The anomerisation of glycosyl thiols and synthesis of multivalent GlcNAc and GalNAc glycoclusters

There are several published procedures available for the synthesis of b-thiopyranoses such as gluco- or galacto-pyranoses. Given the ease with which one can access such b -thiopyranoses, the development of a reproducible anomerisation of these b-thiopyranoses to give the a-thiopyranoses would greatly facilitate the synthesis of various types of a-S-glycoconjugates. This was a major aim of this thesis work. To that end, a variety of thio-glycopyranoses were prepared and their anomerisation reactions investigated using Lewis acid promoters. The anomeristion of benzoylated thiopyranoses have been shown to be achievable in moderate to very good yields. Reactions were carried out for gluco-, galacto-, xylo-, arabino-, fuco- and rhamno-pyranose derivatives. In addition some disaccharide derivatives containing a thiol functional group were anomerised. Alkylation of these glycosyl thiols was also demonstrated during the course of the thesis work. These results are reported in chapter one. The second chapter of the thesis describes the synthesis of glycoclusters containing N-acetyl glucosamine (GlcNAc) for evaluation as bactericidal agents against Helicobacter pylori. This is a spiral shaped bacterium that lives in the stomach and duodenum and infects about half of the world\u27s population with some of these infected individuals developing peptic ulcers, gastric cancer and mucosa-associate lymphoma. This research was based on work showing that O-glycans expressing terminal 1,4-linked a-GlcNAc residues have antimicrobial activity against Helicobacter pylori. Previous work from the Murphy laboratory has identified two bivalent GlcNAc derivatives with activity against two different strains of Helicobacter pylori. Analogues of these bivalent structures were prepared. This included S-glycoside based analogues. The final chapter of this thesis work describes the synthesis of N-acetyl galactosamine containing glycoclusters. In this case bivalent, trivalent and tetravalent structures were prepared, which included a-thiopyranose derivatives. A tetravalent compound synthesised was shown to have very high potency for a macrophage galactose C-type lectin receptor when compared to GalNAc itself. The work on this topic has been published in Organic and Biomolecular Chemistry (Org. Biomol. Chem., 2015, 13, 4190-4203).2019-04-2

Nitrate-barbiburate compounds inhibit matrix metalloproteinase-9 in in-vitro and in-vivo models of intestinal inflammation

THESIS 10793Inflammatory bowel disease is characterised by a dysregulated immune response and a compromised epithelial barrier. The enzyme matrix metalloproteinase-9 (MMP-9) is upregulated in an inflammatory setting and is believed to contribute to the pathogenesis of the disease. Nitric oxide is a gaseous signalling molecule with an, as of yet, unknown regulatory effect on MMP-9. Organic nitrates have been used as NO donors or mimetics to take advantage of NO?s pharmacological effects, but never as part of a hybrid to inhibit an MMP. The aims of my project were to synthesise and test the ability of a series of nitrate- barbiturate compounds to inhibit MMP-9 in both in-vitro and in-vivo models of intestinal inflammation and to determine the contribution of the nitrate moiety in this inhibition

Solid state dual electrode electroanalysis under hydrodynamic conditions: Application to pH-controlled in-line sensing.

While electrochemically driven, pH control-enabled, dual electrode sensing under quiescent conditions is emerging as a viable electroanalytical method, application of this approach under hydrodynamic conditions is less well documented. In this work we report the development of a finite element model (COMSOL Multiphysics™) to simulate electrochemical pH control under both quiescent and hydrodynamic conditions. We used these simulations to elucidate the effect of flowrate on our pH control method. Adjustments to the applied currents were made so as to compensate for the removal of generated protons by hydrodynamic flow, thereby allowing effective pH control under different flow conditions. Once optimised, this approach was applied to the detection of hypochlorous acid under various flow rates. To this end, the sensitivity of the sensors benefitted from both the localized electrochemical pH control and the signal-boosting effect associated with hydrodynamic forces

Glycoclusters as lectin inhibitors: comparative analysis on two plant agglutinins with different folding as a step towards rules for selectivity

The emerging physiological significance of carbohydrate (glycan) protein (lectin) recognition engenders the interest to design synthetic inhibitors with a high level of selectivity among natural sugar receptors. Plant agglutinins are common models to determine structure activity relationships. Focussing on the contribution of valency towards selectivity, copper-catalysed azide (sugar derivative)-alkyne (scaffold) cycloaddition yielded a panel of 10 bi- to tetravalent glycoclusters with N-acetylglucosamine as the bioactive headgroup. They were introduced into assays using (neo)glycoproteins and cell surfaces as platforms to study carbohydrate-dependent lectin binding. The ability of the bivalent compounds, which exhibit a distance profile of the sugar headgroups of about 16-21 angstrom, for intramolecular bridging of two contact sites from the eight hevein domains of wheat germ agglutinin led to comparatively high enhancements of inhibitory potency relative to a tetrameric leguminous lectin (distance profile of 50-70 angstrom between sugar-specific sites), especially for a beta-S-glycoside. The extent of inhibition at fixed concentrations of the sugar depended on the type of matrix used for the assay. Increases to tri- and tetravalency played a less important role than the anomeric position to keep cross-reactivity low, these tested topologies enabling cross-linking for both lectins. The potential for cis-interactions (intramolecular interactions), with glycoclusters serving as molecular rulers, is suggested to help designing selective blocking reagents. (C) 2015 Elsevier Ltd. All rights reserved.2017-09-2

New challenges call for new skills: providing quality education for sustainable destination managers with the WeNaTour project.

Major challenges have altered the status quo of tourism in Europe in the last years: COVID-19 pandemic, the climate crisis, geopolitical instability, the energy crisis, and widespread inflation. Concurrently, significant societal changes in work-life, movement, and recreational patterns are also affecting tourism dynamics and trends. The current tourism landscape is thus profoundly different than it was until 2019, and it is in strong need of finding new solutions and pathways to radically innovate while keeping local communities and the environment at the core of its strategies. Destination Management is the systematic management approach capable of guaranteeing a shared vision of long-lasting development for which integrating tourism international sustainability standards and approaches is essential. However, tourism lacks specific interdisciplinary and governance skills that generally refer to Sustainable Tourism Destination Management, while educational institutes lack curricula that foster the ability of students and professionals to lead the change towards sustainable tourism. Therefore, WeNaTour project, co-founded by the Erasmus+ Programme by the European Union, was developed with the aim to increase the capacity of educational institutes and businesses to integrate research results, innovative practices, and digitalisation into a first-class educational offer to foster sustainable tourism while supporting the creation of new products and services in emerging markets. It will do so by assessing innovation and market potential of novel niches; designing new services in two GSTC-certified Destinations; delivering high-quality multidisciplinary training embedding GSTC-certification; creating an international Alliance on Sustainable Tourism to replicate and exploit results and lead to tourism transformation and long-lasting impacts

The redshift evolution of extragalactic magnetic fields

Faraday rotation studies of distant radio sources can constrain the evolution and the origin of cosmic magnetism. We use data from the LOFAR Two-Metre Sky Survey: Data Release 2 (LoTSS DR2) to study the dependence of the Faraday rotation measure (RM) on redshift. By focusing on radio sources that are close in terms of their projection on the sky, but physically unrelated (\u27random pairs\u27), we measure the RM difference, ΔRM, between the two sources. Thus, we isolate the extragalactic contribution to ΔRM from other contributions. We present a statistical analysis of the resulting sample of random pairs and find a median absolute RM difference |ΔRM| =(1.79 \ub1 0.09) rm rad, m-2, with |ΔRM| uncorrelated both with respect to the redshift difference of the pair and the redshift of the nearer source, and a median excess of random pairs over physical pairs of (1.65 \ub1 0.10) rad , m-2. We seek to reproduce this result with Monte Carlo simulations assuming a non-vanishing seed cosmological magnetic field and a redshift evolution of the comoving magnetic field strength that varies as (1 + z)-γ. We find the best-fitting results B0 Bcomoving(z = 0) (2.0 \ub1 0.2) nG and γ 4.5 \ub1 0.2 that we conservatively quote as upper limits due to an unmodelled but non-vanishing contribution of local environments to the RM difference. A comparison with cosmological simulations shows our results to be incompatible with primordial magnetogenesis scenarios with uniform seed fields of order nG