Targeted ablation of the vitamin D receptor: An animal model of vitamin D-dependent rickets type II with alopecia

Vitamin D, the major steroid hormone that controls mineral ion homeostasis, exerts its actions through the vitamin D receptor (VDR). The VDR is expressed in many tissues, including several tissues not thought to play a role in mineral metabolism. Studies in kindreds with VDR mutations (vitamin D-dependent rickets type II, VDDR II) have demonstrated hypocalcemia, hyperparathyroidism, rickets, and osteomalacia. Alopecia, which is not a feature of vitamin D deficiency, is seen in some kindreds. We have generated a mouse model of VDDR II by targeted ablation of the second zinc finger of the VDR DNA-binding domain. Despite known expression of the VDR in fetal life, homozygous mice are phenotypically normal at birth and demonstrate normal survival at least until 6 months. They become hypocalcemic at 21 days of age, at which time their parathyroid hormone (PTH) levels begin to rise. Hyperparathyroidism is accompanied by an increase in the size of the parathyroid gland as well as an increase in PTH mRNA levels. Rickets and osteomalacia are seen by day 35; however, as early as day 15, there is an expansion in the zone of hypertrophic chondrocytes in the growth plate. In contrast to animals made vitamin D deficient by dietary means, and like some patients with VDDR II, these mice develop progressive alopecia from the age of 4 weeks.

Expression of lipocalin-type prostaglandin D synthase (β-trace) in human heart and its accumulation in the coronary circulation of angina patients

Lipocalin-type prostaglandin D synthase (L-PGDS) is localized in the central nervous system and male genital organs of various mammals and is secreted as β-trace into the closed compartment of these tissues separated from the systemic circulation. In this study, we found that the mRNA for the human enzyme was expressed most intensely in the heart among various tissues examined. In human autopsy specimens, the enzyme was localized immunocytochemically in myocardial cells, atrial endocardial cells, and a synthetic phenotype of smooth muscle cells in the arteriosclerotic intima, and accumulated in the atherosclerotic plaque of coronary arteries with severe stenosis. In patients with stable angina (75–99% stenosis), the plasma level of L-PGDS was significantly (P < 0.05) higher in the great cardiac vein (0.694 ± 0.054 μg/ml, n = 7) than in the coronary artery (0.545 ± 0.034 μg/ml), as determined by a sandwich enzyme immunoassay. However, the veno-arterial difference in the plasma L-PGDS concentration was not observed in normal subjects without stenosis. After a percutaneous transluminal coronary angioplasty was performed to compress the stenotic atherosclerotic plaques, the L-PGDS concentration in the cardiac vein decreased significantly (P < 0.05) to 0.610 ± 0.051 μg/ml at 20 min and reached the arterial level within 1 h. These findings suggest that L-PGDS is present in both endocardium and myocardium of normal subjects and the stenotic site of patients with stable angina and is secreted into the coronary circulation.

N-methyl-D-aspartate receptor-induced proteolytic conversion of postsynaptic class C L-type calcium channels in hippocampal neurons.

Ca2+ influx controls multiple neuronal functions including neurotransmitter release, protein phosphorylation, gene expression, and synaptic plasticity. Brain L-type Ca2+ channels, which contain either alpha 1C or alpha 1D as their pore-forming subunits, are an important source of calcium entry into neurons. Alpha 1C exists in long and short forms, which are differentially phosphorylated, and C-terminal truncation of alpha 1C increases its activity approximately 4-fold in heterologous expression systems. Although most L-type calcium channels in brain are localized in the cell body and proximal dendrites, alpha 1C subunits in the hippocampus are also present in clusters along the dendrites of neurons. Examination by electron microscopy shows that these clusters of alpha 1C are localized in the postsynaptic membrane of excitatory synapses, which are known to contain glutamate receptors. Activation of N-methyl-D-aspartate (NMDA)-specific glutamate receptors induced the conversion of the long form of alpha 1C into the short form by proteolytic removal of the C terminus. Other classes of Ca2+ channel alpha1 subunits were unaffected. This proteolytic processing reaction required extracellular calcium and was blocked by inhibitors of the calcium-activated protease calpain, indicating that calcium entry through NMDA receptors activated proteolysis of alpha1C by calpain. Purified calpain catalyzed conversion of the long form of immunopurified alpha 1C to the short form in vitro, consistent with the hypothesis that calpain is responsible for processing of alpha 1C in hippocampal neurons. Our results suggest that NMDA receptor-induced processing of the postsynaptic class C L-type Ca2+ channel may persistently increase Ca2+ influx following intense synaptic activity and may influence Ca2+-dependent processes such as protein phosphorylation, synaptic plasticity, and gene expression.

Rescue of defective mitogenic signaling by D-type cyclins.

Three gene products, including Myc and the D- and E-type G1 cyclins, are rate limiting for G1 progression in mammalian fibroblasts. Quiescent mouse NIH 3T3 fibroblasts engineered to express a mutant colony-stimulating factor (CSF-1) receptor (CSF-1R 809F) fail to synthesize c-myc and cyclin D1 mRNAs upon CSF-1 stimulation and remain arrested in early G1 phase. Ectopic expression of c-myc or either of three D-type cyclin genes, but not cyclin E, resensitized these cells to the mitogenic effects of CSF-1, enabling them to proliferate continuously in liquid culture and to form colonies in agar in response to the growth factor. Rescue by cyclin D1 was enhanced by c-myc but not by cyclin E and was reversed by infecting cyclin D1-reconstituted cells with a retroviral vector encoding catalytically inactive cyclin-dependent kinase 4. Induction of cyclin D1 mRNA by CSF-1 was restored in cells forced to express c-myc, and vice versa, suggesting that expression of the two genes is interdependent. Cells reconstituted with c-myc were prevented from entering S phase when microinjected with a monoclonal antibody to cyclin D1, and conversely, those rescued by cyclin D1 were inhibited from forming CSF-1-dependent colonies when challenged with a dominant-negative c-myc mutant. Cyclin D mutants defective in binding to the retinoblastoma protein were impaired in rescuing mitogenic signaling. Therefore, Myc and D-type cyclins collaborate during the mitogenic response to CSF-1, whereas cyclin E functions in a separate pathway.

Elevated expression of H type GDP-L-fucose:beta-D-galactoside alpha-2-L-fucosyltransferase is associated with human colon adenocarcinoma progression.

GDP-L-fucose:beta-D-galactoside alpha-2-L-fucosyltransferase (EC 2.4.1.69) is a key enzyme in the biosynthesis of fucosylated type 1 and 2 lactoseries structures, such as Lewis b and the H type 2 and Lewis Y, respectively, that are accumulated in colon adenocarcinoma. Analysis of the mRNA transcript level for the human H gene-encoded beta-D-galactoside alpha-2-L-fucosyltransferase revealed 40- and 340-fold increases in the mRNA levels in all adenocarcinomas and tumor cell lines, respectively, compared to normal colon mucosa where a low level of mRNA transcript was detected. A variable increase in mRNA transcript levels was observed in 50% of adenomatous polyps. Nucleotide sequence analysis of the protein coding region of the cDNAs derived from normal colon, adenoma, and colon adenocarcinoma revealed 100% homology, suggesting that there are no tumor-associated allelic variations within the H beta-D-galactoside alpha-2-L-fucosyltransferase cDNA. These results suggest that beta-D-galactoside alpha-2-L-fucosyltransferase expression highly correlates with malignant progression of colon adenocarcinoma.

Le type physique d'Alexandre le Grand d'après les auteurs anciens et les documents iconographiques,

Mode of access: Internet.

Torrey and Alexander, the story of a world-wide revival; a record and study of the work and personality of the evangelists R. A. Torrey, D. D., and Charles M. Alexander,

Mode of access: Internet.

Solutions Globales Régulières pour Quelques Équations Lineaires D'évolution du Type Pseudo-Différentiel Singulier

2000 Mathematics Subject Classification: 35C15, 35D05, 35D10, 35S10, 35S99.

A qualitative analysis of the congruency of Jungian psychological preferences identified by the Myers-Briggs Type Indicator (MBTI) and the human resource development role of instructor/facilitator

The purpose of this ethnographic study was to describe and explain the congruency of psychological preferences identified by the Myers-Briggs Type Indicator (MBTI) and the human resource development (HRD) role of instructor/facilitator. This investigation was conducted with 23 HRD professionals who worked in the Miami, Florida area as instructors/facilitators with adult learners in job-related contexts.^ The study was conducted using qualitative strategies of data collection and analysis. The research participants were selected through a purposive sampling strategy. Data collection strategies included: (a) administration and scoring of the MBTI, Form G, (b) open-ended and semi-structured interviews, (c) participant observations of the research subjects at their respective work sites and while conducting training sessions, (d) field notes, and (e) contact summary sheets to record field research encounters. Data analysis was conducted with the use of a computer program for qualitative analysis called FolioViews 3.1 for Windows. This included: (a) coding of transcribed interviews and field notes, (b) theme analysis, (c) memoing, and (d) cross-case analysis.^ The three major themes that emerged in relation to the congruency of psychological preferences and the role of instructor/facilitator were: (1) designing and preparing instruction/facilitation, (2) conducting training and managing group process, and (3) interpersonal relations and perspectives among instructors/facilitators.^ The first two themes were analyzed through the combination of the four Jungian personality functions. These combinations are: sensing-thinking (ST), sensing-feeling (SF), intuition-thinking (NT), and intuition-feeling (NF). The third theme was analyzed through the combination of the attitudes or energy focus and the judgment function. These combinations are: extraversion-thinking (ET), extraversion-feeling (EF), introversion-thinking (IT), and introversion-feeling (IF).^ A last area uncovered by this ethnographic study was the influence exerted by a training and development culture on the instructor/facilitator role. This professional culture is described and explained in terms of the shared values and expectations reported by the study respondents. ^

Self -management factors, influences, and conditions for type 2 diabetes among Black ethnic groups in Miami, Florida and Abidjan, Cote d'Ivoire

The Dahlgren and Whitehead ecological theory provides the framework for a cross-sectional design to compare socio-demographic characteristics, living and working conditions, and lifestyle daily habits as well as cultural and ecological factors among six diabetic multiethnic Black groups in Miami and Abidjan. Approximately 180 Black Americans (African-, Caribbean-, and Haitian-) and 180 Black Africans (Akan, Malinke, and Krou) aged 20 years and older were surveyed. During the preliminary of this study participants' attitudes and behaviors were qualitatively assessed (N=60) and a tool was developed to describe, in the main study (N=360), differences in participants' strength of commitment to diabetes lifestyle self-management. Despite similarities found in terms of age and gender, statistically significant differences were also found within and among groups in terms of living and working conditions, education level, and religion. African American groups were more likely to participate in more diabetes classes than Haitian Americans and Caribbean Americans. However, African Americans were less likely to adhere to daily dietary and weight control regimens. Although, Black African groups reported limited access to equipment, facilities, and financial support they were more likely to follow dietary and weight control recommendations than Black American groups. Overall, African American participants showed the poorest attitudes towards recommended foods, Caribbean American respondents reported the best attitudes and behaviors towards weight control regimens, and the Malinke group had significantly more strength of commitment to successful weight control. Furthermore, Black African groups had significantly more strength of commitment to successful dietary adherence and significantly less support for weight control than Black American groups. ^ Significant differences found within Black groups suggest that understanding each patient's conditions may help healthcare professionals in initiating individualized appropriate counseling before goal setting, and in developing culturally relevant type 2 diabetes management programs. Moreover, significant differences exist in strength of commitment to lifestyle adherence among Black groups in Miami and Abidjan. Cultural, socio-demographic factors and self-management habits may explain differences in participants' outcomes. At the policy level, Black groups should not be approached as a homogenous group and assessment of the vulnerability of each ethnic group may be necessary in the decision-making process.^

Étude de l'organisation fonctionnelle du génome humain par un modèle d'interactions entre les séquences répétitives de type LINE-1

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Résolution d'anaphores et identification des chaînes de coréférence selon le type de texte

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Développement d'approches quantitatives de type "structure-activité" pour la modélisation pharmacocinétique

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.