A Candidate Gene Association Study Identifies DAPL1 as a Female-Specific Susceptibility Locus for Age-Related Macular Degeneration (AMD)

Age-related macular degeneration (AMD) is the leading cause of blindness among white caucasians over the age of 50 years with a prevalence rate expected to increase markedly with an anticipated increase in the life span of the world population. To further expand our knowledge of the genetic architecture of the disease, we pursued a candidate gene approach assessing 25 genes and a total of 109 variants. Of these, synonymous single nucleotide polymorphism (SNP) rs17810398 located in death-associated protein-like 1 (DAPL1) was found to be associated with AMD in a joint analysis of 3,229 cases and 2,835 controls from five studies [combined P ADJ = 1.15 × 10(-6), OR 1.332 (1.187-1.496)]. This association was characterized by a highly significant sex difference (P diff = 0.0032) in that it was clearly confined to females with genome-wide significance [P ADJ = 2.62 × 10(-8), OR 1.541 (1.324-1.796); males: P ADJ = 0.382, OR 1.084 (0.905-1.298)]. By targeted resequencing of risk and non-risk associated haplotypes in the DAPL1 locus, we identified additional potentially functional risk variants, namely a common 897-bp deletion and a SNP predicted to affect a putative binding site of an exonic splicing enhancer. We show that the risk haplotype correlates with a reduced retinal transcript level of two, less frequent, non-canonical DAPL1 isoforms. DAPL1 plays a role in epithelial differentiation and may be involved in apoptotic processes thereby suggesting a possible novel pathway in AMSaveD pathogenesis.

The chromosome 3q25 locus associated with fetal adiposity is not associated with childhood adiposity

Increased newborn adiposity is associated with later adverse metabolic outcomes. Previous genome-wide association studies (GWAS) demonstrated strong association of a locus on chromosome 3 (3q25.31) with newborn sum of skinfolds, a measure of overall adiposity. Whether this locus is associated with childhood adiposity is unknown. Genotype and sum of skinfolds data were available for 293 children at birth and age 2, and for 350 children at birth and age 6 from a European cohort (Belfast, UK) who participated in the Hyperglycemia and Adverse Pregnancy Outcome GWAS. We examined single nucleotide polymorphisms (SNPs) at the 3q25.31 locus associated with newborn adiposity. Linear regression analyses under an additive genetic model adjusting for maternal body mass index were performed. In both cohorts, a positive association was observed between all SNPs and sum of skinfolds at birth (P=2.3 × 10(-4), β=0.026 and P=4.8 × 10(-4), β=0.025). At the age of 2 years, a non-significant negative association was observed with sum of skinfolds (P=0.06; β =-0.015). At the age of 6 years, there was no evidence of association (P=0.86; β=0.002). The 3q25.31 locus strongly associated with newborn adiposity had no significant association with childhood adiposity suggesting that its impact may largely be limited to fetal fat accretion.

Polymorphisms near TBX5 and GDF7 are associated with increased risk for Barrett's esophagus

BACKGROUND & AIMS: Barrett's esophagus (BE) increases the risk of esophageal adenocarcinoma (EAC). We found the risk to be BE has been associated with single nucleotide polymorphisms (SNPs) on chromosome 6p21 (within the HLA region) and on 16q23, where the closest protein-coding gene is FOXF1. Subsequently, the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) identified risk loci for BE and esophageal adenocarcinoma near CRTC1 and BARX1, and within 100 kb of FOXP1. We aimed to identify further SNPs that increased BE risk and to validate previously reported associations.

METHODS: We performed a genome-wide association study (GWAS) to identify variants associated with BE and further analyzed promising variants identified by BEACON by genotyping 10,158 patients with BE and 21,062 controls.

RESULTS: We identified 2 SNPs not previously associated with BE: rs3072 (2p24.1; odds ratio [OR] = 1.14; 95% CI: 1.09-1.18; P = 1.8 × 10(-11)) and rs2701108 (12q24.21; OR = 0.90; 95% CI: 0.86-0.93; P = 7.5 × 10(-9)). The closest protein-coding genes were respectively GDF7 (rs3072), which encodes a ligand in the bone morphogenetic protein pathway, and TBX5 (rs2701108), which encodes a transcription factor that regulates esophageal and cardiac development. Our data also supported in BE cases 3 risk SNPs identified by BEACON (rs2687201, rs11789015, and rs10423674). Meta-analysis of all data identified another SNP associated with BE and esophageal adenocarcinoma: rs3784262, within ALDH1A2 (OR = 0.90; 95% CI: 0.87-0.93; P = 3.72 × 10(-9)).

CONCLUSIONS: We identified 2 loci associated with risk of BE and provided data to support a further locus. The genes we found to be associated with risk for BE encode transcription factors involved in thoracic, diaphragmatic, and esophageal development or proteins involved in the inflammatory response.

Applying Health Locus of Control and Latent Class Modelling to food and physical activity choices affecting CVD risk

Health Locus of Control (HLC) classifies our beliefs about the connection between our actions and health outcomes (Skinner, 1996) into three categories: “internal control”, corresponding to health being the result of an individual's effort and habits; “control by powerful others”, whereby health depends on others, such as doctors; and “chance control”, according to which health depends on fate and chance. Using Choice Experiments we investigate the relationship between HLC and willingness to change lifestyle, in terms of eating habits, physical activity and associated cardiovascular disease risk, in a 384 person sample representative of the 40–65 aged population of Northern Ireland administered between February and July 2011. Using latent class analysis we identify three discrete classes of people based on their HLC: the first class is sceptical about their capacity to control their health and certain unhealthy habits. Despite being unsatisfied with their situation, they are reluctant to accept behaviour changes. The second is a group of individuals unhappy with their current situation but willing to change through exercise and diet. Finally, a group of healthy optimists is identified, who are satisfied with their current situation but happy to take more physical activity and improve their diet. Our findings show that any policy designed to modify people's health related behaviour should consider the needs of this sceptical class which represents a considerable proportion of the population in the region.

Autosomal dominant retinitis pigmentosa:a new multi-allelic marker (D3S621) genetically linked to the disease locus (RP4)

We report the characterization of a new eight-allele microsatellite (D3S621) isolated from a human chromosome 3 library. Two-point and multi-locus genetic linkage analysis have shown D3S621 to co-segregate with the previously mapped RP4 (theta m = 0.12, Zm = 4.34) and with other genetic markers on the long arm of the chromosome, including D3S14 (R208) (theta m = 0.00, Zm = 15.10), D3S47 (C17) (theta m = 0.11, Zm = 4.95), Rho (theta m = 0.07, Zm = 1.37), D3S21 (L182) (theta m = 0.07, Zm = 2.40) and D3S19 (U1) (theta m = 0.13, Zm = 2.78). This highly informative marker, with a polymorphic information content of 0.78, should be of considerable value in the extension of linkage data for autosomal dominant retinitis pigmentosa with respect to locii on the long arm of chromosome 3.

A box in the field: modernity and the barn in twentieth-century Ireland

This paper argues that the modern barn in Ireland is a complex social and architectural phenomena that is without, or has yet to find, a satisfactory discourse. Emerging in the middle third of the twentieth century, the modern barn – replete with corrugated iron and I-sections – continues to represent a presence in the Irish landscape whose ubiquity is as emphatic as its flexibility. It is, however, its universal properties that begin to suggest connections with wider narratives. The modernising aspects of the barn that appear in the 1920s and 30s begin to conflate with a rhetoric of architectural modernism which was simultaneously appearing across Europe. But while the relationship between high modernism’s critique of what it divined as the inspirational qualities of utilitarian buildings – Walter Gropius on grain silos, Le Corbusier on aircraft hangers etc. – has been well-documented, in Ireland this relationship perhaps contains another layer of complexity.
The barn’s consolidation as a modern type coincided with the search for a nation’s cultural identity after centuries of colonial rule. This tended to be an introspective vision that prioritised rural space over urban space, agriculture over industry, and imagined the small farm as a central tenet in the construction of a new State. This paper suggests that the twentieth-century barn – as a product of the mechanisation of agriculture promoted by the new administrations – is an iconic structure, emblematic of attempts to reconcile the contradictory forces and imagery of modernity with the mores of a traditional society. Moreover, given a cultural purview that was often ambivalent or even hostile to the ideologies and forms of modernity, the barn in Ireland is, perhaps, not so much the inspiration but the realisation of an architectural modernism in that country at its most pervasive, enduring and unself-conscious.

Personalised and Precision Medicine in Cancer Clinical Trials: Panacea for Progress or Pandora's Box?

Cancer clinical trials have been one of the key foundations for significant advances in oncology. However, there is a clear recognition within the academic, care delivery and pharmaceutical/biotech communities that our current model of clinical trial discovery and development is no longer fit for purpose. Delivering transformative cancer care should increasingly be our mantra, rather than maintaining the status quo of, at best, the often miniscule incremental benefits that are observed with many current clinical trials. As we enter the era of precision medicine for personalised cancer care (precision and personalised medicine), it is important that we capture and utilise our greater understanding of the biology of disease to drive innovative approaches in clinical trial design and implementation that can lead to a step change in cancer care delivery. A number of advances have been practice changing (e.g. imatinib mesylate in chronic myeloid leukaemia, Herceptin in erb-B2-positive breast cancer), and increasingly we are seeing the promise of a number of newer approaches, particularly in diseases like lung cancer and melanoma. Targeting immune checkpoints has recently yielded some highly promising results. New algorithms that maximise the effectiveness of clinical trials, through for example a multi-stage, multi-arm type design are increasingly gaining traction. However, our enthusiasm for the undoubted advances that have been achieved are being tempered by a realisation that these new approaches may have significant cost implications. This article will address these competing issues, mainly from a European perspective, highlight the problems and challenges to healthcare systems and suggest potential solutions that will ensure that the cost/value rubicon is addressed in a way that allows stakeholders to work together to deliver optimal cost-effective cancer care, the benefits of which can be transferred directly to our patients.

Implicit optimality criterion for convex SIP problem with box constrained index set

We consider a convex problem of Semi-Infinite Programming (SIP) with multidimensional index set. In study of this problem we apply the approach suggested in [20] for convex SIP problems with one-dimensional index sets and based on the notions of immobile indices and their immobility orders. For the problem under consideration we formulate optimality conditions that are explicit and have the form of criterion. We compare this criterion with other known optimality conditions for SIP and show its efficiency in the convex case.

O locus amoenus na produção narrativa de Júlio Dinis

No presente trabalho avalia-se o contributo de uma vasta tradição literária na configuração de um topos/motivo – o locus amoenus – patente na produção dinisiana. Analisaram-se as influências da literatura clássica greco-romana, das Sagradas Escrituras, da literatura italiana, e também da literatura produzida em Portugal desde o final da Idade Média até ao Maneirismo. As obras de dois escritores representativos do Romantismo vintista português, Pároco da Aldeia, de Alexandre Herculano, e Os contos do tio Joaquim, de Rodrigo Paganino, tornaram-se tributárias do topos/motivo. A pesquisa centrou-se na narrativa dinisiana com vista a investigar, por um lado, as relações que o locus amoenus, topos/motivo em estudo, mantém com categorias narrativas contíguas, como sejam o espaço ou a descrição; e, por outro, a aferir o eventual contributo do lugar ameno para a dissipação das fronteiras entre a narrativa e a lírica. Pretendeu-se igualmente, sem desprezar uma inclinação natural de Júlio Dinis para os ambientes campestres, demonstrar a existência de três dimensões fundamentais do lugar ameno: a psicológica, cujas origens se perdem no tempo; a social, vertente inovadora no contexto do tópico abordado; e a simbólica, em que a conexão com o locus horrendus se revelou incontornável. Com o estudo do vocabulário configurador do locus amoenus da produção narrativa dinisiana, reflectiu-se mais aprofundadamente sobre as questões tratadas no cômputo geral desta tese. A complexidade que envolve a tentativa de filiação de Júlio Dinis a um movimento ou escola não fica ainda resolvida com este trabalho. Porém surge a proposta de lançar um novo olhar sobre este assunto, à luz dos pressupostos do movimento alemão Biedermeier. Independentemente dos problemas que se levantam, fica a certeza de que muitos escritores do panorama literário nacional se inspiraram nas obras de Júlio Dinis

‘To me, it's like a little box of tricks’: Breaking the depressive interlock as a programme participant in mindfulness-based cognitive therapy

Objectives. Mindfulness meditation practices have become increasingly popular in clinical therapies, changing patterns of depressogenic thinking for individuals who experience consecutive episodes of depression. We were interested in finding out how Mindfulness Based Cognitive Therapy (MBCT) worked for programme participants by focussing on how meditative practices changed their relationships to their thoughts. Design. Data for the study came from six semi-structured research interviews carried out with individuals who had taken part in an 8 week MBCT programme Methods. We used Interpretative Phenomenological Analysis (IPA) to analyse the experiential accounts. Results. We report on two superordinate themes – Engaging the Neutral Mind (with subordinate themes ‘breaking the paralysis of worry’ and ‘choosing to think differently’) and Experiencing the Neutral Mind (with subordinate themes of ‘reflection on previous thinking styles’ and ‘becoming psychologically self-reliant’). Conclusions. Themes from the present study offer support to the assertion that mindfulness meditation helps facilitate a different mode of meta-cognitive processing with which to handle depression-related cognitions. Practitioner Points Participants reported that they experienced an enhanced capacity to differentiate between their thought processes, experiencing an ability to tolerate some more uncomfortable thoughts and experiencing a/more choice in how to respond to thoughts Participants recognised that ruminating over negative thoughts was related to depressive states and experienced a shift in meta-cognitive processes that actively challenged depressogenic cognitions Participants became more psychologically self-reliant and therapeutically independent following MBCT Integrating mindfulness based practices in therapy may be a mediating factor in sustaining psychological wellbeing and may help clients develop self-compassion Future research looks to examining exit cases to understand elements of MBCT which are experienced as less successful by clients

The downy mildew resistance locus Pp523 is located on chromosome C8 of Brassica oleracea L.

We have previously constructed a genetic map of Brassica oleracea L. containing the Pp523 locus that confers downy mildew resistance to adult plants. In this work, 44 SSR markers of reference for the Brassica C genome chromosomes were added to the map, allowing the nine major linkage groups to be assigned to the nine chromosomes of B. oleracea. Locus Pp523 was located on chromosome C8, and a locus determining flower colour was mapped to chromosome C3. In comparison with the first version of the map, the new map is denser and more compact. The available genomic information on B. oleracea was enriched with the chromosome location of two phenotypic traits and 421 DNA markers (RAPD, ISSR, AFLP, SCAR, BAC-end derived STS, SSR and other PCR markers). Conversely, the genomic information on B. oleracea chromosome C8 is being used as an additional tool for the map-based cloning of Pp523, the first gene for adult plant resistance to downy mildew precisely located to a specific chromosome of this crop species.