Rapid synthesis and zebrafish evaluation of a phenanthridine-based small molecule library

A Heck cyclisation approach is described for the rapid synthesis of a library of natural product-like small molecules, based on the phenanthridine core. The synthesis of a range of substituted benzylamine building blocks and their incorporation into the library is reported, together with a highly selective cis-dihydroxylation protocol that enables access to the target compounds in an efficient manner. Biological evaluation of the library using zebrafish phenotyping has led to the discovery of compound 20c, a novel inhibitor of early-stage zebrafish embryo development.

Gifts, Loans and Intergenerational Support for Young Adults

Young adults in the UK are increasingly dependent on family support to offset the costs of living independently. This article explores these complex intergenerational exchanges from the perspective of a group of single young adults in their mid-twenties to mid-thirties who had been in receipt of various forms of financial and material support from family members since leaving the parental home. We outline the nature of this support and then consider how these forms of assistance are understood by those in receipt of them. We conclude that the co-existence of a sense of both gratitude and discomfort which is often generated by these exchanges is managed but by no means resolved by a blurring of the boundaries between gifts and loans, a set of negotiations which may not even be an option amongst less advantaged young adults.

Intermedin (Adrenomedullin-2) a novel counter-regulatory peptide in the cardiovascular and renal systems

Intermedin (IMD) is a novel peptide related to calcitonin gene-related peptide (CGRP) and adrenomedullin (AM). Proteolytic processing of a larger precursor yields a series of biologically active C-terminal fragments, IMD1–53, IMD1–47 and IMD8–47. IMD shares a family of receptors with AM and CGRP composed of a calcitonin-receptor like receptor (CALCRL) associated with one of three receptor activity modifying proteins (RAMP). Compared to CGRP, IMD is less potent at CGRP1 receptors but more potent at AM1 receptors and AM2 receptors; compared to AM, IMD is more potent at CGRP1 receptors but less potent at AM1 and AM2 receptors. The cellular and tissue distribution of IMD overlaps in some aspects with that of CGRP and AM but is distinct from both. IMD is present in neonatal but absent or expressed sparsely, in adult heart and vasculature and present at low levels in plasma. The prominent localization of IMD in hypothalamus and pituitary and in kidney is consistent with a physiological role in the central and peripheral regulation of the circulation and water-electrolyte homeostasis. IMD is a potent systemic and pulmonary vasodilator, influences regional blood flow and augments cardiac contractility. IMD protects myocardium from the deleterious effects of oxidative stress associated with ischaemia-reperfusion injury and exerts an anti-growth effect directly on cardiomyocytes to oppose the influence of hypertrophic stimuli. The robust increase in expression of the peptide in hypertrophied and ischaemic myocardium indicates an important protective role for IMD as an endogenous counter-regulatory peptide in the heart.

Spanish Golden Age Poetry in Motion: The Dynamics of Creation and Conversation.

The fourteen essays of this volume engage in distinct ways with the matter of motion in early modern Spanish poetics, without limiting the dialectic of stasis and movement to any single sphere or manifestation. Interrogation of the interdependence of tradition and innovation, poetry, power and politics, shifting signifiers, the intersection of topography and deviant temporalities, the movement between the secular and the sacred, tensions between centres and peripheries, issues of manuscript circulation and reception, poetic calls and echoes across continents and centuries, and between creative writing and reading subjects, all demonstrate that Helgerson's central notion of conspicuous movement is relevant beyond early sixteenth-century secular poetics, By opening it up we approximate a better understanding of poetry's flexible spatio-temporal co-ordinates in a period of extraordinary historical circumstances and conterminous radical cultural transformation

Circulating and synovial antibody profiling of juvenile arthritis patients by nucleic acid programmable protein arrays.

Introduction Juvenile idiopathic arthritis (JIA) is a heterogeneous disease characterized by chronic joint inflammation of unknown cause in children. JIA is an autoimmune disease and small numbers of auto-antibodies have been reported in JIA patients. The identification of antibody markers could improve the existing clinical management of patients. Methods A pilot study was performed on the application of a high-throughput platform, nucleic acid programmable protein arrays (NAPPA), to assess the levels of antibodies present in the systemic circulation and synovial joint of a small cohort of juvenile arthritis patients. Plasma and synovial fluid from ten JIA patients was screened for antibodies against 768 proteins on NAPPA. Results Quantitative reproducibility of NAPPA was demonstrated with >0.95 intra- and inter- array correlations. A strong correlation was also observed for the levels of antibodies between plasma and synovial fluid across the study cohort (r=0.96). Differences in the levels of 18 antibodies were revealed between sample types across all patients. Patients were segregated into two clinical subtypes with distinct antibody signatures by unsupervised hierarchical cluster analysis. Conclusions NAPPA provides a high-throughput quantitatively reproducible platform to screen for disease specific autoantibodies at the proteome level on a microscope slide. The strong correlation between the circulating antibody levels and those of the inflamed joint represents a novel finding and provides confidence to use plasma for discovery of autoantibodies in JIA, thus circumventing the challenges associated with joint aspiration. We expect that autoantibody profiling of JIA patients on NAPPA could yield antibody markers that can act as criteria to stratify patients, predict outcomes and understand disease etiology at the molecular level.

Cinematic and Architectonic Space in Tarkovsky's Solaris

Architecture plays an important role in Andrei Tarkovsky’s films in defining the atmosphere of a space and memory of a place. This paper is a study of how the settings in Tarkovsky’s Solaris (1972) are used to provoke and convey feelings to the audience through architectonic space depicting the city, library, home and aspects of the home such as paintings and mirrors. The rooms depicted in Solaris (Fig. 1) are filled with symbolism and detail. They are imbued with a poetic quality rarely seen in cinema. The everyday places of city, library and home in Solaris are given an emotional depth not usually found in these spaces in reality. Solaris is an anomaly among Tarkovsky’s films in that the majority of the narrative takes place in an enclosed built set. Rarely do Tarkovsky spaces exert so much control over the actors’ movements within a meticulously designed and detailed set. This paper analyses how the director uses constructed sets in Solaris to confront our perception of memories, dreams and reality.
The intent of this study is to gain better understanding of the link between architecture and other art forms such as painting and cinema through spatial analysis. This study also relates to our imagination and how we perceive architectonic space portrayed through cinematic images. The architectural theory of Juhani Pallasmaa forms the basis of this paper.

Radiation retinopathy--clinical, histopathological, ultrastructural and experimental correlations

Clinical, pathological and experimental studies of radiation retinopathy confirm that the primary vascular event is endothelial cell loss and capillary closure. Pericytes are less susceptible, but typically atrophy as the capillaries become non-functional. The immediate effects of radiation reflect interphase and early mitotic death of injured endothelial cells, whereas later changes may be attributed to delayed mitotic death of compromised endothelial cells as they attempt division in the ordinary course of repair and replacement. Capillary occlusion leads to the formation of dilated capillary collaterals which may remain serviceable and competent for years. Microaneurysms develop in acellular and poorly supported capillaries, predominantly on the arterial side of the circulation and adjacent to regions of poorly perfused retina. Alterations in haemodynamics produce large telangiectatic-like channels which, typically develop a thick collagenous adventitia and may become fenestrated. Limited capillary regeneration occurs, usually evident as recanalisation of arterioles or venules by new capillaries. Vitreo-retinal neovascularisation may occur where retinal ischaemia is widespread. Radiation produces an exaggerated vasculopathy in patients with diabetes mellitus, and five month streptozotocin-induced diabetic rats develop a severe ischaemic retinopathy with vitreoretinal neovascularisation when exposed to 1500 cGy of radiation. Later photocoagulation is useful in containing or reversing microvascular incompetence and vasoproliferation in some patients with advanced radiation retinopathy.

EU Social and Labour Rights and EU Internal Market Law: Study for the EMPL Committee

EU Social and Labour Rights have developed incrementally, originally through a set of legislative initiatives creating selective employment rights, followed by a non-binding Charter of Social Rights. Only in 2009, social and labour rights became legally binding through the Charter of Fundamental Rights for the European Union (CFREU). By contrast, the EU Internal Market - an area without frontiers where goods, persons, services and capital can circulate freely – has been enshrined in legally enforceable Treaty provisions from 1958. These comprise the economic freedoms guaranteeing said free circulation and a system ensuring that competition is not distorted within the Internal Market (Protocol 27 to the Treaty of Lisbon). Tensions between Internal Market law and social and labour rights have been observed in analyses of EU case law and legislation. This study explores responses by socio-economic and political actors at national and EU levels to such tensions, focusing on collective labour rights, rights to fair working conditions and rights to social security and social assistance (Articles 12, 28, 31, 34 Charter of Fundamental Rights for the European Union). On the basis of the current Treaties and the CFREU, the constitutionally conditioned Internal Market emerges as a way to overcome the perception that social and labour rights limit Internal Market law, or vice versa. On this basis, alternative responses to perceived tensions are proposed, focused on posting of workers, furthering fair employment conditions through public procurement and enabling effective collective bargaining and industrial action in the Internal Market.

Biomarkers reveal the effects of hydrography on the sources and fate of marine and terrestrial organic matter in the western Irish Sea

A suite of lipid biomarkers were investigated from surface sediments and particulate matter across hydrographically distinct zones associated with the western Irish Sea gyre and the seasonal bloom. The aim was to assess the variation of organic matter (OM) composition, production, distribution and fate associated with coastal and southern mixed regions and also the summer stratified region. Based on the distribution of a suite of diagnostic biomarkers, including phospholipid fatty acids, source-specific sterols, wax esters and C₂₅ highly branched isoprenoids, diatoms, dinoflagellates and green algae were identified as major contributors of marine organic matter (MOM) in this setting. The distribution of cholesterol, wax esters and C₂₀ and C₂₂ polyunsaturated fatty acids indicate that copepod grazing represents an important process for mineralising this primary production. Net tow data from 2010 revealed much greater phytoplankton and zooplankton biomass in well-mixed waters compared to stratified waters. This appears to be largely reflected in MOM input to surface sediments. Terrestrial organic matter (TOM), derived from higher plants, was identified as a major source of OM regionally, but was concentrated in proximity to major riverine input at the Boyne Estuary and Dundalk Bay. Near-bottom residual circulation and the seasonal gyre also likely play a role in the fate of TOM in the western Irish Sea.

Occupy Differently: Space, Community and Urban Counter-Conduct

This article demonstrates how the concept of counter-conducts helps us understand Occupy by directing attention to the correlation between the way advanced liberalism works to control urban spaces and the way that control is countered through Occupy’s tactics. The first section outlines the term counter-conducts by looking to Foucault’s short and undeveloped theorisation. The second examines how advanced liberalism conducts conduct through the use of urban space, concentrating on London which comes to form a space of and for the mobility and circulation of goods, people and ideas. Occupy’s tactics directly confront and counter such movement while engaging in its own forms of counter-circulation and (im)mobility. The third section examines how advanced liberal techniques have increasingly come to use a particular, heavily instrumentalised understanding of community in order to divide and control urban populations. Occupy’s tactics embody versions of community which confront and oppose such instrumentalisation, ultimately both engaging with that control and partially reproducing it. Through these counter-conducts we can come to a view of Occupy as inevitably succeeding in its failure as a movement and failing in its success, while opening to an (im)possible
futurity of occupying urban space differently.

Systemic recruitment of osteoblastic cells in fracture healing

We hypothesise that following a bone fracture there is systemic recruitment of bone forming cells to a fracture site. A rabbit ulnar osteotomy model was adapted to trace the movement of osteogenic cells. Bone marrow mesenchymal stem cells from 41 NZW rabbits were isolated, culture-expanded and fluorescently labelled. The labelled cells were either re-implanted into the fracture gap (Group A); into a vein (Group B); or into a remote tibial bone marrow cavity 48 h after the osteotomy (Group C) or 4 weeks before the osteotomy was established (Group D), and a control group (Group E) had no labelled cells given. To quantify passive leakage of cells to an injury site, inert beads were also co-delivered in Group B. Samples of the fracture callus tissue and various organs were harvested at discrete sacrifice time-points to trace and quantify the labelled cells. At 3 weeks following osteotomy, the number of labelled cells identified in the callus of Group C, was significantly greater than following IV delivery, Group B, and there was no difference in the number of labelled cells in the callus tissues, between Groups C and A, indicating the labelled bone marrow cells were capable of migrating to the fracture sites from the remote bone marrow cavity. Significantly fewer inert beads than labelled cells were identified in Group B callus, suggesting some of the bone-forming cells were actively recruited and selectively chosen to the fracture site, rather than passively leaked into the circulation and to bone injury site. This investigation supports the hypothesis that some osteoblasts involved in fracture healing were systemically mobilised and recruited to the fracture from remote bone marrow sites. © 2005 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved.

The thermohaline expressway: the Southern Ocean as a centre of origin for deep-sea octopuses

Understanding how environmental forcing has generated and maintained large-scale patterns of biodiversity is a key goal of evolutionary research and critical to predicting the impacts of global climate change. We suggest that the initiation of the global thermohaline circulation provided a mechanism for the radiation of Southern Ocean fauna into the deep sea. We test this hypothesis using a relaxed phylogenetic approach to coestimate phylogeny and divergence times for a lineage of octopuses with Antarctic and deep-sea representatives. We show that the deep-sea lineage had their evolutionary origins in Antarctica, and estimate that this lineage diverged around 33?million years ago (Ma) and subsequently radiated at 15?Ma. Both of these dates are critical in development of the thermohaline circulation and we suggest that this has acted as an evolutionary driver enabling the Southern Ocean to become a centre of origin for deep-sea fauna. This is the first unequivocal molecular evidence that deep-sea fauna from other ocean basins originated from Southern Ocean taxa and this is the first evidence to be dated.

Becoming Bluestockings: Contextualising Hannah More's "The Bas Bleu"

Hannah More's poem 'The Bas Bleu' was the first account of the Bluestockings to be published from within the Bluestocking circle itself. It remained the most significant defence of Bluestocking ideals for many decades thereafter, years in which satirical depictions of the Bluestockings would predominate. This essay locates More's poem in the contexts of its original composition (1783), manuscript circulation and eventual publication (1786). The poem's transformation from a manuscript to a published poem exemplifies its particular significance as a public statement in which the Bluestockings attained prominence and celebrity.

Amplified optomechanics in a unidirectional ring cavity

We investigate optomechanical forces on a nearly lossless scatterer, such as an atom pumped far off-resonance or amicromirror, inside an optical ring cavity. Our model introduces two additional features to the cavity: an isolator is used to prevent circulation and resonant enhancement of the pump laser field and thus to avoid saturation of or damage to the scatterer, and an optical amplifier is used to enhance the effective Q-factor of the counterpropagating mode and thus to increase the velocity-dependent forces by amplifying the back-scattered light. We calculate friction forces, momentum diffusion, and steady-state temperatures to demonstrate the advantages of the proposed setup.