ObjectiveTo observe the effects of modified Chaihu Shugansan on the calmodulin-dependent protein kinase Ⅱ（CaMKⅡ）/cAMP-response element binding protein （CREB） signaling pathway in the hippocampus and heart tissue of a rat model with myocardial ischemia and depression and explore the mechanism by which this formula prevents and treats coronary heart disease combined with depression. MethodsThe model of myocardial ischemia combined with depression was established by high-fat diet， intraperitoneal injection of isoproterenol （ISO）， and chronic unpredictable mild stress （CUMS）. A total of 108 SD male rats were randomly divided into normal group， model group， high （23.4 g·kg^-1）， medium （11.7 g·kg^-1）， and low （5.85 g·kg^-1） dose groups of modified Chaihu Shugansan， CaMKⅡ inhibitor （KN93） group， and KN93 + high， medium， and low dose groups of modified Chaihu Shugansan， with 12 rats in each group. From the first day of modeling to the end of modeling， drugs were administered once a day. In the seventh and eighth weeks， the KN93 group and the KN93 + high， medium， and low dose groups of modified Chaihu Shugansan were intraperitoneally injected with KN93 three times weekly. At the end of the eighth week， behavioral tests including sucrose preference， open field， and elevated plus maze were conducted. Electrocardiogram （ECG） lead Ⅱ changes were observed in each group of rats， and hematoxylin-eosin （HE） staining was performed to observe changes in heart tissue. Serum levels of triglycerides （TG）， total cholesterol （TC）， high-density lipoprotein （HDL）， low-density lipoprotein （LDL）， and lactate dehydrogenase （LDH） were measured by using an enzyme-labeled instrument. Creatine kinase （CK） and creatine kinase-MB （CK-MB） were detected by ultraviolet spectrophotometry， while serum monocyte chemoattractant protein-1 （MCP-1） was measured by enzyme-linked immunosorbent assay （ELISA）. Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） was used to detect mRNA expression of CaMKⅡ and CREB in hippocampal and heart tissue， and Western blot was performed to assess protein expression of CaMKⅡ， phosphorylated （p）-CaMKⅡ， CREB， and p-CREB. ResultsCompared to the normal group， the model group showed significant reductions in sucrose preference rate， total activity distance in the open field， number of entries into the center area of the open field， and percentage of entries into the open arms of the elevated plus maze （P<0.01）. The ECG showed ST-segment elevation， and HE staining showed serious degeneration of myocardial fibers， disordered arrangement， and infiltration of a large number of inflammatory cells. In addition， serum TC and LDL levels increased （P<0.01）， and HDL level decreased （P<0.01）. CK， CK-MB， LDH， and MCP-1 levels significantly increased （P<0.05， P<0.01）. The mRNA expression of CaMKⅡ and CREB and the protein expression of p-CaMKⅡ and p-CREB decreased in the hippocampal tissue （P<0.05， P<0.01）， but those increased in the heart tissue （P<0.01）. Compared to the model group， the high， medium， and low dose groups of modified Chaihu Shugansan showed improvements in these abnormalities. The KN93 group had reduced sucrose preference， total activity distance in the open field， number of entries into the center area of the open field， and percentage of entries into the open arms of the elevated plus maze （P<0.01）， as well as decreased serum CK， CK-MB， LDH， and MCP-1 levels （P<0.05， P<0.01）. KN93 also reduced ST-segment elevation， alleviated the degeneration degree of myocardial fibrosis， and lowered inflammatory cell infiltration. The mRNA expression of CaMKⅡ and CREB and the protein expression of p-CaMKⅡ and p-CREB in both the hippocampal and heart tissue were reduced （P<0.05， P<0.01）. The KN93 + high， medium， and low dose groups of modified Chaihu Shugansan showed further improvements in these abnormalities compared to the KN93 group. ConclusionThe modified Chaihu Shugansan exerts antidepressant and myocardial protective effects in rats with myocardial ischemia and depression， possibly related to bidirectional regulation of the CaMKⅡ/CREB signaling pathway， with the high-dose modified Chaihu Shugansan showing the best effects.

ObjectiveTo explore the mechanism by which Xiaoyaosan regulates HPT axis dysfunction in the rat model with the syndrome of liver depression and spleen deficiency by observing its effect on the glycoprotein hormone α-subunit （CGA）/glutathione peroxidase 2 （GPX2）/thyroid-stimulating hormone β-subunit （TSHβ） pathway for thyroid hormone synthesis. MethodsSeventy-two male SD rats were randomized into six groups： normal， model， high-dose （16.7 g·kg^-1）， medium-dose （8.35 g·kg^-1）， and low-dose （4.175 g·kg^-1） Xiaoyaosan， and fluoxetine （0.001 8 g·kg^-1） groups， with 12 rats in each group. The rat model of liver depression and spleen deficiency was induced by chronic restraint stress for 21 days. The intervention groups were treated with Xiaoyaosan decoctions or fluoxetine suspension， respectively. After modeling， hematoxylin-eosin staining was employed to observe morphological changes in the thyroid and pituitary tissue of the rats. Serum levels of triiodothyronine （T3）， tetraiodothyronine （T4）， and thyroid-stimulating hormone （TSH） were measured by enzyme-linked immunosorbent assay （ELISA）. Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） and Western blot were employed to determine the mRNA and protein levels， respectively， of TSH receptor （TSHR） in the thyroid tissue， thyrotropin-releasing hormone receptor （TRHR） and TSHβ in the pituitary tissue， and thyrotropin-releasing hormone （TRH）， CGA， GPX2， and TSHβ in the hypothalamic tissue. ResultsCompared with the normal group， the model group showed significant atrophy and irregularity of thyroid follicles， a marked reduction in colloid secretion， extensive vacuolar degeneration of adenocytes in the anterior pituitary， lowered serum levels of T3， T4， and TSH （P<0.01）， and down-regulated mRNA and protein levels of TSHR in the thyroid tissue， TRHR and TSHβ in the pituitary tissue， and TRH， CGA， GPX2， and TSHβ in the hypothalamic tissue （P<0.01）. Compared with the model group， high- and medium-dose Xiaoyaosan and fluoxetine alleviated the pathological changes in the thyroid and pituitary tissue， outperforming the low-dose Xiaoyaosan group. Moreover， they elevated the serum levels of T3， T4， and TSH （P<0.05， P<0.01）. The serum TSH level was also elevated in the low-dose Xiaoyaosan group （P<0.05）. The mRNA and protein levels of TSHR in the thyroid， TRHR and TSHβ in the pituitary， and TRH， CGA， GPX2， and TSHβ in the hypothalamus were up-regulated in the high- and medium-dose Xiaoyaosan groups （P<0.05， P<0.01）. Additionally， the mRNA and protein levels of TSHβ in the hypothalamus were up-regulated in the low-dose Xiaoyaosan group （P<0.01）. In the fluoxetine group， the mRNA and protein levels of TSHR in the thyroid， TRHR in the pituitary， and TRH， CGA， and GPX2 in the hypothalamus were up-regulated （P<0.05， P<0.01）. ConclusionThe downregulation of CGA/GPX2/TSHβ pathway may be one of the biological mechanisms underlying HPT axis dysfunction in the rat model with the syndrome of liver depression and spleen deficiency. Xiaoyaosan may regulate the HPT axis dysfunction by up-regulating the CGA/GPX2/TSHβ pathway.

Aldehyde oxidase (AOX) is a molybdoenzyme that is primarily expressed in the liver and is involved in the metabolism of drugs and other xenobiotics. AOX-mediated metabolism can result in unexpected outcomes, such as the production of toxic metabolites and high metabolic clearance, which can lead to the clinical failure of novel therapeutic agents. Computational models can assist medicinal chemists in rapidly evaluating the AOX metabolic risk of compounds during the early phases of drug discovery and provide valuable clues for manipulating AOX-mediated metabolism liability. In this study, we developed a novel graph neural network called AOMP for predicting AOX-mediated metabolism. AOMP integrated the tasks of metabolic substrate/non-substrate classification and metabolic site prediction, while utilizing transfer learning from ¹³C nuclear magnetic resonance data to enhance its performance on both tasks. AOMP significantly outperformed the benchmark methods in both cross-validation and external testing. Using AOMP, we systematically assessed the AOX-mediated metabolism of common fragments in kinase inhibitors and successfully identified four new scaffolds with AOX metabolism liability, which were validated through in vitro experiments. Furthermore, for the convenience of the community, we established the first online service for AOX metabolism prediction based on AOMP, which is freely available at https://aomp.alphama.com.cn.

Hemodynamics plays a vital role in the development and progression of cardiovascular diseases, and is closely associated with changes in morphology and function. Reliable detection of hemodynamic changes is essential to improve treatment strategies and enhance patient prognosis. The combination of computational fluid dynamics with cardiovascular imaging technology has extended the accessibility of hemodynamics. This review provides a comprehensive summary of recent developments in the application of computational fluid dynamics for cardiovascular hemodynamic assessment and a succinct discussion for potential future development.

BACKGROUND:Resistance exercise increases muscle mass and improves muscle strength,but there is a lack of conclusive evidence on its effects on body composition.Controversial results from randomized controlled trials and multiple Meta-analyses pose a problem for clinical decisions on exercise interventions. OBJECTIVE:Based on the methodological paradigm of umbrella review,to explore the efficacy and safety of resistance exercise in improving the body composition of overweight and obese people. METHODS:We searched PubMed,Cochrane Library,Web of Science,and CNKI for systematic reviews on the effect of resistance exercise in overweight and obese people published from database inception to August 31,2022.Chinese search terms included"anti-resistance,resistance,self-weight,Meta,Meta-analysis,body composition,body fat percentage,fat mass,lean body mass,body mass."English search terms included"resistance training,strength training,weight-lifting strengthening program,body composition,body fat distribution,Meta-analysis,data pooling,overviews,clinical trial,clinical trial overviews."PRISMA was used to evaluate the methodological quality of the included studies,and a GRADE evaluation system was used to grade the quality of evidence. RESULTS AND CONCLUSION:A total of 14 Meta-analyses were included,and GRADE evidence quality evaluation showed that 2 outcome indicators were intermediate,12 were low,and 14 were extremely low.Compared with the control group,23 of the 32 outcome measures showed significant improvement.The intervention effect of resistance exercise on body fat percentage has reached a consensus,but the intervention effects on lean body mass,body mass index and visceral fat still need further confirmation.Resistance exercise is an effective and safe method to improve the body composition of overweight and obese people.The overall quality of the research and the evidence quality of the outcome indicators included in the systematic evaluation are generally low.In the future,the initial state,exercise goal and willingness of the subjects should be fully combined on the basis of clarifying the sample characteristics and refining the scheme design.Through multiple,scientific and personalized exercise prescription designs of water,air and elastic resistance,the safety and compliance of resistance exercise can be improved,providing clear evidence-based support and decision-making basis for resistance exercise intervention.

OBJECTIVE:Masks are one of the most important defenses against the virus.However,the impact of wearing masks during daily activities or sports on respiratory and circulatory function remains controversial.A comprehensive quantitative evaluation of the effects of mask-wearing on human heart rate,oxygen saturation and end-expiratory carbon dioxide by Meta-analysis was conducted.The effects of wearing different types of masks at different exercise intensities and time of exercise on the human respiratory and circulatory system were explored. METHODS:By February 2023,with"mask,face mask,N95,training,sports,running,walking,cycling"as the Chinese search terms and"masks,respiratory protective devices,N95 respirators,surgical face masks,exercise,resistance training,explosive training,muscle exercises"as English search terms,the experimental studies addressing the influence of exercise with a mask on hemodynamic indexes were retrieved from CNKI,Web of Science,PubMed,Cochrane Library and WanFang databases.The outcome indicators included three continuous variables-exercise center rate,blood oxygen saturation and end-expiratory carbon dioxide.Stata16.0 software was used to analyze the outcome indicators of the included literature.The PEDro scale was used as a quality assessment tool,and the funnel plot was used to analyze the impact of publication bias. RESULTS:Totally 25 articles involving 857 healthy children and adults were included in this Meta-analysis.The overall methodological quality was high,with 22 studies scoring 6 points on the PEDro scale,2 studies scoring 7 points and 1 study scoring 8 points.The meta-analysis results showed that compared with the control group,exercise with masks had no significant effect on heart rate(SMD=0.02,95%CI:-0.11 to 0.15,P=0.81),but increased end-expiratory carbon dioxide(SMD=0.60,95%CI:0.37 to 0.83,P=0.00),decreased oxygen saturation(SMD=-0.28,95%CI:-0.47 to-0.09,P=0.03).Intensity and duration were the factors that affected the heterogeneity between studies.Wearing a mask during high-intensity exercise significantly increased heart rate(SMD=-0.20,95%CI:-0.36 to-0.04,P=0.02).The effect of high-intensity and short-time exercise on blood oxygen saturation was significantly higher than that of other exercises(SMD=-0.40,95%CI:-0.70 to-0.10;SMD=-0.25,95%CI:-0.45 to-0.04).For end-expiratory carbon dioxide,maintaining a certain intensity and increasing the exercise time or increasing the intensity further increased the index significantly,reaching a moderate effect size(SMD=0.61,95%CI:0.06 to 1.15;SMD=0.58,95%CI:0.04 to 1.13). CONCLUSION:Existing evidence suggests that exercise with masks may have the adverse effect of increasing end-expiratory carbon dioxide and decreasing blood oxygen saturation.The influence of different exercise test time and intensities on the three outcome indexes was different.Wearing a mask during high-intensity exercise can significantly increase heart rate and decrease blood oxygen saturation.Maintaining moderate intensity for a long period or further increasing the intensity of exercise will lead to increased end-expiratory carbon dioxide levels.

Objective:To study the current status of longitudinal extrauterine growth restriction (EUGR) in extremely preterm infants (EPIs) and to develop a prediction model based on clinical data from multiple NICUs.Methods:From January 2017 to December 2018, EPIs admitted to 32 NICUs in North China were retrospectively studied. Their general conditions, nutritional support, complications during hospitalization and weight changes were reviewed. Weight loss between birth and discharge > 1SD was defined as longitudinal EUGR. The EPIs were assigned into longitudinal EUGR group and non-EUGR group and their nutritional support and weight changes were compared. The EPIs were randomly assigned into the training dataset and the validation dataset with a ratio of 7∶3. Univariate Cox regression analysis and multiple regression analysis were used in the training dataset to select the independent predictive factors. The best-fitting Nomogram model predicting longitudinal EUGR was established based on Akaike Information Criterion. The model was evaluated for discrimination efficacy, calibration and clinical decision curve analysis.Results:A total of 436 EPIs were included in this study, with a mean gestational age of (26.9±0.9) weeks and a birth weight of (989±171) g. The incidence of longitudinal EUGR was 82.3%(359/436). Seven variables (birth weight Z-score, weight loss, weight growth velocity, the proportion of breast milk ≥75% within 3 d before discharge, invasive mechanical ventilation ≥7 d, maternal antenatal corticosteroids use and bronchopulmonary dysplasia) were selected to establish the prediction model. The area under the receiver operating characteristic curve of the training dataset and the validation dataset were 0.870 (95% CI 0.820-0.920) and 0.879 (95% CI 0.815-0.942), suggesting good discrimination efficacy. The calibration curve indicated a good fit of the model ( P>0.05). The decision curve analysis showed positive net benefits at all thresholds. Conclusions:Currently, EPIs have a high incidence of longitudinal EUGR. The prediction model is helpful for early identification and intervention for EPIs with higher risks of longitudinal EUGR. It is necessary to expand the sample size and conduct prospective studies to optimize and validate the prediction model in the future.

Objective:To investigate syphilis infection and related factors among HIV-infected patients being followed up for more than one year in Zhejiang Province.Methods:Data were collected from the China Disease Control and Prevention Information System, and information such as demographic characteristics, viral load levels, and syphilis serologic test results was collected from HIV-infected persons who were diagnosed with HIV more than 1 year, aged ≥15 years with a current address in Zhejiang Province through December 31, 2022. The logistic regression model analyzed the prevalence of syphilis and the related factors. The SPSS 19.0 software was used for statistical analysis.Results:A total of 33 734 HIV-infected patients, with the prevalence of syphilis was 5.6% (1 879/33 734). Among the syphilis cases, the prevalence of syphilis was 6.4% (1 774/27 934) of males, 7.5% (640/8 543) of 25-34 years old age group, 7.6% (1 025/13 423) of unmarried, 8.3% (1 239/14 862) of homosexual transmission, 6.9% (214/3 080) with a non-local registered residence and 9.6% (602/6 267) with a history of STD before the HIV diagnosis. Multivariate Logistic regression analysis showed that participants who were male (a OR=2.19, 95% CI:1.77-2.72), 25-34 years old age group (a OR=1.80, 95% CI:1.47-2.20), homosexual transmission (a OR=1.67, 95% CI:1.49-1.88), with other provinces registered residence (a OR=1.26, 95% CI:1.09-1.47), and with a history of sexually transmitted disease (STD) before the HIV diagnosis (a OR=1.98, 95% CI:1.78-2.20) were associated with increased risk of syphilis. Being married (a OR=0.79, 95% CI:0.68-0.92) was associated with a decreased risk of syphilis. Conclusions:Syphilis infections were high in HIV-infected patients followed up more than one year in Zhejiang Province. It is recommended that syphilis surveillance and screening frequency should be strengthened among HIV-infected persons with characteristics such as male, homosexual transmission, and STD history.

Recently,adeno-associated virus(AAV)vectors have been a hotspot in gene therapy and have shown great potential for rare diseases therapy,due to their low pathogenicity,mild immunogenicity and high tissue specificity.The safety and efficacy of AAV vectors,which are essentially infectious viruses,require new bioanalytical techniques to assess.At present,the relevant industry guidelines have specified the needs for the assessment of biodistribution,shedding,and immunogenicity,but the requirements related to bioassay are limited.In this paper,we reviewed the bioanalytical techniques and pharmacokinetics/pharmacodynamics(PK/PD)research of AAV vectors and their challenges from four aspects:biodistribution,shedding,immunogenicity and PK/PD research,with the hope of providing some reference for the clinical development of AAV vectors gene therapy products.

Objective To investigate the serological and molecular biology characteristics of ambiguous blood types a-mong voluntary blood donors in Putian,and to file records for relevant donors for future reference in case of their own trans-fusion needs or emergency donations to others.Methods A total of 68 593 blood samples from voluntary blood donors in Putian Central Blood Station between January 1,2019 and August 31,2023 were collected and tested for blood types using serological methods.ABO gene(including promoters,enhancers and seven exons as well as their flanking sequences and in-tron 6)and FUT1 gene testing were performed on ambiguous blood types.3D models were constructed using Chimira and Py-MOL software to predict the impact of gene mutations on enzyme structure.Results A total of 16 ABO subtypes were identi-fied by serological methods,with the highest detection rate as the para-Bombay phenotype(0.73 per 10 000),followed by the cisAB phenotype(0.44 per 10 000).Gene analysis revealed 12 cases with known mutations(4 cases of FUT1.01N.06/FUT1.01N.06,1 case of FUT1 01W.08/FUT1.01N.06,2 cases of A2.08/B.01,1 case of BA.02/O.01.01,1 case of A3.07/O.01.01,3 cases of cisAB.01/B.01),and key mutations were not found in 4 cases(2 cases of A1.02/B.01,2 cases of A1.02/O.01.02).3D molecular model analysis revealed that both A3.07 and FUT1.01W.08 allele can lead to a decrease in ac-tivity of the corresponding glycosyltransferases,resulting in the emergence of subtypes.Conclusion The most common phe-notype causing discrepancies in ABO blood type testing among voluntary blood donors from Putian is the para-Bombay phe-notype,with the most common allele being FUT1.01N.06.