Deficiency of Tet3 in nucleus accumbens enhances fear generalization and anxiety-like behaviors in mice.

Stress-induced neuroepigenetic programming gains growing more and more interest in the studies of the etiology of posttraumatic stress disorder (PTSD). However, seldom attention is focused on DNA demethylation in fear memory generalization, which is the core characteristic of PTSD. Here, we show that ten-eleven translocation protein 3 (TET3), the most abundant DNA demethylation enzyme of the TET family in neurons, senses environmental stress and bridges neuroplasticity with behavioral adaptation during fear generalization. Foot shock strength dependently induces fear generalization and TET3 expression in nucleus accumbens (NAc) in mice. Inhibition of DNA demethylation by infusing demethyltransferase inhibitors or AAV-Tet3-shRNA virus in NAc enhances the fear generalization and anxiety-like behavior. Furthermore, TET3 knockdown impairs the dendritic spine density, PSD length, and thickness of neurons, decreases DNA hydroxymethylation (5hmC), reduces the expression of synaptic plasticity-related genes including Homer1, Cdkn1a, Cdh8, Vamp8, Reln, Bdnf, while surprisingly increases immune-related genes Stat1, B2m, H2-Q7, H2-M2, C3, Cd68 shown by RNA-seq. Notably, knockdown of TET3 in NAc activates microglia and CD39-P2Y12R signaling pathway, and inhibition of CD39 reverses the effects of TET3 knockdown on the fear memory generalization and anxiety. Overexpression of TET3 by Crispr-dSaCas9 virus delivery to activate endogenous Tet3 in NAc increases dendritic spine density of neurons in NAc and reverses fear memory generalization and anxiety-like behavior in mice. These results suggest that TET3 modulates fear generalization and anxiety via regulating synaptic plasticity and CD39 signaling pathway.

Modulation of STIM1 by a risk insertion/deletion polymorphism underlying genetics susceptibility to sudden cardiac death originated from coronary artery disease.

Stromal interaction molecule 1 (STIM1), as a dynamic calcium signal transducer and key regulator of cardiomyocyte Ca2+ homeostasis, has been implicated in various pathological processes related to sudden cardiac death originated from coronary artery disease (SCD-CAD). In this study, we performed a systematic variant screening on promoter region of STIM1 to filter potential functional genetic variations. Based on the screening results, a 5-bp insertion/deletion (indel) polymorphism (rs3061890) in promoter region of STIM1 was selected as the candidate variant. We investigated the association of rs3061890 with SCD-CAD susceptibility in Chinese Han populations. The homozygote del/del genotype significantly increased risk for SCD-CAD as compared with the ins/ins genotype (odds ratio, 2.86 [95% confidence interval, 1.69-4.29]; P = 2.3 × 10-5). Compared with the common allele, the 5-bp deletion risk allele exhibited lower transcriptional capacity in luciferase assays. Intriguingly, genotype-phenotype correlation studies using human myocardium tissue samples revealed that the expression of STIM1 was associated with the genotype of rs3061890. Computational prediction combined with electrophoretic mobility shift (EMSA) and chromatin immunoprecipitation (ChIP) assays provided convincing evidence for stronger binding affinity of ELF1 (E74 like ETS transcription factor 1) with the deletion allele promoter. Taken together, our findings implied an allele-specific mechanism of regulating the transcription of STIM1 via ELF1, which contribute to SCD-CAD susceptibility. rs3061890 may thus considered as a candidate genetic marker for SCD-CAD prediction and prevention.

Bongkrekic acid poisoning: Severe liver function damage combined with multiple organ failure caused by eating spoiled food.

Bongkrekic acid (BA) poisoning can be caused by eating spoiled or fermented foods contaminated with pseudomonas cocovenenans. Although some in vitro studies have been reported on the use of purified BA to interfere with cell metabolism, few clinical or pathological data of BA poisoning on human due to food-borne factors are available for forensic appraisal. For the first time, we retrospectively report five cases of food-borne poisoning caused by eating rice noodles, a popular traditional food in Guangdong, China, and three of the victims died. All five victims were hospitalized with gastrointestinal symptoms such as nausea, vomiting and diarrhea and were treated with admission diagnosis of liver failure and acute kidney damage. Certain concentrations of BA were detected in the victims' peripheral blood serums at the hospitalization (ranging from 70-345 µg/L) and the suspected poisonous foods (0-810 ng/g) with LC-MS/MS technique. The results of forensic pathological examination showed that all three deceased had severe liver and kidney damage, accompanied by multiple organ congestion and edema, which were consistent with clinical diagnosis. Combined with the clinical records, we found that the difference in blood glucose between the deceased and survivors of the five victims may be an indication of the severity of the disease. In addition, we compared BA poisoning with other diseases that can cause acute liver function damage in terms of pathological characteristics and clinical manifestations, which has important reference significance for the diagnosis and forensic appraisal of this food-borne poisoning.