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In the multicenter, randomized, sham-controlled FAVOR (Comparison of Quantitative Flow Ratio Guided and Angiography Guided Percutaneous Intervention in Patients with Coronary Artery Disease) III China trial, quantitative flow ratio (QFR)-based lesion selection improved 1-year clinical outcomes compared with conventional angiographic guidance for percutaneous coronary intervention (PCI).The purpose of this study was to determine whether the benefits of QFR guidance persist at 2 years, particularly for patients in whom QFR changed the revascularization strategy.Eligible patients were randomized to a QFR-guided strategy (PCI performed only if QFR ≤0.80) or a standard angiography-guided strategy. Major adverse cardiac events (MACE), a composite of all-cause death, myocardial infarction (MI), or ischemia-driven revascularization occurring within 2 years were analyzed in the intention-to-treat population.Among 3,825 randomized participants, 2-year MACE occurred in 161 of 1,913 (8.5%) patients in the QFR-guided group and in 237 of 1,912 (12.5%) patients in the angiography-guided group (HR: 0.66; 95% CI: 0.54-0.81; P 0.0001), driven by fewer MIs (4.0% vs 6.8%; HR: 0.58; 95% CI: 0.44-0.77; P = 0.0002) and ischemia-driven revascularizations (4.2% vs 5.8%; HR: 0.71; 95% CI: 0.53-0.95; P = 0.02) in the QFR-guided group. Landmark analysis showed consistent results within the first year and between 1-2 years (PQFR-guided lesion selection improved 2-year clinical outcomes compared with standard angiography guidance. The benefits were most pronounced among patients in whom QFR assessment altered the planned revascularization strategy. (FAVOR III China Study [The Comparison of Quantitative Flow Ratio Guided and Angiography Guided Percutaneous Intervention in Patients with Coronary Artery Disease] NCT03656848).

Shift work is associated with increased risk of acute myocardial infarction (AMI) and worsened prognosis. However, the mechanisms linking shift work and worsened prognosis in AMI remain unclear.This study sought to investigate the impact of shift work on reperfusion injury, a major determinant of clinical outcomes in AMI.Study patient data were obtained from the database of the EARLY-MYO-CMR (Early Assessment of Myocardial Tissue Characteristics by CMR in STEMI) registry, which was a prospective, multicenter registry of patients with ST-segment elevation myocardial infarction (STEMI) undergoing cardiac magnetic resonance (CMR) imaging after reperfusion therapy. The primary endpoint was CMR-defined post-reperfusion infarct size. A secondary clinical endpoint was the composite of major adverse cardiac events (MACE) during follow-up. Potential mechanisms were explored with the use of preclinical animal AMI models.Of 706 patients enrolled in the EARLY-MYO-CMR registry, 412 patients with STEMI were ultimately included. Shift work was associated with increased CMR-defined infarct size (β = 5.94%; 95% CI: 2.94-8.94; P 0.0001). During a median follow-up of 5.0 years, shift work was associated with increased risks of MACE (adjusted HR: 1.92; 95% CI: 1.12-3.29; P = 0.017). Consistent with clinical findings, shift work simulation in mice and sheep significantly augmented reperfusion injury in AMI. Mechanism studies identified a novel nuclear receptor subfamily 1 group D member 1/cardiotrophin-like cytokine factor 1 axis in the heart that played a crucial role in mediating the detrimental effects of shift work on myocardial injury.The current study provided novel findings that shift work increases myocardial infarction reperfusion injury. It identified a novel nuclear receptor subfamily 1 group D member 1/cardiotrophin-like cytokine factor 1 axis in the heart that might play a crucial role in mediating this process. (Early Assessment of Myocardial Tissue Characteristics by CMR in STEMI [EARLY-MYO-CMR] registry; NCT03768453).

Acute myocardial ischemia/reperfusion (MI/R) is a major determinant of prognosis in myocardial infarction patients, while effective therapies are currently lacking. Nuclear receptor co-repressor 1 (NCoR1) is emerging as a critical regulator of cell survival and death signaling in mammals. However, the role of NCoR1 in the pathogenesis of acute MI/R injury remains unknown. Here, we observed that NCoR1 was highly expressed in the mouse heart and significantly downregulated after acute MI/R injury. Cardiomyocyte-specific NCoR1 deletion led to significantly increased infarct size and exacerbated cardiac dysfunction compared to wild-type littermates. Moreover, cardiomyocyte-specific NCoR1 deficiency exacerbated MI/R-induced mitochondrial dysfunction and apoptotic pathway activation. Transcriptomic profiling results indicated that cardiomyocyte-specific NCoR1 deficiency pivotally promoted activation of inflammatory pathways. Through integrated omics analysis, signal transducer and activator of transcription 1 (STAT1) was identified as a downstream target trans-repressed by NCoR1. STAT1 activation played a key mediating role in the detrimental effects of NCoR1 deficiency in MI/R injury. Collectively, our findings provided the first evidence that cardiomyocyte-expressed NCoR1 functioned as a crucial cardioprotective factor against acute MI/R injury by targeting the STAT1 pathway in heart.

Research question : What is the expression pattern of inflammatory mRNA profiles of dehydroepiandrosterone (DHEA) plus high-fat diet (HFD)-induced polycystic ovary syndrome (PCOS) mouse model? Design : In this study, RNA sequencing was performed to investigate the mRNA expression profiles in the ovarian tissues of a DHEA plus HFD-induced PCOS mouse model. Six samples were divided into two groups (control and PCOS), with three biological replicates in each group. This was followed by hierarchical clustering, gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. The relative expression levels of nine inflammatory genes were validated via quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Results : A total of 436 genes were differentially expressed between the control and PCOS mice. Out of these, 137 genes were up-regulated while 299 genes were down-regulated. Gene ontology analysis indicated that differentially expressed mRNAs were associated with T cell-mediated cytotoxicity and homocysteine metabolic processes. Pathway analysis further showed that these abnormally expressed mRNAs were associated with signaling pathways, such as NF-kB signaling, tyrosine metabolism, and phenylalanine metabolism. All these pathways are involved in chronic inflammation and PCOS. Conclusion : The differentially expressed genes are potentially involved in the inflammation that is evident in PCOS, and so could serve as therapeutic options against the disease. Nevertheless, prospective studies are needed to test this hypothesis.

NUS1 has been recently identified as a candidate gene for Parkinson's disease (PD). Few studies have examined the association of NUS1 variants with PD susceptibility and phenotypes. In the first cohort, whole-exome sequencing was performed to identify variants in NUS1 exon-coding and exon-intron regions in 1542 cases and 1625 controls. 13 variants were totally detected, of which 10 rare variants and 3 low-frequency variants. Burden analysis showed that rare NUS1 variants significantly enriched in PD (p=0.016). We also performed a meta-analysis based on previous and our studies to correlate NUS1 mutations with PD susceptibility. Integrating our previous cohort (3210 cases and 2807 controls) and the first cohort identified the significant association of rs539668656 with PD risk (odds ratio (OR) = 2.82, p = 0.016). The genotype-phenotype association analysis showed that patients carrying rare variants, or rs539668656 were significantly associated with earlier onset age, depression, emotional impairment and severe disease condition. Our results support the role of NUS1 rare variants and rs539668656 towards PD susceptibility and phenotype.

Sodium (Na) metal anodes provide the base for the high specific energy of rechargeable Na batteries. However, non-uniform dendrite growth, volume change, and low Coulombic efficiency of Na metal anodes cause safety concerns and poor cyclability, hindering the practical applications of Na batteries. Herein, we proposed an interfacial design principle to construct sodiophilicity-regulated Na metal anodes. Through modeling the interfacial interaction that appears in a sodiated Sn-O-C system, we discovered and experimentally confirmed that the intermediate phases of Na2O and/or Na15Sn4 lower the nucleation overpotentials and guide the Na deposition because of the strong binding to Na metal. More importantly, the poor cyclability caused by the loss of sodiophilic sites can be dramatically improved by designing a strong interaction between sodiophilic agents and conductive scaffolds. Following the principle, we sandwiched SnO2 nanodots between reduced graphene oxide (rGO) layers to form a monolithic Na metal anode and pre-coated it with artificial solid electrolyte interphase (SEI). The resultant layered sandwich structure enables a unique interlayer Na deposition through the thickness direction, thereby leading to a stable SEI and enhanced cyclability. This interfacial principle provides a rational design basis for durable and efficient Na metal anodes.

The positive- and negative-ion electrospray ionization (ESI) coupled with Fourier transform-ion cyclotron resonance mass spectrometry (FT-ICR MS) was employed to identify the chemical composition of heteroatomic compounds in four distillates of Fushun shale oil, and their catalytic cracking performance was investigated. There are nine classes of basic nitrogen compounds (BNCs) and eleven classes of non-basic heteroatomic compounds (NBHCs) in the different distillates. The dominant BNCs are mainly basic N1 class species. The dominant NBHCs are mainly acidic O2 and O1 class species in the 300–350 °C, 350–400 °C, and 400–450 °C distillates, while the neutral N1, N1O1 and N2 compounds become relatively abundant in the > 450 °C fraction. The basic N1 compounds and acidic O1 and O2 compounds are separated into different distillates by the degree of alkylation (different carbon number) but not by aromaticity (different double-bond equivalent values). The basic N1O1 and N2 class species and neutral N1 and N2 class species are separated into different distillates by the degrees of both alkylation and aromaticity. After the catalytic cracking of Fushun shale oil, the classes of BNCs in the liquid products remain unchanged, while the classes and relative abundances of NBHCs vary significantly.

Historically, most drugs target protein orthosteric sites. The gradual emergence of resistance hampers their therapeutic effectiveness, posing a challenge to drug development. Coadministration of allosteric and orthosteric drugs provides a revolutionary strategy to circumvent drug resistance, as drugs targeting the topologically distinct allosteric sites can restore or even enhance the efficacy of orthosteric drugs. Here, we comprehensively review the latest successful examples of such combination treatments against drug resistance, with a focus on their modes of action and the underlying structural mechanisms. Our work supplies an innovative insight into such promising methodology against the recalcitrant drug resistance conundrum and will be instructive for future clinical therapeutics.

Acyclovir (ACV), an analog of 2′-deoxyguanosine, exhibits poor bioavailability due to limited permeability. In this study, the aim was to improve the bioavailability and permeability of ACV. N,N,N-trimethyl-O-octadecyl chitosan (TMSC) was synthesized by covalently bonding a long alkyl chain and a quaternary ammonium group onto chitosan. The chemical structure of TMSC was characterized by Fourier transform infrared (FT-IR) spectra, proton nuclear magnetic resonance (1H-NMR), thermogravimetry (TG), and differential thermogravimetry (DTG). The biological safety of TMSC was evaluated using a hemolysis experiment, which resulted in a hemolysis rate of 6.63% at the highest concentration (3 mg/mL). TMSC was used to prepare acyclovir nanoparticle (ACV NP) based on the Box–Behnken design, and characterized by transmission electron microscopy (TEM), atomic force microscopy (AFM), and dynamic light scattering (DLS) to determine size and morphology. Furthermore, the permeability of ACV NP was investigated using a non-everted intestinal sac model. ACV NP exerted a 1.9-fold higher effect on the ileum than ACV. In vivo, the relative bioavailability of ACV NP was ∼4.5-fold greater than that of the ACV suspension. These results suggest that ACV NP augment permeability and effectiveness of ACV.

The purpose of this study was to prepare and characterize the microspheres of BBH (Berberine Hydrochloride) and TMP (Trimethoprim) by cross-linking Chitosan and sulfobutyl ether-β-cyclodextrin (SBE7-β-CD). TMP was first complexed with SBE7-β-CD, enhancing the solubility of TMP. then the blank microspheres was prepared by ionic gelation of Chitosan and SBE7-β-CD, and the formation conditions was determined, ranging from 1 mg mL−1 to 5 mg mL−1 Chitosan/SBE7-β-CD concentration and 1:0.5 to 1:1.5 Chitosan/SBE7-β-CD mass ratio. After then, the BBH/TMP microspheres were prepared by ionic gelation of TMP/SBE7-β-CD inclusion complex and Chitosan. The blank microspheres and the BBH/TMP microspheres were further confirmed by the FT-IR, DSC, particle size and zeta potential, the morphology studies was conducted by transmission electron microscope (TEM). The stability experiment show BBH/TMP microspheres were relatively stable at high temperature and strong illumination, but it would be preserved in good dry environment. The dissolution and the transdermal studies indicated that BBH/TMP microspheres possesses sustained release effect, and the antibacterial experiment in vitro also show that antibacterial effect of BBH/TMP microspheres occurred later than physical mixtures. In conclusion, all results indicate that prepared microspheres can be used as a promising vehicle for the encapsulation of BBH and TMP.

Background: Catheter ablation for parahisian ventricular arrhythmias (PHVA) is technically challenging and associated with risks of atrioventricular block (AVB). We developed a stepwise approach to improve the efficacy and safety of PHVA ablation. Methods: Forty-three patients (26 males; average age 65.8 ±10.4 years) with PHVAs were enrolled. A stepwise approach comprising differential electrocardiogram, sequential mapping and ablation beneath/above the septal leaflet of the tricuspid valve (SLTV) and at the neighboring/contralateral regions (the aortic root and sub-aortic valve region) was applied for PHVA. The effectiveness and safety of the stepwise approach was evaluated at the end of one year’s follow-up. Results: Sequential ablation beneath the SLTV (B-SLTV) succeeded in 24 (66.7 %) of 36 with right PHVA and ablation above the SLTV succeeded in 6 of the remaining12 with failed B-SLTV ablation. Target-His bundle (HB) distance > 4.5 mm significantly predicted successful right PHVA ablation (OR 1.703; 95% CI 1.084-2.676, P=0.02). “Seeming” right PHVA by electrocardiogram in 4 and apparent left PHVA in 3 was successfully ablated at the sub-aortic parahisian region. At the end of one year’s follow-up, 27 (75%) of 36 patients with right PHVA and 6 (85.7%) of 7 patients with left PHVA were free of PHVA recurrence off anti-arrhythmic drugs. The total success rate was 76.7% by using the stepwise approach for PHVA. One patient with A-SLTV ablation underwent pacemaker implantation due to complete AVB. Conclusions: The stepwise approach was effective and safe for treating PHVA. The target-HB distance was a significant predictor for right PHVA ablation

BACKGROUND & AIMS Cirrhotic cardiomyopathy is a major complication and cause of morbidity in end-stage primary biliary cholangitis (PBC). However, it is unclear whether there is clinically silent myocardial involvement at the early stage of PBC before cirrhosis and cardiac manifestations. This prospective, three-center, multi-modality cardiac imaging study on the early identification of myocardial impairment in PBC (EARLY-MYO-PBC) was designed to identify silent myocardial impairment in PBC patients without cardiac manifestations. METHODS A total of 112 subjects (56 with PBC and 56 age- and sex-matched controls) undergoing cardiovascular magnetic resonance (CMR) were enrolled. Demographic, serologic, and cardiac imaging data were prospectively collected. All participants had no cardiac discomfort or previous heart disease and had normal electrocardiographic findings. RESULTS Subclinical myocardial involvement, as evidenced by cardiac morphologic, functional, and tissue characterization changes on CMR, including hyperdynamic left ventricular (LV) ejection fraction (median, 75% in PBC patients vs 69% in controls, P = .029), subclinical myocardial edema by T2-short tau inversion recovery (21% vs 2% in controls, P = .001), elevated extracellular matrix indices (30% vs 26% in controls, P < .001), and impaired myocardial viability by positive late gadolinium enhancement (LGE) (36%), was detected in PBC patients. Importantly, a mid-wall "stripe" at the LV septum was identified as a PBC-specific LGE pattern that differs from other known cardiomyopathies. In multivariate analysis, gp210 positivity (odds ratio [OR] = 9.909, P = .010), lower hemoglobin (OR = 0.919, P = .004), and body mass index (OR = 0.638, P = .005) were independent predictors of cardiac abnormalities in PBC. CONCLUSIONS This study demonstrates clinically silent cardiac impairment with specific CMR patterns in PBC, allowing optimal screening for early myocardial impairment and potentially timely therapies. (Trial registration no.: NCT03545672).

The construction of sulfur cathode host which can effectively prevent the diffusion of soluble polysulfides and improve the reaction dynamics is the key to the development of high-performance Li–S batteries. Herein, a nitrogen-doped CuCo2O4 double shell hollow mesoporous sphere structure assembled with ultrafine nanoparticles was reported. As a multifunctional sulfur species carrier, the unique double shell provides multiple confinement spaces, chemisorption and catalytic sites, further impeding the “shuttle effect” of polysulfides. Meanwhile, the higher surface area and abundant porosity reduce the sulfur layer thickness and shorten the charge transfer path respectively, which is conducive to the rapid redox kinetics to polysulfides. Thanks to this enhanced confinement effect, a Li-S cell with the N CuCo2O4@S as the cathode shows excellent cycle stability, high sulfur loading, and rapid charge–discharge capability. This work provides a promising strategy for achieving high performance Li–S batteries by using metal compounds with a unique hollow structure.

Background Papillary thyroid cancer (PTC) is the most common epithelial thyroid tumor, accounting for more than 80% of all thyroid cancers. Though the fine needle aspiration biopsy (FNAB) represents as the golden standard for the diagnostics of thyroid nodules, there is a ∼25% risk of indeterminate cytological features. TMPRSS4 is a newly found transmembrane serine protease which was overexpressed in papillary thyroid cancer (PTC). Aims The aim of this study was to determine its potential as a diagnostic marker to improve the diagnostic accuracy of thyroid cancer. Methods We used pyrosequencing and quantitative real-time PCR (qRT-PCT) approaches to examine BRAFV600E mutation and TMPRSS4 mRNA level in FNAB specimens of thyroid nodules. The detection and analysis were respectively applied to training group with 91, and test group with 88 samples. Results We demonstrated that PTC patients had an increased TMPRSS4 mRNA level as compared with benign subjects. The diagnostic sensitivity, specificity, and accuracy of TMPRSS4 were 93.33, 100, and 96.70%, respectively. Notably, compared with BRAFV600E mutation testing alone, combining with TMPRSS4 mRNA level significantly increased the diagnostic sensitivity and accuracy. Conclusions Our findings indicated BRAFV600E mutation combination with TMPRSS4 mRNA analysis can dramatically improve the sensitivity and accuracy of preoperative diagnosis of thyroid nodules.

Sentrin-specific protease 3 (SENP3), a member of the desumoylating enzyme family, is known as a redox sensor and could regulate multiple cellular signaling pathways. However, its implication in myocardial ischemia reperfusion (MIR) injury is unclear. Here, we observed that SENP3 was expressed and upregulated in the mouse heart depending on reactive oxygen species (ROS) production in response to MIR injury. By utilizing siRNA-mediated cardiac specific gene silencing, SENP3 knockdown was demonstrated to significantly reduce MIR-induced infarct size and improve cardiac function. Mechanistic studies indicated that SENP3 silencing ameliorated myocardial apoptosis mainly via suppression of endoplasmic reticulum (ER) stress and mitochondrial-mediated apoptosis pathways. By contrast, adenovirus-mediated cardiac SENP3 overexpression significantly exaggerated MIR injury. Further molecular analysis revealed that SENP3 promoted mitochondrial translocation of dynamin-related protein 1 (Drp1) in reperfused myocardium. In addition, mitochondrial division inhibitor-1 (Mdivi-1), a pharmacological inhibitor of Drp1, significantly attenuated the exaggerated mitochondrial abnormality and cardiac injury by SENP3 overexpression after MIR injury. Taken together, we provide the first direct evidence that SENP3 upregulation pivotally contributes to MIR injury in a Drp1-dependent manner, and suggest that SENP3 suppression may hold therapeutic promise for constraining MIR injury.

Panisuffrutin A (1), a highly degraded seco-triterpene derivative, together with the known palbinone, has been isolated from the whole plant Paeonia suffruticosa var. papaveracea (Andr.) Kerner. The structure with absolute configuration of 1 was determined via comprehensive NMR and MS analyses, as well as NMR and ECD calculations. A plausible biosynthetic pathway for 1 was proposed. Compound 1 showed weak cytotoxicity against Hela cancer cell line with an IC50 value of 26.2 μM, while palbinone exhibited a moderate inhibition on NO production with an IC50 of 18.3 μM.

Doxorubicin (DOX) is a widely used antitumor drug that causes severe cardiotoxicity in patients; no effective strategy yet exists to address this problem. We previously reported that 8-formylophiopogonanone B (8-FOB), a natural isoflavone in Ophiopogon japonicas, antagonizes paraquat-induced hepatotoxicity. Here, we explored the mechanisms underlying DOX-induced cardiotoxicity as well as whether 8-FOB can alleviate DOX-induced cardiotoxicity. Acute cardiotoxicity was established by injecting C57BL/6J mice with a single dose of DOX (20 mg/kg, intraperitoneal). To elucidate the mechanisms underlying DOX-induced cardiotoxicity, differentially expressed genes between hearts from DOX-treated and control mice were identified from the Gene Expression Omnibus (GEO) database via GEO2R. Using the Cytoscape software plugin cytoHubba, five hub genes associated with DOX-induced cardiotoxicity were identified: CD68, PTEN, SERPINE1, AIF1, and HMOX1. However, of these, only HMOX1 protein expression levels were significantly increased after DOX treatment. We also confirmed that HMOX1-dependent myocardial inflammation and fibrosis were closely associated with DOX-induced cardiotoxicity. More importantly, 8-FOB protected against DOX-cardiotoxicity by ameliorating cardiac injury and dysfunction, reducing cardiac fibrosis and inflammatory cytokine release, and inhibiting HMOX1 expression. In conclusion, our results suggest that inhibition of HMOX1-dependent myocardial inflammatory insults and fibrosis is essential for 8-FOB to ameliorate DOX-caused cardiotoxicity.

Psychological stress has recently been described as a risk factor in the development of pancreatic cancer. Here, we reported that increased neurotransmitter adrenaline was associated with the poor survival in pancreatic cancer patients. Moreover, in the cell model study, we found adrenaline promoted pancreatic cell PANC-1 migration in a dose dependent manner. Block of the β2-adrenoreceptor with ICI118,551, significantly reduced cell migration. Further study found that adrenaline induced a cytoplasmic translocation of RNA binding protein HuR, which in turn activated TGFβ, as shown by the SBE luciferase assay and phosphorylation of Smad2/3. Either HuR knockdown or TGFβ inhibition reduced cell migration induced by adrenaline. Taken together, our study here revealed that adrenaline-HuR-TGFβ regulatory axis at least partially contributes to the psychological stress induced metastasis in PANC-1 cells, shedding light on therapeutic targeting psychological stress in improving the prognosis of pancreatic cancer.

High-throughput estimation of specific activities of an enzyme and its mutants in a group (enzyme/mutants) in cell lysates via high-throughput assay of their activities and separate immunoturbidimetric assay (ITA) of their proteins was proposed. Pseudomonas aeruginosa arylsulfatase (PAAS) and Bacillus fastidious uricase (BFU) served as two models. ITA employed 0.75 mg of antisera against PAAS or BFU as the reference in 96-well microplates to measure the difference of extinction at 340 and 700 nm. According to the calibration curve, ITA quantified the reference from 0.40 to about 2.4 μg. The consistency among the abundance of enzyme/mutants through ITA of proteins in cell lysates prepared under the same conditions supported their consistent immunological reactivity to the antisera. Specific activities of PAAS/mutants or BFU/mutants in cell lysates through ITA of proteins showed excellent proportionality to those carefully determined after purification. Receiver-operating-characteristic (ROC) analysis of specific activities through ITA of proteins gave a higher area-under-curve than those for ROC analyses of other activity indices, which allowed the recognition of a PAAS/mutant of 50% higher activity after cell amplification in high-throughput mode. Therefore, ITA of enzyme/mutants as proteins is promising to estimate their specific activities in cell lysates in high-throughput mode for quantitative comparison.

Micro-arc oxidation coatings were fabricated on 7E04 aluminum drillpipes materials in Na 2 SiO 3 -NaOH electrolyte system containing 3.0 g/L SiC particles at different current density (1, 5, 10, 15 and 20 A/dm 2 ). The oxidation voltage, coating thickness, surface morphologies, surface micro-hardness, phase composition and potentiodynamic polarization curves of the MAO coatings were investigated. The results showed that the oxidation voltage increased and the coatings thickened with the increment of current density. The coating surface morphologies got coarser gradually which led to the reduction of the surface micro-hardness. The phase composition of the coatings consisted of SiO 2 because of the oxidation of SiC particles and the corrosion resistance of the coatings increased slightly.

High capacity electrodes are demanded to increase the energy and power density of lithium ion batteries. However, the cycling and rate properties are severely affected by the large volume changes caused by the lithium insertion and extraction. Structured electrodes with mechanically stable scaffolds are widely developed to mitigate the adverse effects of volume changes. Tin, as a promising anode material, receives great attentions because of its high theoretic capacity. There is a critical value of tin particle size above which tin anodes readily crack, leading to low cyclability. The electrode design using mechanical scaffolds must retain tin particles below the critical size and concurrently enable high volumetric capacity. It is a challenge to guarantee the critical size for high cyclability and space utilization for high volumetric capacity. This study provides a highly conductive TiN nanotubes array with submicron diameters, which enable thin tin coating without sacrificing the volumetric capacity. Such a structured electrode delivers a capacity of 795 mAh g Sn − 1 (Sn basis) and 1812 mAh c m el − 3 (electrode basis). The long-term cycling shows only 0.04% capacity decay per cycle.

Lithium sulfur batteries attract the increasing attentions because of the high energy density. However, sulfur cathodes suffer from several scientific and technical issues which are related to polysulfide ion migration, low conductivity, and volume changes. Many strategies such as porous hosts, polysulfide adsorbents, catalyst, and conductive fillers and so on have been proposed to address these issues, separately. In this study, novel Co3S4 nanotubes are developed to efficiently host sulfur, adsorb polysulfide, and catalyze their conversion. Because of these multifunctional advantages in one structure, the resulting Co3S4@S nanotube electrodes demonstrate superior electrochemical properties for high performance lithium sulfur batteries.

Cathodes have been one of the major challenges of flexible batteries. The traditional slurry-based technologies lead to loose interparticle connection, which is vulnerable upon bending. The direct fabrication of cathode materials requires high temperatures, which may destroy flexible substrates. Here we developed an electrodepostion and solvothermal route to conformally coat cathode material on a flexible scaffold. The monolithic electrode enables an ultra-flexible lithium ion battery because of the close attachment of active materials to flexible scaffolds and the interlock effect between the hard shell and soft core. This ultra-flexible battery retains 58.8% of initial capacity even after bending 4000 cycles.

Objective: Exosomes contain abundant microRNAs (miRNAs/miRs) and play an intermediary role in cell-to-cell communications. Recently, miR-182-5p was found to have cardioprotective effects against ischemia/reperfusion (I/R) injury. However, whether exosomes delivering miR-182-5p functions post I/R injury remains unknown. The present study aimed at exploring whether exosomal miR-182-5p would protect against myocardial I/R injury-induced pyroptosis. Methods: I/R mouse model was developed by left anterior descending coronary artery occlusion. Myocardial cell exposed to hypoxia/reoxygenation (H/R) was also used as in vitro I/R model. Binding relationship between miR-182-5p and gasdermin D (GSDMD) was evaluated by dual-luciferase reporter gene assay. MiR-182-5p and GSDMD loss- and gain-of-function experiments were conducted to explore the effects of miR-182-5p via mesenchymal stem cells (MSCs)-derived exosomes on I/R- or H/R- induced pyroptosis, cell viability, pyroptosis-related proteins and inflammatory cytokines, reactive oxygen species (ROS) production, and lactate dehydrogenase (LDH) release in vitro and in vivo. Results: miR-182-5p expression was decreased while GSDMD increased in I/R-injured myocardial tissues. In addition, miR-182-5p targeted and reduced GSDMD expression. Overexpression of GSDMD facilitated H/R-induced myocardial cell pyroptosis and inhibited viability, accompanied by increased LDH release, ROS production, and levels of pyroptosis markers. Importantly, transfer of miR-182-5p-loaded exosomes derived from MSCs downregulated GSDMD in H/R-exposed cardiomyocytes. Moreover, miR-182-5p-loaded exosome injection significantly improved cardiac function and decreased myocardial infarction and cell damage in I/R mice. Conclusions: Collectively, results from the present study demonstrated that transfer of miR-182-5p-loaded exosomes derived from MSCs downregulated GSDMD and alleviated I/R-induced pyroptosis in cardiomyocytes. Funding Statement: This study was supported by the National Natural Science Foundation of China (81600232), the Key Projects of Education Department of Sichuan Province (17ZA0183), Municipal-School Cooperative Scientific Research Project of Nanchong City (18SXHZ0458; NSMC20170210), and Doctoral Research Initiation Foundation of North Sichuan Medical College (CBY15-QD12). Declaration of Interests: The authors declare that they have no conflicts of interest. Ethics Approval Statement: All animal experiments were in compliance with the Guide for the Care and Use of Laboratory Animal (8th Edition, National Institute of Health, 2011) and approved by Animal Care Committee, North Sichuan Medical College First Affiliated Hospital.

Protein-protein interactions (PPIs) play a pivotal role in extensive biological processes and are thus crucial to human health and the development of disease states. Due to their critical implications, PPIs have been spotlighted as promising drug targets of broad-spectrum therapeutic interests. However, owing to the general properties of PPIs, such as flat surfaces, featureless conformations, difficult topologies, and shallow pockets, previous attempts were faced with serious obstacles when targeting PPIs and almost portrayed them as "intractable" for decades. To date, rapid progress in computational chemistry and structural biology methods has promoted the exploitation of PPIs in drug discovery. These techniques boost their cost-effective and high-throughput traits, and enable the study of dynamic PPI interfaces. Thus, computational methods represent an alternative strategy to target "undruggable" PPI interfaces and have attracted intense pharmaceutical interest in recent years, as exemplified by the accumulating number of successful cases. In this review, we first introduce a diverse set of computational methods used to design PPI modulators. Herein, we focus on the recent progress in computational strategies and provide a comprehensive overview covering various methodologies. Importantly, a list of recently-reported successful examples is highlighted to verify the feasibility of these computational approaches. Finally, we conclude the general role of computational methods in targeting PPIs, and also discuss future perspectives on the development of such aids.

Micro-arc oxidation coatings were deposited on ZL108 aluminum alloys in silicate-hydroxide electrolytes containing 0, 0.2, 0.4, 0.6 and 0.8 g/L Ce(SO 4 ) 2 respectively. The oxidation voltages, surface morphologies, phase composition, polarization curves, micro-hardness and thickness of MAO coatings were investigated. With the increasing of Ce(SO 4 ) 2 , the oxidation voltages increased firstly and decreased gradually along with the variation of the coating thickness. The addition of Ce(SO 4 ) 2 could improve the homogeneity and corrosion resistance of the MAO coatings, while the surface micro-hardness increased firstly and decreased finally. There was little influence of Ce(SO 4 ) 2 on the phase composition of MAO coatings.

The effect of glucagon-like peptide-1 (GLP-1) treatment in patients with type 2 diabetes mellitus (T2DM) remains controversial. The purpose of this study was to compare the effect of GLP-1 and placebo/conventional antidiabetic agents on cardiovascular risk in T2DM patients. PubMed, EmBase and the Cochrane Library were searched to identify its eligible studies as well as manual searches for the reliability of this study. All eligible trials were performed in T2DM patients who received GLP-1 therapy or placebo/conventional antidiabetic agents. The reported outcomes included major cardiovascular events (MACE), and total mortality. Of 490 identified studies, we included 13 trials reporting data on 11,943 T2DM patients. Overall, the pooled results suggested that GLP-1 therapy has no or little effect on MACE (RR: 0.99; 95% CI: 0.88-1.12; P=0.872) and total mortality (RR: 0.90; 95% CI: 0.70-1.15; P=0.399). Furthermore, sensitivity analysis indicated that GLP-1 was associated with lower incidence of total mortality (RR: 0.28; 95% CI: 0.08-0.93; P=0.037). We concluded that GLP-1 therapy was not associated with MACE and total mortality compared with placebo or antidiabetic agents.

Deep hypothermia is known for its organ-preservation properties, which is introduced into surgical operations on the brain and heart, providing both safety in stopping circulation as well as an attractive bloodless operative field. However, the molecular mechanisms have not been clearly identified. This study was undertaken to determine the influence of deep hypothermia on neural apoptosis and the potential mechanism of these effects in PC12 cells following oxygen-glucose deprivation. Deep hypothermia (18°C) was given to PC12 cells while the model of oxygen-glucose deprivation (OGD) induction for 1h. After 24h of reperfusion, the results showed that deep hypothermia decreased the neural apoptosis, and significantly suppressed overexpression of Bax, CytC, Caspase 3, Caspase 9 and cleaved PARP-1, and inhibited the reduction of Bcl-2 expression. While deep hypothermia increased the LC3II/LC3I and Beclin 1, an autophagy marker, which can be inhibited by 3-methyladenine (3-MA), indicating that deep hypothermia-enhanced autophagy ameliorated apoptotic cell death in PC12 cells subjected to OGD. Based on these findings we propose that deep hypothermia protects against neural apoptosis after the induction of OGD by attenuating the mitochondrial apoptosis pathway, moreover, the mechanism of these antiapoptosis effects is related to the enhancement of autophagy, which autophagy might provide a means of neuroprotection against OGD.