Identification of Novel Bisamide-Decorated Benzotriazole Derivatives as Anti-Phytopathogenic Virus Agents: Bioactivity Evaluation and Computational Simulation.

As a notorious phytopathogenic virus, the tobacco mosaic virus (TMV) severely reduced the quality of crops worldwide and caused critical constraints on agricultural production. The development of novel virucides is a persuasive strategy to address this predicament. Herein, a series of novel bisamide-decorated benzotriazole derivatives were elaborately prepared and screened. Biological tests implied that the optimized compound 7d possessed the most brilliant antiviral inactive profile (EC50 = 157.6 µg/mL) and apparently surpassed that of commercial ribavirin (EC50 = 442.1 µg/mL) 2.8-fold. The preliminary antiviral mechanism was elaborately investigated via transmission electron microscopy, microscale thermophoresis (MST) determination, RT-qPCR, and Western blot analysis. The results showed that compound 7d blocked the assembly of TMV by binding with coat protein (Kd = 0.7 µM) and suppressed TMV coat protein gene expression and biosynthesis process. Computational simulations indicated that 7d displayed strong H-bonds and pi interactions with TMV coat protein, affording a lower binding energy (ΔGbind = -17.8 kcal/mol) compared with Ribavirin (ΔGbind = -10.7 kcal/mol). Overall, current results present a valuable perception of bisamide decorated benzotriazole derivatives with appreciably virustatic competence and should be profoundly developed as virucidal candidates in agrochemical.

[Clinical features of CAPOS syndrome caused by maternal ATP1A3 gene variation: a case report].

CAPOS syndrome is an autosomal dominant neurological disorder caused by mutations in the ATP1A3 gene. Initial symptoms, often fever-induced, include recurrent acute ataxic encephalopathy in childhood, featuring cerebellar ataxia, optic atrophy, areflflexia, sensorineural hearing loss, and in some cases, pes cavus. This report details a case of CAPOS syndrome resulting from a maternal ATP1A3 gene mutation. Both the child and her mother exhibited symptoms post-febrile induction,including severe sensorineural hearing loss in both ears, ataxia, areflexia, and decreased vision. Additionally, the patient's mother presented with pes cavus. Genetic testing revealed a c. 2452G>A（Glu818Lys） heterozygous mutation in theATP1A3 gene in the patient . This article aims to enhance clinicians' understanding of CAPOS syndrome, emphasizing the case's clinical characteristics, diagnostic process, treatment, and its correlation with genotypeic findings.

A case report on deficiency of adenosine deaminase 2 with relapse-remission course and analysis of genotype-phenotype correlation.

Deficiency of adenosine deaminase 2 (DADA2) is a monogenic disease caused by biallelic mutations in adenosine deaminase 2 (ADA2). The varying phenotypes of the disease often lead to delayed diagnosis or misdiagnosis. We report an 11-year-old boy with DADA2 and provide a preliminary analysis of genotype-phenotype correlation. The age of onset of the disease was 8 years old. The disease successively involved the brainstem, muscles, joints, and cerebrum. After three relapse-remission episodes over 3 years, the patient was finally diagnosed with DADA2 by whole-exome sequencing. Compound heterozygous variants in the ADA2 gene (NM_001282225.2: c.1072G>A, p.Gly358Arg; c.419dupC, p.Arg141Lysfs*37) were found in the patient. He did not receive anti-TNF therapy and had no relapse after a 8-month follow-up. We identified a novel variant of the ADA2 gene, and the associated disease course may follow a relapse-remission pattern. Homozygous mutations of p.Gly358Arg can cause pure red cell aplasia, whereas compound heterozygous variations may lead to different phenotypes. Variants in the catalytic domain and frameshift mutations may also cause relatively benign phenotypes besides causing hematological disorders. Further studies are needed to clarify the genotypic-phenotypic relationship of this disease.

Transcriptional regulation of SARS-CoV-2 receptor ACE2 by SP1.

Angiotensin-converting enzyme 2 (ACE2) is a major cell entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The induction of ACE2 expression may serve as a strategy by SARS-CoV-2 to facilitate its propagation. However, the regulatory mechanisms of ACE2 expression after viral infection remain largely unknown. Using 45 different luciferase reporters, the transcription factors SP1 and HNF4α were found to positively and negatively regulate ACE2 expression, respectively, at the transcriptional level in human lung epithelial cells (HPAEpiCs). SARS-CoV-2 infection increased the transcriptional activity of SP1 while inhibiting that of HNF4α. The PI3K/AKT signaling pathway, activated by SARS-CoV-2 infection, served as a crucial regulatory node, inducing ACE2 expression by enhancing SP1 phosphorylation-a marker of its activity-and reducing the nuclear localization of HNF4α. However, colchicine treatment inhibited the PI3K/AKT signaling pathway, thereby suppressing ACE2 expression. In Syrian hamsters (Mesocricetus auratus) infected with SARS-CoV-2, inhibition of SP1 by either mithramycin A or colchicine resulted in reduced viral replication and tissue injury. In summary, our study uncovers a novel function of SP1 in the regulation of ACE2 expression and identifies SP1 as a potential target to reduce SARS-CoV-2 infection.

HAGLR, stabilized by m6A modification, triggers PTEN-Akt signaling cascade-mediated RPE cell pyroptosis via sponging miR-106b-5p.

Consistent hyperglycaemia on retinal microvascular tissues is recognized as a vital inducer of diabetic retinopathy (DR) pathogenesis. In view of the essential functionality of long noncoding RNAs (lncRNAs) in multiple human diseases, we aim to figure out the exact role and underlying mechanisms of lncRNA HOXD Cluster Antisense RNA 1 (HAGLR) in DR pathogenesis. Serum specimens from patients with proliferative DR and healthy volunteers were collected for measuring HAGLR levels. Human primary retinal pigment epithelium (HRPE) cells kept in high glucose (HG) condition were applied to simulating hyperglycaemia of DR pathology in vitro. Cell proliferation, apoptosis, either pyroptosis was assess using Cell Counting Kit-8 TUNEL, flow cytometry, and enzyme-linked immunoassay assays. Bioinformatics analysis was subjected to examine the interaction between HAGLR and N6-methyladenosine (m6A)-bind protein IGF2BP2, as determined using RNA immunoprecipitation and RNA pull-down. Luciferase reporter assay was performed to assess the HAGLR-miR-106b-5p-PTEN axis. Levels of pyroptosis-associated biomarkers were detected using western blotting. Aberrantly overexpressed HAGLR was uncovered in the serum samples of DR patients and HG-induced HRPE cells, of which knockdown attenuated HG-induced cytotoxic impacts on cell apoptosis and pyroptosis. Whereas, reinforced HAGLR further aggravated these effects. IGF2BP2 positively regulated HAGLR in a m6A-dependent manner. HAGLR served as a sponge for miR-106b-5p to upregulate PTEN, thereby activating Akt signaling cascade. Rescue assays demonstrated that PTEN overexpression abolished the inhibition of silenced HAGLR on pyroptosis in HRPE cells. HAGLR, epigenetically modified by IGF2BP2 in an m6A-dependent manner, functioned as a sponge for miR-106b-5p, thereby activating PTEN/Akt signaling cascade to accelerate DR pathology.

Improvements in Sperm Motility Following Low- or High-Intensity Dietary Interventions in Men With Obesity.

INTRODUCTION: Obesity increases risks of male infertility, but bariatric surgery does not improve semen quality. Recent uncontrolled studies suggest that a low-energy diet (LED) improves semen quality. Further evaluation within a randomized, controlled setting is warranted. METHODS: Men with obesity (18-60 years) with normal sperm concentration (normal count) (n = 24) or oligozoospermia (n = 43) were randomized 1:1 to either 800 kcal/day LED for 16 weeks or control, brief dietary intervention (BDI) with 16 weeks' observation. Semen parameters were compared at baseline and 16 weeks. RESULTS: Mean age of men with normal count was 39.4 ± 6.4 in BDI and 40.2 ± 9.6 years in the LED group. Mean age of men with oligozoospermia was 39.5 ± 7.5 in BDI and 37.7 ± 6.6 years in the LED group. LED caused more weight loss than BDI in men with normal count (14.4 vs 6.3 kg; P < .001) and men with oligozoospermia (17.6 vs 1.8 kg; P < .001). Compared with baseline, in men with normal count total motility (TM) increased 48 ± 17% to 60 ± 10% (P < .05) after LED, and 52 ± 8% to 61 ± 6% (P < .0001) after BDI; progressive motility (PM) increased 41 ± 16% to 53 ± 10% (P < .05) after LED, and 45 ± 8% to 54 ± 65% (P < .001) after BDI. In men with oligozoospermia compared with baseline, TM increased 35% [26] to 52% [16] (P < .05) after LED, and 43% [28] to 50% [23] (P = .0587) after BDI; PM increased 29% [23] to 46% [18] (P < .05) after LED, and 33% [25] to 44% [25] (P < .05) after BDI. No differences in postintervention TM or PM were observed between LED and BDI groups in men with normal count or oligozoospermia. CONCLUSION: LED or BDI may be sufficient to improve sperm motility in men with obesity. The effects of paternal dietary intervention on fertility outcomes requires investigation.

Identification of natural Rutaecarpine as a potent tobacco mosaic virus (TMV) helicase candidate for managing intractable plant viral diseases.

BACKGROUND: Naturally occurring alkaloids are particularly suitable for use as pesticide precursors and further modifications due to their cost-effectiveness, unique mechanism of action, tolerable degradation, and environmental friendliness. The famous tobacco mosaic virus (TMV) is a persistent plant pathogenic virus that can parasitize many plants and severely reduce crop production. To treat TMV disease, TMV helicase acts as a crucial target by hydrolyzing adenosine triphosphate (ATP) to provide energy for double-stranded RNA unwinding. RESULTS: To seek novel framework alkaloid leads targeting TMV helicase, this work successfully established an efficient screening platform for TMV helicase inhibitors based on natural alkaloids. In vivo activity screening, enzyme activity detection, and binding assays showed that Rutaecarpine from Evodia rutaecarpa (Juss.) Benth exhibited excellent TMV helicase inhibitory properties [dissociation constant (Kd ) = 1.1 µm, half maximal inhibitory concentration (IC50 ) = 227.24 µm] and excellent anti-TMV ability. Molecular docking and dynamic simulations depicted that Rutaecarpine could stably bind in active pockets of helicase with low binding energy (ΔGbind = -17.8 kcal/mol) driven by hydrogen bonding and hydrophobic interactions. CONCLUSION: Given Rutaecarpine's laudable bioactivity and structural modifiability, it can serve as a privileged building block for further pesticide discovery.

Effect of electroacupuncture at "Neiguan" (PC 6) and "Zusanli" (ST 36) on gastrointestinal hormone in the antral tissue of rats with functional dyspepsia. / 电针"å† å ³""足三里"å¯¹åŠŸèƒ½æ€§æ¶ˆåŒ–ä¸è‰¯å¤§é¼ èƒƒçª¦ç»„ç»‡èƒƒè‚ æ¿€ç´ çš„å½±å“.

OBJECTIVES: To observe the effects of electroacupuncture (EA) at "Neiguan" (PC 6) and "Zusanli"(ST 36) on the gastric emptying rate, the level of serotonin (5-HT) and the protein expression of motilin (MTL), ghrelin, substance P (SP) and vasoactive intestinal peptide (VIP) in the antral tissue of the rats with functional dyspepsia (FD) and explore the effect mechanism of EA in treatment of FD. METHODS: A total of 21 SPF male SD rat pups were randomly divided into a normal group, a model group and an EA group, with 7 rats in each group. In the model group and the EA group, FD model was prepared by the gavage with 0.1% sucrose iodoacetamide solution combined with the modified small platform method. After the successful modeling, EA was applied to "Neiguan" (PC 6) and "Zusanli"(ST 36) in the rats of the EA group, with disperse-dense wave, 20 Hz/100 Hz in frequency, stimulated for 30 min, once daily, for 7 days consecutively. Before and after intervention, the general condition of the rats was observed in each group. After the completion of intervention, the gastric emptying rate was measured, the morphological changes of gastric antral tissue were observed using HE staining, the level of 5-HT was detected with ELISA method, and the protein expression of MTL, ghrelin, SP, and VIP was determined with Western blot method in the antral tissue of rats. RESULTS: In the normal group, the rats were in a good mental state, with lustrous fur, flexible movement and the increase of food intake and body mass. In the model group, the rats were poor in mental state, lack of lustre in fur, preference for the body curled up, reduced activity and response; and a part of rats had loose stool, obviously enlarged gastric body and gastric food retention. In the EA group, the general condition of rats, e.g. the mental state, food intake and activity, were improved, the gastric body got smaller obviously and the gastric food retention was reduced when compared with the model group. The antral structure was intact, the glands were rich and no injury of the gastric mucosa was found, e.g. inflammatory reaction and edema in the rats of each group. Compared with the normal group, the gastric emptying rate was decreased (P<0.01), 5-HT level was increased (P<0.01), the protein expression of MTL and ghrelin was reduced (P<0.01) and that of VIP was elevated (P<0.01) in the rats of the model group. The gastric emptying rate was increased (P<0.01), 5-HT level was decreased (P<0.01), and the protein expression of MTL and ghrelin was elevated (P<0.05, P<0.01) in the rats of the EA group when compared with those in the model group. CONCLUSIONS: Electroacupuncture at "Neiguan" (PC 6) and "Zusanli"(ST 36) may effectively relieve gastric dysfunction, strengthen gastric motility and promote gastric emptying so as to alleviate the symptoms of dyspepsia in FD rats, and its mechanism may be related to the regulation of gastrointestinal hormones in the antral tissue.

Prediction model of no-response before the first transarterial chemoembolization for hepatocellular carcinoma: TACF score.

Previous clinic models for patients with hepatocellular carcinoma (HCC) receiving transarterial chemoembolization (TACE) mainly focused on the overall survival, whereas a simple-to-use tool for predicting the response to the first TACE and the management of risk classification before TACE are lacking. Our aim was to develop a scoring system calculated manually for these patients. A total of 437 patients with hepatocellular carcinoma (HCC) who underwent TACE treatment were carefully selected for analysis. They were then randomly divided into two groups: a training group comprising 350 patients and a validation group comprising 77 patients. Furthermore, 45 HCC patients who had recently undergone TACE treatment been included in the study to validate the model's efficacy and applicability. The factors selected for the predictive model were comprehensively based on the results of the LASSO, univariate and multivariate logistic regression analyses. The discrimination, calibration ability and clinic utility of models were evaluated in both the training and validation groups. A prediction model incorporated 3 objective imaging characteristics and 2 indicators of liver function. The model showed good discrimination, with AUROCs of 0.735, 0.706 and 0.884 and in the training group and validation groups, and good calibration. The model classified the patients into three groups based on the calculated score, including low risk, median risk and high-risk groups, with rates of no response to TACE of 26.3%, 40.2% and 76.8%, respectively. We derived and validated a model for predicting the response of patients with HCC before receiving the first TACE that had adequate performance and utility. This model may be a useful and layered management tool for patients with HCC undergoing TACE.

ATM-AMPKα mediated LAG-3 expression suppresses T cell function in prostate cancer.

Immunotherapy for prostate cancer (PCa) faces serious challenges. Therefore, the co-inhibitory receptors that regulate T cell function of PCa must be elucidated. Here we identified that the inhibitory receptor LAG3 was significantly induced in T cells from PCa patients. Gene array analysis revealed that insufficient ataxia telangiectasia mutated (ATM) gene expression in PCa T cells was responsible for the elevated LAG3 expression. Mechanistically, insufficient ATM expression impaired its ability to activate AMPKα signaling and CD4+ T cell functions, which further enhances the binding of the transcription factors XBP1 and EGR2 to LAG3 promoter. Reconstitution of ATM and inhibition of XBP1 or EGR2 in PCa T cells suppressed LAG3 expression and restored the effector function of CD4+ T cells from PCa. Our study revealed the mechanism of LAG3 upregulation in CD4+ T lymphocytes of PCa patients and may provide insights for the development of immunotherapeutic strategies for PCa treatment.

Analysis of the relation between cerebrospinal fluid antibody titers and clinical characteristics in pediatric patients with anti-N-methyl-D-aspartate receptor encephalitis.

OBJECTIVE: This retrospective study aimed to investigate the relationship between cerebrospinal fluid (CSF) antibody titers of N-methyl-d-aspartate receptor (NMDAR), and clinical characteristics in pediatric patients with anti-NMDAR encephalitis. METHODS: The clinical and laboratory characteristics of hospitalized patients with anti-NMDAR encephalitis, stratified by antibody titers in CSF and disease severity, were retrospectively studied. The demographics, clinical characteristics, main accessory examinations, immunotherapy, and prognosis of patients were recorded, and each observed indicator was statistically analyzed. RESULTS: A total of 103 pediatric anti-NMDAR encephalitis patients were enrolled in the study, including 41 males (39.8%) and 62 females (60.2%) with a mean age of 8.0 ± 4.0 years. The proportion of patients with cognitive dysfunction and the positive pathogen was higher in the high-titer group than in the low-titer group (p = 0.023, p = 0.042). Consciousness disturbance that occurred as an initial symptom or during the course in the severe group was higher than in the non-severe group (p = 0.002, p < 0.001). More patients in the high-titer group received plasma exchange (PE) than in the low-titer group (p = 0.022). The cure rate of patients was higher with PE (65.2%) than with Corticosteroids and (or) intravenous immunoglobulin (58.1%). CONCLUSIONS: Patients with symptoms of disturbance of consciousness may be severer. The severity in pediatric anti-NMDAR encephalitis patients was not correlated with anti-NMDAR antibody titers. Patients with high CSF antibody titers had a better prognosis after early PE therapy.

Risk factors and prediction model of nomogram for preoperative calf muscle vein thrombosis in geriatric hip fracture patients.

Introduction: Calf muscular vein thrombosis (CMVT) is a common complication in geriatric hip fracture patients. Despite its high incidence, prior research on the topic is limited. The occurrence of CMVT in patients will prolong the preoperative waiting time and even lead to serious thromboembolic events, which can be detrimental to the patient's prognosis. Therefore, this study aimed to identify the risk factors for preoperative CMVT in geriatric hip fracture patients and construct a nomogram model to predict the risk of preoperative CMVT in patients. Materials and methods: Geriatric hip fracture patients who underwent surgery between January 2019 and January 2022 were included. The patients were categorized into two groups depending on whether they had preoperative CMVT, confirmed through Color Doppler ultrasound or venography examination. Univariate and multivariate logistic regression analyses were used to analyze demographic characteristics, medical history, comorbidities, and laboratory tests. A nomogram was constructed to predict preoperative CMVT in geriatric hip fracture patients based on the results of the multivariate logistic regression. Results: Three hundred and eighty-eight geriatric hip fracture patients, including one hundred and thirty-four patients with CMVT and two hundred and fifty-four patients without CMVT, were ultimately included in our study. After multivariable logistic regression analysis, the time from injury to admission, smoking history, serum albumin levels, and D-dimer levels was identified as independent risk factors and was entered into a nomogram model. The nomogram showed robust discrimination, with an area under the receiver operating characteristic curve of 0.805. The calibration curve showed strong agreement between the CMVT probabilities predicted by the nomogram and the actual probabilities. The decision curve analysis illustrates the excellent clinical utility of the model. Conclusion: We have constructed a new nomogram prediction model that can effectively predict the risk of preoperative CMVT in geriatric hip fracture patients based on their medical history and blood test results. This model can help clinicians make individualized predictions of CMVT that are tailored to each patient's unique circumstances.

The causal association between systemic inflammatory regulators and primary ovarian insufficiency: a bidirectional mendelian randomization study.

BACKGROUND: Recent studies have suggested a potential link between systemic inflammatory regulators and primary ovarian insufficiency (POI); however, a causal relationship between them remains unclear. In this study, we explored the causal link between systemic inflammatory regulators and POI risk using a bidirectional, two-sample Mendelian randomization (MR) strategy. RESULTS: This approach utilized the most extensive genome-wide association study involving 41 systemic inflammatory regulators in a sample of 8,293 Finnish individuals and POI data from the FinnGen consortium (254 cases vs. 118,228 controls). The inverse variance weighting approach served as a primary MR method, and four additional MR techniques (Maximum Likelihood, MR-Egger, Weighted Median, and constrained maximum likelihood and model averaging Bayesian information criterion ) were applied to support and validate results. Cochran's Q statistics were used to assess the heterogeneity of instrumental variables, whereas the MR-Egger and MR Pleiotropy Residual Sum and Outlier tests detected horizontal pleiotropy. The MR Steiger test evaluated the strength of a causal association. Our findings suggest that lower levels of vascular endothelial growth factor (odds ratio [OR] = 0.73, 95% confidence interval [CI]: 0.54-0.99, P = 0.046) and interleukin-10 (OR = 0.54, 95% CI: 0.33-0.85, P = 0.021) are associated with an increased risk of POI. Reverse MR analysis revealed no significant effect of POI on the expression of these 41 systemic inflammatory regulators. No notable heterogeneity or horizontal pleiotropy was observed in the instrumental variables. CONCLUSIONS: This study revealed a causal association between 41 systemic inflammatory regulators and POI, demonstrating that decreased levels of VEGF and IL-10 are linked to an elevated risk of POI. Further investigations are necessary to assess the potential of these biomarkers as early predictors, preventive strategies, and therapeutic targets for POI.

CT-Guided Percutaneous Cryoablation for Lung Metastasis of Colorectal Cancer: A Case Series.

PURPOSE: This study aimed to evaluate the efficacy of computed tomography (CT) guided percutaneous cryoablation (CA) for the management of lung metastases in patients with metastatic colorectal cancer (mCRC). METHODS: Retrospective analysis was performed on 38 mCRC patients with lung metastases, who underwent CT-guided percutaneous CA at our center from May 1, 2020 to November 1, 2021. The technical success rate, 1-year local control (LC) rate, recurrence-free survival (RFS) and treatment-related complications were analyzed. RESULTS: The CA procedure was successfully performed in all patients, with a technical success rate of 100%. The 1-year LC rate was 94.7% (36/38), while 16 patients experienced new distant lung metastases during the follow-up period. The median RFS was 20 months (95% CI: 13.0-27.0). The median RFS of patients with and without extrapulmonary metastasis was 15 and 23 months, respectively. Complications were reported in 18 (47.4%) patients following the CA procedure. Pneumothorax was discovered in 15 (39.5%) patients, and five of these patients (13.2%) required chest tube intubation. Two patients (5.3%) presented with hemoptysis during the CA procedure. One patient developed subcutaneous emphysema as detected in the post-procedure follow-up imaging. All patients tolerated the peri-procedural pain well under local anesthesia, and the mean visual analog scale (VAS) score was 2.8. CONCLUSION: Lung CA is a safe and well-tolerated treatment with a satisfactory local control rate for patients with lung metastases derived from mCRC.

Serum levels of SOCS6 are decreased in diabetic retinopathy and are related to severity of the disease.

BACKGROUND: Diabetic retinopathy (DR) is one of the most common microvascular complications of diabetes mellitus (DM). A recent in vitro study found that the suppressor of cytokine signaling 6 (SOCS6) plays a protective role in DR and DM. However, to date, no clinical studies have focused on the role of SOSC6 in DR development. OBJECTIVES: The present study aimed to investigate the expression and clinical significance of serum SOCS6 in DR. MATERIAL AND METHODS: A total of 159 DR patients were enrolled in the study. Additionally, 156 type 2 DM (T2DM) patients without DR were recruited as controls. Serum levels of SOCS6, C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), interleukin-1ß (IL-1ß), vascular endothelial growth factor (VEGF), and angiopoietin-2 (ANG-2) were measured using enzyme-linked immunosorbent assay (ELISA). Demographic and clinical data were collected. RESULTS: Age, the course of DM, systolic blood pressure (SBP), diastolic blood pressure (DBP), and the levels of low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) were significantly higher in proliferative DR (PDR) patients. Serum SOCS6 levels in PDR patients were remarkably lower than in non-PDR patients or non-DR T2DM patients. The Pearson's analysis showed that SOCS6 was negatively correlated with CRP, IL-6, TNF-α, IL-1ß, VEGF, and ANG-2. The serum levels of CRP, IL-6, TNF-α, IL-1ß, VEGF, and ANG-2 in the SOCS6 low expression group were significantly increased compared to patients with high SOCS6 levels. Receiver operating characteristic (ROC) curves showed that SOCS6 could be a potential diagnostic biomarker for DR. For logistic regression, 3 models were used. It was found that SOCS6, the course of DM, SBP and DBP in model 1, IL-1ß and TNF-α in model 2, and VEGF and ANG-2 in model 3 were risk factors for DR. CONCLUSIONS: The SOCS6 is decreased in DR patients and is related to severity and clinical outcomes, including inflammatory and angiogenic factors.

Collagen VI Is a Gi-Biased Ligand of the Adhesion GPCR GPR126/ADGRG6.

GPR126/ADGRG6, a member of the adhesion G-protein-coupled receptor family, balances cell differentiation and proliferation through fine-tuning of intracellular cAMP levels, which is achieved through coupling to Gs and Gi proteins. While GPR126-mediated cAMP increase has been proven to be essential for differentiation of Schwann cells, adipocytes and osteoblasts, Gi-signaling of the receptor was found to propagate breast cancer cell proliferation. Extracellular ligands or mechanical forces can modulate GPR126 activity but require an intact encrypted agonist sequence, coined the Stachel. Even though coupling to Gi can be seen for constitutively active truncated receptor versions of GPR126 as well as with a peptide agonist derived from the Stachel sequence, all known N-terminal modulators have so far only been shown to modulate Gs coupling. Here, we identified collagen VI as the first extracellular matrix ligand of GPR126 that induces Gi signaling at the receptor, which shows that N-terminal binding partners can mediate selective G protein signaling cascades that are masked by fully active truncated receptor variants.

Discovery of novel phenothiazine derivatives as new agrochemical alternatives for treating plant viral diseases.

BACKGROUND: Plant viral diseases, namely 'plant cancer', are extremely difficult to control. Even worse, few antiviral agents can effectively control and totally block viral infection. There is an urgent need to explore and discover novel agrochemicals with high activity and a unique mode of action to manage these refractory diseases. RESULTS: Forty-one new phenothiazine derivatives were prepared and their inhibitory activity against tobacco mosaic virus (TMV) was assessed. Compound A8 had the highest protective activity against TMV, with a half-maximal effective concentration (EC50 ) of 115.67 µg/mL, which was significantly better than that of the positive controls ningnanmycin (271.28 µg/mL) and ribavirin (557.47 µg/mL). Biochemical assays demonstrated that compound A8 could inhibit TMV replication by disrupting TMV self-assembly, but also enabled the tobacco plant to enhance its defense potency by increasing the activities of various defense enzymes. CONCLUSION: In this study, novel phenothiazine derivatives were elaborately fabricated and showed remarkable anti-TMV behavior that possessed the dual-action mechanisms of inhibiting TMV assembly and invoking the defense responses of tobacco plants. Moreover, new agrochemical alternatives based on phenothiazine were assessed for their antiviral activities and showed extended agricultural application. © 2023 Society of Chemical Industry.

Integrated osteoimmunomodulatory strategies based on designing scaffold surface properties in bone regeneration.

Those who have used traditional biomaterials as bone substitutes have always regarded the immune response as an obstacle leading to implant failure. However, cumulative evidence revealed that blindly minimizing host immune reactions cannot induce successful bone regeneration. With the emergence of the new concept of osteoimmunology, the intimate mutual effects between the skeletal system and the immune system have been gradually recognized, promoting the innovation of biomaterials with osteoimmunomodulatory properties. By tuning the surface properties, biomaterials can precisely manipulate the osteoimmune environment favoring bone regeneration. In this review, we first reviewed the mutual effects between the skeletal system and the immune system to show the importance of immunomodulation on bone regeneration. Subsequently, we summarize the recent developments in surface modification strategies in terms of the surface physicochemical properties and surface coatings and explain how these modification strategies work.

Comprehensive workplace intervention for cancer prevention in China (WECAN): protocol for a stepped-wedge, cluster-randomised controlled trial.

INTRODUCTION: Cancer is the second leading cause of death across the globe with the majority of deaths occurring in low-income and middle-income countries. Evidence has shown that the cancer burden can be substantially reduced by avoiding behavioural risk factors through comprehensive intervention strategies, including workplace health promotion, which has shown to be cost-effective in developed countries while rarely conducted in developing countries. This study aims to explore a feasible and sustainable approach to the prevention and control of cancer in China by developing an evidence-based comprehensive workplace health model equipped with a smartphone application for implementation. METHODS AND ANALYSIS: This study is designed as a stepped-wedge, cluster-randomised controlled trial. We will recruit 15 workplaces from three cities in China. A total of 750 employees will be randomly selected for evaluation that includes five rounds of survey conducted every 6 months. After the second evaluation, workplaces will be randomly allocated to start the intervention sequentially every 6 months in three steps with five workplaces per step. A mobile application 'Healthy Workplace' will be developed to support the intervention. On-line and off-line health-related activities will be carried out among employees. Employers will provide supportive policies, environment and benefits to facilitate the adoption of healthy behaviours. The primary outcome is the change of Healthy Lifestyle Index Score, which consists of five components including smoking, alcohol drinking, physical activity, diet and body mass index. ETHICS AND DISSEMINATION: The study has been approved by Queen Mary University of London Ethics of Research Committee (QMERC22.257) and Chinese Centre for Disease Control and Prevention Institutional Review Board (202210). Written informed consent is required from all participants. Results will be disseminated through presentations, publications and social media. TRIAL REGISTRATION NUMBER: ChiCTR2200058680.

An mHealth-based school health education system designed to scale up salt reduction in China (EduSaltS): A development and preliminary implementation study.

Background: High-salt diet is an important risk factor for several non-communicable diseases. School-based health education has been found effective in reducing salt intake among children and their families in China. However, no such interventions have been scaled up in the real world. For this purpose, a study was launched to support the development and scale-up of an mHealth-based system (EduSaltS) that integrated routine health education and salt reduction and was delivered through primary schools. This study aims to elaborate the framework, development process, features, and preliminary scaling-up of the EduSaltS system. Methods: The EduSaltS system evolved from previously successfully tested interventions to reduce family salt intake by empowering schoolchildren through school health education. EduSaltS was designed by following the WHO's conceptual framework for developing a scaling-up strategy which accounted for the nature of the innovation, the capacity of the implementing organizations, the characteristics of the environment, the resources available, and type of scaling up. The system was then developed step by step from determination of online platform architecture, definition of component interventions and activities, development of specific educational materials and tools, to the development of the online/offline hybridized system. The system was tested and refined by a pilot in two schools and a preliminary scale-up in two cities in China. Results: EduSaltS was developed as an innovative health education system, including an online WeChat-based education platform, a set of offline activities, and an actual administrative website showing the progress and setting the system. The WeChat platform could be installed on users' smartphones to automatically deliver 20 sessions of five-minute well-structured cartoon video classes, followed by other online interactive activities. It also helps support project implementation and real-time performance evaluation. As a first-stage roll-out, a one-year course has been successfully implemented among 54,538 children and their families from 209 schools in two cities, and the average course completion rate was 89.1%. Conclusion: As an innovative mHealth-based health education system, EduSaltS was developed based on successfully tested interventions and an appropriate framework for scaling up. The early-stage roll-out has shown its preliminary scalability, and further evaluation is ongoing.