Growth arrest DNA damage-inducible protein 45 β (GADD45B) has been reported to be a regulatory factor for active DNA demethylation and is implicated in the modulation of synaptic plasticity and chronic stress-related psychopathological processes. However, its precise role and mechanism of action in stress susceptibility remain elusive. In this study, we found a significant reduction in GADD45B expression specifically in the ventral, but not the dorsal hippocampal CA1 (dCA1) of stress-susceptible mice. Furthermore, we demonstrated that GADD45B negatively regulates susceptibility to social stress and NMDA receptor-dependent long-term potentiation (LTP) in the ventral hippocampal CA1 (vCA1). Importantly, through pharmacological inhibition using the NMDA receptor antagonist MK801, we provided further evidence supporting the hypothesis that GADD45B potentially modulates susceptibility to social stress by influencing NMDA receptor-mediated LTP. Collectively, these results suggested that modulation of NMDA receptor-mediated synaptic plasticity is a pivotal mechanism underlying the regulation of susceptibility to social stress by GADD45B.
Animals ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors* ; CA1 Region, Hippocampal/drug effects* ; Male ; Stress, Psychological/physiopathology* ; Mice ; Neuronal Plasticity/drug effects* ; Long-Term Potentiation/drug effects* ; Mice, Inbred C57BL ; Antigens, Differentiation/metabolism* ; Dizocilpine Maleate/pharmacology* ; Excitatory Amino Acid Antagonists/pharmacology* ; GADD45 Proteins

The emergence of AlphaFold has catalyzed a paradigm shift in protein structure prediction, redefining the landscape of computational biology through its iterative evolution. The developmental trajectory spans three transformative iterations: the foundational AlphaFold prototype, its revolutionary successor AlphaFold2, and the recently unveiled AlphaFold3. AlphaFold2 marked a quantum leap in 2020 by introducing an end-to-end deep learning architecture that achieved atomic-level accuracy, decisively solving the decades-old protein folding problem as demonstrated by its unprecedented performance at CASP14 (Critical Assessment of Structure Prediction). Building upon this framework, AlphaFold3 represents an evolutionary leap, expanding predictive capabilities to model intricate biomolecular complexes including ligand-protein binding interfaces and nucleic acid interactions.These advancements have unlocked transformative applications across multiple domains: enabling rapid proteome-scale structural annotations in structural biology, accelerating virtual screening pipelines in drug discovery, and facilitating viral protein characterization in emerging virology research. However, persistent limitations in modeling conformational dynamics and transient binding states underscore the need for continued methodological refinement. This comprehensive analysis examines the algorithmic innovations driving AlphaFold′s progression, evaluates its multidisciplinary applications, and critically assesses current technical constraints-providing a framework to guide future developments at the intersection of artificial intelligence and molecular bioscience.

Objective:To investigate the causal effects of plasma lipidomics on pancreatitis using Mendelian ran-domization(MR)and evaluate the roles of intra-pancreatic fat deposition(IPFD)and gallstone disease in this relation-ship.Methods:A bidirectional MR analysis was conducted,with 179 plasma lipids as exposures and acute pancreati-tis(AP)and chronic pancreatitis(CP)as outcomes.Data were sourced from genome-wide association studies(GWAS),the UK Biobank,and the FinnGen project.Two-step Mendelian randomization(TSMR)and multivariable Mendelian ran-domization(MVMR)analyses were applied to assess the mediating roles of IPFD and gallstone disease in the associa-tion between plasma lipids and pancreatitis.Results:MR analysis identified two sterols negatively associated with AP(P＜0.05)and seven sterols negatively associated with CP(P＜0.05).One phospholipid showed a positive association with CP(P＜0.05).IPFD was positively associated with both AP and CP.Gallstone disease was confirmed as a risk fac-tor for AP.However,TSMR analysis indicated that neither IPFD nor gallstone disease mediated the relationship be-tween plasma lipids and pancreatitis.Conclusion:The causal relationship exists among plasma lipomics and AP/CP,also between IPFD,cholelithiasis and pancreatitis.These findings highlight novel risk factors and potential biomarkers to support early diagnosis and intervention for pancreatitis.

Aim To explore the key components and mechanisms of Lizhong decoction in treating rats with cold-damp diarrhea based on network pharmacology,molecular docking technology and animal experiments.Methods By literature review and database collec-tion,the components of Lizhong decoction,therapeutic targets,and the mapping with diarrhea disease targets were conducted to construct an intersection target pro-tein-protein interaction network for screening core tar-gets,and GO and KEGG pathway enrichment analysis was performed to build an"active component-target-pathway"network,followed by molecular docking vali-dation.Forty-eight rats were randomly divided into the normal control group(K),model group(DG),Lizhong decoction group(LZDG),and Pulsatilla decoction group(BTDG).Subsequently,a rat cold-damp diar-rhea model was established using Senna combined with low-temperature high-humidity environment,and the rats were intervened with Lizhong decoction and Pul-satilla decoction.HE staining was used to detect path-ological changes in intestinal tissue,ELISA was em-ployed to measure the levels of peripheral blood IL-6,IL-10,IL-1 β,and TNF-α,and western blot was used to determine the expression of colon tight junction pro-teins.Results Network pharmacology initially identi-fied 125 compounds in Lizhong decoction,5 186 drug target components,438 disease targets,and 60"drug-disease"shared targets.GO and KEGG enrichment a-nalysis showed that signaling pathways such as IL-17 and TNF were highly enriched.Molecular docking in-dicated that the core components of the drug had good binding activity with corresponding key targets.Liz-hong decoction could effectively improve the clinical symptoms of rats with cold-damp diarrhea,and com-pared with the DG group,the diarrhea rate,diarrhea in-dex,and other related indicators also gradually de-creased to normal levels.Compared with the DG group,the LZDG group showed reduced inflammation levels and a recovery in energy metabolism levels.Conclusion It can regulate targets such as MMP9 and IL-17 signaling pathways through multi-components like Calycosin and formononetin to exert its therapeutic effect on cold-damp diarrhea.

Objective To observe the effectiveness and safety of netupitant/palonosetron in the treat-ment of chemotherapy-induced nausea and vomiting(CINV)in hematologic tumor patients undergoing autol-ogous and allogeneic stem cell transplantation.Methods Adult hematologic tumor patients who received net-upitant/palonosetron to prevent chemotherapy-induced nausea and vomiting CINV during pre-transplant chemotherapy at West China Hospital of Sichuan University from January to September 2022 were collected.On the first and third day of pre-transplant chemotherapy,netupitant/palonosetron was orally administered one hour before the infusion of pre-transplant chemotherapy drugs,for a total of two doses.The nausea and CINV status of the patients from the start of pre-transplant chemotherapy to 7 days after stem cell infusion were recorded.Results As a result,a total of 125 patients with hematological tumors were included,and the complete remission rates during pre-treatment chemotherapy were 72.8%,80.0%and 66.4%in the acute phase,delayed phase,and total phase,respectively.The rates of no vomiting were 89.6%,92.0%and 72.8%,respectively.The rates of no rescue medication were 95.2%,93.6%and 73.6%,respectively.The complete remission rate of 33 plasma cell tumors and 46 leukemia and myelodysplastic syndrome patients exceeded 70%,and the complete remission rate of 46 lymphoma patients exceeded 90%.The complete response rate in the delayed phase of the pre-treatment CHiGCB regimen(chidamide+busulfan+gemcitabine+cladribine)was 93.5%,which was higher than the complete response rate of the BenMel regimen(bendamustine+mel-phalan)(72.7%)and the CHiFAB regimen(chidamide+busulfan+fludarabine+cytarabine)(71.7%).The complete remission rate during the follow-up period of the CHiGCB regimen was 91.3%,which was higher than that of the CHiFAB regimen(65.2%),with the statistically significance(P<0.05).Conclusion Netu-pitant/palonosetron can effectively control CINV in patients undergoing autologous or allogeneic hematopoiet-ic stem cell transplantation for hematologic tumors.

Objectives:The aim is to analyze the cost structure and coefficient of variation for hospitalized patients with malnutrition based on Diagnosis-Related Groups(DRG),providing a reference for the further application and promotion of DRG.Method:Data were collected from patients admitted to Ningxia Hui Autonomous Region People's Hospital between March 2023 and August 2023.A diagnostic system based on artificial intelligence was used to identify malnourished patients.The composition of hospitalization costs for these individuals was described and analyzed,as was the coefficient of variation for various costs within DRG groupings.A multivariate regression analysis was conducted to identify the factors that influence patient hospitalization costs.Results:The average age of hospitalized patients with malnutrition was(68.12±16.43)years,with an average length of stay of(14.55±8.47)days,with an average hospitalization cost of(32 128.89±35 345.61)yuan.Among patients within the same DRG group,the coefficient of variation for various costs was found to be lower in the malnutrition group than in the normal group.This suggests that when assessed individually,the malnutrition group exhibited a higher degree of homogeneity in their cost structures.The factors influencing total hospitalization costs were found to be:length of hospital stay(P=0.001),nutritional monitoring fees(P=0.020),number of chronic diseases(P=0.003),and Karnofsky Performance Status(KPS)score(P=0.038).Hospitalization costs were positively correlated with both length of stay and nutritional assessment fees,but negatively correlated with the number of chronic diseases and KPS scores.Conclusions:Malnutrition has a profound impact on health outcomes,medical expenses,length of hospital stay,and disease severity.The implementation of the DRG system aims to standardize and improve the nutritional diagnosis and treatment process by categorizing different stages of malnutrition.This approach can minimize variations within DRG groups,making it easier to allocate medical resources more precisely and efficiently.Furthermore,it is a valuable reference tool for promoting DRG payment reform in different regions.

ObjectiveTo construct an outcome set for clinical evaluation of traditional Chinese medicine （TCM） for chronic pulmonary heart disease， and to provide consensus outcomes for the evaluation of the clinical effectiveness of TCM for chronic pulmonary heart disease. MethodsWe searched randomised controlled trials of TCM for chronic pulmonary heart disease on China National Knowledge Infrastructure （CNKI）， Wanfang Data Knowledge Service Platform （WF）， VIP Chinese Science Journals Database （VIP）， Chinese Biomedical Literature Service Database （SinoMed）， PubMed， Cochrane Library， and Embase. We also searched Chinese Clinical Trial Registry Platform and the U.S. Clinical Trial Registry database to obtain the outcome indicators reported in the clinical research protocols of TCM for chronic pulmonary heart disease. The outcome indicators were also collected through semi-structured interviews of clinicians and patients. Then integrated the outcome indicators collected by the above methods to construct the indicator pool. Through two rounds of Delphi surveys and a consensus conference， the core outcome set for clinical evaluation of TCM for chronic pulmonary heart disease was determined. ResultsAfter screening， there were 1313 literature meeting the criteria， and 595 outcome indicators were extracted， then combined with the outcomes from semi-structured interviews which clinicians and patients concerned， finally an indicator item pool containing 369 outcome indicators were formed. After the initial screening of indicators in the pool by the steering committee， 58 indicators were established into the initial list of indicator entries. In the first round of Delphi survey， the expert coordination coefficient for the results was 0.401， and the Cronbach coefficient was 0.989. A total of 35 indicators that did not meet the criteria ［＜70% of the participants rated the outcome as 7~9 （critical） and the mean of the expert ratings ＜7］ were deleted， and 23 were retained， with 7 new indicators added that were open to supplementation by the experts， resulting in a total of 30 indicators that were included in the second round of Delphi survey. In the second round of Delphi survey， the expert coordination coefficient was 0.303， and the Cronbach coefficient was 0.974， with a total of 7 indicators that did not meet the criteria being deleted， and 21 indicators being retained for the consensus conference. After the consensus meeting， the core outcome set for clinical evaluation of chronic pulmonary heart disease in two major categories， acute exacerbation stage and stable stage， was finally determined， in which there were four indicators in acute exacerbation stage： N-terminal B-type natriuretic peptide precursor （NT-proBNP）， blood qi analysis， all-cause mortality rate， and complication rate； and there were eight indicators in the stable stage： pulmonary function index， six-minute walk test distance， New York cardiac function classification， all-cause mortality rate， re-hospitalisation rate， Chronic Obstructive Pulmonary Disease Assessment Test （CAT） score， Short Form 36 Health Survey （SF-36）， and TCM syndrome score. ConclusionThe core outcome sets of TCM clinical evaluation in the acute exacerbation stage and stable stage are constructed， which is helpful to improve the practicability， comparability and transparency of TCM clinical research results in pulmonary heart disease.

BACKGROUND:Secondary screw perforation of the articular surface is one of the major complications after locking plate internal fixation of proximal humerus fracture,and cut-out screws can damage shoulder function by abrading the glenoid and causing impingement of the acromion.Therefore,accurate risk prediction has positive clinical significance.OBJECTIVE:To screen risk factors for secondary screw perforation after proximal humerus fracture plating by machine learning methods,and to develop and validate a risk prediction model that facilitates clinicians to identify and intervene in high-risk patients at an early stage.METHODS:Clinical data of 214 patients with proximal humerus fractures who underwent locking plate internal fixation from June 2013 to June 2022 were collected as a training group to establish the model,and 61 similar patients from another hospital in the same period were included in the external validation group.The patients were divided into secondary screw perforation and screw maintenance groups according to whether they developed secondary screw perforation after surgery.The training group used three machine learning algorithms,namely,random forest,support vector machine,and logistic regression,to construct the prediction model.The recursive feature elimination method was used,and 10-fold cross-validation resampling was used as the screening method for the variables,and the intersection of the variables that were included when the accuracy of the three models was the highest was taken as the highly correlated with the secondary screw perforation reliable risk variables.The dynamic predictive model was constructed by R language software and presented as a web calculator,and the model was internally and externally validated.The internal test of the model was conducted by the Bootstrap method with 1 000 resamples,and the area under the receiver operating characteristic curve,the calibration curve,and the clinical decision curve were used to evaluate the differentiation,calibration ability,and clinical application value of the model.The Youden index was used to determine the optimal risk threshold of the prediction model,according to which the patients in the external validation group were divided into high-and low-risk groups,and the stability and extensibility of the model were evaluated according to the accuracy of its risk prediction ability.RESULTS AND CONCLUSION:(1)The machine learning algorithm identified four risk variables that were highly correlated with secondary screw perforation,namely cortical support of the proximal medial humeral column,deltoid tuberosity index,fracture type,and postoperative reduction.(2)The constructed risk prediction model showed good discrimination and accuracy[area under the curve=0.874,95％confidence interval(0.827,0.922)],and the calibration curve showed good agreement between the model predicted risk and the actual occurrence risk.(3)The clinical decision curve suggested that the model had good clinical applicability when the probability of the risk threshold was in the 0.1-0.75 range.(4)A risk probability of 26％was the optimal threshold for model risk stratification,and the external validation group used model risk stratification to predict secondary screw perforation with an overall accuracy rate of 84％.(5)The risk prediction model has good accuracy and extrapolation,and may provide a basis for guiding clinical treatment.

Objective To systematically evaluate and compare the efficacy and safety of different oral Chinese patent medicine combined with hormone replacement therapy(HRT)in the treatment of ovarian hypofunction related diseases.Methods Relevant randomized controlled studies on Chinese patent medicine combined with HRT for the treatment of premature ovarian insufficiency,diminished ovarian reserve,premature ovarian failure were systematically searched in CNKI,WanFang,VIP,SinoMed,PubMed,and WOS databases,and the network Meta-analysis was performed using R 4.1.0 software.Results Eighty-three randomized controlled studies were included,with 3819 cases in the control group and 3844 cases in the experimental group,involving a total of 14 Chinese patent medicine(Kuntai capsule,Peikun pill,Zuogui pill,Heche Dazao capsule,Zishen Yutai pill,Fuke Yangrong capsule,Liuwei Dihuang pill,Rentaipan tablet,Guishen pill,Huanshao capsule,Qilin pill,Tiaojing Cuyun pill,Fufang Ejiao plasma,and Zuogui pill+Ruogui pill).The results of network Meta-analysis showed that:①Lowering of follicle stimulating hormone:the top 3 in the ranking were Zishen Yutai pill,Liuwei Dihuang pill,Fuke Yangrong capsule combined with HRT.② Increasing antral follicle counting:the top 3 in the ranking were Zuogui pill,Fuke Yangrong capsule,Zuogui pill+Ruogui pill combined with HRT.③Elevating of anti-Müllerian tube hormones:the top 3 in the ranking were Rentaipan tablet,Liuwei Dihuang pill,Kuntai capsule combined with HRT.④ Lowering Kupperman's score:the top 1 in the ranking was Kuntai capsule+HRT.⑤ Increasing in overall efficiency:the top 3 in the ranking were Fufang Ejiao plasma+HRT,Guishen pill+HRT,Zishen Yutai pill+HRT.The adverse events of combined HRT with oral Chinese patent medicine were mainly gastrointestinal discomfort,dizziness and headache,breast distension and pain.Conclusion The combination of oral Chinese patent medicine with HRT can better improve ovarian function and alleviate perimenopausal symptoms.For patients with fertility requirements,priority should be given to Fuke Yangrong capsule or Liuwei Dihuang pill combined with HRT to improve FSH levels and increase follicular reserve.For patients with obvious perimenopausal symptoms,priority should be given to Kuntai capsule combined with HRT to alleviate the symptoms.And Fufang Ejiao plasma,Guishen pill,Zishen Yutai pill combined with HRT should be given to increase the overall effective rate of the treatment.

Objectives:To explore the predictive value of angiography-derived index of microcirculatory resistance(Angio-IMR)for early prognosis in patients with acute ST-segment elevation myocardial infarction(STEMI)after percutaneous coronary intervention(PCI).Methods:This multicenter study enrolled 1 629 consecutive STEMI patients who underwent successful PCI at three grade A tertiary hospitals(The Second Affiliated Hospital,Zhejiang University School of Medicine;Shengjing Hospital of China Medical University;Renji Hospital,Shanghai Jiao Tong University School of Medicine)from June 1,2017,to May 31,2020.According to postoperative Angio-IMR,patients was stratified into two groups:the Angio-IMR>40 group(n=508)and the Angio-IMR≤40 group(n=1 121).The incidence of major adverse cardiovascular events(MACE;defined as a composite endpoint including cardiac death,heart failure rehospitalization,cardiogenic shock,malignant arrhythmia,cardiopulmonary resuscitation and stent thrombosis)within 1-month post-PCI was compared between the two groups.Results:The median Angio-IMR after PCI was 32.4(22.3,42.6).The cumulative incidence of early-term MACE was significantly higher in patients with Angio-IMR>40,compared to those with Angio-IMR≤40(5.5%vs.2.3%,log-rank P<0.001).Multivariate Cox regression analysis showed that Angio-IMR>40 was an independent predictor of early-term MACE(HR=2.07,95%CI:1.20-3.58,P=0.009).The addition of Angio-IMR enhanced the predicting performance of the clinical risk model to predict early adverse outcomes(AUC:0.820 vs.0.794,P=0.043).Conclusions:In patients with STEMI after PCI,Angio-IMR can predict the occurrence of early-term MACE.The incorporation of Angio-IMR to clinical models significantly improves the model ability to predict early adverse outcomes in these patients.