Genetic Variants of the Renin Angiotensin System: Effects on Atherosclerosis in Experimental Models and Humans

The renin angiotensin system (RAS) has profound effects on atherosclerosis development in animal models, which is partially complimented by evidence in the human disease. Although angiotensin II was considered to be the principal effector of the RAS, a broader array of bioactive angiotensin peptides have been identified that have increased the scope of enzymes and receptors in the RAS. Genetic interruption of the synthesis of these peptides has not been extensively performed in experimental or human studies. A few studies demonstrate that interruption of a component of the angiotensin peptide synthesis pathway reduces experimental lesion formation. The evidence in human studies has not been consistent. Conversely, genetic manipulation of the RAS receptors has demonstrated that AT1a receptors are profoundly involved in experimental atherosclerosis. Few studies have reported links of genetic variants of angiotensin II receptors to human atherosclerotic diseases. Further genetic studies are needed to define the role of RAS in atherosclerosis

Single nucleotide polymorphism-based genome-wide linkage analysis in Japanese atopic dermatitis families

<p>Abstract</p> <p>Background</p> <p>Atopic dermatitis develops as a result of complex interactions between several genetic and environmental factors. To date, 4 genome-wide linkage studies of atopic dermatitis have been performed in Caucasian populations, however, similar studies have not been done in Asian populations. The aim of this study was to identify chromosome regions linked to atopic dermatitis in a Japanese population.</p> <p>Methods</p> <p>We used a high-density, single nucleotide polymorphism genotyping assay, the Illumina BeadArray Linkage Mapping Panel (version 4) comprising 5,861 single nucleotide polymorphisms, to perform a genome-wide linkage analysis of 77 Japanese families with 111 affected sib-pairs with atopic dermatitis.</p> <p>Results</p> <p>We found suggestive evidence for linkage with 15q21 (LOD = 2.01, NPL = 2.87, <it>P </it>= .0012) and weak linkage to 1q24 (LOD = 1.26, NPL = 2.44, <it>P </it>= .008).</p> <p>Conclusion</p> <p>We report the first genome-wide linkage study of atopic dermatitis in an Asian population, and novel loci on chromosomes 15q21 and 1q24 linked to atopic dermatitis. Identification of novel causative genes for atopic dermatitis will advance our understanding of the pathogenesis of atopic dermatitis.</p

Relationship between amino acid composition and gene expression in the mouse genome

<p>Abstract</p> <p>Background</p> <p>Codon bias is a phenomenon that refers to the differences in the frequencies of synonymous codons among different genes. In many organisms, natural selection is considered to be a cause of codon bias because codon usage in highly expressed genes is biased toward optimal codons. Methods have previously been developed to predict the expression level of genes from their nucleotide sequences, which is based on the observation that synonymous codon usage shows an overall bias toward a few codons called major codons. However, the relationship between codon bias and gene expression level, as proposed by the translation-selection model, is less evident in mammals.</p> <p>Findings</p> <p>We investigated the correlations between the expression levels of 1,182 mouse genes and amino acid composition, as well as between gene expression and codon preference. We found that a weak but significant correlation exists between gene expression levels and amino acid composition in mouse. In total, less than 10% of variation of expression levels is explained by amino acid components. We found the effect of codon preference on gene expression was weaker than the effect of amino acid composition, because no significant correlations were observed with respect to codon preference.</p> <p>Conclusion</p> <p>These results suggest that it is difficult to predict expression level from amino acid components or from codon bias in mouse.</p

Quantification of myelin loss in frontal lobe white matter in vascular dementia, Alzheimer's disease, and dementia with Lewy bodies

The aim of this study was to characterize myelin loss as one of the features of white matter abnormalities across three common dementing disorders. We evaluated post-mortem brain tissue from frontal and temporal lobes from 20 vascular dementia (VaD), 19 Alzheimer’s disease (AD) and 31 dementia with Lewy bodies (DLB) cases and 12 comparable age controls. Images of sections stained with conventional luxol fast blue were analysed to estimate myelin attenuation by optical density. Serial adjacent sections were then immunostained for degraded myelin basic protein (dMBP) and the mean percentage area containing dMBP (%dMBP) was determined as an indicator of myelin degeneration. We further assessed the relationship between dMBP and glutathione S-transferase (a marker of mature oligodendrocytes) immunoreactivities. Pathological diagnosis significantly affected the frontal but not temporal lobe myelin attenuation: myelin density was most reduced in VaD compared to AD and DLB, which still significantly exhibited lower myelin density compared to ageing controls. Consistent with this, the degree of myelin loss was correlated with greater %dMBP, with the highest %dMBP in VaD compared to the other groups. The %dMBP was inversely correlated with the mean size of oligodendrocytes in VaD, whereas it was positively correlated with their density in AD. A two-tier regression model analysis confirmed that the type of disorder (VaD or AD) determines the relationship between %dMBP and the size or density of oligodendrocytes across the cases. Our findings, attested by the use of three markers, suggest that myelin loss may evolve in parallel with shrunken oligodendrocytes in VaD but their increased density in AD, highlighting partially different mechanisms are associated with myelin degeneration, which could originate from hypoxic–ischaemic damage to oligodendrocytes in VaD whereas secondary to axonal degeneration in AD

Relativistic double-zeta, triple-zeta, and quadruple-zeta basis sets for the lanthanides La–Lu

Relativistic basis sets of double-zeta, triple-zeta, and quadruple-zeta quality have been optimized for the lanthanide elements La-Lu. The basis sets include SCF exponents for the occupied spinors and for the 6p shell, exponents of correlating functions for the valence shells (4f, 5d and 6s) and the outer core shells (4d, 5s and 5p), and diffuse functions, including functions for dipole polarization of the 4f shell. A finite nuclear size was used in all optimizations. The basis sets are illustrated by calculations on YbF. Prescriptions are given for constructing contracted basis sets. The basis sets are available as an internet archive and from the Dirac program web site, http://dirac. chem. sdu. dk. © 2010 The Author(s)

Pathogen-Induced Proapoptotic Phenotype and High CD95 (Fas) Expression Accompany a Suboptimal CD8+ T-Cell Response: Reversal by Adenoviral Vaccine

MHC class Ia-restricted CD8+ T cells are important mediators of the adaptive immune response against infections caused by intracellular microorganisms. Whereas antigen-specific effector CD8+ T cells can clear infection caused by intracellular pathogens, in some circumstances, the immune response is suboptimal and the microorganisms survive, causing host death or chronic infection. Here, we explored the cellular and molecular mechanisms that could explain why CD8+ T cell-mediated immunity during infection with the human protozoan parasite Trypanosoma cruzi is not optimal. For that purpose, we compared the CD8+ T-cell mediated immune responses in mice infected with T. cruzi or vaccinated with a recombinant adenovirus expressing an immunodominant parasite antigen. Several functional and phenotypic characteristics of specific CD8+ T cells overlapped. Among few exceptions was an accelerated expansion of the immune response in adenoviral vaccinated mice when compared to infected ones. Also, there was an upregulated expression of the apoptotic-signaling receptor CD95 on the surface of specific T cells from infected mice, which was not observed in the case of adenoviral-vaccinated mice. Most importantly, adenoviral vaccine provided at the time of infection significantly reduced the upregulation of CD95 expression and the proapoptotic phenotype of pathogen-specific CD8+ cells expanded during infection. In parallel, infected adenovirus-vaccinated mice had a stronger CD8 T-cell mediated immune response and survived an otherwise lethal infection. We concluded that a suboptimal CD8+ T-cell response is associated with an upregulation of CD95 expression and a proapoptotic phenotype. Both can be blocked by adenoviral vaccination

P2 receptors are involved in the mediation of motivation-related behavior

The importance of purinergic signaling in the intact mesolimbic–mesocortical circuit of the brain of freely moving rats is reviewed. In the rat, an endogenous ADP/ATPergic tone reinforces the release of dopamine from the axon terminals in the nucleus accumbens as well as from the somatodendritic region of these neurons in the ventral tegmental area, as well as the release of glutamate, probably via P2Y1 receptor stimulation. Similar mechanisms may regulate the release of glutamate in both areas of the brain. Dopamine and glutamate determine in concert the activity of the accumbal GABAergic, medium-size spiny neurons thought to act as an interface between the limbic cortex and the extrapyramidal motor system. These neurons project to the pallidal and mesencephalic areas, thereby mediating the behavioral reaction of the animal in response to a motivation-related stimulus. There is evidence that extracellular ADP/ATP promotes goal-directed behavior, e.g., intention and feeding, via dopamine, probably via P2Y1 receptor stimulation. Accumbal P2 receptor-mediated glutamatergic mechanisms seem to counteract the dopaminergic effects on behavior. Furthermore, adaptive changes of motivation-related behavior, e.g., by chronic succession of starvation and feeding or by repeated amphetamine administration, are accompanied by changes in the expression of the P2Y1 receptor, thought to modulate the sensitivity of the animal to respond to certain stimuli

Three-dimensional cathodoluminescence imaging and electron backscatter diffraction: tools for studying the genetic nature of diamond inclusions

As a step towards resolving the genesis of inclusions in diamonds, a new technique is presented. This technique combines cathodoluminescence (CL) and electron backscatter diffraction (EBSD) using a focused ion beam-scanning electron microscope (FIB-SEM) instrument with the aim of determining, in detail, the three-dimensional diamond zonation adjacent to a diamond inclusion. EBSD reveals that mineral inclusions in a single diamond have similar crystallographic orientations to the host, within ±0. 4°. The chromite inclusions record a systematic change in Mg# and Cr# from core to the rim of the diamond that corresponds with a ~80°C decrease of their formation temperature as established by zinc thermometry. A chromite inclusion, positioned adjacent to a boundary between two major diamond growth zones, is multi-faceted with preferred octahedral and cubic faces. The chromite is surrounded by a volume of non-luminescent diamond (CL halo) that partially obscures any diamond growth structures. The CL halo has apparent crystallographic morphology with symmetrically oriented pointed features. The CL halo is enriched in ~200 ppm Cr and ~80 ppm Fe and is interpreted to have a secondary origin as it overprints a major primary diamond growth structure. The diamond zonation adjacent to the chromite is complex and records both syngenetic and protogenetic features based on current inclusion entrapment models. In this specific case, a syngenetic origin is favoured with the complex form of the inclusion and growth layers indicating changes of growth rates at the diamond-chromite interface. Combined EBSD and 3D-CL imaging appears an extremely useful tool in resolving the ongoing discussion about the timing of inclusion growth and the significance of diamond inclusion studies. © 2010 The Author(s)