Biology subjects

Sharma, P. K.

Publications and source records attributed to Sharma, P. K..

3 recordsLinked to original sources

bioRxiv2022

An in vitro model of fibrosis using crosslinked native extracellular matrix-derived hydrogels to modulate biomechanics without changing composition

Extracellular matrix (ECM) is a dynamic network of proteins, proteoglycans and glycosaminoglycans, providing structure to the tissue and biochemical and biomechanical instructions to the resident cells. In fibrosis, the composition and the organization of the ECM are altered, and these changes influence cellular behaviour. Biochemical (i. e. protein composition) and biomechanical changes in ECM take place simultaneously in vivo. Investigating these changes individually in vitro to examine their (patho)physiological effects has been difficult. In this study, we generated an in vitro model to reflect the altered mechanics of a fibrotic microenvironment through applying fibre crosslinking via ruthenium/sodium persulfate crosslinking on native lung ECM-derived hydrogels. Crosslinking of the hydrogels without changing the biochemical composition of the ECM resulted in increased stiffness and decreased viscoelastic stress relaxation. The altered stress relaxation behaviour was explained using a generalized Maxwell model. Fibre analysis of the hydrogels showed that crosslinked hydrogels had a higher percentage of matrix with a high density and a shorter average fibre length. Fibroblasts seeded on ruthenium-crosslinked lung ECM-derived hydrogels showed myofibroblastic differentiation with a loss of spindle-like morphology together with greater -smooth muscle actin (-SMA) expression, increased nuclear area and circularity without any decrease in the viability, compared with the fibroblasts seeded on the native lung-derived ECM hydrogels. In summary, ruthenium crosslinking of native ECM-derived hydrogels provides an exciting opportunity to alter the biomechanical properties of the ECM-derived hydrogels while maintaining the protein composition of the ECM to study the influence of mechanics during fibrotic lung diseases.

pathology↗

bioRxiv2021

Computational and biochemical analyses reveal that cofilin-2 self assembles into amyloid-like structures and promotes the aggregation of other proteinaceous species: Pathogenic relevance to myopathies

Cofilin-2 is a member of the ADF/cofilin family, expressed extensively in adult muscle cells and involved in muscle maintenance and regeneration. Phosphorylated cofilin-2 is found in pre-fibrillar aggregates formed during idiopathic dilated cardiomyopathy. A recent study shows that phosphorylated cofilin-2, under oxidative distress, forms fibrillar aggregates. However, it remains unknown if cofilin-2 holds an innate propensity to form amyloid-like structures. In the present study, we employed various computational and biochemical techniques to explore the amyloid-forming potential of cofilin-2. We report that cofilin-2 possesses aggregation-prone regions (APRs), and these APRs get exposed to the surface, become solvent-accessible, and are involved in the intermolecular interactions during dimerization, an early stage of aggregation. Furthermore, the cofilin-2 amyloids, formed under physiological conditions, are capable of cross-seeding other monomeric globular proteins and amino acids, thus promoting their aggregation. We further show that Cys-39 and Cys-80 are critical in maintaining the thermodynamic stability of cofilin-2. The destabilizing effect of oxidation at Cys-39 but not that at Cys-80 is mitigated by Ser-3 phosphorylation. Cysteine oxidation leads to partial unfolding and loss of structure, suggesting that cysteine oxidation further induces early events of cofilin-2 aggregation. Overall, our results pose a possibility that cofilin-2 amyloidogenesis might be involved in the pathophysiology of diseases, such as myopathies. We propose that the exposure of APRs to the surface could provide mechanistic insight into the higher-order aggregation and amyloidogenesis of cofilin-2. Moreover, the cross-seeding activity of cofilin-2 amyloids hints towards its involvement in the hetero-aggregation in various amyloid-linked diseases.

biochemistry↗

bioRxiv2021

MM-Deacon: Multimodal molecular domain embedding analysis via contrastive learning

AO_SCPLOWBSTRACTC_SCPLOWMolecular representation learning plays an essential role in cheminformatics. Recently, language model-based approaches have been popular as an alternative to traditional expert-designed features to encode molecules. However, these approaches only utilize a single modality for representing molecules. Driven by the fact that a given molecule can be described through different modalities such as Simplified Molecular Line Entry System (SMILES), The International Union of Pure and Applied Chemistry (IUPAC), and The IUPAC International Chemical Identifier (InChI), we propose a multimodal molecular embedding generation approach called MM-Deacon (multimodal molecular domain embedding analysis via contrastive learning). MM-Deacon is trained using SMILES and IUPAC molecule representations as two different modalities. First, SMILES and IUPAC strings are encoded by using two different transformer-based language models independently, then the contrastive loss is utilized to bring these encoded representations from different modalities closer to each other if they belong to the same molecule, and to push embeddings farther from each other if they belong to different molecules. We evaluate the robustness of our molecule embeddings on molecule clustering, cross-modal molecule search, drug similarity assessment and drug-drug interaction tasks.

bioinformatics↗