Regulation Of Plasma Von Willebrand Factor (Vwf) By Modifier Genes

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106136/1/jth01723.pd

Batalin-Vilkovisky Integrals in Finite Dimensions

The Batalin-Vilkovisky method (BV) is the most powerful method to analyze functional integrals with (infinite-dimensional) gauge symmetries presently known. It has been invented to fix gauges associated with symmetries that do not close off-shell. Homological Perturbation Theory is introduced and used to develop the integration theory behind BV and to describe the BV quantization of a Lagrangian system with symmetries. Localization (illustrated in terms of Duistermaat-Heckman localization) as well as anomalous symmetries are discussed in the framework of BV.Comment: 35 page

Analysis of factor V in zebrafish demonstrates minimal levels needed for early hemostasis

In humans, coagulation factor V (FV) deficiency is a rare, clinically heterogeneous bleeding disorder, suggesting that genetic modifiers may contribute to disease expressivity. Zebrafish possess many distinct advantages including high fecundity, optical clarity, external development, and homology with the mammalian hemostatic system, features that make it ideal for genetic studies. Our aim was to study the role of FV in zebrafish through targeted mutagenesis and apply the model to the study of human F5 variants. CRISPR-mediated genome editing of the zebrafish f5 locus was performed, generating mutants homozygous for a 49 base pair deletion in exon 4. Thrombus formation secondary to vascular endothelial injury was absent in f52/2 mutant embryos and larvae. Despite this severe hemostatic defect, homozygous mutants survived before succumbing to severe hemorrhage in adulthood. Human F5 variants of uncertain significance from patients with FV deficiency were evaluated, and the causative mutations identified and stratified by their ability to restore thrombus formation in larvae. Analysis of these novel mutations demonstrates variable residual FV function, with minimal activity being required to restore hemostasis in response to laser-induced endothelial injury. This in vivo evaluation may be beneficial for patients whose factor activity levels lack correlation with bleeding symptomatology, although limitations exist. Furthermore, homozygous mutant embryos tolerate what is a severe and lethal defect in mammals, suggesting the possibility of species-specific factors enabling survival, and allowing further study not possible in the mouse. Identification of these factors or other genetic modifiers could lead to novel therapeutic modalities

Subobject Transactional Memory

International audienceConcurrent object-oriented programs are hard to write because of the frequent use of state in objects. In a concurrent program, this state must be protected against race-conditions and deadlocks, which costs a lot of effort and is error-prone. Software transactional memory is a mechanism for concurrency control that is similar to mechanisms used in databases. The programmer does not deal with low-level locks, but instead uses transaction demarcation to protect shared memory.We show that in a statically typed subobject-oriented programming language, a transactional program requires less effort than writing a regular object-oriented programming. In addition, we show how transactionality can be added to existing classes without performing code transformations or using a meta-object protocol

Genome editing of factor X in zebrafish reveals unexpected tolerance of severe defects in the common pathway

Deficiency of factor X (F10) in humans is a rare bleeding disorder with a heterogeneous phenotype and limited therapeutic options. Targeted disruption of F10 and other common pathway factors in mice results in embryonic/neonatal lethality with rapid resorption of homozygous mutants, hampering additional studies. Several of these mutants also display yolk sac vascular defects, suggesting a role for thrombin signaling in vessel development. The zebrafish is a vertebrate model that demonstrates conservation of the mammalian hemostatic and vascular systems. We have leveraged these advantages for in-depth study of the role of the coagulation cascade in the developmental regulation of hemostasis and vasculogenesis. In this article, we show that ablation of zebrafish f10 by using genome editing with transcription activator-like effector nucleases results in a major embryonic hemostatic defect. However, widespread hemorrhage and subsequent lethality does not occur until later stages, with absence of any detectable defect in vascular development. We also use f102/2zebrafish to confirm 5 novel human F10 variants as causative mutations in affected patients, providing a rapid and reliable in vivo model for testing the severity of F10 variants. These findings as well as the prolonged survival of f102/2mutants will enable us to expand our understanding of the molecular mechanisms of hemostasis, including a platform for screening variants of uncertain significance in patients with F10 deficiency and other coagulation disorders. Further study as to how fish tolerate what is an early lethal mutation in mammals could facilitate improvement of diagnostics and therapeutics for affected patients with bleeding disorders

Elite Higher Education Admissions in the Arts and Sciences: Is Cultural Capital the Key?

This article examines the extent to which cultural capital helps to explain the link between social background and gaining an offer for study at the University of Oxford. We find that cultural knowledge, rather than participation in the beaux arts, is related to admissions decisions.This effect is particularly pronounced in arts subjects. We only partly support Bourdieu's postulation of cultural capital as the main differentiator between fractions of the middle class. Measures of cultural capital do not account for the gender gap in admission and only explain a small part of the disadvantage faced by South-Asian applicants