Potent anti-inflammatory effects of an H2 S-releasing naproxen (ATB-346) in a human model of inflammation

ATB-346 is a hydrogen sulfide-releasing non-steroidal anti-inflammatory drug (H2 S-NSAID) derived from naproxen, which in preclinical studies has been shown to have markedly reduced gastrointestinal adverse effects. However, its anti-inflammatory properties in humans compared to naproxen are yet to be confirmed. To test this, we used a dermal model of acute inflammation in healthy, human volunteers, triggered by ultraviolet-killed Escherichia coli. This robust model allows quantification of the cardinal signs of inflammation along with cellular and humoral factors accumulating within the inflamed skin. ATB-346 was non-inferior to naproxen in terms of its inhibition of cyclooxygenase activity as well as pain and tenderness. ATB-346 significantly inhibited neutrophil infiltration at the site of inflammation at 4 h, compared to untreated controls. Subjects treated with ATB-346 also experienced significantly reduced pain and tenderness compared to healthy controls. Furthermore, both classical and intermediate monocyte subsets infiltrating the site of inflammation at 48 h expressed significantly lower levels of CD14 compared to untreated controls, demonstrating a shift toward an anti-inflammatory phenotype. Collectively, we have shown for the first time in humans that ATB-346 is potently anti-inflammatory and propose that ATB-346 represents the next generation of H2 S-NSAIDs, as a viable alternative to conventional NSAIDs, with reduced adverse effects profile

Genetic Evaluation of Hip Score in UK Labrador Retrievers

Hip dysplasia is an important and complex genetic disease in dogs with both genetic and environmental influences. Since the osteoarthritis that develops is irreversible the only way to improve welfare, through reducing the prevalence, is through genetic selection. This study aimed to evaluate the progress of selection against hip dysplasia, to quantify potential improvements in the response to selection via use of genetic information and increases in selection intensity, and to prepare for public provision of estimated breeding values (EBV) for hip dysplasia in the UK. Data consisted of 25,243 single records of hip scores of Labrador Retrievers between one and four years old, from radiographs evaluated between 2000 and 2007 as part of the British Veterinary Association (BVA) hip score scheme. A natural logarithm transformation was applied to improve normality and linear mixed models were evaluated using ASREML. Genetic correlations between left and right scores, and total hip scores at one, two and three years of age were found to be close to one, endorsing analysis of total hip score in dogs aged one to three as an appropriate approach. A heritability of 0.35±0.016 and small but significant litter effect (0.07±0.009) were estimated. The observed trends in both mean hip score and mean EBV over year of birth indicate that a small genetic improvement has been taking place, approximately equivalent to avoiding those dogs with the worst 15% of scores. Deterministic analysis supported by simulations showed that a 19% greater response could be achieved using EBV compared to phenotype through increases in accuracy alone. This study establishes that consistent but slow genetic improvement in the hip score of UK Labrador Retrievers has been achieved over the previous decade, and demonstrates that progress may be easily enhanced through the use of EBVs and more intense selection

The Genomic Signature of Crop-Wild Introgression in Maize

The evolutionary significance of hybridization and subsequent introgression has long been appreciated, but evaluation of the genome-wide effects of these phenomena has only recently become possible. Crop-wild study systems represent ideal opportunities to examine evolution through hybridization. For example, maize and the conspecific wild teosinte Zea mays ssp. mexicana, (hereafter, mexicana) are known to hybridize in the fields of highland Mexico. Despite widespread evidence of gene flow, maize and mexicana maintain distinct morphologies and have done so in sympatry for thousands of years. Neither the genomic extent nor the evolutionary importance of introgression between these taxa is understood. In this study we assessed patterns of genome-wide introgression based on 39,029 single nucleotide polymorphisms genotyped in 189 individuals from nine sympatric maize-mexicana populations and reference allopatric populations. While portions of the maize and mexicana genomes were particularly resistant to introgression (notably near known cross-incompatibility and domestication loci), we detected widespread evidence for introgression in both directions of gene flow. Through further characterization of these regions and preliminary growth chamber experiments, we found evidence suggestive of the incorporation of adaptive mexicana alleles into maize during its expansion to the highlands of central Mexico. In contrast, very little evidence was found for adaptive introgression from maize to mexicana. The methods we have applied here can be replicated widely, and such analyses have the potential to greatly informing our understanding of evolution through introgressive hybridization. Crop species, due to their exceptional genomic resources and frequent histories of spread into sympatry with relatives, should be particularly influential in these studies

Build it, but will they come? A geoscience cyberinfrastructure baseline analsys

Understanding the earth as a system requires integrating many forms of data from multiple fields. Builders and funders of the cyberinfrastructure designed to enable open data sharing in the geosciences risk a key failure mode: What if geoscientists do not use the cyberinfrastructure to share, discover and reuse data? In this study, we report a baseline assessment of engagement with the NSF EarthCube initiative, an open cyberinfrastructure effort for the geosciences. We find scientists perceive the need for cross-disciplinary engagement and engage where there is organizational or institutional support. However, we also find a possibly imbalanced involvement between cyber and geoscience communities at the outset, with the former showing more interest than the latter. This analysis highlights the importance of examining fields and disciplines as stakeholders to investments in the cyberinfrastructure supporting science

Genetic Analysis of Central Carbon Metabolism Unveils an Amino Acid Substitution That Alters Maize NAD-Dependent Isocitrate Dehydrogenase Activity

Background: Central carbon metabolism (CCM) is a fundamental component of life. The participating genes and enzymes are thought to be structurally and functionally conserved across and within species. Association mapping utilizes a rich history of mutation and recombination to achieve high resolution mapping. Therefore, applying association mapping in maize (Zea mays ssp. mays), the most diverse model crop species, to study the genetics of CCM is a particularly attractive system. Methodology/Principal Findings: We used a maize diversity panel to test the CCM functional conservation. We found heritable variation in enzyme activity for every enzyme tested. One of these enzymes was the NAD-dependent isocitrate dehydrogenase (IDH, E.C. 1.1.1.41), in which we identified a novel amino-acid substitution in a phylogenetically conserved site. Using candidate gene association mapping, we identified that this non-synonymous polymorphism was associated with IDH activity variation. The proposed mechanism for the IDH activity variation includes additional components regulating protein level. With the comparison of sequences from maize and teosinte (Zea mays ssp. Parviglumis), the maize wild ancestor, we found that some CCM genes had also been targeted for selection during maize domestication. Conclusions/Significance: Our results demonstrate the efficacy of association mapping for dissecting natural variation in primary metabolic pathways. The considerable genetic diversity observed in maize CCM genes underlies heritable phenotypic variation in enzyme activities and can be useful to identify putative functional sites

Sexual Size Dimorphism and Body Condition in the Australasian Gannet

Funding: The research was financially supported by the Holsworth Wildlife Research Endowment. Acknowledgments We thank the Victorian Marine Science Consortium, Sea All Dolphin Swim, Parks Victoria, and the Point Danger Management Committee for logistical support. We are grateful for the assistance of the many field volunteers involved in the study.Peer reviewedPublisher PD

Heterozygosity increases microsatellite mutation rate, linking it to demographic history

<p>Abstract</p> <p>Background</p> <p>Biochemical experiments in yeast suggest a possible mechanism that would cause heterozygous sites to mutate faster than equivalent homozygous sites. If such a process operates, it could undermine a key assumption at the core of population genetic theory, namely that mutation rate and population size are indpendent, because population expansion would increase heterozygosity that in turn would increase mutation rate. Here we test this hypothesis using both direct counting of microsatellite mutations in human pedigrees and an analysis of the relationship between microsatellite length and patterns of demographically-induced variation in heterozygosity.</p> <p>Results</p> <p>We find that microsatellite alleles of any given length are more likely to mutate when their homologue is unusually different in length. Furthermore, microsatellite lengths in human populations do not vary randomly, but instead exhibit highly predictable trends with both distance from Africa, a surrogate measure of genome-wide heterozygosity, and modern population size. This predictability remains even after statistically controlling for non-independence due to shared ancestry among populations.</p> <p>Conclusion</p> <p>Our results reveal patterns that are unexpected under classical population genetic theory, where no mechanism exists capable of linking allele length to extrinsic variables such as geography or population size. However, the predictability of microsatellite length is consistent with heterozygote instability and suggest that this has an important impact on microsatellite evolution. Whether similar processes impact on single nucleotide polymorphisms remains unclear.</p

No effect of 14 day consumption of whole grain diet compared to refined grain diet on antioxidant measures in healthy, young subjects: a pilot study

<p>Abstract</p> <p>Background</p> <p>Epidemiological evidence supports that a diet high in whole grains is associated with lowered risk of chronic diseases included coronary heart disease, obesity, type 2 diabetes, and some types of cancer. One potential mechanism for the protective properties of whole grains is their antioxidant content. The aim of this study was to compare differences in antioxidant measures when subjects consumed either refined or whole grain diets.</p> <p>Methods</p> <p>Twenty healthy subjects took part in a randomized, crossover dietary intervention study. Subjects consumed either a refined grain or whole grain diet for 14 days and then the other diet for the next 14 days. Male subjects consumed 8 servings of grains per day and female subjects consumed 6 servings of grains per day. Blood and urine samples were collected at the end of each diet. Antioxidant measures included oxygen radical absorbance capacity (ORAC) in blood, and isoprostanes and thiobarbituric acid reactive substances (TBARS) in urine.</p> <p>Results</p> <p>The whole grain diet was significantly higher in dietary fiber, vitamin B6, folate, selenium, copper, zinc, iron, magnesium and cystine compared to the refined grain diet. Despite high intakes of whole grains, no significant differences were seen in any of the antioxidant measures between the refined and whole grain diets.</p> <p>Conclusions</p> <p>No differences in antioxidant measures were found when subjects consumed whole grain diets compared to refined grain diets.</p

Genetic Variation and Population Substructure in Outbred CD-1 Mice: Implications for Genome-Wide Association Studies

Outbred laboratory mouse populations are widely used in biomedical research. Since little is known about the degree of genetic variation present in these populations, they are not widely used for genetic studies. Commercially available outbred CD-1 mice are drawn from an extremely large breeding population that has accumulated many recombination events, which is desirable for genome-wide association studies. We therefore examined the degree of genome-wide variation within CD-1 mice to investigate their suitability for genetic studies. The CD-1 mouse genome displays patterns of linkage disequilibrium and heterogeneity similar to wild-caught mice. Population substructure and phenotypic differences were observed among CD-1 mice obtained from different breeding facilities. Differences in genetic variation among CD-1 mice from distinct facilities were similar to genetic differences detected between closely related human populations, consistent with a founder effect. This first large-scale genetic analysis of the outbred CD-1 mouse strain provides important considerations for the design and analysis of genetic studies in CD-1 mice

Rapid Accumulation of Polymorphonuclear Neutrophils in the Corpus luteum during Prostaglandin F2α-Induced Luteolysis in the Cow

Prostaglandin F2α (PGF2α) induces luteolysis within a few days in cows, and immune cells increase in number in the regressing corpus luteum (CL), implying that luteolysis is an inflammatory-like immune response. We investigated the rapid change in polymorphonuclear neutrophil (PMN) numbers in response to PGF2α administration as the first cells recruited to inflammatory sites, together with mRNA of interleukin-8 (IL-8: neutrophil chemoattractant) and P-selectin (leukocyte adhesion molecule) in the bovine CL. CLs were collected by ovariectomy at various times after PGF2α injection. The number of PMNs was increased at 5 min after PGF2α administration, whereas IL-8 and P-selectin mRNA increased at 30 min and 2 h, respectively. PGF2α directly stimulated P-selectin protein expression at 5–30 min in luteal endothelial cells (LECs). Moreover, PGF2α enhanced PMN adhesion to LECs, and this enhancement by PGF2α was inhibited by anti-P-selectin antibody, suggesting that P-selectin expression by PGF2α is crucial in PMN migration. In conclusion, PGF2α rapidly induces the accumulation of PMNs into the bovine CL at 5 min and enhances PMN adhesion via P-selectin expression in LECs. It is suggested that luteolytic cascade by PGF2α may involve an acute inflammatory-like response due to rapidly infiltrated PMNs