The EAHAD blood coagulation factor VII variant database

Hereditary blood coagulation factor VII (FVII) deficiency is a rare autosomal recessive bleeding disorder resulting from variants in the gene encoding FVII (F7 ). Integration of genetic variation with functional consequences on protein function is essential for the interpretation of the pathogenicity of novel variants. Here, we describe the integration of previous locus‐specific databases for F7 into a single curated database with enhanced features. The database provides access to in silico analyses that may be useful in the prediction of variant pathogenicity as well as cross‐species sequence alignments, structural information, and functional and clinical severity described for each variant, where appropriate. The variant data is shared with the F7 Leiden Open Variation Database. The updated database now includes 221 unique variants, representing gene variants identified in 728 individuals. Single nucleotide variants are the most common type (88%) with missense representing 74% of these variants. A number of variants are found with relatively high minor allele frequencies that are not pathogenic but contribute significantly to the likely pathogenicity of coinherited variants due to their effect on FVII plasma levels. This comprehensive collection of curated information significantly aids the assessment of pathogenicity

The European Association for Haemophilia and Allied Disorders (EAHAD) Coagulation Factor Variant Databases: Important resources for haemostasis clinicians and researchers

Haemophilia published by John Wiley & Sons Ltd Introduction: Advances in genomic sequencing have facilitated the sequencing of genes associated with disorders of haemostasis. The identification of variants within genes and access to curated data incorporating structural, functional, evolutionary as well as phenotypic data has become increasingly important in order to ascribe pathogenicity. Aim: The European Association for Haemophilia and Allied Disorders (EAHAD) Coagulation Factor Variant Database Project aims to provide a single port of entry to a web-accessible resource for variants in genes involved in clinical bleeding disorders. Results: New databases have evolved from previously developed single gene variant coagulation database projects, incorporating new data, new analysis tools and a new common database architecture with new interfaces and filters. These new databases currently present information about the genotype, phenotype (laboratory and clinical) and structural and functional effects of variants described in the genes of factor (F) VII (F7), FVIII (F8), FIX (F9) and von Willebrand factor (VWF). Conclusion: The project has improved the quality and quantity of information available to the haemostasis research and clinical communities, thereby enabling accurate classification of disease severity in order to make assessments of likely pathogenicity

Detection of missense mutations by single-strand conformational polymorphism (SSCP) analysis in five dysfunctional variants of coagulation factor VII

Five unrelated subjects with dysfunctional coagulation factor VII (FVII) were studied In order to Identify missense mutations affecting function. Exons 2 to 8 and the Intron-exon Junctions of their FVIl genes were amplified from peripheral white blood cell DNA by PCR and screened by SSCP analysis. DNA fragments showing aberrant mobility were sequenced. The following mutations were Identified: In case 1 (FVII: C <1%, FVIl:Ag 18%) a heterozygous A to G transltion at nucleotlde 8915 In exon 6 results In the amlno acid substitution Lys-137 to Glu near the C-termlnus of the FVlla llght chaln; In case 2 (FVII: C 7%, FVll:Ag 47%) a heterozygous A to G transltion at nucleotide 7834 In exon 5 results in the substitution of Gin-100 by Arg in the second EGF-like domain; In case 3 (FVll:C 20%, FVIl:Ag 76%) a homozygous G to A transition at nucleotide position 6055 in exon 4 was detected resulting in substitution of Arg-79 by Gin in the first EGF-like domain; in case 5 (FVIl:C 10%, FVIl:Ag 52%) a heterozygous C to T transition at nucleotide position 6054 in exon 4 also results in the substitution of Arg79, but in this case it is replaced by Trp; case 4 (FVll:C <1%, FVIl:Ag 100%) was homozygous for a previously reported mutation (G to A) at nucleotide position 10715 in exon 8, substituting Gin for Arg at position 304 in the protease domain. Cases 1,2 and 5 evidently have additional undetected mutation

Human tissue factor pathway inhibitor fused to CD4 binds both FXa and TF/FVIIa at the cell surface

Tissue factor pathway inhibitor (TFPI) is one of the main regulators of the tissue factor (TF) pathway of coagulation. To tether human TFPI to the cell surface, full length or truncated TFPI lacking the third Kunitz domain were fused with domains three and four and the carboxy-terminal sequence of human CD4. Constructs were transfected into a mouse fibroblast cell line and individual clones were checked for expression using monoclonal antibodies directed against the first two TFPI Kunitz domains and against CD4. Specific human FXa binding was detected by flow cytometry using an anti-FX polyclonal antibody, and inhibition of FXa proteolytic activity was verified by chromogenic substrate assay using S-2765. In addition, TFPI-CD4-expressing cells, preincubated with FXa, specifically bound human TF-FVIIa complexes as revealed with an anti-human TF polyclonal antibody. No functional difference was observed between full length or truncated TFPI-CD4. These results demonstrate that functionally intact TFPI can be tethered to the cell surface. Genetic manipulation of, for example, endothelial cells leading to the stable expression of TFPI may inhibit the development of coronary artery heart disease following cardiac allotransplantation, and may inhibit thrombosis in the context of xenotransplantation

University–Industry Linkages in Egypt: A Political Economy Approach

Submitted in partial fulfilment of the requirements for the degrees Master in Economic Analysis and Policy (APE), University of Paris 13 and University of Paris 7 – Diderot Master of Commerce in Development Theory and Policy, University of the Witwatersrand Under the Erasmus Mundus Joint Master Degrees Programme Economic Policies in the Age of Globalisation (EPOG)The Egyptian Science, Technology and Innovation (STI) sector has witnessed several institutional changes in the last ten years. It is slowly becoming more oriented toward satisfying the industrial Research and Development (R&D) needs with a more competitive approach to R&D expenditure. Meanwhile, the state has been in political turbulence since 2011 with a subsequent economic/financial crisis. In this thesis, we ask how the institutional changes that seek to stimulate Technology Transfer (TT) from the R&D institutions to the industrial sector can be understood within a broader political economy context. We break down our question into four main investigations. The first is concerning the economic rents and governance mechanisms as dictated by the state’s industrial policy. The second investigates the relationship between the state and the industrialists given the distribution of power among economic factions while considering changes, if any, in the Political Settlements (PS) before and after 2011. The third question describes the innovation patterns in the manufacturing sector and the financial and knowledge flows within the National System of Innovation (NSI). Finally, we present a case study for the TT Offices (TTOs), providing a narration of their institutional weaknesses. For our analysis, we use a hybrid framework by merging the PS and the NSI approaches. The former is used to check for the compatibility of the industrial policy in Egypt with the prevailing distribution of power among the state factions while the second provides a framework for analyzing financial and knowledge linkages in the Egyptian NSI as well as the University-Industry Linkages (UILs). The research methodology adopted in this thesis is mixed and involves literature review and qualitative analysis of data from conducted interviews. The methodology first relies on analyzing the available literature on the industrial policies and political economy in Egypt. The investigation then proceeds to give a descriptive account of the Egyptian NSI from which we move forward to present the case for TT from university to industry by conducting five semi-structured interviews with officials from TTOs belonging to R&D institutions. Results of our investigation reveal that the variation in manufacturing sector performance is linked with the distribution of economic rents by the state to the capitalists, in return of political support provided by the latter to the former. Hence, in line with the predictions of the PS theory, the industrial policy failed to realize higher competitiveness of the Egyptian manufacturing sector in the international market as the supporting industrial faction (capitalists) had accumulated enough power to weaken the state’s capacity of implementing its active industrial policy. We note that the variation in sector performance reflects not only growth but also innovation rates. While sectors receiving higher economic rents show less rates of innovation, except for beverage industry, those with less rents show the highest 3 innovation rates. The core contribution of the thesis comes with presenting the case for TTOs in Egypt which were recently established to induce UILs. Conducted interviews reveal that the STI policy is still in an early phase of formulation and that the organizational capacity of the STI actors remains low and constricted by various institutional and legal barriers. We infer, from other country experiences, that the PS in Egypt, which has persisted for a long time and without significant changes after 2011, does not indicate substantial changes in the power distribution among its state factions and hence, in the incentives structure and governance mechanisms towards a successful implementation of an industrial policy. Hence, we conclude that while the STI institutions are being reformed slowly, the prevailing PS and the associated inclination towards neoliberal economic policies in which the STI sector is being shaped in Egypt do not allow for an efficient TT through the free-market mechanisms, as perceived by the state.XL201