2,202 research outputs found

    Undergraduate Catalog of Studies, 2023-2024

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    Clinical, immunological and genetic features of histiocytic disorders

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    Novel Neural Network Applications to Mode Choice in Transportation: Estimating Value of Travel Time and Modelling Psycho-Attitudinal Factors

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    Whenever researchers wish to study the behaviour of individuals choosing among a set of alternatives, they usually rely on models based on the random utility theory, which postulates that the single individuals modify their behaviour so that they can maximise of their utility. These models, often identified as discrete choice models (DCMs), usually require the definition of the utilities for each alternative, by first identifying the variables influencing the decisions. Traditionally, DCMs focused on observable variables and treated users as optimizing tools with predetermined needs. However, such an approach is in contrast with the results from studies in social sciences which show that choice behaviour can be influenced by psychological factors such as attitudes and preferences. Recently there have been formulations of DCMs which include latent constructs for capturing the impact of subjective factors. These are called hybrid choice models or integrated choice and latent variable models (ICLV). However, DCMs are not exempt from issues, like, the fact that researchers have to choose the variables to include and their relations to define the utilities. This is probably one of the reasons which has recently lead to an influx of numerous studies using machine learning (ML) methods to study mode choice, in which researchers tried to find alternative methods to analyse travellers’ choice behaviour. A ML algorithm is any generic method that uses the data itself to understand and build a model, improving its performance the more it is allowed to learn. This means they do not require any a priori input or hypotheses on the structure and nature of the relationships between the several variables used as its inputs. ML models are usually considered black-box methods, but whenever researchers felt the need for interpretability of ML results, they tried to find alternative ways to use ML methods, like building them by using some a priori knowledge to induce specific constrains. Some researchers also transformed the outputs of ML algorithms so that they could be interpreted from an economic point of view, or built hybrid ML-DCM models. The object of this thesis is that of investigating the benefits and the disadvantages deriving from adopting either DCMs or ML methods to study the phenomenon of mode choice in transportation. The strongest feature of DCMs is the fact that they produce very precise and descriptive results, allowing for a thorough interpretation of their outputs. On the other hand, ML models offer a substantial benefit by being truly data-driven methods and thus learning most relations from the data itself. As a first contribution, we tested an alternative method for calculating the value of travel time (VTT) through the results of ML algorithms. VTT is a very informative parameter to consider, since the time consumed by individuals whenever they need to travel normally represents an undesirable factor, thus they are usually willing to exchange their money to reduce travel times. The method proposed is independent from the mode-choice functions, so it can be applied to econometric models and ML methods equally, if they allow the estimation of individual level probabilities. Another contribution of this thesis is a neural network (NN) for the estimation of choice models with latent variables as an alternative to DCMs. This issue arose from wanting to include in ML models not only level of service variables of the alternatives, and socio-economic attributes of the individuals, but also psycho-attitudinal indicators, to better describe the influence of psychological factors on choice behaviour. The results were estimated by using two different datasets. Since NN results are dependent on the values of their hyper-parameters and on their initialization, several NNs were estimated by using different hyper-parameters to find the optimal values, which were used to verify the stability of the results with different initializations

    T Follicular Helper cell dynamics in response to vaccination

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    High quality long lived humoral immune responses require significant help from T follicular helper (Tfh) cells located within the germinal centres (GC) of lymph nodes (LN). Cognate interactions established between Tfh cells and GC B cells regulates somatic hypermutation and affinity maturation, determining the quality of antibodies produced. However, the anatomically protected location of Tfh cells, within the LN, poses a significant logistical and ethical obstacle to in vivo interrogation in humans. This study utilised the fine needle biopsy (FNB) technique to directly probe the GCs of human axillary LNs pre- and post- seasonal influenza vaccination, with the aim to interrogate the commitment of CD4+ T cells to the Tfh cell lineage. In this study, peripheral blood and draining and contralateral LN FNBs were collected prior to and 5 days post vaccination. Ex vivo phenotyping of LN FNB samples revealed significant expansion of GC Tfh cells was restricted to draining LNs. This early expansion of GC Tfh cells was characterised by an increase in highly activated, motile, and proliferating cells, measured by CD38, ICOS and Ki67 expression. Further, although no significant increase in the absolute number of Pre Tfh cells was observed, there was an increase in CD38+ICOS+ Pre-Tfh cells post vaccination, implicating this population in the immune response and highlighting the changes in cellular profile. Characterisation of cellular subsets by traditional flow cytometry techniques is limited by the number of parameters available on the instrument. Therefore, we leveraged Smart-Seq2 single cell RNA-sequencing (scRNA-seq) to further examine the heterogeneity within GC Tfh and Pre-Tfh cells. In 3 participants, we identified 7 functionally distinct clusters of cells based on differentially expressed (DE) genes. A proliferating cluster and a motile cluster were observed in all participants. The proliferating cluster exhibited an activated, proinflammatory gene signature and was enriched for Tfh differentiation gene pathways, whereas the motile cluster was enriched for pathways involved in cellular migration and motility, critical for rapid reorganisation of GCs to support dynamic interactions and cellular reactivation. To explore functional flexibility and plasticity of LN GC Tfh and Pre-Tfh, we integrated scRNAseq post vaccination data from 5 participants. Based on DE genes, we identified 5 distinct clusters; Resting, Activated migrating, B cell interacting Tfh, Proliferating and Cytotoxic. Trajectory analysis using inferred pseudotime revealed the transition of cells through activation states and the gain/loss of different CD4+ T cell lineage attributes and effector functions. Using the T cell receptor as a natural cellular barcode, we were able to identify divergent differentiation into different fate lineages from a common precursor cell. Overall, the work presented in this thesis is the first to quantify the selective activation of GC Tfh and Pre-Tfh and provides exciting and promising initial evidence of the functional heterogeneity and plastic potential with the Tfh lineage in vivo in human axillary LNs in response to vaccination, that could be leveraged to develop more effective vaccines

    AI: Limits and Prospects of Artificial Intelligence

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    The emergence of artificial intelligence has triggered enthusiasm and promise of boundless opportunities as much as uncertainty about its limits. The contributions to this volume explore the limits of AI, describe the necessary conditions for its functionality, reveal its attendant technical and social problems, and present some existing and potential solutions. At the same time, the contributors highlight the societal and attending economic hopes and fears, utopias and dystopias that are associated with the current and future development of artificial intelligence

    Undergraduate Catalog of Studies, 2022-2023

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    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

    SUTMS - Unified Threat Management Framework for Home Networks

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    Home networks were initially designed for web browsing and non-business critical applications. As infrastructure improved, internet broadband costs decreased, and home internet usage transferred to e-commerce and business-critical applications. Today’s home computers host personnel identifiable information and financial data and act as a bridge to corporate networks via remote access technologies like VPN. The expansion of remote work and the transition to cloud computing have broadened the attack surface for potential threats. Home networks have become the extension of critical networks and services, hackers can get access to corporate data by compromising devices attacked to broad- band routers. All these challenges depict the importance of home-based Unified Threat Management (UTM) systems. There is a need of unified threat management framework that is developed specifically for home and small networks to address emerging security challenges. In this research, the proposed Smart Unified Threat Management (SUTMS) framework serves as a comprehensive solution for implementing home network security, incorporating firewall, anti-bot, intrusion detection, and anomaly detection engines into a unified system. SUTMS is able to provide 99.99% accuracy with 56.83% memory improvements. IPS stands out as the most resource-intensive UTM service, SUTMS successfully reduces the performance overhead of IDS by integrating it with the flow detection mod- ule. The artifact employs flow analysis to identify network anomalies and categorizes encrypted traffic according to its abnormalities. SUTMS can be scaled by introducing optional functions, i.e., routing and smart logging (utilizing Apriori algorithms). The research also tackles one of the limitations identified by SUTMS through the introduction of a second artifact called Secure Centralized Management System (SCMS). SCMS is a lightweight asset management platform with built-in security intelligence that can seamlessly integrate with a cloud for real-time updates

    Comparative genomics of recent adaptation in Candida pathogens

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    [eng] Fungal infections pose a serious health threat, affecting >1,000 million people and causing ~1.5 million deaths each year. The problem is growing due to insufficient diagnostic and therapeutic options, increased number of susceptible patients, expansion of pathogens partly linked to climate change and the rise of antifungal drug resistance. Among other fungal pathogens, Candida species are a major cause of severe hospital-acquired infections, with high mortality in immunocompromised patients. Various Candida pathogens constitute a public health issue, which require further efforts to develop new drugs, optimize currently available treatments and improve diagnostics. Given the high dynamism of Candida genomes, a promising strategy to improve current therapies and diagnostics is to understand the evolutionary mechanisms of adaptation to antifungal drugs and to the human host. Previous work using in vitro evolution, population genomics, selection inferences and Genome Wide Association Studies (GWAS) have partially clarified such recent adaptation, but various open questions remain. In the three research articles that conform this PhD thesis we addressed some of these gaps from the perspective of comparative genomics. First, we addressed methodological issues regarding the analysis of Candida genomes. Studying recent adaptation in these pathogens requires adequate bioinformatic tools for variant calling, filtering and functional annotation. Among other reasons, current methods are suboptimal due to limited accuracy to identify structural variants from short read sequencing data. In addition, there is a need for easy-to-use, reproducible variant calling pipelines. To address these gaps we developed the “personalized Structural Variation detection” pipeline (perSVade), a framework to call, filter and annotate several variant types, including structural variants, directly from reads. PerSVade enables accurate identification of structural variants in any species of interest, such as Candida pathogens. In addition, our tool automatically predicts the structural variant calling accuracy on simulated genomes, which informs about the reliability of the calling process. Furthermore, perSVade can be used to analyze single nucleotide polymorphisms and copy number-variants, so that it facilitates multi-variant, reproducible genomic studies. This tool will likely boost variant analyses in Candida pathogens and beyond. Second, we addressed open questions about recent adaptation in Candida, using perSVade for variant identification. On the one hand, we investigated the evolutionary mechanisms of drug resistance in Candida glabrata. For this, we used a large-scale in vitro evolution experiment to study adaptation to two commonly-used antifungals: fluconazole and anidulafungin. Our results show rapid adaptation to one or both drugs, with moderate fitness costs and through few mutations in a narrow set of genes. In addition, we characterize a novel role of ERG3 mutations in cross-resistance towards fluconazole in anidulafungin-adapted strains. These findings illuminate the mutational paths leading to drug resistance and cross-resistance in Candida pathogens. On the other hand, we reanalyzed ~2,000 public genomes and phenotypes to understand the signs of recent selection and drug resistance in six major Candida species: C. auris, C. glabrata, C. albicans, C. tropicalis, C. parapsilosis and C. orthopsilosis. We found hundreds of genes under recent selection, suggesting that clinical adaptation is diverse and complex. These involve species-specific but also convergently affected processes, such as cell adhesion, which could underlie conserved adaptive mechanisms. In addition, using GWAS we predicted known drivers of antifungal resistance alongside potentially novel players. Furthermore, our analyses reveal an important role of generally-overlooked structural variants, and suggest an unexpected involvement of (para)sexual recombination in the spread of resistance. Taken together, our findings provide novel insights on how Candida pathogens adapt to human-related environments and suggest candidate genes that deserve future attention. In summary, the results of this thesis improve our knowledge about the mechanisms of recent adaptation in Candida pathogens, which may enable improved therapeutic and diagnostic applications.[cat] Les infeccions fúngiques representen una greu amenaça per a la salut, afectant a més de 1.000 milions de persones i causant aproximadament 1,5 milions de morts cada any. El problema està augmentant a causa d’unes opcions terapèutiques i diagnòstiques insuficients, l'increment del nombre de pacients susceptibles, l'expansió dels patògens parcialment vinculada al canvi climàtic i l'augment de la resistència als fàrmacs antifúngics. D’entre diversos fongs patògens, els llevats del gènere Candida són una causa important d'infeccions nosocomials, amb una alta mortalitat en pacients immunodeprimits. Diverses espècies de Candida constitueixen un problema de salut pública, cosa que requereix més esforços per a desenvolupar nous medicaments, optimitzar els tractaments disponibles i millorar els diagnòstics. Tenint en compte el dinamisme genòmic d’aquests patògens, una estratègia prometedora per millorar les teràpies i diagnòstics actuals és comprendre els mecanismes evolutius d'adaptació als fàrmacs antifúngics i a l’hoste humà. Treballs anteriors utilitzant l'evolució in vitro, la genòmica de poblacions, les inferències de selecció i els estudis d'associació de genoma complet (GWAS, per les sigles en anglès) han aclarit parcialment aquesta adaptació recent, però encara hi ha diverses preguntes obertes. En els tres articles que conformen aquesta tesi doctoral, hem abordat algunes d'aquestes preguntes des de la perspectiva de la genòmica comparativa. En primer lloc, hem abordat qüestions metodològiques relatives a l'anàlisi dels genomes de les espècies Candida. L'estudi de l'adaptació recent en aquests patògens requereix eines bioinformàtiques adequades per a la detecció, filtratge i anotació funcional de variants genètiques. Entre altres raons, els mètodes actuals són subòptims a causa de la limitada precisió per identificar variants estructurals a partir de dades de seqüenciació amb lectures curtes. A més, hi ha una necessitat d’eines computacionals per a la detecció de variants que siguin senzilles d'utilitzar i reproduibles. Per abordar aquestes mancances, hem desenvolupat el mètode bioinformàtic "personalized Structural Variation detection" (perSVade), una eina que permet la detecció, filtratge i anotació de diversos tipus de variants, incloent-hi les variants estructurals, directament des de les lectures. PerSVade permet la identificació precisa de les variants estructurals en qualsevol espècie d'interès, com ara els patògens Candida. A més, la nostra eina prediu automàticament la precisió de la detecció d’aquestes variants en genomes simulats, la qual cosa informa sobre la fiabilitat del procés. Finalment, perSVade es pot utilitzar per analitzar altres tipus de variants, com els polimorfismes de nucleòtid únic o els canvis en el nombre de còpies, facilitant així estudis genòmics integrals i reproduibles. Aquesta eina probablement impulsarà les anàlisis genòmiques en els patògens Candida i també en altres espècies. En segon lloc, hem abordat algunes de les preguntes obertes sobre l'adaptació recent en els llevats Candida, utilitzant perSVade per a la identificació de variants. D'una banda, hem investigat els mecanismes evolutius de resistència als fàrmacs antifúngics en Candida glabrata. Per a això, hem utilitzat un experiment d'evolució in vitro a gran escala per estudiar l'adaptació a dos antifúngics comuns: el fluconazol i l’anidulafungina. Els nostres resultats mostren una adaptació ràpida a un o ambdós fàrmacs, amb un cost per al creixement moderat i a través de poques mutacions en un nombre reduït de gens. A més, hem caracteritzat un paper nou de les mutacions en ERG3 en la resistència creuada al fluconazol en soques adaptades a anidulafungina. Aquests descobriments aclareixen els processos mutacionals que condueixen a la resistència als fàrmacs i a la resistència creuada en els patògens Candida. D'altra banda, hem re-analitzat aproximadament 2.000 genomes i fenotips disponibles en repositoris públics per a comprendre els senyals genòmics de selecció recent i de resistència a fàrmacs antifúngics, en sis espècies rellevants de Candida: C. auris, C. glabrata, C. albicans, C. tropicalis, C. parapsilosis i C. orthopsilosis. Hem trobat centenars de gens sota selecció recent, suggerint que l'adaptació clínica és diversa i complexa. Aquests gens estan relacionats amb funcions específiques de cada espècie, però també trobem processos alterats de manera similar en diferents patògens, com per exemple l’adhesió cel·lular, cosa que indica fenòmens d’adaptació conservats. A part, utilitzant GWAS hem predit mecanismes esperats de resistència a antifúngics i també possibles nous factors. A més, les nostres anàlisis revelen un paper important de les variants estructurals, generalment poc estudiades, i suggereixen una implicació inesperada de la recombinació (para)sexual en la propagació de la resistència. En conjunt, els nostres descobriments proporcionen noves perspectives sobre com els patògens Candida s'adapten als entorns humans, i suggereixen gens candidats que mereixen investigacions futures. En resum, els resultats d’aquesta tesi milloren el nostre coneixement sobre els mecanismes d'adaptació recent en els patògens Candida, cosa que pot permetre el disseny de noves teràpies i diagnòstics
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