In this paper, we consider a run-and-tumble particle (RTP) with stochastic resetting confined to the half line [0,∞) with a sticky boundary at x=0. In the bulk, the RTP tumbles at a constant rate α>0 between velocity states ±v with v>0 and randomly resets to its initial position and orientation (x_{0},k_{0})∈(R^{+},±). When the RTP reaches the target at x=0, it attaches to the boundary for some random waiting time before either detaching and continuing to navigate the bulk domain or (permanently) entering the target. These events are the analogs of adsorption, desorption, and absorption of a particle by a partially reactive surface in physical chemistry. We use renewal theory to characterize the particle trajectory in terms of successive binding events at x=0 under two distinct desorption protocols: via resetting to (x_{0},k_{0}) and via continuous movement from x=0 with velocity +v. First, we derive the nonequilibrium stationary state (NESS) in the case of no absorption and characterize the accumulation at the boundary. Second, we compute the mean first passage time (MFPT) statistics. In addition to observing the usual unimodal dependence of the MFPT on bulk resetting, both the NESS and MFPT strongly depend on the initial orientation k_{0} and the desorption protocol. For instance, if the initial orientation is toward the boundary, we find that the desorption-induced resetting protocol can reduce the MFPT more effectively than the nonresetting desorption protocol. We also show how matching the desorption kinetics with the bulk resetting or tumbling rate introduces a tradeoff between minimizing the adsorption and absorption times. In this setting, we find that the desorption protocol which minimizes the absorption MFPT for a given set of parameters is almost always the opposite of that favored when desorption and bulk kinetics are not the same. These results collectively highlight the utility of the renewal formalism in characterizing two distinct desorption protocols particular to an RTP.
A simple and broadly applicable a posteriori stochastic resetting protocol that enables the exploration of resetting dynamics without physically performing resets during experiments is proposed. To demonstrate the utility and applicability of the method, we apply it to an autonomous Hexbug robot navigating within a confined rectangular arena with reflecting like boundaries and a single absorbing target (hole). In each trial, the Hexbug starts from a fixed initial position and is allowed to move freely until it reaches the target, marking the first passage time (FPT). This process is repeated for 201 independent realizations to build an empirical distribution of FPTs. Instead of applying resets during the experiments, we implement stochastic resetting a posteriori by applying exponentially distributed resets (i.e., Poissonian resetting) to the recorded FPTs. This strategy allows us to compute the mean first passage time (MFPT) at any reset rate without perturbing the experiments. Moreover, this method generates a new set of FPTs every time the algorithm is implemented. This enables one to render a theoretically infinite amount of data from a small experimental dataset. Our results reveal a clear nonmonotonic dependence of the MFPT on the reset rate, with a distinct minimum, a hallmark signature of optimal resetting. Furthermore, the data generated by the algorithm also obey Reuveni universality. This strategy can be indispensable in setups in which physical resetting is not feasible. It circumvents the challenges of repeated experimental resets, offering an accessible platform to investigate optimization strategies and/or first passage phenomena.
Intervertebral disc degeneration (IDD) is the leading pathological cause of low back pain, while current clinical treatments are only palliative and cannot reverse the programmed cellular senescence driven by epigenetic dysregulation. This process is characterized by progressive loss of nucleus pulposus (NP) cell identity and establishment of a self-amplifying senescence-associated microenvironment. In this review, we synthesize recent advances elucidating how heterogeneous senescent cell populations and their secretory phenotype (SASP) orchestrate a destructive vicious cycle in IDD. We further dissect the synergistic interplay among DNA methylation, histone modifications, and non-coding RNAs that constitutes the "epigenetic aging clock" and drives premature cellular aging within the disc. Notably, we evaluate emerging therapeutic strategies aimed at clock reversal, including senolytic clearance of senescent cells, epigenetic remodeling using small-molecule inhibitors or CRISPR-dCas9 editing, and cellular reprogramming approaches ranging from iPSC differentiation to direct lineage conversion. We propose a synergistic "clear, prime, then seed" roadmap that sequentially combines these interventions for optimal regeneration. This work provides a systematic theoretical framework for the clinical translation of epigenetic-targeted therapy for IDD, and breaks through the cognitive limitation of traditional mechanical wear theory.
Skin aging reflects not only the accumulation of molecular damage, but also a progressive decline in the skin's ability to restore equilibrium under continuous environmental stress. Classical models distinguishing intrinsic and extrinsic aging do not fully capture this dynamic process. In this article, we introduce Homeodynamic Rejuvenation as the restoration of functional competence and biological vitality, achieved not through reversal of visible signs of aging, but by re-establishing the skin's ability to detect stress, coordinate adaptive responses, and recover efficiently following perturbation. Central to this framework is the concept of homeodynamic plasticity, which reflects the skin's intrinsic capacity to dynamically sustain function under environmental and metabolic stress. By integrating principles of homeodynamics with exposome biology, this approach targets the reactivation of the cellular systems that govern stress sensing, repair, and recovery. Five core biological processes, namely, intracellular quality control, regenerative competence, metabolic resilience, cellular integrity, and structural integrity, underpin homeodynamic plasticity. Disruption or failure of one or more of these processes results in progressive functional decline, culminating in skin aging, of which dermatoporosis, a chronic cutaneous insufficiency syndrome, represents a terminal manifestation. These interconnected processes provide a coordinated basis for both restoring and assessing skin function. We propose that Homeodynamic Rejuvenation is best evaluated through dynamic perturbation-recovery kinetics, which quantify the skin's ability to respond to and recover from stress. By linking these biological processes to measurable functional and clinical outcomes, Homeodynamic Rejuvenation offers a structured and translational framework for quantifying and restoring skin resilience.
Many plant species can propagate asexually or be regenerated in vitro; but asexual offspring are more likely to maintain environmentally induced epigenetic marks, for instance, inheritance of the prolonged cold-induced 'vernalized state' in overwintering plants through asexual reproduction. Here we demonstrate that 'vernalized state' is reprogrammed during Arabidopsis asexual propagation through somatic embryogenesis. This overturns a long-standing idea, that the vernalized state could not be reset through asexual reproduction, and provides a strategy to erase parental effects on offspring during asexual reproduction.
Two principal strategies have gained prominence among currently recognised approaches to anti-ageing: systemic interventions that modulate the circulatory environment and cellular interventions that reset epigenetic information. Systemic approaches, beginning with experimental heterochronic parabiosis models that are not applicable to humans and extending to clinically applicable therapeutic plasma exchange, test the hypothesis that ageing is promoted by the accumulation of inhibitory blood-borne factors. Cellular reprogramming, particularly partial reprogramming through transient expression of Yamanaka factors, tests the alternative hypothesis that ageing is primarily a cell-intrinsic process associated with loss of epigenetic information. This perspective critically evaluates these two modalities. The dilution hypothesis is examined together with its limitations and the unresolved complexities of systemic interventions. The challenge of cell-autonomous ageing is also considered, particularly the persistence of cell populations that remain refractory to systemic rejuvenation. A conceptual framework integrating these two axes of ageing is then presented. This framework suggests that combined systemic recalibration and targeted partial reprogramming warrant further investigation as a multimodal approach to ageing intervention. Future research priorities include mechanistic clarification of this systemic-cellular interaction and development of robust biomarkers to evaluate multimodal interventions.
In mammals, circadian phase shifting during the daytime is limited by reduced photic responsiveness of the suprachiasmatic nucleus (SCN), restricting the ability to experimentally manipulate the circadian clock during this phase. Reliable methods to induce daytime phase shifts are therefore essential for investigating mechanisms of circadian plasticity and photic entrainment. Complementary genetic and spectral strategies are described to enable robust, temporally precise manipulation of the circadian clock during the day. The first approach, currently limited to mice, employs a chemogenetic strategy involving intravitreal delivery of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to selectively activate intrinsically photosensitive retinal ganglion cells (ipRGCs). This approach permits controlled activation of the retinohypothalamic pathway and induces reproducible daytime phase shifts independent of ambient lighting conditions. The second approach utilizes wavelength-specific optical stimulation as a non-invasive alternative. Exposure to violet light exploits the spectral sensitivity of ipRGCs to reduce depolarization block and promote sustained activation, enabling reliable phase resetting during the subjective day. This method is broadly applicable across mammalian systems and does not require genetic manipulation or pharmacological intervention. Detailed protocols are provided for experimental preparation, stimulation timing, validation of phase shifts using locomotor activity, and assessment of neuronal activation via c-Fos immunohistochemistry. Key considerations, including circadian timing, stimulus parameters, and experimental controls, are outlined to facilitate reproducibility. Together, these approaches provide versatile and experimentally tractable tools for inducing daytime circadian phase shifts and enable direct investigation of mechanisms underlying daytime circadian responsiveness.
The problem of a sharp increase in pain after resolution of a nerve block, known as rebound pain, has been increasingly recognized. It is currently unknown whether rebound pain simply reflects the unmasking of untreated, residual surgical pain, or if it represents a de novo hyperalgesic state driven by a mechanistic resetting of pain thresholds in response to regional anesthesia. In this study, we assessed nociceptive processing after a single-injection axillary brachial plexus block in healthy volunteers, to detect whether a previously blocked arm displayed objective hypersensitivity, in the absence of surgical pain. Healthy volunteers received a single-injection axillary brachial plexus block using 15cc of mepivacaine 1.5%, with their contralateral unblocked arm serving as a control. Pain sensitivity between arms was compared using a range of Quantitative sensory testing (QST), comparing punctate, pressure and heat pain using paired t-tests or Wilcoxon sign-rank-tests. The primary outcome was heat pain threshold to 1/10 pain, compared between previously blocked and control arms at 60-minutes post-motor-resolution (MR), with secondary outcomes being other modalities compared at this timepoint. Additionally, we explored differences in maximally sensitized values during the entire post-block period. All 40 participants (age:19-64 years, 60% female) completed the study. At 60-minutes post-MR, heat pain threshold to 1/10 pain was not significantly different between arms (block:42.8±2.6°C, control:41.1±0.4°C; p=0.157), nor were other sensory modalities, except for heat pain threshold to 5/10 pain, where control arm was more sensitive than block arm. When examining the maximally sensitized values including 3-hours after MR, the control arm showed greater sensitivity in some tested modalities (punctate pain threshold and painful after sensations), but not others (heat and pressure pain thresholds and tolerances, temporal summation of pain). Multimodal pain testing revealed no evidence of post-block hypersensitivity during resolution of a single-injection axillary brachial plexus block.
Optogenetic stimulation of deep brain regions is limited by rapid light divergence in soft tissue, mechanical damage from rigid optical fibers, and the impracticality of active beam control systems that require external power. This study introduces a passive, biocompatible solution based on soft parabolic-index hydrogels that stabilize the phase of propagating Gaussian beams without any external energy. Using beam propagation method simulations and phase-resolved analysis, we demonstrate three main findings: first, the proposed hydrogel maintains periodic focusing and defocusing cycles along the propagation path. Second, the transverse wavenumber becomes discrete and quantized, which confirms preservation of spatial coherence. Third, the optical phase undergoes periodic resetting to its initial value after each oscillation cycle, ensuring predictable beam focus at regular intervals. Furthermore, we show that the phase-intensity correlation stabilizes rapidly after initial propagation, and that the phase accumulation rate can be tuned by adjusting the gradient coefficient of the hydrogel. These findings establish that graded-index hydrogels can function as passive, implantable optical waveguides for delivering phase-stable, focused light to precise neural targets. This technology directly resolves the three major obstacles in optogenetic neural stimulation devices: light delivery, tissue damage, and reliance on external power.
Video foundation models show strong potential for interactive volumetric medical image parsing but can suffer from memory drift when applied directly to 3D medical volumes with severe, patient-specific topological changes. In the evaluated settings, standard reactive memory architectures and geometric prompts provide limited guidance for newly appearing, fragmented, or low-contrast structures, which can lead to accumulated segmentation errors. To mitigate this issue, we introduce a generative anticipatory framework that augments reactive tracking with morphological forecasting. By combining the semantic reasoning of large language models with the continuous latent dynamics of neural stochastic differential equations, our approach forecasts plausible anatomical trajectories. We propose an uncertainty-guided dual-stream memory architecture to integrate these forecasted priors with noisy visual evidence. This mechanism uses predictive spatial variance to balance empirical visual observations and forecasted priors, improving topological consistency under challenging imaging conditions in our benchmarks. We further formulate human-in-the-loop interactive corrections via Bayesian state resetting, translating expert interventions into more efficient volumetric correction. Evaluations across diverse clinical datasets show strong training-free generalization, improved robustness to morphodynamic variation, and higher interactive efficiency among the evaluated methods. These results suggest a promising uncertainty-aware direction for promptable volumetric medical segmentation.
Cancer treatment using immune checkpoint blockade (ICB) with anti-PD-1 and anti-CTLA-4 has been successful. However, primary and acquired resistance limits clinical benefit. To improve the effectiveness of ICB therapies, strategies that reorchestrate anti-tumor immunity through mechanism-based drug combinations are being actively explored. The alkylating chemotherapeutic agent cyclophosphamide (CTX) has direct tumoricidal and immunomodulatory properties, including the induction of homeostatic proliferation of T cells. Since ICB suppresses inhibitory signals in T cells, ICB might be able to augment CTX-induced homeostatic proliferation of antigen-specific T cells, thereby resetting the T cell receptor (TCR) repertoire in favor of tumor-specific T cells. Here, we showed that a single dose of CTX one day prior to starting αPD-1+αCTLA-4 treatment was sufficient to delay tumor progression in established melanoma and prolong survival in tumor-bearing mouse models. These effects extended to other lymphodepleting treatments, such as gemcitabine and radiation therapy. The anti-tumor immune response was mainly driven by the clonal expansion of activated/effector CD8+ tumor infiltrating lymphocytes. Furthermore, combined CTX and αPD-1+αCTLA-4 treatment demonstrated efficacy across additional preclinical tumor models, including colorectal cancer and triple negative breast cancer. Overall, these findings highlight that the combination of CTX and ICB represents a clinically relevant approach in the treatment of immunotherapy-refractory tumors.
Cancer interventions are traditionally described as either "curative" or "palliative," but evolving cancer biology and new treatments have transformed some cancers into chronic diseases where surgery plays a non-curative, disease-targeted role. We conducted semi-structured interviews with cancer surgeons via purposive snowball sampling, exploring two hypothetical scenarios and discussing "disease-control" surgery as a category of neither palliative nor curative surgical intent. Interviews were thematically analyzed. Eighteen surgeons from 16 US institutions described how evolving cancer treatment paradigms challenge existing language for surgical intent. "Disease-control" surgery captured new adjuvant surgical roles including debulking to improve systemic therapy efficacy, resection of treatment-resistant disease, and "resetting the clock" for indolent tumors. Surgical goals are increasingly defined by individual patients' broader multidisciplinary treatment trajectory. Traditional "curative" versus "palliative" categories inadequately describe contemporary cancer surgery. New frameworks aligned with current understandings of cancer biology and new treatment modalities may facilitate clearer communication about surgical goals and enable developing appropriate research outcome measures. These findings highlight a need for standardized surgical intent terminology. Broader validation through multidisciplinary stakeholder engagement is needed to refine and implement this proposed framework.
Rhythmic sniffing is considered intrinsic to active olfaction among terrestrial mammals. However, mice are known to briefly hold food under their nares while feeding, suggesting coordination of oromanual dexterity, breathing, and olfaction for nonrhythmic single sniffs. Here, we recorded kinematics and breathing as mice foraged and fed, finding that mice indeed, with clockwork-like dexterity and millisecond timing, synchronize a single inspiration with rapid head and hand movements. These solitary food sniffs are associated with abrupt resetting of the breathing rhythm, differ from stereotypical rhythmic sniffing, and exhibit behavioral modulations for different food properties. Olfactory and motor circuit manipulations demonstrate motor cortical dependence rather than reflexive neural control. Our study extends the concept of active olfaction to include this distinct form of complex motor-sensory coordination, features of which accord with the idea of discrete "snapshot" olfaction.
Regulatory T cells (Tregs) are pivotal for maintaining immune tolerance, yet their dynamic changes during the transition from active disease to remission in systemic lupus erythematosus (SLE) remain unclear. We assessed whether specific Treg subpopulations can serve as biomarkers of clinical recovery. We conducted longitudinal immunophenotyping in eight patients with SLE across healthy, active, and stable disease states tracking CD3+CD4+CD25^highCD127^low/-FoxP3+ Tregs, natural Tregs, and activated Tregs. In contrast to static deficiency models, our longitudinal analysis revealed a distinct dynamic pattern: FoxP3+ Tregs particularly natural and activated subsets expanded during active disease, consistent with a compensatory response, and contracted toward baseline with clinical stabilization. The transient expansion and subsequent normalization of Treg subsets distinguish active inflammation from stable remission, serving as a potential immunophenotypic signature of successful immune resetting in SLE.
Cell-autonomous circadian clocks are essential for organisms to adapt to daily environmental changes and optimize physiological timing. However, the common initial signaling events shared by diverse synchronizing cues-such as light, temperature, and drugs-remain elusive. Here, we investigated the relationship between clock synchronization and subcellular localization dynamics of core clock proteins, BMAL1 and CLOCK, in NIH-3T3 fibroblasts. We identified an immediate, synchronized nuclear accumulation of BMAL1 immediately following various clock-resetting treatments, termed the "Immediate Synchronization Response" (ISR). This was accompanied by nuclear CLOCK accumulation. ISR phenomenon was also observed in other rodent clock cell models like C6 glioma cells. Mechanistically, phosphorylation of BMAL1 at Ser90 by Casein Kinase 2 (CK2) increased immediately upon stimulation. Consistent with the role of this phosphorylation in promoting nuclear BMAL1, pharmacological CK2 inhibition partially suppressed both the acute increase in Per2 expression and the clock phase shifts. Furthermore, mathematical simulation analysis supported the notion that increased phosphorylation levels of BMAL1 and its subsequent nuclear localization could serve as a driving force for phase shifts in the circadian oscillatory system. In conclusion, our findings suggest that BMAL1-ISR acts as a key integrative "switching signal" linking diverse synchronization cues to molecular clock oscillations.
Foundational work in Neurospora set the stage for recent enormous gains in understanding fungal clocks, revealing in depth their regulatory architecture which parallels that of animal clocks. Mechanistic descriptions of photoreception and light-resetting and a complete inventory of core components accompanied quantal leaps in understanding how components work together to build a compensated clock. These advances are contributing to understanding clocks in myriad other fungi including several of agricultural importance.
Patients with systemic lupus erythematosus (SLE) are at markedly increased risk of premature atherosclerosis (AS) and atherosclerotic cardiovascular disease (ASCVD), and this excess risk is not fully explained by traditional Framingham factors. Increasing evidence suggests that SLE does not merely coexist with AS; rather, persistent immune activation and immunometabolic dysregulation reshape the vascular microenvironment toward endothelial dysfunction, lipoprotein impairment, maladaptive myeloid activation, and immunothrombosis. This review synthesizes current epidemiologic, mechanistic, and translational evidence supporting an immune-metabolic-vascular framework for SLE-accelerated AS. We focus on four interconnected processes: (1) type I interferon (IFN-I)-associated endothelial injury and defective vascular repair; (2) neutrophil extracellular traps (NETs) and oxidative modification of high-density lipoprotein, contributing to dysfunctional or pro-inflammatory HDL; (3) monocyte/macrophage immunometabolic reprogramming, which favors foam-cell formation and inflammasome activation; and (4) T- and B-cell metabolic disequilibrium, which sustains vascular inflammation and autoantibody-driven immune injury. Across these pathways, metabolic rewiring appears to function not merely as a parallel phenomenon, but as a shared amplifier linking systemic autoimmunity to lesion-level vascular progression. Recognizing these shared checkpoints has therapeutic implications. These observations suggest that future strategies may need to integrate upstream metabolic resetting, midstream immune-specific blockade, and downstream lipid or vascular-wall protection, rather than relying solely on lipid lowering or broad immunosuppression. However, most available evidence remains confined to mechanistic studies, biomarker readouts, or surrogate vascular endpoints, and dedicated trials with plaque or cardiovascular event outcomes are still needed.
The monoterpene 1,8-Cineol is a natural plant-based anti-inflammatory agent that is used to treat different respiratory diseases with regard to its mucolytic and anti-microbial properties. 1,8-Cineol has recently been shown to support the natural microbial colonization of the middle ear, the intestinal bacterial community, as well as the clinical inflammatory situation of patients with chronic otitis media (COM). The aim of this study was to understand better the influence of 1,8-Cineol treatment on the systemic balances of inflammatory mediators of the interleukin-10 (IL-10) family of cytokines. Plasma concentrations of cytokines IL-10, IL-19, IL-20, Il-22, IL-24 and IL-26 were analyzed in patients with COM with regard to 1,8-Cineol (CNL-1976®) treatment using ELISA measurements. Data revealed significantly increased concentrations of cytokines IL-19 and IL-26 in plasma samples from patients with COM compared to healthy donors as well as a significant positive correlation between IL-10 and IL-19. Of note, patients with COM revealed significantly reduced plasma levels of IL-26 in response to 14 days of 1,8-Cineol administration. 1,8-Cineol treatment actively modulates the systemic inflammatory environment in patients with chronic otitis media. By resetting disrupted cytokine balances, this plant-based agent offers a promising, target-specific therapeutic strategy for managing persistent middle ear inflammation and potentially mitigating associated systemic comorbidities.
The circadian system aligns behavior and physiology with the 24-hour environmental cycle through a distributed network of clocks including the master pacemaker in the suprachiasmatic nucleus (SCN) and an autonomous retinal clock critical for local retinal physiology and function. Although both clocks are entrained by light, they differ in their photoreceptor inputs and light sensitivity. The specific contributions and mechanisms by which distinct photoreceptor pathways drive their photoentrainment, however, remain incompletely understood.In this study, we conducted a comprehensive transcriptomic and integrative comparative analysis of retinal and SCN circadian responses to 530 nm monochromatic light using mouse models lacking specific photoreceptors or key components of signaling pathways. Under photopic conditions, we found that each tissue displays distinct light-responsive transcriptional signatures across genotypes, yet both shared a conserved cluster of rod-driven immediate early-genes. Strikingly, the light-evoked transcriptional response was not sufficient to shift the phase of the SCN clock, in contrast to its robust phase-shifting effect on the retinal clock. Furthermore, by genetically disrupting rod/cone electrical coupling and pharmacologically isolating rod pathways, we identified the OFF-cone bipolar cell circuit as both necessary and sufficient to mediate light-induced phase resetting of the retinal clock. Together, these findings delineate the specialized retinal circuitry that supports circadian entrainment and highlight a fundamental divergence between retinal and SCN mechanisms of photic timekeeping.
Treating autosomal dominant polycystic kidney disease (ADPKD) has always been a challenge because the disease is too complex for single-target drugs, which are often held back by side effects. This narrative review explores a different strategy: using plant-derived polyphenols to target multiple disease pathways at the same time. Looking at research from 2005 to 2026, we break down how key compounds like resveratrol, curcumin, naringenin, quercetin, and epigallocatechin-3-gallate (EGCG) actually work. Preclinical studies show these molecules can slow down cyst growth by tackling inflammation, rapid cell division, and tissue scarring all at once, while also resetting the skewed energy metabolism of cystic cells. Some mechanisms are strikingly specific, such as naringenin's direct interaction with polycystin-2 and quercetin's ability to clear senescent cells. Yet, the real-world hurdle is poor absorption; a recent clinical trial with standard curcumin fell short simply because the compound could not reach the kidneys in high enough concentrations. Moving forward, the field needs to focus on testing these compounds in realistic animal models, designing smart nanoformulations to improve bioavailability, and exploring combinations that could safely complement current therapies like tolvaptan.