Homo- or heterodimeric compounds that affect dimeric protein function through interaction between monomeric moieties and protein subunits can serve as valuable sources of potent and selective drug candidates. Here, we screened an in-house dimeric natural product collection, and panepocyclinol A (PecA) emerged as a selective and potent STAT3 inhibitor with profound anti-tumor efficacy. Through cross-linking C712/C718 residues in separate STAT3 monomers with two distinct Michael receptors, PecA inhibits STAT3 DNA binding affinity and transcription activity. Molecular dynamics simulation reveals the key conformation changes of STAT3 dimers upon the di-covalent binding with PecA that abolishes its DNA interactions. Furthermore, PecA exhibits high efficacy against anaplastic large T cell lymphoma in vitro and in vivo, especially those with constitutively activated STAT3 or STAT3^Y640F. In summary, our study describes a distinct and effective di-covalent modification for the dimeric compound PecA to disrupt STAT3 function.

The prefrontal cortex (PFC) plays a pivotal role in orchestrating higher-order emotional and cognitive processes, a function that depends on the precise modulation of synaptic activity. Although pharmacological studies have demonstrated that dopamine signaling through dopamine D1 receptor (DRD1) in the PFC is essential for these functions, the cell-type-specific and molecular mechanisms underlying the neuromodulatory effects remain elusive. Using cell-type-specific knockout mice and patch-clamp recordings, we investigated the regulatory role of DRD1 on neurons and astrocytes in synaptic transmission and plasticity. Furthermore, we explored the mechanisms by which DRD1 on astrocytes regulate synaptic transmission and plasticity at the cellular level, as well as emotional and cognitive functions at the behavioral level, through two-photon imaging, microdialysis, high-performance liquid chromatography, transcriptome sequencing, and behavioral testing. We found that conditional knockout of the Drd1 in astrocytes (CKO^AST) increased glutamatergic synaptic transmission and long-term potentiation (LTP) in the medial prefrontal cortex (mPFC), whereas Drd1 deletion in pyramidal neurons did not affect synaptic transmission. The elevated level of d-serine in the mPFC of CKO^AST mice increased glutamatergic transmission and LTP through NMDA receptors. In addition, CKO^AST mice exhibited abnormal emotional and cognitive function. Notably, these behavioral changes in CKO^AST mice could be reversed through the administration of d-serine degrease to the mPFC. These results highlight the critical role of the astrocytic DRD1 in modulating mPFC synaptic transmission and plasticity, as well as higher brain functions through d-serine, and may shed light on the treatment of mental disorders.

Objective: To investigate the current status and influencing factors of quality of life among HIV/AIDS cases, so as to provide the basis for improving HIV/AIDS cases quality of life. Methods: From March to July 2024, HIV/AIDS cases under follow-up management at various community health service centers in Jinshan District, Shanghai Municipality, were selected as the survey subjects using a convenience sampling method. Demographic information and receiving antiretroviral therapy (ART) were collected through questionnaire surveys. Quality of life was assessed using the Chinese version of the World Health Organization Quality of Life Questionnaire for HIV brief version. A multiple linear regression model was employed to analyze the factors affecting quality of life. Results: A total of 179 HIV/AIDS cases were investigated, including 150 males (83.80%) and 29 females (16.20%), with a mean age of (47.00±12.90) years. The subjective self-evaluation score for the quality of life among HIV/AIDS cases was (13.87±2.84) points. The scores in the domains of physical, psychological, independence, social relationship, environment, and spiritual support/religion/personal beliefs were (14.77±2.64) (13.57±2.04) (13.86±2.04) (12.99±2.26) (13.58±1.98) (14.59±3.05) points, respectively. Multiple linear regression analysis revealed statistically significant associations (all P<0.05) between the following factors and quality of life domain scores: educational level (college degree or above, β' =0.162) and receiving ART (β' =-0.197) were associated with the subjective self-evaluation domain score; educational level (college degree or above, β' =0.186) and receiving ART (β' =-0.299) were associated with physical domain score; receiving ART (β' =-0.263) and symptoms related to sexually transmitted diseases (β' =-0.243) were associated with psychological domain score; occupation (retirees, β' =-0.191) and symptoms related to sexually transmitted diseases (β' =-0.220) were correlated with the independence domain score; annual household income per capita (≥30 000 yuan, β' =0.281) and receiving ART (β' =-0.299) were correlated with the social relationship domain score; educational level (college degree or above, β' =0.206) and receiving ART (β' =-0.285) were correlated with the environment domain score; and receiving ART (β' =-0.492) and duration since HIV confirmation (3 to <6 years, β' =0.233; ≥6 years, β' =0.161) were correlated with the spiritual support/religion/personal beliefs domain score. Conclusions The overall quality of life among HIV/AIDS cases in Jinshan District is relatively good, but the domains of psychological, independence, and social relationship were still room for improvement. It is mainly influenced by factors such as occupation, educational level, annual household income per capita, receiving ART, symptoms related to sexually transmitted diseases, and duration since HIV confirmation.

Objective : To investigate the diagnostic value of linear array endoscopic ultrasonography ( EUS) for common bile duct microlithiasis． Methods : Data of patients who attended in the hospital and diagnosed as common bile duct microlithiasis and biliary sludge by EUS were selected．A total of 85 patients with magnetic resonance cholangiopancreatography ( MRCP) examination and ERCP treatment during hospitalization were enrolled．The results of endoscopic retrograde cholangiopancreatography / endoscopic sphincterotomy ( ERCP / EST) were the gold standard for diagnosis．The results of EUS，MRCP，and diagnostic ERCP were compared with the gold standard， and the sensitivity，specificity，positive predictive value，negative predictive value，and diagnostic accuracy of the three methods were calculated，respectively．The chi-square test was used for comparison of the above indices． Results : Of all 85 patients，63 had positive EUS results，among whom 5 had false positive results; 22 had negative EUS results，among whom 1 had false negative results．Of all 85 patients，49 had positive MRCP results，among whom 4 had false positive results; 36 had negative MRCP results，among whom 14 had false negative results．Of all 85 patients，59 had positive diagnostic ERCP results，among whom 10 had false positive results; 26 had negative diagnostic ERCP results，among whom 10 had false negative results．The sensitivity，specificity，positive predictive value( PPV) ，negative predictive value ( NPV) ，and accuracy of EUS in diagnosing common bile duct microlithia- sis were 98. 3% ，80. 8% ，92. 1% ，95. 4% and 92. 9% ，respectively． For MRCP，these values were 76. 3% ， 84. 6% ，91. 8% ，61. 1% and 78. 8% ，respectively．For diagnostic ERCP，these values were 83. 1% ，61. 5% ， 83. 1% ，61. 5% and 76. 5% ，respectively．The EUS group had a significantly higher accuracy than the MRCP group ( χ2 = 6. 986，P ＜0. 05) and diagnostic ERCP group ( χ2 = 8. 900，P ＜0. 05) ．The areas under the ROC curves ( AUC) and 95% CI of EUS group，MRCP group and diagnostic ERCP were 0. 895 ( 95% CI: 0. 802 - 0. 988，P＜0. 001) ，0. 804 ( 95% CI: 0. 702 －0. 907，P ＜0. 001) and 0. 723 ( 95% CI: 0. 598 －0. 848，P = 0. 001) ，respectively． Conclusion EUS has a high diagnostic value in the diagnosis of common bile duct microli- thiasis and thus can be used as the preferred examination before therapeutic ERCP．

Objective : To analyze the clinical characteristics of patients with abdominal type allergic purpura(HSP), to improve their diagnostic level, and to explore the risk factors for gastrointestinal bleeding in HSP patients. Methods : A retrospective analysis was conducted on the clinical manifestations, laboratory data, imaging, endoscopic, and pathological characteristics of 98 patients with abdominal type HSP. Based on the occurrence of gastrointestinal bleeding, 98 patients were divided into a bleeding group and a non-bleeding group, and the risk factors for gastrointestinal bleeding in HSP patients were analyzed. Results : Abdominal HSP often presented with abdominal pain, vomiting, vomiting blood, black stools, and bloody stools. Imaging often showed edema and thickening of the duodenum and jejunum, as well as enlargement of surrounding lymph nodes. Under endoscopy, the descending part of the duodenum and jejunum mucosa were commonly congested and edematous with erosion, and ulcers were seen in the distal ileum. Pathology commonly involved acute and chronic inflammation of the mucosa with congestion, edema, and local erosion. Patients with gastrointestinal bleeding had significantly higher levels of white blood cell count(WBC), neutrophil count(NEUT), C-reactive protein(CRP), D-dimer(D-D), and fibrinolytic products(FDP) compared to non-bleeding patients(P<0.05), while levels of red blood cell count(RBC), hemoglobin(HGB), and albumin(ALB) were significantly lower than those of non bleeding patients(P<0.05). Logistic regression analysis showed that decreased ALB and increased FDP were independent risk factors for gastrointestinal bleeding in patients with abdominal HSP(P<0.05). The areas under the ROC curves of ALB and FDP were(AUC=0.877, 95%CI:0.794-0.960,P<0.01) and(AUC=0.806, 95%CI:0.722-0.890,P<0.01), respectively. The maximum value of the Jordan index for ALB was 0.734, with sensitivity and specificity of 89.6% and 83.9%, respectively, and had a critical value of 38.2 g/L. The maximum value of the Jordan index for FDP was 0.577, with sensitivity and specificity of 64.2% and 93.5%, respectively, and had a critical value of 18.14 μg/ml. There was no statistically significant difference in the ROC curves between ALB and FDP. Conclusion For HSP with abdominal pain as the initial symptom, imaging and endoscopic examination are helpful for early diagnosis. Decreased ALB and elevated FDP are independent risk factors for gastrointestinal bleeding in adult patients with abdominal HSP.

Purpose To design PCR combined probes u-sing TaqMan technology to detect the expression of major driver genes in a variety of soft tissue sarcomas at one time,and to dis-cuss whether the combined probes can better assist clinicopatho-logical diagnosis based on histological features and FISH results.Methods Our research group designed 32 pairs of fusion gene probes related to soft tissue sarcoma based on TaqMan tech-nique,involving 10 types of sarcoma.The histopathological specimens of 70 patients with common fusion gene soft tissue sarcoma in our hospital were examined by fusion gene combina-tion,and the histopathological specimens of 30 patients with oth-er soft tissue sarcoma without fusion gene were set as controls.Individual common sarcoma types were analyzed with FISH probe detection.At the same time,the detection performance of the combined probe was evaluated by various methods.Results The soft tissue sarcoma-related fusion gene probe designed by our research group was used to detect the confirmed soft tissue sarcomas,and the results showed that the highest sensitivity was 100％.Among the three types of tumors,protuberant dermatofi-brosarcoma,synovial sarcoma and mucinous liposarcoma were verified by FISH,and the coincidence rate of the two methods was high,with no statistical significance(P＞0.05).The re-sults of interlot and intralot reproducibility of protuberous derma-tofibrosarcoma,mucinous liposarcoma and synovial sarcoma were consistent.Three different concentration limits were used to de-tect the positive plasmid of all the fused gene RNA,and 25 cop-ies/μL was the lowest concentration limit.Conclusion Com-bined with the pathological diagnosis results,TaqMan technology can be used to design PCR combined probes for soft tissue sarco-ma,which have high sensitivity and high specificity and good methodological performance,and meet the needs of primary medical institutions for one-time and rapid auxiliary pathological diagnosis of common soft tissue sarcoma.It provides a rapid and reliable method for the detection of multiple fusion genes in clin-ical soft tissue sarcoma.

Osteoarthritis(OA),characterized by cartilage degeneration,synovial inflammation,and subchondral bone remodeling,is among the most common musculoskeletal disorders globally in people over 60 years of age.The initiation and progression of OA involves the abnormal metabolism of chondrocytes as an important pathogenic process.Cartilage degeneration features mitochondrial dysfunction as one of the important causative factors of abnormal chondrocyte metabolism.Therefore,maintaining mitochondrial homeostasis is an important strategy to mitigate OA.Mitophagy is a vital process for autophagosomes to target,engulf,and remove damaged and dysfunctional mitochondria,thereby maintaining mitochondrial homeostasis.Cumulative studies have revealed a strong association between mitophagy and OA,suggesting that the regulation of mitophagy may be a novel therapeutic direction for OA.By reviewing the literature on mitophagy and OA published in recent years,this paper elaborates the potential mechanism of mitophagy regulating OA,thus providing a theoretical basis for studies related to mitophagy to develop new treatment options for OA.

The endoplasmic reticulum is a key site for protein production and quality control.More than one-third of proteins are synthesized and folded into the correct three-dimensional conformation in the endoplasmic reticulum.However,during protein folding,unfolded and/or misfolded proteins are prone to occur,which may lead to endoplasmic reticulum stress.Organisms can monitor the quality of the proteins produced by endoplasmic reticulum quality control(ERQC)and endoplasmic reticulum-associated degradation(ERAD),which maintain endoplasmic reticulum protein homeostasis by degrading abnormally folded proteins.The underlying mechanisms of protein folding and ERAD in mammals have not yet been fully explored.Therefore,this paper reviews the process and function of protein folding and ERAD in mammalian cells,in order to help clinicians better understand the mechanism of ERAD and to provide a scientific reference for the treatment of diseases caused by abnormal ERAD.

Objective:To explore the application and teaching effect of TSPV (short for theoretical teaching, simulated surgical skills training, practical surgery training, and video-based review) 4-step teaching in skill training of gynecologic laparoscopic surgery.Methods:A total of 30 trainees who participated in gynecologic laparoscopic surgery training were randomly divided into two groups, with 15 in each group. The experimental group received TSPV 4-step teaching, while the control group adopted traditional teaching and completed training and assessment in stages. The general data, training assessment results, teaching feedback and satisfaction survey of the two groups were compared and analyzed. SPSS 20.0 was used for t-test and Chi-square test. Results:There was no statistical difference in age, gender distribution, education background, clinical working experiences and other general data between the two groups. There was no significant difference in the theoretical examination scores between the two groups [(85.3±4.6) vs. (83.4±4.3), P=0.252]. The scores of simulated operation assessment [(91.7±5.2) vs. [(72.4±5.9), P<0.001] and clinical practice assessment [(88.5±4.8) vs. (82.7±6.7), P=0.011] in the experimental group were better that those in the control group. In addition, the experimental group had a better overall evaluation of teaching satisfaction. Conclusion:TSPV 4-step teaching is a more optimized and popular gynecologic laparoscopic training mode, which is recommended to further promote the validation in teaching.

Objective:To investigate the prognostic value of systemic immune-inflammation index (SII) in patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF).Methods:The clinical data, including age, gender, complications, laboratory examination results post-admission, SII, model for end-stage liver disease (MELD) score, MELD-Na score, Child-Turcotte Pugh (CTP) score of HBV-ACLF patients treated in Huashan Hospital, Fudan University from January 2016 to August 2021 were retrospectively analyzed. The patients were divided into survival group and death group according to the outcome at 90 days of follow-up.Paired sample t test, Mann-Whitney U test and chi-square test were used for statistical analysis.Pearson correlation was used to analyze the correlation between SII and the prognosis prediction model of HBV-ACLF. The area under the curve (AUC) was used to analyze the clinical efficacies of SII, MELD score, MELD-Na score and CTP score in predicting the prognosis of HBV-ACLF patients, and the optimal cut-off value of SII for predicting the prognosis of HBV-ACLF was calculated. Kaplan-Meier method was used for survival analysis. Results:A total of 140 patients with HBV-ACLF were included. There were 88 patients in the survival group, including 65 males and 23 females, with the age of (47.69±11.96) years. There were 52 cases in the death group, including 40 males and 12 females, with the age of (52.73±12.22) years. The age, aspartate aminotransferase, total bilirubin, serum creatinine, international normalized ratio, neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, SII, MELD score, MELD-Na score, CTP score and the incidence of infection in the death group were all significantly higher than those in the survival group, and albumin, lymphocyte count, platelet count, prognostic nutritional index in the death group were all significantly lower than those in the survival group, and the differences were all statistically significant ( t=-2.39, Z=-2.84, t=-4.81, Z=-2.15, Z=-4.91, Z=-3.47, Z=-3.36, Z=-3.83, Z=-4.69, Z=-4.56, Z=-6.31, χ2=24.96, t=3.06, t=3.03, Z=-7.57 and t=4.12, respectively, all P<0.05). Pearson correlation analysis showed that SII was positively correlated with CTP score ( r=0.272 7, P=0.001), MELD score ( r=0.365 8, P<0.001) and MELD-Na score ( r=0.381 1, P<0.001). The AUC of SII was the largest of 0.80, and 0.76 for MELD score, 0.74 for MELD-Na score and 0.73 for CTP score. The optimal cut-off value of SII was 447.49. Kaplan-Meier analysis showed that the 90 days survival rate of patients with SII≥447.49(38.60%(22/57)) was lower than that of SII<447.49 group (79.52%(66/83)), and the difference between the two groups was significant ( χ2=23.80, P<0.001). Conclusions:SII can be used to assess the severity and prognosis of HBV-ACLF patients. SII ≥447.49 indicates poor prognosis.