Search PubMed⌕ Search

Biomedical subjects

M Meier

Publications and source records attributed to M Meier.

At least 19 recordsLinked to original sources
PubMed2001

Structure of human cystathionine beta-synthase: a unique pyridoxal 5'-phosphate-dependent heme protein.

Cystathionine beta-synthase (CBS) is a unique heme- containing enzyme that catalyzes a pyridoxal 5'-phosphate (PLP)-dependent condensation of serine and homocysteine to give cystathionine. Deficiency of CBS leads to homocystinuria, an inherited disease of sulfur metabolism characterized by increased levels of the toxic metabolite homocysteine. Here we present the X-ray crystal structure of a truncated form of the enzyme. CBS shares the same fold with O-acetylserine sulfhydrylase but it contains an additional N-terminal heme binding site. This heme binding motif together with a spatially adjacent oxidoreductase active site motif could explain the regulation of its enzyme activity by redox changes.

Amino Acid Sequence↗
PubMed2001

Two isoforms of trimming glucosidase II exist in mammalian tissues and cell lines but not in yeast and insect cells.

We previously cloned glucosidase II and provided in vivo evidence for its involvement in protein folding quality control. DNA-sequencing of different clones demonstrated the existence of two isoforms of glucosidase II which differed by 66 nucleotides due to alternative splicing. The existence of two enzyme isoforms in various organs of pig and rat as well as human, bovine, rat, and mouse cell lines could be demonstrated by RT-PCR and Western blotting. Furthermore, the two isoforms of glucosidase II could be detected in embryonic and postnatal rat kidney and liver. In yeast, Saccharomyces cerevisiae, and in insects, Drosophila S2 cells, only one isoforms of the enzyme was detectable. The ubiquitous occurrence of the two glucosidase II isoforms in mammalian tissues and cell lines might be indicative of a special function of each isoform.

Animals↗
PubMed2001

Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13.

Congenital generalized lipodystrophy, or Berardinelli-Seip syndrome (BSCL), is a rare autosomal recessive disease characterized by a near-absence of adipose tissue from birth or early infancy and severe insulin resistance. Other clinical and biological features include acanthosis nigricans, hyperandrogenism, muscular hypertrophy, hepatomegaly, altered glucose tolerance or diabetes mellitus, and hypertriglyceridemia. A locus (BSCL1) has been mapped to 9q34 with evidence of heterogeneity. Here, we report a genome screen of nine BSCL families from two geographical clusters (in Lebanon and Norway). We identified a new disease locus, designated BSCL2, within the 2.5-Mb interval flanked by markers D11S4076 and D11S480 on chromosome 11q13. Analysis of 20 additional families of various ethnic origins led to the identification of 11 families in which the disease cosegregates with the 11q13 locus; the remaining families provide confirmation of linkage to 9q34. Sequence analysis of genes located in the 11q13 interval disclosed mutations in a gene homologous to the murine guanine nucleotide-binding protein (G protein), gamma3-linked gene (Gng3lg) in all BSCL2-linked families. BSCL2 is most highly expressed in brain and testis and encodes a protein (which we have called seipin) of unknown function. Most of the variants are null mutations and probably result in a severe disruption of the protein. These findings are of general importance for understanding the molecular mechanisms underlying regulation of body fat distribution and insulin resistance.

Acanthosis Nigricans↗
PubMed2001

Crystallization and preliminary X-ray diffraction analysis of the active core of human recombinant cystathionine beta-synthase: an enzyme involved in vascular disease.

Cystathionine beta-synthase (CBS) is a unique heme enzyme that catalyzes a PLP-dependent condensation of serine and homocysteine to give cystathionine. Deficiency of CBS leads to homocystinuria, an autosomal recessively inherited disease of sulfur metabolism. A truncated form of CBS in which the C-terminal amino-acid residues have been deleted has been prepared. The truncated CBS subunits form a dimer, in contrast to the full-length subunits which form tetramers and higher oligomers. The truncated CBS yielded crystals diffracting to 2.6 A which belong to space group P3(1) or P3(2). This is the first comprehensive structural investigation of a PLP and heme-containing enzyme.

Binding Sites↗
PubMed2001

Biotransformation of various substituted aromatic compounds to chiral dihydrodihydroxy derivatives.

The biotransformation of four different classes of aromatic compounds by the Escherichia coli strain DH5alpha(pTCB 144), which contained the chlorobenzene dioxygenase (CDO) from Pseudomonas sp. strain P51, was examined. CDO oxidized biphenyl as well as monochlorobiphenyls to the corresponding cis-2,3-dihydro-2,3-dihydroxy derivatives, whereby oxidation occurred on the unsubstituted ring. No higher substituted biphenyls were oxidized. The absolute configurations of several monosubstituted cis-benzene dihydrodiols formed by CDO were determined. All had an S configuration at the carbon atom in meta position to the substituent on the benzene nucleus. With one exception, the enantiomeric excess of several 1,4-disubstituted cis-benzene dihydrodiols formed by CDO was higher than that of the products formed by two toluene dioxygenases. Naphthalene was oxidized to enantiomerically pure (+)-cis-(1R,2S)-dihydroxy-1,2-dihydronaphthalene. All absolute configurations were identical to those of the products formed by toluene dioxygenases of Pseudomonas putida UV4 and P. putida F39/D. The formation rate of (+)-cis-(1R,2S)-dihydroxy-1,2-dihydronaphthalene was significantly higher (about 45 to 200%) than those of several monosubstituted cis-benzene dihydrodiols and more than four times higher than the formation rate of cis-benzene dihydrodiol. A new gas chromatographic method was developed to determine the enantiomeric excess of the oxidation products.

Benzene↗
PubMed2001

Tracheobronchial stenosis in Keutel syndrome.

In 1971 Keutel et al. described a new syndrome in two siblings presenting with peripheral pulmonary stenoses, brachytelephalangism, neural hearing loss and abnormal cartilage calcification. Recent investigations provided evidence that mutations in the gene encoding the human matrix GLA protein cause Keutel syndrome. With these new insights in the disease the symptomatology of Keutel syndrome was reassessed. The follow-up of the two siblings was studied by clinical and post mortem examination. As a new feature of Keutel syndrome tracheobronchial stenosis and concentric calcification of pulmonary, coronary, hepatic, renal, meningeal and cerebral arteries were described. Complementary to the results in molecular genetics the symptomatology of Keutel syndrome could be revised by clinical and post mortem examination.

Abnormalities, Multiple↗
PubMed2000

Crystal structure of the carbohydrate recognition domain of the H1 subunit of the asialoglycoprotein receptor.

The human asialoglycoprotein receptor (ASGPR), also called hepatic lectin, is an integral membrane protein and is responsible for the clearance of desialylated, galactose-terminal glycoproteins from the circulation by receptor-mediated endocytosis. It can be subdivided into four functional domains: the cytosolic domain, the transmembrane domain, the stalk and the carbohydrate recognition domain (CRD). The galactose-binding domains belong to the superfamily of C-type (calcium-dependent) lectins, in particular to the long-form subfamily with three conserved intramolecular disulphide bonds. It is able to bind terminal non-reducing galactose residues and N-acetyl-galactosamine residues of desialated tri or tetra-antennary N-linked glycans. The ASGPR is a potential liver-specific receptor for hepatitis B virus and Marburg virus and has been used to target exogenous molecules specifically to hepatocytes for diagnostic and therapeutic purposes.Here, we present the X-ray crystal structure of the carbohydrate recognition domain of the major subunit H1 at 2.3 A resolution. While the overall fold of this and other known C-type lectin structures are well conserved, the positions of the bound calcium ions are not, indicating that the fold is stabilised by alternative mechanisms in different branches of the C-type lectin family. It is the first CRD structure where three calcium ions form an intergral part of the structure. In addition, the structure provides direct confirmation for the conversion of the ligand-binding site of the mannose-binding protein to an asialoglycoprotein receptor-like specificity suggested by Drickamer and colleagues. In agreement with the prediction that the coiled-coil domain of the ASGPR is separated from the CRD and its N-terminal disulphide bridge by several residues, these residues are indeed not alpha-helical, while in tetranectin they form an alpha-helical coiled-coil.

Amino Acid Sequence↗
PubMed2000

Telemetry as a new concept in long term monitoring of SIDS-risk infant.

Sudden Infant Death Syndrome (SIDS) is the most frequent cause of infant death within the period of 2 to 12 months in western countries. It has been found that a suit similar to that worn by the astronauts during the execution of experiments on the Spacelab Mission D-2 is a very simple and useful means to carry the sensors required to monitor vital signs of babies at risk. A small baby-suit has been developed with the same technology used for the Spacelab Mission. The baby s suit is equipped with similar sensors to record thoracic and abdominal respiratory movements as its big -space travel brother-. This is a typical example of a successful technology transfer from medical aerospace activities into fields of daily clinical routine. In addition to the above described sensors, ECG-electrodes were integrated, as well as sensors to record vascular oxygen saturation and the corresponding pulse curve, and the baby s movements. All these vital signs are registered by a medical monitor, and permanently stored and automatically analysed online. In case of a life-threatening situation the system alerts simultaneously the personal at hospital and the parents at home. The requisite software algorithms have been developed by DLR in Cooperation with the pediatricians of the Pediatric Hospital in Köln-Porz, Cologne. When the system registers an alteration of the parameters above described -as a signal of a change in the baby s health condition- all vital signs are transfered in real-time to the supervising hospital via radio data transmission devices, mobile phone or a fixed network phone. The parents are also alerted by the device, and they can carry out the necessary reanimation procedures in case of an emergency. Parents will be trained in such actions when newborns must to be monitored. But nevertheless, they are guided and tele-assisted by an expert via telephone during the action. A clinical field trial, that will start in December 1999 at the Pediatric Hospital in Köln-Porz, Cologne, will evaluate the benefits of teleprotection by home monitoring of SIDS risk-babies.

Humans↗
PubMed2000

The HIV-1 protease inhibitor indinavir impairs insulin signalling in HepG2 hepatoma cells.

AIMS/HYPOTHESIS: Patients treated with human immunodeficiency virus-1 protease inhibitors often develop impaired glucose tolerance or diabetes, most likely due to an induction of insulin resistance. We therefore investigated whether the protease inhibitor indinavir alters insulin signalling. METHODS: We incubated HepG2 cells for 48 h without or with indinavir (100 micromol/l). Subsequently 125I-insulin binding to the cells and the effects of insulin stimulation on insulin-receptor substrate-1-phosphorylation, association of phosphatidylinositol 3-kinase with insulin-receptor substrate-1 and Akt-Thr308-phosphorylation were measured. RESULTS: In cells not exposed to indinavir, insulin (100 nmol/l) led to rapid increases of insulin-receptor substrate-1-phosphorylation, association of phosphatidylinositol 3-kinase with insulin-receptor substrate-1 and Akt-phosphorylation during the first 75 s, followed by subsequent decreases. In indinavir-treated cells, these insulin-stimulated increases during the first 75 s were reduced by 30-60% and this was not associated with alterations in cell number or viability, insulin binding to the cells or cellular insulin-receptor substrate-1-content. CONCLUSION/INTERPRETATION: Effects of indinavir on initial insulin signalling could cause, or contribute to, the metabolic effects of human immunodeficiency virus-1 protease inhibitors.

Carcinoma, Hepatocellular↗
PubMed2000

Number processing and mental calculation in school children aged 7 to 10 years: a transcultural comparison.

Neuropsychological studies of dyscalculic patients show that arithmetical development is not a unidimensional process. In transcultural investigations, cultural, educational and linguistic factors might affect differently the various components of mathematical development. Four hundred and sixty schoolchildren aged 7 to 10 years from Brasilia, Brazil (n = 141), Paris, France (n = 160) and Zurich, Switzerland (n = 159) were asked to perform eleven number processing and calculation tasks. Chronological age, which was almost confounded in this study to educational level, had a strong effect on some tasks (knowledge of the written code of numbers, number comparison, mental calculation, problem solving), but only a slight effect on other tasks (counting dots, counting backwards, estimation). Also, linguistic factors and factors related to the socio-economic level of the family had different effects on the various components of calculation and number processing. Evidence from developmental studies has to be integrated into theoretical models of calculation and number processsing, which are presently based mainly on results from neuropsychological studies of dyscalculic patients.

Brazil↗
PubMed2000

Health care expenditure in the last months of life.

In OECD countries, a considerable share of health care expenditure (HCE) is spent for the care of the terminally ill. This paper derives the demand for HCE in the last 2 years of life from a model that accounts for age, mortality risk and wealth. The empirical tests are based on data of deceased members of a major Swiss sick fund. The empirical evidence confirms most of the hypotheses derived from the model, i.e., (i) HCE increases with closeness to death, (ii) for retired individuals, HCE decreases with age, and (iii) low-income individuals, as compared to high-income individuals, incur lower HCE in the last months of life.

Aged↗
PubMed2000

Teledermatoscopy in Switzerland: a preliminary evaluation.

BACKGROUND: Since devices for digital epiluminescence microscopy and for telemedicine have become affordable, a critical evaluation of this new method has been needed. OBJECTIVE: Our aim was a critical evaluation of teledermatoscopy under routine conditions in private practice. METHODS: Pigmented skin lesions (PSLs) scheduled for excision were documented with a digital epiluminescence microscopy (DELM) system. Images were sent to the PSL consultation at the Department of Dermatology of the University Hospital Geneva, where a diagnosis was established. The histopathologic report including the initial diagnosis was sent afterward. Both approaches were compared concerning diagnostic accuracy. RESULTS: Over a period of 6 months, 55 lesions on 51 patients have been included in this study. Picture quality was good or very good in more than 90%. Diagnostic accuracy of the teledermatoscopy approach was superior to that of the conventional approach for malignant melanocytic lesions. CONCLUSION: We have shown the feasibility of a teledermatoscopic consultation. The gain of diagnostic accuracy in this teledermatoscopic approach, especially for malignant melanocytic lesions, suggests that patients might benefit directly from such a consultation at distance.

Feasibility Studies↗
PubMed2000

Design of a minimal protein oligomerization domain by a structural approach.

Because of the simplicity and regularity of the alpha-helical coiled coil relative to other structural motifs, it can be conveniently used to clarify the molecular interactions responsible for protein folding and stability. Here we describe the de novo design and characterization of a two heptad-repeat peptide stabilized by a complex network of inter- and intrahelical salt bridges. Circular dichroism spectroscopy and analytical ultracentrifugation show that this peptide is highly alpha-helical and 100% dimeric tinder physiological buffer conditions. Interestingly, the peptide was shown to switch its oligomerization state from a dimer to a trimer upon increasing ionic strength. The correctness of the rational design principles used here is supported by details of the atomic structure of the peptide deduced from X-ray crystallography. The structure of the peptide shows that it is not a molten globule but assumes a unique, native-like conformation. This de novo peptide thus represents an attractive model system for the design of a molecular recognition system.

Amino Acid Sequence↗
PubMed2000

Protein kinase C activation and its pharmacological inhibition in vascular disease.

Vascular complications in diabetes mellitus are known to be associated with the activation of the protein kinase C (PKC) pathway through the de novo synthesis of diacylglycerol (DAG) from glycolytic intermediates. Specific PKC isoforms, mainly the beta- and delta-isoforms, have been shown to be persistently activated in diabetic mellitus. Multiple studies have reported that the activation of PKC leads to increased production of extracellular matrix and cytokines, enhances contractility, permeability and vascular cell proliferation, induces the activation of cytosolic phospholipase A2 and inhibits the activity of Na+-K+-ATPase. These events are not only frequently observed in diabetes mellitus but are also involved in the actions of vasoactive agents or oxidative stress. Inhibition of PKC by two different kinds of PKC inhibitors - LY333531, a selective PKC-beta-isoform inhibitor, and vitamin E, d-alpha-tocopheron - were able to prevent or reverse the various vascular dysfunctions in vitro and in vivo. Clinical studies using these compounds are now ongoing to evaluate the significance of DAG-PKC pathway activation in the development of vascular complications in diabetic patients.

Animals↗