Biology subjects

Kara, M.

Publications and source records attributed to Kara, M..

5 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

The calculation of the mutation frequency for humans at different proton doses in a mathematical model and estimation of the mutation risks for the space explorations

DNA is considered a fundamental component of life, yet it remains vulnerable to damage under extreme conditions, such as ionizing radiation exposure. To better understand this fragility, it becomes important to estimate mutation frequencies under different radiation doses. Furthermore, this approach has potential for future applications, especially in the context of deep space exploration, where astronauts are exposed to higher levels of cosmic radiation. For this purpose, we developed a mathematical model by integrating two existing models, the Monte Carlo Excision Repair (MCER) model and the Whack-a-Mole (WAM) model, both specifically adapted for use in manned space missions. The WAM model is supported with the Monte Carlo simulation to address the lack of human experimental data available in previous studies so that by calculating four key variables related to the human cells defined in the WAM model, potential mutations in astronauts during space exploration were estimated. The results showed small deviations from previous studies, which can be attributed to differences in the type of radiation sources as well as the organisms studied being different from those used in previous studies. With this study, researchers can now better predict mutation frequency during deep space missions by considering the impact of cosmic radiation. This is particularly important in the context of future missions to the Moon and Mars, where cosmic radiation will play an important role in mission planning and risk management.

biophysics↗

bioRxiv2023

DESIGN AND GENERATION OF A RECOMBINANT GAMMAHERPESVIRUS ENCODING shRNA FROM NATIVE VIRAL tRNA PROMOTER

Gammaherpesviruses are associated with multiple types of tumour development and understanding the pathogenesis of these viruses has been the subject of many different studies. Throughout the lytic and latent life cycle, these viruses utilize numerous virally encoded miRNAs to regulate the key mechanisms of the infected cell in their favour. Therefore it is important to understand the miRNA and their mRNA target interactions for developing better therapeutics. In this study, the strategy and design of a short hairpin encoding RNA element targeting Blimp1 transcript in the context of viral infection is evaluated. This proof of principle experiment provides a mean to study important miRNA mRNA interactions in vivo. The very short promoter size of the Murine gammaherpesvirus 68 (MHV68) vtRNA4 and its ability to generate two shRNAs from a ~180 nucleotide sequence is useful if there is a size limit for the shRNA construct.

microbiology↗

bioRxiv2023

Validation and characterization of a viral antisense transcript with Northern blot analysis and qRT-PCR

The transcription of mammalian genomes has been shown to possess an intriguing complexity and numerous novel RNA molecules have been identified in the last 10-15 years. Viruses with large DNA genomes, especially herpesviruses, are also shown to generate many different RNA species and some of them may function as long non-coding RNAs. Viral genomes harbor several genes within close proximity to each other and can generate multigenic transcripts in addition to commonly observed antisense transcription. It is essential to study the biological roles of these transcripts aside from the protein-coding counterparts. A transcriptionally complex locus can be studied with a combination of methods. Generally, quantitative PCR assays are very commonly used for expression analyses of the transcripts of interest. Here an example from a gammaherpesvirus is discussed in more detail. A recently developed method, for the resolution of complicated transcriptomes for viral genomes, elucidated multiple antisense transcripts from ORF63-64 locus in murine gammaherpesvirus 68 (MHV68). In order to identify the roles of these new transcripts, quantitative PCR assays may not be enough alone and should be supported by alternative methods such as Northern blots. A more detailed transcriptional map of the locus of interest is useful to design experimental strategies and perform functional studies.

microbiology↗

bioRxiv2020

EBV miRNAs are potent effectors of tumor cell transcriptome remodeling in promoting immune escape.

Epstein Barr virus (EBV) contributes to the tumor phenotype through a limited set of primarily non-coding viral RNAs, including 31 mature miRNAs. Here we investigated the impact of EBV miRNAs on remodeling the tumor cell transcriptome. Strikingly, EBV miRNAs displayed exceptionally abundant expression in primary EBV-associated Burkitts Lymphomas (BLs) and Gastric Carcinomas (GCs). To investigate viral miRNA targeting, we used the high-resolution approach, CLASH in GC and a BL cell models. Affinity constant calculations of targeting efficacies for CLASH hits showed that viral miRNAs bind their targets more effectively than their host counterparts, as did Kaposis sarcoma-associated herpesvirus (KSHV) and murine gammaherpesvirus 68 (MHV68) miRNAs. Using public BL and GC RNA-seq datasets, we found that high EBV miRNA targeting efficacies translates to enhanced reduction of target expression. Pathway analysis of high efficacy EBV miRNA targets showed enrichment for innate and adaptive immune responses. Inhibition of the immune response by EBV miRNAs was functionally validated in vivo through the finding of inverse correlations between EBV miRNAs and immune cell infiltration and T-cell diversity in TCGA GC dataset. Together, this study demonstrates that EBV miRNAs are potent effectors of the tumor transcriptome that play a role in suppressing the host immune response. AUTHOR SUMMARYBurkitts Lymphoma and gastric cancer are both associated with EBV, a prolific DNA tumor virus that latently resides in nearly all human beings. Despite mostly restricting viral gene expression to noncoding RNAs, EBV has important influences on the fitness of infected tumor cells. Here, we show that the miRNA class of viral noncoding RNAs are a major viral contributor to remodeling the tumor cell regulatory machinery in patient tumor samples. First, an assessment of miRNA expression in clinical tumor samples showed that EBV miRNAs are expressed at unexpectedly high levels relative to cell miRNAs. Using a highly specific miRNA target identification approach, CLASH, we comprehensively identified both viral and cellular microRNA targets and the relative abundance of each microRNA-mRNA interaction. We also show that viral microRNAs bind to and alter the expression of their mRNA targets more effectively than their cellular microRNA counterparts. Pathway analysis of the most effectively targeted mRNAs revealed enrichment of immune signaling pathways and we show a corresponding inverse correlation between EBV miRNA expression and infiltrating immune cells in EBV positive primary tumors. Altogether, this study shows that EBV miRNAs are key regulators of the tumor cell phenotype and the immune cell microenvironment.

cancer biology↗