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PubMed1993

Protein binding and hepatobiliary distribution of valproic acid and valproate glucuronide in rats.

The protein binding and hepatobiliary distribution of valproic acid (VPA) and its glucuronide conjugate (V-G) were examined in rats with a combination of in vitro and ex vivo protocols. VPA was moderately bound to proteins in both serum and hepatic cytosol, and the degree of binding was lower ex vivo than in vitro. V-G, which was more highly bound than VPA ex vivo in serum, may have displaced the parent drug from its binding sites when VPA was administered in vivo. Examination of ex vivo hepatic subcellular distribution revealed that VPA localization tended to be high in cytosol and low in the microsomal fraction; V-G appeared to be distributed evenly throughout the cell although V-G concentrations within the liver were very low. The steady-state elimination rate of VPA did not increase proportionately with increasing steady-state concentrations of unbound VPA in serum, consistent with saturable systemic elimination of the drug. In contrast, steady-state VPA elimination was related linearly to unbound cytosolic VPA concentrations. Moreover, a nonlinear relationship between the unbound concentrations of VPA in hepatic cytosol and serum was observed, consistent with saturable distribution of the unbound drug between the two compartments in vivo. These observations suggest that the nonlinear elimination of VPA in rats may be due to concentration-dependent penetration of the drug into the liver as opposed to saturable biotransformation.

Animals↗
PubMed2000

D-Ala-D-X ligases: evaluation of D-alanyl phosphate intermediate by MIX, PIX and rapid quench studies.

BACKGROUND: The D-alanyl-D-lactate (D-Ala-D-Lac) ligase is required for synthesis of altered peptidoglycan (PG) termini in the VanA phenotype of vancomycin-resistant enterococci (VRE), and the D-alanyl-D-serine (D-Ala-D-Ser) ligase is required for the VanC phenotype of VRE. Here we have compared these with the Escherichia coli D-Ala-D-Ala ligase DdlB for formation of the enzyme-bound D-alanyl phosphate, D-Ala(1)-PO(3)(2-) (D-Ala(1)-P), intermediate. RESULTS: The VanC2 ligase catalyzes a molecular isotope exchange (MIX) partial reaction, incorporating radioactivity from (14)C-D-Ser into D-Ala-(14)C-D-Ser at a rate of 0.7 min(-1), which approaches kinetic competence for the reversible D-Ala(1)-P formation from the back direction. A positional isotope exchange (PIX) study with the VanC2 and VanA ligases displayed a D-Ala(1)-dependent bridge to nonbridge exchange of the oxygen-18 label of [gamma-(18)O(4)]-ATP at rates of up to 0.6 min(-1); this exchange was completely suppressed by the addition of the second substrate D-Ser or D-Lac, respectively, as the D-Ala(1)-P intermediate was swept in the forward direction. As a third criterion for formation of bound D-Ala(1)-P, we conducted rapid quench studies to detect bursts of ADP formation in the first turnover of DdlB and VanA. With E. coli DdlB, there was a burst amplitude of ADP corresponding to 26-30% of the DdlB active sites, followed by the expected steady-state rate of 620-650 min(-1). For D-Ala-D-Lac and D-Ala-D-Ala synthesis by VanA, we measured a burst of 25-30% or 51% of active enzyme, respectively. CONCLUSIONS: These three approaches support the rapid (more than 1000 min(-1)), reversible formation of the enzyme intermediate D-Ala(1)-P by members of the D-Ala-D-X (where X is Ala, Ser or Lac) ligase superfamily.

Adenosine Triphosphate↗
PubMed1993

Involvement of a phosphoprotein on the zymogen granule membrane in the control of regulated exocytosis in the exocrine pancreas.

The pancreatic acinar cell is one of a number of cell types in which phosphoproteins are believed to be involved in the control of regulated exocytosis. We have examined the effects of three agents that affect secretion in the acinar cell on the phosphorylation states of proteins on the zymogen granule membrane. We show that Ca2+ and GTP gamma S, which stimulate secretion, also stimulate the phosphorylation of a protein of M(r) 45,000 (p45) on isolated zymogen granules. On the other hand, the protein kinase inhibitor genistein inhibits both secretion and phosphorylation of p45. For all three agents, p45 phosphorylation is affected over concentration ranges identical to those that affect secretion. The stimulatory effect of GTP gamma S and the inhibitory effect of genistein are also seen when the phosphorylation state of p45 on granules within permeabilized cells is examined. Ca2+, however, over the same concentration range, now causes dephosphorylation of p45. Furthermore, the time-course of this effect is similar to that of Ca(2+)-triggered secretion. Phosphorylation of p45 is exclusively on serine, with no detectable phosphorylation on either threonine or tyrosine. We propose that exocytosis in pancreatic acini is controlled at least in part through the phosphorylation/dephosphorylation of p45, with dephosphorylation acting as a trigger for exocytosis.

Animals↗
PubMed2004

Bioisosterism: quantitation of structure and property effects.

The powerful concept of bioisosterism is presented as a method for selecting molecular groups for drug design and lead-compound development. Three group-structure characteristics are described for this purpose. The E-State value for an attached atom is used as a measure of electrotopological group impact. The volume of the group is estimated from counts of sigma, pi, and lone-pair n electrons, as embodied in the valence and simple connectivity delta values for atoms in the group. Polarity is described in terms of the polarity index Q(v). Specific examples are given for commonly used groups. Parameter spaces encoding these three attributes are presented as examples that may be used to guide bioisostere selection in late-stage drug-design procedures. The method presented here is of practical value in the decision processes of molecular modification.

Biodiversity↗
PubMed1994

Lipid intolerance does not account for susceptibility to alcoholic and gallstone pancreatitis.

BACKGROUND/AIMS: Hypertriglyceridemia is an established cause of pancreatitis and has been suggested as a predisposing factor in alcohol and gallstone-induced pancreatitis. The aims of this study were to determine fasting and postprandial triglyceride levels of alcoholics with pancreatitis, alcoholics without pancreatitis, patients with previous gallstone pancreatitis, patients with choledocholithiasis, and healthy controls. METHODS: Oral lipid tolerance studies were performed in the above groups. RESULTS: No relationship was found between alcoholic pancreatitis and hypertriglyceridemia, regardless of whether subjects were studied in the fasting state, after ingestion of fat, or after ingestion of fat with ethanol. Plasma triglyceride levels of alcoholics with pancreatitis remained similar to those of alcoholics without pancreatitis, but levels in both groups varied in relation to recent alcohol intake. Plasma triglyceride levels from both groups of alcoholics were greater than those of nonalcoholic healthy subjects. In addition, the previously reported association between postprandial hypertriglyceridemia and gallstone pancreatitis was not observed. CONCLUSIONS: Plasma triglyceride levels do not account for individual susceptibility to either alcoholic or gallstone pancreatitis.

Alcoholism↗
PubMed2002

Hemichannel and junctional properties of connexin 50.

Lens fiber connexins, cx50 and cx46 (alpha3 and alpha8), belong to a small subset of connexins that can form functional hemichannels in nonjunctional membranes. Knockout of either cx50 or cx46 results in a cataract, so the properties of both connexins are likely essential for proper physiological functioning of the lens. Although portions of the sequences of these two connexins are nearly identical, their hemichannel properties are quite different. Cx50 hemichannels are much more sensitive to extracellular acidification than cx46 hemichannels and differ from cx46 hemichannels both in steady-state and kinetic properties. Comparison of the two branches of the cx50 hemichannel G-V curve with the junctional G-V curve suggests that cx50 gap junctions gate with positive relative polarity. The histidine-modifying reagent, diethyl pyrocarbonate, reversibly blocks cx50 hemichannel currents but not cx46 hemichannel currents. Because cx46 and cx50 have very similar amino acid sequences, one might expect that replacing the two histidines unique to the third transmembrane region of cx50 with the corresponding cx46 residues would produce mutants more closely resembling cx46. In fact this does not happen. Instead the mutant cx50H161N does not form detectable hemichannels but forms gap junctions indistinguishable from wild type. Cx50H176Q is oocyte lethal, and the double mutant, cx50H61N/H176Q, neither forms hemichannels nor kills oocytes.

Amino Acid Sequence↗
PubMedDate not supplied

A comparison of teaching strategies for integrating information technology into clinical nursing education.

As health care becomes more information-intensive and diverse, there is a need to integrate information technology (IT) into clinical education. Little is known, however, about how to design instructional strategies for integrating information technology into clinical nursing education. This article outlines the instructional strategies used by faculty in five nursing programs who taught students to use a point-of-care information technology system. The article also reports students' computer acceptance and summarizes IT clinical teaching recommendations.

Adult↗
PubMed1998

Factor Xa generation at the surface of cultured rat vascular smooth muscle cells in an in vitro flow system.

The purpose of the present investigation was to explore the effects of well-defined flow conditions on the activity of tissue factor (TF) expressed on the surface of cultured rat vascular smooth muscle cells. Cells were cultured to confluence on Permanox brand slides and stimulated to express TF by a 90 min incubation with fresh growth medium containing 10 percent calf serum. The stimulated cells were then placed in a parallel plate flow chamber and perfused with Hank's Balanced Salt Solution containing factor VIIa, factor X (FX), and calcium. The chamber effluent was collected and assayed for factor Xa (FXa) and the steady-state flux of FXa was calculated. The flux values were 68.73, 94.81, 139.75, 138.19, 316.82, and 592.92 fmole/min/cm2 at wall shear rates of 10, 20, 40, 80, 320, and 1280 s-1, respectively. The FXa flux depended on the wall shear rate to a greater degree than predicted by classical mass transport theory. The flux at each shear rate was three to five times less than that calculated according to the Leveque solution. These features of the experimental data imply nonclassical behavior, which may partially result from a direct effect of flow on the cell layer.

Animals↗
PubMed2002

Folding thermodynamics of model four-strand antiparallel beta-sheet proteins.

The thermodynamic properties for three different types of off-lattice four-strand antiparallel beta-strand protein models interacting via a hybrid Go-type potential have been investigated. Discontinuous molecular dynamic simulations have been performed for different sizes of the bias gap g, an artificial measure of a model protein's preference for its native state. The thermodynamic transition temperatures are obtained by calculating the squared radius of gyration R(g)(2), the root-mean-squared pair separation fluctuation Delta(B), the specific heat C(v), the internal energy of the system E, and the Lindemann disorder parameter Delta(L). Despite these models' simplicity, they exhibit a complex set of protein transitions, consistent with those observed in experimental studies on real proteins. Starting from high temperature, these transitions include a collapse transition, a disordered-to-ordered globule transition, a folding transition, and a liquid-to-solid transition. The high temperature transitions, i.e., the collapse transition and the disordered-to-ordered globule transition, exist for all three beta-strand proteins, although the native-state geometry of the three model proteins is different. However the low temperature transitions, i.e., the folding transition and the liquid-to-solid transition, strongly depend on the native-state geometry of the model proteins and the size of the bias gap.

Biophysical Phenomena↗
PubMed1982

Reduced dopaminergic inhibition of thyrotrophin release in states of physiological hyperprolactinaemia.

We have tested the hypothesis that physiological puerperal hyperprolactinaemia may be secondary to reduced hypothalamic dopaminergic inhibition of prolactin (PRL) release. Nine post-partum females with physiological hyperprolactinaemia (aged 19-40 years; mean basal PRL +/- SE, 2099 +/- 257 mU/1, range 1002-3762 mU/1) were studied and results compared with fourteen normoprolactinaemic females (basal PRL less than 400 mU/1; aged 18-36 years). Puerperal hyperprolactinaemic females showed a reduced TSH response to dopamine (DA) receptor blockade with metoclopramide (10 mg i.v.) compared with normal females over a 60-min period following drug administration (total incremental TSH change, mean +/- SE, mU/1; 0.5 +/- 0.3 v. 3.1 +/- 1.0 P less than 0.005). This finding of reduced dopaminergic inhibition of TSH release in females with physiological puerperal hyperprolactinaemia supports the view that an overall reduction in hypothalamic dopaminergic tone may contribute towards hyperprolactinaemia in post-partum women.

Adult↗
PubMed2004

Noise spectroscopy and interlayer phase coherence in bilayer quantum Hall systems.

Bilayer quantum Hall systems develop strong interlayer phase coherence when the distance between layers is comparable to the typical distance between electrons within a layer. The phase-coherent state has until now been investigated primarily via transport measurements. We argue here that interlayer current and charge-imbalance noise studies in these systems will be able to address some of the key experimental questions. We show that the characteristic frequency of current noise is that of the zero wave vector collective mode, which is sensitive to the degree of order in the system. Local electric potential noise measured in a plane above the bilayer system, on the other hand, is sensitive to finite-wave-vector collective modes and, hence, to the soft-magnetoroton picture of the order-disorder phase transition.

Journal Article↗
PubMed1998

Clonal expansion within CD4+ and CD8+ T cell subsets in human T lymphotropic virus type I-infected individuals.

To investigate the diversity of the T cell repertoire involved in human T lymphotropic virus type I (HTLV-I) infections, peripheral blood T cell subsets were analyzed by using a PCR-based assay that permits determination of complementarity-determining region 3 (CDR3) length variation in TCR Vbeta transcripts. In two of four asymptomatic HTLV-I carriers and in four of five patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), mono- or oligoclonal expansions were detected in the CD4+ T cell subset. In one patient with adult T cell leukemia, a specific clone bearing Vbeta7 was detected in the CD4+ T cell subset. In contrast, clonal expansion was not observed in the CD4 T cell subsets of three individuals with asymptomatic HTLV-II infection or in our previous studies of a large number of uninfected individuals. Oligoclonal expansions in the CD8+ T cell subset were detected in all subjects, including the patient with adult T cell leukemia. No differences in the number of expanded clones were noted between asymptomatic carriers and in patients with HAM/TSP and there was no obvious restriction in the TCR V region usage. Direct sequencing revealed no significant bias in the CDR3 motifs utilized by the predominant clones. This report is the first direct demonstration of clonal expansions within fractionated T cell subsets (CD4+ and CD8+) in HTLV-I infections and suggests that 1) clonal expansion of CD4+ T lymphocytes likely occurs as a direct result of infection and 2) polyclonal CD8+ T cell expansion occurs frequently and independently of disease association.

Adult↗
PubMed1990

An electrotopological-state index for atoms in molecules.

A new method for molecular structure description is presented in which both electronic and topological characteristics are combined. The method makes use of the hydrogen-suppressed graph to represent the structure. The focus of the method is on the individual atoms and hydride groups of the molecular skeleton. An intrinsic atom value is assigned to each atom as I = (delta v + 1)/delta, in which delta v and delta are the counts of valence and sigma electrons of atoms associated with the molecular skeleton. The electrotopological-state value, Si, for skeletal atom i is defined as Si = Ii + delta Ii, for second row atoms, where the influence of atom j on atom i, delta Ii, is given as sigma(Ii-Ij)/rij2; rij is the graph separation between atom i and atom j, counted as the number of atoms. The characteristics of the electrotopological state values are indicated by examples of various types of organic structures, including chain lengthening, branching, heteroatoms, and unsaturation. The relation of the E-state value to NMR chemical shift is investigated for a series of alkyl ethers. The E-state oxygen value gives an excellent correlation with the 17O NMR: r = 0.993 for 10 ethers. A biological application of the E-state values in QSAR analysis is given for the binding of barbiturates to beta-cyclodextrin.

Barbiturates↗
PubMed2005

Towards an RTS,S-based, multi-stage, multi-antigen vaccine against falciparum malaria: progress at the Walter Reed Army Institute of Research.

The goal of the Malaria Vaccine Program at the Walter Reed Army Institute of Research (WRAIR) is to develop a licensed multi-antigen, multi-stage vaccine against Plasmodium falciparum able to prevent all symptomatic manifestations of malaria by preventing parasitemia. A secondary goal is to limit disease in vaccinees that do develop malaria. Malaria prevention will be achieved by inducing humoral and cellular immunity against the pre-erythrocytic circumsporozoite protein (CSP) and the liver stage antigen-1 (LSA-1). The strategy to limit disease will target immune responses against one or more blood stage antigens, merozoite surface protein-1 (MSP-1) and apical merozoite antigen-1 (AMA-1). The induction of T- and B-cell memory to achieve a sustained vaccine response may additionally require immunization with an adenovirus vector such as adenovirus serotype 35. RTS,S, a CSP-derived antigen developed by GlaxoSmithKline Biologicals in collaboration with the Walter Reed Army Institute of Research over the past 17 years, is the cornerstone of our program. RTS,S formulated in AS02A (a GSK proprietary formulation) is the only vaccine candidate shown in field trials to prevent malaria and, in one instance, to limit disease severity. Our vaccine development plan requires proof of an individual antigen's efficacy in a Phase 2 laboratory challenge or field trial prior to its integration into an RTS,S-based, multi-antigen vaccine. Progress has been accelerated through extensive partnerships with industrial, academic, governmental, and non-governmental organizations. Recent safety, immunogenicity, and efficacy trials in the US and Africa are presented, as well as plans for the development of a multi-antigen vaccine.

Academies and Institutes↗
PubMed2001

Consequences of a modified putative substrate-activation site on catalysis by yeast pyruvate decarboxylase.

Earlier, it had been proposed in the laboratories at Halle that a cysteine residue is responsible for the hysteretic substrate activation behavior of yeast pyruvate decarboxylase. More recently, this idea has received support in a series of studies from Rutgers with the identification of residue C221 as the site where substrate is bound to transmit the information to H92, to E91, to W412, and finally to the active center thiamin diphosphate. According to steady-state kinetic assays, the C221A/C222A variant is no longer subject to substrate activation yet is still a well-functioning enzyme. Several further experiments are reported on this variant: (1) The variant exhibits lag phases in the product formation progress curves, which can be attributed to a unimolecular step in the pre-steady-state stage of catalysis. (2) The rate of exchange with solvent deuterium of the thiamin diphosphate C2H atom is slowed by a factor of 2 compared to the wild-type enzyme, suggesting that the reduced activity that results from the substitutions some 20 A from the active center is also seen in the first key step of the reaction. (3) The solvent (deuterium oxide) kinetic isotope effect was found to be inverse on V(max)/K(m) (0.62), and small but normal on V(max) (1.26), virtually ruling out residue C221 as being responsible for the inverse effects reported for the wild-type enzyme at low substrate concentrations. The solvent kinetic isotope effects are compared to those on two related enzymes not subject to substrate activation, Zymomonas mobilis pyruvate decarboxylase and benzoylformate decarboxylase.

Alanine↗
PubMed2003

The solid state structure of [b(10)h(11)](-) and its dynamic NMR spectra in solution.

The structure of [PPh(3)(benzyl)][B(10)H(11)] was determined at -123 degrees C and 24 degrees C by single-crystal X-ray analyses. The B(10) core of [B(10)H(11)](-) is similar in shape to that of [B(10)H(10)](2)(-). The 11th H atom asymmetrically caps a polar face of the cluster and shows no tendency for disorder in the solid state. Variable temperature multinuclear NMR studies shed light on the dynamic nature of [B(10)H(11)](-) in solution. In addition to the fluxionality of the cluster H atoms, the boron cage is fluxional at moderate temperatures, in contrast to [B(10)H(10)](2)(-). Multiple exchange processes are believed to take place as a function of temperature. Results of ab initio calculations are presented. Crystal data: [PPh(3)(benzyl)][B(10)H(11)] at -123 degrees C, P2(1)/c, a = 9.988(2) A, b = 18.860(2) A, c = 15.072(2) A, beta = 107.916(8) degrees, V = 2701.5(7) A(3), Z = 4; [PPh(3)(benzyl)][B(10)H(11)] at 24 degrees C, P2(1)/c, a = 10.067(5) A, b = 19.009(9) A, c = 15.247(7) A, beta = 107.952(9) degrees, V = 2775(2) A(3), Z = 4.

Journal Article↗