Congenital myasthenic syndrome in Golden Retrievers is associated with a novel COLQ mutation.

BackgroundCongenital myasthenic syndromes (CMSs) are a group of inherited disorders of neuromuscular transmission that may be presynaptic, synaptic, or postsynaptic. Causative mutations have been identified in 4 breeds including the Labrador Retriever, Jack Russell Terrier, Heideterrier, and Danish Pointing Dog.Hypothesis/objectiveClinical and genetic characterization of a neuromuscular disorder in Golden Retriever (GR) puppies.AnimalsFour GR puppies from California were evaluated for generalized muscle weakness beginning at weaning. Biological specimens were collected from the affected puppies, and familial information was obtained. Blood or buccal swabs were obtained from 63 unaffected GRs.MethodsComplete physical, neurological, electrodiagnostic, and histological evaluations and biochemical quantification of muscle acetylcholine receptors were performed. Polymerase chain reaction was used to amplify the 17 exons of COLQ, and sequences were obtained by Sanger sequencing. Variant frequency was assessed in unrelated GRs and a public database.ResultsClinical, neurological, and electrodiagnostic evaluations confirmed a disorder of neuromuscular transmission in a GR family. Sequencing of all exons and splice sites of a primary candidate gene, COLQ, identified a point mutation that predicts an amino acid substitution (G294R). The primary COLQ transcript was absent from affected muscle samples. All affected puppies were homozygous for the mutation, which was not detected outside this GR family or in other breeds.Conclusions and clinical importanceWe confirmed the diagnosis of a CMS in GR puppies and identified a novel COLQ mutation. The COLQ gene encodes the collagenous tail of acetylcholinesterase, the enzyme responsible for termination of skeletal muscle contraction by clearing acetylcholine at the neuromuscular junction. Clinicians and breeders should be aware of this CMS in GR puppies with an early onset of weakness

Beyond the MHC: A canine model of dermatomyositis shows a complex pattern of genetic risk involving novel loci

Juvenile dermatomyositis (JDM) is a chronic inflammatory myopathy and vasculopathy driven by genetic and environmental influences. Here, we investigated the genetic underpinnings of an analogous, spontaneous disease of dogs also termed dermatomyositis (DMS). As in JDM, we observed a significant association with a haplotype of the major histocompatibility complex (MHC) (DLA-DRB1*002:01/-DQA1*009:01/-DQB1*001:01), particularly in homozygosity (P-val = 0.0001). However, the high incidence of the haplotype among healthy dogs indicated that additional genetic risk factors are likely involved in disease progression. We conducted genome-wide association studies in two modern breeds having common ancestry and detected strong associations with novel loci on canine chromosomes 10 (P-val = 2.3X10-12) and 31 (P-val = 3.95X10-8). Through whole genome resequencing, we identified primary candidate polymorphisms in conserved regions of PAN2 (encoding p.Arg492Cys) and MAP3K7CL(c.383_392ACTCCACAAA\u3eGACT) on chromosomes 10 and 31, respectively. Analyses of these polymorphisms and the MHC haplotypes revealed that nine of 27 genotypic combinations confer high or moderate probability of disease and explain 93% of cases studied. The pattern of disease risk across PAN2 and MAP3K7CL genotypes provided clear evidence for a significant epistatic foundation for this disease, a risk further impacted by MHC haplotypes. We also observed a genotype-phenotype correlation wherein an earlier age of onset is correlated with an increased number of risk alleles at PAN2 and MAP3K7CL. High frequencies of multiple genetic risk factors are unique to affected breeds and likely arose coincident with artificial selection for desirable phenotypes. Described herein is the first three-locus association with a complex canine disease and two novel loci that provide targets for exploration in JDM and related immunological dysfunction

Exome sequencing reveals independent SGCD deletions causing limb girdle muscular dystrophy in Boston terriers

Background: Limb-girdle muscular dystrophies (LGMDs) are a heterogeneous group of inherited autosomal myopathies that preferentially affect voluntary muscles of the shoulders and hips. LGMD has been clinically described in several breeds of dogs, but the responsible mutations are unknown. The clinical presentation in dogs is characterized by marked muscle weakness and atrophy in the shoulder and hips during puppyhood. Methods: Following clinical evaluation, the identification of the dystrophic histological phenotype on muscle histology, and demonstration of the absence of sarcoglycan-sarcospan complex by immunostaining, whole exome sequencing was performed on five Boston terriers: one affected dog and its three family members and one unrelated affected dog. Results: Within sarcoglycan-delta (SGCD), a two base pair deletion segregating with LGMD in the family was discovered, and a deletion encompassing exons 7 and 8 was found in the unrelated dog. Both mutations are predicted to cause an absence of SGCD protein, confirmed by immunohistochemistry. The mutations are private to each family. Conclusions: Here, we describe the first cases of canine LGMD characterized at the molecular level with the classification of LGMD2F.Peer reviewe

On the covariant quantization of tensionless bosonic strings in AdS spacetime

The covariant quantization of the tensionless free bosonic (open and closed) strings in AdS spaces is obtained. This is done by representing the AdS space as an hyperboloid in a flat auxiliary space and by studying the resulting string constrained hamiltonian system in the tensionless limit. It turns out that the constraint algebra simplifies in the tensionless case in such a way that the closed BRST quantization can be formulated and the theory admits then an explicit covariant quantization scheme. This holds for any value of the dimension of the AdS space.Comment: 1+16 pages; v4 two clarifications adde

Thermal Structure and Dynamics of Saturn's Northern Springtime Disturbance

This article combined several infrared datasets to study the vertical properties of Saturn's northern springtime storm. Spectroscopic observations of Saturn's northern hemisphere at 0.5 and 2.5 / cm spectral resolution were provided by the Cassini Composite Infrared Spectrometer (CIRS, 17). These were supplemented with narrow-band filtered imaging from the ESO Very Large Telescope VISIR instrument (16) to provide a global spatial context for the Cassini spectroscopy. Finally, nightside imaging from the Cassini Visual and Infrared Mapping Spectrometer (VIMS, 22) provided a glimpse of the undulating cloud activity in the eastern branch of the disturbance. Each of these datasets, and the methods used to reduce and analyse them, will be described in detail below. Spatial maps of atmospheric temperatures, aerosol opacity and gaseous distributions are derived from infrared spectroscopy using a suite of radiative transfer and optimal estimation retrieval tools developed at the University of Oxford, known collectively as Nemesis (23). Synthetic spectra created from a reference atmospheric model for Saturn and appropriate sources of spectroscopic line data (6, 24) are convolved with the instrument function for each dataset. Atmospheric properties are then iteratively adjusted until the measurements are accurately reproduced with physically-realistic temperatures, compositions and cloud opacities

Growth Strategies of Tropical Tree Species: Disentangling Light and Size Effects

An understanding of the drivers of tree growth at the species level is required to predict likely changes of carbon stocks and biodiversity when environmental conditions change. Especially in species-rich tropical forests, it is largely unknown how species differ in their response of growth to resource availability and individual size. We use a hierarchical Bayesian approach to quantify the impact of light availability and tree diameter on growth of 274 woody species in a 50-ha long-term forest census plot in Barro Colorado Island, Panama. Light reaching each individual tree was estimated from yearly vertical censuses of canopy density. The hierarchical Bayesian approach allowed accounting for different sources of error, such as negative growth observations, and including rare species correctly weighted by their abundance. All species grew faster at higher light. Exponents of a power function relating growth to light were mostly between 0 and 1. This indicates that nearly all species exhibit a decelerating increase of growth with light. In contrast, estimated growth rates at standardized conditions (5 cm dbh, 5% light) varied over a 9-fold range and reflect strong growth-strategy differentiation between the species. As a consequence, growth rankings of the species at low (2%) and high light (20%) were highly correlated. Rare species tended to grow faster and showed a greater sensitivity to light than abundant species. Overall, tree size was less important for growth than light and about half the species were predicted to grow faster in diameter when bigger or smaller, respectively. Together light availability and tree diameter only explained on average 12% of the variation in growth rates. Thus, other factors such as soil characteristics, herbivory, or pathogens may contribute considerably to shaping tree growth in the tropics

The ACS Survey of Galactic Globular Clusters. XII. Photometric Binaries along the Main-Sequence

The fraction of binary stars is an important ingredient to interpret globular cluster dynamical evolution and their stellar population. We investigate the properties of main-sequence binaries measured in a uniform photometric sample of 59 Galactic globular clusters that were observed by HST WFC/ACS as a part of the Globular Cluster Treasury project. We measured the fraction of binaries and the distribution of mass-ratio as a function of radial location within the cluster, from the central core to beyond the half-mass radius. We studied the radial distribution of binary stars, and the distribution of stellar mass ratios. We investigated monovariate relations between the fraction of binaries and the main parameters of their host clusters. We found that in nearly all the clusters, the total fraction of binaries is significantly smaller than the fraction of binaries in the field, with a few exceptions only. Binary stars are significantly more centrally concentrated than single MS stars in most of the clusters studied in this paper. The distribution of the mass ratio is generally flat (for mass-ratio parameter q>0.5). We found a significant anti-correlation between the binary fraction in a cluster and its absolute luminosity (mass). Some, less significant correlation with the collisional parameter, the central stellar density, and the central velocity dispersion are present. There is no statistically significant relation between the binary fraction and other cluster parameters. We confirm the correlation between the binary fraction and the fraction of blue stragglers in the cluster.Comment: 43 Pages, 52 figures, accepted for publication in A&

Dynamical Supersymmetry Breaking

Supersymmetry is one of the most plausible and theoretically motivated frameworks for extending the Standard Model. However, any supersymmetry in Nature must be a broken symmetry. Dynamical supersymmetry breaking (DSB) is an attractive idea for incorporating supersymmetry into a successful description of Nature. The study of DSB has recently enjoyed dramatic progress, fueled by advances in our understanding of the dynamics of supersymmetric field theories. These advances have allowed for direct analysis of DSB in strongly coupled theories, and for the discovery of new DSB theories, some of which contradict early criteria for DSB. We review these criteria, emphasizing recently discovered exceptions. We also describe, through many examples, various techniques for directly establishing DSB by studying the infrared theory, including both older techniques in regions of weak coupling, and new techniques in regions of strong coupling. Finally, we present a list of representative DSB models, their main properties, and the relations between them.Comment: 113 pages, Revtex. Minor changes, references added and corrected. To appear in Reviews of Modern Physic