@article {160489, title = {Inheritable cell-states shape drug-persister correlations and population dynamics in cancer cells.}, journal = {PLoS Comput Biol}, volume = {21}, year = {2025}, month = {2025 Sep}, pages = {e1013446}, abstract = {

Drug tolerant persisters (DTPs) drive cancer therapy resistance by temporarily evading drug action, allowing multiple routes to eventual permanent resistance. Despite clear evidence for DTPs, the timing of their emergence, proliferative nature, and how their population dynamics arise from measured single-cell kinetics remain poorly understood. Here we use time-lapse microscopy data from two cancer cell lines, integrating single-cell and population measurements, to develop a quantitative description of drug persistence. Contrary to the expectation that increasing levels of genotoxic stress should lead to slower times to division and faster times to death, we observe minor changes in the single-cell intermitotic and death time distributions upon increasing cisplatin concentration. Yet, population decay rates increase 3-fold, suggesting a surprising independence of the overall dynamics from the measured birth and death rates. To explain this phenomenon, we argue that the observed lineage correlations and concentration-dependent decay rates imply cell-state dependent fate choices made both pre and post-cisplatin as opposed to just post-drug birth/death rate-based competitive fate choices. We demonstrate that these cell-states, present in the pre-drug ancestors of DTP and sensitive cells, exhibit no difference in cycling speed and are inherited across at least 2-3 cellular generations. Post-drug survival versus death fates are decided with high probability by these pre-existing cell-states, but get modulated to some extent by the drug, leading to a drug concentration dependent state-fate map. A stochastic model implementing these rules simultaneously recapitulates the observed decay rates and cell-fate lineage correlations. The model also demonstrates how the use of barcode diversity change before and after drug might lead to misleading interpretations of the timing of persister fate decisions. Our results provide a conceptual framework for quantifying pre versus post-drug contributions to cell fate, without requiring knowledge of the underlying molecular architecture of the heterogeneous cell states.

}, keywords = {Antineoplastic Agents, Cell Line, Tumor, Cisplatin, Computational Biology, Drug Resistance, Neoplasm, Humans, Models, Biological, Neoplasms, Single-Cell Analysis, Time-Lapse Imaging}, issn = {1553-7358}, doi = {10.1371/journal.pcbi.1013446}, author = {Iyer, Anton and Alva, Adrian and Granada, Adri{\'a}n E and Chakrabarti, Shaon} } @article {142312, title = {A geometrical model of cell fate specification in the mouse blastocyst.}, journal = {Development}, volume = {151}, year = {2024}, month = {2024 Apr 15}, abstract = {

The lineage decision that generates the epiblast and primitive endoderm from the inner cell mass (ICM) is a paradigm for cell fate specification. Recent mathematics has formalized Waddington{\textquoteright}s landscape metaphor and proven that lineage decisions in detailed gene network models must conform to a small list of low-dimensional stereotypic changes called bifurcations. The most plausible bifurcation for the ICM is the so-called heteroclinic flip that we define and elaborate here. Our re-analysis of recent data suggests that there is sufficient cell movement in the ICM so the FGF signal, which drives the lineage decision, can be treated as spatially uniform. We thus extend the bifurcation model for a single cell to the entire ICM by means of a self-consistently defined time-dependent FGF signal. This model is consistent with available data and we propose additional dynamic experiments to test it further. This demonstrates that simplified, quantitative and intuitively transparent descriptions are possible when attention is shifted from specific genes to lineages. The flip bifurcation is a very plausible model for any situation where the embryo needs control over the relative proportions of two fates by a morphogen feedback.

}, keywords = {Animals, Blastocyst, Cell Differentiation, Cell Lineage, Endoderm, Fibroblast Growth Factors, Gene Expression Regulation, Developmental, Germ Layers, Mice, Models, Biological, Signal Transduction}, issn = {1477-9129}, doi = {10.1242/dev.202467}, author = {Raju, Archishman and Siggia, Eric D} } @article {152149, title = {Interplay of geometry and mechanics in epithelial wound healing.}, journal = {Phys Rev E}, volume = {110}, year = {2024}, month = {2024 Nov}, pages = {054411}, abstract = {

Wound healing is a complex biological process critical for maintaining an organism{\textquoteright}s structural integrity and tissue repair following an infection or injury. Recent studies have unveiled the mechanisms involving the coordination of biochemical and mechanical responses in the tissue in wound healing. In this article, we focus on the healing property of an epithelial tissue as a material while the effects of biological mechanisms such as cell proliferation, tissue intercalation, cellular migration, cell crawling, and filopodia protrusion is minimal. We present a mathematical framework that predicts the fate of a wounded tissue based on the wound{\textquoteright}s geometrical features and the tissue{\textquoteright}s mechanical properties. Precisely, adapting the vertex model of tissue mechanics, we predict whether a wound of a specific size in an epithelial monolayer characterized by certain levels of actomyosin contractility and cell-cell adhesion will heal (i.e., close), shrink in size, or rupture the tissue further. Moreover, we show how tissue-mediated mechanisms such as purse-string tension at the wound boundary facilitate wound healing. Finally, we validate the predictions of our model by designing an experimental setup that enables us to create wounds of specific sizes in kidney epithelial cells (MDCK) monolayers. Altogether, this work sets up a basis for interpreting the interplay of mechanical and geometrical features of a tissue in the process of wound healing.

}, keywords = {Animals, Biomechanical Phenomena, Dogs, Epithelial Cells, Epithelium, Madin Darby Canine Kidney Cells, Mechanical Phenomena, Models, Biological, Wound Healing}, issn = {2470-0053}, doi = {10.1103/PhysRevE.110.054411}, author = {Babu, Nandhu Krishna and Sreepadmanabh, M and Dutta, Sayantan and Bhattacharjee, Tapomoy} } @article {126686, title = {Using sensitivity analyses to understand bistable system behavior.}, journal = {BMC Bioinformatics}, volume = {24}, year = {2023}, month = {2023 Apr 06}, pages = {136}, abstract = {

BACKGROUND: Bistable systems, i.e., systems that exhibit two stable steady states, are of particular interest in biology. They can implement binary cellular decision making, e.g., in pathways for cellular differentiation and cell cycle regulation. The onset of cancer, prion diseases, and neurodegenerative diseases are known to be associated with malfunctioning bistable systems. Exploring and characterizing parameter spaces in bistable systems, so that they retain or lose bistability, is part of a lot of therapeutic research such as cancer pharmacology.

RESULTS: We use eigenvalue sensitivity analysis and stable state separation sensitivity analysis to understand bistable system behaviors, and to characterize the most sensitive parameters of a bistable system. While eigenvalue sensitivity analysis is an established technique in engineering disciplines, it has not been frequently used to study biological systems. We demonstrate the utility of these approaches on a published bistable system. We also illustrate scalability and generalizability of these methods to larger bistable systems.

CONCLUSIONS: Eigenvalue sensitivity analysis and separation sensitivity analysis prove to be promising tools to define parameter design rules to make switching decisions between either stable steady state of a bistable system and a corresponding monostable state after bifurcation. These rules were applied to the smallest two-component bistable system and results were validated analytically. We showed that with multiple parameter settings of the same bistable system, we can design switching to a desirable state to retain or lose bistability when the most sensitive parameter is varied according to our parameter perturbation recommendations. We propose eigenvalue and stable state separation sensitivity analyses as a framework to evaluate large and complex bistable systems.

}, keywords = {Computational Biology, Models, Biological}, issn = {1471-2105}, doi = {10.1186/s12859-023-05206-2}, author = {Sreedharan, Vandana and Bhalla, Upinder S and Ramakrishnan, Naren} } @article {74438, title = {Active morphogenesis of epithelial monolayers.}, journal = {Phys Rev E}, volume = {100}, year = {2019}, month = {2019 Aug}, pages = {022413}, abstract = {

During typical early-stage embryo development, single-cell-thick tissues of tightly bound epithelial cells autonomously generate profound changes in their shape, forming the basis of organism anatomy. We report on a (covariant) active-hydrodynamic theory of such monolayer morphogenesis that is closed under its shape-changing dynamics-i.e., the degrees of freedom that encode monolayer geometry appear properly as broken-symmetry variables. In our theory, the salient physics of tissue-scale deformations emerges from a balance between the displacement and/or shear of a low-Reynolds-number embedding fluid (the "yolk") and cell-autonomous stresses, themselves a result of combining apical contractile stresses with an elastic-like mechanical response under the constraint of constant cell volume. The leading-order hydrodynamic instabilities include both passive constrained-buckling and active deformation, which can be further categorized by cell shape changes that are either "squamous to columnar" or "regular-prism to truncated-pyramid." The deformations resulting from the latter qualitatively reproduce in vivo observations of the onset of both mesoderm and posterior midgut invaginations, which take place during gastrulation in the model organism Drosophila melanogaster.

}, keywords = {Epithelium, Hydrodynamics, Models, Biological, Morphogenesis, Thermodynamics}, issn = {2470-0053}, doi = {10.1103/PhysRevE.100.022413}, author = {Morris, Richard G and Rao, Madan} } @article {36260, title = {Diversity, Stability, and Reproducibility in Stochastically Assembled Microbial Ecosystems.}, journal = {Phys Rev Lett}, volume = {120}, year = {2018}, month = {2018 Apr 13}, pages = {158102}, abstract = {

Microbial ecosystems are remarkably diverse, stable, and usually consist of a mixture of core and peripheral species. Here we propose a conceptual model exhibiting all these emergent properties in quantitative agreement with real ecosystem data, specifically species abundance and prevalence distributions. Resource competition and metabolic commensalism drive the stochastic ecosystem assembly in our model. We demonstrate that even when supplied with just one resource, ecosystems can exhibit high diversity, increasing stability, and partial reproducibility between samples.

}, keywords = {Ecosystem, Microbiota, Models, Biological, Stochastic Processes}, issn = {1079-7114}, doi = {10.1103/PhysRevLett.120.158102}, author = {Goyal, Akshit and Maslov, Sergei} } @article {45430, title = {Physiological stress responses in wild Asian elephants Elephas maximus in a human-dominated landscape in the Western Ghats, southern India.}, journal = {Gen Comp Endocrinol}, volume = {266}, year = {2018}, month = {2018 09 15}, pages = {150-156}, abstract = {

Increasing anthropogenic pressures on forests, especially in the tropical regions of the world, have restricted several large mammalian species such as the Asian elephant to fragmented habitats within human-dominated landscapes. In this study, we assessed the effects of an anthropogenic landscape and its associated conflict with humans on the physiological stress responses displayed by Asian elephants in the Anamalai Hills of the Western Ghats mountains in south India. We have quantified faecal glucocorticoid metabolite (FGM) concentrations in focal individual elephants within and across herds, inhabiting both anthropogenic and natural habitats, and evaluated their physiological responses to different socio-ecological situations between November 2013 and April 2014. Physiological stress responses varied significantly among the tested elephant age- and sex categories but not across different types of social organisation. Adults generally showed higher FGM concentrations, even in the absence of stressors, than did any other age category. Males also appeared to have higher stress responses than did females. Although there was no significant variation in mean stress levels between elephants on the plateau in the absence of human interactions and those in adjacent, relatively undisturbed forest habitats, FGM concentrations increased significantly for adult and subadult individuals as well as for calves following drives, during which elephants were driven off aggressively by people. Our study emphasises the general importance of understanding individual variation in physiology and behaviour within a population of a seriously threatened mammalian species, the Asian elephant, and specifically highlights the need for long-term monitoring of the stress physiology and behavioural responses of individual elephants across both human-dominated and natural landscapes. Such studies would not only provide comprehensive insights into the adaptive biology of elephants in changing ecological regimes but also aid in the development of effective management and conservation strategies for endangered populations of the species.

}, keywords = {Animals, Animals, Wild, Elephants, Feces, Female, Forests, Geography, Glucocorticoids, Humans, India, Linear Models, Male, Metabolome, Models, Biological, Stress, Physiological}, issn = {1095-6840}, doi = {10.1016/j.ygcen.2018.05.009}, author = {Vijayakrishnan, Sreedhar and Kumar, Mavatur Ananda and Umapathy, G and Kumar, Vinod and Sinha, Anindya} } @article {863, title = {Homo-FRET imaging highlights the nanoscale organization of cell surface molecules.}, journal = {Methods Mol Biol}, volume = {1251}, year = {2015}, month = {2015}, pages = {151-73}, abstract = {

Several models have been proposed to understand the structure and organization of the plasma membrane in living cells. Predicated on equilibrium thermodynamic principles, the fluid-mosaic model of Singer and Nicholson and the model of lipid domains (or membrane rafts) are dominant models, which account for a fluid bilayer and functional lateral heterogeneity of membrane components, respectively. However, the constituents of the membrane and its composition are not maintained by equilibrium mechanisms. Indeed, the living cell membrane is a steady state of a number of active processes, namely, exocytosis, lipid synthesis and transbilayer flip-flop, and endocytosis. In this active milieu, many lipid constituents of the cell membrane exhibit a nanoscale organization that is also at odds with passive models based on chemical equilibrium. Here we provide a detailed description of microscopy and cell biological methods that have served to provide valuable information regarding the nature of nanoscale organization of lipid components in a living cell.

}, keywords = {Animals, Cell Membrane, CHO Cells, Cricetinae, Cricetulus, Fluorescence Polarization, Fluorescence Resonance Energy Transfer, Lipid Bilayers, Microscopy, Fluorescence, Models, Biological, Nanotechnology}, issn = {1940-6029}, doi = {10.1007/978-1-4939-2080-8_9}, author = {Saha, Suvrajit and Raghupathy, Riya and Mayor, Satyajit} } @article {902, title = {Organelle morphogenesis by active membrane remodeling.}, journal = {Soft Matter}, volume = {11}, year = {2015}, month = {2015 Mar 28}, pages = {2387-93}, abstract = {

Intracellular organelles are subject to a steady flux of lipids and proteins through active, energy consuming transport processes. Active fission and fusion are promoted by GTPases, e.g., Arf-Coatamer and the Rab-Snare complexes, which both sense and generate local membrane curvature. Here we investigate, through Dynamical Triangulation Monte Carlo simulations, the role that these active processes play in determining the morphology and composition segregation in closed membranes. We find that the steady state shapes obtained as a result of such active processes, bear a striking resemblance to the ramified morphologies of organelles in vivo, pointing to the relevance of nonequilibrium fission-fusion in organelle morphogenesis.

}, keywords = {Intracellular Membranes, Membrane Fusion, Models, Biological, Models, Statistical, Monte Carlo Method, Organelles}, issn = {1744-6848}, doi = {10.1039/c4sm02311k}, author = {Ramakrishnan, N and Ipsen, John H and Rao, Madan and Kumar, P B Sunil} }