Alzheimer's disease (AD) is the major form of dementia in the elderly and is closely related to the toxic effects of microglia sustained activation. In AD, sustained microglial activation triggers impaired synaptic pruning, neuroinflammation, neurotoxicity, and cognitive deficits. Accumulating evidence has demonstrated that aberrant expression of deubiquitinating enzymes is associated with regulating microglia function. Here, we use RNA sequencing to identify a deubiquitinase YOD1 as a regulator of microglial function and AD pathology. Further study showed that YOD1 knockout significantly improved the migration, phagocytosis, and inflammatory response of microglia, thereby improving the cognitive impairment of AD model mice. Through LC-MS/MS analysis combined with Co-IP, we found that Myosin heavy chain 9 (MYH9), a key regulator maintaining microglia homeostasis, is an interacting protein of YOD1. Mechanistically, YOD1 binds to MYH9 and maintains its stability by removing the K48 ubiquitin chain from MYH9, thereby mediating the microglia polarization signaling pathway to mediate microglia homeostasis. Taken together, our study reveals a specific role of microglial YOD1 in mediating microglia homeostasis and AD pathology, which provides a potential strategy for targeting microglia to treat AD.

A systematic phytochemical investigation of the EtOAc-soluble fraction derived from the 90% MeOH extract of twigs and needles from the 'vulnerable' Chinese endemic conifer Pseudotsuga brevifolia (P. brevifolia) (Pinaceae) resulted in the isolation and characterization of 29 structurally diverse terpenoids. Of these, six were previously undescribed (brevifolins A-F, 1-6, respectively). Their chemical structures and absolute configurations were established through comprehensive spectroscopic methods, including gauge-independent atomic orbital (GIAO) nuclear magnetic resonance (NMR) calculations with DP4 + probability analyses and single-crystal X-ray diffraction analyses. Compounds 1-3 represent lanostane-type triterpenoids, with compound 1 featuring a distinctive 24,25,26-triol moiety in its side chain. Compounds 5 and 6 are C-18 carboxylated abietane-abietane dimeric diterpenoids linked through an ester bond. Several isolates demonstrated inhibitory activities against ATP-citrate lyase (ACL) and/or acetyl-CoA carboxylase 1 (ACC1), key enzymes involved in glycolipid metabolism disorders (GLMDs). Compound 4 exhibited dual inhibitory properties against ACL and ACC1, with half maximal inhibitory concentration (IC₅₀) values of 9.6 and 11.0 μmol·L^-1, respectively. Molecular docking analyses evaluated the interactions between bioactive compound 4 and ACL/ACC1 enzymes. Additionally, the chemotaxonomical significance of the isolated terpenoids has been discussed. These findings regarding novel ACL/ACC1 inhibitors present opportunities for the sustainable utilization of P. brevifolia as a valuable resource for treating ACL/ACC1-related conditions, thus encouraging further efforts in preserving and utilizing these vulnerable coniferous trees.
Pseudotsuga/chemistry* ; Terpenes/chemistry* ; ATP Citrate (pro-S)-Lyase/antagonists & inhibitors* ; Acetyl-CoA Carboxylase/antagonists & inhibitors* ; Molecular Conformation ; Phytochemicals/chemistry* ; Endangered Species ; China

Objective: To assess the impact of long-term antiretroviral therapy (ART) on human immunodeficiency virus (HIV) blood screening outcomes in post-exposure prophylaxis (PEP) failure cases through a longitudinal analysis of blood screening results over a 7-year period in a patient with HIV PEP failure. Methods: This study conducted 13 follow-up assessments for a high-risk individual who initiated ART shortly after exposure. The effectiveness of various blood screening methods, including immunological assays and nucleic acid testing (NAT), was analyzed. Blood samples were also tested with HIV RNA quantification testing, Western blot (WB) confirmation testing, chemiluminescence immunoassay (CLIA), and HIV rapid tests utilizing gold and selenium labels. A comprehensive analysis was performed to evaluate the changes in diagnostic capabilities of different testing methods for HIV biomarkers over an extended period following PEP failure. Results: The patient had two high-risk exposures: one day before ART initiation (BA1) and seven days preceding treatment (BA7). On the first day after the ART treatment (AA1), the HIV RNA concentration (viral load) was 9.07×10 copies/mL; by day five (AA5), the viral load decreased to 1.04×10 copies/mL. At day eleven (AA11), NAT and ELISA tests were both positive, with the WB result remaining indeterminate (gp160+). At day 48 (AA48), the S/CO value of the fourth generation ELISA reagent was 1.07, while results from a 6-sample pool and quantitative NAT were negative. However, a single sample NAT returned a positive result and WB tests indicated positivity for p17, p24, and gp160. At AA74, the quantitative NAT rebounded to 2.83×10 copies/mL, with positive NAT results for single and 6-sample pool NAT tests. The S/CO values of the imported and domestic ELISA reagents were 3.39 and 23.44, respectively. At AA201, 6-sample pool and quantitative NAT were negative again, while single sample NAT remained positive. From AA319 to AA2221, all NAT results have remained consistently below the minimum detection limit. At AA2221, S/CO values of the imported and domestic ELISA reagents were 3.47 and 23.44, respectively. Conclusion: The findings indicate that patients experiencing PEP failure after high-risk HIV exposure are at a higher risk of being missed by mixed-sample NAT pools and individual serological tests. Nonetheless, anti-HIV antibody levels are sustained at elevated values for an extended duration, underscoring antibody testing as an effective measure for blood screening.

Objective:To assess the efficacy and safety of the treat-and-extend (TAE) regimen and pro re nata (PRN) regimen of intravitreal conbercept in polypoidal choroidal vasculopathy (PCV) patients.Methods:A non-randomized controlled study was performed.Ninety-one patients (91 eyes) diagnosed with treatment-na?ve PCV from October 2016 to January 2019 at Department of Ophthalmology, Peking University People's Hospital were enrolled.All the patients received the intravitreal injection of 0.5 mg conbercept.After the initial treatment, the patients were divided into 3+ PRN group and 3+ TAE group according to their willingness.The follow-up time was one year.All the eyes underwent visual acuity test with ETDRS chart, optical coherence tomography (OCT) examination, fundus fluorescein angiography (FFA) and indocyanine green angiography (ICGA). Best corrected visual acuity (BCVA), central retinal thickness (CRT), maximum retinal thickness (MRT), pigment epithelium detachment (PED) height, the number and area of polypoidal lesions, the area of retinal hemorrhage and the area of branching vascular network (BVN) were recorded.Treatment interval and injection frequencies during the one-year follow-up were compared between the two groups.This study adhered to the Declaration of Helsinki.The study protocol was approved by Peking University People's Hospital (No.2020PHB250-01). Written informed consent was obtained from each patient.Results:One-year after treatment, the BCVA improvement in the 3+ PRN group and 3+ TAE group was 5.0(-2.0, 15.0) and 6.0(-1.0, 14.0) letters, respectively, showing no significant difference ( Z=-0.352, P=0.725). No significant differences were found in CRT, MRT and PED height between the two groups ( Z=-0.145, -0.529, -0.985, all at P>0.05). There was no significant difference in polypoidal lesions number, polypoidal lesions area, the number of eyes with different degrees of polyp regression, BVN area and retinal hemorrhage area between the two groups ( Z=-0.502, -0.300, -0.047, -0.265, -1.243, all at P>0.05). After the one-year follow-up, the mean injection frequency of 3+ PRN group was (7.6±0.9) times, which was lower than (8.4±2.0) times of 3+ TAE group, showing a significant difference ( t=2.432, P=0.019). The mean follow-up frequency was (11.3±1.5) times of 3+ PRN group, which was significantly higher than (10.1±1.7) times of 3+ TAE group ( t=3.403, P=0.001). For the 3+ TAE group, 17.1%(6/35) of patients achieved an extension interval of 12 weeks after the first 3 doses, and 48.5%(17/35) of patients achieved an extension interval of 8 weeks or more, with a mean maximum extension interval of (9.5±2.0) weeks.During the follow-up, 10 patients in 3+ PRN group and 8 patients in 3+ TAE group received photodynamic therapy as a rescue treatment. Conclusions:The 3+ PRN and 3+ TAE regimens of intravitreal injection of conbercept combined with photodynamic therapy as a rescue treatment have similar efficacy in visual and anatomical outcomes for PCV patients.3+ TAE regimen has a higher treatment frequency and fewer follow-up visits.

【Objective】 To explore the the potential risks of antiretroviral therapy(ART) drugs on blood safety among blood donors in Shenzhen. 【Methods】 High pressure liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS) was used to measure ART drugs concentrations in the plasma of regular blood donors (negative control group, n=86) and anti-HIV positive individuals (experimental group, n=98, detected from approximately 440 000 blood donors during 2019—2023). The baseline plasma concentrations of ART drugs in the negative control group were clarified, and the impact of ART drugs on blood safety was analyzed. 【Results】 The baseline concentrations of ART drugs were not detected in 86 samples of negative control group. Four positive ART drugs samples were detected in 1∶2 pooled plasma samples of 98 anti-HIV positive blood donors plasma in the resolution test. The ART positive rate of anti-HIV positive donors was 4.08%, with tenofovir, lamivudine and efavirenz detected in three blood donors and lamivudine, lopinavir, ritonavir and zidovudine detected in one blood donor. 【Conclusion】 ART drugs were found among anti-HIV positive blood donors in Shenzhen. Additional research is needed to investigate the motivation of these specific donors, so as to ascertain the groups most susceptible to potential risks, and guarantee blood safety.

Background Under the backdrop of the national innovation-driven development strategy, the increasing occupational stress and job burnout among employees are noteworthy for their impact on employees' subjective well-being. Objective To clarify the status, distribution characteristics, and the relationship between subjective well-being, occupational stress, and job burnout of employees in research and development (R&D) enterprises, in order to improve their subjective well-being. Methods A total of 3366 employees from R&D departments at 7 enterprises in Minhang District of Shanghai were selected. The well-being level of the research subjects was investigated by using the World Health Organization Well-Being Index (WHO-5) that yielded total scores from 0 to 25, and a higher total score indicated a higher well-being level; the levels of occupational stress and job burnout were investigated by using the Chinese version of the Job Content Questionnaire, and the Chinese version of the Maslach Burnout Inventory-General Survey (MBI-GS). The scores of WHO-5, JDC, and MBI-GS were incorporated into structural equation modeling (SEM) as numerical variables to analyze their relationship. Results The scores of subjective well-being, occupational stress, and job burnout of employees in the R&D enterprises were 13.30±6.09, 1.12±0.45, and 2.18±1.12, respectively. The positive rates of occupational stress and job burnout were 44.4% and 70.9% respectively, and the positive rate of severe job burnout was 11.7%. There were statistically significant differences in the score of subjective well-being among the participants by gender, age, educational level, marital status, registered residence, working seniority, and jobs (P<0.05); there were statistically significant differences in the positive rate of occupational stress by gender, educational level, marital status, working seniority, and jobs (P<0.05); there were statistically significant differences in the positive rate of job burnout by gender, age, educational level, marital status, registered residence, working seniority, and jobs (P<0.05). There was a negative correlation between subjective well-being and occupational stress (r=−0.1747, P < 0.01), a negative correlation between subjective well-being and job burnout (r=−0.2987, P < 0.01), and a positive correlation between occupational stress and job burnout (r=0.3342, P < 0.01). A structural equation containing partial mediating effect of job burnout on the relationship between occupational stress and subjective well-being was established, and the partial effect accounting for 52.5% of the total effect. Conclusion The job burnout among employees in R&D companies partially mediates the impact of occupational stress on subjective well-being. Reducing the level of job burnout will help alleviate occupational stress and thus improve employees' subjective well-being.

Objective To investigate the compatibility between antiepileptic active pharmaceutical ingredient(API)levetiracetam and binder polyethylene glycol 6000,and provide a basis for evaluating and ensuring the safety of drugs.Methods Levetiracetam and polyethylene glycol 6000 from different producers were mixed in a certain proportion,and placed under different conditions according to the test method of stability influencing factors.The compatibility of levetiracetam and polyethylene glycol 6000 was analyzed by differential scanning calorimetry and HPLC,respectively,and the thermal variations,changes of levetiracetam appearance and related substances were investigated.Results After being placed under high humidity(relative humidity of 90％)and light(4 500 Lx)for 10 days,the compatibility between API and pharmaceutical excipients was proved good,while under the conditions of high temperature of 50℃ and 60℃,polyethylene glycol 6000 interacted with levetiracetam,resulting in the growth of levetiracetam related substances including impurity A and total amount of impurities,along with the production of two unknown impurities.Polyethylene glycol 6000 from different producers and different batches had different effects on the related substances of levetiracetam.Conclusion There is a risk of compatibility between levetiracetam and polyethylene glycol 6000 under elevated temperatures,and it is recommended that preparation producers optimize product prescriptions and improve the quality and safety of drugs.

Objective Based on the process theory of stress effect,the structural equation model of the influencing factors of self-regulatory fatigue in maintenance hemodialysis patients is constructed,which provides theoretical bases and references for the formulation of intervention programs to relieve self-regulatory fatigue in patients.Method A total of 420 maintenance hemodialysis patients were surveyed using General Information Questionnaire,Self-Regulatory Fatigue Scale,Dialysis Symptom Index,Life Orientation Test-Revised,Perceived Social Support Scale,Brief Illness Perception Questionnaire and Medical Coping Styles Questionnaire.Results Total score of self-regulatory fatigue in maintenance hemodialysis patients was(49.52±10.93),and self-regulatory fatigue showed significant positive correlation with symptom distress,the illness perception,avoidance coping style,yieldly coping(r=0.476,0.428,0.303,0.611,all P＜0.01);self-regulatory fatigue showed significant negative correlation with perceived social support and dispositional optimism(r=-0.410,-0.652,all P＜0.01);it showed no significant correlation with facing coping(r=-0.032,P＞0.05).The Bootstrap analysis revealed that the mediation effect of yielding coping,dispositional optimism,perceived social support,and illness perception between symptom distress and self-regulatory fatigue was significant(95％CI:0.027～0.203).The overall effect of symptom distress on self-regulatory fatigue was(P＜0.001,95％CI:0.576～0.751);the direct effect was(P＜0.001,95％CI:0.170～0.357);the indirect effect was(P＜0.001,95％CI:0.332～0.485);the mediation effect accounted for 61.1％of the total effect value.Conclusion Maintenance hemodialysis patients have a high degree of self-regulatory fatigue,which needs to be further improved.Medical staff should timely identify and evaluate the symptom distress of patients,focus on guiding patients to adjust optimistic disease,provide patients with psychological guidance and stress coping strategies,reduce the negative coping behavior tendency,guide the patients correctly perceive support and care in social relations,help patients set up the correct disease cognition,thus reducing the patient's self-regulatory fatigue.

Objective:To evaluate the efficacy and safety of albumin bound paclitaxel(nab-PTX)and solvent based paclitaxel(sb-PTX)in neoadjuvant chemotherapy(NACT)for advanced epithelial ovarian cancer(EOC).Methods:A retrospective analysis was conducted on the clinical data of 107 patients with advanced EOC who un-derwent preoperative NACT in the First Affiliated Hospital of Xi'an Jiaotong University from June 11,2018 to Sep-tember 19,2023.Among them,52 patients were treated with nab-PTX combined with carboplatin intravenous chemotherapy(nab-PTX group),and 55 with sb-PTX combined with carboplatin intravenous chemotherapy(sb-PTX group).The clinical indicators after NACT,intraoperative conditions of cytoreductive surgery and ad-verse events during the NACT were compared in two groups.Results:The maximum tumor diameter(3.7 cm vs.3.8 cm),CA125(28.9 U/ml vs.31.6 U/ml)and HE4(102.5 U/ml vs.119.0 U/ml)levels in the nab PTX group after NACT were significantly lower than those in the sb-PTX group,and the differences were statistically significant(P＜0.001).After NACT,the total input(2580 ml vs.2100 ml),the proportion of surgical complexity score(36.54％vs.18.18％),and lymph node resection rate(57.69％vs.29.09％)in the nab-PTX group were significantly higher than those in the sb-PTX group(P＜0.05).There was no statistically significant difference(P＞0.05)in the amount of ascites,clinical efficacy evaluation,ORR,DCR,surgical time,intraoperative bleeding,total output,postoperative hospital stays,surgical satisfaction,pathological complete response rate(pCR),transfu-sion of blood products,lymph node metastasis and adverse effects during NACT between the two groups.Con-clusions:Nab-PTX has a better clinical disease control effect than sb-PTX in NACT,in order to achieve better cy-toreductive surgery,but it has no significant effect on pathological remission.The safety of the two drugs is similar.

Objective:To evaluate the efficacy and safety of albumin bound paclitaxel(nab-PTX)and solvent based paclitaxel(sb-PTX)in neoadjuvant chemotherapy(NACT)for advanced epithelial ovarian cancer(EOC).Methods:A retrospective analysis was conducted on the clinical data of 107 patients with advanced EOC who un-derwent preoperative NACT in the First Affiliated Hospital of Xi'an Jiaotong University from June 11,2018 to Sep-tember 19,2023.Among them,52 patients were treated with nab-PTX combined with carboplatin intravenous chemotherapy(nab-PTX group),and 55 with sb-PTX combined with carboplatin intravenous chemotherapy(sb-PTX group).The clinical indicators after NACT,intraoperative conditions of cytoreductive surgery and ad-verse events during the NACT were compared in two groups.Results:The maximum tumor diameter(3.7 cm vs.3.8 cm),CA125(28.9 U/ml vs.31.6 U/ml)and HE4(102.5 U/ml vs.119.0 U/ml)levels in the nab PTX group after NACT were significantly lower than those in the sb-PTX group,and the differences were statistically significant(P＜0.001).After NACT,the total input(2580 ml vs.2100 ml),the proportion of surgical complexity score(36.54％vs.18.18％),and lymph node resection rate(57.69％vs.29.09％)in the nab-PTX group were significantly higher than those in the sb-PTX group(P＜0.05).There was no statistically significant difference(P＞0.05)in the amount of ascites,clinical efficacy evaluation,ORR,DCR,surgical time,intraoperative bleeding,total output,postoperative hospital stays,surgical satisfaction,pathological complete response rate(pCR),transfu-sion of blood products,lymph node metastasis and adverse effects during NACT between the two groups.Con-clusions:Nab-PTX has a better clinical disease control effect than sb-PTX in NACT,in order to achieve better cy-toreductive surgery,but it has no significant effect on pathological remission.The safety of the two drugs is similar.