3,711 research outputs found

    Graduate Catalog of Studies, 2023-2024

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    Genetic and functional analysis of the adaptive immune response

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    The cells of the adaptive immune system rely on somatic recombination of V, D and J genes to obtain a vast range of specificities. T cells use four chains encoded by three genomic loci, to produce alpha/beta or gamma/delta T cell receptors (TCRs). B cell receptors (BCRs) are encoded by three loci, a single heavy chain and two light chain loci, kappa and lambda. Because these genomic regions are highly polymorphic, the germline TCR and BCR repertoires are individual, shaping the elicited response against infections and vaccines in each person. In this thesis, I used a set of specialized tools and analysis pipelines to explore the adaptive immune receptors at the genomic and functional levels in both humans and non-human primates (NHP), highlighting the benefits of integrating individualized TCR/BCR repertoire analysis with functional studies to understand adaptive immune responses. In paper I, we sequence expressed TCR repertoires of 45 individuals from four human populations: African, East Asian, South Asian, and European. Analysis of these repertoires with the germline gene inference tool, IgDiscover, identified 175 novel V and J alleles, most of which were characterized by codon changes or non-functional variants. The germline TCR repertoires were highly diverse between individuals, with some of the novel alleles identified only in specific populations. Furthermore, we report three introgressed regions inherited from Homo neanderthalensis. One of these regions includes a novel variant of TRGV4, frequent in Eurasians populations, which display altered reactivity to the ligand butyrophilin-like molecule 3 (BTNL3). In papers II and III, we analyzed the humoral immune response in NHPs elicited by a series of immunizations with SARS-CoV-2 Spike-derived subunit proteins. In paper II, we observed detectable neutralization titers after priming with ancestral spike (S) protein with very high antibody titers obtained after boosting. The immunization regimen resulted in durable neutralization titers as well as S-specific memory B cells. In paper III, we used a heterotypic boosting strategy with beta-derived receptor binding domain (RBD) to broaden the response to circulating SARS-CoV-2 variants. The boost elicits potent and protective cross-neutralizing humoral immune responses. In paper IV, we analyzed multi-compartmental longitudinal samples from two macaques used in paper II. We combined single cell and next generation sequencing (NGS) of BCR repertoires to characterize S-specific antibodies and S-specific B cell lineages elicited by immunizations with ancestral SARS-CoV-2 S proteins. Lineage tracing analysis identified persistent antibody lineages that were present after priming and were widely disseminated in blood, bone marrow (BM), spleen and different lymph nodes (LN), including a broadly neutralizing RBD-binding lineage. Through structural cryo-EM studies, we showed that this antibody achieved cross-neutralization by targeting conserved RBD residues with crucial interactions through its heavy chain CDR3 (HCDR3)

    Making friends with failure in STS

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    Brain Computations and Connectivity [2nd edition]

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    This is an open access title available under the terms of a CC BY-NC-ND 4.0 International licence. It is free to read on the Oxford Academic platform and offered as a free PDF download from OUP and selected open access locations. Brain Computations and Connectivity is about how the brain works. In order to understand this, it is essential to know what is computed by different brain systems; and how the computations are performed. The aim of this book is to elucidate what is computed in different brain systems; and to describe current biologically plausible computational approaches and models of how each of these brain systems computes. Understanding the brain in this way has enormous potential for understanding ourselves better in health and in disease. Potential applications of this understanding are to the treatment of the brain in disease; and to artificial intelligence which will benefit from knowledge of how the brain performs many of its extraordinarily impressive functions. This book is pioneering in taking this approach to brain function: to consider what is computed by many of our brain systems; and how it is computed, and updates by much new evidence including the connectivity of the human brain the earlier book: Rolls (2021) Brain Computations: What and How, Oxford University Press. Brain Computations and Connectivity will be of interest to all scientists interested in brain function and how the brain works, whether they are from neuroscience, or from medical sciences including neurology and psychiatry, or from the area of computational science including machine learning and artificial intelligence, or from areas such as theoretical physics

    2022 Review of Data-Driven Plasma Science

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    Data-driven science and technology offer transformative tools and methods to science. This review article highlights the latest development and progress in the interdisciplinary field of data-driven plasma science (DDPS), i.e., plasma science whose progress is driven strongly by data and data analyses. Plasma is considered to be the most ubiquitous form of observable matter in the universe. Data associated with plasmas can, therefore, cover extremely large spatial and temporal scales, and often provide essential information for other scientific disciplines. Thanks to the latest technological developments, plasma experiments, observations, and computation now produce a large amount of data that can no longer be analyzed or interpreted manually. This trend now necessitates a highly sophisticated use of high-performance computers for data analyses, making artificial intelligence and machine learning vital components of DDPS. This article contains seven primary sections, in addition to the introduction and summary. Following an overview of fundamental data-driven science, five other sections cover widely studied topics of plasma science and technologies, i.e., basic plasma physics and laboratory experiments, magnetic confinement fusion, inertial confinement fusion and high-energy-density physics, space and astronomical plasmas, and plasma technologies for industrial and other applications. The final section before the summary discusses plasma-related databases that could significantly contribute to DDPS. Each primary section starts with a brief introduction to the topic, discusses the state-of-the-art developments in the use of data and/or data-scientific approaches, and presents the summary and outlook. Despite the recent impressive signs of progress, the DDPS is still in its infancy. This article attempts to offer a broad perspective on the development of this field and identify where further innovations are required

    Trend assessment of changing climate patterns over the major agro-climatic zones of Sindh and Punjab

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    The agriculture sector, due to its significant dependence on climate patterns and water availability, is highly vulnerable to changing climate patterns. Pakistan is an agrarian economy with 30% of its land area under cultivation and 93% of its water resources being utilized for agricultural production. Therefore, the changing climate patterns may adversely affect the agriculture and water resources of the country. This study was conducted to assess the climate variations over the major agro-climatic zones of Sindh and Punjab, which serve as an important hub for the production of major food and cash crops in Pakistan. For this purpose, the climate data of 21 stations were analyzed using the Mann–Kendall test and Sen's slope estimator method for the period 1990–2022. The results obtained from the analysis revealed that, in Sindh, the mean annual temperature rose by ~0.1 to 1.4°C, with ~0.1 to 1.2°C in cotton-wheat Sindh and 0.8 to 1.4°C in rice-other Sindh during the study period. Similarly, in Punjab, the mean annual temperature increased by ~0.1 to 1.0°C, with 0.6 to 0.9°C in cotton-wheat Punjab and 0.2 to 0.6°C in rainfed Punjab. Seasonally, warming was found to be highest during the spring season. The precipitation analysis showed a rising annual precipitation trend in Sindh (+30 to +60 mm) and Punjab (+100 to 300 mm), while the monsoon precipitation increased by ~50 to 200 mm. For winter precipitation, an upward trend was found in mixed Punjab, while the remaining stations showed a declining pattern. Conclusively, the warming temperatures as found in the analysis may result in increased irrigation requirements, soil moisture desiccation, and wilting of crops, ultimately leading to low crop yield and threatening the livelihoods of local farmers. On the other hand, the increasing precipitation may favor national agriculture in terms of less freshwater withdrawals. However, it may also result in increased rainfall-induced floods inundating the crop fields and causing water logging and soil salinization. The study outcomes comprehensively highlighted the prevailing climate trends over the important agro-climatic zones of Pakistan, which may aid in devising an effective climate change adaptation and mitigation strategy to ensure the state of water and food security in the country

    Proceedings of 14th international symposium Modern trends in livestock production

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    Technologies of information transmission and processing

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    Сборник содержит статьи, тематика которых посвящена научно-теоретическим разработкам в области сетей телекоммуникаций, информационной безопасности, технологий передачи и обработки информации. Предназначен для научных сотрудников в области инфокоммуникаций, преподавателей, аспирантов, магистрантов и студентов технических вузов

    Breaking together: a freedom-loving response to collapse

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    The collapse of modern societies has already begun. That is the conclusion of two years of research by the interdisciplinary team behind the book 'Breaking Together'. How did it come to this? Because monetary systems caused us to harm each other and nature to such an extent it broke the foundations of our societies. So what can we do? This book describes people allowing the full pain of our predicament to liberate them into living more courageously and creatively. They demonstrate we can be breaking together, not apart, in this era of collapse. Professor Jem Bendell argues that reclaiming our freedoms is essential to soften the fall and regenerate the natural world. Escaping the efforts of panicking elites, we can advance an ecolibertarian agenda for both politics and practical action in a broken world. Endorsing the text, the founder of Schumacher College, Satish Kumar, remarked: “this is a prophetic book.

    In the name of safety: identifying, understanding and stopping low-value safety practices

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    Low-value healthcare is a widely recognised problem that detracts from the quality of patient care and places additional pressure on an already over-stretched system. The majority of efforts to identify and remove low-value healthcare practices have focused on clinical practices such as unnecessary tests, treatments and procedures. There is a lack of research that has identified and de-implemented low-value non-clinical practices such as patient safety practices (PSPs) that contribute to the problem of ‘safety clutter’. Eliminating PSPs that drain resources and increase the administrative burden on healthcare staff could release time to carry out practices that enhance patient safety. This PhD therefore aimed to understand how to identify and remove low-value PSPs in healthcare settings. An exploratory survey study (Study 1) was carried out, asking healthcare staff to identify practices they perceived to be of low-value for safety. To identify potential practices for de-implementation, the most frequently mentioned PSPs from Study 1 were taken forward to a consultation exercise, during which healthcare professionals rated the practices to determine candidates for de-implementation. A systematic review and meta-analysis (Study 2) was also conducted to understand what types of interventions have been used in the past to de-implement low-value practices in healthcare and what effect they have had on patient safety measures. To explore the potential barriers and facilitators associated with de-implementation, an interview study (Study 3) was carried out, focusing on two PSPs: intentional rounding and double-checking medicines. The final stage of this PhD involved co-designing a de-implementation intervention with stakeholders targeting a specific form of double-checking medicines. Evidence from this thesis provides a novel way of involving healthcare staff in the identification and prioritisation of low-value PSPs for de-implementation. The findings have also contributed to understanding how theory can be applied to develop strategies to overcome challenges to de-implementation
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