7,504 research outputs found

    Consequences of HIV infection in the bone marrow niche

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    Dysregulation of the bone marrow niche resulting from the direct and indirect effects of HIV infection contributes to haematological abnormalities observed in HIV patients. The bone marrow niche is a complex, multicellular environment which functions primarily in the maintenance of haematopoietic stem/progenitor cells (HSPCs). These adult stem cells are responsible for replacing blood and immune cells over the course of a lifetime. Cells of the bone marrow niche support HSPCs and help to orchestrate the quiescence, self-renewal and differentiation of HSPCs through chemical and molecular signals and cell-cell interactions. This narrative review discusses the HIV-associated dysregulation of the bone marrow niche, as well as the susceptibility of HSPCs to infection by HIV

    Anuário científico da Escola Superior de Tecnologia da Saúde de Lisboa - 2021

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    É com grande prazer que apresentamos a mais recente edição (a 11.ª) do Anuário Científico da Escola Superior de Tecnologia da Saúde de Lisboa. Como instituição de ensino superior, temos o compromisso de promover e incentivar a pesquisa científica em todas as áreas do conhecimento que contemplam a nossa missão. Esta publicação tem como objetivo divulgar toda a produção científica desenvolvida pelos Professores, Investigadores, Estudantes e Pessoal não Docente da ESTeSL durante 2021. Este Anuário é, assim, o reflexo do trabalho árduo e dedicado da nossa comunidade, que se empenhou na produção de conteúdo científico de elevada qualidade e partilhada com a Sociedade na forma de livros, capítulos de livros, artigos publicados em revistas nacionais e internacionais, resumos de comunicações orais e pósteres, bem como resultado dos trabalhos de 1º e 2º ciclo. Com isto, o conteúdo desta publicação abrange uma ampla variedade de tópicos, desde temas mais fundamentais até estudos de aplicação prática em contextos específicos de Saúde, refletindo desta forma a pluralidade e diversidade de áreas que definem, e tornam única, a ESTeSL. Acreditamos que a investigação e pesquisa científica é um eixo fundamental para o desenvolvimento da sociedade e é por isso que incentivamos os nossos estudantes a envolverem-se em atividades de pesquisa e prática baseada na evidência desde o início dos seus estudos na ESTeSL. Esta publicação é um exemplo do sucesso desses esforços, sendo a maior de sempre, o que faz com que estejamos muito orgulhosos em partilhar os resultados e descobertas dos nossos investigadores com a comunidade científica e o público em geral. Esperamos que este Anuário inspire e motive outros estudantes, profissionais de saúde, professores e outros colaboradores a continuarem a explorar novas ideias e contribuir para o avanço da ciência e da tecnologia no corpo de conhecimento próprio das áreas que compõe a ESTeSL. Agradecemos a todos os envolvidos na produção deste anuário e desejamos uma leitura inspiradora e agradável.info:eu-repo/semantics/publishedVersio

    A Decision Support System for Economic Viability and Environmental Impact Assessment of Vertical Farms

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    Vertical farming (VF) is the practice of growing crops or animals using the vertical dimension via multi-tier racks or vertically inclined surfaces. In this thesis, I focus on the emerging industry of plant-specific VF. Vertical plant farming (VPF) is a promising and relatively novel practice that can be conducted in buildings with environmental control and artificial lighting. However, the nascent sector has experienced challenges in economic viability, standardisation, and environmental sustainability. Practitioners and academics call for a comprehensive financial analysis of VPF, but efforts are stifled by a lack of valid and available data. A review of economic estimation and horticultural software identifies a need for a decision support system (DSS) that facilitates risk-empowered business planning for vertical farmers. This thesis proposes an open-source DSS framework to evaluate business sustainability through financial risk and environmental impact assessments. Data from the literature, alongside lessons learned from industry practitioners, would be centralised in the proposed DSS using imprecise data techniques. These techniques have been applied in engineering but are seldom used in financial forecasting. This could benefit complex sectors which only have scarce data to predict business viability. To begin the execution of the DSS framework, VPF practitioners were interviewed using a mixed-methods approach. Learnings from over 19 shuttered and operational VPF projects provide insights into the barriers inhibiting scalability and identifying risks to form a risk taxonomy. Labour was the most commonly reported top challenge. Therefore, research was conducted to explore lean principles to improve productivity. A probabilistic model representing a spectrum of variables and their associated uncertainty was built according to the DSS framework to evaluate the financial risk for VF projects. This enabled flexible computation without precise production or financial data to improve economic estimation accuracy. The model assessed two VPF cases (one in the UK and another in Japan), demonstrating the first risk and uncertainty quantification of VPF business models in the literature. The results highlighted measures to improve economic viability and the viability of the UK and Japan case. The environmental impact assessment model was developed, allowing VPF operators to evaluate their carbon footprint compared to traditional agriculture using life-cycle assessment. I explore strategies for net-zero carbon production through sensitivity analysis. Renewable energies, especially solar, geothermal, and tidal power, show promise for reducing the carbon emissions of indoor VPF. Results show that renewably-powered VPF can reduce carbon emissions compared to field-based agriculture when considering the land-use change. The drivers for DSS adoption have been researched, showing a pathway of compliance and design thinking to overcome the ‘problem of implementation’ and enable commercialisation. Further work is suggested to standardise VF equipment, collect benchmarking data, and characterise risks. This work will reduce risk and uncertainty and accelerate the sector’s emergence

    An Artificial Life Simulation Library Based on Genetic Algorithm, 3-Character Genetic Code and Biological Hierarchy

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    Genetic algorithm (GA) is inspired by biological evolution of genetic organisms by optimizing the genotypic combinations encoded within each individual with the help of evolutionary operators, suggesting that GA may be a suitable model for studying real-life evolutionary processes. This paper describes the design of a Python library for artificial life simulation, Digital Organism Simulation Environment (DOSE), based on GA and biological hierarchy starting from genetic sequence to population. A 3-character instruction set that does not take any operand is introduced as genetic code for digital organism. This mimics the 3-nucleotide codon structure in naturally occurring DNA. In addition, the context of a 3-dimensional world composing of ecological cells is introduced to simulate a physical ecosystem. Using DOSE, an experiment to examine the changes in genetic sequences with respect to mutation rates is presented

    Investigation of the molecular pathogenesis of the multi-host bacterial pathogen Staphylococcus aureus

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    Staphylococcus aureus is a major human and animal bacterial pathogen that causes an array of diseases. The main aim of this thesis is to investigate the key host-pathogen interactions that underpin S. aureus infection. S. aureus abundantly secretes two isoforms of the enzyme lipase into the extracellular milieu, where they scavenge upon polymeric triglycerides. It has previously been suggested that these lipases may interfere with the function of innate immune cells, such as macrophages and neutrophils, but the impact of lipases on phagocytic killing mechanisms remains unknown. We showed that there were no differences in the survival of S. aureus USA300 LAC wild type and its lipase-deficient isogenic mutant after incubation with human whole blood or neutrophils. Furthermore, there was no detectable lipase-dependent effect on phagocytosis, intracellular survival, or escape from both human primary and immortalised cell line macrophages, even upon supplementation with exogenous recombinant lipases. Therefore, we showed that S. aureus lipases do not inhibit bacterial killing mechanisms of human macrophages, neutrophils, or whole blood. Furthermore, the capacity of S. aureus to adapt to distinct host-species ecologies is a major public health and economic concern. Approximately 60 years ago, a human-to-poultry host jump and adaptation of S. aureus belonging to the widespread CC5 clade, led to the avian-adaptation and global expansion of S. aureus in broiler poultry. Our research aims to combine transposon (Tn) mutagenesis of S. aureus with experimental models of infections to identify the immune cell repertoire and bacterial genes involved in avian host-adaptation. To determine the avian immune cell tropism for S. aureus, mCherry-integrated clones from common avian (CC385, CC5) and human (CC8) S. aureus clonal lineages were screened in blood extracted from the transgenic chicken line Runx1-eGFP. We demonstrate that monocytes and heterophils generate the first-line response to S. aureus infection, with avian strains exhibiting differential uptake by heterophils compared to a human strain. Furthermore, our analysis demonstrated that avian S. aureus strains may have adapted to the avian host through the inhibition of degranulation of heterophils as a novel survival mechanism. TraDIS analysis of genes involved in the fitness of S. aureus during infection of peripheral blood leukocytes demonstrated that regulators of the Type VII secretion system and Spl-proteases were required for survival of S. aureus in the face of the innate immune response of PBLs. Taken together, these studies provide new insights into the evolution of S. aureus and the key host-pathogen interactions underpinning S. aureus infections

    Development of novel antimicrobial strategies and surveillance program to fight antimicrobial resistance

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    Bacterial resistance to antibiotics represents a major public health problem and measures to prevent the increase in antibiotic resistant organisms require knowledge of both the dissemination of antibiotic resistance using the surveillance approach and alternative strategies for tackling its. The surveillance of antibiotic resistance is a crucial element for the implementation of intervention strategies aimed at preserving the efficacy of currently available antimicrobial agents, including last-resource antibiotics. Beside conventional pathogens, there is increasing agreement about the importance of monitoring commensal bacteria, which can constitute a natural reservoir not only of resistance strains, but also of resistance genes that are potentially transferable among members of the resident microbiota. As such, there is an urgent need to develop alternatives to conventional antimicrobial strategies against resistant organisms, with a considerable attention to MDR gram-negative bacteria, that could play a major role in development of difficult-to-treat biofilm-related infections. This PhD project aimed at providing novel insights about alternative therapeutic approaches against Gram-negative MDR bacteria and at investigating their dissemination pathways in healthy humans living in remote communities of Bolivian Chaco

    Mathematical models to evaluate the impact of increasing serotype coverage in pneumococcal conjugate vaccines

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    Of over 100 serotypes of Streptococcus pneumoniae, only 7 were included in the first pneumo- coccal conjugate vaccine (PCV). While PCV reduced the disease incidence, in part because of a herd immunity effect, a replacement effect was observed whereby disease was increasingly caused by serotypes not included in the vaccine. Dynamic transmission models can account for these effects to describe post-vaccination scenarios, whereas economic evaluations can enable decision-makers to compare vaccines of increasing valency for implementation. This thesis has four aims. First, to explore the limitations and assumptions of published pneu- mococcal models and the implications for future vaccine formulation and policy. Second, to conduct a trend analysis assembling all the available evidence for serotype replacement in Europe, North America and Australia to characterise invasive pneumococcal disease (IPD) caused by vaccine-type (VT) and non-vaccine-types (NVT) serotypes. The motivation behind this is to assess the patterns of relative abundance in IPD cases pre- and post-vaccination, to examine country-level differences in relation to the vaccines employed over time since introduction, and to assess the growth of the replacement serotypes in comparison with the serotypes targeted by the vaccine. The third aim is to use a Bayesian framework to estimate serotype-specific invasiveness, i.e. the rate of invasive disease given carriage. This is useful for dynamic transmission modelling, as transmission is through carriage but a majority of serotype-specific pneumococcal data lies in active disease surveillance. This is also helpful to address whether serotype replacement reflects serotypes that are more invasive or whether serotypes in a specific location are equally more invasive than in other locations. Finally, the last aim of this thesis is to estimate the epidemiological and economic impact of increas- ing serotype coverage in PCVs using a dynamic transmission model. Together, the results highlight that though there are key parameter uncertainties that merit further exploration, divergence in serotype replacement and inconsistencies in invasiveness on a country-level may make a universal PCV suboptimal.Open Acces

    Targeting Fusion Proteins of HIV-1 and SARS-CoV-2

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    Viruses are disease-causing pathogenic agents that require host cells to replicate. Fusion of host and viral membranes is critical for the lifecycle of enveloped viruses. Studying viral fusion proteins can allow us to better understand how they shape immune responses and inform the design of therapeutics such as drugs, monoclonal antibodies, and vaccines. This thesis discusses two approaches to targeting two fusion proteins: Env from HIV-1 and S from SARS-CoV-2. The first chapter of this thesis is an introduction to viruses with a specific focus on HIV-1 CD4 mimetic drugs and antibodies against SARS-CoV-2. It discusses the architecture of these viruses and fusion proteins and how small molecules, peptides, and antibodies can target these proteins successfully to treat and prevent disease. In addition, a brief overview is included of the techniques involved in structural biology and how it has informed the study of viruses. For the interested reader, chapter 2 contains a review article that serves as a more in-depth introduction for both viruses as well as how the use of structural biology has informed the study of viral surface proteins and neutralizing antibody responses to them. The subsequent chapters provide a body of work divided into two parts. The first part in chapter 3 involves a study on conformational changes induced in the HIV-1 Env protein by CD4-mimemtic drugs using single particle cryo-EM. The second part encompassing chapters 4 and 5 includes two studies on antibodies isolated from convalescent COVID-19 donors. The former involves classification of antibody responses to the SARS-CoV-2 S receptor-binding domain (RBD). The latter discusses an anti-RBD antibody class that binds to a conserved epitope on the RBD and shows cross-binding and cross-neutralization to other coronaviruses in the sarbecovirus subgenus.</p

    It’s a matter of (change over) time: the role of police conduct on the dynamics of attitudes towards legal authority

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    This thesis draws on procedural justice theory and work into legal socialisation and legal cynicism to investigate the dynamics of public perceptions of trustworthiness and legitimacy of legal authority over time. Illustrating how longitudinal data can be theoretically fruitful in studies on public-police relations, I rely upon several analytic strategies that exploit panel data to examine attitudinal change over time. To examine the development of legitimacy judgements during adolescence, the mutual reproduction of different aspects of police trustworthiness over time, and the degree to which police contact leads to attitudinal change, I draw on data from three longitudinal surveys, which are representative of the adult population living in selected neighbourhoods in S˜ao Paulo, Brazil, adolescents who live in S˜ao Paulo, and the adult population living in Australia. At the heart of the thesis are four empirical papers. The first paper suggests that perceptions of overpolicing and underpolicing undermine legitimacy judgements and mutually reproduce each other over time, with implications for people’s recognition of the ruling power of the law. The second paper focuses on the development of legitimacy judgements among adolescents, and shows that exposure to neighbourhood and police violence may damage the process of healthy legal socialisation. The third paper examines whether police-citizen encounters are teachable moments, with the potential of leading to either positive or negative attitudinal change depending upon the perceived appropriateness of the interaction. The fourth paper addresses the issue of causality – an important gap in the procedural justice literature. Analysis suggests that aggressive police stops (e.g., at gunpoint) have a shortterm effect on perceived police fairness and a long-term effect on perceived overpolicing. Overall, results indicate that reliance on coercive policing strategies have several social costs, including public detachment and alienation from from the law. Adolescents who witness cases of police brutality show diminished development in legitimacy judgements, and the experience or expectation that police officers repeatedly intrude in the lives of people (overpolicing) and fail to ensure public safety (underpolicing) undermine people’s recognition of the state’s monopoly of violence. Yet, there is room for improvement. Perceptions of procedural fairness seem to enhance police trustworthiness and legitimacy. In sum, results indicate that people develop legal attitudes throughout the life course, but police (mis)conduct can lead to attitudinal change over time
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