Association between Plasma Brain-derived Neurotrophic Factor Level and Alzheimer's Disease: A Mendelian Randomization Study.

BACKGROUND: High brain-derived neurotrophic factor (BDNF) concentrations have been found to be associated with a decreased risk of Alzheimer's disease (AD) in observational studies, but the causality for this association remains unclear. Therefore, we aimed to examine the association between genetically determined plasma BDNF levels and AD using a two-sample Mendelian randomization (MR) method. METHODS: Twenty single-nucleotide polymorphisms associated with plasma BDNF concentrations were identified as genetic instruments based on a genome-wide association study with 3301 European individuals. Summary-level data on AD were obtained from the International Genomics of Alzheimer's Project, involving 21,982 AD cases and 41,944 controls of European ancestry. To evaluate the relationship between plasma BDNF concentrations and AD, we employed the inverse-variance weighted method along with a series of sensitivity analyses. RESULTS: The inverse-variance weighted MR analysis showed that genetically determined BDNF concentrations were associated with a decreased risk of AD (odds ratio per SD increase, 0.91; 95% confidence interval, 0.86-0.96; p =0.001). The association between plasma BDNF concentrations and AD was further confirmed through sensitivity analyses using different MR methods, and MR-Egger regression suggested no directional pleiotropy for this association. CONCLUSION: Genetically determined BDNF levels were associated with a decreased risk of AD, suggesting that BDNF was implicated in the development of AD and might be a promising target for the prevention of AD.

Genotypic and spatial analysis of transmission dynamics of tuberculosis in Shanghai, China: a 10-year prospective population-based surveillance study.

Background: With improved tuberculosis (TB) control programs, the incidence of TB in China declined dramatically over the past few decades, but recently the rate of decrease has slowed, especially in large cities such as Shanghai. To help formulate strategies to further reduce TB incidence, we performed a 10-year study in Songjiang, a district of Shanghai, to delineate the characteristics, transmission patterns, and dynamic changes of the local TB burden. Methods: We conducted a population-based study of culture-positive pulmonary TB patients diagnosed in Songjiang during 2011-2020. Genomic clusters were defined with a threshold distance of 12-single-nucleotide-polymorphisms based on whole-genome sequencing, and risk factors for clustering were identified by logistic regression. Transmission inference was performed using phybreak. The distances between the residences of patients were compared to the genomic distances of their isolates. Spatial patient hotspots were defined with kernel density estimation. Findings: Of 2212 enrolled patients, 74.7% (1652/2212) were internal migrants. The clustering rate (25.2%, 558/2212) and spatial concentrations of clustered and unclustered patients were unchanged over the study period. Migrants had significantly higher TB rates but less clustering than residents. Clustering was highest in male migrants, younger patients and both residents and migrants employed in physical labor. Only 22.1% of transmission events occurred between residents and migrants, with residents more likely to transmit to migrants. The clustering risk decreased rapidly with increasing distances between patient residences, but more than half of clustered patient pairs lived ≥5 km apart. Epidemiologic links were identified for only 15.6% of clustered patients, mostly in close contacts. Interpretation: Although some of the TB in Songjiang's migrant population is caused by strains brought by infected migrants, local, recent transmission is an important driver of the TB burden. These results suggest that further reductions in TB incidence require novel strategies to detect TB early and interrupt urban transmission. Funding: Shanghai Municipal Science and Technology Major Project (ZD2021CY001), National Natural Science Foundation of China (82272376), National Research Council of Science and Technology Major Project of China (2017ZX10201302-006).

Contact investigation of tuberculosis in Shanghai, China: A 13-year cohort.

OBJECTIVES: Tuberculosis (TB) contact investigation is an effective strategy for TB control. We established a close-contact cohort to evaluate the effect of contact investigation in Shanghai, China. METHODS: Close contacts of bacteria-positive TB cases diagnosed from 2009 to 2018 in the Songjiang District of Shanghai were screened and followed up until 2021 through symptom examination or other alternatives, and the incidence and risk factors for developing active TB among close contacts were assessed by survival analysis and WGS. RESULTS: 7018 close contacts of 2861 bacteria-positive TB cases were investigated. The median follow-up time was 7.4 years. 97 close contacts (185/100,000, 95%CI: 151-226) developed TB. Survival analysis showed that index cases who were in younger age groups, living in urban settings, smear-positive, and reported a healthcare-seeking delay for TB had higher risks of generating contact cases. Close contacts with matched strains developed TB at an average of 26.5 months based on WGS. CONCLUSION: A 2-year ideally longer follow-up for close contacts would be beneficial. To improve early case detection, more attention needs to be paid to those contacts whose index cases were living in urban settings, were smear-positive, had a healthcare-seeking delay for TB, and/or were aged ≤18 years.

Downregulation of CPT1A exerts a protective effect in dextran sulfate sodium-induced ulcerative colitis partially by inhibiting PPARα signaling pathway.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease that may progress to colorectal cancer in severe cases. Carnitine palmitoyltransferase-1A (CPT1A) has been reported to be upregulated in colorectal cancer. This paper aims to explore the role of CPT1A in UC and its pathogenesis. An in vivo mice model of UC was constructed by administrating 3% dextran sulfate sodium (DSS). The expression level of CPT1A was examined by quantitative real-time polymerase chain reaction and Western blot. The intestinal damage, inflammatory response and oxidative stress were assessed by hematoxylin and eosin staining, colon length, and commercial kits. Thereafter, an in vitro cell model of UC was established by stimulating HT-29 cells with 2% DSS. The peroxisome proliferator-activated receptor α (PPARα) signaling agonist GW7647 was used for treatment. Cell viability and apoptosis was assayed by cell counting kit-8 assay and terminal dUTP nick-end labeling assay, respectively. The inflammatory cytokines and oxidative stress-related factors was evaluated using corresponding commercial detection kits. In DSS-induced mice model of UC, CPT1A expression was upregulated. Interference of CPT1A attenuated histological damage, the disease activity index and colon length in colitis. We also found downregulation of CPT1A inhibited inflammatory response and oxidative stress, and inhibited PPARα signaling pathway in UC mice. Additionally, in DSS-induced HT-29 cells, downregulation of CPT1A promoted cell viability, reduced cell apoptosis, inflammatory response, and oxidative stress, which was partly abolished by additional treatment with GW7647. In summary, downregulation of CPT1A exerts a protective effect in DSS-induced UC partially through suppressing PPARα signaling, suggesting that CPT1A might be a potential target for the treatment of UC.

Mining the potential prognostic value of synaptosomal-associated protein 25 (SNAP25) in colon cancer based on stromal-immune score.

BACKGROUND: Colon cancer is one of the deadliest tumors worldwide. Stromal cells and immune cells play important roles in cancer biology and microenvironment across different types of cancer. This study aimed to identify the prognostic value of stromal/immune cell-associated genes for colon cancer in The Cancer Genome Atlas (TCGA) database using bioinformatic technology. METHODS: The gene expression data and corresponding clinical information of colon cancer were downloaded from TCGA database. Stromal and immune scores were estimated based on the ESTIMATE algorithm. Sanger software was used to identify the differentially expressed genes (DEGs) and prognostic DEGs based on stromal and immune scores. External validation of prognostic biomarkers was conducted in Gene Expression Omnibus (GEO) database. Gene ontology (GO) analysis, pathway enrichment analysis, and gene set enrichment analysis (GSEA) were used for functional analysis. STRING and Cytoscape were used to assess the protein-protein interaction (PPI) network and screen hub genes. Quantitative real-time PCR (qRT-PCR) was used to validate the expression of hub genes in clinical tissues. Synaptosomal-associated protein 25 (SNAP25) was selected for analyzing its correlations with tumor-immune system in the TISIDB database. RESULTS: Worse overall survivals of colon cancer patients were found in high stromal score group (2963 vs. 1930 days, log-rank test P = 0.038) and high immune score group (2894 vs. 2230 days, log-rank test P = 0.076). 563 up-regulated and 9 down-regulated genes were identified as stromal-immune score-related DEGs. 70 up-regulated DEGs associated with poor outcomes were identified by COX proportional hazard regression model, and 15 hub genes were selected later. Then, we verified aquaporin 4 (AQP4) and SNAP25 as prognostic biomarkers in GEO database. qRT-PCR results revealed that AQP4 and SNAP25 were significantly elevated in colon cancer tissues compared with adjacent normal tissues (P = 0.003, 0.001). GSEA and TISIDB suggested that SNAP25 involved in cancer-related signaling pathway, immunity and metabolism progresses. CONCLUSION: SNAP25 is a microenvironment-related and immune-related gene that can predict poor outcomes in colon cancer.

Prevalence of Ureaplasma urealyticum, Chlamydia trachomatis, and Neisseria gonorrhoeae in gynecological outpatients, Taizhou, China.

OBJECTIVES: Ureaplasma urealyticum (UU), Chlamydia trachomatis (CT), and Neisseria gonorrhoeae (NG) are highly prevalent worldwide and may lead to some genital diseases. The objective of this large-scale study was to estimate the prevalence characteristics of UU, CT, and NG among women in Taizhou, Zhejiang Province, China. METHODS: A total of 13 303 women who visited the gynecologic outpatient service of Taizhou First People's Hospital in Taizhou from 2013 to 2018 were analyzed. The testing of UU, CT, and NG was performed on the collected vaginal swabs using real-time fluorescence quantitative polymerase chain reaction (RT-PCR) method. RESULTS: The overall infection rates of UU, CT, and NG were 62.04%, 10.20%, and 4.09% in the Taizhou-based population, respectively. The age-specific prevalence showed that younger women (age <25 years) were the preferred period for the positive detection of UU or CT, while elder women (age ≥40 years) had the highest prevalence of NG. In addition, the UU-CT co-infection pattern (7.32%) predominated in the study population, and CT was significantly associated with UU and NG. CONCLUSIONS: Our novel data demonstrated that UU, CT, and NG infection are prevalent among women in Taizhou, and comprehensive UU, CT, and NG screening guidelines and treatment policies for this population are warranted.