Biology subjects

Panchal, P.

Publications and source records attributed to Panchal, P..

3 recordsLinked to original sources

bioRxiv2025

Identifying mood instability and circadian rest-activity patterns using digital remote monitoring and actigraphy in participants at risk for bipolar disorder

Mood instability and circadian rhythm disruptions are both of increasing interest with regard to a number of psychiatric disorders, notably bipolar disorder (BD), but understanding of their nature and their interrelationship are incomplete. By definition, both have an integral temporal component and, as such, measuring them longitudinally and remotely is desirable. We conducted the Cognition and Mood Evolution across Time (COMET) study to assess the feasibility and value of digital devices to capture mood, its instability, and daily rest-activity patterns, over a 10-week period, in two groups of participants. The first group (n=37) were selected as scoring >7 on the Mood Disorder Questionnaire (MDQ) ( high MDQ), thereby having a history of mood elevation and being at risk for BD. They were compared with a group (n=37) scoring <5 on the MDQ ( low MDQ). Over a 10-week period, using a tablet, mood was rated daily, clinical ratings of depression, mania, and anxiety were captured weekly via the True Colours app, and a GENEactiv actigraph was worn to capture rest-activity pattern data. The main findings are that (1) MDQ score predicts mood instability; (2) high MDQ score is associated with more negative affect and mood symptoms than people with low MDQ, and with a different circadian activity profile; and (3) mood instability and circadian indices appear uncorrelated. The implications are that (1) remote monitoring of these domains is feasible and valuable; (2) selection of participants based on MDQ score is useful for studying mood (in)stability; and (3) the approach has potential for studies of clinical populations and for experimental medicine studies assessing interventions to reduce mood instability.

neuroscience↗

bioRxiv2022

How Aberrant N-Glycosylation Can Alter Protein Functionality and Ligand Binding: an Atomistic View

Protein assembly defects due to enrichment of aberrant conformational variants of proteins are emerging as a new frontier in therapeutics design. Understanding, atomistically, structural elements that remodel the energy landscape of proteins, with the consequence of rewiring the conformational dynamics of proteins and pathologically perturbing functionally-oriented ensembles, is key for development of inhibitors. This is particularly relevant for molecular chaperones, hub proteins for the assembly of large multiprotein complexes, where enrichment of aberrant conformers can have a large impact on the cellular proteome, and in turn, on phenotypes. Here, we integrate computational and experimental tools to unveil how N-glycosylation of specific residues in glucose-regulated protein 94 (GRP94) modulates internal dynamics and alters the conformational fitness of regions fundamental for interaction with the nucleotide and synthetic ligands, and impacts substructures dedicated to recognition of interacting proteins. We show how N-glycosylation plays an active role in modulating the energy landscape of the protein, with specific glycosylation patterns determining specific functionally-oriented dynamic signatures. Our results provide support for leveraging the structural-dynamics knowledge on distinct glycosylation variants to design molecules targeting GRP94 disease-associated conformational states and assemblies. Since glycosylation is the most abundant form of post-translational modification, our results and mechanistic models can readily be transferred to other targets and contexts for cancers and other diseases.

biochemistry↗

bioRxiv2017

Systems biology analysis of mitogen activated protein kinase inhibitor resistance in malignant melanoma

Kinase inhibition in the mitogen activated protein kinase (MAPK) pathway is a standard therapy for cancer patients with activating BRAF mutations. However, the anti-tumorigenic effect and clinical benefit are only transient, and tumors are prone to treatment resistance and relapse. To elucidate mechanistic insights into drug resistance, we have established an in vitro cellular model of MAPK inhibitor resistance in malignant melanoma. The cellular model evolved in response to clinical dosage of BRAF inhibitor, vemurafenib, PLX4032. We profiled transcriptomic changes using RNA-Seq and RT-qPCR arrays. Pathways of melanogenesis, MAPK signaling, cell cycle, and metabolism were significantly enriched among the set of differentially expressed genes of vemurafenib-resistant cells vs control. The transcriptomic changes were validated in two distinct melanoma models, SK-MEL-28 and A375. Both cell lines have activating BRAF mutations and display metastatic potential. Downregulation of tumor suppressors and negative MAPK regulators, dual specific phosphatases, reengages mitogenic signaling. Upregulation of growth factors or cytokine receptors triggers signaling pathways circumventing BRAF blockage. Changes in amino acid and one-carbon metabolism support cellular proliferation despite MAPK inhibitor treatment. In addition, an upregulation of pigmentation in inhibitor resistant melanoma cells was observed. Cellular pathways utilized during inhibitor resistance promoted melanogenesis, a pathway which partially overlaps with MAPK signaling. Upstream regulator analysis suggested gene expression changes of forkhead box and hypoxia inducible factor family transcription factors. The established cellular models offer mechanistic insight into cellular changes and therapeutic targets under inhibitor resistance in malignant melanoma. At a systems biology level, the MAPK pathway undergoes major rewiring while acquiring inhibitor resistance. The outcome of this transcriptional plasticity is selection for a set of transcriptional master regulators, which circumvent upstream targeted kinases and provide alternative routes of mitogenic activation. A fine-woven network of redundant signals maintains similar effector genes allowing for tumor cell survival and malignant progression in therapy resistant cancer.

systems biology↗