Biology subjects

Tugrul, M.

Publications and source records attributed to Tugrul, M..

6 recordsLinked to original sources

bioRxiv2026

Stochastic Biophysics of Cellular Radiosensitivity: From Molecular Noise and Repair Kinetics to Evolutionary Demographics

Radiation-induced DNA double-strand breaks (DSBs) drive cellular mortality, mutagenesis, and evolutionary bottlenecks. Classical phenomenological models such as the Linear-Quadratic (LQ) framework predict macroscopic survival but obscure the single-cell stochasticity that governs rare outcomes, including tumor recurrence and radioresistant persistence. We develop a stochastic differential equation framework describing DSB induction and repair as a Feller square-root process. Exact closed-form expressions for the foci mean and variance enable efficient likelihood-based inference of repair kinetics and effective molecular noise from single-cell $\gamma$-H2AX data without repeated Monte Carlo simulation. Coupling these kinetics to a cumulative damage hazard through the Feynman-Kac formalism links microscopic damage dynamics to macroscopic survival and provides a mechanistic mapping to the classical LQ form. Sensitivity analysis further shows that physical damage induction acts additively, whereas survival depends nonlinearly on repair rate, damage hazard, and stochastic noise. Increased noise enhances population survival by broadening the distribution of cumulative damage, consistent with Jensen's inequality and a bet-hedging-like survival advantage for cells experiencing transiently low damage loads. This framework therefore connects stochastic single-cell biophysics with population-level radiosensitivity and provides a tractable basis for studying how cellular heterogeneity shapes survival under radiation stress.

biophysics↗

bioRxiv2025

Population Consequences of Single-Cell Damage Dynamics: Theory and Experiment under Glucose Limitation in E. coli

Microbial population growth arises from the survival and division of individual cells. However, under environmental stress, how reduced population fitness emerges from the single-cell dynamics remains poorly understood. Cellular aging and damage accumulation are often overlooked in linking these levels. Here, we use both theory and experiment to investigate how stochastic and asymmetric damage dynamics shape population outcomes. Theoretically, we apply a jump-diffusion damage model within a structured population framework to explore the roles of damage rate, noise, and partitioning asymmetry. Our theoretical analyses show that these parameters influence population growth both at equilibrium and during transient dynamics, suggesting that their cellular regulation may be a key strategy for sustaining population fitness. Experimentally, we expose Escherichia coli to glucose limitation and monitor stress responses using a RpoS fluorescent reporter, tracking both single-cell behavior in a microfluidic device combined with time-lapse fluorescence microscopy and population growth in a plate reader. Glucose limitation leads to the effects of elevated stress, reduced division, and increased mortality, which are consistently observed across scales. Using parameter estimates from single-cell data, our model deepens insights on population-level dynamics and highlights damage-noise driven, damage-dependent mortality as a key factor under stress. Together, these findings establish a quantitative framework linking intracellular stress to population fitness under environmental stress.

evolutionary biology↗

bioRxiv2025

Optimal division asymmetry in E. coli bacteria

Cell division asymmetry underlies many fundamental biological processes, including the evolution of aging. Despite this importance, understanding whether the observed division asymmetry has been optimized by evolution remains little explored. Here we first show that size and transcription signal asymmetries have evolved to an optimum, as increased or decreased asymmetries lowers population growth. We then highlight how variance and covariance in growth and transcription signal asymmetry influence population growth. This latter exploration reveals how sensitive deviations to the optimum are, and that selective forces act primarily on variance in transcription signal asymmetry and less so on other cell intrinsic noise or growth asymmetries. Our findings are based on advancing integral projection models to two traits and we parameterize these models with single-cell data of mother and daughter E. coli bacterial cells collected using microfluidic devices. We discuss how trade-offs between growth and the transcription signal we explore has shaped this optimum. Our findings provide insights on how division asymmetries and resulting cellular heterogeneity can have profound biological consequences--contributing to processes such as cancer development, antibiotic treatment failure, and the rejuvenation of cell lineages, including in mammalian stem cells.

evolutionary biology↗

bioRxiv2024

Protein aggregation drives cell aging in a size-specific manner in Escherichia coli

Aging, the decline in physiological function over time, is marked by the intracellular accumulation of damaged components. It can be attributed to a trade-off between the investment into organismal maintenance and the production of high-quality offspring, where the parent accumulates damage over time and retains it upon reproduction, while the offspring is rejuvenated. Asymmetric damage partitioning has been observed even in simple unicellular organisms, such as Escherichia coli bacteria, that retain aggregates of misfolded proteins during cell division. However, recent studies presented conflicting evidence on the effect of protein aggregates on fitness, ranging from detrimental effects on cell growth to enhanced stress survival. Here, we show that the decisive factor driving growth decline in E. coli is not the presence of a protein aggregate, but the proportion of the intracellular space occupied by it. By following single-cell E. coli lineages expressing fluorescently labeled DnaK chaperones, we quantified damage accumulation and partitioning across generations in microfluidic devices. Our results suggest that the aggregation of damaged proteins allows cells to keep damage separate from vital processes and compensate for the lost intracellular space by growing to larger sizes. This process results in morphologically asymmetric divisions, a finding that counters the long-assumed symmetry of E. coli cell division. In line with other recent evidence, our findings point to a more complex role of protein aggregation, with implications for our understanding of the cellular mechanisms underlying aging as well as its evolutionary origins.

evolutionary biology↗

bioRxiv2023

Declining old pole physiology gradually enhances gene expression asymmetry in bacteria

Gene expression is a heterogeneous process at the single-cell level. This heterogeneity is often coupled to individual growth rates, which are also highly stochastic, leading to the emergence of multiple physiological states within bacterial populations. Although recent advances have shown that cellular aging acts as a deterministic driver of growth asymmetry, the relationship between aging and gene expression heterogeneity remains elusive. Here we show that old poles undergo a progressive decline in gene expression as mother cells age, contributing to enhance phenotypic heterogeneity in bacterial populations. We quantified the activity of promoters with distinct activity profiles: a constitutive promoter, whose expression positively correlates with growth, and the promoter of RpoS, the general stress response sigma factor, for which growth and expression are mutually inhibitory. We demonstrate that mother cells have lower gene expression for both promoters. This asymmetry could not be explained by metabolic rate differences, but rather by the increasing intracellular heterogeneity of mother cells. As a mother ages, the declining activity of its old pole produces intracellular gradients in gene expression. This intracellular asymmetry manifests in the next generation as mother-daughter asymmetry, thus representing a source of phenotypic heterogeneity for the population. Our results show that bacterial asymmetry is built into the declining physiology of mother cells across generations, illustrating the deterministic nature of aging in bacterial systems. These findings provide further evidence for cellular aging as a mechanism to enhance the variance of metabolic states found in bacterial populations, with possible consequences for stress response and survival.

evolutionary biology↗

bioRxiv2023

Demographic Consequences of Damage Dynamics in Single-Cell Ageing

Ageing is driven by damage accumulation leading to a decline in function over time. In single-cell systems, in addition to this damage accumulation within individuals, asymmetric damage partitioning at cell division can play a crucial role in shaping demographic ageing patterns. Despite empirical single-cell studies providing quantitative data at the molecular and demographic level, a comprehensive theory of how cellular damage production and asymmetric partitioning propagate and influence demographic patterns is still lacking. Here, we present a generic and flexible damage model using a stochastic differential equation approach that incorporates stochastic damage accumulation and asymmetric damage partitioning at cell divisions. We formulate an analytical approximation linking cellular and damage parameters to demographic ageing patterns. Interestingly, the lifespan of cells follows an inverse-gaussian distribution whose underlying properties derive from cellular and damage parameters. We demonstrate how stochasticity (noise) in damage production, asymmetry in damage partitioning, and division frequency shape lifespan distribution. Confronting the model to various empirical E.coli data reveals non-exponential scaling in mortality rates, a scaling that cannot be captured by classical Gompertz-Makeham models. Our findings provide a deep understanding of how fundamental processes contribute to cellular damage dynamics and generate demographic patterns. Our damage models generic nature offers a valuable framework for investigating ageing in diverse biological systems. SignificanceAsymmetries and randomness in cellular events play important roles in establishing the diversity at evolutionary and demographic scales. Looking at single-cells, ageing processes are influenced by stochastic damage accumulation and asymmetric damage partitioning at cell divisions. Utilising stochastic differential equations, we develop a cellular damage model that encapsulate both noisy damage accumulation within cells and asymmetric damage partitioning among cells when they divide. In doing so we bridge molecular stochastic processes, demographic fates of individuals, and population level demographic distributions. Our model aligns with empirical data from E.coli single-cell studies and advances our understanding compared to traditional demographic models. The generic and adaptable nature of our model paves the way for broader applications in ageing research across biological systems, highlighting the influences of stochasticity and asymmetry on cellular biology.

evolutionary biology↗