Showing papers by "McGill University published in 1997"

Maternal Care, Hippocampal Glucocorticoid Receptors, and Hypothalamic-Pituitary-Adrenal Responses to Stress

Abstract: Variations in maternal care affect the development of individual differences in neuroendocrine responses to stress in rats. As adults, the offspring of mothers that exhibited more licking and grooming of pups during the first 10 days of life showed reduced plasma adrenocorticotropic hormone and corticosterone responses to acute stress, increased hippocampal glucocorticoid receptor messenger RNA expression, enhanced glucocorticoid feedback sensitivity, and decreased levels of hypothalamic corticotropin-releasing hormone messenger RNA. Each measure was significantly correlated with the frequency of maternal licking and grooming (all r 9s > −0.6). These findings suggest that maternal behavior serves to “program” hypothalamic-pituitary-adrenal responses to stress in the offspring.

To See or not to See: The Need for Attention to Perceive Changes in Scenes

Abstract: When looking at a scene, observers feel that they see its entire structure in great detail and can immediately notice any changes in it However, when brief blank fields are placed between alternating displays of an original and a modified scene, a striking failure of perception is induced Identification of changes becomes extremely difficult, even when changes are large and made repeatedly Identification is much faster when a verbal cue is provided showing that poor visibility is not the cause of this difficulty Identification is also faster for objects considered to be important in the scene These results support the idea that observers never form a complete, detailed representation of their surroundings In addition, the results indicate that attention is required to perceive change, and that in the absence of localized motion signals attention is guided on the basis of high-level interest

Corrective feedback and learner uptake

Abstract: This article presents a study of corrective feedback and learner uptake (i.e., responses to feedback) in four immersion classrooms at the primary level. Transcripts totaling 18.3 hours of classroom interaction taken from 14 subject-matter lessons and 13 French language arts lessons were analyzed using a model developed for the study and comprising the various moves in an error treatment sequence. Results include the frequency and distribution of the six different feedback types used by the four teachers, in addition to the frequency and distribution of different types of learner uptake following each feedback type. The findings indicate an overwhelming tendency for teachers to use recasts in spite of the latter's ineffectiveness at eliciting student-generated repair. Four other feedback types—elicitation, metalinguistic feedback, clarification requests, and repetition—lead to student-generated repair more successfully and are thus able to initiate what the authors characterize as the negotiation of form.

Current issues in recrystallization: a review

Abstract: The current understanding of the fundamentals of recrystallization is summarized. This includes understanding the as-deformed state. Several aspects of recrystallization are described: nucleation and growth, the development of misorientation during deformation, continuous, dynamic, and geometric dynamic recrystallization, particle effects, and texture. This article is authored by the leading experts in these areas. The subjects are discussed individually and recommendations for further study are listed in the final section.

Specialized membrane domains for water transport in glial cells : high-resolution immunogold cytochemistry of aquaporin-4 in rat brain

Abstract: Membrane water transport is critically involved in brain volume homeostasis and in the pathogenesis of brain edema. The cDNA encoding aquaporin-4 (AQP4) water channel protein was recently isolated from rat brain. We used immunocytochemistry and high-resolution immunogold electron microscopy to identify the cells and membrane domains that mediate water flux through AQP4. The AQP4 protein is abundant in glial cells bordering the subarachnoidal space, ventricles, and blood vessels. AQP4 is also abundant in osmosensory areas, including the supraoptic nucleus and subfornical organ. Immunogold analysis demonstrated that AQP4 is restricted to glial membranes and to subpopulations of ependymal cells. AQP4 is particularly strongly expressed in glial membranes that are in direct contact with capillaries and pia. The highly polarized AQP4 expression indicates that these cells are equipped with specific membrane domains that are specialized for water transport, thereby mediating the flow of water between glial cells and the cavities filled with CSF and the intravascular space.

Enhanced cleavage of type II collagen by collagenases in osteoarthritic articular cartilage.

Abstract: We demonstrate the direct involvement of increased collagenase activity in the cleavage of type II collagen in osteoarthritic human femoral condylar cartilage by developing and using antibodies reactive to carboxy-terminal (COL2-3/4C(short)) and amino-terminal (COL2-1/4N1) neoepitopes generated by cleavage of native human type II collagen by collagenase matrix metalloproteinase (MMP)-1 (collagenase-1), MMP-8 (collagenase-2), and MMP-13 (collagenase-3). A secondary cleavage followed the initial cleavage produced by these recombinant collagenases. This generated neoepitope COL2-1/4N2. There was significantly more COL2-3/4C(short) neoepitope in osteoarthritis (OA) compared to adult nonarthritic cartilages as determined by immunoassay of cartilage extracts. A synthetic preferential inhibitor of MMP-13 significantly reduced the unstimulated release in culture of neoepitope COL2-3/4C(short) from human osteoarthritic cartilage explants. These data suggest that collagenase(s) produced by chondrocytes is (are) involved in the cleavage and denaturation of type II collagen in articular cartilage, that this is increased in OA, and that MMP-13 may play a significant role in this process.

Assessing the predictive validity of two methods of measuring self-image congruence

Abstract: The predictive validity of two measurement methods of self-image congruence—traditional versus new—were compared in six studies involving different consumer populations, products, consumption settings, and dependent variables (brand preference, preference for product form, consumer satisfaction/dissatisfaction, brand attitude, and program choice). The traditional method is based on tapping the subject’s perception of product-user image and the subject’s perception of his/her self-image along a predetermined set of image attributes and adding the self-congruity scores across all image dimensions. Three problems were identified and discussed in relation to the traditional method: (1) the use of discrepancy scores, (2) the possible use of irrelevant images, and (3) the use of the compensatory decision rule. The new method is based on tapping the psychological experience of self-congruity directly and globally. The findings demonstrated the predictive validity of the new method over and beyond the traditional method.

Cloning, chromosomal localization, and functional analysis of the murine estrogen receptor β

Abstract: Estrogen receptor β (ERβ) is a novel steroid receptor that is expressed in rat prostate and ovary We have cloned the mouse homolog of ERβ and mapped the gene, designated Estrb, to the central region of chromosome 12 The cDNA encodes a protein of 485 amino acids that shares, respectively, 97% and 60% identity with the DNA- and ligand-binding domains of mouse (m) ERα Mouse ERβ binds to an inverted repeat spaced by three nucleotides in a gel mobility shift assay and transactivates promoters containing synthetic or natural estrogen response elements in an estradiol (E2)-dependent manner Scatchard analysis indicates that mERβ has slightly lower affinity for E2 [dissociation constant (Kd) = 05 nm] when compared with mERα (Kd = 02 nm) Antiestrogens, including 4-hydroxytamoxifen (OHT), ICI 182,780, and a novel compound, EM-800, inhibit E2-dependent transactivation efficiently However, while OHT displays partial agonistic activity with ERα on a basal promoter linked to estrogen response elements in Cos-1 c

Regulation of Mitochondrial Iron Accumulation by Yfh1p, a Putative Homolog of Frataxin

Abstract: The gene responsible for Friedreich's ataxia, a disease characterized by neurodegeneration and cardiomyopathy, has recently been cloned and its product designated frataxin. A gene in Saccharomyces cerevisiae was characterized whose predicted protein product has high sequence similarity to the human frataxin protein. The yeast gene (yeast frataxin homolog, YFH1) encodes a mitochondrial protein involved in iron homeostasis and respiratory function. Human frataxin also was shown to be a mitochondrial protein. Characterizing the mechanism by which YFH1 regulates iron homeostasis in yeast may help to define the pathologic process leading to cell damage in Friedreich's ataxia.

Differences between males and females in rates of serotonin synthesis in human brain.

Abstract: Rates of serotonin synthesis were measured in the human brain using positron emission tomography. The sensitivity of the method is indicated by the fact that measurements are possible even after a substantial lowering of synthesis induced by acute tryptophan depletion. Unlike serotonin levels in human brain, which vary greatly in different brain areas, rates of synthesis of the indolamine are rather uniform throughout the brain. The mean rate of synthesis in normal males was found to be 52% higher than in normal females; this marked difference may be a factor relevant to the lower incidence of major unipolar depression in males.

Automated labeling of the human brain: A preliminary report on the development and evaluation of a forward-transform method

Abstract: A forward-transform method for retrieving brain labels from the 1988 Talairach Atlas using x-y-z coordinates is presented. A hierarchical volume-occupancy labeling scheme was created to simplify the organization of atlas labels using volume and subvolumetric components. Segmentation rules were developed to define boundaries that were not given explicitly in the atlas. The labeling scheme and segmentation rules guided the segmentation and labeling of 160 contiguous regions within the atlas. A unique three-dimensional (3-D) database label server called the Talairach Daemon (http://ric.uthscsa.edu/projects) was developed for serving labels keyed to the Talairach coordinate system. Given an x-y-z Talairach coordinate, a corresponding hierarchical listing of labels is returned by the server. The accuracy and precision of the forward-transform labeling method is now under evaluation.

Respiration rates in bacteria exceed phytoplankton production in unproductive aquatic systems

Abstract: PLANKTONIC bacteria are a fundamental component of the organic carbon cycle in aquatic systems1. Organic carbon consumption by planktonic bacteria is the sum of bacterial production (BP) and bacterial respiration (BR). It is now estimated that 30–60% of phytoplankton production (the amount of inorganic carbon fixed by phytoplankton photosynthesis, corrected for phytoplankton respiration) in marine and freshwater systems is processed by bacteria1–3. These estimates of carbon flow through bacteria are conservative, however, because losses due to bacterial respiration are seldom directly measured4,5. We report here that bacterial respiration is generally high, and tends to exceed phytoplankton net production in unproductive systems (less than 70 to 120 μg carbon per litre per day). A large proportion of the world's aquatic systems have phytoplankton productivities below this value6. Bacterial growth efficiency (BGE) is the result of BP and BR[BGE = BP/(BR + BP)]. Comparisons of our models of bacterial respiration with published models of bacterial secondary production1,7 show that bacterial growth efficiency must range from less than 10% to 25% in most freshwater and marine systems, well below the values commonly assumed in many current ecological models1,2,8,9. The imbalance between bacterial respiration and phytoplankton production suggests that in unproductive aquatic systems, the biological system is a net source of CO2.

Solubility control of Cu, Zn, Cd and Pb in contaminated soils

Abstract: We developed a semiempirical equation from metal complexation theory which relates the metal activity of soil solutions to the soil's pH, organic matter content (OM) and total metal content (M T ). The equation has the general form: pM = a + bpH - c log(M T OM -1 ), where pM is the negative logarithm (to base 10) of the metal activity, and a, b and c are constants. The equation successfully predicted free Cu 2+ activity in soils with a wide range of properties, including soils previously treated with sewage sludge. The significant correlation of pCu to these measured soil properties in long-contaminated soils suggests that copper activity is controlled by adsorption on organic matter under steady state conditions. An attempt was made from separate published data to correlate total soluble Cu, Zn, Cd and Pb in soils to soil pH, organic matter content and total metal content. For Cu, the total Cu content of the soil was most highly correlated with total soluble Cu Similarly, total soluble Zn and Cd were correlated with total metal content, but were more strongly related to soil pH than was soluble Cu. Smaller metal solubility in response to higher soil pH was most marked for Zn and Cd, metals that tend not to complex strongly with soluble organics. The organic matter content was often, but not always, a statistically significant variable in predicting metal solubility from soil properties. The solubility of Pb was less satisfactorily predicted from measured soil properties than solubility of the other metals. It seems that for Cu at least, solid organic matter limits free metal activity, whilst dissolved organic matter promotes metal solubility, in soils well-aged with respect to the metal pollutant. Although total metal content alone is not generally a good predictor of metal solubility or activity, it assumes great importance when comparing metal solubility in soils having similar pH and organic matter content.

Frataxin is Reduced in Friedreich Ataxia Patients and is Associated with Mitochondrial Membranes

Abstract: Friedreich ataxia is a progressive neurodegenerative disorder caused by loss of function mutations in the frataxin gene. In order to unravel frataxin function we developed monoclonal antibodies raised against different regions of the protein. These antibodies detect a processed 18 kDa protein in various human and mouse tissues and cell lines that is severely reduced in Friedreich ataxia patients. By immunocytofluorescence and immunocytoelectron microscopy we show that frataxin is located in mitochondria, associated with the mitochondrial membranes and crests. Analysis of cellular localization of various truncated forms of frataxin expressed in cultured cells and evidence of removal of an N-terminal epitope during protein maturation demonstrated that the mitochondrial targetting sequence is encoded by the first 20 amino acids. Given the shared clinical features between Friedreich ataxia, vitamin E deficiency and some mitochondriopathies, our data suggest that a reduction in frataxin results in oxidative damage.

The cardiac transcription factors Nkx2-5 and GATA-4 are mutual cofactors

Abstract: The tissue-restricted GATA-4 transcription factor and Nkx2-5 homeodomain protein are two early markers of precardiac cells. Both are essential for heart formation, but neither can initiate cardiogenesis. Overexpression of GATA-4 or Nkx2-5 enhances cardiac development in committed precursors, suggesting each interacts with a cardiac cofactor. We tested whether GATA-4 and Nkx2-5 are cofactors for each other by using transcription and binding assays with the cardiac atrial natriuretic factor (ANF) promoter_the only known target for Nkx2-5. Co-expression of GATA-4 and Nkx2-5 resulted in synergistic activation of the ANF promoter in heterologous cells. The synergy involves physical Nkx2-5-GATA-4 interaction, seen in vitro and in vivo, which maps to the C-terminal zinc finger of GATA-4 and a C-terminus extension; similarly, a C-terminally extended homeodomain of Nkx2-5 is required for GATA-4 binding. Structure/function studies suggest that binding of GATA-4 to the C-terminus autorepressive domain of Nkx2-5 may induce a conformational change that unmasks Nkx2-5 activation domains. GATA-6 cannot substitute for GATA-4 for interaction with Nkx2-5. This interaction may impart functional specificity to GATA factors and provide cooperative crosstalk between two pathways critical for early cardiogenesis. Given the co-expression of GATA proteins and NK2 class members in other tissues, the GATA/Nkx partnership may represent a paradigm for transcription factor interaction during organogenesis.

Eosinophil-associated TGF-beta1 mRNA expression and airways fibrosis in bronchial asthma.

Abstract: The histopathology of bronchial asthma is associated with structural changes within the airways, including subepithelial fibrosis, as well as chronic eosinophilic inflammation. The mechanisms responsible for this tissue remodeling, and in particular the role of inflammatory cells, remain to be established. Transforming growth factor-β (TGF-β) is a potent profibrotic cytokine which may contribute to the thickening of the reticular lamina by the deposition of collagen fibers. To investigate the molecular mechanisms underlying these structural changes, we have investigated the expression of TGF-β1 mRNA and immunoreactivity within the bronchial mucosa of mild to severe asthmatic individuals and normal control subjects using the techniques of in situ hybridization and immunocytochemistry. As eosinophils are prominent within the asthmatic airway and are known to synthesize pro-inflammatory cytokines, the presence of TGF-β1 mRNA and immunoreactive protein in eosinophils was also examined. Asthmatic individuals e...

Regulation of apoptosis by viral gene products.

Abstract: Apoptosis is the process whereby individual cells of multicellular organisms undergo systematic self-destruction in response to a wide variety of stimuli. Apoptosis is a genetically controlled preprogrammed event which eliminates cells during development when they have become redundant or which functions as an emergency response after radiation damage, viral infection, or aberrant growth induced by the activation of oncogenes. In the case of virus-infected cells, the induction of early cell death would severely limit virus production and reduce or eliminate spread of progeny virus in the host. Thus, most animal viruses have evolved strategies to evade or delay early apoptosis to allow production of high yields of progeny virus. Over the past few years both the biochemical basis of apoptosis and its regulation by viral products have become clearer. For example, part of the apoptotic program includes the induction of cellular endonucleases which could target replicating viral DNA and prevent virus production at a very early stage. Thus, the problem facing the virus is to replicate and package large numbers of progeny genomes safely within newly synthesized viral capsids. Many viruses have evolved genes encoding proteins which effectively suppress or delay apoptosis long enough for the production of sufficient quantities of progeny. In addition, a growing number of viruses are now known to induce apoptosis actively at late stages of infection. This process may represent a final and important step in the spread of progeny to neighboring cells while also evading host immune inflammatory responses and protecting progeny virus from host enzymes and antibodies. Such virally induced apoptosis may also contribute to some clinical manifestations and cytotoxicity associated with several human diseases of viral origin. The purpose of this review is to summarize recent information on the induction and suppression of apoptosis by viral products as well as to propose how this knowledge may provide insights into basic cell biology and offer the potential of new therapeutic applications. A recent comprehensive review by Shen and Shenk (75) also deals with some aspects of the subjects covered below.

The Nature of Selection on the Major Histocompatibility Complex

Abstract: Only natural selection can account for the extreme genetic diversity of genes of the major histocompatibility complex (MHC). Although the structure and function of classic MHC genes is well understood at the molecular and cellular levels, there is controversy about how MHC diversity is selectively maintained. The diversifying selection can be driven by pathogen interactions and inbreeding avoidance mechanisms. Pathogen-driven selection can maintain MHC polymorphism based on heterozygote advantage or frequency-dependent selection due to pathogen evasion of MHC-dependent immune recognition. Empirical evidence demonstrates that specific MHC haplotypes are resistant to certain infectious agents, while susceptible to others. These data are consistent with both heterozygote advantage and frequency-dependent models. Additional research is needed to discriminate between these mechanisms. Infectious agents can precipitate autoimmunity and can potentially contribute to MHC diversity through molecular mimicry and by favoring immunodominance. MHC-dependent abortion and mate choice, based on olfaction, can also maintain MHC diversity and probably functions both to avoid genome-wide inbreeding and produce MHC-heterozygous offspring with increased immune responsiveness. Although this diverse set of hypotheses are often treated as competing alternatives, we believe that they all fit into a coherent, internally consistent thesis. It is likely that at least in some species, all of these mechanisms operate, leading to the extreme diversification found in MHC genes.

Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease.

Abstract: Objective: To evaluate the therapeutic effects of selective cholinergic replacement with xanomeline tartrate, an ml and m4 selective muscarinic receptor (mAChR) agonist in patients with probable Alzheimer disease (AD). Design: A 6-month, randomized, double-blind, placebocontrolled, parallel-group trial followed by a 1-month, single-blind, placebo washout. Setting: Outpatients at 17 centers in the United States and Canada. Participants: A total of 343 men and women at least 60 years of age with mild to moderate AD. Interventions: Patients received 75, 150, or 225 mg (low, medium, and high doses) of xanomeline per day or placebo for 6 months. Outcome Measures: Scores on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog), the Clinician's Interview-Based Impression of Change (CIBIC+), the Alzheimer's Disease Symptomatology Scale (ADSS), and the Nurses' Observational Scale for Geriatric Patients (NOSGER). Results: A significant treatment effect existed for ADAS-Cog (high dose vs placebo;P≤.05), and CIBIC+ (high dose vs placebo;P≤.02). Treatment Emergent Signs and Symptoms analysis of the ADSS, which assesses behavioral symptoms in patients with AD, disclosed significant (P≤.002) dose-dependent reductions in vocal Out-bursts, bursts, suspiciousness, delusions, agitation, and hallucinations. On end-point analysis, NOSGER, which assesses memory, instrumental activities of daily living, self-care, mood, social behavior, and disturbing behavior in the elderly, also showed a significant dose-response relationship (P≤.02). In the high-dose arm, 52% of patients discontinued treatment because of adverse events; dose-dependent adverse events were predominantly gastrointestinal in nature. Syncope, defined as loss of consciousness and muscle tone, occurred in 12.6% of patients in the high-dose group. Conclusions: The observed improvements in ADAS-Cog and CIBIC+ following treatment with xanomeline provide the first evidence, from a large-scale, placebo-controlled clinical trial, that a direct-acting muscarinic receptor agonist can improve cognitive function in patients with AD. Furthermore, the dramatic and favorable effects on disturbing behaviors in AD suggest a novel approach for treatment of noncognitive symptoms.