Showing papers by "McGill University published in 1996"
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Université catholique de Louvain1, McGill University2, Stanford University3, Pierre-and-Marie-Curie University4, Ludwig Maximilian University of Munich5, Centre national de la recherche scientifique6, École Normale Supérieure7, Washington University in St. Louis8, John Radcliffe Hospital9, Max Planck Society10, University of Basel11, University of Manchester12
TL;DR: The genome of the yeast Saccharomyces cerevisiae has been completely sequenced through a worldwide collaboration and provides information about the higher order organization of yeast's 16 chromosomes and allows some insight into their evolutionary history.
Abstract: The genome of the yeast Saccharomyces cerevisiae has been completely sequenced through a worldwide collaboration. The sequence of 12,068 kilobases defines 5885 potential protein-encoding genes, approximately 140 genes specifying ribosomal RNA, 40 genes for small nuclear RNA molecules, and 275 transfer RNA genes. In addition, the complete sequence provides information about the higher order organization of yeast's 16 chromosomes and allows some insight into their evolutionary history. The genome shows a considerable amount of apparent genetic redundancy, and one of the major problems to be tackled during the next stage of the yeast genome project is to elucidate the biological functions of all of these genes.
4,254 citations
TL;DR: A unified statistical theory for assessing the significance of apparent signal observed in noisy difference images is presented and an estimate of the P‐value for local maxima of Gaussian, t, χ2 and F fields over search regions of any shape or size in any number of dimensions is estimated.
Abstract: We present a unified statistical theory for assessing the significance of apparent signal observed in noisy difference images. The results are usable in a wide range of applications, including fMRI, but are discussed with particular reference to PET images which represent changes in cerebral blood flow elicited by a specific cognitive or sensorimotor task. Our main result is an estimate of the P-value for local maxima of Gaussian, t, chi(2) and F fields over search regions of any shape or size in any number of dimensions. This unifies the P-values for large search areas in 2-D (Friston et al. [1991]: J Cereb Blood Flow Metab 11:690-699) large search regions in 3-D (Worsley et al. [1992]: J Cereb Blood Flow Metab 12:900-918) and the usual uncorrected P-value at a single pixel or voxel.
2,707 citations
Columbia University1, University of Maryland, Baltimore2, University of North Carolina at Chapel Hill3, Mayo Clinic4, University of Illinois at Chicago5, University of Colorado Denver6, Duke University7, University of Alabama8, University of California, Los Angeles9, Cedars-Sinai Medical Center10, McGill University11, Baylor College of Medicine12, University of Pittsburgh13
TL;DR: As compared with conventional therapy, the continuous intravenous infusion of epoprostenol produced symptomatic and hemodynamic improvement, as well as improved survival in patients with severe primary pulmonary hypertension.
Abstract: Background Primary pulmonary hypertension is a progressive disease for which no treatment has been shown in a prospective, randomized trial to improve survival. Methods We conducted a 12-week prospective, randomized, multicenter open trial comparing the effects of the continuous intravenous infusion of epoprostenol (formerly called prostacyclin) plus conventional therapy with those of conventional therapy alone in 81 patients with severe primary pulmonary hypertension (New York Heart Association functional class III or IV). Results Exercise capacity was improved in the 41 patients treated with epoprostenol (median distance walked in six minutes, 362 m at 12 weeks vs. 315 m at base line), but it decreased in the 40 patients treated with conventional therapy alone (204 m at 12 weeks vs. 270 m at base line; P<0.002 for the comparison of the treatment groups). Indexes of the quality of life were improved only in the epoprostenol group (P<0.01). Hemodynamics improved at 12 weeks in the epoprostenol-treated pat...
2,495 citations
SUNY Downstate Medical Center1, McMaster University2, McGill University3, Harvard University4, Toronto General Hospital5, University of Birmingham6, University of Pisa7, Dalhousie University8, University of Manchester9, University College London10, University of California, Los Angeles11, United Hospitals12, Lund University13, Johns Hopkins University14, St. Vincent's Health System15
TL;DR: This damage index for SLE records damage occurring in patients with SLE regardless of its cause and was demonstrated to have content, face, criterion, and discriminant validity.
Abstract: Objective. To develop and perform an initial validation of a damage index for systemic lupus erythematosus (SLE).
Methods. A list of items considered to reflect damage in SLE was generated through a nominal group process. A consensus as to which items to be included in an index was reached, together with rules for ascertainment. Each center submitted 2 assessments, 5 years apart, on 2 patients with active and 2 with inactive disease, of whom 1 had increased damage and the other had stable disease. Analysis of variance was used to test the factors physician, time, amount of damage, and activity status.
Results. Nineteen physicians completed the damage index on 42 case scenarios. The analysis revealed that the damage index could identify changes in damage seen in patients with both active and inactive disease. Patients who had active disease at both time points had a higher increase in damage. There was good agreement among the physicians on the assessment of damage in these patients.
Conclusion. This damage index for SLE records damage occurring in patients with SLE regardless of its cause. The index was demonstrated to have content, face, criterion, and discriminant validity.
2,095 citations
TL;DR: High-resolution scanning and transmission electron microscopy study of surface textures and internal structures of selected carbonate globules show that the globules contain fine-grained, secondary phases of single-domain magnetite and iron sulfides.
Abstract: Fresh fracture surfaces of the martian meteorite ALH84001 contain abundant polycyclic aromatic hydrocarbons (PAHs). These fresh fracture surfaces also display carbonate globules. Contamination studies suggest that the PAHs are indigenous to the meteorite. High-resolution scanning and transmission electron microscopy study of surface textures and internal structures of selected carbonate globules show that the globules contain fine-grained, secondary phases of single-domain magnetite and Fe-sulfides. The carbonate globules are similar in texture and size to some terrestrial bacterially induced carbonate precipitates. Although inorganic formation is possible, formation of the globules by biogenic processes could explain many of the observed features, including the PAHs. The PAHs, the carbonate globules, and their associated secondary mineral phases and textures could thus be fossil remains of a past martian biota.
1,582 citations
TL;DR: Individuals with thermolabile MTHFR may have a higher folate requirement for regulation of plasma homocysteine concentrations; folate supplementation may be necessary to prevent fasting hyperhomocysteinemia in such persons.
Abstract: Background Methylenetetrahydrofolate reductase (MTHFR) synthesizes 5-methyltetrahydrofolate, the major carbon donor in remethylation of homocysteine to methionine. A common MTHFR mutation, an alanine-to-valine substitution, renders the enzyme thermolabile and may cause elevated plasma levels of the amino acid homocysteine. Methods and Results To assess the potential interaction between this mutation and vitamin coenzymes in homocysteine metabolism, we screened 365 individuals from the NHLBI Family Heart Study. Among individuals with lower plasma folate concentrations (<15.4 nmol/L), those with the homozygous mutant genotype had total fasting homocysteine levels that were 24% greater (P<.05) than individuals with the normal genotype. A difference between genotypes was not seen among individuals with folate levels ≥15.4 nmol/L. Conclusions Individuals with thermolabile MTHFR may have a higher folate requirement for regulation of plasma homocysteine concentrations; folate supplementation may be necessary to ...
1,402 citations
TL;DR: The spinal cord and the entire ventricular neuroaxis of the adult mammalian CNS contain multipotent stem cells, present at variable frequency and with unique in vitro activation requirements.
Abstract: Neural stem cells in the lateral ventricles of the adult mouse CNS participate in repopulation of forebrain structures in vivo and are amenable to in vitro expansion by epidermal growth factor (EGF). There have been no reports of stem cells in more caudal brain regions or in the spinal cord of adult mammals. In this study we found that although ineffective alone, EGF and basic fibroblast growth factor (bFGF) cooperated to induce the proliferation, self-renewal, and expansion of neural stem cells isolated from the adult mouse thoracic spinal cord. The proliferating stem cells, in both primary culture and secondary expanded clones, formed spheres of undifferentiated cells that were induced to differentiate into neurons, astrocytes, and oligodendrocytes. Neural stem cells, whose proliferation was dependent on EGF+bFGF, were also isolated from the lumbar/sacral segment of the spinal cord as well as the third and fourth ventricles (but not adjacent brain parenchyma). Although all of the stem cells examined were similarly multipotent and expandable, quantitative analyses demonstrated that the lateral ventricles (EGF-dependent) and lumbar/sacral spinal cord (EGF+bFGF-dependent) yielded the greatest number of these cells. Thus, the spinal cord and the entire ventricular neuroaxis of the adult mammalian CNS contain multipotent stem cells, present at variable frequency and with unique in vitro activation requirements.
1,286 citations
TL;DR: The results suggest that the PTH/P THrP receptor mediates the effects of Indian Hedgehog and PTHrP on chondrocyte differentiation.
Abstract: The PTH/PTHrP receptor binds to two ligands with distinct functions: the calcium-regulating hormone, parathyroid hormone (PTH), and the paracrine factor, PTH-related protein (PTHrP). Each ligand, in turn, is likely to activate more than one receptor. The functions of the PTH/PTHrP receptor were investigated by deletion of the murine gene by homologous recombination. Most PTH/PTHrP receptor (-/-) mutant mice died in mid-gestation, a phenotype not observed in PTHrP (-/-) mice, perhaps because of the effects of maternal PTHrP. Mice that survived exhibited accelerated differentiation of chondrocytes in bone, and their bones, grown in explant culture, were resistant to the effects of PTHrP and Sonic hedgehog. These results suggest that the PTH/PTHrP receptor mediates the effects of Indian Hedgehog and PTHrP on chondrocyte differentiation.
1,279 citations
TL;DR: In this paper, the insoluble block (PS) contents in the copolymers ranged from 80 to 98 wt % and the micelle cores, formed by aggregation of the PS blocks, were generally monodisperse.
Abstract: Crew-cut micelle-like aggregates of various morphologies prepared from polystyrene-b-poly(acrylic acid), PS-b-PAA, diblock copolymers under near-equilibrium conditions, were studied by transmission electron microscopy (TEM). The insoluble block (PS) contents in the copolymers ranged from 80 to 98 wt %. In spherical micelles, the micelle cores, formed by aggregation of the PS blocks, were generally monodisperse. A comparison between star and crew-cut micelles showed that the latter are distinguished by a low density of corona chains on the core surface and a low degree of stretching of the PS blocks in the cores. As the PAA content in block copolymer decreased, the morphology of the aggregates changed progressively from spheres to cylinders, to bilayers (both vesicles and lamellae), and eventually to compound micelles consisting of an assembly of inverted micelles surrounded by a hydrophilic surface. The compound micelles are believed to be a new morphology for block copolymers. The addition of homopolysty...
1,167 citations
TL;DR: In this article, the authors examined problems with sustained product innovation in 15 firms that averaged 96 years of age, 54,000 employees, and $9.4 billion in annual revenues.
Abstract: We examined problems with sustained product innovation in 15 firms that averaged 96 years of age, 54,000 employees, and $9.4 billion in annual revenues. Findings reveal that the inability to connec...
1,127 citations
TL;DR: A CAG trinucleotide repeat with CAA interruptions that was expanded in patients with SCA2, which is a member of a novel gene family and not highly polymorphic in normal individuals is identified.
Abstract: The gene for spinocerebellar ataxia type 2 (SCA2) has been mapped to 12q24.1. A 1.1-megabase contig in the candidate region was assembled in P1 artificial chromosome and bacterial artificial chromosome clones. Using this contig, we identified a CAG trinucleotide repeat with CAA interruptions that was expanded in patients with SCA2. In contrast to other unstable trinucleotide repeats, this CAG repeat was not highly polymorphic in normal individuals. In SCA2 patients, the repeat was perfect and expanded to 36-52 repeats. The most common disease allele contained (CAG)37, one of the shortest expansions seen in a CAG expansion syndrome. The repeat occurs in the 5'-coding region of SCA2 which is a member of a novel gene family.
Harvard University1, University of Cambridge2, International Agency for Research on Cancer3, Utrecht University4, Osaka University5, University of Sydney6, Heidelberg University7, Dartmouth College8, University of Pisa9, Medical University of Vienna10, Karolinska Institutet11, University of Zurich12, McGill University13, Mayo Clinic14, Université de Montréal15, University of Hamburg16, Cancer Research UK17, Queen's University18
TL;DR: It is suggested that genotype-phenotype correlations do exist and, if made reliably absolute, could prove useful in the future in clinical management with respect to screening, surveillance, and prophylaxis, as well as provide insight into the genetic effects of particular mutations.
Abstract: Objective. —Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant disorder. The 3 recognized subtypes include MEN 2A, characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (pheo), and hyperparathyroidism (HPT); MEN 2B, by MTC, pheo, and characteristic stigmata; and familial MTC (FMTC), by the presence of MTC only. The purpose of this study was to establish the relationship between specific mutations and the presence of certain disease features in MEN 2 which could help in clinical decision making. Design. —Correlative survey study of 477 MEN 2 families. Setting. —Eighteen tertiary referral centers worldwide. Patients. —A total of 477 independent MEN 2 families. Main Outcome Measures. —Association between the position and type of germline mutation in the RET proto-oncogene and the presence or absence of MTC, pheo, HPT, and/or other features in a family. Results. —There is a statistically significant association between the presence of any mutation at a specific position (codon 634) and the presence of pheo and HPT. The presence of a specific mutation, CGC at codon 634, has yet to be associated with FMTC. Conversely, mutations at codons 768 and 804 are thus far seen only with FMTC, while codon 918 mutation is MEN 2B-specific. Rare families with both MEN 2 and Hirschsprung disease were found to have MEN 2-specific codon mutations. Patients with Hirschsprung disease presenting with such mutations should be monitored for the possible development of MEN 2 tumors. Conclusions. —This consortium analysis suggests that genotype-phenotype correlations do exist and, if made reliably absolute, could prove useful in the future in clinical management with respect to screening, surveillance, and prophylaxis, as well as provide insight into the genetic effects of particular mutations.
National Institutes of Health1, Stanford University2, Massachusetts Institute of Technology3, Wellcome Trust Sanger Institute4, University of Oxford5, Wellcome Trust6, University of Michigan7, Rockefeller University8, Laval University9, J. Craig Venter Institute10, Centre national de la recherche scientifique11, Anschutz Medical Campus12, University of Cambridge13, McGill University14
TL;DR: The gene map unifies the existing genetic and physical maps with the nucleotide and protein sequence databases in a fashion that should speed the discovery of genes underlying inherited human disease.
Abstract: The human genome is thought to harbor 50,000 to 100,000 genes, of which about half have been sampled to date in the form of expressed sequence tags. An international consortium was organized to develop and map gene-based sequence tagged site markers on a set of two radiation hybrid panels and a yeast artificial chromosome library. More than 16,000 human genes have been mapped relative to a framework map that contains about 1000 polymorphic genetic markers. The gene map unifies the existing genetic and physical maps with the nucleotide and protein sequence databases in a fashion that should speed the discovery of genes underlying inherited human disease. The integrated resource is available through a site on the World Wide Web at http://www.ncbi.nlm.nih.gov/SCIENCE96/.
TL;DR: The use of anorexic drugs was associated with the development of primary pulmonary hypertension and active surveillance for this disease should be considered, particularly since their use is expected to increase in the near future.
Abstract: Background Recently in France, primary pulmonary hypertension developed in a cluster of patients exposed to derivatives of fenfluramine in appetite suppressants (anorexic agents), which are used for weight control. We investigated the potential role of anorexic agents and other suspected risk factors for primary pulmonary hypertension. Methods In a case–control study, we assessed 95 patients with primary pulmonary hypertension from 35 centers in France, Belgium, the United Kingdom, and the Netherlands and 355 controls recruited from general practices and matched to the patients' sex and age. Results The use of anorexic drugs (mainly derivatives of fenfluramine) was associated with an increased risk of primary pulmonary hypertension (odds ratio with any anorexic-drug use, 6.3; 95 percent confidence interval, 3.0 to 13.2). For the use of anorexic agents in the preceding year, the odds ratio was 10.1 (95 percent confidence interval, 3.4 to 29.9). When anorexic drugs were used for a total of more than three m...
TL;DR: The results suggest that the delta(15)N signatures of nitrogen at the base of the food chain will provide a useful tool in the assessment of anthropogenic nutrient inputs.
Abstract: Recent studies have shown the utility of delta(15)N to model trophic structure and contaminant bioaccumulation in aquatic food webs. However, cross-system comparisons in delta(15)N can be complicated by differences in delta(15)N at the base of the food chain. Such baseline variation in delta(15)N is difficult to resolve using plankton because of the large temporal variability in the delta(15)N of small organisms that have fast nitrogen turnover. Comparisons using large primary consumers, which have stable tissue isotopic signatures because of their slower nitrogen turnover, show that delta(15)N increases markedly with the human population density in the lake watershed. This shift in delta(15)N likely reflects the high delta(15)N of human sewage. Correcting for this baseline variation in delta(15)N, we report that, contrary to expectations based on previous food-web analysis, the food chains leading up to fish varied by about only one trophic level among the 40 lakes studied. Our results also suggest that the delta(15)N signatures of nitrogen at the base of the food chain will provide a useful tool in the assessment of anthropogenic nutrient inputs.
TL;DR: The findings indicate that the early postnatal environment alters the differentiation of hippocampal neurons, and these data provide examples of early environmental programming of neural systems.
Abstract: The adrenal glucocorticoids and catecholamines comprise a frontline of defense for mammalian species under conditions which threaten homeostasis (conditions commonly referred to as stress). Glucocorticoids represent the end product of the hypothalamic-pituitary-adrenal (HPA) axis and along with the catecholamines serve to mobilize the production and distribution of energy substrates during stress. The increased secretion of pituitary-adrenal hormones in response to stress is stimulated by the release of corticotropin-releasing hormone (CRH) and/or arginine vasopressin (AVP) from neurons in the nucleus paraventricularis. In this way, a neural signal associated with the stressor is transduced into a set of endocrine and sympathetic responses. The development of the HPA response to stressful stimuli is altered by early environmental events. Animals exposed to short periods of infantile stimulation or handling show decreased HPA responsivity to stress, whereas maternal separation, physical trauma and endotoxin administration enhance HPA responsivity to stress. In all cases, these effects persist throughout the life of the animal and are accompanied by increased hypothalamic levels of the mRNAs for CRH and often AVP. The inhibitory regulation of the synthesis for these ACTH releasing factors is achieved, in part, through a negative feedback loop whereby circulating glucocorticoids act at various neural sites to decrease CRH and AVP gene expression. Such inhibitory effects are initiated via an interaction between the adrenal steroid and an intracellular receptor (either the mineralocorticoid or glucocorticoid receptor). We have found that these early environmental manipulations regulate glucocorticoid receptor gene expression in the hippocampus and frontal cortex, regions that have been strongly implicated as sites for negative-feedback regulation of CRH and AVP synthesis. When the differences in glucocorticoid receptor density are transiently reversed, so too are those in HPA responses to stress. Taken together, our findings indicate that the early postnatal environment alters the differentiation of hippocampal neurons. This effect involves an altered rate of glucocorticoid receptor gene expression, resulting in changes in the sensitivity of the system to the inhibitory effects of glucocorticoids on the synthesis of CRH and AVP in hypothalamic neurons. Changes in CRH and AVP levels, in turn, determine the responsivity of the axis to subsequent stressors; increased releasing factor production is associated with increased HPA responses to stress. Thus, the early environment can contribute substantially to the development of stable individual differences in HPA responsivity to stressful stimuli. These data provide examples of early environmental programming of neural systems. One major objective of our research is to understand how such programming occurs within the brain.
TL;DR: The addition of ions in micromolar (CaCl2 or HCl) or millimolar (NaCl) concentrations can change the morphology of “crew-cut” aggregates of amphiphilic block copolymers in dilute solutions, resulting in an unusual large compound vesicle morphology.
Abstract: The addition of ions in micromolar (CaCl2 or HCl) or millimolar (NaCl) concentrations can change the morphology of "crew-cut" aggregates of amphiphilic block copolymers in dilute solutions. In addition to spherical, rodlike, and univesicular or lamellar aggregates, an unusual large compound vesicle morphology can be obtained from a single block copolymer. Some features of the spontaneously formed large compound vesicles may make them especially useful as vehicles for delivering drugs and as models of biological cells. Gelation of a dilute spherical micelle solution can also be induced by ions as the result of the formation of a cross-linked "pearl necklace" morphology.
TL;DR: This paper develops the reverse search technique in a general framework and shows its broader applications to various problems in operations research, combinatorics, and geometry, and proposes new algorithms for listing.
TL;DR: Only a subset of HBOC family members are likely to request BRCA1 testing when available and rates of test use may be higher in persons of a higher socioeconomic status and those with more relatives affected with breast cancer.
Abstract: Objectives. —To identify predictors of utilization of breast-ovarian cancer susceptibility ( BRCA1 gene) testing and to evaluate outcomes of participation in a testing program. Design. —Prospective cohort study with baseline interview assessment of predictor variables (eg, sociodemographic factors, knowledge about hereditary cancer and genetic testing, perceptions of testing benefits, limitations, and risks). BRCA1 test results were offered after an education and counseling session in a research setting. Outcome variables (including depression, functional health status, and prophylactic surgery plans [follow-up only]) were assessed at baseline and 1-month follow-up interviews. Participants. —Adult male and female members (n=279) of families with BRCA 1 -linked hereditary breast-ovarian cancer (HBOC). Results. —Of subjects who completed a baseline interview (n=192), 60% requested BRCA 1 test results (43% of all study subjects requested results). Requests for results were more frequent for persons with health insurance (odds ratio [OR], 3.74; 95% confidence interval [CI], 2.06-6.80); more first-degree relatives affected with breast cancer (OR, 1.59; 95% CI, 1.16-2.16); more knowledge about BRCA1 testing (OR, 1.85; 95% CI, 1.36-2.50); and indicating that test benefits are important (OR, 1.45; 95% CI, 1.13-1.86). At follow-up, noncarriers of BRCA1 mutations showed statistically significant reductions in depressive symptoms and functional impairment compared with carriers and nontested individuals. Individuals identified as mutation carriers did not exhibit increases in depression and functional impairment. Among unaffected women with no prior prophylactic surgery, 17% of carriers (2/12) intended to have mastectomies and 33% (4/12) to have oophorectomies. Conclusions. —Only a subset of HBOC family members are likely to request BRCA 1 testing when available. Rates of test use may be higher in persons of a higher socioeconomic status and those with more relatives affected with breast cancer. For some high-risk individuals who receive test results in a research setting that includes counseling, there may be psychological benefits. More research is needed to assess the generalizability of these results and evaluate the long-term consequences of BRCA1 testing. ( JAMA . 1996;275:1885-1892)
TL;DR: In this article, the onset of dynamic recrystallization is treated in terms of a model based on the principles of irreversible thermodynamics, and the model is verified using experimental data obtained during the high temperature compression of nickel and of a type 305 austenitic stainless steel.
TL;DR: Anemia, an easily reversible feature of end- stage renal disease, is an independent risk factor for clinical and echocardiographic cardiac disease, as well as mortality in end-stage renal disease patients.
TL;DR: The results demonstrated that the perception of scripts of goal-directed hand action implicates the cortex in the intraparietal sulcus and the caudal part of the superior temporal sulcus, both in the left hemisphere.
Abstract: To explore the extent to which functional systems within the human posterior parietal cortex and the superior temporal sulcus are involved in the perception of action, we measured cerebral metabolic activity in human subjects by positron emission tomography during the perception of simulations of biological motion with point-light displays. The experimental design involved comparisons of activity during the perception of goal-directed hand action, whole body motion, object motion, and random motion. The results demonstrated that the perception of scripts of goal-directed hand action implicates the cortex in the intraparietal sulcus and the caudal part of the superior temporal sulcus, both in the left hemisphere. By contrast, the rostrocaudal part of the right superior temporal sulcus and adjacent temporal cortex, and limbic structures such as the amygdala, are involved in the perception of signs conveyed by expressive body movements.
TL;DR: It is shown that rapamycin inhibits cap‐dependent, but not cap‐independent, translation in NIH 3T3 cells, and results suggest that 4E‐BP1 phosphorylation is mediated by the FRAP/TOR signalling pathway.
Abstract: The immunosuppressant drug rapamycin blocks progression of the cell cycle at the G1 phase in mammalian cells and yeast. Here we show that rapamycin inhibits cap-dependent, but not cap-independent, translation in NIH 3T3 cells. Cap-dependent translation is also specifically reduced in extracts from rapamycin-treated cells, as determined by in vitro translation experiments. This inhibition is causally related to the dephosphorylation and consequent activation of 4E-BP1, a protein recently identified as a repressor of the cap-binding protein, eIF-4E, function. These effects of rapamycin are specific as FK506, a structural analogue of rapamycin, had no effect on either cap-dependent translation or 4E-BP1 phosphorylation. The rapamycin-FK506 binding protein complex is the effector of the inhibition of 4E-BP1 phosphorylation as excess of FK506 over rapamycin reversed the rapamycin-mediated inhibition of 4E-BP1 phosphorylation. Thus, inactivation of eIF-4E is, at least in part, responsible for inhibition of cap-dependent translation in rapamycin-treated cells. Furthermore, these results suggest that 4E-BP1 phosphorylation is mediated by the FRAP/TOR signalling pathway.
University of Western Ontario1, University of Saskatchewan2, University of Alberta3, University of Toronto4, University of Manitoba5, University of Calgary6, McGill University7, McMaster University8, Dalhousie University9, Memorial University of Newfoundland10, University of Ottawa11, Queen's University12, Stanford University13
TL;DR: The results support genetic epidemiological evidence that several genes interact epistatically to determine heritable susceptibility in multiple sclerosis.
Abstract: The aetiology of multiple sclerosis (MS) is uncertain. There is strong circumstantial evidence to indicate it is an autoimmune complex trait. Risks for first degree relatives are increased some 20 fold over the general population. Twin studies have shown monozygotic concordance rates of 25-30% compared to 4% for dizygotic twins and siblings. Studies of adoptees and half sibs show that familial risk is determined by genes, but environmental factors strongly influence observed geographic differences. Studies of candidate genes have been largely unrewarding. We report a genome search using 257 microsatellite markers with average spacing of 15.2 cM in 100 sibling pairs (Table 1, data set 1 - DS1). A locus of lambda>3 was excluded from 88% of the genome. Five loci with maximum lod scores (MLS) of >1 were identified on chromosomes 2, 3, 5, 11 and X. Two additional data sets containing 44 (Table 1, DS2) and 78 sib pairs (Table 1, DS3) respectively, were used to further evaluate the HLA region on 6p21 and a locus on chromosome 5 with an MLS of 4.24. Markers within 6p21 gave MLS of 0.65 (non-significant, NS). However, D6S461, just outside the HLA region, showed significant evidence for linkage disequilibrium by the transmission disequilibrium test (TDT), in all three data sets (for DS1 chi2 = 10.8, adjusted P < 0.01)(DS2 and DS3 chi2 = 10.9, P < 0.0005), suggesting a modest susceptibility locus in this region. On chromosome 5p results from all three data sets (222 sib pairs) yielded a multipoint MLS of 1.6. The results support genetic epidemiological evidence that several genes interact epistatically to determine heritable susceptibility.
TL;DR: In this article, the formation of ordered phases of acid-hydrolyzed cellulose suspensions was studied as a function of cellulose crystallite concentration and added electrolyte (HCl, NaCl, and KCl) concentrations.
Abstract: The formation of ordered phases of acid-hydrolyzed cellulose suspensions was studied as a function of cellulose crystallite concentration and added electrolyte (HCl, NaCl, and KCl) concentrations. A chiral nematic phase formed when the suspension concentration was higher than 5.14 × 10-6 nm-3 in water. For biphasic samples, the cellulose concentrations in both isotropic and anisotropic phases increase with the total suspension concentration and with added electrolyte. The experimental results were compared with the predictions of the theory of Stroobants, Lekkerkerker, and Odijk for the phase separation of charged rods. The suspensions were not stable at electrolyte concentrations sufficiently high to allow complete evaluation of the electrostatic contribution to the interparticle interactions, but the general behavior was in line with theoretical predictions. The chiral nematic pitch of the anisotropic phase decreased with increasing crystallite concentration and with added electrolyte concentration. App...
TL;DR: The treatment of patients with major depression using an SSRI and pindolol, a 5-HT1A/ beta-adrenoceptor antagonist, markedly reduced the latency of the antidepressant response in previously untreated patients and induced a rapid improvement in treatment-resistant patients.
TL;DR: A preferential role for left PAC in processing temporal aspects of auditory stimuli is suggested and a probabilistic map of the region is produced which can be co-registered with any image of brain structure or function that has been similarly transformed.
Abstract: The gyral morphology of the region of the primary auditory cortex (PAC) in the human brain is highly variable, and possible asymmetries between the hemispheres have been noted since the beginning of the century. We mapped the location and extent of PAC as identified from gross anatomical landmarks in magnetic resonance scans that had been transformed into Talairach-Tournoux stereotaxic space. Individual maps were averaged to produce a probabilistic map of the region which can be co-registered with any image of brain structure or function that has been similarly transformed. The map can be used to localize a region of interest, such as a lesion, or an activation focus from position omission tomography or functional magnetic resonance imaging, within a specified range of probability. We also measured the total volume of the region and found a significant L > R asymmetry both on average and in the majority of subjects. Automatic segmentation of the volumes into grey and white matter revealed larger volumes of white, but not grey matter on the left. This larger volume of cortical connecting fibres may be related to the known left-hemisphere dominance for speech, and a preferential role for left PAC in processing temporal aspects of auditory stimuli is suggested.
TL;DR: A modification of the binomial method (termed BBSR) is introduced that is very simple to implement and performs remarkable well and a careful large-scale evaluation of many recent methods for computing American option prices is conducted.
Abstract: We develop lower and upper bounds on the prices of American call and put options written on a dividend-paying asset. We provide two option price approximations, one based on the lower bound (termed LBA) and one based on both bounds (termed LUBA). The LUBA approximation has an average accuracy comparable to a 1,000-step binomial tree with a computation speed comparable to a 50-step binomial tree. We introduce a modification of the binomial method (termed BBSR) that is very simple to implement and performs remarkable well. We also conduct a careful large-scale evaluation of many recent methods for computing American option prices. Article published by Oxford University Press on behalf of the Society for Financial Studies in its journal, The Review of Financial Studies.
TL;DR: The authors investigated the potential interference between the grammars of French-English bilingual children, aged 2-3 years, examined their acquisition of functional categories, specifically the properties of INFL (finiteness and agreement) and negation, and found that the bilingual children show no evidence of transfer, acceleration, or delay in acquisition.
Abstract: Recent research on pragmatic and syntactic development in bilingual 2-year-olds has shown that these children have differentiated language systems. However, it remains to be shown whether their grammars develop autonomously or interdependently from 2 years onward. The present study investigates the potential interference between the grammars of French-English bilingual children, aged 2–3 years. We examined their acquisition of functional categories, specifically the properties of INFL (finiteness and agreement) and negation, as these grammatical properties differ in both adult French and English and child French and English. Our results indicate that the bilingual children show no evidence of transfer, acceleration, or delay in acquisition, and support the hypothesis that their grammars are acquired autonomously. Some implications of these findings for the debate on continuity in the emergence of functional categories are discussed.
TL;DR: A method for producing error statistics from a representative ensemble of forecast states at the appropriate forecast time is proposed and examined and an attempt is made to simulate the process of error growth in a forecast model.
Abstract: For many aspects of numerical weather prediction it is important to have good error statistics. Here one can think of applications as diverse as data assimilation, model improvement, and medium-range forecasting. In this paper, a method for producing these statistics from a representative ensemble of forecast states at the appropriate forecast time is proposed and examined. To generate the ensemble, an attempt is made to simulate the process of error growth in a forecast model. For different ensemble members the uncertain elements of the forecasts are perturbed in different ways. First the authors attempt to obtain representative initial perturbations. For each perturbation, an independent 6-h assimilation cycle is performed. For this the available observations are randomly perturbed. The perturbed observations are input to the statistical interpolation assimilation scheme, giving a perturbed analysis. This analysis is integrated for 6 h with a perturbed version of the T63 forecast model, using p...