Attenuation of leukocyte sequestration by selective blockade of PECAM-1 or VCAM-1 in murine endotoxemia

Background: Molecular mechanisms regulating leukocyte sequestration into the tissue during endotoxemia and/or sepsis are still poorly understood. This in vivo study investigates the biological role of murine PECAM-1 and VCAM-1 for leukocyte sequestration into the lung, liver and striated skin muscle. Methods: Male BALB/c mice were injected intravenously with murine PECAM-1 IgG chimera or monoclonal antibody (mAb) to VCAM-1 ( 3 mg/kg body weight); controls received equivalent doses of IgG2a ( n = 6 per group). Fifteen minutes thereafter, 2 mg/kg body weight of Salmonella abortus equi endotoxin was injected intravenously. At 24 h after the endotoxin challenge, lungs, livers and striated muscle of skin were analyzed for their myeloperoxidase activity. To monitor intravital leukocyte-endothelial cell interactions, fluorescence videomicroscopy was performed in the skin fold chamber model of the BALB/c mouse at 3, 8 and 24 h after injection of endotoxin. Results: Myeloperoxidase activity at 24 h after the endotoxin challenge in lungs (12,171 +/- 2,357 mU/g tissue), livers ( 2,204 +/- 238 mU/g) and striated muscle of the skin ( 1,161 +/- 110 mU/g) was significantly reduced in both treatment groups as compared to controls, with strongest attenuation in the PECAM-1 IgG treatment group. Arteriolar leukocyte sticking at 3 h after endotoxin (230 +/- 46 cells x mm(-2)) was significantly reduced in both treatment groups. Leukocyte sticking in postcapillary venules at 8 h after endotoxin ( 343 +/- 69 cells/mm(2)) was found reduced only in the VCAM-1-mAb-treated animals ( 215 +/- 53 cells/mm(2)), while it was enhanced in animals treated with PECAM-1 IgG ( 572 +/- 126 cells/mm(2)). Conclusion: These data show that both PECAM-1 and VCAM-1 are involved in endotoxin-induced leukocyte sequestration in the lung, liver and muscle, presumably through interference with arteriolar and/or venular leukocyte sticking. Copyright (C) 2004 S. Karger AG, Basel

Recombining your way out of trouble: the genetic architecture of hybrid fitness under environmental stress

Hybridization between species is a fundamental evolutionary force that can both promote and delay adaptation. There is a deficit in our understanding of the genetic basis of hybrid fitness, especially in non-domesticated organisms. We also know little about how hybrid fitness changes as a function of environmental stress. Here, we made genetically variable F2 hybrid populations from two divergent Saccharomyces yeast species, exposed populations to ten toxins, and sequenced the most resilient hybrids on low coverage using ddRADseq. We expected to find strong negative epistasis and heterozygote advantage in the hybrid genomes. We investigated three aspects of hybridness: 1) hybridity, 2) interspecific heterozygosity, and 3) epistasis (positive or negative associations between non-homologous chromosomes). Linear mixed effect models revealed strong genotype-by-environment interactions with many chromosomes and chromosomal interactions showing species-biased content depending on the environment. Against our predictions, we found extensive selection against heterozygosity such that homozygous allelic combinations from the same species were strongly overrepresented in an otherwise hybrid genomic background. We also observed multiple cases of positive epistasis between chromosomes from opposite species, confirmed by epistasis- and selection-free simulations, which is surprising given the large divergence of the parental species (~15% genome-wide). Together, these results suggest that stress-resilient hybrid genomes can be assembled from the best features of both parents, without paying high costs of negative epistasis across large evolutionary distances. Our findings illustrate the importance of measuring genetic trait architecture in an environmental context when determining the evolutionary potential of hybrid populations

To lead or not to lead: regional powers and regional leadership

Recent trends demonstrate that states with sufficient capabilities to be granted regional power status by its peers (primarily other states within their region) can nonetheless renounce regional leadership. This article analyzes the puzzling behavior of these detached or reluctant regional powers. We argue that resorting to an approach grounded in neoclassical realism is helpful to explain why regional powers might not exercise leadership. In this article regional leadership is conceptualized as an auxiliary goal within the grand strategy of a regional power. This goal will be pursued in the absence of certain structural and domestic constraints. Great power competition determines the incentives for regional leadership at the structural level. Capacity to extract and mobilize resources for foreign policy affects the decision to pursue leadership at the domestic level. We apply the analytical framework to analyze Brazil’s detachment from South America after the Cardoso and Lula presidencies

Bulk Observers in Non-Factorizable Geometries

We consider five dimensional non-factorizable geometries where the transverse dimension is bounded and the remaining (parallel) dimensions are not. We study the construction of effective theories at distances much longer than the transverse size. An observer unable to resolve the transverse direction can only measure distances along the parallel dimensions, but the non-factorizable geometry makes the length of a curve along the parallel dimension sensitive to where on the transverse direction the curve lies. We show that long geodesics that differ in their endpoints only by shifts along the transverse direction all have the same length to within the observer's resolution. We argue that this is the correct notion of distance in the effective theory for a bulk observer. This allows us to present a consistent interpretation of what is measured by observers that live either on a brane or in the bulk