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Showing papers by "Pompeu Fabra University published in 2004"


Journal ArticleDOI
LaDeana W. Hillier1, Webb Miller2, Ewan Birney, Wesley C. Warren1  +171 moreInstitutions (39)
09 Dec 2004-Nature
TL;DR: A draft genome sequence of the red jungle fowl, Gallus gallus, provides a new perspective on vertebrate genome evolution, while also improving the annotation of mammalian genomes.
Abstract: We present here a draft genome sequence of the red jungle fowl, Gallus gallus. Because the chicken is a modern descendant of the dinosaurs and the first non-mammalian amniote to have its genome sequenced, the draft sequence of its genome--composed of approximately one billion base pairs of sequence and an estimated 20,000-23,000 genes--provides a new perspective on vertebrate genome evolution, while also improving the annotation of mammalian genomes. For example, the evolutionary distance between chicken and human provides high specificity in detecting functional elements, both non-coding and coding. Notably, many conserved non-coding sequences are far from genes and cannot be assigned to defined functional classes. In coding regions the evolutionary dynamics of protein domains and orthologous groups illustrate processes that distinguish the lineages leading to birds and mammals. The distinctive properties of avian microchromosomes, together with the inferred patterns of conserved synteny, provide additional insights into vertebrate chromosome architecture.

2,579 citations


Journal ArticleDOI
TL;DR: This paper introduces an estimator that is both well-conditioned and more accurate than the sample covariance matrix asymptotically, that is distribution-free and has a simple explicit formula that is easy to compute and interpret.

2,497 citations


Journal ArticleDOI
TL;DR: In this paper, the authors extend the standard new Keynesian model to allow for the presence of rule-of-thumb consumers and show how the interaction of the latter with sticky prices and deficit financing can account for the existing evidence on the effects of government spending.
Abstract: Recent evidence suggests that consumption rises in response to an increase in government spending. That finding cannot be easily reconciled with existing optimizing business cycle models. We extend the standard new Keynesian model to allow for the presence of rule-of-thumb consumers. We show how the interaction of the latter with sticky prices and deficit financing can account for the existing evidence on the effects of government spending. (JEL: E32, E62)

1,542 citations


Book
12 Jan 2004
TL;DR: In this article, the authors provide a systematic treatment of the economics of antitrust (or competition policy) in a global context, drawing on the literature of industrial organisation and on original analyses to deal with such important issues as cartels, joint-ventures, mergers, vertical contracts, predatory pricing, exclusionary practices, and price discrimination.
Abstract: This is the first book to provide a systematic treatment of the economics of antitrust (or competition policy) in a global context. It draws on the literature of industrial organisation and on original analyses to deal with such important issues as cartels, joint-ventures, mergers, vertical contracts, predatory pricing, exclusionary practices, and price discrimination, and to formulate policy implications on these issues. The interaction between theory and practice is one of the main features of the book, which contains frequent references to competition policy cases and a few fully developed case studies. The treatment is written to appeal to practitioners and students, to lawyers and economists. It is not only a textbook in economics for first year graduate or advanced undergraduate courses, but also a book for all those who wish to understand competition issues in a clear and rigorous way. Exercises and some solved problems are provided.

1,356 citations


Journal ArticleDOI
TL;DR: This paper analyses a single-leg reserve management problem in which the buyers' choice behavior is modeled explicitly and develops an estimation procedure based on the expectation-maximization (EM) method that jointly estimates arrival rates and choice model parameters when no-purchase outcomes are unobservable.
Abstract: Customer choice behavior, such as buy-up and buy-down, is an important phenomenon in a wide range of revenue management contexts. Yet most revenue management methodologies ignore this phenomenon - or at best approximate it in a heuristic way. In this paper, we provide an exact and quite general analysis of this problem. Specifically, we analyze a single-leg reserve management problem in which the buyers' choice behavior is modeled explicitly. The choice model is very general, simply specifying the probability of purchase for each fare product as a function of the set of fare products offered. The control problem is to decide which subset of fare products to offer at each point in time. We show that the optimal policy for this problem has a quite simple form. Namely, it consists of identifying an ordered family of "efficient" subsets S 1 ,..., S m , and at each point in time opening one of these sets S k , where the optimal index k is increasing in the remaining capacity x and decreasing in the remaining time. That is, the more capacity (or less time) available, the further the optimal set is along this sequence. We also show that the optimal policy is a nested allocation policy if and only if the sequence of efficient sets is nested, that is S 1 ? S 2 ?... ? S m . Moreover, we give a characterization of when nesting by fare order is optimal. We also develop an estimation procedure for this setting based on the expectation-maximization (EM) method that jointly estimates arrival rates and choice model parameters when no-purchase outcomes are unobservable. Numerical results are given to illustrate both the model and estimation procedure.

1,025 citations


Journal ArticleDOI
TL;DR: In this paper, the authors estimate the effect of international trade on average labor productivity at the country level and conclude that trade works through labor efficiency, while institutional quality works through physical and human capital accumulation.
Abstract: We estimate the effect of international trade on average laborproductivity at the country level. Our empirical approach relies onsummary measures of trade that, we argue, are preferable on boththeoretical and empirical grounds to the one conventionally used. Incontrast to the marginally significant and non-robust effects of tradeon productivity found previously, our estimates are highly significantand robust even when we include institutional quality and geographicfactors in the empirical analysis. We also examine the channels throughwhich trade and institutional quality affect average labor productivity.Our finding is that trade works through labor efficiency, whileinstitutional quality works through physical and human capitalaccumulation. We conclude with an exploratory analysis of the role oftrade policies for average labor productivity.

970 citations


Journal ArticleDOI
TL;DR: Shrinkage as mentioned in this paper is a matrix obtained from the sample covariance matrix through a transformation called shrinkage, which pulls the most extreme coefficients toward more central values, systematically reducing estimation error when it matters most.
Abstract: The central message of this article is that no one should use the sample covariance matrix for portfolio optimization. It is subject to estimation error of the kind most likely to perturb a mean-variance optimizer. Instead, a matrix can be obtained from the sample covariance matrix through a transformation called shrinkage. This tends to pull the most extreme coefficients toward more central values, systematically reducing estimation error when it matters most. Statistically, the challenge is to know the optimal shrinkage intensity. Shrinkage reduces portfolio tracking error relative to a benchmark index, and substantially raises the manager9s realized information ratio.

769 citations


Journal ArticleDOI
01 Dec 2004-Blood
TL;DR: Data support that HCMV infection selectively shapes the natural killer cell receptor (NKR) repertoire of NK and T cells from healthy carrier individuals.

739 citations


Book ChapterDOI
TL;DR: This tutorial introduces the techniques that are used to obtain results in the form of so-called error bounds in statistical learning theory.
Abstract: The goal of statistical learning theory is to study, in a statistical framework, the properties of learning algorithms. In particular, most results take the form of so-called error bounds. This tutorial introduces the techniques that are used to obtain such results.

602 citations


Journal ArticleDOI
TL;DR: Gender differences in effects were related to family responsibilities and social class, and understanding the effects of unemployment on mental health requires consideration of the interactions among gender, family responsibilities, andsocial class.
Abstract: Objectives. We examined gender differences in the effects of unemployment on mental health and assessed whether such effects are associated with interactions among gender, family roles, and social class. Methods. Our analysis included 3881 employed and 638 unemployed workers, aged 25 to 64 years, interviewed in the 1994 Catalonian Health Survey. Results. Unemployment had more of an effect on the mental health of men (age-adjusted odds ratio [OR] = 2.98; 95% confidence interval [CI] = 2.30, 3.87) than on that of women (age-adjusted OR = 1.51; 95% CI = 1.11, 2.06). Gender differences in effects were related to family responsibilities and social class. Conclusions. Understanding the effects of unemployment on mental health requires consideration of the interactions among gender, family responsibilities, and social class.

554 citations


BookDOI
TL;DR: In this paper, the authors study the apparent contradiction between two strands of the literature on the effects of financial intermediation on economic activity and find that a positive long-run relationship between financial intermediary and output growth coexists with a mostly negative short run relationship, and further develop an explanation for these contrasting effects by relating them to recent theoretical models.
Abstract: The authors study the apparent contradiction between two strands of the literature on the effects of financial intermediation on economic activity. On the one hand, the empirical growth literature finds a positive effect of financial depth as measured by, for instance, private domestic credit and liquid liabilities (for example, Levine, Loayza, and Beck 2000). On the other hand, the banking and currency crisis literature finds that monetary aggregates, such as domestic credit, are among the best predictors of crises and their related economic downturns (for example, Kaminski and Reinhart 1999). The authors account for these contrasting effects based on the distinction between the short- and long-run impacts of financial intermediation. Working with a panel of cross-country and time-series observations, they estimate an encompassing model of short- and long-run effects using the Pooled Mean Group estimator developed by Pesaran, Shin, and Smith (1999). Their conclusion from this analysis is that a positive long-run relationship between financial intermediation and output growth coexists with a mostly negative short-run relationship. The authors further develop an explanation for these contrasting effects by relating them to recent theoretical models, by linking the estimated short-run effects to measures of financial fragility (namely, banking crises and financial volatility), and by jointly analyzing the effects of financial depth and fragility in classic panel growth regressions.

Posted Content
TL;DR: In this article, the authors investigate the long-run effects of financial intermediation on economic activity and find that a positive long run relationship exists with a negative short-run relationship, and further develop an explanation for these contrasting effects by relating them to recent theoretical models.
Abstract: This paper studies the apparent contradiction between two strands of the literature on the effects of financial intermediation on economic activity. On the one hand, the empirical growth literature finds a positive effect of financial depth as measured by, for instance, private domestic credit and liquid liabilities (e.g., Levine, Loayza, and Beck 2000). On the other hand, the banking and currency crisis literature finds that monetary aggregates, such as domestic credit, are among the best predictors of crises and their related economic downturns (e.g., Kaminski and Reinhart 1999). The paper accounts for these contrasting effects based on the distinction between the short- and long-run impacts of financial intermediation. Working with a panel of cross-country and time-series observations, the paper estimates an encompassing model of short- and long-run effects using the Pooled Mean Group estimator developed by Pesaran, Shin, and Smith (1999). The conclusion from this analysis is that a positive long-run relationship between financial intermediation and output growth co-exists with a, mostly, negative short-run relationship. The paper further develops an explanation for these contrasting effects by relating them to recent theoretical models, by linking the estimated short-run effects to measures of financial fragility (namely, banking crises and financial volatility), and by jointly analyzing the effects of financial depth and fragility in classic panel growth regressions.

Journal ArticleDOI
TL;DR: A model of invariant visual object recognition in the brain that incorporates feedback biasing effects of top-down attentional mechanisms on a hierarchically organized set of visual cortical areas with convergent forward connectivity, reciprocal feedback connections, and local intra-area competition is described.

Journal ArticleDOI
22 Jan 2004-Nature
TL;DR: Data indicate that targeting of the Rpd3 histone deacetylase to osmoresponsive promoters by the MAPK Hog1 is required to induce gene expression on stress.
Abstract: Regulation of gene expression by mitogen-activated protein kinases (MAPKs) is essential for proper cell adaptation to extracellular stimuli. Exposure of yeast cells to high osmolarity results in rapid activation of the MAPK Hog1, which coordinates the transcriptional programme required for cell survival on osmostress. The mechanisms by which Hog1 and MAPKs in general regulate gene expression are not completely understood, although Hog1 can modify some transcription factors. Here we propose that Hog1 induces gene expression by a mechanism that involves recruiting a specific histone deacetylase complex to the promoters of genes regulated by osmostress. Cells lacking the Rpd3-Sin3 histone deacetylase complex are sensitive to high osmolarity and show compromised expression of osmostress genes. Hog1 interacts physically with Rpd3 in vivo and in vitro and, on stress, targets the deacetylase to specific osmostress-responsive genes. Binding of the Rpd3-Sin3 complex to specific promoters leads to histone deacetylation, entry of RNA polymerase II and induction of gene expression. Together, our data indicate that targeting of the Rpd3 histone deacetylase to osmoresponsive promoters by the MAPK Hog1 is required to induce gene expression on stress.

Journal ArticleDOI
23 Sep 2004-Oncogene
TL;DR: The characterization of a human SNAIL promoter that contains the initiation of transcription and regulates the expression of this gene in tumor cells is described, indicating that Snail transcription is driven by signaling pathways known to induce epithelial to mesenchymal transition, reinforcing the role of Snail in this process.
Abstract: Expression of Snail transcriptional factor is a determinant in the acquisition of a mesenchymal phenotype by epithelial tumor cells. However, the regulation of the transcription of this gene is still unknown. We describe here the characterization of a human SNAIL promoter that contains the initiation of transcription and regulates the expression of this gene in tumor cells. This promoter was activated in cell lines in response to agents that induce Snail transcription and the mesenchymal phenotype, as addition of the phorbol ester PMA or overexpression of integrin-linked kinase (ILK) or oncogenes such as Ha-ras or v-Akt. Although other regions of the promoter were required for a complete stimulation by Akt or ILK, a minimal fragment (−78/+59) was sufficient to maintain the mesenchymal specificity. Activity of this minimal promoter and SNAIL RNA levels were dependent on ERK signaling pathway. NFκB/p65 also stimulated SNAIL transcription through a region located immediately upstream the minimal promoter, between −194 and −78. These results indicate that Snail transcription is driven by signaling pathways known to induce epithelial to mesenchymal transition, reinforcing the role of Snail in this process.

Journal ArticleDOI
TL;DR: It is shown that different syntactic dependency networks (from Czech, German, and Romanian) share many nontrivial statistical patterns such as the small world phenomenon, scaling in the distribution of degrees, and disassortative mixing.
Abstract: Many languages are spoken on Earth. Despite their diversity, many robust language universals are known to exist. All languages share syntax, i.e., the ability of combining words for forming sentences. The origin of such traits is an issue of open debate. By using recent developments from the statistical physics of complex networks, we show that different syntactic dependency networks (from Czech, German, and Romanian) share many nontrivial statistical patterns such as the small world phenomenon, scaling in the distribution of degrees, and disassortative mixing. Such previously unreported features of syntax organization are not a trivial consequence of the structure of sentences, but an emergent trait at the global scale.

Journal ArticleDOI
TL;DR: The findings suggest that among men, part of the association between social class positions and poor health can be accounted for psychosocial and physical working conditions and job insecurity, as well as working conditions, material well being at home and amount of household labour.

Journal ArticleDOI
TL;DR: It is shown that the SNAIL transcription factor represses VDR gene expression in human colon cancer cells and blocks the antitumor action of EB1089, a 1,25(OH)2D3 analog, in xenografted mice.
Abstract: Several non-hypercalcemic analogs of 1alpha,25-dihydroxyvitamin D3 (1,25(OH)(2)D(3)) show antitumor activity in a subset of cancer patients. High vitamin D receptor (VDR) expression, which is associated with good prognosis but is lost during tumor progression. We show that the SNAIL transcription factor represses VDR gene expression in human colon cancer cells and blocks the antitumor action of EB1089, a 1,25(OH)(2)D(3) analog, in xenografted mice. In human colon cancers, elevated SNAIL expression correlates with downregulation of VDR.

Journal ArticleDOI
01 Feb 2004-Thorax
TL;DR: GOLD stage 0 was characterised by the presence of the same risk factors as COPD and by the same high demand for medical assistance, with no difference between stage 0 and COPD.
Abstract: Background: The recently published GOLD guidelines provide a new system for staging chronic obstructive pulmonary disease (COPD) from mild (stage I) to very severe (stage IV) and introduce a stage 0 (chronic cough and phlegm without airflow obstruction) that includes subjects “at risk” of developing the disease. Methods: In order to assess the prevalence of GOLD stages of COPD in high income countries and to evaluate their association with the known risk factors for airflow obstruction, data from the European Community Respiratory Health Survey on more than 18 000 young adults (20–44 years) were analysed. Results: The overall prevalence was 11.8% (95% CI 11.3 to 12.3) for stage 0, 2.5% (95% CI 2.2 to 2.7) for stage I, and 1.1% (95% CI 1.0 to 1.3) for stages II–III. Moderate to heavy smoking (⩾15 pack years) was significantly associated with both stage 0 (relative risk ratio (RRR) = 4.15; 95% CI 3.55 to 4.84) and stages I+ (RRR = 4.09; 95% CI 3.17 to 5.26), while subjects with stages I+ COPD had a higher likelihood of giving up smoking (RRR = 1.39; 95% CI 1.04 to 1.86) than those with GOLD stage 0 (RRR = 1.05; 95% CI 0.86 to 1.27). Environmental tobacco smoke had the same degree of positive association in both groups. Respiratory infections in childhood and low socioeconomic class were significantly and homogeneously associated with both groups, whereas occupational exposure was significantly associated only with stage 0. All the GOLD stages showed a significantly higher percentage of healthcare resource users than healthy subjects (p Conclusions: A considerable percentage of young adults already suffered from COPD. GOLD stage 0 was characterised by the presence of the same risk factors as COPD and by the same high demand for medical assistance.

Journal ArticleDOI
TL;DR: In this paper, the authors examined the impact of market reforms on productivity and profitability in Colombia during the early 1990s and found that the increase in aggregate productivity was largely driven by the improved allocation of activity.

Journal ArticleDOI
TL;DR: The olive oil phenolic content modulated the oxidative/antioxidative status of healthy men who consumed a very low-antioxidant diet.
Abstract: The aim of the present study was to evaluate whether olive oils high in phenolic compounds influence the oxidative/antioxidative status in humans. Healthy men (n = 12) participated in a double-blind, randomized, crossover study in which 3 olive oils with low (LPC), moderate (MPC), and high (HPC) phenolic content were given as raw doses (25 mL/d) for 4 consecutive days preceded by 10-d washout periods. Volunteers followed a strict very low-antioxidant diet the 3 d before and during the intervention periods. Short-term consumption of olive oils decreased plasma oxidized LDL (oxLDL), 8-oxo-dG in mitochondrial DNA and urine, malondialdehyde in urine (P < 0.05 for linear trend), and increased HDL cholesterol and glutathione peroxidase activity (P < 0.05 for linear trend), in a dose-dependent manner with the phenolic content of the olive oil administered. At d 4, oxLDL after MPC and HPC, and 8-oxo-dG after HPC administration (25 mL, respectively), were reduced when the men were in the postprandial state (P < 0.05). Phenolic compounds in plasma increased dose dependently during this stage with the phenolic content of the olive oils at 1, 2, 4, and 6 h, respectively (P < 0.01). Their concentrations increased in plasma and urine samples in a dose-dependent manner after short-term consumption of the olive oils (P < 0.01). In conclusion, the olive oil phenolic content modulated the oxidative/antioxidative status of healthy men who consumed a very low-antioxidant diet.

Journal ArticleDOI
TL;DR: The hypothesis that virgin olive oil consumption could provide benefits in the prevention of oxidative processes is supported, as dose-dependent changes in oxidative stress markers, and phenolic compounds in urine, were observed with the phenolic content of the olive oil administered.
Abstract: Evidence from in vitro studies suggests that antioxidant olive oil phenolic compounds can prevent LDL oxidation. However, in vivo evidence in support of this hypothesis is sparse. to establish the antioxidant effect of olive oils with differences in their phenolic compounds content in humans A controlled, double blind, cross-over, randomized, clinical trial using three similar olive oils with increasing phenolic concentration (from 0 to 150 mg/Kg) was conducted in 30 healthy volunteers. Olive oils were administered over three periods of 3 weeks preceded by two-week washout periods. Urinary tyrosol and hydroxytyrosol increased (p < 0.020), in vivo plasma oxidized LDL decreased (p = 0.006), and ex vivo resistance of LDL to oxidation increased (p = 0.012) with the phenolic content of the olive oil administered. After virgin olive oil administration, an increase (p = 0.029) was observed in HDL cholesterol levels. Sustained consumption of virgin olive oil with the high phenolic content was more effective in protecting LDL from oxidation and in rising HDL cholesterol levels than that of other type of olive oils. Dose-dependent changes in oxidative stress markers, and phenolic compounds in urine, were observed with the phenolic content of the olive oil administered. Our results support the hypothesis that virgin olive oil consumption could provide benefits in the prevention of oxidative processes.

Journal ArticleDOI
TL;DR: The theory of global games has shown that coordination games with multiple equilibria may have a unique equilibrium if certain parameters of the payoff function are private information instead of common knowledge as discussed by the authors.
Abstract: The theory of global games has shown that coordination games with multiple equilibria may have a unique equilibrium if certain parameters of the payoff function are private information instead of common knowledge. We report the results of an experiment designed to test the predictions of this theory. Comparing sessions with common and private information, we observe only small differences in behavior. For common information, subjects coordinate on threshold strategies that deviate from the global game solution towards the payoff-dominant equilibrium. For private information, thresholds are closer to the global game solution than for common information. Variations in the payoff function affect behavior as predicted by comparative statics of the global game solution. Predictability of coordination points is about the same for both information conditions.

Journal ArticleDOI
TL;DR: Graph theory tools are used to provide necessary and sufficient conditions regarding the architecture of networks for the subgame perfect equilibrium of the bargaining game to coincide with the Walrasian outcome.

Journal ArticleDOI
TL;DR: The Met66 variant is strongly associated to all ED subtypes, and the -270C BDNF variant has an effect on BN and late age at onset of weight loss, the first two variants associated with the pathophysiology of ED in different populations and support a role for BDNF in the susceptibility to aberrant eating behaviors.
Abstract: Several genes with an essential role in the regulation of eating behavior and body weight are considered candidates involved in the etiology of eating disorders (ED), but no relevant susceptibility genes with a major effect on anorexia nervosa (AN) or bulimia nervosa (BN) have been identified. Brain-derived neurotrophic factor (BDNF) has been implicated in the regulation of food intake and body weight in rodents. We previously reported a strong association of the Met66 allele of the Val66Met BDNF variant with restricting AN (ANR) and low minimum body mass index in Spanish patients. Another single nucleotide polymorphism located in the promoter region of the BDNF gene (-270C > T) showed lack of association with any ED phenotype. In order to replicate these findings in a larger sample, we performed a case-control study in 1142 Caucasian patients with ED consecutively recruited in six different centers from five European countries (France, Germany, Italy, Spain and UK) participating in the 'Factors in Healthy Eating' project. We have found that the Met66 variant is strongly associated to all ED subtypes (AN, ANR, binge-eating/purging AN and BN), and that the -270C BDNF variant has an effect on BN and late age at onset of weight loss. These are the first two variants associated with the pathophysiology of ED in different populations and support a role for BDNF in the susceptibility to aberrant eating behaviors.

Journal ArticleDOI
TL;DR: It is shown that Hog1 regulates cell cycle progression at the G1 phase by a dual mechanism that involves downregulation of cyclin expression and direct targeting of the CDK-inhibitor protein Sic1.
Abstract: Activation of stress-activated protein kinases (SAPKs) is essential for proper cell adaptation to extracellular stimuli. The exposure of yeast cells to high osmolarity, or mutations that lead to activation of the Hog1 SAPK, result in cell-cycle arrest1,2,3,4. The mechanisms by which Hog1 and SAPKs in general regulate cell-cycle progression are not completely understood5,6,7,8. Here we show that Hog1 regulates cell cycle progression at the G1 phase by a dual mechanism that involves downregulation of cyclin expression and direct targeting of the CDK-inhibitor protein Sic1. Hog1 interacts physically with Sic1 in vivo and in vitro, and phosphorylates a single residue at the carboxyl terminus of Sic1, which, in combination with the downregulation of cyclin expression, results in Sic1 stabilization and inhibition of cell-cycle progression. Cells lacking Sic1 or containing a Sic1 allele mutated in the Hog1 phosphorylation site are unable to arrest at G1 phase after Hog1 activation, and become sensitive to osmostress. Together, our data indicate that the Sic1 CDK-inhibitor is the molecular target for the SAPK Hog1 that is required to modulate cell-cycle progression in response to stress.

Journal ArticleDOI
TL;DR: It is shown that activated Notch and Notch target genes actively repress completion of an acinar cell differentiation program in developing mouse and zebrafish pancreas, defining a normal inhibitory role for Notch in the regulation of exocrine pancreatic differentiation.
Abstract: Notch signaling regulates cell fate decisions in a variety of adult and embryonic tissues, and represents a characteristic feature of exocrine pancreatic cancer. In developing mouse pancreas, targeted inactivation of Notch pathway components has defined a role for Notch in regulating early endocrine differentiation, but has been less informative with respect to a possible role for Notch in regulating subsequent exocrine differentiation events. Here, we show that activated Notch and Notch target genes actively repress completion of an acinar cell differentiation program in developing mouse and zebrafish pancreas. In developing mouse pancreas, the Notch target gene Hes1 is co-expressed with Ptf1-P48 in exocrine precursor cells, but not in differentiated amylase-positive acinar cells. Using lentiviral delivery systems to induce ectopic Notch pathway activation in explant cultures of E10.5 mouse dorsal pancreatic buds, we found that both Hes1 and Notch1-IC repress acinar cell differentiation, but not Ptf1-P48 expression, in a cell-autonomous manner. Ectopic Notch activation also delays acinar cell differentiation in developing zebrafish pancreas. Further evidence of a role for endogenous Notch in regulating exocrine pancreatic differentiation was provided by examination of zebrafish embryos with homozygous mindbomb mutations, in which Notch signaling is disrupted. mindbomb-deficient embryos display accelerated differentiation of exocrine pancreas relative to wild-type clutchmate controls. A similar phenotype was induced by expression of a dominant-negative Suppressor of Hairless [Su(H)] construct, confirming that Notch actively represses acinar cell differentiation during zebrafish pancreatic development. Using transient transfection assays involving a Ptf1-responsive reporter gene, we further demonstrate that Notch and Notch/Su(H) target genes directly inhibit Ptf1 activity, independent of changes in expression of Ptf1 component proteins. These results define a normal inhibitory role for Notch in the regulation of exocrine pancreatic differentiation.

Proceedings Article
25 Jul 2004
TL;DR: A domain-independent formulation of temporal planning based on Constraint Programming is introduced that successfully combines a POCL branching scheme with powerful and sound pruning rules and is competitive with the best parallel planners in the special case in which actions have all the same duration.
Abstract: A key feature of modern optimal planners such as Graphplan and Blackbox is their ability to prune large parts of the search space. Previous Partial Order Causal Link (POCL) planners provide an alternative branching scheme but lacking comparable pruning mechanisms do not perform as well. In this paper, a domain-independent formulation of temporal planning based on Constraint Programming is introduced that successfully combines a POCL branching scheme with powerful and sound pruning rules. The key novelty in the formulation is the ability to reason about supports, precedences, and causal links involving actions that are not in the plan. Experiments over a wide range of benchmarks show that the resulting optimal temporal planner is much faster than current ones and is competitive with the best parallel planners in the special case in which actions have all the same duration.

Journal ArticleDOI
TL;DR: These methods were both highly efficient and very reproducible, resulting in a new strategy to obtain insulin-containing cells from stem cells with a near 100% success rate, while actively promoting the maturation of the exocytotic machinery.
Abstract: Aims/hypothesis. We recently demonstrated that insulin-producing cells derived from embryonic stem cells normalise hyperglycaemia in transplanted diabetic mice. The differentiation and selection procedure, however, was successful in less than 5% of the assays performed. Thus, to improve its effectiveness, new strategies have been developed, which increase the number of islet cells or islet progenitors. Methods. Mouse embryonic stem cells transfected with a plasmid containing the Nkx6.1 promoter gene followed by a neomycin-resistance gene, were cultured with factors known to participate in endocrine pancreatic development and factors that modulate signalling pathways involved in these processes. Neomycin was used to select the Nkx6.1-positive cells, which also express insulin. The transfected cells were differentiated using several exogenous agents, followed by selection of Nkx6.1-positive cells. The resulting cells were analysed for pancreatic gene and protein expression by immunocytochemistry, RT-PCR and radioimmunoassay. Also, proliferation assays were performed, as well as transplantation to streptozotocin-induced diabetic mice. Results. The protocols yielded cell cultures with approximately 20% of cells co-expressing insulin and Pdx-1. Cell trapping selection yielded an almost pure population of insulin-positive cells, which expressed the beta cell genes/proteins Pdx-1, Nkx6.1, insulin, glucokinase, GLUT-2 and Sur-1. Subsequent transplantation to streptozotocin-induced diabetic mice normalised their glycaemia during the time period of experimentation, proving the efficiency of the protocols. Conclusions/interpretation. These methods were both highly efficient and very reproducible, resulting in a new strategy to obtain insulin-containing cells from stem cells with a near 100% success rate, while actively promoting the maturation of the exocytotic machinery.

Journal ArticleDOI
TL;DR: The BK-beta(1E65K) channel might offer a more efficient negative-feedback effect on vascular smooth muscle contractility, consistent with a protective effect of the K allele against the severity of diastolic hypertension.
Abstract: Hypertension is the most prevalent risk factor for cardiovascular diseases, present in almost 30% of adults. A key element in the control of vascular tone is the large-conductance, Ca(2+)-dependent K(+) (BK) channel. The BK channel in vascular smooth muscle is formed by an ion-conducting alpha subunit and a regulatory beta(1) subunit, which couples local increases in intracellular Ca(2+) to augmented channel activity and vascular relaxation. Our large population-based genetic epidemiological study has identified a new single-nucleotide substitution (G352A) in the beta(1) gene (KCNMB1), corresponding to an E65K mutation in the protein. This mutation results in a gain of function of the channel and is associated with low prevalence of moderate and severe diastolic hypertension. BK-beta(1E65K) channels showed increased Ca(2+) sensitivity, compared with wild-type channels, without changes in channel kinetics. In conclusion, the BK-beta(1E65K) channel might offer a more efficient negative-feedback effect on vascular smooth muscle contractility, consistent with a protective effect of the K allele against the severity of diastolic hypertension.