Serpins in thrombosis, hemostasis and fibrinolysis.

Hemostasis and fibrinolysis, the biological processes that maintain proper blood flow, are the consequence of a complex series of cascading enzymatic reactions. Serine proteases involved in these processes are regulated by feedback loops, local cofactor molecules, and serine protease inhibitors (serpins). The delicate balance between proteolytic and inhibitory reactions in hemostasis and fibrinolysis, described by the coagulation, protein C and fibrinolytic pathways, can be disrupted, resulting in the pathological conditions of thrombosis or abnormal bleeding. Medicine capitalizes on the importance of serpins, using therapeutics to manipulate the serpin-protease reactions for the treatment and prevention of thrombosis and hemorrhage. Therefore, investigation of serpins, their cofactors, and their structure-function relationships is imperative for the development of state-of-the-art pharmaceuticals for the selective fine-tuning of hemostasis and fibrinolysis. This review describes key serpins important in the regulation of these pathways: antithrombin, heparin cofactor II, protein Z-dependent protease inhibitor, alpha(1)-protease inhibitor, protein C inhibitor, alpha(2)-antiplasmin and plasminogen activator inhibitor-1. We focus on the biological function, the important structural elements, their known non-hemostatic roles, the pathologies related to deficiencies or dysfunction, and the therapeutic roles of specific serpins.

Resistance to change as a function of concurrent reinforcer magnitude.

Six pigeons responded on two keys in each of three signalled multiple-schedule components, and resistance to disruption of responding on one (target) key by extinction and by response-independent food presented during inter-component blackouts was studied. Alternative reinforcement of different magnitudes was contingent on pecking a non-target key in two components, and in the third only the target response was reinforced. Resistance to change varied with the overall quantity of reinforcement in the component, regardless of whether reinforcers were contingent on the target or non-target response, but did not differ across the two key locations. These results using different magnitudes of reinforcement confirm previous findings using rate of reinforcement as the variable, and suggest that resistance to change is dependent on stimulus-reinforcer rather than response-reinforcer contingencies.