FLT1 Genetic Variation Predisposes to Neovascular AMD in Ethnically Diverse Populations and Alters Systemic FLT1 Expression

Purpose: Current understanding of the genetic risk factors for age-related macular degeneration (AMD) is not sufficiently predictive of the clinical course. The VEGF pathway is a key therapeutic target for treatment of neovascular AMD; however, risk attributable to genetic variation within pathway genes is unclear. We sought to identify single nucleotide polymorphisms (SNPs) associated with AMD within the VEGF pathway.
Methods: Using a tagSNP, direct sequencing and meta-analysis approach within four ethnically diverse cohorts, we identified genetic risk present in FLT1, though not within other VEGF pathway genes KDR, VEGFA, or VASH1. We used ChIP and ELISA in functional analysis.
Results: The FLT1 SNPs rs9943922, rs9508034, rs2281827, rs7324510, and rs9513115 were significantly associated with increased risk of neovascular AMD. Each association was more significant after meta-analysis than in any one of the four cohorts. All associations were novel, within noncoding regions of FLT1 that do not tag for coding variants in linkage disequilibrium. Analysis of soluble FLT1 demonstrated higher expression in unaffected individuals homozygous for the FLT1 risk alleles rs9943922 (P = 0.0086) and rs7324510 (P = 0.0057). In silico analysis suggests that these variants change predicted splice sites and RNA secondary structure, and have been identified in other neovascular pathologies. These data were supported further by murine chromatin immunoprecipitation demonstrating that FLT1 is a target of Nr2e3, a nuclear receptor gene implicated in regulating an AMD pathway.
Conclusions: Although exact variant functions are not known, these data demonstrate relevancy across ethnically diverse genetic backgrounds within our study and, therefore, hold potential for global efficacy.

Islands: Nature and Culture

Islands are contradictory places: they can be remote, mysterious spots, or lively centres of holiday revelry. They are associated alternately with escape, imprisonment, holiday and exile, and their exotic, otherworldly beauty has inspired artists and writers across the centuries. Islands have been sites of immense political, creative and scientific importance from Charles Darwin's enlightening voyage to the Gálapagos Islands, which resulted in his groundbreaking theory of evolution, to the moat-encased prisons incarcerating the world's most dangerous convicts.
Despite the common view of islands as earthly paradises, their often small size means they have restricted resources and limited opportunities for their inhabitants to thrive. In response, islanders have welcomed or sternly rejected, the fresh opportunities offered by turning their homes into tourist destinations. For people seeking beautiful landscapes, solitude or exciting adventure, islands are the most popular holiday spots in the world. They entice the rich and famous, and their allure has provided refuge and inspiration for artists and writers, from Paul Gauguin in Tahiti to George Orwell on Jura in the Hebrides, and general visitors alike.
Filled with illustrations, Islands is a comprehensive exploration of the geographical and cultural aspects of island life – their habitations and environments, their permanent residents and vast transitional populace, their colonial history and their enduring appeal to people around then world.

Clarifying the acquis humanitaire: a transnational legal perspective on the internalization of humanitarian norms

Although the international obligations and institutional frameworks for disaster response are not yet settled, as evidenced by the International Law Commission’s work on the protection of persons in the event of disasters and the on-going promotion of disaster laws by the Red Cross Movement; the diverse source and nature of such initiatives suggests that the international community is engaged in a process of norm creation, elaboration and interpretation reflecting a desire for legal clarity in humanitarian operations. Situated within the framework of transnational law, this paper argues that an acquis humanitaire, based on the principle of humanity, encapsulates the evolving body of law and practice specifically relating to the protection of persons in times of humanitarian crisis in both armed conflicts and natural or human-made disasters. Reflecting the non-traditional, non-statist, dynamic and normative basis of transnational legal process, as elaborated by Harold Koh, the constant flow of ideas and principles between the national, regional and international spheres provides an analytical framework for the on-going transnational dialogues on the social, political and legal internalization of humanitarian norms. Drawing on the internalization of humanitarian norms within the United Kingdom, this paper concludes that as the international community examines the codification of a universal legal framework for the protection of persons in the event of disasters it is necessary to understand the transnational process of interpretation and internalization of humanitarian norms, and how this may vary across different regions and countries.

A Novel Bradykinin-Related Dodecapeptide (RVALPPGFTPLR) from the Skin Secretion of the Fujian Large-Headed Frog (Limnonectes fujianensis) Exhibiting Unusual Structural and Functional Features

Bradykinin-related peptides (BRPs) are significant components of the defensive skin secretions of many anuran amphibians, and these secretions represent the source of the most diverse spectrum of such peptides so far encountered in nature. Of the many families of bioactive peptides that have been identified from this source, the BRPs uniquely appear to represent homologues of counterparts that have specific distributions and receptor targets within discrete vertebrate taxa, ranging from fishes through mammals. Their broad spectra of actions, including pain and inflammation induction and smooth muscle effects, make these peptides ideal weapons in predator deterrence. Here, we describe a novel 12-mer BRP (RVALPPGFTPLR-RVAL-(L1, T6, L8)-bradykinin) from the skin secretion of the Fujian large-headed frog (Limnonectes fujianensis). The C-terminal 9 residues of this BRP (-LPPGFTPLR) exhibit three amino acid substitutions (L/R at Position 1, T/S at Position 6 and L/F at Position 8) when compared to canonical mammalian bradykinin (BK), but are identical to the kinin sequence present within the cloned kininogen-2 from the Chinese soft-shelled turtle (Pelodiscus sinensis) and differ from that encoded by kininogen-2 of the Tibetan ground tit (Pseudopodoces humilis) at just a single site (F/L at Position 8). These data would imply that the novel BRP is an amphibian defensive agent against predation by sympatric turtles and also that the primary structure of the avian BK, ornithokinin (RPPGFTPLR), is not invariant within this taxon. Synthetic RVAL-(L1, T6, L8)-bradykinin was found to be an antagonist of BK-induced rat tail artery smooth muscle relaxation acting via the B2-receptor.

Angels with dirty faces? European identity, politics of representation and recognition of Romani interests

The contradiction between acknowledgement of cultural differences and their accommodation in public has been a constant theme in studies of diverse societies. This review essay discusses five volumes that grapple with questions of Romani inclusion and the problems Roma face across Europe. The volumes under review point to problems faced by Romani communities and analyse the various legal, political and social challenges that situation of the Roma poses to institutions of contemporary societies. The essay reviews the challenging nature of the status of Roma as we move away from the one-sided towards more reciprocal relationship engagement of state with society in general, and the multiply excluded groups, in particular. The essay finds that the role Roma play in these relationships is either over-, or under-estimated by the literature, largely as a result of limited opportunities to acknowledge and, in effect, accommodate Roma who are rarely understood as actors in their own right.

The Nature of Religious Diversity: A Cultural Ecosystem Approach

Studies of religious and other cultural groups tend to be particularistic or focus on one or more axes of variation. In this article we develop a more comprehensive approach to studying cultural diversity that emulates the study of biological diversity. We compare our cultural ecosystem approach with the axis approach, using the distinction between “tight” and “loose” cultures as an example. We show that while the axis approach is useful, the cultural ecosystem approach adds considerable value to the axis approach. We end by advocating the establishment of field sites for the study of religious and cultural diversity, comparable to biological field sites.

Ecopoetics: The Language of Nature, The Nature of Language by Scott Knickerbocker (review)

Review of Ecopoetics: The Language of Nature, The Nature of Language by Scott Knickerbocker Boston: University of Massachusetts Press, 2012. Pp. x + 203.
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Viscosity and Carbon Dioxide Solubility for LiPF6, LiTFSI, and LiFAP in Alkyl Carbonates: Lithium Salt Nature and Concentration Effect