The hippocampus and parahippocampal cortices exhibit theta oscillations during spatial navigation in animals and humans, and in the former are thought to mediate spatial memory formation. Functional specificity of human hippocampal theta, however, is unclear. Neuromagnetic activity was recorded with a whole-head 275-channel magnetoencephalographic (MEG) system as healthy participants navigated to a hidden platform in a virtual reality Morris water maze. MEG data were analyzed for underlying oscillatory sources in the 4 -8 Hz band using a spatial filtering technique (i.e., synthetic aperture magnetometry). Source analyses revealed greater theta activity in the left anterior hippocampus and parahippocampal cortices during goal-directed navigation relative to aimless movements in a sensorimotor control condition. Additional analyses showed that left anterior hippocampal activity was predominantly observed during the first one-half of training, pointing to a role for this region in early learning. Moreover, posterior hippocampal theta was highly correlated with navigation performance, with the former accounting for 76% of the variance of the latter. Our findings suggest human spatial learning is dependent on hippocampal and parahippocampal theta oscillations, extending to humans a significant body of research demonstrating such a pivotal role for hippocampal theta in animal navigation.

Abstract-The development of congestive heart failure (CHF) is associated with left ventricle (LV) dilation and myocardial remodeling. The matrix metalloproteinases (MMPs) play a significant role in extracellular remodeling, and recent studies have demonstrated increased MMP expression and activity with CHF. Whether increased MMP activity directly contributes to the LV remodeling with CHF remains unknown. Accordingly, this study examined the effects of chronic MMP inhibition (MMPi) on LV size and function during the progression of CHF. Pigs were assigned to the following groups: (1) CHF, rapid pacing for 3 weeks at 240 bpm (nϭ12); (2)

Matrix metalloproteinases are a family of highly regulated peptidases that are collectively responsible for the degradation of extracellular matrix during tissue remodeling. Dysregulated activity has long been implicated in the pathologies of cancer and arthritis, and the number of diseases more recently associated with these enzymes has been increasing. In the past year, new transgenic models of matrix metalloproteinase knockouts have been described, allowing the direct assessment of specific enzyme activity in particular disease models. In addition, more selective inhibitors with improved pharmacokinetic profiles have entered clinical trials, allowing the assessment of the safety and efficacy of this strategy.

Several matrix metalloproteinases, including the 92-kDa and 72-kDa gelatinases, macrophage metalloelastase (MME), and matrilysin degrade insoluble elastin. Because elastolytically active MME and matrilysin consist only of a catalytic domain (CD), we speculated that the homologous CDs of the 92-kDa and 72-kDa gelatinases would confer their elastolytic activities. In contrast to the MME CD, the 92 and 72 CDs expressed in Escherichia coli (lacking the internal fibronectin type II-like repeats) had no elastase activity, although both were gelatinolytic and cleaved a thiopeptolide substrate at rates comparable to the full-length gelatinases. Elastin is an extracellular matrix protein composed of highly cross-linked, hydrophobic tropoelastin monomers which provides resilience to elastic fibers. The hydrophobicity and extensive cross-linking of tropoelastin monomers result in an insoluble elastic fiber which is highly resistant to proteolysis (1). Thus, under normal physiologic conditions, elastin undergoes minimal turnover (2). However, certain pathologic situations, including pulmonary emphysema (3) and abdominal aortic aneurysm (4), are characterized by proteolytic destruction of elastic fibers. The involvement of serine proteases in such pathologies has long been suspected. More recently, participation of cysteine proteinases (5) and matrix metalloproteinases (MMPs, 1 6 -8) in these diseases has been proposed. The MMPs comprise a gene family that collectively is capable of degrading all components of extracellular matrix in physiologic and pathologic states (9, 10). As presently recognized, this family consists of fibroblast (11), neutrophil (12), and breast carcinoma-derived (13) collagenases, three stromelysins, 92-kDa and 72-kDa gelatinases, macrophage metalloelastase (MME, MMP-12), matrilysin, and a recently described 66-kDa membrane-type metalloproteinase (14). These enzymes are organized into homologous structural domains, with some differences in domain composition and number. All members share a zymogen domain, containing a conserved PRCGXPD motif involved in enzyme latency, and a zinc-binding CD. Most members also contain a hemopexin-like domain at their C terminus, the exception being matrilysin, which lacks this domain completely. Unique to the 72-kDa and 92-kDa gelatinases is an additional domain composed of three fibronectin type II-like repeats inserted in tandem within the zinc-binding CD. The 92-kDa gelatinase also contains an ␣2(V) collagen-like domain not found in any of the other family members.The issue of substrate specificity has received considerable attention recently in MMP biology. The determinants which confer substrate specificity to these enzymes appear to be localized within discrete structural domains. For example, the ability of the collagenases to degrade triple-helical collagen requires the presence of the C-terminal hemopexin-like domain (15)(16)(17). In contrast, the stromelysins degrade a variety of substrates in a manner which is independent of the C-terminal hemopexin-like dom...

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