Division of labor within the DNA damage tolerance system reveals non-epistatic and clinically actionable targets for precision cancer medicine

Crosslink repair depends on the Fanconi anemia pathway and translesion synthesis polymerases that replicate over unhooked crosslinks. Translesion synthesis is regulated via ubiquitination of PCNA, and independently via translesion synthesis polymerase REV1. The division of labor between PCNA-ubiquitination and REV1 in interstrand crosslink repair is unclear. Inhibition of either of these pathways has been proposed as a strategy to increase cytotoxicity of platinating agents in cancer treatment. Here, we defined the importance of PCNA-ubiquitination and REV1 for DNA in mammalian ICL repair. In mice, loss of PCNA-ubiquitination, but not REV1, resulted in germ cell defects and hypersensitivity to cisplatin. Loss of PCNA-ubiquitination, but not REV1 sensitized mammalian cancer cell lines to cisplatin. We identify polymerase Kappa as essential in tolerating DNA damage-induced lesions, in particular cisplatin lesions. Polk-deficient tumors were controlled by cisplatin treatment and it significantly delayed tumor outgrowth and increased overall survival of tumor bearing mice. Our results indicate that PCNA-ubiquitination and REV1 play distinct roles in DNA damage tolerance. Moreover, our results highlight POLK as a critical TLS polymerase in tolerating multiple genotoxic lesions, including cisplatin lesions. The relative frequent loss of Polk in cancers indicates an exploitable vulnerability for precision cancer medicine.     

一株生防圆突起链霉菌的分类鉴定

菌株SCY311是从河南省凤凰山土壤样品中分离到的对多种植物病原真菌具有拮抗活性的一株放线菌。为了明确其分类地位, 在形态特征、培养特征、生理生化特征、细胞壁组分测定等传统分类学方法的基础上, 测定和分析了菌株的16S rRNA基因序列。结果表明, 菌株SCY311在高氏一号培养基上生长良好, 基内菌丝呈褐色; 气生菌丝灰色至鼠灰色, 不产生可溶性色素, 无吸水现象; 孢子链卷曲, 末端形成闭合或开放螺旋; 孢子椭圆或圆柱状, 表面形成结节状突起; 生理生化特征和在国际链霉菌计划(ISP)培养基上的培养特     

ALKBH5/MAP3K8 axis regulates PD-L1+ macrophage infiltration and promotes hepatocellular carcinoma progression

Hepatocellular carcinoma is one of the most common malignant tumors.M6A is a novel epigenetic modification that have been emerged as vital regulators for the progression of HCC. However, the regulatory role, clinical significance and the details of the modification, such as the impact on the local tumor environment, remain largely unclear. Our study showed that ALKBH5 was highly expressed in HCC and high ALKBH5 expression predicted a worse prognosis of HCC patients. Prediction of ALKBH5 function by tissue samples and single cell sequencing Gene Set Variation Analysis. Primary CD3 + T lymphocytes and bone marrow-derived macrophages were used to evaluate the effect of ALKBH5 on immune microenvironment. The results indicated that ALKBH5 promote HCC cell proliferation, metastasis and PD-L1+macrophage recruitment. Mechanistically the results showed that ALKBH5 regulates MAP3K8 expression in a m6A dependent manner which mediates the proliferation and metastasis of HCC cells. ALKBH5 also promotes the activation of JNK and ERK pathways through upregulating MAP3K8, thus regulating the expression of IL-8 and promoting macrophage recruitment. Taken together, these data show that ALKBH5 promotes HCC growth, metastasis and macrophage recruitment through ALKBH5/MAP3K8 axis and it may serve as a potential diagnostic marker and target for treatment of HCC patients.     

猪肌肉的转录组学研究进展

猪在中国的畜牧业及人类疾病的研究中有着不可或缺的作用,一方面猪提供了人类日常所需的肉类食物,另一方面在人类的器官移植方面的研究甚为广泛.因此,对于猪的各方面的研究都较为广泛,但在肌肉mRNA转录组方面涉及不深.转录组包括编码RNA和非编码RNA,根据测序结果,通过对不同品种的同位基因进行比较,用来分析相互之间的差异,进...     

kpsE和kpsD双基因缺失显著降低肠道外致病性大肠杆菌的毒力

【目的】探究荚膜对肠道外致病性大肠杆菌致病作用的影响。【方法】选取负责荚膜多糖转运的基因kpsE和kpsD,利用λRed重组系统构建APEC E058和UPEC U17荚膜缺失株E058ΔkpsED和U17ΔkpsED,并通过一系列的体内及体外试验对其生物学特性及致病性进行研究。【结果】双基因缺失株的生长速度较野生株没有明显差异,但缺失株抗血清补体杀菌能力和抗鸡巨噬细胞HD-11细胞吞噬能力显著下降。1日龄雏鸡LD50致病性试验结果显示,缺失株E058ΔkpsED和U17ΔkpsED对鸡失去致病力,而回复株毒力恢复至野生株水平;35日龄SPF鸡体内动态分布和竞争试验显示ΔkpsED缺失株在鸡体内定殖能力和竞争性生长能力显著下降,表明kpsED双基因的缺失能显著降低APEC E058和UPEC U17的致病力。【结论】荚膜与肠道外致病性大肠杆菌的致病性相关,是其重要的毒力因子。     

流行性出血热地鼠肾细胞灭活疫苗人体试用细胞免疫反应观察

观察了20位志愿者在接种试验性流行性出血热(EHF)地鼠肾细胞(GHKC)双价灭活疫苗后的细胞免疫反应,并以其体液免疫反应作对照观察。用淋巴细胞转化试验测定细胞免疫水平。结果首针疫苗接种后42天和56天,特异性刺激指数(SSI)和非特异性刺激指数(NSI)均较免疫前显著增高(P_(SSI)<0.001;P_(NSI)<0.02),免疫后SSI累计阳转率为100％,NSI累计阳转率为60％,免疫后6个月二者均降低至正常水平。免疫后56天测定抗体,荧光抗体阳转率为100％;微量感染性中和试验表明,针对家鼠型病毒L99株中和抗体阳转率为95％,而针对野鼠型病毒JR株阳转率为65％。     

禽病原性大肠杆菌1型菌毛的分离与鉴定

以旋涡混合法使禽病原性大肠杆菌分离株566、1794和TK3菌毛脱落,经硫酸铵沉淀、透析后进行蔗糖密度梯度离心,收集密度为110至115g/cm3的蛋白带,经SDSPAGE测定,3株菌菌毛蛋白的分子量分别在175、170和170kD;提纯菌毛保留了甘露糖敏感性凝集豚鼠红细胞的能力,证明它们为1型菌毛;从1794株提取的1型菌毛免疫BALB/C小鼠产生的高免血清在Western blot中与3个菌株的相应菌毛蛋白均呈阳性反应。上述结果表明,受检的3株禽病原性大肠杆菌均表达了1型菌毛,其分子量在175～170kD之间,3个菌株的1型菌毛间具有较强的抗原相关性。