PCDH17 restricts dendritic spine morphogenesis by regulating ROCK2-dependent control of the actin cytoskeleton,modulating emotional behavior

Proper regulation of synapse formation and elimination is critical for establishing mature neuronal circuits and maintaining brain function.Synaptic abnormalities,such as defects in the density and morphology of postsynaptic dendritic spines,underlie the pathology of various neuropsychiatric disorders.Protocadherin 17(PCDH17)is associated with major mood disorders,including bipolar disorder and depression.However,the molecular mechanisms by which PCDH17 regulates spine number,morphology,and behavior remain elusive.In this study,we found that PCDH17 functions at postsynaptic sites,restricting the number and size of dendritic spines in excitatory neurons.Selective overexpression of PCDH17 in the ventral hippocampal CA1 results in spine loss and anxiety-and depression-like behaviors in mice.Mechanistically,PCDH17 interacts with actin-relevant proteins and regulates actin filament(F-actin)organization.Specifically,PCDH17 binds to ROCK2,increasing its expression and subsequently enhancing the activity of downstream targets such as LIMK1 and the phosphorylation of cofilin serine-3(Ser3).Inhibition of ROCK2 activity with belumosudil(KD025)ameliorates the defective F-actin organization and spine structure induced by PCDH17 overexpression,suggesting that ROCK2 mediates the effects of PCDH17 on F-actin content and spine development.Hence,these findings reveal a novel mechanism by which PCDH17 regulates synapse development and behavior,providing pathological insights into the neurobiological basis of mood disorders.

Genetic variation of circHIBADH enhances prostate cancer risk through regulating HNRNPA1-related RNA splicing

The current study aimed to investigate associations of circRNAs and related genetic variants with the risk of prostate cancer(PCa)as well as to elucidate biological mechanisms underlying the associations.We first compared expression levels of circRNAs between 25 paired PCa and adjacent normal tissues to identify riskassociated circRNAs by using the MiOncoCirc database.We then used logistic regression models to evaluate associations between genetic variants in candidate circRNAs and PCa risk among 4662 prostate cancer patients and 3114 healthy controls,and identified circHIBADH rs11973492 T>C as a significant risk-associated variant(odds ratio=1.20,95%confidence interval:1.08-1.34,P=7.06×10^(-4))in a dominant genetic model,which altered the secondary structure of the corresponding RNA chain.In the in silico analysis,we found that circHIBADH sponged and silenced 21 RNA-binding proteins(RBPs)enriched in the RNA splicing pathway,among which HNRNPA1 was identified and validated as a hub RBP using an external RNA-sequencing data as well as the in-house(four tissue samples)and publicly available single-cell transcriptomes.Additionally,we demonstrated that HNRNPA1 influenced hallmarks including MYC target,DNA repair,and E2F target signaling pathways,thereby promoting carcinogenesis.In conclusion,genetic variants in circHIBADH may act as sponges and inhibitors of RNA splicing-associated RBPs including HNRNPA1,playing an oncogenic role in PCa.

Genetic variants in C1GALT1 are associated with gastric cancer risk by influencing immune infiltration

Core 1 synthase glycoprotein-N-acetylgalactosamine 3-β-galactosyltransferase 1(C1GALT1)is known to play a critical role in the development of gastric cancer,but few studies have elucidated associations between genetic variants in C1GALT1 and gastric cancer risk.By using the genome-wide association study data from the database of Genotype and Phenotype(dbGAP),we evaluated such associations with a multivariable logistic regression model and identified that the rs35999583 G>C in C1GALT1 was associated with gastric cancer risk(odds ratio,0.83;95% confidence interval[CI],0.75-0.92;P=3.95×10^(-4)).C1GALT1 mRNA expression levels were significantly higher in gastric tumor tissues than in normal tissues,and gastric cancer patients with higher C1GALT1 mRNA levels had worse overall survival rates(hazards ratio,1.33;95%CI,1.05-1.68;P_(log-rank)=1.90×10^(-2)).Furthermore,we found that C1GALT1 copy number differed in various immune cells and that C1GALT1 mRNA expression levels were positively correlated with the infiltrating levels of CD4^(+)T cells and macrophages.These results suggest that genetic variants of C1GALT1 may play an important role in gastric cancer risk and provide a new insight for C1GALT1 into a promising predictor of gastric cancer susceptibility and immune status.

Genetic variant in a BaP-activated super-enhancer increases prostate cancer risk by promoting AhR-mediated FAM227A expression

Genetic variants in super-enhancers(SEs)are increasingly implicated as a disease risk-driving mechanism.Previous studies have reported an associations between benzo[a]pyrene(BaP)exposure and some malignant tumor risk.Currently,it is unclear whether BaP is involved in the effect of genetic variants in SEs on prostate cancer risk,nor the associated intrinsic molecular mechanisms.In the current study,by using logistic regression analysis,we found that rs5750581T>C in 22q-SE was significantly associated with prostate cancer risk(odds ratio=1.26,P=7.61×10^(-5)).We also have found that the rs6001092T>G,in a high linkage disequilibrium with rs5750581T>C(r^(2)=0.98),is located in a regulatory aryl hydrocarbon receptor(AhR)motif and may interact with the FAM227A promoter in further bioinformatics analysis.We then performed a series of functional and BaP acute exposure experiments to assess biological function of the genetic variant and the target gene.Biologically,the rs6001092-G allele strengthened the transcription factor binding affinity to AhR,thereby upregulating FAM227A,especially upon exposure to BaP,which induced the malignant phenotypes of prostate cancer.The current study highlights that AhR acts as an environmental sensor of BaP and is involved in the SE-mediated prostate cancer risk,which may provide new insights into the etiology of prostate cancer associated with the inherited SE variants under environmental carcinogen stressors.

Causal genetic regulation of DNA replication on immune microenvironment in colorectal tumorigenesis: Evidenced by an integrated approach of trans-omics and GWAS

The interplay between DNA replication stress and immune microenvironment alterations is known to play a crucial role in colorectal tumorigenesis,but a comprehensive understanding of their association with and relevant biomarkers involved in colorectal tumorigenesis is lacking.To address this gap,we conducted a study aiming to investigate this association and identify relevant biomarkers.We analyzed transcriptomic and proteomic profiles of 904 colorectal tumor tissues and 342 normal tissues to examine pathway enrichment,biological activity,and the immune microenvironment.Additionally,we evaluated genetic effects of single variants and genes on colorectal cancer susceptibility using data from genome-wide association studies(GWASs)involving both East Asian(7062 cases and 195745 controls)and European(24476 cases and 23073 controls)populations.We employed mediation analysis to infer the causal pathway,and applied multiplex immunofluorescence to visualize colocalized biomarkers in colorectal tumors and immune cells.Our findings revealed that both DNA replication activity and the flap structure-specific endonuclease 1(FEN1)gene were significantly enriched in colorectal tumor tissues,compared with normal tissues.Moreover,a genetic variant rs4246215 G>T in FEN1 was associated with a decreased risk of colorectal cancer(odds ratio=0.94,95%confidence interval:0.90–0.97,P_(meta)=4.70×10^(-9)).Importantly,we identified basophils and eosinophils that both exhibited a significantly decreased infiltration in colorectal tumors,and were regulated by rs4246215 through causal pathways involving both FEN1 and DNA replication.In conclusion,this trans-omics incorporating GWAS data provides insights into a plausible pathway connecting DNA replication and immunity,expanding biological knowledge of colorectal tumorigenesis and therapeutic targets.

Establishment and characterization of a canine chondrosarcoma cell line:Mango

In the global progress of bone tumor research,established stable and long-lasting transgenic chondrosarcoma(CSA)cell lines are rare,mainly of murine and human origin,while the establishment of canine CSA cell lines has yet to be reported.This study established a canine CSA cell line to facilitate the basic clinical study of canine CSA.Fifty fve cases of canine osteolytic disease were collected,and more than 10 bone tumor samples from dogs with typical clinical signs were used for primary cell culture.A cell line with stable passaging for more than 100 generations and mouse tumorigenic ability was successfully cultured.According to the clinical characteristics of the dog and the histopathological results of the primary tumor,CSA was diagnosed,and the CSA cell line was designated Mango.Immunohistochemical(IHC)results showed that the immunoreactivity of bone gamma-carboxyglutamate protein(BGLAP),secreted protein acidic and rich in cysteine(SPARC),alkaline phosphatase(ALPL),vimentin(VIM)and S100 were positive.However,the immunoreactivity of pan-cytokeratin(PCK),chromogranin A(CGA),and platelet endothelial cell adhesion molecule-1(CD31)was negative.Immunofuorescence(IF)results showed that the protein expressions in the Mango cell line were consistent with the IHC identifcation of the primary tumor.The Mango cell line’s doubling time was 43.92 h,and the cell formation rate exceeded 20%.There were abnormal chromosome numbers,hetero staining with toluidine blue,and certain calcifcation abilities.It could be passaged stably and continuously without changing the cell morphology and characteristics.In vivo,the cells were successfully injected into the nude mice model with a tumorigenic rate of 100%.The immunophenotype of the xenograft tumor was consistent with that of the primary tumor.Therefore,we efectively established a canine CSA cell line.As a promising cell material,this cell line can be used to construct a tumor-bearing model conducive to the subsequent basic research of canine CSA.Moreover,because of its similarity to human CSA,the animal model of CSA is also indispensable for investigating human CSA.

基于OBE理念的开放大学线上教学质量评价研究

相比于传统的课堂教学,线上教学是开放大学主要的教学形式,也是开放大学教育教学的主要特色与优势。质量是制约学校发展的主要因素,是学校发展的生命线。线上教学质量关系到开放大学转型办学的成功。开放教育正面临新时代赋予的新使命和新机遇,有效提升线上教学质量是开放大学未来发展的关键。针对目前开放大学线上教学质量评价现状,分析其存在的问题,并基于OBE教育理论,强调以“学生”为中心,构建以计划、实施、督导、反馈以及改进等五环多维教学质量评价体系,形成线上教学质量评价的闭环管理,促进教学效果的提升。

Biological functions and potential implications of circular RNAs

Circular RNAs(circRNAs) are characterized by a covalent closed-loop structure with an absence of both 5′ cap structure and 3′ polyadenylated tail. Numerous studies have found that circRNAs play an important role in various diseases and have a variety of biological regulatory mechanisms, including acting as microRNA sponges,interacting with proteins, modulating the expression of related genes and translating into peptides or proteins.CircRNAs have also been used as biomarkers for a number of diseases, which could improve clinical practice.This review summarizes the most recent advances in biogenesis and knowledge of the biological functions of circRNAs as well as the related bioinformatics databases. We specifically describe developments in understanding of circRNA functions in the field of environmental exposure-induced diseases. Finally, we focus on potential clinical implications of circRNAs to facilitate their clinical transformation into disease treatment.

开放大学网络核心课程教学团队建设实践的思考

网络核心课程教学团队的建设是开放大学人才培养模式改革与发展的需要,是适应“互联网+教育”时代背景的需要,更是提升开放教育教学质量、改革教学方式与方法、提升教学服务水平的必然要求。网络核心课程教学团队不同于传统课程教学团队,它的组建与运行是开放大学教学团队建设探索的新模式。在实践摸索过程中,网络教学团队建设存在认知、师资、机制等方面的不足。完善网络教学团队建设,实现网络教学团队功能的全面发挥是促进开放大学教学团队建设持续发展的新动力。

基于教学团队视角下的开放大学师资队伍建设

开放大学转型期师资队伍建设是重要内容。师资队伍建设是学校工作事项中的主要内容。师资队伍水平是学校教学质量评价的重要指标。开放大学转型期要实现平稳、持续、稳定的发展,离不开师资队伍这块重要基石。转型期开放大学师资队伍建设面临新的问题与挑战。要解决这些问题,需要重新审视,认清形势,发挥开放教育系统优势,探索课程教学团队模式,突破师资队伍发展瓶颈,实现师资队伍由外延式发展向内涵式发展迈进。

Flavonoids of Rosa rugosa Thunb.inhibit tumor proliferation and metastasis in human hepatocellular carcinoma HepG2 cells

Rosa rugosa Thunb.is recognized as both medicine and edible in China.The article investigated the antitumor activity of rose flavonoids.Water-extracted rose flavonoids(RFW)and ethanol-extracted rose flavonoids(RFE)were achieved by extracting with distilled water and 70%ethanol,respectively.The effects of the two extracts on proliferation inhibition,apoptosis inducement and metastasis prevention of human HepG2 hepatocellular carcinoma cell lines were tested,via optical/fluorescence microscopy,MTT detection,Transwell assay,flow cytometry and Western blot,etc.The results indicated that rose flavonoids at low concentration(10-40μg/mL)had a better inhibitory effect on migration and invasion of HepG2 cells in a dose-dependent manner,while rose flavonoids at high concentration(80-160μg/mL)could induce apoptosis of HepG2 cells by up-regulating the expression of pro-apoptotic proteins p53 and Bax,and down-regulating the expression of anti-apoptotic proteins Bcl-2,leading to the functioning of caspase-3 and caspase-9.The effect of RFE at the same concentration was significantly better than that of RFW.Conclusion,this study found that rose flavonoids had a certain inhibitory effect on proliferation and metastasis of human liver cancer cells HepG2,indicating the application of rose flavonoids in preventing and treating of liver cancer.

Bladder cancer epidemiology and genetic susceptibility

Bladder cancer is the most common malignancy of the urinary system. The incidence of bladder cancer of men is higher than that of women （approximately 4：1）. Here, we summarize the bladder cancer-related risk factors, in- cluding environmental and genetic factors. In recent years, although the mortality rate induced by bladder cancer has been stable or decreased gradually, the public health effect may be pronounced. The well-established risk fac- tors for bladder cancer are cigarette smoking and occupational exposure. Genetic factors also play important roles in the susceptibility to bladder cancer. A recent study demonstrated that hereditary non-polyposis colorectal cancer is associated with increased risk of bladder cancer. Since 2008, genome-wide association study （GWAS） has been used to identify the susceptibility loci for bladder cancer. Further gene-gene or gene-environment interaction stud- ies need to be conducted to provide more information for the etiology of bladder cancer.

Association oftransforming growth factor-β1 gene variants with risk of coal workers'pneumoconiosis

Objective： The aim of this case-control study was to explore whether five tagging single nucleotide poly- morphisms （tSNPs） within the transforming growth factor-ill （TGF-fll） gene were involved in manifestation of inflammatory and fibrotic processes associated with coal workers pneumoconiosis （CWP）. Methods： The study included 508 CWP patients and 526 controls who were underground coal miners from Xuzhou Mining Business Group. Five tSNPs were selected from the HapMap and detected by polymerase chain reaction-restriction fragment length polymorphism （PCR-RFLP） method. Results： The single SNP analysis showed that the genotype frequencies of SNP2 （rs1800470, ＋869T/C, extron 1） and SNP5 （rs11466345, intron 5） in CWP cases were significantly different from those in controls. Multivariate logistic regression analysis revealed that SNP2 （rs1800470） CC genotype was associated with decreased risk of CWP （OR = 0.50, 95% CI = 0.32-0.78）, which was evident among subgroups of those never smoke （OR = 0.40, 95%CI = 0.24-0.66）, cases with stage Ⅱ（OR = 0.41, 95%CI = 0.22-0.76） and exposure period （〈 28 y： OR = 0.54, 95%CI = 0.31-0.95; ≥ 28 y： OR = 0.52, 95%CI = 0.32-0.96）. However, the SNP5 （rs11466345） GG genotype was associated with an increased risk of CWP （OR = 2.5, 95%CI = 1.36-4.57）, and further stratification analysis showed that the risk of CWP was increased in both smoking and nonsmoking groups, shorter and longer exposure groups, while the risk of CWP was only increased in patients with stage I and Ⅱ. Conclusion： This study suggests that TGF-β1 polymorphisms may contribute to susceptibility of CWP.

Genetic variants in the Hedgehog signaling pathway genes are associated with gastric cancer risk in a Chinese Han population

The Hedgehog signaling pathway participates in the occurrence and progression of cancers including gastric cancer.We conducted this study to evaluate whether genetic variants in the Hedgehog signaling pathway genes would affect gastric cancer risk.Multi-marker Analysis of GenoMic Annotation(MAGMA)was used to investigate the aggregated genetic effects of single nucleotide polymorphisms(SNPs)assigned to candidate genes.The relationship between SNPs and gastric cancer risk was estimated by multivariate logistic regression analyses.Gene expression was calculated using databases obtained from The Cancer Genome Atlas(TCGA)and The Gene Expression Omnibus(GEO).Kaplan‐Meier plotter was used to evaluate the association between gene expression with gastric cancer survival.Tumor Immune Estimation Resource 2.0(TIMER 2.0)was applied to determine the correlation between selected gene expression and the immune cell infiltration degree.We identified that the G allele of rs2990912 in KIF27 was associated with higher gastric cancer risk,especially in the young and male subgroups.The expression of KIF27 in gastric cancer tissues was higher than that in normal tissues,leading to poor survival in gastric cancer patients.Besides,KIF27 expression was related to immune cell infiltration and positively correlated with PD-L1 expression.Our findings highlight the key role of genetic variation in the Hedgehog signaling pathway genes in gastric cancer susceptibility,which may provide important insights into the diagnosis,prognosis,and treatment of gastric cancer.

P53 codon 72 polymorphism and ovarian cancer risk:a meta-analysis

Objective： p53 is a tumor suppressor gene and is involved in the etiology of ovarian cancer. Studies investigating the associations between the p53 codon 72 polymorphism and ovarian cancer risk showed conflicting results. We performed this meta-analysis from eligible studies to evaluate this purported relationship. Methods： This meta-analysis was performed from 9 case-control studies, including 825 ovarian cases and 1073 controls. The fixed and random effect models were used to estimate the odds ratios（ORs） for various contrasts of this polymorphism. Results： The combined results based on all studies showed that a significantly decreased risk was associated with the variant Pro/Pro genotype, compared with Arg/Pro＋Arg/Arg genotypes（OR, 0.70; 95%CI, 0.51-0.95）. When stratifying the studies by ethnicity, we found that individuals with the variant genotype Pro/pro had a significantly decreased risk of ovarian cancer compared with Arg/Arg genotype（OR, 0.43; 95%CI, 0.20-0.89） and Arg/Pro＋Arg/Arg genotypes（OR, 0.61; 95%CI, 0.37-0.99） among Africans. Conclusion： This meta-analysis suggests that the p53 codon 72 polymorphism may contribute to genetic susceptibility to ovarian cancer. More studies based on larger sample size should be performed to confirm the findings.

全基因组关联研究发现中国人群前列腺癌两个新易感位点9q31.2和19q13.4

0前言在全球范围内，前列腺癌的发病率和病死率存在着巨大差异。该病在西方发达国家发病率最高，在非裔美国人群病死率最高，而在亚洲人群中发病率及病死率均为全球最低，提示不同人种在前列腺癌的遗传方面存在异质性。在欧美和日本人群中，全基因组关联研究（GWAS）技术已经被用于检测前列腺癌的遗传易感性位点，但至今尚无关于GWAS检测中国人群前列腺癌易感位点的报道。

Molecular epidemiology of DNA repair gene polymorphisms and head and neck cancer

Although tobacco and alcohol consumption are two common risk factors of head and neck cancer （HNC）, other specific etiologic causes, such as viral infection and genetic susceptibility factors, remain to be understood. Hu- man DNA is often damaged by numerous endogenous and exogenous mutagens or carcinogens, and genetic vari- ants in interaction with environmental exposure to these agents may explain interindividual differences in HNC risk. Single nucleotide polymorphisms （SNPs） in genes involved in the DNA damage-repair response are reported to be risk factors for various cancer types, including HNC. Here, we reviewed epidemiological studies that have assessed the associations between HNC risk and SNPs in DNA repair genes involved in base-excision repair, nucleotide-excision repair, mismatch repair, double-strand break repair and direct reversion repair pathways. We found, however, that only a few SNPs in DNA repair genes were found to be associated with significantly in- creased or decreased risk of HNC, and, in most cases, the effects were moderate, depending upon locus-locus in- teractions among the risk SNPs in the pathways. We believe that, in the presence of exposure, additional pathway- based analyses of DNA repair genes derived from genome-wide association studies （GWASs） in HNC are needed.

CASP8 promoter polymorphism,mRNA expression and risk of prostate cancer among Chinese men

Caspase-8 （CASPS） plays a key role in apoptosis. We examined by genotyping whether the -652 six-nucleotide insertion-deletion （6N ins/del） polymorphism in the CASP8 promoter region was associated with prostate cancer risk in a hospital-based case-control study of 406 Chinese prostate cancer patients and 408 age-matched cancerfree controls. Additionally, 23 prostate cancer tissues were analyzed for CASP8 mRNA expression. We found a significantly decreased prostate cancer risk for the 6N ins/del genotype [adjusted odds ratio （OR）=0.68; 95% confidence interval （C/）=0.51-0.92] and del/del genotype （OR=0.34; 95% CI=0.19-0.63） compared with the ins/ins genotype. The 6N del allele was associated dose-dependently with decreased prostate cancer risk （Ptrend = 0.001）. RT-PCR showed that individuals with the 6N del allele had lower CASP8 mRNA levels than those with the ins/ ins genotype （P = 0.024）. These findings suggested that the CASPS-652 6N ins/del polymorphism may affect the susceptibility to prostate cancer and reduce prostate cancer risk among Chinese men.

Structure design and rice threshing performance of the variable-speed inertial pulley for simulating artificial threshing

Due to the small models and compact structures,small harvesters have also caused problems such as poor threshing separation performance and large loss rates.In order to solve unstable cleaning effects of small harvesters when they facing different working conditions,this study selected rice plants in hilly areas for the experiment.Tensile breaking force of different parts of mature rice was tested,which revealed the fracture mechanism of each part under the combined force.Inertial threshing method was used to simulate artificial plate bin and design three kinds of non-circular pulley variable speed transmission threshing mechanism.With the help of transient inertia force,threshing force was compensated.This paper tested the harvesting performance of the variable speed threshing device with the help of the harvest performance test.Results show when facing the small rice planting area,the T/2 variable speed threshing device has better cleaning performance,and also the harvest loss rate of T/4 variable speed threshing device is the lowest.Compared with the constant speed threshing device,the impurity content rate of the variable speed threshing device is increased by 0.64%to 8.76%;the loss rate is reduced by 0.45%to 1.79%,which provides a basis for the optimization design of small combine harvester in hilly areas.

Ni_(4)-thiacalix[4]arene sandwiched Mo_8 polyoxometalate bimetallic nanoclusters for electrocatalytic glucose oxidation

Available online two new Ni_(8)Mo_(8) bimetallic coordination clusters,[Ni_(4)(TC4A)]_(2)[(Mo_5~VMo_(3)~ⅥO_(24))(PO_(4))](+Solvent)(Ni_(8)PMo_(8),H_(4)TC4A=p-tert-butylthiacalix[4]arene) and[Ni_(4)(TC4A)]_(2)[(Mo_5~VMo_(3)~ⅥO_(24))(OH)(CO_(3))](+Solvent)(Ni_(8)Mo_(8)),were synthesized by solvothermal method and structurally characterized by single-crystal X-ray diffraction,powder X-ray diffraction,FT-IR spectroscopy,and TGA experiments,respectively.The usage of H_(3)PMo_(12)O_(40) as source for Ni_(8)PMo_(8) resulted a sandwich like structure built from two Ni_(4)-thiacalix[4]arene units and a Mo_(8) polyoxometalate with inner spaces of PO_(4)^(3-).Ni_(8)Mo_(8) with the similar structure to that of Ni_(8)PMo_(8) is from H_(2)MoO_(4) starting reagent with OH^(-)and CO_(3)^(2-)anions encapsulated in the center.The two clusters can be directly loaded on carbon paper and utilized as working electrodes which showed distinguishable performances for glucose detection and oxidation.This work provides a better understanding of the structure-property relationships in using substituted polyoxometalates for electrochemical applications and is helpful for building calixarene-based or polyoxometalatebased functional materials.