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Aims Cereblon (CRBN) is a substrate receptor of the E3 ubiquitin ligase complex that was reported to target ion channel proteins. L-type voltage-dependent Ca2+ channel (LTCC) density and dysfunction is a critical player in heart failure with reduced ejection fraction (HFrEF). However, the underlying cellular mechanisms by which CRBN regulates LTCC subtype Cav1.2α during cardiac dysfunction remain unclear. Here, we explored the role of CRBN in HFrEF by investigating the direct regulatory role of CRBN in Cav1.2α activity and examining how it can serve as a target to address myocardial dysfunction. Methods and results Cardiac tissues from HFrEF patients exhibited increased levels of CRBN compared with controls. In vivo and ex vivo studies demonstrated that whole-body CRBN knockout (CRBN−/−) and cardiac-specific knockout mice (Crbnfl/fl/Myh6Cre+) exhibited enhanced cardiac contractility with increased LTCC current (I CaL) compared with their respective controls, which was modulated by the direct interaction of CRBN with Cav1.2α. Mechanistically, the Lon domain of CRBN directly interacted with the N-terminal of Cav1.2α. Increasing CRBN levels enhanced the ubiquitination and proteasomal degradation of Cav1.2α and decreased I CaL. In contrast, genetic or pharmacological depletion of CRBN via TD-165, a novel PROTAC-based CRBN degrader, increased surface expression of Cav1.2α and enhanced I CaL. Low CRBN levels protected the heart against cardiomyopathy in vivo. Conclusion Cereblon selectively degrades Cav1.2α, which in turn facilitates cardiac dysfunction. A targeted approach or an efficient method of reducing CRBN levels could serve as a promising strategy for HFrEF therapeutics.

Wormlike micelles (WLMs), which are the self-assemblies of amphiphilic surfactants, have gained attention in various applications due to their unique ‘living’ nature (i.e., union-scission). However, the industrial production of the WLMs has rarely been discussed. Moreover, given that the system hardly reaches the desired viscosity without appropriate control actions within a reasonable operation time, a model-based controller has been implemented to the production of WLMs where CTAB/NaCl in a semi-batch reactor is used as a case study. For this, a high-fidelity model was developed by integrating thermodynamic, kinetic, and rheology models and validated with experimental results. Subsequently, to alleviate the computational burden of such a high-fidelity model, the model reduction was carried out by the multivariable output error state space algorithm. The developed reduced-order model (ROM) was able to reproduce the essential features of the high-fidelity model and utilized in the formulated model predictive control (MPC) system. Herein, the manipulated variables (i.e., surfactant volume fraction, salt concentration, and temperature) are adjusted to give the desired WLM length of 3700 nm (i.e., a zero-shear viscosity of 100 Pa-s). Finally, the developed MPC scheme resulted in optimal input sequences to successfully reach the setpoint within practical constraints.

Objectives: Insomnia is one of the most common sleep disorders and is difficult to completely treat because of the undesirable side effects of hypnotics. The present study was designed to investigate the hypnotic effect of acupuncture stimulation at HT7 on caffeine-induced sleep disorders and locomotor activity in rats. We also evaluated neuronal activity changes in the arousal region of the basal forebrain. Methods: Rats received intraperitoneal injections of caffeine, and then electroencephalogram power spectrum analysis and locomotor activity measurements were performed. Stimulation at HT7 was performed using a mechanical acupuncture instrument (MAI) before caffeine injection, and its effects on caffeine-induced changes in sleep architecture, locomotor activity and c-Fos expression were examined. Results: Caffeine injection (7.5 mg/kg) produced a significant decrease in slow-wave sleep and an increase in wake time compared with saline injection. Caffeine injection also increased locomotor activity and c-Fos expression in the medial septum–vertical limb of the diagonal band of Broca (MS-VDB), one of the arousal regions of the basal forebrain. Stimulation at HT7 with the MAI alleviated the caffeine-induced sleep disturbance and the increase in locomotor activity. In addition, MAI treatment at HT7, compared with treatment at a location not corresponding to any traditional acupuncture point, reduced the caffeine-induced increase in c-Fos expression. Conclusion: These results indicate that the hypnotic effect of HT7 acupuncture stimulation on caffeine-induced insomnia was associated with suppression of neuronal activity in the basal forebrain.

Perovskite light-emitting devices have drawn considerable attention for their favorable optoelectronic properties. High carrier mobilities make perovskites excellent candidates as host materials in...

Transcriptional coactivator PGC-1α and its splice variant NT-PGC-1α regulate metabolic adaptation by modulating many gene programs. Selective ablation of PGC-1α attenuates diet-induced obesity through enhancing fatty acid oxidation and thermogenesis by upregulation of NT-PGC-1α in brown adipose tissue (BAT). Recently, we have shown that selective ablation of NT-PGC-1α reduces fatty acid oxidation in BAT. Thus, the objective of this study was to test our hypothesis that NT-PGC-1α−/− mice would be more prone to diet-induced obesity. Male and female NT-PGC-1α+/+ (WT) and NT-PGC-1α−/− mice were fed a regular chow or 60% high-fat (HF) diet for 16 weeks. Contrary to our expectations, both male and female NT-PGC-1α−/− mice fed HFD were protected from diet-induced obesity, with more pronounced effects in females. This lean phenotype was primarily driven by reduced dietary fat intake. Intriguingly, HFD-fed female, but not male, NT-PGC-1α−/− mice further exhibited decreased feed efficiency, which was closely associated with increased fecal fat excretion and decreased uptake of fatty acids by the intestinal enterocytes and adipocytes with a concomitant decrease in fatty acid transporter gene expression. Collectively, our results highlight the role for NT-PGC-1α in regulating whole body lipid homeostasis under HFD conditions.

Background: The self-perceived level of disability for stroke survivors in community is little known. We aimed to characterize HRQoL 1 year after stroke and to investigate how socio-demographic and stroke-related factors and medical adherence explain the self-perceived level of disability among a Korean stroke population.Methods: This study was a multi-center and cross-sectional study. A total of 426 ischemic stroke survivors at 1 year after onset recruited from 11 university hospitals underwent a one-session assessment including: socioeconomic variables, the modified Rankin Scale (mRS), various neurological sequelae, the modifed Morisky scale (MMS), and the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) 36-items. The relationship between disability and different variables was analyzed using ordinal logistic regression. Results: The prevalence of disability by global WHODAS 2.0 score was 62.6% (41.6% for mild; 16.0% for moderate; 5.0% for severe) in subjects. Prevalence of severe disability was higher in Participation in society (16.8%) and Getting around (11.8%) than in the other domains. Low MMS motivation was the only factor determining the significant association between all six domains of disability after adjustment. Different predictors for specific domains were age, mRS, dysarthria, trouble seeing, cognition problem and MMS-motivation for Understanding and communicating; age, recurrent stroke, mRS, hemiplegia, facial palsy, general weakness and MMS-motivation for Getting around; age, education, mRS, hemiplegia and MMS-motivation for Self-care; age, education, recurrent stroke, hemiplegia, dysarthria and MMS-motivation for Getting along with people; age, education, income, mRS, hemiplegia, dysarthria, MMS-knowledge and MMS-motivation for Life activities; living without spouse, recurrent stroke, mRS, hemiplegia, dysarthria, trouble seeing, cognition problem, general weakness and MMS-motivation for Participation in society.Conclusions: Self-perceived disability by the WHODAS 2.0 had almost double the prevalence compared to hemiplegia, one of the most common neurological sequelae 1 year after stroke. Each domain of disability increased with various associated factors. Interventions promoting medical adherence of motivation seem to help high HRQoL in all domains.

Brown and beige adipocytes are specialized to dissipate energy as heat. Sgk2, encoding a serine/threonine kinase, has been identified as a brown and beige adipocyte-specific gene in rodents and humans; however, its function in brown/beige adipocytes remains unraveled. Here, we examined the regulation and role of Sgk2 in brown/beige adipose tissue thermogenesis. We found that transcriptional coactivators PGC-1α and NT-PGC-1α activated by the β3 adrenergic receptor-cAMP-PKA pathway are recruited to the Sgk2 promoter, triggering Sgk2 transcription in response to cold. SGK2 elevation was closely associated with increased serine/threonine phosphorylation of proteins carrying the consensus RxRxxS/T phosphorylation site. However, despite cold-dependent activation of SGK2, mice lacking Sgk2 exhibited normal cold tolerance at 4°C. In addition, Sgk2+/+ and Sgk2−/− mice induced comparable increases in energy expenditure during pharmacological activation of brown and beige adipose tissue with a β3AR agonist. In vitro loss- and gain-of-function studies further demonstrated that Sgk2 ablation or activation does not alter thermogenic gene expression and mitochondrial respiration in brown adipocytes. Collectively, our results reveal a new signaling component SGK2, although dispensable for cold-induced thermogenesis that adds an additional layer of complexity to the β3AR signaling network in brown/beige adipose tissue.

ATPase inhibitory factor 1 (IF1) is an ATP synthase–interacting protein that suppresses the hydrolysis activity of ATP synthase. In this study, we observed that the expression of IF1 was up-regulated in response to electrical pulse stimulation of skeletalmuscle cells and in exercized mice and healthy men. IF1 stimulates glucose uptake viaAMPKin skeletalmuscle cells and primary culturedmyoblasts.Reactive oxygen species and Rac family small GTPase 1 (Rac1) function in the upstream and downstream of AMPK, respectively, in IF1-mediated glucose uptake. In diabetic animal models, the administration of recombinant IF1 improved glucose tolerance and down-regulated blood glucose level. In addition, IF1 inhibitsATPhydrolysis byb-F1-ATPase inplasmamembrane, thereby increasing extracellular ATP and activating the protein kinase B (Akt) pathway, ultimately leading to glucose uptake. Thus, we suggest that IF1 is a novel myokine and propose amechanismby which AMPK and Akt contribute independently to IF1-mediated improvement of glucose tolerance impairment. These results demonstrate the importance of IF1 as a potential antidiabetic agent.

We evaluated the effect of manganese ferrite nanoparticles (MFN) on radiosensitization and immunologic responses using the murine hepatoma cell line Hepa1-6 and the syngeneic mouse model. The clonogenic survival of Hepa1-6 cells was increased by hypoxia, while being restricted by ionizing radiation (IR) and/or MFN. Although MFN suppressed HIF-1α under hypoxia, the combination of IR and MFN enhanced apoptosis and DNA damage in Hepa1-6 cells. In the Hepa1-6 syngeneic mouse model, the combination of IR and MFN notably limited the tumor growth compared to the single treatment with IR or MFN, and also triggered more frequent apoptosis in tumor tissues than that observed under other conditions. Increased expression of PD-L1 after IR was not observed with MFN alone or the combination of IR and MFN in vitro and in vivo, and the percentage of tumor-infiltrating T cells and cytotoxic T cells increased with MFN, regardless of IR, in the Hepa1-6 syngeneic mouse model, while IR alone led to T cell depletion. MFN might have the potential to overcome radioresistance by alleviating hypoxia and strengthening antitumor immunity in the tumor microenvironment.

Hybrid organic-inorganic lead halide perovskites have attracted much attention in the field of optoelectronic devices because of their desirable properties such as high crystallinity, smooth morphology, and well-oriented grains. Recently, it was shown that thermal nanoimprint lithography (NIL) is an effective method not only to directly pattern but also to improve the morphology, crystallinity, and crystallographic orientations of annealed perovskite films. However, the underlining mechanisms behind the positive effects of NIL on perovskite material properties have not been understood. In this work, we study the kinetics of perovskite grain growth with surface energy calculations by first-principles density functional theory (DFT) and reveal that the surface energy-driven preferential grain growth during NIL, which involves multiplex processes of restricted grain growth in the surface-normal direction, abnormal grain growth, crystallographic reorientation, and grain boundary migration, is the enabler of the material quality enhancement. Moreover, we develop an optimized NIL process and prove its effectiveness by employing it in a perovskite light-emitting electrochemical cell (PeLEC) architecture, in which we observe a fourfold enhancement of maximum current efficiency and twofold enhancement of luminance compared to a PeLEC without NIL, reaching a maximum current efficiency of 0.07598 cd/A at 3.5 V and luminance of 1084 cd/m

The oxidative dehydrogenation (ODH) of butene has been recently developed as a viable alternative for the synthesis of 1,3-butadiene due to its advantages over other conventional methods. Various catalytic reactors for this process have been previously studied, albeit with a focus on lab-scale design. In this study, a multi-tubular reactor model for the butadiene synthesis via ODH of butene was developed using computational fluid dynamics (CFD). For this, the 3D multi-tubular model, which combines complex reaction kinetics with a shell-side coolant fluid over a series of individual reactor tubes, was generated using OpenFOAM&reg, Then, the developed model was validated and analyzed with the experimental results, which gave a maximum error of 7.5%. Finally, parametric studies were conducted to evaluate the effect of thermodynamic conditions (isothermal, non-isothermal and adiabatic), feed temperature, and gas velocity on reactor performance. The results showed the formation of a hotspot at the reactor exit, which necessitates an efficient temperature control at that section of the reactor. It was also found that as the temperature increased, the conversion and yield increased whilst the selectivity decreased. The converse was found for increasing velocities.

One major hurdle in the progress of hyperbolic metamaterials (HMMs) is their lossy nature due to the metal constituent. In this work, we design a gain-assisted active HMM utilizing the recently emerged, solution-processed perovskite gain material. Our HMM is consisted of MAPbI3 perovskite and Au subwavelength multi-layer. We theoretically and experimentally investigate the strong emission polarization anisotropy that is unique to HMMs. Our work opens the way towards applications such as high-speed light emission, super resolution imaging and lithography, electro-optical modulators and perfect light absorbers.