosa and Klebsiella pneumoniae in both the co-factor-bound and apo forms. We demonstrate that the absence of the cofactor ThDP leads to a disordered loop close to the active site and may be important for the design of potent DXPS inhibitors, albeit being different in both structures. In addition, we report the complex structure of paDXPS with a fluoropyruvate adduct, shedding more light on the structural basis of DXPS catalysis. Lastly, we have determined a complex structure of paDXPS with a thiamine analogue, opening up a route for structure-based drug design of this essential enzyme of the MEP pathway.

molecular biology↗

bioRxiv2020

Choline Transporter regulates olfactory habituation via a neuronal triad of excitatory, inhibitory and mushroom body neurons

Choline is an essential component of Acetylcholine (ACh) biosynthesis pathway which requires high-affinity Choline transporter (ChT) for its uptake into the presynaptic terminals of cholinergic neurons. Previously, we reported a predominant expression of ChT in memory processing and storing region of Drosophila brain called mushroom bodies (MB). It is unknown how ChT contributes to the functional principles of MB operation. Here, we demonstrate the role of ChT in non-associative form of learning, Habituation. Odour driven habituation traces are laid down in ChT dependent manner in antennal lobes (AL), projection neurons (PN) and MB. We observed that reduced habituation due to knockdown of ChT in MB causes hypersensitivity towards odour, suggesting that ChT also regulates incoming stimulus suppression. Importantly, we show for the first time that ChT is not unique to cholinergic neurons but is also required in inhibitory GABAergic neurons to drive habituation behaviour. Our results support a model in which ChT regulates both habituation and incoming stimuli through multiple circuit loci via an interplay between excitatory and inhibitory neurons. Strikingly, the lack of ChT in MB recapitulates major features of Autism spectrum disorders (ASD) including attenuated habituation, sensory hypersensitivity as well as defective GABAergic signalling. Our data establish the role of ChT in habituation learning and suggest that its dysfunction may contribute to neuropsychiatric disorders like ASD.

neuroscience↗

bioRxiv2020

Identifying digenic disease genes using machine learning in the undiagnosed diseases network

Rare diseases affect hundreds of millions of people worldwide, and diagnosing their genetic causes is challenging. The Undiagnosed Diseases Network (UDN) was formed in 2014 to identify and treat novel rare genetic diseases, and despite many successes, more than half of UDN patients remain undiagnosed. The central hypothesis of this work is that many unsolved rare genetic disorders are caused by multiple variants in more than one gene. However, given the large number of variants in each individual genome, experimentally evaluating even just pairs of variants for potential to cause disease is currently infeasible. To address this challenge, we developed DiGePred, a random forest classifier for identifying candidate digenic disease gene pairs using features derived from biological networks, genomics, evolutionary history, and functional annotations. We trained the DiGePred classifier using DIDA, the largest available database of known digenic disease causing gene pairs, and several sets of non-digenic gene pairs, including variant pairs derived from unaffected relatives of UDN patients. DiGePred achieved high precision and recall in cross-validation and on a held out test set (PR area under the curve >77%), and we further demonstrate its utility using novel digenic pairs from the recent literature. In contrast to other approaches, DiGePred also appropriately controls the number of false positives when applied in realistic clinical settings like the UDN. Finally, to facilitate the rapid screening of variant gene pairs for digenic disease potential, we freely provide the predictions of DiGePred on all human gene pairs. Our work facilitates the discovery of genetic causes for rare non-monogenic diseases by providing a means to rapidly evaluate variant gene pairs for the potential to cause digenic disease.

bioinformatics↗

bioRxiv2018

Choline Transporter in α/β core neurons of Drosophila mushroom body non-canonically regulates pupal eclosion and maintains neuromuscular junction integrity

Insect mushroom bodies (MB) have an ensemble of synaptic connections well-studied for their role in experience-dependent learning and several higher cognitive functions. MB requires neurotransmission for an efficient flow of information across synapses with the different flexibility to meet the demand of the dynamically changing environment of an insect. Neurotransmitter transporters coordinate appropriate changes for an efficient neurotransmission at the synapse. Till date, there is no transporter reported for any of the previously known neurotransmitters in the intrinsic neurons of MB. In this study, we report a highly enriched expression of Choline Transporter (ChT) in Drosophila MB. We demonstrate that knockdown of ChT in a sub-type of MB neurons called /{beta} core (/{beta}c) neurons leads to eclosion failure, peristaltic defect in larvae, and altered NMJ phenotype. These defects were neither observed on knockdown of proteins of the cholinergic locus in /{beta}c neurons nor by knockdown of ChT in cholinergic neurons. Thus, our study provides insights into non-canonical roles of ChT in MB.

developmental biology↗

bioRxiv2018

Programmatic Detection of Diploid-Triploid Mixoploidy via Whole Genome Sequencing

PurposeMixoploidy is a type of mosaicism where an organism is a mixture of cells with different numbers of chromosomes. There are a broad range of phenotypes associated with mixoploidy that vary greatly depending on the fraction of cells that are non-diploid, their chromosome number, their distribution, and presumably the specific variation present in the patient. Clinical detection of mixoploidy is important for diagnosis.\n\nMethodsWe developed a method to detect mixoploidy from clinical whole genome sequencing (WGS) data through the identification of excess of variant calls centered on unusual B-allele frequencies. Our method isolates the signal from these variants using trio calls and then solves a basic linear equation to estimate levels of diploid-triploid mixoploidy within the sample.\n\nResultsWe show that our method reflects the results from a cytogenetic test. We provide examples detailing how our method has been used to identify diploid-triploid mixoploid individuals from within the NIH Undiagnosed Diseases Network. We present confirmatory findings obtained by clinical cytogenetic testing and show that our method can be used to identify the diploid-triploid ratio in these cases.\n\nConclusionWGS data from patients with rare diseases can be used to identify mixoploid individuals. Individuals with certain characteristics as discussed should be tested for mixoploidy as part of standard clinical pipeline procedures. Scripts that perform this calculation are publicly available at https://github.com/HudsonAlpha/mixoviz.

genomics↗