A single IGF1 allele is a major determinant of small size in dogs

The domestic dog exhibits greater diversity in body size than any other terrestrial vertebrate. We used a strategy that exploits the breed structure of dogs to investigate the genetic basis of size. First, through a genome-wide scan, we identified a major quantitative trait locus (QTL) on chromosome 15 influencing size variation within a single breed. Second, we examined genetic variation in the 15-megabase interval surrounding the QTL in small and giant breeds and found marked evidence for a selective sweep spanning a single gene (IGF1), encoding insulin-like growth factor 1. A single IGF1 single-nucleotide polymorphism haplotype is common to all small breeds and nearly absent from giant breeds, suggesting that the same causal sequence variant is a major contributor to body size in all small dogs.     

Compartmentalized control of skin immunity by resident commensals

Intestinal commensal bacteria induce protective and regulatory responses that maintain host-microbial mutualism. However, the contribution of tissue-resident commensals to immunity and inflammation at other barrier sites has not been addressed. We found that in mice, the skin microbiota have an autonomous role in controlling the local inflammatory milieu and tuning resident T lymphocyte function. Protective immunity to a cutaneous pathogen was found to be critically dependent on the skin microbiota but not the gut microbiota. Furthermore, skin commensals tuned the function of local T cells in a manner dependent on signaling downstream of the interleukin-1 receptor. These findings underscore the importance of the microbiota as a distinctive feature of tissue compartmentalization, and provide insight into mechanisms of immune system regulation by resident commensal niches in health and disease.     

Inactivation of TNF signaling by rationally designed dominant-negative TNF variants

Tumor necrosis factor (TNF) is a key regulator of inflammatory responses and has been implicated in many pathological conditions. We used structure-based design to engineer variant TNF proteins that rapidly form heterotrimers with native TNF to give complexes that neither bind to nor stimulate signaling through TNF receptors. Thus, TNF is inactivated by sequestration. Dominant-negative TNFs represent a possible approach to anti-inflammatory biotherapeutics, and experiments in animal models show that the strategy can attenuate TNF-mediated pathology. Similar rational design could be used to engineer inhibitors of additional TNF superfamily cytokines as well as other multimeric ligands.     

Topography of the northern hemisphere of Mercury from MESSENGER laser altimetry

Laser altimetry by the MESSENGER spacecraft has yielded a topographic model of the northern hemisphere of Mercury. The dynamic range of elevations is considerably smaller than those of Mars or the Moon. The most prominent feature is an extensive lowland at high northern latitudes that hosts the volcanic northern plains. Within this lowland is a broad topographic rise that experienced uplift after plains emplacement. The interior of the 1500-km-diameter Caloris impact basin has been modified so that part of the basin floor now stands higher than the rim. The elevated portion of the floor of Caloris appears to be part of a quasi-linear rise that extends for approximately half the planetary circumference at mid-latitudes. Collectively, these features imply that long-wavelength changes to Mercury's topography occurred after the earliest phases of the planet's geological history.     

Equine hyperimmune serum protects mice against Clostridium difficile spore challenge

Clostridium (C.) difficile is a common cause of nosocomial diarrhea in horses. Vancomycin and metronidazole have been used as standard treatments but are only moderately effective, which highlights the need for a novel alternative therapy. In the current study, we prepared antiserum of equine origin against both C. difficile toxins A and B as well as whole-cell bacteria. The toxin-neutralizing activities of the antibodies were evaluated in vitro and the prophylactic effects of in vivo passive immunotherapy were demonstrated using a conventional mouse model. The data demonstrated that immunized horses generated antibodies against both toxins A and B that possessed toxin-neutralizing activity. Additionally, mice treated with the antiserum lost less weight without any sign of illness and regained weight back to a normal range more rapidly compared to the control group when challenged orally with 10⁷ C. difficile spores 1 day after serum injection. These results indicate that intravenous delivery of hyperimmune serum can protect animals from C. difficile challenge in a dose-dependent manner. Hence, immunotherapy may be a promising prophylactic strategy for preventing C. difficile infection in horses.     

Ultra‐long‐acting recombinant insulin for the treatment of diabetes mellitus in dogs

BackgroundFor the treatment of diabetes mellitus (DM) in dogs, novel insulins with decreased injection frequency while maintaining safety and efficacy are desirable. Insulin fused with immunoglobulin‐fragment‐crystallizable (Fc) has an ultra‐long plasma half‐life because it recycles through cells, protected from proteolysis.HypothesisGlycemic control can be achieved in diabetic dogs with a recombinant fusion protein of a synthetic insulin and canine Fc (AKS‐218d) administered subcutaneously once‐weekly.AnimalsFive client‐owned dogs with naturally occurring DM.MethodsProspective clinical trial in dogs with DM that were recruited from the UC Davis Veterinary Teaching Hospital and local veterinary clinics. Dogs previously controlled using intermediate‐acting insulin q12h were transitioned to once‐weekly injections of a preliminary construct identified as AKS‐218d. The dose of AKS‐218d was titrated weekly for 8 weeks based on clinical response and continuous interstitial glucose monitoring. Clinical signs, body weight, serum fructosamine concentrations, and mean interstitial glucose concentrations (IG) over the preceding week were compared between baseline (before AKS‐218d) and during the last week of treatment. Data were compared using nonparametric paired tests.ResultsOnce‐weekly AKS‐218d, compared to baseline twice‐daily insulin therapy, resulted in no significant changes in clinical signs, median (range) body weight (+0.4 kg [−0.5‐1.1]; P = .6), fructosamine concentration (−75 mmol/L [−215 to +126]; P = .4), or mean IG (+81 mg/dL [−282 to +144]; P = .8). No adverse reactions were reported.ConclusionControl of clinical signs, body weight, and maintenance of glycemia was achieved with this once‐weekly novel insulin construct in 4 of 5 dogs.     

Post-mortem findings in 54 cases of anesthetic associated death in cats from two spay-neuter programs in New York State

Anesthetic-associated death (AAD) in cats is infrequent, but occurs far more frequently than in people. Post-mortem investigations of AAD in cats are uncommon, and results only sporadically published. Here we report the findings in 54 cases of AAD in cats. Significant gross and/or microscopic pre-existing disease, including pulmonary, cardiac, and systemic disease, was detected in 33% of cases. Pulmonary disease was most frequently diagnosed (24% of cases), and included cases of Aelurostrongylus abstrusus infection (9% of cases). Heart disease, including two cases of hypertrophic cardiomyopathy, was less frequent (11% of cases). Four percent died from surgical complications. No?significant gross or microscopic disease was detected in 63% of cases. Additional studies are needed to determine if these findings are representative of AAD in cats in other geographic areas or with access to veterinary care. This study demonstrates that post-mortem investigation of AADs is an important and worthwhile endeavor.