Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis

Human osteoarthritis is a progressive disease of the joints characterized by degradation of articular cartilage. Although disease initiation may be multifactorial, the cartilage destruction appears to be a result of uncontrolled proteolytic extracellular matrix destruction. A major component of the cartilage extracellular matrix is aggrecan, a proteoglycan that imparts compressive resistance to the tissue. Aggrecan is cleaved at a specific 'aggrecanase' site in human osteoarthritic cartilage; this cleavage can be performed by several members of ADAMTS family of metalloproteases. The relative contribution of individual ADAMTS proteases to cartilage destruction during osteoarthritis has not been resolved. Here we describe experiments with a genetically modified mouse in which the catalytic domain of ADAMTS5 (aggrecanase-2) was deleted. After surgically induced joint instability, there was significant reduction in the severity of cartilage destruction in the ADAMTS5 knockout mice compared with wild-type mice. This is the first report of a single gene deletion capable of abrogating the course of cartilage destruction in an animal model of osteoarthritis. These results demonstrate that ADAMTS5 is the primary 'aggrecanase' responsible for aggrecan degradation in a murine model of osteoarthritis, and suggest rational strategies for therapeutic intervention in osteoarthritis.     

Chromatin fluorescence by pyronin staining

Summary Human, chicken and mouse cells from different tissues show a bright red-orange fluorescence of the chromatin after staining with pyronin Y. The possibility that intercalation of the dye into double helical nucleic acids accounts for this fluorescence pattern is briefly discussed.This work was partially supported by a grant from the Comisión Asesora de Investigación Científica y Técnica, Spain.     

Severe weather event attribution: Why values won't go away

We start by reviewing the complicated situation in methods of scientific attribution of climate change to extreme weather events. We emphasize the social values involved in using both so-called ″storyline″ and ordinary probabilistic or ″risk-based″ methods, noting that one important virtue claimed by the storyline approach is that it features a reduction in false negative results, which has much social and ethical merit, according to its advocates. This merit is critiqued by the probabilistic, risk-based, opponents, who claim the high ground; the usual probabilistic approach is claimed to be more objective and more ″scientific″, under the grounds that it reduces false positive error. We examine this mostly-implicit debate about error, which apparently mirrors the old Jeffrey-Rudner debate. We also argue that there is an overlooked component to the role of values in science: that of second-order inductive risk, and that it makes the relative role of values in the two methods different from what it first appears to be. In fact, neither method helps us to escape social values, and be more scientifically ″objective″ in the sense of being removed or detached from human values and interests. The probabilistic approach does not succeed in doing so, contrary to the claims of its proponents. This is important to understand, because neither method is, fundamentally, a successful strategy for climate scientists to avoid making value judgments.     

The role of ‘complex’ empiricism in the debates about satellite data and climate models

Climate scientists have been engaged in a decades-long debate over the standing of satellite measurements of the temperature trends of the atmosphere above the surface of the earth. This is especially significant because skeptics of global warming and the greenhouse effect have utilized this debate to spread doubt about global climate models used to predict future states of climate. I use this case from an understudied science to illustrate two distinct philosophical approaches to the relations among data, scientist, measurement, models, and theory. I argue that distinguishing between ‘direct’ empiricist and ‘complex’ empiricist approaches helps us understand and analyze this important scientific episode. I also introduce a complex empiricist account of testing and evaluation, and contrast it with the basic Hypothetico-Deductive approach to the climate models used by the direct empiricists. This more developed complex empiricist approach will serve philosophy of science well, as computational models become more widespread in the sciences.     

5-羟色胺在F344大鼠下丘脑释放及其免疫调节作用

在F344雄性大鼠腹腔注射血蓝蛋白(KLH),研究T 细胞依赖抗原初始免疫反应对中枢神经系统5 羟色胺(5 HT)代谢的影响。当免疫刺激大鼠4天后,其下丘脑匀浆5 羟色胺水平出现降低,同时应用在体脑微透析技术研究发现清醒大鼠腹腔注射血蓝蛋白4天后,其下丘脑前叶细胞外液的5 羟色胺水平增加。为了评价在免疫反应中大鼠下丘脑5 羟色胺释放效应,本文应用氯苯丙胺(PCA)选择性预先耗竭5 羟色胺释放,并测定这些动物在注射血蓝蛋白后抗体产生情况。结果显示在应用氯苯丙胺预处理的血蓝蛋白免疫动物特异抗体IgM和IgG与未用氯苯丙胺预处理的动物比较均有明显增加(P<0.01)。上述资料表明,对于T 细胞依赖抗原,其初始抗体产生的量是由位于下丘脑5 羟色胺神经终端抑制性递质释放所调节。