Function of the PDLIM2 protein in oncogenic Wnt signalling pathways

Aberrant regulation of the Wnt signalling pathway is a recurrent theme in cancer biology. Hyper activation due to oncogenic mutations and paracrine activity has been found in both colon cancer and breast cancer, and continues to evolve as a central mechanism in oncogenesis. PDLIM2, a cytoskeletal PDZ protein, is an IGF-1 regulated gene that is highly expressed in cancer cell lines derived from metastatic tumours. Suppression of PDLIM2 inhibits polarized cell migration, reverses the Epithelial to Mesenchymal transition (EMT) phenotype, suppresses the transcription of β-catenin target genes, and regulates gene expression of key transcription factors in EMT. This thesis investigates the mechanism by which PDLIM2 contributes to the maintenance of Wnt signalling in cancer cells. Here we show that PDLIM2 is a critical regulator of the Wnt pathway by regulating β-catenin at the adherens juctions, as also its transcriptional activity by the interaction of PDLIM2 with TCF4 at the nucleus. Evaluation of PDLIM2 in macrophages and co-culture studies with cancer cells and fibroblasts showed the influence exerted on PDLIM2 by paracrine cues. Thus, PDLIM2 integrates cytoskeleton signalling with gene expression by modulating the Wnt signalling pathway and reconciling microenvironmental cues with signals in epithelial cells. Negative correlation of mRNA and protein levels in the triple negative breast cancer cell BT549 suggests that PDLIM2 is part of a more complex mechanism that involves transcription and posttranslational modifications. GST pulldown studies and subsequent mass spectrometry analysis showed that PDLIM2 interacts with 300 proteins, with a high biological function in protein biosynthesis and Ubiquitin/proteasome pathways, including 13 E3 ligases. Overall, these data suggest that PDLIM2 has two distinct functions depending of its location. Located at the cytoplasm mediates cytoskeletal re-arrangements, whereas at the nucleus PDLIM2 acts as a signal transduction adaptor protein mediating transcription and ubiquitination of key transcription factors in cancer development.

UV-Induced Melanoma Mouse Model Dependent on Endothelin 3 Over-Expression

Melanoma is one of the most aggressive types of cancer. It originates from the transformation of melanocytes present in the epidermal/dermal junction of the human skin. It is commonly accepted that melanomagenesis is influenced by the interaction of environmental factors, genetic factors, as well as tumor-host interactions. DNA photoproducts induced by UV radiation are, in normal cells, repaired by the nucleotide excision repair (NER) pathway. The prominent role of NER in cancer resistance is well exemplified by patients with Xeroderma Pigmentosum (XP). This disease results from mutations in the components of the NER pathway, such as XPA and XPC proteins. In humans, NER pathway disruption leads to the development of skin cancers, including melanoma. Similar to humans afflicted with XP, Xpa and Xpc deficient mice show high sensibility to UV light, leading to skin cancer development, except melanoma. The Endothelin 3 (Edn3) signaling pathway is essential for proliferation, survival and migration of melanocyte precursor cells. Excessive production of Edn3 leads to the accumulation of large numbers of melanocytes in the mouse skin, where they are not normally found. In humans, Edn3 signaling pathway has also been implicated in melanoma progression and its metastatic potential. The goal of this study was the development of the first UV-induced melanoma mouse model dependent on the over-expression of Edn3 in the skin. The UV-induced melanoma mouse model reported here is distinguishable from all previous published models by two features: melanocytes are not transformed a priori and melanomagenesis arises only upon neonatal UV exposure. In this model, melanomagenesis depends on the presence of Edn3 in the skin. Disruption of the NER pathway due to the lack of Xpa or Xpc proteins was not essential for melanomagenesis; however, it enhanced melanoma penetrance and decreased melanoma latency after one single neonatal erythemal UV dose. Exposure to a second dose of UV at six weeks of age did not change time of appearance or penetrance of melanomas in this mouse model. Thus, a combination of neonatal UV exposure with excessive Edn3 in the tumor microenvironment is sufficient for melanomagenesis in mice; furthermore, NER deficiency exacerbates this process.

Age determination of seven sediment cores from the South Pacific Ocean

During the last deglaciation, the opposing patterns of atmospheric CO2 and radiocarbon activities (D14C) suggest the release of 14C-depleted CO2 from old carbon reservoirs. Although evidences point to the deep Pacific as a major reservoir of this 14C-depleted carbon, its extent and evolution still need to be constrained. Here we use sediment cores retrieved along a South Pacific transect to reconstruct the spatio-temporal evolution of D14C over the last 30,000 years. In ~2,500-3,600 m water depth, we find 14C-depleted deep waters with a maximum glacial offset to atmospheric 14C (DD14C = -1,000 per mil). Using a box model, we test the hypothesis that these low values might have been caused by an interaction of aging and hydrothermal CO2 influx. We observe a rejuvenation of circumpolar deep waters synchronous and potentially contributing to the initial deglacial rise in atmospheric CO2. These findings constrain parts of the glacial carbon pool to the deep South Pacific.

The gendered effects of family migration law: contextual interpretation as a possible judicial remedy

At all normative levels, family migration law can disproportionally and negatively affect immigrant women’s rights in this field, producing gendered effects. In some cases, such effects are related to the normative and judicial imposition of unviable family-related models (e.g., the ʻgood mother ̕ the one-breadwinner family, or a rigid distinction between productive and reproductive work). In other cases, they are due to family migration law’s overlooking of the specific needs and difficulties of immigrant women, within their families and in the broader context of their host countries’ social and normative framework.To effectively expose and correct this gender bias, in this article I propose an alternative view of immigrant women’s right to family life, as a cluster of rights and entitlements rather than as a mono-dimensional right. As a theoretical approach, this construction is better equipped to capture the complex experiences of immigrant women in the European legal space, and to shed light on the gendered effects generated not by individual norms but by the interaction of norms that are traditionally assigned to separated legal domains (e.g., immigration law and criminal law). As a judicial strategy, this understanding is capable of prompting a consideration by domestic and supranational courts of immigrant women not as isolated individuals, but as ‘individuals in context’. I shall define this type of approach as ‘contextual interpretation’, understood as the consideration of immigrant women in the broader contexts of their families, their host societies and the normative frameworks applicable to them. Performed in a gendersensitive manner, a contextual judicial interpretation has the potential to neutralize the gendered effects of certain family migration norms. To illustrate these points, I will discuss selected judicial examples offered by the European Court on Human Rights, as well as from domestic jurisdictions of countries with a particularly high incidence of immigrant women (Italy and Spain).

Rotational velocities of single and binary O-type stars in the Tarantula Nebula

Rotation is a key parameter in the evolution of massive stars, affecting their evolution, chemical yields, ionizing photon budget, and final fate. We determined the projected rotational velocity, υ e sin i, of ~330 O-type objects, i.e. ~210 spectroscopic single stars and ~110 primaries in binary systems, in the Tarantula nebula or 30 Doradus (30 Dor) region. The observations were taken using VLT/FLAMES and constitute the largest homogeneous dataset of multi-epoch spectroscopy of O-type stars currently available. The most distinctive feature of the υ e sin i distributions of the presumed-single stars and primaries in 30 Dor is a low-velocity peak at around 100 km s^-1. Stellar winds are not expected to have spun-down the bulk of the stars significantly since their arrival on the main sequence and therefore the peak in the single star sample is likely to represent the outcome of the formation process. Whereas the spin distribution of presumed-single stars shows a well developed tail of stars rotating more rapidly than 300 km s^-1, the sample of primaries does not feature such a high-velocity tail. The tail of the presumed-single star distribution is attributed for the most part - and could potentially be completely due - to spun-up binary products that appear as single stars or that have merged. This would be consistent with the lack of such post-interaction products in the binary sample, that is expected to be dominated by pre-interaction systems. The peak in this distribution is broader and is shifted toward somewhat higher spin rates compared to the distribution of presumed-single stars. Systems displaying large radial velocity variations, typical for short period systems, appear mostly responsible for these differences.

The VLT-FLAMES tarantula survey:XII. Rotational velocities of the single O-type stars

Context. The 30 Doradus (30 Dor) region of the Large Magellanic Cloud, also known as the Tarantula nebula, is the nearest starburst region. It contains the richest population of massive stars in the Local Group, and it is thus the best possible laboratory to investigate open questions on the formation and evolution of massive stars. Aims. Using ground-based multi-object optical spectroscopy obtained in the framework of the VLT-FLAMES Tarantula Survey (VFTS), we aim to establish the (projected) rotational velocity distribution for a sample of 216 presumably single O-type stars in 30 Dor. The sample is large enough to obtain statistically significant information and to search for variations among subpopulations - in terms of spectral type, luminosity class, and spatial location - in the field of view. Methods. We measured projected rotational velocities, 3e sin i, by means of a Fourier transform method and a profile fitting method applied to a set of isolated spectral lines. We also used an iterative deconvolution procedure to infer the probability density, P(3e), of the equatorial rotational velocity, 3e. Results. The distribution of 3e sin i shows a two-component structure: a peak around 80 km s1 and a high-velocity tail extending up to 600 km s^-1 This structure is also present in the inferred distribution P(3e) with around 80% of the sample having 0 <3e ≤ 300 km s^-1 and the other 20% distributed in the high-velocity region. The presence of the low-velocity peak is consistent with what has been found in other studies for late O- and early B-type stars. Conclusions. Most of the stars in our sample rotate with a rate less than 20% of their break-up velocity. For the bulk of the sample, mass loss in a stellar wind and/or envelope expansion is not efficient enough to significantly spin down these stars within the first few Myr of evolution. If massive-star formation results in stars rotating at birth with a large portion of their break-up velocities, an alternative braking mechanism, possibly magnetic fields, is thus required to explain the present-day rotational properties of the O-type stars in 30 Dor. The presence of a sizeable population of fast rotators is compatible with recent population synthesis computations that investigate the influence of binary evolution on the rotation rate of massive stars. Even though we have excluded stars that show significant radial velocity variations, our sample may have remained contaminated by post-interaction binary products. That the highvelocity tail may be populated primarily (and perhaps exclusively) by post-binary interaction products has important implications for the evolutionary origin of systems that produce gamma-ray bursts. © 2013 Author(s).

Resolved Stars' Insights into Galaxy Physics

Thesis (Ph.D.)--University of Washington, 2016-08

Myths and Realities of Inter-professional Working

Introduction: Childhood cancers are rare and community based health care professionals have limited experience in caring for these children and often even less experience in providing their palliative care. It is well recognised that the provision of palliative care falls beyond the remit of any one profession, thus inter professional working is the standard model. This qualitative study aims to examine the experiences of the range of health care professionals involved in providing palliative care at home for children with cancer, focusing on how knowledge is exchanged; the level of communication and support both interprofessionally and at the community/specialist interface. It also aims to examine interprofessional collaboration in palliative care; identifying healthcare professional's perceptions of problems involved, interprofessional boundaries, specific areas of the organisation or provision of care that could be enhanced through changes in practice, support issues and the educational needs of health professionals. Methods The study involves three types of data collection; in-depth interviews, facilitated case discussion (FCD) and field notes from up to 20 cases (a "case" refers to the provision of palliative care to one child). Cases are selected from children who were treated at one regional childhood caner centre. For each case the community based health care professionals (for example the GP, community nurse or health visitor) involved in the care of the child at home are invited to participate in a one-to-one tape recorded in-depth interview followed by a group discussion in the form of a FCD. Field notes are completed following each interview. Data analysis follows a grounded theory approach. The term "social worlds theory" (SWT) his used to define a type of social organisation with no fixed or formal boundaries (such as membership boundaries), for example the range of health professionals that work together to provide palliative care. The boundaries of SW's are determined by the interaction and communication between recognised organisations, such as community nursing teams and general practitioners. SWT examines encounters between different professional groups and can be used to extend knowledge in both the organisation (for example general practice) and the content of what is being provisioned (for example, palliative care). The use of SWT in the analysis of the data is through examining the ethos of the different professions and the associated individual approaches to palliative care, exploring how this determines their roles in the provision of palliative care. Results 10 cases have so far been completed: 47 1:1 interviews (with a range of between 2-7 health care professionals being involved in each case): ( 9 x GP, 19 x CCN, 4 x DN, 3 x HV, 1 x HV assistant 7 x paediatric palliative care nurses, 1 x home support worker, 1 x OT, 1 x physiotherapist, 1 x community paediatrician) and 5 x FCD. The range of participants in the FCDs reflected that of the individual interview sampler. Data obtained to date gives clear insight into the personal experience of the individual health care professional in providing palliative care. Two themes emerging from the data will be focused upon: the continuity of care provision throughout treatment and palliation and the emotional burden experiences by the health care professional. Conclusions SWT can provide a useful framework in examining the social worlds of a disparate group of health care professionals working together for the first and maybe, the only time. A wide variation in the continuity of care provision has been found not only between professions, but also within professions. The emotional burden is evident across the professions.

PHYSICA: A multiphysics computational framework and its application to casting simulations

Metal casting is a process governed by the interaction of a range of physical phenomena. Most computational models of this process address only what are conventionally regarded as the primary phenomena – heat conduction and solidification. However, to predict other phenomena, such as porosity formation, requires modelling the interaction of the fluid flow, heat transfer, solidification and the development of stressdeformation in the solidified part of the casting. This paper will describe a modelling framework called PHYSICA[1] which has the capability to stimulate such multiphysical phenomena.

Marcadores de diagnóstico da doença periodontal

A periodontite é uma patologia inflamatória, causada pela interação entre o biofilme bacteriano e a resposta imune do hospedeiro e é caracterizada pela degradação de fibras colágenas do periodonto. Os avanços científicos possibilitaram o desenvolvimento de novas técnicas que possibilitem o diagnóstico precoce da doença, ou seja, prevenir a perda de inserção e progressão da periodontite. O diagnóstico da doença periodontal baseia-se em parâmetros clínicos como profundidade de sondagem, perda de inserção, hemorragia a sondagem e exames radiográficos. A análise dos biomarcadores presentes no fluido crevicular gengival (FCG) e saliva tem sido alvo de inúmeros artigos, uma vez que o fluido crevicular gengival (FCG) é composto de uma gama de biomarcadores celulares e moleculares. O presente trabalho teve como objetivo fazer uma revisão narrativa da literatura publicada a cerca dos métodos utilizados para diagnóstico precoce e prognóstico dos processos patológicos que podem estar presentes no periodonto. Foi realizada uma pesquisa bibliográfica online entre Dezembro de 2015 e Maio de 2016, com o objetivo de fazer uma revisão bibliográfica acerca do tema. Não foi estabelecido restrição quanto a data de publicação. Através da identificação da concentração de determinadas proteínas presentes no FCG é possível avaliar a atividade da doença periodontal e o prognóstico. Um importante número de marcadores como a elastase neutrofílica, prostaglandina E2, catepsinas, osteocalcina, -glucoronidase, colagenase, fosfatase alcalina, aspartato aminotransferase são citados (Genco et al., 1992). De acordo com a literatura publicada pode-se concluir que há alguns marcadores promissores para o diagnóstico precoce e prognóstico da doença periodontal, entretanto, não há ainda um marcador que possa identificar a futura perda de inserção ou a suscetibilidade à doença periodontal. São necessários estudos longitudinais para melhor entendimento do papel dos biomarcadores do FCG.

Investigating bias in recreational fishing surveys: Fishers listed in public telephone directories fish similarly to their unlisted counterparts

Several recent offsite recreational fishing surveys have used public landline telephone directories as a sampling frame. Sampling biases inherent in this method are recognised, but are assumed to be corrected through demographic data expansion. However, the rising prevalence of mobile-only households has potentially increased these biases by skewing raw samples towards households that maintain relatively high levels of coverage in telephone directories. For biases to be corrected through demographic expansion, both the fishing participation rate and fishing activity must be similar among listed and unlisted fishers within each demographic group. In this study, we tested for a difference in the fishing activity of listed and unlisted fishers within demographic groups by comparing their avidity (number of fishing trips per year), as well as the platform used (boat or shore) and species targeted on their most recent fishing trip. 3062 recreational fishers were interviewed at 34 tackle stores across 12 residential regions of Queensland, Australia. For each fisher, data collected included their fishing avidity, the platform used and species targeted on their most recent trip, their gender, age, residential region, and whether their household had a listed telephone number. Although the most avid fishers were younger and less likely to have a listed phone number, cumulative link models revealed that avidity was not affected by an interaction of phone listing status, age group and residential region (p > 0.05). Likewise, binomial generalized linear models revealed that there was no interaction between phone listing, age group and avidity acting on platform (p > 0.05), and platform was not affected by an interaction of phone listing status, age group, and residential region (p > 0.05). Ordination of target species using Bray-Curtis dissimilarity indices found a significant but irrelevant difference (i.e. small effect size) between listed and unlisted fishers (ANOSIM R < 0.05, p < 0.05). These results suggest that, at this time, the fishing activity of listed and unlisted fishers in Queensland is similar within demographic groups. Future research seeking to validate the assumptions of recreational fishing telephone surveys should investigate fishing participation rates of listed and unlisted fishers within demographic groups.

Heat dissipation from carbon nano-electronics

The incorporation of graphitic compounds such as carbon nanotubes (CNTs) and graphene into nano-electronic device packaging holds much promise for waste heat management given their high thermal conductivities. However, as these graphitic materials must be used in together with other semiconductor/insulator materials, it is not known how thermal transport is affected by the interaction. Using different simulation techniques, in this thesis, we evaluate the thermal transport properties - thermal boundary conductance (TBC) and thermal conductivity - of CNTs and single-layer graphene in contact with an amorphous SiO2 (a-SiO2) substrate. First, the theoretical methodologies and concepts used in our simulations are presented. In particular, two concepts are described in detail as they are necessary for the understanding of the subsequent chapters. The first is the linear response Green-Kubo (GK) theory of thermal boundary conductance (TBC), which we develop in this thesis, and the second is the spectral energy density method, which we use to directly compute the phonon lifetimes and thermal transport coefficients. After we set the conceptual foundations, the TBC of the CNT-SiO2 interface is computed using non- equilibrium molecular dynamics (MD) simulations and the new Green-Kubo method that we have developed. Its dependence on temperature, the strength of the interaction with the substrate, and tube diameter are evaluated. To gain further insight into the phonon dynamics in supported CNTs, the scattering rates are computed using the spectral energy density (SED) method. With this method, we are able to distinguish the different scattering mechanisms (boundary and CNT-substrate phonon-phonon) and rates. The phonon lifetimes in supported CNTs are found to be reduced by contact with the substrate and we use that lifetime reduction to determine the change in CNT thermal conductivity. Next, we examine thermal transport in graphene supported on SiO2. The phonon contribution to the TBC of the graphene-SiO2 interface is computed from MD simulations and found to agree well with experimentally measured values. We derive the theory of remote phonon scattering of graphene electrons and compute the heat transfer coefficient dependence on doping level and temperature. The thermal boundary conductance from remote phonon scattering is found to be an order of magnitude smaller than that of the phonon contribution. The in-plane thermal conductivity of supported graphene is calculated from MD simulations. The experimentally measured order of magnitude reduction in thermal conductivity is reproduced in our simulations. We show that this reduction is due to the damping of the flexural (ZA) modes. By varying the interaction between graphene and the substrate, the ZA modes hybridize with the substrate Rayleigh modes and the dispersion of the hybridized modes is found to linearize in the strong coupling limit, leading to an increased thermal conductance in the composite structure.

Place, policy and practitioners: on rehabilitation, independence and the therapeutic landscape in the changing geography of care provision to older people in the United Kingdom

A growing body of literature in geography and other social sciences considers the role of place in the provision of healthcare. Authors have focused on various aspects of place and care, with particular interests emerging around the role of the psychological, social and cultural aspects of place in care provision. As healthcare stretches increasingly beyond the traditional four walls of the hospital, so questions of the role of place in practices of care become ever more pertinent. In this paper, we examine the relationship between place and practice in the care and rehabilitation of older people across a range of settings, using qualitative material obtained from interviews and focus groups with nursing, care and rehabilitation staff working in hospitals, clients’ homes and other sites. By analysing their testimony on the characteristics of different settings, the aspects of place which facilitate or inhibit rehabilitation and the ways in which place mediates and is mediated by social interaction, we consider how various dimensions of place relate to the power-inscribed relationships between service users, informal carers and professionals as they negotiate the goals of the rehabilitation process. We seek to demonstrate how the physical, psychological and social meanings of place and the social processes engendered by the rehabilitation encounter interact to produce landscapes that are more or less therapeutic, considering in particular the structuring role of state policy and formal healthcare provision in this dynamic.

Spectral damage model for lighted museum paintings: Oil, acrylic and gouache

A spectral aging test was developed to estimate the photochemical damage of oil, acrylic and gouache paints exposed to permanent lighting. The paints were irradiated at seven different wavelengths in the optical range to control and evaluate their spectral behaviour. To reach this objective, boxes with isolated aging cells were made. In each of box, one LED of a different wavelength and one photodiode were installed. Inside the boxes, the temperature of an exhibit area was recreated through a thermocouple sensor that controlled the temperature using a fan. The heat produced by the LED was dissipated by a thermal radiator. Moreover, to evaluate the exposure time dependence of the irradiation level, the test was performed using two different irradiation levels in ten exposure series. After each series, the spectral reflectance was measured, and the data collected for each paint and wavelength were used to develop a model of damage produced by the interaction between the spectral radiant exposure and the paint.

New ethnicities online: reflexive racialisation and the internet

In this article we analyse the emergence of Internet activity addressing the experiences of young people in two British communities: South Asian and Chinese.We focus on two web sites: www.barficulture.com and www.britishbornchinese.org.uk, drawing on interviews with site editors, content analysis of the discussion forums, and E-mail exchanges with site users. Our analysis of these two web sites shows how collective identities still matter, being redefined rather than erased by online interaction. We understand the site content through the notion of reflexive racialisation. We use this term to modify the stress given to individualisation in accounts of reflexive modernisation. In addition we question the allocation of racialised meaning from above implied by the concept of racialisation. Internet discussion forums can act as witnesses to social inequalities and through sharing experiences of racism and marginalisation, an oppositional social perspective may develop. The online exchanges have had offline consequences: social gatherings, charitable donations and campaigns against adverse media representations. These web sites have begun to change the terms of engagement between these ethnic groups and the wider society,and they have considerable potential to develop new forms of social action.