In Silico Discovery of a Compound with Nanomolar Affinity to Antithrombin Causing Partial Activation and Increased Heparin Affinity

The medical and socioeconomic relevance of thromboembolic disorders promotes an ongoing effort to develop new anticoagulants. Heparin is widely used as activator of antithrombin but incurs side effects. We screened a large database in silico to find alternative molecules and predicted d-myo-inositol 3,4,5,6-tetrakisphosphate (TMI) to strongly interact with antithrombin. Isothermal titration calorimetry confirmed a TMI affinity of 45 nM, higher than the heparin affinity (273 nM). Functional studies, fluorescence analysis, and citrullination experiments revealed that TMI induced a partial activation of antithrombin that facilitated the interaction with heparin and low affinity heparins. TMI improved antithrombin inhibitory function of plasma from homozygous patients with antithrombin deficiency with a heparin binding defect and also in a model with endothelial cells. Our in silico screen identified a new, non-polysaccharide scaffold able to interact with the heparin binding domain of antithrombin. The functional consequences of this interaction were experimentally characterized and suggest potential anticoagulant therapeutic applications

Convergence in per-capita GDP across European regions: a reappraisal

Regional convergence, Median unbiased estimation, Heterogeneous panel models, C23, O40, O52, R11,

SPATIAL EFFECTS ON PROVINCIAL CONVERGENCE AND INCOME DISTRIBUTION IN SPAIN: 1985-2003

This paper examines the role of space (geographical location) in provincial income convergence and income distribution in Spain. To do that, and after showing the presence of spatial dependence in our income data, the paper compares two sample series: actual versus filtered (spaceless) data. The comparison of these two series comes out to two important differences: first, the speed of convergence is higher and, second, the income distribution is more concentrated (less biased) around the national average with filtered data. Besides this, the paper also shows that geographical location particularly explains relative income improvement in provinces with per capita income slightly above average. These results confirm that, as for Spain, space does indeed matter. Copyright (c) 2009 by the Royal Dutch Geographical Society KNAG.

Panel data stochastic convergence analysis of the Mexican regions

Stochastic convergence, β-Convergence, Non-stationarity panel data tests, Cross-section dependence, Multiple structural breaks, C12, C22, C32, O40, R11,

A spatially filtered mixture of β-convergence regressions for EU regions, 1980–2002

Regional growth, Convergence patterns, Mixture regression, Spatial effects, C21, O40, R11,