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Rosmarinic acid (RosA), a hydrophilic phenolic compound found in various plants, has several biological effects such as anti-inflammatory and anti-apoptosis activities. However, its potential impact on chronic obstructive pulmonary disease (COPD) and its underlying mechanism has not been investigated. In this study, we explored the potential therapeutic effects and mechanism of RosA on COPD airway inflammation and alveolar epithelial apoptosis in vivo and in vitro . Our data suggested that RosA may be a therapeutic candidate for COPD with low toxicity. The corresponding mechanism lies in its anti-inflammatory effect on macrophage and bronchial epithelial cells, as well as protective effect on lung epithelial apoptosis via the jointly cross-target spleen tyrosine kinase (Syk).

Background: Systemic Lupus Erythematosus (SLE) is acknowledged for its significant influence on systemic health. This study sought to explore potential crosstalk genes, pathways, and immune cells in the relationship between SLE and moyamoya disease (MMD)., Methods: We obtained data on SLE and MMD from the Gene Expression Omnibus (GEO) database. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were conducted to identify common genes. Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on these shared genes. Hub genes were further selected through the least absolute shrinkage and selection operator (LASSO) regression, and a receiver operating characteristic (ROC) curve was generated based on the results of this selection. Finally, single-sample Gene Set Enrichment Analysis (ssGSEA) was utilized to assess the infiltration levels of 28 immune cells in the expression profile and their association with the identified hub genes., Results: By intersecting the important module genes from WGCNA with the DEGs, the study highlighted CAMP, CFD, MYO1F, CTSS, DEFA3, NLRP12, MAN2B1, NMI, QPCT, KCNJ2, JAML, MPZL3, NDC80, FRAT2, THEMIS2, CCL4, FCER1A, EVI2B, CD74, HLA-DRB5, TOR4A, GAPT, CXCR1, LAG3, CD68, NCKAP1L, TMEM33 , and S100P as key crosstalk genes linking SLE and MMD. GO analysis indicated that these shared genes were predominantly enriched in immune system process and immune response. LASSO analysis identified MPZL3 as the optimal shared diagnostic biomarkers for both SLE and MMD. Additionally, the analysis of immune cell infiltration revealed the significant involvement of activation of T and monocytes cells in the pathogenesis of SLE and MMD., Conclusion: This study is pioneering in its use of bioinformatics tools to explore the close genetic relationship between MMD and SLE. The genes CAMP, CFD, MYO1F, CTSS, DEFA3, NLRP12, MAN2B1, NMI, QPCT, KCNJ2, JAML, MPZL3, NDC80, FRAT2, THEMIS2, CCL4, FCER1A, EVI2B, CD74, HLA-DRB5, TOR4A, GAPT, CXCR1, LAG3, CD68, NCKAP1L, TMEM33 , and S100P have been identified as key crosstalk genes that connect MMD and SLE. Activation of T and monocytes cells-mediated immune responses are proposed to play a significant role in the association between MMD and SLE., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Guo, Fan, Xie, Wang, Li, Liu, Wang, Yu, Zou, Gao, Zhang, Hao, Feng, Yang, Wang, Fu, Bao and Duan.)

Lycium Barbarum Polysaccharides (LBP) can benefit lipid parameters such as total cholesterol, triglyceride, and high-density lipoprotein levels and upregulate the level of Firmicutes , increase the diversity of gut microbiota and reduce metabolic disorders, finally relieving weight gain of obese rats. But it cannot reverse the outcome of obesity. Over 30 differential metabolites and four pathways are altered by LBP.

The functions of natural killer (NK) and T cells in innate and adaptive immunity, as well as their functions in tumor eradication, are complementary and intertwined. Here we show that utilization of multi-specific antibodies or nano-antibodies capable of simultaneously targeting both NK and T cells could be a valuable approach in cancer immunotherapy. Here, we introduce a tri-specific Nano-Antibody (Tri-NAb), generated by immobilizing three types of monoclonal antibodies (mAbs), using an optimized albumin/polyester composite nanoparticle conjugated with anti-Fc antibody. This Tri-NAb, targeting PDL1, 4-1BB, and NKG2A (or TIGIT) simultaneously, effectively binds to NK and CD8 + T cells, triggering their activation and proliferation, while facilitating their interaction with tumor cells, thereby inducing efficient tumor killing. Importantly, the antitumor efficacy of Tri-NAb is validated in multiple models, including patient-derived tumor organoids and humanized mice, highlighting the translational potential of NK and T cell co-targeting., (© 2024. The Author(s).)

Objective: To explore the related factors of thrombocytopenia (TCP) occurrence in patients with cirrhosis. Methods: A cross-sectional study was conducted. Inpatients with an initial diagnosis of cirrhosis at Peking University First Hospital from January 1, 2010 to December 31, 2020 were included. Clinical data such as demographic characteristics, etiology of cirrhosis, complications of cirrhosis, laboratory indicators, Child-Pugh grade, invasive procedures, and mortality during hospitalization were collected. A logistic regression model was used to explore the related factors of TCP occurrence in patients with cirrhosis. Categorical variables were compared by the χ (2) test. The inter-group comparison was performed using continuous variables, a t -test, one-way analysis of variance (ANOVA), or a nonparametric test. Results: There were a total of 2 592 cases of cirrhosis. 75 cases with incomplete clinical data were excluded. 2 517 cases were included for analysis. The median age was 58 (50, 67) years. Males accounted for 64%. 1 435 cases (57.0%) developed TCP, and 434 cases (17.2%) had grade 3-4 TCP. Gender, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and concomitant esophagogastric varices (EGV) were the major factors associated with TCP. Females were more prone to combine with TCP ( OR =1.32, 95% CI : 1.12-1.56, P =0.001). Patients combined with EGV ( OR =3.09, 95% CI : 2.63-3.65, P <0.001) were more prone to develop TCP, which was associated with the increased incidence of hypersplenism ( P <0.001). Patients with PBC ( OR =0.64, 95% CI : 0.50-0.82, P <0.001) and PSC ( OR =0.23, 95% CI : 0.06-0.65, P =0.010) were less prone to develop TCP, which was due to the shorter prothrombin time and better coagulation function of PBC patients ( P <0.001), and the lower proportion of hypersplenism in combined PSC patients ( P =0.004). Patients with TCP and grade 3-4 TCP had a higher rate of hemostatic procedures ( P <0.05), but a lower rate of liver biopsy ( P <0.05). Patients with grade 3-4 TCP had a higher nosocomial mortality rate compared to those without ( P =0.004). Conclusion: TCP is common in patients with cirrhosis. However, TCP occurrence is higher in female patients with EGV and lower in patients combined with PBC and PSC. TCP affects invasive procedures and is associated with adverse outcomes.

Introduction: We designed and implemented a patient-centered, data-driven, holistic care model with evaluation of its impacts on clinical outcomes in patients with young-onset type 2 diabetes (T2D) for which there is a lack of evidence-based practice guidelines., Research Design and Methods: In this 3-year Precision Medicine to Redefine Insulin Secretion and Monogenic Diabetes-Randomized Controlled Trial, we evaluate the effects of a multicomponent care model integrating use of information and communication technology (Joint Asia Diabetes Evaluation (JADE) platform), biogenetic markers and patient-reported outcome measures in patients with T2D diagnosed at ≤40 years of age and aged ≤50 years. The JADE-PRISM group received 1 year of specialist-led team-based management using treatment algorithms guided by biogenetic markers (genome-wide single-nucleotide polymorphism arrays, exome-sequencing of 34 monogenic diabetes genes, C-peptide, autoantibodies) to achieve multiple treatment goals (glycated hemoglobin (HbA1c) <6.2%, blood pressure <120/75 mm Hg, low-density lipoprotein-cholesterol <1.2 mmol/L, waist circumference <80 cm (women) or <85 cm (men)) in a diabetes center setting versus usual care (JADE-only). The primary outcome is incidence of all diabetes-related complications., Results: In 2020-2021, 884 patients (56.6% men, median (IQR) diabetes duration: 7 (3-12) years, current/ex-smokers: 32.5%, body mass index: 28.40±5.77 kg/m 2 , HbA1c: 7.52%±1.66%, insulin-treated: 27.7%) were assigned to JADE-only (n=443) or JADE-PRISM group (n=441). The profiles of the whole group included positive family history (74.7%), general obesity (51.4%), central obesity (79.2%), hypertension (66.7%), dyslipidemia (76.4%), albuminuria (35.4%), estimated glomerular filtration rate <60 mL/min/1.73 m 2 (4.0%), retinopathy (13.8%), atherosclerotic cardiovascular disease (5.2%), cancer (3.1%), emotional distress (26%-38%) and suboptimal adherence (54%) with 5-item EuroQol for Quality of Life index of 0.88 (0.87-0.96). Overall, 13.7% attained ≥3 metabolic targets defined in secondary outcomes. In the JADE-PRISM group, 4.5% had pathogenic/likely pathogenic variants of monogenic diabetes genes; 5% had autoantibodies and 8.4% had fasting C-peptide <0.2 nmol/L. Other significant events included low/large birth weight (33.4%), childhood obesity (50.7%), mental illness (10.3%) and previous suicide attempts (3.6%). Among the women, 17.3% had polycystic ovary syndrome, 44.8% required insulin treatment during pregnancy and 17.3% experienced adverse pregnancy outcomes., Conclusions: Young-onset diabetes is characterized by complex etiologies with comorbidities including mental illness and lifecourse events., Trial Registration Number: NCT04049149., Competing Interests: Competing interests: JCNC and RCWM hold patents for using genetic markers to predict diabetes and its complications for personalized care. JCNC, RCWM and CL are cofounders of a start-up biotech company partially supported by the Technology Start-up Support Scheme for Universities (TSSSU) of the Hong Kong Government Innovation and Technology Commission., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The value of normative models in research and clinical practice relies on their robustness and a systematic comparison of different modelling algorithms and parameters; however, this has not been done to date. We aimed to identify the optimal approach for normative modelling of brain morphometric data through systematic empirical benchmarking, by quantifying the accuracy of different algorithms and identifying parameters that optimised model performance. We developed this framework with regional morphometric data from 37 407 healthy individuals (53% female and 47% male; aged 3-90 years) from 87 datasets from Europe, Australia, the USA, South Africa, and east Asia following a comparative evaluation of eight algorithms and multiple covariate combinations pertaining to image acquisition and quality, parcellation software versions, global neuroimaging measures, and longitudinal stability. The multivariate fractional polynomial regression (MFPR) emerged as the preferred algorithm, optimised with non-linear polynomials for age and linear effects of global measures as covariates. The MFPR models showed excellent accuracy across the lifespan and within distinct age-bins and longitudinal stability over a 2-year period. The performance of all MFPR models plateaued at sample sizes exceeding 3000 study participants. This model can inform about the biological and behavioural implications of deviations from typical age-related neuroanatomical changes and support future study designs. The model and scripts described here are freely available through CentileBrain., Competing Interests: Declaration of interests SSH is supported by the US National Institutes of Health (NIH)'s National Institute of Mental Health (T32MH122394) and received a travel award from the Society of Biological Psychiatry to attend the annual meeting in 2023. HB declares an institutional grant from the Australian National Health and Medical Research Council; has received compensation for being on an advisory board or a consultant to Biogen, Eisai, Eli Lilly, Roche, and Skin2Neuron; payment for being on the Cranbrook Care Medical Advisory Board; and honoraria for being on the Montefiore Homes Clinical Advisory Board. RMB and HEHP declare partial funding through the Geestkracht programme of the Dutch Health Research Council (Zon-Mw, grant No 10–000–1001) and matching funds from participating pharmaceutical companies (ie, Lundbeck, AstraZeneca, Eli Lilly, and Janssen Cilag), universities (Academic Psychiatric Centre of the Academic Medical Center, University Medical Center Groningen, Maastricht University Medical Centre, and University Medical Center Utrecht), and mental health care organisations (GGZ Ingeest, Arkin, Dijk en Duin, GGZ Rivierduinen, Erasmus Medical Centre, GGZ Noord Holland Noord, Lentis, GGZ Friesland, GGZ Drenthe, Dimence, Mediant, GGNet Warnsveld, Yulius Dordrecht, Parnassia psycho-medical center The Hague, GGzE, GGZ Breburg, GGZ Oost-Brabant, Vincent van Gogh voor Geestelijke Gezondheid, Mondriaan, Virenze riagg, Zuyderland GGZ, MET GGZ, Universitair Centrum Sint-Jozef Kortenberg, CAPRI University of Antwerp, PC Ziekeren Sint-Truiden, PZ Sancta Maria Sint-Truiden, GGZ Overpelt, OPZ Rekem, Altrecht, and GGZ Centraal and Delta); and received funding from Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO 51·02·061 to HEHP, NWO 51·02·062 to DIB, NWO–NIHC Programs of excellence 433–09–220 to HEHP, NWO-MagW 480–04–004 to DIB, and NWO/SPI 56–464–14192 to DIB), FP7 Ideas: European Research Council (ERC-230374 to DIB), and Universiteit Utrecht (High Potential Grant to HEHP). RB declares funding by the NIH's National Institute on Aging (R01AG067420); received compensation for being on the scientific advisory board from Alkermes and Cognito Therapeutics with no conflict to the present work; received honoraria from academic institutions for talks (all under $1000) and $1000 for speaking at a Massachusetts General Hospital and Harvard Medical School course; received travel fees for services to attend the annual meeting from the Simons Foundation; serves as a Director on the Simons Foundation Collaborative Initiative on Aging; is a paid scientific advisory board member for philanthropic grants for The Foundation for OCD Research and the Klarman Family Foundation. BF has received educational speaking fees from Medice. DG reports funding from the NIH. UD is funded through the German Research Foundation (DFG; DA 1151/9–1, DA 1151/10–1, DA 1151/11–1). GS declares funding from the European Commission, DFG, and National Science Foundation of China. CKT has received grants from the Research Council of Norway and the Norwegian Regional Health Authority, unrelated to the current work. HW reports funding from the German Research Foundation (WA 1539/11–1). NJ reports funding from the NIH and compensation from the International Neuropsychological Society. PMT declares a grant from the NIH and travel funded by NIH grants. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

We investigated the long-term outcomes of encephaloduroarteriosynangiosis (EDAS) for stroke prevention in toddlers with moyamoya disease (MMD) using nomogram. Between January 2005 and December 2018, 74 toddlers with MMD underwent surgery in the Fifth Medical Centre, Chinese PLA General Hospital, 69 were < 4 years of age and included in the analysis. The modified Rankin scale (mRS) during follow-up evaluated clinical outcomes. To measure the effectiveness of EDAS, the annual risk of symptomatic infarction within the operated brain hemispheres was calculated. The event-free survival rate was determined using Kaplan-Meier curves. A nomogram generated using multivariate logistic regression analysis identified potential predictors associated with unfavorable outcomes. Additionally, discrimination, calibration, and clinical utility were assessed. A favorable clinical outcome was observed in 81.2% of the patients. The operated hemispheres showed an annual risk of 0.87% of symptomatic infarction and 0.23% of hemorrhage. Moreover, the 10-year event-free survival rates were 92.8% and 97.0% for symptomatic infarction and hemorrhage. Multivariate logistic analysis indicated that onset with infarction, initial mRS ≥ 3, and perioperative adverse events had significant and independent associations with unfavorable outcomes. However, an age at diagnosis of ≥ 2 years showed an association with favorable outcomes. Using these four factors, our model attained a concordance index of 0.912 (95% confidence interval, 0.842-0.982), well-fitted calibration curve, and cutoff value of 0.212 for predicting unfavorable outcomes. EDAS may prevent recurrent stroke and improve overall long-term clinical outcomes in toddlers with MMD. The developed nomogram accurately predicted unfavorable outcomes and assisted surgeons in patient evaluation., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Immune cells are indispensable defenders of the human body, clearing exogenous pathogens and toxicities or endogenous malignant and aging cells. Immune cell dysfunction can cause an inability to recognize, react, and remove these hazards, resulting in cancers, inflammatory diseases, autoimmune diseases, and infections. Immune cells regulation has shown great promise in treating disease, and immune agonists are usually used to treat cancers and infections caused by immune suppression. In contrast, immunosuppressants are used to treat inflammatory and autoimmune diseases. However, the key to maintaining health is to restore balance to the immune system, as excessive activation or inhibition of immune cells is a common complication of immunotherapy. Nanoparticles are efficient drug delivery systems widely used to deliver small molecule inhibitors, nucleic acid, and proteins. Using nanoparticles for the targeted delivery of drugs to immune cells provides opportunities to regulate immune cell function. In this review, we summarize the current progress of nanoparticle-based strategies for regulating immune function and discuss the prospects of future nanoparticle design to improve immunotherapy., Competing Interests: Conflicts of interests: Authors state no conflict of interest., (© 2023 the author(s), published by De Gruyter, Berlin/Boston.)

The Yangtze River Economic Belt is one of the major strategic development regions in China. It is of great significance to clarify the characteristics and sources of heavy metal pollution in farmland soil of the Yangtze River Economic Belt for the prevention and control of heavy metal pollution and to ensure safe agricultural production. After collecting extensive literature data, we analyzed the pollution characteristics, environmental risk, and potential sources of heavy metals (Cd, Cr, Hg, As, Pb, Cu, Zn, and Ni) in farmland soil of the Yangtze River Economic Belt through the integrated use of spatial and geo-accumulation index analyses. The results showed that:① the proportion of soil samples exceeding the risk screening values for soil contamination of agricultural land of Cd, Cu, Pb, Hg, Zn, and As were 39.8%, 18.5%, 8.3%, 6.9%, 6.9%, and 6.4%, respectively. Compared with the risk standard, soil Cd had the highest rate of exceeding the standard. ② The contents of Cr, Cu, Zn, and Ni in the upper reaches were higher than those in the middle and lower reaches, and the contents of Cd, As, and Pb in the middle reaches were higher than those in the upper and lower reaches. ③ The results of the geo-accumulation index analysis showed that the contamination degree of the eight heavy metals decreased in the order of Cd(0.42)>Hg(-0.28)>Pb(-0.32)>Zn(-0.39)>Cu(-0.42)>Cr(-0.7)>As(-0.81)>Ni(-0.73), where the accumulation risk of soil Cd and Hg was relatively higher. ④ Higher environmental background and mining activities were the main factors affecting the accumulation of heavy metals in soils in the upper and middle reaches. By contrast, rapid urbanization, industrial production, and intensive agricultural activities were the main factors affecting the heavy metal accumulation in soils in the middle and lower reaches. In view of the current status and control needs of heavy metal pollution in the Yangtze River Economic Belt, it is recommended to strengthen source prevention and control and to also carry out hierarchical control and regional classification management of heavy metal pollution in farmland soils according to the degree of heavy metal pollution, geological background, and quality of agricultural products. The ultimate objective of this research was to archive the farmland soil environmental quality safety and agricultural green sustainable production in the Yangtze River Economic Belt.

Objective: To explore the protective effect and underlying mechanism of Lycium barbarum polysaccharides (LBP) in a non-alcoholic fatty liver disease (NAFLD) cell model., Methods: Normal human hepatocyte LO2 cells were treated with 1 mmol/L free fatty acids (FFA) mixture for 24 h to induce NAFLD cell model. Cells were divided into 5 groups, including control, model, low-, medium- and high dose LBP (30,100 and 300 µg/mL) groups. The monosaccharide components of LBP were analyzed with high performance liquid chromatography. Effects of LBP on cell viability and intracellular lipid accumulation were assessed by cell counting Kit-8 assay and oil red O staining, respectively. Triglyceride (TG), alanine aminotransferase (ALT), aspartate aminotransferase (AST), adenosine triphosphate (ATP) and oxidative stress indicators were evaluated. Energy balance and mitochondrial biogenesis related mRNA and proteins were determined by quantitative real-time polymerase chain reaction and Western blot, respectively., Results: Heteropolysaccharides with mannose and glucose are the main components of LBP. LBP treatment significantly decreased intracellular lipid accumulation as well as TG, ALT, AST and malondialdehyde levels (P<0.05 or P<0.01), increased the levels of superoxide dismutase, phospholipid hydroperoxide glutathione peroxidase, catalase, and ATP in NAFLD cell model (P<0.05). Meanwhile, the expression of uncoupling protein 2 was down-regulated and peroxisome proliferator-activated receptor gamma coactivator-1α/nuclear respiratory factor 1/mitochondrial transcription factor A pathway was up-regulated (P<0.05)., Conclusion: LBP promotes mitochondrial biogenesis and improves energy balance in NAFLD cell model., (© 2021. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

By designing a tetraphenylethylene (TPE)-based AIEgen-ligand with reduced symmetry, we obtained two alkaline-earth metal-based MOFs (LIFM-102 and LIFM-103) with dense packing structures and low porosity as proved by single-crystal X-ray diffraction and CO 2 sorption data. Excitingly, the desolvated MOFs with rigid environment and reduced lattice free solvent exhibit high quantum yields (QY, 64.9 % and 79.4 %) and excellent two-photon excited photoluminescence (TPA cross-sections, 2946.6 GM and 2899.0 GM), while maintaining the external-stimuli-responsive properties suitable for anticounterfeit fields. The effect of ligand conformation was validated by comparing the structure and fluorescence properties of the samples before and after desolvation and further verified by theoretical calculations. This work expands the study on TPE-cored materials to symmetry-reduced ligand and might bring forward novel structures and excellent photoluminescent properties in the future., (© 2022 Wiley-VCH GmbH.)

Adsorptive separation based on porous solid adsorbents has emerged as an excellent effective alternative to energy-intensive conventional separation methods in a low energy cost and high working capacity manner. However, there are few stable mesoporous metal-organic frameworks (MOFs) for efficient purification of methane from other light hydrocarbons in natural gas. Herein, we report a series of stable mesoporous MOFs, MIL-101-Cr/Fe/Fe-NH 2 , for efficient separation of CH 4 and C 3 H 8 from a ternary mixture CH 4 /C 2 H 6 /C 3 H 8 . Experimental results show that all three MOFs possess excellent thermal, acid/basic, and hydrothermal stability. Single-component adsorption suggested that they have high C 3 H 8 adsorption capacity and commendable selectivity for C 3 H 8 and C 2 H 6 over CH 4 . Transient breakthrough experiments further certified the ability of direct separation of CH 4 from simulated natural gas and indirect recovery of C 3 H 8 from the packing column. Theoretical calculations illustrated that the van der Waals force proportional to the molecular weight is the key factor and that the structural integrity and defect can impact separation performances.

This study aimed to evaluate the efficacy and safety of entecavir(ETV) versus ETV maleate in Chinese patients with chronic hepatitis B(CHB). This was a randomized, double-blind, double-dummy, controlled, multicentre study. Patients were randomly assigned to receive 48 weeks of treatment with 0.5 mg/day ETV (group A) or 0.5 mg/day ETV maleate (group B), then, all patients received treatment with 0.5 mg/day ETV maleate from week 49 onwards. Patients were regularly followed up. Serum hepatitis B virus (HBV) markers were detected. Adverse events (AE) were recorded. The primary endpoint was the decline in HBV DNA in each group at the end of treatment. Secondary endpoints included the rate of HBV DNA below the lower limit of detection (LLOD) (20 I U/ml) at the end of treatment, the rate of hepatitis B e antigen (HBeAg) loss, the rate of HBeAg seroconversion and serum alanine aminotransferase (ALT) normalization. One hundred and thirty-seven (71 in group A) patients with HBeAg-positive CHB and 46 (21 in group A) patients with HBeAg-negative CHB completed the 240-week treatment and follow-up. Baseline characteristics were well balanced between the two groups. For the HBeAg-positive CHB patients, the mean HBV DNA level had similarly decreased from baseline in both groups (A: by 6.67 log 10 IU/ml vs. B: by 6.74 log 10 IU/ml; p > .05) at Week 240. Patients who achieved undetectable levels of serum HBV DNA (<20 IU/ml) at Week 240 were similar between groups (A:91.55% vs. B:87.88%; p > .05). Both groups achieved similar HBeAg seroconversion rates at week 240 (A:26.98% vs. B:20.97%; p > .05). Both groups achieved similar normalization of ALT (A:87.32% vs. B:83.61%; p > .05) at Week 240 (p > .05). For the HBeAg-negative CHB patients, the mean HBV DNA level had similarly decreased from baseline in both groups (A: by 6.05 log 10 IU/ml vs. B: by 6.10 log 10 IU/ml; p > .05) at Week 240. Patients who achieved undetectable levels of serum HBV DNA at Week 240 were similar between groups (A:100% vs. B:100%). Both groups achieved similar normalization rates (A:90.91% vs. B: 95.45%; p > .05) of ALT at Week 240 (p > .05). In conclusion, long-term ETV maleate treatment was safe and efficient in Chinese CHB predominantly of genotype B or C., (© 2022 The Authors. Journal of Viral Hepatitis published by John Wiley & Sons Ltd.)

Manipulating firing-rate neuronal homeostasis, which enables neurons to regulate their intrinsic excitability, offers an attractive opportunity to prevent seizures. However, to date, no drug-based interventions have been reported that manipulate this type of neuronal homeostatic mechanism. Here, we used a combination of Drosophila and mouse, and, in the latter, both a pentylenetetrazole (PTZ)-induced seizure model and an electrically induced seizure model for refractory seizures to evaluate the anticonvulsant efficacy of a novel class of anticonvulsant compounds, based on 4-tert-butyl-benzaldehyde (4-TBB). The mode of action included increased expression of the firing rate homeostatic regulator Pumilio (PUM). Knockdown of pum expression, in Drosophila, blocked anticonvulsive effects of 4-TBB, while analysis of validated PUM targets in mouse brain revealed significant reductions following exposure to this compound. A structure-activity study identified the active parts of the molecule and, further, showed that the pyrazole analogue demonstrates highest efficacy, being active against both PTZ-induced and electrically induced seizures. This study provides a proof of principle that anticonvulsant effects can be achieved through regulation of firing rate neuronal homeostasis and identifies a possible chemical compound for future development., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)

Atrial fibrillation (AF) is the most common sustained heart rhythm disorder associated with high mortality and morbidity. Limited studies have been conducted to assess the relationship between short-term exposure to ambient air pollution and AF attacks. This study aimed to explore the association between short-term ambient nitrogen dioxide (NO 2 ) exposure and outpatient visits for AF in Xi'an, China. Data on daily AF outpatient visits and air pollutants from 2013 to 2019 (2555 days) were obtained. A time-series approach using over-dispersed Poisson generalized additive model (GAM) was employed, and stratified analyses were performed to investigate the potential modifying effects by season, age, and gender. A total of 8307 outpatient visits for AF were recorded. Increased levels of NO 2 were associated with increased AF outpatient visits, and the most significant effect estimates were observed at lag 03: A 10 μg/m 3 increase of NO 2 at lag 03 was related to an elevation of 5.59% (95% CI: 2.67%, 8.51%) in daily outpatient visits for AF. Stratified analyses showed that there were no gender and age difference in the effect of NO 2 , while more obvious association was observed in cool seasons (October to March) than in warm seasons (April to September). In summary, short-term ambient NO 2 exposure can be positively associated with daily outpatient visits for AF, especially in cool seasons. This work provided novel data that the association between air pollutants and AF can vary by seasons, further supporting that the prevention of cardiovascular health effects should be strengthened in winter., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The Drosophila connectome project aims to map the synaptic connectivity of entire larval and adult fly neural networks, which is essential for understanding nervous system development and function. So far, the project has produced an impressive amount of electron microscopy data that has facilitated reconstructions of specific synapses, including many in the larval locomotor circuit. While this breakthrough represents a technical tour de force, the data remain underutilized, partly because of a lack of functional validation of reconstructions. Attempts to validate connectivity posited by the connectome project, have mostly relied on behavioral assays and/or GFP reconstitution across synaptic partners (GRASP) or GCaMP imaging. While these techniques are useful, they have limited spatial or temporal resolution. Electrophysiological assays of synaptic connectivity overcome these limitations. Here, we combine patch-clamp recordings with optogenetic stimulation in male and female larvae, to test synaptic connectivity proposed by connectome reconstructions. Specifically, we use multiple driver lines to confirm that several connections between premotor interneurons and the anterior corner cell motoneuron are, as the connectome project suggests, monosynaptic. In contrast, our results also show that conclusions based on GRASP imaging may provide false-positive results regarding connectivity between cells. We also present a novel imaging tool, based on the same technology as our electrophysiology, as a favorable alternative to GRASP imaging. Finally, of eight Gal4 lines tested, five are reliably expressed in the premotor interneurons they are targeted to. Thus, our work highlights the need to confirm functional synaptic connectivity, driver line specificity, and use of appropriate genetic tools to support connectome projects. SIGNIFICANCE STATEMENT The Drosophila connectome project aims to provide a complete description of connectivity between neurons in an organism that presents experimental advantages over other models. It has reconstructed hundreds of thousands of synaptic connections of the fly larva by manual identification of anatomic landmarks present in serial section transmission electron microscopy (ssTEM) volumes of the larval CNS. We use a highly reliable electrophysiological approach to verify these connections, providing useful insight into the accuracy of work based on ssTEM. We also present a novel imaging tool for validating excitatory monosynaptic connections between cells and show that several genetic driver lines designed to target neurons of the larval connectome exhibit nonspecific and/or unreliable expression., (Copyright © 2022 the authors.)

Nonalcoholic steatohepatitis (NASH) is a subtype of nonalcoholic fatty liver disease (NAFLD). Either Lycium barbarum polysaccharide (LBP) or aerobic exercise (AE) has been reported to be beneficial to hepatic lipid metabolism. However, whether the combination of LBP with AE improves lipid accumulation of NASH remains unknown. Our study investigated the influence of 10 weeks of treatment of LBP, AE, and the combination (LBP plus AE) on high-fat-induced NASH in Sprague-Dawley rats. The results showed that LBP or AE reduced the severity of the NASH. LBP plus AE treatment more effectively ameliorated liver damage and lowered levels of serum lipid and inflammation. In addition, the combination can also regulate genes involved in hepatic fatty acid synthesis and oxidation. LBP plus AE activated AMPK, thereby increasing the expression of PPARα which controls hepatic fatty acid oxidation and its coactivator PGC-1α. Our study demonstrated the improvement of LBP plus AE on NASH via enhancing fatty acid oxidation (FAO) which was dependent on AMPK/PPARα/PGC-1α pathway.

Organic LPL (long-persistent luminescence) materials have sparked extensive research interest due to the ultralong-lived triplet states. Although numerous organic LPL materials have been reported, most of the triplet emission was static and monotonous. Therefore, LPL materials with dynamic triplet emission are urgently required. A triamino-s-triazine derivative 1 with dynamic LPL was fabricated. The single-crystal structure shows that the abundant intermolecular interactions and small free volume restrict the molecular motion and avoid the quenchers. Spectral and theoretical calculations upheld the existence of multiple excited states in 1, and the migration of electrons between multiple excited states is very sensitive to external stimuli. By modulating the stimulus, the residence of electrons in different triplet states can be manipulated to achieve RGB LPL. Importantly, blue LPL was achieved by manipulating the anti-Kasha emission. And the red LPL can still be observed at high temperature., (© 2022 Wiley-VCH GmbH.)

Background: This study aimed to identify the subgroups of individuals sharing similar blood pressure (BP) trajectories from childhood to youth and explore the associations of these trajectories with arterial stiffness in adulthood., Methods: A group-based trajectory model was used to identify BP trajectories among 2,082 individuals in the Hanzhong adolescent hypertension cohort by using BP values repeatedly measured at four visits from childhood (6-15 years) to youth (14-23 years). The brachial-ankle pulse wave velocity (baPWV) was examined 30 years after the baseline survey. Mixed linear regression models were used to examine the associations of these trajectories with adult baPWV., Results: Among the 2,082 individuals, three trajectory groups of systolic BP were identified as follows: the low-level group ( n = 889), medium-level group ( n = 1,021), and high-level group ( n = 172). The baPWV in adulthood was higher in medium-level and high-level groups compared with the low-level group (1271.4 ± 224.7 cm/s, 1366.1 ± 249.8 cm/s vs. 1190.1 ± 220.3 cm/s, all p < 0.001). After adjustment for potential confounding factors, the association between baPWV and systolic BP trajectories was statistically significant (adjusted β = 49.4 cm/s; p < 0.001 for the medium-level group and β = 107.6 cm/s; p < 0.001 for the high-level group compared with the low-level group). Similar results were obtained for the association of baPWV with the trajectories of diastolic BP and mean arterial pressure (MAP), except for pulse pressure., Conclusion: Our investigation demonstrates different BP trajectories from childhood to youth and shows the trajectories of systolic BP, diastolic BP, and MAP are significant predictors of arterial stiffness in adulthood., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chu, Liao, He, Ma, Zheng, Yan, Hu, Xu, Fan, Yang and Mu.)

Objective: To understand the clinical characteristics of hospitalized patients with liver cirrhosis, so as to provide theoretical basis for disease diagnosis and treatment, formulation of intervention measures, and improve the level of disease diagnosis and treatment. Methods: Hospitalized patients who were initially diagnosed with liver cirrhosis at Peking University First Hospital from August 2017 to December 2018 were selected retrospectively as the research objects. Liver cirrhosis demographic data, etiology, severity classification, incidence of complications, diagnosis and prognosis were recorded. Statistical analysis was performed using SPSS software. Results: Among all liver cirrhosis cases, there were 291 males and 209 females, with a male-to-female ratio of 1.4:1 and an age of 59.5±12.9 years as at August 2017 to December 2018. HBV infection, alcoholic liver disease, and autoimmune liver diseases were the most common etiology of liver cirrhosis. HBV infection alone, HBV infection combined with other factors, alcoholic liver disease alone, alcoholic liver disease combined with other factors, autoimmune liver disease alone, and autoimmune liver disease combined with other factors were presented in 163 (32.6%), 57 (11.4%), 47 (9.4%), 63 (12.6%), 85 (17.0%), and 22 (4.4.0%) cases, respectively. Ascites (221 cases, 44.2%), followed by esophagogastric varices (214 cases, 42.8%), and other including hypersplenism (137 cases), liver cancer (126 cases), upper digestive system tract hemorrhage (66 cases), hepatic encephalopathy (40 cases), infection (37 cases), portal vein thrombosis (23 cases), hepatorenal syndrome (20 cases) were the most common complications. The most common site of infection was the abdominal cavity (20 cases), accounting for 54.1%; followed by respiratory tract infection (8 cases), accounting for 21.6% in patients with liver cirrhosis with concurrent infection. Among them, there were 32 cases of bacterial infection alone, one case of bacterial infection combined with fungal infection, one case of bacterial infection combined with viral infection, and three cases of unknown pathogens. There were 69 cases in Child Pugh grade C, and the average hospitalization times were 12.6 days in terms of prognosis. There were total seven cases of death, of which five cases were due to upper gastrointestinal hemorrhage and two due to hepatic encephalopathy. Conclusion: HBV infection, ascites, and upper gastrointestinal bleeding were the most common etiologies, complications, and causes of death in patients with liver cirrhosis at our hospital.

Background and Purpose: To explore the genetic basis and molecular mechanism of native arteriogenesis and therapeutic synangiosis in moyamoya disease (MMD)., Methods: An angiography-based study using patients from a prospective trial of encephaloduroarteriosynangiosis (EDAS) surgery was performed. The spontaneous collaterals grades were evaluated according to the system described by a new grading system. Blood samples were collected from all the recruited patients before EDAS and during the second hospitalization 3 months post-EDAS. We performed Boolean analysis using a combination of specific cell surface markers of CD34 bri CD133 + CD45 dim KDR + . Genotyping of p.R4810K was also performed. The correlation of age, sex, initial symptoms at diagnosis, collateral grade, Suzuki stages, the RNF213 genotype, time to peak (TTP), and endothelial progenitor cell (EPC) count with good collateral circulation was evaluated., Results: Eighty-five patients with MMD were included in this study. The mutation rate of RNF213 p.R4810K in our study was 25.9% (22/85). The heterozygous mutations were occurred significantly more frequently in the cases that were presented with infarction, worse neurological status, severe posterior cerebral artery (PCA) stenosis, and longer TTP delay. Further, the heterozygous mutations occurred significantly more frequently in the poor collateral stage group. Lower grades were significantly correlated with severe ischemia symptoms, worse neurological status, and a longer TTP delay. The post-operative angiographic findings showed that a good Matsushima grade was correlated with heterozygous mutations, a lower collateral stage, and a longer TTP delay. The CD34 bri CD133 + CD45 dim KDR + cell count in patients 3 months post-EDAS was significantly higher as compared to the count before EDAS in the good Matsushima grade group. However, this change was not observed in the poor Matsushima grade group., Conclusions: These data imply that mutations of RNF213 p.R4810K affect the establishment of spontaneous collateral circulation, and EPCs are involved in the process of formation of new EDAS collaterals., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bao, Fan, Wang, Wang, Yang, Zou, Zhang, Li, Duan and Yu.)

The indoor air quality is of prime importance for human daily life and health, for which the adsorbents like zeolites and silica-gels are widely used for air dehumidification and harmful gases capture. Herein, we develop a pore-nanospace post-engineering strategy to optimize the hydrophilicity, water-uptake capacity and air-purifying ability of metal-organic frameworks (MOFs) with long-term stability, offering an ideal candidate with autonomous multi-functionality of moisture control and pollutants sequestration. Through variant tuning of organic-linkers carrying hydrophobic and hydrophilic groups in the pore-nanospaces of prototypical UiO-67, a moderately hydrophilic MOF (UiO-67-4Me-NH 2 -38 %) with high thermal, hydrolytic and acid-base stability is screened out, featuring S-shaped water sorption isotherms exactly located in the recommended comfortable and healthy ranges of relative humidity for indoor ventilation (45 %-65 % RH) and adverse health effects minimization (40-60 % RH). Its exceptional attributes of water-uptake working capacity/efficiency, contaminants removal, recyclability and regeneration promise a great potential in confined indoor environment application., (© 2021 Wiley-VCH GmbH.)

m6A (N6-methyladenosine) methylation, a well-known modification in tumour epigenetics, dynamically and reversibly fine tunes the entire process of RNA metabolism. Aberrant levels of m6A and its regulators, which can predict the survival and outcomes of cancer patients, are involved in tumorigenesis, metastasis and resistance. Ovarian cancer (OC) ranks first among gynaecological tumours in the causes of death. At first diagnosis, patients with OC are usually at advanced stages owing to a lack of early biomarkers and effective targets. After treatment, patients with OC often develop drug resistance. This article reviews the recent experimental advances in understanding the role of m6A modification in OC, raising the possibility to treat m6A modification and its regulators as promising diagnostic markers and therapeutic targets for OC., (© 2021. The Author(s).)

The emergence of coordinated network function during nervous system development is often associated with critical periods. These phases are sensitive to activity perturbations during, but not outside, of the critical period, that can lead to permanently altered network function for reasons that are not well understood. In particular, the mechanisms that transduce neuronal activity to regulating changes in neuronal physiology or structure are not known. Here, we take advantage of a recently identified invertebrate model for studying critical periods, the Drosophila larval locomotor system. Manipulation of neuronal activity during this critical period is sufficient to increase synaptic excitation and to permanently leave the locomotor network prone to induced seizures. Using genetics and pharmacological manipulations, we identify nitric oxide (NO)-signaling as a key mediator of activity. Transiently increasing or decreasing NO-signaling during the critical period mimics the effects of activity manipulations, causing the same lasting changes in synaptic transmission and susceptibility to seizure induction. Moreover, the effects of increased activity on the developing network are suppressed by concomitant reduction in NO-signaling and enhanced by additional NO-signaling. These data identify NO signaling as a downstream effector, providing new mechanistic insight into how activity during a critical period tunes a developing network., (© 2021. The Author(s).)

Background: Non-alcohol fatty liver disease (NAFLD) is the most common chronic liver disease in the world, with a high incidence and no effective treatment. At present, the targeted therapy of intestinal microbes for NAFLD is highly valued. Lycium barbarum polysaccharide (LBP), as the main active ingredient of Lycium barbarum, is considered to be a new type of prebiotic substance, which can improve NAFLD by regulating the gut microbiota. The purpose of this study is to evaluate the safety and efficacy of LBP supplementation in modulating gut microbiota for NAFLD patients., Methods: This randomized, double-blind, placebo-control study will be conducted in the physical examination center of the Ningxia Hui Autonomous Region People's Hospital. A total of 50 patients with NAFLD confirmed by abdominal ultrasound, laboratory tests, and questionnaire surveys will be recruited and randomly assigned into the control group (maltodextrin placebo capsules) and the intervention group (LBP supplementation capsules) for 3 months. Neither patients, nor investigators, nor data collectors will know the contents in each capsule and the randomization list. The primary outcome measure is the level of ALT concentration relief after the intervention. Secondary outcomes include gut microbiota abundance and diversity, intestinal permeability, patient's characteristic demographic data and body composition, adverse effects, and compliance from patients., Discussion: LBPs are potential prebiotics with the property of regulating host gut microbiota. Our previous studies have documented that LBP supplement can improve the liver damage and the gut microflora dysbiosis in NAFLD rats. This treatment would provide a more in-depth understanding of the effect of this LBP supplementation., Trial Registration: Chinese Clinical Trial Register, ChiCTR2000034740 . Registered on 17 July 2020., (© 2021. The Author(s).)

Gut microbiota and intestinal permeability have been demonstrated to be the key players in the gut-liver cross talk in nonalcoholic fatty liver disease (NAFLD). Lycium barbarum polysaccharides (LBPs), which seem to be a potential prebiotic, and aerobic exercise (AE) have shown protective effects on NAFLD. However, their combined effects on intestinal microecology remain unclear. This study evaluated the effects of LBP, AE, and its combination (LBP + AE) on gut microbiota composition, intestinal barrier, and hepatic inflammation in NAFLD. LBP + AE showed high abundance and diversity of gut microbiota, restored the gut microbiota composition, increased some Bacteroidetes, short chain fatty acids, but decreased Proteobacteria and the ratio of Firmicutes/Bacteroidetes. Simultaneously, LBP, AE, and LBP + AE could restore the colonic and ileum tight junctions by increasing the expression of zonula occludens-1 and occludin. They also downregulated gut-derived lipopolysaccharides (LPSs), hepatic LPS-binding proteins, inflammatory factors, and related indicators of the LPS/TLR4/NF-κB signaling pathway for the liver. Our results implied that LBP could be considered a prebiotic agent, and LBP + AE might be a promising treatment for NAFLD because it could maintain gut microbiota balance, thereby restoring intestinal barrier and exerting hepatic benefits., (Copyright © 2021. Published by Elsevier B.V.)

Background: Tenofovir disoproxil fumarate (TDF) is a prodrug of a nucleotide analogue. As an antiviral drug, TDF has been proposed in the first-line treatment of chronic hepatitis B (CHB). Qingzhong, a brand name of TDF, commercialized by Jiangsu Chia-tai Tianqing Pharmaceutical Co Ltd., and Viread, another brand name of TDF, commercialized by GlaxoSmithKline, have both been approved by the State Food and Drug Administration, China., Aim: To investigate the efficacy and safety of the two TDF agents in the treatment of Chinese CHB patients., Methods: This trial was registered at ClinicalTrials.gov with the identifier number of NCT02287857. A total of 330 Chinese CHB patients, among which 232 were hepatitis B e antigen (HBeAg)-positive, were included in this 5-year-long, multicenter, double-blinded, double-dummy, randomized-controlled, non-inferiority phase III trial. The participants were initially randomized into two groups: Group A ( n = 161), in which the participants received 300 mg Qingzhong once a day for 48 wk; and Group B, in which the participants received 300 mg Viread once a day for 48 wk. Starting from week 49, all the participants in Groups A and B received 300 mg Qingzhong once a day until the 96 th week. In this study, the primary endpoint was the decrease in plasma level of hepatitis B virus (HBV) DNA at the 96 th week, while the secondary endpoints were suppression of HBV replication, alanine aminotransferase (ALT) normalization, HBeAg loss, and HBeAg seroconversion rates., Results: For the participants with HBeAg-positive CHB, the decrease in mean HBV DNA level relative to the baseline value was comparable between Groups A and B (5.77 vs 5.73 log 10 IU/mL, P > 0.05) at the 96 th week. In addition, similar percentages of HBeAg-positive participants in the two groups exhibited undetectable levels of HBV DNA, HBeAg loss, and HBeAg seroconversion (71.05% vs 77.97%, 31.00% vs 27.27%, and 20.22% vs 15.79%, respectively, in Group A vs Group B; P > 0.05). For the participants with HBeAg-negative CHB, the decrease in mean HBV DNA level relative to the baseline value was also comparable between Groups A and B (4.46 vs 4.70 log 10 IU/mL, P > 0.05) at the 96 th week. In addition, similar percentages of HBeAg-negative participants in the two groups exhibited undetectable levels of HBV DNA (87.23% vs 94.12% in Group A vs Group B, respectively; P > 0.05). Finally, similar percentages of CHB patients (HBeAg-positive or HBeAg-negative) in the two groups exhibited normalization of ALT (80.14% vs 84.57% in Group A vs Group B, respectively; P > 0.05), and similar incidences of adverse events were observed (106 vs 104 in Group A vs Group B, respectively; P > 0.05)., Conclusion: Both Qingzhong and Viread are effective and safe in the treatment of Chinese CHB patients according to the results of our clinical trial., Competing Interests: Conflict-of-interest statement: Nothing to declare., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Anxiety, a common and devastating mental disorder, has raised widespread interests. The impacts of air pollution on physical health are well known, whereas few studies have explored the association of atmospheric pollution, especially short-term air pollution exposure, with the risk of anxiety disorders. In addition, there are increasing concerns in emerging evidence supporting a possible etiological link. Therefore, our aim was to evaluate the relationship between short-term exposure to atmospheric pollutants and anxiety outpatient visits in Xi'an, a city of northwestern China and a metropolis with relatively heavy air pollution. We collected the data of both daily outpatient visits and daily air pollution (SO 2 , NO 2 , and PM 10 ) between January 1, 2010 and January 31, 2016 (2222 days). To clarify the association between short-term ambient atmospheric pollution exposure and anxiety outpatient visits, an over-dispersed Poisson generalized additive model was applied by adjusting the day of the week and weather conditions (including temperature, humidity, sunlight hours, and rainfalls). Positive association between gaseous air pollutants (SO 2 and NO 2 ) and anxiety daily outpatient visits was observed. Moreover, the largest estimated values of both SO 2 and NO 2 were evidence at lag 03 (4-day moving average lag), with 10 μg/m 3 increase corresponded to the increase of outpatient anxiety visits at 4.11% (95% CI: 2.15%, 6.06%) for SO 2 and 3.97% (95% CI: 1.90%, 6.06%) for NO 2 . However, there was no differences in susceptibility to air pollutants between different genders as well as different ages. Taken together, short-term exposure to ambient air pollutants, especially gaseous air pollutants (NO 2 and SO 2 ), can be related to higher risk of anxiety outpatient visits., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Perilla frutescens (L.) Britton is a classic herbal plant used widely against asthma in China. But its mechanism of beneficial effect remains undermined. In the study, the antiallergic asthma effects of Perilla leaf extract (PLE) were investigated, and the underlying mechanism was also explored. Results showed that PLE treatment significantly attenuated airway inflammation in OVA-induced asthma mice, by ameliorating lung pathological changes, inhibiting recruitment of inflammatory cells in lung tissues and bronchoalveolar lavage fluid (BALF), decreasing the production of inflammatory cytokines in the BALF, and reducing the level of immunoglobulin in serum. PLE treatment suppressed inflammatory response in antigen-induced rat basophilic leukemia 2H3 (RBL-2H3) cells as well as in OVA-induced human peripheral blood mononuclear cells (PBMCs). Furthermore, PLE markedly inhibited the expression and phosphorylation of Syk, NF- κ B, PKC, and cPLA 2 both in vivo and in vitro . By cotreating with inhibitors (BAY61-3606, Rottlerin, BAY11-7082, and arachidonyl trifluoromethyl ketone) in vitro , results revealed that PLE's antiallergic inflammatory effects were associated with the inhibition of Syk and its downstream signals NF- κ B, PKC, and cPLA 2 . Collectively, the present results suggested that PLE could attenuate allergic inflammation, and its mechanism might be partly mediated through inhibiting the Syk pathway., Competing Interests: There are no conflicts of interest concerning this work., (Copyright © 2021 Hui Yang et al.)

Modulating effector immune cells via monoclonal antibodies (mAbs) and facilitating the co-engagement of T cells and tumor cells via chimeric antigen receptor- T cells or bispecific T cell-engaging antibodies are two typical cancer immunotherapy approaches. We speculated that immobilizing two types of mAbs against effector cells and tumor cells on a single nanoparticle could integrate the functions of these two approaches, as the engineered formulation (immunomodulating nano-adaptor, imNA) could potentially associate with both cells and bridge them together like an 'adaptor' while maintaining the immunomodulatory properties of the parental mAbs. However, existing mAbs-immobilization strategies mainly rely on a chemical reaction, a process that is rough and difficult to control. Here, we build up a versatile antibody immobilization platform by conjugating anti-IgG (Fc specific) antibody (αFc) onto the nanoparticle surface (αFc-NP), and confirm that αFc-NP could conveniently and efficiently immobilize two types of mAbs through Fc-specific noncovalent interactions to form imNAs. Finally, we validate the superiority of imNAs over the mixture of parental mAbs in T cell-, natural killer cell- and macrophage-mediated antitumor immune responses in multiple murine tumor models.

Objective: To explore the risk factors of overt hepatic encephalopathy (OHE) in patients with liver cirrhosis. Methods: A retrospective study was designed. Patients with liver cirrhosis combined with /without OHE who were hospitalized to our hospital during the same period were selected as the case/control group. Clinical and laboratory data of both groups of patients were compared to analyze the risk factors affecting the occurrence of OHE. SPSS software was used for statistical analysis. A t-test or rank-sum test was used to compare the measurement data. Chi-square test or Fisher's exact probability method was used to compare the count data. Logistic regression was used for multivariate analysis. Results: A total of 500 patients with liver cirrhosis diagnosed in our hospital from August 2017 to December 2018 were selected as the case group, and 40 cases with cirrhosis without OHE who were hospitalized during the same period were randomly selected as the control group. The gender composition and age of the case and control group were comparable. Viral hepatitis (mainly hepatitis B) was the main etiology of liver cirrhosis in both groups. There were 52.5% patients in the case group and 57.5% patients in the control group, respectively. Alcoholic liver disease, autoimmune liver disease and so on were the other included causes. With regard to blood biochemical indicators, the serum creatinine levels of both groups were comparable, but in the case group, the serum total bilirubin level was higher (34.30 μmol / L vs. 18.65 μ mol/L, Z = -3.185, P < 0.05), while the serum sodium level was lower (137.00 mmol/L vs. 140.08 mmol/L, Z = -2.348, P < 0.05), and the prothrombin time was longer (14.60 s vs. 12.20 s) s. 078, P < 0.05), and international normalized ratio (1.33 vs. 1.07, Z = - 5.632, P < 0.05), and serum albumin level (30.6 g/L vs. 35.6 g/L, t = 3.386, P < 0.05) was lower. In terms of complications, patients in the case group had a higher proportion of combined gastrointestinal bleeding (30.0% vs. 10.0%, χ(2) = 5.000, P < 0.05), ascites (87.5% vs. 30.0%, χ(2) = 27.286, P < 0.05) and secondary infection (32.5% vs. 10.0%, χ(2) = 7.813, P < 0.05). In terms of severity classification, the proportion of Child-Pugh C in the case group was higher (62.5% vs. 10.0%, χ(2) =26.593, P < 0.05). In terms of outcome, there were 3 deaths in the case group and no deaths in the control group. Multivariate analysis showed that Child-Pugh class C ( OR = 12.696), and combined ascites ( OR = 10.655) were an independent risk factor for OHE in patients with liver cirrhosis. Conclusion: Our single-center retrospective clinical study shows that patients with cirrhosis combined with OHE are more critical and have more complications. In order to promptly diagnose and treat OHE, more attention should be paid to patients with combined ascites and Child-Pugh class C.

Phthalate pollution in soil and vegetables in plastic agricultural greenhouses has attracted wide concern. Investigating airborne phthalates in this environment can improve understanding of air-soil or air-vegetable phthalate migration. However, studies of phthalates in plastic agricultural greenhouse air are rare. To fill this gap, 25 gas-phase and 23 particle-phase samples were collected from 12 typical plastic greenhouses in Shaanxi. 16 types of phthalates were measured by a gas chromatography-mass spectrometry system (GC-MS) to analyse their pollution features and variations. Results showed that in the air of the plastic greenhouses, the median concentration of the sum of sixteen type phthalates (∑ 16 phthalates) was 5305 ng m -3 , with 5th-95th value of 1214-9616 ng m -3 . Phthalates in gas-phase samples were over 100 times higher than the levels in particle-phase samples. Air phthalate concentrations in the plastic greenhouses were higher than those in the control groups (P < 0.05). Air bis (2-ethylhexyl) phthalate (DEHP) and di-n-butyl phthalate (DnBP) accounted for 66.9% and 29.3% of total ∑ 16 phthalate concentrations, respectively. Air phthalate concentrations in the plastic greenhouses in winter were 1.1-5.3 times higher than the levels in summer respectively (P < 0.05). Gas-particle partition coefficients (K P ) values of DEHP in summer (median of 1.52 × 10 -4  m 3  μg -1 ) were higher than K P values of DnBP in summer (0.60 × 10 -4  m 3  μg -1 ). Log-transformed K P values of DnBP and DEHP were linear correlated to the reciprocal of air temperatures, respectively (P < 0.05)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Ageing and chronic diseases lead to muscle loss and impair the regeneration of skeletal muscle. Thus, it's crucial to seek for effective intervention to improve the muscle regeneration. Tid1, a mitochondrial co-chaperone, is important to maintain mitochondrial membrane potential and ATP synthesis. Previously, we demonstrated that mice with skeletal muscular specific Tid1 deficiency displayed muscular dystrophy and postnatal lethality. Tid1 can interact with STAT3 protein, which also plays an important role during myogenesis. In this study, we used GMI, immunomodulatory protein of Ganoderma microsporum, as an inducer in C2C12 myoblast differentiation. We observed that GMI pretreatment promoted the myogenic differentiation of C2C12 myoblasts. We also showed that the upregulation of mitochondria protein Tid1 with the GMI pre-treatment promoted myogenic differentiation ability of C2C12 cells. Strikingly, we observed the concomitant elevation of STAT3 acetylation (Ac-STAT3) during C2C12 myogenesis. Our study suggests that GMI promotes the myogenic differentiation through the activation of Tid1 and Ac-STAT3., Competing Interests: The authors have declared that no competing interests exist.

Nanotechnology has shown great promise in treating diverse diseases. However, developing nanomedicines that can cure autoimmune diseases without causing systemic immunosuppression is still quite challenging. Herein, we propose an all-in-one nanomedicine comprising an autoantigen peptide and CRISPR-Cas9 to restore specific immune tolerance by engineering dendritic cells (DCs) into a tolerogenic phenotype, which can expand autoantigen-specific regulatory T (Treg) cells. In brief, we utilized cationic lipid-assisted poly(ethylene glycol)- b -poly(lactide- co -glycolide) (PEG-PLGA) nanoparticles to simultaneously encapsulate an autoimmune diabetes-relevant peptide (2.5mi), a CRISPR-Cas9 plasmid (pCas9), and three guide RNAs (gRNAs) targeting costimulatory molecules (CD80, CD86, and CD40). We demonstrated that the all-in-one nanomedicine was able to effectively codeliver these components into DCs, followed by simultaneous disruption of the three costimulatory molecules and presentation of the 2.5mi peptide on the genome-edited DCs. The resulting tolerogenic DCs triggered the generation and expansion of autoantigen-specific Treg cells by presenting the 2.5mi peptide to CD4 + T cells in the absence of costimulatory signals. Using autoimmune type 1 diabetes (T1D) as a typical disease model, we demonstrated that our nanomedicine prevented autoimmunity to islet components and inhibited T1D development. Our all-in-one nanomedicine achieved codelivery of CRISPR-Cas9 and the peptide to DCs and could be easily applied to other autoimmune diseases by substitution of different autoantigen peptides.

Due to spontaneous organization of cellulose nanocrystals (CNCs) into the chiral nematic structure that can selectively reflect circularly polarized light within a visible-light region, fabricating stretching deformation-responsive CNC materials is of great interest but is still a big challenge, despite such a function widely observed from existing creatures, like a chameleon, because of the inherent brittleness. Here, a flexible network structure is introduced in CNCs, exerting a bridge effect for the rigid nanomaterials. The as-prepared films display high flexibility with a fracture strain of up to 39%. Notably, stretching-induced structural color changes visible to the naked eye are realized, for the first time, for CNC materials. In addition, the soft materials show humidity- and compression-responsive properties in terms of changing apparent structural colors. Colored marks left by ink-free writing can be shown or hidden by controlling the environmental humidities. This biobased photonic film, acting as a new "smart skin", is potentially used with multifunctions of chromogenic sensing, encryption, and anti-counterfeit.

Osteonecrosis of the femoral head is a common orthopedic disease. Based on years of clinical experience and significant imaging data, this study aimed to elucidate a new type of it, to help improve prognosis in young adults and provide a basis for hip preservation treatment.From January 2014 to December 2016, a total of 211 patients undergoing hip preservation surgery for femoral head necrosis at our hospital were enrolled in this study. Coronal plane classification and cross-sectional area analysis were performed by nuclear magnetic resonance imaging (computed tomography optional) in cases meeting the inclusion criteria. Meanwhile, a new method of classification and calculating the necrotic area was proposed. The application simulation was conducted using sample cases. Additionally, treatment methods were recommended. We used our method to compare the outcome of the selected patients with the JIC classification so as to judge the advantages and disadvantages.The " pressure bone trabecular angle " of the femoral head was measured, and the "sclerotic band" (Zhang Ying) type of classification system and the "quartile" (Zhang Ying) method of measurement were used in 2 sample cases. After analysis, it is more accurate than JIC.The "Sclerotic band" type of classification system and 'quartile' methods are new methods to evaluate the stability of femoral head necrosis. They are convenient for clinical application and easily adopted.

Objective: To investigate the sensitivity of carotid body to hypoxia and the effect of dopamine on the sensitivity of carotid body to hypoxia after acute intermittent hypoxia stimulation in rats. Methods: The isolated carotid body-sinus nerve in rat was transferred to incubator, and then the isolated sinus nerve was inhaled into the recorded glass electrode for recording electrical signals. The baseline buffer was bubbled with 95% O 2 + 5% CO 2 mixture gas, and the hypoxic stress was treated with 5% O 2 + 5% CO 2 + 90% N 2 mixture gas, hypoxic stimulation was given for 30 seconds, 95% O 2 + 5% CO 2 for 90 seconds, a total of 10 cycles. No less than 5 rats in each group. Results: In this experiment, the electrical activity of sinus nerve isolated from rats was enhanced by hypoxia stimulation after acute intermittent hypoxia, but the response of sinus nerve to hypoxia was inhibited by dopamine. Before acute intermittent hypoxic stress, dopamine also inhibited the firing activity of sinus nerve, but after acute intermittent hypoxic cycle, the inhibition of dopamine on the firing activity of sinus nerve was strengthened. Conclusion: Acute intermittent hypoxia enhances the response of sinus nerve isolated from rats to hypoxia, dopamine inhibits the enhancement of carotid body sensitivity to hypoxia induced by acute intermittent hypoxic.

Tumor-infiltrating dendritic cells (TIDCs) are mostly immature and immunosuppressive, usually mediating immune inhibition. The utilization of cytosine-guanine oligodeoxynucleotides (CpG ODNs) to stimulate the activation of TIDCs has been demonstrated to be effective for improving antitumor immunity. However, a series of biological barriers has limited the efficacy of previous nanocarriers for delivering CpG to TIDCs. Herein, we developed a dual-sensitive dendrimer cluster-based nanoadjuvant for delivering CpG ODNs into TIDCs. We show that the tumor acidity triggers the rapid release of CpG conjugated polyamidoamine (PAMAM) dendrimers from the nanoadjuvant, thus facilitating its perfusion deep into tumors and phagocytosis by TIDCs. Thereafter, the reductive condition of the endolysosomes led to the subsequent release of CpG, which promotes the DCs activation and enhances antitumor immunotherapies. Programmable delivery of immune adjuvant efficiently overcomes the barriers for targeted delivery to TIDCs and provides a promising strategy for improving cancer immunotherapy.

Known for excellent stability, porosity and functionality, the high-valent Zr 4+ metal-organic frameworks (Zr-MOFs) still meets synthetic challenge in modulating the strength of Zr-O carboxylate linkage. Herein we explore the unusual coordination dynamics of fluorinated Zr-MOFs by designing two trifluoromethyl modified ligands with distinct geometry preference to form a family of thermodynamic and kinetic products. The low-connecting kinetic Zr-MOFs possess substitutable coordination sites to endow Zr 6 -cluster with extra dynamic behaviors, thus opening a post-synthetic pathway to sequential reassembly/disassembly processes. Comprehensive factors, including ligand geometry, Zr 6 -cluster connectivity, acid modulator and reaction temperature/concentration, have been studied for controllable syntheses. The stability, hydrophobicity and gas adsorption/separation properties of obtained Zr-MOFs are explored. This work sheds light on the understanding of the dynamic coordination chemistry of Zr-MOFs beyond strong Zr-O bond, which poses a versatile platform for modification and functionalization of Zr-MOFs., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Metastasis is the leading cause of death for patients with cancer. Consequently it is imperative that we improve our understanding of the molecular mechanisms that underlie progression of tumor growth toward malignancy. Advances in genome characterization technologies have been very successful in identifying commonly mutated or misregulated genes in a variety of human cancers. However, the difficulty in evaluating whether these candidates drive tumor progression remains a major challenge. Using the genetic amenability of Drosophila melanogaster we generated tumors with specific genotypes in the living animal and carried out a detailed systematic loss-of-function analysis to identify conserved genes that enhance or suppress epithelial tumor progression. This enabled the discovery of functional cooperative regulators of invasion and the establishment of a network of conserved invasion suppressors. This includes constituents of the cohesin complex, whose loss of function either promotes individual or collective cell invasion, depending on the severity of effect on cohesin complex function., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Carbon monoxide (CO) is a well-known "toxic gas". It represents a toxic inhalation hazard at high concentration and is commonly found in polluted air. However, a series of recent studies have suggested that low concentration of CO can also produce protective functions. This study was performed to investigate the association between ambient CO exposure and vaginitis outpatient visits. Daily baseline outpatient data of vaginitis from January 1, 2013 to December 31, 2015 were obtained from Xi'an, a heavily-polluted metropolis in China. The over-dispersed Poisson generalized additive model was applied to discover the relations between short-term ambient CO exposure and the number of vaginitis outpatient visits by adjusting day of the week and weather conditions. A total of 16,825 outpatient hospital visits for vaginitis were recorded. The mean daily concentration of carbon monoxide (CO) was well below Chinese and WHO guidelines. During the study period, increased levels of ambient CO was associated with reduced outpatient-visits through concurrent to lag 5 days, and the most significant association was evidenced at lag 05. A 0.1 mg/m 3 increase in daily average CO at lag 05 corresponded to -1.25% (95%CI: -1.85%, -0.65%) change in outpatient-visits for vaginitis. Moreover, the association was more significant in those women aged 20-29 years. After adjustment for PM 10 , PM 2.5 , SO 2 , and NO 2 , and O 3 , the negative associations of CO with vaginitis kept significant, suggesting relative stability of effect estimates. In summary, this is the first evidence that increased ambient CO exposure can be related to reduced daily outpatient visits for vaginitis. The results of our study may not only help to establish more comprehensive understanding of the health effects of ambient air on vaginitis and other gynecological diseases, but also provide a clue to new potential interventions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Glutamate and its receptors have been demonstrated to promote both basal and nicotine-evoked catecholamine release in bovine chromaffin cells. Multiple glutamate receptors, including metabotropic glutamate receptors (mGluRs), are found in the adrenal glands of several species, as well as in chromaffin cells. However, there is limited information available regarding the expression of glutamate metabotropic receptor (GRM)1-8 mRNAs and the detailed localization of group I mGluRs (mGluR1 and mGluR5) in the rat and human adrenal cortex and medulla. Therefore, we examined mRNA expression of GRM1-8 subunits using reverse transcription-polymerase chain reaction (RT-PCR) and the distribution of mGluR1 and mGluR5 by immunostaining. The results showed that the GRM1-8 mRNAs were expressed in both the cortex and medulla of rat and human adrenal glands with the exception of GRM1 , which was not detectable in the rat adrenal cortex. Immunostaining of mGluR1 revealed that it was localized only in the adrenal medulla of rats but was present in both the adrenal cortex and medulla in humans. In the adrenal medulla, the central part of the adrenal glands, mGluR1 was detected in chromaffin cells but not in nerve fibers and ganglion cells. Immunoactivity of mGluR5 was visible in the capillary wall throughout the adrenal cortex and medulla in rat and human samples. Its immunoactivity was also observed in ganglion cells in the rat adrenal medulla. There was no mGluR5 immunoactivity detected in chromaffin cells and nerve fibers in the rat and human adrenal medulla. Using dissected rat adrenal medulla as a model, we found that treatment with a mGluR1 agonist activated extracellular signal-regulated kinase (ERK) 1/2 and increased the expression of tyrosine hydroxylase (TH), the rate-limiting enzyme of catecholamine synthesis. Moreover, these results showed that mGluR1 signaling was involved in hypoxia-induced upregulation of TH in the rat adrenal medulla. This study shows the expression of GRM1-8 mRNAs in rat and human adrenal glands and indicates that glutamate, through the activation of mGluRs, may play various physiological roles in the adrenal gland. Furthermore, mGluR1 may be involved in catecholamine biosynthesis by regulating TH, and mGluR5 may affect cortical and medullar hormone levels by regulating microvascular function., (Copyright © 2020 Fan, Li, Huang, Chen, Tang, Han and Liu.)

This study explored the expression of BACE1 (β-amyloid precursor protein cleaving enzyme 1) in the rat carotid body and the effect of CIH (cyclic intermittent hypoxia) on the expression of BACE1. We found that BACE1 was expressed in the rat carotid body and located in the nerve endings and type II cells but not in type I cells. CIH reduced BACE1 level in the carotid body, and reoxygenation or ROS scavenger alleviated this reduction. Furthermore, we found that CIH augmented the mRNA level of PGC-1α but attenuated the mRNA level of BACE1 in the carotid body. Taken together, our results suggest that CIH promotes the production of ROS that upregulates the level of PGC-1α, which may in turn inhibits the transcription of BACE1, and that a reduction in the BACE1 level may be related to CIH-induced reversible and ROS-dependent carotid body plasticity. Our study provides a new candidate molecule for further study of the mechanism of carotid body plasticity., (Copyright © 2020 Li, Zhao, Fan, Jia and Liu.)

Menstrual disorders are common diseases among reproductive-aged women with increasing concerns. Until now, there have been limited studies about the association between menstrual disorders and air pollution. This study aimed to investigate the association between short-term (concurrent day and within 1 week prior) ambient air pollution exposure and menstrual disorder outpatient visits in Xi'an, a metropolis in northwestern China. Daily baseline outpatient data of menstrual disorders from January 1, 2010 to February 18, 2016 (2239 days) were obtained. An over-dispersed Poisson generalized additive model was applied to discover the relationship between short-term air pollution exposure and the number of menstrual disorder outpatient visits by adjusting the day of the week and weather conditions. A total of 51,893 outpatient visits for menstrual disorders were recorded. A 10 μg/m 3 increase of PM 10 and NO 2 concentrations corresponded to 0.236% (95% Cl: 0.075%, 0.397%) and 2.173% (95% Cl: 0.990%, 3.357%) elevations in outpatient-visits for menstrual disorders at lag 7 and lag 01 (concurrent day and previous 1 day), respectively. The association was more significant in young females (18-29 years) and there was no obvious association observed between SO 2 and menstrual disorder outpatient visits. This is the first evidence that short-term exposure to ambient air pollution can be associated with an increased risk of menstrual disorder attacks. The results of our study may help to establish more comprehensive understanding of the health effects of ambient air pollution on menstrual disorders and other reproductive diseases., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)