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Research has been conducted on gamma-secretase whose substrate indlude Notch and amyloid precursor protein. Results demonstrate that both Notch and amyloid precursor protein undergo cleavages within the transmembrane domain.

Presenilin heterodimers apparently contain the active site of [gamma]-secretase, a polytopic aspartyl protease involved in the trans-membrane processing of both the Notch receptor and the amyloid-[beta] precursor protein. Although critical to embryonic development and the pathogenesis of Alzheimer's disease, this protease is difficult to characterize, primarily because it is a multicomponent complex of integral membrane proteins. Here the functional [gamma]-secretase complex was isolated by using an immobilized active site-directed inhibitor of the protease. Presenilin heterodimers and nicastrin bound specifically to this inhibitor under conditions tightly correlating with protease activity, whereas several other presenilin-interacting proteins ([beta]-catenin, calsenilin, and presenilin-associated protein) did not bind. Moreover, anti-nicastrin antibodies immunoprecipitated [gamma]-secretase activity from detergent-solubilized microsomes. Unexpectedly, C83, the major endogenous amyloid-[beta] precursor protein substrate of [gamma]-secretase, was also quantitatively associated with the complex. These results provide direct biochemical evidence that nicastrin is a member of the active [gamma]-secretase complex, indicate that [beta]-catenin, calsenilin, and presenilin-associated protein are not required for [gamma] activity, and suggest an unprecedented mechanism of substrate-protease interaction.

Amyloid propagation by a template-dependent dock-lock mechanism has been hypothesized and modeled. It has been shown that the growth of amyloid plaque is mediated by two distinct kinetic processes, a dock phase, which is first, and a lock phase, which is second. Amyloid plaques are integral in Alzheimer's disease (AD) pathogenesis. They are made up of the peptide A(beta) and were modeled by monitoring the deposition of soluble A(beta) onto amyloid in AD brain tissue or synthetic amyloid fibrils.

Senile plaques made of the peptide Abeta contribute to the pathogenesis of Alzheimer's disease. The process of amyloid plaque growth in human brain was studied by employing size exclusion chromatography, translational diffusion measured by NMR and in vitro models of Abeta amyloid growth to identify the oligomerization state of Abeta that competent to add onto an existing amyloid deposit. Findings showed that, at least in vitro, Abeta exists as a monomer at physiological concentrations and deposition of monomers, rather than of oligomeric Abeta assemblies, mediates the growth of existing amyloid in human brain preparations.

Alzheimer's disease is pathologically characterized by the presence of many insoluble amyloid plaques in the brain composed mainly of a 40-43 amino acid peptide, the human beta-amyloid peptide (A-beta). To study the significance of the central hydrophobic cluster of A-beta for in vitro A-beta deposition, an A-beta(10-35)-NH2 analog with a single point substitution was synthesized and analyzed. Findings agree with previous investigations suggesting that the plaque competence of A-beta correlates with peptide folding.

The first-order kinetics of the formation of amyloid plaques in the brains of patients with Alzheimer's disease (AD) was studied using an in vitro model of plaque growth. The mechanism of aggregation and deposition of the human beta-amyloid peptide (Abeta) in intact sections and homogenates of unfixed AD brain cortex were analyzed by autoradiographic densitometry and radioisotope counting. There were no significant differences in the mechanism of plaque growth in the two systems, suggesting that the aggregation and deposition of Abeta follows distinct biochemical processes.

Acetyl-CoA carboxylase (ACC) is an enzyme within the de novo lipogenesis (DNL) pathway and plays a role in regulating lipid metabolism. Pharmacologic ACC inhibition has been an area of interest for multiple potential indications including oncology, acne vulgaris, metabolic diseases such as type 2 diabetes mellitus, and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. A critical role for ACC in de novo synthesis of long-chain fatty acids during fetal development has been demonstrated in studies in mice lacking Acc1 , where the absence of Acc1 results in early embryonic lethality. Following positive predictions of developmental toxicity in the alternative in vitro assays (positive in murine embryonic stem cell [mESC] assay and rat whole embryo culture, but negative in zebrafish), developmental toxicity (growth retardation and dysmorphogenesis associated with disrupted midline fusion) was observed with the oral administration of the dual ACC1 and 2 inhibitors, PF-05175157, in Sprague Dawley rats and New Zealand White rabbits. The results of these studies are presented here to make comparisons across the assays, as well as mechanistic insights from the mESC assay demonstrating high ACC expression in the mESC and that ACC-induced developmental toxicity can be rescued with palmitic acid providing supportive evidence for DNL pathway inhibition as the underlying mechanism. Ultimately, while the battery of alternative approaches and weight-of-evidence case were useful for hazard identification, the embryo-fetal development studies were necessary to inform the risk assessment on the adverse fetal response, as malformations and/or embryo-fetal lethality were limited to doses that caused near-complete inhibition of DNL. [ABSTRACT FROM AUTHOR]

Argues that, as scientists learn more about the chemistry and physiology of the human brain, it is incumbent upon educators and educational psychologists to begin to build models of brain function that reflect growing scientific knowledge. (FL)

Water rockets are used to present Newton's three laws of motion to high school physics students. Described is an outdoor activity which uses four students per group. Provides a launch data sheet to record height, angle of elevation, amount of water used, and launch number. (MVL)

This article reports a study conducted with fourteen learning-disabled elementary students to determine the growth of achievement and conservation abilities after using the "Sink or Float" unit of the Elementary Science Study. (MK)

Investigates the differences in the improvement in communication deficiencies of selected third- and fifth-grade children who participated in a science-based remediation program and of third- and fifth-grade children who did not participate. (HM)

An experiment in science instruction designed to help third- and fifth-grade students overcome reading deficiencies is detailed. The results of the study indicate that the activities may be a valuable supplement to the more common activities for teaching communication skills. (MP)

Speculates that physiological changes resulting from repeated, long-term stimulation in human and laboratory animal brains are related to short- and long-term memory processes. Describes a physiological-based model which may explain many current learning theory principles and can serve as a foundation for developing new learning theories based on brain physiology. (Author/JN)

The relationships among several suggested indices of school desegregation were examined. The measures were discussed for their utility in the remedy process. Issues involved in the formulation of desegregation indices were related to kinds of information they yielded. Recommendations were made for the properties of an effective index. (Author)