Recent studies have suggested that under high or near-maximal mitochondrial respiratory activity, ion-translocating proteins within the inner mitochondrial membrane may generate transient nonequilibrium temperature fluctuations in the adjacent mitochondrial matrix and intermembrane space. Such nonequilibrium temperature fluctuations may, in principle, influence mitochondrial mechanics and morphology. Building on elastocapillary models of mitochondrial dynamics, we investigate whether these nonequilibrium temperature fluctuations can modulate the stability of mitochondrial tubules through temperature-dependent changes in effective membrane tension and elasticity. Our numerical analysis predicts that this effect is strongly threshold-dependent: in deeply unstable states, thermal modulation remains insufficient to restore stability, whereas closer to the threshold, temperature-dependent reduction of effective membrane tension can overcome temperature-dependent elastic softening, thereby increasing the elastocapillary number, suppressing unstable modes, and shifting mitochondria toward mechanically more stable tubular states. In other words, when mitochondria begin shifting toward fission-promoting states, elevated respiratory activity, which increases the magnitude and cumulative temporal occupancy of transient thermal perturbations, tends to shift the system back toward mechanical stability. However, when mitochondria are already far within the mechanically unstable regime, transient thermal activity is no longer sufficient to restore stability. This stabilizing regime is qualitatively consistent with experimental observations linking elevated oxidative phosphorylation to mitochondrial elongation, fusion, or hyperfusion rather than fragmentation.
The retina is both metabolically active and exposed to light, resulting in persistent heat generation. However, the quantitative contributions of metabolic and irradiative heat sources, and the mechanisms responsible for dissipating this thermal load, remain incompletely characterized. Here we develop a steady-state quantitative thermal balance model of the retina that integrates heat production from metabolic activity and light absorption with multiple heat dissipation pathways into a unified energy balance framework. Metabolic heat was estimated from reported ATP consumption rates under dark-and light-adapted conditions, while irradiative heat input was quantified based on environmental luminance, pupil size, and ocular optics. These inputs were incorporated into a lumped energy balance in the form of, allowing calculation of the retinal temperature elevation relative to blood,. Heat dissipation pathways, including conduction to surrounding tissue, choroidal blood perfusion, convection, and radiation, were expressed as thermal conductances,and analyzed within the same framework,. Under sunlight, total retinal heat input reached approximately 10 mW, approximately threefold higher than at night. Despite this, the predicted steady-state retinal temperature elevation remained very small (∼10-3K), suggesting that heat is dissipated highly efficiently. The analysis shows that conduction and choroidal blood perfusion dominate retinal heat removal under physiological conditions, whereas radiation and convection contribute negligibly. The results suggest that retinal heat redistribution via conduction plays a major role in retinal thermal homeostasis, whereas choroidal blood perfusion primarily contributes to subsequent systemic heat removal rather than acting as a dominant limiting mechanism itself. This analysis provides quantitative support for the long-standing hypothesis that the choroid functions as a heat sink for the retina.
High mobility group box-1 (HMGB1) is a damage-associated molecular pattern and a ligand for multiple immune receptors, including receptors for advanced glycation endproducts (RAGE) and toll-like receptor 4 (TLR4). Binding of HMGB1 to these receptors initiates inflammatory signaling cascades implicated in diseases such as septic shock, chronic inflammation, and autoimmune disorders. The spatial and molecular mechanisms underlying HMGB1-mediated receptor signaling at the plasma membrane remain poorly understood. Here, single-particle tracking was used to investigate the effects of extracellular HMGB1 on RAGE's and TLR4's diffusion properties in human embryonic kidney 293 (HEK293) cells. HMGB1 treatment reduced the Brownian diffusion coefficients by 27% and 24% for RAGE (with and without TLR4 co-expression, respectively) and by 40% and 21% for TLR4 (with and without RAGE co-expression, respectively). HMGB1 treatment reduced the size of the confined domains the receptors diffuse into and increased the number of times the two receptors came in close proximity. In contrast, HMGB1 had no detectable effect on the diffusion properties of an S391A RAGE mutant, which lacks the ability to recruit adapter proteins. Lipid diffusion measurements revealed that HMGB1 treatment decreases lipid membrane fluidity in all cell lines studied. Similarly, phalloidin staining revealed no detectable HMGB1-induced changes in actin organization in RAGE expressing cells. Functionally, HMGB1 treatment activated the extracellular signal-regulated kinase (ERK) (1/2) signaling pathway through both RAGE and TLR4, whereas ERK (1/2) and p38 MAPK activation by HMGB1 were abolished in cells expressing S391A RAGE. Together, these findings show that HMGB1 reduced confined receptor diffusion and increased nanoscale proximity while promoting MAPK signaling. This work sheds new light on the nanoscale regulation of innate immune receptors by HMGB1 and emphasizes membrane biophysics as one critical component of inflammatory signaling outcomes.
Co-transcriptional splicing and protein self-assembly are governed by coupled kinetic and thermodynamic constraints, such that modest changes in exon processing can propagate into substantial shifts in isoform-dependent mesoscale behavior. Here, we develop a cross-scale physical framework to examine whether transcription-associated kinetic pressure could differentially bias CPEB4 microexon selection and thereby reshape downstream isoform behavior. Using a simplified transcriptional kinetic model, we define an acetylation-associated high-throughput regime as a coarse-grained proxy for reduced time available for co-transcriptional exon recognition. Comparative sequence and structural analyses identify microexon 4 (me4) as less robust than microexon 3 (me3), with weaker cis-regulatory support and lower thermodynamic stability, consistent with greater susceptibility to omission under kinetically constrained conditions. A reduced probabilistic splicing framework accordingly predicts a directional bias against me4, superimposed on a basal transcript landscape in which the full-length isoform remains present. As a complementary downstream analysis, scaled-particle-theory calculations indicate that representative Δ4-enriched scenarios thermodynamically favor homotypic self-association under macromolecular crowding, suggesting a plausible physical amplification route for modest splicing bias. Orthogonal measurements in a yeast perturbation system identify oxidative and spectroscopic signatures compatible with strong butyrate-associated physicochemical stress, but these are interpreted as perturbation readouts rather than direct measurements of neuronal histone acetylation or splicing. Together, these results define a testable cross-scale framework linking transcription-associated kinetic constraints, directional microexon susceptibility, and crowding-dependent remodeling of the CPEB4 isoform assembly landscape.
In this article, we integrate the release of Wolbachia-carrying male mosquitoes with chemical insecticide spraying to formulate a coupled model that incorporates mosquito stage structure and malaria transmission dynamics. The model accounts for mating competition influenced by cytoplasmic incompatibility and employs a Holling-II type saturated release mechanism to dynamically match the release intensity of infected male mosquitoes with the density of wild mosquitoes. The study first verifies the positive invariance and boundedness of solutions of the model. It then derives the basic reproduction number, followed by the existence conditions and stability properties of equilibria. Subsequently, it reveals saddle-node bifurcation, forward bifurcation, backward bifurcation and their compound phenomena, thereby elucidating the abrupt dynamic changes near parameter thresholds of the system. Numerical simulations validate the theoretical results, quantify the regulatory effects of key parameters, and confirm that the combined strategy effectively suppresses mosquito population growth and interrupts malaria transmission through synergistic effects. The results illustrate that accurate tuning of critical parameters for the integrated control strategy and exploitation of synergism between Wolbachia and chemical insecticides can effectively modulate mosquito populations and block malaria transmission.
