Biology subjects

Mandal, B.

Publications and source records attributed to Mandal, B..

4 recordsLinked to original sources

bioRxiv2023

ACSL4 activity drives TNBC metastasis by positively regulating Histone H3 Acetylation mediated SNAIL expression

Triple-Negative Breast Cancer (TNBC) has profound unmet medical need globally for its devastating clinical outcome associated with rapid metastasis and lack of targeted therapies. Recently, lipid metabolic reprogramming has emerged as a major driver of breast cancer metastasis. Here, we unveil a strong association between the heightened expression of fatty acid metabolic enzyme, acyl-CoA synthetase 4 (ACSL4) and TNBC, which is primarily attributed by the selective absence of progesterone receptor (PR). Loss of ACSL4 function, either through genetic ablation or pharmacological inhibition significantly reduces metastatic potential of TNBC. Global transcriptome analysis reveals that ACSL4 activity markedly influences the gene expression pattern associated with TNBC migration. Mechanistically, ACSL4 alters fatty acid oxidation (FAO) and cellular acetyl-CoA levels, leading to the hyper-acetylation of particularly H3K27Ac and H3K9Ac marks resulting in overexpression of SNAIL during the course of TNBC metastatic spread to lymph node and lungs. Further, human TNBC metastasis exhibits positive correlation between ACSL4 and SNAIL expression. Altogether, our findings provide new molecular insights regarding the intricate interplay between metabolic alterations and epigenetic modifications, intertwined to orchestrate TNBC metastasis and posit a rational understanding for the development of ACSL4 inhibitors as a targeted therapy against TNBC.

cancer biology↗

bioRxiv2023

The Role of Binding Site Specificity in the Disaggregation of Aβ42 Fibrils through a Synthetic Paratope

Amyloid-{beta} (A{beta}) fibrils are the characteristic hallmark of Alzheimers disease(AD), and most drug development approaches for AD are focused on preventing and reversing the formation of these fibrillar aggregates. Previous studies show that synthetic antibodies have demonstrated great potential to inhibit the A{beta} aggregation and disaggregate the preformed A{beta} fibrils. Here, we perform explicit molecular dynamics(MD) simulation to elucidate the molecular mechanism of disaggregation of preformed LS-shaped A{beta}42 protofibril with a flexible, hairpin-like synthetic paratope (SP) which, in a recent experimental study, has shown promising results. Our simulations demonstrate various potential binding sites for SP on A{beta}42 protofibril. However, binding of SP at the amyloidogenic core region (KLVFF) shows pronounced structural disruption of A{beta}42 protofibril. Our results show heavy loss of {beta} sheet content, dismantling of K28-A42 salt bridge, and destruction of key contacts in the hydrophobic cores of A{beta}42 protofibril in the presence of SP. We found the aromatic and hydrophobic residues of A{beta}42 protofibril participating primarily in the binding with SP. Also, we found that{pi} -{pi} stacking and hydrophobic interactions are the most dominant mode of interaction between SP and A{beta}42 protofibril. This work provides a detailed atomistic perspective on the A{beta}42 protofibril disaggregation mechanism with SP, and the findings can help develop more effective drugs for AD in the future.

biophysics↗

bioRxiv2023

Avifaunal Species diversity from Southern West part of West Bengal, India

Birds are essential for stabilizing the balance between various ecosystems. To estimate their diversity, we studied species distribution and made an annotated checklist along with their feeding habitats in the Southwest part of West Bengal, India. We studied the bird diversity using the point count method on various habitats, including agroforest, grassland, sub-tropical forest, and plateau forest regions. A total of 343 species were identified during our study period (2015-2019). We found high species diversity and sightings in the study sites, with 55 new records for the region. The whole study was conducted using a citizen science approach and amateur bird watchers community. This study will emphasize the future biodiversity conservation practice for the avifauna.

ecology↗

bioRxiv2020

Pro-drug peptide and its metabolites disrupt amyloid fibrils by destabilizing salt bridge interaction and planar beta-sheet topology

The most common age-related neurodegenerative disorder, Alzheimers disease, is clinically characterized by continuous neuronal loss resulting in loss of memory and dementia with no cure to date. Amyloid-{beta} (A{beta}) aggregates and tau protein are believed to be the causative agents of this pathogenesis. In the present study, we have investigated the effect of the Pro-Drug peptide (PDp) and its metabolites (-aspartyl & {beta}-aspartyl) on the A{beta} aggregates using atomistic molecular dynamics simulations. One of the key findings in our work is in the presence of -aspartyl as a ligand, the salt bridges which hold the N-terminals together are completely disrupted, thus setting the N-terminals free and exposed entirely to the solvent which can make the aggregation of A{beta} less severe. The efficiency of the ligands, which are responsible for the disruption of A{beta}, depends on the alignment and strength of the repulsive interactions. Besides repulsive interactions, we found that there is a need for hydrogen bonding, which acts as a support for the ligand to stay in the vicinity of the aggregate. Moreover, we have noticed that one of the metabolites, namely {beta}-aspartyl, formed more hydrogen bonds with the aggregate than the other ligands and had a different mode of action with the chains of A{beta} due to its unique flexible kink in the backbone.

biophysics↗