Conditional knockout mice with targeted disruption of B-cell associated protein (BAP)31 in adult mouse liver were generated and challenged with a high-fat diet (HFD) for 36 or 96 days and markers of ...obesity, diabetes, and hepatic steatosis were determined. Mutant mice were indistinguishable from WT littermates, but exhibited increased HFD-induced obesity. BAP31-deletion in hepatocytes increased the expression of SREBP1C and the target genes, including acetyl-CoA carboxylase 1 and stearoyl-CoA desaturase-1, and increased hepatic lipid accumulation and HFD-induced liver steatosis. Immunoprecipitation assay showed that BAP31 interacts with SREBP1C and insulin-induced gene 1 (INSIG1), and BAP31-deletion reduces INSIG1 expression, suggesting that BAP31 may regulate SREBP1C activity by modulating INSIG1 protein levels. Additionally, BAP31-deletion induced glucose and insulin intolerance, decreased Akt and glycogen synthase kinase 3β phosphorylation, and enhanced hepatic glucose production in mice. Expression of endoplasmic reticulum (ER) stress markers was significantly induced in BAP31-mutant mice. HFD-induced inflammation was aggravated in mutant mice, along with increased c-Jun N-terminal kinase and nuclear factor-κB activation. These findings demonstrate that BAP31-deletion induces SREBP activation and promotes hepatic lipid accumulation, reduces insulin signaling, impairs glucose/insulin tolerance, and increases ER stress and hepatic inflammation, explaining the protective roles of BAP31 in the development of liver steatosis and insulin resistance in HFD-induced obesity in animal models.
Electrochemical water splitting is one of the most economical and sustainable methods for large-scale hydrogen production. However, the development of low-cost and earth-abundant non-noble-metal ...catalysts for the hydrogen evolution reaction remains a challenge. Here we report a two-dimensional coupled hybrid of molybdenum carbide and reduced graphene oxide with a ternary polyoxometalate-polypyrrole/reduced graphene oxide nanocomposite as a precursor. The hybrid exhibits outstanding electrocatalytic activity for the hydrogen evolution reaction and excellent stability in acidic media, which is, to the best of our knowledge, the best among these reported non-noble-metal catalysts. Theoretical calculations on the basis of density functional theory reveal that the active sites for hydrogen evolution stem from the pyridinic nitrogens, as well as the carbon atoms, in the graphene. In a proof-of-concept trial, an electrocatalyst for hydrogen evolution is fabricated, which may open new avenues for the design of nanomaterials utilizing POMs/conducting polymer/reduced-graphene oxide nanocomposites.
Since December 2019, novel coronavirus infected pneumonia emerged in Wuhan city and rapidly spread throughout China. In severe novel coronavirus pneumonia cases, the number of platelets, their ...dynamic changes during the treatment, platelet‐to‐lymphocyte ratio (PLR) were a concern. We sought to describe the platelet feature of these cases. Single‐center case series of the 30 hospitalized patients with confirmed coronavirus disease (COVID)‐19 in Huizhou municipal central hospital from January 2020 to February 2020 were retrospectively analyzed. Demographic, clinical, blood routine results, other laboratory results, and treatment data were collected and analyzed. Outcomes of severe patients and nonsevere patients were compared. Univariate analysis showed that: age, platelet peaks, and PLR at peak platelet were the influencing factors in severe patients, multivariate analysis showed that the PLR value at peak platelet during treatment was an independent influencing factor in severe patients. The average hospitalization day of patients with platelet peaks during treatment was longer than those without platelet peaks (P < .05). The average age of patients with platelet peaks during treatment was older than those without platelet peaks (P < .05). The patients with significantly elevated platelets during treatment had longer average hospitalization days. And the higher PLR of patients during treatment had longer average hospitalization days. Single‐center case series of the 30 hospitalized patients with confirmed COVID‐19 in Huizhou Municipal Central Hospital, presumed that the number of platelets and their dynamic changes during the treatment may have a suggestion on the severity and prognosis of the disease. The patient with markedly elevated platelets and longer average hospitalization days may be related to the cytokine storm. The PLR of patients means the degree of cytokine storm, which might provide a new indicator in the monitoring in patients with COVID‐19.
The electrochemical nitrogen reduction reaction (NRR) is a very efficient method for sustainable NH3 production, but it requires effective catalysts to expedite the NRR kinetics and inhibit the ...concomitant hydrogen evolution reaction (HER). Two-dimensional (2D)/2D interface engineering is an effective method to design powerful catalysts due to intimate face-to-face contact of two 2D materials that facilitates the strong interfacial electronic interactions. Herein, we explored a 2D/2D MoS2/C3N4 heterostructure as an active and stable NRR catalyst. MoS2/C3N4 exhibited a conspicuously improved NRR performance with an NH3 yield of 18.5 μg h–1 mg–1 and a high Faradaic efficiency (FE) of 17.8% at −0.3 V, far better than those of the individual MoS2 or C3N4 component. Density functional theory calculations revealed that the interfacial charge transport from C3N4 to MoS2 could enhance the NRR activity of MoS2/C3N4 by promoting the stabilization of the key intermediate *N2H on Mo edge sites of MoS2 and concurrently decreasing the reaction energy barrier. Meanwhile, MoS2/C3N4 rendered a more favorable *H adsorption free energy on S edge sites than on Mo edge sites of MoS2, thereby protecting the NRR-active Mo edge sites from the competing HER and leading to a high FE.
Background Statins are widely used for treating patients with ischemic stroke at risk of secondary cerebrovascular events. It is unknown whether Asian populations benefit from more intensive ...statin‐based therapy for stroke recurrence. Therefore, in the present study we evaluated the effectiveness and safety of high‐dose and moderate‐dose statins for patients who had experienced mild ischemic stroke during the acute period. Methods and Results This multicenter prospective study included patients with mild ischemic stroke who presented within 72 hours of symptom onset. The outcomes of patients in the high‐intensity and moderate‐intensity statin treatment groups were compared, with the main efficacy outcome being stroke recurrence and the primary safety end point being intracranial hemorrhage. The propensity score matching method was employed to control for imbalances in baseline variables. Subgroup analyses were conducted to evaluate group differences. In total, the data of 2950 patients were analyzed at 3 months, and the data of 2764 patients were analyzed at 12 months due to loss to follow‐up. According to the multivariable Cox analyses adjusted for potential confounders, stroke recurrence occurred similarly in the high‐intensity statin and moderate‐intensity statin groups (3 months: adjusted hazard ratio HR, 1.12 95% CI, 0.85–1.49; P =0.424; 12 months: adjusted HR, 1.08 95% CI, 0.86–1.34; P =0.519). High‐intensity statin therapy was associated with an increased risk of intracranial hemorrhage (3 months: adjusted HR, 1.81 95% CI, 1.00–3.25; P =0.048; 12 months: adjusted HR, 1.86 95% CI, 1.10–3.16; P =0.021). The results from the propensity score‐matched analyses were consistent with those from the Cox proportional hazards analysis. Conclusions Compared with moderate‐intensity statin therapy, high‐dose statin therapy may not decrease the risk of mild, noncardiogenic ischemic stroke recurrence but may increase the risk of intracranial hemorrhage. Registration URL: www.chictr.org.cn/ . Unique Identifier: ChiCTR1900025214.
Object detection has been a challenging task in computer vision. Although significant progress has been made in object detection with deep neural networks, the attention mechanism has yet to be fully ...developed. In this paper, we propose a hybrid attention mechanism for single-stage object detection. First, we present the modules of spatial attention, channel attention and aligned attention for single-stage object detection. In particular, dilated convolution layers with symmetrically fixed rates are stacked to learn spatial attention. A channel attention mechanism with the cross-level group normalization and squeeze-and-excitation operation is proposed. Aligned attention is constructed with organized deformable filters. Second, the three types of attention are unified to construct the hybrid attention mechanism. We then plug the hybrid attention into Retina-Net and propose the efficient single-stage HAR-Net for object detection. The attention modules and the proposed HAR-Net are evaluated on the COCO detection dataset. The experiments demonstrate that hybrid attention can significantly improve the detection accuracy and that the HAR-Net can achieve a state-of-the-art 45.8% mAP, thus outperforming existing single-stage object detectors.
Stretchable self‐healing supercapacitors (SCs) can operate under extreme deformation and restore their initial properties after damage with considerably improved durability and reliability, expanding ...their opportunities in numerous applications, including smart wearable electronics, bioinspired devices, human–machine interactions, etc. It is challenging, however, to achieve mechanical stretchability and self‐healability in energy storage technologies, wherein the key issue lies in the exploitation of ideal electrode and electrolyte materials with exceptional mechanical stretchability and self‐healing ability besides conductivity. Conductive hydrogels (CHs) possess unique hierarchical porous structure, high electrical/ionic conductivity, broadly tunable physical and chemical properties through molecular design and structure regulation, holding tremendous promise for stretchable self‐healing SCs. Hence, this review is innovatively constructed with a focus on stretchable and self‐healing CH based electrodes and electrolytes for SCs. First, the common synthetic approaches of CHs are introduced; then the stretching and self‐healing strategies involved in CHs are systematically elaborated; followed by an explanation of the conductive mechanism of CHs; then focusing on CH‐based electrodes and electrolytes for stretchable self‐healing SCs; subsequently, application of stretchable and self‐healing SCs in wearable electronics are discussed; finally, a conclusion is drawn along with views on the challenges and future research directions regarding the field of CHs for SCs.
Conductive hydrogels (CHs) are a new class of soft functional materials that have recently found application in flexible energy storage devices such as batteries and supercapacitors (SCs). Herein, the promise of CHs in this emerging field is demonstrated through summarizing their roles as ideal electrode and electrolyte materials for stretchable and self‐healing SCs.
Emerging evidence suggests that epithelial‐mesenchymal transitions (EMTs) play important roles in tumor metastasis and recurrence. Understanding molecular mechanisms that regulate the EMT process is ...crucial for improving treatment of hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) play important roles in HCC; however, the mechanisms by which miRNAs target the EMT and their therapeutic potential remains largely unknown. To better explore the roles of miRNAs in the EMT process, we established an EMT model in HCC cells by transforming growth factor beta 1 treatment and found that several tumor‐related miRNAs were significantly decreased. Among these miRNAs, miR‐125b expression was most strongly suppressed. We also found down‐regulation of miR‐125b in most HCC cells and clinical specimens, which correlated with cellular differentiation in HCC patients. We then demonstrated that miR‐125b overexpression attenuated EMT phenotype in HCC cancer cells, whereas knockdown of miR‐125b promoted the EMT phenotype in vitro and in vivo. Moreover, we found that miR‐125b attenuated EMT‐associated traits, including chemoresistance, migration, and stemness in HCC cells, and negatively correlated with EMT and cancer stem cell (CSC) marker expressions in HCC specimens. miR‐125b overexpression could inhibit CSC generation and decrease tumor incidence in the mouse xenograft model. Mechanistically, our data revealed that miR‐125b suppressed EMT and EMT‐associated traits of HCC cells by targeting small mothers against decapentaplegic (SMAD)2 and 4. Most important, the therapeutic delivery of synthetic miR‐125b mimics decreased the target molecule of CSC and inhibited metastasis in the mice model. These findings suggest a potential therapeutic treatment of miR‐125b for liver cancer. Conclusion: miR‐125b exerts inhibitory effects on EMT and EMT‐associated traits in HCC by SMAD2 and 4. Ectopic expression of miR‐125b provides a promising strategy to treat HCC. (Hepatology 2015;62:801–815)
In high‐temperature proton exchange membrane fuel cells (HT‐PEMFCs), the poisoning of Pt by phosphoric species severely affects the kinetics of the oxygen reduction reaction, which restricts their ...commercialized application. Herein, for the first time, the phosphate tolerance of PtFe ordered intermetallic alloys is enhanced by a doping‐modulated strain strategy via employing a low amount of Cu as a dopant to boost HT‐PEMFCs. This Cu doping facilitates the formation of compressive strain in PtFe crystals, consequently altering the electronic structure of electrocatalysts and then benefiting for weakening the adsorption energy between phosphoric acid and Pt surfaces. In addition, the high temperature phosphate adsorption tests also reveal that the dopant of Cu in Pt based electrocatalysts can improve the tolerance of phosphoric acid. The HT‐PEMFCs assembled by those cathodic electrocatalysts with the low‐Pt loading of 0.5 mgPt cm−2 achieve a preeminent peak power of 793.5 and 432.6 mW cm−2 under the condition of H2–O2 and H2–air atmosphere, respectively, or nearly 1.53 and 1.34 times higher as compared with commercial Pt/C electrocatalysts. Moreover, those electrocatalysts also exhibit robust stability under harsh condition in H2–O2 atmosphere with negligible activity loss for at least 100 h, exceeding most of other reported ORR electrocatalysts.
This Cu doping in PtFe crystals facilitates the formation of compressive strain, consequently altering the electronic structure and then enhancing the phosphate tolerance. The maximum output power of Cu‐PtFe/NC in HT‐PEMFC reaches as high as 793.5 and 432.6 mW cm−2 under the condition of H2–O2 and H2–air atmosphere, respectively, exceeding that of most reported ORR electrocatalysts.
Bone marrow (BM) niche responds to chemotherapy-induced cytokines secreted from acute lymphoblastic leukemia (ALL) cells and protects the residual cells from chemotherapeutics in vivo. However, the ...underlying molecular mechanisms for the induction of cytokines by chemotherapy remain unknown. Here, we found that chemotherapeutic drugs (e.g., Ara-C, DNR, 6-MP) induced the expression of niche-protecting cytokines (GDF15, CCL3 and CCL4) in both ALL cell lines and primary cells in vitro. The ATM and NF-κB pathways were activated after chemotherapy treatment, and the pharmacological or genetic inhibition of these pathways significantly reversed the cytokine upregulation. Besides, chemotherapy-induced NF-κB activation was dependent on ATM-TRAF6 signaling, and NF-κB transcription factor p65 directly regulated the cytokines expression. Furthermore, we found that both pharmacological and genetic perturbation of ATM and p65 significantly decreased the residual ALL cells after Ara-C treatment in ALL xenograft mouse models. Together, these results demonstrated that ATM-dependent NF-κB activation mediated the cytokines induction by chemotherapy and ALL resistance to chemotherapeutics. Inhibition of ATM-dependent NF-κB pathway can sensitize ALL to chemotherapeutics, providing a new strategy to eradicate residual chemo-resistant ALL cells.
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