CD39, or vascular adenosine triphosphate diphosphohydrolase, has been considered an important inhibitor of platelet activation. Unexpectedly, cd39-deficient mice had prolonged bleeding times with minimally perturbed coagulation parameters. Platelet interactions with injured mesenteric vasculature were considerably reduced in vivo and purified mutant platelets failed to aggregate to standard agonists in vitro. This platelet hypofunction was reversible and associated with purinergic type P2Y1 receptor desensitization. In keeping with deficient vascular protective mechanisms, fibrin deposition was found at multiple organ sites in cd39-deficient mice and in transplanted cardiac grafts. Our data indicate a dual role for adenosine triphosphate diphosphohydrolase in modulating hemostasis and thrombotic reactions.

The circulating blood platelet is produced by the bone marrow megkarocyte. In response to a decrease in the platelet count, megryocytes increase in number and ploidy. Although this feedback loop has long been thought to be medlated by a circulating hematopoletic factor, no such factor has been purified. Using a model ofthrombocytopenia in sheep, we have identified an active substance called megapoetin, which simulated an increase in the number and ploldy of meg-karyocytes in bone marrow culture. Circulating levels of this factor could be quantified with this assay and were found to be Inversely proportional to the platelet count of the sheep. Megakaryocytes are unusual bone marrow cells, which are responsible for producing circulating blood platelets. Although comprising <0.25% of the bone marrow cells in most species, they have >10 times the volume of typical marrow cells (1, 2). In addition, megakaryocytes undergo a process known as endomitosis whereby they replicate their nuclei but fail to undergo cell division and thereby give rise to polyploid cells. In response to a decreased platelet count, the endomitotic rate increases (3, 4), higher ploidy megakaryocytes are formed, and the number of megakaryocytes may increase up to 3-fold (1). In contrast, in response to an elevated platelet count, the endomitotic rate decreases (3, 4), lower ploidy megakaryocytes are formed, and the number of megakaryocytes may decrease by 50%o (1).The physiological feedback mechanism by which the mass of circulating platelets regulates the endomitotic rate and number of bone marrow megakaryocytes is not known. A circulating thrombopoietic factor has long been assumed to be involved but to date no such factor has been purified. Moreover, none of the recombinant cytokines with thrombopoietic activity, such as interleukin 6 (5), is known to be involved in mediating this physiological feedback loop.To characterize this putative thrombopoietic factor, we have analyzed the physiological relationship between the bone marrow megakaryocytes and the circulating platelets. We have found that the magnitude of the changes in the number and ploidy of megakaryocytes was inversely and proportionally related to the circulating platelet mass (3) and that megakaryocyte number and ploidy were therefore markers of this feedback loop in vivo. We next developed a bone marrow assay in which increases in the number and ploidy of megakaryocytes in vitro (6) were used to identify an active substance in thrombocytopenic plasma that we have named megapoietin (3,7). Levels of megapoietin could be quantified with this assay and were inversely proportional to the platelet mass (3, 7). Once elevated in thrombocytopenic animals, the megapoietin level could be reduced to normal by transfusion of platelets (3).These results suggested that megapoietin was an ideal candidate to be the thrombopoietic factor mediating the feedback loop between the circulating platelets and the bone marrow megakaryocytes. We now report the development of a sheep model of thromboc...

Primates are highly attuned not just to social characteristics of individual agents, but also to social interactions between multiple agents. Here we report a neural correlate of the representation of social interactions in the human brain. Specifically, we observe a strong univariate response in the posterior superior temporal sulcus (pSTS) to stimuli depicting social interactions between two agents, compared with (i) pairs of agents not interacting with each other, (ii) physical interactions between inanimate objects, and (iii) individual animate agents pursuing goals and interacting with inanimate objects. We further show that this region contains information about the nature of the social interaction—specifically, whether one agent is helping or hindering the other. This sensitivity to social interactions is strongest in a specific subregion of the pSTS but extends to a lesser extent into nearby regions previously implicated in theory of mind and dynamic face perception. This sensitivity to the presence and nature of social interactions is not easily explainable in terms of low-level visual features, attention, or the animacy, actions, or goals of individual agents. This region may underlie our ability to understand the structure of our social world and navigate within it.

The activity of the coagulation system is regulated, in part, by the interaction of thrombin with the endothelial cell receptor thrombomodulin with subsequent generation of activated protein C and suppression of thrombin production. Our previous investigation demonstrated that ablation of the thrombomodulin gene in mice causes embryonic lethality before the assembly of a functional cardiovascular system, indicating a critical role for the receptor in early development. In the current study, we show that a single amino acid substitution in thrombomodulin dissociates the developmental function of the receptor from its role as a regulator of blood coagulation. Homozygous mutant mice with severely reduced capacity to generate activated protein C or inhibit thrombin develop to term, and possess normal reproductive performance. The above animals exhibit increased fibrin deposition in selected organs, which implies tissue specific regulation of the coagulation system that is supported by further evidence from the examination of mice with defects in fibrinolysis. The thrombomodulin-deficient animals provide a murine model to examine known or identify unknown genetic and environmental factors that lead to the development of thrombosis.