Accurate timing of myelination is crucial for the proper functioning of the central nervous system. Here, we identified a de novo heterozygous mutation in TMEM63A (c.1894G>A; p. Ala632Thr) in a 7-year-old boy exhibiting hypomyelination. A Ca²⁺ influx assay suggested that this is a loss-of-function mutation. To explore how TMEM63A deficiency causes hypomyelination, we generated Tmem63a knockout mice. Genetic deletion of TMEM63A resulted in hypomyelination at postnatal day 14 (P14) arising from impaired differentiation of oligodendrocyte precursor cells (OPCs). Notably, the myelin dysplasia was transient, returning to normal levels by P28. Primary cultures of Tmem63a^-/- OPCs presented delayed differentiation. Lentivirus-based expression of TMEM63A but not TMEM63A_A632T rescued the differentiation of Tmem63a^-/- OPCs in vitro and myelination in Tmem63a^-/- mice. These data thus support the conclusion that the mutation in TMEM63A is the pathogenesis of the hypomyelination in the patient. Our study further demonstrated that TMEM63A-mediated Ca²⁺ influx plays critical roles in the early development of myelin and oligodendrocyte differentiation.
Animals ; Cell Differentiation/physiology* ; Oligodendroglia/metabolism* ; Mice, Knockout ; Mice ; Male ; Myelin Sheath/metabolism* ; Humans ; Child ; Cells, Cultured ; Oligodendrocyte Precursor Cells/metabolism*

To investigate the pharmacological substances basis and anti-vitiligo mechanism of Carum carvi L. (caraway) fruits, chemical and blood-absorbed components were identified using mass spectrometry combined with literature study and database analysis. A “blood-absorbed components–target genes–pathways” network was constructed through network pharmacology. The pharmacological effects of Carum carvi L. extract and its key blood-absorbed component, acacetin, were validated in vitro. 72 chemical components were identified in the extract, with 11 prototype blood-absorbed components and 26 metabolites being detected in the plasma of SD rats. 14 key active components and 24 key targets were predicted. In vitro experiments demonstrated that acacetin at 10 μmol/L exhibited melanogenesis-promoting and tyrosinase-activating effects compared with the positive control, significantly upregulating the expression of microphthalmia-associated transcription factor (MITF) and tyrosinase (tyrosinase, TYR). This study comprehensively analyzes the chemical and blood-absorbed components of Carum carvi L. and elucidates its pharmacological substances basis, which provides a theoretical foundation for the anti-vitiligo effects of acacetin.

Objective:To examine the impact of varied surgical treatment strategies on the prognosis of patients with initial resectable gastric cancer liver metastases (IR-GCLM).Methods:This is a retrospective cohort study. Employing a retrospective cohort design, the study selected clinicopathological data from the national multi-center retrospective cohort study database, focusing on 282 patients with IR-GCLM who underwent surgical intervention between January 2010 and December 2019. There were 231 males and 51 males, aging ( M(IQR)) 61 (14) years (range: 27 to 80 years). These patients were stratified into radical and palliative treatment groups based on treatment decisions. Survival curves were generated using the Kaplan-Meier method and distinctions in survival rates were assessed using the Log-rank test. The Cox risk regression model evaluated HR for various factors, controlling for confounders through multivariate analysis to comprehensively evaluate the influence of surgery on the prognosis of IR-GCLM patients. A restricted cubic spline Cox proportional hazard model assessed and delineated intricate associations between measured variables and prognosis. At the same time, the X-tile served as an auxiliary tool to identify critical thresholds in the survival analysis for IR-GCLM patients. Subgroup analysis was then conducted to identify potential beneficiary populations in different surgical treatments. Results:(1) The radical group comprised 118 patients, all undergoing R0 resection or local physical therapy of primary and metastatic lesions. The palliative group comprised 164 patients, with 52 cases undergoing palliative resections for gastric primary tumors and liver metastases, 56 cases undergoing radical resections for gastric primary tumors only, 45 cases undergoing palliative resections for gastric primary tumors, and 11 cases receiving palliative treatments for liver metastases. A statistically significant distinction was observed between the groups regarding the site and the number of liver metastases (both P<0.05). (2) The median overall survival (OS) of the 282 patients was 22.7 months (95% CI: 17.8 to 27.6 months), with 1-year and 3-year OS rates were 65.4% and 35.6%, respectively. The 1-year OS rates for patients in the radical surgical group and palliative surgical group were 68.3% and 63.1%, while the corresponding 3-year OS rates were 42.2% and 29.9%, respectively. A comparison of OS between the two groups showed no statistically significant difference ( P=0.254). Further analysis indicated that patients undergoing palliative gastric cancer resection alone had a significantly worse prognosis compared to other surgical options ( HR=1.98, 95% CI: 1.21 to 3.24, P=0.006). (3) The size of the primary gastric tumor significantly influenced the patients′ prognosis ( HR=2.01, 95% CI: 1.45 to 2.79, P<0.01), with HR showing a progressively increasing trend as tumor size increased. (4) Subgroup analysis indicates that radical treatment may be more effective compared to palliative treatment in the following specific cases: well/moderately differentiated tumors ( HR=2.84, 95% CI 1.49 to 5.41, P=0.001), and patients with liver metastases located in the left lobe of the liver ( HR=2.06, 95% CI 1.19 to 3.57, P=0.010). Conclusions:In patients with IR-GCLM, radical surgery did not produce a significant improvement in the overall prognosis compared to palliative surgery. However, within specific patient subgroups (well/moderately differentiated tumors, and patients with liver metastases located in the left lobe of the liver), radical treatment can significantly improve prognosis compared to palliative approaches.

Objective To investigate the application of synchronized immersion course(SIC)in teaching of clinical practice of surgery for eight-year program students.Methods A total of 94 eight-year program students in French class and 4+4 class who received SIC in the study of surgery in Ruijin Clinical School,Shanghai Jiao Tong University from September 2017 to June 2019 were selected as the pilot group.A total of 91 students in English class who were taught in the traditional way in the same period were selected as a horizontal control group.A total of 84 students in French class and 4+4 class who were studying from September 2015 to June 2017 were selected as the longitudinal control group.Teaching satisfaction evaluation,examination results and specialization choice were compared among students in each group to assess teaching effectiveness.Results The total score(3.8±0.3)and satisfaction rate(98.9%)of the questionnaire in the pilot group were better than those in the horizontal control group(3.6±0.4,90.1%)(P=0.001,P=0.008).For the case analysis station in objective structured clinical examination(OSCE),the mean score(86.2±6.9)and pass rate(97.9%)in the pilot group were better than those in the horizontal control group(79.7±11.4,89.0%)(P=0.001,P=0.014),as well as better than those in the longitudinal control group(79.5±13.5,88.1%)(P=0.001,P=0.009).For the history inquiry station,the mean score(86.3±10.7)and pass rate(96.8%)in the pilot group were better than those in the horizontal control group(81.4±11.6,86.8%)(P=0.003,P=0.013).The proportion of students choosing the surgical specialty was higher in the pilot group(55.3%)than in the horizontal control group(46.2%)and the longitudinal control group(44.0%)without statistically significant difference.Conclusions SIC can help eight-year program students strengthen their clinical thinking and practice skills.Meanwhile,SIC can increase students'satisfaction with teaching and their interest in surgery.

Objective:To analyze the level and clinical significance of IL-18 and IL-18-binding protein (BP) in the bone marrow of patients with myelodysplastic syndrome (MDS) .Methods:A total of 43 newly diagnosed patients with MDS who were admitted to the Department of Hematology, Tianjin Medical University General Hospital, from July 2020 to February 2021 were randomly selected. The control group consisted of 14 patients with acute myeloid leukemia (AML) and 25 patients with iron-deficiency anemia (IDA). The levels of IL-18 and IL-18 BP in the bone marrow supernatant were measured, and their correlations with MDS severity, as well as the functionality of CD8 + T cells and natural killer cells, was analyzed. Results:The levels of IL-18, IL-18 BP, and free IL-18 (fIL-18) in the bone marrow supernatant of patients with MDS were higher than in the IDA group. The level of fIL-18 was linearly and negatively correlated with the MDS-International Prognostic Scoring System (IPSS) score. IL-18 receptor (IL-18Rα) expression on CD8 + T cells in the MDS group was lower than in the IDA group, and the levels of fIL-18 and IL-18Rα were positively correlated with CD8 + T-cell function in the MDS group. Conclusion:IL-18 BP antagonizes IL-18, leading to a decrease in fIL-18 in the bone marrow microenvironment of patients with MDS, affecting CD8 + T-cell function, which is closely related to MDS severity; therefore, it may become a new target for MDS treatment.

Objective:To investigate the effects of self-made Gujin Xiaoji Mixture combined with warming needle therapy on the clinical efficacy and immune function of patients with advanced non-small cell lung cancer (NSCLC) with qi and yin deficiency syndrome.Methods:This experiment was a randomized controlled trial study. 180 patients with advanced NSCLC qi and yin deficiency syndrome in the oncology centre of Qingdao Hospital of Traditional Chinese Medicine were selected as the observation subjects from March 2021 to August 2022, and were divided into 2 groups using the random number table method, with 90 cases in each group. The control group received conventional chemotherapy combined with Sintilimab injection, 21 days as a cycle, with a total of 4 cycles of treatment; and the observation group received Gujin Xiaoji Mixture combined with warming needle therapy based on the control group, 7 days as one course of treatment, with a total of 12 courses. Both groups were followed up for 12 months. The TCM syndrome scores were performed before and after treatment. The functional assessment of cancer therapy-lung (FACT-L) was used to evaluate the quality of life of patients; flow cytometry was used to detect the levels of CD3 +, CD4 +, CD8 + and NK cell, and the CD4 +/CD8 + ratio was calculated; adverse drug reactions and progression free survival of patients during treatment were observed and recorded, the efficacy of TCM syndrome and objective efficacy of solid tumors were evaluated. Results:After treatment, the observation group's post-treatment TCM syndrome score (5.67±1.99 vs. 7.12±2.31, t=-4.53) was lower than that of the control group ( P<0.001); mobility (23.03±2.80 vs. 20.69±2.46, t=5.96), daily living (23.06±2.56 vs. 20.71± 2.33, t=6.42), emotional status (18.44±2.32 vs. 16.12±2.71, t=6.18), and other factors (33.14±4.11 vs. 27.39±4.64, t=8.81) and total score (97.68±7.23 vs. 84.91±7.49, t=11.64) were higher than those in the control group ( P<0.01). In the observation group, after treatment, the levels of CD3 + [(65.14±6.06)% vs. (59.84±5.74)%, t=6.02], CD4 + [(40.09±4.09)% vs. (35.69±3.86)%, t=7.43], NK cell [(29.11±4.81)% vs. (22.38±4.51)%, t=9.68] and CD4 +/CD8 + [(1.52±0.27) vs. (1.14±0.12), t=12.63] were higher than those in the control group ( P<0.01), and CD8 + [(26.82±3.79)% vs. (31.76±4.65)%, t=-7.81] level was lower than that of the control group ( P<0.01). After treatment, the objective remission rate in the observation group was 7.8% (7/90), and the disease control rate was 87.8% (79/90), while the objective remission rate after treatment in the control group was 5.5% (5/90), and the disease control rate was 82.2% (74/90), and there were no statistical significance in the comparison of objective remission rate and disease control rate of the 2 groups ( χ2=0.09, 0.70, P=0.765, 0.407). The total effective rate after treatment was 62.2% (56/90) in the observation group and 34.4% (31/90) in the control group, and the difference between the 2 groups was statistically significant ( Z=-3.89, P<0.001). WBC [(4.27±1.12)×10 9/L vs. (3.84±1.11)×10 9/L, t=2.58] and haemoglobin [(119.93±17.25)g/L vs. (109.76±15.61)g/L, t=4.15] levels of the observation group were higher than those in the control group after treatment ( P<0.01). During follow-up, the median progression-free survival was 6.2 months in the observation group and 5.5 months in the control group patients, and the difference between the 2 groups was not statistically different ( t=0.11, P>0.05). Conclusion:The combination of Gujin Xiaoji Mixture with warming needle therapy can effectively improve the clinical symptoms of patients with advanced NSCLC with deficiency of qi and yin syndrome, improve the immunity and clinical efficacy of patients, alleviate the adverse effects of drugs, and prolong the progression-free survival period.

Objective:To examine the impact of varied surgical treatment strategies on the prognosis of patients with initial resectable gastric cancer liver metastases (IR-GCLM).Methods:This is a retrospective cohort study. Employing a retrospective cohort design, the study selected clinicopathological data from the national multi-center retrospective cohort study database, focusing on 282 patients with IR-GCLM who underwent surgical intervention between January 2010 and December 2019. There were 231 males and 51 males, aging ( M(IQR)) 61 (14) years (range: 27 to 80 years). These patients were stratified into radical and palliative treatment groups based on treatment decisions. Survival curves were generated using the Kaplan-Meier method and distinctions in survival rates were assessed using the Log-rank test. The Cox risk regression model evaluated HR for various factors, controlling for confounders through multivariate analysis to comprehensively evaluate the influence of surgery on the prognosis of IR-GCLM patients. A restricted cubic spline Cox proportional hazard model assessed and delineated intricate associations between measured variables and prognosis. At the same time, the X-tile served as an auxiliary tool to identify critical thresholds in the survival analysis for IR-GCLM patients. Subgroup analysis was then conducted to identify potential beneficiary populations in different surgical treatments. Results:(1) The radical group comprised 118 patients, all undergoing R0 resection or local physical therapy of primary and metastatic lesions. The palliative group comprised 164 patients, with 52 cases undergoing palliative resections for gastric primary tumors and liver metastases, 56 cases undergoing radical resections for gastric primary tumors only, 45 cases undergoing palliative resections for gastric primary tumors, and 11 cases receiving palliative treatments for liver metastases. A statistically significant distinction was observed between the groups regarding the site and the number of liver metastases (both P<0.05). (2) The median overall survival (OS) of the 282 patients was 22.7 months (95% CI: 17.8 to 27.6 months), with 1-year and 3-year OS rates were 65.4% and 35.6%, respectively. The 1-year OS rates for patients in the radical surgical group and palliative surgical group were 68.3% and 63.1%, while the corresponding 3-year OS rates were 42.2% and 29.9%, respectively. A comparison of OS between the two groups showed no statistically significant difference ( P=0.254). Further analysis indicated that patients undergoing palliative gastric cancer resection alone had a significantly worse prognosis compared to other surgical options ( HR=1.98, 95% CI: 1.21 to 3.24, P=0.006). (3) The size of the primary gastric tumor significantly influenced the patients′ prognosis ( HR=2.01, 95% CI: 1.45 to 2.79, P<0.01), with HR showing a progressively increasing trend as tumor size increased. (4) Subgroup analysis indicates that radical treatment may be more effective compared to palliative treatment in the following specific cases: well/moderately differentiated tumors ( HR=2.84, 95% CI 1.49 to 5.41, P=0.001), and patients with liver metastases located in the left lobe of the liver ( HR=2.06, 95% CI 1.19 to 3.57, P=0.010). Conclusions:In patients with IR-GCLM, radical surgery did not produce a significant improvement in the overall prognosis compared to palliative surgery. However, within specific patient subgroups (well/moderately differentiated tumors, and patients with liver metastases located in the left lobe of the liver), radical treatment can significantly improve prognosis compared to palliative approaches.

ObjectiveTo explore the risk of different levels of pre-pregnancy obesity on trimester-specific thyroid dysfunction. MethodsQuestionnaire information， blood samples， and urine samples from a 2017 pregnancy cohort study in Shanghai， China were collected. A total of 2 455 pregnant women were included in the analysis. Pre-pregnancy BMI was calculated based on the height and self-reported pre-pregnancy weight. Serum TSH， total thyroxine （TT4）， free thyroxine （FT4）， total triiodothyronine （TT3）， free triiodothyronine （FT3）， thyroid globulin antibody（TgAb）， and Thyroid peroxidase antibody （TPOAb） were measured using the electrochemiluminescence method. Urine iodine levels were measured using the acid digestion method. Levels of thyroid function indexes of pregnant women with different degrees of obesity during pre-pregnancy were compared， and trimester-specific thyroid dysfunction was evaluated according to the reference range of trimester-specific thyroid hormone established by this cohort. Multivariate logistic regressions analysis was used to assess the correlation between pre-pregnancy obesity and trimester-specific thyroid dysfunction. ResultsAs the degree of obesity increased， maternal levels of FT3 and TT3 gradually increased during pregnancy （P<0.001， P=0.001）， while FT4 levels gradually decreased （P=0.001）. Multivariate logistic regression analysis showed that compared with the normal weight group， pregnant women who were overweight or obesity before pregnancy had a significantly higher risk of hypothyroxinemia （OR=3.85， 95%CI： 2.08‒7.14， P<0.001） and high TT3 （OR=2.78， 95%CI： 1.45‒5.26， P=0.002） during pregnancy. ConclusionPre-pregnancy overweight or obesity can increase the risk of thyroid dysfunction during pregnancy.

Objective To investigate the protective effect of NDUFA13 protein against acute liver injury and liver fibrosis in mice and explore the possible mechanisms.Methods BALB/C mice(7 to 8 weeks old)were divided into normal group,CCl4 group,CCl4+AAV-NC group and CCl4+AAV-NDU13 group(n=18).Mouse models of liver fibrosis were established by intraperitoneal injection of CCl4 twice a week for 3,5 or 7 weeks,and the recombinant virus AAV8-TBG-NC or AAV8-TBG-NDUFA13 was injected via the tail vein 7-10 days prior to CCl4 injection.After the treatments,pathological changes in the liver of the mice were observed using HE and Masson staining.Hepatic expression levels of NDUFA13 and α-SMA were detected with Western blotting,and the coexpression of NDUFA13 and NLRP3,TNF-α and IL-1β,and α-SMA and collagen Ⅲ was analyzed with immunofluorescence assay.Results HE and Masson staining showed deranged liver architecture,necrotic hepatocytes and obvious inflammatory infiltration and collagen fiber deposition in mice with CCl4 injection(P<0.001).NDUFA13 expression markedly decreased in CCl4-treated mice(P<0.001),while a significant reduction in inflammatory aggregation and fibrosis was observed in mice with AAV-mediated NDUFA13 overexpression(P<0.001).In CCl4+AAV-NDU13 group,immunofluorescence assay revealed markedly weakened activation of NLRP3 inflammasomes(P<0.001),significantly decreased TNF-α and IL-1β secretion(P<0.001),and inhibited hepatic stellate cell activation(P<0.05)and collagen formation in the liver(P<0.001).Conclusion Mitochondrial NDUFA13 overexpression in hepatocytes protects against CCl4-induced liver fibrosis in mice by inhibiting activation of NLRP3 signaling.

Objective:To analyze the equality of health resource allocation in functional areas of Beijing from 2012 to 2022, so as to provide reference for optimizing the allocation of health resources during the 14th Five-Year Plan and long-term planning.Methods:According to the new urban master plan and the functional positioning of the capital, 16 districts in Beijing were divided into 4 functional regions(capital core area, urban functional expansion area, urban development new area, and ecological conservation area). Based on the analysis of permanent population, the levels of health resources in each region and each administrative district were compared, and the equity of health resources was measured by using the Dagum Gini coefficient.Results:In 2022, the Gini coefficients of medical and health resources in Beijing, including the number of beds, number of health technicians, and number of practicing(assistant) physicians, were 0.71, 0.65, and 0.63, respectively, with no significant change compared to 2012. While the Gini coefficient for equipment priced over 10 000 yuan was 0.75, slightly lower than 0.79 in 2012. The differences in resource allocation mainly came from different regions. The Gini coefficient of the above four indicators in the urban functional expansion area was the lowest, followed by the capital core area, and the Gini coefficient of the ecological conservation area was the highest. The Dagum Gini coefficient of the four indicators of urban development new area showed a decreasing trend year by year.Conclusions:In recent years, there has been no significant change in the overall equality of medical and health resource allocation in Beijing. Only the Gini coefficient of urban development new area has shown a downward trend. It is necessary to further promote the fair and reasonable allocation of medical and health resources among functional areas in Beijing.