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Abstract: Human skin is dramatically exposed to toxic pollutants such as ozone. To counteract the skin disorders induced by the air pollution, natural antioxidants such as mangiferin could be employed. A formulative study for the development of vesicular systems for mangiferin based on phosphatidylcholine and the block copolymer pluronic is described. Plurethosomes were designed for mangiferin transdermal administration and compared to ethosome and transethosome. Particularly, the effect of vesicle composition was investigated on size distribution, inner and outer morphology by photon correlation spectroscopy, small angle X-ray diffraction, and transmission electron microscopy. The potential of selected formulations as vehicles for mangiferin was studied, evaluating encapsulation efficiency and in vitro diffusion parameters by Franz cells. The mangiferin antioxidant capacity was verified by the 2,2-diphenyl-1-picrylhydrazyl assay. Vesicle size spanned between 200 and 550 nm, being influenced by phosphatidylcholine concentration and by the presence of polysorbate or pluronic. The vesicle supramolecular structure was multilamellar in the case of ethosome or plurethosome and unilamellar in the case of transethosome. A linear diffusion of mangiferin in the case of ethosome and transethosomes and a biphasic profile in the case of plurethosomes indicated the capability of multilamellar vesicles to retain the drug more efficaciously than the unilamellar ones. The antioxidant and anti-inflammatory potential effect of mangiferin against pollutants was evaluated on 3D human skin models exposed to O3. The protective effect exerted by plurethosomes and transethosomes suggests their possible application to enhance the cutaneous antioxidant defense status.

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Abstract: The release of glucose from lignocellulosic waste for subsequent fermentation into biofuels holds promise for securing humankind's future energy needs. The discovery of a set of copper dependent enzymes known as lytic polysaccharide monooxygenases (LPMOs) has galvanized new research in this area. LPMOs act by oxidatively introducing chain breaks into cellulose and other polysaccharides, boosting the ability of cellulases to act on the substrate. Although several proteins have been implicated as electron sources in fungal LPMO biochemistry, no equivalent bacterial LPMO electron donors have been previously identified, although the proteins Cbp2D and E from Cellvibrio japonicus have been implicated as potential candidates. Here we analyze a small c-type cytochrome (CjX183) present in Cellvibrio japonicus Cbp2D, and show that it caninitiate bacterial CuII/I LPMO reduction and also activate LPMO-catalyzed cellulose-degradation. In the absence of cellulose, CjX183-driven reduction of the LPMO results in less H2O2 production from O2, and correspondingly less oxidative damage to the enzyme than when ascorbate is used as the reducing agent. Significantly, using CjX183 as the activator maintained similar cellulase boosting levels relative to the use of an equivalent amount of ascorbate. Our results therefore add further evidence to the impact that the choice of electron source can have on LPMO action. Furthermore, the study of Cbp2D and other similar proteins may yet reveal new insight into the redox processes governing polysaccharide degradation in bacteria.

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Abstract: Background: A significant portion of COVID-19 sufferers have asthma. The impacts of asthma on COVID-19 progression are still unclear but a modifying effect is plausible as respiratory viruses are acknowledged to be an important trigger for asthma exacerbations and a different, potentially type-2 biased, immune response might occur. In this study, we compared the blood circulating cytokine response to COVID-19 infection in patients with and without asthma. Methods: Plasma samples and clinical information were collected from 80 patients with mild (25), severe (36) or critical (19) COVID-19 and 29 healthy subjects at the John Radcliffe Hospital, Oxford, UK. The concentrations of 51 circulating proteins in the plasma samples were measured with Luminex and compared between groups. Results: Total 16 pre-existing asthma patients were found (3 in mild, 10 in severe, and 3 in critical COVID-19). The prevalence of asthma in COVID-19 severity groups did not suggest a clear correlation between asthma and COVID-19 severity. Within the same COVID-19 severity group, no differences were observed between patients with or without asthma on oxygen saturation, CRP, neutrophil counts, and length of hospital stay. The mortality in the COVID-19 patients with asthma (12.5%) was not higher than that in patients without asthma (17.2%). No significant difference was found between asthmatic and non-asthmatic in circulating cytokine response in different COVID-19 severity groups, including the cytokines strongly implicated in COVID-19 such as CXCL10, IL-6, CCL2, and IL-8. Conclusions: Pre-existing asthma was not associated with an enhanced cytokine response after COVID-19 infection, disease severity or mortality.

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Abstract: The electron-ion collider (EIC) will be built at the Brookhaven National Laboratory over the next ten years, with the purpose of giving insight into nucleon structure, origins of nucleon mass and spin, and quark and gluon confinement. This thesis pertains to the silicon vertex tracker for an EIC experiment; the detector closest to the interaction point. The purpose of a silicon vertex tracker is to locate the origin vertex position of charged particles and measure the particle momentum, and the EIC physics goals require detector resolutions beyond current state-of-the-art silicon vertex trackers. The aim of this thesis is to find a suitable silicon sensor technology for further developments by tests performed in a lab and at a testbeam, and to find a silicon vertex tracker geometry with performance matching the EIC physics requirements using simulations. The baseline sensor for the studies comes from the ALICE inner tracker upgrade, and is called the ALPIDE sensor. A new monolithic silicon sensor development designed to increase depletion is tested and compared to the performance of an ALPIDE-like sensor, and found to improve charge collection performance while keeping the sensor capacitance low. This aids tracking performance, and the new development is thus considered a possible path for development of an EIC-specific sensor. Simulations of different silicon vertex tracker geometries and parameters are performed using GEANT4, and a high-performing layout consisting of inner and outer silicon sensor layers surrounded by a gaseous detector and silicon disks is developed. It is also found that if a more compact tracker is desired, an all-silicon concept outperforms a combination of silicon and gaseous detectors. Further simulations of the best-performing layouts with current projections of possible silicon sensor material thickness and pixel size show that they meet the requirements of the EIC physics goals in terms of momentum resolution if a 3 T solenoidal magnetic field is used, and pointing resolution regardless of magnetic field strength. The silicon vertex tracker developed in this work is one of two baseline tracker concepts used in the ongoing development of an EIC reference detector. The performance of different detector concepts is also studied using realistic electron-proton collision events generated using PYTHIA and propagated through the detector simulation, with a focus on charmed meson reconstruction. It is found that a compact all-silicon tracker can perform as well as an all-silicon concept with a larger radius in these studies, but a large-radius combination of silicon and gaseous detectors is always better than all-silicon concepts in the studied open charm case.

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Abstract: The work reported in this thesis involves the design and fabrication of millifluidic devices suitable for the investigation of viscoelastic materials by small-angle X-ray scattering (SAXS). It was found that existing designs of micro- or millifluidic devices presented in literature were unsuitable for the study of viscous materials due to the larger pressures exerted on the walls of devices by the fluid. Leakage was observed in prototypes similar to those observed in the literature, specifically at the inlet and window areas. A range of design criteria necessary for the fabrication of successful millifluidic devices for viscoelastic materials were developed. The features of such a device, created as a result of the prototypes trialled, included the use of Luer lock inlets, enclosed channels and a threaded sealed window port providing access to the sample using scattering and visualisation techniques. Stereolithography (SLA) three-dimensional (3D) printing was utilised to provide an inexpensive, rapid and straight-forward fabrication method, using a commercially available printer. Devices could be produced with very few fabrication and assembly steps providing good print resolution and leading to a smooth internal surface non-interfering with flow. This fabrication method was found to be a viable alternative to the traditional, time-consuming and expensive, soft lithography techniques often used for microfluidic manufacture. The design criteria formulated in this work could be employed to fabricate a range of millifluidic geometries, with straight channel and cross slot geometries demonstrated in this thesis as the most representative examples for shear and extensional flow, respectively. The devices produced could be combined with a variety of techniques, in particular optical microscopy and X-ray scattering were utilised extensively in this work. Both geometries were shown to possess a stable and reproducible laminar flow field for the materials tested at all Q values. This was confirmed by Reynolds number (Re) values estimated from finite element analysis (FEA) simulations as well as by experimental techniques such as particle tracing. Two types of polymeric materials forming anisotropic morphologies under flow conditions were utilised as model materials within the millifluidic devices; an aqueous solution of modified cellulose and water dispersions of worm-like micelles formed by self-assembled block copolymers. The straight channel millifluidic device shows flow behaviour analogous to a slit rheometer, with polarised optical microscopy (POM) and SAXS measurements indicating alignment of the worm-like micelles under flow. Despite the fact that the cellulosic materials demonstrated optical birefringence under flow, suggesting the formation of an orientated morphologies, this morphology was not detectable by SAXS possibly because of a small volume of oriented material. The cross-slot millifluidic device has strong extensional forces along the outlet plane as seen by POM and SAXS. Extensive mapping of the cross-slot region using a synchrotron SAXS beamline in a microfocus configuration identifies regions of orientation of the worm-like micelles where extensional flow is present, as well as remarkable stability in the flow field over time.