Showing papers by "Pompeu Fabra University published in 2003"
TL;DR: This work identified selenoprotein genes in sequenced mammalian genomes by methods that rely on identification of selenocysteine insertion RNA structures, the coding potential of UGA codons, and the presence of cysteine-containing homologs.
Abstract: In the genetic code, UGA serves as a stop signal and a selenocysteine codon, but no computational methods for identifying its coding function are available. Consequently, most selenoprotein genes are misannotated. We identified selenoprotein genes in sequenced mammalian genomes by methods that rely on identification of selenocysteine insertion RNA structures, the coding potential of UGA codons, and the presence of cysteine-containing homologs. The human selenoproteome consists of 25 selenoproteins.
2,096 citations
TL;DR: In this paper, the covariance matrix of stock returns is estimated by an optimally weighted average of two existing estimators: the sample covariance and single-index covariance matrices.
1,609 citations
01 Jan 2003
TL;DR: Iterated Local Search (ILS) as mentioned in this paper is a general purpose metaheuristic for finding good solutions of combinatorial optimization problems, which is based on building a sequence of (locally optimal) solutions by perturbing the current solution and applying local search to that modified solution.
Abstract: This is a survey of "Iterated Local Search", a general purpose metaheuristic for finding good solutions of combinatorial optimization problems. It is based on building a sequence of (locally optimal) solutions by: (1) perturbing the current solution; (2) applying local search to that modified solution. At a high level, the method is simple, yet it allows for a detailed use of problem-specific properties. After giving a general framework, we cover the uses of Iterated Local Search on a number of well studied problems.
969 citations
TL;DR: This article explains how language evolution can take advantage of a communicative phase transition and suggests that Zipf's law is a hallmark of symbolic reference and not a meaningless feature.
Abstract: The emergence of a complex language is one of the fundamental events of human evolution, and several remarkable features suggest the presence of fundamental principles of organization. These principles seem to be common to all languages. The best known is the so-called Zipf's law, which states that the frequency of a word decays as a (universal) power law of its rank. The possible origins of this law have been controversial, and its meaningfulness is still an open question. In this article, the early hypothesis of Zipf of a principle of least effort for explaining the law is shown to be sound. Simultaneous minimization in the effort of both hearer and speaker is formalized with a simple optimization process operating on a binary matrix of signal-object associations. Zipf's law is found in the transition between referentially useless systems and indexical reference systems. Our finding strongly suggests that Zipf's law is a hallmark of symbolic reference and not a meaningless feature. The implications for the evolution of language are discussed. We explain how language evolution can take advantage of a communicative phase transition.
540 citations
TL;DR: The authors showed that reduced labour market flexibility may protect some native workers from immigrant competition but can increase negative effects on equilibrium employment, which motivated an analysis of immigration effects interacted with institutions, and that reduced flexibility increases negative immigration effects.
Abstract: Reduced labour market flexibility may protect some native workers from immigrant competition but can increase negative effects on equilibrium employment. This motivates an analysis of immigration effects interacted with institutions. OLS estimates for European countries show small, mostly negative immigration effects while an IV strategy based on immigrants from former Yugoslavia generates larger though mostly insignificant negative estimates. Specifications allowing interactions between immigration and measures of labour and product market rigidity are consistent with the view that reduced flexibility increases negative immigration effects. The estimates typically imply more native job losses in countries with restrictive institutions, especially restricted product markets.
452 citations
TL;DR: This work analyzed human and chimpanzee sequence data to search for the patterns of divergence and polymorphism predicted by a theoretical model of speciation, and found that protein evolution was more than 2.2 times faster in chromosomes that had undergone structural rearrangements compared with colinear chromosomes.
Abstract: Humans and their closest evolutionary relatives, the chimpanzees, differ in ∼1.24% of their genomic DNA sequences. The fraction of these changes accumulated during the speciation processes that have separated the two lineages may be of special relevance in understanding the basis of their differences. We analyzed human and chimpanzee sequence data to search for the patterns of divergence and polymorphism predicted by a theoretical model of speciation. According to the model, positively selected changes should accumulate in chromosomes that present fixed structural differences, such as inversions, between the two species. Protein evolution was more than 2.2 times faster in chromosomes that had undergone structural rearrangements compared with colinear chromosomes. Also, nucleotide variability is slightly lower in rearranged chromosomes. These patterns of divergence and polymorphism may be, at least in part, the molecular footprint of speciation events in the human and chimpanzee lineages.
428 citations
TL;DR: It is found that, if reproductive isolation is produced by the accumulation in parapatry of sets of alleles compatible within but incompatible across species, chromosomal rearrangements are far more likely to favor it than classical genetic barriers without chromosomal changes.
Abstract: Chromosomal rearrangements can promote reproductive isolation by reducing recombination along a large section of the genome. We model the effects of the genetic barrier to gene flow caused by a chromosomal rearrangement on the rate of accumulation of postzygotic isolation genes in parapatry. We find that, if reproductive isolation is produced by the accumulation in parapatry of sets of alleles compatible within but incompatible across species, chromosomal rearrangements are far more likely to favor it than classical genetic barriers without chromosomal changes. New evidence of the role of chromosomal rearrangements in parapatric speciation suggests that postzygotic isolation is often due to the accumulation of such incompatibilities. The model makes testable qualitative predictions about the genetic signature of speciation.
384 citations
TL;DR: This unit describes the usage of geneid, an efficient gene-finding program that allows for the analysis of large genomic sequences, including whole mammalian chromosomes, which can be partially annotated and used to refine this initial annotation.
Abstract: This unit describes the usage of geneid, an efficient gene-finding program that allows for the analysis of large genomic sequences, including whole mammalian chromosomes. These sequences can be partially annotated, and geneid can be used to refine this initial annotation. Training geneid is relatively easy, and parameter configurations exist for a number of eukaryotic species. geneid produces output in a variety of standard formats. The results, thus, can be processed by a variety of software tools, including visualization programs. geneid software is in the public domain, and is undergoing constant development. It is easy to install and use. Exhaustive benchmark evaluations show that geneid compares favorably with other existing gene-finding tools. © 2018 by John Wiley & Sons, Inc.
373 citations
TL;DR: This study determined the exact deletion size and LCR copy number in 74 patients with WBS, as well as precisely defined deletion breakpoints in 30 of them, using LCR-specific nucleotide differences, and proposed models for the specific pairing and precise aberrant recombination leading to each of the different germline rearrangements that occur in this region.
Abstract: Williams-Beuren syndrome (WBS) is a segmental aneusomy syndrome that results from a heterozygous deletion of contiguous genes at 7q11.23. Three large region-specific low-copy repeat elements (LCRs), composed of different blocks (A, B, and C), flank the WBS deletion interval and are thought to predispose to misalignment and unequal crossing-over, causing the deletions. In this study, we have determined the exact deletion size and LCR copy number in 74 patients with WBS, as well as precisely defined deletion breakpoints in 30 of them, using LCR-specific nucleotide differences. Most patients (95%) exhibit a 1.55-Mb deletion caused by recombination between centromeric and medial block B copies, which share ∼99.6% sequence identity along 105–143 kb. In these cases, deletion breakpoints were mapped at several sites within the recombinant block B, with a cluster (>27%) occurring at a 12 kb region within the GTF2I/GTF2IP1 gene. Almost one-third (28%) of the transmitting progenitors were found to be heterozygous for an inversion between centromeric and telomeric LCRs. All deletion breakpoints in the patients with the inversion occurred in the distal 38-kb block B region only present in the telomeric and medial copies. Finally, only four patients (5%) displayed a larger deletion (∼1.84 Mb) caused by recombination between centromeric and medial block A copies. We propose models for the specific pairing and precise aberrant recombination leading to each of the different germline rearrangements that occur in this region, including inversions and deletions associated with WBS. Chromosomal instability at 7q11.23 is directly related to the genomic structure of the region.
333 citations
Proceedings Article•
09 Jun 2003TL;DR: This paper introduces a labeling scheme into RTDP that speeds up its convergence while retaining its good anytime behavior, and shows that Labeled RTDP (LRTDP) converges orders of magnitude faster than RTDP, and faster also than another recent heuristic-search DP algorithm, LAO*.
Abstract: RTDP is a recent heuristic-search DP algorithm for solving non-deterministic planning problems with full observability. In relation to other dynamic programming methods, RTDP has two benefits: first, it does not have to evaluate the entire state space in order to deliver an optimal policy, and second, it can often deliver good policies pretty fast. On the other hand, RTDP final convergence is slow. In this paper we introduce a labeling scheme into RTDP that speeds up its convergence while retaining its good anytime behavior. The idea is to label a state s as solved when the heuristic values, and thus, the greedy policy defined by them, have converged over s and the states that can be reached from s with the greedy policy. While due to the presence of cycles, these labels cannot be computed in a recursive, bottom-up fashion in general, we show nonetheless that they can be computed quite fast, and that the overhead is compensated by the recomputations avoided. In addition, when the labeling procedure cannot label a state as solved, it improves the heuristic value of a relevant state. This results in the number of Labeled RTDP trials needed for convergence, unlike the number of RTDP trials, to be bounded. From a practical point of view, Labeled RTDP (LRTDP) converges orders of magnitude faster than RTDP, and faster also than another recent heuristic-search DP algorithm, LAO*. Moreover, LRTDP often converges faster than value iteration, even with the heuristic h = 0, thus suggesting that LRTDP has a quite general scope.
326 citations
TL;DR: Results indicate that p120 catenin acts as a docking protein facilitating the activation of Fer/Fyn tyrosine kinases by Yes and demonstrate the role of these p 120 caten in-associated kinases in the regulation of β-catenin-α-catanin interaction.
Abstract: Cell-cell contacts among epithelial cells have a crucial function in organized tissues and are mainly mediated by adherens junctions and desmosomes. In adherens junctions, although the extracellular domain of E-cadherin is essential for connecting cells through homophilic interactions, its intracellular domain is required for regulating cell-cell adhesion. The latter domain is indirectly associated with the actin cytoskeleton through either β-catenin or plakoglobin and α-catenin. These interactions are essential for proper cell adhesion (3, 28, 36). Another catenin, p120, also binds to the cytosolic region of E-cadherin through a different subdomain (11, 37, 48).
Tyrosine phosphorylation of the cadherin-catenin complex has been implicated in the regulation of adhesion (12, 14, 23). Indeed, stimulation of growth factor receptors or oncogenic Src kinases is implicated in the negative regulation of intercellular contacts (6, 26, 31, 41, 42). On the other hand, ectopic expression of phosphotyrosine (PTyr) phosphatases strengthens cell-cell adhesion (27, 45). Two components of the adherens junction complex have been considered the main targets of tyrosine kinases/phosphatases: β-catenin and p120 catenin. p120 catenin is highly phosphorylated by Src tyrosine kinase (25) and phosphorylation by this kinase increases the affinity of p120 catenin for E-cadherin (39). However, the exact role of p120 catenin in the regulation of adherens junction is not clear since different authors have suggested negative and positive effects (reviewed in reference 4). On the other hand, increased tyrosine phosphorylation of β-catenin is associated with adherens junction disruption (22; see references 12 and 23 for reviews). Using direct in vitro measurements, we have reported that phosphorylation of β-catenin by Src kinase decreases the interaction of this protein with E-cadherin. The modified residue was identified as Tyr-654 (39), which contributes to E-cadherin binding by establishing an ionic pair with E-cadherin Asp-667 (19). Although Src kinase can phosphorylate Tyr-654, it does it inefficiently, indicating that other tyrosine kinases are responsible for this modification in vivo. Indeed, the epidermal growth factor receptor and its homologue erbB2 both phosphorylate and interact with β-catenin (17, 42) and share the same binding domain, i.e., the C-terminal armadillo repeats of β-catenin, where Tyr-654 is located. Moreover, other tyrosine kinases such as Fer, Fyn, or Yes, interact with several members of the adhesion complex (21, 38, 46).
Besides the interaction of β-catenin with E-cadherin, the binding to α-catenin is also regulated by tyrosine phosphorylation. For instance, addition of the tyrosine phosphatase inhibitor peroxyvanadate to several cell lines disrupts β-catenin-α-catenin association (18, 32). The α-catenin-binding site in β-catenin has been assigned to a short sequence (amino acids 118 to 146) placed between the N-tail and the first armadillo repeat (1). This sequence contains only one tyrosine, Tyr-142, which is essential for the interaction with α-catenin (2). This residue is required for the stabilization of the β-catenin structure involved in this binding: the aromatic ring of Tyr-142 forms van der Waals contacts with several residues of α-catenin (35). Moreover, the hydroxyl group of Tyr-142 lies very close to β-catenin Asp-144 and Glu-147. We hypothesized that phosphorylation of this residue may interfere with β-catenin-α-catenin association.
We report here that Tyr-142 can be phosphorylated by the nonreceptor tyrosine kinases Fer or Fyn. As expected, modification of this amino acid disrupts β-catenin-α-catenin binding. Phosphorylation of Tyr-142 occurs in experimental conditions that decrease the β-catenin-α-catenin interaction, such as after K-ras transfection. Fer and Fyn kinases are normally found associated with p120 catenin; phosphorylation of this catenin on Tyr residues increases the binding of Fer/Fyn-p120 catenin complex to E-cadherin. This interaction is increased by K-ras transfection. These results suggest a role for p120 catenin as a regulatory protein in adherens junctions by recruiting to the complex tyrosine kinases that can modulate α-catenin-β-catenin interaction.
TL;DR: In this paper, the authors study a general equilibrium model in which entrepreneurs finance investment with optimal financial contracts and show that limited enforceability amplifies the impact of technological innovations on aggregate output.
Abstract: We study a general equilibrium model in which entrepreneurs finance investment with optimal financial contracts. Because of enforceability problems, contracts are constrained efficient. We show that limited enforceability amplifies the impact of technological innovations on aggregate output. More generally, we show that lower enforceability of contracts will be associated with greater aggregate volatility. A key assumption for this result is that defaulting entrepreneurs are not excluded from the market.
TL;DR: From the results, approximately 98% of hydroxytyrosol appears to be present in plasma and urine in conjugated forms, mainly glucuronoconjugates, suggesting extensive first-pass intestinal/hepatic metabolism of the ingested hydroxyTYrosol.
Abstract: Background: Animal and in vitro studies suggest that phenolic compounds in virgin olive oil are effective antioxidants. In animal and in vitro studies, hydroxytyrosol and its metabolites have been shown to be strong antioxidants. One of the prerequisites to assess their in vivo physiologic significance is to determine their presence in human plasma.
Methods: We developed an analytical method for both hydroxytyrosol and 3- O -methyl-hydroxytyrosol in plasma. The administered dose of phenolic compounds was estimated from methanolic extracts of virgin olive oil after subjecting them to different hydrolytic treatments. Plasma and urine samples were collected from 0 to 12 h before and after 25 mL of virgin olive oil intake, a dose close to that used as daily intake in Mediterranean countries. Samples were analyzed by capillary gas chromatography–mass spectrometry before and after being subjected to acidic and enzymatic hydrolytic treatments.
Results: Calibration curves were linear ( r >0.99). Analytical recoveries were 42–60%. Limits of quantification were <1.5 mg/L. Plasma hydroxytyrosol and 3- O -methyl-hydroxytyrosol increased as a response to virgin olive oil administration, reaching maximum concentrations at 32 and 53 min, respectively ( P <0.001 for quadratic trend). The estimated hydroxytyrosol elimination half-life was 2.43 h. Free forms of these phenolic compounds were not detected in plasma samples.
Conclusions: The proposed analytical method permits quantification of hydroxytyrosol and 3- O -methyl-hydroxytyrosol in plasma after real-life doses of virgin olive oil. From our results, ∼98% of hydroxytyrosol appears to be present in plasma and urine in conjugated forms, mainly glucuronoconjugates, suggesting extensive first-pass intestinal/hepatic metabolism of the ingested hydroxytyrosol.
Pasteur Institute1, Tel Aviv University2, Hebrew University of Jerusalem3, St James's University Hospital4, VCU Medical Center5, Royal Children's Hospital6, University of Iowa7, Pompeu Fabra University8, University of Antwerp9, State University of Campinas10, Rabin Medical Center11, University of Melbourne12, Seconda Università degli Studi di Napoli13
TL;DR: A deletion truncating the GJB6 gene (encoding connexin-30) is present in most of the screened populations, with higher frequencies in France, Spain, and Israel, where the percentages of unexplained GJB2 heterozygotes fell to 16.0%-20.9% after screening for the del(GJB6-D13S1830) mutation.
Abstract: Mutations in GJB2, the gene encoding connexin-26 at the DFNB1 locus on 13q12, are found in as many as 50% of subjects with autosomal recessive, nonsyndromic prelingual hearing impairment. However, genetic diagnosis is complicated by the fact that 10%–50% of affected subjects with GJB2 mutations carry only one mutant allele. Recently, a deletion truncating the GJB6 gene (encoding connexin-30), near GJB2 on 13q12, was shown to be the accompanying mutation in ∼50% of these deaf GJB2 heterozygotes in a cohort of Spanish patients, thus becoming second only to 35delG at GJB2 as the most frequent mutation causing prelingual hearing impairment in Spain. Here, we present data from a multicenter study in nine countries that shows that the deletion is present in most of the screened populations, with higher frequencies in France, Spain, and Israel, where the percentages of unexplained GJB2 heterozygotes fell to 16.0%–20.9% after screening for the del(GJB6-D13S1830) mutation. Our results also suggest that additional mutations remain to be identified, either in DFNB1 or in other unlinked genes involved in epistatic interactions with GJB2. Analysis of haplotypes associated with the deletion revealed a founder effect in Ashkenazi Jews and also suggested a common founder for countries in Western Europe. These results have important implications for the diagnosis and counseling of families with DFNB1 deafness.
TL;DR: Using two distinct computational approaches, most of the sequences in the human genome that have undergone recent segmental duplications are identified and a significant subset of single-nucleotide polymorphisms in the public databases that are not true SNPs but are potential paralogous sequence variants are identified.
Abstract: Previous studies have suggested that recent segmental duplications, which are often involved in chromosome rearrangements underlying genomic disease, account for some 5% of the human genome. We have developed rapid computational heuristics based on BLAST analysis to detect segmental duplications, as well as regions containing potential sequence misassignments in the human genome assemblies. Our analysis of the June 2002 public human genome assembly revealed that 107.4 of 3,043.1 megabases (Mb) (3.53%) of sequence contained segmental duplications, each with size equal or more than 5 kb and 90% identity. We have also detected that 38.9 Mb (1.28%) of sequence within this assembly is likely to be involved in sequence misassignment errors. Furthermore, we have identified a significant subset (199,965 of 2,327,473 or 8.6%) of single-nucleotide polymorphisms (SNPs) in the public databases that are not true SNPs but are potential paralogous sequence variants. Using two distinct computational approaches, we have identified most of the sequences in the human genome that have undergone recent segmental duplications. Near-identical segmental duplications present a major challenge to the completion of the human genome sequence. Potential sequence misassignments detected in this study would require additional efforts to resolve.
TL;DR: A comprehensive home care intervention in selected chronic obstructive pulmonary disease exacerbations appears as cost effective because the home hospitalisation intervention generates better outcomes at lower costs than conventional care.
Abstract: It was postulated that home hospitalisation (HH) of selected chronic obstructive pulmonary disease (COPD) exacerbations admitted at the emergency room (ER) could facilitate a better outcome than conventional hospitalisation. To this end, 222 COPD patients (3.2% female; 71 +10 yrs (mean+SD)) were randomly assigned to HH (n =121) or conventional care (n =101). During HH, integrated care was delivered by a specialised nurse with the patient 's free-phone access to the nurse ensured for an 8-week follow-up period. Mortality (HH: 4.1%; controls: 6.9%) and hospital readmissions (HH: 0.24 +0.57; controls: 0.38 +0.70) were similar in both groups. However, at the end of the follow-up period, HH patients showed: 1) a lower rate of ER visits (0.13 +0.43 versus 0.31+0.62); and 2) a noticeable improvement of quality of life ( D St George's Respiratory Questionnaire (SGRQ), -6.9 versus -2.4). Furthermore, a higher percentage of patients had a better knowledge of the disease (58% versus 27%), a better self-management of their condition (81% versus 48%), and the patient 's satisfaction was greater. The average overall direct cost per HH patient was 62% of the costs of conventional care, essentially due to fewer days of inpatient hospitalisation (1.7 +2.3 versus 4.2+4.1 days). A comprehensive home care intervention in selected chronic obstructive pulmonary disease exacerbations appears as cost effective. The home hospitalisation intervention generates better outcomes at lower costs than conventional care.
TL;DR: In this paper, a stochastic calculus for fractional Brownian motion with Hurst parameter H > 1/2 was developed using the techniques of the Malliavin calculus, and the authors established estimates in L p, maximal inequalities and a continuity criterion for the Stochastic integral.
Abstract: We develop a stochastic calculus for the fractional Brownian motion with Hurst parameter H > 1/2 using the techniques of the Malliavin calculus. We establish estimates in L p , maximal inequalities and a continuity criterion for the stochastic integral. Finally, we derive an Ito's formula for integral processes.
TL;DR: This article provided an analytical characterization of Markov perfect equilibria in a model with repeated voting, where agents vote over distortionary income redistribution, and showed that the future constituency for redistributive policies depends positively on current redistribution since this affects both private investments and the future distribution of voters.
Abstract: This paper provides an analytical characterization of Markov perfect equilibria in a model with repeated voting, where agents vote over distortionary income redistribution. A key result is that the future constituency for redistributive policies depends positively on current redistribution, since this affects both private investments and the future distribution of voters. The model features multiple equilibria. In some equilibria, positive redistribution persists forever. In other equilibria, even a majority of beneficiaries of redistribution vote strategically so as to induce the end of the welfare state next period. Skill-biased technical change makes the survival of the welfare state less likely.
TL;DR: SGP2 is described, a gene prediction program that combines ab initio gene prediction with TBLASTX searches between two genome sequences to provide both sensitive and specific gene predictions that provides a high enough specificity that its predictions can be experimentally verified at a reasonable cost.
Abstract: The completion of the sequencing of the mouse genome promises to help predict human genes with greater accuracy. While current ab initio gene prediction programs are remarkably sensitive (i.e., they predict at least a fragment of most genes), their specificity is often low, predicting a large number of false-positive genes in the human genome. Sequence conservation at the protein level with the mouse genome can help eliminate some of those false positives. Here we describe SGP2, a gene prediction program that combines ab initio gene prediction with TBLASTX searches between two genome sequences to provide both sensitive and specific gene predictions. The accuracy of SGP2 when used to predict genes by comparing the human and mouse genomes is assessed on a number of data sets, including single-gene data sets, the highly curated human chromosome 22 predictions, and entire genome predictions from ENSEMBL. Results indicate that SGP2 outperforms purely ab initio gene prediction methods. Results also indicate that SGP2 works about as well with 3x shotgun data as it does with fully assembled genomes. SGP2 provides a high enough specificity that its predictions can be experimentally verified at a reasonable cost. SGP2 was used to generate a complete set of gene predictions on both the human and mouse by comparing the genomes of these two species. Our results suggest that another few thousand human and mouse genes currently not in ENSEMBL are worth verifying experimentally.
TL;DR: Two domains of PRB, ERID-I and -II are identified, mediating a direct interaction with the ligand-binding domain of ERα, necessary and sufficient for progestin activation of the endogenous Src/Erk pathway.
Abstract: In breast cancer cells, estrogens activate the Src/Erk pathway through an interaction of the estrogen receptor alpha (ERalpha) with the SH2 domain of c-Src. Progestins have been reported to activate also this pathway either via an interaction of the progesterone receptor isoform B (PRB) with ERalpha, which itself activates c-Src, or by direct interaction of PRB with the SH3 domain of c-Src. Here we identify two domains of PRB, ERID-I and -II, mediating a direct interaction with the ligand-binding domain of ERalpha. ERID-I and ERID-II flank a proline cluster responsible for binding of PRB to c-Src. In mammalian cells, the interaction of PRB with ERalpha and the progestin activation of the Src/Erk cascade are abolished by deletion of either ERID-I or ERID-II. These regions are not required for transactivation of a progesterone-responsive reporter gene. Mutations in the proline cluster of PRB that prevent a direct interaction with c-Src do not affect the strong activation of c-Src by progestins in the presence of ERalpha. Thus, in cells with ERalpha, ERID-I and ERID-II are necessary and sufficient for progestin activation of the endogenous Src/Erk pathway.
TL;DR: In this article, a new approach to estimating time-varying covariance matrices in the framework of the diagonal-vech version of the multivariate GARCH(1,1) model is proposed.
Abstract: This paper offers a new approach to estimating time-varying covariance matrices in the framework of the diagonal-vech version of the multivariate GARCH(1,1) model. Our method is numerically feasible for large-scale problems, produces positive semidefinite conditional covariance matrices, and does not impose unrealistic a priori restrictions. We provide an empirical application in the context of international stock markets, comparing the new estimator with a number of existing ones.
TL;DR: These findings show the existence in tumor cells of an effective and fine-tuning nontranscriptional mechanism of regulation of Snail activity dependent on the extracellular environment.
Abstract: The Snail gene product is a transcriptional repressor of E-cadherin expression and an inducer of the epithelial-to-mesenchymal transition in several epithelial tumor cell lines. This report presents data indicating that Snail function is controlled by its intracellular location. The cytosolic distribution of Snail depended on export from the nucleus by a CRM1-dependent mechanism, and a nuclear export sequence (NES) was located in the regulatory domain of this protein. Export of Snail was controlled by phosphorylation of a Ser-rich sequence adjacent to this NES. Modification of this sequence released the restriction created by the zinc finger domain and allowed nuclear export of the protein. The phosphorylation and subcellular distribution of Snail are controlled by cell attachment to the extracellular matrix. Suspended cells presented higher levels of phosphorylated Snail and an augmented extranuclear localization with respect to cells attached to the plate. These findings show the existence in tumor cells of an effective and fine-tuning nontranscriptional mechanism of regulation of Snail activity dependent on the extracellular environment.
01 Jan 2003
TL;DR: Iterated Local Search (ILS) as mentioned in this paper is a general purpose metaheuristic for finding good solutions of combinatorial optimization problems, which is based on building a sequence of (locally optimal) solutions by perturbing the current solution and applying local search to that modified solution.
Abstract: This is a survey of "Iterated Local Search", a general purpose metaheuristic for finding good solutions of combinatorial optimization problems. It is based on building a sequence of (locally optimal) solutions by: (1) perturbing the current solution; (2) applying local search to that modified solution. At a high level, the method is simple, yet it allows for a detailed use of problem-specific properties. After giving a general framework, we cover the uses of Iterated Local Search on a number of well studied problems.
TL;DR: Investigation of the pH-dependent passive and active transport of weakly basic drugs across the human intestinal epithelium found that this component may take part in vivo and contribute to drug-drug interactions involving P-gp.
Abstract: Purpose. The purpose of this study was to investigate the pH-dependent passive and active transport of weakly basic drugs across the human intestinal epithelium.
Methods. The bidirectional pH-dependent transport of weak bases was studied in Caco-2 cell monolayers in the physiologic pH range of the gastrointestinal tract.
Results. A net secretion of atenolol and metoprolol was observed when a pH gradient was applied. However, the bidirectional transport of both compounds was equal in the nongradient system. Hence, at lower apical than basolateral pH a change in passive transport caused by an imbalance in the concentration of the uncharged drug species resulted in a “false” asymmetry (efflux ratio). Furthermore, a mixture of pH-dependent passive and active efflux was found for the P-glycoprotein (P-gp, MDR1, ABCB1) substrates, talinolol and quinidine, but not for the neutral drug, digoxin. However, the clinically important digoxin-quinidine interaction depended on the presence of a pH gradient. Hence, the degree of interaction depends on the amount of quinidine available at the binding site of the P-gp.
Conclusions. Active efflux of weak bases can only be accounted for when the fraction of unionized drug species is equal in all compartments because the transport is biased by a pH-dependent passive component. However, this component may take part in vivo and contribute to drug-drug interactions involving P-gp.
TL;DR: The results suggest that the BDNF Met66 variant may be a susceptibility factor to ED, mainly to ANR and low MBMI.
Abstract: Several lines of evidence support a role for brain-derived neurotrophic factor (BDNF) alterations in the etiology of eating disorders (EDs). BDNF heterozygous knockout mice show alterations in eating behavior, increased body weight and adipocyte hypertrophy. BDNF also regulates the synaptic efficiency through the modulation of key neurotransmitter systems previously known to be involved in ED. These findings, together with the fact that this neurotrophin is expressed in the hypothalamus nuclei associated with weight regulation and feeding control, led us to propose BDNF as a candidate gene for ED. To investigate the possible involvement of this neurotrophin in eating behavior, we screened the BDNF gene in 95 ED patients and identified four sequence variants. Two of them, −374A/T and −256G/A, were found in two patients with anorexia nervosa (AN) and consisted of single-nucleotide mutations within the 5′ untranslated region (5′UTR). The other two polymorphisms resulted in a C to T transition located at the 5′UTR of the BDNF gene and an amino-acid substitution within the BDNF precursor protein (Val66Met). We performed a case–control study for these two Single-nucleotide polymorphisms in a sample of 143 ED patients and 112 unrelated controls and found a strong association of restricting AN (ANR) with the Met allele of the Val66Met BDNF polymorphism (2p=0.002). There was also evidence for a significant effect of this sequence variant on the minimum body mass index (MBMI) (2p=0.006). These results suggest that the BDNF Met66 variant may be a susceptibility factor to ED, mainly to ANR and low MBMI.
TL;DR: An exhaustive review of research on automatic classification of sounds from musical instruments presents and discusses different techniques for similarity-based clustering of sounds and for classification into pre-defined instrumental categories.
Abstract: We present an exhaustive review of research on automatic classification of sounds from musical instruments. Two different but complementary approaches are examined, the perceptual approach and the taxonomic approach. The former is targeted to derive perceptual similarity functions in order to use them for timbre clustering and for searching and retrieving sounds by timbral similarity. The latter is targeted to derive indexes for labeling sounds after culture- or user-biased taxonomies. We review the relevant features that have been used in the two areas and then we present and discuss different techniques for similarity-based clustering of sounds and for classification into pre-defined instrumental categories.
TL;DR: In this paper, the optimal location of hubs in airline networks is investigated by taking into account the congestion effects, and the model is solved using a heuristic based on tabu search.
TL;DR: It is shown that assembly of the general transcription machinery at Hot1‐dependent promoters depends on the presence of Hot1 and active Hog1 MAPK, and recruitment of RNA polymerase (Pol) II complex to target promoters does not depend on the phosphorylation of the Hot1 activator by the MAPK.
Abstract: In budding yeast, the mitogen-activated protein kinase (MAPK) Hog1 coordinates the transcriptional program required for cell survival upon osmostress. The Hot1 transcription factor acts downstream of the MAPK and regulates a subset of Hog1-responsive genes. In response to high osmolarity, Hot1 targets Hog1 to specific osmostress-responsive promoters. Here, we show that assembly of the general transcription machinery at Hot1-dependent promoters depends on the presence of Hot1 and active Hog1 MAPK. Unexpectedly, recruitment of RNA polymerase (Pol) II complex to target promoters does not depend on the phosphorylation of the Hot1 activator by the MAPK. Hog1 interacts with the RNA Pol II and with general components of the transcription machinery. More over, when tethered to a promoter as a LexA fusion protein, Hog1 activates transcription in a stress- regulated manner. Thus, anchoring of active Hog1 to promoters by the Hot1 activator is essential for recruitment and activation of RNA Pol II. The mammalian p38 also interacts with the RNA Pol II, which might suggest a conserved mechanism for regulation of gene expression by SAPKs among eukaryotic cells.
TL;DR: In this article, the authors examine social cleavages and the impact of political legacies on Chile's post-authoritarian party system and argue that cleavage appearance in a party system depends on political agency, which can even create social identities and social conflicts.
Abstract: This article examines social cleavages and the impact of political legacies on Chile's post-authoritarian party system. In contrast to society-oriented approaches to party system formation, we argue that cleavage appearance in a party system depends on political agency, which can even (re)create social identities and social conflicts. The Chilean case illustrates this point; the structure of the party system is deeply influenced by distinctive political legacies of the authoritarian period. The cleavage between those who supported authoritarian rule and those who opposed it has powerfully shaped the party system during the new democratic period. In post-authoritarian Chile (1990-2001), a societal approach does not adequately explain the formation of cleavages or the contours of the party system. A class cleavage has appeared between the governing coalition and the conservative opposition, but this cleavage is politically constructed and maintained. The Chilean case also shows that it is important to examine the ways in which political elites craft party systems from above during the transition period. Political agency from the supply side played a decisive role in emphasizing or diminishing some of the political and cultural conflicts existing after the authoritarian experience and, therefore, an essential role in party system formation in post-authoritarian Chile. We have undertaken this enterprise of examining social cleavages and the impact of political legacies on Chile's post-authoritarian party system as a way of exploring how post-authoritarian party systems in general are structured. Because a party system is formed and/or re-established when democracy is restored, new democracies provide an ideal context in which to discuss theoretically important aspects of cleavages and the formation
TL;DR: A greater degree of severity of the metabolic syndrome is associated with a progressively worse antioxidant/oxidant balance, which is consistent with increased oxidative stress and lower antioxidant PON1 enzymatic capacity.
Abstract: lower, and lipid peroxide concentrations significantly higher, in subjects with the metabolic syndrome compared with unaffected subjects (P 0.033 and < 0.001, respectively). Study subjects showed a significant decreasing trend in PON1 activity levels and a significant increasing trend in lipid peroxide concentrations, with the increase in the number of metabolic disturbances. No differences in the prevalence of PON1 codon 192 genotypes were found among the categories of metabolic abnormalities. In conclusion, a greater degree of severity of the metabolic syndrome is associated with a progressively worse antioxidant/oxidant balance, which is consistent with increased oxidative stress and lower antioxidant PON1 enzymatic capacity. (J Clin Endocrinol Metab 88: 5422–5426, 2003)