11,158 research outputs found
Investigating neural differentiation capacity in Alzheimer’s disease iPSC-derived neural stem cells
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
Nudging towards autonomy:The effect of nudging on autonomous learning behavior in tertiary education
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Into the Multiverse: Methods for Studying Developmental Neuroscience
One major challenge in developmental neuroscience research is the sheer number of choices researchers face when addressing even a single research question. Even once data collection is complete, the journey from raw data to interpretation of findings may depend on numerous decisions. To address this issue, this dissertation explores “multiverse” analysis techniques for following many analytical paths at once in the same dataset.
In chapter 1, multiverses are used to examine which analyses of age-related change in amygdala-medial prefrontal cortex circuitry are robust versus sensitive to researcher decisions. Chapter 2 uses multiverse analysis to identify optimal solutions for mitigating breathing-induced artifacts in resting-state functional magnetic resonance imaging data. Chapter 3 uses a variety of model specifications to characterize simultaneous reward learning strategies in youth contingent on both visual task cues and spatial-motor information.
Despite varied approaches and goals, each of the three studies highlight the benefits of conducting multiple parallel analyses for both addressing questions in developmental neuroscience and deepening understanding of the methods used to address them
Increased lifetime of Organic Photovoltaics (OPVs) and the impact of degradation, efficiency and costs in the LCOE of Emerging PVs
Emerging photovoltaic (PV) technologies such as organic photovoltaics (OPVs) and perovskites (PVKs) have the potential to disrupt the PV market due to their ease of fabrication (compatible with cheap roll-to-roll processing) and installation, as well as their significant efficiency improvements in recent years. However, rapid degradation is still an issue present in many emerging PVs, which must be addressed to enable their commercialisation. This thesis shows an OPV lifetime enhancing technique by adding the insulating polymer PMMA to the active layer, and a novel model for quantifying the impact of degradation (alongside efficiency and cost) upon levelized cost of energy (LCOE) in real world emerging PV installations.
The effect of PMMA morphology on the success of a ternary strategy was investigated, leading to device design guidelines. It was found that either increasing the weight percent (wt%) or molecular weight (MW) of PMMA resulted in an increase in the volume of PMMA-rich islands, which provided the OPV protection against water and oxygen ingress. It was also found that adding PMMA can be effective in enhancing the lifetime of different active material combinations, although not to the same extent, and that processing additives can have a negative impact in the devices lifetime.
A novel model was developed taking into account realistic degradation profile sourced from a literature review of state-of-the-art OPV and PVK devices. It was found that optimal strategies to improve LCOE depend on the present characteristics of a device, and that panels with a good balance of efficiency and degradation were better than panels with higher efficiency but higher degradation as well. Further, it was found that low-cost locations were more favoured from reductions in the degradation rate and module cost, whilst high-cost locations were more benefited from improvements in initial efficiency, lower discount rates and reductions in install costs
Church growth models and the early Quakers
This thesis explores numeric church growth generally, and the early Quaker movement specifically, within the paradigm of models. A wide variety of practitioner church-growth models have appeared since the 1890s. The emergence of Quakerism in the mid-1650s, however, has never before been explored as a model of church growth. This thesis argues that models are effective at theoretically conceptualizing church growth. Its results elevate the theoretical above the descriptive, providing generalizability. With this approach, several original contributions are made in developing a construct-based model framework and establishing a theoretical system of comparison to analyze both modern and primary texts. It is argued that the Quaker pattern of church growth, as outlined by George Fox in his journal, presents a uniquely provocative model, not elsewhere documented among church-growth model authors. Additionally, the model approach provides a systemic perspective of prior scholarship on the Quaker growth phenomenon
TLC : une architecture photovoltaïque concentrée (CPV) au potentiel d’efficacité élevé à faible coût
Abstract: Human civilization has grown dependent on ready access to low-cost energy, but the fossil fuels that currently meet the bulk of humanity’s energy needs are causing environmental destruction, including potentially catastrophic global warming. Solar energy has to potential to halt global warming, and, if low enough in cost, to also bring the whole world’s population to a first world living standard. Silicon PV has dramatically reduced costs largely through decreasing the cost and increasing the efficiency of the silicon cells, but silicon is nearing its theoretical efficiency limits, and even if the cells were free, silicon PV would still be too expensive to meet these goals. Tandem CPV cells are roughly twice as efficient as silicon, but previous CPV designs have been unable to compete with silicon on cost in spite of the efficiency advantage. A new CPV architecture, called TLC for its trough, lens and cone concentration stages, proposed using initial concentration by a low-cost trough mirror to shrink the rest of an CPV module by 40X and thus reduce overall module costs. But before this PhD research project, TLC was only a paper study. This PhD research project was started to answer the question of whether TLC could work out as well as it appeared, or whether there were hidden flaws that precluded beating silicon PV on cost, or possibly even precluded TLC from working at all. Thesis chapter 3 details the main optical design aspects, and chapter 4 covers the design of the rest of the TLC module, including leading variations where there is more than one plausible way to achieve low cost and high reliability. The work included building a unified analytical model spreadsheet that linked known aspects of the TLC design together and estimated costs for a given design variation. Thesis chapter 5 covers the economics of the proposed design, with a focus on materials costs since these dominate PV overall costs, and a section on reliability since product lifetime strongly influences life-cycle cost. The work included building 3D-CAD models to refine the TLC design, and then the prototyping of individual parts and processes, and finally building a physical prototype of a TLC mini-module and putting it in sun. This physical confirmation was necessary because even after TLC has been “built” many times, in visualization, on paper, on spreadsheets, and then in COMSOL, until TLC was physically built, hidden flaws could arise at any time. Chapter 6 of this thesis covers the simulation and validation carried out to show that it is plausible that TLC can meet its cost targets. The conclusion of this thesis summarizes the overall project. The project was a success, producing a TLC design with high potential efficiency, very low materials cost, and low estimated process costs, with the potential to beat even the US Department of Energy’s goal for PV pricing in 2030. Ray-tracing a 3D model showed that the design could achieve high concentration with adequate acceptance angles, and tests showed that the prototyping cells were suitable for TLC’s massively parallel microcell-array receiver configuration. The project also successfully tested the proposed manufacturing process for molding semi-dense arrays of tertiary optical elements on the back of a lens tile and assembled a TLC mini module which was tested on sun at the focus of a trough mirror. Four papers have already been published, with a fifth paper accepted, as result of this work.La civilisation humaine est devenue de plus en plus dépendante d'un accès facile à une énergie à faible coût, mais les combustibles fossiles qui répondent actuellement à la majeure partie des besoins énergétiques de l'humanité causent la destruction de l'environnement, y compris un réchauffement climatique potentiellement catastrophique. L'énergie solaire a le potentiel d'arrêter le réchauffement climatique et, si son coût est suffisamment bas, d'amener également la population mondiale entière à un niveau de vie du premier monde. Les coûts de photovoltaïque (PV) à base de silicium ont été considérablement réduits en grande partie en diminuant le prix et en augmentant l'efficacité des cellules en silicium, cependant l’utilisation de silicium a ses limites d'efficacité théoriques, et même si les cellules étaient gratuites, la PV à base de silicium serait encore trop chère pour atteindre ces objectifs. Les cellules de photovoltaïque concentré (CPV) Tandem sont environ deux fois plus efficaces que celles à base de silicium, mais malgré l'avantage de leur efficacité, les architectures des années précédentes de CPV n'ont pas été en mesure de rivaliser avec le silicium en termes de coût. Une nouvelle architecture CPV, appelée TLC (Trough-Lens-Cone) utilise la concentration initiale par un miroir parabolique à faible coût combiné avec un module CPV de 40X et ainsi réduire les coûts globaux du module. Avant ce projet de recherche de doctorat, TLC n'était qu'une étude sur papier. Cette thèse a pour but de répondre à la question de savoir si l’approche TLC pouvait fonctionner aussi bien qu'elle était apparue, ou s'il y avait des défauts cachés qui empêchaient de battre le silicium PV sur le coût, ou pourrait même empêcher la TLC de fonctionner. Ce travail comprenait la construction d'un modèle de tableur unifié qui reliait les aspects connus de la conception TLC et les coûts estimés pour une variation de conception donnée. Nous présentons également la construction de modèles 3D-CAD pour raffiner la conception TLC, puis le prototypage de pièces individuelles et de processus, et enfin la construction d'un prototype physique d'un mini-module TLC qui est mis au soleil. Cette validation physique était nécessaire car même après que TLC ait été théoriquement et numériquement « construit » à plusieurs reprises soit, en visualisation, sur papier, sur des feuilles de calcul, puis dans COMSOL, avant que TLC soit physiquement construit, des défauts cachés pouvaient survenir à tout moment. La mise en œuvre de ce projet a réussi, produisant une conception TLC cohérente qui avait un rendement élevé avec un coût des matériaux très bas et des faibles coûts estimatifs de processus, avec un potentiel de battre même l’objectif du département américain de l'énergie pour la tarification du silicium photovoltaïque en 2030. Le suivi de raies (Ray-tracing) avec un modèle 3D a montré que la conception pouvait atteindre une concentration élevée avec des angles d'acceptation adéquats. Les tests ont également montré que les cellules de prototypage ont été bien adaptées à la nouvelle configuration de TLC de récepteur à matrice de microcellules massivement parallèle. Le projet a également testé avec succès le processus de fabrication proposé pour le moulage de réseaux semi-denses d'éléments optiques tertiaires à l'arrière d'un carreau de lentille. Le projet a également réussi à assembler un mini-module TLC et à tester sous le soleil avec le focus d'un miroir parabolique. Quatre articles ont déjà été publiés, avec un cinquième article accepté, à la suite de ce travail
World Development Report 2022
This new World Development Report focuses on the interrelated economic risks that households, businesses, financial institutions, and governments worldwide are facing as a consequence of the COVID-19 crisis. The Report offers new insights from research on the
interconnectedness of balance sheets and the potential spillover effects across sectors. It
also offers policy recommendations based on these insights. Specifically, it addresses the
question of how to reduce the financial risks stemming from the extraordinary policies
adopted in response to the COVID-19 crisis while supporting an equitable recovery.
The unfolding COVID-19 pandemic has already led to millions of deaths, job losses,
business failures, and school closings, triggering the most encompassing economic crisis
in almost a century. Poverty rates have soared and inequality has widened both across
and within countries. Disadvantaged groups that had limited financial resilience to begin
with and workers with lower levels of education—especially younger ones and women—
have been disproportionately affected.
The response by governments has included a combination of cash transfers to households,
credit guarantees for firms, easier liquidity conditions, repayment grace periods for much of
the private sector, and accounting and regulatory forbearance for many financial institutions. Although these actions have helped to partially mitigate the economic and social consequences of the pandemic, they have also resulted in elevated risks, including public overindebtedness, increased financial fragility, and a general erosion in transparency. Emerging
economies have been left with very limited fiscal space, and they will be made even more
vulnerable by the impending normalization of monetary policy in advanced economies.
This Report highlights several priority areas for action.
First is the need for early detection of significant financial risks. Because the balance
sheets of households, firms, financial sector institutions, and governments are tightly
interrelated, risks may be hidden. The share of nonperforming loans has generally
remained below what was feared at the beginning of the crisis. But this could be due to
forbearance policies that delayed debt repayments and relaxed accounting standards.
Firm surveys in emerging economies reveal that many businesses expect to be in payment
arrears in the coming months, and so private debt could suddenly become public debt, as
in many past crises.
The interdependence of economic policies across countries matters as well. Public debt
has reached unprecedented levels. As monetary policy tightens in advanced economies,
interest rates will need to increase in emerging economies as well, and their currencies
will likely depreciate. Higher interest rates make debt service more expensive, reinforcing the trend of recent years, and weaker currencies make debt service more burdensome
relative to the size of the economy. Liquidity problems could suddenly morph into solvency
problems
InEx: A Show About Inclusive Design
What does the term “inclusive design” mean to you?
Broadly speaking, the colloquial definition of “inclusive design” is the intersection between “something that looks inclusive” and “something that looks like it was designed.” This stands in contrast to the more holistic approach which makes up the Inclusive Design program at OCAD University, whose program is focused from the start on seeking out and empowering marginalized, minoritized and historically underinvested communities through all phases of product design.
The effect of this more superficial interpretation above taking hold is in shaping public perception. Embracing that superficiality by aligning the term to often fundamentally wrong-headed “design for” projects acts not only to further marginalize the purported users of these products, but to devalue the work of people trained in equity design, participatory action research and co-design, among other techniques and methodologies. Attention (and resources) flow to simple feel-good stories, at the expense of the more complex reality of inclusion and equity work in design roles: that they take time and effort, and don’t fit neatly in PR-friendly boxes.
To address this gap in understanding, as well as the range of constituencies involved in defining, or at least narrowing down, the term “inclusive design,” I conducted a series of interviews with six professionals in fields exploring inclusion and equity in design. The resulting conversations showed an expansive set of lived experiences, personal insights into academia and industry, critique into the theory of its inclusive design and how it is claimed, and a look at where we go from here
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