A Novel Dimeric Inhibitor Targeting Beta2GPI in Beta2GPI/Antibody Complexes Implicated in Antiphospholipid Syndrome

Background: b2GPI is a major antigen for autoantibodies associated with antiphospholipid syndrome (APS), an autoimmune disease characterized by thrombosis and recurrent pregnancy loss. Only the dimeric form of b2GPI generated by anti-b2GPI antibodies is pathologically important, in contrast to monomeric b2GPI which is abundant in plasma. Principal Findings: We created a dimeric inhibitor, A1-A1, to selectively target b2GPI in b2GPI/antibody complexes. To make this inhibitor, we isolated the first ligand-binding module from ApoER2 (A1) and connected two A1 modules with a flexible linker. A1-A1 interferes with two pathologically important interactions in APS, the binding of b2GPI/antibody complexes with anionic phospholipids and ApoER2. We compared the efficiency of A1-A1 to monomeric A1 for inhibition of the binding of b2GPI/antibody complexes to anionic phospholipids. We tested the inhibition of b2GPI present in human serum, b2GPI purified from human plasma and the individual domain V of b2GPI. We demonstrated that when b2GPI/antibody complexes are formed, A1-A1 is much more effective than A1 in inhibition of the binding of b2GPI to cardiolipin, regardless of the source of b2GPI. Similarly, A1-A1 strongly inhibits the binding of dimerized domain V of b2GPI to cardiolipin compared to the monomeric A1 inhibitor. In the absence of anti-b2GPI antibodies, both A1-A1 and A1 only weakly inhibit the binding of pathologically inactive monomeric b2GPI to cardiolipin. Conclusions: Our results suggest that the approach of using a dimeric inhibitor to block b2GPI in the pathologica

Ergodic properties of fibered rational maps

We study the ergodic properties of fibered rational maps of the Riemann sphere. In particular we compute the topological entropy of such mappings and construct a measure of maximal relative entropy. The measure is shown to be the unique one with this property. We apply the results to selfmaps of ruled surfaces and to certain holomorphic mapping of the complex projective plane P 2 .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43942/1/11512_2006_Article_BF02384321.pd

CLINICAL AND DIAGNOSTIC FEATURES OF EPILEPSY WITH ACCOMPANYING (INACTIVE) ORGANIC ENCEPHALOPATHY

Clinical, anamnestic and immunological features, type of interrelation between organic and neurophysiologic brain disorders as well as peculiarities of pharmacotherapy were investigated in 166 patients suffering from epilepsy (E) combined with organic encephalopathy (OE). The morbid state in E and OE patients was found to be manifested by syndrome complexes, with each of them dominating at a certain stage. E intencity was noticed to depend on the type of cerebral structural-morphological disorders. The evaluation criteria of the severity degree (diagnostic algorithm to assessment of condition) of E progressing in interconnection with OE were developed. Specificity of topographic interrelations of morphological and neurophysiological brain defects were found to influence epileptogenesis level. The conclusion is that maladaptive influence of OE on mechanisms of cerebral homeostasis compensation in E results in lowering of OE responsiveness to pharmacologic treatment and requires more intensive therapy