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*

Objective To investigate the neurodevelopmental characteristics of children with autism spectrum disorder(ASD),analyze the correlation between neurodevelopmental indicators and cerebral blood flow(CBF),and explore the potential mechanisms of neurodevelopment in ASD children.Methods A retrospective study was conducted on 145 children aged 2-6 years with newly-diagnosed ASD.Scores from the Gesell Developmental Diagnosis Scale and the Autism Behavior Checklist(ABC)and CBF results were collected to compare gender differences in the development of children with ASD and analyze the correlation between CBF and neurodevelopmental indicators.Results Fine motor and personal-social development quotient in boys with ASD were lower than those in girls with ASD(P<0.05).Gross motor development quotient in ASD children was negatively correlated with CBF in the left frontal lobe(r=-0.200,P=0.016),right frontal lobe(r=-0.279,P=0.001),left parietal lobe(r=-0.208,P=0.012),and right parietal lobe(r=-0.187,P=0.025).The total ABC score was positively correlated with CBF in the left amygdala(r=0.295,P<0.001).Conclusions Early intervention training should pay attention to gender and developmental structural characteristics for precise intervention in ASD children.CBF has the potential to become a biological marker for assessing the severity of ASD.

Bladder cancer is the most common malignancy of the urinary system. Compound Kushen Injection (CKI) is a Chinese medicinal preparation that has been widely used in the treatment of various types of cancers in the past two decades. However, the pharmacological effect of CKI on bladder cancer is not still completely understood. In the current study, network pharmacology combined with bioinformatics was used to elucidate the therapeutic mechanism and potential targets of CKI in bladder cancer. The mechanism by which CKI was effective against bladder cancer was further verified in vitro using human bladder cancer cell line T24. Network pharmacology analysis identified 35 active compounds and 268 target genes of CKI. Bioinformatics data indicated 5500 differentially expressed genes associated with bladder cancer. Common genes of CKI and bladder cancer suggested that CKI exerted anti-bladder cancer effects by regulating genes such as MMP-9, JUN, EGFR, and ERK1. Functional enrichment analysis indicated that CKI exerted therapeutic effects on bladder cancer by regulating certain biological processes, including cell proliferation, cell migration, and cell apoptosis. In addition, Kyoto Encyclopedia of Genes and Genomes enrichment analysis implicated pathways related to cancer, bladder cancer, and the PI3K-Akt signaling pathway. Consistently, cell experiments indicated that CKI inhibited the proliferation and migration of T24 cells, and induced their apoptosis. Moreover, RT-qPCR and Western blot results demonstrated that CKI was likely to treat bladder cancer by down-regulating the gene and protein expression of MMP-9, JUN, EGFR, and ERK1. CKI inhibited the proliferation and migration, and induced the apoptosis of T24 bladder cancer cells through multiple biological pathways and targets. CKI also exhibited significant effects on the regulation of key genes and proteins associated with bladder cancer. Overall, our findings provide solid evidence and deepen current understanding of the therapeutic effects of CKI for bladder cancer, and further support its clinical use.
Computational Biology ; Drugs, Chinese Herbal ; Humans ; Network Pharmacology ; Phosphatidylinositol 3-Kinases ; Urinary Bladder Neoplasms/genetics*

This study aimed to explore the characteristic role of Puerariae Lobatae Radix(PLR) in Gegen Decoction for the treatment of primary dysmenorrhea(PD). Estrogen(E_2) was combined with oxytocin to establish a mouse model of PD. The mice were randomly divided into a normal group, a model group, a Gegen Decoction group, a PLR-free Gegen Decoction group, a PLR group, and a positive drug group(ibuprofen). Writhing response times and writhing incubation of mice in each group were tested by behavio-ral assessment, and the serum levels of prostaglandin F_(2α)(PGF_(2α)), prostaglandin E_2(PGE_2), E_2, and progesterone(PROG) were detected by ELISA kits. Western blot method was adopted to detect cyclooxygenase-2(COX-2) and estrogen receptor alpha(ER_α) expression levels in uterine tissues. Doppler ultrasound was employed to detect changes in uterine artery blood flow in mice, including peak systolic blood flow velocity(maximum velocity), end-diastolic velocity(minimum velocity), peak systolic blood flow velocity/end-diastolic velocity(S/D), pulsatility index(PI), and resistive index(RI). Histopathological changes in the uterus were detected by HE staining. Based on the oxytocin-induced isolated uterine contraction model, the effects of Gegen Decoction, PLR-free Gegen Decoction, and PLR on the amplitude, frequency, and activity of isolated uterine contraction were compared to investigate the role of PLR in Gegen Decoction for the treatment of PD. The results showed that compared with the Gegen Decoction group, the PLR-free Gegen Decoction improved the indicators of PD except for E_2 content, ER_α expression, and uterine artery blood flow. PLR could significantly down-regulate the serum content of E_2 and the protein expression of uterine ER_α, and improve the uterine artery blood flow. The data suggested that PLR, as the sovereign drug of Gegen Decoction, might function in Gegen Decoction for the treatment of PD by mediating E_(2 )and improving the uterine artery blood flow.
Animals ; Drugs, Chinese Herbal ; Dysmenorrhea/drug therapy* ; Humans ; Mice ; Plant Roots ; Pueraria ; Uterus

Objective To study the iodine nutritional status in the key population in Tianjin before and after the implementation of the new standards of iodized salt content, and to provide a scientific basis for iodine supplementation. Methods According to the method of population proportion sampling, the family edible salt samples, the urinary iodine and goiter of children aged 8-10 years and the urinary iodine level of pregnant women were investigated before the adjustment of salt iodine content (2005, 2011) and after the adjustment (2014, 2017). The results were compared and analyzed. Results The median of salt iodine after the adjustment (26.05mg/kg) was significantly lower than that of before (30.20mg/kg, Z=12.867, P<0.001). After adjustment, the coverage of iodized salt, the qualified rate of iodized salt, and the qualified iodized salt consumption rate were 78.68%, 81.01%, and 63.74%, respectively, and there were statistically significant differences from before adjustment (92.44%, 96.78%, 89.47%, respectively) (χ²=221.916, 309.405, 540.148, respectively, P <0.001). The median urinary iodine in children aged 8 to 10 years decreased from 210.10μg/L to 172.08μg/L, and the difference was statistically significant before and after adjustment (Z=3.351, P<0.001). The thyroid goiter rate of children decreased from 2.21% to 2.05%, and the difference was not statistically significant between the groups (χ²=0.196, P=0.658). After stratified analysis based on salt iodine content, it was found that among children who took iodized salt and qualified iodized salt, the median urine iodine after adjustment was lower than that before adjustment, and the difference was statistically significant (Z=2.726, 2.742, all P<0.001), but the proportion of urine iodine at an appropriate level was higher than before adjustment. The median urine iodine of pregnant women increased from 145.20μg/L to 147.17μg/L, and there was no significant difference before and after adjustment (Z=1.121, P=0.162). The proportion of pregnant women with median urinary iodine from 150 to 250μg/L was significantly higher in post-adjustment (31.02%) than that of pre-adjustment (24.53%, χ²=4.769, P=0.029). Conclusion After adjusting the salt iodine content in Tianjin, children's iodine nutrition was optimized from a higher level to an appropriate level, and thyroid goiter rate of children remained at low level. The iodine nutrition of pregnant women was slightly lower than adequate level, but the proportion of pregnant women at the adequate level increased. The new standard of iodine salt was appropriate, but the proportion of children with urine iodine <100μg/L increased, which needs to be monitored. At the same time, the iodized salt coverage rate and the qualified iodized salt consumption rate did not reach the elimination standard of iodine deficiency diseases, and the supervision of the salt industry market should be strengthened.

The systematic treatment based on gemcitabine plus cisplatin is recommended as the current standard chemotherapy for unresectable or metastatic biliary tract cancers.However,the exact benefits from the recognized regime are still dismal.We thus elicit this study in an attempt to analyze whether targeted therapy coupled with various chemotherapy could produce improvement of survival benefits.The clinical trials were searched electronically from databases till July 2016 published in English and Chinese.Nine hundred and sixty-four patients from 7 trials were identified in our analysis.The overall analysis achieved a significantly higher overall response rate (ORR) among the patients treated with targeted drugs plus chemotherapy than chemotherapy alone (OR=1.87;95％ CI:1.37-2.57;P=0.000),but failed in the overall progression-free survival (PFS) [mean difference (MD)=0.63;95％ CI:-0.45-1.72;P=0.26] and overall survival (OS) (MD=-0.67;95％ CI:-2.54-1.20;P=0.49).In the sub analysis,better ORR was obtained with the addition of EGFR (OR=1.75;95％ CI:1.20-2.56;P=0.004) and VEGFR (OR=2.5;95％ CI:1.28-4.87;P=0.007) targeted therapy.Furthermore,the sub analysis of EGFR target showed an significant improvement on PFS (MD=l.36;95％ CI:0.29-2.43;P=0.01).No significant differences were observed in the incidences ofneutropenia (OR=1.37;95％ CI:0.89-2.12),thrombocytopenia (OR=l.40;95％ CI:0.83-2.39),anemia (OR=l.21;95％ CI:0.62-2.38),peripheral neuropathy (OR=1.52;95％ CI:0.81-2.88),increased AST/ALT (OR=l.40;95％ CI:0.82-2.39) as well as fatigue (OR=1.65;95％ CI:0.96-2.84) in either of the treatment groups.In conclusion,better ORR associated with chemotherapy combined with targeted therapy (both targeting EGFR and VEGF) is found in the present mcta-analysis without the cost of increased unacceptable toxicities,but regretfully not for the OS.The sub-analysis of targeting EGFR instead of VEGF obtains a superior PFS.Otherwise,there is no statistically significant difference in the overall PFS between the combination regime and chemotherapy alone.Given the paucity of favorable data,we need further studies to characterize optimal targeted agents to confirm the potential value to biliary tract cancer.

Aim To explore the alterations of blood corticosterone (CORT) level and adrenal steroidogenic function,as well as its sex specificity in intrauterine growth retardation (IUGR) rats induced by prenatal nicotine exposure (PNE) with high-fat diet (HFD) after birth,and to make clear its mechanism through insulin-like growth factor-1 (IGF-1) signaling pathway.Methods IUGR model was established by PNE (2.0mL · kg-1 · d-1),and the offspring rats were administered with HFD until postnatal week (PW) 24 after weaning.Blood CORT concentration,adrenal steroidogenesis enzymes,expressions of IGF-1 signaling pathway and 11β-HSDs/CR system were tested.Results Compared with HFD control group,the CORT concentration in male offspring of PNE group represented a decrease trend,while an increase trend in female;the expressions of adrenal steroidogenesis enzymes (such as StAR,3β-HSD and P450cll) in male offspring decreased,while increased in female offspring (such as SF-1 and P450c21);the expressions of IGF-1 signalling pathway (IGF-1 and IGF-1R) in male offspring increased,and they significantly increased in female offspring;the expression levels of 11 β-HSD2 and GR decreased,but 11β-HSD1/11β-HSD2 ratio was enhanced in male PNE group,while in female PNE group,the corresponding gene expressions increased.Conclusions PNE could induce abnormal alterations of adrenal steroidogenic function,and exhibit apparent gender differences.The potential mechanism is related to low adrenal steroidogenesis function programming induced by nicotine and catch-up growth mediated by IGF-1 after birth.

BACKGROUNDIncreased blood pressure and elevated total cholesterol (TC) level are the two most important modifiable risk factors of cardiovascular disease (CVD) in the world. Hypertension and hypercholesterolemia co-exist more often than would be expected and whether there is a synergistic impact on fatal CVD between elevated TC and hypertension need to be further examined in Chinese population.

METHODSWe conducted a cohort study which recruited 5092 Chinese male steelworkers aged 18 - 74 years in 1974 - 1980 and followed up for an average of 20.84 years. Totally 302 fatal CVD events were documented by the year of 2001. Cox proportional hazards regression models were undertaken to adjust for baseline variables with fatal CVD events as the outcome variable. Additive interaction model was used to evaluate the interaction between elevated TC and hypertension.

RESULTSHypercholesterolemia and hypertension were significantly associated with an increased hazard ratio (HR) of fatal CVD (1.67 (95%CI 1.18 - 2.38) and 2.91 (95%CI 2.23 - 3.80) respectively. Compared to participants with normotension and TC < 240 mg/dl, the HRs were 1.11 (95%CI 0.56 - 2.21), 2.74 (95%CI 2.07 - 3.64) for hypercholesterolemia and hypertension respectively, and 5.51 (95%CI 3.58 - 8.46) for participants with both risk factors. There was an additive interaction with a 2.65 (95%CI 0.45 - 4.85) relative excess risk (RERI) between hypercholesterolemia and hypertension on CVD.

CONCLUSIONWe found that the risk of fatal CVD was significantly associated with an additive interaction due to hypercholesterolemia and hypertension besides a conventional main effect derived from either of them, which highlights that the prevention and treatment of both risk factors might improve the individual risk profile thus reduce the CVD mortality.

Adolescent ; Adult ; Aged ; Asian Continental Ancestry Group ; Cardiovascular Diseases ; blood ; etiology ; mortality ; Cholesterol ; blood ; Humans ; Hypercholesterolemia ; blood ; complications ; Hypertension ; blood ; complications ; Male ; Middle Aged ; Steel ; Young Adult

OBJECTIVETotal cholesterol (TC) is an important risk factor for myocardial infarction (MI), but the effect of TC on MI in Chinese male hypertension population has not been well documented. We conducted a prospective cohort study to determine the incidence and relative risk for MI across a wide range of TC levels in Chinese male hypertension population.

METHODSA cohort of 5298 male employees aged 18-74 years recruited from Capital Steel and Iron Company in Beijing of China in 1974-1980 was followed up for an average of 20.84 years. A total of 122 incident MI cases were identified during the period of follow-up.

RESULTSThe incidence of MI among participants with elevated TC and those with desirable TC in male non-hypertension population was 137.20 and 63.81 per 100,000 person-years, respectively; and the corresponding incidence in male hypertension population was 279.80 and 130.96 per 100,000 person-years, respectively. After adjustment for important covariables, 10.38%, 16.71%, and 23.80% of MI cases were attributable to hypertension, elevated TC, and hypertension plus elevated TC, respectively. In male hypertension population, the multivariate adjusted hazard ratios of MI were 1.21, 2.39, 3.38, and 3.95 for participants with TC level of 5.17-5.68, 5.69-6.20, 6.21-6.71, and > or = 6.72 mmol/L, compared with those with TC < 5.17 mmol/L. The corresponding population attributable risks were 2.92%, 9.20%, 8.87%, and 9.84%, respectively.

CONCLUSIONElevated TC is an important independent risk factor of MI both in male non-hypertension and hypertension populations. There is a linear association between TC level and MI incidence in Chinese male hypertension population.

Adolescent ; Adult ; Aged ; China ; epidemiology ; Cholesterol ; blood ; Humans ; Hypertension ; blood ; complications ; epidemiology ; Incidence ; Longitudinal Studies ; Male ; Middle Aged ; Myocardial Infarction ; blood ; complications ; epidemiology ; Proportional Hazards Models ; Risk Factors ; Young Adult

Animals ; Carbon Tetrachloride ; Collagen ; blood ; Hyaluronic Acid ; blood ; Laminin ; blood ; Liver ; drug effects ; pathology ; Liver Cirrhosis, Experimental ; blood ; drug therapy ; pathology ; Liver Function Tests ; Male ; Materia Medica ; administration & dosage ; pharmacology ; Mice ; Periplaneta ; chemistry ; Random Allocation ; Severity of Illness Index ; Treatment Outcome