BCAT-induced autophagy regulates Aß load through an interdependence of redox state and PKC phosphorylation-implications in Alzheimer's disease.

Leucine, nutrient signal and substrate for the branched chain aminotransferase (BCAT) activates the mechanistic target of rapamycin (mTORC1) and regulates autophagic flux, mechanisms implicated in the pathogenesis of neurodegenerative conditions such as Alzheimer's disease (AD). BCAT is upregulated in AD, where a moonlighting role, imparted through its redox-active CXXC motif, has been suggested. Here we demonstrate that the redox state of BCAT signals differential phosphorylation by protein kinase C (PKC) regulating the trafficking of cellular pools of BCAT. We show inter-dependence of BCAT expression and proteins associated with the P13K/Akt/mTORC1 and autophagy signalling pathways. In response to insulin or an increase in ROS, BCATc is trafficked to the membrane and docks via palmitoylation, which is associated with BCATc-induced autophagy through PKC phosphorylation. In response to increased levels of BCATc, as observed in AD, amyloid ß (Aß) levels accumulate due to a shift in autophagic flux. This effect was diminished when incubated with leucine, indicating that dietary levels of amino acids show promise in regulating Aß load. Together these findings show that increased BCATc expression, reported in human AD brain, will affect autophagy and Aß load through the interdependence of its redox-regulated phosphorylation offering a novel target to address AD pathology.

BCAA Metabolism and NH3 Homeostasis.

The branched chain amino acids (BCAA) are essential amino acids required not only for growth and development, but also as nutrient signals and as nitrogen donors to neurotransmitter synthesis and glutamate/glutamine cycling. Transamination and oxidative decarboxylation of the BCAAs are catalysed by the branched-chain aminotransferase proteins (BCATm, mitochondrial and BCATc, cytosolic) and the branched-chain α-keto acid dehydrogenase enzyme complex (BCKDC), respectively. These proteins show tissue, cell compartmentation, and protein-protein interactions, which call for substrate shuttling or channelling and nitrogen transfer for oxidation to occur. Efficient regulation of these pathways is mediated through the redox environment and phosphorylation in response to dietary and hormonal stimuli. The wide distribution of these proteins allows for effective BCAA utilisation. We discuss how BCAT, BCKDC, and glutamate dehydrogenase operate in supramolecular complexes, allowing for efficient channelling of substrates. The role of BCAAs in brain metabolism is highlighted in rodent and human brain, where differential expression of BCATm indicates differences in nitrogen metabolism between species. Finally, we introduce a new role for BCAT, where a change in function is triggered by oxidation of its redox-active switch. Our understanding of how BCAA metabolism and nitrogen transfer is regulated is important as many studies now point to BCAA metabolic dysregulation in metabolic and neurodegenerative conditions.

Vitamin B12 and folate bioavailability from two prenatal multivitamin/multimineral supplements.

In this crossover, single-blind study, the bioavailability of B12 and folate, fasting and postprandially, was measured in 30 pregnant women for two prenatal multivitamin/multimineral supplements (Stuartnatal Plus and Materna, Wyeth-Ayerst Pharmaceuticals, Philadelphia, PA) and a placebo. Blood samples were obtained before supplementation and at 1, 3, 6, and 8 hr after supplementation serum levels of the two vitamins were measured by radioimmunoassay. The maximum postabsorption serum level was multiplied by the total body plasma levels to obtain the total rate of body absorption. The absorption peak of both vitamins occurred at 3 hours after ingestion of a supplement. The total body absorption of the two vitamins was greater during fasting than it was postprandially. There was 30% greater B12 absorption for Stuartnatal Plus (371 +/- 56 vs. 285 +/- 34 pmol) and 33% for Materna (315 +/- 34 vs. 236 +/- 4 pmol, p < or = 0.05). Similarly, there was 117% greater folate absorption fasting for Stuartnatal Plus (163 +/- 15 vs. 75 +/- 15 nmol, p < or = 0.001) and 57% greater absorption for Materna (207 +/- 21 vs. 132 +/- 13 nmol, p < or = 0.01). Both vitamins were readily absorbed (within 3 hours) into the maternal hepatic portal circulation. The absorption of both vitamins was significantly less when ingested after the test meal than when fasting.

Bioavailability of iron in two prenatal multivitamin/multimineral supplements.

OBJECTIVE: To determine the iron bioavailability in two popular prenatal multivitamin/multimineral supplement tablets containing 27 mg elemental iron. STUDY DESIGN: Iron absorption during an eight-hour period following ingestion of a multivitamin/multimineral formulation, both fasting and with a standardized meal, was measured in a group of 30 pregnant women (24-32 weeks of gestation) and statistically compared. The prenatal formulations were Stuartnatal Plus and Materna (Wyeth-Ayerst Pharmaceuticals, Philadelphia, Pennsylvania), and each contains 27 mg of elemental iron. A placebo was included in the study for the control group in this crossover, single-blind study. RESULTS: The net iron bioavailability (mean +/- SE) of Stuartnatal Plus and Materna, accounting for diurnal variation, and the iron ingested with the standardized meal was 5.4 +/- 0.4 and 4.6 +/- 0.2 mg, respectively, while fasting and 2.9 +/- 0.4 and 2.7 +/- 0.4 mg, respectively, postprandially. The total amount of iron absorption in the fasting states from both prenatal formulations exceeded the 3 mg of supplemental iron absorption per day recommended by the National Academy of Sciences. CONCLUSION: The results of this study indicate that these two prenatal multivitamin/multimineral formulations provide > 3.0 mg of supplemental iron absorption (fasting) as recommended by the National Academy of Sciences and 2.7 mg of iron absorption above the levels achieved following ingestion of a standard, low-iron test meal.

The optimal environment for socialization of the nurse-scientist.

Tangible elements or factors that contribute to the successful socialization of student scholars seeking the PhD degree in nursing are generally well known. Included among these are the university itself-its faculty, its resources, such as laboratories and libraries, and its research productivity. Less well known are some intangibles in the learning environment that make the difference between an acceptable learning environment and an optimal one, such as, the frequency and quality of informal interaction between faculty and students. The author identifies several characteristics of the pre-doctoral learning environment for nurse PhD students that faculty and administrators should seek to provide if they wish to support truly successful socialization of the scholar/scientist.

Toward greater specificity in defining nursing's metaparadigm.

The thesis presented is that nursing in its disciplinary context cannot appropriately be considered a concept in the metaparadigm of nursing science. Nursing as a discipline is guided by theories and prescriptions that emanate from puzzles solved in the domain of nursing science. Failure to distinguish between the science of nursing and its disciplinary aspects in building conceptual frameworks will retard the growth of science. The merits of three competing paradigms--normal science, historical facts, and social facts-are discussed. None of these paradigms is adequate for discovery in nursing science. Efforts to develop knowledge around the phenomena of central concern to nursing may advance more rapidly if theory building follows a set of rules, as yet undefined, that incorporates the methods of both normal science and historical tradition.