Search Results (320)

The reproductive stage is a critical time in a plant’s life history when dealing with heat stress as the specific processes of meiosis, gametogenesis, anthesis, pollination, fertilization, and early seed development all occur within comparatively narrow temperature limits. Much of the importance of flowering is tied directly to temperature, both for the timing of reproductive transition and the ability for male and female reproductive tissues to survive exposure to damaging heat. Ambient-temperature sensing is linked to flowering via regulatory modules that involve phytochrome B, EARLY FLOWERING 3 (ELF3), PHYTOCHROME INTERACTING FACTOR 4 (PIF4), FLOWERING LOCUS T (FT), FLOWERING LOCUS M (FLM), SHORT VEGETATIVE PHASE (SVP), and the light–circadian components. Conversely, when temperature is harmful, protective responses involve other cellular mechanisms such as activation of heat-shock transcription factors (HSFs), heat-shock proteins (HSPs), endoplasmic-reticulum protein quality control, calcium and reactive oxygen species (ROS) signaling, antioxidant systems, hormone regulation, metabolic reprogramming, autophagy and DNA-repair pathways. Male reproductive development is often very sensitive, especially at meiosis, during formation of the tetrad, microspore development, during the maturation of pollen, and during the growth of the pollen tubes, although injury to pistils, ovules and the post-fertilization tissues may solely have an effect on the restriction of fertilization and seed set. Phenological heat escape and intrinsic reproductive thermotolerance are genetically separable but can be complementary aspects of adaptation, as revealed by natural allelic variation, QTL mapping, genomic prediction and marker assisted selection. This review summarizes molecular, genetic and physiological evidence, to propose that, to ensure stable yields at high temperatures, there is a need to coordinate optimization of reproductive timing, cell and development thermotolerance, and post-fertilization sink stability. Full article

Circadian–behavioral misalignment, defined as a mismatch between internal circadian timing and daily sleep activity behavior, is associated with sleep quality, daytime function, cognitive performance, and long-term health risks. However, practical approaches for integrating circadian-phase-related physiological markers with behavioral and environmental sensing under free-living conditions remain limited. This study presents a multimodal wearable and lifelog monitoring workflow that combines a heat-flux-based wearable temperature-estimation sensor, a wrist-worn actigraph, melanopic equivalent daylight illuminance (EDI) measurement, and web-based lifelog entries. Ten healthy young adults were monitored for approximately one week in daily life. The midpoint between the descending and ascending mid-level crossings of the nocturnal temperature rhythm was extracted as a circadian-phase-related temperature rhythm marker. In a practical comparison with gastrointestinal temperature measured using an ingestible capsule, the wearable-derived rhythm marker showed a mean absolute difference of 27.1 ± 16.6 min. The temporal difference between the two markers was defined as the phase angle, and coupling stability was evaluated using phase angle variability and the correlation between the markers. After excluding one participant who traveled overseas, clustering and principal component analyses were used to visualize exploratory participant-level differences in circadian–behavioral coupling. Integrated analysis with melanopic EDI, activity, and lifelog-derived features suggested that light exposure, activity timing, and behavioral timing may provide contextual information for interpreting coupling patterns in this small cohort. These findings support the feasibility of a sensing system application that integrates physiological, behavioral, environmental, and lifelog data for the exploratory assessment of circadian–behavioral coupling under free-living conditions, rather than the development of new sensor hardware. Full article

Obesity affects nearly one in three women of reproductive age worldwide and consistently reduces success rates in in vitro fertilization, yet the molecular basis for this reduction remains fragmented across separate lines of evidence. Circadian clock genes, particularly BMAL1, orchestrate metabolic and reproductive physiology through transcription–translation feedback loops present in adipose tissue, ovarian granulosa cells, and endometrial stroma. Adiposity-driven metabolic shifts, including altered PPAR-γ signaling and reduced glutamine–methionine uptake, degrade BMAL1 expression and flatten its rhythmic oscillation in peripheral tissues. Within granulosa cells, loss of BMAL1 rhythmicity impairs mitochondrial biogenesis and disrupts UPRmt-mediated proteostasis, driving reactive oxygen species accumulation and compromising oocyte competence. Parallel disruption of clock-controlled transcription factors in endometrial epithelium and stroma is proposed to alter decidualization programs and displace the window of implantation, which would produce a receptivity defect independent of oocyte quality if confirmed directly in human tissue. Clinical data are consistent with a dual mechanism: obese women undergoing donor-oocyte cycles—where oocyte quality is controlled for—show reduced implantation rates in several but not all cohorts—a pattern compatible with an endometrial contribution distinct from oocyte-level damage, rather than proof of it. Synthesizing evidence from adipocyte biology, ovarian physiology, and endometrial receptivity research drawn largely from rodent models, cultured cell systems, and observational human cohorts, this review proposes BMAL1 dysregulation as a candidate unifying mechanism connecting obesity to impaired IVF outcomes at the gametic and uterine level, while acknowledging that direct causal evidence in humans is still lacking. Chronotherapeutic strategies, including melatonin supplementation and the timing of weight-loss interventions relative to ovarian stimulation, are discussed as hypotheses for future testing rather than current clinical recommendations. BMAL1 dysregulation is presented here as one candidate contributor among several interacting mechanisms, and any translational strategy would need to be part of a broader, coordinated approach to obesity-related IVF failure rather than a stand-alone intervention. Full article

The stress response is essential for cellular and organismal survival as it acts as a protective and adaptive mechanism to maintain homeostasis. At the organismal level, physical stressors induce responses in mammals that are mediated primarily by the hypothalamic–pituitary–adrenal (HPA) axis, which regulates glucocorticoid secretion. The HPA axis functions as a circadian-regulated, multi-oscillator system, in which the paraventricular nucleus, the pituitary, and the adrenal gland exhibit intrinsic rhythmicity while remaining coordinated by the output from the suprachiasmatic nucleus. Glucocorticoids act both as stress effectors and systemic zeitgebers that synchronize peripheral clocks. At the cellular level, cellular stressors are sensed by four protein kinases of eukaryotic translation initiation factor 2α (eIF2α) and activate the evolutionarily conserved integrated stress response (ISR), which converges on phosphorylation of Serine 51 on eIF2α. ISR signaling is temporally regulated by the circadian clock and controls time-of-day-dependent protein synthesis. In parallel, ISR pathways feed back onto the circadian clock through transcriptional, translational and epigenetic mechanisms, directly influencing core clock gene expression and stability of circadian oscillations. Physiological ISR activity supports circadian robustness and resetting, whereas excessive ISR activation dampens rhythmic gene expression and destabilizes behavioral rhythms. The current review summarizes recent advances in our understanding of the crosstalk mechanisms between the HPA axis, ISR, and the circadian clock to provide new insights into disease mechanisms and inform chronotherapeutic strategies to target dysregulated HPA and ISR activities and restore temporal homeostasis. Full article

Background/Objectives: Diabetes mellitus is a chronic metabolic disorder characterized by impaired regulation of blood glucose due to defects in insulin secretion, insulin action, or both. Physiological and lifestyle factors vary among individuals. General medicine is not applicable to all patients. In this scenario, personalized medicine for each individual becomes costly. Effective management of continuous glucose levels with accurate insulin dosage is challenging. To overcome this, a digital twin (DT)-based insulin dosage simulator with an individual’s metabolic system is proposed in this work. Methods: Various machine learning techniques, mathematical models of physiology, and risk assessment using probability are used to predict the dynamics of patient-specific glucose–insulin. Parameters such as carbohydrate intake, sleep patterns, medications, and physical activity were incorporated into this model to capture real-world variations in daily life. For glucose–insulin interactions, the Bergman Minimal Model (BMM) is used; for time-of-day variability, a circadian insulin sensitivity model is used; and for predicting metabolic risks, Bayesian risk estimation (BRE) is used, which includes hyperglycemia risk. To enhance transparency and interpret model predictions, explainable artificial intelligence (XAI) methods are employed. Results: The simulation results showed improved glucose prediction accuracy, enhanced detection of hypoglycemia risk, and optimized insulin dosing strategies compared with traditional approaches. Conclusions: Overall, the proposed digital twin model offers a scalable solution using the latest techniques A “Prescriptive Analytical Framework” is provided using the BMM and BRE for personalized diabetes management and decision support for clinicians. Full article

Background/Objectives: Insulin clearance is a key determinant of circulating insulin availability, but its diurnal variation and relationship with circadian metabolic programs in metabolic dysfunction associated steatotic liver disease (MASLD) remain unclear. This study aimed to explore diurnal insulin clearance in humans and examine associated metabolic gene signatures in MASLD. Methods: A single-subject pilot assessment was performed to explore daytime-nighttime differences in insulin clearance rate (ICR) surrogate index, followed by evaluation using public hyperinsulinemic-euglycemic clamp datasets from healthy individuals and patients with MASLD. Public circadian transcriptomic datasets, spatial transcriptomic data, and a time course high-fat diet (HFD)-induced mouse dataset were integrated. A predefined panel of insulin clearance-related and circadian genes, including carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), insulin receptor (INSR), insulin-degrading enzyme (IDE), clock circadian regulator (CLOCK), basic helix-loop-helix ARNT like 1 (BMAL1), nuclear receptor subfamily 1 group D member 1/2 (NR1D1/2), period circadian regulator 1/2 (PER1/2), and cryptochrome 1/2 (CRY1/2), was analyzed. Results: The pilot assessment showed higher nighttime than daytime ICR, and independent clamp datasets showed a similar pattern in healthy individuals. In MASLD, nighttime ICR remained relatively higher, whereas overall insulin clearance was reduced compared with controls. Human blood-based circadian transcriptomic datasets identified rhythmic expression patterns of selected genes involved in insulin clearance and circadian regulation, including CEACAM1, CLOCK, NR1D1, CRY1, PER1, and PER2. MASLD liver datasets showed reduced expression of insulin clearance-related and circadian genes, while spatial transcriptomics suggested altered lobular distribution of these signatures. In HFD mouse model, rhythmic expression of selected genes was attenuated. Conclusions: These integrative findings suggest that insulin clearance may exhibit diurnal variation and may be linked to circadian metabolic gene signatures across systemic and hepatic datasets in MASLD. Larger controlled human studies are needed to validate the temporal regulation of insulin clearance and its metabolic relevance. Full article

The circadian clock, located in the mammalian hypothalamus, regulates biological rhythms with a period of approximately 24 h, influencing nearly all body functions. Its timing is synchronised daily by external cues, primarily light, which align internal rhythms with the environmental cycle. Through this entrainment, the circadian system orchestrates physiological processes such as the sleep–wake cycle, feeding behaviour, gene expression and body temperature regulation. Melatonin, secreted by the pineal gland, also plays a key role as a synchroniser by facilitating sleep onset. Changes in environmental time cues, such as those experienced by shift workers, can disrupt the body’s natural 24-h rhythms. This situation can lead to fatigue, significantly impacting accident rates and productivity, and, in the long term, to an increased risk of various health conditions. A Phase Response Curve (PRC) illustrates how the clock’s phase is affected by stimuli administered at different points in the circadian cycle. In particular, both light and melatonin can induce phase shifts, but the direction and magnitude of this shift depend on the timing of administration. Understanding the PRC enables the design of interventions to realign circadian rhythms and improve adaptation to shift work. This review explores the physiological and clinical effects of circadian disruption in shift workers and discusses strategies to mitigate its impact. Full article

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of morbidity and mortality worldwide, driven by complex interactions among dyslipidemia, chronic inflammation, insulin resistance, endothelial dysfunction, and gut microbiome-derived metabolites. This review synthesizes mechanistic and clinical evidence on non-pharmacological strategies that modulate these pathways and contribute to ASCVD risk reduction. Dietary patterns such as Mediterranean, DASH, and plant-based diets improve lipid metabolism, attenuate inflammation, and enhance endothelial function. Chrononutrition approaches, including time-restricted feeding and structured fasting protocols, influence circadian regulation of glucose and lipid homeostasis. Circadian misalignment—including irregular sleep timing, shift work, and disrupted feeding–fasting cycles—independently contributes to ASCVD through impaired glucose tolerance, dyslipidemia, endothelial dysfunction, and systemic inflammation. Modulation of the gut microbiome, particularly through increased short-chain fatty acid production and reduced TMAO formation, provides additional cardiometabolic benefits. Key nutraceuticals—phytosterols, omega-3 fatty acids, and berberine—demonstrate clinically meaningful effects through micellar competition, inflammation-resolving lipid mediators, and AMPK activation, respectively. When combined with evidence-based pharmacotherapy, these interventions exert synergistic effects on cardiometabolic risk factors. This integrative biomedical framework highlights the importance of combining lifestyle, metabolic, microbiome-targeted, and nutraceutical strategies for comprehensive ASCVD prevention. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder in which circadian rhythm disruption (CRD) emerges as both a prodromal feature and a potential pathogenic driver. Elucidating the bidirectional interplay between PD and CRD is essential for identifying early biomarkers and developing chronotherapeutic strategies. We narratively synthesized literature published over the past two decades in PubMed, Web of Science, and CNKI, focusing on molecular mechanisms, clinical manifestations, biomarker development, and interventional studies addressing the PD–CRD interface. In the CRD-PD direction, circadian disruption accelerates dopaminergic neurodegeneration through four convergent mechanisms: (i) REV-ERBα–mediated dysregulation of dopamine biosynthesis and NF-κB/NLRP3-driven neuroinflammation; (ii) impaired sleep-dependent glymphatic clearance of α-synuclein (α-syn); (iii) NAD⁺–SIRT1–BMAL1–PGC-1α axis dysfunction leading to mitochondrial bioenergetic failure; and (iv) C/EBPβ-dependent autophagic rhythm disruption coupled with pro-inflammatory microglial activation, collectively establishing a dual pro-inflammatory–autophagy-suppressive milieu permissive for α-syn aggregation. In the reverse PD-CRD direction, PD pathology destabilizes the circadian system via Braak-stage degeneration of rhythm-regulatory nuclei, retinal dopaminergic denervation attenuating SCN photic entrainment, pineal–melatonin axis suppression, iatrogenic effects of dopaminergic pharmacotherapy, and gut microbiota dysbiosis propagated through the microbiota–gut–brain axis. Emerging multi-modal chronobiomarkers—including peripheral clock gene expression profiles, melatonin secretion patterns, tryptophan–kynurenine metabolites, and gut microbial oscillation signatures—show promise for prodromal diagnosis and disease subtyping. Circadian-targeted precision interventions—encompassing timed bright light therapy, exogenous melatonin, and chronopharmacological interventions—represent a promising translational paradigm for the early identification and management of PD. Full article

Genomic instability is a defining feature of cancer progression and therapeutic resistance, yet contemporary oncology interprets it largely through tumor-intrinsic genetic alterations, with less attention to the evolving host physiological context in which DNA damage accumulates and genome maintenance operates. In this perspective, we propose a longitudinal host-transfer-state framework that treats host physiology not as a static background but as a continuously evolving adaptive system. Gut microbial ecology, micronutrient physiology, inflammatory signaling, circadian organization, hydration, environmental exposures, and chronic stress are framed as interacting biologic transfer systems that shape DNA repair fidelity, oxidative buffering, immune coordination, and adaptive tumor behavior over time. These influences are proposed to vary by tumor type, treatment context, and individual physiologic reserve, and clinically observable disease may lag behind deeper latent biologic dynamics. We further outline how longitudinal multi-omic integration and constrained, bounded artificial intelligence—used for longitudinal data integration, normalization, contextualization, and bounded analytical support rather than autonomous decision-making—could identify patient-specific constraints on genome maintenance and treatment tolerance. Host-directed strategies are presented as complementary to, not replacements for, established tumor-directed therapies. Full article

The circadian rhythm is an internal timing system formed by the body’s adaptation to the Earth’s rotation, which helps maintain homeostasis by regulating physiological, metabolic, and behavioral activities. The gut microbiota (GM), the largest microbial ecosystem in the human body, exhibits a bidirectional regulatory relationship with the host circadian clock. Emerging evidence indicates that circadian rhythm disruption (CRD) is linked to disturbances in the diurnal oscillations and compositional balance of the GM, accompanied by reduced short-chain fatty acid levels, increased lipopolysaccharide leakage, and altered tryptophan metabolism. These microbial abnormalities may be involved in anxiety-like behaviors through three major pathways: neuroendocrine (hyperactivation of the HPA axis), immune (microglia-mediated neuroinflammation), and neurotransmitter (imbalance of the serotonergic and dopaminergic systems). Conversely, microbial metabolites such as butyrate and secondary bile acids may reciprocally regulate peripheral clock gene expression, forming a complex “circadian rhythm–GM–anxiety” interaction network. This review summarizes the molecular basis of circadian–GM interactions, potential GM-mediated mechanisms linking CRD with anxiety, and emerging intervention strategies including chrononutrition (time-restricted feeding, sequential nutrient intake), microbiota-targeted therapies (probiotics/prebiotics, fecal microbiota transplantation), and light therapy and melatonin supplementation. Future directions should focus on cell-specific mechanisms using single-cell and spatial transcriptomics, developing personalized interventions that integrate chronotype and microbiome profiling, and conducting large-scale randomized controlled trials to facilitate clinical translation. This review provides a framework for understanding the integrative role of circadian biology and gut microbiota in anxiety and may help develop precision intervention paradigms. Full article

Heritable thoracic aortic diseases (HTADs) comprise a genetically heterogeneous group of disorders predisposing patients to thoracic aortic aneurysm and dissection, yet current medical therapies remain limited to slowing disease progression rather than preventing aortic wall failure. Although pathogenic variants affect diverse genes encoding extracellular matrix (ECM) components, smooth muscle contractile proteins, and signaling molecules, these defects converge on disruption of the mechanobiological systems that maintain aortic wall integrity. The thoracic aorta functions as a mechanically integrated tissue in which endothelial cells, vascular smooth muscle cells, fibroblasts, immune cells and ECM continuously sense and respond to pulsatile biomechanical forces. Genetic perturbations affecting ECM architecture, contractile force generation, or growth factor signaling alter force transmission across this multicellular network, leading to maladaptive mechanotransduction, cellular phenotypic modulation, and progressive aneurysm formation. Using Marfan syndrome as a paradigmatic ECM-driven aortic disease, this review synthesizes current understanding of how altered biomechanics, biochemical signaling and immune responses reshape intercellular communication and activate disease-associated signaling pathways, including dysregulated TGF-β, nitric oxide, angiotensin receptor, calcium-dependent, and metabolic signaling. We highlight how single-cell transcriptomic analyses have elaborated changes in different cell-level functions including, ECM degradation, iron homeostasis, circadian/stress responses. Changes in iron metabolism in different cell types in the aorta suggest possible coordinated metabolic changes in aneurysm progression. These mechanistic insights enable the identification of cell-type–specific pathogenic programs and therapeutic discovery through systems-level approaches. We highlight the translational opportunities and challenges emerging from mouse models and human studies, emphasizing that therapeutic efficacy depends not only on pathway selection but also on disease stage, cellular context, and timing of intervention. Together, these findings support a model in which HTAD progression reflects dynamic, multicellular failure of mechanobiological homeostasis and provide a framework for the development of more precise, mechanism-based therapies. Full article

Human fertility has declined sharply since 1950, and a growing body of evidence suggests that while conventional socioeconomic factors are well-established drivers of the broader demographic transition, they do not fully account for the timing and breadth of this trend. This review examines the Circadian-Light-Hygiene hypothesis, which proposes that daily light exposure is a fundamental regulator of reproductive health. We synthesize findings from photobiology, endocrinology, reproductive medicine, and epidemiology to evaluate how artificial light at night, insufficient daytime light, and irregular light–dark patterns may disrupt the hormonal timing systems that support reproduction. The available evidence indicates that such disruption can alter melatonin signaling, circadian gene regulation, and neuroendocrine rhythms, with downstream effects on ovulation, sperm quality, endometriosis, polycystic ovary syndrome, pregnancy outcomes, and developmental programming. Urbanization, screen use, and shift work appear to amplify these effects, while genetic variation may modify individual susceptibility. Although direct causal evidence in humans remains limited for several endpoints, the convergence of observational, experimental, and translational data supports circadian-light misalignment as a plausible, additional modulator of fertility decline, and a potentially modifiable contributor. Optimizing daily light exposure may therefore represent a low-cost and scalable strategy for improving reproductive health. Full article

The global prevalence of type 2 diabetes continues to rise at an alarming pace, challenging existing strategies for disease prevention and management. Beyond traditional risk factors, increasing evidence indicates that glucose metabolism is temporally regulated by the body’s 24 h biological clock and oscillates based on the time of day. Disturbances of the circadian clock function are linked to impairments in glucose homeostasis and increased risk of obesity and diabetes. This review explores the intricate relationship between the circadian system and glucose homeostatic control. We begin with an introduction to the hierarchical organization of the circadian system. Next, we examine the role of the circadian clock in regulating organs and tissues that are involved in glucose metabolism, i.e., the pancreas, skeletal muscles, the liver and adipose tissue. We next review evidence that supports the involvement of circadian disturbances in the pathogenesis of diabetes. Finally, we discuss chronotherapy and its potential application in clinical intervention of diabetes. As type 2 diabetes becomes increasingly common worldwide, understanding how the body’s internal clock shapes this disease may open new and powerful opportunities for its prevention and treatment. Full article

Circadian clocks are endogenous timing systems that coordinate plant physiology, metabolism, development, and stress responses with daily and seasonal environmental cycles. In crops, circadian and photoperiodic pathways influence agronomically important traits including photosynthesis, carbon allocation, flowering time, growth, stress resilience, and nutritional quality. Although flowering time and photoperiod response pathways have long been indirectly exploited during domestication and breeding, the broader potential of circadian regulation for crop improvement and time-sensitive management remains only partially developed. This review examines the role of plant circadian clocks in crop productivity, with emphasis on molecular mechanisms, crop-specific clock-associated loci, breeding strategies, and chrono-agricultural applications. We summarize conserved and divergent features of the plant clock, including transcriptional repression and activation modules, environmental entrainment, and post-transcriptional regulatory layers. We then discuss how circadian regulation shapes productivity traits and highlight examples from rice, wheat, barley, maize, soybean, sorghum, tomato, and other crops. These examples show that agricultural adaptation often involves fine-tuning or rewiring circadian and photoperiodic outputs rather than maintaining a universal optimal clock state. Finally, we evaluate chrono-agriculture as an emerging framework for aligning management practices with biological timing. While controlled-environment agriculture and high-value horticultural systems are currently the most practical settings for testing chrono-agricultural strategies, open-field applications require careful consideration of environmental variability, sensor limitations, labour, machinery logistics, economic feasibility, and multi-environment validation. Integrating circadian biology with crop genetics, phenotyping, modelling, and agronomy may provide new opportunities to improve productivity, resilience, resource-use efficiency, and quality traits in sustainable agricultural systems. Full article