Biomedical subjects

M Wastney

Publications and source records attributed to M Wastney.

4 recordsLinked to original sources

PubMed1999

The Niemann-Pick C1 protein resides in a vesicular compartment linked to retrograde transport of multiple lysosomal cargo.

Niemann-Pick C disease (NP-C) is a neurovisceral lysosomal storage disorder. A variety of studies have highlighted defective sterol trafficking from lysosomes in NP-C cells. However, the heterogeneous nature of additional accumulating metabolites suggests that the cellular lesion may involve a more generalized block in retrograde lysosomal trafficking. Immunocytochemical studies in fibroblasts reveal that the NPC1 gene product resides in a novel set of lysosome-associated membrane protein-2 (LAMP2)(+)/mannose 6-phosphate receptor(-) vesicles that can be distinguished from cholesterol-enriched LAMP2(+) lysosomes. Drugs that block sterol transport out of lysosomes also redistribute NPC1 to cholesterol-laden lysosomes. Sterol relocation from lysosomes in cultured human fibroblasts can be blocked at 21 degrees C, consistent with vesicle-mediated transfer. These findings suggest that NPC1(+) vesicles may transiently interact with lysosomes to facilitate sterol relocation. Independent of defective sterol trafficking, NP-C fibroblasts are also deficient in vesicle-mediated clearance of endocytosed [14C]sucrose. Compartmental modeling of the observed [14C]sucrose clearance data targets the trafficking defect caused by mutations in NPC1 to an endocytic compartment proximal to lysosomes. Low density lipoprotein uptake by normal cells retards retrograde transport of [14C]sucrose through this same kinetic compartment, further suggesting that it may contain the sterol-sensing NPC1 protein. We conclude that a distinctive organelle containing NPC1 mediates retrograde lysosomal transport of endocytosed cargo that is not restricted to sterol.

Amino Acid Sequence↗

PubMed1999

Absorption of calcium oxalate does not require dissociation in rats.

Calcium absorption is thought to occur only if calcium is in a soluble or dissociated form, although experimental evidence is lacking. The intestinal absorption of calcium oxalate, a small, neutral and virtually insoluble calcium salt, was elucidated in the whole body of awake rats. Suspensions of 45Ca ascorbate, 14C-oxalic acid and doubly labeled 45Ca-[14C]-oxalate were given by gavage to separate groups of rats. Following dosing, blood samples were drawn for up to 240 min through a previously inserted intravenous catheter. Serum was assayed for radioactive tracers, and data were then plotted as fraction of dose over time. Calcium absorption was 15% [with a loading of 0.3 mmol (15 mg) calcium], oxalic acid absorption was 22% and Ca-oxalate absorption was <2%. Appearance of 45Ca from calcium ascorbate and 14C from oxalic acid differed, whereas 45Ca and 14C from doubly labeled Ca-oxalate had identical serum appearance profiles. Therefore, we conclude that calcium oxalate was absorbed intact. Addition of excess, unlabeled calcium to the doubly-labeled calcium oxalate did not alter the relationship of the serum level of the two tracers, confirming absorption of calcium oxalate as the intact salt. Thus, calcium bound as a small, neutral, calcium salt such as calcium oxalate does not have to be dissociated prior to absorption. Possibly other small compounds would be similarly absorbed. These results alter our current understanding of calcium bioavailability from foods and therapeutic agents.

Absorption↗

PubMed1998

Balancing needs, efficiency, and functionality in the provision of modeling software: a perspective of the NIH WinSAAM Project.

The development of new software or the refinement of existing software for new operating environments each calls for judicious balancing. On the one hand, we strive for simplicity, predictability, and operational protection as it is well recognized that software with these attributes will attract an audience of satisfied users. But, on the other hand, these attributes do not conjure a sense of power, efficiency, or flexibility, and these other properties are also appreciated by users, albeit a somewhat different group of users. The goal is to achieve a blend which isolates critical functionality, flexible control, and user support while meeting the needs of the broadest collection of serious users. In this chapter, we discuss the issues impacting the migration of SAAM to the Windows environment, the NIH WinSAAM Project, and we outline the steps taken to ensure its feasibility. In addition, we describe a new paradigm for software development and use which ensures the durability of the software for modeling.

Computer Simulation↗

PubMed1997

Magnesium kinetics in adolescent girls determined using stable isotopes: effects of high and low calcium intake.

Magnesium kinetics were measured in five adolescent girls who were participating in a calcium balance study. Two calcium levels were fed in a randomized crossover design. After an acclimation period, 26Mg was consumed orally and 25Mg was given intravenously, and then blood, urine, and feces were collected for 14 days. Total magnesium and percent enrichment were determined, and data were fitted to a eight-compartment model. There was no significant difference between high and low calcium intakes for any of the parameters examined. Mean values for control (800 mg/day) and high (1,800 mg/day) calcium intake were as follows: Mg intake, 305 +/- 30 and 286 +/- 9 mg/day; absorption (percent), 44 +/- 7 and 39 +/- 9; absorption (mg/day), 134 +/- 35 and 110 +/- 28; urinary excretion, 96 +/- 22 and 101 +/- 31 mg/day; fecal excretion, 175 +/- 32 and 200 +/- 11 mg/day; and magnesium balance, 13 +/- 35 and -34 +/- 48 mg/day, respectively. In conclusion, high calcium intake did not alter magnesium kinetics or balance in adolescent girls.

Absorption↗