Time-dependent metabolic phenotyping of inflammatory dysregulation

A rich and functional description of a patient health status is the fundamental basis for the personalisation of treatment and the targeting of interventions. The function of inflammation in the healing process as well as its involvement in most major diseases is well established, yet the specific mechanism by which it contributes to the pathogenesis is still not fully understood. If conditions arising from a dysregulation of the inflammatory process are to be treated before they become irreversible, a novel understanding of these pathologies must be achieved and a stratification of patients based on their inflammatory status undertaken. The work presented in this thesis aims to deliver new analytical and statistical approaches to support the investigation of the time-dependent dysregulation of inflammation. Lipid mediators have been described as exerting a major role in the initiation and regulation of the inflammatory response, yet analytical platforms for their large-scale characterisation in human biofluids are lacking. This thesis reports the validation of an assay for the simultaneous quantification of pro- and anti-inflammatory signalling molecules in multiple human biofluids. The coverage of the assay in each biofluid is subsequently established, characterising inflammatory signalling across biological compartments. A second study explores the assay’s applicability in a clinical context; investigating the relationship between lipid mediators, current clinical markers of inflammation and post-operative complications. Characterising the interplay between signalling and regulatory networks is key to understanding a living system’s response to perturbations, yet few statistical approaches are suited for the detection of time-dependent patterns in short and irregularly sampled longitudinal datasets. This thesis reports the development of a statistical approach to support the identification of altered time-trajectories in such studies. The method’s wide applicability is subsequently demonstrated on two investigations covering the diversity of metabolic phenotyping data generation platforms. This thesis is a proof of concept for the characterisation of patient-specific inflammatory status in a clinical context and the identification of altered time-dependent patterns. Both analytical and statistical developments have been motivated by the needs of real world applications and provide a template for the characterisation and analysis of the molecular basis for treatment.Open Acces

Natural variation in heat tolerance of corals on the Great Barrier Reef

Josephine Nielsen investigated patterns of acute heat tolerance in corals along the Great Barrier Reef. She found that differential acute heat tolerance was driven by coral host transcriptomics, symbiont community, and thermal disturbance history. Her thesis has direct implications for conservation management of corals under continued climate change

State of the Art Review of High Voltage Insulation Monitoring

The devastating effects of global warming and climate change are now well understood and there is broad unity that fundamental changes are needed. This is clearly addressed in the United Nations Sustainable Development Goals. The main perpetrator contributing to global warming and climate change is how we consume energy, which will need to transition from fossil fuels to renewable energy. The mass integration of renewable energy sources aimed to mitigate the effects of global warming, will greatly alter how we generate, transmit and consume energy. If we combine this with the large shift in load consumption, due to the integration of electrical vehicles, there is no doubt that the electrical transmission system will be subjected to major changes in future decades. The existing transmission grid is an aged and mature system, with large parts being installed all the way back in 60s and 70s, thus nearing the end of service. The existing grid has continuous performance issues and the knowledge on fault and ageing mechanisms are still insufficient. A thorough assessment of the current state of the grid is necessary in order to properly gauge its ability to cope with mass integration of HV systems, predominantly HVDC. A key part in assessing the current state of the grid while simultaneously increase its resilience is the utilization of high voltage monitoring methods, as they are key to prevent and predict transmission faults. Due to the increased requirement of long distance high capacity transmission, especially in submarine conditions, the knowledge and monitoring of cables will be of high importance. Compared to AC technology, DC have been regarded as niche and specialist field, thus have been allocated far less attention and research, hence the knowledge and technology of DC is still limited. This thesis will assess the state of the art of high voltage monitoring while simultaneously explore its role towards achieving the UN Sustainable Development Goals. Keywords: UN Sustainability Goals, Partial Discharges, Tan Delta, SF6, XLPE, High Voltage MonitoringMasteroppgave i energiENERGI399MAMN-ENER

The Vascular Link Between Intrauterine Hypoxia and Postnatal Cardiovascular Pathology

The effect of intrauterine hypoxia on arterial development was evaluated with use of large and small animal models. Analyses included expression and deposition of extracellular matrix (ECM) proteins, differentiation and proliferation of vascular smooth muscle cells (VSMCs), intima formation and wall thickening. A comprehensive investigation of possible molecular, mechanical and hormonal mediators of altered arterial development was afforded by a sheep model with both acute and chronic hypoxemia studies, whereas a guinea pig model allowed for long-term study. Our findings show that chronically hypoxic fetal sheep and intrauterine growth restricted (IUGR) guinea pigs exhibit a reduction in elastic fibre content of the aorta. In adulthood, the deficiency in aortic elastic fibre content in growth restricted guinea pig offspring was amplified compared to the subtle changes observed in late fetal life. In severely hypoxic fetal sheep, more marked reduction in elastin content occurred with increases in wall thickness and VSMC content. Increased collagen paralleled elevated mRNA levels of procollagen I and transforming growth factor beta (TGF-β 1). Matrix metalloproteinase-2 (MMP-2) mRNA levels were inversely correlated with fetal arterial oxygen saturation and expression of its activator, membrane-type MMP (MTI-MMP), was elevated in severely hypoxic sheep. Marked neointima formation was also apparent in severely hypoxic fetuses concomitant with increased mRNA levels of E-selectin, indicating endothelial inflammation. These structural and molecular changes of the aorta in chronically hypoxic ovine fetuses occurred without changes in pressure or circulating cortisol levels. Further, while the hypoxic sheep showed no change in VSMC maturation, aortae of IUGR guinea pig fetuses and offspring had increased content of myosin heavy chain B (MHC-B), a marker iv of undifferentiated VSMCs. Aortae of growth impaired guinea pig offspring exhibited a left shift in the length-tension curve as measured ex vivo. Thus altered aortic development in association with chronic hypoxia or IUGR leads to persistent structural abnormalities and reduced compliance in later life. In contrast, acute hypoxic study in fetal sheep demonstrated increased elastin content of the carotid artery in association with intermittent hemodynamic changes and elevated cortisol and thus highlight that beneficial adaptations are possible under certain intrauterine insults

Models and Tools for Studying Enteroendocrine Cells.

Gut hormones produced by gastrointestinal enteroendocrine cells modulate key physiological processes including glucose homeostasis and food intake, making them potential therapeutic candidates to treat obesity and diabetes. Understanding the function of enteroendocrine cells and the molecular mechanisms driving hormone production is a key step toward mobilizing endogenous hormone reserves in the gut as a therapeutic strategy. In this review, we will discuss the variety of ex vivo and in vitro model systems driving this research and their contributions to our current understanding of nutrient-sensing mechanisms in enteroendocrine cells

VAD in failing Fontan: simulation of ventricular, cavo-pulmonary and biventricular assistance in systolic/diastolic ventricular dysfunction and in pulmonary vascular resistance increase.

Aim: Due to the lack of donors, VADs could be an alternative to heart transplantation for Failing Fontan patients (PTs). Considering the complex physiopathology and the type of VAD connection, a numerical model (NM) could be useful to support clinical decisions. The aim of this work is to test a NM simulating the VADs effects on failing Fontan for systolic dysfunction (SD), diastolic dysfunction (DD) and pulmonary vascular resistance increase (PRI). Methods: Data of 10 Fontan PTs were used to simulate the PTs baseline using a dedicated NM. Then, for each PTs a SD, a DD and a PRI were simulated. Finally, for each PT and for each pathology, the VADs implantation was simulated. Results: NM can well reproduce PTs baseline. In the case of SD, LVAD increases the cardiac output (CO) (35%) and the arterial systemic pressure (ASP) (25%). With cavo-pulmonary assistance (RVAD) a decrease of inferior vena cava pressure (IVCP) (39%) was observed with 34% increase of CO. With the BIVAD an increase of ASP (29%) and CO (37%) was observed. In the case of DD, the LVAD increases CO (42%), the RVAD decreases the IVCP. In the case of PRI, the highest CO (50%) and ASP (28%) increase is obtained with an RVAD together with the highest decrease of IVCP (53%). Conclusions: The use of NM could be helpful in this innovative field to evaluate the VADs implantation effects on specific PT to support PT and VAD selection

Effects of 17 β-estradiol and Progesterone on Acropora cervicornis and Porites astreoides Growth and Reproduction

Reef-building coral populations throughout the world are being threatened by numerous stressors and continue to decline. As potent endocrine-disrupting compounds, exogenous sex steroid contamination has been a largely overlooked stressor to corals. Previous research indicates these compounds are prevalent in marine environments, fluctuate annually along with reproductive cycles, can bioaccumulate, and have had variable effects on growth and reproduction in several cnidarian species. This project had three primary objectives: (1) establish environmental estradiol and progesterone concentrations in Broward County and lower Florida Keys reef environments, (2) conduct 17 β-estradiol and progesterone larval assays on P. astreoides larvae to determine the effects of these compounds on settlement and viability, and (3) conduct 17 β-estradiol and progesterone dosing experiments on adult Acropora cervicornis and Porites astreoides fragments to determine the effects on growth, zooxanthellae, reproduction, and overall tissue health. Estradiol was detected in surface and at-depth water samples from Broward County and lower Keys reef sites at effect level concentrations for marine organisms. Broward County larvae treated with low progesterone (5 ng/L) had decreased survival, while lower Keys larvae in low estradiol treatments (1 ng/L) had increased on-disc settlement. No other treatment effects were observed, however, lower Keys larvae had greater overall survival in comparison to Broward County larvae. There were no significant differences between estradiol and progesterone treatments in the adult-dosing experiment for growth, zooxanthellae density, reproduction, and overall tissue health. This is the first study to detect estradiol at Broward County reefs sites and our results, while inconclusive, indicate these compounds may have the potential to affect coral reef ecosystems

Diagnostic circulating biomarkers to detect vision-threatening diabetic retinopathy: Potential screening tool of the future?

With the increasing prevalence of diabetes in developing and developed countries, the socio-economic burden of diabetic retinopathy (DR), the leading complication of diabetes, is growing. Diabetic retinopathy (DR) is currently one of the leading causes of blindness in working-age adults worldwide. Robust methodologies exist to detect and monitor DR; however, these rely on specialist imaging techniques and qualified practitioners. This makes detecting and monitoring DR expensive and time-consuming, which is particularly problematic in developing countries where many patients will be remote and have little contact with specialist medical centres. Diabetic retinopathy (DR) is largely asymptomatic until late in the pathology. Therefore, early identification and stratification of vision-threatening DR (VTDR) is highly desirable and will ameliorate the global impact of this disease. A simple, reliable and more cost-effective test would greatly assist in decreasing the burden of DR around the world. Here, we evaluate and review data on circulating protein biomarkers, which have been verified in the context of DR. We also discuss the challenges and developments necessary to translate these promising data into clinically useful assays, to detect VTDR, and their potential integration into simple point-of-care testing devices