Abstract: The synthesis of (2 S ,3 S ,4 S )-4-[1-(4-azidobenzamidomethyl)ethenyl]-2-carboxy-3-pyrrolidineacetic acid (ABCPA) is described. This novel kainic acid analogue, bearing a photolabile functionality on the isopropenyl side chain, was proven to be a good inhibitor of [3H]CNQX and [3H]kainic acid binding on chick cerebellar membranes. [3H]ABCPA was photoaffinity cross-linked on the membrane fraction of chick cerebellum. Electrophoretic analysis with sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed two major radioactive bands with apparent molecular masses of 45 and 33.5 kDa. [3H]ABCPA incorporation in both bands was completely blocked by 2 m M CNQX. When photoaffinity labeling was performed in the presence of 2 m M kainic acid, incorporation of [3H]ABCPA was blocked by ∼70% in the 45-kDa band and by 18% in the 33.5-kDa band. Incorporation of radioactivity in both bands was blocked by ∼30% with 10 m M glutamate. 相似文献
Fractures have largely been assessed by their impact on quality of life or health care costs. We conducted this study to evaluate the relation between fractures and mortality.
Methods
A total of 7753 randomly selected people (2187 men and 5566 women) aged 50 years and older from across Canada participated in a 5-year observational cohort study. Incident fractures were identified on the basis of validated self-report and were classified by type (vertebral, pelvic, forearm or wrist, rib, hip and “other”). We subdivided fracture groups by the year in which the fracture occurred during follow-up; those occurring in the fourth and fifth years were grouped together. We examined the relation between the time of the incident fracture and death.
Results
Compared with participants who had no fracture during follow-up, those who had a vertebral fracture in the second year were at increased risk of death (adjusted hazard ratio [HR] 2.7, 95% confidence interval [CI] 1.1–6.6); also at risk were those who had a hip fracture during the first year (adjusted HR 3.2, 95% CI 1.4–7.4). Among women, the risk of death was increased for those with a vertebral fracture during the first year (adjusted HR 3.7, 95% CI 1.1–12.8) or the second year of follow-up (adjusted HR 3.2, 95% CI 1.2–8.1). The risk of death was also increased among women with hip fracture during the first year of follow-up (adjusted HR 3.0, 95% CI 1.0–8.7).
Interpretation
Vertebral and hip fractures are associated with an increased risk of death. Interventions that reduce the incidence of these fractures need to be implemented to improve survival.Osteoporosis-related fractures are a major health concern, affecting a growing number of individuals worldwide. The burden of fracture has largely been assessed by the impact on health-related quality of life and health care costs.1,2 Fractures can also be associated with death. However, trials that have examined the relation between fractures and mortality have had limitations that may influence their results and the generalizability of the studies, including small samples,3,4 the examination of only 1 type of fracture,4–10 the inclusion of only women,8,11 the enrolment of participants from specific areas (i.e., hospitals or certain geographic regions),3,4,7,8,10,12 the nonrandom selection of participants3–11 and the lack of statistical adjustment for confounding factors that may influence mortality.3,5–7,12We evaluated the relation between incident fractures and mortality over a 5-year period in a cohort of men and women 50 years of age and older. In addition, we examined whether other characteristics of participants were risk factors for death. 相似文献
Adipose tissue–derived mesenchymal stromal cells (AT-MSCs), widely known as multipotent progenitors, release several cytokines that support cell survival and repair. There are in vitro and in vivo studies reporting the regenerative role of AT-MSCs possibly mediated by their protective effects on functional islet cells as well as their capacity to differentiate into insulin-producing cells (IPCs).
Methods
On such a basis, our goal in the present study was to use three different models including direct and indirect co-cultures and islet-derived conditioned medium (CM) to differentiate AT-MSCs into IPCs and to illuminate the molecular mechanisms of the beneficial impact of AT-MSCs on pancreatic islet functionality. Furthermore, we combined in vitro co-culture of islets and AT-MSCs with in vivo assessment of islet graft function to assess whether co-transplantation of islets with AT-MSCs can reduce marginal mass required for successful islet transplantation and prolong graft function in a diabetic rat model.
Results
Our findings demonstrated that AT-MSCs are suitable for creating a microenvironment favorable for the repair and longevity of the pancreas β cells through the improvement of islet survival and maintenance of cell morphology and insulin secretion due to their potent properties in differentiation. Most importantly, hybrid transplantation of islets with AT-MSCs significantly promoted survival, engraftment and insulin-producing function of the graft and reduced the islet mass required for reversal of diabetes.
Conclusions
This strategy might be of therapeutic potential solving the problem of donor islet material loss that currently limits the application of allogeneic islet transplantation as a more widespread therapy for type 1 diabetes. 相似文献
目的:探讨钙离子拮抗剂拉西地平对高温高湿应激大鼠血管平滑肌细胞内内质网应激相关因子葡萄糖调节蛋白78(glucose-regulated protein of 78kD,GRP78)和C/EBP环磷酸腺苷反应元件结合转录因子同源蛋白(CAAT/enhancer binding protein homologous protein,CHOP)表达的影响。方法:将60只雄性SD大鼠随机分为对照组、高温高湿组、拉西地平组,每组20只。按实验时间(2w、4w、6w、8w)的不同,各组又分为4个亚组,每个亚组5只大鼠。用颈动脉插管法测定各组大鼠的平均动脉压(MAP);用免疫组织化学法检测GRP78和CHOP的表达水平。结果:①高温高湿各组的MAP随着实验时间的延长呈逐渐递增的趋势,高温高湿4w、6w、8w亚组的MAP均显著高于相应的对照组和拉西地平组(P<0.05)。②随着实验时间的延长,高温高湿组GRP78表达量不断增加,6w达到最大值,8w表达减弱。高温高湿4w、6w、8w亚组GRP78表达量均高于相应对照组和拉西地平组,有显著性差异(P<0.05)。③高温高湿组2w、4w、6w、8w亚组CHOP表达量组间比较有显著性差异(P<0.05),8w亚组表达达到最高值;高温高湿组6w、8w亚组与相应对照组和拉西地平组比较有显著性差异(P<0.05)。结论:高温高湿应激可引起血管平滑肌细胞内质网应激反应,导致GRP78表达及CHOP表达的不对称增加,提示高温高湿应激可引起血管平滑肌细胞的损害;拉西地平可以减轻内质网应激,逆转高温高湿应激所致的血管平滑肌细胞的损伤作用,对血管平滑肌细胞有保护作用。 相似文献
The Balkan chamois (Rupicapra rupicapra balcanica) is widespread on the Balkan Peninsula, along mountain massifs from Croatia in the north to Greece in the south and Bulgaria in the east. Knowledge on the genetic structure of Balkan chamois populations is limited and restricted to local studies. Therefore, the main objective of this study was to use nuclear (16 microsatellites) and mitochondrial (partial 376 base pairs control region) markers to investigate the genetic structure of this chamois subspecies throughout its distribution range and to obtain information on the degree of connectivity of the different (sub)populations. We extracted DNA from bone, dried skin and muscle tissue and successfully genotyped 92 individuals of Balkan chamois and sequenced the partial control region in 44 individuals. The Bayesian analysis suggested 3 genetic clusters and assigned individuals from Serbia and Bulgaria to two separate clusters, while individuals from the other countries belonged to the same cluster. Thirty new haplotypes were obtained from partial mitochondrial DNA sequences, with private haplotypes in all analyzed populations and only two haplotypes shared among populations, indicating the possibility of past translocations. The subspecies genetic composition presented here provides the necessary starting point to assess the conservation status of the Balkan chamois and allows the development of conservation strategies necessary for its sustainable management and conservation.