Biology subjects

Vijayan, D.

Publications and source records attributed to Vijayan, D..

3 recordsLinked to original sources

bioRxiv2026

Alternative promoters used during myeloid differentiation and upon activation change the gene products available for innate immune programs.

Macrophages are innate immune cells present in most tissues of the body, whose molecular programs are determined by their ontogeny and environment. From the earliest stages of embryonic development, macrophages are recruited into developing tissues where they support organogenesis with trophic factors such as WNT, VEGF and PDGF. While macrophage subsets have been described in different tissues at single cell resolution, little is known about transcript isoforms and proteoforms that underpin their differentiation and function. Here we assessed enhancer, promoter, transcript and proteomic variation as pluripotent stem cells differentiate to macrophages, identifying over 200 previously uncharacterised genes and over 20,000 new mRNA isoforms, updating our current understanding of the human genome, its regulation and potential output. Newly discovered myeloid-expressed transcripts and proteins were enriched for motifs associated with secreted proteins, and these included previously uncharacterised isoforms of growth factors, in which we predict N-terminal changes impact on their location and function. Activation of primary adult monocytes and monocyte-derived macrophages was also characterised by the expression of diverse transcript isoforms, largely arising from alternate transcription initiation sites and predicted to impact on the acute response to bacterial or fungal stimuli. Understanding the full spectrum of gene products expressed by these cells further extends our understanding of the phenotypic plasticity and trophic potential of macrophages in human development and may lead to the discovery of new clinical targets for tissue engineering or immune-related studies. Graphical AbstractIn this manuscript, Berrocal-Rubio and colleagues examined the differentiation of human macrophages using an iPSC model of tissue macrophage biology. Combining long-read sequencing technology with promoter profiling identified over 17, 700 genes implicated in pluripotency-myeloid specification. 7% of transcripts profiled from previously characterised genes were predicted to encode new proteins, and a further 3% of transcripts were derived from genes newly discovered in this project. They confirmed that a high proportion of these alternate transcripts were detectable in primary monocytes but also discovered that activation of primary monocytes led to further alternate promoter usage, with the potential to further diversify the innate immune responses to a broad set of pathogens. The newly described macrophage genes and transcripts encoded proteins enriched for motifs associated with secreted peptides. These data suggest that alternate transcription of macrophage genes leads to new effectors of innate immune function, that include a substantially expanded number of growth factors or secreted proteins. Created in BioRender. Berrocal, M. (2025) https://BioRender.com/d0n47le O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=193 SRC="FIGDIR/small/703142v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@454cf0org.highwire.dtl.DTLVardef@1be28e8org.highwire.dtl.DTLVardef@16fb2e8org.highwire.dtl.DTLVardef@4aca30_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2024

Improving the accuracy of pose prediction by incorporating symmetry-related molecules

Accurate prediction of biologically relevant binding poses is crucial for the success of computer-aided drug development. In this study, we describe a general strategy to enhance the precision of pose prediction in molecular docking by incorporating symmetry-related molecules (SRMs). Our objective was to demonstrate the significant impact of SRMs on the accuracy of pose prediction. To achieve this, we evaluated our method on high-quality protein-ligand complex structures, focusing on the presence and absence of SRMs during molecular docking studies. We have extracted the co-crystal ligands from the selected crystal structure and were redocked in presence and absence of SRM to assess their influence. Additionally, we calculated the free energy of the docked poses using the Molecular Mechanics Generalized Born Surface Area (MM-GBSA) method, comparing the results in the presence and absence of SRMs. The findings revealed that redocking performed in the presence of SRMs significantly improved the prediction of biologically significant/crystallographically relevant poses. Consequently, our proposed strategy offers a robust method for enhancing pose prediction in current molecular docking programs, potentially leading to more effective and reliable drug development processes.

bioinformatics↗

bioRxiv2021

Neuroprotective derivatives of tacrine that target NMDA receptor and acetyl cholinesterase - Design, synthesis and biological evaluation

The complex and multifactorial nature of neuropsychiatric diseases demands multi-target drugs that can intervene with various sub-pathologies underlying disease progression. Targeting the impairments in cholinergic and glutamatergic neurotransmissions with small molecules has been suggested as one of the potential disease-modifying approaches for Alzheimers disease (AD). Tacrine, apotent inhibitor of acetylcholinesterase (AChE) is the first FDA approved drug for the treatment of AD. Tacrine is also a low affinity antagonist of N-methyl-D-aspartate receptor (NMDAR). However, tacrine was withdrawn from its clinical use later due to its hepato-toxicity. With an aim to develop novel high affinity multi-target directed ligands (MTDLs) against AChE and NMDAR, with reduced hepatotoxicity, we performed in silico structure-based modifications on tacrine, chemical synthesis of the derivatives and in vitro validation of their activities. Nineteen such derivatives showed inhibition with IC50 values in the range of 18.53{+/-}2.09 to 184.09{+/-}19.23 nM against AChE and 0.27{+/-}0.05 to 38.84{+/-}9.64 M against NMDAR. Some of the selected compounds also protected rat primary cortical neurons from glutamate induced excitotoxicity. Two of the tacrine derived MTDLs, 201 and 208 exhibited in vivo efficacy in rats by protecting against behavioral impairment induced by administration of the excitotoxic agent, monosodium glutamate. Additionally, several of these synthesized compounds also exhibited promising inhibitory activities against butyrylcholinesterase and {beta}-secretase. Given the therapeutic potential of MTDLs in disease-modifying therapy, our studies revealed several promising MTDLs of which 201 appears to be a potential candidate for immediate preclinical and clinical evaluations.

neuroscience↗