Le clade des invertébrés cristallise en 2017 de grandes problématiques sociétales à la fois économiques et sanitaires. En effet un certain nombre des organismes présent dans ce groupe phylétique sont des vecteurs des grandes pandémies infectieuses telles que le paludisme (Anopheles sp), Zika, Chinkungunya, Fièvre jaune, etc (Aedes sp), Chagas (Triatoma sp) ou encore la bilharziose (Biomphalaria sp, Bulinus sp). La compréhension du système immunitaire de ces organismes vecteurs doit aider la communauté scientifique à proposer des solutions pour réduire la transmission de toutes ces maladies sur le terrain. Biomphalaria glabrata est le vecteur unique de la Bilharziose intestinale (Schistosomamansoni) en Amérique Latine. Depuis un premier cas de résistance induite par une première infection en 1998, de nombreux travaux ont exploré la réponse immunitaire mémoire innée de cet escargot tropical d’eau douce. Dans le cadre de ce travail de thèse, différents aspects de cette immunité (également appelé priming, résistance acquise) ont été explorés, de la mise en place phénotypiques, aux bases moléculaires et cellulaires. En premier lieu,nous avons pu démontrer qu’elle était dépendante d’une bascule phénotypique (d’une réponse cellulaire d’encapsulation à une réponse humorale) et transcriptomique qui lui permet de mieux répondre lors d’une seconde infection. La spécificité de cette réponse est portée par la production de répertoire complexe de récepteurs et d’effecteurs immunitaire spécifiques qui sont capables de différencier jusqu’aux différents stades de développement parasitaire d’une même espèce de parasite. Nous avons également pu montrer que cette interaction dépendait de microARN circulants ainsi que de Biomphalysines, des ß-PFT acquises par transferts horizontaux depuis le monde bactérien. Enfin, cette résistance semble posséder une proximité avec l’immunité mémoire entraînée des cellules immunitaires innées des vertébrés en particulier sur la base des mécanismes moléculaires sous-jacent qui seraient liés chez Biomphalaria comme chez les Vertébrés à unereprogrammation épigénétique des cellules du système immunitaire innée. / Invertebrates focus in 2017 among the major economical and societal issuesacross Earth. Some members are vectors of important infectious pandemic as malaria(Anopheles sp), Zika, Chinkungunya, Yellow fever, etc (Aedes sp), Chagas (Triatoma sp) andtrematodes (Biomphalaria sp, Bulinus sp). Comprehension of immune system of thesevectors has to help scientist to decrease transmission on endemic area. Biomphalariaexposed first failure to be reinfected following first infection as soon as 1998. In my thesiswe explore this immune priming (innate immune memory) and describe an immune shiftfrom cellular to humoral immune response both in phenotype and transcriptomic response.A specificity is handle by specific immune receptor and effector repertoire to distinguish upto different developmental stage of same parasite species. This interaction is alsodependent of mRNAs and Biomphalysin, a ß-PFT coming from bacterial kingdom. Finally,this resistance seems to look alike the trained immune memory of innate cells in vertebrates.

Peak oxygen uptake (VO2PEAK) in endurance exercise trained (ET =8) subjects (VO2PEAK = 61.7 1.6 ml 02.kg.min-1) was compared to the V02 PEAK of untrained (UT = 8) subjects (V02 PEAK = 38.4 1.7 ml 02 -kg.min1) after four hours of -6* head-down rest (HDR).Although both groups showed a reduction in blood volume (BV) following HDR, this decrement was greater for ET subjects (delta BV = -3.23 0.46 mi/kg; P <0.05). The ET subjects had a greater decrease in VO2=(delta 02E -5.58 1.05 ml 02-kg.min-1; P <0.05) than their UT peers (VO2PEAK = -2.44 0.79 ml02-kg.min-1). These data suggest that the greater reductions in VO2PE, observed for the ET group were associated with a greater BV loss resulting from 4 h of HDR prior to exercise.

Magister Curationis - MCur / The nurse preceptors underwent a preceptorship training programme offered by the University of the Western Cape, School of Nursing, which prepared them for this teaching role. A quantitative study was done following this preceptorship training programme but no qualitative study since. It is vital to explore the experiences of these trained nurse preceptors regarding clinical teaching practice post the training programme. The aim of the study was to explore trained nurse preceptors‟ experiences regarding their clinical teaching practice in the Western Cape. The objective was to describe trained nurse preceptors‟ experiences of their clinical teaching practice in the service settings in the Western Cape. An exploratory, descriptive, contextual design was used to describe the experiences of trained nurse preceptors in the Western Cape. A purposive sample was selected from three levels of healthcare service settings. Semi-structured interviews were conducted by the researcher with nine individual nurse preceptors who voluntarily agreed to participate in the study. Data analysis was done following Collaizi‟s‟ steps which led to coding of categories and themes. The findings indicated that preceptorship training programme had changed the nurse preceptors‟ perceptions. These nurse preceptors were prepared by the programme and ready for the preceptor role. Their teaching skills were strengthened and improved. They accepted the training programme as adequate preparation to facilitate clinical teaching and learning of students and found it to be effective for their self-development. These findings will inform v the managers about clinical teaching practice, assist the offering institution with the evaluation of the preceptorship training programme and add to an existing literature about the experiences of nurse preceptors. This research recommends that the education institutions, in collaboration with the clinical facilities initiate a qualitative study to explore the experiences of students preceptored by trained nurse preceptors. Such a study will further explore the effectiveness of the preceptorship training programme from the perspective of the students. With the positive feedback from the participants, it is essential that the training of preceptors remains one of the continuing education programme offered by the University of the Western Cape. Permission to conduct this research was obtained from the University of Western Cape, Senate Higher Degrees Committee, and Western Cape of Provincial Department Research Team in Western Cape as well as from the Chief Executive Officers of the three levels of healthcare service settings.

Community cohesion in Britain has been an issue of policy concern in recent years in which the role of migrants in the UK has been scrutinised in terms of their sense of belonging, integration and their economic and social contribution to society. However, much of the existing literature, in this area relates to the experiences of low/unskilled labour migrants. This thesis redresses this imbalance and examines the experiences of overseas-trained South Asian doctors. It provides unique insights into the debates about integration, cultural identity and community cohesion based on an empirical study of overseas-trained South Asian General Practitioners who are elite migrants. A mixed method approach was employed that included secondary data analysis of the GP Workforce Statistics and in-depth interviews with 27 overseas-trained South Asian doctors in three different geographical locales in England with varying ethnic populations. The quantitative analysis shows that a significant and increasing proportion of NHS doctors continue to be overseas-trained South Asian doctors. It also provides evidence of geographical clustering with South Asian doctors being over represented in deprived areas with high and low ethnic minority concentrations. The case studies and interviews with the GPs reveal a complex intertwining of macro-, micro- and meso- structures in the migratory process, related, in part, to the legacy of empire and also to the inner workings and opportunities provided by an organisation such as the NHS. In order to overcome blocked social mobility within the NHS hospital structure, entry into General Practice appears to be an entrepreneurial step for overseas-trained South Asian doctors, also facilitated by regional NHS institutional structures like Primary Care Trusts. Evidence shows that doctors have integrated their cultural/religious values creatively in their adaptation to Britain importing innovation into their everyday experiences. The findings show that there are parallels to be drawn with the experiences of low/unskilled South Asians, in particular, in the area of structural integration. However, there is variation as to how these elite professionals approach issues related to socio-cultural integration thus adding a new dimension to our existing understanding of community cohesion in the UK.

Malarial infection in naïve individuals induces a robust innate immune response, but our understanding of the mechanisms by which the innate immune system recognizes malaria and regulates its response remain incomplete. Our group previously showed that stimulation of macrophages with Plasmodium falciparum genomic DNA (gDNA) and AT-rich oligodeoxynucleotides (ODNs) derived from this gDNA induces the production of type I interferons (IFN-I) through a STING/TBK1/IRF3-dependent pathway; however, the identity of the upstream cytosolic DNA receptor remained elusive. Here, we demonstrate that this IFN-I response is dependent on cyclic GMP-AMP synthase (cGAS). cGAS produced the cyclic dinucleotide 2’3’-cGAMP in response to P. falciparum gDNA and AT-rich ODNs, inducing IRF3 phosphorylation and IFNB transcription. In the recently described model of innate immune memory, an initial stimulus primes the innate immune system to either hyperrespond (termed “training”) or hyporespond (“tolerance”) to subsequent immune challenge. Previous work in mice and humans demonstrated that infection with malaria can both serve as a priming stimulus and promote tolerance to subsequent infection. In this study, we demonstrate that initial stimulation with P. falciparum-infected red blood cells (iRBCs) or the malaria crystal hemozoin (Hz) induced human adherent peripheral blood mononuclear cells (PBMCs) to hyperrespond to subsequent Toll-like receptor (TLR) challenge. This hyperresponsiveness correlated with increased H3K4me3 at important immunometabolic promoters, and these epigenetic modifications were also seen in monocytes from Kenyan children naturally infected with malaria. However, the use of epigenetic and metabolic inhibitors indicated that malaria-induced trained immunity may occur via previously unrecognized mechanism(s).

The global population is rapidly aging. It is estimated that over the next thirty years, the number of individuals >60 years of age will increase by over a billion, and the number of individuals over age 80 may increase by 300 million. As humans age, our immune system becomes progressively weaker through a process called immune senescence. This age-related decrease in immune function increases susceptibility to infection and chronic diseases. Sepsis is a leading cause of death worldwide. Over the past two decades, there has been an increased incidence of sepsis which is due, in part, to our aging population and immune senescence. The gut microbiome, which plays an essential role in health and disease, is altered in aging and sepsis. Specifically, the commensal microorganisms of the gut microbiota are replaced with potentially pathogenic bacteria. This contributes to immune dysfunction and worsened outcomes in critical illness. The innate immune system can be “trained” to respond more effectively to pathogens. We examined trained immunity as an approach to modulating immunosenescence and microbiome diversity in aging. We investigated the effect of trained immunity on: i) immune cells from healthy aging subjects and sepsis patients and ii) the diversity of the microbiome in aging and sepsis. Our results indicate that trained immunity is effective in combatting age-related immunosenescence. We found that β-glucan induced trained immunity enhances monocyte metabolism, increases functionality as well as alters the transcriptome and epigenome in aging individuals and sepsis patients. We also found that trained immunity induced the expansion of a unique population of myeloid cells in sepsis. These cells are defined as FSChi, CD11b+, GR-1hi and express high levels of immunosuppressive PD-L1. In addition, we found that trained immunity reversed age-related changes to the microbiome and prevented alterations to the microbiome in septic mice. We found that the Firmicutes/Bacteroidetes ratio increased in aging; however, trained immunity reversed this increase and increased Clostridia in aged mice. In sepsis, trained immunity prevented expansion of Proteobacteria observed in control mice. Thus, our results indicate that trained immunity may be effective in modulating immune senescence and the microbiome in aging and sepsis.

Energy efficiency of district heating systems is of great interest to energy stakeholders. However, it is not uncommon that district heating systems fail to achieve the expected performance due to inappropriate operations. Night setback is one control strategy, which has been proved to be not a suitable setting for well-insulated modern buildings in terms of both economic and energy efficiency. Therefore, identification of a night setback control is vital to district heating companies to smoothly manage their heat energy distribution to their customers. This study is motivated to automate this identification process. The method used in this thesis is a Convolutional Neural Network(CNN) approach using the concept of transfer learning. 133 substations in Oslo are used in this case study to design a machine learning model that can identify a substation as night setback or non-night setback series. The results show that the proposed method can classify the substations with approximately 97% accuracy and 91% F1-score. This shows that the proposed method has a high potential to be deployed and used in practice to identify a night setback control in district heating substations.

Chronic kidney disease (CKD) affects 13.4% of adults in America; and 38% in people aged 65 years or older[1]. In addition, cardiovascular disease (CVD) is the leading cause of death in CKD patients with end-stage kidney disease. CKD is associated with chronic inflammation, which contributes to the progression of CVD[2]. Furthermore, CKD alter apolipoprotein profile and elevate plasma lipid levels. It has been reported that 68.8% of CKD patients are associated with hyperlipidemia[3]. Therefore, hyperlipidemia is the critical risk factor for cardiovascular morbidity and mortality in CKD patients [4, 5]. In addition, trained immunity has been shown to play a critical role in chronic inflammatory diseases[6]. However, whether trained immunity promotes the inflammation in hyperlipidemia-CKD remains unclear. Circulating lipopolysaccharide (LPS) is significantly increased in atherosclerotic and CKD patients[7]. Clinical data indicates that circulating LPS is positively associated with the progression of CKD, and its levels even higher in patients with hemodialysis or dialysis[8]. Studies found that circulating LPS is delivered into cytosol for caspase-4/11 activation[9]. The Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) involving 10,061 patients found that targeting interleukin-1β (IL-1β) innate immunity pathway is significantly lowered the rate of recurrent cardiovascular events independent of lipid-level lowering[10]. Therefore, inhibiting the secretion of proinflammatory cytokine IL-1β has high potential to future development of novel therapeutics for hyperlipidemia-CKD accelerated CVD. Gasdermin D (GSDMD) is cleaved by inflammatory caspase-1 and caspase-4. N-terminal GSDMD binds to plasma membrane forming protein channel [11] and mediates the secretion of IL-1β[12, 13]. We found that caspase-1 activation was significantly decreased in caspase-4/11 deficient high-fat diet (HFD)-CKD mice, indicating that caspase-4 could regulate caspase-1 activation in HFD-CKD. Whether increased cytosolic LPS contribute to the increased vascular inflammation via caspase-4/11-GSDMD-IL-1β pathway remains unknown. In this study, we used HFD fed 5/6 nephrectomy CKD mice in vivo and cytosolic LPS stimulation in human aortic endothelial cell (HAECs) in vitro. We made the following results: 1) Inflammatory pathways are significantly increased in the aorta of HFD-CKD compared to HFD-Sham, normal diet (ND)-CKD, and ND-Sham. 2) Expression levels of endothelial cell activation markers (ICAM1 and VCAM1) are significantly increased in the aorta of HFD-CKD mice compared to HFD-Sham, ND-CKD, and ND-Sham. 3) Caspase-4 activation and N-GSDMD cleavage are significantly increased in the aorta of HFD-CKD mice compared to HFD-Sham, ND-CKD, and ND-Sham and in cytosolic LPS stimulated HAECs. 4) The increased inflammatory pathways and increased expression of adhesion molecules are decreased in the deficiency of caspase-4 in vivo and in the presence of caspase-4 inhibitor and N-terminal GSDMD cleavage inhibitor in vitro. 5) The increased mitochondrial ROS promote endothelial cell activation via caspase-4-GSDMD axis. Taken together, the caspase-4/11-GSDMD axis mediates endothelial cell activation and vascular inflammation in the aorta of HFD-CKD mice compared to controls. Furthermore, the increased endothelial cell activation and vascular inflammation are restored by caspase-4/11 deficiency in the aorta of HFD-CKD mice. These evidence indicate that inhibiting caspase-4/11-GSDMD axis could be a potential therapeutic target for inhibiting vascular inflammation associated with hyperlipidemia-CKD. / Biomedical Sciences

Readability assessment (RA) is to assign a score or a grade to a given document, which measures the degree of difficulty to read the document. RA originated in language education studies and was used to classify reading materials for language learners. Later, RA was applied to many other applications, such as aiding automatic text simplification.  This thesis is aimed at improving the way of using Transformer for RA. The motivation is the “pipeline” effect (Tenney et al., 2019) of pretrained Transformers: lexical, syntactic, and semantic features are best encoded with different layers of a Transformer model.  After a preliminary test of a basic RA model that resembles the previous works, we proposed several methods to enhance the performance: by using a Transformer layer that is not the last, by concatenating or mixing the outputs of all layers, and by using syntax-augmented Transformer layers. We examined these enhanced methods on three datasets: WeeBit, OneStopEnglish, and CommonLit.  We observed that the improvements showed a clear correlation with the dataset characteristics. On the OneStopEnglish and the CommonLit datasets, we achieved absolute improvements of 1.2% in F1 score and 0.6% in Pearson’s correlation coefficients, respectively. We also show that an 𝑛-gram frequency- based baseline, which is simple but was not reported in previous works, has superior performance on the classification datasets (WeeBit and OneStopEnglish), prompting further research on vocabulary-based lexical features for RA.

Döden är ett kontroversiellt ämne som väcker starka känslor hos många människor. Syftet med föreliggande litteraturstudie var att undersöka sjuksköterskors upplevelser i samband med omvårdnaden av den döende patienten och hur sjuksköterskan hanterar sina upplevelser. Litteratursökning gjordes i sex databaser. 12 vetenskapliga artiklar granskades och resultatet visade att sjuksköterskors upplevelser är av både positiv, styrkande art och av negativ, energikrävande art. Resultat uppkom även om sjuksköterskans förhållningssätt till yrkesrollen och hantering av upplevelser. Genomgående uppvisas ett stort behov av handledning i yrkesrollen. / Death is a controversial subject and arises strong emotions in many human beings. The purpose of the present literature review was to examine nurses´ experiences during the care of dying patients and how nurses handle these experiences. Search for literature were done in six databases. Twelve scientific articles were studied and results show that nurses have experiences of both positive (strengthening) and a negative (draining energy) kind. We discovered how nurses acted based on there professional role and how they dealt with experiences. A recurring theme is the significant need for supervision in there professional role.