Showing papers by "Katholieke Universiteit Leuven published in 2002"

Functional profiling of the Saccharomyces cerevisiae genome.

Abstract: Determining the effect of gene deletion is a fundamental approach to understanding gene function. Conventional genetic screens exhibit biases, and genes contributing to a phenotype are often missed. We systematically constructed a nearly complete collection of gene-deletion mutants (96% of annotated open reading frames, or ORFs) of the yeast Saccharomyces cerevisiae. DNA sequences dubbed 'molecular bar codes' uniquely identify each strain, enabling their growth to be analysed in parallel and the fitness contribution of each gene to be quantitatively assessed by hybridization to high-density oligonucleotide arrays. We show that previously known and new genes are necessary for optimal growth under six well-studied conditions: high salt, sorbitol, galactose, pH 8, minimal medium and nystatin treatment. Less than 7% of genes that exhibit a significant increase in messenger RNA expression are also required for optimal growth in four of the tested conditions. Our results validate the yeast gene-deletion collection as a valuable resource for functional genomics.

Least Squares Support Vector Machines

Abstract: Support Vector Machines Basic Methods of Least Squares Support Vector Machines Bayesian Inference for LS-SVM Models Robustness Large Scale Problems LS-SVM for Unsupervised Learning LS-SVM for Recurrent Networks and Control.

The genome sequence of Schizosaccharomyces pombe

Abstract: We have sequenced and annotated the genome of fission yeast (Schizosaccharomyces pombe), which contains the smallest number of protein-coding genes yet recorded for a eukaryote: 4,824. The centromeres are between 35 and 110 kilobases (kb) and contain related repeats including a highly conserved 1.8-kb element. Regions upstream of genes are longer than in budding yeast (Saccharomyces cerevisiae), possibly reflecting more-extended control regions. Some 43% of the genes contain introns, of which there are 4,730. Fifty genes have significant similarity with human disease genes; half of these are cancer related. We identify highly conserved genes important for eukaryotic cell organization including those required for the cytoskeleton, compartmentation, cell-cycle control, proteolysis, protein phosphorylation and RNA splicing. These genes may have originated with the appearance of eukaryotic life. Few similarly conserved genes that are important for multicellular organization were identified, suggesting that the transition from prokaryotes to eukaryotes required more new genes than did the transition from unicellular to multicellular organization.

R&D cooperation and spillovers: Some empirical evidence from Belgium

Abstract: Successful innovation depends on the development and integration of new knowledge in the innovation process. Part of this knowledge will reach the firm from external sources. Several authors have documented the existence of these external information flows and have commented on their importance for decisions at the firm level (Adam B. Jaffe, 1986; Jeffrey I. Bernstein and M. Ishaq Nadiri, 1988) and ultimately for economic growth (Paul M. Romer, 1990; Gene M. Grossman and Elhanan Helpman, 1991; Zvi Griliches, 1992). One challenge facing this literature has been the measurement of these information flows or “spillovers” between firms and gauging their effect on different innovation management decisions by the firm. While assessing spillovers, it is important to distinguish between incoming spillovers, which affect the rate of innovation of the firm, and appropriability, which affects the ability of the firm to appropriate the returns from innovation. The information sources for incoming spillovers are usually situated in the public domain, and their usefulness to the firm depend on the firm’s ability to create information flows from this public pool of knowledge. But firms also attempt to appropriate the benefits of their innovations by controlling the information flows out of the company into the pool of publicly available information. The relevance of distinguishing between incoming spillovers and appropriability is revealed when we use these measures to analyze their impact on the decision of firms to engage in cooperative RD Morton I. Kamien et al., 1992; Raymond De Bondt, 1997). On the other hand, imperfect appropriability increases the incentive of firms to free ride on each other’s RD Katrien Kesteloot and Veugelers, 1995) and encourages free-riding on the RD Veugelers: Katholieke Universiteit Leuven and CEPR, Naamsestraat 69, 3000 Leuven, Belgium (e-mail: Reinhilde.Veugelers@econ.kuleuven.ac.be). The authors would especially like to thank an anonymous referee, as well as Raymond De Bondt, Paul Geroski, Mort Kamien, Steve Martin, Marno Verbeek, Gary Charness, James Costain, and Harry Bowen, for very helpful comments. We also thank the seminar participants at the London Business School, IESE Business School, Universidad Carlos III, Universitat Autonoma de Barcelona, Universidad de Zaragoza, Universidad Publica de Navarra, the Universite Libre de Bruxelles, and Paris I and Paris XII, and the participants in ASSET (Bologna), LASEM (Cancun), and EARIE (Turin). The DWTC and IWT generously provided the data for this research. Cassiman acknowledges support from BEC2000-1026 and CIRIT 1997SGR00138, and Veugelers from CNRS, Enjeux Economiques de l’Innovation, and NFWO (G.0131.98). The paper was to a large extent written while Cassiman was assistant professor at the Universitat Pompeu Fabra in Barcelona and Veugelers was visiting the Universitat Autonoma de Barcelona and MIT [Sloan School (ICRMOT)].

Passage of inhaled particles into the blood circulation in humans.

Abstract: Background — Pollution by particulates has been consistently associated with increased cardiovascular morbidity and mortality. However, the mechanisms responsible for these effects are not well-elucidated. Methods and Results — To assess to what extent and how rapidly inhaled pollutant particles pass into the systemic circulation, we measured, in 5 healthy volunteers, the distribution of radioactivity after the inhalation of “Technegas,” an aerosol consisting mainly of ultrafine 99m Technetium-labeled carbon particles ( 99m Tc, ie, pertechnetate, there was also a species corresponding to particle-bound 99m Tc. Gamma camera images showed substantial radioactivity over the liver and other areas of the body. Conclusions — We conclude that inhaled 99m Tc-labeled ultrafine carbon particles pass rapidly into the systemic circulation, and this process could account for the well-established, but poorly understood, extrapulmonary effects of air pollution.

uPAR: a versatile signalling orchestrator

Abstract: The plasminogen system has been implicated in clot lysis, wound healing, tissue regeneration, cancer and many other processes that affect health and disease. The urokinase receptor uPAR was originally thought to assist the directional invasion of migrating cells, but it is now becoming increasingly evident that this proteinase receptor elicits a plethora of cellular responses that include cellular adhesion, differentiation, proliferation and migration in a non-proteolytic fashion.

Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1

Abstract: The therapeutic potential of placental growth factor (PlGF) and its receptor Flt1 in angiogenesis is poorly understood. Here, we report that PlGF stimulated angiogenesis and collateral growth in ischemic heart and limb with at least a comparable efficiency to vascular endothelial growth factor (VEGF). An antibody against Flt1 suppressed neovascularization in tumors and ischemic retina, and angiogenesis and inflammatory joint destruction in autoimmune arthritis. Anti-Flt1 also reduced atherosclerotic plaque growth and vulnerability, but the atheroprotective effect was not attributable to reduced plaque neovascularization. Inhibition of VEGF receptor Flk1 did not affect arthritis or atherosclerosis, indicating that inhibition of Flk1-driven angiogenesis alone was not sufficient to halt disease progression. The anti-inflammatory effects of anti-Flt1 were attributable to reduced mobilization of bone marrow-derived myeloid progenitors into the peripheral blood; impaired infiltration of Flt1-expressing leukocytes in inflamed tissues; and defective activation of myeloid cells. Thus, PlGF and Flt1 constitute potential candidates for therapeutic modulation of angiogenesis and inflammation.

Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide.

Abstract: OBJECTIVE: Glomerulonephritis is a severe manifestation of systemic lupus erythematosus (SLE) that is usually treated with an extended course of intravenous (IV) cyclophosphamide (CYC). Given the side effects of this regimen, we evaluated the efficacy and the toxicity of a course of low-dose IV CYC prescribed as a remission-inducing treatment, followed by azathioprine (AZA) as a remission-maintaining treatment. METHODS: In this multicenter, prospective clinical trial (the Euro-Lupus Nephritis Trial [ELNT]), we randomly assigned 90 SLE patients with proliferative glomerulonephritis to a high-dose IV CYC regimen (6 monthly pulses and 2 quarterly pulses; doses increased according to the white blood cell count nadir) or a low-dose IV CYC regimen (6 fortnightly pulses at a fixed dose of 500 mg), each of which was followed by AZA. Intent-to-treat analyses were performed. RESULTS: Followup continued for a median of 41.3 months in the low-dose group and 41 months in the high-dose group. Sixteen percent of those in the low-dose group and 20% of those in the high-dose group experienced treatment failure (not statistically significant by Kaplan-Meier analysis). Levels of serum creatinine, albumin, C3, 24-hour urinary protein, and the disease activity scores significantly improved in both groups during the first year of followup. Renal remission was achieved in 71% of the low-dose group and 54% of the high-dose group (not statistically significant). Renal flares were noted in 27% of the low-dose group and 29% of the high-dose group. Although episodes of severe infection were more than twice as frequent in the high-dose group, the difference was not statistically significant. CONCLUSION: The data from the ELNT indicate that in European SLE patients with proliferative lupus nephritis, a remission-inducing regimen of low-dose IV CYC (cumulative dose 3 gm) followed by AZA achieves clinical results comparable to those obtained with a high-dose regimen.

Towards measuring anonymity

Abstract: This paper introduces an information theoretic model that allows to quantify the degree of anonymity provided by schemes for anonymous connections. It considers attackers that obtain probabilistic information about users. The degree is based on the probabilities an attacker, after observing the system, assigns to the different users of the system as being the originators of a message. As a proof of concept, the model is applied to some existing systems. The model is shown to be very useful for evaluating the level of privacy a system provides under various attack scenarios, for measuring the amount of information an attacker gets with a particular attack and for comparing different systems amongst each other.

Working Group on Blood Pressure Monitoring of the European Society of Hypertension International Protocol for validation of blood pressure measuring devices in adults

Abstract: Working Group on Blood Pressure Monitoring of the European Society of Hypertension International Protocol for validation of blood pressure measuring devices in adults Eoin O’Brien,Thomas Pickering, Roland Asmar, Martin Myers, Gianfranco Parati, Jan Staessen, Thomas Mengden, Yutaka Imai, Bernard Waeber and Paolo Palatini and with the statistical assistance of Neil Atkins and William Gerin, on behalf of the Working Group on Blood Pressure Monitoring of the European Society of Hypertension

The Monopolization Hypothesis and the dispersal–gene flow paradox in aquatic organisms

Abstract: Many aquatic organisms rely on passive transport of resting stages for their dispersal. In this review, we provide evidence pointing to the high dispersal capacity of both animals (cladocerans, rotifers and bryozoans) and aquatic macrophytes inhabiting lentic habitats. This evidence includes direct observation of dispersal by vectors such as wind and waterfowl and the rapid colonization of new habitats. Such high dispersal capacity contrasts with the abundant evidence of pronounced genetic differentiation among neighbouring populations in many pond-dwelling organisms. We provide an overview of the potential mechanisms causing a discrepancy between high dispersal rates and reduced levels of gene flow. We argue that founder events combined with rapid local adaptation may underlie the striking patterns of genetic differentiation for neutral markers in many aquatic organisms. Rapid population growth and local adaptation upon colonization of a new habitat result in the effective monopolization of resources, yielding a strong priority effect. Once a population is locally adapted, the presence of a large resting propagule bank provides a powerful buffer against newly invading genotypes, so enhancing priority effects. Under this Monopolization Hypothesis, high genetic differentiation among nearby populations largely reflects founder events. Phylogeographic data support a scenario of low effective dispersal among populations and persistent effects of historical colonization in cyclical parthenogens. A comparison of patterns of gene flow in taxa with different life cycles suggests an important role of local adaptation in reducing gene flow among populations. We argue that patterns of regional genetic differentiation may often reflect historical colonization of new habitats rather than contemporary gene flow.

Intermanual coordination: from behavioural principles to neural-network interactions.

Abstract: Locomotion in vertebrates and invertebrates has a long history in research as the most prominent example of interlimb coordination However, the evolution towards upright stance and gait has paved the way for a bewildering variety of functions in which the upper limbs interact with each other in a context-specific manner The neural basis of these bimanual interactions has been investigated in recent years on different scales, ranging from the single-cell level to the analysis of neuronal assemblies Although the prevailing viewpoint has been to assign bimanual coordination to a single brain locus, more recent evidence points to a distributed network that governs the processes of neural synchronization and desynchronization that underlie the rich variety of coordinated functions The distributed nature of this network accounts for disruptions of interlimb coordination across various movement disorders

Estimating parameters of the diffusion model: Approaches to dealing with contaminant reaction times and parameter variability

Abstract: Three methods for fitting the diffusion model (Ratcliff, 1978) to experimental data are examined. Sets of simulated data were generated with known parameter values, and from fits of the model, we found that the maximum likelihood method was better than the chi-square and weighted least squares methods by criteria of bias in the parameters relative to the parameter values used to generate the data and standard deviations in the parameter estimates. The standard deviations in the parameter values can be used as measures of the variability in parameter estimates from fits to experimental data. We introduced contaminant reaction times and variability into the other components of processing besides the decision process and found that the maximum likelihood and chi-square methods failed, sometimes dramatically. But the weighted least squares method was robust to these two factors. We then present results from modifications of the maximum likelihood and chi-square methods, in which these factors are explicitly modeled, and show that the parameter values of the diffusion model are recovered well. We argue that explicit modeling is an important method for addressing contaminants and variability in nondecision processes and that it can be applied in any theoretical approach to modeling reaction time.

Numerical bifurcation analysis of delay differential equations using DDE-BIFTOOL

Abstract: We describe DDE-BIFTOOL, a Matlab package for numerical bifurcation analysis of systems of delay differential equations with several fixed, discrete delays. The package implements continuation of steady state solutions and periodic solutions and their stability analysis. It also computes and continues steady state fold and Hopf bifurcations and, from the latter, it can switch to the emanating branch of periodic solutions. We describe the numerical methods upon which the package is based and illustrate its usage and capabilities through analysing three examples: two models of coupled neurons with delayed feedback and a model of two oscillators coupled with delay.

Loss of HIF-2α and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice

Abstract: Loss of HIF-2α and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice

The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling but not for alpha-secretase activity in fibroblasts.

Abstract: The metalloprotease ADAM 10 is an important APP alpha-secretase candidate, but in vivo proof of this is lacking. Furthermore, invertebrate models point towards a key role of the ADAM 10 orthologues Kuzbanian and sup-17 in Notch signalling. In the mouse, this function is, however, currently attributed to ADAM 17/TACE, while the role of ADAM 10 remains unknown. We have created ADAM 10-deficient mice. They die at day 9.5 of embryogenesis with multiple defects of the developing central nervous system, somites, and cardiovascular system. In situ hybridization revealed a reduced expression of the Notch target gene hes-5 in the neural tube and an increased expression of the Notch ligand dll-1, supporting an important role for ADAM 10 in Notch signalling in the vertebrates as well. Since the early lethality precluded the establishment of primary neuronal cultures, APPs alpha generation was analyzed in embryonic fibroblasts and found to be preserved in 15 out of 17 independently generated ADAM 10-deficient fibroblast cell lines, albeit at a quantitatively more variable level than in controls, whereas a severe reduction was found in only two cases. The variability was not due to differences in genetic background or to variable expression of the alternative alpha-secretase candidates ADAM 9 and ADAM 17. These results indicate, therefore, either a regulation between ADAMs on the post-translational level or that other, not yet known, proteases are able to compensate for ADAM 10 deficiency. Thus, the observed variability, together with recent reports on tissue-specific expression patterns of ADAMs 9, 10 and 17, points to the existence of tissue-specific 'teams' of different proteases exerting alpha-secretase activity.

Four qubits can be entangled in nine different ways

Abstract: We consider a single copy of a pure four-partite state of qubits and investigate its behavior under the action of stochastic local quantum operations assisted by classical communication (SLOCC). This leads to a complete classification of all different classes of pure states of four qubits. It is shown that there exist nine families of states corresponding to nine different ways of entangling four qubits. The states in the generic family give rise to Greenberger-Horne-Zeilinger-like entanglement. The other ones contain essentially two-or three-qubit entanglement distributed among the four parties. The concept of concurrence and 3-tangle is generalized to the case of mixed states of four qubits, giving rise to a seven-parameter family of entanglement monotones. Finally, the SLOCC operations maximizing all these entanglement monotones are derived, yielding the optimal single-copy distillation protocol.

Tumours of histiocytes and accessory dendritic cells: an immunohistochemical approach to classification from the International Lymphoma Study Group based on 61 cases

Abstract: Neoplasms of histiocytes and dendritic cells are rare, and their phenotypic and biological definition is incomplete. Seeking to identify antigens detectable in paraffin-embedded sections that might allow a more complete, rational immunophenotypic classification of histiocytic/dendritic cell neoplasms, the International Lymphoma Study Group (ILSG) stained 61 tumours of suspected histiocytic/dendritic cell type with a panel of 15 antibodies including those reactive with histiocytes (CD68, lysozyme (LYS)), Langerhans cells (CD1a), follicular dendritic cells (FDC: CD21, CD35) and S100 protein. This analysis revealed that 57 cases (93%) fit into four major immunophenotypic groups (one histiocytic and three dendritic cell types) utilizing six markers: CD68, LYS, CD1a, S100, CD21, and CD35. The four (7%) unclassified cases were further classifiable into the above four groups using additional morphological and ultrastructural features. The four groups then included: (i) histiocytic sarcoma (n =18) with the following phenotype: CD68 (100%), LYS (94%), CD1a (0%), S100 (33%), CD21/35 (0%). The median age was 46 years. Presentation was predominantly extranodal (72%) with high mortality (58% dead of disease (DOD)). Three had systemic involvement consistent with `malignant histiocytosis'; (ii) Langerhans cell tumour (LCT) (n =26) which expressed: CD68 (96%), LYS (42%), CD1a (100%), S100 (100%), CD21/35 (0%). There were two morphological variants: cytologically typical (n =17) designated LCT; and cytologically malignant (n =9) designated Langerhans cell sarcoma (LCS). The LCS were often not easily recognized morphologically as LC-derived, but were diagnosed based on CD1a staining. LCT and LCS differed in median age (33 versus 41 years), male:female ratio (3.7:1 versus 1:2), and death rate (31% versus 50% DOD). Four LCT patients had systemic involvement typical of Letterer-Siwe disease; (iii) follicular dendritic cell tumour/sarcoma (FDCT) (n =13) which expressed: CD68 (54%), LYS (8%), CD1a (0%), S100 (16%), FDC markers CD21/35 (100%), EMA (40%). These patients were adults (median age 65 years) with predominantly localized nodal disease (75%) and low mortality (9% DOD); (iv) interdigitating dendritic cell tumour/sarcoma (IDCT) (n =4) which expressed: CD68 (50%), LYS (25%), CD1a (0%), S100 (100%), CD21/35 (0%). The patients were adults (median 71 years) with localized nodal disease (75%) without mortality (0% DOD). In conclusion, definitive immunophenotypic classification of histiocytic and accessory cell neoplasms into four categories was possible in 93% of the cases using six antigens detected in paraffin-embedded sections. Exceptional cases (7%) were resolvable when added morphological and ultrastructural features were considered. We propose a classification combining immunophenotype and morphology with five categories, including Langerhans cell sarcoma. This simplified scheme is practical for everyday diagnostic use and should provide a framework for additional investigation of these unusual neoplasms.