In Situ Imaging of Two-Dimensional Crystal Growth Using a Heat-Resistant Optical Microscope.

Revealing low-dimensional material growth dynamics is critical for crystal growth engineering. However, in a practical high-temperature growth system, the crystal growth process is a black box because of the lack of heat-resistant imaging tools. Here, we develop a heat-resistant optical microscope and embed it in a chemical vapor deposition (CVD) system to investigate two-dimensional (2D) crystal growth dynamics. This in situ optical imaging CVD system can tolerate temperatures of ≤900 °C with a spatial resolution of ∼1 µm. The growth of monolayer MoS2 crystals was studied as a model for 2D crystal growth. The nucleation and growth process have been imaged. Model analysis and simulation have revealed the growth rate, diffusion coefficient, and spatial distribution of the precursor. More importantly, a new vertex-kink-ledge model has been suggested for monolayer crystal growth. This work provides a new technique for in situ microscopic imaging at high temperatures and fundamental insight into 2D crystal growth.

Liquid Phase Edge Epitaxy of Transition-Metal Dichalcogenide Monolayers.

Precise monolayer epitaxy is important for two-dimensional (2D) semiconductors toward future electronics. Here, we report a new self-limited epitaxy approach, liquid phase edge epitaxy (LPEE), for precise-monolayer epitaxy of transition-metal dichalcogenides. In this method, the liquid solution contacts 2D grains only at the edges, which confines the epitaxy only at the grain edges and then precise monolayer epitaxy can be achieved. High-temperature in situ imaging of the epitaxy progress directly supports this edge-contact epitaxy mechanism. Typical transition-metal dichalcogenide monolayers (MX2, M = Mo, W, and Re; X = S or Se) have been obtained by LPEE with a proper choice of molten alkali halide solvents (AL, A = Li, Na, K, and Cs; L = Cl, Br, or I). Furthermore, alloying and magnetic-element doping have also been realized by taking advantage of the liquid phase epitaxy approach. This LPEE method provides a precise and highly versatile approach for 2D monolayer epitaxy and can revolutionize the growth of 2D materials toward electronic applications.

Study on Microelectrochemical Inhomogeneity of an SA508-309L/308L Overlay Welded Joint.

The corrosion behavior of the dissimilar metal welded joint (DMWJ) is highly dependent on its heterogeneous microstructures. However, directly measuring the electrochemical properties of microstructures in different heat-affected zones (HAZs) is a formidable challenge, because traditional bulk electrochemistry can only offer an average signal. Herein, the microelectrochemical properties of an SA508-309L/308L DMWJ were measured in 3.5 wt % NaCl solution using lithography and capillary techniques. Specifically, high-throughput microelectrochemical tests, including open circuit potential (OCP), electrochemical impedance spectroscopy (EIS), and potentiodynamic polarization (PDP), were conducted on 168 spots (Φ 12 µm). Results revealed five typical EIS responses and seven varieties of PDP curves (different magnitudes of the current density). The maps of thermodynamic and kinetic metrics, such as polarization resistance derived from EIS, corrosion potentials, and corrosion currents extracted from potentiodynamic polarization curves, demonstrated good consistency. The uniform corrosion tendency of the SA508 HAZ subregions during the immersion tests is basically consistent with its Ecorr_avg order of subcritical HAZ (C5, -371 mV) < intercritical HAZ (C4, -546 mV) < fine-grained HAZ2 (C3, -579 mV) < fine-grained HAZ1 (C2, -593 mV). The random presence of inclusions leads to highly heterogeneous microelectrochemical properties of the DMWJ, thereby causing localized corrosion to occur preferentially. Moreover, the macroscopic corrosion behavior is affected by the corrosion products, which display a protective effect that modifies the local electrochemical activity of the SA508 HAZ. The combination of microelectrochemical properties allows for a more comprehensive understanding of the macroscopic corrosion behavior of metals and the galvanic effect between the heterogeneous microstructures.

Circadian period 2: a missing beneficial factor in sickle cell disease by lowering pulmonary inflammation, iron overload, and mortality.

The circadian clock is important for cellular and organ function. However, its function in sickle cell disease (SCD), a life-threatening hemolytic disorder, remains unknown. Here, we performed an unbiased microarray screen, which revealed significantly altered expression of circadian rhythmic genes, inflammatory response genes, and iron metabolic genes in SCD Berkeley transgenic mouse lungs compared with controls. Given the vital role of period 2 (Per2) in the core clock and the unrecognized role of Per2 in SCD, we transplanted the bone marrow (BM) of SCD mice to Per2Luciferase mice, which revealed that Per2 expression was up-regulated in SCD mouse lung. Next, we transplanted the BM of SCD mice to period 1 (Per1)/Per2 double deficient [Per1/Per2 double knockout (dKO)] and wild-type mice, respectively. We discovered that Per1/Per2 dKO mice transplanted with SCD BM (SCD → Per1/Per2 dKO) displayed severe irradiation sensitivity and were more susceptible to an early death. Although we observed an increase of peripheral inflammatory cells, we did not detect differences in erythrocyte sickling. However, there was further lung damage due to elevated pulmonary congestion, inflammatory cell infiltration, iron overload, and secretion of IL-6 in lavage fluid. Overall, we demonstrate that Per1/Per2 is beneficial to counteract elevated systemic inflammation, lung tissue inflammation, and iron overload in SCD.-Adebiyi, M. G., Zhao, Z., Ye, Y., Manalo, J., Hong, Y., Lee, C. C., Xian, W., McKeon, F., Culp-Hill, R., D' Alessandro, A., Kellems, R. E., Yoo, S.-H., Han, L., Xia, Y. Circadian period 2: a missing beneficial factor in sickle cell disease by lowering pulmonary inflammation, iron overload, and mortality.

PML regulates PER2 nuclear localization and circadian function.

Studies have suggested that the clock regulator PER2 is a tumour suppressor. A cancer network involving PER2 raises the possibility that some tumour suppressors are directly involved in the mammalian clock. Here, we show that the tumour suppressor promyelocytic leukaemia (PML) protein is a circadian clock regulator and can physically interact with PER2. In the suprachiasmatic nucleus (SCN), PML expression and PML-PER2 interaction are under clock control. Loss of PML disrupts and dampens the expression of clock regulators Per2, Per1, Cry1, Bmal1 and Npas2. In the presence of PML and PER2, BMAL1/CLOCK-mediated transcription is enhanced. In Pml(-/-) SCN and mouse embryo fibroblast cells, the cellular distribution of PER2 is primarily perinuclear/cytoplasmic. PML is acetylated at K487 and its deacetylation by SIRT1 promotes PML control of PER2 nuclear localization. The circadian period of Pml(-/-) mice displays reduced precision and stability consistent with PML having a role in the mammalian clock mechanism.

5'-adenosine monophosphate mediated cooling treatment enhances ΔF508-Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) stability in vivo.

BACKGROUND: Gene mutations that produce misprocessed proteins are linked to many human disorders. Interestingly, some misprocessed proteins retained their biological function when stabilized by low temperature treatment of cultured cells in vitro. Here we investigate whether low temperature treatment in vivo can rescue misfolded proteins by applying 5'-AMP mediated whole body cooling to a Cystic Fibrosis (CF) mouse model carrying a mutant cystic fibrosis transmembrane conductance regulator (CFTR) with a deletion of the phenylalanine residue in position 508 (ΔF508-CFTR). Low temperature treatment of cultured cells was previously shown to be able to alleviate the processing defect of ΔF508-CFTR, enhancing its plasma membrane localization and its function in mediating chloride ion transport. RESULTS: Here, we report that whole body cooling enhanced the retention of ΔF508-CFTR in intestinal epithelial cells. Functional analysis based on ß-adrenergic dependent salivary secretion and post-natal mortality rate revealed a moderate but significant improvement in treated compared with untreated CF mice. CONCLUSIONS: Our findings demonstrate that temperature sensitive processing of mutant proteins can be responsive to low temperature treatment in vivo.

The impacts of carbon emissions trading scheme on green finance: evidence from China.

China enacted and implemented a carbon emissions trading pilot policy in 2011, and whether this carbon emissions trading scheme (ETS) can promote the development of green finance is crucial to realizing a win-win situation for both environmental and economic performance. Based on the panel data of 30 provinces in China from 2007 to 2019, this study constructs a multi-period double-difference model (DID) to explore the impact of carbon ETS on the development of green finance and uses the spatial Durbin model (SDM) to test whether there is a spatial spillover effect of the carbon ETS on the development of green finance. The results show that (a) the implementation of carbon ETS significantly promotes the development of green finance, and this conclusion still holds through a series of robustness tests; (b) the promotion effect of the carbon ETS on the development of green finance is more significant in eastern and western provinces, non-resource-based provinces, and provinces with a high level of openness to the outside world; (c) industrial structural upgrading and green innovation play pivotal roles in achieving the desired outcomes of carbon ETS; (d) carbon ETS have spatial spillover effects on the development of green finance, with the indirect effects being more significant than the direct effects. The findings of this study can serve as a valuable reference for expediting the establishment of a unified national carbon market and the development of a robust green financial system. This holds immense significance in effectively implementing the "dual-carbon" strategy.

The intention of college students to use electronic cigarettes: A study based on the theory of innovation diffusion.

INTRODUCTION: The purpose of this study is to examine the use of electronic cigarettes (e-cigarettes) among college students in Hangzhou, and to analyze the influencing factors of their intention to use e-cigarettes. METHODS: Using a stratified cluster sampling method, 775 students from two universities in Hangzhou were selected for an on-site questionnaire survey from March to April 2022. Adjusted logistic regression analysis was conducted on the influencing factors of use intention, based on innovation diffusion theory. RESULTS: Within our sample of college students, 16.5% of students had tried e-cigarettes; 6.32% had used e-cigarettes in the past month, and 8.0% had the intention to use e-cigarettes. There were significant differences in willingness to use e-cigarettes among different genders, economic status, smoking status of close friends around them, and their own use of tobacco and alcohol (p<0.05). The logistic regression model showed that the observability of e-cigarettes (AOR=1.28; p<0.05), personal factors (AOR=1.39; p<0.05), and social systems (AOR=1.63; p<0.05), were all influencing factors of intention to use e-cigarettes. CONCLUSIONS: College students in Hangzhou have a high intention to use e-cigarettes, and the impacts of the product itself, individual characteristics and the living environment are crucial. It is necessary to strengthen the promotion of tobacco knowledge at the social and family levels to reduce the occurrence of vaping.

Circadian behavior of mice deficient in PER1/PML or PER2/PML.

BACKGROUND: Our recent studies demonstrate that the murine homolog of the human tumor suppressor promyelocytic leukemia (PML) regulates circadian behavior of mice. To further gather insight into PML's contribution to circadian behavior, we generated two strains of mice deficient in one of the two period (Per) genes and the PML gene, with Per1-/-/Pml-/- and Per2-/-/Pml-/- genotypes. RESULTS: Here we report the circadian behavior of these mice based on wheel-running behavioral analysis. In a free-running environment, the Per1-/-/Pml-/- mice maintained circadian rhythm but displayed a significantly shorter period of 22.2 h. In addition, these mice displayed significantly enhanced phase response to a light pulse given at zeitgeber time (ZT) 14 and 22. The Per2-/-/Pml-/- mice lose persistent rhythm when in a free-running environment, as also the case for Per2-/- mice. A transient post-light pulse rhythm seen in the arrhythmic Per2-/- mice was less apparent in Per2-/-/Pml-/- mice. Both the Per1-/-/Pml-/- and Per2-/-/Pml-/- mice displayed a more advanced phase angle of entrainment activity during light-dark cycles than the single gene deficient mice. CONCLUSIONS: Beyond merely regulating PER1 and PER2, the current behavioral studies suggest PML has additional roles in mouse circadian behavior.

Blockage of transient receptor potential vanilloid 4 prevents postoperative atrial fibrillation by inhibiting NLRP3-inflammasome in sterile pericarditis mice.

The incidence of atrial fibrillation (AF) increases after surgery and is associated with the activation of NLRP3-inflammation. Our previous studies have found that transient receptor potential vanilloid 4 (TRPV4) blockade reduces the susceptibility to AF, but its molecular mechanisms remains unclear. Therefore, we hypothesized that blockage of TRPV4 reduces the incidence of AF by inhibiting NLRP3-inflammasome in sterile pericarditis (SP) mice. In this study, we established SP mice by dusting talcum powder on atrial surfaces. We first confirmed that genetic or pharmacological TRPV4 inhibition reduced the susceptibility to AF in SP mice. We also found that the expression level of NLRP3-inflammasome and inflammatory cytokines significantly increased in the atria of SP mice, which further increased in application the TRPV4 agonist GSK1016790A (GSK101) and decreased in application the TRPV4 antagonist GSK2193874. More importantly, ERK inhibitor (U0126) or NF-κB inhibitor (Bay11-7082) could partially reverse GSK101-induced NLRP3-inflammasome up-regulation. Interestingly, U0126 can reversed GSK101-induced NF-κB phosphorylation, but Bay11-7082 cannot change GSK101-induced ERK phosphorylation. Finally, we shown that the activation of NLRP3-inflammasome and ERK/NF-κB signaling pathway significantly reduced in TRPV4-knockout SP mice. Collectively, our studies indicate that blockage of TRPV4 prevents AF in SP mice by inhibiting NLRP3-inflammasome through the ERK/NF-κB signaling pathway.

Hepatic gene expression profiling of 5'-AMP-induced hypometabolism in mice.

There is currently much interest in clinical applications of therapeutic hypothermia. Hypothermia can be a consequence of hypometabolism. We have recently established a procedure for the induction of a reversible deep hypometabolic state in mice using 5'-adenosine monophosphate (5'-AMP) in conjunction with moderate ambient temperature. The current study aims at investigating the impact of this technology at the gene expression level in a major metabolic organ, the liver. Our findings reveal that expression levels of the majority of genes in liver are not significantly altered by deep hypometabolism. However, among those affected by hypometabolism, more genes are differentially upregulated than downregulated both in a deep hypometabolic state and in the early arousal state. These altered gene expression levels during 5'-AMP induced hypometabolism are largely restored to normal levels within 2 days of the treatment. Our data also suggest that temporal control of circadian genes is largely stalled during deep hypometabolism.

A role of erythrocytes in adenosine monophosphate initiation of hypometabolism in mammals.

Biochemical and mechanistic aspects into how various hypometabolic states are initiated in mammals are poorly understood. Here, we show how a state of hypometabolism is initiated by 5'-AMP uptake by erythrocytes. Wild type, ecto-5'-nucleotidase-deficient, and adenosine receptor-deficient mice undergo 5'-AMP-induced hypometabolism in a similar fashion. Injection of 5'-AMP leads to two distinct declining phases of oxygen consumption (VO(2)). The phase I response displays a rapid and steep decline in VO(2) that is independent of body temperature (T(b)) and ambient temperature (T(a)). It is followed by a phase II decline that is linked to T(b) and moderated by T(a). Altering the dosages of 5'-AMP from 0.25- to 2-fold does not change the phase I response. For mice, a T(a) of 15 degrees C is effective for induction of DH with the appropriate dose of 5'-AMP. Erythrocyte uptake of 5'-AMP leads to utilization of ATP to synthesize ADP. This is accompanied by increased glucose but decreased lactate levels, suggesting that glycolysis has slowed. Reduction in glycolysis is known to stimulate erythrocytes to increase intracellular levels of 2,3-bisphosphoglycerate, a potent allosteric inhibitor of hemoglobin's affinity for oxygen. Our studies showed that both 2,3-bisphosphoglycerate and deoxyhemoglobin levels rose following 5'-AMP administration and is in parallel with the phase I decline in VO(2). In summary, our investigations reveal that 5'-AMP mediated hypometabolism is probably triggered by reduced oxygen transport by erythrocytes initiated by uptake of 5'-AMP.

Quantum chemical study of reaction mechanism between plutonium and nitrogen.

The study of the reaction between plutonium and nitrogen is helpful in further understanding the interaction between plutonium and air molecules. Currently, there is no research on the microscopic reaction mechanism of plutonium nitridation reactions. Therefore, the microscopic mechanism of the Pu with N2 gas phase reaction is explored in this study, based on density functional theory (DFT) using different basis functions. In this paper, the geometry of stationary points on the potential energy surface is optimized. In addition, the transition states are verified by frequency analysis and intrinsic reaction coordination (IRC). Finally, we obtained the reaction potential energy curve and micro reaction pathways. Analysis of the reaction mechanism shows that the reaction of Pu with N2 has two pathways. Pathway 1 (Pu + N2 → R1 → TS1 → PuN2) has a T-shaped transition state and pathway 2 (Pu + N2 → R2 → TS2 → PuN + N) has an L-shaped transition state. Both transition states have only one imaginary frequency. According to the comparison of the energy at each stagnation point along the two pathways, and the heat energy emitted by the two reaction paths, we found that pathway 1 is the main reaction pathway. The nature of Pu-N bonding evolution along the pathways was studied by atoms in molecules (AIM) and electron localization function (ELF) topological approaches. In order to analyze the role of the plutonium atom 5f orbital in the reaction, the variation in density state along the pathways was measured. Results show that the 5f orbital mainly contributes to the formation of Pu-N bonds, and the influence of temperature on the reaction rate is revealed by calculating the rate constants of the two reaction pathways.

TRPV4 blockade suppresses atrial fibrillation in sterile pericarditis rats.

Atrial fibrillation (AF) commonly occurs after surgery and is associated with atrial remodeling. TRPV4 is functionally expressed in the heart, and its activation affects cardiac structure and functions. We hypothesized that TRPV4 blockade alleviates atrial remodeling and reduces AF induction in sterile pericarditis (SP) rats. TRPV4 antagonist GSK2193874 or vehicle was orally administered 1 day before pericardiotomy. AF susceptibility and atrial function were assessed using in vivo electrophysiology, ex vivo optical mapping, patch clamp, and molecular biology on day 3 after surgery. TRPV4 expression increased in the atria of SP rats and patients with AF. GSK2193874 significantly reduced AF vulnerability in vivo and the frequency of atrial ectopy and AF with a reentrant pattern ex vivo. Mechanistically, GSK2193874 reversed the abnormal action potential duration (APD) prolongation in atrial myocytes through the regulation of voltage-gated K+ currents (IK); reduced the activation of atrial fibroblasts by inhibiting P38, AKT, and STAT3 pathways; and alleviated the infiltration of immune cells. Our results reveal that TRPV4 blockade prevented abnormal changes in atrial myocyte electrophysiology and ameliorated atrial fibrosis and inflammation in SP rats; therefore, it might be a promising strategy to treat AF, particularly postoperative AF.

An Improved High-Throughput Data Processing Based on Combinatorial Materials Chip Approach for Rapid Construction of Fe-Cr-Ni Composition-Phase Map.

The combinatorial materials chip approach is vastly superior to the conventional one that characterizes one sample at a time in the efficiency of composition-phase map construction. However, the resolution of its high-throughput characterization and the correct rate of automated composition-phase mapping are often affected by inherent experimental limitations and imperfect automated analyses, respectively. Therefore, effective data preprocessing and refined automated analysis methods are required to automatically process huge amounts of experiment data to score a higher correct rate. In this work, the pixel-by-pixel structural and compositional characterization of the Fe-Cr-Ni combinatorial materials chip annealed at 750 °C was performed by microbeam X-ray at a synchrotron light source and by electron probe microanalysis, respectively. The severe baseline drift and system noise in the X-ray diffraction patterns were successfully eliminated by the three-step automated preprocessing (baseline drift removal, noise elimination, and baseline correction) proposed, which was beneficial to the subsequent quantitative analysis of the patterns. Through the injection of human experience, hierarchy clustering analyses, based on three dissimilarity measures (the cosine, Pearson correlation coefficient, and Jenson-Shannon divergence), were further accelerated by the simplified vectorization of the preprocessed X-ray diffraction patterns. As a result, a correct rate of 91.15% was reached for the whole map built automatically in comparison with the one constructed manually, which confirmed that the present data processing could assist humans to improve and expedite the processing of X-ray diffraction patterns and was feasible for composition-phase mapping. The constructed maps were generally consistent with the corresponding isothermal section of the Fe-Cr-Ni ternary alloy system in the ASM Alloy Phase Diagram Database except the inexistence of the σ phase under insufficient annealing.

Blockade of Transient Receptor Potential Vanilloid 4 Enhances Antioxidation after Myocardial Ischemia/Reperfusion.

Antioxidative stress provides a cardioprotective effect during myocardial ischemia/reperfusion (I/R). Previous research has demonstrated that the blockade of transient receptor potential vanilloid 4 (TRPV4) attenuates myocardial I/R injury. However, the underlying mechanism remains unclear. The current study is aimed at investigating the antioxidative activity of TRPV4 inhibition and elucidating the underlying mechanisms in vitro and ex vivo. We found that the inhibiting TRPV4 by the selective TRPV4 blocker HC-067047 or specific TRPV4-siRNA significantly reduces reactive oxygen species (ROS) and methane dicarboxylic aldehyde (MDA) levels in H9C2 cells exposed to hypoxia/reoxygenation (H/R). Meanwhile, the activity of antioxidative enzymes, particularly superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), is enhanced. Furthermore, after H/R, HC-067047 treatment increases the expression of P-Akt and the translocation of nuclear factor E2-related factor 2 (Nrf2) and related antioxidant response element (ARE) mainly including SOD, GSH-Px, and catalase (CAT). LY294002, an Akt inhibitor, suppresses HC-067047 and specific TRPV4-siRNA-induced Nrf2 expression and its nuclear accumulation. Nrf2 siRNA attenuates HC-067047 and specific TRPV4-siRNA-induced ARE expression. In addition, treatment with LY294002 or Nrf2 siRNA significantly attenuates the antioxidant and anti-injury effects of HC-067047 in vitro. Finally, in experiments on isolated rat hearts, we confirmed the antioxidative stress roles of TRPV4 inhibition during myocardial I/R and the application of exogenous H2O2. In conclusion, the inhibition of TRPV4 exerts cardioprotective effects through enhancing antioxidative enzyme activity and expressions via the Akt/Nrf2/ARE pathway.

New insights on the regulation of the adenine nucleotide pool of erythrocytes in mouse models.

The observation that induced torpor in non-hibernating mammals could result from an increased AMP concentration in circulation led our investigation to reveal that the added AMP altered oxygen transport of erythrocytes. To further study the effect of AMP in regulation of erythrocyte function and systemic metabolism, we generated mouse models deficient in key erythrocyte enzymes in AMP metabolism. We have previously reported altered erythrocyte adenine nucleotide levels corresponding to altered oxygen saturation in mice deficient in both CD73 and AMPD3. Here we further investigate how these Ampd3-/-/Cd73-/- mice respond to the administered dose of AMP in comparison with the control models of single enzyme deficiency and wild type. We found that Ampd3-/-/Cd73-/- mice are more sensitive to AMP-induced hypometabolism than mice with a single enzyme deficiency, which are more sensitive than wild type. A dose-dependent rightward shift of erythrocyte p50 values in response to increasing amounts of extracellular AMP was observed. We provide further evidence for the direct uptake of AMP by erythrocytes that is insensitive to dipyridamole, a blocker for ENT1. The uptake of AMP by the erythrocytes remained linear at the highest concentration tested, 10mM. We also observed competitive inhibition of AMP uptake by ATP and ADP but not by the other nucleotides and metabolites tested. Importantly, our studies suggest that AMP uptake is associated with an erythrocyte ATP release that is partially sensitive to inhibition by TRO19622 and Ca++ ion. Taken together, our study suggests a novel mechanism by which erythrocytes recycle and maintain their adenine nucleotide pool through AMP uptake and ATP release.

Interactive Organization of the Circadian Core Regulators PER2, BMAL1, CLOCK and PML.

The BMAL1 and CLOCK heterodimer in the mammalian circadian transcriptional complex is thought to be repressed by PER2 and CRY1 via direct interactions. We recently reported that PER2 is largely cytosolic in Pml(-/-) cells and did not co-immunoprecipitate (co-IP) with BMAL1 or CLOCK. Here, using multi-color immunofluorescence (IF) staining and co-IP, we observed a nuclear distribution of BMAL1 and a predominately cytosolic distribution of CLOCK in Pml(-/-) MEF. In the presence of WT PML, PER2 co-localized with BMAL1 in the nucleus. In Pml(-/-) MEF transfected with mutant K487R PML, we observed that BMAL1 and PER2 co-localized with K487R PML in the cytosol. Furthermore, cytosolic CLOCK and PER2 displayed a significant non-overlapping IF staining pattern. In Bmal1(-/-) MEF, CLOCK was primarily cytosolic while PML and PER2 were nuclear. Together, our studies suggest that PML mediates the binding of PER2 to BMAL1 in the BMAL1/CLOCK heterodimer and is an important component in the organization of a functional clock complex in the nucleus. Our studies also support that BMAL1 is important for CLOCK nuclear localization.

The Small Molecule Nobiletin Targets the Molecular Oscillator to Enhance Circadian Rhythms and Protect against Metabolic Syndrome.

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.