Andrew Baker

Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure.

Cardiac rupture is a fatal complication of acute myocardial infarction lacking treatment. Here, acute myocardial infarction resulted in rupture in wild-type mice and in mice lacking tissue-type plasminogen activator, urokinase receptor, matrix metalloproteinase stromelysin-1 or metalloelastase. Instead, deficiency of urokinase-type plasminogen activator (u-PA–/–) completely protected against rupture, whereas lack of gelatinase-B partially protected against rupture. However, u-PA–/– mice showed impaired scar formation and infarct revascularization, even after treatment with vascular endothelial growth factor, and died of cardiac failure due to depressed contractility, arrhythmias and ischemia. Temporary administration of PA inhibitor-1 or the matrix metalloproteinase-inhibitor TIMP-1 completely protected wild-type mice against rupture but did not abort infarct healing, thus constituting a new approach to prevent cardiac rupture after acute myocardial infarction.

A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2

Tissue inhibitor of metalloproteinases-3 (TIMP3) is one of four members of a family of proteins that were originally classified according to their ability to inhibit matrix metalloproteinases (MMP). TIMP3, which encodes a potent angiogenesis inhibitor, is mutated in Sorsby fundus dystrophy, a macular degenerative disease with submacular choroidal neovascularization. In this study we demonstrate the ability of TIMP3 to inhibit vascular endothelial factor (VEGF)–mediated angiogenesis and identify the potential mechanism by which this occurs: TIMP3 blocks the binding of VEGF to VEGF receptor-2 and inhibits downstream signaling and angiogenesis. This property seems to be independent of its MMP-inhibitory activity, indicating a new function for this molecule.

In Vitro and In Vivo Properties of Adenovirus Vectors with Increased Affinity to CD46

ABSTRACT Gene transfer vectors containing adenovirus (Ad) serotype 35 (Ad35) fibers have shown promise for cancer and stem cell gene therapy. In this study, we attempted to improve the in vitro and in vivo infection properties of these vectors by increasing their affinity to the Ad35 fiber receptor CD46. We constructed Ad vectors containing either the wild-type Ad35 fiber knob (Ad5/35) or Ad35 knob mutants with 4-fold- and 60-fold-higher affinity to CD46 (Ad5/35+ and Ad5/35++, respectively). In in vitro studies with cell lines, the higher affinities of Ad5/35+ and Ad5/35++ to CD46 did not translate into correspondingly higher transduction efficiencies, regardless of the CD46 receptor density present on cells. However, in vivo, in a mouse model with preestablished CD46high liver metastases, intravenous injection of Ad5/35++ resulted in more-efficient tumor cell transduction. We conclude that Ad5/35 vectors with increased affinity to CD46 have an advantage in competing with non-CD46-mediated sequestration of vector particles after intravenous injection.

Differential alterations in the expression and activity of matrix metalloproteinases 2 and 9 after transient cerebral ischemia in mice

Abnormal expression and activity of matrix metalloproteinases (MMPs) may contribute to the pathophysiology of cerebral disease such as ischemic injury. In this study, we compared the cellular localization, expression, and activity of MMP-2 and -9 in relation to the evolution of neuronal damage 24 and 72 h after transient global ischemia. In response to ischemia, there was a generalized increase in cellular MMP-2 immunoreactivity at 24-h reperfusion (in neurons, glia and vessels) whereas at 72-h reperfusion the increase in MMP-2 was predominantly in glia. These glial alterations contributed to a significant increase in pro MMP-2 levels in ischemic regions (P < 0.01) as measured by zymography. In contrast, MMP-9 was predominantly upregulated in neurons and this was significantly different to shams at 24- and 72-h reperfusion after ischemia (P < 0.05). Notably, a dramatic increase in proteolytic activity in neurons was observed 24 h after ischemia and this response was absent at 72 h post-ischemia. The present data are supportive of a role for MMPs in contributing to neuronal injury after ischemia.

RIGHT EIGENVALUES FOR QUATERNIONIC MATRICES : A TOPOLOGICAL APPROACH

Abstract We apply the Lefschetz Fixed Point Theorem to show that every square matrix over the quaternions has right eigenvalues. We classify them and discuss some of their properties such as an analogue of Jordan canonical form and diagonalization of elements of the compact symplectic group Sp( n ).

On the Kummer congruences and the stable homotopy of U

We study the torsion-free part of the stable homotopy groups of the space BU, by considering upper and lower bounds. The upper bound is furnished by the ring PK. (BU) of coaction primitives into which nrs(BU) is mapped by the complex K-theoretic Hurewicz homomorphism Xs(BU) -* PK*(BU). We characterize PK* (B U) in terms of symmetric numerical polynomials and describe systematic families of elements by utilizing the classical Kummer congruences among the Bernoulli numbers. For a lower bound we choose the ring of those framed bordism classes which may be represented by singular hypersurfaces in BU. From among these we define families of classes constructed from regular neighborhoods of embeddings of iterated Thom complexes in Euclidean space. Employing techniques of duality theory, we deduce that these two families correspond, except possibly in the lowest dimensions, under the Hurewicz homomorphism, which thus provides a link between the algebra and the geometry. In the course of this work we greatly extend certain e-invariant calculations of J. F. Adams.

Neuroprotective effect of adenoviral-mediated gene transfer of TIMP-1 and -2 in ischemic brain injury.

Gene therapy may be a promising approach for treatment of brain ischemia. We and others previously demonstrated that increased activity of matrix metalloproteinases (MMPs) contributes to the tissue damage that results from ischemic injury. The proteolysis of MMPs is tightly controlled by tissue inhibitors of MMPs (TIMPs). In this study, we examined whether adenoviral-mediated gene transfer of TIMP-1 and TIMP-2 could protect against neuronal damage induced by global cerebral ischemia in mice. An adenovirus expressing TIMP-1 or TIMP-2 (AdTIMP-1 or AdTIMP-2) or a control adenovirus (RAd60) or vehicle was injected into the striatum 3 days before transient global cerebral ischemia. The extent of neuronal damage was quantified 3 days post-ischemia. There was no significant difference in the extent of neuronal damage in vehicle as compared to RAd60-treated mice. In contrast, neuronal damage was reduced, by approximately 50%, after gene transfer of AdTIMP-1 (P<0.001) and AdTIMP-2 (P< 0.01) as compared to controls. This study provides the first in vivo evidence of the protective effects of TIMP-1 and TIMP-2 via gene transfer in global ischemia.

Realizability of algebraic Galois extensions by strictly commutative ring spectra

We discuss some of the basic ideas of Galois theory for commutative S-algebras originally formulated by John Rognes. We restrict our attention to the case of finite Galois groups and to global Galois extensions. We describe parts of the general framework developed by Rognes. Central roles are played by the notion of strong duality and a trace mapping constructed by Greenlees and May in the context of generalized Tate cohomology. We give some examples where algebraic data on coefficient rings ensures strong topological consequences. We consider the issue of passage from algebraic Galois extensions to topological ones by applying obstruction theories of Robinson and Goerss-Hopkins to produce topological models for algebraic Galois extensions and the necessary morphisms of commutative S-algebras. Examples such as the complex

Hecke operators as operations in elliptic cohomology

K-theory spectrum as a KO-algebra indicate that more exotic phenomena occur in the topological setting. We show how in certain cases topological abelian Galois extensions are classified by the same Harrison groups as algebraic ones, and this leads to computable Harrison groups for such spectra. We end by proving an analogue of Hilberts theorem 90 for the units associated with a Galois extension.

Therapeutic angiogenesis in diabetic apolipoprotein E-deficient mice using bone marrow cells, functional hemangioblasts and metabolic intervention.

We construct stable operations Tn:Ell∗( ) → Ell (ln)∗( ) for n> in the version of elliptic cohomology where the coefficient ring Ell∗ agrees with the ring of modular forms for SL2(Z) which are meromorphic at ∞, and Tn restricts to the nth Hecke operator Tn on Ell∗.