Showing papers by "Université de Montréal published in 2003"

A neural probabilistic language model

Abstract: A goal of statistical language modeling is to learn the joint probability function of sequences of words in a language. This is intrinsically difficult because of the curse of dimensionality: a word sequence on which the model will be tested is likely to be different from all the word sequences seen during training. Traditional but very successful approaches based on n-grams obtain generalization by concatenating very short overlapping sequences seen in the training set. We propose to fight the curse of dimensionality by learning a distributed representation for words which allows each training sentence to inform the model about an exponential number of semantically neighboring sentences. The model learns simultaneously (1) a distributed representation for each word along with (2) the probability function for word sequences, expressed in terms of these representations. Generalization is obtained because a sequence of words that has never been seen before gets high probability if it is made of words that are similar (in the sense of having a nearby representation) to words forming an already seen sentence. Training such large models (with millions of parameters) within a reasonable time is itself a significant challenge. We report on experiments using neural networks for the probability function, showing on two text corpora that the proposed approach significantly improves on state-of-the-art n-gram models, and that the proposed approach allows to take advantage of longer contexts.

The International HapMap Project

Abstract: The goal of the International HapMap Project is to determine the common patterns of DNA sequence variation in the human genome and to make this information freely available in the public domain. An international consortium is developing a map of these patterns across the genome by determining the genotypes of one million or more sequence variants, their frequencies and the degree of association between them, in DNA samples from populations with ancestry from parts of Africa, Asia and Europe. The HapMap will allow the discovery of sequence variants that affect common disease, will facilitate development of diagnostic tools, and will enhance our ability to choose targets for therapeutic intervention.

Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.

Abstract: Autosomal dominant hypercholesterolemia (ADH; OMIM144400), a risk factor for coronary heart disease, is characterized by an increase in low-density lipoprotein cholesterol levels that is associated with mutations in the genes LDLR (encoding low-density lipoprotein receptor) or APOB (encoding apolipoprotein B). We mapped a third locus associated with ADH, HCHOLA3 at 1p32, and now report two mutations in the gene PCSK9 (encoding proprotein convertase subtilisin/kexin type 9) that cause ADH. PCSK9 encodes NARC-1 (neural apoptosis regulated convertase), a newly identified human subtilase that is highly expressed in the liver and contributes to cholesterol homeostasis.

Continuity of care: a multidisciplinary review

Abstract: The concept—and reality—of continuity of care crosses disciplinary and organisational boundaries. The common definitions provided here should help healthcare providers evaluate continuity more rigorously and improve communication Patients are increasingly seen by an array of providers in a wide variety of organisations and places, raising concerns about fragmentation of care. Policy reports and charters worldwide urge a concerted effort to enhance continuity,1–3 but efforts to describe the problem or formulate solutions are complicated by the lack of consensus on the definition of continuity. To add to the confusion, other terms such as continuum of care, coordination of care, discharge planning, case management, integration of services, and seamless care are often used synonymously. This synthesis was commissioned by three Canadian health services policy and research bodies. The aim was to develop a common understanding of the concept of continuity as a basis for valid and reliable measurement of practice in different settings. We searched academic and policy literature for documents in which the principal focus was continuity of patient care or continuity. We searched electronic databases (Medline, HealthSTAR, Embase, CINAHL, Current Contents, PsychINFO, AIDSLINE, CancerLit, Cochrane Library, Dissertation abstracts, Papers1st (conferences and paper abstracts), Web of Science, WorldCat) as well as web library catalogues, peer reviewed internet sites, internet search engines, and several in-house databases. The search included documents dated from 1966 to November 2001 written in English, French, or Spanish. The reviewers (RJR, JLH, RMcK) used a data abstraction form to summarise relevant documents from every health discipline, and all reviewers read key documents. We presented the results of an initial review of 314 documents to participants of a workshop on continuity held in Vancouver in June 2001. We obtained structured feedback to a discussion paper, problem based scenarios, and expert presentations. Participants validated the common themes …

Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial.

Abstract: ContextThe worldwide explosive increase in type 2 diabetes mellitus and its cardiovascular morbidity are becoming major health concerns.ObjectiveTo evaluate the effect of decreasing postprandial hyperglycemia with acarbose, an α-glucosidase inhibitor, on the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance (IGT).Design, Setting, and ParticipantsInternational, multicenter double-blind, placebo-controlled, randomized trial, undertaken in hospitals in Canada, Germany, Austria, Norway, Denmark, Sweden, Finland, Israel, and Spain from July 1998 through August 2001. A total of 1429 patients with IGT were randomized with 61 patients (4%) excluded because they did not have IGT or had no postrandomization data, leaving 1368 patients for a modified intent-to-treat analysis. Both men (49%) and women (51%) participated with a mean (SD) age of 54.5 (7.9) years and body mass index of 30.9 (4.2). These patients were followed up for a mean (SD) of 3.3 (1.2) years.InterventionPatients with IGT were randomized to receive either placebo (n = 715) or 100 mg of acarbose 3 times a day (n = 714).Main Outcome MeasuresThe development of major cardiovascular events (coronary heart disease, cardiovascular death, congestive heart failure, cerebrovascular event, and peripheral vascular disease) and hypertension (≥140/90 mm Hg).ResultsThree hundred forty-one patients (24%) discontinued their participation prematurely, 211 in the acarbose-treated group and 130 in the placebo group; these patients were also followed up for outcome parameters. Decreasing postprandial hyperglycemia with acarbose was associated with a 49% relative risk reduction in the development of cardiovascular events (hazard ratio [HR], 0.51; 95% confidence interval [CI]; 0.28-0.95; P = .03) and a 2.5% absolute risk reduction. Among cardiovascular events, the major reduction was in the risk of myocardial infarction (HR, 0.09; 95% CI, 0.01-0.72; P = .02). Acarbose was also associated with a 34% relative risk reduction in the incidence of new cases of hypertension (HR, 0.66; 95% CI, 0.49-0.89; P = .006) and a 5.3% absolute risk reduction. Even after adjusting for major risk factors, the reduction in the risk of cardiovascular events (HR, 0.47; 95% CI, 0.24-0.90; P = .02) and hypertension (HR, 0.62; 95% CI, 0.45-0.86; P = .004) associated with acarbose treatment was still statistically significant.ConclusionThis study suggests that treating IGT patients with acarbose is associated with a significant reduction in the risk of cardiovascular disease and hypertension.

Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells

Abstract: An emerging concept in the field of cancer biology is that a rare population of 'tumour stem cells' exists among the heterogeneous group of cells that constitute a tumour. This concept, best described with human leukaemia, indicates that stem cell function (whether normal or neoplastic) might be defined by a common set of critical genes. Here we show that the Polycomb group gene Bmi-1 has a key role in regulating the proliferative activity of normal stem and progenitor cells. Most importantly, we provide evidence that the proliferative potential of leukaemic stem and progenitor cells lacking Bmi-1 is compromised because they eventually undergo proliferation arrest and show signs of differentiation and apoptosis, leading to transplant failure of the leukaemia. Complementation studies showed that Bmi-1 completely rescues these proliferative defects. These studies therefore indicate that Bmi-1 has an essential role in regulating the proliferative activity of both normal and leukaemic stem cells.

Stereoselective Cyclopropanation Reactions

Abstract: Organic chemists have always been fascinated by the cyclopropane subunit.1 The smallest cycloalkane is found as a basic structural element in a wide range of naturally occurring compounds.2 Moreover, many cyclopropane-containing unnatural products have been prepared to test the bonding features of this class of highly strained cycloalkanes3 and to study enzyme mechanism or inhibition.4 Cyclopropanes have also been used as versatile synthetic intermediates in the synthesis of more functionalized cycloalkanes5,6 and acyclic compounds.7 In recent years, most of the synthetic efforts have focused on the enantioselective synthesis of cyclopropanes.8 This has remained a challenge ever since it was found that the members of the pyrethroid class of compounds were effective insecticides.9 New and more efficient methods for the preparation of these entities in enantiomerically pure form are still evolving, and this review will focus mainly on the new methods that have appeared in the literature since 1989. It will elaborate on only three types of stereoselective cyclopropanation reactions from olefins: the halomethylmetal-mediated cyclopropanation reactions (eq 1), the transition metal-catalyzed decomposition of diazo compounds (eq 2), and the nucleophilic addition-ring closure sequence (eqs 3 and 4). These three processes will be examined in the context of diastereoand enantiocontrol. In the last section of the review, other methods commonly used to make chiral, nonracemic cyclopropanes will be briefly outlined.

Long-Term Angiographic Recurrences After Selective Endovascular Treatment of Aneurysms With Detachable Coils

Abstract: Background and Purpose— Our aim in this study was to assess the incidence and determining factors of angiographic recurrences after endovascular treatment of aneurysms. Methods— A retrospective analysis of all patients with selective endosaccular coil occlusion of intracranial aneurysms prospectively collected from 1992 to 2002 was performed. There were 501 aneurysms in 466 patients (mean±SD age, 54.20±12.54 years; 74% female). Aneurysms were acutely ruptured (54.1%) or unruptured (45.9%). Mean±SD aneurysm size was 9.67±5.91 mm with a 4.31±1.97-mm neck. The most frequent sites were basilar bifurcation (27.7%) and carotid ophthalmic (18.0%) aneurysms. Recurrences were subjectively divided into minor and major (ideally necessitating re-treatment). The most significant predictors of angiographic recurrence were determined by logistic regression. These results were confirmed by χ2, t tests, or ANOVAs followed, when appropriate, by Tukey’s contrasts. Results— Short-term (≤1 year) follow-up angiograms were available in 353 aneurysms (70.5%) and long-term (>1 year) follow-up angiograms, in 277 (55%), for a total of 383 (76.5%) followed up. Recurrences were found in 33.6% of treated aneurysms that were followed up and that appeared at a mean±SD time of 12.31±11.33 months after treatment. Major recurrences presented in 20.7% and appeared at a mean of 16.49±15.93 months. Three patients (0.8%) bled during a mean clinical follow-up period of 31.32±24.96 months. Variables determined to be significant predictors ( P <0.05) of a recurrence included aneurysm size ≥10 mm, treatment during the acute phase of rupture, incomplete initial occlusions, and duration of follow-up. Conclusions— Long-term monitoring of patients treated by endosaccular coiling is mandatory.

Developmental Trajectories of Childhood Disruptive Behaviors and Adolescent Delinquency: A Six-Site, Cross-National Study

Abstract: This study used data from 6 sites and 3 countries to examine the developmental course of physical aggression in childhood and to analyze its linkage to violent and nonviolent offending outcomes in adolescence The results indicate that among boys there is continuity in problem behavior from childhood to adolescence and that such continuity is especially acute when early problem behavior takes the form of physical aggression Chronic physical aggression during the elementary school years specifically increases the risk for continued physical violence as well as other nonviolent forms of delinquency during adolescence However, this conclusion is reserved primarily for boys, because the results indicate no clear linkage between childhood physical aggression and adolescent offending among female samples despite notable similarities across male and female samples in the developmental course of physical aggression in childhood

Molecular mechanisms of N-acetylcysteine actions.

Abstract: Oxidative stress generated by an imbalance between reactive oxygen species (ROS) and antioxidants contributes to the pathogenesis of arthritis, cancer, cardiovascular, liver and respiratory diseases. Proinflammatory cytokines and growth factors stimulate ROS production as signaling mediators. Antioxidants such as N-acetylcysteine (NAC) have been used as tools for investigating the role of ROS in numerous biological and pathological processes. NAC inhibits activation of c-Jun N-terminal kinase, p38 MAP kinase and redox-sensitive activating protein-1 and nuclear factor kappa B transcription factor activities regulating expression of numerous genes. NAC can also prevent apoptosis and promote cell survival by activating extracellular signal-regulated kinase pathway, a concept useful for treating certain degenerative diseases. NAC directly modifies the activity of several proteins by its reducing activity. Despite its nonspecificity, ability to modify DNA and multiple molecular modes of action, NAC has therapeutic value for reducing endothelial dysfunction, inflammation, fibrosis, invasion, cartilage erosion, acetaminophen detoxification and transplant prolongation.

Diagnosis and Complications of Cushing’s Syndrome: A Consensus Statement

Abstract: In October 2002, a workshop was held in Ancona, Italy, to reach a Consensus on the management of Cushing's syndrome. The workshop was organized by the University of Ancona and sponsored by the Pituitary Society, the European Neuroendocrine Association, and the Italian Society of Endocrinology. Invited international participants included almost 50 leading endocrinologists with specific expertise in the management of Cushing's syndrome. The consensus statement on diagnostic criteria and the diagnosis and treatment of complications of this syndrome reached at the workshop is hereby summarized.

The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): Liver regeneration and neuronal differentiation

Abstract: Seven secretory mammalian kexin-like subtilases have been identified that cleave a variety of precursor proteins at monobasic and dibasic residues. The recently characterized pyrolysin-like subtilase SKI-1 cleaves proproteins at nonbasic residues. In this work we describe the properties of a proteinase K-like subtilase, neural apoptosis-regulated convertase 1 (NARC-1), representing the ninth member of the secretory subtilase family. Biosynthetic and microsequencing analyses of WT and mutant enzyme revealed that human and mouse pro-NARC-1 are autocatalytically and intramolecularly processed into NARC-1 at the (Y,I)VV(V,L)(L,M)↓ motif, a site that is representative of its enzymic specificity. In vitro peptide processing studies and/or Ala substitutions of the P1–P5 sites suggested that hydrophobic/aliphatic residues are more critical at P1, P3, and P5 than at P2 or P4. NARC-1 expression is highest in neuroepithelioma SK-N-MCIXC, hepatic BRL-3A, and in colon carcinoma LoVo-C5 cell lines. In situ hybridization and Northern blot analyses of NARC-1 expression during development in the adult and after partial hepatectomy revealed that it is expressed in cells that have the capacity to proliferate and differentiate. These include hepatocytes, kidney mesenchymal cells, intestinal ileum, and colon epithelia as well as embryonic brain telencephalon neurons. Accordingly, transfection of NARC-1 in primary cultures of embryonic day 13.5 telencephalon cells led to enhanced recruitment of undifferentiated neural progenitor cells into the neuronal lineage, suggesting that NARC-1 is implicated in the differentiation of cortical neurons.

Out-of-Sample Extensions for LLE, Isomap, MDS, Eigenmaps, and Spectral Clustering

Abstract: Several unsupervised learning algorithms based on an eigendecomposition provide either an embedding or a clustering only for given training points, with no straightforward extension for out-of-sample examples short of recomputing eigenvectors. This paper provides a unified framework for extending Local Linear Embedding (LLE), Isomap, Laplacian Eigenmaps, Multi-Dimensional Scaling (for dimensionality reduction) as well as for Spectral Clustering. This framework is based on seeing these algorithms as learning eigenfunctions of a data-dependent kernel. Numerical experiments show that the generalizations performed have a level of error comparable to the variability of the embedding algorithms due to the choice of training data.

Heavy metal–induced oxidative stress in algae†

Abstract: Heavy metals, depending on their oxidation states, can be highly reactive and, as a consequence, toxic to most organisms. They are produced by an expanding variety of anthropogenic sources suggesting an increasingly important role for this form of pollution. The toxic effect of heavy metals appears to be related to production of reactive oxygen species (ROS) and the resulting unbalanced cellular redox status. Algae respond to heavy metals by induction of several antioxidants, including diverse enzymes such as superoxide dismutase, catalase, glutathione peroxidase and ascorbate peroxidase, and the synthesis of low molecular weight compounds such as carotenoids and glutathione. At high, or acute, levels of metal pollutants, damage to algal cells occurs because ROS levels exceed the capacity of the cell to cope. At lower, or chronic, levels algae accumulate heavy metals and can pass them on to organisms of other trophic levels such as mollusks, crustaceans, and fishes. We review here the evidence linking metal accumulation, cellular toxicity, and the generation of ROS in aquatic environments.

Lubrication by charged polymers

Abstract: Long-ranged forces between surfaces in a liquid control effects from colloid stability to biolubrication, and can be modified either by steric factors due to flexible polymers, or by surface charge effects. In particular, neutral polymer 'brushes' may lead to a massive reduction in sliding friction between the surfaces to which they are attached, whereas hydrated ions can act as extremely efficient lubricants between sliding charged surfaces. Here we show that brushes of charged polymers (polyelectrolytes) attached to surfaces rubbing across an aqueous medium result in superior lubrication compared to other polymeric surfactants. Effective friction coefficients with polyelectrolyte brushes in water are lower than about 0.0006-0.001 even at low sliding velocities and at pressures of up to several atmospheres (typical of those in living systems). We attribute this to the exceptional resistance to mutual interpenetration displayed by the compressed, counterion-swollen brushes, together with the fluidity of the hydration layers surrounding the charged, rubbing polymer segments. Our findings may have implications for biolubrication effects, which are important in the design of lubricated surfaces in artificial implants, and in understanding frictional processes in biological systems.

Caveolae/raft-dependent endocytosis.

Abstract: Although caveolae are well-characterized subdomains of glycolipid rafts, their distinctive morphology and association with caveolins has led to their internalization being considered different from that of rafts. In this review, we propose that caveolae and rafts are internalized via a common pathway, caveolae/raft-dependent endocytosis, defined by its clathrin independence, dynamin dependence, and sensitivity to cholesterol depletion. The regulatory role of caveolin-1 and ligand sorting in this complex endocytic pathway are specifically addressed.

Phagosomes are competent organelles for antigen cross-presentation

Abstract: The ability to process microbial antigens and present them at the surface of cells is an important aspect of our innate ability to clear infections. It is generally accepted that antigens in the cytoplasm are loaded in the endoplasmic reticulum and presented at the cell surface on major histocompatibility complex (MHC) class I molecules, whereas peptides present in endo/phagocytic compartments are presented on MHC class II molecules. Despite the apparent segregation of the class I and class II pathways, antigens from intracellular pathogens including mycobacteria, Escherichia coli, Salmonella typhimurium, Brucella abortus and Leishmania, have been shown to elicit an MHC class-I-dependent CD8+ T-cell response, a process referred to as cross-presentation. The cellular mechanisms allowing the cross-presentation pathway are poorly understood. Here we show that phagosomes display the elements and properties needed to be self-sufficient for the cross-presentation of exogenous antigens, a newly ascribed function linked to phagocytosis mediated by the endoplasmic reticulum.

Modularity of music processing.

Abstract: The music faculty is not a monolithic entity that a person either has or does not. Rather, it comprises a set of neurally isolable processing components, each having the potential to be specialized for music. Here we propose a functional architecture for music processing that captures the typical properties of modular organization. The model rests essentially on the analysis of music-related deficits in neurologically impaired individuals, but provides useful guidelines for exploring the music faculty in normal people, using methods such as neuroimaging.

Varieties of musical disorders. The Montreal Battery of Evaluation of Amusia.

Abstract: Multiple disorders of musical abilities can occur after brain damage. Conversely, early brain anomalies or vast brain injuries may sometimes spare ordinary musical skills in individuals who experience severe cognitive losses. To document these incidences, comprehensive behavioral testing is required. We propose to use the Montreal Battery of Evaluation of Amusia (MBEA) because it is arguably the best tool currently available. Over the last decade, this battery was developed and validated in populations with brain damage of various etiologies. Furthermore, the MBEA is theoretically motivated and satisfies important psychometric properties. It is sensitive, normally distributed, reliable on test-retest, and correlates with Gordon's Musical Aptitude Profile, another more widely used battery of tests. To promote its wide usage, the MBEA is now available upon request. In addition, individual MBEA data of 160 normal participants of variable age and education have been made available to all via the internet.

Social Networks, Social Integration, and Social Engagement Determine Cognitive Decline in Community-Dwelling Spanish Older Adults

Abstract: Objectives. To examine the influence of social networks and social engagement on cognitive decline in a population-based cohort of elderly people, and to assess gender differences in the effect of social relations on cognition. Methods. A longitudinal study of community-dwelling people over 65 was carried out. Cognitive function (orientation and memory) in 1997 and cognitive decline (absent, mild, and severe) over 4 years (1993–1997) were assessed using an instrument previously validated for populations with a low level of education. The effect of social networks, social integration, and social engagement with friends, children, and relatives on cognitive function and cognitive decline was estimated by multiple linear and logistic regressions after adjusting for age, sex, education, depressive symptoms, systolic and diastolic blood pressure, and functional status. Results. Poor social connections, infrequent participation in social activities, and social disengagement predict the risk of cognitive decline in elderly individuals. The probability of cognitive decline was lower for both men and women with a high frequency of visual contact with relatives and community social integration. Engagement with friends seemed to be protective for cognitive decline in women but not in men. Discussion. This longitudinal study indicates that few social ties, poor integration, and social disengagement are risk factors for cognitive decline among community-dwelling elderly persons. The nature of the ties that influence cognition may vary in men and women.

Saturated Fatty Acids Synergize with Elevated Glucose to Cause Pancreatic β-Cell Death

Abstract: We have proposed the “glucolipotoxicity” hypothesis in which elevated free fatty acids (FFAs) together with hyperglycemia are synergistic in causing islet β-cell damage because high glucose inhibits fat oxidation and consequently lipid detoxification. The effects of 1–2 d culture of both rat INS 832/13 cells and human islet β-cells were investigated in medium containing glucose (5, 11, 20 mm) in the presence or absence of various FFAs. A marked synergistic effect of elevated concentrations of glucose and saturated FFA (palmitate and stearate) on inducing β-cell death by apoptosis was found in both INS 832/13 and human islet β-cells. In comparison, linoleate (polyunsaturated) synergized only modestly with high glucose, whereas oleate (monounsaturated) was not toxic. Treating cells with the acyl-coenzyme A synthase inhibitor triacsin C, or the AMP kinase activators metformin and 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside that redirect lipid partitioning to oxidation, curtailed glucolipotoxicity. In...

Recent trends in the determination of nuclear masses

Abstract: The mass of the nucleus, through its binding energy, continues to be of capital importance not only for various aspects of nuclear physics, but also for other branches of physics, notably weak-interaction studies and astrophysics. The authors first describe the modern experimental techniques dedicated to the particularly challenging task of measuring the mass of exotic nuclides and make detailed comparisons. Though tremendous progress in these and the associated production techniques has been made, allowing access to nuclides very far from stability, it is still not yet possible to produce many nuclides involved in stellar nucleosynthesis, especially the $r$ process, leaving no choice but to resort to theory. The review thus goes on to describe and critically compare the various modern mass formulas that may be used to extrapolate from the data towards the neutron drip line. Special attention is devoted to the crucial interplay between theory and experiment, showing how new measurements far from stability can considerably reduce the ambiguity in extrapolations to nuclides even further away.