Biomedical subjects

Mark A Wilson

Publications and source records attributed to Mark A Wilson.

24 records · Page 2Linked to original sources

PubMed2003

2.4 A resolution crystal structure of the prototypical hormone-processing protease Kex2 in complex with an Ala-Lys-Arg boronic acid inhibitor.

This paper reports the first structure of a member of the Kex2/furin family of eukaryotic pro-protein processing proteases, which cleave sites consisting of pairs or clusters of basic residues. Reported is the 2.4 A resolution crystal structure of the two-domain protein ssKex2 in complex with an Ac-Ala-Lys-boroArg inhibitor (R = 20.9%, R(free) = 24.5%). The Kex2 proteolytic domain is similar in its global fold to the subtilisin-like superfamily of degradative proteases. Analysis of the complex provides a structural basis for the extreme selectivity of this enzyme family that has evolved from a nonspecific subtilisin-like ancestor. The P-domain of ssKex2 has a novel jelly roll like fold consisting of nine beta strands and may potentially be involved, along with the buried Ca(2+) ion, in creating the highly determined binding site for P(1) arginine.

Amino Acid Sequence↗

PubMed2003

Immune-enhancing enteral diet increases blood flow and proinflammatory cytokines in the rat ileum.

BACKGROUND: Enteral feeding improves outcome following surgery. Benefits depend on timing, route (enteral vs parenteral), and nutrient composition (standard vs immune-enhancing diets; IED). IED augments intestinal immunity and stimulates gut blood flow during absorption in a nutrient-specific manner. We hypothesize that a mechanism for the gut protective effect of IED is augmentation of blood flow to the gut-associated lymphoid tissue (GALT) in the terminal ileum. METHODS: Male Sprague-Dawley rats (200-230 g) were fed for 5 days either an IED (Impact, Novartis) or an isocaloric, isonitrogenous control diet (CD, Boost, Mead-Johnson) matched to the daily caloric intake (rat chow). Rats were then anesthetized and cannulated for microsphere determination of whole organ blood flow. Blood glucose levels and blood flow to abdominal organs were determined at baseline and 30, 60, 90, and 120 min after gastric gavage (2 ml) with IED or CD. Intestinal tissues were harvested for cytokine levels (ELISA: IL-4, IL-10, IFN-gamma, and IgA). RESULTS: Chronic IED increased baseline blood flow in the distal third of the small intestine compared to chow-fed and CD. Baseline blood flow was comparable between IED and CD in all other organs. CD and IED produced different blood flow patterns after gavage. CD increased blood flow compared to baseline and IED in antrum, duodenum, and jejunum. Ileal blood flow remained elevated in IED rats for 2 h, perhaps suggesting maximal blood flow. IED increased blood glucose compared to CD. Chronic IED increased IL-4 and decreased IL-10 in the terminal ileum. CONCLUSIONS: Chronic IED exposure increases and sustains ileal blood flow compared to CD with altered proinflammatory cytokine expression. Our data suggest that a mechanism for the IED effect involves the selective perfusion of the terminal ileum and contiguous GALT during IED nutrient absorption.

Animals↗

PubMed2003

Regional changes in rat brain inositol monophosphatase 1 (IMPase 1) activity with chronic lithium treatment.

Myo-inositol monophosphatase 1 (IMPase 1) is one of the targets for the mood-stabilizing action of lithium. Inhibition of IMPase is the basis for the "inositol depletion hypothesis" for the molecular action of lithium. To better understand the precise action of chronic (up to 4 weeks) lithium treatment on IMPase 1 activity, we measured IMPase 1 activity using both a colorimetric and a radiometric assay in rats (53-58 days old) fed a diet containing 0.2% lithium carbonate. Our results show that IMPase 1 activity increases substantially in the various brain regions analyzed, even doubling in some regions in the following order, after chronic treatment: hippocampus>cerebellum>striatum>cerebral cortex>brain stem. Both the qualitative and quantitative increases of IMPase 1 activity by chronic lithium treatment were substantiated by Western blot analysis of hippocampal and cerebral cortex regions. We conclude that the increased IMPase 1 activity is an adaptational response to chronic lithium treatment, and may involve direct or indirect stimulation of IMPA1 (which encodes IMPase 1) and/or turnover of the enzyme. The increased enzyme activity may alter critical neurochemical processes involving either free myo-inositol, the precursor of inositol based signaling system or other metabolic pathways, since IMPase 1 also utilizes selective sugar phosphates, such as galactose-1-phosphate, as substrates. One or more of these signal and metabolic pathways may be associated with lithium's psychotherapeutic mood-stabilizing action.

Administration, Oral↗

PubMed2003

A meta-analysis of job analysis reliability.

Average levels of interrater and intrarater reliability for job analysis data were investigated using meta-analysis. Forty-six studies and 299 estimates of reliability were cumulated. Data were categorized by specificity (generalized work activity or task data), source (incumbents, analysts, or technical experts), and descriptive scale (frequency, importance, difficulty, time-spent, and the Position Analysis Questionnaire). Task data initially produced higher estimates of interrater reliability than generalized work activity data and lower estimates of intrarater reliability. When estimates were corrected for scale length and number of raters by using the Spearman-Brown formula, task data had higher interrater and intrarater reliabilities. Incumbents displayed the lowest reliabilities. Scales of frequency and importance were the most reliable. Implications of these reliability levels for job analysis practice are discussed.

Employment↗

PubMed2003

Characterization of Pasteurella multocida isolates from wetland ecosystems during 1996 to 1999.

We cultured 126 Pasteurella multocida isolates, 92 from water and 34 from sediment samples collected from wetlands in the Pacific and Central flyways of the United States between 1996 and 1999. Most (121) of the isolates were P. multocida serotype 1, but serotypes 3, 3/4, 10, and 11 were also found. Many (82) of the isolates were further characterized by DNA fingerprinting procedures and tested in Pekin ducks for virulence. Almost all the serotype 1 isolates we tested caused mortality in Pekin ducks. Serotype 1 isolates varied in virulence, but the most consistent pattern was higher mortality in male ducks than in females. We found no evidence that isolates found in sediment vs. water, between Pacific and Central flyways, or during El Niño years had consistently different virulence. We also found a number of non-serotype 1 isolates that were avirulent in Pekin ducks. Isolates had DNA fingerprint profiles similar to those found in birds that died during avian cholera outbreaks.

Animals↗

PubMed2002

Omega-3 fatty acids in immune-enhancing enteral diets selectively increase blood flow to the ileum by a bile acid dependent mechanism.

BACKGROUND: The immune-enhancing diet (IED) (Impact, Novartis Corp, Minneapolis, Minn) initiates a delayed and sustained increase in blood flow to the ileum and gut-associated lymphoid tissue. The immune-enhancing benefits of Impact (Novartis Corp) are attributed to the addition of L-arginine, fish oil (FO), and RNA fragments to a standard enteral diet. The sustained increase in blood flow to the gut-associated lymphoid tissue during IED exposure might account for these immune effects. We hypothesized that the increase in ileal blood flow with IED might be a result of ileal omega-3 fatty acid absorption in the ileum by a bile-dependent mechanism. METHODS: Male Sprague-Dawley rats (200 g-230 g) were anesthetized and cannulated for microsphere measurement of whole organ blood flow. Rats received gastric gavage (2 mL) with either IED, an isocaloric, isonitrogenous control diet (CD) (Boost, Mead-Johnson, Evansville, Ind), CD plus menhaden FO (CD+FO), or CD+FO plus bile duct ligation (BDL). Blood flow was determined at baseline and 30, 60, and 120 minutes after short-term gavage. RESULTS: Baseline blood flow and central hemodynamics were comparable in all groups. In the ileum, at 120 minutes postgavage, blood flow was increased by IED and CD+FO compared with baseline and CD. BDL prevented the increase in blood flow in the CD+FO+BDL rats. All groups exhibited differences in splanchnic blood flow distribution after gavage: CD and CD+FO+BDL increased blood flow compared with baseline early in the proximal gut and spleen. IED and CD+FO produced a delayed, sustained hyperemia to the distal gut. CONCLUSIONS: Gastrointestinal blood flow distribution after feeding is dependent on nutrient composition. These findings suggest that omega-3 fatty acids are the components of the enteral IED, Impact (Novartis Corp), which produce the increased blood flow to the terminal ileum and its contiguous gut-associated lymphoid tissue. Our data suggests that an intact enterohepatic bile pathway is needed for the IED blood flow effect.

Animals↗