Showing papers by "University of Geneva published in 1997"

Inhibition of death receptor signals by cellular FLIP

Abstract: The widely expressed protein Fas is a member of the tumour necrosis factor receptor family which can trigger apoptosis1 However, Fas surface expression does not necessarily render cells susceptible to Fas ligand-induced death signals1,2, indicating that inhibitors of the apoptosis-signalling pathway must exist Here we report the characterization of an inhibitor of apoptosis, designated FLIP (for FLICE-inhibitory protein), which is predominantly expressed in muscle and lymphoid tissues The short form, FLIPS, contains two death effector domains and is structurally related to the viral FLIP inhibitors of apoptosis3, whereas the long form, FLIPL, contains in addition a caspase-like domain in which the active-centre cysteine residue is substituted by a tyrosine residue FLIPS and FLIPL interact with the adaptor protein FADD4,5 and the protease FLICE6,7, and potently inhibit apoptosis induced by all known human death receptors1 FLIPL is expressed during the early stage of T-cell activation, but disappears when T cells become susceptible to Fas ligand-mediated apoptosis High levels of FLIPL protein are also detectable in melanoma cell lines and malignant melanoma tumours Thus FLIP may be implicated in tissue homeostasis as an important regulator of apoptosis

The PROSITE database, its status in 1997

Abstract: The PROSITE database consists of biologically significant patterns and profiles formulated in such a way that with appropriate computational tools it can help to determine to which known family of protein (if any) a new sequence belongs, or which known domain(s) it contains.

The SWISS-PROT protein sequence data bank and its supplement TrEMBL

Abstract: SWISS-PROT is a curated protein sequence database which strives to provide a high level of annotations (such as the description of the function of a protein, structure of its domains, post-translational modifications, variants, etc.), a minimal level of redundancy and high level of integration with other databases. Recent developments of the database include: an increase in the number and scope of model organisms; cross-references to two additional databases; a variety of new documentation files and the creation of TrEMBL, a computer annotated supplement to SWISS-PROT. This supplement consists of entries in SWISS-PROT-like format derived from the translation of all coding sequences (CDS) in the EMBL nucleotide sequence database, except the CDS already included in SWISS-PROT.

Positional cloning of the APECED gene

Abstract: Autoimmune polyglandular syndrome type I (APS 1, also called APECED) is an autosomal-recessive disorder that maps to human chromosome 21q22.3 between markers D21S49 and D21S171 by linkage studies. We have isolated a novel gene from this region, AIRE (autoimmune regulator), which encodes a protein containing motifs suggestive of a transcription factor including two zinc-finger (PHD-finger) motifs, a proline-rich region and three LXXLL motifs. Two mutations, a C-->T substitution that changes the Arg 257 (CGA) to a stop codon (TGA) and an A-->G substitution that changes the Lys 83 (AAG) to a Glu codon (GAG), were found in this novel gene in Swiss and Finnish APECED patients. The Arg257stop (R257X) is the predominant mutation in Finnish APECED patients, accounting for 10/12 alleles studied. These results indicate that this gene is responsible for the pathogenesis of APECED. The identification of the gene defective in APECED should facilitate the genetic diagnosis and potential treatment of the disease and further enhance our general understanding of the mechanisms underlying autoimmune diseases.

Long-term evaluation of non-submerged ITI implants. Part 1: 8-year life table analysis of a prospective multi-center study with 2359 implants.

Abstract: In the present multi-center study. non-submerged ITI implants were prospectively followed to evaluate their long-term prognosis in fully and partially edentulous patients. In a total of 1003 patients, 2359 implants were consecutively inserted. Following a healing period of 3–6 months, the successfully integrated implants were restored with 393 removable and 758 fixed restorations. Subsequently, all consecutive implants were documented annually up to 8 years. At each examination, the clinical status of all implants was evaluated according to predefined criteria of success. Therefore, the data base allowed the evaluation of 8-year cumulative survival and success rates for 2359 implants. In addition, cumulative success rates were calculated for implant subgroups divided per implant type, implant length. and implant location. Furthermore, the actual 5-year survival and success rates could be determined for 488 implants. During the healing period, 13 implants did not successfully integrate, whereas 2346 implants fulfilled the predefined criteria of success. This corresponds with an early failure rate of 0.55%. During follow-up, 19 implants were classified as failures due to several reasons. In addition, 17 implants (= 0.8%) demonstrated at the last annual examination a suppurative periimplant infection. Including 127 drop out implants (= 5.4% drop out rate) into the calculation, the 8-year cumulative survival and success rates resulted in 96.7% and 93.3%, respectively. The analysis of implant subgroups showed slightly more favorable cumulative success rates for screw type implants (> 95%) compared to hollow-cylinder implants (91.3%). and clearly better success rates for mandibular implants (= 95%) when compared to maxillary implants (= 87%). The actual 5-year survival and success rates of 488 implants with 98.2% and 97.3%. respectively, were slightly better than the estimated 5-year cumulative survival and success rates of 2359 implants indicating that the applied life table analysis is a reliable statistical method to evaluate the long-term prognosis of dental implants. It can be concluded that non-submerged ITI implants maintain success rates well above 90% in different clinical centers for observation periods up to 8 years.

Regulatory Phosphorylation of AMPA-Type Glutamate Receptors by CaM-KII During Long-Term Potentiation

Abstract: Long-term potentiation (LTP), a cellular model of learning and memory, requires calcium-dependent protein kinases. Induction of LTP increased the phosphorus-32 labeling of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPA-Rs), which mediate rapid excitatory synaptic transmission. This AMPA-R phosphorylation appeared to be catalyzed by Ca2+- and calmodulin-dependent protein kinase II (CaM-KII): (i) it correlated with the activation and autophosphorylation of CaM-KII, (ii) it was blocked by the CaM-KII inhibitor KN-62, and (iii) its phosphorus-32 peptide map was the same as that of GluR1 coexpressed with activated CaM-KII in HEK-293 cells. This covalent modulation of AMPA-Rs in LTP provides a postsynaptic molecular mechanism for synaptic plasticity.

The UDP glycosyltransferase gene superfamily: recommended nomenclature update based on evolutionary divergence.

Abstract: This review represents an update of the nomenclature system for the UDP glucuronosyltransferase gene superfamily, which is based on divergent evolution. Since the previous review in 1991, sequences of many related UDP glycosyltransferases from lower organisms have appeared in the database, which expand our database considerably. At latest count, in animals, yeast, plants and bacteria there are 110 distinct cDNAs/genes whose protein products all contain a characteristic 'signature sequence' and, thus, are regarded as members of the same superfamily. Comparison of a relatedness tree of proteins leads to the definition of 33 families. It should be emphasized that at least six cloned UDP-GlcNAc N-acetylglucosaminyltransferases are not sufficiently homologous to be included as members of this superfamily and may represent an example of convergent evolution. For naming each gene, it is recommended that the root symbol UGT for human (Ugt for mouse and Drosophila), denoting 'UDP glycosyltransferase,' be followed by an Arabic number representing the family, a letter designating the subfamily, and an Arabic numeral denoting the individual gene within the family or subfamily, e.g. 'human UGT2B4' and 'mouse Ugt2b5'. We recommend the name 'UDP glycosyltransferase' because many of the proteins do not preferentially use UDP glucuronic acid, or their nucleotide sugar preference is unknown. Whereas the gene is italicized, the corresponding cDNA, transcript, protein and enzyme activity should be written with upper-case letters and without italics, e.g. 'human or mouse UGT1A1.' The UGT1 gene (spanning > 500 kb) contains at least 12 promoters/first exons, which can be spliced and joined with common exons 2 through 5, leading to different N-terminal halves but identical C-terminal halves of the gene products; in this scheme each first exon is regarded as a distinct gene (e.g. UGT1A1, UGT1A2, ... UGT1A12). When an orthologous gene between species cannot be identified with certainty, as occurs in the UGT2B subfamily, sequential naming of the genes is being carried out chronologically as they become characterized. We suggest that the Human Gene Nomenclature Guidelines (http://www.gene.acl.ac.uk/nomenclature/guidelines.html++ +) be used for all species other than the mouse and Drosophila. Thirty published human UGT1A1 mutant alleles responsible for clinical hyperbilirubinemias are listed herein, and given numbers following an asterisk (e.g. UGT1A1*30) consistent with the Human Gene Nomenclature Guidelines. It is anticipated that this UGT gene nomenclature system will require updating on a regular basis.

Nucleocytoplasmic transport: signals, mechanisms and regulation

Abstract: In eukaryotic organisms, DNA replication and RNA biogenesis occur in the cell nucleus, whereas protein synthesis occurs in the cytoplasm. Integration of these activities depends on selective transport of proteins and ribonucleoprotein particles between the two compartments. Transport across the nuclear envelope occurs through large multiprotein structures, termed nuclear pore complexes. It is signal-mediated and requires both energy and soluble factors, including shuttling carriers. Here I summarize current understanding of nucleocytoplasmic transport and illustrate the importance of regulated transport for signal transduction.

The determinants of voluntary financial disclosure by Swiss listed companies

Abstract: The aim of this paper is to relate the extent of disclosure in the annual reports of Swiss listed companies to possible determinants representing agency and political costs. The choice of Switzerland is based on the fact that, prior to the implementation of the new company law on 1 July 1992 Swiss disclosure requirements were very low, so that the major part of the content of the annual report could be considered as voluntarily disclosed. The sample includes the 1991 annual report of 161 industrial and commercial firms. The extent of disclosure is measured by an index based on information whose disclosure is required by the Fourth and Seventh EU Directives. Independent variables are measures of company size, leverage, profitability, ownership structure, internationality, auditor's size, percentage of fixed assets and industry type. Relations are assessed using univariate analyses and multiple regressions. The main result is that size and internationality play a major role in the disclosure policy of firms...

The asymmetric distribution of the constituents of the Ran system is essential for transport into and out of the nucleus

Abstract: The GTPase Ran is essential for nuclear import of proteins with a classical nuclear localization signal (NLS). Ran's nucleotide-bound state is determined by the chromatin-bound exchange factor RCC1 generating RanGTP in the nucleus and the cytoplasmic GTPase activating protein RanGAP1 depleting RanGTP from the cytoplasm. This predicts a steep RanGTP concentration gradient across the nuclear envelope. RanGTP binding to importin-beta has previously been shown to release importin-alpha from -beta during NLS import. We show that RanGTP also induces release of the M9 signal from the second identified import receptor, transportin. The role of RanGTP distribution is further studied using three methods to collapse the RanGTP gradient. Nuclear injection of either RanGAP1, the RanGTP binding protein RanBP1 or a Ran mutant that cannot stably bind GTP. These treatments block major export and import pathways across the nuclear envelope. Different export pathways exhibit distinct sensitivities to RanGTP depletion, but all are more readily inhibited than is import of either NLS or M9 proteins, indicating that the block of export is direct rather than a secondary consequence of import inhibition. Surprisingly, nuclear export of several substrates including importin-alpha and -beta, transportin, HIV Rev and tRNA appears to require nuclear RanGTP but may not require GTP hydrolysis by Ran, suggesting that the energy for their nuclear export is supplied by another source.

Optimal Quantum Cloning Machines

Abstract: We present quantum cloning machines that transform $N$ identical qubits into $MgN$ identical copies and we prove that the fidelity (quality) of these copies is optimal. The connection between cloning and measurement is discussed in detail. When the number of clones $M$ tends towards infinity, the fidelity of each clone tends towards the optimal fidelity that can be obtained by a measurement on the input qubits. More generally, quantum cloning machines are universal devices to translate quantum information into classical information.

A Protein-Counting Mechanism for Telomere Length Regulation in Yeast

Abstract: In the yeast Saccharomyces cerevisiae, telomere elongation is negatively regulated by the telomere repeat-binding protein Rap1p, such that a narrow length distribution of telomere repeat tracts is observed. This length regulation was shown to function independently of the orientation of the telomere repeats. The number of repeats at an individual telomere was reduced when hybrid proteins containing the Rap1p carboxyl terminus were targeted there by a heterologous DNA-binding domain. The extent of this telomere tract shortening was proportional to the number of targeted molecules, consistent with a feedback mechanism of telomere length regulation that can discriminate the precise number of Rap1p molecules bound to the chromosome end.

Expression of MHC class II molecules in different cellular and functional compartments is controlled by differential usage of multiple promoters of the transactivator CIITA

Abstract: The highly complex pattern of expression of major histocompatibility complex class II (MHC-II) molecules determines both the immune repertoire during development and subsequently the triggering and the control of immune responses. These distinct functions result from cell type-restricted expression, developmental control and either constitutive or inducible expression of MHC-II genes. Yet, in these various situations, MHC-II gene expression is always under the control of a unique transactivator, CIITA. Here we show that the CIITA gene is controlled by several distinct promoters, two of which direct specific constitutive expression in dendritic cells and B lymphocytes respectively, while another mediates gamma-interferon-induced expression. Thus the cellular, temporal and functional diversity of MHC-II expression is ultimately controlled by differential activation of different promoters of a single transactivator gene. This provides novel experimental tools to dissect compartment-specific gain or loss of MHC-II function in vivo.

Elements of Grammar

Abstract: The aim of this handbook is to provide a forum in which some of the generative syntacticians whose work has had an impact on theoretical syntax over the past 20 years are invited to present their views on one or more aspects of current syntactic theory. The handbook is destined for an audience of linguists working in the generative framework. A general background knowledge of generative syntax is essential for the understanding of this book, but I hope that the introduction below will make the book accessible not only to a specialized audience but also to advanced students who are relatively new to the field.

Optimal eavesdropping in quantum cryptography. i. information bound and optimal strategy

Abstract: We consider the Bennett-Brassard cryptographic scheme, which uses two conjugate quantum bases. An eavesdropper who attempts to obtain information on qubits sent in one of the bases causes a disturbance to qubits sent in the other basis. We derive an upper bound to the accessible information in one basis, for a given error rate in the conjugate basis. Independently fixing the error rates in the conjugate bases, we show that both bounds can be attained simultaneously by an optimal eavesdropping probe. The probe interaction and its subsequent measurement are described explicitly. These results are combined to give an expression for the optimal information an eavesdropper can obtain for a given average disturbance when her interaction and measurements are performed signal by signal. Finally, the relation between quantum cryptography and violations of Bell's inequalities is discussed.

p55 Tumor Necrosis Factor Receptor Fusion Protein in the Treatment of Patients With Severe Sepsis and Septic Shock: A Randomized Controlled Multicenter Trial

Abstract: Objective. —To evaluate the safety and efficacy of p55 tumor necrosis factor receptor fusion protein, a recombinant chimeric protein of human p55 (type I) tumor necrosis factor receptor (CD120a) extracellular domain and lgG1 sequences (referred to as p55-lgG), in the treatment of patients with severe sepsis or septic shock. Design. —Randomized, prospective, multicenter, double-blind, placebo-controlled clinical trial. Setting. —Forty-four community and university-affiliated hospitals in the United States and Europe. patients. —There were 498 patients enrolled in this clinical trial. Intervention. —Patients prospectively stratified within each site into refractory shock or severe sepsis groups were randomized to receive a single infusion of p55IgG, 0.083 mg/kg, 0.042 mg/kg, or 0.008 mg/kg, or placebo. Patients received standard aggressive medical/surgical care during the 28-day postinfusion period. Outcome Measure. —Twenty-eight—day all-cause mortality. Results. —The distribution of variables describing demographics, organ system dysfunction or failure, infecting microorganisms, predicted mortality, plasma interleukin 6 levels, and plasma tumor necrosis factor α (TNF-α) levels were similar among patients in the p55-lgG and placebo treatment arms. A planned interim analysis was performed after 201 patients were enrolled. Because a statistically nonsignificant trend toward increased mortality was present in patients who had received 0.008 mg/kg, this treatment arm was discontinued, and the study continued with 3 arms. Among all infused patients, there was a statistically nonsignificant trend toward reduced 28-day all-cause mortality in those who received p55-lgG compared with placebo-treated patients (5% reduction, 0.042 mg/kg vs placebo; 15% reduction, 0.083 mg/kg vs placebo;P=.30). However, in patients with severe sepsis and early septic shock (n=247), therapy with p55-lgG, 0.083 mg/kg, was associated with a 36% reduction in 28-day all-cause mortality compared with placebo (P=.07): 20 (23%) of 87 patients died among those treated with p55-lgG, 0.083 mg/kg; 30 (37%) of 82 among those treated with p55-lgG, 0.042 mg/kg; and 28 (36%) of 78 in the placebo group. A prospectively planned logistic regression analysis to assess treatment effect on 28-day all-cause mortality by means of predicted mortality and serum interleukin 6 levels as continuous covariates demonstrated a significant improvement in outcome for the patients with severe sepsis treated with p55-lgG, 0.083 mg/kg, compared with placebo (P=.01). Serious adverse events, including death and the development of new organ system dysfunction, were reported in 65% of patients infused with placebo, with no increased frequency (56%) present in the 2 p55-lgG treatment arms. There were no reports of immediate hypersensitivity reactions caused by p55-lgG. Conclusions. —In this dose-finding study, there was no decrease in mortality between placebo and p55-lgG in all infused patients. In the prospectively defined population of patients with severe sepsis who received p55-lgG, 0.083 mg/kg, there was a trend toward reduced mortality at day 28 that became significant when predicted mortality and plasma interleukin 6 levels were included in a logistic regression analysis.

Dodecamer repeat expansion in cystatin B gene in progressive myoclonus epilepsy

Abstract: Progressive myoclonus epilepsy of the Unverricht-Lundborg type (EPM1; MIM 254800) is an autosomal recessive disorder with onset between 6 and 13 years followed by variable progression to mental deterioration and cerebellar ataxia. It is a rare disorder but more common in Finland (1 in 20,000) and the western Mediterranean. Two point mutations in the cysteine proteinase inhibitor gene cystatin B (CSTB), proved that this gene is responsible for EPM1 (ref. 3). An extensive search in the CSTB gene revealed mutations accounting only for 14% of the 58 unrelated EPM1 alleles studied. Here we report that the majority of EPM1 alleles contain expansions of a dodecamer (12-mer) repeat located about 70 nucleotides upstream of the transcription start site nearest to the 5' end of the CSTB gene. Normal alleles contain 2 or 3 copies of this repeat whereas mutant alleles contain more than 60 such repeats and have reduced levels of CSTB messenger RNA in blood but not in cell lines. 'Premutation' CSTB alleles with 12-17 repeats show marked instability when transmitted to offspring.

Of fingers, toes and penises

Abstract: Vertebrate Hox genes are essential for limb development. The posterior-most Hoxd and Hoxa genes are required for growth and patterning of digits and are also strongly expressed in the genital bud, which gives rise to the urogenital system, including the penis. Here, we show that removal of posterior Hox gene function results in a concomitant loss of digits and genital bud-derivatives, illustrating that similar developmental mechanisms are at work in these different buds.

Detailed peptide characterization using PEPTIDEMASS : a World-Wide-Web-accessible tool

Abstract: In peptide mass fingerprinting, there are frequently peptides whose masses cannot be explained. These are usually attributed to either a missed cleavage site during the chemical or enzymatic cutting process, the lack of reduction and alkylation of a protein, protein modifications like the oxidation of methionine, or the presence of protein post-translational modifications. However, they could equally be due to database errors, unusual splicing events, variants of a protein in a population, or artifactual protein modifications. Unfortunately the verification of each of these possibilities can be tedious and time-consuming. To better utilize annotated protein databases for the understanding of peptide mass fingerprinting data, we have written the program "PEPTIDEMASS". This program generates the theoretical peptide masses of any protein in the SWISS-PROT database, or of any sequence specified by the user. If the sequence is derived from the SWISS-PROT database, the program takes into account any annotations for that protein in order to generate the peptide masses. In this manner, the user can obtain the predicted masses of peptides from proteins which are known to have signal sequences, propeptides, transit peptides, simple post-translational modifications, and disulfide bonds. Users are also warned if any peptide masses are subject to change from protein isoforms, database conflicts, or an mRNA splicing variation. The program is freely accessible to the scientific community via the ExPASy World Wide Web server, at the URL address: http://www.expasy.ch/www/tools.html.