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Biomedical subjects

A Ruby

Publications and source records attributed to A Ruby.

15 recordsLinked to original sources
PubMed2006

Characterization and prediction of highway runoff constituent event mean concentration.

Highway stormwater runoff quality data were collected from throughout California during 2000-2003. Samples were analyzed for conventional pollutants (pH, conductivity, hardness, and temperature); aggregates (TSS, TDS, TOC, DOC); total and dissolved metals (As, Cd, Cr, Cu, Ni, Pb, and Zn); and nutrients (NO(3)-N, TKN, total P, and ortho-P). Storm event and site characteristics for each sampling site were recorded. A statistical summary for chemical characteristics of highway runoff is provided based on statewide urban and non-urban highways. Constituent event mean concentrations (EMCs) were generally higher in urban highways than in non-urban highways. The chemical characteristics of highway runoff in California were compared with national highway runoff chemical characterization data. The results obtained in California were generally similar to those found in other states. The median EMC for Pb measured in studies conducted in previous decades was much higher than the current median Pb EMC in California. The lower Pb EMC in California compared to previous highway runoff monitoring is believed to be due to the elimination of leaded gasoline. An attempt was also made to identify surrogate constituents within a general family of water quality categories using Spearman correlations and selected pairs with Spearman coefficients greater than 0.8. The strongest correlations were observed among parameters associated with dissolved minerals (EC, TDS, and chloride); organic carbon (TOC and DOC); petroleum hydrocarbons (TPH and O & G); and particulate matter (TSS and turbidity). Within the metals category, total iron concentration was highly correlated with most total metal concentrations. The correlations between total and dissolved concentrations were all less than 0.8, even between total and dissolved concentrations of the same metals. Multiple linear regression (MLR) analyses were performed to evaluate the impact of various site and storm event variables on highway runoff constituent EMCs. Parameters found to have significant impacts on highway runoff constituent EMCs include: total event rainfall (TER); cumulative seasonal rainfall (CSR); antecedent dry period (ADP); contributing drainage area (DA); and annual average daily traffic (AADT). Surrounding land use and geographic regions were also determined to have a significant impact on runoff quality. The MLR model was also used to predict constituent EMCs. Model performance determined by comparing predicted and measured values showed good agreement for most constituents.

California↗
PubMed2000

ATPase kinetic characterization and single molecule behavior of mutant human kinesin motors defective in microtubule-based motility.

Conventional kinesin is a microtubule-based motor protein that is an important model system for understanding mechanochemical transduction. To identify regions of the kinesin protein that participate in microtubule binding and force production, Woehlke et al. [(1997) Cell 90, 207-216] generated 35 alanine mutations in solvent-exposed residues. Here, we have performed presteady-state kinetic and single molecule motility analyses on three of these mutants [Y138A, loop 11 triple (L248A/D249A/E250A), and E311A] that exhibited a similar approximately 3-fold reduction in both microtubule gliding velocity and microtubule-stimulated ATPase activity. All mutants showed normal second-order ATP binding kinetics, indicating correct folding of the active site. The Y138A and loop 11 triple mutants were defective both in nucleotide hydrolysis and in microtubule-stimulated ADP release rates, the latter suggesting a defect in allosteric communication between the microtubule and the active site. A single molecule fluorescence assay further revealed that the loop 11 mutant is defective in initiating processive motion, suggesting that this loop is important for the initial contact between kinesin and the microtubule. Y138A, on the other hand, can bind to the microtubule normally but cannot move processively. For E311A, neither the rate of nucleotide hydrolysis nor ADP release could account for its slower ATPase and gliding velocity, which suggests that either phosphate release or a conformational transition is rate-limiting in this mutant. The single molecule assay showed that E311A has a reduced velocity of movement, but is not defective in processivity. Thus, while these mutants behave similarly in solution ATPase and multiple motor gliding assays, kinetic and single molecule analyses reveal defects in distinct processes in kinesin's mechanochemical cycle.

Adenosine Triphosphatases↗
PubMed1999

Clinical pharmacokinetics of 1-[((S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl]cytosine in human immunodeficiency virus-infected patients.

The pharmacokinetics and bioavailability of 1-[((S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl]cytosi ne (cyclic HPMPC) were examined at four doses in 22 patients with human immunodeficiency virus infection. Two groups of six patients received a single dose of cyclic HPMPC at 1.5 or 3.0 mg/kg of body weight by each of the oral and intravenous routes in a random order with a 2-week washout period between administrations. Additional patients received single intravenous doses of cyclic HPMPC at 5.0 mg/kg (n = 6) or 7.5 mg/kg (n = 4). Serial serum and urine samples were collected at intervals over 24 h after dosing. The concentrations of cyclic HPMPC and cidofovir in serum and urine samples were determined by validated reverse-phase ion-pairing high-performance liquid chromatography methods with derivatization and fluorescence detection. After intravenous administration of cyclic HPMPC, concentrations of cyclic HPMPC declined in a biexponential manner, with a mean +/- standard deviation half-life of 1.09 +/- 0.12 h (n = 22). The pharmacokinetics of cyclic HPMPC were independent of dose over the dose range of 1.5 to 7.5 mg/kg. The total clearance of cyclic HPMPC from serum and the volume of distribution of intravenous cyclic HPMPC were 198 +/- 39.6 ml/h/kg and 338 +/- 65.1 ml/kg, respectively (n = 22). The renal clearance of cyclic HPMPC (132 +/- 27.3 ml/h/kg; n = 22) exceeded the creatinine clearance (86.2 +/- 16.3 ml/h/kg), indicating active tubular secretion. The cyclic HPMPC excreted in urine in 24 h accounted for 71.3% +/- 16.0% of the administered dose. Cidofovir was formed from cyclic HPMPC in vivo with a time to the maximum concentration in serum of 1.64 +/- 0.23 h (n = 22). Cidofovir levels declined in an apparent monoexponential manner, with a mean terminal half-life of 3.98 +/- 1.26 h (n = 22). The cidofovir excreted in urine in 24 h accounted for 9.40% +/- 2.33% of the administered cyclic HPMPC dose. Exposure to cidofovir after intravenous administration of cyclic HPMPC was dose proportional and was 14.9% of that from an equivalent dose of cidofovir. The present study suggests that intravenous cyclic HPMPC also has a lower potential for nephrotoxicity in humans compared to that of intravenous cidofovir. The oral bioavailabilities of cyclic HPMPC were 1.76% +/- 1.48% and 3.10% +/- 1.16% with the administration of doses of 1.5 and 3.0 mg/kg, respectively (n = 6 per dose). The maximum concentrations of cyclic HPMPC in serum were 0.036 +/- 0.021 and 0.082 +/- 0.038 microgram/ml after the oral administration of doses of 1.5 and 3.0 mg/kg, respectively. Cidofovir reached quantifiable levels in the serum of only one patient for each of the 1.5- and 3.0-mg/kg oral cyclic HPMPC doses.

Administration, Oral↗
PubMed1998

Direction determination in the minus-end-directed kinesin motor ncd.

Motor proteins of the kinesin superfamily transport intracellular cargo along microtubules. Although different kinesin proteins share 30-50% amino-acid identity in their motor catalytic cores, some move to the plus end of microtubules whereas others travel in the opposite direction. Crystal structures of the catalytic cores of conventional kinesin (a plus-end-directed motor involved in organelle transport) and ncd (a minus-end-directed motor involved in chromosome segregation) are nearly identical; therefore, the structural basis for their opposite directions of movement is unknown. Here we show that the ncd 'neck' made up of 13 class-specific residues next to the superfamily-conserved catalytic core, is essential for minus-end-directed motility, as mutagenesis of these neck residues reverses the direction of ncd motion. By solving the 2.5 A structure of a functional ncd dimer, we show that the ncd neck (a coiled-coil) differs from the corresponding region in the kinesin neck (an interrupted beta-strand), although both necks interact with similar elements in the catalytic cores. The distinct neck architectures also confer different symmetries to the ncd and kinesin dimers and position these motors with appropriate directional bias on the microtubule.

Cloning, Molecular↗
PubMed1996

Chemical safety of U.S. Navy Fleet soda lime.

Contamination was suspected of U.S. Navy Fleet soda lime (High Performance Sodasorb) when an ammonia-like odor was reported during its use in August 1992. This material contained indicator dye and was used for carbon dioxide absorption during diving. This incident had a major impact on the U.S Navy diving program when the Navy temporarily banned use of Sodasorb and authorized Sofnolime as an interim replacement. The Naval Medical Research Institute was assigned to investigate. Testing involved sampling from the headspace (gas space) inside closed buckets and from an apparatus simulating conditions during operational diving. Volatile organic compounds were analyzed by gas chromatography and mass spectrometry; ammonia and amines were measured by infrared spectroscopy. Significant amounts of ammonia (up to 30 ppm), ethyl and diethyl amines (up to several ppm), and various aliphatic hydrocarbons (up to 60 ppm) were detected during testing of both Sodasorb and Sofnolime. Contaminants were slowly removed by gas flow and did not return. The source(s) of the ammonia and amines are unknown, although they may result from the breakdown of the indicator dye. Hydrocarbon contamination seems to result from the materials of which the bucket is constructed. Unfortunately, evaluation of potential hazards associated with this contamination is difficult, due in part to the large number of variables of operational use and the absence of appropriate exposure limits. Based on these findings, the U.S. Navy has begun to phase in, for all diving, non-indicating soda lime that will be required to meet defined contaminant limits.

Amines↗
PubMed1995

The economics of orphan drug policy in the US. Can the legislation be improved?

This review of the US Orphan Drug Act (ODA) 1983 outlines how the ODA is intended to stimulate orphan drug research and development of drugs for rare diseases. We also evaluate the effectiveness of the ODA in the past decade and provide recommendations for ODA improvements in the future. The economic incentives embedded in the ODA are presented in a simple economic model, in which a guarantee of market exclusivity plays a central role in encouraging firms to pursue the development of orphan products. Some evidence suggests that this provision has been a major impetus for the rise in orphan drug applications and designations in the last decade. Market exclusivity is the key incentive for orphan drug research, and should be retained. Concerns about a limited number of highly successful 'blockbuster' orphan drugs should be evaluated in terms of the useful economic incentives. In the future, exceptionally high profits could be limited by more precise evaluation of disease prevalence, elasticity of demand, and the other uses of orphan compounds. We further recommend an expansion of the ODA tax credits and research grants programme and targeting of 'priority' diseases. We conclude that the ODA has been a valuable legislative initiative, but it can be strengthened with some simple extensions of the current incentives that it contains.

Drug Industry↗
PubMed1971

Abnormal membrane protein of red blood cells in hereditary spherocytosis.

We present evidence that the hereditable hemolytic disease, hereditary spherocytosis (HS), involves an abnormality in protein of the red cell membrane. Unlike that from normal red cells, lipid-free proteins extracted from HS red cell membranes fail to increase in sedimentation rate when treated with cations; such treatment of normal membrane proteins has been shown by others to cause the formation of microfilaments. That microfilament formation might be defective in HS red cell membranes is supported by observations with vinblastine. This compound, a potent precipitant of filamentous, structure proteins throughout phylogeny, precipitates significantly less HS membrane protein than normal. The resistance of HS membrane protein to changes in conformation by cations is observable at the cellular level as well. That is, both normal and HS red cells agglutinate after repeated washing and suspension in electrolyte-free media. Tiny concentrations of Ca(++) (5 x 10(-5) M) changes the surfaces of normal cells in such a way as to cause disagglutination; HS red cells resist this change and remain agglutinated unless Ca(++) concentrations are increased many-fold. We conclude that membrane ("structure") proteins of HS red cells are genetically altered in such a way as to interfere with their proper conformation, perhaps into fibrils. Potentially many mutations in membrane proteins might preclude this alignment, with the result that normal erythrocyte biconcavity and plasticity is prevented and the clinical syndrome of hereditary spherocytosis is manifest.

Blood Protein Disorders↗
PubMed1970

Precipitation of proteins by vinblastine and calcium ions.

We have found that vinblastine sulfate can precipitate a number of proteins in addition to microtubule protein. Those proteins which precipitate with vinblastine sulfate, all of which were derived from structure, also precipitate with Ca(2+) ions. Our results suggest that vinblastine sulfate, presumably acting as a cation, precipitates proteins by combining with sites which can also combine with Ca(2+) ions.

Animals↗