Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus

BACKGROUND: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. METHOD: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. RESULTS: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10(-4)) identified in the general populations, and rs113824616 (P = 7 × 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. CONCLUSION: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk

Strength of the Iberian intraplate lithosphere: Cenozoic deformations and seismicity

Previous studies about the strength of the lithosphere in the Iberia centre fail to resolve the depth of earthquakes because of the rheological uncertainties. Therefore, new contributions are considered (the crustal structure from a density model) and several parameters (tectonic regime, mantle rheology, strain rate) are checked in this paper to properly examine the role of lithospheric strength in the intraplate seismicity and the Cenozoic evolution. The strength distribution with depth, the integrated strength, the effective elastic thickness and the seismogenic thickness have been calculated by a finite element modelling of the lithosphere across the Central System mountain range and the bordering Duero and Madrid sedimentary basins. Only a dry mantle under strike-slip/extension and a strain rate of 10-15 s-1, or under extension and 10-16 s-1, causes a strong lithosphere. The integrated strength and the elastic thickness are lower in the mountain chain than in the basins. These anisotropies have been maintained since the Cenozoic and determine the mountain uplift and the biharmonic folding of the Iberian lithosphere during the Alpine deformations. The seismogenic thickness bounds the seismic activity in the upper–middle crust, and the decreasing crustal strength from the Duero Basin towards the Madrid Basin is related to a parallel increase in Plio–Quaternary deformations and seismicity. However, elasto–plastic modelling shows that current African–Eurasian convergence is resolved elastically or ductilely, which accounts for the low seismicity recorded in this region.

Revisiting the Late Jurassic-Early Cretaceous of the NW South Iberian Basin: new ages and sedimentary environments

The study of the Upper Jurassic-Lower Cretaceous deposits (Higueruelas, Villar del Arzobispo and Aldea de Cortés Formations) of the South Iberian Basin (NW Valencia, Spain) reveals new stratigraphic and sedimentological data, which have significant implications on the stratigraphic framework, depositional environments and age of these units. The Higueruelas Fm was deposited in a mid-inner carbonate platform where oncolitic bars migrated by the action of storms and where oncoid production progressively decreased towards the uppermost part of the unit. The overlying Villar del Arzobispo Fm has been traditionally interpreted as an inner platform-lagoon evolving into a tidal-flat. Here it is interpreted as an inner-carbonate platform affected by storms, where oolitic shoals protected a lagoon, which had siliciclastic inputs from the continent. The Aldea de Cortés Fm has been previously interpreted as a lagoon surrounded by tidal-flats and fluvial-deltaic plains. Here it is reinterpreted as a coastal wetland where siliciclastic muddy deposits interacted with shallow fresh to marine water bodies, aeolian dunes and continental siliciclastic inputs. The contact between the Higueruelas and Villar del Arzobispo Fms, classically defined as gradual, is also interpreted here as rapid. More importantly, the contact between the Villar del Arzobispo and Aldea de Cortés Fms, previously considered as unconformable, is here interpreted as gradual. The presence of Alveosepta in the Villar del Arzobispo Fm suggests that at least part of this unit is Kimmeridgian, unlike the previously assigned Late Tithonian-Middle Berriasian age. Consequently, the underlying Higueruelas Fm, previously considered Tithonian, should not be younger than Kimmeridgian. Accordingly, sedimentation of the Aldea de Cortés Fm, previously considered Valangian-Hauterivian, probably started during the Tithonian and it may be considered part of the regressive trend of the Late Jurassic-Early Cretaceous cycle. This is consistent with the dinosaur faunas, typically Jurassic, described in the Villar del Arzobispo and Aldea de Cortés Fms.

Relaciones de poder y memoria de un linaje. La intervención de la Casa de Moscoso en la Compostela de los siglos XIV-XVI

La ciudad ofrecía en la Baja Edad Media claras oportunidades para aquellos nobles que supieran situarse en el complejo juego de la política urbana y sus diversas instancias de poder. Para ello siempre se hace necesario contar con los apoyos sociales y físicos adecuados. La dinámica de enfrentamientos entre el Arzobispo de Santiago y el concello compostelano presenta un ejemplo inmejorable para valorar en su justa medida la inserción de la nobleza territorial en las relaciones de poder. Para abordar este caso se analizará la participación en la vida pública –también las revueltas urbanas– de la Casa de Moscoso tanto a través de su larga trayectoria de enfrentamientos con la Iglesia como mediante el estudio de su patrimonio urbano, incluyendo aquellos elementos relacionados con la creación de una memoria específica del linaje dentro de la ciudad.

Hypoxia-induced DNA hypermethylation in human pulmonary fibroblasts is associated with Thy-1 promoter methylation and the development of a pro-fibrotic phenotype

BACKGROUND: Pulmonary fibrosis is a debilitating and lethal disease with no effective treatment options. Understanding the pathological processes at play will direct the application of novel therapeutic avenues. Hypoxia has been implicated in the pathogenesis of pulmonary fibrosis yet the precise mechanism by which it contributes to disease progression remains to be fully elucidated. It has been shown that chronic hypoxia can alter DNA methylation patterns in tumour-derived cell lines. This epigenetic alteration can induce changes in cellular phenotype with promoter methylation being associated with gene silencing. Of particular relevance to idiopathic pulmonary fibrosis (IPF) is the observation that Thy-1 promoter methylation is associated with a myofibroblast phenotype where loss of Thy-1 occurs alongside increased alpha smooth muscle actin (α-SMA) expression. The initial aim of this study was to determine whether hypoxia regulates DNA methylation in normal human lung fibroblasts (CCD19Lu). As it has been reported that hypoxia suppresses Thy-1 expression during lung development we also studied the effect of hypoxia on Thy-1 promoter methylation and gene expression.

METHODS: CCD19Lu were grown for up to 8 days in hypoxia and assessed for global changes in DNA methylation using flow cytometry. Real-time PCR was used to quantify expression of Thy-1, α-SMA, collagen I and III. Genomic DNA was bisulphite treated and methylation specific PCR (MSPCR) was used to examine the methylation status of the Thy-1 promoter.

RESULTS: Significant global hypermethylation was detected in hypoxic fibroblasts relative to normoxic controls and was accompanied by increased expression of myofibroblast markers. Thy-1 mRNA expression was suppressed in hypoxic cells, which was restored with the demethylating agent 5-aza-2'-deoxycytidine. MSPCR revealed that Thy-1 became methylated following fibroblast exposure to 1% O2.

CONCLUSION: These data suggest that global and gene-specific changes in DNA methylation may play an important role in fibroblast function in hypoxia.

Job-demand for Learning and Job-related Learning: the Mediating Effect of Job Performance Improvement Initiatives

This study examined whether job-performance-improvementinitiatives mediate the relationship between individuals’ job-demand for learning and job-related learning. Data were obtained from 115 full-time employees in a diverse range of occupations. A partial least squares analysis revealed that job-performance-improvement-initiatives mediate partially the effects of job-demand for learning on job-related learning. Several implications for future research and policy are drawn from the findings.

Vocational Rehabilitation in Early Psychosis: Cluster Randomised Trial

Background Individual placement and support (IPS) is effective in helping patients return to work but is poorly implemented because of clinical ambivalence and fears of relapse. Aims To assess whether a motivational intervention (motivational interviewing) directed at clinical staff to address ambivalence about employment improved patients’ occupational outcomes. Method Two of four early intervention teams that already provided IPS were randomised to receive motivational interviewing training for clinicians, focused on attitudinal barriers to employment. The trial was registered with the International Standard Randomised Controlled Trial Register (ISRCTN71943786). Results Of 300 eligible participants, 159 consented to the research. Occupational outcomes were obtained for 134 patients (85%) at 12-month follow-up. More patients in the intervention teams than in the IPS-only teams achieved employment by 12 months (29/68 v. 12/66). A random effects logistic regression accounting for clustering by care coordinator, and adjusted for participants’ gender, ethnicity, educational and employment history and clinical status scores, confirmed superiority of the intervention (odds ratio = 4.3, 95% CI 1.5-16.6). Conclusions Employment outcomes were enhanced by addressing clinicians’ ambivalence about their patients returning to work.

Layers of Listening: Qualitative Analysis of the Impact of Early Intervention Services for First-episode Psychosis on Carers' Experiences

Background Early intervention services (EIS) comprise low-stigma, youth-friendly mental health teams for young people undergoing first-episode psychosis (FEP). Engaging with the family of the young person is central to EIS policy and practice. Aims By analysing carers' accounts of their daily lives and affective challenges during a relative's FEP against the background of wider research into EIS, this paper explores relationships between carers' experiences and EIS. Method Semi-structured longitudinal interviews with 80 carers of young people with FEP treated through English EIS. Results Our data suggest that EIS successfully aid carers to support their relatives, particularly through the provision of knowledge about psychosis and medications. However, paradoxical ramifications of these user-focused engagements also emerge; they risk leaving carers' emotions unacknowledged and compounding an existing lack of help-seeking. Conclusions By focusing on EIS's engagements with carers, this paper draws attention to an urgent broader question: as a continuing emphasis on care outside the clinic space places family members at the heart of the care of those with severe mental illness, we ask: who can, and should, support carers, and in what ways?

Exercise Prescription for Patients with Non-specific Chronic Low Back Pain: a Qualitative Study of Patients' Experiences in Decision Making

Background The culture of current clinical practice calls for collaboration between therapists and patients, sharing power and responsibility. This paper reports on the findings of a qualitative study of exercise prescription for patients with NSCLBP, taking into account issues such as decision making and how this accords with patient preferences and experiences. Objective To understand the treatment decision making experiences, information and decision support needs of patients with NSCLBP who have been offered exercise as part of their management plan. Design A qualitative study using a philosophical hermeneutic approach. Methods Semi-structured interviews with eight patients (including use of brief patient vignettes) was undertaken to explore their personal experiences of receiving exercise as part of the management of their NSCLBP, and their involvement in decisions regarding their care. Findings The findings provide a detailed insight into patients’ perceptions and experiences of receiving exercise-based management strategies. Four themes were formed from the texts: (1) patients’ expectations and patients’ needs are not synonymous, (2) information is necessary but often not sufficient, (3) not all decisions need to be shared, and (4) wanting to be treated as an individual. Conclusions Shared decision making did not appear to happen in physiotherapy clinical practice, but equally may not be what every patient wants. The overall feeling of the patients was that the therapist was dominant in structuring the interactions, leaving the patients feeling disempowered to question and contribute to the decision making.

Diferenciação pedagógica e o olhar do educador de infância

Relatório de estágio para a obtenção do grau de Mestre em Educação Pré-Escolar

Shifting development in mid-childhood: the influence of between-task interference

Performance on the task-switching paradigm is greatly affected by the amount of conflict between tasks. Compared to adults, children appear to be particularly influenced by this conflict, suggesting that the ability to resolve interference between tasks improves with age. We used the task-switching paradigm to investigate how this ability develops in mid-childhood. Experiment 1 compared 5- to 8-year-olds’ and 9- to 11-year-olds’ ability to switch between decisions about the colour of an object and its shape. The 5- to 8-year-olds were slower to switch task and experienced more interference from the irrelevant task than the 9-to 11-year-olds, suggesting a developmental improvement in resolving conflict between tasks during mid-childhood. Experiment 2 explored this further, examining the influence of stimulus and response interference at different ages. This was done by separating the colour and shape dimensions of the stimulus and reducing overlap between responses. The results supported the development of conflict resolution in task-switching during mid-childhood. They also revealed that a complex interplay of factors, including the tasks used and previous experience with the task, affected children’s shifting performance.

Association of the solute carrier family 11 member 1 gene polymorphisms with susceptibility to leprosy in a Brazilian sample

Natural resistance-associated macrophage protein 1/solute carrier family 11 member 1 gene (Nramp1/Slc11a1) is a gene that controls the susceptibility of inbred mice to intracellular pathogens. Polymorphisms in the human Slc11a1/Nramp1 gene have been associated with host susceptibility to leprosy. This study has evaluated nine polymorphisms of the Slc11a1/Nramp1 gene [(GT)n, 274C/T, 469+14G/C, 577-18G/A, 823C/T, 1029 C/T, 1465-85G/A, 1703G/A, and 1729+55del4] in 86 leprosy patients (67 and 19 patients had the multibacillary and the paucibacillary clinical forms of the disease, respectively), and 239 healthy controls matched by age, gender, and ethnicity. The frequency of allele 2 of the (GT)n polymorphism was higher in leprosy patients [p = 0.04, odds ratio (OR) = 1.49], whereas the frequency of allele 3 was higher in the control group (p = 0.03; OR = 0.66). Patients carrying the 274T allele (p = 0.04; OR = 1.49) and TT homozygosis (p = 0.02; OR = 2.46), such as the 469+14C allele (p = 0.03; OR = 1.53) of the 274C/T and 469+14G/C polymorphisms, respectively, were more frequent in the leprosy group. The leprosy and control groups had similar frequency of the 577-18G/A, 823C/T, 1029C/T, 1465-85G/A, 1703G/A, and 1729+55del4 polymorphisms. The 274C/T polymorphism in exon 3 and the 469+14G/C polymorphism in intron 4 were associated with susceptibility to leprosy, while the allele 2 and 3 of the (GT)n polymorphism in the promoter region were associated with susceptibility and protection to leprosy, respectively.