Biology subjects

Kant, A.

Publications and source records attributed to Kant, A..

3 recordsLinked to original sources

bioRxiv2023

Chemo-Mechanical Regulation of Tau Phosphorylation Following Traumatic Brain Injuries

Traumatic brain injuries are characterized by damage to axonal cytoskeletal proteins. Here, we present a mathematical model predicting the chemo-mechanical disruption of intra-axonal micro-tubule assembly in terms of hyperphosphorylation-led dysfunction of tubulin-binding tau proteins. Intracellular calcium accumulation following a trauma leads to calpain activation, disturbing the downstream kinase-phosphatase activity balance which causes tau hyperphosphorylation. We develop a computational framework, using finite element methods, predicting the spatiotemporal evolution of mechanical stress and ensuing tau hyperphosphorylation in the human brain after traumatic brain injury-inducing loads. We compare our predictions with previously reported experimental and clinical observations to validate the model. Our model provides important insights into the secondary effects of traumatic brain injuries and can be essential in their clinical management.

biophysics↗

bioRxiv2023

Active Transcription and Epigenetic Reactions Synergistically RegulateMeso-Scale Genomic Organization

In interphase nuclei, chromatin is organized into interspersed dense domains with characteristic sizes, both in the nuclear interior and periphery. However, the quantitative impact of transcription and histone modifications on the size and distribution of these domains remains unclear. Here, we introduce a mesoscale theoretical model that investigates the relationship between heterochromatic domain sizes and loop extrusion rates from these domains. The model considers chromatin-chromatin and chromatin-lamina interactions, methylation and acetylation kinetics, and diffusion of epigenetic marks and nucleoplasm. Our model generates testable predictions that help reveal the biophysics underlying chromatin organization in the presence of transcription-driven loop extrusion. This process is kinetically captured through the conversion of heterochromatin to euchromatin in response to RNAPII activity. We discovered that a balance between diffusive and reactive fluxes governs the steady-state sizes of heterochromatin domains. Using theory and simulations, we predicted that a loss of transcription results in increased chromatin compaction and larger heterochromatin domain sizes. To validate our predictions, we employed complementary super-resolution and nano-imaging techniques on five different cell lines with impaired transcription. We quantitatively assessed how domain sizes scale with loop extrusion rates at the hetero-euchromatin interfaces. Our analysis of previously obtained super-resolution images of nuclei revealed that excessive loop extrusion leads to smaller heterochromatin domains. The model successfully recapitulated these observations, explaining how transcription loss can counteract the effects of cohesin overloading. As the general biophysical mechanisms regulating heterochromatin domain sizes are independent of cell type, our findings have significant implications for understanding the role of transcription in global genome organization.

biophysics↗

bioRxiv2022

Lipid droplets are intracellular mechanical stressors in fatty hepatocytes

Matrix stiffening and external mechanical stress have been linked to disease and cancer development in multiple tissues, including the liver, where cirrhosis (which increases stiffness markedly) is the major risk factor for hepatocellular carcinoma. Patients with non-alcoholic fatty liver disease and lipid-droplet-filled hepatocytes, however, can develop cancer in non-cirrhotic, relatively soft tissue. Here, we show that lipid droplets are intracellular mechanical stressors with similar effects to tissue stiffening, including nuclear deformation, chromatin condensation, and hepatocyte dedifferentiation. Mathematical modelling of lipid droplets as inclusions that have only mechanical interactions with other cellular components generated results consistent with our experiments. These data show that lipid droplets are intracellular sources of mechanical stress and suggest that nuclear membrane tension integrates cell responses to combined internal and external stresses. Significance StatementDeformation of the nucleus as a result of extracellular sources of stress, including increased substrate stiffness, constricted migration, and compression, has been well documented to lead to increased nuclear rupture, changes in gene expression, and accumulation of DNA damage. Lipid droplet accumulation in hepatocytes provides a unique scenario to investigate potential intracellular mechanical stresses and sources of nuclear deformation. Our results show that lipid droplets are significant mechanical elements in the cell, deforming the nucleus in a way that promotes hepatocyte dedifferentiation and resisting cytoskeletal contraction and alignment.

cell biology↗