The function of FUS in neurodevelopment revealed by the brain and spinal cord organoids.

The precise control of proliferation and differentiation of neural progenitors is crucial for the development of the central nervous system. Fused in sarcoma (FUS) is an RNA-binding protein pathogenetically linked to Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD) disease, yet the function of FUS on neurodevelopment is remained to be defined. Here we report a pivotal role of FUS in regulating the human cortical brain and spinal cord development via the human iPSCs-derived organoids. We found that depletion of FUS via CRISPR/CAS9 leads to an enhancement of neural proliferation and differentiation in cortical brain-organoids, but intriguingly an impairment of these phenotypes in spinal cord-organoids. In addition, FUS binds to the mRNA of a Trk tyrosine kinase receptor of neurotrophin-3 (Ntrk3) and regulates the expression of the different isoforms of Ntrk3 in a tissue-specific manner. Finally, alleviated Ntrk3 level via shRNA rescued the effects of FUS-knockout on the development of the brain- and spinal cord-organoids, suggesting that Ntrk3 is involved in FUS-regulated organoids developmental changes. Our findings uncovered the role of FUS in the neurodevelopment of the human CNS.

[Efficacy and Safety Evaluation of Liujin Runzao Concentrated Decoction in Treating Primary Sjögren's Syndrome].

Objective To evaluate the efficacy and safety of Liujin Runzao Concentrated Decoction (LRCD) for the treatment of primary Sjögren's syndrome (pSS). Methods Forty pSS patients with fluid depletion and distribution obstacles syndrome (FDDOS) were randomly assigned to the experimen- tal group and the control group according to 1:1 proportion. All patients received standard therapy: Radix Paeoniae alba total glycosides 600 mg, twice per day. Patients in the experimental group additionally took LRCD, 30 mL each time, twice per day. The therapeutic course for all was 4 weeks, and two courses for all. The improvement of dry mouth and dry eyes were comprehensively evaluated. Each outcome of composite index constitutions (integrals of dry eyes and dry mouth, salivary flow rate, Schirmer test) was respectively reported. Schirmer test and salivary flow rate were determined as well. Score of TCM syndrome, blood sedimentation,'immunoglobulin, and adverse drug reactions were observed. Results The effective rate of comprehensive effect for dry eyes and dry mouth improvement at the end of 8 weeks was 80% in the experimental group and 35% in the control group, with statistical difference (X² =8. 286, P <0. 05). As for the composition of comprehensive effect for dry eyes and dry mouth improvement: The score for dry eyes and dry mouth decreased in the two groups more after treatment than before treatment. The difference in pre-post treatment score for dry eyes and dry mouth at week 8 was higher in the experimental group than in the control group. The difference in pre-post treatment score at week 8 was 1. 71 (95% Cl: -0. 37 -3. 78) between the two groups (P <0. 05). The difference in pre-post treatment Schirmer test and salivary flow rate at week 8 was higher in the experimental group than in the control group, but with on statistical difference (P >0. 05). The difference in pre-post treatment Schirmer test and salivary flow rate at week 8 was 2. 74 mL/15 min (95% Cl: 0. 49 -4.98) and 0. 13 mm/5 min (95% Cl: 0. 92 -1. 23) between the two groups (P <0. 05). The score of TCM syndrome decreased more in the two groups, as compared with before treatment. The difference in pre-post treatment score of TCM syn- drome at week 8 was 1. 71 (95% CI: -1. 40 -4. 81) between the two groups (P >0. 05). One case of uri- nary tract infections occurred in the control group, while no obvious adverse event occurred in the exper- imental group. Conclusion Standard treatment combined LRCD showed better comprehensive effect for dry eyes and dry mouth in pSS patients with FDDOS, and was more safe.

Relationship between ambient fine particles and ventricular repolarization changes and heart rate variability of elderly people with heart disease in Beijing, China.

OBJECTIVE: To explore the effects of particulate matters less than 2.5 µm in aerodynamic diameter (PM2.5) on heart repolarization/depolarization and heart rate variability (HRV). METHODS: We conducted a panel study for elderly subjects with heart disease in Beijing from 2007 to 2008. PM2.5 was measured at a fixed station for 20 h continuously each day while electrocardiogram (ECG) indexes of 42 subjects were also recorded repeatedly. Meteorological data was obtained from the China Meteorological Data Sharing Service System. A mixed linear regression model was used to estimate the associations between PM2.5 and the ECG indexes. The model was adjusted for age, body mass index, sex, day of the week and meteorology. RESULTS: Significant adverse effects of PM2.5 on ECG indexes reflecting HRV were observed statistically and the strongest effect of PM2.5 on HRV was on lag 1 day in our study. However, there were no associations between PM2.5 and ECG indexes reflecting heart repolarization/depolarization. Additionally, the effects of PM2.5 on subjects with hypertension were larger than on the subjects without hypertension. CONCLUSION: This study showed ambient PM2.5 could affect cardiac autonomic function of the elderly people with heart disease, and subjects with hypertension appeared to be more susceptive to the autonomic dysfunction induced by PM2.5.

[Association between ambient PM10/PM2.5 levels and population mortality of circulatory diseases: a case-crossover study in Beijing].

OBJECTIVE: To explore the association between levels of ambient particulate matters (PM10 and PM2.5) and population mortality of circulatory diseases (ICD10: I00~I99) in Beijing. METHODS: The daily data of ambient PM2.5 levels were monitored by the research team in Peking University from Jan. 1, 2007 to Dec. 31, 2008, and the corresponding meteorological and other air quality data (PM10, SO2 and NO2) were collected from National Meteorological Information Center (NMIC) of China and Beijing Environmental Monitoring Center. The data of daily death for the circulatory diseases were collected from the local center for Disease Control and Prevention of Haidian District in Beijing. The symmetric bidirectional case-crossover design and conditional logistic regression model were used for the data analysis. The cases were stratified by gender, age and seasons. The lagged effect was analyzed and the related confounders from meteorological factors and other air pollutants were adjusted. RESULTS: For a 10 µg/m(3) increase of the ambient concentration of PM2.5, the corresponding increase of daily mortality of the circulatory diseases, cardiovascular diseases and cerebrovascular diseases was 0.78% (95% CI: 0.07% to 1.49%), 0.85% (95% CI: -0.28% to 1.99%), and 0.75% (95% CI: -0.17% to 1.68%), respectively, for a 10 µg/m(3) increase of the ambient concentration of PM10, the corresponding increase of daily mortality of the circulatory diseases, cardiovascular diseases and cerebrovascular diseases was 0.36% (95% CI: -0.07% to 0.78%), 0.63% (95% CI: -0.02% to 1.28%), and 0.33% (95% CI: -0.26% to 0.92%),respectively. The significant positive associations were observed statistically between PM2.5 and the circulatory diseases (P<0.05). The association between ambient PMs and the population mortality was stronger in "warm season (April to September)" than in "cool season (October to the next March)" in Beijing (P<0.05). CONCLUSION: The elevated levels of ambient PM2.5 and PM10 were positively associated with the increase of the population mortality of the circulatory diseases, and the association is stronger in warm season, and the adverse effect of PM2.5 is greater than that of PM10.

[Relationship between daily mean temperature and emergency department visits for respiratory diseases: a time-series analysis].

OBJECTIVE: To quantitatively evaluate the influences of daily mean air temperature (DMT) on Emergency Department Visits (EDVs) for the respiratory diseases. METHODS: The EDV data from medical records for respiratory diseases in Peking University Third Hospital between January 2004 and June 2009 were collected. The data of the air pollutants (SO(2), NO(2) and PM(10)) and meteorological factors at the same time periods were also collected from the local authorities of Beijing. Time-series analysis and generalized additive models (GAM) were used to explore the exposurrre-response relationship between DMT and EDVs for respiratory diseases. RESULTS: A total of 35 073 patients [males 14 707(41.93%,14 707/35 073), females 19 122(54.52%,19 122/35 073) and gender missing 1 244(3.55%, 1 244/35 073)] EDVs for respiratory diseases were included. The relationship between DMT and EDVs for the respiratory diseases was mainly of "V" shape, the optimum temperature(OT) was about 4 °C and the effect of DMT was significant with a 0-3 day lag structure for most of the models. When DMT≤OT, each 1°C decrease in DMT corresponded to 3.75% (95% CI of RR: 0.938 3-0.965 3), 3.10% (95% CI of RR:0.949 2-0.989 1), 4.09% (95% CI of RR:0.940 7-0.977 8) increase of EDVs for the overall, male, and female, respectively. When DMT>OT, the value caused by each increase in 1°C in DMT was 1.54% (95% CI of RR:1.006 6-1.024 3), 1.80% (95% CI of RR:1.005 3-1.030 9), and 1.51 (95% CI of RR:1.003 2- 1.027 2), respectively. The effect was statistically significant within the 0-3 day lag. When DMT≤OT, the effect was stronger for the older people, while the effect was strongest for the 45-59 years old people. CONCLUSION: The relationship between DMT and EDVs for respiratory diseases is mainly of "V" type, with an optimum temperature of 4 °C.Both DMT decrease when DMT≤OT and increase when DMT>OT correspond to different increase of EDVs for respiratory diseases. Low DMT has stronger effect than high DMT. Different age group and gender have different effects.

Comparison of two different size needles in endoscopic ultrasound-guided fine-needle aspiration for diagnosing solid pancreatic lesions: A meta-analysis of prospective controlled trials.

BACKGROUND: This meta-analysis aimed to provide a pooled analysis of prospective controlled trials comparing the diagnostic accuracy of 22-G and 25-G needles on endoscopic ultrasonography (EUS-FNA) of the solid pancreatic mass. METHODS: We established a rigorous study protocol according to Cochrane Collaboration recommendations. We systematically searched the PubMed and Embase databases to identify articles to include in the meta-analysis. Sensitivity, specificity, and corresponding 95% confidence intervals were calculated for 22-G and 25-G needles of individual studies from the contingency tables. RESULTS: Eleven prospective controlled trials included a total of 837 patients (412 with 22-G vs 425 with 25-G). Our outcomes revealed that 25-G needles (92% [95% CI, 89%-95%]) have higher sensitivity than 22-G needles (88% [95% CI, 84%-91%]) on solid pancreatic mass EUS-FNA (P = 0.046). However, there were no significant differences between the 2 groups in overall diagnostic specificity (P = 0.842). The pooled positive and negative likelihood ratio of the 22-G needle were 12.61 (95% CI, 5.65-28.14) and 0.16 (95% CI, 0.12-0.21), respectively. The pooled positive likelihood ratio was 12.61 (95% CI, 5.65-28.14), and the negative likelihood ratio was 0.16 (95% CI, 0.12-0.21) for the 22-G needle. The pooled positive likelihood ratio was 8.44 (95% CI, 3.87-18.42), and the negative likelihood ratio was 0.13 (95% CI, 0.09-0.18) for the 25-G needle. The area under the summary receiver operating characteristic curve was 0.97 for the 22-G needle and 0.96 for the 25-G needle. CONCLUSION: Compared to the study of 22-G EUS-FNA needles, our study showed that 25-G needles have superior sensitivity in the evaluation of solid pancreatic lesions by EUS-FNA.

Dichloroacetate induces protective autophagy in esophageal squamous carcinoma cells.

Dichloroacetate (DCA) is an inhibitor of pyruvate dehydrogenase kinase, which promotes the flux of carbohydrates into mitochondria and enhances the aerobic oxidation of glucose. DCA has previously been demonstrated to exhibit antitumor properties. The present study revealed that treatment with DCA induced increased levels of autophagy-associated proteins in esophageal squamous carcinoma cells while minimally affecting apoptosis. The present study examined the localization of light chain (LC)-3 by adenovirus infection with a green fluorescent protein (FP)-red FP-LC3 reporter construction and confirmed that DCA treatment induced significant autophagy. Furthermore, the inhibition of DCA-induced autophagy facilitated cell apoptosis and improved the drug sensitivity of esophageal squamous carcinoma cells to DCA and 5-FU (5-fluorouracil). The proliferation of TE-1 cells was markedly inhibited at low concentrations of DCA and 5-FU treatment when subjected to Atg5 mRNA interference, indicating that autophagy performed a protective role in cell survival upon DCA treatment. To determine the underlying mechanism of DCA-induced autophagy, the present study measured alterations in autophagy-associated signaling pathways. Notably, the protein kinase B (Akt)-mechanistic target of rapamycin (mTOR) signaling pathway, an important negative regulator of autophagy, was demonstrated to be suppressed by DCA treatment. These results may direct the development of novel strategies for the treatment of esophageal squamous carcinoma based on the combined use of DCA and autophagy inhibitors.