1,676 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

    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

    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

    Physical sketching tools and techniques for customized sensate surfaces

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    Sensate surfaces are a promising avenue for enhancing human interaction with digital systems due to their inherent intuitiveness and natural user interface. Recent technological advancements have enabled sensate surfaces to surpass the constraints of conventional touchscreens by integrating them into everyday objects, creating interactive interfaces that can detect various inputs such as touch, pressure, and gestures. This allows for more natural and intuitive control of digital systems. However, prototyping interactive surfaces that are customized to users' requirements using conventional techniques remains technically challenging due to limitations in accommodating complex geometric shapes and varying sizes. Furthermore, it is crucial to consider the context in which customized surfaces are utilized, as relocating them to fabrication labs may lead to the loss of their original design context. Additionally, prototyping high-resolution sensate surfaces presents challenges due to the complex signal processing requirements involved. This thesis investigates the design and fabrication of customized sensate surfaces that meet the diverse requirements of different users and contexts. The research aims to develop novel tools and techniques that overcome the technical limitations of current methods and enable the creation of sensate surfaces that enhance human interaction with digital systems.Sensorische Oberflächen sind aufgrund ihrer inhärenten Intuitivität und natürlichen Benutzeroberfläche ein vielversprechender Ansatz, um die menschliche Interaktionmit digitalen Systemen zu verbessern. Die jüngsten technologischen Fortschritte haben es ermöglicht, dass sensorische Oberflächen die Beschränkungen herkömmlicher Touchscreens überwinden, indem sie in Alltagsgegenstände integriert werden und interaktive Schnittstellen schaffen, die diverse Eingaben wie Berührung, Druck, oder Gesten erkennen können. Dies ermöglicht eine natürlichere und intuitivere Steuerung von digitalen Systemen. Das Prototyping interaktiver Oberflächen, die mit herkömmlichen Techniken an die Bedürfnisse der Nutzer angepasst werden, bleibt jedoch eine technische Herausforderung, da komplexe geometrische Formen und variierende Größen nur begrenzt berücksichtigt werden können. Darüber hinaus ist es von entscheidender Bedeutung, den Kontext, in dem diese individuell angepassten Oberflächen verwendet werden, zu berücksichtigen, da eine Verlagerung in Fabrikations-Laboratorien zum Verlust ihres ursprünglichen Designkontextes führen kann. Zudem stellt das Prototyping hochauflösender sensorischer Oberflächen aufgrund der komplexen Anforderungen an die Signalverarbeitung eine Herausforderung dar. Diese Arbeit erforscht dasDesign und die Fabrikation individuell angepasster sensorischer Oberflächen, die den diversen Anforderungen unterschiedlicher Nutzer und Kontexte gerecht werden. Die Forschung zielt darauf ab, neuartigeWerkzeuge und Techniken zu entwickeln, die die technischen Beschränkungen derzeitigerMethoden überwinden und die Erstellung von sensorischen Oberflächen ermöglichen, die die menschliche Interaktion mit digitalen Systemen verbessern

    Beam scanning by liquid-crystal biasing in a modified SIW structure

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    A fixed-frequency beam-scanning 1D antenna based on Liquid Crystals (LCs) is designed for application in 2D scanning with lateral alignment. The 2D array environment imposes full decoupling of adjacent 1D antennas, which often conflicts with the LC requirement of DC biasing: the proposed design accommodates both. The LC medium is placed inside a Substrate Integrated Waveguide (SIW) modified to work as a Groove Gap Waveguide, with radiating slots etched on the upper broad wall, that radiates as a Leaky-Wave Antenna (LWA). This allows effective application of the DC bias voltage needed for tuning the LCs. At the same time, the RF field remains laterally confined, enabling the possibility to lay several antennas in parallel and achieve 2D beam scanning. The design is validated by simulation employing the actual properties of a commercial LC medium

    Modern meat: the next generation of meat from cells

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    Modern Meat is the first textbook on cultivated meat, with contributions from over 100 experts within the cultivated meat community. The Sections of Modern Meat comprise 5 broad categories of cultivated meat: Context, Impact, Science, Society, and World. The 19 chapters of Modern Meat, spread across these 5 sections, provide detailed entries on cultivated meat. They extensively tour a range of topics including the impact of cultivated meat on humans and animals, the bioprocess of cultivated meat production, how cultivated meat may become a food option in Space and on Mars, and how cultivated meat may impact the economy, culture, and tradition of Asia

    Biomaterials for Bone Tissue Engineering 2020

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    This book presents recent advances in the field of bone tissue engineering, including molecular insights, innovative biomaterials with regenerative properties (e.g., osteoinduction and osteoconduction), and physical stimuli to enhance bone regeneration

    Developmental Bootstrapping of AIs

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    Although some current AIs surpass human abilities in closed artificial worlds such as board games, their abilities in the real world are limited. They make strange mistakes and do not notice them. They cannot be instructed easily, fail to use common sense, and lack curiosity. They do not make good collaborators. Mainstream approaches for creating AIs are the traditional manually-constructed symbolic AI approach and generative and deep learning AI approaches including large language models (LLMs). These systems are not well suited for creating robust and trustworthy AIs. Although it is outside of the mainstream, the developmental bootstrapping approach has more potential. In developmental bootstrapping, AIs develop competences like human children do. They start with innate competences. They interact with the environment and learn from their interactions. They incrementally extend their innate competences with self-developed competences. They interact and learn from people and establish perceptual, cognitive, and common grounding. They acquire the competences they need through bootstrapping. However, developmental robotics has not yet produced AIs with robust adult-level competences. Projects have typically stopped at the Toddler Barrier corresponding to human infant development at about two years of age, before their speech is fluent. They also do not bridge the Reading Barrier, to skillfully and skeptically draw on the socially developed information resources that power current LLMs. The next competences in human cognitive development involve intrinsic motivation, imitation learning, imagination, coordination, and communication. This position paper lays out the logic, prospects, gaps, and challenges for extending the practice of developmental bootstrapping to acquire further competences and create robust, resilient, and human-compatible AIs.Comment: 102 pages, 29 figure
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