Showing papers by "McGill University published in 1998"
TL;DR: A novel approach to correcting for intensity nonuniformity in magnetic resonance (MR) data is described that achieves high performance without requiring a model of the tissue classes present, and is applied at an early stage in an automated data analysis, before a tissue model is available.
Abstract: A novel approach to correcting for intensity nonuniformity in magnetic resonance (MR) data is described that achieves high performance without requiring a model of the tissue classes present. The method has the advantage that it can be applied at an early stage in an automated data analysis, before a tissue model is available. Described as nonparametric nonuniform intensity normalization (N3), the method is independent of pulse sequence and insensitive to pathological data that might otherwise violate model assumptions. To eliminate the dependence of the field estimate on anatomy, an iterative approach is employed to estimate both the multiplicative bias field and the distribution of the true tissue intensities. The performance of this method is evaluated using both real and simulated MR data.
4,613 citations
TL;DR: The lifetime risk of breast cancer appears similar to the risk in BRCA1 carriers, but there was some suggestion of a lower risk in bRCA2 carriers <50 years of age.
Abstract: The contribution of BRCA1 and BRCA2 to inherited breast cancer was assessed by linkage and mutation analysis in 237 families, each with at least four cases of breast cancer, collected by the Breast Cancer Linkage Consortium. Families were included without regard to the occurrence of ovarian or other cancers. Overall, disease was linked to BRCA1 in an estimated 52% of families, to BRCA2 in 32% of families, and to neither gene in 16% (95% confidence interval [CI] 6%-28%), suggesting other predisposition genes. The majority (81%) of the breast-ovarian cancer families were due to BRCA1, with most others (14%) due to BRCA2. Conversely, the majority of families with male and female breast cancer were due to BRCA2 (76%). The largest proportion (67%) of families due to other genes was found in families with four or five cases of female breast cancer only. These estimates were not substantially affected either by changing the assumed penetrance model for BRCA1 or by including or excluding BRCA1 mutation data. Among those families with disease due to BRCA1 that were tested by one of the standard screening methods, mutations were detected in the coding sequence or splice sites in an estimated 63% (95% CI 51%-77%). The estimated sensitivity was identical for direct sequencing and other techniques. The penetrance of BRCA2 was estimated by maximizing the LOD score in BRCA2-mutation families, over all possible penetrance functions. The estimated cumulative risk of breast cancer reached 28% (95% CI 9%-44%) by age 50 years and 84% (95% CI 43%-95%) by age 70 years. The corresponding ovarian cancer risks were 0.4% (95% CI 0%-1%) by age 50 years and 27% (95% CI 0%-47%) by age 70 years. The lifetime risk of breast cancer appears similar to the risk in BRCA1 carriers, but there was some suggestion of a lower risk in BRCA2 carriers <50 years of age.
2,892 citations
TL;DR: A positive relation between circulating IGF-I concentration and risk of breast cancer was found among premenopausal but not postmenopausal women, and may be useful in the identification of women at high risk of Breast cancer and in the development of risk reduction strategies.
1,820 citations
TL;DR: The authors present a realistic, high-resolution, digital, volumetric phantom of the human brain, which can be used to simulate tomographic images of the head and is the ideal tool to test intermodality registration algorithms.
Abstract: After conception and implementation of any new medical image processing algorithm, validation is an important step to ensure that the procedure fulfils all requirements set forth at the initial design stage. Although the algorithm must be evaluated on real data, a comprehensive validation requires the additional use of simulated data since it is impossible to establish ground truth with in vivo data. Experiments with simulated data permit controlled evaluation over a wide range of conditions (e.g., different levels of noise, contrast, intensity artefacts, or geometric distortion). Such considerations have become increasingly important with the rapid growth of neuroimaging, i.e., computational analysis of brain structure and function using brain scanning methods such as positron emission tomography and magnetic resonance imaging. Since simple objects such as ellipsoids or parallelepipedes do not reflect the complexity of natural brain anatomy, the authors present the design and creation of a realistic, high-resolution, digital, volumetric phantom of the human brain. This three-dimensional digital brain phantom is made up of ten volumetric data sets that define the spatial distribution for different tissues (e.g., grey matter, white matter, muscle, skin, etc.), where voxel intensity is proportional to the fraction of tissue within the voxel. The digital brain phantom can be used to simulate tomographic images of the head. Since the contribution of each tissue type to each voxel in the brain phantom is known, it can be used as the gold standard to test analysis algorithms such as classification procedures which seek to identify the tissue "type" of each image voxel. Furthermore, since the same anatomical phantom may be used to drive simulators for different modalities, it is the ideal tool to test intermodality registration algorithms. The brain phantom and simulated MR images have been made publicly available on the Internet (http://www.bic.mni.mcgill.ca/brainweb).
1,811 citations
TL;DR: It is demonstrated that aged humans with significant prolonged cortisol elevations showed reduced hippocampal volume and deficits in hippocampus-dependent memory tasks compared to normal-cortisol controls, and the degree of hippocampal atrophy correlated strongly with both the degree and current basal cortisol levels.
Abstract: Elevated glucocorticoid levels produce hippocampal dysfunction and correlate with individual deficits in spatial learning in aged rats. Previously we related persistent cortisol increases to memory impairments in elderly humans studied over five years. Here we demonstrate that aged humans with significant prolonged cortisol elevations showed reduced hippocampal volume and deficits in hippocampus-dependent memory tasks compared to normal-cortisol controls. Moreover, the degree of hippocampal atrophy correlated strongly with both the degree of cortisol elevation over time and current basal cortisol levels. Therefore, basal cortisol elevation may cause hippocampal damage and impair hippocampus-dependent learning and memory in humans.
1,564 citations
TL;DR: It is suggested that maternal care during infancy serves to "program" behavioral responses to stress in the offspring by altering the development of the neural systems that mediate fearfulness.
Abstract: The mothers of infant rats show individual differences in the frequency of licking/grooming and arched-back nursing (LG-ABN) of pups that contribute to the development of individual differences in behavioral responses to stress. As adults, the offspring of mothers that exhibited high levels of LG-ABN showed substantially reduced behavioral fearfulness in response to novelty compared with the offspring of low LG-ABN mothers. In addition, the adult offspring of the high LG-ABN mothers showed significantly (i) increased central benzodiazepine receptor density in the central, lateral, and basolateral nuclei of the amygdala as well as in the locus ceruleus, (ii) increased α2 adrenoreceptor density in the locus ceruleus, and (iii) decreased corticotropin-releasing hormone (CRH) receptor density in the locus ceruleus. The expression of fear and anxiety is regulated by a neural circuitry that includes the activation of ascending noradrenergic projections from the locus ceruleus to the forebrain structures. Considering the importance of the amygdala, notably the anxiogenic influence of CRH projections from the amygdala to the locus ceruleus, as well as the anxiolytic actions of benzodiazepines, for the expression of behavioral responses to stress, these findings suggest that maternal care during infancy serves to “program” behavioral responses to stress in the offspring by altering the development of the neural systems that mediate fearfulness.
1,353 citations
TL;DR: It is concluded that this mathematical model of the human atrial AP reproduces a variety of observed AP behaviors and provides insights into the mechanisms of clinically important AP properties.
Abstract: The mechanisms underlying many important properties of the human atrial action potential (AP) are poorly understood. Using specific formulations of the K+, Na+, and Ca2+ currents based on data recorded from human atrial myocytes, along with representations of pump, exchange, and background currents, we developed a mathematical model of the AP. The model AP resembles APs recorded from human atrial samples and responds to rate changes, L-type Ca2+ current blockade, Na+/Ca2+ exchanger inhibition, and variations in transient outward current amplitude in a fashion similar to experimental recordings. Rate-dependent adaptation of AP duration, an important determinant of susceptibility to atrial fibrillation, was attributable to incomplete L-type Ca2+ current recovery from inactivation and incomplete delayed rectifier current deactivation at rapid rates. Experimental observations of variable AP morphology could be accounted for by changes in transient outward current density, as suggested experimentally. We conclude that this mathematical model of the human atrial AP reproduces a variety of observed AP behaviors and provides insights into the mechanisms of clinically important AP properties.
1,134 citations
TL;DR: The findings suggest that oncogenic RARs mediate leukaemogenesis through aberrant chromatin acetylation, and that pharmacological manipulation of nuclear receptor co-factors may be a useful approach in the treatment of human disease.
Abstract: Non-liganded retinoic acid receptors (RARs) repress transcription of target genes by recruiting the histone deacetylase complex1,2,3 through a class of silencing mediators termed SMRT or N-CoR4,5. Mutant forms of RARα, created by chromosomal translocations with either the PML (for promyelocytic leukaemia)6,7,8 or the PLZF (for promyelocytic leukaemia zinc finger)9,10 locus, are oncogenic and result in human acute promyelocytic leukaemia (APL). PML–RARα APL patients achieve complete remission following treatments with pharmacological doses of retinoic acids (RA); in contrast, PLZF–RARα patients respond very poorly, if at all11. Here we report that the association of these two chimaeric receptors with the histone deacetylase (HDAC) complex helps to determine both the development of APL and the ability of patients to respond to retinoids. Consistent with these observations, inhibitors of histone deacetylase dramatically potentiate retinoid-induced differentiation of RA-sensitive, and restore retinoid responses of RA-resistant, APL cell lines. Our findings suggest that oncogenic RARs mediate leukaemogenesis through aberrant chromatin acetylation, and that pharmacological manipulation of nuclear receptor co-factors may be a useful approach in the treatment of human disease.
1,120 citations
TL;DR: In this article, the authors present a cost-effective new alternative for the decontamination of metal-containing effluents by using metal biosorption of non-living biomass.
1,000 citations
TL;DR: In this paper, the particle size of cellulose microcrystallites was characterized with transmission electron microscopy and photon correlation spectroscopy, and the surface charge was determined by conductometric titration.
Abstract: Stable colloidal suspensions of cellulose microcrystallites may be prepared from filter paper by sulfuric acid hydrolysis. Above a critical concentration, the suspensions form a chiral nematic ordered phase, or ‘colloid crystal’. The preparation conditions govern the properties of the individual cellulose microcrystallites, and hence the liquid crystalline phase separation of the cellulose suspensions. The particle properties and the phase separation of the suspensions were strongly dependent on the hydrolysis temperature and time, and on the intensity of the ultrasonic irradiation used to disperse the particles. The particle size of the microcrystallites was characterized with transmission electron microscopy and photon correlation spectroscopy. The surface charge was determined by conductometric titration. It was possible to fractionate the microcrystallites by size using the partitioning between isotropic and liquid crystalline phases; the longer microcrystallites migrate to the liquid crystalline phase
981 citations
TL;DR: Allelic analysis of patients with HPV-associated tumours revealed a striking overrepresentation of homozygous arginine-72 p53 compared with the normal population, which indicated that individuals homozygously for arginin 72 are about seven times more susceptible to HPV- associated tumorigenesis than heterozygotes.
Abstract: The E6 oncoprotein derived from tumour-associated human papillomaviruses (HPVs) binds to and induces the degradation of the cellular tumour-suppressor protein p53 A common polymorphism that occurs in the p53 amino-acid sequence results in the presence of either a proline or an arginine at position 72 The effect of this polymorphism on the susceptibility of p53 to E6-mediated degradation has been investigated and the arginine form of p53 was found to be significantly more susceptible than the proline form Moreover, allelic analysis of patients with HPV-associated tumours revealed a striking overrepresentation of homozygous arginine-72 p53 compared with the normal population, which indicated that individuals homozygous for arginine 72 are about seven times more susceptible to HPV-associated tumorigenesis than heterozygotes The arginine-encoding allele therefore represents a significant risk factor in the development of HPV-associated cancers
TL;DR: It is demonstrated that food restriction lengthens life span by a mechanism distinct from that of dauer-formation mutants, and it is found thatFood restriction does not further increase the life span of long-lived clk-1 mutants, suggesting that clK-1 and caloric restriction affect similar processes.
Abstract: Low caloric intake (caloric restriction) can lengthen the life span of a wide range of animals and possibly even of humans. To understand better how caloric restriction lengthens life span, we used genetic methods and criteria to investigate its mechanism of action in the nematode Caenorhabditis elegans. Mutations in many genes (eat genes) result in partial starvation of the worm by disrupting the function of the pharynx, the feeding organ. We found that most eat mutations significantly lengthen life span (by up to 50%). In C. elegans, mutations in a number of other genes that can extend life span have been found. Two genetically distinct mechanisms of life span extension are known: a mechanism involving genes that regulate dauer formation (age-1, daf-2, daf-16, and daf-28) and a mechanism involving genes that affect the rate of development and behavior (clk-1, clk-2, clk-3, and gro-1). We find that the long life of eat-2 mutants does not require the activity of DAF-16 and that eat-2; daf-2 double mutants live even longer than extremely long-lived daf-2 mutants. These findings demonstrate that food restriction lengthens life span by a mechanism distinct from that of dauer-formation mutants. In contrast, we find that food restriction does not further increase the life span of long-lived clk-1 mutants, suggesting that clk-1 and caloric restriction affect similar processes.
TL;DR: In children with severe osteogenesis imperfecta, cyclic administration of intravenous pamidronate improved clinical outcomes, reduced bone resorption, and increased bone density.
Abstract: Background Severe osteogenesis imperfecta is a disorder characterized by osteopenia, frequent fractures, progressive deformity, loss of mobility, and chronic bone pain. There is no effective therapy for the disorder. We assessed the effects of treatment with a bisphosphonate on bone resorption. Methods In an uncontrolled observational study involving 30 children who were 3 to 16 years old and had severe osteogenesis imperfecta, we administered pamidronate intravenously (mean [±SD] dose, 6.8±1.1 mg per kilogram of body weight per year) at 4-to-6-month intervals for 1.3 to 5.0 years. Clinical status, biochemical characteristics reflecting bone turnover, the bone mineral density of the lumbar spine, and radiologic changes were assessed regularly during treatment. Results Administration of pamidronate resulted in sustained reductions in serum alkaline phosphatase concentrations and in the urinary excretion of calcium and type I collagen N-telopeptide. There was a mean annualized increase of 41.9±29.0 percent ...
TL;DR: Interestingly, virus infection resulted in the association of IRF-3 with the CREB binding protein (CBP) coactivator, as detected by coimmunoprecipitation with anti-CBP antibody, an interaction mediated by the C-terminal domains of both proteins.
Abstract: The interferon regulatory factors (IRF) consist of a growing family of related transcription proteins first identified as regulators of the alpha beta interferon (IFN-alpha/beta) gene promoters, as well as the interferon-stimulated response element (ISRE) of some IFN-stimulated genes. IRF-3 was originally identified as a member of the IRF family based on homology with other IRF family members and on binding to the ISRE of the ISG15 promoter. IRF-3 is expressed constitutively in a variety of tissues, and the relative levels of IRF-3 mRNA do not change in virus-infected or IFN-treated cells. In the present study, we demonstrate that following Sendai virus infection, IRF-3 is posttranslationally modified by protein phosphorylation at multiple serine and threonine residues, which are located in the carboxy terminus of IRF-3. A combination of IRF-3 deletion and point mutations localized the inducible phosphorylation sites to the region -ISNSHPLSLTSDQ- between amino acids 395 and 407; point mutation of residues Ser-396 and Ser-398 eliminated virus-induced phosphorylation of IRF-3 protein, although residues Ser-402, Thr-404, and Ser-405 were also targets. Phosphorylation results in the cytoplasm-to-nucleus translocation of IRF-3, DNA binding, and increased transcriptional activation. Substitution of the Ser-Thr sites with the phosphomimetic Asp generated a constitutively active form of IRF-3 that functioned as a very strong activator of promoters containing PRDI-PRDIII or ISRE regulatory elements. Phosphorylation also appears to represent a signal for virus-mediated degradation, since the virus-induced turnover of IRF-3 was prevented by mutation of the IRF-3 Ser-Thr cluster or by proteasome inhibitors. Interestingly, virus infection resulted in the association of IRF-3 with the CREB binding protein (CBP) coactivator, as detected by coimmunoprecipitation with anti-CBP antibody, an interaction mediated by the C-terminal domains of both proteins. Mutation of residues Ser-396 and Ser-398 in IRF-3 abrogated its binding to CBP. These results are discussed in terms of a model in which virus-inducible, C-terminal phosphorylation of IRF-3 alters protein conformation to permit nuclear translocation, association with transcriptional partners, and primary activation of IFN- and IFN-responsive genes.
Journal Article•
TL;DR: A new algorithm to correct for PVEs by characterizing the geometric interaction between the PET system and the brain activity distribution, which allows the correction for Pves simultaneously in all identified brain regions, independent of tracer levels.
Abstract: The accuracy of PET for measuring regional radiotracer concentra tions in the human brain is limited by the finite resolution capability of the scanner and the resulting partial volume effects (PVEs). We designed a new algorithm to correct for PVEs by characterizing the geometric interaction between the PETsystem and the brain activity distribution. Methods: The partial volume correction (PVC) algo rithm uses high-resolution volumetric MR Âimages correlated with the PET volume. We used a PET simulator to calculate recovery and cross-contamination factors of identified tissue components in the brain model. These geometry-dependent transfer coefficients form a matrix representing the fraction of true activity from each distinct brain region observed in any given set of regions of interest. This matrix can be inverted to correct for PVEs,independent of the tracer concentrations in each tissue component. A sphere phantom was used to validate the simulated point-spread function of the PET scanner. Accuracy and precision of the PVC method were assessed using a human basal ganglia phantom. A constant contrast experi ment was performed to explore the recovery capability and statistic error propagation of PVC in various noise conditions. In addition, a dual-isotope experiment was used to evaluate the ability of the PVC algorithm to recover activity concentrations in small structures surrounded by background activity with a different radioactive half-life. This models the time-variable contrast between regions that is often seen in neuroreceptor studies. Results: Data from the three-dimensional brain phantom demonstrated a full recovery ca pability of PVC with less than 10% root mean-square error in terms of absolute values, which decreased to less than 2% when results from four PET slices were averaged. Inaccuracy in the estimation of 18Ftracer half-life in the presence of11C background activity was in the range of 25%-50% before PVC and 0%-6% after PVC, for resolution varying from 6 to 14 mm FWHM. In terms of noise propagation, the degradation of the coefficient of variation after PVC was found to be easily predictable and typically on the order of 25%. Conclusion: The PVC algorithm allows the correction for PVEs simultaneously in all identified brain regions, independent of tracer levels.
TL;DR: It is demonstrated that the PI 3-kinase-Akt signaling pathway, in concert with FRAP/mTOR, induces the phosphorylation of 4E-BP1.
Abstract: Growth factors and hormones activate protein translation by phosphorylation and inactivation of the translational repressors, the eIF4E-binding proteins (4E-BPs), through a wortmannin- and rapamycin-sensitive signaling pathway. The mechanism by which signals emanating from extracellular signals lead to phosphorylation of 4E-BPs is not well understood. Here we demonstrate that the activity of the serine/threonine kinase Akt/PKB is required in a signaling cascade that leads to phosphorylation and inactivation of 4E-BP1. PI 3-kinase elicits the phosphorylation of 4E-BP1 in a wortmannin- and rapamycin-sensitive manner, whereas activated Akt-mediated phosphorylation of 4E-BP1 is wortmannin resistant but rapamycin sensitive. A dominant negative mutant of Akt blocks insulin-mediated phosphorylation of 4E-BP1, indicating that Akt is required for the in vivo phosphorylation of 4E-BP1. Importantly, an activated Akt induces phosphorylation of 4E-BP1 on the same sites that are phosphorylated upon serum stimulation. Similar to what has been observed with serum and growth factors, phosphorylation of 4E-BP1 by Akt inhibits the interaction between 4E-BP1 and eIF-4E. Furthermore, phosphorylation of 4E-BP1 by Akt requires the activity of FRAP/mTOR. FRAP/mTOR may lie downstream of Akt in this signaling cascade. These results demonstrate that the PI 3-kinase-Akt signaling pathway, in concert with FRAP/mTOR, induces the phosphorylation of 4E-BP1.
TL;DR: The most difficult items to translate were physical functioning items, which used examples of activities and distances that are not common outside of the United States; items that used colloquial expressions such as pep or blue; and the social functioning items.
TL;DR: A 3-Mb P1-derived artificial chromosome contig spanning the MM candidate region clarified the order of genetic markers across the MM locus, provided five new polymorphic markers within it and narrowed the locus to approximately 2 Mb.
Abstract: Miyoshi myopathy (MM) is an adult onset, recessive inherited distal muscular dystrophy that we have mapped to human chromosome 2p13. We recently constructed a 3-Mb P1-derived artificial chromosome (PAC) contig spanning the MM candidate region. This clarified the order of genetic markers across the MM locus, provided five new polymorphic markers within it and narrowed the locus to approximately 2 Mb. Five skeletal muscle expressed sequence tags (ESTs) map in this region. We report that one of these is located in a novel, full-length 6.9-kb muscle cDNA, and we designate the corresponding protein 'dysferlin'. We describe nine mutations in the dysferlin gene in nine families; five are predicted to prevent dysferlin expression. Identical mutations in the dysferlin gene can produce more than one myopathy phenotype (MM, limb girdle dystrophy, distal myopathy with anterior tibial onset).
TL;DR: In this article, a review of recent findings on the MAP kinase signalling pathway that leads to phosphorylation of eIF4E and on pathways that regulate repression of eif4E function is presented.
TL;DR: This paper investigated the relationship among error types, feedback types, and immediate learner repair in 4 French immersion classrooms at the elementary level, and found that the negotiation of form proved more effective at leading to immediate repair than did recasts or explicit correction, particularly for lexical and grammatical errors.
Abstract: This article presents a study of the relationships among error types, feedback types, and immediate learner repair in 4 French immersion classrooms at the elementary level. The database is drawn from transcripts of audio-recordings of 13 French language arts lessons and 14 subject-matter lessons totaling 18.3 hours and including 921 error sequences. Wecoded the 921 learner errors initiating each sequence as grammatical, lexical, or phonological, or as unsolicited uses of L1 (English) and corrective feedback moves as negotiation of form (i.e., elicitation, metalinguistic clues, clarification requests, or repetition of error), recasts, or explicit correction. Findings indicate that lexical errors favoured the negotiation of form; grammatical and phonological errors invited recasts, but with differential effects in terms of learner repair. Overall, the negotiation of form proved more effective at leading to immediate repair than did recasts or explicit correction, particularly for lexical and grammatical errors, but not for phonological errors. Phonological repairs resulted primarily from recasts.
TL;DR: Pathological expansions of the polyalanine tract may cause mutated PABP2 oligomers to accumulate as filament inclusions in nuclei to cause autosomal recessive OPMD.
Abstract: Autosomal dominant oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disease with a world-wide distribution. It usually presents in the sixth decade with progressive swallowing difficulties (dysphagia), eyelid drooping (ptosis) and proximal limb weakness. Unique nuclear filament inclusions in skeletal muscle fibres are its pathological hallmark. We isolated the poly(A) binding protein 2 gene (PABP2) from a 217-kb candidate interval on chromosome 14q11 (B.B. et al., manuscript submitted). A (GCG)6 repeat encoding a polyalanine tract located at the N terminus of the protein was expanded to (GCG)8-13 in the 144 OPMD families screened. More severe phenotypes were observed in compound heterozygotes for the (GCG)9 mutation and a (GCG)7 allele that is found in 2% of the population, whereas homozygosity for the (GCG)7 allele leads to autosomal recessive OPMD. Thus the (GCG)7 allele is an example of a polymorphism which can act either as a modifier of a dominant phenotype or as a recessive mutation. Pathological expansions of the polyalanine tract may cause mutated PABP2 oligomers to accumulate as filament inclusions in nuclei.
TL;DR: In this article, the authors develop a general framework to study the relationship between the structure of these neighbourhoods and the process of social learning, and identify a property of neighbourhood structures-local independence which greatly facilitates social learning.
Abstract: When payoffs from different actions are unknown, agents use their own past experience as well as the experience of their neighbours to guide their decision making. In this paper, we develop a general framework to study the relationship between the structure of these neighbourhoods and the process of social learning. We show that, in a connected society, local learning ensures that all agents obtain the same payoffs in the long run. Thus, if actions have different payoffs, then all agents choose the same action, and social conformism obtains. We develop conditions on the distribution of prior beliefs, the structure of neighbourhoods and the informativeness of actions under which this action is optimal. In particular, we identify a property of neighbourhood structures-local independencewhich greatly facilitates social learning. Simulations of the model generate spatial and temporal patterns of adoption that are consistent with empirical work.
TL;DR: In this article, the authors examined aspects of communicative classroom discourse that may affect the potential of recasts to be noticed as negative evidence by young learners, and found that teachers frequently use positive feedback to express approval of the content of learners' messages, irrespective of their well-formedness, to accompany recasts, non-corrective repetition, and even topic-continuation moves following errors.
Abstract: This study examines aspects of communicative classroom
discourse that may affect the potential of recasts to be noticed as negative evidence by young
second language learners. The database comprises transcripts of over 18 hours of interaction
recorded during 27 lessons in 4 immersion classrooms at the primary level. The 377 recasts in
the database have been classified according to their pragmatic functions in classroom
discourse and then compared to the teachers' even more frequent use of noncorrective
repetition. Findings reveal that recasts and noncorrective repetition fulfill identical functions
distributed in equal proportions and, furthermore, that teachers frequently use positive
feedback to express approval of the content of learners' messages, irrespective of
well-formedness, to accompany, also in equal proportions, recasts, noncorrective repetition,
and even topic-continuation moves following errors. The findings suggest that, from the
perspective of both learners and teachers, the corrective reformulations entailed in recasts
may easily be overridden by their functional properties in meaning-oriented classrooms.
TL;DR: The results suggest that regulated targeting of BAX to mitochondria in response to a death signal is mediated by discrete domains within the BAX polypeptide.
Abstract: The proapoptotic protein BAX contains a single predicted transmembrane domain at its COOH terminus. In unstimulated cells, BAX is located in the cytosol and in peripheral association with intracellular membranes including mitochondria, but inserts into mitochondrial membranes after a death signal. This failure to insert into mitochondrial membrane in the absence of a death signal correlates with repression of the transmembrane signal-anchor function of BAX by the NH2-terminal domain. Targeting can be instated by deleting the domain or by replacing the BAX transmembrane segment with that of BCL-2. In stimulated cells, the contribution of the NH2 terminus of BAX correlates with further exposure of this domain after membrane insertion of the protein. The peptidyl caspase inhibitor zVAD-fmk partly blocks the stimulated mitochondrial membrane insertion of BAX in vivo, which is consistent with the ability of apoptotic cell extracts to support mitochondrial targeting of BAX in vitro, dependent on activation of caspase(s). Taken together, our results suggest that regulated targeting of BAX to mitochondria in response to a death signal is mediated by discrete domains within the BAX polypeptide. The contribution of one or more caspases may reflect an initiation and/or amplification of this regulated targeting.
TL;DR: This review focuses on the process of enamel maturation, a series of events associated with slow, progressive growth in the width and thickness of apatitic crystals that causes gradual physical hardening and transformation of soft, newly formed enamel into one of the most durable mineralized tissues produced biologically.
Abstract: This review focuses on the process of enamel maturation, a series of events associated with slow, progressive growth in the width and thickness of apatitic crystals. This developmental step causes gradual physical hardening and transformation of soft, newly formed enamel into one of the most durable mineralized tissues produced biologically. Enamel is the secretory product of specialized epithelial cells, the ameloblasts, which make this covering on the crowns of teeth in two steps. First, they roughly "map out" the location and limits (overall thickness) of the entire extracellular layer as a protein-rich, acellular, and avascular matrix filled with thin, ribbon-like crystals of carbonated hydroxyapatite. These initial crystals are organized spatially into rod and interrod territories as they form, and rod crystals are lengthened by Tomes' processes in tandem with appositional movement of ameloblasts away from the dentin surface. Once the full thickness of enamel has been formed, ameloblasts initiate a series of repetitive morphological changes at the enamel surface in which tight junctions and deep membrane infoldings periodically appear (ruffle-ended), then disappear for short intervals (smooth-ended), from the apical ends of the cells. As this happens, the enamel covered by these cells changes rhythmically in net pH from mildly acidic (ruffle-ended) to near-physiologic (smooth-ended) as mineral crystals slowly expand into the "spaces" (volume) formerly occupied by matrix proteins and water. Matrix proteins are processed and degraded by proteinases throughout amelogenesis, but they undergo more rapid destruction once ameloblast modulation begins. Ruffle-ended ameloblasts appear to function primarily as a regulatory and transport epithelium for controlling the movement of calcium and other ions such as bicarbonate into enamel to maintain buffering capacity and driving forces optimized for surface crystal growth. The reason ruffle-ended ameloblasts become smooth-ended periodically is unknown, although this event seems to be crucial for sustaining long-term crystal growth.
TL;DR: Major sources of differences in somatization among ethnocultural groups include styles of expressing distress, the ethnomedical belief systems in which these styles are rooted, and each group's relative familiarity with the health care system and pathways to care.
Abstract: Objectives The cross-cultural prevalence of somatization and the limitations of current nosology and psychiatric theory for interpreting cultural variations in somatization are reviewed. Method Selective review was conducted of recent research literature and research findings from an epidemiological survey and ethnographic study of help-seeking and health care utilization of a random sample of 2246 residents in a Canadian urban multicultural milieu. Results Somatization is common in all ethnocultural groups and societies studied to date. However, significant differences in somatization across ethnocultural groups persist even where there is relatively equitable access to health care services. Analysis of illness narratives collected from diverse ethnocultural groups suggests that somatic symptoms are located in multiple systems of meaning that serve diverse psychological and social functions. Depending on circumstances, these symptoms can be seen as an index of disease or disorder, an indication of psychopathology, a symbolic condensation of intrapsychic conflict, a culturally coded expression of distress, a medium for expressing social discontent, and a mechanism through which patients attempt to reposition themselves within their local worlds. Conclusion Major sources of differences in somatization among ethnocultural groups include styles of expressing distress ("idioms of distress"), the ethnomedical belief systems in which these styles are rooted, and each group's relative familiarity with the health care system and pathways to care. Psychological theories of somatization focused on individual characteristics must be expanded to recognize the fundamental social meanings of bodily distress.
TL;DR: In this article, the authors examined the AdS-CFT correspondence when gauge theory is considered on a compactified space with supersymmetry-breaking boundary conditions and found that the corresponding supergravity solution has a negative energy, in agreement with the expected negative Casimir energy in the field theory.
Abstract: We examine the AdS-CFT correspondence when gauge theory is considered on a compactified space with supersymmetry-breaking boundary conditions. We find that the corresponding supergravity solution has a negative energy, in agreement with the expected negative Casimir energy in the field theory. The stability of the gauge theory would imply that this supergravity solution has minimum energy among all solutions with the same boundary conditions. Hence we are led to conjecture a new positive energy theorem for asymptotically locally anti--de Sitter spacetimes. We show that the candidate minimum energy solution is stable against all quadratic fluctuations of the metric.
TL;DR: Lesbian, gay, and bisexual youngsters, aged 14-21 and living at home, were studied for patterns of disclosure of sexual orientation to families and reported verbal and physical abuse by family members and acknowledged more suicidality than those who had not "come out" to their families.
Abstract: Lesbian, gay, and bisexual youngsters, aged 14-21 and living at home, were studied for patterns of disclosure of sexual orientation to families. Three-quarters had told at least one parent, more often the mother than the father. Those who had disclosed were generally more open about their sexual orientation than those who had not, and few of the nondisclosed expected parental acceptance. Those who had disclosed reported verbal and physical abuse by family members, and acknowledged more suicidality than those who had not "come out" to their families. Language: en
TL;DR: In this paper, the authors developed a series of structured tasks to objectively measure laparoscopic skills and used a linear regression model to test for the effects of level of training and practice on performance.
Abstract: Background: Interest in the training and evaluation of laparoscopic skills is extending beyond the realm of the operating room to the use of laparoscopic simulators. The purpose of this study was to develop a series of structured tasks to objectively measure laparoscopic skills. This model was then used to test for the effects of level of training and practice on performance. Methods: Forty-two subjects (6 each of surgical residents PGY1 to PGY5, 6 surgeons who practice laparoscopy and 6 who do not) were evaluated. Each subject viewed a 20-minute introductory video, then was tested performing 7 laparoscopic tasks (peg transfers, pattern cutting, clip and divide, endolooping, mesh placement and fixation, suturing with intracorporeal or extracorporeal knots). Performance was measured using a scoring system rewarding precision and speed. Each candidate repeated all 7 tasks and was rescored. Data were analyzed by linear regression to assess the relationship of performance with level of residency training for each task, and by ANOVA with repeated measures to test for effects of level of training, of repetition, and of the interaction between level of training and repetition on overall performance. Student's t test was used to evaluate differences between laparoscopic and nonlaparoscopic surgeons and between each of these groups and the PGY 5 level of surgical residents. Results: Significant predictors of overall performance were (a) level of training ( P = 0.002), (b) repetition ( P P = 0.001). There was also a significant interaction between level of training and the specific task on performance scores ( P = 0.006). When each task was evaluated individually for the 30 residents, 4 of the 7 tasks (tasks 1, 2, 6, 7) showed significant correlation between PGY level and score. A significant difference in performance scores between laparoscopic and nonlaparoscopic surgeons was seen for tasks 1, 2, and 6. Conclusions: A model was developed to evaluate laparoscopic skills. Construct validity was demonstrated by measuring significant improvement in performance with increasing residency training, and with practice. Further validation will require correlation of performance in the model with skill in vivo.
TL;DR: Analysis of a candidate gene (SURF1) of unknown function revealed several mutations that suggest a role for SURF1 in the biogenesis of the COX complex and define a new class of gene defects causing human neurodegenerative disease.
Abstract: Leigh Syndrome (LS) is a severe neurological disorder characterized by bilaterally symmetrical necrotic lesions in subcortical brain regions that is commonly associated with systemic cytochrome c oxidase (COX) deficiency. COX deficiency is an autosomal recessive trait and most patients belong to a single genetic complementation group. DNA sequence analysis of the genes encoding the structural subunits of the COX complex has failed to identify a pathogenic mutation. Using microcell-mediated chromosome transfer, we mapped the gene defect in this disorder to chromosome 9q34 by complementation of the respiratory chain deficiency in patient fibroblasts. Analysis of a candidate gene (SURF1) of unknown function revealed several mutations, all of which predict a truncated protein. These data suggest a role for SURF1 in the biogenesis of the COX complex and define a new class of gene defects causing human neurodegenerative disease.