8,941 research outputs found

    Investigating neural differentiation capacity in Alzheimer’s disease iPSC-derived neural stem cells

    Get PDF
    Neurodegeneration in Alzheimer’s disease (AD) may be exacerbated by dysregulated hippocampal neurogenesis. Neural stem cells (NSC) maintain adult neurogenesis and depletion of the NSC niche has been associated with age-related cognitive decline and dementia. We hypothesise that familial AD (FAD) mutations bias NSC toward premature neural specification, reducing the stem cell niche over time and accelerating disease progression. Somatic cells derived from patients with FAD (PSEN1 A246E and PSEN1 M146L heterozygous mutations) and healthy controls were reprogrammed to generate induced pluripotent stem cells (iPSC). Pluripotency for patient and control iPSC lines was confirmed, then cells were amplified and cryopreserved as stores. iPSC were subjected to neural specification to rosette-forming SOX2+/nestin+ NSCs for comparative evaluations between FAD and age-matched controls. FAD patient and control NSC were passaged under defined steady state culture conditions to assess stem cell maintenance using quantitative molecular markers (SOX2, nestin, NeuN, MAP2 and βIII-tubulin). We observed trends towards downregulated expression of the nestin coding gene NES (p=0.051) and upregulated expression of MAP2 (p=0.16) in PSEN1 NSC compared with control NSC, indicative of a premature differentiation phenotype induced by presence of the PSEN1 mutation. Cell cycle analysis of PSEN1 NSC showed that compared with controls, a greater number of PSEN1 NSC were retained in G0/G1 phase of the cell cycle (p=0.39), fewer progressed to S-phase (p=0.11) and fewer still reached G2 phase (p=0.23), suggesting cell cycle progression may be impaired in PSEN1 NSC. Nuclear DNA fragmentation was increased (p=0.10) in FAD NSC compared with controls, indicative of elevated cell death/apoptosis. Flow cytometry-based analysis of live, nestin+ NSC and NPC indicated increased apoptosis (p=0.14) in FAD NSC compared with controls, as well as increasing levels of apoptosis (p=0.33) in FAD NSC as they specified to neural progenitor cells. Global RNA sequencing was used to identify transcriptomic changes occurring during both disease and control neural specification. GO analysis of DEGs between PSEN1 and control NSC at P3 revealed significant upregulation (FDR<0.0000259) of 5 biological processes related to transcription and gene expression as well as significant upregulation (FDR<0.000000725) of 12 molecular functions related to DNA binding and transcription factor activity. These data suggest significant changes in gene expression were occurring in PSEN1 NSC at P3 compared with control NSC at the same stage in neural specification. The number of DEGs (p<0.05) between PSEN1 and control NSC at P3 was 9.92-fold higher than the number of DEGs between PSEN1 and control NSC at P2, suggesting transcriptomic differences between PSEN1 and control NSC become more pronounced as cells specify further down the neural lineage. Gene ontology (GO) analysis of differentially expressed genes (DEGs) specific to AD neural differentiation revealed significant dysregulation (FDR p<0.05) of genes related to neurogenesis, apoptosis, cell cycle, transcriptional control, and cell growth/maintenance as PSEN1 NSC matured from P2 to P3. The number of DEGs (p<0.05) in PSEN1 neural differentiation was 4.7-fold higher than the number of DEGs seen in control neural differentiation, indicating more transcriptional changes occurred in PSEN1 NSC than in controls at the same time point in neural specification. Dysregulation of Notch signalling was specific to PSEN1 neural differentiation and Notch related DEGs significantly upregulated (p<0.05) in PSEN1 NSC at P3 compared with P2 included NCOR2, JAG2, CHAC1 and RFNG. qPCR based validation displayed significant upregulation of RFNG (p=0.04) in PSEN1 NSC at P3 compared with PSEN1 NSC at P2, and indicated a trend towards upregulation of JAG2 expression, correlating with RNA sequencing data. Data generated in this study indicate that presence of the PSEN1 mutation significantly increases the number of transcriptional changes occurring during neural differentiation. It is plausible that transcriptional changes to Notch signalling cause dysregulated neural specification and increased apoptosis in PSEN1 NSC, ultimately resulting in depletion of the NSC niche

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

    Get PDF
    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

    Interdisciplinarity in the Scholarly Life Cycle

    Get PDF
    This open access book illustrates how interdisciplinary research develops over the lifetime of a scholar: not in a single project, but as an attitude that trickles down, or spirals up, into research. This book presents how interdisciplinary work has inspired shifts in how the contributors read, value concepts, critically combine methods, cope with knowledge hierarchies, write in style, and collaborate. Drawing on extensive examples from the humanities and social sciences, the editors and chapter authors show how they started, tried to open up, dealt with inconsistencies, had to adapt, and ultimately learned and grew as researchers. The book offers valuable insights into the conditions and complexities present for interdisciplinary research to be successful in an academic setting. This is an open access book

    Play/writing histories: investigating the dramaturgical potential of architectural drawing practices in exploring the hidden histories of built spaces. An architextural study of the Citizens Theatre

    Get PDF
    This practice research project investigates the dramaturgical potential of architectural drawing techniques and proposes ‘architexting’ as creative methodology for exploring the hidden histories of built spaces. Architexting exploits the relationship between architectural drawing and playwriting as allographic practices, identifying generative territory in their mutual preoccupation with shaping provisional spaces. I suggest that architexting can be used as a tool for a spatial approach to historiography that is organised by site rather than time. In doing so, architexting seeks to reveal and celebrate diachronic communities separated by time but created and connected by the places they share. This thesis is in three parts. In the first, ‘Project Plan and Methodology,’ I provide an overview of my interdisciplinary approach. In the second, ‘Site Analysis,’ I excavate relevant theoretical fields including architectural theory, dramaturgy, historiography and cultural geography to construct a theoretical framework for architexting. The third section, ‘Portfolio,’ forms the practical output of this project and consists of three architexts: Blueprint, Perspective and Axonometric or How to Build a Place from Memory, each with accompanying critical reflections. While architexting is a methodology that may be applied to any building, this project specifically investigates the hidden histories of the Citizens Theatre in Glasgow which, in 2018, underwent the most significant redevelopment in its 144-year history. My architexts have been created using material from oral histories and workshops with over sixty adults and young people connected to the Citizens theatre, as well as archival material from relevant collections held by the Scottish Theatre Archives at the University of Glasgow

    Engineering Blockchain Based Software Systems: Foundations, Survey, and Future Directions

    Full text link
    Many scientific and practical areas have shown increasing interest in reaping the benefits of blockchain technology to empower software systems. However, the unique characteristics and requirements associated with Blockchain Based Software (BBS) systems raise new challenges across the development lifecycle that entail an extensive improvement of conventional software engineering. This article presents a systematic literature review of the state-of-the-art in BBS engineering research from a software engineering perspective. We characterize BBS engineering from the theoretical foundations, processes, models, and roles and discuss a rich repertoire of key development activities, principles, challenges, and techniques. The focus and depth of this survey not only gives software engineering practitioners and researchers a consolidated body of knowledge about current BBS development but also underpins a starting point for further research in this field

    Dialogue without barriers. A comprehensive approach to dealing with stuttering

    Get PDF
    publishedVersio

    Improving public policy using behavioural understanding:The behavioural insights group Rotterdam

    Get PDF

    Combining Metabolic Engineering and Synthetic Biology Approaches for the Production of Abscisic Acid in Yeast

    Get PDF
    Nature presents us with a myriad of complex and diverse molecules. Many of these molecules prove to be useful to humans and find applications as pharmaceuticals, biofuels, agrochemicals, cosmetic ingredients or food additives. One highly promising natural product with a broad range of potential applications is the terpenoid abscisic acid (ABA). ABA fulfils a pivotal role in higher plants by regulating various developmental processes as well as abiotic stress responses. However, ABA is also produced in many other organisms, including humans. It appears to be a ubiquitous and evolutionary conserved signalling molecule throughout nature. Genetically engineered microorganisms, referred to as microbial cell factories, can be a sustainable source of natural products. In this thesis, a cell factory for the heterologous production of ABA was established and optimized employing the yeast Saccharomyces cerevisiae. Cell factory development is an inherently time-consuming process. As an enabling technology for subsequent work on the ABA cell factory, we expanded the modular cloning toolkit for yeast and made it more applicable for common genetic engineering tasks (Paper I). The ABA biosynthetic pathway of Botrytis cinerea was used to construct an ABA-producing S. cerevisiae strain (Paper II). The activity of two B. cinerea proteins, BcABA1 and BcABA2, was found to limit ABA titers. Two optimization approaches were devised for the following studies. Firstly, various rational engineering targets were explored, of which the native yeast gene PAH1 was identified as the most promising candidate (Paper III). Knockdown of PAH1 benefited ABA production without affecting growth. Secondly, platform strains for screening BcABA1 and BcABA2 enzyme libraries were developed, which utilize an ABA biosensor and enable a high throughput screening approach (Paper IV). In this work, we combined metabolic engineering and synthetic biology approaches for the heterologous production of ABA, and furthermore provided tools and insights that will be useful beyond the scope of this project

    International Academic Symposium of Social Science 2022

    Get PDF
    This conference proceedings gathers work and research presented at the International Academic Symposium of Social Science 2022 (IASSC2022) held on July 3, 2022, in Kota Bharu, Kelantan, Malaysia. The conference was jointly organized by the Faculty of Information Management of Universiti Teknologi MARA Kelantan Branch, Malaysia; University of Malaya, Malaysia; Universitas Pembangunan Nasional Veteran Jakarta, Indonesia; Universitas Ngudi Waluyo, Indonesia; Camarines Sur Polytechnic Colleges, Philippines; and UCSI University, Malaysia. Featuring experienced keynote speakers from Malaysia, Australia, and England, this proceeding provides an opportunity for researchers, postgraduate students, and industry practitioners to gain knowledge and understanding of advanced topics concerning digital transformations in the perspective of the social sciences and information systems, focusing on issues, challenges, impacts, and theoretical foundations. This conference proceedings will assist in shaping the future of the academy and industry by compiling state-of-the-art works and future trends in the digital transformation of the social sciences and the field of information systems. It is also considered an interactive platform that enables academicians, practitioners and students from various institutions and industries to collaborate
    • …
    corecore