5,916 research outputs found

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

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    The development of bioinformatics workflows to explore single-cell multi-omics data from T and B lymphocytes

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    The adaptive immune response is responsible for recognising, containing and eliminating viral infection, and protecting from further reinfection. This antigen-specific response is driven by T and B cells, which recognise antigenic epitopes via highly specific heterodimeric surface receptors, termed T-cell receptors (TCRs) and B cell receptors (BCRs). The theoretical diversity of the receptor repertoire that can be generated via homologous recombination of V, D and J genes is large enough (>1015 unique sequences) that virtually any antigen can be recognised. However, only a subset of these are generated within the human body, and how they succeed in specifically recognising any pathogen(s) and distinguishing these from self-proteins remains largely unresolved. The recent advances in applying single-cell genomics technologies to simultaneously measure the clonality, surface phenotype and transcriptomic signature of pathogen- specific immune cells have significantly improved understanding of these questions. Single-cell multi-omics permits the accurate identification of clonally expanded populations, their differentiation trajectories, the level of immune receptor repertoire diversity involved in the response and the phenotypic and molecular heterogeneity. This thesis aims to develop a bioinformatic workflow utilising single-cell multi-omics data to explore, quantify and predict the clonal and transcriptomic signatures of the human T-cell response during and following viral infection. In the first aim, a web application, VDJView, was developed to facilitate the simultaneous analysis and visualisation of clonal, transcriptomic and clinical metadata of T and B cell multi-omics data. The application permits non-bioinformaticians to perform quality control and common analyses of single-cell genomics data integrated with other metadata, thus permitting the identification of biologically and clinically relevant parameters. The second aim pertains to analysing the functional, molecular and immune receptor profiles of CD8+ T cells in the acute phase of primary hepatitis C virus (HCV) infection. This analysis identified a novel population of progenitors of exhausted T cells, and lineage tracing revealed distinct trajectories with multiple fates and evolutionary plasticity. Furthermore, it was observed that high-magnitude IFN-Îł CD8+ T-cell response is associated with the increased probability of viral escape and chronic infection. Finally, in the third aim, a novel analysis is presented based on the topological characteristics of a network generated on pathogen-specific, paired-chain, CD8+ TCRs. This analysis revealed how some cross-reactivity between TCRs can be explained via the sequence similarity between TCRs and that this property is not uniformly distributed across all pathogen-specific TCR repertoires. Strong correlations between the topological properties of the network and the biological properties of the TCR sequences were identified and highlighted. The suite of workflows and methods presented in this thesis are designed to be adaptable to various T and B cell multi-omic datasets. The associated analyses contribute to understanding the role of T and B cells in the adaptive immune response to viral-infection and cancer

    Complexity Science in Human Change

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    This reprint encompasses fourteen contributions that offer avenues towards a better understanding of complex systems in human behavior. The phenomena studied here are generally pattern formation processes that originate in social interaction and psychotherapy. Several accounts are also given of the coordination in body movements and in physiological, neuronal and linguistic processes. A common denominator of such pattern formation is that complexity and entropy of the respective systems become reduced spontaneously, which is the hallmark of self-organization. The various methodological approaches of how to model such processes are presented in some detail. Results from the various methods are systematically compared and discussed. Among these approaches are algorithms for the quantification of synchrony by cross-correlational statistics, surrogate control procedures, recurrence mapping and network models.This volume offers an informative and sophisticated resource for scholars of human change, and as well for students at advanced levels, from graduate to post-doctoral. The reprint is multidisciplinary in nature, binding together the fields of medicine, psychology, physics, and neuroscience

    Interdisciplinarity in the Scholarly Life Cycle

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    This open access book illustrates how interdisciplinary research develops over the lifetime of a scholar: not in a single project, but as an attitude that trickles down, or spirals up, into research. This book presents how interdisciplinary work has inspired shifts in how the contributors read, value concepts, critically combine methods, cope with knowledge hierarchies, write in style, and collaborate. Drawing on extensive examples from the humanities and social sciences, the editors and chapter authors show how they started, tried to open up, dealt with inconsistencies, had to adapt, and ultimately learned and grew as researchers. The book offers valuable insights into the conditions and complexities present for interdisciplinary research to be successful in an academic setting. This is an open access book

    Spirit and Healing in Africa

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    There is a great need for healing in Africa. This need is in itself no different elsewhere in the world, but it is greatly determined by the involvement of religious communities and traditions. Faith communities and religious institutions play a major role in assisting African believers to find health, healing and completeness in everyday life

    The role of the aryl hydrocarbon receptor interacting protein (AIP) in pituitary tumorigenesis: A novel animal model for investigating the role of AIP during embryogenesis and pituitary tumour formation

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    Pituitary adenomas (PAs) have a 1:1000 prevalence and carry significant morbidity despite their benign nature. Mutations in the AIP (aryl hydrocarbon receptor interacting protein) gene have been unambiguously associated with higher predisposition for PAs. These tumours pose a challenge in treatment due to delayed diagnosis, increased size, earlier onset, aggressive nature and considerable resistance to therapy. The exact mechanism of the tumour formation due to loss of AIP and the role of AIP in pituitary organogenesis is still unknown. A large-cohort retrospective (225 patients) and prospective (876 patients) clinical study was carried out on the pituitary adenoma patients of a tertiary referral centre in London assessing the prevalence of FIPA (familial isolated pituitary adenomas). 20% of FIPA patients are reported to harbour an AIP mutation, but half of the AIP mutation-positive probands are not aware of a positive family history. This study has shown that active inquiry of family history increases detection of previously unknown family history with nearly 3-fold, enabling the genetic screening of these families for early diagnosis and better customised therapy. The novel, pituitary- specific, biallelic Aip-knockout murine model (AipFlox/Flox; Hesx1Cre/+) generated within this study allowed for the first time to investigate the role of AIP during the embryonic stages. There is phenotypical difference (enlarged anterior lobe, incomplete fusion of the sphenoid bone) in the pituitaries 17.5 dpc AipFlox/Flox; Hesx1Cre/+ embryos when compared with the wildtype of the same embryonic stage, with no difference in cell lineage determination (dpc 15.5). A decrease in growth hormone and prolactin producing cells is described at terminal differentiation (dpc 17.5), which is intriguing because patients harbouring AIP mutations most commonly present with growth hormone and/or prolactin secreting 7 PAs. Further research has since been done efficiently using this model focusing on postnatal tumour formation, which is not part of this thesis. Deregulation of the Hippo signalling components has been increasingly investigated in relation to pituitary tumorigenesis, especially in human hormone secreting PAs, but no study had investigated the role of Hippo signalling in AIP-mediated tumour formation. A bioinformatic-based analysis was performed for the expression of 41 Hippo pathway associated genes in AIP-silenced rat pituitary somatomammotroph GH3 cells, pituitary specific AIP-knockout mice, humans with AIP mutation-positive and AIP mutation-negative familial and sporadic PAs. Both up- and downstream members of the Hippo signalling show significantly altered expression in the different subgroups, which warrants more targeted future studies. Additionally, in the analysed exome and whole genome sequencing of PA patients, variants of several key Hippo pathway components show segregation within families. These data (along with a global phosphorylation analysis) suggest that further studies are needed to investigate the role of Hippo signalling in AIP-mediated tumorigenesis

    Orvosképzés 2023

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    Development and application of methodologies and infrastructures for cancer genome analysis within Personalized Medicine

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    [eng] Next-generation sequencing (NGS) has revolutionized biomedical sciences, especially in the area of cancer. It has nourished genomic research with extensive collections of sequenced genomes that are investigated to untangle the molecular bases of disease, as well as to identify potential targets for the design of new treatments. To exploit all this information, several initiatives have emerged worldwide, among which the Pan-Cancer project of the ICGC (International Cancer Genome Consortium) stands out. This project has jointly analyzed thousands of tumor genomes of different cancer types in order to elucidate the molecular bases of the origin and progression of cancer. To accomplish this task, new emerging technologies, including virtualization systems such as virtual machines or software containers, were used and had to be adapted to various computing centers. The portability of this system to the supercomputing infrastructure of the BSC (Barcelona Supercomputing Center) has been carried out during the first phase of the thesis. In parallel, other projects promote the application of genomics discoveries into the clinics. This is the case of MedPerCan, a national initiative to design a pilot project for the implementation of personalized medicine in oncology in Catalonia. In this context, we have centered our efforts on the methodological side, focusing on the detection and characterization of somatic variants in tumors. This step is a challenging action, due to the heterogeneity of the different methods, and an essential part, as it lays at the basis of all downstream analyses. On top of the methodological section of the thesis, we got into the biological interpretation of the results to study the evolution of chronic lymphocytic leukemia (CLL) in a close collaboration with the group of Dr. ElĂ­as Campo from the Hospital ClĂ­nic/IDIBAPS. In the first study, we have focused on the Richter transformation (RT), a transformation of CLL into a high-grade lymphoma that leads to a very poor prognosis and with unmet clinical needs. We found that RT has greater genomic, epigenomic and transcriptomic complexity than CLL. Its genome may reflect the imprint of therapies that the patients received prior to RT, indicating the presence of cells exposed to these mutagenic treatments which later expand giving rise to the clinical manifestation of the disease. Multiple NGS- based techniques, including whole-genome sequencing and single-cell DNA and RNA sequencing, among others, confirmed the pre-existence of cells with the RT characteristics years before their manifestation, up to the time of CLL diagnosis. The transcriptomic profile of RT is remarkably different from that of CLL. Of particular importance is the overexpression of the OXPHOS pathway, which could be used as a therapeutic vulnerability. Finally, in a second study, the analysis of a case of CLL in a young adult, based on whole genome and single-cell sequencing at different times of the disease, revealed that the founder clone of CLL did not present any somatic driver mutations and was characterized by germline variants in ATM, suggesting its role in the origin of the disease, and highlighting the possible contribution of germline variants or other non-genetic mechanisms in the initiation of CLL
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