Enhancing protein C interaction with thrombin results in a clot-activated anticoagulant.

Human protein C is a vitamin K-dependent plasma glycoprotein that circulates as an inactive zymogen. At the endothelial cell surface, thrombin in complex with the integral membrane protein thrombomodulin converts protein C to its active form by specific cleavage of an activation peptide. The activated form of protein C has potent anticoagulant activity as a feedback regulator of thrombin generation (reviewed in refs 4-6), and also has profibrinolytic, anti-ischaemic and anti-inflammatory properties. Protein C is effective in the treatment of model and human thrombotic diseases but, except when it has been used to treat genetic or acquired deficiencies and microvascular thrombosis, it is administered as the activated enzyme, which has a short biological half-life. We have altered two putative inhibitory acidic residues near the thrombin cleavage site, which results in a 30-fold increase in substrate utilization by alpha-thrombin. We combined these changes with a genetically altered glycoform to generate a zymogen protein C with a 60-fold increased cleavage rate by free alpha-thrombin, independent of its cofactor thrombomodulin. We show that this 'proform' of protein C, unlike the natural circulating zymogen, can be activated by thrombin generated in clotting human plasma, resulting in an inhibition of further clot formation. Our data therefore show that we have engineered a site-activated agent, which only has anticoagulant activity when significant amounts of thrombin are being generated.     

The Left Vienna Circle, Part 1. Carnap, Neurath, and the Left Vienna Circle thesis

Recent scholarship resuscitates the history and philosophy of a ‘left wing’ in the Vienna Circle, offering a counterhistory to the conventional image of analytic philosophy as politically conformist. This paper disputes the historical claim that early logical empiricists developed a political philosophy of science. Though some individuals in the Vienna Circle, including Rudolf Carnap and Otto Neurath, believed strongly in the importance of science to social progress, they did not construct a political philosophy of science. Both Carnap and Neurath were committed to forms of political neutralism that run strongly against a political reading of their logical empiricism. In addition, Carnap and Neurath sharply differ on precisely the subject of the place of politics in logical empiricism, throwing into question the construct of the ‘Left Vienna Circle’ as a coherent, sociohistorical, programmatic unit within the Vienna Circle.     

The geometry of knowledge: Lewis, Becker, Carnap and the formalization of philosophy in the 1920s

On an ordinary view of the relation of philosophy of science to science, science serves only as a topic for philosophical reflection, reflection that proceeds by its own methods and according to its own standards. This ordinary view suggests a way of writing a global history of philosophy of science that finds substantially the same philosophical projects being pursued across widely divergent scientific eras. While not denying that this view is of some use regarding certain themes of and particular time periods, this essay argues that much of the epistemology and philosophy of science in the early twentieth century in a variety of projects (neo-Kantianism, logical empiricism, pragmatism, phenomenology) looked to the then current context of the exact sciences, especially geometry and physics, not merely for its topics but also for its conceptual resources and technical tools. This suggests a more variable project of philosophy of science, a deeper connection between early twentieth-century philosophy of science and its contemporary science, and a more interesting and richer history of philosophy of science than is ordinarily offered.     

A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC

The proteins encoded by the classical HLA class I and class II genes in the major histocompatibility complex (MHC) are highly polymorphic and are essential in self versus non-self immune recognition. HLA variation is a crucial determinant of transplant rejection and susceptibility to a large number of infectious and autoimmune diseases. Yet identification of causal variants is problematic owing to linkage disequilibrium that extends across multiple HLA and non-HLA genes in the MHC. We therefore set out to characterize the linkage disequilibrium patterns between the highly polymorphic HLA genes and background variation by typing the classical HLA genes and >7,500 common SNPs and deletion-insertion polymorphisms across four population samples. The analysis provides informative tag SNPs that capture much of the common variation in the MHC region and that could be used in disease association studies, and it provides new insight into the evolutionary dynamics and ancestral origins of the HLA loci and their haplotypes.     

Simulating the European economies under alternative monetary policy assumptions

This paper examines the implications of alternative monetary policy rules for economic stabilization within Europe, using the OECD world model, INTERLINK. The results suggest that policy linkage through the Exchange Rate Mechanism will have differing effects on the effectiveness of stabilization policies depending on the nature of economic shocks. For demand shocks, the choice of monetary rule in the country of the ‘anchor’ currency is of more consequence than the flexibility of exchange rates. For supply shocks, exchange rate rigidity is likely to have more problematic effects on economic adjustment. Spillover effects are also important when the shock is felt primarily by the ‘anchor’ economy.     

Neural crest origins of the neck and shoulder

The neck and shoulder region of vertebrates has undergone a complex evolutionary history. To identify its underlying mechanisms we map the destinations of embryonic neural crest and mesodermal stem cells using Cre-recombinase-mediated transgenesis. The single-cell resolution of this genetic labelling reveals cryptic cell boundaries traversing the seemingly homogeneous skeleton of the neck and shoulders. Within this assembly of bones and muscles we discern a precise code of connectivity that mesenchymal stem cells of both neural crest and mesodermal origin obey as they form muscle scaffolds. The neural crest anchors the head onto the anterior lining of the shoulder girdle, while a Hox-gene-controlled mesoderm links trunk muscles to the posterior neck and shoulder skeleton. The skeleton that we identify as neural crest-derived is specifically affected in human Klippel-Feil syndrome, Sprengel's deformity and Arnold-Chiari I/II malformation, providing insights into their likely aetiology. We identify genes involved in the cellular modularity of the neck and shoulder skeleton and propose a new method for determining skeletal homologies that is based on muscle attachments. This has allowed us to trace the whereabouts of the cleithrum, the major shoulder bone of extinct land vertebrate ancestors, which seems to survive as the scapular spine in living mammals.