Relationships between accelerometer-measured and multiple sclerosis: a 2-sample Mendelian randomization study.

BACKGROUND: Observational studies suggest that physical activity (PA) can independently modify the risk of developing multiple sclerosis (MS). OBJECTIVE: To investigate the causal effect of PA on MS by Mendelian randomization (MR) approaches. METHODS: Through a genome-wide association study including 91,105 participants from UK Biobank, we obtained 5 single-nucleotide polymorphisms (SNPs) associated with accelerometer-measured PA (P < 5 × 10-8). Summary-level data for MS were obtained from a meta-analysis, incorporating 14,802 subjects with MS and 26,703 healthy controls of European ancestry. MR analyses were performed using the inverse-variance-weighted method, weighted median estimator, and MR-PRESSO method. Additional analyses were further performed using MR-Egger intercept and Cochran's Q statistic to verify the robustness of our findings. RESULTS: We failed to detect a causal effect of PA on MS (OR, 0.60; 95% confidence interval [CI], 0.30-1.20; P = 0.15) per in the random-effects IVW analysis. Additional MR methods yielded consistent results. MR-Egger regression suggested no evidence of horizontal pleiotropy (Intercept = 0.14, P = 0.21) and there seemed no substantial heterogeneity (I2 = 29.8%, P = 0.22) among individual SNPs. CONCLUSION: Our findings suggest that enhancing PA might not modify the risk of developing MS independent of established risk factors.

Sleep Duration and Stroke: A Mendelian Randomization Study.

Study Objectives: To clarify the effects of sleep duration on stroke and stroke subtypes, we adopted a Mendelian randomization (MR) approach to evaluate their causal relationship. Methods: A genome-wide association study including 446,118 participants from UK biobank was used to identify instruments for short sleep, long sleep and sleep duration. Summary-level data for all stroke, ischemic stroke, intracerebral hemorrhage, and their subtypes were obtained from meta-analyses conducted by the MEGASTROKE consortium. MR analyses were performed using the inverse-variance-weighted method, weighted median estimator, MR pleiotropy residual sum and outlier (MR-PRESSO) test, and MR-Egger regression. Sensitivity analyses were further performed using leave-one-out analysis, MR-PRESSO global test and Cochran's Q test to verify the robustness of our findings. Results: By two-sample MR, we didn't find causal associations between sleep duration and risk of stroke. However, in the subgroup analysis, we found weak evidence for short sleep in increasing risk of cardio-embolic stroke (odds ratio [OR], 1.33; 95% confidence interval [CI], 1.11-1.60; P = 0.02) and long sleep in increasing risk of large artery stroke [OR, 1.41; 95% CI, 1.02-1.95; P = 0.04]. But the associations were not significant after Bonferroni correction for multiple comparisons. Conclusions: Our study suggests that sleep duration is not causally associated with risk of stroke and its subtypes.

Detailed Echocardiographic Measurements of Individual Chamber in a Chinese Cohort of Hypoplastic Left Heart Syndrome and Comparison with Normal Fetuses via Z-score Modeling.

Hypoplastic left heart syndrome (HLHS) is a rare, but exceptionally serious, congenital heart defect. We aimed to explore the best-fitted Z-score models for individual chamber dimension and to draw a comparison between fetuses with HLHS and the normal Chinese cohort. We made measurements of 1674 healthy fetuses and 79 fetuses with HLHS, undertaking echocardiography. Normal fetal cardiovascular Z-score formulae were established by curve-fitting with 5 algorithmic functions and weighted regression of absolute residuals. Classic linear models were fitted for left ventricular diameter against gestational age, and log-transformed linear-power models-were statistically better for left ventricular length, diameter of left atrium and ascending aorta. Fetuses with HLHS manifested significantly lower Z-score means (≤3.5) for these 4 parameters and the vast majority (∼90%) lay beyond -2. Overall, cardiovascular Z-score equations were reliably constructed in a larger Chinese cohort, and their application should benefit evaluation and diagnosis of HLHS.

BMP4 knockdown of NCSCs leads to aganglionosis in the middle embryonic stage.

Transplacental bone morphogenetic protein (BMP)4 RNA interference (RNAi) is a technique used to knockdown genes in embryos. BMP4 are essential for the development of nervous system in the differentiation of neural crest stem cells (NCSCs). The failure of differentiation and migration of NCSCs may lead to aganglionosis. In the present study, pregnant mice were divided into three groups: Ringer's group, pSES group and RNAi­BMP4 group. In order to silence the BMP4 gene in the first generation (F1), 11.5 day pregnant mice were injected with the small interfering RNA BMP4 plasmid, pSES or Ringer's solution via the tail vein. Semi­quantitative reverse transcriptase­polymerase chain reaction (RT­PCR)and western blotting were employed to ensure the downregulation of BMP4. Finally, X­rays were performed following a barium enema. Aganglionosis was diagnosed by general anatomy and immunohistochemistry. Compared with the control group, transplacental RNAi was able to downregulate the BMP4­Smad4 of 11.5 day embryos, as determined by semi­quantitative RT­PCR and western blotting. The megacolons of the mice were demonstrated by X­ray and confirmed by general anatomy. Aganglionosis of colonic mucosa and submucosa were diagnosed by pathology, and immunohistochemistry. Knockdown of BMP4 in pregnant mice at the middle embryonic stage led to aganglionosis. It was therefore demonstrated that BMP­Smad was essential to the NCSCs of middle stage embryos. BMP­Smad served important roles in the generation of aganglionosis. This technique of knockdown BMP4 gene may be used to establish an aganglionosis mouse model.

The effect of melatonin on the proliferation of neural stem cells in rats with cerebral ischemia reperfusion and its mechanism / 中华神经科杂志

Objective To investigate the effects of melatonin on the proliferation of neural stem cells (NSCs) in cerebral ischemia reperfusion (IR) rats, and to explore the possible mechanisms. Methods Seventy-two rats were randomly divided into the normal control group (n=12), model group (n=30) and melatonin group (n=30) according to the random number table. The rats in the model group and melatonin group were divided into four subgroups: 6 h, 24 h, 72 h and 7 d subgroups according to the time after IR. The morphological changes of the subventricular zone (SVZ) were examined by HE staining;the effects of melatonin on NSCs proliferation were examined by immunofluorescence staining;the effects of melatonin on toll-like receptor 4 (TLR4) and nuclear factor (NF)-κB p65 protein were examined by immunohistochemistry staining and Western blotting analysis. The correlation between the proliferating NSCs and TLR4 protein or the NF-κB p65 protein was analyzed by linear regression analysis. Results HE staining showed that the cells in the SVZ of rats in the model group were in disorder and irregular in shape. In the melatonin group, the cells in the SVZ of the injured side were relatively well arranged. Immunofluorescence staining showed that the number of proliferating cell nuclear antigen (PCNA)+Nestin+4',6-diamidino-2-phenylindole (DAPI)+cells in the SVZ of the model (498.47 ± 26.44/mm2) and melatonin groups (623.10 ± 39.70/mm2) increased gradually, and reached a higher level after IR for 7 days, which were significantly higher than the normal control group (203.91 ± 32.23/mm2) (F=35.193, 170.344, 277.536, 285.947, all P＜0.01). The number of PCNA+Nestin+DAPI+cells in the melatonin group rats at each time points was significantly higher than that in the model group (F=102.561, 91.244, 168.502, 38.013, all P＜0.01). Immunohistochemistry staining showed that the numbers of TLR4+and NF-κB p65+cells in the SVZ of the model (740.02±31.63/mm2;710.01± 26.59/mm2) and melatonin groups (555.57 ± 25.28/mm2;528.85 ± 30.60/mm2) increased gradually, and reached a higher level 7 d after IR, which were significantly higher than the normal control group (107.97±12.84/mm2;109.80±13.89/mm2) (F=21.413, 263.059, 873.691, 1 037.098, all P＜0.01;F=26.374, 372.940, 854.826, 929.018, all P＜0.01). There were less TLR4+(F=7.641, 25.135, 66.094, 103.753, all P＜0.05) and NF-κB p65+cells (F=18.612, 69.597, 113.113, 119.814, all P＜0.01) in the melatonin group as compared with those in the model group at each time points. Western blotting analysis showed that the expression of TLR4 (0.87±0.08;0.68±0.06) and NF-κB p65 (0.72±0.05;0.58±0.05) protein was higher in the model and melatonin groups as compared with the normal control group (0.35±0.04, 0.31±0.03;F=107.43, F=132.51, both P＜0.01). The expression of the TLR4 and NF-κB p65 protein was lower in the melatonin group as compared with that in the model group (P＜0.01). Linear regression analysis showed that the differences of PCNA+Nestin+DAPI+cells were all negatively correlated with that of the TLR4+cells and NF-κB p65+cells in the melatonin group (r2=0.838, r2=0.813, both P＜0.01). Conclusion Melatonin can inhibit the expression of TLR4 and NF-κB p65 protein, thus promote the proliferation of endogenous NSCs in cerebral ischemia reperfusion rats.

Molecular imprinting and immobilization of cellulase onto magnetic Fe3O4@SiO2 nanoparticles.

Supermagnetic Fe3O4@SiO2 nanoparticles were molecular-imprinted prepared with cellulase as the template. The molecular imprinted nanoparticles were used as support to immobilization of cellulase. The transmission electron microscopy confirmed the core-shell structure and revealed that the size of the nanoparticles was around 10 nm. It was observed that cellulase was immobilized on the nanoparticles successfully from the Fourier transform infrared spectra. The adsorption of cellulase on the nanoparticles was specific and rapid. A high immobilization efficiency of 95% was achieved after the optimization. At 70 degrees C, the half-life of the immobilized cellulase was 3.3-fold of the free enzyme. Compared with the free enzyme, the immobilized cellulase has the same optimal pH, higher optimal temperature, better thermal stability and higher catalytic efficiency. The results strongly suggest that the immobilized cellulase on molecular imprinted Fe3O4@SiO2 has the potential applications in the production of bioethanol, paper and pulp industry, and pharmaceutical industry.