Dysregulation of circadian rhythms is associated with metabolic dysfunction, yet it is unclear whether enhancing clock function can ameliorate metabolic disorders. In an unbiased chemical screen ...using fibroblasts expressing PER2::Luc, we identified Nobiletin (NOB), a natural polymethoxylated flavone, as a clock amplitude-enhancing small molecule. When administered to diet-induced obese (DIO) mice, NOB strongly counteracted metabolic syndrome and augmented energy expenditure and locomotor activity in a Clock gene-dependent manner. In db/db mutant mice, the clock is also required for the mitigating effects of NOB on metabolic disorders. In DIO mouse liver, NOB enhanced clock protein levels and elicited pronounced gene expression remodeling. We identified retinoid acid receptor-related orphan receptors as direct targets of NOB, revealing a pharmacological intervention that enhances circadian rhythms to combat metabolic disease via the circadian gene network.
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•High-throughput screening identified Nobiletin as a clock amplitude enhancer•Nobiletin potently protects against metabolic syndrome in a clock-dependent manner•Nobiletin remodels circadian and metabolic gene expression•Nobiletin is an agonist for the ROR nuclear receptors in the circadian oscillator
In a high-throughput chemical screen, He et al. identify the small molecule Nobiletin (NOB), a naturally occurring compound enriched in citrus peels, as a circadian clock amplitude enhancer, which protects against metabolic disease. NOB is an agonist for the ROR nuclear receptors in the circadian oscillator.
Segregation of objects from their backgrounds is a fundamental visual function and one that is particularly effective when objects are in motion. Theoretically, suppressive center-surround mechanisms ...are well suited for accomplishing motion segregation. This longstanding hypothesis, however, has received limited empirical support. We report converging correlational and causal evidence that spatial suppression of background motion signals is critical for rapid segmentation of moving objects. Motion segregation ability is strongly predicted by both individual and stimulus-driven variations in spatial suppression strength. Moreover, aging-related superiority in perceiving background motion is associated with profound impairments in motion segregation. This segregation deficit is alleviated via perceptual learning, but only when motion segregation training also causes decreased sensitivity to background motion. We argue that perceptual insensitivity to large moving stimuli effectively implements background subtraction, which, in turn, enhances the visibility of moving objects and accounts for the observed link between spatial suppression and motion segregation.
The coherence and dephasing of vibrational motions of molecules constitute an integral part of chemical dynamics, influence material properties and underpin schemes to control chemical reactions. ...Considerable progress has been made in understanding vibrational coherence through spectroscopic measurements, but precise, direct measurement of the structure of a vibrating excited-state polyatomic organic molecule has remained unworkable. Here, we measure the time-evolving molecular structure of optically excited N-methylmorpholine through scattering with ultrashort X-ray pulses. The scattering signals are corrected for the differences in electron density in the excited electronic state of the molecule in comparison to the ground state. The experiment maps the evolution of the molecular geometry with femtosecond resolution, showing coherent motion that survives electronic relaxation and seems to persist for longer than previously seen using other methods.
The demand for essential pixel components with ever-decreasing size and enhanced performance is central to current optoelectronic applications, including imaging, sensing, photovoltaics and ...communications. The size of the pixels, however, are severely limited by the fundamental constraints of lightwave diffraction. Current development using transmissive filters and planar absorbing layers can shrink the pixel size, yet there are two major issues, optical and electrical crosstalk, that need to be addressed when the pixel dimension approaches wavelength scale. All these fundamental constraints preclude the continual reduction of pixel dimensions and enhanced performance. Here we demonstrate subwavelength scale color pixels in a CMOS compatible platform based on anti-Hermitian metasurfaces. In stark contrast to conventional pixels, spectral filtering is achieved through structural color rather than transmissive filters leading to simultaneously high color purity and quantum efficiency. As a result, this subwavelength anti-Hermitian metasurface sensor, over 28,000 pixels, is able to sort three colors over a 100 nm bandwidth in the visible regime, independently of the polarization of normally-incident light. Furthermore, the quantum yield approaches that of commercial silicon photodiodes, with a responsivity exceeding 0.25 A/W for each channel. Our demonstration opens a new door to sub-wavelength pixelated CMOS sensors and promises future high-performance optoelectronic systems.
Cereblon (CRBN), a substrate receptor for the cullin-RING ubiquitin ligase 4 (CRL4) complex, is a direct protein target for thalidomide teratogenicity and antitumor activity of immunomodulatory drugs ...(IMiDs). Here we report that glutamine synthetase (GS) is an endogenous substrate of CRL4CRBN. Upon exposing cells to high glutamine concentration, GS is acetylated at lysines 11 and 14, yielding a degron that is necessary and sufficient for binding and ubiquitylation by CRL4CRBN and degradation by the proteasome. Binding of acetylated degron peptides to CRBN depends on an intact thalidomide-binding pocket but is not competitive with IMiDs. These findings reveal a feedback loop involving CRL4CRBN that adjusts GS protein levels in response to glutamine and uncover a new function for lysine acetylation.
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•GS is an endogenous substrate of CRL4CRBN•CRL4CRBN directly mediates the glutamine-induced degradation of GS•Glutamine-stimulated acetylation of lysines 11 and 14 regulates GS degradation•The thalidomide-binding domain of CRBN binds to an acetyllysine degron of GS
Nguyen et al. demonstrate that glutamine induces acetylation of GS at lysines 11 and 14 to create an acetylated degron that binds CRL4CRBN, resulting in ubiquitylation and degradation of GS.
Explosions are spectacular and intriguing phenomena that expose the dynamics of matter under extreme conditions. We investigated, using time-resolved imaging, explosions induced by ultraintense X-ray ...laser pulses in water drops and jets. Our observations revealed an explosive vaporization followed by high-velocity interacting ows of liquid and vapour, and by the generation of shock trains in the liquid jets. These ows are dierent from those previously observed in laser ablation, owing to a simpler spatial pattern of X-ray absorption. We show that the explosion dynamics in our experiments is consistent with a redistribution of absorbed energy, mediated by a pressure or shock wave in the liquid, and we model the eects of explosions, including their adverse impact on X-ray laser experiments. X-ray laser explosions have predictable dynamics that may prove useful for controlling the state of pure liquids over broad energy scales and timescales, and for triggering pressure-sensitive molecular dynamics in solutions.
Cancer chronotherapy, treatment at specific times during circadian rhythms, endeavors to optimize anti-tumor effects and to lower toxicity. However, comprehensive characterization of clock genes and ...their clinical relevance in cancer is lacking. We systematically characterized the alterations of clock genes across 32 cancer types by analyzing data from The Cancer Genome Atlas, Cancer Therapeutics Response Portal, and The Genomics of Drug Sensitivity in Cancer databases. Expression alterations of clock genes are associated with key oncogenic pathways, patient survival, tumor stage, and subtype in multiple cancer types. Correlations between expression of clock genes and of other genes in the genome were altered in cancerous versus normal tissues. We identified interactions between clock genes and clinically actionable genes by analyzing co-expression, protein-protein interaction, and chromatin immunoprecipitation sequencing data and also found that clock gene expression is correlated to anti-cancer drug sensitivity in cancer cell lines. Our study provides a comprehensive analysis of the circadian clock across different cancer types and highlights potential clinical utility of cancer chronotherapy.
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•Transcription dysregulation and clinical relevance of clock genes in cancer•Disruption and reprogramming of circadian rhythms in cancer•Strong interactions between clock genes and clinically actionable genes•Potential therapeutic effects of clock genes in cancer chronotherapy
Ye et al. comprehensively analyzed alterations of clock genes and circadian rhythms across multiple human cancers and revealed strong interactions between clock genes and clinically actionable genes, which highlights the clinical utility of circadian timing in cancer chronotherapy.
The circadian clock coordinates daily oscillations of essential physiological and behavioral processes. Conversely, aberrant clocks with damped amplitude and/or abnormal period have been associated ...with chronic diseases and aging. To search for small molecules that perturb or enhance circadian rhythms, we conducted a high-throughput screen of approximately 200,000 synthetic compounds using Per2::lucSV reporter fibroblast cells and validated 11 independent classes of molecules with Bmal1:luciferase reporter cells as well as with suprachiasmatic nucleus and peripheral tissue explants. Four compounds were found to lengthen the period in both central and peripheral clocks, including three compounds that inhibited casein kinase Iε in vitro and a unique benzodiazepine derivative acting through a non-GABAA receptor target. In addition, two compounds acutely induced Per2::lucSV reporter bioluminescence, delayed the rhythm, and increased intracellular cAMP levels, but caused rhythm damping. Importantly, five compounds shortened the period of peripheral clocks; among them, four compounds also enhanced the amplitude of central and/or peripheral reporter rhythms. Taken together, these studies highlight diverse activities of drug-like small molecules in manipulating the central and peripheral clocks. These small molecules constitute a toolbox for probing clock regulatory mechanisms and may provide putative lead compounds for treatment of clock-associated diseases.
Cardiovascular disease (CVD) is common and overall graft survival is suboptimal among kidney transplant recipients. Although albuminuria is a known risk factor for adverse outcomes among persons with ...native chronic kidney disease, the relationship of albuminuria with cardiovascular and kidney outcomes in transplant recipients is uncertain.
Post hoc longitudinal cohort analysis of the Folic Acid for Vascular Outcomes Reduction in Transplantation (FAVORIT) Trial.
Stable kidney transplant recipients with elevated homocysteine levels from 30 sites in the United States, Canada, and Brazil.
Urine albumin-creatinine ratio (ACR) at randomization.
Allograft failure, CVD, and all-cause death.
Multivariable Cox models adjusted for age; sex; race; randomized treatment allocation; country; systolic and diastolic blood pressure; history of CVD, diabetes, and hypertension; smoking; cholesterol; body mass index; estimated glomerular filtration rate (eGFR); donor type; transplant vintage; medications; and immunosuppression.
Among 3,511 participants with complete data, median ACR was 24 (Q1-Q3, 9-98) mg/g, mean eGFR was 49±18 (standard deviation) mL/min/1.73m2, mean age was 52±9 years, and median graft vintage was 4.1 (Q1-Q3, 1.7-7.4) years. There were 1,017 (29%) with ACR < 10mg/g, 912 (26%) with ACR of 10 to 29mg/g, 1,134 (32%) with ACR of 30 to 299mg/g, and 448 (13%) with ACR ≥ 300mg/g. During approximately 4 years, 282 allograft failure events, 497 CVD events, and 407 deaths occurred. Event rates were higher at both lower eGFRs and higher ACR. ACR of 30 to 299 and ≥300mg/g relative to ACR < 10mg/g were independently associated with graft failure (HRs of 3.40 95% CI, 2.19-5.30 and 9.96 95% CI, 6.35-15.62, respectively), CVD events (HRs of 1.25 95% CI, 0.96-1.61 and 1.55 95% CI, 1.13-2.11, respectively), and all-cause death (HRs of 1.65 95% CI, 1.23-2.21 and 2.07 95% CI, 1.46-2.94, respectively).
No data for rejection; single ACR assessment.
In a large population of stable kidney transplant recipients, elevated baseline ACR is independently associated with allograft failure, CVD, and death. Future studies are needed to evaluate whether reducing albuminuria improves these outcomes.
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