The interactions between apoptotic cells and macrophages within the murine omentum and peritoneal cavity

Inflammation is the response of higher multicellular animals to injury and noxious pathogens and is followed by the remodeling of damaged tissues to their previous healthy state. Many specialized cells are recruited to orchestrate the inflammatory response but these cells must be removed to allow the restoration of normal tissue structure and function. Some recruited cells leave inflamed tissues by emigration to lymph nodes whilst others, having served their purpose, die by 'apoptosis' or programmed cell death. Apoptotic 'corpses' are removed by phagocytosis, a process by which cells or similar particles, are captured, engulfed and ingested by other cells. In higher animals, 'professional' phagocytes, such as Macrophages (Mφ), are primarily responsible for the removal of apoptotic cells from inflamed tissues.The removal of apoptotic cells prevents their inner contents from being released and inflicting secondary damage upon healthy cells. Furthermore, the act of phagocytosis of an apoptotic cell induces an anti-inflammatory, reparative phenotype in Mcp. It has now become clear that human diseases can arise from, or be exacerbated by defective clearance of apoptotic cells by Mcp. The processes by which Mcp remove apoptotic cells is clearly of importance in our understanding of inflammatory disease.I began this thesis by examining the rate at which Mcp phagocytosed apoptotic cells in vivo using the murine peritoneal cavity as a model system. I noted that the number of Mcp recovered from the peritoneal cavity fell dramatically as apoptotic cells were phagocytosed. This disappearance of Mcp was not merely a non-specific effect of manipulating the peritoneal cavity but was a consequence of the phagocytosis of apoptotic cells. The mechanism underlying this 'Macrophage Disappearance Reaction' (MDR) was investigated and two manipulations - the instillation of hyularonidase enzyme or unfractionated heparin - respectively increased or decreased the magnitude of the MDR without affecting the rate of apoptotic cell clearance.I then turned my attention to the fate of the disappearing Mcp, focusing on the omentum, an organ within the peritoneal membrane highly adapted for the initiation of acute inflammatory reactions and innate immunity. A series of adoptive transfer experiments showed that, after phagocytosing apoptotic cells, intraperitoneal Mcp migrated to specialized coelomicassociated lymphoid tissue (CALT) called 'Milky Spots' within the omentum. Further experiments showed that some Mcp subsequently left the peritoneal cavity and migrated to parathymic lymph nodes, a known destination for inflammatory peritoneal Mcp during the resolution of peritonitis. I then returned to the starting point of this thesis, ie the rate of phagocytosis of apoptotic cells in vivo, and developed a powerful new in vivo phagocytosis assay using omental milky spots as the experimental model.This thesis has contributed to a wider and deeper understanding of the clearance of apoptotic cells by Mcp and the fate of phagocytic peritoneal Mcp. The hitherto unrecognized role of the omentum in the clearance of peritoneal apoptotic cells and Mcp emigration should increase the level of general scientific interest in the omentum which I believe to be a true organ of innate immunity.This thesis has contributed to a wider and deeper understanding of the clearance of apoptotic cells by Mφ and the fate of phagocytic peritoneal Mφ. The hitherto unrecognized role of the omentum in the clearance of peritoneal apoptotic cells and Mφ emigration should increase the level of general scientific interest in the omentum which I believe to be a true organ of innate immunity

Mesoscale modelling of the UK offshore wind resource

Knowledge of the wind conditions at a potential offshore wind farm site is key in reducing investment risk. This is normally done through the use of large meteorological masts. However, the increasing scale of the turbines offshore requires higher and more expensive masts, driving interest in the use of alternatives to extend accurate assessment of the resource. This work examines the use of the WRF mesoscale model for assessing the wind resource at UK offshore sites. A comparison is made with existing data at two offshore sites, Scroby Sands and Shell Flats. In addition, a projection is made of the wind conditions and variability at a potential UK Round 3 site

Condition monitoring of wind turbine blades using MEMS accelerometers

Wind turbine rotors in operation are subject to fatigue which is reflected as cracks and delamination in composite blades. Blade condition monitoring is becoming important to operators and insurers alike as the cost of damaged-blade repairs or replacement is very high and hence, the need for cheaper long-term solutions in the current strives for sustainable energy. In this paper, vibration/modal analysis non-destructive testing (NDT) method was used in conjunction with Signal Processing techniques to investigate the feasibility of integrating low-cost micro electro-mechanical systems (MEMS) accelerometers for blade condition monitoring as an alternative to the conventional piezoelectric accelerometers which are bulky and expensive. A rig-mounted 4.5m long blade from a 25kW Carter wind turbine was retrofitted with five MEMS accelerometers of type ADXL335 and vibration response measurements were recorded and analysed as the blade’s angle of orientation was changed by 10° from 0° to 180°. Results showed that the MEMS accelerometers are capable of measuring the blade response at each set angle of orientation. This shows potential for MEMS accelerometer integration for condition monitoring as in reality, wind turbine blades will continuously be in rotation in order to generate energy. Thus these accelerometers can perform as normal when there is a change in the blade’s orientation. In conclusion, MEMS accelerometers have a great potential to be integrated easily either retrofitted externally or embedded in blades at manufacture for condition monitoring at marginal cost

Feasibility of a fully autonomous wireless monitoring system for a wind turbine blade

Condition monitoring (CM) of wind turbine blades has significant benefits for wind farm operators and insurers alike. Blades present a particular challenge in terms of operations and maintenance: the wide range of materials used in their construction makes it difficult to predict lifetimes; loading is stochastic and highly variable; and access can be problematic due to the remote locations where turbines are frequently located, particularly for offshore installations. Whilst previous works have indicated that Micro Electromechanical Systems (MEMS) accelerometers are viable devices for measuring the vibrations from which diagnostic information can be derived, thus far there has been no analysis of how such a system would be powered. This paper considers the power requirement of a self-powered blade-tip autonomous system and how those requirements can be met. The radio link budget is derived for the system and the average power requirement assessed. Following this, energy harvesting methods such as photovoltaics, vibration, thermal and radio frequency (RF) are explored. Energy storage techniques and energy regulation for the autonomous system are assessed along with their relative merits. It is concluded that vibration (piezoelectric) energy harvesting combined with lithium-ion batteries are suitable selections for such a system

A study on the inclusion of forest canopy morphology data in numerical simulations for the purpose of wind resource assessment

A series of numerical simulations of the flow over a forest stand have been conducted using two different turbulence closure models along with various levels of canopy morphology data. Simulations have been validated against Stereoscopic Particle Image Velocimetry measurements from a wind tunnel study using one hundred architectural model trees, the porosities of which have been assessed using a photographic technique. It has been found that an accurate assessment of the porosity of the canopy, and specifically the variability with height, improves simulation quality regardless of the turbulence closure model used or the level of canopy geometry included. The observed flow field and recovery of the wake is in line with characteristic canopy flows published in the literature and it was found that the shear stress transport turbulence model was best able to capture this detail numerically

Revenue-sharing clubs provide economic insurance and incentives for sustainability in common-pool resource systems

Harvesting behaviors of natural resource users, such as farmers, fishermen and aquaculturists, are shaped by season-to-season and day-to-day variability, or in other words risk. Here, we explore how risk mitigation strategies can lead to sustainable use and improved management of common-pool natural resources. Over-exploitation of unmanaged natural resources, which lowers their long-term productivity, is a central challenge facing societies. While effective top-down management is a possible solution, it is not available if the resource is outside the jurisdictional bounds of any management entity, or if existing institutions cannot effectively impose sustainable-use rules. Under these conditions, alternative approaches to natural resource governance are required. Here, we study revenue-sharing clubs as a mechanism by which resource users can mitigate their income volatility and importantly, as a co-benefit, are also incentivized to reduce their effort, leading to reduced over-exploitation and improved resource governance. We use game theoretic analyses and agent-based modeling to determine the conditions in which revenue-sharing can be beneficial for resource management as well as resource users. We find that revenue-sharing agreements can emerge and lead to improvements in resource management when there is large variability in production/revenue and when this variability is uncorrelated across members of the revenue-sharing club. Further, we show that if members of the revenue-sharing collective can sell their product at a price premium, then the range of ecological and economic conditions under which revenue-sharing can be a tool for management greatly expands. These results have implications for the design of bottom-up management, where resource users themselves are incentivized to operate in ecologically sustainable and economically advantageous ways. (C) 2018 Elsevier Ltd. All rights reserved

Positive Imagery-Based Cognitive Bias Modification as a Web-Based Treatment Tool for Depressed Adults: A Randomized Controlled Trial.

Depression is a global health problem requiring treatment innovation. Targeting neglected cognitive aspects may provide a useful route. We tested a cognitive-training paradigm using positive mental imagery (imagery cognitive bias modification, imagery CBM), developed via experimental psychopathology studies, in a randomized controlled trial. Training was delivered via the Internet to 150 individuals with current major depression. Unexpectedly, there was no significant advantage for imagery CBM compared with a closely matched control for depression symptoms as a whole in the full sample. In exploratory analyses, compared with the control, imagery CBM significantly improved anhedonia over the intervention and improved depression symptoms as a whole for those participants with fewer than five episodes of depression and those who engaged to a threshold level of imagery. Results suggest avenues for improving imagery CBM to inform low-intensity treatment tools for depression. Anhedonia may be a useful treatment target for future work

Reduced density and altered regulation of rat atrial L-type Ca²⁺ current in heart failure

Constitutive regulation by PKA has recently been shown to contribute to L-type Ca2+current ( ICaL) at the ventricular t-tubule in heart failure. Conversely, reduction in constitutive regulation by PKA has been proposed to underlie the downregulation of atrial ICaLin heart failure. The hypothesis that downregulation of atrial ICaLin heart failure involves reduced channel phosphorylation was examined. Anesthetized adult male Wistar rats underwent surgical coronary artery ligation (CAL, N=10) or equivalent sham-operation (Sham, N=12). Left atrial myocytes were isolated ~18 wk postsurgery and whole cell currents recorded (holding potential=-80 mV). ICaLactivated by depolarizing pulses to voltages from -40 to +50 mV were normalized to cell capacitance and current density-voltage relations plotted. CAL cell capacitances were ~1.67-fold greater than Sham ( P ≤ 0.0001). Maximal ICaLconductance ( Gmax) was downregulated more than 2-fold in CAL vs. Sham myocytes ( P &lt; 0.0001). Norepinephrine (1 μmol/l) increased Gmax&gt;50% more effectively in CAL than in Sham so that differences in ICaLdensity were abolished. Differences between CAL and Sham Gmaxwere not abolished by calyculin A (100 nmol/l), suggesting that increased protein dephosphorylation did not account for ICaLdownregulation. Treatment with either H-89 (10 μmol/l) or AIP (5 μmol/l) had no effect on basal currents in Sham or CAL myocytes, indicating that, in contrast to ventricular myocytes, neither PKA nor CaMKII regulated basal ICaL. Expression of the L-type α1C-subunit, protein phosphatases 1 and 2A, and inhibitor-1 proteins was unchanged. In conclusion, reduction in PKA-dependent regulation did not contribute to downregulation of atrial ICaLin heart failure.NEW &amp; NOTEWORTHY Whole cell recording of L-type Ca2+currents in atrial myocytes from rat hearts subjected to coronary artery ligation compared with those from sham-operated controls reveals marked reduction in current density in heart failure without change in channel subunit expression and associated with altered phosphorylation independent of protein kinase A.</jats:p