Highlights • GS-4774 is being developed as a therapeutic vaccine for chronic HBV infection. • GS-4774 consists of yeast cells that express well-conserved regions of HBV proteins. • GS-4774 was safe ...and well-tolerated in healthy subjects at all doses evaluated. • GS-4774 led to HBV-specific immune responses after weekly and monthly immunization. • GS-4774 is being tested in patients with chronic HBV infection.
The elongation of high-strength copper alloy with tensile strength over 1300 MPa is generally less than 3%. In this paper, a novel Cu–20Ni–20Mn-0.3Nb-0.3Cr-0.1Zr(wt.%) alloy was prepared, of which ...the tensile strength, elastic modulus and elongation is 1445 MPa, 147 GPa and 6.8%, respectively. The flow stress strain and microstructure evolution during high temperature deformation at different strain temperatures and strain rates are studied to obtain the high temperature deformation law and dynamic recrystallization mechanism of the alloy. The research shows that the flow stress of the design alloy increases rapidly with the increase of the strain during the initial stage of thermal deformation. When the strain rate is higher and the strain temperature is lower, the peak value of flow stress is larger. The thermal activation energy of the designed alloy is 353.31 kJ/mol. When the strain temperature is 650°C–720 °C and the strain rate is 0.1s−1-5s−1, the alloy is in the hot deformation instability zone. The optimal deformation temperature of the alloy is 750°C–850 °C. When the deformation temperature reaches 800 °C, dynamic recrystallization occurs in the alloy structure. When the design alloy is deformed at a temperature of 850 °C, the recrystallization power of the alloy is mainly the deformation stress energy, and the degree of recrystallization mainly depends on the strain rate. At this time, the faster the strain rate is, the more obvious the recrystallization effect is, and even the recrystallization grain growth will occur.
•A novel Cu–20Ni–20Mn–0.3Nb–0.3Cr–0.1Zr alloy with high strength and high elasticity are designed.•The tensile strength of the alloy is 1445 MPa, the elastic modulus is 147 GPa, and the elongation is 6.8%.•High-temperature deformation behavior of the Cu–20Ni–20Mn–0.3Nb–0.3Cr–0.1Zr alloy are systematic studied.
With the development of wearable electronic devices towards flexibility, safety, and functionality, supercapacitors are required to simultaneously possess satisfactory energy density and flexibility. ...Although the environmental friendliness, high theoretical capacity and tunable structure of CuS, the instability of their corresponding compounds on the flexible substrate as well as its poor conductivity limit its development. To address these issues, a pea-like hollow CuS nanoparticle structure is fabricated on the surface of carbon fiber with Cu plating, and a novel kind of flexible electrode named CPCC@CuO@CuS-H is synthesized. The inner copper plating of the electrode brings good electronic conductivity, and the hollow structure effectively improves the charge diffusion ability. CPCC@CuO@CuS-H has ultra-high mass specific capacity of 1387.1 F g−1 in an electrolyte of 2.0 M KOH solution under 2 A g−1. Moreover, the construction of disulfide bond in electrode can effectively improve the stability of hollow structure. The electrode has satisfactory rate performance and long cycle life at an ultra-high current density of 20 A g−1. Especially, by assembling a flexible all-solid-state supercapacitor (CPCC@CuO@CuS-H//CC@AC), the operating voltage closes to 1.8 V, and the energy density achieves the aim of 139.5 Wh kg−1 when the high-power density is located at 1800 W kg−1, with 82.9% electric capacity retaining after 10000 cycles, showing its promising potential in flexible devices.
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•Hollow porous materials with good stability can be prepared by simple S-S bonds.•The electrode has high capacity (1387.1 F g−1 at 2 A g−1) and decent flexibility.•The electrode achieves a high electron conductivity with Rct values 0.30 Ω.•The FASC has a high energy density (139.5 W h kg−1 at 1800 W kg−1).•The FASC exhibits outstanding cycle performance (higher than 10,000 cycles).
This meta-analysis was to investigate the efficacy and safety of new oral anticoagulant (NOAC) in atrial fibrillation (AF) patients with renal function insufficiency, and to explore whether renal ...decline occurs in AF patients with NOAC and its impact on outcomes.
In AF patients with mild renal insufficiency, the NOAC was associated with significantly lower rates of stroke (odds ratio OR, 0.78; 95% confidence interval CI, 0.67-0.91; P < .05). Lower rates of bleeding were significantly observed in NOAC group (OR, 0.85; 95% CI, 0.75-0.97; P < .05). In AF patients with moderate renal impairment, similar results were revealed (OR for stroke or systemic embolism, 0.80; 95% CI, 0.67-0.95, P < .05; OR for major bleeding, 0.78; 95% CI, 0.59-1.03; P = .07). During the follow-up, pooled data revealed that NOAC showed a less renal toxicity, but the difference did not reach statistical significance (creatinine clearance decline: -0.12 mL/min -0.84, 0.61 mL/min). We have revealed that the NOACs were associated with significantly lower rates of stroke or systemic embolism (hazard ratio HR, 0.66; 95% CI, 0.42-0.89; P < .05) and lower rates of bleeding (HR, 0.93; 95% CI, 0.70-1.16; P = .153) in AF patients with worsening renal function.
NOAC may have the potentiality to be at least as effective as warfarin and may equal safety outcomes in AF patients with renal impairment. Renal decline during therapeutics may be less likely happened in NOAC than warfarin dose. NOAC may reveal good efficacy and safety outcomes in these scenarios. Further detailed research is needed to gain more clear profile on this new anticoagulant.
We previously found that the intestinal epithelial chemokine (C-C motif) ligand 7 (CCL7) plays an important role in the development of toxin-induced acute liver damage. The detailed effects of ...intestinal epithelial CCL7 on chronic diseases; however, are still unclear. Here, we aimed to investigate the impact of intestinal epithelial CCL7 overexpression on high-fat diet (HFD)-induced obesity and steatohepatitis in mice.
Intestinal epithelial CCL7 overexpression (CCL7) mice and their wild-type (WT) littermates were fed with normal chow or HFD for 16 weeks to induce obesity and non-alcoholic fatty liver disease. Body weight gain, as well as adipose tissue index were assessed. Liver injury was monitored by histological analysis and real time polymerase chain reaction. Gut microbial composition was analyzed by 16S rRNA gene sequencing.
We found that the CCL7 mice on a HFD had markedly decreased weight gain (8.9 vs. 17.0 g, P < 0.05) and a lower adipose tissue index that include mesenteric fat (1.0% vs. 1.76%, P < 0.05), gonadal fat (2.1% vs. 6.1%, P < 0.05), subcutaneous fat (1.0% vs. 2.8%, P < 0.05) compared to WT animals. HFD-induced glucose intolerance and insulin resistance were also significantly improved in CCL7 mice compared to WT. Furthermore, HFD-fed CCL7 mice displayed less hepatic lipid accumulation and lower expression of inflammatory factors than WT mice. 16S rRNA gene sequencing demonstrated that CCL7 overexpression in intestinal epithelial cells improved HFD-induced gut microbial dysbiosis.
Our study revealed that CCL7 overexpression in the intestinal epithelium protects mice against the progression of diet-induced obesity, hepatic steatosis, and enteric dysbiosis.
Summary
Recent genome‐wide single nucleotide polymorphism (SNP) association studies (GWAS) have identified a number of SNPs that were significantly associated with coronary artery disease and ...myocardial infarction (MI). However, many independent replication studies in other populations are needed to unequivocally confirm the GWAS association. To assess GWAS association, we have established a case‐control cohort consisting of 1231 well‐characterised MI patients and 560 controls without detectable coronary stenosis, all selected from the Cleveland Genebank population. The Genebank cohort has sufficient power to detect the association between MI and four GWAS SNPs, including rs17465637 within the MIA3 gene, rs2943634 (intergenic), rs6922269 in MTHFD1L, and rs599839 near SORT1. SNPs were genotyped by TaqMan assays and follow‐up multivariate logistic regression analysis with incorporation of significant covariates showed significant association with MI for MIA3 SNP rs17465637 (P‐adj= 0.0034) and SORT1 SNP rs599839 (P‐adj= 0.009). The minor allele G of rs599839 was also associated with a decreased LDL‐C level of 5–9 mg/dL per allele, but not with HDL‐C or triglyceride levels. No association for MI or lipid levels was found for SNPs rs2943634 and rs6922269 (P‐adj > 0.05). Our results establish two SNPs, rs17465637 in MIA3 and rs599839 near SORT1 as significant risk factors for MI in the American Genebank Caucasian population.
The analysis of progressive failure process is one of the critical issues in the research of composite adhesive joints. In view of this point, acoustic emission (AE) is applied to real-time ...monitoring of the dynamic damage process of composite adhesive joints in some loading modes such as Mode I (double cantilever beam (DCB)) and Mode II (end notch flexures (ENF)). Furthermore, the high speed camera and scanning electron microscopy are carried to analyses the damage mechanisms of composite bonded joints. Results show that there are significant differences in the load- deflection curves of the specimens under the loads of Mode I and II. The main failure mode of the two types of loading modes is adhesion failure, and the accumulation of damage observed at the edge of the adhesively bonded layer cause defeat of the composite bonded joints. In addition, AE parameters including amplitude, hits, energy, and duration are connected with the fail mechanism. Furthermore, the dynamic characteristics of the AE signal, especially amplitude spectrum distribution, can provide evidences for studying progressive failure behaviors of composite adhesive joints.
BACKGROUND:Acid-reducing agents are commonly used co-medications by HIV-1–infected patients receiving antiretroviral treatment. The effects of various representative acid-reducing agents on the ...pharmacokinetics (PK) of boosted elvitegravir were evaluated by 1-way interaction in 4 studies.
METHODS:Healthy subjects received ritonavir-boosted elvitegravir (EVG/r; 50/100 mg QD) administered alone or with antacid simultaneously in Study 1, staggered (±2 or ±4 hours) or with omeprazole in Study 2; Studies 3 and 4 evaluated cobicistat-boosted elvitegravir (EVG/co; 150/150 mg QD) administered simultaneously or staggered (+12 hours) with famotidine or omeprazole. Lack of PK alteration was defined as 90% confidence intervals about the geometric least squares means ratio (coadministration:alone) being within 70%–143% for elvitegravir Cmax (maximum concentration), Ctau (trough), and AUCtau (area under plasma concentration–time curve; 0–24 hours); cobicistat PK were explored.
RESULTS:EVG exposures were 40%–50% lower upon simultaneous dosing of EVG/r and antacids, probably due to local complexation with cations in gastrointestinal tract, and were unaffected with ≥2 hours staggered dosing. No relevant drug interactions were observed between EVG/co and famotidine or between EVG/r or EVG/co and omeprazole, indicating the absence of a broader pH effect on boosted EVG PK. In all studies, study treatments were well tolerated, with adverse events being generally mild to moderate in severity and primarily gastrointestinal disorders.
CONCLUSIONS:There are no clinically relevant interactions between boosted elvitegravir, and thus elvitegravir/cobicistat/emtricitabine/tenofovir DF single-tablet regimen, and H2-receptor antagonists or proton pump inhibitors; staggered antacid administration by ≥2 hours is recommended.
OBJECTIVE—Recent genome-wide association studies have identified 4 SNPs on chromosome 9p21 associated with CAD (rs10757274 and rs2383206) and myocardial infarction (MIrs2383207 and rs10757278) in ...White populations in Northern Europe and North America. We aimed to determine whether this locus confers significant susceptibility to CAD in a South Korean population, and thus cross-race susceptibility to CAD.
METHODS AND RESULTS—We performed a case-control association study with 611 unrelated CAD patients and 294 normal controls from South Korea. Allelic associations of SNPs and SNP haplotypes with CAD were evaluated. Multivariate logistic regression analysis was used to adjust effects of clinical covariates. We found that 4 SNPs on chromosome 9p21 were associated with susceptibility to CAD in a South Korean population. The association remained significant after adjusting for significant clinical covariates (P=0.001 to 0.024). We identified one risk haplotype (GGGG; P=0.017) and one protective haplotype (AAAA; P=0.007) for development of CAD. Further analysis suggested that the SNPs probably confer susceptibility to CAD in a dominance model (covariates-adjusted P=0.001 to 0.024; OR=2.37 to 1.54). This represents the first study that expands association of these 9p21 SNPs with CAD beyond White populations.
CONCLUSION—Chromosome 9p21 is an important susceptibility locus that confers high cross-race risk for development of CAD.
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