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• Elevated serum Hcy levels were associated with higher risk of mortality from all-cause, CVD, and cancer among middle-aged and elderly Chinese. • The weighted genetic risk score constructed on 18 established Hcy-related genetic variants had significant interaction with Hcy on CHD mortality. • The rs7130284 and rs957140 on NOX4 gene modified the association between Hcy and mortality from CVD and CHD. • The rs154657 on DPEP1 gene modified the association between Hcy and CHD mortality. The associations of homocysteine (Hcy) and gene-Hcy interactions with the risk of all-cause and cause-specific mortality remain unclear. A total of 19,826 middle-aged and elderly Chinese adults were included from the Dongfeng-Tongji cohort in 2013–2014 and were followed-up to 31 December 2018. Cox regression was used to examine the association between Hcy and mortality. We selected 18 well-established Hcy-associated genetic variants to constructed the weighted genetic risk score (GRS) among 15,434 participants with genetic data, and interactions between genetic susceptibility and Hcy on mortality were assessed. After multivariate adjustment, elevated serum Hcy levels were associated with higher risk of mortality from all-cause, CVD, coronary heart disease (CHD), stroke, and cancer. We also observed a significant interaction between GRS and Hcy on CHD mortality. Moreover, the rs7130284 and rs957140 on NOX4 modified the association between Hcy and mortality from CVD and CHD, and rs154657 on DPEP1 modified the association between Hcy and CHD mortality. Elevated Hcy levels were associated with increased risk of all-cause and cause-specific mortality among middle-aged and elderly Chinese. Hcy-related genetic variants on NOX4 and DPEP1 might modify the associations of Hcy with CVD mortality or CHD mortality. [ABSTRACT FROM AUTHOR]

[Display omitted] • A general route was proposed to construct chemiluminescence nanoprobe by extensively exploiting the charge transfer of electron-rich SiQDs. • A highly sensitive and selective chemiluminescence sensing platform with real time monitoring for ferrous in PM 2.5 was established. • The sensing mechanism was explained by the electron hole annihilation between chemically injected exogenous holes and pre-existing endogenous CB electrons in SiQDs/ferrous CL system. Quantum dots (QDs) assist chemiluminescence (CL) sensor, especially metal-free QDs, are currently attracting considerable attention in the establishment of new CL systems to expand their analytical applications with good biocompatibility, controllable properties, and easy functionalization, while the fundamental CL process from QDs are still far from clear by now. Herein, A strategy of constructing CL probe is developed by carefully studying the charge transfer process in the electron-rich QDs. We purposefully synthesized silicon QDs (SiQDs) with electron-rich property, which can react with hole injector (oxidants) forming extraordinary CL emission. According to the characterization of reactive intermediates and emitting species, a possible CL mechanism was proposed, where radiative recombination of the exogenous holes-injected and existing electrons SiQDs resulted in the surprising SiQDs CL behavior. Interestingly, when Fe2+ were added, more exogenous holes and active sites were formed on the surface of SiQDs during Fe2+/Fe3+ conversion, which can significantly amplify CL signal. On this basis, a new CL system for the detection of ferrous in airborne fine particulate matter (PM 2.5) was constructed. This work provides a charge transfer-based path for designing a simple and highly sensitive CL probe. [ABSTRACT FROM AUTHOR]

Abstract: The 8-SF5 analog of mefloquine was synthesized in nine steps from commercially available starting materials and in five steps from a novel ortho-SF5–substituted aniline intermediate. [ABSTRACT FROM AUTHOR]

Objective. The aim of the study was to explore the application and the effect of the triple prerehabilitation nursing model in the perioperative period of knee arthroplasty in diabetic patients. Methods. The prospectively included 60 patients with diabetes who underwent total knee replacement were admitted from August 2021 to April 2022 and were divided into 2 groups according to the (1 : 1) ratio. The control group was mainly given routine nursing care. On the basis of the control group, the observation group received triple prerehabilitation nursing. The postoperative knee flexion, hospital for the special surgery knee score (HSS), the daily living ability (Barthel) score, the modified fall efficacy scale (MFES) score, the recovery of the lower-limb muscle strength, and the incidence of complications were compared between the two groups. Results. The knee flexion degree and lower-limb muscle recovery of the observation group were better than those of the control group at 3 d, 7 d, and 14 d after operation (P < 0.05). The HSS score, Barthel score, and MFES score of the observation group were higher than those of the control group (P < 0.05). There was no significant difference in postoperative complications between the two groups (P > 0.05). Conclusion. The triple prerehabilitation nursing care for diabetic patients undergoing total knee replacement can promote the recovery of limb function. [ABSTRACT FROM AUTHOR]

To establish a gold/silica hybrid, nanomaterials (Au/SiO2) were incorporated into a gelatin methacrylate/chitosan matrix. By using FESEM, compressive strength testing, and conductivity/resistance measurements on gelatin (G)/chitosan (C), G/C-Au@SiO2 hydrogels developed. Biocompatibility investigations on osteoblasts MG-63 cells were carried out to determine whether the cell was compatible with the conductive hydrogel as it had been created. The results indicated that HNPs had improved compressive strength and conductivity without losing the favourable features such as biodegradable nature and porous shape of G/C hydrogel. The mechanical properties and Elastic modulus of composites hydrogels were enhanced twofold when hybrid nanomaterials were added to the mixture. The cyclic compressive analysis shows that pure G/C hydrogels lost their mechanical stability within the first few cycles, but G/C-Au@SiO2 hydrogels lasted for up to fifty cycles. It was demonstrated that osteoblast proliferation and adhesion were increased on the hydrogel in the CCK-8 experiment. Further, the cell survival of the hydrogels with G/C-Au@SiO2 conductivity was enhanced by 15% compared to that of pure G/C hydrogels. The morphological features of the MG-63 cells experiments were performed by using a Fluorescein diacetate hydrolysis (FDA) staining assay. This work offers a unique method for enhancing mechanical integrity and electrical properties in gelatin-based G/C hydrogels by adding bifunctional hybrid nanomaterials (HNPs) for bone fracture tissue engineering applications. [ABSTRACT FROM AUTHOR]

Autophagy is a reparative life-sustaining process. Dysfunctions of autophagy play an important role in the progression of chronic liver diseases. The role of autophagy in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) is still controversial. This study aimed to analyse the roles and molecular mechanisms of autophagy in NAFLD. In hepatic L02 and liver cancer cells (HuH-7), nonalcoholic fatty liver (NAFL) cell model was induced by free fatty acids (FFA). The cytotoxic effect was measured by MTS assay. Lipid droplets were detected by immunofluorescence assay and flow cytometry. The autophagy-related genes were measured by Western blot analysis. The autophagy inhibitor 3-methyladenine (3-MA) was used to block the autophagy. FFA induced a significant increase in the intracellular content of lipid droplets, and the accumulation of fatty droplets was dose-dependent in L02 and HuH-7 cells. FFA (800 µM) had no cytotoxic effect on L02 and HuH-7 cells. The levels of LC3-II/LC3-I and BECN1 were increased, but the level of p62 was decreased in the NAFL cell models. The expression of these genes was dose-dependent in the NAFL cell models. Intracellular lipid accumulation was associated with the upregulation of LC3-II/LC3-I and BECN1 and the deregulation of p62 in the NAFL cell models. The autophagy inhibitor 3-MA suppressed the FFA-induced autophagy in the NAFL cell models. Furthermore, 3-MA treatment significantly alleviated the accumulation of lipid droplets in L02 and HuH-7 cells. Our results suggest that autophagy has a significant effect on lipid accumulation in the NAFL cell models. Inhibition of autophagy impairs FFA-induced excessive lipid accumulation in hepatocellular carcinoma and hepatic cells. [ABSTRACT FROM AUTHOR]

COVID-19 has caused numerous infections with diverse clinical symptoms. To identify human genetic variants contributing to the clinical development of COVID-19, we genotyped 1457 (598/859 with severe/mild symptoms) and sequenced 1141 (severe/mild: 474/667) patients of Chinese ancestry. We further incorporated 1401 genotyped and 948 sequenced ancestry-matched population controls, and tested genome-wide association on 1072 severe cases versus 3875 mild or population controls, followed by trans-ethnic meta-analysis with summary statistics of 3199 hospitalized cases and 897,488 population controls from the COVID-19 Host Genetics Initiative. We identified three significant signals outside the well-established 3p21.31 locus: an intronic variant in FOXP4-AS1 (rs1853837, odds ratio OR = 1.28, P = 2.51 × 10−10, allele frequencies in Chinese/European AF = 0.345/0.105), a frameshift insertion in ABO (rs8176719, OR = 1.19, P = 8.98 × 10−9, AF = 0.422/0.395) and a Chinese-specific intronic variant in MEF2B (rs74490654, OR = 8.73, P = 1.22 × 10−8, AF = 0.004/0). These findings highlight an important role of the adaptive immunity and the ABO blood-group system in protection from developing severe COVID-19. Chaolong Wang and colleagues report a large genome-wide association study for COVID-19 severity in Chinese individuals. By meta-analysis with European data, they identify 3 loci associated with severe disease that suggest key roles for the adaptive immune system and the ABO blood group system in development of severe COVID-19. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum (ER) stress-induced apoptosis and autophagy flux blockade significantly contribute to neuronal pathology of spinal cord injury (SCI). Yet, the molecular interplay between these two distinctive pathways in mediating the pathology of SCI remains largely unexplored. Currently, we aimed at exploring the crucial role of Stub1 in maintaining ER homeostasis and regulating autophagic flux after SCI. Our results demonstrate that Stub1 reduces ER stress induced neuronal apoptosis, promotes axonal regeneration, inhibits glial scar formation and fosters functional recovery by restoring autophagic flux following SCI. Stub1 enhances autophagic flux following SCI by alleviating the permeabilization of lysosomal membrane through activating TFEB. Importantly, we showed that Stub1 promotes the activation of TFEB by targeting HDAC2 for ubiquitination and degradation. Furthermore, the neuroprotective effect of Stub1 on SCI was abrogated by chloroquine administration, underscoring the essential role of Stub1-mediated enhancement of autophagic flux in its protective effects against SCI. Collectively, our data highlights the vital role of Stub1 in regulating ER stress and autophagy flux after SCI, and propose its potential as a promising target for neuroprotective interventions in SCI. • Stub1 overexpression significantly protects against spinal cord injury. • Stub1 plays a vital role in managing ER stress and autophagy flux post SCI. • Stub1 reduces ER stress-induced neuronal apoptosis by restoring the obstructed autophagy flux after SCI. • Stub1 promotes autophagic flux by activating TFEB and targeting HDAC2 for degradation. • Stub1 emerges as a promising target for neuroprotective interventions in SCI. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Aidi injection is one of the most commonly used Chinese patent medicines for advanced non-small cell lung cancer (NSCLC). It is made from an extraction of Mylabris Phalerata, Radix Astragalus, Radix Ginseng, and Acanthopanax Senticosus. Aim of the study The objective of this study is to evaluate the efficacy and safety of Aidi injection in combination with platinum-based chemotherapy for stage IIIB/IV NSCLC. Materials and methods A systematic review and meta-analysis were performed following the PRISMA (the Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Trials were combined using Review Manager 5.3 and Comprehensive Meta-Analysis(CMA) 2.0. Dichotomous data were expressed as risk ratio (RR) and continuous outcomes as weighted mean difference (WMD), with their 95% confidence intervals (CI) respectively. All randomized controlled trials (RCTs) comparing Aidi injection plus platinum-based chemotherapy versus platinum-based chemotherapy, with efficacy and safety outcomes were selected. Disease Control Rate (DCR) was the primary outcome, Objective Response Rate (ORR), survival rate, quality of life (QOL), and toxic effects were the secondary outcomes. Results 42 RCTs recruiting 4081 patients with stage IIIB/IV NSCLC were included, with overall low-moderate methodological quality. Compared with platinum-based chemotherapy alone, Aidi injection plus platinum-based chemotherapy can increase relative benefit of DCR (RR = 1.13, 95% CI 1.09–1.16, P  < 0.00001), ORR (RR = 1.26, 95% CI 1.18–1.36, P  < 0.00001) , improve 1-, 2-, 3-year survival rates (RR = 1.14, 95% CI 1.02–1.28, P  = 0.03; RR = 1.31, 95% CI 1.05–1.64, P  = 0.02; and RR = 1.88, 95% CI 1.32–2.67, P  = 0.0005, respectively), QOL (RR = 1.80, 95% CI 1.61–2.01, P  < 0.00001), and reduce severe (grade 3 and 4) toxicities by 36% (RR = 0.64, 95% CI 0.58–0.70, P  < 0.00001). Conclusions From the available evidence, compared with platinum-based chemotherapy alone, Aidi injection plus platinum-based chemotherapy improves the clinical efficacy and alleviates the toxicity of chemotherapy in patients with stage IIIB/IV NSCLC. However, considering the intrinsic limitations of the included RCTs, well-designed, rigorously performed, high-quality trials are still required to further assess and confirm the results. [ABSTRACT FROM AUTHOR]

Benzo(a)pyrene (BaP) is a widespread environmental contaminant that has been associated with neurotoxicity in mammals. It has strong toxic effects on the developing central nervous system. Cerebellum is associated with locomotor activity and anxiety behavior, but there is very little research about the toxic effects of BaP in cerebellum. The present study aims to investigate the global influence of BaP subacute exposure on the metabolome of rat cerebellum. Male neonatal rats (postnatal day 5) were divided into two groups: control group and BaP-treated group (2 mg/kg/day for 7 weeks). Open field test and transmission electron microscopy were performed to analyze neurobehavior and ultramicrostructure alteration. Gas chromatography-mass spectrometry (GC-MS) was used to analyze metabolites of the cerebellum in both groups. The results revealed that postnatal exposure to BaP promoted pathological changes in the cerebellum and increased locomotor and anxiety activities in early adulthood. Twenty differential significant metabolites were identified by multivariate statistical analysis. Further metabolic pathway impact analysis and network analysis suggested that the primary metabolic pathways affected included pathway involved in energy metabolism, methionine and cysteine metabolism, and glutathione metabolism. These findings suggest that BaP-induced cerebellum injury may be correlated with metabolic changes and provide an area to target to reduce the negative effects of BaP. [ABSTRACT FROM AUTHOR]

• Zein nanoparticles for sustained-release chloroquine were successfully prepared. • Zein nanoparticles reduced chloroquine toxicity through sustained release. • Chloroquine released from zein nanoparticles inhibited neuroinflammation. • Degradation products of zein nanoparticles promoted M2 microglia polarization. Inflammation is a pivotal molecular event in secondary spinal cord injury (SCI). However, chloroquine (CQ) is an anti-malarial drug with remarkable anti-inflammatory effects. Zein is a biodegradable biomaterial derived from natural-plant protein and is widely applied in drug sustained-release carriers due to its promising biocompatibility and biodegradability. In this research, we investigated the significant effects and underlying molecular mechanisms of zein nanoparticles (NPs) loaded with CQ in SCI. More importantly, we found that local delivery of Zein-CQ NPs after SCI could significantly improved functional recovery, inhibited neuronal apoptosis, alleviated neuroinflammation and enhanced M2 phenotype microglia polarization. Mechanistically, our findings further demonstrated that local administration of Zein-CQ NPs inhibited activation of the MAPK/NF-κB signaling pathway after SCI in rats. Moreover, Zein-CQ NPs reduced the release of pro-inflammatory factors and augmented the protein expression of M2 phenotype microglia in lipopolysaccharide (LPS)-stimulated BV2 cells. Our findings imply that local delivery of Zein-CQ NPs produces promising therapeutic benefits for the treatment and management of SCI. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS) is a common and complex endocrine disorder that is also an important cause of infertility. Adverse psychological stress can aggravate the occurrence and development of PCOS. Bushen Jieyu Tiaochong Formula (BJTF), a prescription of Traditional Chinese Medicine (TCM), has been used in the treatment of PCOS and shown to be effective in reducing negative emotion. However, the therapeutic mechanism has yet to be clearly elucidated. In the current study, we investigated the potential mechanism of action of BJTF. To investigate the role of PERK-ATF4-CHOP signaling in the molecular mechanisms that mediate the effects of BJTF in a rat model of PCOS, with chronic stress induced by letrozole and a chronic unpredictable mild stress (CUMS) paradigm. In addition to the normal control group, the PCOS combined with CUMS model rats were randomly assigned to a model group, a Diane-35 (ethinylestradiol 35 μg/cyproterone acetate 2 mg)-treated positive control group, or one of three BJTF-treated groups receiving a low, medium, or high dose. Behavioral testing, including the sucrose preference test and open field test, was conducted, and hematoxylin and eosin (H&E) staining was used to observe changes in the pathological morphology of ovarian tissue. Free testosterone (FT), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) levels in serum were quantified by enzyme-linked immunosorbent assays (ELISA). The hippocampal levels of norepinephrine (NE), 5-hydroxytryptamine/serotonin (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) were measured using high-performance liquid chromatography–electrochemical detection (HPLC-ECD). Apoptotic granulosa cells were detected using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Furthermore, quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry were used to detect the expression of glucose-regulated protein 78 (GRP78) and CHOP in the ovarian tissues. The expression levels of GRP78, CHOP, PERK, and ATF4 in ovarian tissues were also measured by western blotting. Treatment with either BJTF or Diane-35 ameliorated the abnormal cystic dilatation of follicles in the model rats and reduced the serum levels of FT and LH, and the LH/FSH ratio. BJTF treatment also attenuated chronic psychological stress-like behavior and regulated the expression and metabolism of cerebral monoamine neurotransmitters. The efficacy of BJTF was greater than that of Diane-35, with the optimal effects observed at the medium dose. BJTF also lowered the apoptotic index of ovarian granulosa cells and downregulated the expression of GRP78, CHOP, and ATF4. Although the expression level of PERK was not significantly altered by BJTF, the mean PERK expression level was the lowest in the medium-dose BJTF group. Administration of BJTF has the therapeutic potential to promote the homeostasis of the reproductive endocrine environment and to restore follicular development and ovulation, possibly through the inhibition of the PERK-ATF4-CHOP signaling pathway, leading to downregulation of GRP78 expression to further delay ovarian granule cell apoptosis mediated by endoplasmic reticulum stress (ERS). Moreover, BJTF could improve behavioral performance by regulating cerebral monoamine neurotransmitters in this rat model. These findings provide a new perspective for treating PCOS related to psychological stress using TCM. [Display omitted] • Chronic unpredictable mild stress (CUMS) worsens polycystic ovary syndrome (PCOS). • Bushen Jieyu Tiaochong Formula (BJTF) is a traditional Chinese medicine. • BJTF is efficacious in rat PCOS with CUMS models via an unknown mechanism. • PERK-ATF4-CHOP modulates endoplasmic reticulum stress (ERS)-induced apoptosis. • BJTF is efficacious in a PCOS with CUMS model via modulation of PERK-ATF4-CHOP. [ABSTRACT FROM AUTHOR]

A fully integrated dual-channel multiband RF receiver is designed and implemented for next-generation global navigation satellite systems (GNSSs) in a 0.18-\mu\ m CMOS process. Its two reconfigurable signal channels can simultaneously process any two types of 2-, 4-, or 20-MHz bandwidth signals mainly located around the RF bands of 1.2 and 1.57 GHz for GPS, Galileo, and BD-2 (aka Compass) systems, while achieving better performance (die area, noise figure, gain dynamic range) than other state-of-the-art GNSS receivers. A digital automatic gain control loop consisting of a variable gain amplifier and nonuniform 4-bit ADC is utilized to improve the receiver's robustness and performance in the presence of interferences. While drawing 25-mA current per channel from a 1.8-V supply, this RF receiver achieves a total noise figure of 2.5 dB/2.7 dB at 1.2/1.57 GHz, an image rejection of 28 dB, a maximum voltage gain of 110 dB, a gain dynamic range of 73 dB, and an input-referred 1-dB compression point of -58 dBm, with an active die area of 2.4 \ mm^2 for single channel. [ABSTRACT FROM PUBLISHER]