Iodine quantification and detectability thresholds among major dual-energy CT platforms.

Objectives: To estimate the minimum detectable iodine concentration on multiple dual-energy CT (DECT) platforms.

Methods And Materials: A phantom containing iodine concentrations ranging from 0 to 10 mg ml was scanned with five dual-energy platforms (two rapid kilo volt switching (r-kVs), one dual source (DS), one sequential acquisition and one split-filter). Serial dilutions of 300 mg ml iodinated contrast material were used to generate concentrations below 2 mg ml.

Regulation of the pH sensitivity of human P2X receptors by N-linked glycosylation.

The human (h) P2X(3) receptor and its mutants deficient in one out of four N-glycosylation sites were expressed in HEK293 cells. Concentration-response curves were generated by whole-cell recordings of alpha,beta-methylene ATP (alpha,beta-meATP)-induced currents. A gradual change of external pH from the alkaline 8.

Conserved lysin and arginin residues in the extracellular loop of P2X(3) receptors are involved in agonist binding.

Wild-type human (h) P2X(3) receptors expressed in HEK293 cells responded to the prototypic agonist alpha,beta-methylene ATP (alpha,beta-meATP) with rapidly desensitizing inward currents and an increase in the intracellular Ca(2+) concentration. In contrast to electrophysiological recordings, Ca(2+) microfluorimetry showed a lower maximum of the concentration-response curve of alpha,beta-meATP in the transiently than in the permanently transfected HEK293 cells. However, the concentrations causing 50% of the maximum possible effect (EC(50) values) were identical, when measured with either method.

The h-P2X3 glycoprotein receptor as an example of integrating bioinformatics and structural research.

This review deals with the molecular modelling of a subtype of the membrane-embedded purinoreceptor P2X family, which belongs to the large class of membrane-embedded glycoproteins. The P2X family has two transmembrane domains and a core of five extracellularly occurring disulfide bonds. At present, seven different P2X receptor subtypes (P2X1 - X7) have been cloned.

Quantitative structure-activity relationship analysis of the cation permeability of the P2X2 channel.

The membrane-embedded, ligand-gated P2X glycoprotein receptor is a monovalent-bivalent cation channel that is activated by physiological concentrations of extracellular ATP. A quantitative structure-activity relationship (QSAR) analysis was developed to model the cation permeability of the P2X2 channel and its mutants. As chemical properties, the helix-coil equilibrium constants and the distribution coefficients of the system octanol/water at pH 7.

The monomers of the P2X1 receptor model and KcsA protein share a similar structural fold.

There is evidence that the P2X1 receptor subunit is involved in apoptosis, platelet aggregation, and smooth muscle contraction. The conformation of the membrane-embedded, ligand-gated mouse P2X1 glycoprotein, a monovalent-bivalent cation channel-forming receptor, is predicted. The first step is based on secondary structure prediction.

Regulation of human recombinant P2X3 receptors by ecto-protein kinase C.

The whole-cell patch-clamp technique was used to record current responses to nucleotides and nucleosides in human embryonic kidney HEK293 cells transfected with the human purinergic P2X3 receptor. When guanosine 5'-O-(3-thiodiphosphate) was included into the pipette solution, UTP at concentrations that did not alter the holding current facilitated the alpha,beta-methylene ATP (alpha,beta-meATP)-induced current. ATP and GTP, but not UDP or uridine, had an effect similar to that of UTP.

Bridging the gap between structural bioinformatics and receptor research: the membrane-embedded, ligand-gated, P2X glycoprotein receptor.

Motivation: No details on P2X receptor architecture had been known at the atomic resolution level. Using comparative homology-based molecular modelling and threading, it was attempted to predict the three-dimensional structure of P2X receptors. This prediction could not be carried out, however, because important properties of the P2X family differ considerably from that of the potential template proteins.

Structural bioinformatics and QSAR analysis applied to the acetylcholinesterase and bispyridinium aldoximes.

The methods of bioinformatics, molecular modelling, and quantitative structure-activity relationships (QSARs) using regression and artificial neural network (ANN) analyses were applied to develop safer aldoxime antidotes against poisoning by organophosphorus (OP) agents with high, mean, and low aging rates. We start here from a molecular modelling of the mouse AChE at an atomistic level. Aim is to predict qualitatively the structural requirements of an aldoxime that shows an unique reactivating activity against the three classes of OPs.

Brain-derived neurotrophic factor controls functional differentiation and microcircuit formation of selectively isolated fast-spiking GABAergic interneurons.

GABAergic interneurons with high-frequency firing, fast-spiking (FS) cells, form synapses on perisomatic regions of principal cells in the neocortex and hippocampus to control the excitability of cortical networks. Brain-derived neurotrophic factor (BDNF) is essential for the differentiation of multiple interneuron subtypes and the formation of their synaptic contacts. Here, we examined whether BDNF, alone or in conjunction with sustained KCl-induced depolarization, drives functional FS cell differentiation and the formation of inhibitory microcircuits.

Interactions of the dimeric triad of HIV-1 aspartyl protease with inhibitors.

Strong hydrogen-bonding forces between the Thr26 and Thr26' of the protease stabilize the internal cage of the dimeric triad of the aspartyl HIV-1 protease (Asp25Thr26Gly27 and Asp25' Thr26'Gly27', respectively). The interaction of reversible inhibitors of HIV-1 protease is based on (i) strong hydrogen-bonding forces between the main chain (--CONH--) oxygen atoms of Gly27 and/or Gly27' and hydrogen-bond donating moieties of a drug, and (ii) hydrogen bonds between the oxygen of the catalytic Asp25 and/or Asp25' carboxylates and aliphatic hydroxyl groups of a drug. The free entry of natural substrates into the active-site cavity is sterically hindered by inhibitors, so that the catalytic Asp carboxylates cannot interact with natural substrates.

Hybrid canonical-correlation neural-network approach applied to nonnucleoside HIV-1 reverse transcriptase inhibitors (HEPT derivatives).

Beneficial antiviral HIV-1 chemotherapy is associated with adverse reactions. To optimize the desired actions and to lower the side effects of nonnucleoside HIV-1 reverse transcriptase (RT) inhibitors (NNRTIs), quantitative structure-activity relationships (QSARs) were studied by using a series of HEPT derivatives of NNRTIs. Hypothesis testing requires that certain assumptions are approximately satisfied in statistically based QSARs, however.

Pathological peptide folding in Alzheimer's disease and other conformational disorders.

Main neuropathological hallmarks of Alzheimer's disease (AD) and other neurodegenerative disorders are the deposition of neurofibrillary tangles consisting of abnormally phosphorylated protein tau and of senile plaques largely containing insoluble beta-amyloid peptides (A beta), containing up to 43 amino acid residues derived from the beta-amyloid precursor protein. Such A beta-sheets become visible by using suitable histochemical methods. Molecular simulation showed that the central, alpha-helical, lipophilic, antigenic folding domain of the A beta-peptide loop is a promising molecular target of beta-sheet breakers that thus prevent the polymerization of A beta into aggregates.

The active site of HIV-1 protease.

The active site of the homodimeric HIV-1 protease includes six amino acids (triads AspThrGly found in each monomer) in amino acid positions 25 to 27 and 25' to 27'. Up to now, the role of Thr26 and Thr26', and Gly27 and Gly27', is unknown. It is hypothesized that strong hydrogen-bonding forces between the Thr26 and Thr26' residues stabilize the conformational state of the active site, and that the function of Gly27 and Gly27' is to accommodate and bind a substrate in a position in which the catalytic Asp25 and Asp25' carboxylate groups can attack the amide moiety of a substrate.

Knowledge representation and indexing using the unified medical language system.

Ontologies and semantic frameworks can be used to improve the accuracy and expressiveness of natural language processing for the purpose of extracting meaning from technical documents. This is especially true when a rich ontology such as the Unified Medical Language System (UMLS) is available. This paper reports on some tools being developed to make this possible and on some experience with a user interface based on ontologies and semantic networks that allows for interactive knowledge exploration.

A comparison of backpropagation and generalized-regression genetic-neural network models.

The results of the backpropagation (BP) and generalized-regression genetic-neural (GRGN) network were compared using a series of nonpeptide arginine vasopressin VI antagonists. It was shown that both approaches are equivalent with respect to the recognition process while the BP network is superior over GRGN if the sample sizes are lowered by cross-validation.

Molecular simulation of the primary and secondary structures of the Abeta(1-42)-peptide of Alzheimer's disease.

The major protein constituent of the deposits of Alzheimer's disease is the so-called amyloid beta-peptide (Abeta) which was derived from proteolysis of a large transmembrane amyloid precursor protein. Some physicochemical and biological properties of the Abeta(1-42) peptide are described in this paper. Three functional areas of the soluble Abeta(1-42) peptide were found: (i) a lipophilic region in the middle of the peptide (Lys16 to Ala21), (ii) a second lipophilic core at the end (Lys28 to Val40), and (iii) polarized and charged, solvent-exposed areas.

Evidence of a butterfly-like configuration of structurally diverse allosteric inhibitors of the HIV-1 reverse transcriptase.

Although many physicochemical properties of chemically diverse nonnucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) differ, there is a common three-dimensional feature. This shape is a rigid butterfly-like configuration which fits well into a sizable internal cavity of the allosteric area of the enzyme. The number of amino acids of the allosteric receptor sites that contribute to NNRTIs binding correlates with the degree of the butterfly-like shape.

A hydrophilic omega-loop (Tyr181 to Tyr188) in the nonsubstrate binding area of HIV-1 reverse transcriptase.

Using the molecular "cloud" of the HIV-1 reverse transcriptase (RT) as starting point, the peptide backbone of the polymerase subunit was visualized by molecular modelling. Then, the two subregions 98-106 and 179-190 of the allosteric area were "isolated". From the latter subregion, the Tyr181 to Tyr188 segment containing two amino acids (Asp185, Asp186) of the catalytic aspartyl triad and two amino acids (Tyr181, Tyr188) of the nonnucleoside RT inhibitor (NNRTI) binding sites, was excised.

Molecular simulation of the folding patterns of the omega-loop (Tyr181 to Tyr188) of HIV-1 reverse transcriptase.

A large, highly hydrophilic and constrained omega-loop was dissected from the allosteric area of HIV-1 reverse transcriptase (segment Tyr181 to Tyr188). The loop contains two amino acids (Asp185, Asp186) of the catalytic aspartyl triad (Asp110, Asp185, Asp186) and two amino acids (Tyr181, Tyr188) of the nonnucleoside RT inhibitor (NNRTI) binding sites. Hydrogen-bonding forces between the two folded peptide chains play the greatest role in holding the two chains together and in specifying the folding patterns.

Investigation of the conformational behaviour of permethylated cyclodextrins by molecular modelling.

Conformations of manually built native and permethylated alpha-, beta-, and gamma-cyclodextrins (CD) were investigated using various computer assisted molecular modelling methods. Calculations were carried by applying the MM+ and the Tripos force field. The influences of atomic charges on the macrocyclic conformations during the optimization procedure were analyzed.