Tranylcypromine upregulates Sestrin 2 expression to ameliorate NLRP3-related noise-induced hearing loss

Noise-induced hearing loss is the primary non-genetic factor contributing to auditory dysfunction.However,there are currently no effective pharmacological interventions for patients with noise-induced hearing loss.Here,we present evidence suggesting that the lysine-specific demethylase 1 inhibitor–tranylcypromine is an otoprotective agent that could be used to treat noise-induced hearing loss,and elucidate its underlying regulatory mechanisms.We established a mouse model of permanent threshold shift hearing loss by exposing the mice to white broadband noise at a sound pressure level of 120 d B for 4 hours.We found that tranylcypromine treatment led to the upregulation of Sestrin2(SESN2)and activation of the autophagy markers light chain 3B and lysosome-associated membrane glycoprotein 1 in the cochleae of mice treated with tranylcypromine.The noise exposure group treated with tranylcypromine showed significantly lower average auditory brainstem response hearing thresholds at click,4,8,and 16 k Hz frequencies compared with the noise exposure group treated with saline.These findings indicate that tranylcypromine treatment resulted in increased SESN2,light chain 3B,and lysosome-associated membrane glycoprotein 1 expression after noise exposure,leading to a reduction in levels of 4-hydroxynonenal and cleaved caspase-3,thereby reducing noise-induced hair cell loss.Additionally,immunoblot analysis demonstrated that treatment with tranylcypromine upregulated SESN2 expression via the autophagy pathway.Tranylcypromine treatment also reduced the production of NOD-like receptor family pyrin domaincontaining 3(NLRP3)production.In conclusion,our results showed that tranylcypromine treatment ameliorated cochlear inflammation by promoting the expression of SESN2,which induced autophagy,thereby restricting NLRP3-related inflammasome signaling,alleviating cochlear hair cell loss,and protecting hearing function.These findings suggest that inhibiting lysine-specific demethylase 1 is a potential therapeutic strategy for preventing hair cell loss and noise-induced hearing loss.

Comparison of yield performance between direct-seeded and transplanted double-season rice using ultrashort-duration varieties in central China

Labor scarcity requires double-season rice to be planted by direct seeding as an alternative to transplanting. Only ultrashort-duration varieties can be used in direct-seeded, double-season rice(DSD) in central China where thermal time is limited. Whether ultrashort-duration varieties grown in DSD can be as productive and efficient in nitrogen(N) use as transplanted double-season rice(TPD) remains unclear. Field experiments were conducted in Hubei province, central China with two establishment methods(DSD,TPD) and three N rates in the early and late seasons of 2017 and 2018. Nitrogen treatments included zero-N control(N0), total N rate of 60 kg N ha;with equal splits at basal, midtillering, and panicle initiation(N1), and weekly N application at 15 kg ha;from seeding/transplanting to heading(N2). Both early-and late-season rice under DSD matured within 95 days, on average 9 days shorter than rice under TPD. The grain yield of DSD was comparable to or higher than that of TDP in both seasons, although the daily yield was significantly higher under DSD than under TDP. Before heading, DSD had higher leaf area,stem number, intercepted radiation, and radiation use efficiency than TPD, which compensated for the negative effect of short growth duration on biomass production. Total dry weight and harvest index under DSD were comparable to or higher than those under TDP. In general, the recovery efficiency of fertilizer-N under DSD was higher than that under TPD, but the reverse was true for physiological N use efficiency. Thus, there was no significant difference in agronomic N use efficiency between DSD and TPD. These results suggested that DSD with ultrashort-duration varieties is a promising alternative to TPD in central China for maintaining high grain yield and N fertilizer use efficiency with less labor input.

Reflections on the New Classification of Tumors by the WHO and Changes in Esophageal Cancer in a High-risk Area

ABSTRACT In year 2000, a book entitled the Pathology and Genetics of Tumors of the Digestive System was published by the WHO, presenting some new diagnostic criteria and treatment principles. I have analyzed the epidemiologic change of tumors in over 30 years in the high-risk area with esophageal cancer. The following phenomenon was found： accompanied by the sharp decrease in the incidence and mortality of esophageal cancer, there was an increase in the incidence and death rate of stomach cancer involving cardiac cancer. This fact should be considered when analyzing the sharp decrease in esophageal cancer incidence and mortality rate. More attention was given to diagnosis of cardiac cancer; at the same time it is more practical to improve the early screening of cancers. To observe the development of high and low - grade intraepithelial neoplasms will be an urgent task for esophageal cancer research in the high risk area, according to WHO＇s new classification.

相变存储材料相变机理的研究进展

相变存储技术作为下一代极具竞争力的新型存储技术之一,其基础研究也蓬勃发展,但相变存储的机理研究滞后于应用研究。本文在简要介绍相变存储技术和相变机理的基础上,从纳秒级相变机理和超快(皮秒级)相变机理的角度综述了近年来相变存储材料相变机理的主要研究进展,指出了纳秒量级相变源于热效应,而皮秒量级相变可能源于热效应或电子效应,且与材料的尺寸、衬层及激发源密切相关,同时指出了超快相变机理研究中一些值得关注的问题,提出了今后的发展方向。

Regulation of RNA methylation and immune infiltration patterns by m5C regulators in head and neck squamous cell carcinoma

5-Methylcytosine(m5C)methylation contributes to the development and progression of various malignant tumors.This study aimed to explore the potential role of m5C methylation regulators(m5CMRs)in head and neck squamous cell carcinoma(HNSCC).Methods:The transcription data of HNSCC samples were obtained from The Cancer Genome Atlas(TCGA)and the Gene Expression Omnibus(GEO)databases.Subsequently,the m5C patterns in HNSCC were evaluated based on 14 m5CMRs.Then,the m5Cscore was developed to quantify m5C patterns by using principal component analysis(PCA)algorithms.Two single-cell RNA sequencing datasets and various methods were employed to assess the prognostic value and sensitivity to immunotherapy.Finally,key prognostic m5CMRs were identified using univariate COX regression analysis,and their clinical significance was validated based on the Human Protein Atlas(HPA)database and by using immunohistochemistry.Results:Two distinct m5C clusters were identified.m5C cluster A is characterized by an immune-activated microenvironment and is associated with a favorable prognosis.Notable differences were observed in prognosis,immune infiltration,and immunotherapy response between the high-and low-m5Cscore groups.Patients in the high-m5Cscore group exhibited high TMB,which is correlated with poor prognosis.The m5Cscore of epithelial cells in HNSCC was higher than that in other cells.Key prognostic m5CMRs,including NSUN2,DNMT3B,ALKBH1,and Y-Box Binding Protein 1(YBX1),were associated with poor prognosis.Conclusion:Our research indicates that in head and neck squamous cell carcinoma,the m5C modification profoundly affects the TME’s diversity and complexity,influencing prognosis and the success of immunotherapy.Targeting m5C regulatory elements may be a new method for enhancing the efficacy of immunotherapy in HNSCC.

The Relationship between a Cohort Endoscopic Screening of 15,000 Subjects and the Death of Patients with Esophageal and Gastric Cancers in High-Risk Areas

OBJECTIVE Ci-xian County is located in the north of Chinaand is a high-risk area for esophageal cancer(EC).In 2004,theincidence rate of EC in the county was 127/100,000 and 93/100,000in the male and female population,respectively,and that ofgastric cancer(GC)was 72/100,000 and 36/100,000.Since 2001 acohort screening,supported by a special national fund,utilizingendoscopic examination with iodine staining for the targetpopulation at the age ranging from 40 to 69 years was carried out,so as to reduce the incidence and mortality rates in the high-riskareas of EC.METHODS In October 2001,4 townships in the Ci-xian County,Hebei,China were selected,with 22,016 cases in the interventiongroup(IVG)and 33,410 in the control group(CG).The totalpopulation coverage reached 55,000.There were 3257 males and3339 females in the IVG with the age ranging from 40 to 69 years,and 4299 males and 4430 females in the CG with the same rangeof the age.Endoscopic screening with iodine staining was used inthe IVG,with a screening rate of 53.2%.During the screening byendoscopic examination,97 cases were found to have esophagealsquamous epithelium,carcinoma-in-situ at the cardiac glandularepithelium or intra-mucosal carcinoma.Additionally,102cases were identified to have severe atypical hyperplasia in theesophagus and gastric cardia.The natural incidence rate of cancerand the mortality were observed in the CG.The ICD-0 version wasused in the tumor incidence and death registration coding.Duringa period from June to September 2008,based on the information ofthe tumor registration database of the incidence and mortality inthe Ci-xian County,the cohort groups were studied and followed.RESULTS There were 133 patients with untreatable EC and48 with GC in the IVG,while there were 259 and 37 patients inthe CG who died of esophageal and gastric cancer,respectively.The relative risk(RR)of death was 0.76 in the male patients withEC,95%CI(0.59-0.98),P=0.038,and in the female patients theRR was 0.51,95%CI(0.35-0.75),P=0.000.The RR of death in theGC patients was 2.45,(1.40-4.29)in the male,P=0.01,and 0.99,(0.47-1.99),in the female cases,P=0.906.CONCLUSION Six years after a cohort screening of a largepopulation by endoscopic examination with iodine staining inareas at high risk for EC,the death risk in the male and femalepatients with EC has decreased compared with that in the controlgroup.The difference between the 2 groups was statisticallysignificant.However,no protective method used to decrease thedeath risk in GC patients has been found during this period ofendoscopic screening.

Computing Persistent Homology by Spanning Trees and Critical Simplices

Topological data analysis can extract effective information from higher-dimensional data.Its mathematical basis is persistent homology.The persistent homology can calculate topological features at different spatiotemporal scales of the dataset,that is,establishing the integrated taxonomic relation among points,lines,and simplices.Here,the simplicial network composed of all-order simplices in a simplicial complex is essential.Because the sequence of nested simplicial subnetworks can be regarded as a discrete Morse function from the simplicial network to real values,a method based on the concept of critical simplices can be developed by searching all-order spanning trees.Employing this new method,not only the Morse function values with the theoretical minimum number of critical simplices can be obtained,but also the Betti numbers and composition of all-order cavities in the simplicial network can be calculated quickly.Finally,this method is used to analyze some examples and compared with other methods,showing its effectiveness and feasibility.

Efficient inversions and duplications of mammalian regulatory DNA elements and gene clusters by CRISPR/Cas9

The human genome contains millions of DNA regulatory elements and a large number of gene clusters,most of which have not been tested experimentally.The clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated nuclease 9(Cas9)programed with a synthetic single-guide RNA(sgRNA)emerges as a method for genome editing in virtually any organisms.Here we report that targeted DNA fragment inversions and duplications could easily be achieved in human and mouse genomes by CRISPR with two sgRNAs.Specifically,we found that,in cultured human cells and mice,efficient precise inversions of DNA fragments ranging in size froma few tens of bp to hundreds of kb could be generated.In addition,DNA fragment duplications and deletions could also be generated by CRISPR through trans-allelic recombination between the Cas9-induced double-strand breaks(DSBs)on two homologous chromosomes(chromatids).Moreover,junctions of combinatorial inversions and duplications of the protocadherin(Pcdh)gene clusters induced by Cas9 with four sgRNAs could be detected.In mice,we obtained founders with alleles of precise inversions,duplications,and deletions of DNA fragments of variable sizes by CRISPR.Interestingly,we found that very efficient inversions were mediated by microhomology-mediated end joining(MMEJ)through short inverted repeats.We showed for the first time that DNA fragment inversions could be transmitted through germlines in mice.Finally,we applied this CRISPR method to a regulatory element of the Pcdha cluster and found a new role in the regulation of members of the Pcdhg cluster.This simple and efficient method should be useful in manipulating mammalian genomes to study millions of regulatory DNA elements as well as vast numbers of gene clusters.

Ticagrelor inhibits the NLRP3 inflammasome to protect against inflammatory disease independent of the P2Y_(12 ) signaling pathway

Ticagrelor is the first reversibly binding oralP2Y_(12) receptor antagonist to inhibit platelet activation and has been approved by the Food and Drug Administration for the treatment of coronary artery disease. At present, the other pharmacological functions of ticagrelor remain poorly understood. The NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome plays a critical role in the innate immune system, but its excessive activation also contributes to the pathogenesis of complex diseases. In this study, we systematically examined the effects of ticagrelor on the NLRP3 inflammasome and found that ticagrelor inhibits NLRP3 inflammasome activation in macrophages independent of its classic inhibitory effect on theP2Y_(12) signaling pathway. Further mechanistic studies demonstrate that ticagrelor attenuates the oligomerization of apoptosis-associated speck-like protein containing a CARD (ASC) by blocking chloride efflux, an effect achieved through the degradation of chloride intracellular channel proteins (CLICs) and blockade of the translocation of CLICs to the plasma membrane. Moreover, experiments on lipopolysaccharide-induced sepsis and alum-induced peritonitis in mice confirmed that ticagrelor mitigates the severity of systemic inflammation independent ofP2Y_(12) receptor antagonism. Importantly, oral administration of ticagrelor rapidly and strongly inhibited NLRP3 inflammasome activation in peripheral blood mononuclear cells from patients with acute coronary syndrome. Overall, our study reveals a novel pharmacological function of ticagrelor in addition to its classic antiplatelet properties, which suggests that ticagrelor may serve as a potential therapeutic agent for use in NLRP3-associated diseases.