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Abstract: We report on the lyotropic phase behaviour of fully-hydrated mixtures of α-tocopherol (α-toc) with the unsaturated phospholipid dioleoyl phosphatidylcholine (DOPC), as studied by synchrotron small-angle x-ray diffraction. Increasing amounts of α-toc progressively swell the layer spacing of the fluid lamellar Lα phase of DOPC, and then induce a transition to an inverse hexagonal HII phase. Low-resolution electron density profiles show that this increase is largely due to an increased thickness of the bilayer, with little change in the water layer thickness. In the range 30 – 50 mol% α-toc, additional weak low-angle peaks were observed, whose characteristic ratios are in agreement with the presence of swollen inverse bicontinuous cubic phases of spacegroups Im3m / Pn3m. This research has applications both in the biological field and for industrial product development. We show that the effect of α-toc addition in DOPC membranes has some similarities to that of cholesterol by stabilizing inverse curvature structures, which play crucial roles in cell division, membrane trafficking and endocytosis. Concerning industrial applications, the stabilization of inverted hexagonal (HII) and swollen bicontinuous cubic phases offers the opportunity to develop new delivery systems.

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Abstract: Ultrasound standing waves (USW) produce a force capable of displacing micrometer-sized free-flowing particles in a fluid, wherein this phenomenon is also referred to as acoustophoresis. However, the effect of acoustophoresis on dynamically changing and growing crystal networks is unclear. An example of such a system are monoglyceride (MG)-based oleogels, which are free-flowing lipids (e.g., vegetable oils) structured with a lipid-crystal network. In this work, we use MG oleogels as an example system to investigate the acoustophoretic effect on the structuration of a growing crystal network. For this purpose, multifaceted characterization is conducted utilizing optical and coded excitation scanning acoustic microscopy as well as small-angle X-ray scattering, respectively. The optical microscopy results show that USW produces local density differences of the structuring crystalline material and induces the orientation of the MG platelets. X-ray diffraction measurements confirm these findings and show a 23% average increase in MG platelet correlation length, which can be linked to platelet thickness, as well as an increase in the MG nanoplatelet surface smoothness. These findings produce a foundation for better understanding the effect of acoustophoresis in dynamically developing lipid-based materials and illuminate the mechanical changes that arise because of USW treatment.

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Abstract: Adequate drug solubility in the gastrointestinal tract is essential for systemic therapy of orally administered medications. In order to measure the solubility of poorly soluble drugs in vitro, simulated intestinal fluid (SIF) is often used in place of human intestinal fluid (HIF). A suite of fasted state SIF, based on variability observed in a range of fasted state HIF samples was designed and used to study the relationship between the solubility of eight poorly soluble biopharmaceutics classification system class II drugs and the particle size of the colloidal structures formed by the drugs in the fluid. The drugs of interest included three acidic drugs (naproxen, indomethacin and phenytoin), three neutral drugs (felodipine, fenofibrate, griseofulvin) and two basic drugs (carvedilol and tadalafil). The overall aim of this research is to work towards a better understanding of the colloidal structures formed in SIF. Solubility was measured using high performance liquid chromatography and results indicated that the solubility was typically greater in the acidic drugs than in the neutrals or bases and that the solubility tended to increase with increasing media point (pH × [TAC]). Particle size was determined using both dynamic light scattering and nanoparticle tracking analysis. Dynamic light scattering data confirmed the polydispersity of size distribution within the samples analysed. Typically, as the concentration of amphiphiles (total amphiphile concentration ([TAC])) is increased, the particle size of the structures measured decreases. A comparison with the solubility data revealed that the general trend indicated that while solubility is to some extent affected by pH and [TAC] or (pH × [TAC]), the relationship between solubility and particle size is linked with [TAC]. Small angle X-ray scattering (SAXS) analysis was carried out at the Diamond Light Source national facility, using the laboratory SAXS (labSAXS) beamline on drug and drug free SIF samples and the data was processed at the University of Strathclyde. Unfortunately, there was no significant scattering measured in the sample fluids which is thought to be a result of samples that are too weakly scattering to be detected by a labSAXS instrument. The data obtained serves as excellent preliminary data for a future beamtime application using a synchrotron beamline. The final work explores a model, using simple mathematics, to estimate the number of drug molecules per colloid or mixed micelle structure in a series of SIF. The experimental data, collected in earlier chapters, was applied in both this calculation and a calculation to estimate the solubility enhancement provided in the SIF media. Analysis of the data and results indicates that there is a direct relationship between particle size of the colloidal structures and the number of estimated drug molecules per structure. As expected, as the particle size decreases, as does the estimated number of drug molecules per micelle. The larger structures can accommodate a greater number of drug molecules per micelle. Solubility enhancement was also calculated, with the acidic drugs, naproxen and indomethacin proving to be most solubility enhanced in the suite of simulated intestinal fluid.

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Abstract: Pseudomonas aeruginosa employs the Type VI secretion system (T6SS) to outcompete other bacteria in its environment. Among the effectors secreted by the T6SS of P. aeruginosa PAO1, Tse4 is known for its potent antibacterial activity. This study elucidates the molecular function of Tse4, which promotes cell depolarization in competing bacteria. Our results show that Tse4 spontaneously incorporates into lipid monolayers and forms multiionic channels in planar bilayers, with either ohmic conduction or diode-like rectifying currents and a preference for cations over anions. These observations allow us to propose a model of action whereby Tse4 channels couple cell depolarization with K+ efflux. These insights into Tse4’s pore-forming activity enhance our understanding of bacterial competition and exemplify a finely tuned antibacterial strategy, coupling its ability to cause membrane depolarization with potassium efflux that synergises with other T6SS effectors. These results highlight the sophistication of Pseudomonas aeruginosa’s competitive arsenal.

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Abstract: Chirality and non-covalent chemistry are essential features in the construction of complex molecular systems that constitute living organisms. The specific interactions between molecular components with defined geometric orientations enable nature’s dynamism, responsiveness, specificity, and selection. The precision with which nature controls its homochirality and functional structures inspired the design of synthetic supramolecular systems. These systems have aimed at understanding the origins of these properties and mimicking their complexity. Research in the last decades has led to many insights into synthetic and natural supramolecular polymerization processes and principles of amplification of asymmetry. However, the complexity observed in nature remains far from being understood. In particular, detailed studies of assembly mechanisms and amplification of asymmetry principles in water-compatible supramolecular systems are scarce due to the challenging contribution of hydrophobic effects leading to non-equilibrium states of supramolecular assemblies. Valuable contributions to this field have been made in recent years, including the introduction of in situ chemical modifications and dissipative non-equilibrium assembly states, leading to evolutionary features such as self-replication. This chapter introduces the concepts of supramolecular polymerization and shows the analogies between natural and synthetic systems. In particular, the influence of homochirality in natural macroscopic structures is emphasized, showing the importance of this property in water-compatible supramolecular systems. Therefore, key developments in research on the origin of homochirality and challenges for future research to understand this essential feature of life are outlined.