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.

Sigma-1 receptor (σ ₁R) has become a focus point of drug discovery for central nervous system (CNS) diseases. A series of novel 1-phenylethan-1-one O-(2-aminoethyl) oxime derivatives were synthesized. In vitro biological evaluation led to the identification of 1a, 14a, 15d and 16d as the most high-affinity (K _i < 4 nmol/L) and selective σ ₁R agonists. Among these, 15d, the most metabolically stable derivative exhibited high selectivity for σ ₁R in relation to σ ₂R and 52 other human targets. In addition to low CYP450 inhibition and induction, 15d also exhibited high brain permeability and excellent oral bioavailability. Importantly, 15d demonstrated effective antipsychotic potency, particularly for alleviating negative symptoms and improving cognitive impairment in experimental animal models, both of which are major challenges for schizophrenia treatment. Moreover, 15d produced no significant extrapyramidal symptoms, exhibiting superior pharmacological profiles in relation to current antipsychotic drugs. Mechanistically, 15d inhibited GSK3β and enhanced prefrontal BDNF expression and excitatory synaptic transmission in pyramidal neurons. Collectively, these in vivo proof-of-concept findings provide substantial experimental evidence to demonstrate that modulating σ ₁R represents a potential new therapeutic approach for schizophrenia. The novel chemical entity along with its favorable drug-like and pharmacological profile of 15d renders it a promising candidate for treating schizophrenia.

Objective Sequencing depth is a key parameter in next generation sequencing,which is closely related to the accuracy of sequencing results.Forensic biological evidence examination requires extremely high accuracy.It is crucial to scientifically and reasonably set the sequencing depth analysis threshold for forensic next generation sequencing testing.Methods This study used targeted sequencing data of microhaplotypes from 50 samples with known genotypes.By calculating the accuracy,precision,recall,and F1 score of each locus under various threshold conditions,two types of analysis threshold setting methods,which were based on fixed read count and fixed sequencing depth ratio,were studied extensively.Results The results showed that false positives were observed when the analysis threshold was set at 50×or 100×.When the analysis threshold was set at 200×,false negatives were observed.When the analysis threshold was set at 1.5%,3.0%,or 4.5%,false positives were observed.This study further proposed a third type of analysis threshold setting method,which was based on sequencing depth ratio scatter plots.With this method,no false positive or false negative was observed in the results.This article then explored four factors that lead to significant differences in the sequencing depth of forensic next generation sequencing experiments,compared with the analysis threshold setting method for capillary electrophoresis technology,and discussed the correlation between analysis thresholds and the ability to distinguish mixed DNA.Conclusion Employing the sequencing depth ratio scatter plot method to set analysis threshold has significant application value in next generation sequencing-based forensic genetic marker genotyping.

Objective To develop an expert consensus on subcutaneous injection for allergen-specific immunotherapy.Methods Relevant domestic and intemational literature was reviewed,and nursing experts who had experiences in subcutaneous injection of allergen-specific immunotherapy were interviewed to form the initial draft of the consensus.A total of 85 experts from 42 hospitals nationwide were invited to participate in discussions.2 rounds of expert consultations,adjustments,revisions,and improvements were made to the initial draft,and an online meeting was held to form the final version of the consensus.The content approved by more than 75％of the expert group is adopted,or it will be discussed or deleted.Results The expert consensus includes operational standards for subcutaneous injection of allergen-specific immunotherapy,identification and management of adverse reactions,and health education.Conclusion The consensus demonstrates strong scientific rigor and practicality,providing guidance for nursing practices in the field of clinical allergology.

Objective:To investigate the surgical method of preoperative computed tomography angiography(CTA) combined with color Doppler ultrasonography(CDU) vascular localization assisted by downstream vascularized medial femoral condylar bone flap and its clinical effect in the treatment of refractory scaphoid fracture nonunion.Methods:Retrospective analysis of case data from January 2018 to June 2022 in the Department of Orthopedics at Xingtai General Hospital of North China Medical and Health Group, using a free medial femoral condylar bone flap with descending knee artery as the blood supply to repair old fractures of the scaphoid bone with bone damage. Prior to surgery, CTA combined with CDU technology was used to locate the descending knee artery, and the medial femoral condylar bone flap was designed based on the localization result and bone defects. Follow-up was conducted using outpatient and telephone method. The degree of wrist pain was evaluated using the visual analogue scale (VAS), wrist function was evaluated using the improved Mayo scoring method, the degree of scaphoid arch back deformity was evaluated based on the angle of the scaphoid bone, and stability between the carpal bones was evaluated based on the angle of the scaphoid moon. The normal distribution metric data was represented as Mean±SD, and paired sample t-tests were used to compare the preoperative CDU measurement and the actual intraoperative measurement of the vessel diameter at the origin of the descending knee artery, as well as the distance to the inferior edge of the medial femoral condyle. The VAS score for pain before and after surgery, the Mayo score for wrist function, wrist grip strength, range of motion, scaphoid angle, and scaphoid angle are also compared. Results:A total of 12 patients were enrolled, including 9 males and 3 females; age ranged from 23 to 56 years old, with an average of 36 years old. There were 7 cases of right side fractures, 5 cases of left side fractures, 8 cases of scaphoid waist fractures, and 4 cases of proximal pole fractures. There was no difference between the preoperative CDU location and the actual vessel diameter at the origin of the descending geniculate artery [(1.7±0.5) mm vs. (1.8±0.7) mm] and the distance to the inferior border of the medial femoral condyle [(11.9±2.1) cm vs. (12.1±1.9) cm]( P>0.05). All patients were followed up after the operation, the specific time ranged from 6 months to 2 years, with an average of 13 months. The X-ray films showed that the scaphoid bone healed in all patients after operation, and the average healing time was 15 weeks. After 6 months of follow-up, the VAS scores (3.7±0.9 vs. 0.5±0.1), Mayo scores (46.1±3.8 vs. 86.2±6.1), scapholunar angle [(65.3±4.1)° vs. (47.9±3.5)°], scaphoid angle [(37.1±3.9)° vs. (22.8±2.3)°], wrist flexion and extension range of motion [(79.0±11.7)° vs. (118.5±15.8)°], grip strength [(6.7±4.6) kg vs. (26.1±5.3) kg]were compared before and after surgery, the differences were statistically significant (all P<0.05). Conclusion:The free medial femoral condyle bone flap with a vascular pedicle is one of the ideal method to repair the old navicular fracture with osteonecrosis. The preoperative vascular positioning technique effectively guides the design and cutting of the bone flap and ensures fast and accurate operation during the operation.

Objective:To investigate the surgical method of preoperative computed tomography angiography(CTA) combined with color Doppler ultrasonography(CDU) vascular localization assisted by downstream vascularized medial femoral condylar bone flap and its clinical effect in the treatment of refractory scaphoid fracture nonunion.Methods:Retrospective analysis of case data from January 2018 to June 2022 in the Department of Orthopedics at Xingtai General Hospital of North China Medical and Health Group, using a free medial femoral condylar bone flap with descending knee artery as the blood supply to repair old fractures of the scaphoid bone with bone damage. Prior to surgery, CTA combined with CDU technology was used to locate the descending knee artery, and the medial femoral condylar bone flap was designed based on the localization result and bone defects. Follow-up was conducted using outpatient and telephone method. The degree of wrist pain was evaluated using the visual analogue scale (VAS), wrist function was evaluated using the improved Mayo scoring method, the degree of scaphoid arch back deformity was evaluated based on the angle of the scaphoid bone, and stability between the carpal bones was evaluated based on the angle of the scaphoid moon. The normal distribution metric data was represented as Mean±SD, and paired sample t-tests were used to compare the preoperative CDU measurement and the actual intraoperative measurement of the vessel diameter at the origin of the descending knee artery, as well as the distance to the inferior edge of the medial femoral condyle. The VAS score for pain before and after surgery, the Mayo score for wrist function, wrist grip strength, range of motion, scaphoid angle, and scaphoid angle are also compared. Results:A total of 12 patients were enrolled, including 9 males and 3 females; age ranged from 23 to 56 years old, with an average of 36 years old. There were 7 cases of right side fractures, 5 cases of left side fractures, 8 cases of scaphoid waist fractures, and 4 cases of proximal pole fractures. There was no difference between the preoperative CDU location and the actual vessel diameter at the origin of the descending geniculate artery [(1.7±0.5) mm vs. (1.8±0.7) mm] and the distance to the inferior border of the medial femoral condyle [(11.9±2.1) cm vs. (12.1±1.9) cm]( P>0.05). All patients were followed up after the operation, the specific time ranged from 6 months to 2 years, with an average of 13 months. The X-ray films showed that the scaphoid bone healed in all patients after operation, and the average healing time was 15 weeks. After 6 months of follow-up, the VAS scores (3.7±0.9 vs. 0.5±0.1), Mayo scores (46.1±3.8 vs. 86.2±6.1), scapholunar angle [(65.3±4.1)° vs. (47.9±3.5)°], scaphoid angle [(37.1±3.9)° vs. (22.8±2.3)°], wrist flexion and extension range of motion [(79.0±11.7)° vs. (118.5±15.8)°], grip strength [(6.7±4.6) kg vs. (26.1±5.3) kg]were compared before and after surgery, the differences were statistically significant (all P<0.05). Conclusion:The free medial femoral condyle bone flap with a vascular pedicle is one of the ideal method to repair the old navicular fracture with osteonecrosis. The preoperative vascular positioning technique effectively guides the design and cutting of the bone flap and ensures fast and accurate operation during the operation.

Objective: To explore the relationship between dietary behavior, dietary frequency and central precocious puberty (CPP) among children in Wuhan, so as to provide a scientific basis for elucidating the possible and related dietary factors leading to precocious puberty. Methods: From February to December 2023, 100 children with CPP and 100 healthy children were collected in Wuhan Children s Hospital for a case control study. Questionnaires and interviews were used to collect demographic information, child lifestyle, as well as dietary behavior and dietary frequency in the past six months. Conditional Logistic regression model was used to analyze the relationship of children s dietary behavior and dietary frequency with CPP. Results: No associations were found between three dietary behavior, including emotional eating, restrictive eating, and external eating, with CPP at baseline ( P >0.05). In the association analysis of dietary frequency and CPP, the risk of CPP was higher in those who consumed red meat >5 times/week ( OR =1.93, 95% CI =1.01-3.68), carbonated beverages ≥4 times/month ( OR =2.70, 95% CI =1.03-7.08), fruit juices ≥4 times/month ( OR =2.31, 95% CI =1.02-5.25), and nutritional supplementation ( OR =2.77, 95% CI =1.47- 5.22 ), whereas the risk of CPP was lower in those who consumed nuts ≥4 times/month ( OR =0.21, 95% CI =0.08-0.57) ( P < 0.05 ). Conclusion Consumption of higher amounts of red meat, high frequency of carbonated and juice based sugary drinks, and nutrient supplementation may be contributing factors to the development of CPP, whereas regular consumption of nuts is less likely to be associated with the development of CPP.

Objective To investigate the efficacy and safety of camrelizumab monoclonal antibody combined with molecular-targeted therapy in elderly patients with unresectable or advanced hepatocellular carcinoma(HCC).Methods A retrospective analysis was performed for the patients with unresectable/advanced HCC who attended six hospitals from January 1,2019 to March 31,2021,and all patients received camrelizumab monoclonal antibody treatment,among whom 84.8%also received targeted therapy.According to the age of the patients,they were divided into elderly group(≥65 years)and non-elderly group(＜65 years).The two groups were assessed in terms of overall survival(OS),progression-free survival(PFS),objective response rate(ORR),disease control rate(DCR),and immune-related adverse events(irAE).The chi-square test or the Fisher's exact test was used for comparison of categorical data between groups;the independent samples t-test was used for comparison of normally distributed continuous data,and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups.The Kaplan-Meier method was used for survival analysis,and the log-rank test was used for comparison of survival curves.Univariate and multivariate Cox proportional hazards regression analyses were used to determine the independent influencing factors for PFS and DCR at 6 months.Results A total of 99 HCC patients were enrolled,with 27 in the elderly group and 72 in the non-elderly group.The elderly group had an OS rate of 67.8%,an ORR of 44.4%,and a DCR of 74.1%at 12 months and a median PFS of 6.4(95%confidence interval[CI]:3.0-12.4)months,with no significant differences compared with the non-elderly group(all P＞0.05).The median OS was unavailable for the elderly group,while the non-elderly group had an OS of 18.9(95%CI:13.0-24.8)months;there was no significant difference between the two groups(P=0.485).The univariate and multivariate Cox regression analyses showed that major vascular invasion(MVI)was an independent risk factor for PFS(hazard ratio[HR]=2.603,95%CI:1.136-5.964,P=0.024)and DCR(HR=3.963,95%CI:1.671-9.397,P=0.002)at 6 months,while age,sex,etiology of HBV infection,presence of extrahepatic metastasis,Child-Pugh class B,and alpha-fetoprotein＞400 ng/mL were not associated with PFS or DCR at 6 months.For the elderly group,the incidence rates of any irAE and grade 3/4 irAE were 51.9%and 25.9%,respectively,with no significant differences compared with the non-elderly group(P＞0.05),and skin disease was the most common irAE in both groups(39.4%).Conclusion Camrelizumab monoclonal antibody combined with molecular-targeted therapy has similar efficacy and safety in patients with unresectable/advanced HCC aged≥65 years and those aged＜65 years.MVI is associated with suboptimal response to immunotherapy and poor prognosis.

Objective:To evaluate the effect of age factors on the pharmacodynamics of intranasal dexmedetomidine for sedation in the pediatric patients undergoing transthoracic echocardiography(TTE).Methods:American Society of Anesthesiologists Physical Status classification Ⅰ-Ⅲ pediatric patients, aged 1-24 months, undergoing TTE from August 2019 to May 2022, were selected. This trial was performed in two parts. Part Ⅰ Pediatric patients were divided into 4 age groups: 1-6 month group, 7-12 month group, 13-18 month group and 19-24 month group. The initial dose of dexmedetomidine was 2.0 μg/kg in 0.1 μg/kg increment/decrement. The dose of dexmedetomidine was determined by using modified Dixon′s up-and-down method. The ED 50 and 95% confidence interval of intranasally administered dexmedetomidine for sedation were calculated by the Dexon-Massey method. Part Ⅱ One hundred patients were divided into 4 age groups ( n= 25 each): 1-6 month group, 7-12 month group, 13-18 month group and 19-24 month group. The 4 groups were further divided into 5 subgroups ( n=5 each) according to the dose of dexmedetomidine: 2.1 μg/kg subgroup, 2.2 μg/kg subgroup, 2.3 μg/kg subgroup, 2.4 μg/kg subgroup, and 2.5 μg/kg subgroup. Part Ⅰ and part Ⅱ trials were combined, and the ED 95 and 95% confidence interval of intranasally administered dexmedetomidine for sedation were calculated using the probit method. Results:A total of 220 pediatric patients were enrolled. There was no significant difference in ED 50 and ED 95 of dexmedetomidine intranasally administered for sedation among groups ( P>0.05). Conclusions:The pharmacodynamics of intranasal dexmedetomidine for sedation shows no significant difference in age in the pediatric patients aged 1-24 months undergoing TTE.

Objective To investigate the regulatory effect of poria cocos on gastrointestinal motility in mice. Methods A total of 130 Kunming mice were randomly divided into negative control group, low-dose and high-dose groups of raw poria cocos powder, low-dose and high-dose groups of cooked poria cocos powder, low-dose and high-dose groups of poria cocos surrogate culture powder, low-dose, medium-dose and high-dose groups of poria cocos water extract, and low-dose, medium-dose and high-dose groups of poria cocos alcohol extract, with 10 mice in each group. The animals were administered by gavage for 7 days, once a day. After the last administration, the intestinal propulsion function test and gastric solid emptying test were conducted to observe the regulating effect of poria cocos on gastrointestinal motility of mice. Results Compared with the negative control group, the small intestine propulsion rate in the low-dose group of poria cocos surrogate culture powder was significantly increased (P<0.01). Except the high-dose group of raw poria cocos powder, the other poria cocos groups had higher gastric residual rate (P<0.05). Conclusion Poria cocos does not promote intestinal propulsion of mice under normal physiological condition, but it can inhibit gastric empting and exert a moderating effect on gastrointestinal function in normal mice.