Genomic momentum for hemostasis and thrombosis

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151255/1/jth14582.pd

COVID‐19: 2020 a year in turmoil

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154960/1/jth14816.pd

Simplify, simplify

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149226/1/jth14436.pd

Fifty years new

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147037/1/jth14351.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147037/2/jth14351_am.pd

2020 – Year of COVID‐19

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156451/2/jth15041_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156451/1/jth15041.pd

A virtual ISTH Congress

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/156005/1/jth14883.pd

Polyphosphate in thrombosis, hemostasis, and inflammation

This illustrated review focuses on polyphosphate as a potent modulator of the plasma clotting cascade, with possible roles in hemostasis, thrombosis, and inflammation. Polyphosphates are highly anionic, linear polymers of inorganic phosphates that are widespread throughout biology. Infectious microorganisms accumulate polyphosphates with widely varying polymer lengths (from a few phosphates to over a thousand phosphates long), while activated human platelets secrete polyphosphate with a very narrow size distribution (about 60‐100 phosphates long). Work from our lab and others has shown that long‐chain polyphosphate is a potent trigger of clotting via the contact pathway, while polyphosphate of the size secreted by platelets accelerates factor V activation, blocks the anticoagulant activity of tissue factor pathway inhibitor, promotes factor XI activation by thrombin, and makes fibrin fibrils thicker and more resistant to fibrinolysis. Polyphosphate also modulates inflammation by triggering bradykinin release, inhibiting the complement system, and modulating endothelial function. Polyphosphate and nucleic acids have similar physical properties and both will trigger the contact pathway—although polyphosphate is orders of magnitude more procoagulant than either DNA or RNA. Important caveats in these studies include observations that nucleic acids and polyphosphate may co‐purify, and that these preparations can be contaminated with highly procoagulant microparticles if silica‐based purification methods are employed. Polyphosphate has received attention as a possible therapeutic, with some recent studies exploring the use of polyphosphate in a variety of formulations to control bleeding. Other studies are investigating treatments that block polyphosphate function as novel antithrombotics with the possibility of reduced bleeding side effects.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147856/1/rth212162_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147856/2/rth212162.pd

Platelet polyphosphate induces fibroblast chemotaxis and myofibroblast differentiation

BackgroundPlatelets secrete many pro‐wound healing molecules such as growth factors and cytokines. We found that releasates from activated human platelets induced the differentiation of cultured murine and human fibroblasts into a myofibroblast phenotype. Surprisingly, most of this differentiation‐inducing activity was heat‐stable, suggesting it was not due to the protein component of the releasates. Inorganic polyphosphate is a major constituent of platelet‐dense granules and promotes blood coagulation and inflammation.ObjectivesWe aim to investigate the contribution of polyphosphate on myofibroblast differentiating activity of platelet releasates.MethodsUsing NIH‐3T3 cells and primary human fibroblasts, we examined the effect of human platelet releasates and chemically synthesized polyphosphate on fibroblast differentiation and migration.ResultsWe found that the myofibroblast‐inducing activity of platelet releasates was severely attenuated after incubation with a polyphosphate‐degrading enzyme, and that fibroblasts responded to platelet‐sized polyphosphate by increased levels of α‐smooth muscle actin, stress fibers, and collagen. Furthermore, fibroblasts were chemotactic toward polyphosphate.ConclusionsThese findings indicate that platelet‐derived polyphosphate acts as a cell signaling molecule by inducing murine and human fibroblasts to differentiate into myofibroblasts, a cell type known to drive both wound healing and fibrosing diseases. Polyphosphate therefore not only promotes early wound responses through enhancing fibrin clot formation, but also may play roles in the later stages of wound healing, and, potentially, progression of fibrotic diseases, by recruiting fibroblasts and inducing their differentiation into myofibroblasts.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163376/2/jth15066_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163376/1/jth15066.pd

Holomorphic selection rules, the origin of the mu term, and thermal inflation

When an abelian gauge theory with integer charges is spontaneously broken by the expectation value of a charge Q field, there remains a Z_Q discrete symmetry. In a supersymmetric theory, holomorphy adds additional constraints on the operators that can appear in the effective superpotential. As a result, operators with the same mass dimension but opposite sign charges can have very different coupling strengths. In the present work we characterize the operator hierarchies in the effective theory due to holomorphy, and show that there exist simple relationships between the size of an operator and its mass dimension and charge. Using such holomorphy-induced operator hierarchies, we construct a simple model with a naturally small supersymmetric mu term. This model also provides a concrete realization of late-time thermal inflation, which has the ability to solve the gravitino and moduli problems of weak-scale supersymmetry.Comment: 18 pages, 1 figur