Upregulation of hepatic bile acid synthesis via fibroblast growth factor 19 is defective in gallstone disease but functional in overweight individuals

Background: Fibroblast growth factor 19 (FGF19) is an enteric hormone regulating bile acid de novo synthesis by sensing ileal bile acid flux. However, the role of FGF19 in cholelithiasis has not yet been elucidated and therefore is investigated in the present study. Methods: Total mRNA and protein were isolated from ileal biopsies and used for tissue expression analysis. FGF19, 7α-hydroxycholesterol (7α-OH-Chol), 27-hydroxycholesterol (27-OH-Chol), and different bile acids were determined in the blood samples. Results: FGF19 serum levels did not differ between gallstone carriers and controls but were significantly decreased in the overweight individuals (−32%, p = 0.0002), irrespective of gallstone status (normalweight to overweight controls −29%, p = 0.0017; normalweight to overweight gallstone carriers −44%, p = 0.0338), and correlated inversely with bodyweight (p < 0.0001, ρ = −0.3317). Compared to non-overweight controls, apical sodium-dependent bile acid transporter expression was significantly diminished in the non-overweight gallstone carriers (−42%, PmRNA = 0.0393; −52%, pprotein = 0.0169) as well as in the overweight controls (−24%, PmRNA = 0.0148; −43%, pprotein = 0.0017). FGF19 expression varied widely and was similar in all groups. A significant negative correlation was noted between 7α-OH-Chol, 27-OH-Chol, and FGF19 serum levels (p < 0.01; ρ7α-OH-Chol = −0.2155; ρ27-OH-Chol = −0.2144) in obesity. Conclusion: Upregulation of hepatic bile acid synthesis via FGF 19 is defective in gallstone disease but functional in overweight individuals

Re-imagining the Borders of US Security after 9/11: Securitisation, Risk, and the Creation of the Department of Homeland Security

The articulation of international and transnational terrorism as a key issue in US security policy, as a result of the 9/11 attacks, has not only led to a policy rethink, it has also included a bureaucratic shift within the US, showing a re-thinking of the role of borders within US security policy. Drawing substantively on the 'securitisation' approach to security studies, the article analyses the discourse of US security in order to examine the founding of the Department of Homeland Security, noting that its mission provides a new way of conceptualising 'borders' for US national security. The securitisation of terrorism is, therefore, not only represented by marking terrorism as a security issue, it is also solidified in the organisation of security policy-making within the US state. As such, the impact of a 'war on terror' provides an important moment for analysing the re-articulation of what security is in the US, and, in theoretical terms, for reaffirming the importance of a relationship between the production of threat and the institutionalisation of threat response. © 2007 Taylor & Francis

Construction and immunogenicity evaluation of recombinant influenza A viruses containing chimeric hemagglutinin genes derived from genetically divergent influenza A H1N1 subtype viruses

Citation: McCormick, K., Jiang, Z., Zhu, L., Lawson, S. R., Langenhorst, R., Ransburgh, R., . . . Fang, Y. (2015). Construction and immunogenicity evaluation of recombinant influenza A viruses containing chimeric hemagglutinin genes derived from genetically divergent influenza A H1N1 subtype viruses. Plos One, 10(6). doi:10.1371/journal.pone.0127649Background and Objectives: Influenza A viruses cause highly contagious diseases in a variety of hosts, including humans and pigs. To develop a vaccine that can be broadly effective against genetically divergent strains of the virus, in this study we employed molecular breeding (DNA shuffling) technology to create a panel of chimeric HA genes. Methods and Results: Each chimeric HA gene contained genetic elements from parental swine influenza A viruses that had a history of zoonotic transmission, and also from a 2009 pandemic virus. Each parental virus represents a major phylogenetic clade of influenza A H1N1 viruses. Nine shuffled HA constructs were initially screened for immunogenicity in mice by DNA immunization, and one chimeric HA (HA-129) was expressed on both a A/Puerto Rico/8/34 backbone with mutations associated with a live, attenuated phenotype (PR8LAIV- 129) and a A/swine/Texas/4199-2/98 backbone (TX98-129). When delivered to mice, the PR8LAIV- 129 induced antibodies against all four parental viruses, which was similar to the breadth of immunity observed when HA-129 was delivered as a DNA vaccine. This chimeric HA was then tested as a candidate vaccine in a nursery pig model, using inactivated TX98-129 virus as the backbone. The results demonstrate that pigs immunized with HA-129 developed antibodies against all four parental viruses, as well as additional primary swine H1N1 influenza virus field isolates. Conclusion: This study established a platform for creating novel genes of influenza viruses using a molecular breeding approach, which will have important applications toward future development of broadly protective influenza virus vaccines. © 2015 McCormick et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

The vertebrate taxonomy ontology: a framework for reasoning across model organism and species phenotypes

Background: A hierarchical taxonomy of organisms is a prerequisite for semantic integration of biodiversity data. Ideally, there would be a single, expansive, authoritative taxonomy that includes extinct and extant taxa, information on synonyms and common names, and monophyletic supraspecific taxa that reflect our current understanding of phylogenetic relationships. Description: As a step towards development of such a resource, and to enable large-scale integration of phenotypic data across vertebrates, we created the Vertebrate Taxonomy Ontology (VTO), a semantically defined taxonomic resource derived from the integration of existing taxonomic compilations, and freely distributed under a Creative Commons Zero (CC0) public domain waiver. The VTO includes both extant and extinct vertebrates and currently contains 106,947 taxonomic terms, 22 taxonomic ranks, 104,736 synonyms, and 162,400 cross-references to other taxonomic resources. Key challenges in constructing the VTO included (1) extracting and merging names, synonyms, and identifiers from heterogeneous sources; (2) structuring hierarchies of terms based on evolutionary relationships and the principle of monophyly; and (3) automating this process as much as possible to accommodate updates in source taxonomies. Conclusions: The VTO is the primary source of taxonomic information used by the Phenoscape Knowledgebase (http://phenoscape.org/ webcite), which integrates genetic and evolutionary phenotype data across both model and non-model vertebrates. The VTO is useful for inferring phenotypic changes on the vertebrate tree of life, which enables queries for candidate genes for various episodes in vertebrate evolution. Keywords: Data integration; Evolutionary biology; Paleontology; Taxonomic ran

Phenoscape: Identifying Candidate Genes for Evolutionary Phenotypes

Phenotypes resulting from mutations in genetic model organisms can help reveal candidate genes for evolutionarily important phenotypic changes in related taxa. Although testing candidate gene hypotheses experimentally in nonmodel organisms is typically difficult, ontology-driven information systems can help generate testable hypotheses about developmental processes in experimentally tractable organisms. Here, we tested candidate gene hypotheses suggested by expert use of the Phenoscape Knowledgebase, specifically looking for genes that are candidates responsible for evolutionarily interesting phenotypes in the ostariophysan fishes that bear resemblance to mutant phenotypes in zebrafish. For this, we searched ZFIN for genetic perturbations that result in either loss of basihyal element or loss of scales phenotypes, because these are the ancestral phenotypes observed in catfishes (Siluriformes). We tested the identified candidate genes by examining their endogenous expression patterns in the channel catfish, Ictalurus punctatus. The experimental results were consistent with the hypotheses that these features evolved through disruption in developmental pathways at, or upstream of, brpf1 and eda/edar for the ancestral losses of basihyal element and scales, respectively. These results demonstrate that ontological annotations of the phenotypic effects of genetic alterations in model organisms, when aggregated within a knowledgebase, can be used effectively to generate testable, and useful, hypotheses about evolutionary changes in morphology