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TLR9-ligation in naive B cells activates NF-κB and PKM2 tetramer shift for glycolytic reprogramming and TNF expression
Get PDFThe innate-like function of B cell is dependent on pattern recognition receptors, such as Toll-like receptors (TLR). TLR ligation and activation of downstream signaling pathways drives metabolic changes in cells and promotes effector functions (e.g., cytokine secretion). However, the immunometabolic profile of B cells during the initial recognition of pathogen associated molecular patterns via Toll-like receptor 9 in the innate immune response is limited. TLR9-activation in B cells by CpG elicits an increased glycolytic response mediated by NF-κB, which in and of itself is a strong mediator of metabolism and immune function. However, we further define the role of NF-kB mediated metabolic switch to facilitate a temporal shift in PKM2 tetramerization status sensitive to IKK inhibition that induces B cell expression of TNF (Figure 1)
Locating gender in space: Emily Dickinson's conception of gender
Get PDFIn her poems, Emily Dickinson defines, locates, reshapes, and forms new concepts of gender. She achieves this by employing spatial metaphors and images that locate female identity in a new territory. Her poetry overcomes gendered dualisms and dichotomies by unmasking opposites as constructs and by accommodating them within the same sphere. As the spaces in Dickinson’s poems are abstract, strangely limitless, and ambiguous in their dimensions, her new female subjects have to reside in a paradoxical space. This paradoxical mapping allows for conceptualizations of identity as being simultaneously at the center and at the margin of a certain space, being at once inside and outside. In Dickinson’s nineteenth-century New England, the spaces of nature, the house, and the grave or afterlife are highly saturated with cultural and ideological meaning. Therefore, the transgression of boundaries between nature and culture, the public and the private, and life and death bestows Dickinson’s speakers with power, freedom, and a sense of the arbitrariness of the concepts attached to these boundaries. Through the exploitation of marginal spaces such as swamps, closets, the space within walls, and the dead body, Dickinson relocates desire and relationships between men and women. By reorganizing the asymmetrical attributions of power and gender to which her speakers are subjected, Dickinson carves out space for unconventional identities and rebellious acts
The power of immersive technologies: a sociopsychological analysis of the relationship between immersive environments, storytelling, sentiment, and the impact on user experience
Get PDFThis dissertation initially focused on exploring the potential of immersive technologies for the distant future. However, the emergence of the COVID-19 virus in late 2019 disrupted the world, causing a pause in many areas. Nevertheless, the butterfly effect of the pandemic spurred the development of immersive technologies, resulting in the rise of the metaverse, web3, non-fungible tokens (NFT), and avatars, which are gaining increasing popularity. The excitement for the metaverse is growing in both academia and industry, leading to new avenues of research, digital marketing, video games, tourism, and social media. This dissertation explores this rapidly emerging technological revolution and its effects on user experience (UX)
Kinetics of nitrous oxide production from ammonia oxidation in the Eastern Tropical North Pacific
No full textMarine oxygen-deficient zones represent a natural source of nitrous oxide (N 2 O), a potent greenhouse gas and ozone-depleting agent. To investigate controls on N 2 O production, the responses of ammonia oxidation (AO) to nitrite (NO À 2) and N 2 O with respect to oxygen (O 2), ammonium (NH þ 4) and NO À 2 concentrations were evaluated using 15 N À NH þ 4 tracer incubations in the Eastern Tropical North Pacific. Within the oxycline, additions of NH þ 4 and O 2 stimulated N 2 O production according to Michaelis-Menten kinetics, indicating that both substrates were limiting, and that N 2 O production, even if the exact mechanisms remain uncertain, is mediated by predictable kinetics. Low half-saturation constants for NH þ 4 (12-28 nM) and O 2 (460 AE 130 nM) during N 2 O production indicate that AO communities are well adapted to low concentrations of both substrates. Hybrid N 2 O formation (i.e., from one 15 NH þ 4 and one unlabeled nitrogen (N) source, e.g., NO À 2 , NO) accounted for $ 90% of the N 2 O production from NH þ 4 and was robust across the different O 2 , NO À 2 , and NH þ 4 conditions. Lack of response to variable substrate concentrations implies that the unlabeled N source was not limiting for N 2 O production. Although both O 2 and NH þ 4 were key modulators of N 2 O production rates, N 2 O yield (N 2 O produced per NO À 2 produced) seemed to be controlled solely by O 2. The N 2 O yield increased when O 2 concentrations dropped below the half-saturation concentration for AO to NO À 2 (< 1.4 μM), the range where NO À 2 production decreased faster than N 2 O production. Our study shows that O 2 control on N 2 O yield from AO is robust across stations and depths
ModelCIF: An extension of PDBx/mmCIF data representation for computed structure models
No full textModelCIF (github.com/ihmwg/ModelCIF) is a data information framework developed for and by computational structural biologists to enable delivery of Findable, Accessible, Interoperable, and Reusable (FAIR) data to users worldwide. ModelCIF describes the specific set of attributes and metadata associated with macromolecular structures modeled by solely computational methods and provides an extensible data representation for deposition, archiving, and public dissemination of predicted three-dimensional (3D) models of macromolecules. It is an extension of the Protein Data Bank Exchange / macromolecular Crystallographic Information Framework (PDBx/mmCIF), which is the global data standard for representing experimentally-determined 3D structures of macromolecules and associated metadata. The PDBx/mmCIF framework and its extensions (e.g., ModelCIF) are managed by the Worldwide Protein Data Bank partnership (wwPDB, wwpdb.org) in collaboration with relevant community stakeholders such as the wwPDB ModelCIF Working Group (wwpdb.org/task/modelcif). This semantically rich and extensible data framework for representing computed structure models (CSMs) accelerates the pace of scientific discovery. Herein, we describe the architecture, contents, and governance of ModelCIF, and tools and processes for maintaining and extending the data standard. Community tools and software libraries that support ModelCIF are also described
A basis for molecular factories: multifunctionality and immobilization of biomolecule-polymer assemblies
Get PDFBio-inspired planar polymer membranes are synthetic membranes designed to be combined with biomolecules such as proteins, enzymes or peptides. These membranes provide both an increased mechanical stability as well as an environment to preserve the functionality of the biomolecules. In this thesis, two different kinds of planar membrane systems are demonstrated. In the first project, a sensor for phenolic compounds based on a bio-inspired polymer membrane was developed. Functional surfaces were generated by combining enzymes with polymer membranes composed of an amphiphilic, asymmetric block copolymer. Firstly, polymer films which were formed at the air-water interface were transferred onto silica solid support, by using the Langmuir-Blodgett method. The films were characterized according to their properties, including film thickness, wettability, topography, and roughness. The most promising membranes were used for enzyme attachment. Two model enzymes, laccase and tyrosinase, were adsorbed to the surface and their activity regarding the conversion of phenolic compounds was measured. This project is described in Chapter 1 in detail. In the second project, the interaction of the model pore-forming peptide melittin was studied in combination with a planar synthetic membrane. The investigation focused the interaction of melittin with amphiphilic block copolymer-based synthetic planar membranes as well as the insertion of melittin into these membranes to induce pore formation. Some specific molecular properties of the block copolymers and of the resulting membranes were selected for the investigation, such as hydrophilic to hydrophobic block ratio, membrane thickness and surface roughness. Through melittin addition to the synthetic membranes, melittin insertion requirements were better understood. This project is described in Chapter 2 in detail. Each chapter contains a separate introduction, material and methods section and conclusion and outlook specific to the project.20
In summary, in this thesis the properties of different combinations and applications of polymer-based membranes with biomolecules were investigated to a deeper level
Developing a reflection and analysis tool (We-ReAlyse) for readmissions to the intensive care unit: A quality improvement project
Get PDFReadmissions to the intensive care unit are associated with poorer patient outcomes and health prognoses, alongside increased lengths of stay and mortality risk. To improve quality of care and patients' safety, it is essential to understand influencing factors relevant to specific patient populations and settings. A standardized tool for systematic retrospective analysis of readmissions would help healthcare professionals understand risks and reasons affecting readmissions; however, no such tool exists.; This study's purpose was to develop a tool (We-ReAlyse) to analyze readmissions to the intensive care unit from general units by reflecting on affected patients' pathways from intensive care discharge to readmission. The results will highlight case-specific causes of readmission and potential areas for departmental- and institutional-level improvements.; A root cause analysis approach guided this quality improvement project. The tool's iterative development process included a literature search, a clinical expert panel, and a testing in January and February 2021.; The We-ReAlyse tool guides healthcare professionals to identify areas for quality improvement by reflecting the patient's pathway from the initial intensive care stay to readmission. Ten readmissions were analyzed by using the We-ReAlyse tool, resulting in key insights about possible root causes like the handover process, patient's care needs, the resources on the general unit and the use of different electronic healthcare record systems.; The We-ReAlyse tool provides a visualization/objectification of issues related to intensive care readmissions, gathering data upon which to base quality improvement interventions. Based on the information on how multi-level risk profiles and knowledge deficits contribute to readmission rates, nurses can target specific quality improvements to reduce those rates.; With the We-ReAlyse tool, we have the opportunity to collect detailed information about ICU readmissions for an in-depth analysis. This will allow health professionals in all involved departments to discuss and either correct or cope with the identified issues. In the long term, this will allow continuous, concerted efforts to reduce and prevent ICU readmissions. To obtain more data for analysis and to further refine and simplify the tool, it may be applied to larger samples of ICU readmissions. Furthermore, to test its generalizability, the tool should be applied to patients from other departments and other hospitals. Adapting it to an electronic version would facilitate the timely and comprehensive collection of necessary information. Finally, the tool's emphasis comprises reflecting on and analyzing ICU readmissions, allowing clinicians to develop interventions targeting the identified problems. Therefore, future research in this area will require the development and evaluation of potential interventions
Autoantibodies as biomarkers in autoimmune diseases
Get PDFThe immune system plays a critical role in the homeostasis and protection of our body, but its dysregulation is often associated with the pathogenesis of autoimmune diseases. The cellular and molecular components of the immune system have been explored as therapeutic targets or biomarkers with the aim of curing autoimmunity. Although studied since decades, autoantibodies’ use as biomarker in clinical trials is still limited to a handful of well-known markers. The aim of the thesis was to test autoantibody profiling as an exploratory tool to identify new biomarkers in the context of clinical trials conducted in three autoimmune diseases.
In the first part of the PhD, I tested a large set of autoantibodies on baseline serum samples from a phase III anti-IL17 clinical trial of Psoriatic Arthritis, with the aim of identifying a group of biomarkers that could discriminate between responders and non-responders to the treatment. Numerous autoantibodies of either IgG, IgM and IgA isotype were found more expressed in clinical non-responders when compared to responders. Such autoantibodies were directed against molecules related to IL17 pathway, a commensal bacterium (Lachnospiraceae) and antigens linked to Rheumatoid Arthritis. Overall, these markers allowed a discrimination of 40% of non-responders from responders population, which was judged as a too low sensitivity in order to start the development of a companion diagnostic. However, the technical knowledge acquired during this first project was fundamental for the rest of the PhD. In the second part of the PhD, I applied autoantibody profiling, using a targeted set of antigens, on serum samples from a phase II anti-IL17 treatment clinical trial of Hidradenitis Suppurativa (HS). The aim of this project was to demonstrate the presence of autoantibodies that could support the hypothesis of an autoimmune component of HS pathogenesis. We found IgG anti-Carboxyethyl-lysine (CEL) autoantibodies with specific high levels in HS when compared to healthy volunteers and other comorbidities such as Crohn’s disease and Ulcerative Colitis. B-cells producing anti-CEL antibodies were detected in HS lesional skin as well. Sera with high levels of anti-CEL autoantibodies activated macrophages and complement pathway in presence of CEL-BSA. The majority of IgG anti-CEL antibodies was of IgG2 subclass and no cross-reactivity with similar molecules such as Carboxymethyl-lysine and Octopine was found. Overall, these results suggested a role for oxidative stress and advanced glycation events in the pathogenesis of HS. In the third part of the PhD, I detected anti-FceR1a autoantibodies in serum from Chronic Spontaneous Urticaria (CSU) from a phase II clinical trial of anti-IgE treatment. It was hypothesized that patients expressing anti-FceR1a autoantibodies may activate mast cells degranulation in an IgE-free manner, which would make them resistant to anti-IgE treatment. The results showed no correlation between the presence of anti-FceR1a autoantibodies and clinical response to IgE treatment. The detection of the soluble form of FceR1a (sFceR1a) at different time-points throughout the treatment showed a dose-dependent decrease of sFceR1a concentration, similarly to what already published for FceR1a expression on basophils surface. The data showed in this thesis suggested that sFceR1a might be a substitute mechanistic marker of cell-bound FceR1a.
In conclusion, although autoantibody profiling did not allow identifying specific markers for anti-IL17 treatment response in PsA, the knowledge acquired during this project was critically important. Indeed, the same approach allowed the finding of anti-CEL autoantibodies abundance and specificity in HS and the testing of anti-FceR1a autoantibodies and sFceR1a in CSU, which gave new insights in these diseases. The results presented in this thesis show the potential and limitations of autoantibodies profiling when applied to clinical trials of autoimmune diseases
