Myocardial fibrosis is a serious cause of heart failure and even sudden cardiac death. However, the mechanisms underlying myocardial ischemia-induced cardiac fibrosis remain unclear. Here, we identified that the expression of sterile alpha and TIR motif containing 1 (SARM1), was increased significantly in the ischemic cardiomyopathy patients, dilated cardiomyopathy patients (GSE116250) and fibrotic heart tissues of mice. Additionally, inhibition or knockdown of SARM1 can improve myocardial fibrosis and cardiac function of myocardial infarction (MI) mice. Moreover, SARM1 fibroblasts-specific knock-in mice had increased deposition of extracellular matrix and impaired cardiac function. Mechanically, elevated expression of SARM1 promotes the deposition of extracellular matrix by directly modulating P4HA1. Notably, by using the Click-iT reaction, we identified that the increased expression of ZDHHC17 promotes the palmitoylation levels of SARM1, thereby accelerating the fibrosis process. Based on the fibrosis-promoting effect of SARM1, we screened several drugs with anti-myocardial fibrosis activity. In conclusion, we have unveiled that palmitoylated SARM1 targeting P4HA1 promotes collagen deposition and myocardial fibrosis. Inhibition of SARM1 is a potential strategy for the treatment of myocardial fibrosis. The sites where SARM1 interacts with P4HA1 and the palmitoylation modification sites of SARM1 may be the active targets for anti-fibrosis drugs.

Alzheimer's disease (AD) is the most common senile neurodegenerative disease characterized by progressive cognitive dysfunction, psychological and behavioral abnormalities, and impaired ability of activities of daily living. A family with a total of 3 patients were admitted to the Department of Neurology of Xiangya Hospital, Central South University in 2018. The proband showed memory decline as the presenting symptoms, and subsequently showed psychological and behavioral abnormalities, personality changes, seizures, and motor retardation. Definite diagnosis of early-onset familial AD (EOFAD) with missense mutation of presenilin 2 (PSEN2) (c.715A>G p.M239V) was established by whole exome sequencing (WES) technology. We reported the mutation in Chinese Han population for the first time, which expanded the mutation spectrum ofPSEN2 gene and aid to enrich the characterization of clinical phenotype in EOFAD associated to PSEN2 mutations. Patients with early onset age and complex clinical manifestations of AD can be diagnosed with the help of genetic testing to avoid misdiagnosis.
Activities of Daily Living ; Alzheimer Disease/genetics* ; Humans ; Mutation ; Neurodegenerative Diseases ; Presenilin-1/genetics* ; Presenilin-2/genetics*

To establish a simple, quick and effective method to get a large amount of spider toxin JZTX-26 (35 aa) and JZTX-51 (27 aa) with 3 disulfide bonds each, the mature peptides coding gene fragments were constructed and fused with maltose-binding protein (MBP) tag in an Escherichia coli expression vector pMAL-p2x. The recombinant constructs pMAL-jz26 and pMAL-jz51 were transformed and cultured in E. coli TB1 and BL21 (DE3). After being induced by isopropyl-β-d-thiogalactoside (IPTG), the periplasmic proteins were purified by amylose affinity chromatography and analyzed by SDS-PAGE. The fusion proteins were digested with factor X, and purified by Sizes-Exclusion chromatography and Reversed Phase HPLC. Molecular weights of the purified peptides were obtained by using a MALDI-TOF-TOF mass spectrometer, which were consistent with the theoretical molecular weights. Five milligram of target protein could be purified from 1 L of culture medium. The results indicate that the peptides with three disulfide bonds can be expressed by using the prokaryotic expression system with MBP tag. Our findings suggest the possibility of genetic engineering to obtain large amount of spider peptide toxins.

Objective To investigate the clinical value and safety of cedilanid, esmolol in the treatment of atrial fibrillation. Methods From August 2014 to August 2016 our Hospital from 117 patients with atrial fibrillation clinical data, according to the random number distribution principle, the patients were divided into observation group 59 cases and control group of 58 cases, all patients were given the treatment of primary disease, the clinical symptoms, the patients in the observation group were given oxygen, has given furosemide, cedilanid, after micro injection pump intravenous nitroglycerin, 5-20 g/min. Start after the injection of nitroglycerin, establish another vein channel, every 30 min to 0.2 mg patients, the treatment group were treated with intravenous injection of small dose esmolol. The clinical efficacy, ventricular rate, systolic blood pressure, diastolic blood pressure and adverse reactions were observed in two groups. Results The early and late effective rates of the two groups were not significantly different. The observation showed that after treatment, the ventricular rate, systolic pressure and diastolic pressure in the observation group were significantly higher than those in the control group (P<0.05), and the incidence of adverse reactions in the two groups was significantly different (P<0.05). Conclusion High dose cedilanid combined with small dose esmolol in treatment of atrial fibrillation, obvious curative effect, high safety, can choose the appropriate application.

Objective:To examine the relation between the alteration of condylar endochondral in response to mandibular protrusion and the action time length by establishing a model of mandibular protrusion on young adult rats. Methods: 75 female Sprague-Dawley rats aged 9 weeks were divided into two experimental groups and one control group. In two experimental groups, bite jumping appliances created forward positioning of the condyle for twelve hours and whole day, respectively. The experimental rats, together with the control rats, were sacrificed on days 3, 7, 14, 21 and 30, respectively. Tissue sections were cut in the sagittal plane through the mandibular condyle and were processed for in situ hybridization and immunostaining of type X collagen. Results: The peak of type X collagen protein expression in 24-hour experimental groups appeared on day 21 which was on the top of all experimental groups, while in 12-hour experimental groups it was found on day 30. The results of in situ hybridization were basically in agreement with the results of immunostaining. Conclusion: Both intermittent and continuous mandibular advancement can provoke endochondral ossification in young adult rat condylar, while 24-hour ones can produce more obvious and quicker effect.

Objective:To examine the relation between the alteration of condylar endochondral in response to mandibular protrusion and the action time length by establishing a model of mandibular protrusion on young adult rats.Methods:75 female Sprague-Dawley rats aged 9 weeks were divided into two experimental groups and one control group.In two experimental groups,bite jumping appliances created forward positioning of the condyle for twelve hours and whole day,respectively.The experimental rats,together with the control rats,were sacrificed on days 3,7,14,21 and 30,respectively.Tissue sections were cut in the sagittal plane through the mandibular condyle and were processed for in situ hybridization and immunostaining of type X collagen.Results:The peak of type X collagen protein expression in 24-hour experimental groups appeared on day 21 which was on the top of all experimental groups,while in 12-hour experimental groups it was found on day 30.The results of in situ hybridization were basically in agreement with the results of immunostaining.Conclusion:Both intermittent and continuous mandibular advancement can provoke endochondral ossification in young adult rat condylar,while 24-hour ones can produce more obvious and quicker effect.