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:To evaluate the correlation between the degree of posterior longitudinal ligament (PLL) injury and various parameters of vertebral body injury in patients with thoracolumbar burst fractures.Methods:A total of 48 patients with thoracolumbar burst fractures were admitted to the Spine Surgery Center of the Second Affiliated Hospital of Inner Mongolia Medical University between December 2022 and January 2024. The cohort consisted of 31 males and 17 females, with a mean age of 44.1±11.8 years (range, 18-65 years). Based on the PLL injury grading method proposed by Sun Zhaoyun, patients were classified into three groups: mild, moderate, and severe. However, due to an insufficient number of patients in the severe group ( n=3), the moderate and severe groups were combined for statistical analysis, resulting in two groups: mild, and moderate-to-severe. Patient demographic and clinical data were collected. Local kyphosis (LK), inversion angle (IA), horizontal rotation angle (HRA), increased interspinous distance (IISD), anterior vertebral body compression ratio (AVBCR), posterior vertebral body compression ratio (PVBCR), middle vertebral body compression ratio (MVBCR), the ratio of height of bone fragment (RHBF), the ratio of width of bone fragment (RWBF), and mid-sagittal canal diameter compression ratio (MSDCR) were measured. Statistical analyses were performed using SPSS 25.0. Categorical variables were expressed as frequency (percentage) and analyzed using chi-square and Fisher exact tests. Continuous variables were tested for normality, with non-normally distributed data analyzed using the rank-sum test and expressed as median (interquartile range). Multivariate logistic regression analysis was performed to identify independent risk factors, and receiver operating characteristic (ROC) curves were plotted to calculate the area under the curve (AUC) to evaluate predictive performance. Results:Among the 48 patients, only 3 were found to have severe PLL injury, necessitating the combination of the moderate and severe groups for statistical purposes. Patients in the moderate-to-severe group demonstrated significantly higher AVBCR, PVBCR, RHBF, MVBCR, MSDCR, and IA compared to the mild group ( P<0.05). Multivariate logistic regression identified AVBCR, PVBCR, MSDCR, and IA as independent risk factors for moderate-to-severe PLL injury ( OR>1, P<0.05). ROC curve analysis revealed that AVBCR, PVBCR, MSDCR, IA, and their combined index could effectively predict moderate-to-severe PLL injury ( P<0.05). Notably, the combined index showed superior predictive performance (AUC=0.970) compared to individual parameters. Threshold values were determined as follows: AVBCR>45.30%, PVBCR>12.17%, MSDCR>27.13%, IA>5.90°, and the combined index >0.61, indicating PLL damage. Conclusion:AVBCR, PVBCR, MSDCR, IA, and their combined index are significantly associated with moderate-to-severe PLL injury in thoracolumbar burst fractures. The combined index demonstrates superior predictive ability compared to single parameters, providing a reliable tool for assessing PLL integrity.

【Objective】 To investigate the development of adaptability in children aged 2 - 6, and to explore its influencing factors, so as to provide reference for promoting the development of adaptability in young children. 【Methods】 Data were from the National Nutrition and Health Systematic Survey for Children in China, and 3 319 children aged 2 - 6 and their parents from 28 sites across 14 provinces were recruited in this study.The Development Scale for Children Aged 0 - 6 years (WS/T 580-2017) was used to measure the developmental quotient of children′s adaptive ability, and a survey questionnaire was used to collect relevant information about children and their parents. 【Results】 Among 3 319 children aged 2 - 6, the proportion of slightly low or low level of adaptability, moderate adaptability development, good and excellent adaptability development was 7.68%,66.25% and 26.06%, respectively.The proportion of children aged 5 - 6 with good and excellent adaptability was lower in 3-year-old and 4-year-old groups (χ²=59.29, P<0.05).Multiple stepwise linear regression showed that children′s gender (β=0.06), gestational age of birth (β=-0.05), only child (β=-0.04), left-behind child (β=-0.04), the main caregiver (β=-0.06), and the education level of parents (β=0.09, 0.10), whether parents actively pay attention to children′s emotions (β=-0.06) and whether children play with homemade toys (β=-0.04) were the influencing factors of children′s adaptive development quotient.Girls, full-term children, only children, non-left-behind children, children with parents as main caregivers, parents with a high level of education, parents who often take the initiative to pay attention to children′s emotions, and children who play with homemade toys had a higher level of adaptability development quotient. 【Conclusions】 The development level of adaptability in children aged 2 - 6 in China is mostly above the average level and is related to multiple factors.Targeted intervention work can be carried out on relevant factors in order to promote the development of children′s adaptability.

Objective:To evaluate the incidence of arrhythmias and electrocardiographic (ECG) characteristics in cancer patients treated with immune checkpoint inhibitors (ICIs).Methods:This was a cohort study conducted in the Fourth Hospital of Hebei Medical University. Cancer patients initiating ICIs treatments from November 2020 to September 2022 were included in this study. Baseline 12-leads ECG before ICIs initiation and post-treatment ECG were analyzed. An abnormal ECG was defined as the presence of any of the following changes: sinus arrhythmias, atrial fibrillation, atrial flutter, paroxysmal supraventricular tachycardia, ventricular tachycardia, premature contractions, conduction disorder, and ST-T changes.Results:A total of 87 patients were enrolled, aged 63 (57, 68) years, with 66 (75.9%) males. And 44.8% (39/87) of patients presented with at least one confirmed cardiovascular disease or cardiovascular risk factor at baseline. The incidence of abnormal ECG increased from 31.0% (27/87) at baseline to 65.5% (57/87) after receiving (5.0±2.7) cycles of ICIs treatment ( P<0.001). The incidence of sinus arrhythmias was significantly increased after ICIs treatment (23.0% (20/87) vs. 9.2% (8/87), P=0.023), of which only the incidence of sinus tachycardia was significantly increased (11.5% (10/87) vs. 2.3% (2/87), P=0.039). There was also a significantly increased incidence of ST-T changes after ICIs treatment (31.0% (27/87) vs. 17.2% (15/87), P=0.012), which mainly attributed to the T wave changes (29.9% (26/87) vs. 13.8% (12/87), P=0.001). The incidence of premature contractions was also significantly increased after ICIs treatment (9.2% (8/87) vs. 0, P=0.008). Additionally, compared with baseline, the P wave axis was significantly increased after ICIs treatment ((56.94±21.01)° vs. (52.00±22.69)°, P=0.043). After ICIs treatment, the heart rate was significantly increased ((79.07±15.37) beats/min vs. (75.64±13.37) beats/min, P=0.029). Sokolow-Lyon index ((2.21±0.81)mV vs. (2.33±0.75)mV, P=0.138), QTc interval ((431.44±36.04)ms vs. (428.00±30.05)ms, P=0.415) all showed signs of change after treatment, but did not reach the traditional significant level. Conclusions:The incidence of abnormal ECG is significantly increased after ICIs treatment, especially for sinus tachycardia, premature contractions and T wave changes; the P wave axis and heart rate is also significantly increased after treatment. It is important to perform regular ECG monitoring in patients receiving ICIs treatment.

Objective To explore the relationship between the ratio of small dense low density lipoprotein(HDL-C)and high-density lipoprotein(HDL-C)and contrast nephropathy(CIN)after emergency percutaneous coronary intervention(PCI)in patients with acute ST segment elevation myocardial infarction(STEMI)complicated with type 2 diabetes mellitus(T2DM).Method Totally 187 patients with STEMI complicated with T2DM from May 2021 to November 2023 were selected for emergency percutaneous coronary intervention.The creatinine level was measured within 48-72 hours after operation,which was divided into 52 cases in CIN group and 135 cases in non CIN group.The levels of sdLDL and HDL-c in all patients were measured,and the ratio between them was calculated.The difference of sdLDL/HDL-c between the two groups was compared,and its relationship with contrast nephropathy after emergency percutaneous coronary intervention was analyzed.Results SdLDL-C(1.283±0.432)mmol/L in CIN group was higher than that in non CIN group(0.884±0.436)mmol/L.HDL-C(0.822±0.213)mmol/L in CIN group was lower than that in non CIN group(1.013±0.224)mmol/L.sdLDL/HDL-C(1.712±0.793)in CIN group was higher than that in non CIN group(0.843±0.484).The difference was statistically significant(P＜0.05).Logistic regression analysis showed that among the risk factors of coronary heart disease,sdLDL-C/HDL-C was an independent risk factor for CIN after emergency intervention in STEMI patients with T2DM[OR=9.003,95％CI:3.510-23.089,P＜0.001].ROC curve showed that the area under the curve of sdLDL-C/HDL-C to predict the occurrence of CIN in STEMI patients with T2DM was 0.836,optimal truncation was 1.159,the sensitivity was 76.1％,and the specificity was 83.7％.Conclusion SdLDL-C/HDL-C is closely related to the occurrence of CIN after emergency percutaneous coronary intervention in patients with STEMI complicated with T2DM.It may be used as an indicator for predicting the risk of CIN and has clinical guiding significance.

Objective:To explore the values of ultrasound, pathology combined with inflammatory indicators in predicting high nodal burden (HNB) in patients with early breast cancer and to construct a nomogram to provide reference for individualized diagnosis and treatment.Methods:The ultrasonographic, pathological features and preoperative inflammatory indicators of 378 female patients diagnosed with early breast cancer confirmed by pathology in the South Hospital of the Sixth People′s Hospital Affiliated to Shanghai Jiaotong University from January 2014 to July 2022 were retrospectively analyzed. They were randomly divided into training set ( n=302) and test set ( n=76) in a ratio of 8∶2, and the baseline data of the two groups were compared. The optimal cutoff values of neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR) and lymphocyte to monocyte ratio (LMR) were obtained by ROC curve. In the training set, with axillary high lymph node load (≥3 metastatic lymph nodes) as the dependent variable, independent influencing factors of HNB were identified by univariate and multivariate Logistic regression analyses, and the nomogram was established. The test set data were used to verify the model. The discrimination, calibration and clinical applicability of the model were assessed by the area under the ROC curve (AUC), C-index, the calibration curve, Brier score and the decision curve analysis, respectively. Results:There were no significant differences in all variables between the training set and the test set (all P>0.05). ROC curve analysis results showed that AUCs of NLR, PLR and LMR were 0.578, 0.547 and 0.516, respectively, and the optimal cut-off values were 2.184, 150 and 3.042, respectively. Univariate Logistic regression analysis showed that age, pathological type, histological grade, Ki-67, lymphovascular invasion, NLR, PLR, ultrasonic characteristics (maximum diameter of primary tumor, shape, long/short diameter of lymph node, cortical thickness, cortical and medullary boundary, lymph node hilum, lymph node blood flow pattern) were correlated with HNB of early breast cancer (all P<0.05). Multivariate Logistic regression analysis showed that ultrasonic characteristics (maximum diameter of primary tumor >2 cm, effacement of lymph node hilum, non-lymphatic portal blood flow), lymphovascular invasion, Ki-67>14% and NLR>2.184 were independent risk factors for HNB in early breast cancer ( OR=7.258, 8.784, 6.120, 8.031, 3.394 and 3.767, respectively; all P<0.05) and were used to construct the nomogram model. The AUC of the training set was 0.914 (95% CI=0.878-0.949), C-index was 0.914; The AUC of the test set was 0.871 (95% CI=0.769-0.973), C-index was 0.871, indicating good discrimination. Calibration curve and Brier score were 0.090, indicating high calibration degree of the model. The clinical decision curve indicated good clinical benefit. Conclusions:The nomogram based on ultrasonic characteristics (maximum diameter of primary tumor, lymph node hilum, lymph node blood flow pattern), lymphovascular invasion, Ki-67 and NLR can effectively predict the risk of HNB in patients with early breast cancer, and provide a reference for precision diagnosis and treatment to avoid excessive or insufficient treatment.

OBJECTIVE To provide reference for clarifying improvement effects of Anemarrhena asphodeloides on sepsis- induced myocardial injury and potential material basis. METHODS Water extract of A. asphodeloides was extracted by thermal reflux method. Total xanthone and total saponins in A. asphodeloides were separated by macroporous adsorption resin. The mice model of sepsis-induced myocardial injury was established by intraperitoneal injection of lipopolysaccharide. The effects of the location of three extraction fractions and the monomers of A. asphodeloides as mangiferin， timosaponin AⅢ and timosaponin BⅡ on the survival rate of the model mice were explored. HE staining was used to observe the effects of mangiferin， timosaponin AⅢ and timosaponin BⅡ on myocardial morphology in model mice. The effects of mangiferin on mRNA expressions of inflammatory cytokines [interleukin-6 （IL-6）， IL-1β and tumor necrosis factor-α （TNF-α）] and the level of reactive oxygen species （ROS） in myocardial tissue of model mice were detected. RESULTS Compared with the model group， the survival rate of mice in the intervention group of total xanthone， total saponins and water extract was increased to different extents， especially total xanthone fraction. Mangiferin， timosaponin AⅢ and timosaponin BⅡcould improve the degree of myocardial cell swelling and muscle bundle arrangement disorder in model mice， especially mangiferin. Compared with model group， mRNA expressions of IL-6， IL- 1β and TNF- α， ROS level in myocardium of mice after mangiferin intervention were decreased to different extents. CONCLUSIONS The different extraction fractions of A. asphodeloides can improve survival rate of mice with sepsis-induced myocardial injury， especially total xanthone fraction. Mangiferin is the best among the three monomers of A. asphodeloides to improve sepsis-induced myocardial injury， which may play a role in anti-sepsis myocardial injury by anti-inflammation and antioxidantion.

Purpose The aim of this study is to explore the application value of ALK(1A4)in ALK fused non-small cell lung cancer(NSCLC).Methods A total of 1 035 NSCLC specimens were collected.The expression of ALK(1A4)and ALK(D5F3)antibodies was detected by immunohistochemical(IHC)staining,and their consistency was analyzed.FISH and next-generation sequencing(NGS)were used to detect ALK positive,and the sensitivity and specificity of ALK in the two groups were evaluated.Results ALK fused NSCLC patients accounted for about 5.4％(56/1 035).The positive rate of ALK(1A4)was 7.2％(75/1 035),and that of ALK(D5F3)was 5.7％(59/1 035).The consistency between them was high,with a Kappa value of 0.874.The consistency of ALK(1A4)and ALK(D5 F3)antibodies with FISH was high,with Kappa values of 0.845 and 0.954,respectively.The consisten-cy of ALK(1A4)and ALK(D5F3)with NGS was also high,with Kappa values of 0.836 and 0.988,respectively.According to the FISH results,the sensitivities of ALK(1A4)and ALK(D5F3)antibodies were 100％and 98.2％,and the specifici-ties were 98.1％and 99.6％,respectively.Conclusion ALK(1A4)antibody has high sensitivity and slightly low specificity,and can be used for clinical screening of ALK fused NSCLC.

Objective:To investigate the effect of free thenar perforator flap on repair of finger pulp defect.Methods:From September 2019 to November 2021, 79 cases of finger injuries complicated with defects in the pulp of fingers received free thenar perforator flap transfer surgery for reconstruction of finger pulps in the Department of Hand and Foot Surgery, Taizhou Hospital, Zhejiang Province. The patients were 51 males and 28 females, aged from 17 to 52(37.5±5.2) years old. There were 34 finger-pulp defects of index fingers, 15 of middle fingers, 26 of ring fingers and 4 of little fingers. All patients were treated with free thenar perforator flaps sized 2.0 cm×2.5 cm-3.0 cm×3.5 cm. All thenar perforator flaps were pedicled with the perforator artery and subcutaneous superficial vein in the thenar region, and the vessels were anastomosed with the proper palmar digital artery and dorsal digital vein, respectively. At the same time, subcutaneous nerve and proper palmar digital nerve were sutured to reconstruct the sensation of flaps. During the operation, the dominant perforating branch of thenar was found being originated from the superficial palmar branch of radial artery in 27 cases, from the superficial palmar arch in 21 cases, from the perforating branch of metacarpophalangeal proper artery of thumb in 11 cases, from the radial artery in 10 cases and from the main artery of thumb in 10 cases. The origins of nerves within the flaps were found from the superficial branch of radial nerve(24 cases), the terminal branch of lateral cutaneous nerve of forearm(22 cases) and the palmar branch of median nerve(33 cases). The operation time was (96.7±10.7) minutes. The donor site for the flap was closed directly without skin grafting. Most of the follow-up were conducted through the visit of outpatient clinic and the patients from other regions were reviewed via telephone or WeChat.Results:All perforator flaps survived completely and the flap donor sites healed smoothly. Follow-up lasted for (20.5±3.8) months. The reconstructed finger pulp was not bulky and the texture was satisfactory. TPD of the flaps was (5.6±0.9) mm. Only a linear scar left in the flap donor sites without significant affect on thenar function.Conclusion:The vascular anatomy of thenar perforator flap is constant, which helps to regain sensations of the flap. The texture and thickness of the flap are similar to those of the finger. It is ideal for reconstruction of defect of finger pulp.