1,943 research outputs found

    Decomposition of sequential and concurrent models

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    Le macchine a stati finiti (FSM), sistemi di transizioni (TS) e le reti di Petri (PN) sono importanti modelli formali per la progettazione di sistemi. Un problema fodamentale è la conversione da un modello all'altro. Questa tesi esplora il mondo delle reti di Petri e della decomposizione di sistemi di transizioni. Per quanto riguarda la decomposizione dei sistemi di transizioni, la teoria delle regioni rappresenta la colonna portante dell'intero processo di decomposizione, mirato soprattutto a decomposizioni che utilizzano due sottoclassi delle reti di Petri: macchine a stati e reti di Petri a scelta libera. Nella tesi si dimostra che una proprietà chiamata ``chiusura rispetto all'eccitazione" (excitation-closure) è sufficiente per produrre un insieme di reti di Petri la cui sincronizzazione è bisimile al sistema di transizioni (o rete di Petri di partenza, se la decomposizione parte da una rete di Petri), dimostrando costruttivamente l'esistenza di una bisimulazione. Inoltre, è stato implementato un software che esegue la decomposizione dei sistemi di transizioni, per rafforzare i risultati teorici con dati sperimentali sistematici. Nella seconda parte della dissertazione si analizza un nuovo modello chiamato MSFSM, che rappresenta un insieme di FSM sincronizzate da due primitive specifiche (Wait State - Stato d'Attesa e Transition Barrier - Barriera di Transizione). Tale modello trova un utilizzo significativo nella sintesi di circuiti sincroni a partire da reti di Petri a scelta libera. In particolare vengono identificati degli errori nell'approccio originale, fornendo delle correzioni.Finite State Machines (FSMs), transition systems (TSs) and Petri nets (PNs) are important models of computation ubiquitous in formal methods for modeling systems. Important problems involve the transition from one model to another. This thesis explores Petri nets, transition systems and Finite State Machines decomposition and optimization. The first part addresses decomposition of transition systems and Petri nets, based on the theory of regions, representing them by means of restricted PNs, e.g., State Machines (SMs) and Free-choice Petri nets (FCPNs). We show that the property called ``excitation-closure" is sufficient to produce a set of synchronized Petri nets bisimilar to the original transition system or to the initial Petri net (if the decomposition starts from a PN), proving by construction the existence of a bisimulation. Furthermore, we implemented a software performing the decomposition of transition systems, and reported extensive experiments. The second part of the dissertation discusses Multiple Synchronized Finite State Machines (MSFSMs) specifying a set of FSMs synchronized by specific primitives: Wait State and Transition Barrier. It introduces a method for converting Petri nets into synchronous circuits using MSFSM, identifies errors in the initial approach, and provides corrections

    Graduate Catalog of Studies, 2023-2024

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    Differential spectrum modeling and sensitivity for keV sterile neutrino search at KATRIN

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    Starting in 2026, the KATRIN experiment will conduct a high-statistics measurement of the differential tritium β\beta-spectrum to energies deep below the kinematic endpoint. This enables the search for keV sterile neutrinos with masses less than the kinematic endpoint energy m4E0=18.6keVm_\mathrm{4} \leq E_0 = 18.6\,\mathrm{keV}, aiming for a statistical sensitivity of Ue42=sin2θ106|U_\mathrm{e4}|^2=\sin^2\theta\sim 10^{-6} for the mixing amplitude. The differential spectrum is obtained by decreasing the retarding potential of KATRIN\u27s main spectrometer, and by determining the β\beta-electron energies by their energy deposition in the new TRISTAN SDD array. In this mode of operation, the existing integral model of the tritium spectrum is insufficient, and a novel differential model is developed in this work. The new model (TRModel) convolves the differential tritium spectrum using responese matrices to predict the energy spectrum of registered events after data acquisition. Each response matrix encodes the spectral spectral distrortion from individual experimental effects, which depend on adjustable systematic parameters. This approach allows to efficiently assess the sensitivity impact of each systematics individually or in combination with others. The response matrices are obtained from monte carlo simulations, numerical convolution, and analytical computation. In this work, the sensitivity impact of 20 systematic parameters is assessed for the TRISTAN Phase-1 measurement for which nine TRISTAN SDD modules are integrated into the KATRIN beamline. Furthermore, it is demonstrated that the sensitivity impact is significantly mitigated with several beamline field adjustments and minimal hardware modifications

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

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    Serverless Strategies and Tools in the Cloud Computing Continuum

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    Tesis por compendio[ES] En los últimos años, la popularidad de la computación en nube ha permitido a los usuarios acceder a recursos de cómputo, red y almacenamiento sin precedentes bajo un modelo de pago por uso. Esta popularidad ha propiciado la aparición de nuevos servicios para resolver determinados problemas informáticos a gran escala y simplificar el desarrollo y el despliegue de aplicaciones. Entre los servicios más destacados en los últimos años se encuentran las plataformas FaaS (Función como Servicio), cuyo principal atractivo es la facilidad de despliegue de pequeños fragmentos de código en determinados lenguajes de programación para realizar tareas específicas en respuesta a eventos. Estas funciones son ejecutadas en los servidores del proveedor Cloud sin que los usuarios se preocupen de su mantenimiento ni de la gestión de su elasticidad, manteniendo siempre un modelo de pago por uso de grano fino. Las plataformas FaaS pertenecen al paradigma informático conocido como Serverless, cuyo propósito es abstraer la gestión de servidores por parte de los usuarios, permitiéndoles centrar sus esfuerzos únicamente en el desarrollo de aplicaciones. El problema del modelo FaaS es que está enfocado principalmente en microservicios y tiende a tener limitaciones en el tiempo de ejecución y en las capacidades de computación (por ejemplo, carece de soporte para hardware de aceleración como GPUs). Sin embargo, se ha demostrado que la capacidad de autoaprovisionamiento y el alto grado de paralelismo de estos servicios pueden ser muy adecuados para una mayor variedad de aplicaciones. Además, su inherente ejecución dirigida por eventos hace que las funciones sean perfectamente adecuadas para ser definidas como pasos en flujos de trabajo de procesamiento de archivos (por ejemplo, flujos de trabajo de computación científica). Por otra parte, el auge de los dispositivos inteligentes e integrados (IoT), las innovaciones en las redes de comunicación y la necesidad de reducir la latencia en casos de uso complejos han dado lugar al concepto de Edge computing, o computación en el borde. El Edge computing consiste en el procesamiento en dispositivos cercanos a las fuentes de datos para mejorar los tiempos de respuesta. La combinación de este paradigma con la computación en nube, formando arquitecturas con dispositivos a distintos niveles en función de su proximidad a la fuente y su capacidad de cómputo, se ha acuñado como continuo de la computación en la nube (o continuo computacional). Esta tesis doctoral pretende, por lo tanto, aplicar diferentes estrategias Serverless para permitir el despliegue de aplicaciones generalistas, empaquetadas en contenedores de software, a través de los diferentes niveles del continuo computacional. Para ello, se han desarrollado múltiples herramientas con el fin de: i) adaptar servicios FaaS de proveedores Cloud públicos; ii) integrar diferentes componentes software para definir una plataforma Serverless en infraestructuras privadas y en el borde; iii) aprovechar dispositivos de aceleración en plataformas Serverless; y iv) facilitar el despliegue de aplicaciones y flujos de trabajo a través de interfaces de usuario. Además, se han creado y adaptado varios casos de uso para evaluar los desarrollos conseguidos.[CA] En els últims anys, la popularitat de la computació al núvol ha permès als usuaris accedir a recursos de còmput, xarxa i emmagatzematge sense precedents sota un model de pagament per ús. Aquesta popularitat ha propiciat l'aparició de nous serveis per resoldre determinats problemes informàtics a gran escala i simplificar el desenvolupament i desplegament d'aplicacions. Entre els serveis més destacats en els darrers anys hi ha les plataformes FaaS (Funcions com a Servei), el principal atractiu de les quals és la facilitat de desplegament de petits fragments de codi en determinats llenguatges de programació per realitzar tasques específiques en resposta a esdeveniments. Aquestes funcions són executades als servidors del proveïdor Cloud sense que els usuaris es preocupen del seu manteniment ni de la gestió de la seva elasticitat, mantenint sempre un model de pagament per ús de gra fi. Les plataformes FaaS pertanyen al paradigma informàtic conegut com a Serverless, el propòsit del qual és abstraure la gestió de servidors per part dels usuaris, permetent centrar els seus esforços únicament en el desenvolupament d'aplicacions. El problema del model FaaS és que està enfocat principalment a microserveis i tendeix a tenir limitacions en el temps d'execució i en les capacitats de computació (per exemple, no té suport per a maquinari d'acceleració com GPU). Tot i això, s'ha demostrat que la capacitat d'autoaprovisionament i l'alt grau de paral·lelisme d'aquests serveis poden ser molt adequats per a més aplicacions. A més, la seva inherent execució dirigida per esdeveniments fa que les funcions siguen perfectament adequades per ser definides com a passos en fluxos de treball de processament d'arxius (per exemple, fluxos de treball de computació científica). D'altra banda, l'auge dels dispositius intel·ligents i integrats (IoT), les innovacions a les xarxes de comunicació i la necessitat de reduir la latència en casos d'ús complexos han donat lloc al concepte d'Edge computing, o computació a la vora. L'Edge computing consisteix en el processament en dispositius propers a les fonts de dades per millorar els temps de resposta. La combinació d'aquest paradigma amb la computació en núvol, formant arquitectures amb dispositius a diferents nivells en funció de la proximitat a la font i la capacitat de còmput, s'ha encunyat com a continu de la computació al núvol (o continu computacional). Aquesta tesi doctoral pretén, doncs, aplicar diferents estratègies Serverless per permetre el desplegament d'aplicacions generalistes, empaquetades en contenidors de programari, a través dels diferents nivells del continu computacional. Per això, s'han desenvolupat múltiples eines per tal de: i) adaptar serveis FaaS de proveïdors Cloud públics; ii) integrar diferents components de programari per definir una plataforma Serverless en infraestructures privades i a la vora; iii) aprofitar dispositius d'acceleració a plataformes Serverless; i iv) facilitar el desplegament d'aplicacions i fluxos de treball mitjançant interfícies d'usuari. A més, s'han creat i s'han adaptat diversos casos d'ús per avaluar els desenvolupaments aconseguits.[EN] In recent years, the popularity of Cloud computing has allowed users to access unprecedented compute, network, and storage resources under a pay-per-use model. This popularity led to new services to solve specific large-scale computing challenges and simplify the development and deployment of applications. Among the most prominent services in recent years are FaaS (Function as a Service) platforms, whose primary appeal is the ease of deploying small pieces of code in certain programming languages to perform specific tasks on an event-driven basis. These functions are executed on the Cloud provider's servers without users worrying about their maintenance or elasticity management, always keeping a fine-grained pay-per-use model. FaaS platforms belong to the computing paradigm known as Serverless, which aims to abstract the management of servers from the users, allowing them to focus their efforts solely on the development of applications. The problem with FaaS is that it focuses on microservices and tends to have limitations regarding the execution time and the computing capabilities (e.g. lack of support for acceleration hardware such as GPUs). However, it has been demonstrated that the self-provisioning capability and high degree of parallelism of these services can be well suited to broader applications. In addition, their inherent event-driven triggering makes functions perfectly suitable to be defined as steps in file processing workflows (e.g. scientific computing workflows). Furthermore, the rise of smart and embedded devices (IoT), innovations in communication networks and the need to reduce latency in challenging use cases have led to the concept of Edge computing. Edge computing consists of conducting the processing on devices close to the data sources to improve response times. The coupling of this paradigm together with Cloud computing, involving architectures with devices at different levels depending on their proximity to the source and their compute capability, has been coined as Cloud Computing Continuum (or Computing Continuum). Therefore, this PhD thesis aims to apply different Serverless strategies to enable the deployment of generalist applications, packaged in software containers, across the different tiers of the Cloud Computing Continuum. To this end, multiple tools have been developed in order to: i) adapt FaaS services from public Cloud providers; ii) integrate different software components to define a Serverless platform on on-premises and Edge infrastructures; iii) leverage acceleration devices on Serverless platforms; and iv) facilitate the deployment of applications and workflows through user interfaces. Additionally, several use cases have been created and adapted to assess the developments achieved.Risco Gallardo, S. (2023). Serverless Strategies and Tools in the Cloud Computing Continuum [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/202013Compendi

    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/

    Graduate Catalog of Studies, 2023-2024

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    Design of new algorithms for gene network reconstruction applied to in silico modeling of biomedical data

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    Programa de Doctorado en Biotecnología, Ingeniería y Tecnología QuímicaLínea de Investigación: Ingeniería, Ciencia de Datos y BioinformáticaClave Programa: DBICódigo Línea: 111The root causes of disease are still poorly understood. The success of current therapies is limited because persistent diseases are frequently treated based on their symptoms rather than the underlying cause of the disease. Therefore, biomedical research is experiencing a technology-driven shift to data-driven holistic approaches to better characterize the molecular mechanisms causing disease. Using omics data as an input, emerging disciplines like network biology attempt to model the relationships between biomolecules. To this effect, gene co- expression networks arise as a promising tool for deciphering the relationships between genes in large transcriptomic datasets. However, because of their low specificity and high false positive rate, they demonstrate a limited capacity to retrieve the disrupted mechanisms that lead to disease onset, progression, and maintenance. Within the context of statistical modeling, we dove deeper into the reconstruction of gene co-expression networks with the specific goal of discovering disease-specific features directly from expression data. Using ensemble techniques, which combine the results of various metrics, we were able to more precisely capture biologically significant relationships between genes. We were able to find de novo potential disease-specific features with the help of prior biological knowledge and the development of new network inference techniques. Through our different approaches, we analyzed large gene sets across multiple samples and used gene expression as a surrogate marker for the inherent biological processes, reconstructing robust gene co-expression networks that are simple to explore. By mining disease-specific gene co-expression networks we come up with a useful framework for identifying new omics-phenotype associations from conditional expression datasets.In this sense, understanding diseases from the perspective of biological network perturbations will improve personalized medicine, impacting rational biomarker discovery, patient stratification and drug design, and ultimately leading to more targeted therapies.Universidad Pablo de Olavide de Sevilla. Departamento de Deporte e Informátic

    Supporting Safety Analysis of Deep Neural Networks with Automated Debugging and Repair

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