No description available.

A study has been made of the transport of noradrenaline into human red cells and resealed ghosts. In cells uptake appeared to obey the kinetics of simple diffusion, whilst in metabolically inert ghosts, uptake was identified as a low affinity high capacity saturable transport mechanism. Uptake was markedly temperature sensitive but not dependent upon cellular metabolism, consistent mth facilitated diffusion rather than active transport of noradrenaline. Non-competitive inhibition of uptake was achieved by a variety of structurally related compounds when present at either the inner or outer membrane surface. The ionic requirements for noradrenaline transport by red cells and ghosts have been examined. VJhen external sodium was replaced isosmotically by N-methyl-D-glucamine the apparent affinity for uptake by ghosts was modestly inhibited. Replacement of external sodium by potassium was ineffective, suggesting a requirement for both sodium and/or potassium. Specific sodium transport inhibitors were without effect and it was shown that the mechanism has no requirement for calcium or magnesium. Replacement of external chloride by either nitrate or methylsulphate stimulated red cell noradrenaline accumulation, but was ineffective in ghosts. It is suggested that anion substitution may act secondarily on transport by affecting binding and/or catecholamine metabolism. Noradrenaline uptake was inversely proportional to external hydrogen ion concentration, suggesting that lipophilic substrate is favoured for transport. It is concluded that noradrenaline transport does not occur via the "uptake 1" or "uptake 2" pathways characterised in other tissues. It has been shown that the slowly metabolised noradrenaline analogue, guanethidine, is accumulated by red cells. Guanethidine transport is saturable, sodium and chloride independent, and inhibition studies reveal separate routes of entry for this compound and noradrenaline. Noradrenaline has no effect upon red cell cation transport. Therefore, abnormalities reported in clinical disorders, such as essential hypertension, are not attributable to increased plasma noradrenaline concentration.

No description available.

No description available.

The fundamental structure of all biological membranes is the lipid bilayer. At- tributed to the multifaceted features of lipids and its dynamical interaction with other membrane-integrated molecules, the lipid bilayer is involved in a variety of physiological phenomena such as transmembrane transportation, cellular signalling transduction, energy storage, etc. Due to the nanoscale but high complexity of the lipid bilayer system, experimental investigation into many important processes at the molecular level is still challenging. Molecular dynamics (MD) simulation has been emerging as a powerful tool to study the lipid membrane at the nanoscale. Utilizing atomistic MD, we have quantitatively investigated the effect of lamellar and nonlamellar lipid composition changes on a series of important bilayer properties, and how membranes behave when exposed to a high-pressure environment. A series of membrane properties such as lateral pressure and dipole potential pro les are quanti ed. Results suggest the hypothesis that compositional changes, involving both lipid heads and tails, modulate crucial mechanical and electrical features of the lipid bilayer, so that a range of biological phenomena, such as the permeation through the membrane and conformational equilibria of membrane proteins, may be regulated. Furthermore, water also plays an essential role in the biomembrane system. To balance accuracy and efficiency in simulations, a coarse-grained ELBA water model was developed. Here, the ELBA water model is stress tested in terms of temperature- and pressure-related properties, as well as hydrating properties. Results show that the accuracy of the ELBA model is almost as good as conventional atomistic water models, while the computational efficiency is increased substantially.

The aim of the thesis project was to examine what form(s) of Amyloid beta (Aβ) (25-­‐35) peptide interact with phospholipids in vitro and the implications of this for the mechanism of Alzheimer’s Diseases (AD). The mechanism of AD is thought to involve protein folding and misfolding. An increasing amount of evidence has shown that protein misfolding plays an important role in the biological and pathological processes of AD. Although seen as the biomedical markers of those diseases, the roles of amyloid aggregates themselves are still not fully understood. Whether the aggregates, or the monomer, or some other intermediates of Aβ cause AD is still unknown. In order to investigate the membrane-­‐interaction of Aβ and its implications for AD, two forms of Aβ, namely levorotary and dextrorotary (L-­‐ and D-­‐) Aβ isomers were used. Evidence has shown that L-­‐ and D-­‐ peptide can each form aggregates in a humid environment. However, when mixed together, L-­‐ and D-­‐ peptides tend not to form any aggregates. Using the mixtures of L-­‐ and D-­‐ peptides at different proportions and as well as using L-­‐ and D-­‐ alone can help us to determine the toxic form of Aβ. Phospholipids have been used to mimic membrane bilayers. Biological membranes in vivo are a complicated system. They contain three types of lipids, namely phospholipids, glycolipids, and steroids. Different types of cells and different membranes have different proportions of those lipids. Studying the interaction between Aβ and membranes in vivo can be extremely difficult. Artificial membranes, which only contains one kind of lipids, on the other hand, are a useful tool for the study of molecular interactions. Phospholipids are the most abundant type of membrane lipid and thus that can be seen as representative of cell membranes. The interactions of Aβ and different kinds of phospholipids have been investigated in this project. This thesis discusses the secondary structure of Aβ in different environment, the interaction between Aβ and phospholipids at the air-­‐water surface, and the location of Aβ in membranes during the interaction. The study provides useful information of the mechanisms and the origin of AD. At the end of the thesis, a discussion chapter analyses the difficulties of studying Aβ and AD and the potentials and inadequacies of this research.

In the last few decades, an increasing number of physicists specialized in soft matter, including polymers, have turned their attention to biologically relevant materials. The properties of various molecules and fibres, such as DNA, RNA, proteins, and filaments of all sorts, are studied to better understand their behaviours and functions. Self-assembled biological membranes, or lipid bilayers, are also the focus of much attention as many life processes depend on these. Small lipid bilayers vesicles dubbed liposomes are also frequently used in the pharmaceutical and cosmetic industries. In this thesis, work is presented on both the elastic properties of polymers and the response of lipid bilayer vesicles to extrusion in narrow-channels. These two areas of research may seem disconnected but they both concern deformed soft materials. The thesis contains four articles: the first presenting a fundamental study of the entropic elasticity of circular chains; the second, a simple universal description of the effect of sequence on the elasticity of linear polymers such as DNA; the third, a model of the symmetric thermophoretic stretch of a nano-confined polymer; the fourth, a model that predicts the final sizes of vesicles obtained by pressure extrusion. These articles are preceded by an extensive introduction that covers all of the essential concepts and theories necessary to understand the work that has been done.

In the last few decades, an increasing number of physicists specialized in soft matter, including polymers, have turned their attention to biologically relevant materials. The properties of various molecules and fibres, such as DNA, RNA, proteins, and filaments of all sorts, are studied to better understand their behaviours and functions. Self-assembled biological membranes, or lipid bilayers, are also the focus of much attention as many life processes depend on these. Small lipid bilayers vesicles dubbed liposomes are also frequently used in the pharmaceutical and cosmetic industries. In this thesis, work is presented on both the elastic properties of polymers and the response of lipid bilayer vesicles to extrusion in narrow-channels. These two areas of research may seem disconnected but they both concern deformed soft materials. The thesis contains four articles: the first presenting a fundamental study of the entropic elasticity of circular chains; the second, a simple universal description of the effect of sequence on the elasticity of linear polymers such as DNA; the third, a model of the symmetric thermophoretic stretch of a nano-confined polymer; the fourth, a model that predicts the final sizes of vesicles obtained by pressure extrusion. These articles are preceded by an extensive introduction that covers all of the essential concepts and theories necessary to understand the work that has been done.

Membrane proteins which comprise approximately a third of all proteins are classified for their roles in specific cell signalling, catalysis of metabolic reactions and transport of ions and molecules. One specific membrane protein, called proteorhodopsin (PR) belongs to the family of microbial rhodopsins and functions as a light-driven proton pump. Its lysine residue (Lys231) on helix G forms a Schiff base (C=N) with retinal, its chromophore which photo-isomerizes from the all-trans to the 13-cis form. Photo-isomerization initiates a photocycle, with distinct intermediates (K, M, N, and O). This study tries to emphasize the importance of interactions occurring between the membrane bilayer and PR by examining the kinetics of its photocycle and structure of the retinal chromophore using time-resolved spectroscopy in the visible range and static Raman spectroscopy. Some of the parameters of the membrane that were found to be important include protein to lipid ratio, bilayer thickness, bilayer fluidity and surface charge. The main conclusion is that PR has a very fast photocycle in negatively charged membranes, but a slower photocycle in positively charged ones, as well as in more rigid, thicker membranes. These slower cycles can originate from 1) suppression of conformational changes by the rigid bilayer or dehydration; 2) lack of available protons due to surface charge and 3) impeded isomerization.

Vesicles are simple structures, but display complex, non-linear dynamics in fluid flow. I investigate the deformation of nanometer-sized vesicles, both fully-inflated and those with excess area, as they travel in tightly confined capillaries. By varying both channel size and flow strength, I simulate vesicles as they transition from steady-state to unstable shapes, and then rupture in strong flow fields. By employing a molecular dynamics model of the vesicle, fluid, and capillary system one is able to rupture the lipid bilayer of these vesicles. This is unique in that most other numerical methods for modelling vesicles are unable to show rupture. The rupture of fully-inflated vesicles is applicable to drug delivery in which the release of the encapsulated medicine needs to be controlled. The deformation and rupture of vesicles with excess area could be applicable to red blood cells which have similar rheological properties.