3,726 research outputs found

    Exploring missing heritability in neurodevelopmental disorders:Learning from regulatory elements

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    In this thesis, I aimed to solve part of the missing heritability in neurodevelopmental disorders, using computational approaches. Next to the investigations of a novel epilepsy syndrome and investigations aiming to elucidate the regulation of the gene involved, I investigated and prioritized genomic sequences that have implications in gene regulation during the developmental stages of human brain, with the goal to create an atlas of high confidence non-coding regulatory elements that future studies can assess for genetic variants in genetically unexplained individuals suffering from neurodevelopmental disorders that are of suspected genetic origin

    Converging organoids and extracellular matrix::New insights into liver cancer biology

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    Converging organoids and extracellular matrix::New insights into liver cancer biology

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    Primary liver cancer, consisting primarily of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), is a heterogeneous malignancy with a dismal prognosis, resulting in the third leading cause of cancer mortality worldwide [1, 2]. It is characterized by unique histological features, late-stage diagnosis, a highly variable mutational landscape, and high levels of heterogeneity in biology and etiology [3-5]. Treatment options are limited, with surgical intervention the main curative option, although not available for the majority of patients which are diagnosed in an advanced stage. Major contributing factors to the complexity and limited treatment options are the interactions between primary tumor cells, non-neoplastic stromal and immune cells, and the extracellular matrix (ECM). ECM dysregulation plays a prominent role in multiple facets of liver cancer, including initiation and progression [6, 7]. HCC often develops in already damaged environments containing large areas of inflammation and fibrosis, while CCA is commonly characterized by significant desmoplasia, extensive formation of connective tissue surrounding the tumor [8, 9]. Thus, to gain a better understanding of liver cancer biology, sophisticated in vitro tumor models need to incorporate comprehensively the various aspects that together dictate liver cancer progression. Therefore, the aim of this thesis is to create in vitro liver cancer models through organoid technology approaches, allowing for novel insights into liver cancer biology and, in turn, providing potential avenues for therapeutic testing. To model primary epithelial liver cancer cells, organoid technology is employed in part I. To study and characterize the role of ECM in liver cancer, decellularization of tumor tissue, adjacent liver tissue, and distant metastatic organs (i.e. lung and lymph node) is described, characterized, and combined with organoid technology to create improved tissue engineered models for liver cancer in part II of this thesis. Chapter 1 provides a brief introduction into the concepts of liver cancer, cellular heterogeneity, decellularization and organoid technology. It also explains the rationale behind the work presented in this thesis. In-depth analysis of organoid technology and contrasting it to different in vitro cell culture systems employed for liver cancer modeling is done in chapter 2. Reliable establishment of liver cancer organoids is crucial for advancing translational applications of organoids, such as personalized medicine. Therefore, as described in chapter 3, a multi-center analysis was performed on establishment of liver cancer organoids. This revealed a global establishment efficiency rate of 28.2% (19.3% for hepatocellular carcinoma organoids (HCCO) and 36% for cholangiocarcinoma organoids (CCAO)). Additionally, potential solutions and future perspectives for increasing establishment are provided. Liver cancer organoids consist of solely primary epithelial tumor cells. To engineer an in vitro tumor model with the possibility of immunotherapy testing, CCAO were combined with immune cells in chapter 4. Co-culture of CCAO with peripheral blood mononuclear cells and/or allogenic T cells revealed an effective anti-tumor immune response, with distinct interpatient heterogeneity. These cytotoxic effects were mediated by cell-cell contact and release of soluble factors, albeit indirect killing through soluble factors was only observed in one organoid line. Thus, this model provided a first step towards developing immunotherapy for CCA on an individual patient level. Personalized medicine success is dependent on an organoids ability to recapitulate patient tissue faithfully. Therefore, in chapter 5 a novel organoid system was created in which branching morphogenesis was induced in cholangiocyte and CCA organoids. Branching cholangiocyte organoids self-organized into tubular structures, with high similarity to primary cholangiocytes, based on single-cell sequencing and functionality. Similarly, branching CCAO obtain a different morphology in vitro more similar to primary tumors. Moreover, these branching CCAO have a higher correlation to the transcriptomic profile of patient-paired tumor tissue and an increased drug resistance to gemcitabine and cisplatin, the standard chemotherapy regimen for CCA patients in the clinic. As discussed, CCAO represent the epithelial compartment of CCA. Proliferation, invasion, and metastasis of epithelial tumor cells is highly influenced by the interaction with their cellular and extracellular environment. The remodeling of various properties of the extracellular matrix (ECM), including stiffness, composition, alignment, and integrity, influences tumor progression. In chapter 6 the alterations of the ECM in solid tumors and the translational impact of our increased understanding of these alterations is discussed. The success of ECM-related cancer therapy development requires an intimate understanding of the malignancy-induced changes to the ECM. This principle was applied to liver cancer in chapter 7, whereby through a integrative molecular and mechanical approach the dysregulation of liver cancer ECM was characterized. An optimized agitation-based decellularization protocol was established for primary liver cancer (HCC and CCA) and paired adjacent tissue (HCC-ADJ and CCA-ADJ). Novel malignancy-related ECM protein signatures were found, which were previously overlooked in liver cancer transcriptomic data. Additionally, the mechanical characteristics were probed, which revealed divergent macro- and micro-scale mechanical properties and a higher alignment of collagen in CCA. This study provided a better understanding of ECM alterations during liver cancer as well as a potential scaffold for culture of organoids. This was applied to CCA in chapter 8 by combining decellularized CCA tumor ECM and tumor-free liver ECM with CCAO to study cell-matrix interactions. Culture of CCAO in tumor ECM resulted in a transcriptome closely resembling in vivo patient tumor tissue, and was accompanied by an increase in chemo resistance. In tumor-free liver ECM, devoid of desmoplasia, CCAO initiated a desmoplastic reaction through increased collagen production. If desmoplasia was already present, distinct ECM proteins were produced by the organoids. These were tumor-related proteins associated with poor patient survival. To extend this method of studying cell-matrix interactions to a metastatic setting, lung and lymph node tissue was decellularized and recellularized with CCAO in chapter 9, as these are common locations of metastasis in CCA. Decellularization resulted in removal of cells while preserving ECM structure and protein composition, linked to tissue-specific functioning hallmarks. Recellularization revealed that lung and lymph node ECM induced different gene expression profiles in the organoids, related to cancer stem cell phenotype, cell-ECM integrin binding, and epithelial-to-mesenchymal transition. Furthermore, the metabolic activity of CCAO in lung and lymph node was significantly influenced by the metastatic location, the original characteristics of the patient tumor, and the donor of the target organ. The previously described in vitro tumor models utilized decellularized scaffolds with native structure. Decellularized ECM can also be used for creation of tissue-specific hydrogels through digestion and gelation procedures. These hydrogels were created from both porcine and human livers in chapter 10. The liver ECM-based hydrogels were used to initiate and culture healthy cholangiocyte organoids, which maintained cholangiocyte marker expression, thus providing an alternative for initiation of organoids in BME. Building upon this, in chapter 11 human liver ECM-based extracts were used in combination with a one-step microfluidic encapsulation method to produce size standardized CCAO. The established system can facilitate the reduction of size variability conventionally seen in organoid culture by providing uniform scaffolding. Encapsulated CCAO retained their stem cell phenotype and were amendable to drug screening, showing the feasibility of scalable production of CCAO for throughput drug screening approaches. Lastly, Chapter 12 provides a global discussion and future outlook on tumor tissue engineering strategies for liver cancer, using organoid technology and decellularization. Combining multiple aspects of liver cancer, both cellular and extracellular, with tissue engineering strategies provides advanced tumor models that can delineate fundamental mechanistic insights as well as provide a platform for drug screening approaches.<br/

    Exploring missing heritability in neurodevelopmental disorders:Learning from regulatory elements

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    Enhancing the forensic comparison process of common trace materials through the development of practical and systematic methods

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    An ongoing advancement in forensic trace evidence has driven the development of new and objective methods for comparing various materials. While many standard guides have been published for use in trace laboratories, different areas require a more comprehensive understanding of error rates and an urgent need for harmonizing methods of examination and interpretation. Two critical areas are the forensic examination of physical fits and the comparison of spectral data, which depend highly on the examiner’s judgment. The long-term goal of this study is to advance and modernize the comparative process of physical fit examinations and spectral interpretation. This goal is fulfilled through several avenues: 1) improvement of quantitative-based methods for various trace materials, 2) scrutiny of the methods through interlaboratory exercises, and 3) addressing fundamental aspects of the discipline using large experimental datasets, computational algorithms, and statistical analysis. A substantial new body of knowledge has been established by analyzing population sets of nearly 4,000 items representative of casework evidence. First, this research identifies material-specific relevant features for duct tapes and automotive polymers. Then, this study develops reporting templates to facilitate thorough and systematic documentation of an analyst’s decision-making process and minimize risks of bias. It also establishes criteria for utilizing a quantitative edge similarity score (ESS) for tapes and automotive polymers that yield relatively high accuracy (85% to 100%) and, notably, no false positives. Finally, the practicality and performance of the ESS method for duct tape physical fits are evaluated by forensic practitioners through two interlaboratory exercises. Across these studies, accuracy using the ESS method ranges between 95-99%, and again no false positives are reported. The practitioners’ feedback demonstrates the method’s potential to assist in training and improve peer verifications. This research also develops and trains computational algorithms to support analysts making decisions on sample comparisons. The automated algorithms in this research show the potential to provide objective and probabilistic support for determining a physical fit and demonstrate comparative accuracy to the analyst. Furthermore, additional models are developed to extract feature edge information from the systematic comparison templates of tapes and textiles to provide insight into the relative importance of each comparison feature. A decision tree model is developed to assist physical fit examinations of duct tapes and textiles and demonstrates comparative performance to the trained analysts. The computational tools also evaluate the suitability of partial sample comparisons that simulate situations where portions of the item are lost or damaged. Finally, an objective approach to interpreting complex spectral data is presented. A comparison metric consisting of spectral angle contrast ratios (SCAR) is used as a model to assess more than 94 different-source and 20 same-source electrical tape backings. The SCAR metric results in a discrimination power of 96% and demonstrates the capacity to capture information on the variability between different-source samples and the variability within same-source samples. Application of the random-forest model allows for the automatic detection of primary differences between samples. The developed threshold could assist analysts with making decisions on the spectral comparison of chemically similar samples. This research provides the forensic science community with novel approaches to comparing materials commonly seen in forensic laboratories. The outcomes of this study are anticipated to offer forensic practitioners new and accessible tools for incorporation into current workflows to facilitate systematic and objective analysis and interpretation of forensic materials and support analysts’ opinions

    Introduction to Drone Detection Radar with Emphasis on Automatic Target Recognition (ATR) technology

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    This paper discusses the challenges of detecting and categorizing small drones with radar automatic target recognition (ATR) technology. The authors suggest integrating ATR capabilities into drone detection radar systems to improve performance and manage emerging threats. The study focuses primarily on drones in Group 1 and 2. The paper highlights the need to consider kinetic features and signal signatures, such as micro-Doppler, in ATR techniques to efficiently recognize small drones. The authors also present a comprehensive drone detection radar system design that balances detection and tracking requirements, incorporating parameter adjustment based on scattering region theory. They offer an example of a performance improvement achieved using feedback and situational awareness mechanisms with the integrated ATR capabilities. Furthermore, the paper examines challenges related to one-way attack drones and explores the potential of cognitive radar as a solution. The integration of ATR capabilities transforms a 3D radar system into a 4D radar system, resulting in improved drone detection performance. These advancements are useful in military, civilian, and commercial applications, and ongoing research and development efforts are essential to keep radar systems effective and ready to detect, track, and respond to emerging threats.Comment: 17 pages, 14 figures, submitted to a journal and being under revie

    Investigation into Photon Emissions as a Side-Channel Leakage in Two Microcontrollers: A Focus on SRAM Blocks

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    Microcontrollers are extensively utilized across a diverse range of applications. However, with the escalating usage of these devices, the risk to their security and the valuable data they process correspondingly intensifies. These devices could potentially be susceptible to various security threats, with side channel leakage standing out as a notable concern. Among the numerous types of side-channel leakages, photon emissions from active devices emerge as a potentially significant concern. These emissions, a characteristic of all semiconductor devices including microcontrollers, occur during their operation. Depending on the operating point and the internal state of the chip, these emissions can reflect the device’s internal operations. Therefore, a malicious individual could potentially exploit these emissions to gain insights into the computations being performed within the device. This dissertation delves into the investigation of photon emissions from the SRAM blocks of two distinct microcontrollers, utilizing a cost-effective setup. The aim is to extract information from these emissions, analyzing them as potential side-channel leakage points. In the first segment of the study, a PIC microcontroller variant is investigated. The quiescent photon emissions from the SRAM are examined. A correlation attack was successfully executed on these emissions, which led to the recovery of the AES encryption key. Furthermore, differential analysis was used to examine the location of SRAM bits. The combination of this information with the application of an image processing method, namely the Structural Similarity Index (SSIM), assisted in revealing the content of SRAM cells from photon emission images. The second segment of this study, for the first time, emphasizes on a RISC-V chip, examining the photon emissions of the SRAM during continuous reading. Probing the photon emissions from the row and column detectors led to the identification of a target word location, which is capable of revealing the AES key. Also, the content of target row was retrieved through the photon emissions originating from the drivers and the SRAM cells themselves. Additionally, the SSIM technique was utilized to determine the address of a targeted word in RISC-V photon emissions which cannot be analyzed through visual inspection. The insights gained from this research contribute to a deeper understanding of side-channel leakage via photon emissions and demonstrate its potential potency in extracting critical information from digital devices. Moreover, this information significantly contributes to the development of innovative security measures, an aspect becoming increasingly crucial in our progressively digitized world

    Advances and Applications of DSmT for Information Fusion. Collected Works, Volume 5

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    This fifth volume on Advances and Applications of DSmT for Information Fusion collects theoretical and applied contributions of researchers working in different fields of applications and in mathematics, and is available in open-access. The collected contributions of this volume have either been published or presented after disseminating the fourth volume in 2015 in international conferences, seminars, workshops and journals, or they are new. The contributions of each part of this volume are chronologically ordered. First Part of this book presents some theoretical advances on DSmT, dealing mainly with modified Proportional Conflict Redistribution Rules (PCR) of combination with degree of intersection, coarsening techniques, interval calculus for PCR thanks to set inversion via interval analysis (SIVIA), rough set classifiers, canonical decomposition of dichotomous belief functions, fast PCR fusion, fast inter-criteria analysis with PCR, and improved PCR5 and PCR6 rules preserving the (quasi-)neutrality of (quasi-)vacuous belief assignment in the fusion of sources of evidence with their Matlab codes. Because more applications of DSmT have emerged in the past years since the apparition of the fourth book of DSmT in 2015, the second part of this volume is about selected applications of DSmT mainly in building change detection, object recognition, quality of data association in tracking, perception in robotics, risk assessment for torrent protection and multi-criteria decision-making, multi-modal image fusion, coarsening techniques, recommender system, levee characterization and assessment, human heading perception, trust assessment, robotics, biometrics, failure detection, GPS systems, inter-criteria analysis, group decision, human activity recognition, storm prediction, data association for autonomous vehicles, identification of maritime vessels, fusion of support vector machines (SVM), Silx-Furtif RUST code library for information fusion including PCR rules, and network for ship classification. Finally, the third part presents interesting contributions related to belief functions in general published or presented along the years since 2015. These contributions are related with decision-making under uncertainty, belief approximations, probability transformations, new distances between belief functions, non-classical multi-criteria decision-making problems with belief functions, generalization of Bayes theorem, image processing, data association, entropy and cross-entropy measures, fuzzy evidence numbers, negator of belief mass, human activity recognition, information fusion for breast cancer therapy, imbalanced data classification, and hybrid techniques mixing deep learning with belief functions as well

    Toward Efficient and Robust Computer Vision for Large-Scale Edge Applications

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    The past decade has been witnessing remarkable advancements in computer vision and deep learning algorithms, ushering in a transformative wave of large-scale edge applications across various industries. These image processing methods, however, still encounter numerous challenges when it comes to meeting real-world demands, especially in terms of accuracy and latency at scale. Indeed, striking a balance among efficiency, robustness, and scalability remains a common obstacle. This dissertation investigates these issues in the context of different computer vision tasks, including image classification, semantic segmentation, depth estimation, and object detection. We introduce novel solutions, focusing on utilizing adjustable neural networks, joint multi-task architecture search, and generalized supervision interpolation. The first obstacle revolves around the ability to trade off between speed and accuracy in convolutional neural networks (CNNs) during inference on resource-constrained platforms. Despite their progress, CNNs are typically monolithic at runtime, which can present practical difficulties since computational budgets may vary over time. To address this, we introduce Any-Width Network, an adjustable-width CNN architecture that utilizes a novel Triangular Convolution module to enable fine-grained control over speed and accuracy during inference. The second challenge focuses on the computationally demanding nature of dense prediction tasks such as semantic segmentation and depth estimation. This issue becomes especially problematic for edge platforms with limited resources. To tackle this, we propose a novel and scalable framework named EDNAS. EDNAS leverages the synergistic relationship between Multi-Task Learning and hardware-aware Neural Architecture Search to significantly enhance on-device speed and accuracy of dense predictions. Finally, to improve the robustness of object detection, we introduce a novel data mixing augmentation. While mixing techniques such as Mixup have proven successful in image classification, their application to object detection is non-trivial due to spatial misalignment, foreground/background distinction, and instance multiplicity. To address these issues, we propose a generalized data mixing principle, Supervision Interpolation, and its simple yet effective implementation, LossMix. By addressing these challenges, this dissertation aims to facilitate better efficiency, accuracy, and scalability of computer vision and deep learning algorithms and contribute to the advancement of large-scale edge applications across different domains.Doctor of Philosoph
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