Searching for "monogenic diabetes" in dogs using a candidate gene approach

BACKGROUND: Canine diabetes is a common endocrine disorder with an estimated breed-related prevalence ranging from 0.005% to 1.5% in pet dogs. Increased prevalence in some breeds suggests that diabetes in dogs is influenced by genetic factors and similarities between canine and human diabetes phenotypes suggest that the same genes might be associated with disease susceptibility in both species. Between 1-5% of human diabetes cases result from mutations in a single gene, including maturity onset diabetes of the adult (MODY) and neonatal diabetes mellitus (NDM). It is not clear whether monogenic forms of diabetes exist within some dog breeds. Identification of forms of canine monogenic diabetes could help to resolve the heterogeneity of the condition and lead to development of breed-specific genetic tests for diabetes susceptibility. RESULTS: Seventeen dog breeds were screened for single nucleotide polymorphisms (SNPs) in eighteen genes that have been associated with human MODY/NDM. Six SNP associations were found from five genes, with one gene (ZFP57) being associated in two different breeds. CONCLUSIONS: Some of the genes that have been associated with susceptibility to MODY and NDM in humans appear to also be associated with canine diabetes, although the limited number of associations identified in this study indicates canine diabetes is a heterogeneous condition and is most likely to be a polygenic trait in most dog breeds. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/2052-6687-1-8) contains supplementary material, which is available to authorized users

Efficient Computation of Casimir Interactions between Arbitrary 3D Objects

We introduce an efficient technique for computing Casimir energies and forces between objects of arbitrarily complex 3D geometries. In contrast to other recently developed methods, our technique easily handles non-spheroidal, non-axisymmetric objects and objects with sharp corners. Using our new technique, we obtain the first predictions of Casimir interactions in a number of experimentally relevant geometries, including crossed cylinders and tetrahedral nanoparticles.Comment: 4 pages, 4 figure

In adult onset myositis, the presence of interstitial lung disease and myositis specific/associated antibodies are governed by HLA class II haplotype, rather than by myositis subtype

The aim of this study was to investigate HLA class II associations in polymyositis (PM) and dermatomyositis (DM), and to determine how these associations influence clinical and serological differences. DNA samples were obtained from 225 UK Caucasian idiopathic inflammatory myopathy patients (PM = 117, DM = 108) and compared with 537 randomly selected UK Caucasian controls. All cases had also been assessed for the presence of related malignancy and interstitial lung disease (ILD), and a number of myositis-specific/myositis-associated antibodies (MSAs/MAAs). Subjects were genotyped for HLA-DRB1, DQA1 and DQB1. HLA-DRB1*03, DQA1*05 and DQB1*02 were associated with an increased risk for both PM and DM. The HLA-DRB1*03-DQA1*05-DQB1*02 haplotype demonstrated strong association with ILD, irrespective of myositis subtype or presence of anti-aminoacyl-transfer RNA synthetase antibodies. The HLA-DRB1*07-DQA1*02-DQB1*02 haplotype was associated with risk for anti-Mi-2 antibodies, and discriminated PM from DM (odds ratio 0.3, 95% confidence interval 0.1–0.6), even in anti-Mi-2 negative patients. Other MSA/MAAs showed specific associations with other HLA class II haplotypes, irrespective of myositis subtype. There were no genotype, haplotype or serological associations with malignancy. The HLA-DRB1*03-DQA1*05-DQB1*02 haplotype associations appear to not only govern disease susceptibility in Caucasian PM/DM patients, but also phenotypic features common to PM/DM. Though strongly associated with anti-Mi-2 antibodies, the HLA-DRB1*07-DQA1*02-DQB1*02 haplotype shows differential associations with PM/DM disease susceptibility. In conclusion, these findings support the notion that myositis patients with differing myositis serology have different immunogenetic profiles, and that these profiles may define specific myositis subtypes

Spectroscopic studies of Dy-168,170 using CLARA and PRISMA

Preliminary results from an experiment aiming at Dy-170. Submitted to the LNL Annual Report 2008.Comment: 2 pages, 4 figures, Submitted to the LNL Annual Report 200

Dog leucocyte antigen (DLA) class II haplotypes and risk of canine diabetes mellitus in specific dog breeds

Abstract: Background: Canine diabetes mellitus (DM) is a common endocrine disease in domestic dogs. A number of pathological mechanisms are thought to contribute to the aetiopathogenesis of relative or absolute insulin deficiency, including immune-mediated destruction of pancreatic beta cells. DM risk varies considerably between different dog breeds, suggesting that genetic factors are involved and contribute susceptibility or protection. Associations of particular dog leucocyte antigen (DLA) class II haplotypes with DM have been identified, but investigations to date have only considered all breeds pooled together. The aim of this study was to analyse an expanded data set so as to identify breed-specific diabetes-associated DLA haplotypes. Methods: The 12 most highly represented breeds in the UK Canine Diabetes Register were selected for study. DLA-typing data from 646 diabetic dogs and 912 breed-matched non-diabetic controls were analysed to enable breed-specific analysis of the DLA. Dogs were genotyped for allelic variation at DLA-DRB1, -DQA1, -DQB1 loci using DNA sequence-based typing. Genotypes from all three loci were combined to reveal three-locus DLA class II haplotypes, which were evaluated for statistical associations with DM. This was performed for each breed individually and for all breeds pooled together. Results: Five dog breeds were identified as having one or more DLA haplotype associated with DM susceptibility or protection. Four DM-associated haplotypes were identified in the Cocker Spaniel breed, of which one haplotype was shared with Border Terriers. In the three breeds known to be at highest risk of DM included in the study (Samoyed, Tibetan Terrier and Cairn Terrier), no DLA haplotypes were found to be associated with DM. Conclusions: Novel DLA associations with DM in specific dog breeds provide further evidence that immune response genes contribute susceptibility to this disease in some cases. It is also apparent that DLA may not be contributing obvious or strong risk for DM in some breeds, including the seven breeds analysed for which no associations were identified

Observational study on variability between biobanks in the estimation of DNA concentration.

BACKGROUND: There is little confidence in the consistency of estimation of DNA concentrations when samples move between laboratories. Evidence on this consistency is largely anecdotal. Therefore there is a need first to measure this consistency among different laboratories and then identify and implement remedies. A pilot experiment to test logistics and provide initial data on consistency was therefore conceived. METHODS: DNA aliquots at nominal concentrations between 10 and 300 ng/mul were dispensed into the wells of 96-well plates by one participant - the coordinating centre. Participants estimated the concentration in each well and returned estimates to the coordinating centre. RESULTS: Considerable overall variability was observed among estimates. There were statistically significant differences between participants' measurements and between fluorescence emission and absorption spectroscopy. CONCLUSION: Anecdotal evidence of variability in DNA concentration estimation has been substantiated. Reduction in variability between participants will require the identification of major sources of variation, specification of effective remedies and their implementation

Vibrational and structural properties of P2O5P_2O_5 glass: Advances from a combined modeling approach

We present experimental measurements and ab initio simulations of the crystalline and amorphous phases of $P_2O_5$. The calculated Raman, infrared, and vibrational density of states (VDOS) spectra are in excellent agreement with experimental measurements and contain the signatures of all the peculiar local structures of the amorphous phase, namely, bridging and nonbridging (double-bonded or terminal) oxygens and tetrahedral $PO_4$ units associated with $Q^2$, $Q^3$, and $Q^4$ species ($Q^n$ denotes the various types of $PO_4$ tetrahedra, with $n$ being the number of bridging oxygen atoms that connect the tetrahedra to the rest of the network). In order to reveal the internal structure of the vibrational spectrum, the characteristics of vibrational modes in different frequency ranges are investigated using a mode-projection approach at different symmetries based on the $T_d$ symmetry group. In particular, the VDOS spectrum in the range from $∼ 600$ to $870$ $cm^-$$^1$ is dominated by bending ($F_2$$_b$) motions related to bridging oxygen and phosphorus ($∼ 800$ $cm^-$$^1$ band) atoms, while the high-frequency doublet zone ($∼ 870 – 1250$ $cm^-$$^1$ is associated mostly with the asymmetric (($F_2$$_s$) and symmetric ($A_1$) stretching modes, and most prominent peak around $1400$ $cm^-$$^1$ (exp. $1380$ $cm^-$$^1$) is mainly due to asymmetric stretching vibrations supported by double-bonded oxygen atoms. The lower-frequency range below $600$ $cm^-$$^1$ is shown to arise from a mixture of bending ($E$ and ($F_2$$_b$) and rotation ($F_1$) modes. The scissors bending ($E$) and rotation ($F_1$) modes are well localized below $600$ $cm^-$$^1$, whereas the ($F_2$$_b$ bending modes spread further into the range $∼ 600 – 870$ $cm^-$$^1$. The projections of the eigenmodes onto $Q^2$, $Q^3$, and $Q^4$ species yield well-defined contributions at frequencies in striking correspondence with the positions of the Raman and infrared bands