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1.
Identification of a membrane-associated element (MAE) in the C-terminal region of SARS-CoV-2 nsp6 that is essential for viral replication.
Han, Y, Yuan, Z, Yi, Z
Journal of virology. 2024;:e0034924
Abstract
The coronavirus disease 2019 (COVID-19) pandemic, caused by the novel coronavirus severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), has rapidly spread worldwide since its emergence in late 2019. Its ongoing evolution poses challenges for antiviral drug development. Coronavirus nsp6, a multiple-spanning transmembrane protein, participates in the biogenesis of the viral replication complex, which accommodates the viral replication-transcription complex. The roles of its structural domains in viral replication are not well studied. Herein, we predicted the structure of the SARS-CoV-2 nsp6 protein using AlphaFold2 and identified a highly folded C-terminal region (nsp6C) downstream of the transmembrane helices. The enhanced green fluorescent protein (EGFP)-fused nsp6C was found to cluster in the cytoplasm and associate with membranes. Functional mapping identified a minimal membrane-associated element (MAE) as the region from amino acids 237 to 276 (LGV-KLL), which is mainly composed of the α-helix H1 and the α-helix H2; the latter exhibits characteristics of an amphipathic helix (AH). Mutagenesis studies and membrane flotation experiments demonstrate that AH-like H2 is required for MAE-mediated membrane association. This MAE was functionally conserved across MERS-CoV, HCoV-OC43, HCoV-229E, HCoV-HKU1, and HCoV-NL63, all capable of mediating membrane association. In a SARS-CoV-2 replicon system, mutagenesis studies of H2 and replacements of H1 and H2 with their homologous counterparts demonstrated requirements of residues on both sides of the H2 and properly paired H1-H2 for MAE-mediated membrane association and viral replication. Notably, mutations I266A and K274A significantly attenuated viral replication without dramatically affecting membrane association, suggesting a dual role of the MAE in viral replication: mediating membrane association as well as participating in protein-protein interactions.IMPORTANCESevere acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) assembles a double-membrane vesicle (DMV) by the viral non-structural proteins for viral replication. Understanding the mechanisms of the DMV assembly is of paramount importance for antiviral development. Nsp6, a multiple-spanning transmembrane protein, plays an important role in the DMV biogenesis. Herein, we predicted the nsp6 structure of SARS-CoV-2 and other human coronaviruses using AlphaFold2 and identified a putative membrane-associated element (MAE) in the highly conserved C-terminal regions of nsp6. Experimentally, we verified a functionally conserved minimal MAE composed of two α-helices, the H1, and the amphipathic helix-like H2. Mutagenesis studies confirmed the requirement of H2 for MAE-mediated membrane association and viral replication and demonstrated a dual role of the MAE in viral replication, by mediating membrane association and participating in residue-specific interactions. This functionally conserved MAE may serve as a novel anti-viral target.
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2.
Tumor iron homeostasis and immune regulation.
Zhang, YY, Han, Y, Li, WN, Xu, RH, Ju, HQ
Trends in pharmacological sciences. 2024;(2):145-156
Abstract
Abnormal iron metabolism has long been regarded as a key metabolic hallmark of cancer. As a critical cofactor, iron contributes to tumor progression by participating in various processes such as mitochondrial electron transport, gene regulation, and DNA synthesis or repair. Although the role of iron in tumor cells has been widely studied, recent studies have uncovered the interplay of iron metabolism between tumor cells and immune cells, which may affect both innate and adaptive immune responses. In this review, we discuss the current understanding of the regulatory networks of iron metabolism between cancer cells and immune cells and how they contribute to antitumor immunity, and we analyze potential therapeutics targeting iron metabolism. Also, we highlight several key challenges and describe potential therapeutic approaches for future investigations.
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3.
Experimental study on the impact of "IDS + JFCS" complex wetting agent on the characteristics of coal bodies.
Wang, H, Xu, L, Qin, Z, Li, X, Cao, X, Han, Y, Li, S, Ma, Y, Gao, S, Du, L, et al
Scientific reports. 2024;(1):7163
Abstract
As China's coal mines have transitioned to deep mining, the ground stress within the coal seams has progressively increased, resulting in reduced permeability and poor wetting ability of conventional wetting agents. Consequently, these agents have become inadequate in fulfilling the requirements for preventing washouts during deep mining operations. In response to the aforementioned challenges, a solution was proposed to address the issues by formulating a composite wetting agent. This composite wetting agent combines a conventional surfactant with a chelating agent called tetrasodium iminodisuccinate (IDS). By conducting a meticulous screening of surfactant monomer solutions, the ideal formulation for the composite wetting agent was determined by combining the monomer surfactant with IDS. Extensive testing, encompassing evaluations of the composite solution's apparent strain, contact angle measurements, and alterations in the oxygenated functional groups on the coal surface, led to the identification of the optimal composition. This composition consisted of IDS serving as the chelating agent and fatty alcohol polyoxyethylene ether (JFCS).Subsequent assessment of the physical and mechanical performance of the coal briquettes treated with the composite wetting agent revealed notable enhancements. These findings signify significant advancements in the field and hold promising implications. Following the application of the composite wetting agent, notable reductions were observed in the dry basis ash and dry basis full sulfur of coal. Additionally, the water content within the coal mass increased significantly, leading to a substantial enhancement in the wetting effect of the coal body. This enhanced wetting effect effectively mitigated the coal body's inclination towards impact, thereby offering technical support for optimizing water injection into coal seams and preventing as well as treating impact ground pressure.
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4.
Quality reporting of randomized controlled trials on SGLT2 inhibitors for heart failure: a comprehensive assessment.
Yang, Y, Yang, S, Han, Y, Zou, G, Wang, R, Liu, L
Scientific reports. 2024;(1):6819
Abstract
Randomised controlled trials (RCTs) provide clinicians with the best evidence of the effectiveness of an intervention, and complete and transparent trial reports help to critically assess and use trial results. The objective of our study was to assess the quality of reporting in RCTs of sodium-glucose co-transporter protein 2 (SGLT2) inhibitors for heart failure (HF) and identify factors associated with improved reporting quality. Two researchers conducted a comprehensive search in four databases (PubMed, Web of Science, EMBASE, and Cochrane). The quality of each report was assessed using a 25-point Overall Quality Score (OQS) based on the guidelines provided in the 2010 Consolidated Standards for Reporting of Trials (CONSORT) statement. We included a total of 58 relevant RCTs. The median OQS in the 2010 CONSORT statement was 15 (range 7.5-24). The missing items were primarily found in the 'Methods' and 'Results' sections of the 2010 CONSORT statement. Multivariate regression modeling revealed that a more recent publication year, high impact factor, and large sample size were significant predictors of OQS improvement. The findings suggest that the overall quality of reported RCTs of SGLT2 inhibitors in HF is unsatisfactory, which reduces their potential usefulness.
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5.
Application Effects of Individualized Diet Nursing Combined with the Modified Glasgow-Blatchford Scoring System in Upper Gastrointestinal Bleeding.
Liu, M, Wang, H, Shao, F, Xu, Y, Huang, J, Zhang, H, Han, Y
Alternative therapies in health and medicine. 2024
Abstract
BACKGROUND Upper gastrointestinal bleeding encompasses bleeding arising from esophageal, gastric, duodenal, or pancreaticobiliary lesions above the Treitz ligament. Research indicates a close association between improper diet and upper gastrointestinal bleeding. OBJECTIVE This study aims to investigate the application effects of individualized diet nursing combined with the modified Glasgow-Blatchford scoring system in patients with upper gastrointestinal bleeding. DESIGN A randomized controlled study was conducted. SETTING The study took place at the First Hospital of Hebei Medical University. PARTICIPANTS From January 2021 to October 2022, 80 patients with upper gastrointestinal bleeding were selected at our hospital. Using a random number table, they were divided into a control group and an observation group, each comprising 40 cases. INTERVENTIONS The control group received routine nursing, while the observation group received individualized diet nursing based on the Glasgow-Blatchford score in addition to routine nursing. PRIMARY OUTCOME MEASURES (1) bleeding frequency, hemostasis time, and hospital stay; (2) re-bleeding rate; (3) Glasgow-Blatchford scores; (4) quality of life; and (5) nursing satisfaction. RESULTS In the observation group, bleeding frequency, hemostasis time, and hospital stay significantly reduced compared to the control (P < .05). Post-nursing, the observation group had a lower re-bleeding rate (χ2=11.25, P < .05). Before nursing, no statistical differences existed in Glasgow-Blatchford and quality of life scores between groups (P > .05). Post-nursing, both groups saw reduced Glasgow-Blatchford scores, more so in the observation group (P < .05). Quality of life scores increased in both, more notably in the observation group (P < .05). Overall nursing satisfaction was higher in the observation group (P < .05). CONCLUSIONS Individualized diet nursing, based on the Glasgow-Blatchford score, improves cure rates and quality of life and warrants promotion.
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6.
Genomic approaches to enhance adaptive plasticity to cope with soil constraints amidst climate change in wheat.
Bhoite, R, Han, Y, Chaitanya, AK, Varshney, RK, Sharma, DL
The plant genome. 2024;(1):e20358
Abstract
Climate change is varying the availability of resources, soil physicochemical properties, and rainfall events, which collectively determines soil physical and chemical properties. Soil constraints-acidity (pH < 6), salinity (pH ≤ 8.5), sodicity, and dispersion (pH > 8.5)-are major causes of wheat yield loss in arid and semiarid cropping systems. To cope with changing environments, plants employ adaptive strategies such as phenotypic plasticity, a key multifaceted trait, to promote shifts in phenotypes. Adaptive strategies for constrained soils are complex, determined by key functional traits and genotype × environment × management interactions. The understanding of the molecular basis of stress tolerance is particularly challenging for plasticity traits. Advances in sequencing and high-throughput genomics technologies have identified functional alleles in gene-rich regions, haplotypes, candidate genes, mechanisms, and in silico gene expression profiles at various growth developmental stages. Our review focuses on favorable alleles for enhanced gene expression, quantitative trait loci, and epigenetic regulation of plant responses to soil constraints, including heavy metal stress and nutrient limitations. A strategy is then described for quantitative traits in wheat by investigating significant alleles and functional characterization of variants, followed by gene validation using advanced genomic tools, and marker development for molecular breeding and genome editing. Moreover, the review highlights the progress of gene editing in wheat, multiplex gene editing, and novel alleles for smart control of gene expression. Application of these advanced genomic technologies to enhance plasticity traits along with soil management practices will be an effective tool to build yield, stability, and sustainability on constrained soils in the face of climate change.
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7.
Efficacy and safety of psychedelics for the treatment of mental disorders: A systematic review and meta-analysis.
Yao, Y, Guo, D, Lu, TS, Liu, FL, Huang, SH, Diao, MQ, Li, SX, Zhang, XJ, Kosten, TR, Shi, J, et al
Psychiatry research. 2024;:115886
Abstract
We aim to systematically review and meta-analyze the effectiveness and safety of psychedelics [psilocybin, ayahuasca (active component DMT), LSD and MDMA] in treating symptoms of various mental disorders. Web of Science, Embase, EBSCO, and PubMed were searched up to February 2024 and 126 articles were finally included. Results showed that psilocybin has the largest number of articles on treating mood disorders (N = 28), followed by ayahuasca (N = 7) and LSD (N = 6). Overall, psychedelics have therapeutic effects on mental disorders such as depression and anxiety. Specifically, psilocybin (Hedges' g = -1.49, 95% CI [-1.67, -1.30]) showed the strongest therapeutic effect among four psychedelics, followed by ayahuasca (Hedges' g = -1.34, 95% CI [-1.86, -0.82]), MDMA (Hedges' g = -0.83, 95% CI [-1.33, -0.32]), and LSD (Hedges' g = -0.65, 95% CI [-1.03, -0.27]). A small amount of evidence also supports psychedelics improving tobacco addiction, eating disorders, sleep disorders, borderline personality disorder, obsessive-compulsive disorder, and body dysmorphic disorder. The most common adverse event with psychedelics was headache. Nearly a third of the articles reported that no participants reported lasting adverse effects. Our analyses suggest that psychedelics reduce negative mood, and have potential efficacy in other mental disorders, such as substance-use disorders and PTSD.
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8.
Efficacy and Safety of Inclisiran in Asian Patients: Results From ORION-18.
Huo, Y, Lesogor, A, Lee, CW, Chiang, CE, Mena-Madrazo, J, Poh, KK, Jeong, MH, Maheux, P, Zhang, M, Wei, S, et al
JACC. Asia. 2024;(2):123-134
Abstract
BACKGROUND Management of low-density lipoprotein cholesterol (LDL-C) in Asia remains suboptimal, with ∼50% of patients who are treated with lipid-lowering therapies (LLTs) unable to achieve their guideline-recommended LDL-C goals. Asian-representative studies of the use of inclisiran are needed. OBJECTIVES The authors sought to evaluate the efficacy and safety of inclisiran in Asian patients with atherosclerotic cardiovascular disease (ASCVD) or high risk of ASCVD, as an adjunct to diet and maximally tolerated statin dose, with or without additional LLTs. METHODS The ORION-18 was a phase 3 double-blind trial in which patients were randomized 1:1 to receive either 300 mg inclisiran sodium or matching placebo on days 1, 90, and 270. Percentage change in LDL-C from baseline to day 330 was the primary endpoint. RESULTS A total of 345 patients (mean age 59.5 years, mean baseline LDL-C 109 mg/dL, 74.7% male) were randomized to inclisiran or placebo. Baseline characteristics were similar in both groups. The percentage decrease in LDL-C from baseline to day 330 was 57.2% (P < 0.001); proprotein convertase subtilisin/kexin type 9 was reduced by 78.3% (P < 0.001). Time-adjusted percentage reduction in LDL-C from baseline after day 90 and up to day 360 was 56.3%. At day 330, 71.7% of participants with inclisiran achieved ≥50% reduction in LDL-C compared with 1.5% with placebo. Over the study period, total cholesterol, apolipoprotein B, and non-high-density lipoprotein cholesterol (HDL-C) levels were decreased significantly, and HDL-C levels increased. The incidence of adverse events with inclisiran was similar to that with placebo. CONCLUSIONS In Asian patients with ASCVD or high risk of ASCVD, inclisiran was effective and safe. (Study of Efficacy and Safety of Inclisiran in Asian Participants With Atherosclerotic Cardiovascular Disease [ASCVD] or ASCVD High Risk and Elevated Low-Density Lipoprotein Cholesterol [LDL-C] [ORION-18]; NCT04765657).
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9.
A comprehensive review of ethnopharmacology, chemical constituents, pharmacological effects, pharmacokinetics, toxicology, and quality control of gardeniae fructus.
Wang, L, Chen, S, Liu, S, Biu, AM, Han, Y, Jin, X, Liang, C, Liu, Y, Li, J, Fang, S, et al
Journal of ethnopharmacology. 2024;:117397
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Gardeniae Fructus (GF), the desiccative mature fruitage of Gardenia jasminoides J. Ellis (G. jasminoides), belongs to the Rubiaceae family. It has abundant medicinal value, such as purging fire and eliminating annoyance, clearing heat and diuresis, cooling blood, and detoxifying. GF is usually used in combination with other drugs to treat diseases such as fever and jaundice in damp heat syndrome in traditional Chinese medicines (TCMs) clinical practice. THE AIM OF THE REVIEW This review comprehensively summarizes the research progress in botany, traditional medical use, processing method, phytochemistry, pharmacological activity, quality control, pharmacokinetics, and toxicology, which aims to provide a scientific basis for the rational application and future research of GF. MATERIALS AND METHODS ScienceDirect, PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), Embase, Scopus etc. databases were retrieved to gain the comprehensive information of GF. RESULTS At present, more than 215 compounds were isolated and identified from GF, including iridoids, diterpenes, triterpenoids, flavonoids, organic esters, and so on. The traditional application of GF mainly focused on clearing heat and detoxification. Pharmacological studies proved that GF had anti-inflammatory, antioxidation, antifatigue, antithrombotic, liver and gallbladder protection, and other pharmacological effects. In addition, many improved processing methods can alleviate the side effects and toxic reactions caused by long-term use of GF, so controlling its quality through multi-component content measurement has become an important means of research. CONCLUSION GF has a wide range of applications, the mechanisms by which some effective substances exert their pharmacological effects have not been clearly explained due to the complexity and diversity of its components. This review systematically elaborates on the traditional medical use, processing method, phytochemistry, pharmacological activity, quality control, and toxicology of GF, and it is expected to become a candidate drug for treating diseases, such as depression, pancreatitis, alcoholic or non-alcoholic fatty liver.
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10.
Electronic Interactive Games for Glycemic Control in Individuals With Diabetes: Systematic Review and Meta-Analysis.
Yao, W, Han, Y, Yang, L, Chen, Y, Yan, S, Cheng, Y
JMIR serious games. 2024;:e43574
Abstract
BACKGROUND Several electronic interventions have been used to improve glycemic control in patients with diabetes. Electronic interactive games specific to physical activity are available, but it is unclear if these are effective at improving glycemic control in patients with diabetes. OBJECTIVE This study aimed to determine the effects of electronic game-based interventions on glycemic control in patients with diabetes. METHODS Relevant studies that were published before April 1, 2023, were searched from 5 databases: PubMed, Embase, Web of Science, Scopus, and Cochrane Library. Eligibility criteria included prospective studies examining the relationship between electronic games with physical activities or diet education and glycemic control as the outcome. The risk of bias was assessed using the Cochrane risk-of-bias tool. All analyses were conducted using RevMan5.4.1. Depending on the heterogeneity across studies, the pooled effects were calculated using fixed-effects or random-effects models. RESULTS Participants from 9 studies were included and assessed. Glycated hemoglobin (HbA1c) and fasting blood glucose improved in the intervention group, although the analysis revealed no significant reduction in HbA1c (-0.09%, 95% CI -0.29% to 0.10%) or fasting blood glucose (-0.94 mg/dL, 95% CI -9.34 to 7.46 mg/dL). However, the physical activity of individuals in the intervention group was significantly higher than that of those in the control group (standardized mean difference=0.84, 95% CI 0.30 to 1.38; P=.002). Other outcomes, such as weight and blood lipids, exhibited no significant improvement (all P>.05). CONCLUSIONS Electronic games had a good impact on participants' physical activity and offered an advantage in glycemic control without reaching statistical significance. Electronic games are convenient for reminders and education. Low-intensity exercise games may not be considered a better adjuvant intervention to improve diabetes self-management care.