Mineralocorticoid receptor antagonism induces browning of white adipose tissue through impairment of autophagy and prevents adipocyte dysfunction in high-fat-diet-fed mice.

The mineralocorticoid receptor (MR) controls adipocyte function, but its role in the conversion of white adipose tissue (WAT) into thermogenic fat has not been elucidated. We investigated responses to the MR antagonists spironolactone (spiro; 20 mg/kg/d) and drospirenone (DRSP; 6 mg/kg/d) in C57BL/6 mice fed a high-fat (HF) diet for 90 d. DRSP and spiro curbed HF diet-induced impairment in glucose tolerance, and prevented body weight gain and white fat expansion.

A Footprint Family extended MRIO model to support Europe's transition to a One Planet Economy.

Currently, the European economy is using nearly three times the ecological assets that are locally available. This situation cannot be sustained indefinitely. Tools are needed that can help reverse the unsustainable trend.

Cardiomyocyte mineralocorticoid receptors are essential for deoxycorticosterone/salt-mediated inflammation and cardiac fibrosis.

Because the role of mineralocorticoid receptors in specific cell types in cardiac remodeling remains unknown, we have compared cardiac responses with deoxycorticosterone/salt in cardiomyocyte mineralocorticoid receptor-null (MyoMRKO) and wild-type (WT) mice at 8 days and 8 weeks. No differences in cardiac function between untreated WT and MyoMRKO mice were found, whereas profibrotic markers were reduced in MyoMRKO hearts at baseline. At 8 days, MyoMRKO showed monocyte/macrophage recruitment equivalent to WT mice in response to deoxycorticosterone/salt but a suppression of markers of fibrosis compared with WT.

Carbon, land, and water footprint accounts for the European Union: consumption, production, and displacements through international trade.

A nation's consumption of goods and services causes various environmental pressures all over the world due to international trade. We use a multiregional input-output model to assess three kinds of environmental footprints for the member states of the European Union. Footprints are indicators that take the consumer responsibility approach to account for the total direct and indirect effects of a product or consumption activity.

Macrophage mineralocorticoid receptor signaling plays a key role in aldosterone-independent cardiac fibrosis.

Mineralocorticoid receptor (MR) activation promotes the development of cardiac fibrosis and heart failure. Clinical evidence demonstrates that MR antagonism is protective even when plasma aldosterone levels are not increased. We hypothesize that MR activation in macrophages drives the profibrotic phenotype in the heart even when aldosterone levels are not elevated.

Platinum-based inhibitors of amyloid-beta as therapeutic agents for Alzheimer's disease.

Amelyoid-beta peptide (Abeta) is a major causative agent responsible for Alzheimer's disease (AD). Abeta contains a high affinity metal binding site that modulates peptide aggregation and toxicity. Therefore, identifying molecules targeting this site represents a valid therapeutic strategy.

Neurotoxicity from glutathione depletion is mediated by Cu-dependent p53 activation.

Loss of intracellular neuronal glutathione (GSH) is an important feature of neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The consequences of GSH depletion include increased oxidative damage to proteins, lipids, and DNA and subsequent cytotoxic effects. GSH is also an important modulator of cellular copper (Cu) homeostasis and altered Cu metabolism is central to the pathology of several neurodegenerative diseases.

Fission yeast mutants that alleviate transcriptional silencing in centromeric flanking repeats and disrupt chromosome segregation.

In the fission yeast Schizosaccharomyces pombe genes are transcriptionally silenced when placed within centromeres, within or close to the silent mating-type loci or adjacent to telomeres. Factors required to maintain mating-type silencing also affect centromeric silencing and chromosome segregation. We isolated mutations that alleviate repression of marker genes in the inverted repeats flanking the central core of centromere I.

Defects in components of the proteasome enhance transcriptional silencing at fission yeast centromeres and impair chromosome segregation.

Fission yeast centromeres are transcriptionally silent and form a heterochromatin-like structure essential for normal centromere function; this appears analogous to heterochromatin and position effect variegation in other eukaryotes. Conditional mutations in three genes designated cep (centromere enhancer of position effect) were found to enhance transcriptional silencing within centromeres. Cloning of the cep1(+) and cep2(+) genes by functional complementation revealed that they are identical to the previously described genes pad1(+) and mts2(+), respectively, which both encode subunits of the proteasome 19S cap.

Transient inhibition of histone deacetylation alters the structural and functional imprint at fission yeast centromeres.

Histone acetylation may act to mark and maintain transcriptionally active or inactive chromosomal domains through the cell cycle and in different lineages. A novel role for histone acetylation in centromere regulation has been identified. Exposure of fission yeast cells to TSA, a specific inhibitor of histone deacetylase, interferes with repression of marker genes in centromeric heterochromatin, causes chromosome loss, and disrupts the localization of Swi6p, a component of centromeric heterochromatin.

Fission yeast genes which disrupt mitotic chromosome segregation when overexpressed.

An interference assay has been devised in Schizosaccharomyces pombe to rapidly identify and clone genes involved in chromosome segregation. Random S.pombe cDNAs were overexpressed from an inducible promoter in a strain carrying an additional, non-essential minichromosome.

Mutations in the fission yeast silencing factors clr4+ and rik1+ disrupt the localisation of the chromo domain protein Swi6p and impair centromere function.

Transcriptional silencing is known to occur at centromeres, telomeres and the mating type region in the nucleus of fission yeast, Schizosaccharomyces pombe. Mating-type silencing factors have previously been shown also to affect transcriptional repression within centromeres and to some extent at telomeres. Mutations in the clr4+, rik1+ and swi6+ genes dramatically reduce silencing at certain centromeric regions and cause elevated chromosome loss rates.

The chromodomain protein Swi6: a key component at fission yeast centromeres.

Centromeres attach chromosomes to the spindle during mitosis, thereby ensuring the equal distribution of chromosomes into daughter cells. Transcriptionally silent heterochromatin of unknown function is associated with centromeres in many organisms. In the fission yeast Schizosaccharomyces pombe, the silent mating-type loci, centromeres, and telomeres are assembled into silent heterochromatin-like domains.

Mutations derepressing silent centromeric domains in fission yeast disrupt chromosome segregation.

The ura4+ gene displays phenotypes consistent with variegated expression when inserted at 11 sites throughout fission yeast centromere 1. An abrupt transition occurs between the zone of centromeric repression and two adjacent expressed sites. Mutations in six genes alleviate repression of the silent-mating type loci and of ura4+ expressed from a site adjacent to the silent locus, mat3-M.

Telomere-associated chromosome breakage in fission yeast results in variegated expression of adjacent genes.

The sequence requirements for in vivo telomere function in the fission yeast, Schizosaccharomyces pombe, have been investigated. A 258 bp tract of previously characterized cloned fission yeast terminal repeats adjacent to 800 bp of telomere-associated sequences is sufficient to seed new telomeres onto linearized ars-containing plasmids when introduced into cells. The resulting transformants contain unrearranged, acentric, linear episomes.

Position effect variegation at fission yeast centromeres.

Chromatin structure at Schizosaccharomyces pombe centromeres is unusual. The insertion of the ura4 gene within these centromeres resulted in genetically identical cells mosaic for its expression. Placement of the ade6 gene within cen1 or cen3 resulted in red-white sectored colonies, demonstrating the instability of gene expression.

The care management form.

The primary care physician and the continuing care unit administrator at Providence Center in Scarborough, ON collaborate with Bridget Campion, clinical ethicist at St. Joseph's Health Center in Toronto to describe a process and form that staff has developed to elicit and convey patient treatment preferences in long term care. Meant to be completed as soon after the patient's admission as possible, and subject to review and revision, the Care Management Form is one attempt to promote patient autonomy in long term care.

Allele losses on chromosome 17 in human epithelial ovarian carcinoma.

16 epithelial ovarian carcinomas (12 serous, 2 mucinous and 2 endometrioid) and 2 benign ovarian adenomas were studied using recombinant DNA technology to compare loci on chromosome 17 in germ-line and tumour DNA. Four polymorphic probes mapping to 17p and one mapping to 17q were used. There was a high frequency of allele loss on 17q/(77%) and a slightly lower frequency on 17p (69%).

Evidence that p53 behaves as a tumour suppressor gene in sporadic breast tumours.

Using the polymerase chain reaction, we have amplified exons 5 and 6 of the human p53 gene from paired samples of tumour and blood DNA of 60 patients with sporadic breast tumours and from placental or tonsil DNA of 30 normal controls. The patients' DNAs were previously examined for loss of heterozygosity of markers distal to the p53 gene on chromosome 17p and tumour samples were assayed for p53 mRNA levels. Hydroxylamine modification of mismatched base pairs was used to identify mutations in the amplified product.

Evidence implicating at least two genes on chromosome 17p in breast carcinogenesis.

The DNA of paired tumour and blood leucocyte samples from a large series of breast cancer patients was analysed to map regions of loss of heterozygosity on chromosome 17. The high frequency of loss of heterozygosity on 17p was confirmed, and a third of informative tumours had also lost an allele at the long arm locus THH59. On the short arm two distinct regions of loss of heterozygosity were identified, in bands p13-3 and p13-1.

Telomeric repeat from T. thermophila cross hybridizes with human telomeres.

The ends (telomeres) of eukaryotic chromosomes must have special features to ensure their stability and complete replication. Studies in yeast, protozoa, slime moulds and flagellates show that telomeres are tandem repeats of simple sequences that have a G-rich and a C-rich strand. Mammalian telomeres have yet to be isolated and characterized, although a DNA fragment within 20 kilobases of the telomeres of the short arms of the human sex chromosomes has been isolated.

HRAS1-selected chromosome transfer generates markers that colocalize aniridia- and genitourinary dysplasia-associated translocation breakpoints and the Wilms tumor gene within band 11p13.

We show that chromosome-mediated gene transfer can provide an enriched source of DNA markers for predetermined, subchromosomal regions of the human genome. Forty-four human DNA recombinants isolated from a HRAS1-selected chromosome-mediated gene transformant map exclusively to chromosome 11, with several sublocalizing to the Wilms tumor region at 11p13. We present a detailed molecular map of the deletion chromosomes 11 from five WAGR (Wilms tumor/aniridia/genitourinary abnormalities/mental retardation) syndrome patients, three of which are at the limits of cytogenetic resolution but shown here to be molecularly distinguishable and overlapping.

A fission yeast chromosome can replicate autonomously in mouse cells.

To test the functional capacity of a fission yeast chromosome in mouse cells, a strain of the fission yeast Schizosaccharomyces pombe, ED628 Int5, was constructed. A plasmid bearing the SV2NEO gene, which can confer G418 resistance to mouse cells, was integrated at the ura4 locus on S. pombe chromosome III.