Physical biology最新文献

{"title":"Both sides now: modeling motor regulation of microtubule length at both ends.","authors":"Maria-Veronica Ciocanel, Bhargav R Karamched","doi":"10.1088/1478-3975/ae600a","DOIUrl":"10.1088/1478-3975/ae600a","url":null,"abstract":"<p><p>Microtubules are dynamic biopolymers whose lengths are continuously regulated by the concerted actions of polymerization, depolymerization, and motor-protein activity. While numerous mathematical models have explored the regulation of filament length, most have been formulated in the context of growth and shrinking at a single tip of a microtubule, effectively ignoring the mechanistic description of complex phenomena such as treadmilling. Here, we develop a multiscale model for microtubule length regulation that explicitly couples the kinetics of two classes of kinesin molecular motors to filament dynamics at both microtubule tips. Motor densities along the filament are modeled using one-dimensional parabolic partial differential equations. The microtubule length evolves dynamically through a shrinkage term that depends on motor density and which closes the system. In the adiabatic regime, where motor kinetics are fast relative to length dynamics, we derive a reduced model amenable to analytic study and identify simple parameter relationships distinguishing growth, disassembly, and treadmilling behavior. Numerical simulations of the full system reveal qualitatively distinct dynamical regimes and demonstrate how bidirectional motor transport modulates filament length distributions. We parametrize our model with both<i>in vivo</i>and<i>in vitro</i>data and thus lay the foundation for developing mathematical models yielding a better understanding of cytoskeleton dynamics in living cells.</p>","PeriodicalId":20207,"journal":{"name":"Physical biology","volume":" ","pages":""},"PeriodicalIF":1.5,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13107569/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147691811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Encounter times of intermittently running particles.","authors":"Lizzy Teryoshin, Mario Hidalgo-Soria, Elena F Koslover","doi":"10.1088/1478-3975/ae5d10","DOIUrl":"10.1088/1478-3975/ae5d10","url":null,"abstract":"<p><p>Intracellular processes often rely on the timely encounter of mobile reaction partners, including intermittently motor-driven organelles. The underlying cytoskeletal network presents a complex landscape that both directs particle movement and introduces quenched disorder through filament organization. We investigate the mean first encounter times for pairs of intermittently processive and diffusive particles, moving in two dimensions with and without a fixed filament network. In unstructured domains, increasing particle run-length enhances exploration of the domain, but tends to slow down the encounter times compared to equivalent diffusing particles. Encounters for long-running particles occur preferentially near the periphery, contrasting with bulk encounters for the purely diffusive case. When particles are unbiased in their runs along dense filament networks, encounters are shown to be well approximated by a continuum run-and-tumble model. For biased particles, regions of convergent filament orientation serve as traps that slow the overall spatial exploration but can allow for faster encounter rates by funneling particles into regions of reduced dimensionality. These findings provide a framework for estimating intracellular encounter kinetics, highlighting the role of key physical features such as the effective diffusivity, run times, and network architecture.</p>","PeriodicalId":20207,"journal":{"name":"Physical biology","volume":" ","pages":""},"PeriodicalIF":1.5,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147639666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AC electro-osmosis in bacterial communities with fluorescence-based electrophysiology measurements using exogeneous fluorophores.","authors":"Victor Carneiro da Cunha Martorelli, Emmanuel Akabuogu, Raveen Tank, Rok Krašovec, Ian S Roberts, Thomas A Waigh","doi":"10.1088/1478-3975/ae51fd","DOIUrl":"10.1088/1478-3975/ae51fd","url":null,"abstract":"<p><p>Synthetic cationic fluorophores are widely used as probes to measure the membrane potentials of bacterial cells, eukaryotic cells, and organelles (such as mitochondria) in electrophysiology experiments and live/dead assays. We applied an external oscillating electric field to<i>Escherichia coli</i>using microelectrodes and observed that AC electro-osmosis caused fluorescence transients independent of bacterial electrophysiology, which could be mistaken for membrane depolarisation events. The fluorophores migrated within the microfluidic device in vortices, leading to concentration fluctuations manifested as dips in fluorescence. These fluorescent dips were universally present when using cationic fluorophores such as thioflavin-T, propidium iodide, Syto9, and Sytox Green, with or without<i>E. coli</i>present, whenever AC voltages were applied. Furthermore, we also demonstrate that fluorescence dips in dense bacterial communities can arise from AC electro-osmosis rather than ion-channel activity. This cautionary tale highlights how electrical stimulation experiments in microbial communities can yield misleading results if electrokinetic effects are not accounted for. We quantified the relaxation times of fluorophores under AC electro-osmosis, which depended on the community, the cells, and the dye used: PI showed the shortest relaxation time and Syto9 the longest. Removing cells resulted in longer relaxation times, and introducing dense communities did not significantly alter the relaxation times compared with single-cell experiments. Furthermore, fluorescently labelled DNA and fluorescent colloidal beads (30-130 nm) also exhibited fluorescence dips due to AC electro-osmosis, demonstrating that charged molecules and particles readily penetrate and accumulate within these assemblies. To our knowledge, this is the first study to characterise AC electro-osmosis in dense bacterial communities, revealing the high mobility of charged molecules in such systems and suggesting possible applications for enhancing antibiotic delivery.</p>","PeriodicalId":20207,"journal":{"name":"Physical biology","volume":" ","pages":""},"PeriodicalIF":1.5,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147459398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of G₄C₂repeat expansions on the motion of lysosomes inside neurites.","authors":"Maria Mytiliniou, Joeri A J Wondergem, Marleen Feliksik, Thomas Schmidt, Thomas Fuhs, Doris Heinrich","doi":"10.1088/1478-3975/ae5143","DOIUrl":"10.1088/1478-3975/ae5143","url":null,"abstract":"<p><p>The G₄C₂hexanucleotide repeat expansion (HRE) in the c9orf72 locus is a mutation associated with amyotrophic lateral sclerosis. Recent evidence suggests a link with disrupted axonal trafficking in neurons. Here, using a neuronal-like cell line without or transfected with G₄C₂repeats, we characterize the motion of lysosomes inside neurites. The neurites grew either aligned to patterned lines, or oriented freely on a 2D-substrate. Implementing time-resolved (local) mean squared displacement analysis lysosome trajectories were split into sub-diffusive, diffusive, and super-diffusive parts. Our results suggest that in the presence of the G₄C₂repeats, lysosome trafficking is hampered, exhibiting overall decreased mean squared displacement and speed, more prominently inside aligned neurites. Moreover, a prominent effect in the super-diffusive drift velocity and diffusive motion diffusion coefficient was evident when the motion occurred inside aligned neurites. Trajectories which included super-diffusive motion, exhibited a varied ratio of anterograde/retrograde/neutral for both neurite geometries in the presence of G₄C₂repeats but a similar velocity decrease for both directions in each neurite geometry. Our findings support the hypothesis that impaired axonal trafficking emerges in the presence of the G₄C₂HRE, and demonstrate that this effect is more prominent when the neurites are aligned.</p>","PeriodicalId":20207,"journal":{"name":"Physical biology","volume":" ","pages":""},"PeriodicalIF":1.5,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147444632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modeling reveals temperature compensation and entrainment in the peroxiredoxin-based redox oscillator as an ancient circadian timekeeper.","authors":"Xuesong Luo, Qi Ouyang, Hongli Wang","doi":"10.1088/1478-3975/ae51fe","DOIUrl":"10.1088/1478-3975/ae51fe","url":null,"abstract":"<p><p>Peroxiredoxins (PRXs) are antioxidant enzymes that exhibit ∼24 h redox-state oscillations across diverse life forms. These non-transcriptional rhythms operate independently of the canonical transcription-translation feedback loops, suggesting an ancient, conserved timekeeping mechanism. However, whether this redox oscillator meets the core circadian criteria-entrainment and temperature compensation-remains a key question. To address this, we developed and calibrated a mathematical model of the mitochondrial PRX/ sulfiredoxin/thioredoxin redox cycle using physiologically meaningful parameters. The model quantitatively reproduced experimental redox oscillations in<i>A. thaliana, D. melanogaster</i>, and<i>M. musculus</i>. Simulations revealed that the PRX redox oscillator possesses both temperature-compensated periodicity and the capacity for entrainment by periodic thermal and oxidative signals, thereby fulfilling the core criteria of a circadian clock. The inverse angular speed, when integrated over the closed orbit, is largely temperature-invariant, thus providing a mathematical basis for the observed period stability. The calculated phase response curves, which show phase-dependent shifts, together with the broad Arnold tongue for 1:1 resonance, demonstrate a substantial entrainment range that enables the internal rhythm to robustly lock onto periodic environmental Zeitgebers.</p>","PeriodicalId":20207,"journal":{"name":"Physical biology","volume":" ","pages":""},"PeriodicalIF":1.5,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147459433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome size and nucleotide skews as predictors of bacterial growth rate.","authors":"Parthasarathi Sahu, Sashikanta Barik, Koushik Ghosh, Hemachander Subramanian","doi":"10.1088/1478-3975/ae5015","DOIUrl":"10.1088/1478-3975/ae5015","url":null,"abstract":"<p><p>Bacterial growth rates are constrained by genome replication, yet the role of replication kinetics in bacterial growth rates remains incompletely understood. Here, we examine if genome size, replichore organization, and nucleotide compositional asymmetry are reasonable predictors of bacterial doubling times. In free-living bacteria, both genome size and the length of the longest replichore are found to correlate positively with doubling time, pointing to an influence of replication dynamics on bacterial growth rates. Moreover, fast-growing bacteria are shown to exhibit stronger nucleotide compositional skew. Incorporating skew into the model substantially improves predictive accuracy, suggesting that compositional asymmetry in genomes may facilitate replication fork progression and thereby enhance growth rates. Based on these observations, we speculate that nucleotide skew may play a potential adaptive role in bacterial genome replication. To assess whether the observed association between genome architecture and growth rate reflects an evolutionary signature or a mechanistic link, we reconstructed ancestral states and found that the model fits ancestral traits more strongly, with predictive strength (<i>R</i>²) decreasing progressively along the evolutionary tree as successive speciations occur. We speculate that this association has been stronger early in bacterial evolution and became subsequently screened as organisms diversified and increased in ecological and physiological complexity.</p>","PeriodicalId":20207,"journal":{"name":"Physical biology","volume":" ","pages":""},"PeriodicalIF":1.5,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147435120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Androgen receptor activation stabilizes a hybrid epithelial/mesenchymal phenotype in presence of Notch-Jagged signaling.","authors":"Souvik Guha, Soundharya R, Baishakhi Tikader, Mohit Kumar Jolly","doi":"10.1088/1478-3975/ae5016","DOIUrl":"10.1088/1478-3975/ae5016","url":null,"abstract":"<p><p>Metastasis is a key cause of mortality in cancer. It is driven majorly by clusters of circulating tumor cells which are often comprised of cells in a hybrid epithelial/mesenchymal (E/M) phenotype. Hybrid E/M phenotype has also been shown to be more tumor-initiating and therapy-resistant, but how cells maintain the hybrid E/M phenotype(s) remains an active area of investigation. Here, we develop a mathematical model that couples the intracellular dynamics of key players of epithelial-mesenchymal transition with the androgen receptor (AR), and cell-cell communication through Notch-Delta-Jagged signaling, in the context of prostate cancer (PCa). Our simulations show that AR can stabilize a hybrid E/M phenotype predominantly in the presence of Notch-Jagged, but not Notch-Delta, signaling. Implementing this model on a multi-cellular lattice, we observed that AR can alter the fraction of cells exhibiting a hybrid E/M and a mesenchymal phenotype. Finally, through analysis of transcriptomic and patient survival data, we found that the co-expression of AR and Jagged correlated with worse outcomes. Together, these results highlight the outcome of emergent dynamics between the Notch and AR signaling axis in promoting PCa aggressiveness.</p>","PeriodicalId":20207,"journal":{"name":"Physical biology","volume":" ","pages":""},"PeriodicalIF":1.5,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147435128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liquid-liquid phase separation induces stochastic oscillations in gene regulation.","authors":"Lijun Hong, Zhenquan Zhang, Zihao Wang, Jiajun Zhang","doi":"10.1088/1478-3975/ae4afa","DOIUrl":"10.1088/1478-3975/ae4afa","url":null,"abstract":"<p><p>Rhythmic gene expression underlies core physiological processes across organisms, from circadian timekeeping to stress responses. Recent experiments suggest that the regulation of such rhythmic dynamics involves protein compartmentalization mediated by liquid-liquid phase separation (LLPS), yet the mechanisms by which LLPS feeds back onto oscillatory behaviour remain unclear. Here we develop a minimal two-phase gene-expression model in which proteins are synthesized in the dilute phase, reversibly partition into a protein-dense droplet phase, and repress their own production via condensate-mediated regulation. In the deterministic limit, LLPS does not generate limit cycles; instead, nonlinear partitioning and timescale separation between phase separation and protein turnover convert purely relaxational dynamics into damped oscillatory transients, altering the approach to equilibrium without producing sustained oscillations. In the stochastic regime, intrinsic noise interacting with this near-focus dynamics is amplified into noise-sustained, near-periodic fluctuations with a characteristic timescale, as revealed by the power spectral density and autocorrelation functions. These results show how LLPS reshapes oscillatory signatures by encoding and filtering temporal signals in phase-specific ways, providing a quantitative framework for interpreting LLPS-rhythm coupling and for engineering biomolecular systems with tunable dynamic behaviour.</p>","PeriodicalId":20207,"journal":{"name":"Physical biology","volume":" ","pages":""},"PeriodicalIF":1.5,"publicationDate":"2026-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147309308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative thermodynamic and kinetic properties governing the nucleic acid interactions of CRISPR-Cas9 and Cas12a.","authors":"Camila E Molina, Alexa L Knight, George P Lisi","doi":"10.1088/1478-3975/ae4b7f","DOIUrl":"10.1088/1478-3975/ae4b7f","url":null,"abstract":"<p><p>Clustered regularly interspaced short palindromic repeat-associated proteins (CRISPR-Cas) biochemistry has been leveraged for genome editing applications in biochemical research and therapeutics. CRISPR-Cas9 and CRISPR-Cas12a are the two most widely used RNA-guided endonucleases and while Cas9 and Cas12a have a shared function, both have unique biophysical properties that alter their specificity and efficiency. The thermodynamic and kinetic properties governing their molecular interactions, recognition and binding of target DNA, and R-loop formation can differ. In some cases, these critical biophysical metrics have not been resolved. Distinctions between Cas9 and Cas12a enzymes are also prevalent in RNA:DNA hybrid binding affinities, DNA localization relative to the preferred PAM site and the DNA cleavage mechanism. In this review, we examine the thermodynamic and kinetic properties of both endonucleases, focused on the nucleic acid interactions that confer specificity and function. Complementing this biophysical overview, we discuss case studies in disparate model organisms that compare the genome editing and fidelity of Cas9 and Cas12a.</p>","PeriodicalId":20207,"journal":{"name":"Physical biology","volume":" ","pages":""},"PeriodicalIF":1.5,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147318056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic modeling predicts efficacy of CISH knockout in tumor-infiltrating lymphocytes with synergistic gene editing.","authors":"Nikolaos Memmos, Kamran Kaveh, Beau R Webber, Branden S Moriarity, David J Odde","doi":"10.1088/1478-3975/ae4705","DOIUrl":"10.1088/1478-3975/ae4705","url":null,"abstract":"<p><p>Tumor-infiltrating lymphocyte (TIL) therapy is a type of adoptive cell therapy, where the lymphocytes of a cancer patient's tumor are harvested, expanded<i>in vitro</i>using IL-2 stimulation, and then infused back into the patient Rosenberg and Restifo (2015<i>Science</i><b>348</b>62-68), Bonini and Mondino (2015<i>Eur. J. Immunol.</i><b>45</b>2457-69). However, even with the use of TIL therapy, cancer cells can survive for various reasons, such as poor lymphocyte infiltration into tumors, chronic activation of the T cell receptor and the immunosuppressive tumor microenvironment Morgan<i>et al</i>(1976<i>Science</i><b>193</b>1007-8). Cytokine-inducible SH2-containing (CISH) protein is a negative regulator of T cell activation, and in a recent clinical trial was knocked out in TILs to improve TIL therapy efficacy Rosenberg<i>et al</i>(1985<i>J. Exp. Med.</i><b>161</b>1169-88). A mechanistic signaling pathway model was developed to theoretically evaluate the efficacy of<i>CISH</i>knockout (<i>CISH</i>KO) in T cell activation and examine potential alternative target genes that can theoretically be targeted using multiplex gene-editing or drugs to further improve T cell activation and function Donohue<i>et al</i>(1984<i>J. Immunol.</i><b>132</b>2123-8). Based on the results,<i>CISH</i>knockout increases the transcription of activation biomarkers IL-2 and TNF-<i>α</i>, but also inhibitory biomarkers such as PD1 and FasL. Using global sensitivity analysis, we also found that<i>GSK3B</i>, which is responsible for the deactivation of NFAT, is also predicted to further increase T cell activation when knocked out. In addition, it was predicted that<i>PDCD1, FAS</i>and<i>CTLA4</i>can be knocked out in combination with<i>CISH</i>to further enhance T cell activation and prevent exhaustion and apoptosis.</p>","PeriodicalId":20207,"journal":{"name":"Physical biology","volume":" ","pages":""},"PeriodicalIF":1.5,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146213877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}