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PubMed2002

Requirements and prototyping of a home health care application based on emerging JAVA technology.

IT support for home health care is an expanding area within health care IT development. Home health care differs from other in- or outpatient care delivery forms in a number of ways, and thus, the introduction of home health care applications must be based on a rigorous analysis of necessary requirements to secure safe and reliable health care. This article reports early experiences from the development of a home health care application based on emerging JAVA technologies. A prototype application for the follow-up of diabetes patients is presented and discussed in relation to a list of general requirements on home health care applications.

Blood Glucose Self-Monitoring↗

PubMed2003

Bacterial serine palmitoyltransferase: a water-soluble homodimeric prototype of the eukaryotic enzyme.

Serine palmitoyltransferase (SPT, EC 2.3.1.50) is a key enzyme in sphingolipid biosynthesis and catalyzes the decarboxylative condensation of L-serine and palmitoyl coenzyme A (CoA) to 3-ketodihydrosphingosine (KDS). We found that the gram-negative obligatory aerobic bacteria Sphingomonas paucimobilis EY2395(T) have significant SPT activity, and purified SPT to homogeneity. Unlike eukaryotic enzymes, this enzyme was a water-soluble homodimeric protein. We isolated the SPT gene encoding 420 amino acid residues (M(r) 45,041) and succeeded in overproducing the SPT protein in Escherichia coli, in which the product amounted to about 10-20% of the total protein of the cell extract. Sphingomonas SPT showed about 30% homology with the enzymes of the alpha-oxamine synthase family, and amino acid residues supposed to be involved in catalysis are conserved. The purified recombinant-SPT showed the characteristic absorption spectrum derived from its coenzyme pyridoxal 5'-phosphate (PLP). The addition of the substrate, L-serine, caused spectral changes indicating the formation of the external aldimine intermediate. Sphingomonas SPT is a prototype of the eukaryotic enzyme and would be a useful model to elucidate the reaction mechanism of SPT.

Acyltransferases↗

PubMed1979

Haemagglutination-inhibiting (HI) antibodies against four prototype strains of influenza A virus in different age groups.

Sera of 197 apparently well persons were tested for residual haemagglutination-inhibiting antibodies against live Hong Kong/68, A/FM/47 and A/PR/34 strains. Sera of 62 well persons, regularly exposed to contacts with swine, were tested against an inactivated A/New Jersey/76 antigen. Those born some time before and during a certain influenza era showed a significantly greater proportion of homologous residual titres against the subtype prevailing in that influenza era, than those born after the termination of the same era. In each of the seven age groups tested both the percentage of positives and the geometric mean titres were usually highest against the Hong Kong strain (representing the most recent era); the next highest were those against the FM1 strain and the lowest were those against the PR8 strain (representing the most distant of these three influenza eras). The serological involvement of donors exposed to regular contacts with swine was relatively stronger against the New Jersey antigen than the response of other serum donors shown against the other three, more recent, prototypes of influenza virus A. The oldest age groups showed significantly lower antibody response against the PR8, FM1 and Hong Kong strains (but not against the New Jersey antigen) than the next one or two of the younger age groups.

Adolescent↗

PubMed1973

Antigenic analysis of prototype influenza A (H3N2) strains by the antiserum absorption method.

Prototype strains of the influenza A (H3N2) virus can be arranged on a gradient showing the degree of the antigenic drift which the haemagglutinins of the strains have undergone. The demonstration of fine antigenic differences is based on an antiserum absorption test which allows a detailed antigenic analysis of strains. The gradient provides information on variation in strains occurring in different geographical areas and its use may be helpful in differentiating between introduced strains and locally developing variants.

Absorption↗

PubMed2003

Rapid prototyping of 2D structures with feature sizes larger than 8 microm.

This paper extends rapid prototyping for several types of lithography to the 8-25-microm size range, using transparency photomasks prepared by photoplotting. It discusses the technical improvement in photomask quality achieved by photoplotting, compared to the currently used image setting, and demonstrates differences in the resolution that can be obtained with photomasks with features in the 8-100-microm size range. These high-resolution photomasks were used to microfabricate microelectrodes, microlenses, and stamps for microcontact printing, following methods described previously.

Biological Assay↗

PubMed2000

Fabrication of topologically complex three-dimensional microfluidic systems in PDMS by rapid prototyping.

This paper describes a procedure for making topologically complex three-dimensional microfluidic channel systems in poly(dimethylsiloxane) (PDMS). This procedure is called the "membrane sandwich" method to suggest the structure of the final system: a thin membrane having channel structures molded on each face (and with connections between the faces) sandwiched between two thicker, flat slabs that provide structural support. Two "masters" are fabricated by rapid prototyping using two-level photolithography and replica molding. They are aligned face to face, under pressure, with PDMS prepolymer between them. The PDMS is cured thermally. The masters have complementary alignment tracks, so registration is straightforward. The resulting, thin PDMS membrane can be transferred and sealed to another membrane or slab of PDMS by a sequence of steps in which the two masters are removed one at a time; these steps take place without distortion of the features. This method can fabricate a membrane containing a channel that crosses over and under itself, but does not intersect itself and, therefore, can be fabricated in the form of any knot. It follows that this method can generate topologically complex microfluidic systems; this capability is demonstrated by the fabrication of a "basketweave" structure. By filling the channels and removing the membrane, complex microstructures can be made. Stacking and sealing more than one membrane allows even more complicated geometries than are possible in one membrane. A square coiled channel that surrounds, but does not connect to, a straight channel illustrates this type of complexity.

Dimethylpolysiloxanes↗

PubMed1995

Gramicidin S synthetase 1 (phenylalanine racemase), a prototype of amino acid racemases containing the cofactor 4'-phosphopantetheine.

The biosynthesis of the decapeptide antibiotic gramicidin S in Bacillus brevis ATCC 9999 is catalyzed by a multienzyme system consisting of two multifunctional proteins, gramicidin S synthetase 1 and 2, encoded by the grsA and grsB genes, respectively. Gramicidin S synthetase 1 (phenylalanine racemase, EC 5.1.1.11, GS1) racemizes phenylalanine in the thioester-bound stage. The amount of 4'-phosphopantetheine liberated from highly purified GS1 was determined microbiologically using Lacto-bacillus plantarum as the test organism. It matches exactly with the amount of L-[14C]phenylalanine covalently incorporated by GS1 as thioester. The reaction center of GS1 for L-phenylalanine thiolation and racemization was labeled with [3H]iodoacetic acid. After tryptic fragmentation of the 3H-carboxymethylated enzyme, the active site peptide for thioester binding and racemization of phenylalanine was isolated in pure form by multistep methodology and investigated by sequence, amino acid, and mass spectrometric analysis. A 4'-phosphopantetheine carrier was found to be attached to the active site serine of the consensus motif LGGDSI forming the thiolation site of phenylalanine. These specific properties establish GS1 as a prototype of amino acid racemases using 4'-phosphopantetheine as a cofactor and yield further evidence that multiple Pan carriers are involved in gramicidin S formation. Our results are strong evidence for the "multiple carrier model" as a new concept of nonribosomal peptide biosynthesis at protein templates as recently proposed [Stein, T., et al. (1994) FEBS Lett. 340, 39-44].

Amino Acid Isomerases↗

PubMed1992

Experimental and computational infrared CD studies of prototypical peptide conformations.

The infrared vibrational circular dichroism (VCD) spectral features of prototypical peptide secondary structures were reported previously by Yasui and Keiderling [Yasui, S.C., & Keiderling, T.A. (1986) Biopolymers 25, 5]. These results demonstrated that the "random coil" peptide conformation exhibits VCD signals which are approximately mirror-image features of those exhibited by alpha-helical conformers. We report here a comparison of observed VCD spectra with those computed for several secondary structures, using the extended coupled oscillator formalism employed previously to compute VCD spectra of model DNA [Zhong et al. (1990) Biochemistry 29, 7485]. These studies suggest that the so-called random-coil peptide conformation has distinct short-range order and appears to be a left-handed, helical structure.

Circular Dichroism↗

PubMed1988

Structural and dynamic aspects of binding of a prototype lexitropsin to the decadeoxyribonucleotide d(CGCAATTGCG)2 deduced from high-resolution 1H NMR Studies.

Structural and dynamic properties of the self-complementary decadeoxyribonucleotide d(CGCAATTGCG)2 and the interaction between a prototype lexitropsin, or information-reading oligopeptide, and the decadeoxyribonucleotide are deduced by using high-resolution 1H NMR techniques. The nonexchangeable and imino proton resonances of d(CGCAATTGCG)2 have been completely assigned by two-dimensional NMR studies. The decadeoxyribonucleotide exists as a right-handed B-DNA. In the 1H NMR spectrum of the 1:1 complex, the selective chemical shifts and removal of degeneracy of AH2(4), AH2(5), T-CH3(6), and T-CH3(7) due to the anisotropy effects of the heterocyclic moieties of the ligand, and with lesser effects at the flanking base sites C(3) and G(8), locate the drug centrally in the decadeoxyribonucleotide. This conclusion is supported by plots of individual chemical shift changes across the decadeoxyribonucleotide. Similarly, imino protons IV and V experience larger shifts and II and III smaller shifts in accord with this conclusion while drug complexation permits the detection of imino proton I. Strong nuclear Overhauser effects (NOEs) between pyrrole H5 and AH2(5), and weaker NOEs to AH1'(5), TH3'(6), and AH2'(5), firmly locate the ligand in the minor groove. Intraligand NOEs between the adjacent heterocyclic moieties indicate that the lexitropsin is subject to propeller twisting about the N6-C9 bond in both the bound and free forms. Nuclear Overhauser effect spectroscopy (NOESY) and correlated spectroscopy (COSY) experiments also indicate that the removal of degeneracy of the C16 methylene protons upon complexation may arise from restricted rotation about the C15-N9, C15-C16, and C16-C17 bonds. Specific hydrogen bonds between amide NH groups on the concave face of the ligand (N4H, N6H, N9H) and adenine N3 or thymine O2 on the floor of the minor groove are in accord with displacement of the hydration shell by the drug. NOE measurements on the decadeoxyribonucleotide in the 1:1 complex confirm it exists as a right-handed helix and belongs to the B family. Exchange NMR effects permit an estimate of a rate of approximately equal to 44 s-1 for the two-site exchange of the lexitropsin between two equivalent sites on the decamer with delta G++ approximately equal to 70 +/- 5 kJ mol-1 at 294 K. Alternative mechanisms for this exchange process are considered.

Base Sequence↗

PubMed1997

In vitro biosynthesis of a decasaccharide prototype of multiply branched polylactosaminoglycan backbones.

Multiply branched polylactosaminoglycans are expressed in glycoproteins and glycolipids of many cells. Interest in their biology stems from their abundant expression in early embryonal cells and from their ability to carry multiple lectin-binding determinants, which makes them prominent ligands and antagonists of cell adhesion proteins. A prototype of their backbones is represented by the decasaccharide LacNAc beta1-3'(LacNAc beta1-6')LacNAc beta1-3'(LacNAc beta1-6')LacNAc (5), where LacNAc is the disaccharide Gal beta1-4GlcNAc. Here, we describe in vitro biosynthesis of glycan 5. Incubation of the linear hexasaccharide LacNAc beta1-3'LacNAc beta1-3'LacNAc (1) with UDP-GlcNAc and alpha midchain beta1,6-GlcNAc transferase activity (GlcNAc to Gal), present in rat serum [Gu, J., Nishikawa, A., Fujii, S., Gasa, S., & Taniguchi, N. (1992) J. Biol. Chem. 267, 2994-2999], gave the doubly branched octasaccharide LacNAc beta1-3'(GlcNAc beta1-6')LacNAc beta1-3'(GlcNAc beta1-6')LacNAc (4). The latter was converted to 5 by enzymatic beta1,4-galactosylation. In the initial branching reaction of 1, two isomeric heptasaccharide intermediates, LacNAc beta1-3'LacNAc beta1-3'(GlcNAc beta1-6')LacNAc (2) and LacNAc beta1-3'(GlcNAc beta1-6')LacNAc beta1-3'LacNAc (3), were formed first at comparable rates. Later, both intermediates were converted to 4, revealing two distinct pathways of the reaction: 1 --> 2 --> 4 and 1 --> 3 --> 4. These data suggest that, regardless of their chain length, linear polylactosamines similar to 1 contain potential branching sites at each of the internal galactoses. The enzyme-binding epitope of 1 is probably LacNAc beta1-3'LacNAc, because the trisaccharides GlcNAc beta1-3'LacNAc and LacNAc beta1-3Gal as well as the tetrasaccharide GlcNAc beta1-3'LacNAc beta1-3Gal were poor acceptors, while LacNAc beta1-3'LacNAc was a good one. Midchain beta1,6-GlcNAc transferase activities present in serum of several mammalian species, including man, resembled closely the rat serum activity in their mode of action and in their acceptor specificity. We suggest that analogous membrane-bound Golgi enzymes are involved in the biosynthesis of multiply branched polylactosamines in vivo.

Amino Sugars↗

PubMed2002

Pyrazolyl-bridged iridium dimers. 18.(1) influence of metal-metal bonding on the geometry of diiridium(II) adducts and hydrido-diiridium complexes formed from the diiridium(I) prototype [Ir(mu-pz)(PPh(3))(CO)](2) (pzH = Pyrazole) by dihydrogen addition or protonation.

Slow uptake of molecular dihydrogen by the diiridium(I) prototype [Ir(mu-pz)(PPh(3))(CO)](2) (1: pzH = pyrazole) is accompanied by formation of a 1,2-dihydrido-diiridium(II) adduct [IrH(mu-pz)(PPh(3))(CO)](2) (2), for which an X-ray crystal structure determination reveals that (unlike in 1) the PPh(3) ligands are axial, with the hydrides occupying trans coequatorial positions across the Ir-Ir bond (2.672 A). Reaction with CCl(4) effects hydride replacement in 2, affording the monohydride Ir(2)H(Cl)(mu-pz)(2)(PPh(3))(2)(CO)(2) (3) in which Ir-Ir = 2.683 A. At one metal center, H is equatorial and PPh(3) is axial, while at the other, Cl is axial as is found in the symmetrically substituted product [Ir(mu-pz)(PPh(3))(CO)Cl](2) (4) (Ir-Ir = 2.754 A) that is formed by action of CCl(4) on 1. Treatment of 1 with I(2) yields the diiodo analogue 5 of 4, which reacts with LiAlH(4) to afford the isomorph Ir(2)H(I)(mu-pz)(2)(PPh(3))(2)(CO)(2) (6) of 3 (Ir-Ir = 2.684 A). Protonation (using HBF(4)) of 1 results in formation of the binuclear cation Ir(2)H(mu-pz)(2)(PPh(3))(2)(CO)(2)(+) (7: BF(4)(-) salt), which shows definitive evidence (from NMR) for a terminally bound hydride in solution (CH(2)Cl(2) or THF), but 7 crystallizes as an axially symmetric unit in which Ir-Ir = 2.834 A. Reaction of 7 with water or wet methanol leads to isolation of the cationic diiridium(III) products [Ir(2)H(2)(mu-OX)(mu-pz)(2)(PPh(3))(2)(CO)(2)]BF(4) (8, X = H; 9, X = Me).

Journal Article↗

PubMed1996

Selective Azide Oxidation of 1,2-Bis(diphenylphosphino)benzene and Related Ethylenebis(phosphines) to Asymmetric Multifunctional Phosphorus Ligands and Formation of Rhodium(I) Complexes of These Ligands. Structural Characterization of the Prototypical Ligand 1-(((Trimethylsilyl)imino)diphenylphosphorano)-2-(diphenylphosphino)benzene and Its Rhodium(I) Complex: 1-Ph(2)P=N(SiMe(3))C(6)H(4)-2-(Ph(2)P)Rh(CO)Cl.

Selective azide mono-oxidation of o-bis(phosphines) such as o-bis(diphenylphosphino)benzene and other bis(phosphines) with cis-substituents on a rigid backbone such as an ethylene structure occurs as the result of the steric control exerted during the azide oxidation (Staudinger) reaction process. The azides used were the trimethylsilyl, 4-cyanotetrafluorophenyl, benzyl, and diphenoxyphosphonyl azides. The prototypical ligand 1-Ph(2)P=N(SiMe(3))-2-(Ph(2)P)C(6)H(4), 2, has been structurally characterized. Crystal data for 2: crystal dimensions, 0.38 x 0.38 x 0.57 mm; space group, monoclinic, P2(1)/c, (No. 14); a = 11.093(5) Å, b = 14.898(5) Å, c = 18.811(2) Å, beta = 102.76(2) degrees, V = 3031 Å(3), Z = 4. Final R, R(w) and GOF values were 0.068, 0.074, and 1.92 respectively. The P=N-SiMe(3) angle was wide, 152.7(3) degrees, and the P=N bond length short (1.529(5) Å) relative to arylated iminophosphoranes but in keeping with the trends for silylated analogs. The iminophosphorane center can be selectively transformed with other agents in a Wittig type reaction converting the azides to the monooxide, monosulfide, etc. The iminophosphoranophosphines are also good complexing agents and the Rh(I) complex derived from 2, 1-Ph(2)P=N(SiMe(3))-C(6)H(4)-2-(Ph(2)P)Rh(CO)Cl, 15 was structurally characterized. Crystal data for 15: crystal dimensions, 0.32 x 0.44 x 0.66 mm; space group, monoclinic, P2(1)/c (No. 14); a = 13.793(3) Å, b = 12.622(11) Å, c = 20.436(6) Å, beta = 105.93(2) degrees, V = 3421.2 Å(3), Z = 4. Final R, R(w), and GOF values were 0.064, 0.061, and 1.45 respectively. The complex shows typical square planar geometry about Rh, a cis phosphine-CO relationship, and no exceptional steric crowding of the coordination site.

Journal Article↗

PubMed2003

Marine natural products as prototype agrochemical agents.

In the interest of identifying new leads that could serve as prototype agrochemical agents, 18 structurally diverse marine-derived compounds were examined for insecticidal, herbicidal, and fungicidal activities. Several new classes of compounds have been shown to be insecticidal, herbicidal, and fungicidal, which suggests that marine natural products represent an intriguing source for the discovery of new agrochemical agents.

Agrochemicals↗

PubMed1995

(+/-)-(Z)-2-(aminomethyl)-1-phenylcyclopropanecarboxamide derivatives as a new prototype of NMDA receptor antagonists.

(+/-)-(Z)-2-(Aminomethyl)-1-phenylcyclopropane-N,N-diethylcarbo xamide (milnacipran, 1), a clinically useful antidepressant, and its derivatives were prepared by an improved method and were evaluated as NMDA receptor antagonists. Of these, milnacipran (1), its N-methyl and N,N-dimethyl derivatives, 7 and 8, respectively, and its homologue 12 at the aminomethyl moiety had binding affinity for the receptor in vitro (IC50: 1, 6.3 +/- 0.3 microM; 7, 13 +/- 2.1 microM; 8, 88 +/- 1.4 microM; 12, 10 +/- 1.2 microM). These also protected mice from NMDA-induced lethality. These compounds would be important as anovel prototype for designing potent NMDA-receptor antagonists because of their characteristic structure, which clearly differentiated them from known competitive and noncompetitive antagonists to the receptor.

Animals↗

PubMed1989

Metabolism of 3-(p-chlorophenyl)pyrrolidine. Structural effects in conversion of a prototype gamma-aminobutyric acid prodrug to lactam and gamma-aminobutyric acid type metabolites.

By use of rat liver or brain homogenate supernatants containing microsomes and/or mitochondria, it was found that the prototype GABAergic prodrug [3-(p-chlorophenyl)pyrrolidine (1)] underwent a series of alpha-oxidation transformations to a pair of amino acid metabolites and a pair of lactam metabolites [4-amino-3-(p-chlorophenyl)butanoic acid, baclofen (5); 4-amino-2-(p-chlorophenyl)butanoic acid (10); 4-(chlorophenyl)pyrrolidin-2-one and 3-(p-chlorophenyl)pyrrolidine-2-one (11)]. With the liver homogenates, the formation of the lactam metabolites was approximately 2 orders of magnitude greater than that of the amino acid metabolites, while with the brain homogenates, the amino acid and lactam pathways were of similar magnitude. For either tissue, for both the lactam and the amino acid series, attack at the less sterically hindered 5-position of the pyrrolidine ring was greater than the attack at the 2-position (5 greater than 10 and 6 greater than 11) with the exception of the liver homogenate mitochondrial fraction (6 less than 11). The parenteral administration of the prodrug 1 was found to give detectable brain levels of 5 as well as activity in an isoniazid-induced (GABA-inhibited) convulsion model.

Amino Acids↗

PubMed1986

Bioisosteric prototype design of biaryl imidazolyl and triazolyl competitive histamine H2-receptor antagonists.

The structural relationship of the competitive histamine H2-receptor antagonist 3-amino-5-(2-amino-4-pyridyl)-1,2,4-triazole (1) to the agonist histamine and to antagonists of the cimetidine type was explored by the design and synthesis of four series of bioisosterically designed prototypes. Biological data from these series was best interpreted as indicating a similarity between the imidazole moiety of histamine and cimetidine and the 2-amino-4-pyridyl moiety of 1. On the basis of this data, sequential replacement of 2-amino-4-pyridyl by 2-[(dimethylamino)methyl]-5-furyl and 2-guanidino-4-triazolyl moieties led to a structurally more potent series of biaryl histamine H2-receptor antagonists. The best of these, 2-methyl-4-(2-guanidino-4-thiazolyl)imidazole (29, CP-57,361-1) was 120 times more potent as a histamine H2-receptor antagonist than 1.

Animals↗

PubMed1999

High-resolution NMR and computer modeling studies of the cannabimimetic aminoalkylindole prototype WIN-55212-2.

Aminoalkylindoles (AAIs), although structurally dissimilar from the classical cannabinoids (CCs), are known to be capable of binding to cannabinoid receptors and of evoking cannabimimetic responses. However, their mode of binding remains unknown. In this communication, we have carried out further studies on the AAI prototype (R)-[2, 3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1, 4-benzoxazin-6-yl](1-naphthalenyl)methanone (WIN-55212-2, 1) by the combined use of high-resolution 2D NMR and computer modeling. Our results suggest that the minimum energy conformations of the molecule 1 have distinct pharmacophoric features: (i) The naphthyl ring is oriented off the plane of the benzoxazine ring by approximately 59 degrees with the carbonyl C=O group pointing toward the C2-CH(3) group. (ii) At the C10-position the axial morpholinomethyl conformation is preferred over the equatorial in order to relieve a steric interaction with the C2-methyl group. The preferred conformer as defined by the three key pharmacophores, naphthyl, morpholino, and 3-keto groups, shows that the morpholinyl ring of the molecule 1 deviates from the plane of the benzoxazine ring by about 32 degrees and orients in the left molecular quadrant. This model supports the hypothesis that a certain deviation of the morpholino group from the plane of the indole ring in compound 1 is essential for cannabimimetic activity. We postulate that such an alignment by the respective pharmacophores allows them to interact optimally with the receptor. The results should help us to better understand the pharmacophoric requirements of the AAIs and serve as a basis for future SAR studies and drug design.

Benzoxazines↗

PubMed1999

Clustering of CD spectral data as a prototype QSAR model for neuropeptides.

An analytical method that might eventually qualify as a general quality control assay procedure for polypeptide drug forms was described in the companion article to this paper. The detector is visible range circular dichroism spectroscopy. Multivariate data analysis reduced the spectral data to essentially four principal components (or factors) that are characteristic of each analyte. The level of analytical selectivity achieved among 51 analytes is very high. Using an alternative factor analysis algorithm, the selectivity is even more conveniently accomplished in the form of a 2-D cluster diagram presentation that has the potential of being a prototypical predictive in vitro model for correlating experimental data with structure-activity or structure-function relationships. Clustering of the analytes is a consequence not only of the chiral interactions associated with ligand exchange in the immediate primary coordination sphere of the host derivatizing reagent, but also of long-range intermolecular interactions between the coordination architecture of the host and the chiral polypeptides.

Circular Dichroism↗