Search

Introduction: A pan-genotypic and effective treatment regimen for patients with chronic hepatitis C virus (HCV) infection remains an unmet medical need in China. Alfosbuvir is a novel potent HCV NS5B polymerase inhibitor in development for the treatment of chronic HCV infection. We conducted a phase 3 study to evaluate the efficacy and safety of alfosbuvir in combination with daclatasvir in Chinese patients with HCV infection. Methods: All patients received 600 mg alfosbuvir tablets plus 60 mg daclatasvir tablets once daily for 12 weeks. The primary endpoint was sustained virological response 12 weeks after the end of treatment (SVR12). A follow-up visit was done at week 4 and 12, and those who achieved SVR12 were followed up at post-treatment week 24. Results: Of the 326 patients who received at least one dose of the study drug, 320 (98.2% [95% confidence interval (CI): 96.5%–99.5%]) achieved sustained virological response at post-treatment week 12 (SVR12), which was superior to the historical SVR12 rate of 88% (p < 0.0001). The SVR12 rates were similar regardless of most baseline characteristics. The most common adverse event (AE) (≥ 10%) was hypercholesterolemia. Serious adverse events (SAEs) were reported in 25 (7.7%) patients, none of which was judged to be related to the study drug. The majority of AEs were mild to moderate in severity. Conclusions: Alfosbuvir plus daclatasvir for 12 weeks was highly effective and safe in Chinese patients infected with HCV genotype 1, 2, 3, or 6, suggesting that this regimen could be a promising option for HCV treatment in China irrespective of genotype. Trial Registration: ClinicalTrial.gov identifier, NCT04070235. [ABSTRACT FROM AUTHOR]

Let U ħ (g ^) be the untwisted affinization of a symmetrizable quantum Kac-Moody algebra U ħ (g) . For ℓ ∈ C , we construct an ħ -adic quantum vertex algebra V g ^ , ħ (ℓ , 0) , and establish a one-to-one correspondence between ϕ -coordinated V g ^ , ħ (ℓ , 0) -modules and restricted U ħ (g ^) -modules of level ℓ . Suppose that ℓ is a positive integer. We construct a quotient ħ -adic quantum vertex algebra L g ^ , ħ (ℓ , 0) of V g ^ , ħ (ℓ , 0) , and establish a one-to-one correspondence between certain ϕ -coordinated L g ^ , ħ (ℓ , 0) -modules and restricted integrable U ħ (g ^) -modules of level ℓ . Suppose further that g is of finite type. We prove that L g ^ , ħ (ℓ , 0) / ħ L g ^ , ħ (ℓ , 0) is isomorphic to the simple affine vertex algebra L g ^ (ℓ , 0) . [ABSTRACT FROM AUTHOR]

Batch normalization is one of the most widely used components in deep neural networks. It can accelerate training, and boost model performance on normal samples. However, batch normalization induces vulnerability to models on adversarial examples, especially in medical images, and the reason is still not clear. In this paper, we aim to explain the vulnerability aroused by batch normalization under adversarial images. Specifically, we first discover that both natural and medical images contain a large number of trivial features, whose weights will be enlarged under adversarial attacks, and batch normalization can further enlarge their weights. Additionally, we find that batch normalization will reduce the inter-class margin of high-level features, leading to less tolerance to adversarial perturbations, thereby decreasing the model robustness. Moreover, we hypothesize that the smaller inter-class margin, the more difficult to attain the optimal classification space, which means batch normalization will restrict the performance of adversarial training. This further verifies that a narrower inter-class margin induced by batch normalization reduces the model robustness. Experiments on four benchmark datasets demonstrate our discovery, interpretation and hypothesis. [ABSTRACT FROM AUTHOR]

Objective: Adenoid or adenotonsillar hypertrophy (AATH) causes upper airway obstruction, leading to cardiovascular complications. This meta-analysis was conducted to evaluate the efficacy of adenoidectomy or adenotonsillectomy (AATE) on the cardiovascular system. Methods: Using the Cochrane Central Register of Controlled Trials, PubMed, and EMBASE databases, we identified studies involving a comparison of preoperative and postoperative cardiovascular function in children with AATH. The Cochrane Collaboration's Review Manager 5.3 software was used for meta-analysis. Results: A total of 13 studies with 706 participants were included. The meta-analysis demonstrated a significant reduction in mean pulmonary artery pressure (mPAP) of patients after AATE compared with preoperative values. The left ventricular myocardial function index (LVMPI) and the right ventricular myocardial function index (RVMPI) showed a significant decrease after the operation. Moreover, AATE prominently increased left ventricular ejection time (LVET) and right ventricular ejection time (RVET) and reduced the left ventricular interventricular septum diameter (LVIVSD) and the right ventricular end-diastolic diameter (RVedD). There was no significant difference in mPAP, LVMPI, RVMPI, LVET, RVET, LVIVSD, and RVedD between postoperative patients and healthy children (P > 0.05). Conclusion: AATE can improve cardiovascular function in pediatric patients with AATH. Specifically, it reduces mPAP and LVMPI/RVMPI in pediatric patients. Furthermore, AATE increases LVET and RVET and reduces LVIVSD and RVedD. [ABSTRACT FROM AUTHOR]

This study aims to produce a biodegradable active packaging film that is pH sensitive, and has a good antioxidant and antimicrobial activity. To do this, a novel phenolic extract was interfacially assembled onto a cellulose film, resulting in a film with a pH-triggered release mechanism of the active polyphenol agent. First, an aqueous extraction of cashew nut testa (CTE) was performed and subsequently, the CTE was characterized. The disc diffusion assay showed that CTE exhibited antimicrobial activity towards the food pathogens Escherichia coli (6 mm) and Staphylcoccus aureus (12 mm). CTE was also cytotoxic against cancer HepG2 and HEK293 cells, reducing the viability to 52% and 47%, respectively. It was incorporated into a cellulose-based packaging film, prepared from the by-product, sugarcane bagasse (SC) through interfacial assembly. The incorporation of CTE resulted in a film with good antimicrobial activity, excellent antioxidant content (91%), and has extremely high thermal stability (290 °C). FTIR indicated the formation of hydrogen bond between the SC cellulose-based film and CTE. The hydrogen bonds formed between the cellulose film and CTE became the driving force behind the pH-triggered release mechanism. It was found that the active agent, tannic acid, could be controllably released from the film, depending on the pH of the environment. Our strategy to produce a cellulose-based film impregnated with a phenolic extract, using interfacial assembly, resulted in an active packaging film with pH-triggered release mechanism. This film could be useful to extend the shelf life of perishable food items. [ABSTRACT FROM AUTHOR]

Lipotoxicity has been implicated in pancreatic β-cell dysfunction in type 2 diabetes, but the exact mechanisms remain unknown. The current study explored the role of the endoplasmic reticulum (ER) stress pathway in cholesterol-induced lipotoxicity. Two different insulinoma cell lines were treated with cholesterol with or without inhibitors. ER stress-associated proteins glucose-regulated protein (GRP) 78, activating transcription factor (ATF) 4 and C/EBP homologous protein (CHOP), as was phosphorylation of eukaryotic initiation factor (EIF) 2α, were all up-regulated by cholesterol. Cholesterol also up-regulated microtubule-associated protein 1 light chain 3 (LC3)-II and stimulated the formation of autophagic vacuoles and LC3-II aggregates. Cholesterol-induced autophagy and cell injuries were suppressed by pretreatment with the ER stress inhibitor 4-phenylbutyrate (4-PBA). Pretreatment with autophagy inhibitors E-64d/pepstatin A increased ER stress-induced cell injuries as indicated by increased cell apoptosis and decreased insulin secretion. These results suggest that cholesterol treatment induces apoptosis and dysfunction of β-cells, and enhances autophagy through activation of the ER stress pathway. More importantly, autophagy induced by cholesterol may protect β-cells against ER stress-associated cell damages. [ABSTRACT FROM AUTHOR]

Glioma treatment remains a challenge owing to unsatisfactory targeted chemotherapy, where the blood–brain barrier (BBB) hinders the efficient uptake of therapeutics into the brain. Vasculogenic mimicry (VM) formed by invasive glioma cells negatively affects the treatment of glioma. Herein, we developed a targeted biomimetic drug delivery system comprising a doxorubicin-loaded platelet membrane-coated nanogel (DOX@PNGs). The nanogels provide great redox/pH dual responsiveness, while the platelet membrane (PLTM) promotes stability and circulation time. In vitro cellular uptake and in vivo imaging experiments demonstrated that the DOX@PNGs delivery system could penetrate the BBB, target gliomas, and destruct VM. DOX@PNGs increased drug penetration and prolonged mouse survival time during the treatment of orthotopic gliomas. These results indicate this biomimetic drug delivery system to be promising for glioma treatment and may be clinically translated in the future. [ABSTRACT FROM AUTHOR]

Key message: FLO15encodes a plastidic glyoxalase I protein, OsGLYI7, which affects compound starch granule formation and starch synthesis in rice endosperm.Abstract: Starch synthesis in rice (Oryza sativa) endosperm is a sophisticated process, and its underlying molecular machinery still remains to be elucidated. Here, we identified and characterized two allelic rice floury endosperm 15 (flo15) mutants, both with a white-core endosperm. The flo15 grains were characterized by defects in compound starch granule development, along with decreased starch content. Map-based cloning of the flo15 mutants identified mutations in OsGLYI7, which encodes a glyoxalase I (GLYI) involved in methylglyoxal (MG) detoxification. The mutations of FLO15/OsGLYI7 resulted in increased MG content in flo15 developing endosperms. FLO15/OsGLYI7 localizes to the plastids, and the in vitro GLYI activity derived from flo15 was significantly decreased relative to the wild type. Moreover, the expression of starch synthesis-related genes was obviously altered in the flo15 mutants. These findings suggest that FLO15 plays an important role in compound starch granule formation and starch synthesis in rice endosperm. [ABSTRACT FROM AUTHOR]

Single-molecule nuclear magnetic resonance is a current challenge in the field of magnetic resonance spectroscopy and has important applications in chemical analysis and quantum computing. Through decoherence measurements of nitrogen-vacancy centres under dynamical decoupling control, the sensing of a single 13C nuclear spin at nanometre distance has recently been realized. A further step towards the ultimate goal of structure analysis of single molecules would be the direct measurement of the interactions within single nuclear-spin clusters. Here we sense a single 13C-13C nuclear-spin dimer located about 1 nm from the nitrogen-vacancy centre and characterize the interaction (∼690 Hz) between the two nuclear spins. From the measured interaction we derive the spatial configuration of the dimer with atomic-scale resolution. These results indicate that, in combination with advanced material-surface engineering, central spin decoherence under dynamical decoupling control may be a useful probe for nuclear magnetic resonance single-molecule structure analysis. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) infection greatly increases the risk of nephropathy. In this observational study, we aimed to explore the relationship between viral hepatitis infection and chronic kidney disease (CKD), identify risk factors, and determine the effect of antiviral treatment on CKD in Chinese patients with chronic HCV infection. A total of 2,435 study subjects were enrolled and divided into four groups: the HCV infection, HBV infection, HBV and HCV co-infection, and uninfected control groups. Of these, 207 patients with chronic hepatitis C (CHC) were given standard dual therapy [subcutaneous injection of recombinant interferon (IFN)-α2b and oral ribavirin (RBV)] for 48 weeks. We found that the prevalence of CKD gradually increased with age in all groups and was significantly increased in patients 60 years or older. Multivariate logistic regression analyses showed that persistent HCV infection was significantly associated with CKD [odds ratio (OR), 1.33; 95% confidence interval (CI), 1.06-1.66; P = 0.013], whereas there was no significant link between CKD and spontaneous HCV clearance (OR, 1.23; 95% CI, 0.79-1.90; P = 0.364), HBV infection (OR, 0.73; 95% CI, 0.44-1.19; P = 0.201), or HBV/HCV co-infection (OR, 1.40; 95% CI, 0.81-2.40; P = 0.234). Notably, after anti-HCV therapy, the serum creatinine concentration was significantly decreased (76.0, 75.5-79.4 μmol/L) from the pretreatment level (95.0, 93.0-97.2 μmol/L), both in patients who showed an end of treatment virological response (ETVR) and those who did not (P < 0.001). Also, in both the ETVR and non-ETVR groups, the percentages of patients with an estimated glomerular filtration rate (eGFR) ≥90 ml/min/1.73 m2 increased significantly (P < 0.001), whereas the percentages of those with an eGFR <60 ml/min/1.73 m2 significantly decreased (P < 0.001). In conclusion, persistent HCV infection was independently associated with CKD, and antiviral treatment with IFN plus RBV can improve renal function and reverse CKD in HCV-infected patients. [ABSTRACT FROM AUTHOR]