Rôle des plaquettes dans la physiopathologie du sepsis

Le sepsis est défini depuis 2016 comme la présence d'une infection associée à la survenue de dommages tissulaires à distance du foyer infecté. Le choc septique en est une des complications les plus graves. Le sepsis est une pathologie inflammatoire médiée par l'activation du système immun inné avec la reconnaissance par l'hôte de produits microbiens et de signaux de danger par des récepteurs cellulaires spécifiques et l'activation de multiples voies de signalisation cellulaires. Le sepsis entraîne un état d'hypercoagulabilité caractérisé par l'apparition de thrombi dans la microcirculation, de dépôts de fibrine, la formation de NETs (Neutrophil Extracellular Traps) et de lésions endothéliales. La formation de thrombi particulièrement dans la microcirculation entraîne un défaut de perfusion des organes. L'inhibition de l'activation plaquettaire réduit les interactions plaquettes-cellules inflammatoires-cellules endothéliales, ce qui théoriquement pourrait bloquer la réaction en cascade entre l'inflammation et la coagulation. Le potentiel des médicaments antiplaquettaires pour réduire les défaillances d'organes et améliorer le pronostic du sepsis est discuté. Cependant, l'activation plaquettaire et le détail de la cinétique d'activation plaquettaire dans le sepsis restent peu décrits, particulièrement chez l'Homme. Parallèlement, la crise COVID-19 a soulevé de nombreuses interrogations quant à la pathogénicité du virus et son impact sur la coagulation des patients de réanimation, présentant plus d'évènements thrombo-emboliques que de façon habituelle. Le rôle des plaquettes dans la physiopathologie de l'infection grave à SARS-CoV-2 reste encore à préciser. Ainsi le but de ce travail de thèse était double, travailler sur les fonctions plaquettaires au cours du sepsis puis, dans un second temps, mieux comprendre le rôle des plaquettes dans la pathogenèse de l'infection à SARS-CoV-2. Dans un premier temps, nous avons tenté de 2 déterminer le modèle animal précis d'étude du sepsis nous permettant une analyse de la cinétique d'activation plaquettaire. Nous avons ensuite utilisé ce modèle pour caractériser la cinétique d'activation des plaquettes au cours du choc septique. Nous avons dans un troisième temps réalisé la comparaison de l'activation plaquettaire chez des patients admis en réanimation polyvalente pour choc septique avec des sujets sains. Nous avons parallèlement étudié si le volume moyen plaquettaire (VMP) pouvait constituer un biomarqueur d'intérêt pour prédire la mortalité du choc septique chez l'Homme. Enfin, nous avons caractérisé le rôle des plaquettes dans la physiopathologie du syndrome de détresse respiratoire aigu sévère COVID-19 en réanimation.Sepsis has been defined since 2016 as the presence of an infection associated with the occurrence of tissue damage at a distance from the infected site. Septic shock is one of the most serious complications. Sepsis is an inflammatory pathology mediated by activation of the innate immune system with host recognition of microbial products and danger signals by specific cellular receptors and the activation of multiple cell signaling pathways. Sepsis leads to a state of hypercoagulability characterized by the appearance of thrombi in the microcirculation, fibrin deposits, the formation of NETs (Neutrophil Extracellular Traps) and endothelial lesions. The formation of thrombi, particularly in the microcirculation, leads to a defect in organ perfusion. Inhibition of platelet activation reduces platelet-inflammatory cell-endothelial inflammatory cells-endothelial cells interactions, which could theoretically block the cascade reaction between inflammation and coagulation. The potential of antiplatelet drugs to reduce organ failure and improve prognosis and improve the prognosis of sepsis is discussed. However, platelet activation and the details of the kinetics of platelet activation in sepsis remain poorly described, particularly in humans. In parallel, the COVID-19 crisis has raised many questions about the pathogenicity of the virus and its impact on the coagulation of patients in ICU, presenting more thrombo-embolic events than usual. The role of platelets in the pathophysiology of severe SARS-CoV-2 infection remains to be to be clarified. Thus, the aim of this thesis was twofold: to work on platelet functions during sepsis and then, in a second step, to better understand the role of platelets in the pathogenesis of SARS-CoV-2 infection. First, we tried to determine the precise animal model for the study of sepsis that would allow us to analyze the kinetics of platelet activation. We then used this model to characterize the kinetics of platelet activation during septic shock. In a third step, we compared platelet activation thirdly, we compared platelet activation in patients admitted to a polyvalent intensive care unit for septic shock with healthy subjects. In parallel, we studied whether the mean platelet volume (MPV) could be a biomarker of interest to predict mortality in human septic shock. Finally, we characterized the role of platelets in the pathophysiology of severe acute respiratory distress syndrome COVID-19 in intensive care

Accounting for water use by wildlife–conceptual and practical issues and a case study from Botswana

Use of water by wildlife is not explicitly considered in any part of the System of Environmental-Economic Accounting (SEEA). However, wildlife uses water and in some cases this may be in conflict with other water uses (e.g. irrigation). To examine the magnitude of this problem and the conceptual and practical challenges of including wildlife water use in the SEEA, estimates of water use for 31 mammals in Botswana were developed using readily available data on their abundance and coefficients of water use. Three recording options were considered for the physical supply and use tables: (1) water use by wildlife shown in a new column entitled “Wildlife”; (2) shown as a use by industry under “Operation of nature reserves” and; (3) the preferred option, shown as a split between the first two options, reflecting the location of wildlife inside or outside national parks. The key conceptual issue for recording is the delineation of the production boundary, determined in this case by the extent to which wildlife is deemed managed and hence akin to a cultivated resource in the SEEA. Despite some data limitations, wildlife water use in Botswana was significant, with 21 species accounting for 19,345 ML in 2012–13, equivalent to 10% of the previously estimated water consumption in that year. Water account producers now have clear options for including wildlife, providing water planners and wildlife managers with improved information to help balance competing demands for water that may occur at particular times and places

Hydrothermal liquefaction for energy recovery from high-moisture waste biomass

Hydrothermal liquefaction is promising technology for converting high-moisture waste biomass into energy dense “biocrude” oil that can be used for direct combustion or refined for transportation grade fuels. This study investigates the influence of biomass composition on the chemical characteristics of hydrothermal liquefaction biocrude oil, and the potential of algal biomass as a feedstock for combined wastewater treatment and bioenergy production. Hydrothermal liquefaction was examined for converting various types of waste biomass into biocrude oil to determine the effect of biomass composition on product yields and biocrude oil chemical characteristics. Feedstocks tested included Spirulina algae, swine manure, and digested anaerobic sludge. Bulk biocrude oil properties (e.g., oil yield, elemental analysis, higher heating value) and physico-chemical characteristics (e.g., molecular constituents, functional group allocation, proton and carbon speciation, molecular weight distribution, boiling point distribution) were compared for the varying feedstocks as well as with published results for petroleum crudes and tar sand bitumens. Results demonstrated that although the biocrude oils displayed similar higher heating values (32-35 MJ/kg), widely varying biocrude oil yields were observed, ranging from 9.4% with digested sludge to 33% with Spirulina. High total nitrogen and oxygen content was observed in the biocrude oils (19-23%), greatly differentiating them from petroleum crude oils which are typically less than 4% total. Detailed characterization also revealed significant differences in biocrude oil chemistry. Feedstock composition influenced the individual compounds identified in the low-boiling fraction of the biocrude oil as well as the functional group chemistry. Biocrude oil molecular weights tracked with the feedstock obdurate carbohydrate content and followed the order of Spirulina < swine manure < digested sludge. A similar trend was observed in the biocrude oil boiling point distributions and the long branched aliphatic contents. After examining the hydrothermal liquefaction of various waste biomass sources, a detailed analysis of the hydrothermal liquefaction of Spirulina and Scenedesmus algal biomass was undertaken. Algal biomass was analyzed due to its potential integration into wastewater treatment plant operations for nutrient removal, carbon dioxide capture, and bioenergy production. Recently, much work has focused on extracting high value chemicals (e.g., nutraceuticals) and energy-dense lipids (e.g., for biodiesel) from algae, but effective utilization of residual “defatted” algal biomass will be necessary to achieve favorable energy balances and production costs. Therefore, hydrothermal liquefaction product yields, biocrude oil properties, and energy balance for raw and defatted Scenedesmus biomass were compared against slow pyrolysis, an alternative thermochemical process. Biocrude oil chemistries from both processes were then evaluated against Illinois shale oil as a representative low-quality petroleum crude oil. While both thermochemical conversion routes produced energy dense biocrude oil (35-37 MJ/kg), biocrude oil yields and physico-chemical characteristics were highly influenced by the conversion route and algal biomass composition. Biocrude oils derived from hydrothermal liquefaction and slow pyrolysis of Spirulina and raw and defatted Scenedesmus displayed similar elemental compositions and chemical functionalities; however, pyrolysis biocrude oils were lower in molecular weight and boiling point distribution compared to hydrothermal liquefaction biocrude oils. The high lignin and cellulose content of raw and defatted Scenedesmus biomass also significantly affected the hydrothermal liquefaction biocrude oils properties, and increased the molecular weight and boiling point distribution compared to hydrothermal liquefaction biocrude oil derived from Spirulina. Analysis of the energy consumption ratio revealed that for wet algal biomass (e.g., 80% moisture content), hydrothermal liquefaction is more energetically favorable compared to slow pyrolysis due to water volatilization required in the latter technique. The high heteroatom content of the biocrude oils greatly differentiated them from Illinois shale oil, and imparts negative properties such as poor storage stability, high viscosity, increased boiling point range, and undesirable emissions during combustion. In summary, this study demonstrated that hydrothermal liquefaction is effective for recovering energy from high-moisture waste biomass in the form of energy-dense biocrude oil. Biomass composition was shown to greatly influence biocrude oil chemical properties, and algae hold potential for combined wastewater treatment and bioenergy production. However, the high heteroatom content of biocrude oil is problematic and will likely require removal prior to downstream applications. Further efforts are needed to examine the upgradation of biocrude oils and examine the integration of hydrothermal processing with algal cultivation and wastewater treatment

Reactive transport of chemicals in compacted bentonite under non-isothermal water infiltration

This paper presents an investigation of coupled thermal, hydraulic, and chemical behavior of a compacted bentonite buffer under the heating and hydration conditions of geological disposal of high-level nuclear waste. The study presented provides further insight into the evolution of hydro-geochemistry of the compacted bentonite and the clay microstructure effects through a numerical modelling development of the reactive transport of multicomponent chemicals. The application/validation case study is based on a series of laboratory tests on heating and hydration of compacted bentonite for a period of 0.5-7.6 years reported in the literature. The effects of microstructure evolution during hydration and dehydration on the transport phenomena are included via a new approach that links the geochemistry of clay hydration/dehydration with the transport properties. The analysis results related to the moisture flow and chloride transport demonstrate close correlation with the experimental results by the inclusion of the effects of microstructure evolution in the transport phenomena. The results of numerical analysis of reactive transport of chemicals highlight the importance of accessory minerals present in bentonite on the distribution of some anionic species. The behavior of major cationic species is shown to be mainly governed by the transport processes. Further insights into the chemically driven processes in clay buffer due to coupled hydraulic and thermal effects are presented and discussed that are captured from the results of modeling the clay-water-chemical system.Green Open Access added to TU Delft Institutional Repository ‘You share, we take care!’ – Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.Geo-engineerin

Three-dimensional behaviour of a prototype radioactive waste repository in fractured granitic rock

An investigation of the three-dimensional coupled thermohydromechanical behaviour of a prototype repository in fractured granitic rock is presented. The pre-placement behaviour of the repository is first considered, making use of a full three-dimensional simulation of the problem. An effective continuum approach, augmented with discrete features with a high hydraulic conductivity, is employed. The method adopted is found to be able to simulate accurately the highly anisotropic flow regime observed at the pre-placement phase. The major features of the full repository experiment under applied heating conditions were then successfully simulated. The range of buffer hydration rates, the thermal response of the repository, and the associated mechanical response were successfully simulated. Approaches to capture both the transient microstructural behaviour of the compacted bentonite (MX-80 type) and a MX-80 pellet material are incorporated. The repository behaviour was shown to be strongly influenced by complex coupled processes, including interactions between the system components. The adoption of a three-dimensional modelling approach proved to be essential to realistically simulate the behaviour of a repository incorporating anisotropic flow behaviour. Finally, potential impacts of the processes considered on performance of the barrier system and in safety assessment are considered

Integrated catalysis for upgrading microbial derived carboxylic acids to renewable fuels and value-added chemicals

In order to transition to a renewable carbon society, economically and environmentally sustainable technologies are needed to displace our dependence on petroleum. Carboxylic acids are a diverse class of biological metabolites that can be converted to renewable fuels and chemicals to offset our consumption of petroleum. However, significant challenges occur when integrating catalysis with biological processes, which include: (1) biological conversion produces carboxylic acids at relatively dilute levels (<20 wt%) in broth that can contain residual impurities, creating separation and downstream process challenges, (2) microbial acids can contain unique chemical moieties (e.g., polyunsaturated bonds, hydroxyl groups, ester linkages) compared to aliphatic petroleum, requiring tailored catalytic upgrading strategies to produce fuels and chemicals, and (3) carboxylic acid valorization can occur through a multitude of unit process schemes, necessitating early-stage techno-economic analysis to identify key bottlenecks for further development. To address these challenges, this thesis investigates integrated catalysis for upgrading microbial derived acids to renewable fuels and value-added chemicals. To target both renewable fuels and value-added chemicals from microbial acids, the following research objectives were pursued: (1) hydrothermal catalysis was investigated for deoxygenating monocarboxylic acids to diesel-grade hydrocarbons with in situ hydrogen production from renewable organic donors, (2) separation and catalysis was examined for recovering and cis,cis-muconic acid from culture broth and converting it to adipic acid, the latter compound being a high-value polymer precursor for nylon-6,6 production, and (3) key economic drivers and technical targets were identified for the downstream processing of muconic acid to adipic acid using preliminary techno-economic analysis. Initially, hydrothermal catalysis was investigated for converting long chain saturated and unsaturated carboxylic acids to hydrocarbon fuels using a Pt-Re catalyst supported on activated carbon (AC). The addition of Re as a secondary metal was shown to enhance the rate of carboxylic acid deoxygenation and modify the chemisorption behavior of Pt, suggesting alloy formation. Decarboxylation/decarbonylation of the carboxylate group was observed as the primary reaction pathway, and characterization of the Pt-Re/AC catalyst by x-ray photoelectron spectroscopy determined that hydrogen in the headspace resulted in a reduced oxidation state of the metals after exposure to hydrothermal conditions. Lastly, the addition of glycerol as an in situ hydrogen donor proved effective at meeting process hydrogen demands through aqueous phase reforming reactions. The application of the Pt-Re/AC catalyst system was then evaluated using a complex monocarboxylic acid feedstock derived biologically from lignin. The microorganism Pseudomonas putida KT2440 was initially used to biologically “funnel” lignin derived monomers to intracellular medium chain length polyhydroxyalkanoates (mcl-PHAs). Shake flask studies demonstrated that P. putida produces mcl-PHAs from both mixed model compounds and complex lignin derived monomers derived from corn stover. Extraction and characterization of lignin derived mcl-PHAs showed similar physicochemical properties compared to mcl-PHAs produced from clean glucose, and thermal depolymerization readily converted mcl-PHAs to alkenoic acid monomers. Subsequent catalytic processing of alkenoic acids in hydrothermal media with Pt-Re/AC produced linear hydrocarbons, similar to the model compound fatty acid study, demonstrating the integrated biological and catalytic conversion of lignin to hydrocarbon fuel. In order to target value-added chemicals from microbial acids, the downstream separation and catalytic upgrading of cis,cis-muconic was evaluated for the production of adipic acid, the latter molecule being a high-value polymer precursor for nylon-6,6 production. Expanding on previous work, a metabolically engineered strain of P. putida KT2440 was used to produce muconic acid extracellularly from both model and lignin derived monomers. Following fed-batch biological conversion of p-coumaric acid, activated carbon purification was shown to effectively remove broth non-target upstream metabolites, color compounds, and unconverted substrate. Muconic acid was then recovered from culture broth by pH/temperature shift crystallization in high purity (>97%) and yield. Catalyst batch screening studies of commercial Pd, Pt, Ru identified Pd as a highly active metal for muconic acid hydrogenation, although leaching was observed. As a follow-up, the downstream separation and catalysis of muconic acid was further examined to improve the separation purity, evaluate catalyst stability, and demonstrate bio-adipic acid polymerization to nylon-6,6. Following crystallization, dissolution of muconic acid crystals in ethanol with membrane filtration removed insoluble inorganic salts, producing muconic acid at 99.8% purity. In house catalysts were synthesized on both carbon and silica supports and tested in batch hydrogenation screening reactions. Pd and Rh were identified as highly active on both carbon and silica supports when compared to Ru and Pt, although Pd leached significantly, with a greater extent on silica. To further evaluate the stability of Rh/AC, continuous trickle bed hydrogenation demonstrated steady state partial conversion for 48 h, followed by complete conversion until 96 h, with a return to partial steady state conversion for 120 h of time on stream. Characterization of the post reaction Rh/AC catalyst showed a modest increase in support surface area and pore volume, moderate loss in active metal surface area, and minor increase in metal crystallite size. Bio-adipic acid derived catalytically from muconic acid was then polymerized to nylon-6,6, and characterization of the polymer confirmed properties comparable to nylon produced from adipic acid of petrochemical origin. Lastly, preliminary techno-economic analysis was conducted to evaluate key economic drivers and technical targets for the downstream processing of muconic acid to adipic acid. An nth-generation downstream plant was modeled to produce 75 million kg of adipic acid per year. For the base-case process model, the following technical parameters were employed: cell free culture broth containing 50 g/L muconate and 2 g/L of non-target aromatic compounds was purified continuously with activated carbon. Muconic acid was then recovered by pH/temperature shift crystallization, dissolved in ethanol, and filtered to provide a condensed phase for catalytic processing. Muconic acid in ethanol was catalytically converted to adipic acid over a packed bed reactor containing 2%Rh/AC, and a second train of evaporative crystallization with rotary filtration and drying recovered adipic acid as the final product. The largest capital costs for the base case model were activated carbon regeneration kilns and the packed bed hydrogenation reactor. Variable operating costs were comparable throughout, excluding the cost of incoming muconate broth which was the largest variable expense by far. Economic analysis of the base case model determined a minimum selling price of bio-based adipic acid of \$1.90/kg, within the 5-year historical range (\$1.75-2.50/kg) for petroleum derived adipic acid. Lastly, single point sensitivity analysis determined that the broth ratio of muconate to non-target aromatic compounds was a major non-linear cost driver, as well as the required reactor throughput for the 2%Rh/AC catalyst. Overall, this thesis demonstrated that integrated catalysis can convert both model and complex microbial acids derived from lignocellulosic feedstocks to renewable fuels and value-added chemicals. Upstream biological funneling is uniquely suited to address the heterogeneity of complex biomass monomer streams, while tailored separation schemes have potential to produce carboxylate feedstocks of suitable purity for value-added chemical production. The unique functional moieties of microbial acids will require tuned reaction conditions and catalytic formulations depending when targeting renewable fuels and chemicals, while the challenges of substrate acidity, residual impurities, and potentially harsh reactions conditions will require robust catalyst development

Phenomena exposure from the large scale gas injection test (Lasgit) dataset using a bespoke data analysis toolkit

The Large Scale Gas Injection Test (Lasgit) is a field-scale experiment designed to study the impact of gas buildup and subsequent migration through an engineered barrier system. Lasgit has a substantial experimental dataset containing in excess of 21 million datum points. The dataset is anticipated to contain a wealth of information, ranging from long-term trends and system behaviours to small-scale or ‘second-order’ features. In order to interrogate the Lasgit dataset, a bespoke computational toolkit, designed to expose difficult to observe phenomena, has been developed and applied to the dataset. The preliminary application of the toolkit, presented here, has resulted in a large number of phenomena being indicated/quantified, including highlighting of second-order events (small gas flows, perturbations in stress/pore-water sensors, etc.) and quantification of temperature record frequency content. Localized system behaviour has been shown to occur along with systematic aberrant behaviours that remain unexplained

Development of in/outflow boundary conditions for MPM simulation of uniform and non-uniform open channel flows

This paper describes the development and application of inflow and outflow boundary conditions (BCs) for the material point method (MPM) in order to simulate fluid flow problems. This corresponds to velocity and pressure controlled BCs. Due to the coupled Lagrangian and Eulerian description of the fluid motion in MPM it is necessary to add and remove material points, with appropriate kinematic properties, to and from the computational domain. The newly-developed BCs have been used to simulate uniform open channel flow and the phenomenon of free overfall in open channels, which is transient conditions leading to non-uniform flow due to a sudden bed level drop. It is shown that the numerical results predict well the flow geometry including end depth ratio, pressure distribution and accelerations, therefore the velocities and displacements.Fundamental Research Funds for the Central Universities (2017B12214) of the Ministry of Education of China, NWO Project MPM-FLOW: Understanding flowslides in flood defences (Grant No. 13889

The Saliency of Gestural Misinformation in the Perception of a Violent Crime

This is the accepted manuscript version of the following article: Daniel J. gurney, Louise R. Ellis & Emily Vardn-Hynard, ‘The saliencey of gestural misinformation in the perception of a violent crime’, Psychology, Crime & Law, Vol. 22(7): 651-665, first published online 18 April 2016. The version of record is available online via doi: http://dx.doi.org/10.1080/1068316X.2016.1174860 Published by Taylor & Francis Online.Recent research has revealed that misinformation from gestures can influence eyewitness memory. However, while the effects of verbal influence have been shown to have major impacts on prosecution, gestural misinformation is yet to demonstrate misinformation effects to this extent. To investigate the salience of suggestions provided nonverbally, and how these compare to those made verbally, two experiments were conducted. In Experiment 1, participants watched footage of a crime scene and were presented with one of two types of gestures during questioning that suggested different interpretations of the crime. The results confirmed that the gestures influenced responses with participants altering their interpretation of the crime according to the information gestured to them. Experiment 2 built on this to investigate how comparable this gestural influence was to verbal influence. The results revealed that gestural misinformation caused participants to alter their interpretation of the crime and elicited the same effects as verbal misinformation. Additionally, participants were less likely to have felt misled from gestures as they were from speech. These results reveal new insights into the strength of gestural misinformation and show that, despite their subtle nature in communication, gestures can exert a powerful influence in eyewitness interviews.Peer reviewedFinal Accepted Versio

A three-dimensional numerical investigation of the thermo-hydro-mechanical behaviour of a large-scale prototype repository

This thesis describes the modelling of the thermo-hydro-mechanical behaviour of a large-scale experiment, carried out at SKB's underground research laboratory in Aspo, Sweden. The experiment, known as the Prototype Repository Project, was constructed in highly fractured granite rock and is scheduled to last 20 years. Results from the experiment are collected systematically by SKB from the initial rock characterisation to the highly instrumented installed material. The model applied is the thermo-hydro-mechanical model previously developed at the Geoenvironmental Research Centre (GRC). The GRC's current model was extended to successfully accommodate three-dimensional THM behaviour, including the development of a high-performance computing algorithm using both multi-threaded and message-passing programming paradigms to enable simulations to be completed in significantly reduced time. Model simulations have been conducted of both the pre-placement stage of the experiment and the post-placement operational phase. The results of the pre-placement phase have been used to aid the calibration of the simulation and provide confidence in the development of the operational phase simulation. In the pre-placement phase simulation, a pragmatic approach using a combination of an effective continuum model and a number of key discontinuities was employed. A domain of 100 x 100 x 160m was used, discretised into over 550,000 finite-elements. The simulations were able to reproduce three-dimensional highly anisotropic flow conditions shown in the experimental results. The post-placement operational stage was then simulated in three-dimensions using the same rock domain as for the pre-placement analyses, including the buffer material, and discretised into over 920,000 elements. A number of key features, including the anisotropic hydraulic behaviour, were captured. It was concluded that the geological conditions, backfill re-saturation and buffer re-saturation, including the micro-structural effects of the bentonite, are all important to the simulation of a high-level waste repository. Long term simulation results were also presented. A number of aspects were explored using two-dimensional analyses, including the macro/micro- structural interactions of the bentonite buffer. A time-dependant form of the hydraulic conductivity relationship was developed and yielded significantly improved results in long-term analyses. The behaviour of a fracture intersecting a deposition-hole was also investigated highlighting the importance of discrete fractures on hydration behaviour