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Biomedical subjects

G Schneider

Publications and source records attributed to G Schneider.

At least 19 recordsLinked to original sources
PubMed1996

A trial of artemether or quinine in children with cerebral malaria.

BACKGROUND: Cerebral malaria has a mortality rate of 10 to 30 percent despite treatment with parenteral quinine, a situation that may worsen with the spread of quinine resistance. Artemether is a new antimalarial agent that clears parasites from the circulation more rapidly than quinine, but its effect on mortality is unclear. METHODS: We conducted a randomized, unblinded comparison of intramuscular artemether and intramuscular quinine in 576 Gambian children with cerebral malaria. The primary end points of the study were mortality and residual neurologic sequelae. RESULTS: Fifty-nine of the 288 children treated with artemether died in the hospital (20.5 percent), as compared with 62 of the 288 treated with quinine (21.5 percent). Among the 418 children analyzed at approximately five months for neurologic disease, residual neurologic sequelae were detected in 7 of 209 survivors treated with artemether (3.3 percent) and 11 of 209 survivors treated with quinine (5.3 percent, P = 0.5). After adjustment for potential confounders, the odds ratio for death was 0.84 (95 percent confidence interval, 0.53 to 1.32) in the artemether group, and for residual neurologic sequelae, 0.51 (95 percent confidence interval, 0.17 to 1.47). There were fewer local reactions at the injection site with artemether than with quinine (0.7 percent vs. 5.9 percent, P = 0.001). CONCLUSIONS: Artemether is as effective as quinine in the treatment of cerebral malaria in children.

Antimalarials↗
PubMed1996

Structure optimization of an artificial neural filter detecting membrane-spanning amino acid sequences.

An artificial neural network has been developed for the recognition and prediction of transmembrane regions in the amino acid sequences of human integral membrane proteins. It provides an additional prediction method besides the common hydrophobicity analysis by statistical means. Membrane/nonmembrane transition regions are predicted with 92% accuracy in both training and independent test data. The method used for the development of the neural filter is the algorithm of structure evolution. It subjects both the architecture and parameters of the system to a systematical optimization process and carries out local search in the respective structure and parameter spaces. The training technique of incomplete induction as part of the structure evolution provides for a comparatively general solution of the problem that is described by input-output relations only. Seven physiochemical side-chain properties were used to encode the amino acid sequences. It was found that geometric parameters like side-chain volume, bulkiness, or surface area are of minor importance. The properties polarity, refractivity, and hydrophobicity, however, turned out to support feature extraction. It is concluded that membrane transition regions in proteins are encoded in sequences as a characteristic feature based on the respective side-chain properties. The method of structure evolution is described in detail for this particular application and suggestions for further development of amino acid sequence filters are made.

Algorithms↗
PubMed1996

Bringing home the mission of the Fourth World Conference on Women.

The objective of the Public Initiative of The American Dietetic Association's 1996-1999 Strategic Framework (see page 559 of this issue for details) is to influence the public's access to sound, scientifically based nutrition information. One way the ADA is promoting this objective is by identifying and targeting the nutrition needs and concerns of specific populations. In June 1993, the ADA became a major player in the effort to improve the health of America's women by launching the Nutrition & Health Campaign for Women. To target the nutrition needs of women most effectively, information about how women live is fundamental.

China↗
PubMed1996

[X-ray microscopy].

Owing to the short wavelengths of X-radiation X-ray microscopes allow higher resolution than optical microscopes. In contrast to electron microscopes, X-radiation can be used to study relatively thick aqueous specimens in their natural environment. X-ray microscopes require intense X-radiation, which is best provided by electron storage rings, as well as efficient X-ray optics. X-ray microscopes with zone plate optics are installed at the storage ring BESSY in Berlin for studies in the fields of biology, medicine, biophysics, colloid chemistry, and soil sciences.

Animals↗
PubMed1995

His103 in yeast transketolase is required for substrate recognition and catalysis.

Crystallographic studies of thiamin-diphosphate-dependent transketolase from Saccharomyces cerevisiae suggested the invariant active-site residue H103 as a possible enzymic group binding the C1 hydroxyl group of the donor substrate and stabilizing the reaction intermediate. To test this hypothesis, H103 was replaced by alanine, asparagine and phenylalanine using site-directed mutagenesis. The crystallographic analysis of the mutant transketolases verified that no structural changes occurred as a consequence of the side-chain replacements. The residual catalytic activities of the mutant enzymes were 4.3% for the H103A, 2.4% for the H103N and 0.1% for the H103F mutant transketolase. Further kinetic analysis of the H103A and H103N mutant enzymes showed that the Km values for the coenzyme were increased by about eightfold. The Km values for the acceptor substrate ribose 5-phosphate were similar to the Km value for wild-type transketolase. However, the Km value for the donor substrate, xylulose 5-phosphate is increased more than tenfold in these two mutants. Circular dichroism spectra of the mutant enzymes also indicated a weaker binding of the donor substrate and/or a less stable reaction intermediate. These observations provide further evidence in support of the proposed role for this invariant residue in recognition of the donor substrate by forming a hydrogen bond between the side chain of H103 and the C1 hydroxyl group of the sugar phosphate. The significant decrease in catalytic activity suggests that this residue also facilitates catalysis, possibly by maintaining the optimal orientation of the donor substrate and reaction intermediates.

Binding Sites↗
PubMed1995

Mechanism of an ATP-dependent carboxylase, dethiobiotin synthetase, based on crystallographic studies of complexes with substrates and a reaction intermediate.

The crystal structures of six complexes of homodimeric Escherichia coli dethiobiotin synthetase with a variety of substrates, substrate analogs, and products have been determined to high resolution. These include (1) the binary complex of dethiobiotin synthetase and the N7-carbamate of 7,8-diaminononanoic acid, (2) the binary complex of enzyme and the alternate substrate, 3-(1-aminoethyl)-nonanedioic acid, (3) the binary complex of enzyme with the product ADP, (4) the quaternary complex of enzyme, ADP, the N7-carbamate of 7,8-diaminononanoic acid, and Ca2+, (5) the ternary complex of enzyme, the ATP analog adenylyl (beta, gamma-methylene)diphosphonate, and the N7-carbamate of 7,8-diaminononanoic acid, and (6) the quaternary complex of enzyme, the ATP analog adenylyl (beta, gamma-methylene)diphosphonate, 7,8-diaminononanoic acid, and Mn2+. One molecule of each substrate binds to one monomer of the enzyme. ADP and the ATP analogue bind to the classical mononucleotide binding fold with the phosphate groups close to the phosphate binding loop Gly8--Thr16 between beta-strand beta 1 and the N-terminus of alpha-helix alpha 1. The adenine ring is bound in a pocket between beta-strands beta 6 and beta 7. In the quaternary complex with Mn2+, the metal binding site is found in the vicinity of the beta- and gamma-phosphate groups. Two oxygen atoms from the phosphates and oxygen atoms from the side chains of Asp54, Thr16, and Glu115 are ligands to the Mn2+ ion in the quaternary complex. In the complex with ADP and the N7-carbamate of 7,8-diaminononanoic acid prepared in the presence of Ca2+ ions, a different metal binding site is found. The Ca2+ ion is coordinated to an oxygen atom of the alpha-phosphate group of the nucleotide, the side chain of Asp54, and solvent molecules. The 7,8-diaminononanoic acid substrate molecule interacts with residues from both subunits, making the dimer the minimal functional unit. The diamino group binds between the loops after beta 2 and beta 4, and the terminal carboxyl group at the hydrophobic tail of the substrate interacts with the amino terminus of helix alpha 5 and with the side chain of Tyr187 in helix alpha 6 of the second subunit at the monomer-monomer interface. Strong additional electron density close to the N7 nitrogen atom of the 7,8-diaminononanoic acid substrate in some complexes indicates that, even in the absence of added bicarbonate in the crystallization mixture, the carbamylated intermediate is formed in the crystal.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine Diphosphate↗
PubMed1995

Structural studies on corn nitrate reductase: refined structure of the cytochrome b reductase fragment at 2.5 A, its ADP complex and an active-site mutant and modeling of the cytochrome b domain.

The refined crystal structures of the recombinant cytochrome b reductase fragment of corn (Zea mays) nitrate reductase, its ADP complex and the active-site mutant Cys242Ser are reported here. The native structure has been refined at 2.5 A resolution to a crystallographic R-factor of 18.7% with root-mean-square (r.m.s) deviations from standard bond lengths and angles of 0.013 A and 2.0 degrees. The diffraction pattern of the crystals is highly anisotropic and correction of this effect lowered the crystallographic R-factor by 5% during the refinement. The structure of the enzyme co-crystallized with ADP has been solved at 2.7 A resolution and refined to an R-factor of 18.6% with r.m.s. deviations from standard bond lengths and angles of 0.014 A and 2.1 degrees. It revealed the binding site of the ADP moiety of the NADH cofactor, which is the electron donor for nitrate reduction. Based on this structure, a model of NADH at the active site of the enzyme was built and the implications for electron transfer from NADH to the flavin cofactor are discussed. The crystal structure of an active-site mutant enzyme, Cys242Ser, has been solved by difference Fourier synthesis and refined to an R-factor of 19.0% to 3.0 A resolution with standard deviations of bond lengths and angles of 0.017 A and 2.5 degrees. This structure analysis suggests that the observed decrease in catalytic activity of this mutant might be due to misalignment of the nicotinamide ring in its binding site. A model of the heme-containing domain of nitrate reductase has been built based on the X-ray structure of bovine cytochrome b5 and has been docked with the cytochrome b reductase fragment of nitrate reductase. The model of the complex contains six salt-bridges at the domain-domain interface and a hydrophobic core. In this model, His48, an invariant residue in the cytochrome b reductase family, forms an interaction with the propionic acid group of the D-ring of the heme cofactor. This group is in contact with the C-8 methyl group of the flavin ring. Residues that might influence the redox potential of the flavin cofactor are proposed and their possible role in electron transfer is discussed.

Adenosine Diphosphate↗
PubMed1995

Purification and preliminary X-ray crystallographic studies of recombinant L-ribulose-5-phosphate 4-epimerase from Escherichia coli.

The araD gene from Escherichia coli, coding for L-ribulose-5-phosphate 4-epimerase, was overexpressed and the resulting enzyme was purified to homogeneity. Crystals of L-ribulose-5-phosphate 4-epimerase, obtained with 4.0 M sodium formate as precipitant, belong to space group P4212 with unit cell dimensions a = b = 107.8 A and c = 281.4 A and diffract to at least 2.2 A resolution. Density measurements of these crystals are consistent with eight subunits in the asymmetric unit.

Base Sequence↗
PubMed1995

Immunodetection of alpha-actinin in focal adhesions is limited by antibody inaccessibility.

In this study we demonstrate that alpha-actinin is a prominent component of the focal adhesions of nonmuscle cells but that the alpha-actinin in focal adhesions is largely inaccessible to staining with antibodies against alpha-actinin. Our results explain a controversy that has existed in the literature. Investigators who microinject alpha-actinin into nonmuscle cells have routinely observed significant incorporation of alpha-actinin into focal adhesions as well as stress fibers. Immunofluorescence and immunoelectron microscopy have, however, indicated that alpha-actinin is located farther from the membrane than either talin or vinculin. Immunofluorescence studies of smooth muscle dense plaques and myotendinous junctions have also yielded conflicting results regarding the presence or absence of alpha-actinin at these sites. Here, we confirm that alpha-actinin immunofluorescence of fibroblasts yields weak or absent staining of focal adhesions. We also demonstrate that microinjected alpha-actinin readily incorporates into focal adhesions. However, various antisera against either the cell's endogenous alpha-actinin or against the microinjected chicken gizzard alpha-actinin fail to stain focal adhesions despite the presence of microinjected alpha-actinin at these sites. Furthermore, disassembly of stress fibers induced by dibutyrl cAMP demonstrates that alpha-actinin persists in focal adhesions in the absence of associated stress fibers, suggesting that alpha-actinin's association with focal adhesions is independent of stress fibers.

Actinin↗
PubMed1995

Development of simple fitness landscapes for peptides by artificial neural filter systems.

The applicability of artificial neural filter systems as fitness functions for sequence-oriented peptide design was evaluated. Two example applications were selected: classification of dipeptides according to their hydrophobicity and classification of proteolytic cleavage-sites of protein precursor sequences according to their mean hydrophobicities and mean side-chain volumes. The cleavage-sites covered 12 residues. In the dipeptide experiments the objective was to separate a selected set of molecules from all other possible dipeptide sequences. Perceptrons, feedforward networks with one hidden layer, and a hybrid network were applied. The filters were trained by a (1, lambda) evolution strategy. Two types of network units employing either a sigmoidal or a unimodal transfer function were used in the feedforward filters, and their influence on classification was investigated. The two-layer hybrid network employed gaussian activation functions. To analyze classification of the different filter systems, their output was plotted in the two-dimensional sequence space. The diagrams were interpreted as fitness landscapes qualifying the markedness of a characteristic peptide feature which can be used as a guide through sequence space for rational peptide design. It is demonstrated that the applicability of neural filter systems as a heuristic method for sequence optimization depends on both the appropriate network architecture and selection of representative sequence data. The networks with unimodal activation functions and the hybrid networks both led to a number of local optima. However, the hybrid networks produced the best prediction results. In contrast, the filters with sigmoidal activation produced good reclassification results leading to fitness landscapes lacking unreasonable local optima. Similar results were obtained for classification of both dipeptides and cleavage-site sequences.

Amino Acid Sequence↗
PubMed1995

Peptide design in machina: development of artificial mitochondrial protein precursor cleavage sites by simulated molecular evolution.

Artificial neural networks were used for extraction of characteristic physiochemical features from mitochondrial matrix metalloprotease target sequences. The amino acid properties hydrophobicity and volume were used for sequence encoding. A window of 12 residues was employed, encompassing positions -7 to +5 of precursors with cleavage sites. Two sets of noncleavage site examples were selected for network training which was performed by an evolution strategy. The weight vectors of the optimized networks were visualized and interpreted by Hinton diagrams. A neural filter system consisting of 13 perceptron-type networks accurately classified the data. It served as the fitness function in a simulated molecular evolution procedure for sequence-oriented de novo design of idealized cleavage sites. A detailed description of the strategy is given. Several putative high-quality cleavage sites were obtained revealing the critical nature of the residues in the positions -2 and -5. Charged residues seem to have a major influence on cleavage site function.

Amino Acid Sequence↗
PubMed1995

[Experiences with the endovascular embolization therapy of aneurysms of the splanchnic arteries--a report on 13 cases].

PURPOSE: The authors report on their experience in endovascular embolization therapy in 13 cases with splanchnic artery aneurysms or pseudoaneurysms. PATIENTS AND METHODS: Three patients suffered from true aneurysms, ten patients presented pseudoaneurysms of different origin. Eight patients were transferred to our department for life-threatening intestinal bleeding. Five patients showed transpapillary bleeding, four of whom presented with haemobilia and one patient had intermittent bleeding into the pancreatic duct due to a true aneurysm of the splenic artery. Embolization was performed using a coaxial microcatheter coil delivery system. In 4 patients the aneurysm-bearing vessel was temporarily blocked during the intervention. RESULTS: In 11 patients definite occlusion of the aneurysm was obtained without surgical intervention. In one patient, suffering from a splenic aneurysm, we observed a partial inadvertent embolisation of the spleen which did not require further treatment. In one case, rupture of an hepatic aneurysm during embolization occurred. One patient with pseudoaneurysm due to displacement of a port catheter showed severe rebleeding one day after embolisation. CONCLUSION: Transcatheter embolization is an effective method for treatment of aneurysms of the splanchnic arteries. To avoid life-threatening bleeding due to rupture of the aneurysm, the feeding vessel should be temporarily blocked during embolization therapy.

Adult↗
PubMed1995

Effect of renal function on neuromuscular block induced by continuous infusion of mivacurium.

We have studied the effect of renal function on the pharmacodynamics of mivacurium. Sixty patients were allocated to three groups according to creatinine clearance: group C (control), creatinine clearance > 50 ml min-1; group P (preterminal renal failure), creatinine clearance < 50 ml min-1 > 20 ml min-1; group T(terminal renal failure), creatinine clearance < 20 ml min-1. Neuromuscular transmission (train-of-four) was monitored using electromyography from the hypothenar muscle with stimulation of the ulnar nerve. After an initial bolus, mivacurium was administered continuously to maintain a T1 of 5 (4)% of baseline. The dose of mivacurium necessary to maintain 95% neuromuscular block was similar in patients with normal renal function and patients with different levels of renal impairment. Recovery from neuromuscular block after ceasing mivacurium infusion was significantly prolonged in patients with preterminal renal impairment. There was a close correlation between mivacurium pharmacodynamics and pseudocholinesterase activity, but not creatinine clearance.

Adolescent↗
PubMed1995

Lack of isodisomy for chromosome 22 in disomic meningiomas.

Loss of one copy of chromosome 22 is the most prevalent chromosomal change in meningioma, indicative of a tumor suppressor on chromosome 22. Meningioma retaining both copies of chromosome 22 could be possibly be explained by isodisomy for a meningioma suppressor gene. To investigate whether the chromosomal situation in meningioma is consistent with this hypothesis, we studied 53 cases, using polymorphic probes localized on chromosome 22. loss of one copy of chromosome 22 was found in 14 cases when polymorphic DNA markers were used. Thirty-nine meningiomas studied by karyotyping and molecular probes retained both copies of chromosome 22. The majority of cases (30/39, or 77%) displayed heterozygous banding patterns, indicating the presence of heterologous copies of chromosome 22. Hence, our data provide no evidence for duplication of one parental homolog as a general mechanism in diploid meningioma.

Chromosome Aberrations↗