Abstract In mammals, the circadian clock consists of transcriptional and translational feedback loops through DNA cis -elements such as E-box RRE. The E-box-mediated core loop is interlocked with RRE-mediated loop, but biological significance has been elusive. this study, we established mutant cells mice deficient for rhythmic transcription Bmal1 gene by deleting its upstream RRE elements hence disrupted loop. We observed apparently normal rhythms in mice, a combination mathematical modeling...

Tribulus terrestris fruits are well known for their usage in pharmaceutical preparations and food supplements. The methanol extract of T. showed potent inhibition against the papain-like protease (PLpro), an essential proteolylic enzyme protection to pathogenic virus bacteria. Subsequent bioactivity-guided fractionation this led six cinnamic amides (1–6) ferulic acid (7). Compound 6 emerged as new compound possessing very rare carbinolamide motif. These compounds (1–7) were evaluated severe...

Chronotherapy is a pharmaceutical intervention that considers the patient's internal circadian time to adjust dosing time. Although it can dramatically improve drug efficacy and reduce toxicity, large variability in across within individuals has prevented chronotherapies from progressing beyond clinical trials. To translate chronotherapy developments into real-world outpatient scenario, personalized characterization analysis of essential. Here, we describe recent advances wearable technology...

Significance Circadian rhythms including wake-sleep cycles are driven by molecular time cues generated a self-sustaining transcriptional negative feedback loop. Among all clock proteins, PERIOD (PER) is considered the pacemaker protein because its rhythm of accumulation and nuclear entry generates timing duration inhibition. Here we provide new understanding how robust PER generated: collective action interacting molecules, not random mass individual allows compensation spatial temporal...

BACKGROUNDChronotherapy is a drug intervention at specific times of the day to optimize efficacy and minimize adverse effects. Its value in hematologic malignancy remains be explored, particular adult patients.METHODSWe performed chronotherapeutic analysis using 2 cohorts patients with diffuse large B cell lymphoma (DLBCL) undergoing chemotherapy dichotomized schedule (morning or afternoon). The effect morning afternoon rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone...

In mammals, the master circadian clock synchronizes daily rhythms of physiology and behavior with day-night cycle. Failure synchrony, which increases risk for numerous chronic diseases, can be treated by phase adjustment pharmacologically, example, melatonin, or a CK1δ/ε inhibitor. Here, using in silico experiments systems pharmacology model describing molecular interactions, pharmacokinetic behavioral cynomolgus monkeys, we find that delay caused inhibition is more strongly attenuated light...

Identifying the sources of cell-to-cell variability in signaling dynamics is essential to understand drug response and develop effective therapeutics. However, it challenging because not all intermediate reactions can be experimentally measured simultaneously. This overcome by replacing them with a single random time delay, but resulting process non-Markovian, making difficult infer heterogeneity reaction rates delays. To address this, we developed an efficient scalable moment-based Bayesian...

The circadian (∼24h) clock is based on a negative-feedback loop centered around the PERIOD protein (PER), translated in cytoplasm and then enters nucleus to repress its own transcription at right time of day. Such precise entry mysterious because thousands PER molecules transit through crowded arrive perinucleus across several hours. To understand this, we developed mathematical model describing complex spatiotemporal dynamics as single random delay. We find that spatially coordinated...

Laboratory studies have made unprecedented progress in understanding circadian physiology. Quantifying rhythms outside of laboratory settings is necessary to translate these findings into real-world clinical practice. Wearables been considered promising way measure rhythms. However, their limited validation remains an open problem. One major barrier implementing large-scale the lack reliable and efficient methods for assessment from wearable data. Here, we propose approximation-based...

All proteins are translated in the cytoplasm, yet many, including transcription factors, play vital roles nucleus. While previous research has concentrated on molecular motors for transport of these to nucleus, recent observations reveal perinuclear accumulation even absence an energy source, hinting at alternative mechanisms. Here, we propose that structural properties cellular environment, specifically endoplasmic reticulum (ER), can promote perinucleus without requiring additional...

To meet the ever-increasing global food demand, production rate needs to be increased significantly in near future. Speed breeding is considered as a promising agricultural technology solution achieve zero-hunger vision specified United Nations Sustainable Development Goal 2. In speed breeding, photoperiod of artificial light has been manipulated enhance crop productivity. particular, regulating different qualities rather than solely white can further improve breading. However, identifying...

While circadian disruption is recognized as a potential driver of depression, its real-world impact poorly understood. A critical step to addressing this the noninvasive collection physiological time-series data outside laboratory settings in large populations. Digital tools offer promise endeavor. Here, using wearable data, we first quantify degrees disruption, both between different internal rhythms and each rhythm sleep-wake cycle. Our analysis, based on over 50,000 days from 800...

The yeast strain Metschnikowia persimmonesis Kang and Choi et al., sp. nov. [type KIOM_G15050 = Korean Collection for Type Cultures (KCTC) 12991BP] was isolated from the stalk of native persimmon cultivars (Diospyros kaki Thumb) obtained different regions South Korea characterized phenotypically, genetically, physiologically. isolate grew between 4 40 °C (optimum temperature: 24–28 °C), pH 3–8 (pH optimum 6.0), in 0–4% NaCl solution (with optimal growth absence NaCl). It also exhibited...

.The circadian clock is an internal timer that coordinates the daily rhythms of behavior and physiology, including sleep hormone secretion. Accurately tracking state clock, or phase, holds immense potential for precision medicine. Wearable devices present opportunity to estimate phase in real world, as they can noninvasively monitor various physiological outputs influenced by clock. However, accurately estimating from wearable data remains challenging, primarily due lack methods integrate...

Wearable devices have become commonplace tools for tracking behavioral and physiological parameters in real-world settings. Nonetheless, the practical utility of these data clinical research applications, such as sleep analysis, is hindered by their noisy, large-scale, multidimensional characteristics. Here, we develop a neural network algorithm that predicts stages topological features (TFs) wearable model-driven clock proxies (CPs) reflecting circadian propensity sleep. To evaluate its...

Summary The accurate estimation of circadian phase in the real‐world has a variety applications, including chronotherapeutic drug delivery, reduction fatigue, and optimal jet lag or shift work scheduling. Recent developed adapted algorithms to predict time‐consuming costly laboratory measurements using mathematical models with actigraphy other wearable data. Here, we validate extend these results home‐based cohort later‐life adults, ranging age from 58 86 years. Analysis this population...