2,719 research outputs found

    Therapeutic and prognostic strategies in neuroblastoma : exploring nuclear hormone receptors, MYC targets, and DIAPH3

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    Neuroblastoma (NB) is a pediatric cancer derived from the cells of neural crest origin that form the sympathoadrenal system. Typically, the tumor cells migrate along the spinal cord and spread to the chest, neck, and/or abdomen. Different clinical behaviors are observed in this disease: some tumors spontaneously regress without treatment, while others are highly aggressive and resistant to current therapies. Approximately 40% of high-risk NB patients have MYCN amplification while 10% have MYC (i.e. encoding c-MYC) overexpression. These patients have undifferentiated tumors with a poor prognosis. Our group previously found that the expression and activation of nuclear hormone receptors (NHRs) estrogen receptor alpha (ERα) by 17-β-estradiol (E2), and the glucocorticoid receptor (GR) by dexamethasone (DEX), could trigger differentiation by disrupting the regulation of the miR-17 ~ 92 microRNA cluster by MYCN. In paper I, we sought to investigate whether the simultaneous activation of both ERα and GR has a more beneficial effect compared to the activation of either ERα or GR alone. We examined cell survival, alterations in cell shape as indicated by neurite extension, variations in metabolic pathways, accumulation of lipid droplets, and performed xenograft experiments. Our findings revealed that the simultaneous activation of GR and ERα, compared to their single activation, led to reduced viability and a more robust differentiation. This dual activation also caused changes in glycolysis and oxidative phosphorylation, increased lipid droplet accumulation, and decreased aggressiveness in mouse models. The triple activation with an additional activation of the retinoic acid receptor using all trans-retinoic acid (ATRA), amplified the differentiation phenotype. Bulk-sequencing analysis showed that patients with high levels of NHRs are related to favorable survival and clinical outcome. In summary, our data suggest that combination activation of these NHRs could be a potential differentiation induction treatment. Paper II investigates target genes of c-MYC and MYCN to explore if it is possible to obtain a better prognosis prediction using the expression of this group of genes, instead of the expression of MYC and/or MYCN alone. In addition, we analyzed if there are different prediction power capabilities between c-MYC and MYCN target genes, and their different role during sympathoadrenal development. We screened lists of target genes by using comprehensive approaches, including differential expression analysis between clinical risk groups, INSS stages, MYCN amplification status, progression status; Univariate Cox regression analysis to select the target genes related to prognosis prediction power, and protein interaction network analysis to select genes that share a meaningful biology function. Following the training and validation of (LASSO) regression prediction models in three different patient cohorts (SEQC, Kocak, and Versteeg), we found that a risk score computed on c-MYC/MYCN target genes with prognostic value, could effectively classify patients in groups with different survival probabilities. The high-risk group of patients exhibited unfavorable clinical outcomes and low survival rates. Further, single cell RNA sequencing analysis revealed that c-MYC and MYCN targets have different expression patterns during sympathoadrenal development. Notably, genes linked to adverse outcomes were predominantly expressed in sympathoblasts in comparison to chromaffin cells. In summary, our research provides new insights into the importance of c-MYC/MYCN target genes during sympathoadrenal development and their value in predicting patient outcome. In paper III we studied the function of one member of the formin protein family involved in cytoskeleton modulation: Diaphanous Related Formin 3 (DIAPH3). We found that high DIAPH3 expression in NB tumors are associated with MYCN amplification, higher stage, risk, progression and negative clinical outcome. Elevated DIAPH3 expression was also found in specific cells during mouse sympathoadrenal development and in progenitor cells of the post- natal human adrenal gland. Furthermore, the knockdown of DIAPH3 resulted in a slight decrease in cell growth and cell cycle arrest. Our study suggests that DIAPH3 could be a promising target for new therapeutic strategies

    An Exploration of Life With a Chronic Skin Condition

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    Despite considerable prevalence and clinical impact, chronic skin conditions have received little sociological attention. This research examines the social implications of living with a chronic skin condition, based on the thematic analysis of in-depth interviews featuring 24 adults with experiences of eczema, psoriasis or acne. Drawing on Bourdieusian field theory and corporeal phenomenology, this thesis brings new insight to the disembodying experiences of disordered skin, strategies enacted for their management, and the wider implications of disordered skin on social participation. Illustrating experiences of social dys-appearance, individuals are found to negotiate stigma, both enacted and perceived, based on normative expectations of bodily presentation. Employing the notion of aesthetic capital, disordered skin is shown to impair possibilities for aesthetic distinction and undermine a sense of capability in personal and working roles. Faced with disabling spatialities and difficulties surrounding disclosure, individuals develop anticipatory dispositions and a range of time-space tactics. The corporeal dys-appearance of disordered skin demands that individuals respond through laborious practices which often take on Sisyphean attributes. A novel concept of “containing” is introduced as a type of skin work reflecting how managing disordered skin requires attention to clearing up exudations of “dirty” bodily substances, such as skin flakes, blood, pus, and the remnants of topical treatments, to avoid soiling external environments. Pharmaceutical treatments are found to be a source of deep ambivalence. Moreover, individuals value agency in their treatment protocols and, where capital resources allow, enact resistance to medical authority through experimentation with alternative strategies and practices of self-medication. This study highlights a need to accommodate the additional labour demands of life with chronic skin conditions, and the desire for agency in treatment, through policy and practice measures. Further efforts are needed to address the impact of inequalities of access to resources on the burden of managing chronic illness

    Planetary Hinterlands:Extraction, Abandonment and Care

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    This open access book considers the concept of the hinterland as a crucial tool for understanding the global and planetary present as a time defined by the lasting legacies of colonialism, increasing labor precarity under late capitalist regimes, and looming climate disasters. Traditionally seen to serve a (colonial) port or market town, the hinterland here becomes a lens to attend to the times and spaces shaped and experienced across the received categories of the urban, rural, wilderness or nature. In straddling these categories, the concept of the hinterland foregrounds the human and more-than-human lively processes and forms of care that go on even in sites defined by capitalist extraction and political abandonment. Bringing together scholars from the humanities and social sciences, the book rethinks hinterland materialities, affectivities, and ecologies across places and cultural imaginations, Global North and South, urban and rural, and land and water

    Climate Change and Critical Agrarian Studies

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    Climate change is perhaps the greatest threat to humanity today and plays out as a cruel engine of myriad forms of injustice, violence and destruction. The effects of climate change from human-made emissions of greenhouse gases are devastating and accelerating; yet are uncertain and uneven both in terms of geography and socio-economic impacts. Emerging from the dynamics of capitalism since the industrial revolution — as well as industrialisation under state-led socialism — the consequences of climate change are especially profound for the countryside and its inhabitants. The book interrogates the narratives and strategies that frame climate change and examines the institutionalised responses in agrarian settings, highlighting what exclusions and inclusions result. It explores how different people — in relation to class and other co-constituted axes of social difference such as gender, race, ethnicity, age and occupation — are affected by climate change, as well as the climate adaptation and mitigation responses being implemented in rural areas. The book in turn explores how climate change – and the responses to it - affect processes of social differentiation, trajectories of accumulation and in turn agrarian politics. Finally, the book examines what strategies are required to confront climate change, and the underlying political-economic dynamics that cause it, reflecting on what this means for agrarian struggles across the world. The 26 chapters in this volume explore how the relationship between capitalism and climate change plays out in the rural world and, in particular, the way agrarian struggles connect with the huge challenge of climate change. Through a huge variety of case studies alongside more conceptual chapters, the book makes the often-missing connection between climate change and critical agrarian studies. The book argues that making the connection between climate and agrarian justice is crucial

    Memory built-in self-repair and correction for improving yield: a review

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    Nanometer memories are highly prone to defects due to dense structure, necessitating memory built-in self-repair as a must-have feature to improve yield. Today’s system-on-chips contain memories occupying an area as high as 90% of the chip area. Shrinking technology uses stricter design rules for memories, making them more prone to manufacturing defects. Further, using 3D-stacked memories makes the system vulnerable to newer defects such as those coming from through-silicon-vias (TSV) and micro bumps. The increased memory size is also resulting in an increase in soft errors during system operation. Multiple memory repair techniques based on redundancy and correction codes have been presented to recover from such defects and prevent system failures. This paper reviews recently published memory repair methodologies, including various built-in self-repair (BISR) architectures, repair analysis algorithms, in-system repair, and soft repair handling using error correcting codes (ECC). It provides a classification of these techniques based on method and usage. Finally, it reviews evaluation methods used to determine the effectiveness of the repair algorithms. The paper aims to present a survey of these methodologies and prepare a platform for developing repair methods for upcoming-generation memories

    The Radical Right in England and Wales: Permission to Hate?

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    Despite the prominence of the radical right in the UK, scant research has been undertaken to explore the influence that these organisations have on the perpetration of hate crime. Whilst current literature on hate crime predominantly looks at the impacts these crimes have on victims, it does not sufficiently investigate the conditions under which these crimes occur. The few studies on this issue have been conducted in the USA and Canada, the most recent of which was conducted by Perry and Scrivens (2019) who presented a new theoretical framework to account for this relationship. This framework - permission to hate - establishes a general environment of hate. This thesis contributes to the field by developing permission to hate to a more racialised social structure, and identifies the ways in which the radical right influences hate crime in England and Wales. Thus, this thesis is theory testing, adopting a similar sequential mixed-methods approach used by Perry and Scrivens. Due to the anti-minority ideology of the radical right, this thesis uses official crime statistics measuring racially and religiously aggravated crimes and demographic data to determine whether there is a correlation between these crimes and both the electoral performance of radical right parties and the protest activities of radial right organisations at the local level. In order to identify the causal mechanisms, a case study of the West Midlands is undertaken using semi-structured interviews with individuals who worked at Third Party Reporting Centres, media reports of radical right protests and more localised crime data. By combining these methods this thesis expands upon the work by Perry and Scrivens, contributing towards the theory permission to hate, whilst also highlighting the ways in which the radical right influence racially and religiously aggravated crimes. This study finds that the radical right achieve this through the consumption of alcohol during their protests, inserting themselves into local issues and how they emphasise the risks minority communities pose to British society, especially in the aftermath of high profile events

    AI: Limits and Prospects of Artificial Intelligence

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    The emergence of artificial intelligence has triggered enthusiasm and promise of boundless opportunities as much as uncertainty about its limits. The contributions to this volume explore the limits of AI, describe the necessary conditions for its functionality, reveal its attendant technical and social problems, and present some existing and potential solutions. At the same time, the contributors highlight the societal and attending economic hopes and fears, utopias and dystopias that are associated with the current and future development of artificial intelligence

    The cultural humility program: ensuring awareness, training, and effort as an occupational therapy practitioner

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    Culturally diverse clients often face barriers to accessing and using health and education services, which may affect the clients’ performance outcomes and impact the quality of services. These barriers include practitioners’ insufficient cultural competence and humility and an ineffective health care system. The Cultural Humility program aims to train and educate occupational therapy practitioners to gain confidence and improve their cultural humility and practical communication skills to maintain, establish, and manage therapeutic relationships. The program duration will be twelve 2-hour biweekly sessions over 6 months, in person at clinical settings or on a virtual platform. The program includes learning modules, such as lectures, simulation or video modeling, and discussion sessions with brain-based learning for occupational therapy practitioners. The program will provide meaningful opportunities for practitioners to reflect on their practice attitudes, gain confidence, change their mindsets, and learn practical communication skills for use with clients from various cultural backgrounds. The aim of the Cultural Humility program is to apply these practical techniques related to cultural humility, bringing synergy and authenticity to practitioners’ daily practice, and improving their clients’ performance and outcomes

    You Are What You Wear: A Vital Materialism of Textiles

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    Intermedial artworks are deemed effective when they draw from the roots of the most basic, universal elements of materiality, concept, sensation, and/or experience, melding disparate elements into an inextricable novelty. As hybrid artifacts, they take up an unusual degree of substance in one dimension or another, and can at times be difficult to categorize, describe, or document. Nonetheless, the potential for intermedial expressions to resonate with their viewership is strengthened by the depths to which the artist ventures, and through such a process the most far-reaching and complexly interconnected issues of our time can be made approachable on the personal level. The work documented and realized herein developed from the idea of addressing the issue of global textile waste on a personal level. Inspired by the need to perform basic clothing repair, I began exploring textile-based art practices during the 2020 pandemic lockdown, studied them formally at the University of Maine from Fall ’20 to the time of publication, and greatly benefitted from the culture of ecological ethics, forest management, and community-engaged art flourishing at and around the University. My path of research-oriented artistic production has led me to participate directly in many facets of the reuse economy of central Maine and beyond; at times I have operated as a volunteer in a Catholic mission’s thrift store, and as an employee of a donation-based shop. I have both attended and hosted workshops, “skill-shares”, and other events in a variety of settings, from guest presenter at a public high school to spontaneous runway model at a fashion show for upcycled streetwear. Focusing primarily on ubiquitous textile artifacts, such as the graphic t-shirt, in conjunction with universally attainable and applicable projects such as tote bags, pockets, written messages, and drawstring pouches, I have developed an artistic practice geared towards inspiring in the viewer/wearer a newfound appreciation for textile materiality as a function of their embodied experience—ideally empowering them to begin independently addressing their textile footprint. The body of artwork associated with my studies culminated in a gallery-centered event, named You Are What You Wear, where participants were encouraged to wear, and offered from a shared selection, garments with visible repair work and customization—thus allowing an imaginative glimpse at the potential for healing and self-expression through textile work. With the abundance of textile material available for those of us on this side of the manufacturing cycle, the means by which we address the inefficiencies and injustices of global textile production cannot be solely derived from a sustainability mindset; there must also be celebration of abundance: freedom to make mistakes, generosity, gratitude, and discovery. Through analysis of my work and the concepts which support it, I intend to show that worn textiles and the associated actions of repair are inherent parts of the human experience, and how creative work can encourage a more mindful and harmonious relationship with textile materiality. Aided by a series of informal interviews conducted over the last two years, I will also present analysis derived from a variety of perspectives that I hope will show that the reuse economy as found across donation centers, second hand retail, volunteer labor, sewing workshops, and other social structures, is a viable and important lens through which one can perceive a community

    Making Connections: A Handbook for Effective Formal Mentoring Programs in Academia

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    This book, Making Connections: A Handbook for Effective Formal Mentoring Programs in Academia, makes a unique and needed contribution to the mentoring field as it focuses solely on mentoring in academia. This handbook is a collaborative institutional effort between Utah State University’s (USU) Empowering Teaching Open Access Book Series and the Mentoring Institute at the University of New Mexico (UNM). This book is available through (a) an e-book through Pressbooks, (b) a downloadable PDF version on USU’s Open Access Book Series website), and (c) a print version available for purchase on the USU Empower Teaching Open Access page, and on Amazon
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