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Pancreatic cancer (PC) is a very aggressive digestive system tumor, known for its high mortality rate, low cure rate, low survival rate and poor prognosis. In particular, pancreatic ductal adenocarcinoma (PADC), which accounts for more than 90% of PC cases, has an overall 5-year survival rate of only 5%, which is an extremely critical situation. Early detection and effective treatment of PC is extremely difficult, which leads many patients to despair. In the current medical context, targeted therapy, as an important strategy for cancer treatment, is expected. However, the problems of immune escape and drug resistance in PC have become two major obstacles that are difficult to be overcome by targeted therapy. How to break through these two difficulties has become a key issue to be solved in the field of PC therapy. In recent years, non-coding RNAs (ncRNAs) have continued to heat up in the field of cancer research. NcRNAs play a pivotal role in gene regulation, cell differentiation, development, and disease processes, and their important roles in the genesis, development, and therapeutic response of PC have been gradually revealed. More importantly, ncRNAs have many advantages as therapeutic targets, such as high specificity and low side effects, making them a new favorite in the field of PC therapy. Therefore, the aim of this paper is to provide new ideas and methods for the targeted therapy of PC by reviewing the mechanism of action of four major ncRNAs (circRNAs, lncRNAs, miRNAs, siRNAs) in both immune escape and drug resistance of PC. It is expected that an effective way to overcome immune escape and drug resistance can be found through in-depth study of ncRNA, bringing a ray of hope to PC patients.

CHAC1, an essential regulator of oxidative stress and ferroptosis, is increasingly recognized for its significant roles in these cellular processes and its impact on various human diseases and cancers. This review aims to provide a comprehensive overview of CHAC1’s molecular functions, regulatory mechanisms, and effects in different pathological contexts. Specifically, the study objectives are to elucidate the biochemical pathways involving CHAC1, explore its regulatory network, and discuss its implications in disease progression and potential therapeutic strategies. As a γ-glutamyl cyclotransferase, CHAC1 degrades glutathione, affecting calcium signaling and mitochondrial function. Its regulation involves transcription factors like ATF4 and ATF3, which control CHAC1 mRNA expression. CHAC1 is crucial for maintaining redox balance and regulating cell death pathways in cancer. Its elevated levels are associated with poor prognosis in many cancers, indicating its potential as a biomarker and therapeutic target. Additionally, CHAC1 influences non-cancerous diseases such as neurodegenerative and cardiovascular disorders. Therapeutically, targeting CHAC1 could increase cancer cell sensitivity to ferroptosis, aiding in overcoming resistance to standard treatments. This review compiles current knowledge and recent discoveries, emphasizing CHAC1’s vital role in human diseases and its potential in diagnostic and therapeutic applications.

IntroductionSystemic lupus erythematosus (SLE) is a complex autoimmune disease, and despite the availability of multiple treatments, striking a balance between long-term efficacy and side effects remains a major clinical challenge. B-cell–directed therapy has attracted much attention because of its unique mechanism of action. Belimumab and obinutuzumab, as representative drugs for B-cell–directed therapy, have shown their respective advantages for SLE treatment. However, data on combination therapy with obinutuzumab and belimumab are currently unavailable.Case presentationWe present the severe case report of a patient who was diagnosed with lupus nephritis (LN) with gastrointestinal involvement and developed acute renal failure. The patient responded to the first dose of obinutuzumab but failed to achieve a complete response to LN. The repeated use of obinutuzumab was limited by persistently low IgG levels and frequent infections. This is a real-world challenge that must be addressed. Therefore, the patient was subsequently treated with a novel sequential regimen of obinutuzumab followed by belimumab. After 18 months of follow-up, the patient achieved a complete clinical response with a favourable safety profile, along with the conversion of all autoantibodies from positive to negative and sustained negativity. To date, the patient has achieved a dual clinical and serological response.ConclusionThere is a reason to believe that this novel combination regimen could be developed as a therapeutic strategy, with the expectation of balancing efficacy and safety.

PurposeRhubarb (Rheum palmatum L.) and astragalus (Radix astragali) find widespread used in clinical formulations for treating chronic kidney disease (CKD). Notably, the key active components, total rhubarb anthraquinone (TRA) and total astragalus saponin (TAS), exhibit superiority over rhubarb and astragalus in terms of their clear composition, stability, quality control, small dosage, and efficacy for disease treatment. Additionally, astragalus polysaccharides (APS) significantly contribute to the treatment of renal fibrosis by modulating the gut microbiota. However, due to differences in the biopharmaceutical properties of these components, achieving synergistic effects remains challenging. This study aims to develop combined pellets (CPs) and evaluate the potential effect on unilateral ureteral obstruction (UUO)-induced renal fibrosis.MethodsThe CPs pellets were obtained by combining TRA/TAS-loaded SNEDDS pellets and APS-loaded pellets, prepared using the fluidized bed coating process. The prepared pellets underwent evaluation for morphology, bulk density, hardness, and flowing property. Moreover, the in vitro release of the payloads was evaluated with the CHP Type I method. Furthermore, the unilateral ureteral obstruction (UUO) model was utilized to investigate the potential effects of CPs pellets on renal fibrosis and their contribution to gut microbiota modulation.ResultsThe ex-vivo study demonstrated that the developed CPs pellets not only improved the dissolution of TRA and TAS but also delivered TRA/TAS and APS spatiotemporally to the appropriate site along the gastrointestinal tract. In an animal model of renal fibrosis (UUO rats), oral administration of the CPs ameliorated kidney histological pathology, reduced collagen deposition, and decreased the levels of inflammatory cytokines. The CPs also restored the disturbed gut microbiota induced by UUO surgery and protected the intestinal barrier.ConclusionThe developed CPs pellets represent a promising strategy for efficiently delivering active components in traditional Chinese medicine formulas, offering an effective approach for treating CKD.

BackgroundCOVID-19 vaccines are crucial for reducing the threat and burden of the pandemic on global public health, yet the epigenetic, especially RNA editing in response to the vaccines remains unelucidated.ResultsOur current study performed an epitranscriptomic analysis of RNA-Seq data of 260 blood samples from 102 healthy and SARS-CoV-2 naïve individuals receiving different doses of the COVID-19 vaccine and revealed dynamic, transcriptome-wide adenosine to inosine (A-to-I) RNA editing changes in response to COVID-19 vaccines (RNA editing in response to COVID-19 vaccines). 5592 differential RNA editing (DRE) sites in 1820 genes were identified, with most of them showing up-regulated RNA editing and correlated with increased expression of edited genes. These deferentially edited genes were primarily involved in immune- and virus-related gene functions and pathways. Differential ADAR expression probably contributed to RNA editing in response to COVID-19 vaccines. One of the most significant DRE in RNA editing in response to COVID-19 vaccines was in apolipoprotein L6 (APOL6) 3’ UTR, which positively correlated with its up-regulated expression. In addition, recoded key antiviral and immune-related proteins such as IFI30 and GBP1 recoded by missense editing was observed as an essential component of RNA editing in response to COVID-19 vaccines. Furthermore, both RNA editing in response to COVID-19 vaccines and its functions dynamically depended on the number of vaccine doses.ConclusionOur results thus underscored the potential impact of blood RNA editing in response to COVID-19 vaccines on the host’s molecular immune system.

BackgroundAn escalating body of clinical trials and observational studies hints at a plausible link between gut flora and postpartum depression (PPD). The definitive causal dynamics between these two entities remain shrouded in ambiguity. Therefore, in this study, we employed the two-sample Mendelian randomization approach to ascertain the causal link between gut microbiota and PPD.MethodsSummary-level GWAS data related to the human gut microbiota were obtained from the international consortium MiBioGen and the Dutch Microbiome Project (species). For PPD, GWAS data were derived from the FinnGen biobank, consisting 57,604 cases and 596,601 controls. The inverse variance weighted method (IVW) as the cornerstone of our analytical approach. Subsequent to this, a comprehensive suite of tests for pleiotropy and heterogeneity were conducted to ensure the reliability and robustness of our findings.ResultsWe identified 12 bacterial taxa associated with the risk of PPD. Veillonellaceae, Ruminococcaceae UCG 011, Bifidobacterium adolescentis, Paraprevotella clara, Clostridium leptum, Eubacterium siraeum, Coprococcus catus exhibited an inversely associated with the risk of PPD. Alphaproteobacteria, Roseburia, FamilyXIIIAD3011group, Alistipes onderdonkii, Bilophila wadsworthia showed a positive correlation with the risk of PPD.LimitationsThe GWAS data derived from the MiBioGen consortium, DMP, and FinnGen consortium, may introduce selection bias. Moreover, the data primarily originates from European populations, hence extrapolating these results to diverse populations should be approached with caution. The etiological factors behind PPD remain enigmatic, alluding to the existence of potential undisclosed confounders.ConclusionBased on this MR analysis, we found a causal relationship between certain gut microbial communities and PPD. Future clinical studies can further explore the treatment of PPD through the combined use of microorganisms. This not only offers insights into the pathogenesis of PPD but also lays the foundation for utilizing gut microbiota as biotherapeutics in treating neurological disorders.

IntroductionHigh density lipoproteins (HDL) exert cardiovascular protection in part through their antioxidant capacity and cholesterol efflux function. Effects of exercise training on HDL function are yet to be well established, while impact on triacylglycerol (TG)-lowering has been often reported. We previously showed that a short-term high-intensity interval training (HIIT) program improves insulin sensitivity but does not inhibit inflammatory pathways in immune cells in insulin-resistant subjects. The purpose of this study is to evaluate HDL function along with changes of lipoproteins after the short-term HIIT program in lean, obese nondiabetic, and obese type 2 diabetic (T2DM) subjects.MethodsAll individuals underwent a supervised 15-day program of alternative HIIT for 40 minutes per day. VO2peak was determined before and after this training program. A pre-training fasting blood sample was collected, and the post-training fasting blood sample collection was performed 36 hours after the last exercise session.ResultsBlood lipid profile and HDL function were analyzed before and after the HIIT program. Along with improved blood lipid profiles in obese and T2DM subjects, the HIIT program affected circulating apolipoprotein amounts differently. The HIIT program increased HDL-cholesterol levels and improved the cholesterol efflux capacity only in lean subjects. Furthermore, the HIIT program improved the antioxidant capacity of HDL in all subjects. Data from multiple logistic regression analysis showed that changes in HDL antioxidant capacity were inversely associated with changes in atherogenic lipids and changes in HDL-TG content.DiscussionWe show that a short-term HIIT program improves aspects of HDL function depending on metabolic contexts, which correlates with improvements in blood lipid profile. Our results demonstrate that TG content in HDL particles may play a negative role in the anti-atherogenic function of HDL.

BackgroundLung cancer is a major health burden globally and smoking is a well-known risk factor. It has been observed that chronic inflammation contributes to lung cancer progression, with immune cells and inflammatory cytokines implicated in tumor development. Clarifying the causal links between these immune components and lung cancer could enhance prevention and therapy.MethodsWe performed Mendelian randomization (MR) to explore causal connections between immune cells, inflammatory markers, and lung cancer risk, using genetic variants as instruments. Data from GWAS on these variables underpinned our MR analyses.ResultsOur findings indicated an inverse association between some immune cells and lung cancer risk, implying that more immune cells might be protective. NK T cells (CD16-CD56) and myeloid cells (HLA DR+ on CD33dim HLA DR+ CD11b+) had an inverse correlation with lung cancer risk. Furthermore, a direct relationship was observed between inflammatory cytokines and these immune cells. In contrast, IL-18 was inversely associated with lung cancer, while IL-13 showed a direct correlation.ConclusionThe study underscores the role of immune and inflammatory factors in lung cancer. These insights could lead to new therapeutic strategies for combating lung cancer.

BackgroundThe association between birth weight and childhood body mass index (BMI) and frailty has been extensively studied, but it is currently unclear whether this relationship is causal.MethodsWe utilized a two-sample Mendelian randomization (MR) methodology to investigate the causal effects of birth weight and childhood BMI on the risk of frailty. Instrumental variables (p 0.05).ConclusionThis MR study provides evidence supporting a causal relationship between lower birth weight, higher childhood BMI, and an increased risk of frailty.

This document summarizes the physics schemes used in two configurations of the first version of the operational Hurricane Analysis and Forecast System (HAFSv1) at NOAA NCEP. The physics package in HAFSv1 is the same as that used in NCEP global forecast system (GFS) version 16 except for an additional microphysics scheme and modifications to sea surface roughness lengths, boundary layer scheme, and the entrainment rate in the deep convection scheme. Those modifications are specifically designed for improving the simulation of tropical cyclones (TCs). The two configurations of HAFSv1 mainly differ in the adopted microphysics schemes and TC-specific modifications in addition to model initialization. Experiments are made to highlight the impacts of TC-specific modifications and different microphysics schemes on HAFSv1 performance. Challenges and developmental plans of physics schemes for future versions of operational HAFS are discussed.

ObjectiveTo predict mortality in severe patients with COVID-19 at admission to the intensive care unit (ICU) using thromboelastography (TEG).MethodsThis retrospective, two-center, observational study involved 87 patients with PCR-and chest CT-confirmed severe COVID-19 who were admitted to at Wuhan Huoshenshan Hospital and the 908th Hospital of Chinese PLA Logistic Support Force between February 2020 and February 2023. Clinic demographics, laboratory results, and outcomes were compared between those who survived and those who died during hospitalization.ResultsThromboelastography showed that of the 87 patients, 14 were in a hypercoagulable state, 25 were in a hypocoagulable state, and 48 were normal, based on the time to maximum amplitude (TMA). Patients who died showed significantly lower α angle, but significantly longer R-time, K-time and TMA than patients who survived. Random forest selection showed that K-time, TMA, prothrombin time (PT), international normalized ratio (INR), D-dimer, C-reactive protein (CRP), aspartate aminotransferase (AST), and total bilirubin (Tbil) were significant predictors. Multivariate logistic regression identified that TMA and CRP were independently associated with mortality. TMA had a greater predictive power than CRP levels based on time-dependent AUCs. Patients with TMA ≥ 26.4 min were at significantly higher risk of mortality (hazard ratio 3.99, 95% Confidence Interval, 1.92–8.27, p

IntroductionTaurine has a prominent lipid-lowering effect on hyperlipidemia. However, a comprehensive analysis of the effects of taurine on endogenous metabolites in hyperlipidemia has not been documented. This study aimed to explore the impact of taurine on multiple metabolites associated with hyperlipidemia.MethodsThe hyperlipidemic mouse model was induced by high-fat diet (HFD). Taurine was administered via oral gavage at doses of 700 mg/kg/day for 14 weeks. Evaluation of body weight, serum lipid levels, and histopathology of the liver and adipose tissue was performed to confirm the lipid-lowering effect of taurine. Ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS)-based metabonomics analyses of serum, urine, feces, and liver, coupled with multivariate data analysis, were conducted to assess changes in the endogenous metabolites.Results and discussionBiochemical and histological examinations demonstrated that taurine administration prevented weight gain and dyslipidemia, and alleviated lipid deposition in the liver and adipose tissue in hyperlipidemic mice. A total of 76 differential metabolites were identified by UPLC-MS-based metabolomics approach, mainly involving BAs, GPs, SMs, DGs, TGs, PUFAs and amino acids. Taurine was found to partially prevent HFDinduced abnormalities in the aforementioned metabolites. Using KEGG database and MetaboAnalyst software, it was determined that taurine effectively alleviates metabolic abnormalities caused by HFD, including fatty acid metabolism, sphingolipid metabolism, glycerophospholipid metabolism, diacylglycerol metabolism, amino acid metabolism, bile acid and taurine metabolism, taurine and hypotaurine metabolism. Moreover, DGs, GPs and SMs, and taurine itself may serve as active metabolites in facilitating various anti-hyperlipidemia signal pathways associated with taurine. This study provides new evidence for taurine to prevent hyperlipidemia.

BackgroundThe role of drug repositioning in the treatment of ovarian cancer has received increasing attention. Although promising results have been achieved, there are also major controversies.MethodsIn this study, we conducted a drug-target Mendelian randomisation (MR) analysis to systematically investigate the reported effects and relevance of traditional drugs in the treatment of ovarian cancer. The inverse-variance weighted (IVW) method was used in the main analysis to estimate the causal effect. Several MR methods were used simultaneously to test the robustness of the results.ResultsBy screening 31 drugs with 110 targets, FNTA, HSPA5, NEU1, CCND1, CASP1, CASP3 were negatively correlated with ovarian cancer, and HMGCR, PLA2G4A, ITGAL, PTGS1, FNTB were positively correlated with ovarian cancer.ConclusionStatins (HMGCR blockers), lonafarnib (farnesyltransferase inhibitors), the anti-inflammatory drug aspirin, and the anti-malarial drug adiponectin all have potential therapeutic roles in ovarian cancer treatment.

Objectives: Nadroparin, a low-molecular-weight-heparin is commonly used off-label in neonates and infants for thromboembolic events prevention. However, the recommended dosing regimen often fails to achieve therapeutic target ranges. This study aimed to develop a population pharmacokinetic (PK) model of nadroparin to determine an appropriate dosing regimen for neonates and infants less than 8 months.Methods: A retrospective chart review was conducted on patients treated with nadroparin at Children’s Hospital of Fudan University between July 2021 and December 2023. A population PK model was developed using anti-Xa levels, and its predictive performance was evaluated internally. Monte Carlo simulations were performed to design an initial dosing schedule targeting anti-Xa levels between 0.5 and 1 IU/mL.Results: A total of 40 neonates and infants aged less than 8 months with gestational age ranging from 25 to 41 weeks treated with nadroparin were enrolled in the study for analysis. A one-compartment PK model with first order absorption and elimination was adequately fitted to the data. Creatinine clearance was identified as a significant factor contributing to inter-individual variability in clearance. The typical population parameter estimates of clearance, distribution volume and absorption rate in this population were 0.211 L/h, 1.55 L and 0.495 h-1, respectively. Our findings suggest that current therapeutic doses of nadroparin (150–200 IU/kg q12 h) may result in subtherapeutic exposure, thus higher doses might be required.Conclusion: The present study offers the first estimation of PK parameters for nadroparin in preterm or term neonates and infants less than 8 months utilizing the model. Our findings have potential implications for recommending initial personalized dosages, particularly among patient populations exhibiting similar characteristics.

Affected by geology and mining, a certain number of low-yield wells will appear after a period of production in coalbed methane wells, and technical repairs are urgently needed to restore their production capacity to the maximum. Therefore, it is of great significance to establish a reasonable and feasible theoretical standard to evaluate the workover priority of CBM wells for the efficient utilization of CBM resources. From the perspectives of technical feasibility and economic rationality, eight key indicators that affect the cost performance of CBM well workover are screened. Combining the entropy value method and the TOPSIS comprehensive ranking method, the surface coalbed methane well repair priority entropy value-TOPSIS comprehensive evaluation model was constructed, and the surface coalbed methane well repair priority evaluation was carried out by taking 9 surface coalbed methane wells that urgently needed to be repaired in a mine as the evaluation objects. The evaluation results show that among the economic indicators, the average gas production per meter in the 30 days before the coal bed methane well was stopped and the cumulative gas production per meter before the stop had a relatively high weight, which were 29.68% and 13.83% respectively, This shows that in coalbed methane well workover operations, the long-term gas production potential of the coalbed methane well and the gas production capacity when disturbed by harmful factors are the decisive factors affecting the priority of coalbed methane well workover; Among the technical indicators, the degree of casing deformation and the depth of the coalbed methane well have a relatively high weight, accounting for 11.34% and 9.90% respectively, This shows that the smaller the deformation of the wellbore casing and the shallower the depth of the coalbed methane well, the higher the priority of the workover of the coalbed methane well; The ranking of the production recovery rates of the three coalbed methane wells in the Pingdingshan mining area after workover operations is consistent with the results output by the evaluation model, which proves that the evaluation model is reasonable for determining the priority of workovers for damaged wellbores; This evaluation model can provide a theoretical reference for small and medium-sized coalbed methane development companies to determine the priority of workovers.

Immunoassay is a powerful tool for the rapid detection of small harmful organic molecules. In this study, a simple and sensitive fluoroimmunoassay (FIA) based on a nanobody-alkaline phosphatase fusion protein (VHHjd8-ALP) and blue-emissive carbon dots (bCDs) was developed for the rapid detection of fenitrothion. The bCDs were synthesized using the one-step hydrothermal method. Citric acid and urea were used as carbon and nitrogen sources, respectively. The synthesized bCDs were characterized by fluorescence spectrum, high-resolution transmission electron microscopy, x-ray photoelectron spectroscopy, and Fourier transform infrared spectroscopy. After one step of competitive immunoassay, the VHHjd8-ALP bound to the microplate and catalyzed the substrate p-nitrophenylphosphate (pNPP) into p-nitrophenol (pNP); the latter can quench the blue of bCDs due to an inner-filter effect. After condition optimization, an FIA calibration curve was finally created, which showed an IC50 value of 16.25 ng/mL and a limit of detection (LOD) of 0.19 ng/mL. Compared with the pNPP-based one-step conventional indirect competitive enzyme-linked immunoassay (icELISA), the developed FIA showed an 11-fold sensitivity improvement. Furthermore, the analysis period of FIA only takes approximately 55 min, which was obviously faster than that of the conventional icELISA. The recovery test showed recoveries from 81.8 to 119% with fruits and vegetable samples, which verified the practicability and accuracy of the developed FIA.

BackgroundPrevious observational studies have reported inconsistent findings regarding the incidence of cancer in patients with schizophrenia compared to the general population. The causal relationship between schizophrenia and cancer remains unclear and requires further investigation.ObjectiveTo investigate the causal relationship between schizophrenia and cancer.MethodsIn this study, a two-sample Mendelian randomization (MR) analysis was conducted using publicly available genome-wide association studies to determine the causal relationship. The effect estimates were calculated using the random-effects inverse-variance-weighted method.ResultsWe determined a causal relationship between genetic predisposition to schizophrenia and cancer, with schizophrenia increasing lung cancer (odds ratio (OR) = 1.0007; 95% confidence interval (CI), 1.0001-1.0013; p = 0.0192), thyroid cancer (OR = 1.5482; CI, 1.1112-2.1569; p =0.0098),colorectal cancer (OR = 1.0009; CI, 1.0001-1.0018; p = 0.0344), ovarian cancer (OR = 1.0770; CI, 1.0352-1.1203; p = 0.0002), breast cancer (OR = 1.0011; CI, 1.0001- 1.0022; p =0.0352) and reduced the risk of malignant neoplasm of the stomach (OR = 0.8502; CI, 0.7230-0.9998; p = 0.0496).ConclusionsThis study conducted a two-sample MR analysis and discovered a positive causal relationship between schizophrenia and breast, ovarian, thyroid, lung, and colorectal cancers. On the other hand, an inverse causal relationship was found between schizophrenia and malignant neoplasm of the stomach.

Background: Oral squamous cell carcinoma (OSCC) is one of the most common types of cancer worldwide. Although overall losses of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) have been previously observed, a genome-wide, single-base-resolution, and simultaneous mapping of 5mC and 5hmC in OSCC is still unaccomplished. Similarly, the mechanism of how 5mC and 5hmC collectively lead to abnormal gene expression in OSCC is largely unexplored. Using parallel whole-genome bisulfite sequencing (WGBS) and whole-genome oxidative bisulfite sequencing (oxWGBS), we characterized 5mC- and 5hmC-profiles at single-nucleotide resolution in paired primary OSCC samples and their normal adjacent tissues (NATs). We also analyzed the effect of 5mC- and 5hmC-modifications on differential gene expression in OSCC using multi-omics analysis.Results: An overall reduction of both 5mC and 5hmC in various genomic regions have been observed in OSCC samples. At promoter regions, a total of 6,921 differentially methylated regions and 1,024 differentially hydroxymethylated regions were identified in OSCC. Interestingly, compared to bidirectional modification with 5mC and 5hmC, unidirectional modification with 5mC and 5hmC at the promoters is associated with bigger change in the gene expression. Additionally, genes bearing unidirectional modification with 5mC and 5hmC at the promoters are enriched in signaling pathways like cell proliferation, cell differentiation, and receptor tyrosine kinase pathway that are essential for the tumorigenesis. Finally, the grouped expression signature of top 20 genes bearing promoter-unidirectional-modification with 5mC and 5hmC tends to correlate with the clinical outcome of certain subtypes of head and neck squamous cell carcinoma.Conclusion: Using parallel WGBS and oxWGBS analyses, we observed an overall reduction of 5mC- and 5hmC-modifications at various genomic regions in OSCC. Unidirectional modification with 5mC and 5hmC at the promoters is associated with enhanced changes in gene expression in OSCC tissues. Furthermore, such differentially expressed genes bearing unidirectional modifications with 5mC and 5hmC at the promoters might have clinical relevance to the outcome of OSCC.

During the 2022 hurricane season, real-time forecasts were conducted using an experimental version of the Hurricane Analysis and Forecast System (HAFS). The version of HAFS detailed in this paper (HAFSV0.3S, hereafter HAFS-S) featured the moving nest recently developed at NOAA AOML, and also model physics upgrades: TC-specific modifications to the planetary boundary layer (PBL) scheme and introduction of the Thompson microphysics scheme. The real-time forecasts covered a large dataset of cases across the North Atlantic and eastern North Pacific 2022 hurricane seasons, providing an opportunity to evaluate this version of HAFS ahead of planned operational implementation of a similar version in 2023. The track forecast results show that HAFS-S outperformed the 2022 version of the operational HWRF model in the Atlantic, and was the best of several regional hurricane models in the eastern North Pacific for track. The intensity results were more mixed, with a dropoff in skill at Days 4–5 in the Atlantic but increased skill in the eastern North Pacific. HAFS-S also showed some larger errors than the long-time operational Hurricane Weather Research and Forecasting (HWRF) model in the radius of 34-knot wind, but other radii metrics are improved. Detailed analysis of Hurricane Ian in the Atlantic highlights both the strengths of HAFS and opportunities for further development and improvement.

BackgroundChildhood trauma has been found to have an important impact on mental health. However, little is known regarding the intercorrelations between childhood trauma and mental health during the COVID-19 pandemic. This study aimed to investigate such complex interplay between childhood trauma, depression, anxiety, post-traumatic stress level during the COVID-19 pandemic, and fear of COVID-19 using network analysis.MethodsA total of 1,247 college students were recruited and were asked to complete a series of questionnaires, including the Childhood Trauma Questionnaire, Patient Health Questionnaire, Generalized Anxiety Disorder Scale, Post-traumatic Stress Checklist—Civilian version, and Fear of COVID-19 Scale. The Gaussian graphical model with the scores of the questionnaires as nodes was estimated. The partial correlations between nodes were calculated as edges. Moreover, network comparison tests were conducted to compare the network patterns between participants with high levels of childhood trauma and low levels of childhood trauma.ResultsChildhood trauma was found to be connected to depression, anxiety, and post-traumatic stress level. The node of childhood trauma exhibited the strongest strength and the highest expected influence in the network. Participants with high levels of childhood trauma and participants with low levels of childhood trauma showed comparable network structure and global strength.ConclusionOur findings revealed a complex network pattern between childhood trauma and different mental health problems, indicating that childhood trauma might be a risk factor for mental health during the COVID-19 pandemic.

Alcohol-related liver disease (ALD) from excessive alcohol intake has a unique gut microbiota profile. The disease progression-free survival in ALD patients has been associated with the degree of gut dysbiosis. The vicious cycles between gut dysbiosis and the disease progression in ALD including: an increase of acetaldehyde production and bile acid secretion, impaired gut barrier, enrichment of circulating microbiota, toxicities of microbiota metabolites, a cascade of pro-inflammatory chemokines or cytokines, and augmentation in the generation of reactive oxygen species. The aforementioned pathophysiology process plays an important role in different disease stages with a spectrum of alcohol hepatitis, ALD cirrhosis, neurological dysfunction, and hepatocellular carcinoma. This review aims to illustrate the pathophysiology of gut microbiota and clarify the gut-brain crosstalk in ALD, which may provide the opportunity of identifying target points for future therapeutic intervention in ALD.

Introduction: Familial adenomatous polyposis (FAP) is the second most commonly inherited colorectal cancer (CRC) predisposition caused by germline mutations within the adenomatous polyposis coli (APC) gene. The molecular defects and clinical manifestations of two FAP families were analyzed, and individual prevention strategies suitable for mutation carriers in different families were proposed.Methods and results: The pathogenic gene mutations were identified among the two families using whole-exome sequencing and verified with Sanger sequencing or quantitative polymerase chain reaction (qPCR). One novel (GRCh37:Chr5: 112145676–112174368, del, 28,692 bp) and a known (c.C847T:p.R283X) mutation in the APC gene were pathogenic mutations for FAP, according to the sequencing data and tumorigenesis pattern among the family members. The two mutations led to a premature translational stop signal, synthesizing an absent or disrupted protein product.Conclusion: Our findings expand the known germline mutation spectrum of the APC gene among the Chinese population. This reaffirms the importance of genetic testing in FAP. Genetic consultation and regular follow-ups are necessary for the individualized treatment of cancer-afflicted families with APC expression deficiency. Additional work is required to develop safe and effective chemotherapy and immunotherapy for FAP based on the mutation type.

BackgroundSymptomatic intracranial atherosclerotic stenosis (sICAS) is one of the common causes of ischemic stroke. However, the treatment of sICAS remains a challenge in the past with unfavorable findings. The purpose of this study was to explore the effect of stenting versus aggressive medical management on preventing recurrent stroke in patients with sICAS.MethodsWe prospectively collected the clinical information of patients with sICAS who underwent percutaneous angioplasty and/or stenting (PTAS) or aggressive medical therapy from March 2020 to February 2022. Propensity score matching (PSM) was employed to ensure well-balanced characteristics of two groups. The primary outcome endpoint was defined as recurrent stroke or transient ischemic attack (TIA) within 1 year.ResultsWe enrolled 207 patients (51 in the PTAS and 156 in the aggressive medical groups) with sICAS. No significant difference was found between PTAS group and aggressive medical group for the risk of stroke or TIA in the same territory beyond 30 days through 6 months (P = 0.570) and beyond 30 days through 1 year (P = 0.739) except for within 30 days (P = 0.003). Furthermore, none showed a significant difference for disabling stroke, death and intracranial hemorrhage within 1 year. These results remain stable after adjustment. After PSM, all the outcomes have no significant difference between these two groups.ConclusionThe PTAS has similar treatment outcomes compared with aggressive medical therapy in patients with sICAS across 1-year follow-up.

Grid-connected permanent magnet synchronous generator (PMSG) wind farms may be susceptible to oscillation when connected to weak grids. This paper explores the root causes of the oscillations from two perspectives: the model and the oscillation frequency band. First, the small signal model of PMSG wind farm grid-side system is established, and the small disturbance comparison with the PMSGA full-order electromagnetic transient model in MATLAB/Simulink is carried out. Then, we calculatue the eigenvalues of the small signal model and use model analysis techniques such as participation factors calculation and root locus method to identify the critical factors that cause the oscillation modes to be dominant. Finally, time-domain simulation is used to verify the theoretical analysis. Two dominant modes are identified: the subsynchronous oscillation mode and the low-frequency oscillation mode. The subsynchronous oscillation mode is closely related to the direct current (DC) voltage control and the dynamics of DC link. The low-frequency oscillation is significantly weakened with the decrease in grid strength, and it is closely related to the phase-locked loop (PLL) control. The conclusions can provide a reference for tuning the control parameters of PMSG converter.

In order to enhance self-monitoring and self-diagnosis capabilities in smart distribution networks, this paper proposes a method for assessing the health level of the network based on multivariate information. First, we construct an evaluation indicator system for the health of the smart distribution network by integrating the smart distribution network information system. Next, we utilize the improved back propagation (BP) neural network and multivariate indicator information to calculate the health indexes of both the grid layer and equipment. We then solve the health index of the equipment layer based on network topology and goal-oriented methodology. Furthermore, by utilizing the health information of both the equipment and grid layer, we apply fuzzy evaluation and Dempster-Shafer (D-S) evidence theory to obtain the health level of the distribution network. We provide a comprehensive evaluation of the overall health status of the smart distribution network. Finally, the proposed method is validated using data from a regional distribution network. The results demonstrate its effectiveness in improving the smart distribution networks’ overall health and stability by enabling more effective self-monitoring and self-diagnosis.

Introduction: The tumor microenvironment (TME) is mainly characterized by abnormally elevated intracellular redox levels and excessive oxidative stress. However, the balance of the TME is also very fragile and susceptible to be disturbed by external factors. Therefore, several researchers are now focusing on intervening in redox processes as a therapeutic strategy to treat tumors. Here, we have developed a liposomal drug delivery platform that can load a Pt(IV) prodrug (DSCP) and cinnamaldehyde (CA) into a pH-responsive liposome to enrich more drugs in the tumor region for better therapeutic efficacy through enhanced permeability and retention effect.Methods: Using the glutathione-depleting properties of DSCP together with the ROS-generating properties of cisplatin and CA, we synergistically altered ROS levels in the tumor microenvironment to damage tumor cells and achieve anti-tumor effects in vitro.Results: A liposome loaded with DSCP and CA was successfully established, and this liposome effectively increased the level of ROS in the tumor microenvironment and achieved effective killing of tumor cells in vitro.Conclusion: In this study, novel liposomal nanodrugs loaded with DSCP and CA provided a synergistic strategy between conventional chemotherapy and disruption of TME redox homeostasis, leading to a significant increase in antitumor effects in vitro.

BackgroundRepetitive transcranial magnetic stimulation (rTMS) has been increasingly used as a treatment modality for chronic insomnia disorder (CID). However, our understanding of the mechanisms underlying the efficacy of rTMS is limited.ObjectiveThis study aimed to investigate rTMS-induced alterations in resting-state functional connectivity and to find potential connectivity biomarkers for predicting and tracking clinical outcomes after rTMS.MethodsThirty-seven patients with CID received a 10-session low frequency rTMS treatment applied to the right dorsolateral prefrontal cortex. Before and after treatment, the patients underwent resting-state electroencephalography recordings and a sleep quality assessment using the Pittsburgh Sleep Quality Index (PSQI).ResultsAfter treatment, rTMS significantly increased the connectivity of 34 connectomes in the lower alpha frequency band (8–10 Hz). Additionally, alterations in functional connectivity between the left insula and the left inferior eye junction, as well as between the left insula and medial prefrontal cortex, were associated with a decrease in PSQI score. Further, the correlation between the functional connectivity and PSQI persisted 1 month after the completion of rTMS as evidenced by subsequent electroencephalography (EEG) recordings and the PSQI assessment.ConclusionBased on these results, we established a link between alterations in functional connectivity and clinical outcomes of rTMS, which suggested that EEG-derived functional connectivity changes were associated with clinical improvement of rTMS in treating CID. These findings provide preliminary evidence that rTMS may improve insomnia symptoms by modifying functional connectivity, which can be used to inform prospective clinical trials and potentially for treatment optimization.

BackgroundMultinational studies have reported that the implementation of nonpharmaceutical interventions (NPIs) to control severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission coincided with the decline of other respiratory viruses, such as influenza viruses and respiratory syncytial virus.ObjectiveTo investigate the prevalence of common respiratory viruses during the coronavirus disease 2019 (COVID-19) pandemic.MethodsRespiratory specimens of children with lower respiratory tract infections (LRTIs) hospitalized at the Children’s Hospital of Chongqing Medical University from January 1, 2018 to December 31, 2021 were collected. Seven common pathogens, including respiratory syncytial virus (RSV), adenovirus (ADV), influenza virus A and B (Flu A, Flu B), and parainfluenza virus types 1–3 (PIV1–3), were detected by a multiplex direct immunofluorescence assay (DFA). Demographic data and laboratory test results were analyzed.Results1) A total of 31,113 children with LRTIs were enrolled, including 8141 in 2018, 8681 in 2019, 6252 in 2020, and 8059 in 2021.The overall detection rates decreased in 2020 and 2021 (P < 0.001). The detection rates of RSV, ADV, Flu A, PIV-1, and PIV-3 decreased when NPIs were active from February to August 2020, with Flu A decreasing most predominantly, from 2.7% to 0.3% (P < 0.05). The detection rates of RSV and PIV-1 resurged and even surpassed the historical level of 2018–2019, while Flu A continued decreasing when NPIs were lifted (P < 0.05). 2) Seasonal patterns of Flu A completely disappeared in 2020 and 2021. The Flu B epidemic was observed until October 2021 after a long period of low detection in 2020. RSV decreased sharply after January 2020 and stayed in a nearly dormant state during the next seven months. Nevertheless, the detection rates of RSV were abnormally higher than 10% in the summer of 2021. PIV-3 decreased significantly after the COVID-19 pandemic; however, it atypically surged from August to November 2020.ConclusionThe NPIs implemented during the COVID-19 pandemic affected the prevalence and seasonal patterns of certain viruses such as RSV, PIV-3, and influenza viruses. We recommend continuous surveillance of the epidemiological and evolutionary dynamics of multiple respiratory pathogens, especially when NPIs are no longer necessary.

BackgroundLymph node (LN) metastasis is strongly associated with distant metastasis of renal cell carcinoma (RCC) and indicates an adverse prognosis. Accurate LN-status prediction is essential for individualized treatment of patients with RCC and to help physicians make appropriate surgical decisions. Thus, a prediction model to assess the hazard index of LN metastasis in patients with RCC is needed.MethodsPartial data were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Data of 492 individuals with RCC, collected from the Southwest Hospital in Chongqing, China, were used for external validation. Eight indicators of risk of LN metastasis were screened out. Six machine learning (ML) classifiers were established and tuned, focused on predicting LN metastasis in patients with RCC. The models were integrated with big data analytics and ML algorithms. Based on the optimal model, we developed an online risk calculator and plotted overall survival using Kaplan–Meier analysis.ResultsThe extreme gradient-boosting (XGB) model was superior to the other models in both internal and external trials. The area under the curve, accuracy, sensitivity, and specificity were 0.930, 0.857, 0.856, and 0.873, respectively, in the internal test and 0.958, 0.935, 0.769, and 0.944, respectively, in the external test. These parameters show that XGB has an excellent ability for clinical application. The survival analysis showed that patients with predicted N1 tumors had significantly shorter survival (p

BackgroundDiversion colitis (DC) is nonspecific inflammation of the distal intestinal mucosa following disruption of colonic continuity with colonic dysfunction. The colonscopic score is a good tool for differentiating the severity of patients with DC. At present, no studies have analyzed the pathogenesis of DC from the perspective of the diversity and and differences of intestinal flora.MethodsRetrospective study: Clinical information were collected from patients with low rectal cancer admitted to the Department of Anorectal Surgery, Changzheng Hospital, from April 2017 to April 2019. These patients underwent laparoscopic low anterior resection (LAR) combined with terminal ileum enterostomy (dual-chamber). We used chi-square test to comparethe clinical baseline information, clinical symptoms, and colonscopic characteristics between different severity of DC. Propsective oberservational study: We recruited 40 patients with laparoscopic anterior low resection combined with terminal ileum enterostomy and they were further classified into mild group and severe group according to the scores of colonscopic examinations for DC. 16s-rDNA sequencing was carried out to analyze the diversity and and differences of intestinal flora in the intestinal lavage fluid of the two groups.ResultsIn retrospective study, we found that age, BMI, history of diabetes, and symptoms associated with the stoma state were the independent risk factors that affect DC severity (P

A 54-year-old man complained of episodic stinging in his left eye along with weakness and numbness in his right upper and lower extremities for 1 month. The neurological examination was negative. MRI showed bilateral paraventricular demyelination. CTA showed significant stenosis of the left internal carotid (60%) and vertebral arteries (70%). He underwent left internal carotid stenting and was intubated during the procedure. After the procedure, he did not wake up from anesthesia, and he developed flexion and spasticity in the right arm immediately. Thereafter, he was sent to the neurocritical unit (NCU). Anti-seizure treatment was adopted due to recurrent general tonic-clonic seizures. Two days later (day 15 of hospitalization), brain edema and meningitis appeared in MRI, and contrast-induced encephalopathy (CIE) was mainly considered, with the support of CSF results. After 18 days (day 21 of hospitalization), serum anti-neurexin-3α IgG was detected at a dilution of 1:10. Anti-neurexin-3α-associated encephalitis was diagnosed. The patient was fully recovered 7 months after taking immunoglobulin, steroids, mortimycophenate, and cyclophosphamide. Meanwhile, anti-neurexin-3α antibody IgG was negative in both CSF and serum. MRI was also normal. Although scarce evidence clarified the relationship between CIE and anti-neurexin-3α-associated encephalitis, we inferred that the BBB damaged by CIE may result in the anti-neurexin-3α antibody entrance into the CSF from serum, which led to autoimmune encephalitis (AIE).

Chromatin accessibility is a generic property of the eukaryotic genome, which refers to the degree of physical compaction of chromatin. Recent studies have shown that chromatin accessibility is cell type dependent, indicating chromatin heterogeneity across cell lines and tissues. The identification of markers used to distinguish cell types at the chromosome level is important to understand cell function and classify cell types. In the present study, we investigated transcriptionally active chromosome segments identified by sci-ATAC-seq at single-cell resolution, including 69,015 cells belonging to 77 different cell types. Each cell was represented by existence status on 20,783 genes that were obtained from 436,206 active chromosome segments. The gene features were deeply analyzed by Boruta, resulting in 3897 genes, which were ranked in a list by Monte Carlo feature selection. Such list was further analyzed by incremental feature selection (IFS) method, yielding essential genes, classification rules and an efficient random forest (RF) classifier. To improve the performance of the optimal RF classifier, its features were further processed by autoencoder, light gradient boosting machine and IFS method. The final RF classifier with MCC of 0.838 was constructed. Some marker genes such as H2-Dmb2, which are specifically expressed in antigen-presenting cells (e.g., dendritic cells or macrophages), and Tenm2, which are specifically expressed in T cells, were identified in this study. Our analysis revealed numerous potential epigenetic modification patterns that are unique to particular cell types, thereby advancing knowledge of the critical functions of chromatin accessibility in cell processes.

IntroductionIn marine ecosystems, microbial communities are important drivers of material circulation and energy flow. The complex interactions between phytoplankton and bacterial communities constitute one of the most crucial ecological relationships in the marine environment. Inorganic nitrogen can affect the type of relationship between algae and bacteria. However, the quantitative relationship between the bacterial communities, inorganic nitrogen, and phytoplankton remains unclear.MethodsUnder laboratory conditions, we altered the forms (nitrate and ammonium) and amounts of nitrogen sources to study the dynamics of bacterial biomass, diversity, and community structure in the phycosphere of the marine model species Phaeodactylum tricornutum. The bacterial community structure during P. tricornutum growth was analyzed using Illumina HiSeq sequencing of 16S rDNA amplicons.ResultsThe results indicated that inorganic nitrogen concentration was the main factor promoting P. tricornutum biomass growth. The change in the algal biomass would significantly increase the phycosphere bacterial biomass. The bacterial biomass in the algal-bacteria co-culture system was 1.5 ~ 5 times that of the conditional control groups without microalgae under the same culture conditions. The variation of P. tricornutum biomass also affected the bacterial communities in the phycosphere. When P. tricornutum was in the exponential phase (96 ~ 192 h), the bacterial community structure differed between the high- and low-concentration groups. The difference in the bacterial communities over time in the high-concentration groups was more prominent than in the low-concentration groups. Under high-concentration groups (HA and HN), the relative abundance of Marivita and Marinobacter, engaged in the transformation of aquatic inorganic nitrogen, gradually decreased with time. However, the relative abundance of Oceanicaulis, closely related to algal growth, gradually increased with time.DiscussionThe above phenomena might be related to the change in P. tricornutum biomass. Our results explain when and how the phycosphere bacterial communities responded to algal biomass variations. The study provides a foundation for the quantitative relationship among nutrients, microalgae, and bacteria in this system.

Main pointOur retrospective analysis of a large number of cases found in patients with primary colorectal cancer (CRC) carrying positive HBsAg inhibited the occurrence of synchronous liver metastases (SLM). However, liver cirrhosis caused by non-HBV factors promoted the occurrence of SLM.ObjectivesThis study aimed to investigate the effect of HBV on the occurrence of synchronous liver metastases (SLM) of colorectal cancer (CRC).MethodsUnivariate and multivariate analyses were used to analyze the influence of clinical parameters on the occurrence of SLM.ResultsA total of 6, 020 patients with primary CRC were included in our study, of which 449 patients carrying HBsAg(+) accounted for 7.46%. 44 cases of SLM occurred in the HBsAg(+) group, accounting for 9.80%, which was much lower than 13.6% (758/5571) in the HBsAg(-) group (X=5.214, P=0.022). Among CRC patients with HBsAg(-), the incidence of SLM was 24.9% and 14.9% in the group with high APRI and FIB-4 levels, respectively, which were significantly higher than that in the compared groups (12.3% and 12.5%, all P

Objective: This study’s purpose was to investigate the effects of different intensities of physical activity on cardiovascular metabolism in obese children and adolescents based on an isochronous replacement model.Methods: A total of 196 obese children and adolescents (mean age, 13.44 ± 1.71 years) who met the inclusion criteria and attended a summer camp from July 2019 to August 2021 were recruited for this study, and all subjects wore a GT3X + triaxial motion accelerometer uniformly around the waist to record physical activity levels. We collected the subjects’ height, weight, and cardiovascular risk factors such as waist circumference, hip circumference, fasting lipids, blood pressure, fasting insulin, and fasting glucose before and after 4 weeks of camp and constructed cardiometabolic risk score (CMR-z). We analyzed the effects of different intensities of physical activity on cardiovascular metabolism in obese children using isotemporal substitution model (ISM).Results: After 4 weeks, cardiovascular risk factors such as body weight, waist circumference, triglyceride, and total cholesterol were reduced in adolescents with obesity (p

ObjectiveTo explore the use of 99mTc-rituximab tracer injection for internal mammary sentinel lymph node (IM-SLN) detection in patients with primary breast cancer.MethodsThis prospective observational study enrolled female patients with primary breast cancer between September 2017 and June 2022 at Fujian Provincial Hospital. The participants were divided into the peritumoral group (two subcutaneous injection points on the surface of the tumor), two-site group (injections into the glands at 6 and 12 o’clock around the areola area), and four-site group (injections into the gland at 3, 6, 9, and 12 o’clock around the areola area). The outcomes were the detection rates of the IM-SLNs and axillary sentinel lymph nodes (A-SLNs).ResultsFinally, 133 patients were enrolled, including 53 in the peritumoral group, 60 in the two-site group, and 20 in the four-site group. The detection rate of the IM-SLNs in the peritumoral group (9.4% [5/53]) was significantly lower than in the two-site (61.7% [37/60], P

BackgroundThis study aims to analyze the research hotspots, evolution, and developing trends in pediatric bronchiectasis over the past 20 years using bibliometric analysis and visualization tools to identify potential new research directions.MethodsPublications related to bronchiectasis in children were retrieved from the Web of Science Core Collection (WoSCC) database from 2003 to 2022. Knowledge maps were performed through VOSviewer1.6.18 and CiteSpace6.1 R2.ResultsA total of 2,133 publications were searched, while only 1,351 original articles written in English between 2003 and 2022 were incorporated. After removing duplicates, we finally included 1,350 articles published by 6,593 authors from 1,865 institutions in 80 countries/regions in 384 different academic journals with an average citation frequency of 24.91 times. The number of publications shows an extremely obvious binomial growth trend. The majority of publications originated from the United States, Australia, and England. The institutes in Australia, especially Charles Darwin University, published the most articles associated with pediatric bronchiectasis. In addition, Pediatric Pulmonology was the most published journal. In terms of authors, Chang AB was the most productive author, while Gangell CL had the highest average citation frequency. The five keywords that have appeared most frequently during the last two decades were “children,” “cystic fibrosis,” “bronchiectasis,” “ct,” and “pulmonary-function.” According to keyword analysis, early diagnosis and intervention and optimal long-term pediatric-specific management were the most concerned topics for researchers.ConclusionThis bibliometric analysis indicates that bronchiectasis in children has drawn increasing attention in the last two decades as its recognition continues to rise, providing scholars in the field with significant information on current topical issues and research frontiers.

Background: Under the guidance of carbon peak and carbon neutral targets, China’s economic development is facing unprecedented challenges. It is of great strategic significance and value to study the integrated development of regional low-carbon economy. The harmonious development of Beijing-Tianjin-Hebei (Beijing-Tianjin-Hebei) has become a national strategy, and its importance is prominent.Objective: To promote the regional economic integration of Beijing-Tianjin-Hebei is the top priority of promoting the development of Beijing-Tianjin-Hebei integration at present, and is the key to achieving the coordinated development and mutual benefit of Beijing-Tianjin-Hebei.Methods: In this context, this paper studies the fuzzy control evaluation algorithm of regional economy based on SDM model. Realized the prediction of the expansion of the low-carbon economy in Beijing-Tianjin-Hebei, and put forward the development strategy of the economic integration of Beijing-Tianjin-Hebei. The ranking of regional competitiveness of fuzzy control evaluation method is in line with the reality of today’s economic expansion. The application of fuzzy rules improves the speed, accuracy and objectivity of evaluation.Results: The final experiment shows that the accuracy of the algorithm is very high, reaching 95.14%. In addition, the algorithm has higher efficiency and better performance. The fuzzy control evaluation algorithm of regional economy can better predict the economic growth of Beijing, Tianjin and Hebei.Conclusion: Propose the development strategy of Beijing-Tianjin-Hebei low-carbon economic integration to further promote the development of Beijing-Tianjin-Hebei integration and promote the adjustment and optimization of China’s economic structure.

Objective: This study aims to explore the dose-response relationship between the daily duration of moderate to vigorous physical activity and the improvement of cardiometabolic risk indicators in obese children and adolescents.Methods: Seventy-seven obese children and adolescents aged 10–17 years were randomly recruited for a 4-week exercise intervention in a closed camp during 2019–2021, physical activity was monitored by ActiGraph GT3X + to obtain daily MVPA duration, and the improvement of CMR indicators were reflected by the changes (Δ) of waist circumference, systolic blood pressure, diastolic blood pressure, total cholesterol, triglyceride , high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, fasting insulin, fasting plasma glucose, and homeostasis model assessment of insulin resistance before and after the intervention, calculated as ‘‘Δ+indicator” = values after intervention–values before intervention. The groups were divided into different doses of Q1∼Q3 according to the daily MVPA duration from low to high. The differences in the improvement of different dose groups were compared by one-way analysis of covariance, and the dose-response relationship between MVPA duration and CMR indicators improvement was analyzed by linear regression and piecewise regression. The nonlinear relationship was analyzed by restricted cubic spline.Results: 1) Compared with indicators before the intervention, WC, SBP, DBP, TC, TG, HDL-C, LDL-C, FINS, and HOMA-IR were significantly lower after the intervention (p-value < 0.05). 2) The dose-response relationship between MVPA and LDL-C improvement was non-linear (P-Nonlinear < 0.05). When MVPA >77.1min/day, ΔLDL-C further decreased with the increase of MVPA duration [β = −0.009, 95% confidence interval (CI): −0.013, −0.005], and when MVPA ≤77.1min/day, increasing the MVPA duration did not increase the improvement of ΔLDL-C.Conclusion: There was a nonlinear dose-response relationship between the daily MVPA duration and LDL-C improvement in obese children and adolescents. In order to obtain more significant improvement in LDL-C through increased MVPA duration, MVPA duration should be higher than 77.1 min/day.

Compared to conventional DC transmission, Voltage source converter based high voltage direct current transmission (VSC-HVDC) has the advantages of independently controllable transmission power, no commutation failure, no reactive power compensation and low harmonic levels. However, VSC-HVDC transmission cannot provide effective frequency support and regulation for the system after grid connection. For this reason, an adaptive neural fuzzy virtual inertia control method is proposed to impose a control strategy on the converter at the receiving end of a VSC-HVDC transmission. The method uses the frequency change rate and the amount of change of frequency as constraints to dynamically adjust the virtual inertia and damping coefficients. It provides larger inertial support when the frequency fluctuation is large and smaller inertial support when the frequency fluctuation is small, thus adapting to different operating conditions. Finally, a hardware-in-the-loop simulation platform is built. The superiority and application prospect of the proposed strategy in frequency stability of the system are verified by comparing the proposed strategy with the traditional virtual control strategy.

BackgroundHepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide, and CD4+ T lymphocytes can inhibit hepatocarcinogenesis and mediate tumor regression. However, few studies have focused on the prognostic power of CD4+ Tconv-related lncRNAs in HCC patients.MethodWe obtained data from TCGA and GEO databases and identified CD4+Tconv-related lncRNAs in HCC. The risk score was constructed using lasso regression and the model was validated using two validation cohorts. The RS was also assessed in different clinical subgroups, and a nomogram was established to further predict the patients’ outcomes. Furthermore, we estimated the immune cell infiltration and cancer-associated fibroblasts (CAFs) through TIMER databases and assessed the role of RS in immune checkpoint inhibitors response.ResultsWe constructed a CD4+ Tconv-related lncRNAs risk score, including six lncRNAs (AC012073.1, AL031985.3, LINC01060, MKLN1-AS, MSC-AS1, and TMCC1-AS1), and the RS had good predictive ability in validation cohorts and most clinical subgroups. The RS and the T stage were included in the nomogram with optimum prediction and the model had comparable OS prediction power compared to the AJCC. Patients in the high-risk group had a poor immune response phenotype, with high infiltrations of macrophages, CAFs, and low infiltrations of NK cells. Immunotherapy and chemotherapy response analysis indicated that low-risk group patients had good reactions to immune checkpoint inhibitors.ConclusionWe constructed and validated a novel CD4+ Tconv-related lncRNAs RS, with the potential predictive value of HCC patients’ survival and immunotherapy response.

New anti-cancer drugs are constantly being developed, especially targeted drugs. Although these drugs have achieved significant clinical efficacy, they do not play a significant role in ovarian cancer. Moreover, the research cycle and costs of such drugs are often huge. The repositioning of conventional drugs has gradually become a concern. Statins, as traditional lipid-lowering drugs, play a role mainly by inhibiting HMGCR. In recent years, epidemiological studies and in vitro experiments have confirmed its anti-cancer effect, especially the effect of anti-ovarian cancer. The mutation rate of TP53 in ovarian cancer is as high as 95%, while HMGCR is often highly expressed in TP53 mutant tumors. However, the effect of prospective clinical trials is not ideal. This result seems understandable considering that it seems unrealistic for a lipid-lowering drug to completely inhibit tumor growth. Therefore, statins play more synergistic roles in the treatment of ovarian cancer. Because ovarian cancer is a highly heterogeneous tumor, it may be a good choice to deeply understand the mechanism of statins in the treatment of ovarian cancer and achieve precise treatment by combining it with other drugs.

IntroductionSpinal muscular atrophy (SMA) is a rare autosomal-recessive neuromuscular disease. Health state utility values (HSUV) are used in health economic evaluation regarding the desirability of health outcomes such as a certain health state or change in health states over time. There is no utility data of Chinese patients with SMA.Materials and methodsVignettes were developed for 10 pediatric neurologists to value the utility of Chinese patients with Type I SMA. A mixed patient/proxy derived approach using EQ-5D-Y-3L, EQ-5D-3L, and CHU9D was adopted to estimate the HSUV data of patients with Type II and III SMA, including 112 patients and 301 caregivers.ResultThe utility of Type I SMA patients ranged from 0.19 to 0.72 with the health state improved from “permanent ventilation” to “walking”. The utility of children patients with Type II and III SMA derived from EQ-5D-Y-3L ranged from 0.33 to 0.82 while that derived from CHU9D ranged from 0.46 to 0.75. The utility of adult patients with Type II and III SMA measured by EQ-5D-3L ranged from 0.30 to 0.83.ConclusionThe better health states the patients with SMA were in, the higher were the HSUV. The utilities derived from population with different age and disease subtypes were not statistically different when patients with SMA were in the same health states. We recommend further studies on the Chinese specific value set for EQ-5D-Y-3L and other PBMs for children to derive more robust utility data.

Stigmasterol is a phytosterol derived from multiple herbaceous plants such as herbs, soybean and tobacco, and it has received much attention for its various pharmacological effects including anti-inflammation, anti-diabetes, anti-oxidization, and lowering blood cholesterol. Multiple studies have revealed that stigmasterol holds promise as a potentially beneficial therapeutic agent for malignant tumors because of its significant anti-tumor bioactivity. It is reported that stigmasterol has anti-tumor effect in a variety of malignancies (e.g., breast, lung, liver and ovarian cancers) by promoting apoptosis, inhibiting proliferation, metastasis and invasion, and inducing autophagy in tumor cells. Mechanistic study shows that stigmasterol triggers apoptosis in tumor cells by regulating the PI3K/Akt signaling pathway and the generation of mitochondrial reactive oxygen species, while its anti-proliferative activity is mainly dependent on its modulatory effect on cyclin proteins and cyclin-dependent kinase (CDK). There have been multiple mechanisms underlying the anti-tumor effect of stigmasterol, which make stigmasterol promising as a new anti-tumor agent and provide insights into research on its anti-tumor role. Presently, stigmasterol has been poorly understood, and there is a paucity of systemic review on the mechanism underlying its anti-tumor effect. The current study attempts to conduct a literature review on stigmasterol for its anti-tumor effect to provide reference for researchers and clinical workers.

Introduction: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal-dominant systemic vascular disease that primarily involves small arteries. Patients with CADASIL experience migraines, recurrent ischemic strokes, cognitive decline, and dementia. The NOTCH3 gene, which is located on chromosome 19p13.12, is one of the disease-causing genes in CADASIL. Herein, we investigate the genetic and phenotypic features in a Chinese CADASIL family with heterozygous NOTCH3 mutation.Methods and Results: In the family, the proband suffered from dizziness, stroke, and cognitive deficits. Brain magnetic resonance imaging (MRI) demonstrated symmetrical white matter lesions in the temporal lobe, outer capsule, lateral ventricle, and deep brain. Whole-exome sequencing identified a known missense mutation in the proband, c.397C>T (p.Arg133Cys), which was identified in his son and granddaughter using Sanger sequencing. The proband’s younger brother and younger sister also have a history of cognitive impairment or cerebral infarction, but do not have this genetic mutation, which may highlight the impact of lifestyle on this neurological disease.Conclusion: We identified a known CADASIL-causing mutation NOTCH3 (c.397C>T, p.Arg133Cys) in a Chinese family. The clinical manifestations of mutation carriers in this family are highly heterogeneous, which is likely a common feature for the etiology of different mutations in CADASIL. Molecular genetic analyses are critical for accurate diagnosis, as well as the provision of genetic counselling for CADASIL.

IntroductionMicrobial contamination in farmlands is usually underestimated and understudied. Different fertilization times and manure origins might introduce and change the microorganism diversity in farmland soils and thus might influence the abundance and persistence of microbial contamination including antibiotic resistance genes (ARGs), human bacterial pathogens (HBPs), and virulence factor genes (VFGs).MethodsA 0.5-/1.5-year fertilization experiment was performed, and metagenomic sequencing was conducted to quantify microbial contamination. The resistomes of soil samples revealed that ARGs against antibiotics which were extensively used in veterinary medicine as well as clinically critical ARGs (CCARGs) persisted in manure-amended soils. Here the extended-spectrum beta-lactamase and carbapenemase bla genes, the high-level mobilized colistin resistance gene mcr, the tigecycline resistance gene tet(X), and the vancomycin resistance gene van, all of which can circumvent the defense line of these “last-resort” antibiotics were selected to investigate CCARG pollution in farm environments.ResultsA total of 254 potential HBPs and 2106 VFGs were detected in soil samples. Overall, our results revealed that (1) farmland soils could serve as a reservoir of some important bla, mcr, tet(X), and van gene variants, (2) the diversity and relative abundance of HBPs and VFGs increased significantly with incremental fertilization times and were discrepant among different manureamended soils, and (3) most CCARGs and VFGs coexisted in HBPs.DisscusionThe results of this study suggested a biological risk of manure in spreading antimicrobial resistance and pathogenicity.