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Biomedical subjects

S Park

Publications and source records attributed to S Park.

At least 217 records · Page 12Linked to original sources
PubMed2000

Secretagogues and the somatotrope: signaling and proliferation.

Somatotrope function requires consideration of both growth hormone (GH) secretion and cellular proliferation. The regulation of these processes is, to a large extent, controlled by three hypothalamic hormones: GH-releasing hormone (GHRH), somatostatin (SRIF), and an as-yet-unidentified GH secretagogue (GHS). Each binds to G protein-linked membrane receptors through which signaling occurs. Our laboratory has used a series of genetic and transgenic models with perturbations of individual components of the GH regulatory system to study both somatotrope signaling and proliferation. Impaired GHRH signaling is present in the lit mouse, which has a GHRH receptor (R) mutation, and the dw rat, which has a post-receptor signaling defect. Both models also have impaired responses to a GHS, implying an interaction between the two signaling systems. The spontaneous dwarf rat (SDR), in which a mutation of the GH gene results in total absence of the hormone, shows characteristic changes in the hypothalamic regulatory hormones due to an absence of GH feedback and alterations in the expression of each of their pituitary receptors. Treatment of SDRs with GHRH and a GHS has allowed demonstration of a stimulatory effect of GHRH on GHRH-R, GHS-R, and SRIF type 2 receptor (SSTR-2) expression and an inhibitory effect on SSTR-5 expression. GH also modifies the expression of these receptors, though its effects are seen at later time periods and appear to be indirect. Overall, the results indicate a complex regulation of GH secretion in which somatotrope receptor, as well as ligand expression, exerts an important physiological role. Both the SDR and the GH-R knockout (ko) mouse have small pituitaries and decreased somatotropes, despite elevated GHRH secretion and intact GHRH-R signaling. Introduction of the hGHRH transgene into GH-R ko mice confirmed that the proliferative effects of GHRH require GH/insulin-like growth factor-I (IGF-I) action. The results offer new insights into factors participating in somatotrope proliferation.

Animals↗
PubMed1999

Increased binding at 5-HT(1A), 5-HT(1B), and 5-HT(2A) receptors and 5-HT transporters in diet-induced obese rats.

5-Hydroxytryptamine (5-HT, serotonin), synthesized in midbrain raphe nuclei and released in various hypothalamic sites, decreases food intake but the specific 5-HT receptor subtypes involved are controversial. Here, we have studied changes in the regional density of binding to 5-HT receptors and transporters and the levels of tryptophan hydroxylase, in rats with obesity induced by feeding a palatable high-energy diet for 7 weeks. We mapped binding at 5-HT receptor subtypes and transporters using quantitative autoradiography and determined tryptophan hydroxylase protein levels by Western blotting. In diet-induced obese (DiO) rats, specific binding to 5-HT(1A) receptors ([3H]8-OH-DPAT) was significantly increased in the dorsal and median raphe by 90% (P<0.01) and 132% (P<0.05), respectively, compared with chow-fed controls. 5-HT(1B) receptor binding sites ([125I]cyanopindolol) were significantly increased in the hypothalamic arcuate nucleus (ARC) of DiO rats (58%; P<0.05), as were 5-HT(2A) receptor binding sites ([3H]ketanserin) in both the ARC (44%; P<0.05) and lateral hypothalamic area (LHA) (121%; P<0.05). However, binding to 5-HT(2C) receptors ([3H]mesulgergine) in DiO rats was not significantly different from that in controls in any hypothalamic region. Binding to 5-HT transporters ([3H]paroxetine) was significantly increased (P<0.05) in both dorsal and median raphe, paraventricular nuclei (PVN), ventromedial nuclei (VMH), anterior hypothalamic area (AHA) and LHA of DiO rats, by 47%-165%. Tryptophan hydroxylase protein levels in the raphe nuclei were not significantly different between controls and DiO rats. In conclusion, we have demonstrated regionally specific changes in binding to certain 5-HT receptor subtypes in obesity induced by voluntary overeating of a palatable diet. Overall, these changes are consistent with reduced 5-HT release and decreased activity of the 5-HT neurons. Reduction in the hypophagic action of 5-HT, possibly acting at 5-HT(1A), 5-HT(1B) and 5-HT(2A) receptors, may contribute to increased appetite in rats presented with highly palatable diet.

Animals↗
PubMed1999

Spatial working memory: absence of gender differences in schizophrenia patients and healthy control subjects.

BACKGROUND: Spatial working memory dysfunction has been suggested to be a cardinal feature of schizophrenia. But schizophrenia is heterogeneous in its clinical profile, course, and outcome. One fundamental contributor to this heterogeneity may be gender. No report has yet addressed gender differences in spatial working memory, as measured by the delayed-response task (DRT). METHODS: We aggregated data from three previously published studies of spatial working memory in schizophrenia and also collected DRT data from a new sample of subjects in order to examine potential gender differences in DRT performance. RESULTS: As previously reported, schizophrenia patients (n = 71) showed deficits in spatial working memory relative to normal control subjects (n = 213), however, no within-group or between-group gender differences were present. CONCLUSIONS: These findings provide evidence for the absence of gender differences in spatial working memory function.

Adult↗
PubMed1999

Phosphorylation at Tyr-838 in the kinase domain of EphA8 modulates Fyn binding to the Tyr-615 site by enhancing tyrosine kinase activity.

Eph-related receptors and their ephrin ligands are highly conserved protein families which play important roles in targeting axons and migrating cells. In this study we have examined the functional roles of two major autophosphorylation sites, Tyr-615 and Tyr-838, in the EphA8 receptor. Two-dimensional phosphopeptide mapping analysis demonstrated that Tyr-615 and Tyr-838 constitute major autophosphorylation sites in EphA8. Tyr-615 was phosphorylated to the highest stoichiometry, suggesting that phosphorylation at this site may have a physiologically important role. Upon conservative mutation of Tyr-838 located in the tyrosine kinase domain, the catalytic activity of EphA8 was strikingly reduced both in vitro and in vivo, whereas a mutation at Tyr-615 in the juxtamembrane domain did not impair the tyrosine kinase activity. In vitro binding experiments revealed that phosphorylation at Tyr-615 in EphA8 mediates the preferential binding to Fyn-SH2 domain rather than Src and Ras GTPase-activating protein (Ras GAP)-SH2 domains. Additionally, a high level of EphA8 was detected in Fyn immunoprecipitates in intact cells, indicating that EphA8 and Fyn can physically associate in vivo. In contrast, the association of full-length Fyn to EphA8 containing mutation at either Tyr-615 or Tyr-838 was greatly reduced. These data indicate that phosphorylation of Tyr-615 is critical for determining the association with Fyn whereas the integrity of Tyr-838 phosphorylation is required for efficient phosphorylation at Tyr-615 as well as other major sites. Finally, it was observed that cell attachment responses are attenuated by overexpression of wild type EphA8 receptor but to much less extent by EphA8 mutants lacking phosphorylation at either Tyr-615 or Tyr-838. Furthermore, transient expression of kinase-inactive Fyn in EphA8-overexpressing cells blocked cell attachment responses attenuated by the EphA8 signaling. We therefore propose that Fyn kinase is one of the major downstream targets for the EphA8 signaling pathway leading to a modification of cell adhesion, and that autophosphorylation at Tyr-838 is critical for positively regulating the EphA8 signaling event.

Amino Acid Sequence↗
PubMed1999

A metal complex that binds alpha-amino acids with high and predictable stereospecificity.

Molecular recognition is the key step in a wide range of controlled separation and chemical transformation processes, with enzymes performing this task with an unsurpassed degree of selectivity. Enzymes contain only 20 simple amino acids, yet it remains difficult to rationalize or even predict these stereospecific recognition events. Nonetheless, the rational design of receptors able to recognize amino acids stereospecifically is attracting considerable interest because therapeutic drugs, that may be developed from chiral amino acid intermediates, are increasingly required in enantiomerically pure form. Early work has stimulated the development of efficient receptors based on small molecules, but binding of amino acids with high and predictable stereospecificity remains difficult to achieve. Directed molecular evolution, on the other hand, does select for RNA sequences or antibodies that bind amino acids with high specificity, but typically without providing insights into the molecular recognition mechanisms involved. Here we show that a rationally designed metal complex formed from a trivalent cobalt ion and a tetradentate ligand binds natural amino acids, including the simple yet challenging amino acid alanine, with high and predictable regio- and stereospecificity. We expect that our approach will allow the binding as well as separation and stereospecific catalytic formation of its target amino acids.

Amino Acids↗
PubMed1999

Characterization of ephrin-A1 and ephrin-A4 as ligands for the EphA8 receptor protein tyrosine kinase.

The Eph receptors are the largest known family of receptor protein tyrosine kinases, which play important roles with their ligands called ephrin in the neural development, angiogenesis, and vascular network assembly. It was previously shown that ephrin-A2, -A3 and -A5 bind to, and activate the EphA8 receptor tyrosine kinase, respectively. In this study, we have examined if there are other additional ephrin ligands interacting with the EphA8 receptor tyrosine kinase expressed in NIH3T3 fibroblasts. For this purpose, we have constructed chimeric ephrin-A1, -A4, -B1, -B2 or -B3 ligands consisting of the Fc portion of human IgG fused to their carboxyl-terminus. Both ephrin-A1 and ephrin-A4 chimeric ligands efficiently bound to the EphA8 receptor expressed in NIH3T3 fibroblasts, whereas the transmembrane ligands including ephrin-B1, -B2 and -B3 did not. Additionally we have demonstrated that both the EphA8-TrkB chimeric receptor and the EphA8 receptor expressed in NIH3T3 fibroblasts are efficiently tyrosine-phosphorylated upon stimulating with epthin-A1 or -A4 but none of transmembrane ephrin-B proteins. These results strongly indicate that the EphA8 receptor functions exclusively as an glycosyl phosphatidylinositol (GPI)-linked ephrin ligand-dependent receptor protein tyrosine kinase.

3T3 Cells↗
PubMed1999

Spatial working memory deficits and clinical symptoms in schizophrenia: a 4-month follow-up study.

BACKGROUND: Our goal was to examine spatial working memory function in relation to clinical symptoms of schizophrenia over a period of 4 months. METHODS: We assessed spatial working memory, spatial detection and clinical symptoms in 34 acutely psychotic schizophrenia patients within the first 2 weeks of hospitalization, and 4 months later. Spatial working memory was assessed by a delayed response task. A spatial control task was included to rule out simple sensorimotor deficits. Positive and negative symptoms were assessed by the Positive and Negative Syndrome Scale (PANSS). Thirty-nine matched normal control subjects were also examined on the same tasks over the same period. RESULTS: Patients showed deficits in working memory, but they performed well on the spatial control task. Both positive and negative symptoms improved at the 4-month follow up. Spatial working memory also improved over time but there was still a significant deficit at the follow-up session. CONCLUSIONS: These results indicate that both symptoms and spatial working memory improved 4 months after the initial hospitalization but spatial working memory, hypothesized to be mediated by the dorsolateral prefrontal system, did not normalize. Thus, spatial working memory deficit may be a stable marker for schizophrenia.

Acute Disease↗
PubMed1999

Trinitrophenylated reactive lysine residue in myosin detects lever arm movement during the consecutive steps of ATP hydrolysis.

Trinitrophenylation of the reactive lysine (Lys84) in skeletal myosin subfragment 1 (S1) introduces a chiral probe (TNP) into an interface of the catalytic and lever arm domains of S1 [Muhlrad (1977) Biochim. Biophys. Acta 493, 154-166]. Characteristics of the TNP absorption and circular dichroism (CD) spectra in TNP-modified S1 (TNP-Lys84-S1), and the Lys84 trinitrophenylation rate in native S1, indicate a one-to-one correspondence between ATPase transients and trapped phosphate analogues. Phosphate analogue-induced structures of TNP-Lys84-S1 were modeled using the crystallographic coordinates of S1 [Rayment et al. (1993) Science 261, 50-58] with swivels at Gly699 and Gly710 to approximate conformational changes during ATPase. The CD and absorption spectral characteristics of the model structures were compared to those observed for analogue-induced structures. The model calculations, first tested on a trinitrophenylated hexapeptide with known structure, were applied to TNP-Lys84-S1. They showed that ATP binding initiates swiveling at Gly699 and that swiveling at both Gly710 and Gly699 accompanied ATP splitting just prior to product release. The computed lever arm trajectory during ATPase suggests (i) a plausible mechanism for the nucleotide-induced inhibition of Lys84 trinitrophenylation, and (ii) trinitrophenylation-induced changes in S1 Mg2+- and K+-EDTA ATPase are from collision of the lever arm with TNP at Lys84. TNP is a site-specific structural perturbant of S1 and a chiral reporter group for the effect of Lys84 modification on dynamic S1 structure. As such, TNP-Lys84-S1 is equivalent to a genetically engineered mutant with intrinsic sensitivity to structure local to the modified residue.

Adenosine Triphosphate↗
PubMed1999

Surface geochemistry of the clay minerals.

Clay minerals are layer type aluminosilicates that figure in terrestrial biogeochemical cycles, in the buffering capacity of the oceans, and in the containment of toxic waste materials. They are also used as lubricants in petroleum extraction and as industrial catalysts for the synthesis of many organic compounds. These applications derive fundamentally from the colloidal size and permanent structural charge of clay mineral particles, which endow them with significant surface reactivity. Unraveling the surface geochemistry of hydrated clay minerals is an abiding, if difficult, topic in earth sciences research. Recent experimental and computational studies that take advantage of new methodologies and basic insights derived from the study of concentrated ionic solutions have begun to clarify the structure of electrical double layers formed on hydrated clay mineral surfaces, particularly those in the interlayer region of swelling 2:1 layer type clay minerals. One emerging trend is that the coordination of interlayer cations with water molecules and clay mineral surface oxygens is governed largely by cation size and charge, similarly to a concentrated ionic solution, but the location of structural charge within a clay layer and the existence of hydrophobic patches on its surface provide important modulations. The larger the interlayer cation, the greater the influence of clay mineral structure and hydrophobicity on the configurations of adsorbed water molecules. This picture extends readily to hydrophobic molecules adsorbed within an interlayer region, with important implications for clay-hydrocarbon interactions and the design of catalysts for organic synthesis.

Journal Article↗
PubMed1999

Inhibition of myosin ATPase by metal fluoride complexes.

Magnesium (Mg2+) is the physiological divalent cation stabilizing nucleotide or nucleotide analog in the active site of myosin subfragment 1 (S1). In the presence of fluoride, Mg2+ and MgADP form a complex that traps the active site of S1 and inhibits myosin ATPase. The ATPase inactivation rate of the magnesium trapped S1 is comparable but smaller than the other known gamma-phosphate analogs at 1.2 M-1 s-1 with 1 mM MgCl2. The observed molar ratio of Mg/S1 in this complex of 1.58 suggests that magnesium occupies the gamma-phosphate position in the ATP binding site of S1 (S1-MgADP-MgFx). The stability of S1-MgADP-MgFx at 4 degrees C was studied by EDTA chase experiments but decomposition was not observed. However, removal of excess fluoride causes full recovery of the K+-EDTA ATPase activity indicating that free fluoride is necessary for maintaining a stable trap and suggesting that the magnesium fluoride complex is bonded to the bridging oxygen of beta-phosphate more loosely than the other known phosphate analogs. The structure of S1 in S1-MgADP-MgFx was studied with near ultraviolet circular dichroism, total tryptophan fluorescence, and tryptophan residue 510 quenching measurements. These data suggest that S1-MgADP-MgFx resembles the M**.ADP.Pi steady-state intermediate of myosin ATPase. Gallium fluoride was found to compete with MgFx for the gamma-phosphate site in S1-MgADP-MgFx. The ionic radius and coordination geometry of magnesium, gallium and other known gamma-phosphate analogs were compared and identified as important in determining which myosin ATPase intermediate the analog mimics.

Acrylamide↗
PubMed1999

Purification and characterization of a novel chitinase from the entomopathogenic fungus, Metarhizium anisopliae.

A novel chitinase was detected in extracellular culture fluids of the entomopathogenic fungus Metarhizium anisopliae (ATCC 20500) grown in liquid medium containing chitin as a sole carbon source. A chitinase was purified to near homogeneity from culture broth of M. anisopliae by DEAE-Sephacel, CM-Sepharose CL-6B ion-exchange chromatography, and gel filtration with Superose 12HR. The molecular mass of the enzyme determined by SDS-polyacrylamide gel electrophoresis was approximately 60 kDa and the optimum pH of the enzyme was 5.0. This molecular mass is different from values of 33, 43.5, and 45 kDa for endochitinases and 110 kDa for an exochitinase (N-acetylglucosaminidase) from M. anisopliae ME-1 published previously. In addition, N-terminal sequences of 60-kDa chitinase are different from those of 43.4- and 45-kDa endochitinases. The purified enzyme showed high chitinolytic activity against colloidal, crystalline chitin of crab shells as well as against p-nitrophenyl-beta-d-N-acetylglucosamide, p-nitrophenyl-beta-d-N, N'-diacetylchitobiose, and p-nitrophenyl-N, N'-N"-triacetylchitotriose, indicating that this enzyme has both endo- and exochitinase activity.

Chitinases↗
PubMed1999

Effect of ovariectomy and estrogen replacement on cardiovascular disease in heart failure-prone SHHF/Mcc- fa cp rats.

The importance of endogenous and exogenous estrogen levels to the development of cardiovascular disease in women in controversial. The purpose of our study was to examine the effect of estrogen on the development of hypertension, cardiac hypertrophy, ventricular function, and gene expression for atrial natriuretic peptide (ANP) and components of the renin angiotensin system in spontaneously hypertensive heart failure rats (SHHF/Mcc- facp). Development of hypertension was prevented in 3-month-old ovariectomized rats receiving subcutaneous 17 beta -estradiol implants (EST) compared to ovariectomized (OVX) and controls (CON). EST had the least left ventricular hypertrophy, CON were intermediate, and OVX had the most (P<0.05), correlating well with systolic blood pressure. OVX had significantly lower percentage V(1)myosin isoform compared to EST and CON, indicating reversion to a more immature phenotype associated with hypertrophy. Similarly, OVX had decreased percentage left ventricular shortening fraction by echocardiography compared to EST and CON. These changes were not accompanied by alterations in plasma ANP, or in expression of mRNA for left ventricular ANP, renal renin, or hepatic angiotensinogen. Serum angiotensin converting enzyme activity was lower in EST compared to CON or OVX. When 17 beta -estradiol was given to 17-month-old rats that had naturally ceased estrous cycling, there was no effect on hypertension, progression of cardiac functional decline, or survival. In conclusion, estradiol treatment given prior to the development of hypertension in SHHF prevented left ventricular hypertrophy and hypertension. Development of congestive heart failure was not delayed if 17 beta -estradiol was begun in the post-menopausal period. Effectiveness of estrogen therapy may depend on age or whether hypertension is already established at the time treatment is begun.

Animals↗
PubMed1999

Mechanisms mediating lipoprotein responses to diets with medium-chain triglyceride and lauric acid.

Medium-chain triglycerides (MCT) are often used in specialized formula diets or designer fats because of their special properties. Yet their influence on lipid metabolism is not completely understood. In this two-period cross-over study, the effects of MCT (8:0 + 10:0) in contrast to a similar saturated fatty acid (12:0) were compared. Eighteen healthy women ate a baseline diet [polyunsaturated (PUFA)/saturated fat = 0.9] for 1 wk. Then, they consumed test diets (PUFA/saturated fat = 0.2) for 4 wk. Monounsaturated fat and cholesterol were constant in baseline and treatment diets. MCT and 12:0, substituted for part of the PUFA, provided 14 energy (en)% of the test diets. In comparison to the PUFA baseline diet, a 16% increase in mean serum low density lipoprotein (LDL)-cholesterol (C) on the 12:0 diet was accompanied by a 21% decrease in mean receptor-mediated degradation of LDL by freshly isolated mononuclear cells (MNC) in vitro. The MNC assay theoretically gives an indication of receptor-mediated degradation of LDL. In contrast, the MCT diet raised mean receptor-mediated degradation of LDL by 42%, a finding out of line with the mean 11% increase in serum LDL-C. Perhaps MCT, by increasing the rate of LDL-C production, overcame the rate of LDL-C clearance. The 12:0 diet enhanced some factors involved in reverse cholesterol transport (e.g., high density lipoprotein fractions) while MCT had a different or less pronounced effect. The overall effects of MCT on cholesterol metabolism may or may not be desirable, whereas those of 12:0 appear largely undesirable as previously reported.

Adult↗
PubMed1999

Hemispheric asymmetry of spatial working memory deficit in schizophrenia.

Spatial working memory function was assessed in schizophrenia patients, hypothetically 'psychosis-prone' individuals who report unusual perceptual experiences and normal control subjects with an oculomotor delayed response task. Past studies point to the important role of dorsolateral prefrontal system in spatial working memory deficits of schizophrenia patients. In order to better understand the processes precipitating in working memory deficit, two types of working memory errors were examined: never-corrected vs. immediately-corrected errors. In schizophrenia patients, the loss of spatial representation in working memory, as captured by the presence of never-corrected errors, was much more severe when the target was presented in the right visual hemifield than when the target was presented in the left visual field. The same pattern was observed in healthy, psychometrically ascertained 'psychosis-prone' subjects. Therefore, the observed asymmetry of spatial working memory deficit seems unlikely to be a mere side-effect of medication or hospitalization. Normal control subjects did not show hemispheric asymmetry in error patterns. These results suggest that the loss of spatial representation during a delay period may be more severe in the left hemisphere in patients with schizophrenia and in 'psychosis-prone' individuals.

Adult↗
PubMed1999

Control of fed-batch fermentations.

Fed-batch fermentation is used to prevent or reduce substrate-associated growth inhibition by controlling nutrient supply. Here we review the advances in control of fed-batch fermentations. Simple exponential feeding and inferential methods are examined, as are newer methods based on fuzzy control and neural networks. Considerable interest has developed in these more advanced methods that hold promise for optimizing fed-batch techniques for complex fermentation systems.

Journal Article↗
PubMed1999

Hip muscle co-contraction: evidence from concurrent in vivo pressure measurement and force estimation.

The biomechanical literature over the past three decades reports direct measurements of human hip joint contact forces from instrumented implants which in general are quite different than estimates of contact forces based on external kinematic-ground reaction force data and inverse Newtonian analyses. Because direct physical measurement establishes veridical values in science, the higher analytical estimates may overestimate the balanced muscle force increments in agonist-antagonistic muscles about the joint (called co-contraction) which control joint impedance and contribute to joint stability. We studied the extent of muscle co-contraction by comparing in vivo endoprosthesis pressure measurements on hip articular cartilage and intersegmental force estimations from concurrent kinetic-kinematic data. Muscle co-contraction was evident from pressure magnitudes higher than those consistent with external data, from pressure rises before foot-floor contact, and substantial differences in the locations on the acetabulum of the highest pressures compared with the corresponding force vectors estimated from external data. Therefore, joint force and pressure inferences from external kinematic and kinetic data, without corroborating direct, internal measurements, should be made with more caution than is evident in the current literature.

Aged↗
PubMed1999

Portal vein embolization with use of a new liquid embolic material: an experimental study.

PURPOSE: To evaluate the efficacy and safety of a new liquid embolic material in portal vein embolization (PVE). MATERIALS AND METHODS: A new embolic material (Embol) was percutaneously injected into the left portal vein of 13 swine, using a balloon catheter to prevent reflux. The swine were killed immediately (n = 6), 2 weeks (n = 4), and 4 weeks (n = 3) after the PVE, and the volumes of the right and left lobes were measured. The changes in body temperature, aspartate aminotransferase (AST) (formerly SGOT), alanine aminotrasferase (ALT) (formerly SGPT), and bilirubin levels after the PVE were studied, and the histopathologic changes in the embolized and nonembolized lobes were examined with light microscopy. RESULTS: The average volume ratio of the right:left lobe immediately after the PVE was 55(+/-2):45(+/-1), and changed to 71(+/-3):29(+/-3) at 2 weeks and 82(+/-3):18(+/-3) at 4 weeks after embolization. There were only mild changes in AST, ALT, and bilirubin levels, and only one pig showed a significant elevation in body temperature after PVE. Microscopically, the embolized lobe showed contraction of hepatocyte without any sign of necrosis and the nonembolized lobe expansion of hepatocyte. CONCLUSIONS: The new embolic material seems effective and safe for PVE.

Animals↗