13,512 research outputs found

    Sensitivity analysis for ReaxFF reparameterization using the Hilbert-Schmidt independence criterion

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    We apply a global sensitivity method, the Hilbert-Schmidt independence criterion (HSIC), to the reparameterization of a Zn/S/H ReaxFF force field to identify the most appropriate parameters for reparameterization. Parameter selection remains a challenge in this context as high dimensional optimizations are prone to overfitting and take a long time, but selecting too few parameters leads to poor quality force fields. We show that the HSIC correctly and quickly identifies the most sensitive parameters, and that optimizations done using a small number of sensitive parameters outperform those done using a higher dimensional reasonable-user parameter selection. Optimizations using only sensitive parameters: 1) converge faster, 2) have loss values comparable to those found with the naive selection, 3) have similar accuracy in validation tests, and 4) do not suffer from problems of overfitting. We demonstrate that an HSIC global sensitivity is a cheap optimization pre-processing step that has both qualitative and quantitative benefits which can substantially simplify and speedup ReaxFF reparameterizations.Comment: author accepted manuscrip

    Cost-effective non-destructive testing of biomedical components fabricated using additive manufacturing

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    Biocompatible titanium-alloys can be used to fabricate patient-specific medical components using additive manufacturing (AM). These novel components have the potential to improve clinical outcomes in various medical scenarios. However, AM introduces stability and repeatability concerns, which are potential roadblocks for its widespread use in the medical sector. Micro-CT imaging for non-destructive testing (NDT) is an effective solution for post-manufacturing quality control of these components. Unfortunately, current micro-CT NDT scanners require expensive infrastructure and hardware, which translates into prohibitively expensive routine NDT. Furthermore, the limited dynamic-range of these scanners can cause severe image artifacts that may compromise the diagnostic value of the non-destructive test. Finally, the cone-beam geometry of these scanners makes them susceptible to the adverse effects of scattered radiation, which is another source of artifacts in micro-CT imaging. In this work, we describe the design, fabrication, and implementation of a dedicated, cost-effective micro-CT scanner for NDT of AM-fabricated biomedical components. Our scanner reduces the limitations of costly image-based NDT by optimizing the scanner\u27s geometry and the image acquisition hardware (i.e., X-ray source and detector). Additionally, we describe two novel techniques to reduce image artifacts caused by photon-starvation and scatter radiation in cone-beam micro-CT imaging. Our cost-effective scanner was designed to match the image requirements of medium-size titanium-alloy medical components. We optimized the image acquisition hardware by using an 80 kVp low-cost portable X-ray unit and developing a low-cost lens-coupled X-ray detector. Image artifacts caused by photon-starvation were reduced by implementing dual-exposure high-dynamic-range radiography. For scatter mitigation, we describe the design, manufacturing, and testing of a large-area, highly-focused, two-dimensional, anti-scatter grid. Our results demonstrate that cost-effective NDT using low-cost equipment is feasible for medium-sized, titanium-alloy, AM-fabricated medical components. Our proposed high-dynamic-range strategy improved by 37% the penetration capabilities of an 80 kVp micro-CT imaging system for a total x-ray path length of 19.8 mm. Finally, our novel anti-scatter grid provided a 65% improvement in CT number accuracy and a 48% improvement in low-contrast visualization. Our proposed cost-effective scanner and artifact reduction strategies have the potential to improve patient care by accelerating the widespread use of patient-specific, bio-compatible, AM-manufactured, medical components

    Towards A Graphene Chip System For Blood Clotting Disease Diagnostics

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    Point of care diagnostics (POCD) allows the rapid, accurate measurement of analytes near to a patient. This enables faster clinical decision making and can lead to earlier diagnosis and better patient monitoring and treatment. However, despite many prospective POCD devices being developed for a wide range of diseases this promised technology is yet to be translated to a clinical setting due to the lack of a cost-effective biosensing platform.This thesis focuses on the development of a highly sensitive, low cost and scalable biosensor platform that combines graphene with semiconductor fabrication tech-niques to create graphene field-effect transistors biosensor. The key challenges of designing and fabricating a graphene-based biosensor are addressed. This work fo-cuses on a specific platform for blood clotting disease diagnostics, but the platform has the capability of being applied to any disease with a detectable biomarker.Multiple sensor designs were tested during this work that maximised sensor ef-ficiency and costs for different applications. The multiplex design enabled different graphene channels on the same chip to be functionalised with unique chemistry. The Inverted MOSFET design was created, which allows for back gated measurements to be performed whilst keeping the graphene channel open for functionalisation. The Shared Source and Matrix design maximises the total number of sensing channels per chip, resulting in the most cost-effective fabrication approach for a graphene-based sensor (decreasing cost per channel from £9.72 to £4.11).The challenge of integrating graphene into a semiconductor fabrication process is also addressed through the development of a novel vacuum transfer method-ology that allows photoresist free transfer. The two main fabrication processes; graphene supplied on the wafer “Pre-Transfer” and graphene transferred after met-allisation “Post-Transfer” were compared in terms of graphene channel resistance and graphene end quality (defect density and photoresist). The Post-Transfer pro-cess higher quality (less damage, residue and doping, confirmed by Raman spec-troscopy).Following sensor fabrication, the next stages of creating a sensor platform involve the passivation and packaging of the sensor chip. Different approaches using dielec-tric deposition approaches are compared for passivation. Molecular Vapour Deposi-tion (MVD) deposited Al2O3 was shown to produce graphene channels with lower damage than unprocessed graphene, and also improves graphene doping bringing the Dirac point of the graphene close to 0 V. The packaging integration of microfluidics is investigated comparing traditional soft lithography approaches and the new 3D printed microfluidic approach. Specific microfluidic packaging for blood separation towards a blood sampling point of care sensor is examined to identify the laminar approach for lower blood cell count, as a method of pre-processing the blood sample before sensing.To test the sensitivity of the Post-Transfer MVD passivated graphene sensor de-veloped in this work, real-time IV measurements were performed to identify throm-bin protein binding in real-time on the graphene surface. The sensor was function-alised using a thrombin specific aptamer solution and real-time IV measurements were performed on the functionalised graphene sensor with a range of biologically relevant protein concentrations. The resulting sensitivity of the graphene sensor was in the 1-100 pg/ml concentration range, producing a resistance change of 0.2% per pg/ml. Specificity was confirmed using a non-thrombin specific aptamer as the neg-ative control. These results indicate that the graphene sensor platform developed in this thesis has the potential as a highly sensitive POCD. The processes developed here can be used to develop graphene sensors for multiple biomarkers in the future

    Design Justice Principles and Do-It-Yourself Assistive Technology: Case Study

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    In this project, we focus on the Principles of Design Justice, as developed by the Design Justice Network, a community committed to challenging structural inequalities of design. Our thesis research project is aligned with the premise of user-centered design and the situated knowledge in third paradigm of HCI. We examine some of the current processes for Do-It-Yourself Assistive Technology (DIY-AT) development and deployment using the works of Makers Making Change (MMC). MMC connects the makers of DIY-AT devices to people who need AT devices. We also examine the impacts of the ongoing COVID-19 pandemic on the need for DIY-AT and the challenges it might have caused. Our findings include MMC's positive impact regarding DIY-AT service delivery, engaging local makers into making DIY-AT, and a modest job in integrating Design Justice Principles. The findings of our study also suggest an increase in the demand for AT due to the pandemic

    Socio-endocrinology revisited: New tools to tackle old questions

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    Animals’ social environments impact their health and survival, but the proximate links between sociality and fitness are still not fully understood. In this thesis, I develop and apply new approaches to address an outstanding question within this sociality-fitness link: does grooming (a widely studied, positive social interaction) directly affect glucocorticoid concentrations (GCs; a group of steroid hormones indicating physiological stress) in a wild primate? To date, negative, long-term correlations between grooming and GCs have been found, but the logistical difficulties of studying proximate mechanisms in the wild leave knowledge gaps regarding the short-term, causal mechanisms that underpin this relationship. New technologies, such as collar-mounted tri-axial accelerometers, can provide the continuous behavioural data required to match grooming to non-invasive GC measures (Chapter 1). Using Chacma baboons (Papio ursinus) living on the Cape Peninsula, South Africa as a model system, I identify giving and receiving grooming using tri-axial accelerometers and supervised machine learning methods, with high overall accuracy (~80%) (Chapter 2). I then test what socio-ecological variables predict variation in faecal and urinary GCs (fGCs and uGCs) (Chapter 3). Shorter and rainy days are associated with higher fGCs and uGCs, respectively, suggesting that environmental conditions may impose stressors in the form of temporal bottlenecks. Indeed, I find that short days and days with more rain-hours are associated with reduced giving grooming (Chapter 4), and that this reduction is characterised by fewer and shorter grooming bouts. Finally, I test whether grooming predicts GCs, and find that while there is a long-term negative correlation between grooming and GCs, grooming in the short-term, in particular giving grooming, is associated with higher fGCs and uGCs (Chapter 5). I end with a discussion on how the new tools I applied have enabled me to advance our understanding of sociality and stress in primate social systems (Chapter 6)

    Transporte sedimentar de misturas arenosas em ambientes costeiros

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    Sediment dynamics is a complex subject, playing an important role in coastal areas. The interaction between the wave action and sediment particles is determinant to understand sediment transport. The knowledge of sediment transport in sand mixtures is relevant as the coastal zone usually presents large heterogeneities of sediment particles sizes in the horizontal and vertical directions, which denote the existence of selective transport process. The goal of the present study was to understand selective sand transport mechanisms associated with wave-dominated conditions. To achieve the proposed objective, the work was supported by several approaches to give insights into the processes associated with heterometric sediment transport. The first approach consisted in a review of the literature to understand what is known and the lack of knowledge in the subject. The second approach consisted in performing a set of experiments with fluorescent sand tracers in natural conditions, at the field, and in a controlled environment, at the laboratory. The experiment conducted at Patos beach, Spain, aimed to observe the behavior of the native sand in the natural environment. The one performed at a large wave flume (Großer Wellenkanal, GWK) in Hannover, considered distinct sediment mixtures under two wave conditions. In both, measurements of the total and fractional transport were made. Finally, a quasi-steady and a semi-unsteady model were considered to calculate the net sediment transport of a large data set, for uniform and graded sand, allowing to identify limitations of the models and to propose new methodologies to obtain more adequate results. The experimental results obtained in the field allowed to observe the tracer transport towards the beach, in the wave direction, and to characterize the transport of the different fractions of the tracer in terms of the hydrodynamic processes. The laboratory experiment allowed to verify the occurrence of interaction between the sand fractions, with the finer (coarser) sediment decreasing (increasing) their transport, as the percentage of coarse sand in the bed mixture increases. The validation of the models was conducted and their performance was improved with the introduction of parameters related to surface wave streaming effects and bedforms.A dinâmica sedimentar é um tema complexo, desempenhando um papel importante nas zonas costeiras. A interação entre a ação das ondas e as partículas de sedimento é determinante para compreender o transporte sedimentar. O conhecimento do transporte de sedimentos heterométricos é relevante uma vez que a zona costeira apresenta geralmente grandes heterogeneidades na dimensão das partículas sedimentares nas direções horizontal e vertical, o que denota a existência de processos seletivos de transporte. O presente estudo teve como objetivo compreender os mecanismos de transporte seletivo de areia associados a condições hidrodinâmicas dominadas pelas ondas e considerou diferentes abordagens para evidenciar os processos que intervêm no transporte de sedimentos heterométricos. A primeira abordagem consistiu numa revisão da literatura para compreender o conhecimento atual e as lacunas existentes. A segunda abordagem consistiu na realização de um conjunto de experiências com traçadores de areia fluorescente em condições naturais, no campo, e em ambiente controlado, no laboratório. A experiência realizada na praia de Patos, Espanha, visou observar o comportamento da areia nativa em ambiente natural. A experiência realizada no grande canal de ondas (Großer Wellenkanal, GWK) em Hannover, considerou misturas de sedimentos com granulometrias distintas sob duas condições de ondas. Em ambas as experiências, foram feitas medições do transporte total e fracionado. Finalmente, um modelo quase-estacionário e um modelo semi-não estacionário foram considerados para calcular as taxas de transporte sedimentar de um grande conjunto de dados experimentais, para areia uniforme e heterométrica, permitindo identificar limitações dos modelos e propor novas metodologias para obter resultados mais adequados. Os resultados experimentais obtidos no campo permitiram observar o transporte do traçador em direcção à praia, na direcção das ondas, e caracterizar o transporte das diferentes frações do traçador em termos dos processos hidrodinâmicos. A experiência laboratorial permitiu verificar a ocorrência de processos de interação no transporte das diferentes frações de areia, com a fração mais fina do sedimento (mais grosseira) a diminuir (aumentar) o seu transporte, à medida que a percentagem de areia grosseira na mistura do leito de fundo aumenta. A validação dos modelos foi realizada e o seu desempenho foi melhorado com a introdução de parâmetros relacionados com os efeitos de streaming e formas de fundo.Programa Doutoral em Ciência, Tecnologia e Gestão do Ma

    Cis-Regulation of Gremlin1 Expression during Mouse Limb Bud Development and its Diversification during Vertebrate Evolution

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    Embryonic development and organogenesis rely on tightly controlled gene expression, which is achieved by cis-regulatory modules (CRMs) interacting with distinct transcription factors (TFs) that control spatio-temporal and tissue-specific gene expression. During organogenesis, gene regulatory networks (GRNs) with selfregulatory feedback properties coordinately control growth and patterning and provide systemic robustness against genetic and/or environmental perturbations. During limb bud development, various interlinked GRNs control outgrowth and patterning along all three limb axes. A paradigm network is the epithelial-mesenchymal (e-m) SHH/GREM1/AER-FGF feedback signaling system which controls limb bud outgrowth and digit patterning. The BMP antagonist GREMLIN1 (GREM1) is central to this e-m interactions as its antagonism of BMP activity is essential to maintain both AER-Fgf and Shh expression. In turn, SHH signaling upregulates Grem1 expression, which results in establishment of a self-regulatory signaling network. One previous study provided evidence that several CRMs could regulate Grem1 expression during limb bud development. However, the cis-regulatory logics underlying the spatio-temporal regulation of the Grem1 expression dynamics remained obscure. From an evolutionary point of view, diversification of CRMs can result in diversification of gene regulation which can drive the establishment of morphological novelties and adaptions. This was evidenced by the observed differences in Grem1 expression in different species that correlates with the evolutionary plasticity of tetrapod digit patterning. Hence, a better understanding of spatio-temporal regulation of the Grem1 expression dynamics and underlying cis-regulatory logic is of interest from both adevelopmental and an evolutionary perspective. Recently, multiple candidate CRMs have been identified that might be functionally relevant for Grem1 expression during mouse limb bud development. For my PhD project, I genetically analyzed which of these CRMs are involved in the regulation of the spatial-temporal Grem1 expression dynamics in limb buds. Therefore, we generated various single and compound CRM mutant alleles using CRISPR/Cas9. Our CRMs allelic series revealed a complex Grem1 cis-regulation among a minimum of six CRMs, where a subset of CRMs regulates Grem1 transcript levels in an additive manner. Surprisingly, phenotypic robustness depends not on threshold transcript levels but the spatial integrity of the Grem1 expression domain. In particular, interactions among five CRMs control the characteristic asymmetrical and posteriorly biased Grem1 expression in mouse limb buds. Our results provide an example of how multiple seemingly redundant limb-specific CRMs provide phenotypical robustness by cooperative/synergistic regulation of the spatial Grem1 expression dynamics. Three CRMs are conserved along the phylogeny of extant vertebrates with paired appendages. Of those, the activities of two CRMs recapitulate the major spatiotemporal aspects of Grem1 expression in mouse limb buds. In order to study their functions in species-specific regulation of Grem1 expression and their functional diversification in tetrapods, I tested the orthologous of both CRMs from representative species using LacZ reporter assays in transgenic mice, in comparison to the endogenous Grem1 expression in limb buds of the species of origin. Surprisingly, the activities of CRM orthologues display high evolutionary plasticity, which correlates better with the Grem1 expression pattern in limb buds of the species of origin than its mouse orthologue. This differential responsiveness to the GRNs in mouse suggests that TF binding site alterations in CRMs could underlie the spatial diversification of Grem1 in limb buds during tetrapod evolution. While the fish fin and tetrapod limb share some homologies of proximal bones, the autopod is a neomorphic feature of tetrapods. The Grem1 requirement for digit patterning and conserved expression in fin buds prompted us to assess the enhancer activity of fish CRM orthologues in transgenic mice. Surprisingly, all tested fish CRMs are active in the mouse autopod primordia providing strong evidence that Grem1 CRMs are active in fin buds and that they predate the fin-to-limb transition. Our results corroborate increasing evidence that CRMs governing autopodial gene expression have been co-opted during the emergence of tetrapod autopod. Furthermore, as part of a collaboration with Dr. S. Jhanwar, I contributed to the study of shared and species-specific epigenomic and genomic variations during mouse and chicken limb bud development. In this analysis, Dr. S. Jhanwar identified putative enhancers that show higher chicken-specific sequence turnover rates in comparison to their mouse orthologues, which defines them as so-called chicken accelerated regions (CARs). Here, I analyzed the CAR activities in comparison to their mouse orthologues by transgenic LacZ reporter assays, which was complemented by analysis of the endogenous gene expression in limb buds of both species. This analysis indicates that diversified activity of CARs and their mouse orthologues could be linked to the differential gene expression patterns in limb buds of both species
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