Prevention of type I diabetes in nonobese diabetic mice by virus infection

The nonobese diabetic (NOD) mouse is an animal model of type I diabetes and develops a characteristic autoimmune lesion in the islets of Langerhans with lymphocytic infiltration and destruction of pancreatic beta cells. The result is hypoinsulinemia, hyperglycemia, ketoacidosis, and death. Diabetes usually begins by the sixth month of age but can occur earlier when young NOD mice are infused with lymphocytes from older NOD donors. When newborn or adult NOD mice were infected with a lymphotropic virus they did not become diabetic. The interaction between viruses and lymphocytes is pivotal in aborting diabetes, as established by experiments in which lymphocytes from virus-infected donors failed to transfer diabetes. In contrast, lymphocytes from age- and sex-matched uninfected donors caused disease. Therefore, viruses and, presumably, their products can be developed to be beneficial and may have potential as a component for treatment of human diseases. Further, these results point to the utility of viruses as probes for dissecting the pathogenesis of a nonviral disease.     

Reversal of diabetes in non-obese diabetic mice without spleen cell-derived beta cell regeneration

Autoimmune destruction of beta cells is the predominant cause of type 1 diabetes mellitus (T1DM) in humans and is modeled in non-obese diabetic (NOD) mice. Many therapeutic interventions prevent the development of T1DM in NOD mice, but few can induce its reversal once established. Intervention with Freund's complete adjuvant, semi-allogeneic splenocytes, and temporary islet transplantation has been reported to cure NOD mice of established T1DM. Using the same approach, we report here that this treatment cured 32% of NOD mice of established diabetes (>340 milligrams per deciliter blood glucose), although beta cells in these mice were not derived from donor splenocytes.     

Effects of cyclosporine immunosuppression in insulin-dependent diabetes mellitus of recent onset

Type I diabetes may be an autoimmune disorder, although the evidence is largely circumstantial. The natural history of the disease after diagnosis includes partial remission in most patients, but only about 3 percent achieve transient insulin independence. beta Cell function, as indicated by the plasma concentration of C-peptide, is lost over 6 to 30 months and islet cell antibodies disappeared over 1 to 2 years. This article describes a pilot study in which 41 patients were treated with the immunosuppressive agent cyclosporine for 2 to 12 months. Of 30 patients treated within 6 weeks of diagnosis, 16 became insulin independent with concentrations of plasma C-peptide in the normal range and decreasing titers of islet cell antibodies. Of 11 patients who entered the study 8 to 44 weeks after diagnosis, two achieved this state. These results indicate that a controlled trial of the effects of cyclosporine in type I diabetes should be conducted.     

Spontaneous mutation rates at five coat-color loci in mice

Examination of 1.5 million mice yielded natural mutation rates estimnated from 5.2 million gene reproductions at five specific coat-color loci. The average rates were 11.1 x 10(-6) for forward mutations and 2.7 x 10(-6) for reverse mutations. Differences between the frequencies of mutations at the individual loci were evident.     

Hemoglobin loci: mice classified for their Hb and Sol alleles

Two loci which influence the structure of the alpha and beta chains of hemoglobin have been identified and are designated Sol and Hb. At least four alleles at Sol and two at Hb have been distinguished among inbred strains.     

Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels

New strategies for prevention and treatment of type 2 diabetes (T2D) require improved insight into disease etiology. We analyzed 386,731 common single-nucleotide polymorphisms (SNPs) in 1464 patients with T2D and 1467 matched controls, each characterized for measures of glucose metabolism, lipids, obesity, and blood pressure. With collaborators (FUSION and WTCCC/UKT2D), we identified and confirmed three loci associated with T2D-in a noncoding region near CDKN2A and CDKN2B, in an intron of IGF2BP2, and an intron of CDKAL1-and replicated associations near HHEX and in SLC30A8 found by a recent whole-genome association study. We identified and confirmed association of a SNP in an intron of glucokinase regulatory protein (GCKR) with serum triglycerides. The discovery of associated variants in unsuspected genes and outside coding regions illustrates the ability of genome-wide association studies to provide potentially important clues to the pathogenesis of common diseases.     

Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes

The molecular mechanisms involved in the development of type 2 diabetes are poorly understood. Starting from genome-wide genotype data for 1924 diabetic cases and 2938 population controls generated by the Wellcome Trust Case Control Consortium, we set out to detect replicated diabetes association signals through analysis of 3757 additional cases and 5346 controls and by integration of our findings with equivalent data from other international consortia. We detected diabetes susceptibility loci in and around the genes CDKAL1, CDKN2A/CDKN2B, and IGF2BP2 and confirmed the recently described associations at HHEX/IDE and SLC30A8. Our findings provide insight into the genetic architecture of type 2 diabetes, emphasizing the contribution of multiple variants of modest effect. The regions identified underscore the importance of pathways influencing pancreatic beta cell development and function in the etiology of type 2 diabetes.     

降糖益肾方干预胰岛素信号通路改善转基因 2型糖尿病1VIKR鼠肾损伤的研究

目的观察降糖益肾方对高脂饮食转基因2型糖尿病MKR鼠血糖、血胰岛素及肾皮质中胰岛素受体、磷脂酞肌醇-3一激酶蛋白表达的影响、方法选取MKR鼠40只经鉴定后,随机分为MKR鼠组、MKR鼠高脂组、降糖益肾方组和糖适贝那组〔MKR鼠组用基础饲料喂养,MKR鼠高脂组、降糖益肾方组和糖适贝那组用高脂饲料喂养,连续喂养8周后,降糖益肾方组给予降糖益肾方,糖适贝那组给予糖适平加贝那普利,同时MKR鼠组和MKR鼠高脂组分别给予蒸馏水灌胃4周〔4周后处死小鼠收集标本,免疫组织化学SABC法检测肾小球中胰岛素受体1(IRS-1),磷脂酞肌醇-3一激}(PI-3K)的蛋白表达〔结果降糖益肾方明显降低高脂饮食MKR鼠肾小球中IRS-1和PI-3 K的蛋白表达水平,与MKR鼠高脂组比较,差异有统计学意义(P<0.01)、结论降糖益肾方改善糖尿病肾病系膜细胞增殖的机制可能与千预胰岛素信号通路有关、     

Segregation of loci for C-type virus induction in strains of mice with high and low incidence of leukemia

Multiple genetic loci for induction of murine leukemia viruses are demonstrated in cells of the high leukemic incidence C58 mouse strain. The biologic properties of viruses at C58 inducibility loci are clearly distinguishable from those of viruses activated from mouse cells containing a locus for virus induction of the low leukemia incidence BALB/c strain. These findings are consistent with the hypothesis that the genes for virus induction in normal mouse embryo cells represent viral structural information.     

Islet regeneration during the reversal of autoimmune diabetes in NOD mice

Nonobese diabetic (NOD) mice are a model for type 1 diabetes in humans. Treatment of NOD mice with end-stage disease by injection of donor splenocytes and complete Freund's adjuvant eliminates autoimmunity and permanently restores normoglycemia. The return of endogenous insulin secretion is accompanied by the reappearance of pancreatic beta cells. We now show that live donor male or labeled splenocytes administered to diabetic NOD females contain cells that rapidly differentiate into islet and ductal epithelial cells within the pancreas. Treatment with irradiated splenocytes is also followed by islet regeneration, but at a slower rate. The islets generated in both instances are persistent, functional, and apparent in all NOD hosts with permanent disease reversal.     

四氧嘧啶与链脲佐菌素诱导小鼠糖尿病模型的效果比较

用相同总剂量的四氧嘧啶1次给药和2次给药及较大剂量链脲佐菌素1次给药3种方法诱导小白鼠糖尿病模型,多次测定血糖,体重等糖尿病相关指标,以确定糖尿病模型建立的最佳方法。结果表明,四氧嘧啶建模率为91．94％,高于链脲佐菌素建模率(66．7％)(P<0．05);四氧嘧啶建模组的死亡率为15％及体重下降率为 18．1％,均高于链脲佐菌素建模组(死亡率3．3％,体重下降率12．0％)(P<0．05);四氧嘧啶连续2次小剂量给药的建模效果优于1次性大剂量给药。两种药物比较,虽然四氧嘧啶的建模率高于链脲佐菌素,但其对建模小鼠的损害亦明显大于链脲佐菌素,建模时连续小剂量给药,并于4．5～5 h后灌胃质量分数50％葡萄糖,可以降低死亡率, 提高建模率。     

UDP-glucose dehydrogenase required for cardiac valve formation in zebrafish

Cardiac valve formation is a complex process that involves cell signaling events between the myocardial and endocardial layers of the heart across an elaborate extracellular matrix. These signals lead to marked morphogenetic movements and transdifferentiation of the endocardial cells at chamber boundaries. Here we identify the genetic defect in zebrafish jekyll mutants, which are deficient in the initiation of heart valve formation. The jekyll mutation disrupts a homolog of Drosophila Sugarless, a uridine 5'-diphosphate (UDP)-glucose dehydrogenase required for heparan sulfate, chondroitin sulfate, and hyaluronic acid production. The atrioventricular border cells do not differentiate from their neighbors in jekyll mutants, suggesting that Jekyll is required in a cell signaling event that establishes a boundary between the atrium and ventricle.     

固始白鹅体尺性状微卫星DNA标记的筛选

【目的】筛选固始白鹅体尺性状的微卫星DNA标记。【方法】测定固始白鹅的体尺性状。选用11对微卫星引物(WD136、WD206、G06、G07、CKW21、CKW23、TTUCG5、TTUCG4、TTUCG2、Aalu1、TTUCG1),对固始白鹅进行遗传检测,计算各微卫星位点的等位基因频率、多态信息含量、杂合度和有效等位基因数。利用最小二乘法拟合线性模型,探索11个微卫星位点与固始白鹅体尺性状的关系。【结果】11个微卫星位点中的8个位点(WD136、WD206、G07、TTUCG4、CKW21、TTUCG2、TTUCG1和TTUCG5)在固始白鹅上有较好的多态性,其平均等位基因数为4.25(3~6)、平均杂合度为0.598(0.273~0.695)、平均多态信息含量为0.635(0.530~0.769)、平均有效等位基因数为3.345(2.383~4.984)。通过最小二乘分析,检测到WD136、WD206、CKW21、TTUCG1等4个位点与9项体尺性状间存在显著相关性。【结论】WD136位点有望作为体质量、体斜长、骨盆宽的早期选择辅助标记;WD206位点有望作为体质量、胸宽、龙骨长、骨盆宽、胫长、半潜水长和颈长的早期选择辅助标记;CKW21位点有望作为体质量、龙骨长、胫长、半潜水长、颈长的早期选择辅助标记;TTUCG1位点有望作为体质量、体斜长、胫长、龙骨长的早期选择辅助标记。     

苦荞叶黄酮对糖尿病小鼠的肝肾保护效果及机制

[目的]探讨苦荞叶黄酮(Fagopyrum tataricum leaf flavone,FLF)对糖尿病小鼠肝和肾的保护效果及机制。[方法]通过高脂饮食联合链脲佐菌素制备糖尿病(Diabetes mellitus,DM)小鼠模型,设立模型对照组(Model)、盐酸二甲双胍(Metformin Hydrochloride,Met/150 mg·kg~(-1)bw)治疗组和3个FLF干预组(200、150、100/mg·kg~(-1)bw),另设正常对照组(Normal)。各组饲喂标准饲料,每日灌胃对应受试物或生理盐水(N,M),连续4周后,测定肝、肾器官指数和组织抗氧化活性并观察组织形态学变化。[结果]FLF可显著抑制DM小鼠的体重下降并显著降低肝、肾器官指数,显著提高DM小鼠的肝、肾组织的T-SOD和GSH-PX含量,显著降低MDA含量,且剂量越大,效果越明显;组织形态学观察结果表明,FLF呈剂量依赖性地改善受损肝、肾组织的炎症、出血、水肿和坏死情况。[结论]FLF通过增加肝肾组织的抗氧化活性,减少氧化应激损伤,消除炎症和组织坏死来修复DM小鼠受损肝脏和肾脏的组织结构,恢复其生理功能,且具有量效关系。     

奶牛隐性乳房炎三种致病菌的多重PCR检测方法的建立

为建立快速并能同时检测无乳链球菌、金黄色葡萄球菌、绿脓杆菌3种奶牛隐性乳房炎致病菌的方法,根据无乳链球菌16S rRNA基因、金黄色葡萄球菌NUC耐热基因、绿脓杆菌ETA基因序列并参考文献各合成一对特异性引物,通过对PCR反应各项参数的调整优化,建立多重PCR检测体系,并同时进行灵敏性试验和特异性试验。结果显示:该检测方法可以同时扩增出无乳链球菌270 bp、金黄色葡萄球菌153 bp和绿脓杆菌375 bp的特异性片段以及细菌16S rRNA 1 500 bp的通用片段,而对于其他的6种病原菌只能扩增出1 500 bp的通用片段,具有较强的特异性。三种特异性引物扩增条带与GenBank上的细菌基因序列同源性为99%。增菌培养24 h,该体系对无乳链球菌、金黄色葡萄球菌、绿脓杆菌的最低灵敏度分别为8×10⁴、4×10⁴、1.5×10⁵ CFU·mL^-1。本研究建立的检测方法能够完成无乳链球菌、金黄色葡萄球菌、绿脓杆菌的快速检测,对于生产上奶牛隐性乳房炎的鉴别诊断和快速检测具有重大意义。