Conduct disorder : the achievement of a diagnosis'

This paper explores the historical shapings behind the diagnosis of conduct disorders. We take as our point of purchase oppositional ways of knowing the subject of conduct disorder—as either pathologically motivated or as the victim of a repressive mandate to control disorderly conduct. We take our cue from Foucault's suggestion that the pursuit of singular motivations behind a phenomenon is not the most fruitful means of understanding its historical appearance. We explore the emergence of the individual with conduct disorder as an appearance contingent upon dispersed agencies of government—an artefact of dispersed technologies for channelling and directing a population

Investigation of a role for GPR35 as a novel therapeutic target in cardiovascular disease

G protein-coupled receptors (GPCRs) are often described as ‘gate-keepers’ of the eukaryotic cell and their roles primarily involve translating extra-cellular stimuli via G protein coupling and intracellular signalling to govern various physiological responses. These functional parameters are wide ranging and include the modulation of visual sensory organs, to the control of vasoreactivity and heart rate. Importantly, their flexible architecture can facilitate small molecule interaction within a ‘binding-pocket’ and GPCR research often focuses on this relationship to identify and design novel and effective ligands to manipulate GPCR activation and signalling. GPR35 is a poorly characterised, Class A GPCR and despite reports of two potential endogenous activators; kynurenic acid (KYNA) and lysophosphatidic acid (LPA) in recent years, it is still widely acknowledged as an ‘orphaned’ GPCR. This is reflected by the propensity of its ligands, both endogenous and synthetic, to demonstrate extreme species orthologue-selective properties. Despite this, investigators have highlighted various roles for GPR35 relating to pain, inflammation, hypertension and heart failure, and investigations have suggested that activation of GPR35 leads to a selective coupling of Gα13, a G-protein understood to mediate Rho A and ROCK 1/2 signalling. However, a lack of functional ligand pairs has hampered further research to examine a role for GPR35 and subsequent Gα13 signalling in these disease models. In this study, we have characterised a series of highly-potent, synthetic ligands at human, rat and mouse orthologues of GPR35, revealing that GPR35 agonist, pamoic acid and antagonists, CID-2745687 and ML-145, are highly potent and selective for the human orthologue of GPR35. This has provided us with the opportunity to assess a functional role for GPR35 within a cardiovascular disease setting using functional ligand pairs in cells of a human origin, for the first time. Vascular smooth muscle cell (VSMC) migration and proliferation are central to neointima formation in vein graft failure. Despite a detailed understanding of VSMC migration and proliferation mechanisms, there are no pharmacological interventions which effectively prevent vein graft failure through intimal occlusion. In this study, we demonstrated that primary vascular cells expressed robustly detectable levels of GPR35, and these were comparable to those demonstrated in the colon, which has been previously reported to highly express GPR35. Human GPR35 is potently activated by the selective agonist pamoic acid and reference ligand zaprinast and blocked by antagonists CID-2745687 and ML-145. Following exposure of VSMC to pamoic acid or zaprinast, cell migration was enhanced and these effects were blocked by co-incubation with CID-2745687 or ML-145. Pamoic acid induced HSV SMC migration was also blocked in the presence of two distinct Rho A pathway inhibitors, Y-16 and Y-27632. Activation of this pathway was also reflected by remodelling of the cytoskeletal architecture in HSV SMCs to significantly elongate the cell and promote a contractile, migratory phenotype following pamoic acid stimulation and this effect was also blocked following co-administration with either antagonist. Additionally, we also demonstrated that following exposure to pamoic acid or zaprinast, human saphenous vein endothelial cell (HSV EC) integrity and proliferation were significantly improved and this was blocked following co-administration with either antagonist, suggesting a protective role for GPR35 in the vascular endothelium. Results from a previous study demonstrated that lack of GPR35 expression resulted in an elevation in systolic blood pressure (SBP) by up to 37.5mmHg in mice. The recent identification of mast-cell stabilising compounds as highly potent agonists at GPR35 provided the opportunity to pharmacologically target GPR35 within a rodent model of hypertension. Therefore, we also aimed to test if pharmacological manipulation of GPR35 via stimulation with the novel, rodent selective agonist amlexanox, modulated blood pressure and end-organ related damage in 6-12 weeks of age stroke prone spontaneously hypertensive rats (SHRSPs). Radiotelemetry acquisition of haemodynamic properties highlighted that pharmacological agonism of GPR35 exacerbated hypertension and end-organ damage in the SHRSP and this was evident following an elevation in SBP by 20mmHg throughout the trial. Moreover, quantification of heart mass and cardiomyocyte size revealed that GPR35 agonism induced cardiac hypertrophy. Collagen staining revealed enhanced renal fibrosis in both the interstitial and perivascular regions of the kidney from amlexanox treated animals, compared to vehicle controls. Additionally, large vessel myography highlighted that endothelium-dependent vasorelaxation was reduced by 20% in amlexanox treated SHRSPs. Fundamentally, these results suggest that GPR35 is involved in regulating vascular tone and we hypothesise that this may involve the Gα13-Rho A-ROCK1/2 signalling pathway demonstrated to mediate a contractile, migratory phenotype in human primary VSMCs. Taking these data together, the results suggest that GPR35 antagonists might be of clinical use to therapeutically target and inhibit activation of GPR35 in the setting of vascular remodelling during acute vascular injury, and hypertension and its related end organ damage

On innocence lost: How children are made dangerous

This article explores continuities of despotism within liberal governance. It introduces recent government investments in the need to protect children from institutional and organisational abuse in the context of which loss of innocence is conceptualised as a moment in a biography, following exposure to violence. The article contrasts those investments with contemporaneous claims by the state that as other-than-innocent, certain children in its care are legitimately exempted from moral-ethical norms embedded elsewhere in the logic of governing childhood proper. The article turns to historical understandings of the welfare of children in the state of Victoria, Australia, to explore the conditions and the means by which children in state care came to be figured as other-than-innocent exceptions, rightly exposed to forms of authoritarian violence. Loss of innocence is explored as an enduring achievement of government in the context of aspirations to do with population, territory and national security

Barriers to evidence use for sustainability: Insights from pesticide policy and practice.

Calls for supporting sustainability through more and better research rest on an incomplete understanding of scientific evidence use. We argue that a variety of barriers to a transformative impact of evidence arises from diverse actor motivations within different stages of evidence use. We abductively specify this variety in policy and practice arenas for three actor motivations (truth-seeking, sense-making, and utility-maximizing) and five stages (evidence production, uptake, influence on decisions, effects on sustainability outcomes, and feedback from outcome evaluations). Our interdisciplinary synthesis focuses on the sustainability challenge of reducing environmental and human health risks of agricultural pesticides. It identifies barriers resulting from (1) truth-seekers' desire to reduce uncertainty that is complicated by evidence gaps, (2) sense-makers' evidence needs that differ from the type of evidence available, and (3) utility-maximizers' interests that guide strategic evidence use. We outline context-specific research-policy-practice measures to increase evidence use for sustainable transformation in pesticides and beyond

The Arabidopsis B3 domain protein VERNALIZATION1 is involved in processes essential for development with structural and mutational studies revealing its DNA binding surface

The B3 DNA-binding domain is a plant-specific domain found throughout the plant kingdom from the alga Chlamydomonas to grasses and flowering plants. Over 100 B3 domain-containing proteins are found in the model plant Arabidopsis thaliana, and one of these is critical for accelerating flowering in response to prolonged cold treatment, an epigenetic process called vernalization. Despite the specific phenotype of genetic vrn1 mutants, the VERNALIZATION1 (VRN1) protein localizes throughout the nucleus and shows sequence-nonspecific binding in vitro. In this work, we used a dominant repressor tag that overcomes genetic redundancy to show that VRN1 is involved in processes beyond vernalization that are essential for Arabidopsis development. To understand its sequence-nonspecific binding, we crystallized VRN1(208-341) and solved its crystal structure to 1.6 angstrom resolution using selenium/single-wavelength anomalous diffraction methods. The crystallized construct comprises the second VRN1 B3 domain and a preceding region conserved among VRN1 orthologs but absent in other B3 domains. We established the DNA-binding face using NMR and then mutated positively charged residues on this surface with a series of 16 Ala and Glu substitutions, ensuring that the protein fold was not disturbed using heteronuclear single quantum correlation NMR spectra. The triple mutant R249E/R289E/R296E was almost completely incapable of DNA binding in vitro. Thus, we have revealed that although VRN1 is sequence-nonspecific in DNA binding, it has a defined DNA-binding surface

Using decision analysis to support proactive management of emerging infectious wildlife diseases

Despite calls for improved responses to emerging infectious diseases in wildlife, management is seldom considered until a disease has been detected in affected populations. Reactive approaches may limit the potential for control and increase total response costs. An alternative, proactive management framework can identify immediate actions that reduce future impacts even before a disease is detected, and plan subsequent actions that are conditional on disease emergence. We identify four main obstacles to developing proactive management strategies for the newly discovered salamander pathogen Batrachochytrium salamandrivorans (Bsal). Given that uncertainty is a hallmark of wildlife disease management and that associated decisions are often complicated by multiple competing objectives, we advocate using decision analysis to create and evaluate trade-offs between proactive (pre-emergence) and reactive (post-emergence) management options. Policy makers and natural resource agency personnel can apply principles from decision analysis to improve strategies for countering emerging infectious diseases

Genomic Restructuring in the Tasmanian Devil Facial Tumour: Chromosome Painting and Gene Mapping Provide Clues to Evolution of a Transmissible Tumour

Devil facial tumour disease (DFTD) is a fatal, transmissible malignancy that threatens the world's largest marsupial carnivore, the Tasmanian devil, with extinction. First recognised in 1996, DFTD has had a catastrophic effect on wild devil numbers, and intense research efforts to understand and contain the disease have since demonstrated that the tumour is a clonal cell line transmitted by allograft. We used chromosome painting and gene mapping to deconstruct the DFTD karyotype and determine the chromosome and gene rearrangements involved in carcinogenesis. Chromosome painting on three different DFTD tumour strains determined the origins of marker chromosomes and provided a general overview of the rearrangement in DFTD karyotypes. Mapping of 105 BAC clones by fluorescence in situ hybridisation provided a finer level of resolution of genome rearrangements in DFTD strains. Our findings demonstrate that only limited regions of the genome, mainly chromosomes 1 and X, are rearranged in DFTD. Regions rearranged in DFTD are also highly rearranged between different marsupials. Differences between strains are limited, reflecting the unusually stable nature of DFTD. Finally, our detailed maps of both the devil and tumour karyotypes provide a physical framework for future genomic investigations into DFTD

Barriers to evidence use for sustainability: Insights from pesticide policy and practice

Calls for supporting sustainability through more and better research rest on an incomplete understanding of scientific evidence use. We argue that a variety of barriers to a transformative impact of evidence arises from diverse actor motivations within different stages of evidence use. We abductively specify this variety in policy and practice arenas for three actor motivations (truth-seeking, sense-making, and utility-maximizing) and five stages (evidence production, uptake, influence on decisions, effects on sustainability outcomes, and feedback from outcome evaluations). Our interdisciplinary synthesis focuses on the sustainability challenge of reducing environmental and human health risks of agricultural pesticides. It identifies barriers resulting from (1) truth-seekers’ desire to reduce uncertainty that is complicated by evidence gaps, (2) sense-makers’ evidence needs that differ from the type of evidence available, and (3) utility-maximizers’ interests that guide strategic evidence use. We outline context-specific research–policy–practice measures to increase evidence use for sustainable transformation in pesticides and beyond

Experimental Demonstration of the Fitness Consequences of an Introduced Parasite of Darwin's Finches

Introduced parasites are a particular threat to small populations of hosts living on islands because extinction can occur before hosts have a chance to evolve effective defenses. An experimental approach in which parasite abundance is manipulated in the field can be the most informative means of assessing a parasite's impact on the host. The parasitic fly Philornis downsi, recently introduced to the Galápagos Islands, feeds on nestling Darwin's finches and other land birds. Several correlational studies, and one experimental study of mixed species over several years, reported that the flies reduce host fitness. Here we report the results of a larger scale experimental study of a single species at a single site over a single breeding season.We manipulated the abundance of flies in the nests of medium ground finches (Geospiza fortis) and quantified the impact of the parasites on nestling growth and fledging success. We used nylon nest liners to reduce the number of parasites in 24 nests, leaving another 24 nests as controls. A significant reduction in mean parasite abundance led to a significant increase in the number of nests that successfully fledged young. Nestlings in parasite-reduced nests also tended to be larger prior to fledging.Our results confirm that P. downsi has significant negative effects on the fitness of medium ground finches, and they may pose a serious threat to other species of Darwin's finches. These data can help in the design of management plans for controlling P. downsi in Darwin's finch breeding populations

Evaluating Patterns of a White-Band Disease (WBD) Outbreak in Acropora palmata Using Spatial Analysis: A Comparison of Transect and Colony Clustering

. Likewise, there is little known about the spatiality of outbreaks. We examined the spatial patterns of WBD during a 2004 outbreak at Buck Island Reef National Monument in the US Virgin Islands. colonies with and without WBD.As the search for causation continues, surveillance and proper documentation of the spatial patterns may inform etiology, and at the same time assist reef managers in allocating resources to tracking the disease. Our results indicate that the spatial scale of data collected can drastically affect the calculation of prevalence and spatial distribution of WBD outbreaks. Specifically, we illustrate that higher resolution sampling resulted in more realistic disease estimates. This should assist in selecting appropriate sampling designs for future outbreak investigations. The spatial techniques used here can be used to facilitate other coral disease studies, as well as, improve reef conservation and management