Search Results (2,908)

The recent identification of early-onset mutational signatures with geographic variations by Diaz-Gay et al. is a significant finding, since early-onset colorectal cancer has emerged as an alarming public health challenge in the past two decades, and the pathomechanism remains unclear. Environmental risk factors, including lifestyle and diet, are highly suspected. The identification of colibactin from Escherichia coli as a potential pathogenic source is a major step forward in addressing this public health challenge. Therefore, the following opinion manuscript aims to outline the likely onset of the pathomechanism and the critical role of acquired Piezo2 channelopathy in early-onset colorectal cancer, which skews proton availability and proton motive force regulation toward E. coli within the microbiota–host symbiotic relationship. In addition, the colibactin produced by the pks island of E. coli induces host DNA damage, which likely interacts at the level of Wnt signaling with Piezo2 channelopathy-induced pathological remodeling. This transcriptional dysregulation eventually leads to tumorigenesis of colorectal cancer. Mechanotransduction converts external physical cues to inner chemical and biological ones. Correspondingly, the proposed quantum mechanical free-energy-stimulated ultrafast proton-coupled tunneling, initiated by Piezo2, seems to be the principal and essential underlying novel oscillatory signaling that could be lost in colorectal cancer onset. Hence, Piezo2 channelopathy not only contributes to cancer initiation and impaired circadian regulation, including the proposed hippocampal ultradian clock, but also to proliferation and metastasis. Full article

Background/Objectives: Prostate cancer (PCa) is diagnosed at an earlier median age, more advanced stage, and has worse clinical outcomes in African American (AA) men compared to European Americans (EA). Methods: To investigate the role of aberrant DNA methylation in tumor-adjacent stroma (TAS), methyl binding domain sequencing (MBD-seq) was performed on AA (n = 17) and EA (n = 15) PCa patients. This was independently confirmed using the long interspersed nuclear element-1 (LINE-1) assay. Pathway analysis was performed on statistically significantly differentially methylated genes for AA and EA TAS. DNA methylation profiles of primary cultured AA and EA carcinoma-associated fibroblasts (CAFs) were compared with AA and EA TAS. AA and EA CAFs were treated with demethylating agent 5-Azacytidine (5-AzaC). Results: AA TAS exhibited higher global DNA methylation than EA TAS (p-value < 0.001). Of the 3268 differentially methylated regions identified (DMRs, p-value < 0.05), 85% (2787 DMRs) showed increased DNA methylation in AA TAS, comprising 1648 genes, of which 1379 were protein-coding genes. Based on DNA methylation levels, two AA subgroups were identified. Notably, AA patients with higher DNA methylation were predominantly those with higher Gleason scores. Pathway analysis linked methylated genes in AA TAS to several key signaling pathways (p-value < 0.05), including immune response (e.g., IL-1, IL-15, IL-7, IL-8, IL-3, and chemokine), Wnt/β-catenin, androgen, PTEN, p53, TGF-β, and circadian clock regulation. A total of 168 concordantly methylated genes were identified, with 109 genes (65%) showing increased methylation in AA CAFs and TAS (p-value < 0.05). Treatment with 5-AzaC significantly reduced DNA methylation of concordant genes in AA CAFs (p-value < 0.001). Conclusions: These findings suggest a distinct stromal methylome in AA, providing a foundation for integrating demethylating agents into standard therapies. This approach targets the tumor microenvironment, potentially addressing PCa disparities in AA men. Full article

With 493 taxa and 63 sections, Astragalus L. is the largest genus in Türkiye. Most of these are narrow endemics and usually found in marginal habitats or require edaphic specializations (about 42% of the species are endemic). Due to the genus’s extensive diversity of species and common economic use, numerous scientific studies have concentrated on specific species. Taxonomic categorization based on morphological characteristics is insufficient to distinguish certain taxonomic groups. However, there is no systematic molecular phylogenetic analysis of Turkish species that deals with speciation in this genus. To concentrate on molecular-level speciation, fresh leaves from 152 samples representing 30 species across six sections native to Türkiye were collected over several months of comprehensive field studies and analyzed with regard to the internal transcribed spacer (ITS) of nrDNA and the trn L5′-L3′ + L3′-F(GAA) + mat K of cpDNA regions. Additionally, molecular clock estimations and biogeographical histories were analyzed to clearly understand the species’ divergence. Based on all studied regions, the Poterion section was found to be the newest and most divergent section, while the Megalocystis Bunge and Halicacabus Bunge sections were the closest and older ones. Furthermore, A. vaginans from section Hymenocoleus Bunge were included not only in this section but also in several other lineages. It is noteworthy that A. dipodurus and A. oleaefolius species from the section Macrophyllium Bunge are usually put together in a distinct sub-branch from other species members of the section in phylogenetic trees generated using both researched cpDNA and nrDNA regions. Moreover, some of the species are divided by the Anatolian diagonal, and the speciation of a significant number of species began during the Pleistocene geological time period. Geographical isolations or other weak isolation mechanisms preceded speciation in Astragalus, which requires more research in the future. Full article

After the interruption of the timing service, the increase in clock offset is a critical issue for the global navigation satellite system (GNSS)-disciplined oven-controlled crystal oscillator (OCXO). Current timekeeping methods for GNSS-disciplined OCXO have some drawbacks, such as high computational complexity, inadequate consideration of temperature effects, and insufficient separation of the impacts of temperature and aging. To address this issue, this study proposes a timekeeping method using a dual iterative algorithm. First, the external iteration separates the clock offset caused by temperature and aging. Then, the internal Gauss–Seidel iterative algorithm estimates the temperature and aging coefficients. During the timing service interruption phase, the model estimates and compensates for the frequency offset in real time using the coefficients. The proposed method demonstrates improved performance compared with OCXO in the free state and compensated by a second-order polynomial model, with better accuracy, drift rate, and long-term stability. The time offset is better than 4 μs over 24 h, representing an improvement of over 95% compared with the OCXO in the free state. Full article

Background: More than merely determining our sleep pattern, our body’s internal clock also improves the quality of our sleep, alleviates the symptoms of depression, and maintains the balance of our gut flora. Methods: We carried out a 12-week randomized controlled trial with 99 adults from Kolkata, New Delhi, and Pune who reported sleep problems and symptoms of depression or anxiety. Participants received either a probiotic formulated to improve sleep quality and reduce depressive symptoms or a placebo. We tracked sleep using overnight studies and wearable devices, assessed depressive symptoms with standardized questionnaires, and analyzed stool samples to profile gut bacteria and their metabolites using gene sequencing and metabolomics. Advanced statistics and machine learning helped us pinpoint the key microbial and metabolic factors tied to sleep and mental health. Results: At the start, participants with disrupted sleep and depressive symptoms had fewer beneficial gut bacteria like Bifidobacterium and Lactobacillus, more inflammation-related microbes, and lower levels of helpful short-chain fatty acids. These imbalances were linked to poorer sleep efficiency, less REM sleep, and higher depression and anxiety scores. After 12 weeks, those taking the circadian-supporting probiotic saw a statistically significant increase in beneficial gut bacteria, improved sleep efficiency (+7.4%, p = 0.02), and greater reductions in depression and anxiety compared to the placebo. Increases in SCFA-producing bacteria most strongly predicted improvements. Conclusions: Our results show that taking a probiotic supplement can help bring your gut back into balance, support better sleep, and lift symptoms of depression and anxiety. This offers a hopeful and practical option for people looking for real relief from these deeply connected challenges. Full article

The circadian clock is a self-sustaining oscillator with a period of approximately 24 h, enabling organisms to anticipate daily recurring events, such as sunrise and sunset. Since the circadian period is not exactly 24 h and the environmental day length varies throughout the year, the clock must be periodically reset to align an organism’s physiology with the natural light/dark cycle. This synchronization, known as entrainment, is primarily regulated by nocturnal light, which can be replicated in laboratory settings using a 15 min light pulse (LP) and by assessing locomotor activity. An LP during the early part of the dark phase delays the onset of locomotor activity, resulting in a phase delay, whereas an LP in the late dark phase advances activity onset, causing a phase advance. The clock gene Period 2 (Per2) plays a key role in this process. To investigate its contributions, we examined the effects of Per2 deletion in neurons versus astrocytes using glia-specific GPer2 (Per2/GfapCre) knockout (KO) and neuronal-specific NPer2KO (Per2/NesCre) mice. All groups were subjected to Aschoff type II protocol, where an LP was applied at ZT14 or ZT22 and the animals were released into constant darkness. As control, no LP was applied. Phase shift, period, amplitude, total activity count, and rhythm instability were assessed. Our findings revealed that mice lacking Per2 in neurons (NPer2) exhibited smaller phase delays and larger phase advances compared to control animals. In contrast, mice with Per2 deletion specifically in glial cells including astrocytes (GPer2) displayed normal clock resetting. Interestingly, the absence of Per2 in either of the cell types resulted in a shorter circadian period compared to control animals. These results suggest that astrocytic Per2 is important for maintaining the circadian period but is not required for phase adaptation to light stimuli. Full article

Cold shock represents a prevalent but harmful environmental stress factor that poses significant threats to fish survival and reproductive success. In fish, the brain acts as a central regulator of thermoregulatory processes. Nevertheless, how different brain regions respond molecularly to cold exposure remains largely unknown. To address this, this study systematically investigated the effects of acute cold stress on five specific brain regions of Leiocassis longirostris using RNA-seq. The findings demonstrated that all five brain regions were significantly impacted by cold treatment, with the mesencephalon (MB) showing the most substantial changes. GO and KEGG enrichment analyses indicated that cold stress disrupted processes including gene expression regulation, circadian rhythms, and immune function within brain tissues. Through Weighted Gene Co-Expression Network Analysis (WGCNA), the MB was identified as the core responsive region, and the brain’s reaction to cold stress was strongly correlated with circadian rhythm, spliceosome, and ubiquitination. In summary, our investigation demonstrates that the MB represents a principal region for cold stress response in L. longirostris, involving alterations in circadian clocks, immune function, and inflammatory responses, alongside suppression of gene expression processes and ubiquitination-mediated proteolysis. Full article

The advancement of Internet of Things (IoT) technology has enabled battery-powered devices to be deployed across a wide range of applications; however, it also introduces challenges such as high energy consumption and security vulnerabilities. To address these issues, adiabatic logic circuits offer a promising solution for achieving energy efficiency and enhancing the security of IoT devices. Adiabatic logic circuits are well suited for energy harvesting systems, especially in applications such as sensor nodes, RFID tags, and other IoT implementations. In these systems, the harvested bipolar sinusoidal RF power is directly used as the power supply for the adiabatic logic circuit. However, adiabatic circuits require a peak detector to provide bulk biasing for pMOS transistors. To meet this requirement, a diode-connected MOS transistor-based voltage doubler circuit is used to convert the sinusoidal input into a usable DC signal. In this paper, we propose a novel adiabatic logic design that maintains low power consumption while optimizing energy and current fluctuations across various input transitions. By ensuring uniform and complementary current flow in each transition within the logic circuit’s functional blocks, the design reduces energy variation and enhances resistance against power analysis attacks. Evaluation under different clock frequencies and load capacitances demonstrates that the proposed adiabatic logic circuit exhibits lower fluctuation and improved security, particularly at load capacitances of 50 fF and 100 fF. The results show that the proposed circuit achieves lower power dissipation compared to conventional designs. As an application example, we implemented an ultrasonic transmitter circuit within a LoRaWAN network at the end-node sensor level, which serves as both a communication protocol and system architecture for long-range communication systems. Full article

Alzheimer’s Disease (AD) is the most common type of dementia. The circadian system, which is controlled by the master clock in the Suprachiasmatic Nucleus (SCN) of the hypothalamus, is crucial for various physiological processes. Studies have shown that changes in the circadian rhythms can deteriorate neurodegenerative diseases. Changes in the SCN are associated with cognitive decline in AD. The cognitive impairments in AD, especially memory dysfunctions, may be related to Circadian Rhythm Disturbances (CRDs). Moreover, rhythmic expression of clock genes is disrupted in AD patients. There is a circadian pattern of inflammatory processes in AD, and dysregulation of core clock genes promotes neuroinflammation. The present narrative review addresses the intricate link between CRDs and AD, revisiting the relevant cellular and molecular mechanisms. The association between CRDs and AD highlights the need for further investigation of the underlying mechanisms. Full article

Background/Objectives: Advances in nanopore sequencing have opened new avenues for studying DNA methylation at single-base resolution, yet their application in epigenetic ageing research remains underdeveloped. Methods: We present a novel framework that leverages the unique capabilities of nanopore sequencing to profile and interpret age-associated methylation patterns in native DNA. Results: Unlike conventional array-based approaches, long reads sequencing captures full CpG context, accommodates diverse and repetitive genomic regions, removes bisulfite conversion steps, and is compatible to the latest reference genome. Conclusions: This work establishes nanopore sequencing as a powerful tool for next-generation epigenetic ageing studies, offering a scalable and biologically rich platform for anti-ageing interventions monitoring and longitudinal ageing studies. Full article

Brain muscle ARNT-like1 (Bmal1) is a transcriptional factor, consisting of basic helix–loop–helix (bHLH) and PER-ARNT-SIM (PAS) domains, that plays a central role in circadian clock activity. However, the precise roles of the BMAL1-PAS domain, a circadian rhythm-regulating structure, remain unexplored in monocytes. Here, we highlight the BMAL1-PAS domain as a key structure in monocyte pleiotropic functions by using human monocytic cell line THP-1. THP-1 cells lacking the BMAL1-PAS-B domain (THP-1#207) abrogated the circadian expression of core clock genes. THP-1#207 cells exhibited less proliferation, glycolysis and oxidative phosphorylation activity, and LPS-induced IL-1β production, but exhibited more production of LPS-induced IL-10 than THP-1 cells. A quantitative proteomics analysis revealed significant expression changes in ~10% metabolic enzymes in THP-1#207 cells compared to THP-1 cells, including reduction in a rate-limiting enzyme hexokinase2 (HK2) in the glycolytic pathway. Importantly, treatment of THP-1 with 2-deoxy-D-glucose (2-DG), an HK2 inhibitor, largely recapitulated the phenotypes of THP-1#207 cells. These findings suggest that the BMAL1-PAS-B domain is an important structure for the regulation of proliferation, cellular energetics, and inflammatory response in THP-1 cells, at least in part, via the control of glycolytic activity. Thus, the BMAL1-PAS-B domain may become a promising pharmacological target to control inflammation. Full article

Morningness-eveningness is usually assessed as either a trait or a state using either a morning–evening preference scale or sleep timing reported for free days, respectively. These assessments were implemented in numerous studies exploring the associations between morningness-eveningness and health, mood, and sleep problems. Evening types almost always had more problems than morning types. We examined these associations in university students with conflicting results of trait and state assessments of morningness-eveningness and tried to confirm their chronotype using a multidimensional chronotyping approach that recognizes four types other than morning and evening (lethargic, vigilant, napping, and afternoon). The conflicting trait and state assessments of morningness-eveningness were found in 141 of 1582 students. Multidimensional chronotyping supported morningness of morning types with late weekend sleep timing, and the associations with health, mood, and sleep problems resembled the associations of other morning types (i.e., these associations persisted despite late sleep timing). In contrast, evening types with early weekend sleep timing were more likely classified as lethargic or napping types rather than evening types. They did not resemble evening types in their associations with health, mood, and sleep problems (i.e., early sleep timing did not change these associations). Model-based simulations of the sleep–wake cycles of students with conflicting trait and state assessments suggested that their bedtimes cannot be solely determined by their biological clocks. On weekdays or weekends, mind-bedtime procrastination can lead to missing the bedtime signal from their biological clocks (i.e., self-deprivation of sleep or, in other words, voluntary prolongation of the wake phase of the sleep–wake cycle). Full article

This essay argues that several of Bernadette Mayer’s major works foreground and develop experiences of subjective time as moments of resistance to the standardizing force of objective clock and calendric time that governs daily material existence. Basing my argument on a framework for subjective time developed in the field of linguistics, I show how Mayer’s play with duration, temporal recursiveness, and moments of stopped time in works including Memory, Midwinter Day, Works and Days, and Milkweed Smithereens function as subversions of the normative material every day, and I argue that throughout her work Mayer is preoccupied with not merely representing time, its content, and its passage, but rather with gaining mastery over objective time and subverting its authority altogether. This essay joins the scant research on time and temporality in Mayer’s work and offers an invitation to further study of subjective time as a mode of resistance in contemporary poetry. Full article

Lymphoid neoplasms (LN), a diverse group of malignancies arising from lymphocytes, exhibit a striking increase in incidence with chronological age, suggesting a deep connection with the aging process. While chronological age remains a primary risk factor, the concept of biological age, reflecting an individual’s physiological state and susceptibility to age-related diseases, offers a more nuanced understanding of this relationship. Aging clocks, particularly epigenetic clocks based on DNA methylation, provide quantitative measures of biological age and have revealed associations between accelerated aging and increased cancer risk, including LN. Immunosenescence, the age-related decline in immune function characterized by thymic involution, altered lymphocyte populations, and chronic inflammation (inflammaging), appears to be a key mechanistic link between aging and LN development, potentially providing a more accurate predictor of cancer risk than mutation accumulation alone. Accelerated biological aging, measured by various clocks, correlates with LN risk and progression (e.g., in chronic lymphocytic leukemia), and may influence treatment tolerance and outcomes, particularly in older adults who are often burdened by frailty and comorbidities like sarcopenia. Integrating biological age assessments into clinical practice holds promise for refining diagnosis, prognosis, and personalizing treatment strategies (including guiding intensity and considering anti-aging interventions), and improving outcomes for patients with LN. This review synthesizes the current understanding of the intricate relationship between LN, immunosenescence, biological age, and aging clocks, highlighting clinical implications and key future research directions aimed at translating these insights into better patient care. Full article

The ‘ring by spring’ (RBS) phenomenon entails pressures for college seniors on Christian campuses to become engaged by the spring semester of their senior year. These marital pressures often run counter to national trends in the USA as the median age at first marriage continues to climb. The social clock theory suggests that society places a normative timetable on major events such as marriage. But the social clock may not happen the same way for all people, and influences on Christian campus may represent deviations from most normative social clocks. This study investigated RBS awareness, experiences, pressures, and perceptions, along with assessing for differences in gender and religiosity across multiple universities, both Christian and not, across two different states. Results show wide awareness and experience with RBS at many universities along with some notable differences by gender and religiosity. Implications are provided for researchers and practitioners based on study findings. Full article