In this paper, the slipping friction is considered in the problem of a progressive wave of real fluids propagating over a permeable bottom. In the interface of soil and fluid, the ¡§no-slip¡¨ condition is relaxed and a sliding friction coefficient is introduced. Thus, the slipping effect and the permeability of bottom on the velocity near the seabed can be studied. The results indicate that the joint effect of slipping friction and permeability is crucial. The overshooting phenomena also can be explained by this joint effect.

Sickle cell anemia is a hematological disorder that is caused by a single point mutation in the beta-globin chain of hemoglobin. It results in several complications related to the small and large vessels in patients with the disease. Large vessel complications include cerebral infarcts, which are observed in children under ten years old. The mechanism behind this complication is not completely understood. It is the goal of this project to begin to understand the role sickle erythrocytes may play in causing endothelial dysfunction as a precursor to sickle related complications. The hypothesis of this work is that exposure of large vessel endothelium to sickle erythrocytes causes an increase in endothelial permeability through loosening of adherens junctions. In the first goal of this work, bovine aortic endothelial cells (BAECs) are grown on coverslips and exposed to sickle erythrocytes for 5 minutes and either immediately fixed or incubated in 30 minutes and then fixed. Immunofluorescent studies labeling VE cadherin show changes in VE cadherin dynamics, suggesting sickle erythrocytes may be involved in this observation. Next, BAECs were grown on transwell inserts and exposed to sickle erythrocytes for 5 minutes. The erythrocytes are washed off and the BAEC are incubated with 10,000 MW dextran conjugated to lucifer yellow or FITC-BSA or to determine BAEC permeability. When dextran is used as the test molecule, endothelial permeability did not show a significant change from baseline. However, when BSA is used as the test molecule, increases in endothelial permeability are observed. Explanations into the differences between the transport mechanisms of the two molecules are discussed. These experiments show changes in VE cadherin localization due to sickle erythrocyte exposure. This may cause increases in endothelial permeability and an experimental model and preliminary studies are performed. This study provides potential mechanisms to explain the changes in VE cadherin localization and provide suggestions for further studies to test the effect of sickle erythrocytes on endothelial permeability. This work provides a strong foundation for continuing studies on the effects of sickle erythrocytes on endothelial dysfunction within the confines of sickle related complications.

Most drugs undergo passive transport during absorption and distribution in the body. It is desirable to predict passive permeation of future drug candidates in order to increase the productivity of the drug discovery process. Unlike drug-receptor interactions, there is no receptor map for passive permeability because the process of transport across the lipid bilayer involves multiple mechanisms. This work intends to increase the understanding of permeation of drug-like molecules through lipid bilayers. Drug molecules in solution typically form various species due to ionization, complexation, etc. Therefore, species specific properties must be obtained to bridge the experiment and simulations. Due to the volume contrast between intra- and extravesicular compartments of liposomes, minor perturbations in ionic and binding equilibria become significant contributors to transport rates. Using tyramine as a model amine, quantitative numerical models were developed to determine intrinsic permeability coefficients. The microscopic ionization and binding constants needed for this were independently measured. The partition coefficient in 1,9-decadiene was measured for a series of compounds as a quantitative surrogate for the partitioning into the hydrocarbon region of the bilayer. These studies uncovered an apparent long-range interaction between the two polar substituents that caused deviations in the microscopic pKa values and partition coefficient of tyramine from the expected values. Additionally the partition coefficients in the preferred binding region of the bilayer were also measured by equilibrium uptake into liposomes. All-atom molecular dynamics simulations of lipid bilayers containing tyramine, 4- ethylphenol, or phenylethylamine provided free energies of transfer of these solutes from water to various locations on the transport path. The experimentally measured partition coefficients were consistent with the free energy profiles in showing the barrier in the hydrocarbon region and preferred binding region near the interface. The substituent contributions to these free energies were also quantitatively consistent between the experiments and simulations. Specific interactions between solutes and the bilayer suggest that amphiphiles are likely to show preferred binding in the head group region and that the most of hydrogen bonds involving solutes located inside the bilayer are with water molecules. Solute re-orientation inside the bilayer lowers the partitioning barrier by allowing favorable interactions.

Active and passive transport of substances between the microcirculation in the brain and the central nervous system is regulated by the Blood-Brain Barrier (BBB). This barrier allows for chronic and acute modulation of the CNS microenvironment, and protects the brain from potentially noxious compounds carried in the circulatory system. In-vitro modeling of the BBB has become the target of much research over the past decade, as there are many unanswered questions regarding modulations in the permeability of this barrier. Additionally, the development of a practical and inexpensive model of the BBB would facilitate a much more efficient drug development process. The goal of this project is to investigate the formation of the BBB through assessment of tight junction formation and endothelial cell monolayer permeability. Accomplishment of this goal will include completion of the two primary aims of this thesis, which are 1) development of an immunohistochemical staining protocol for the labeling of tight junctional proteins, and 2) characterization of permeability across a porous membrane co-cultured with bovine aortic endothelial cells (BAECs) and C6 glioma cells. Both of these aims were met, as a reliable IF protocol for tight junctional staining was developed, and permeability values across a permeable membrane seeded with BAECs and C6s were collected. The completion of these aims has helped to accomplish the goal of investigating the formation of tight junctions in an in-vitro model of the BBB. The IF protocol that has been developed, along with the collected permeability data will aid the development of a more dynamic in-vitro model of the BBB to aid in research surrounding acute modulation of the BBB, along with facilitating a timelier drug development process.

Natural soils in work-sites are sometimes detrimental to the construction of engineering projects. Problematic soils such as soft and expansive soils are a real source of concern to the long-term stability of structures if care is not taken. Expansive soils could generate immense distress due to their volume change in response to a slight change in their water content. On the other hand, soft soils are characterised by their low shear strength and poor workability. In earthwork, replacing these soils is sometimes economically and sustainably unjustifiable in particular if they can be stabilised to improve their behaviour. Several techniques have evolved to enable construction on problematic soils such as reinforcement using fibre and planar layers and piled reinforced embankments. Chemical treatment using, e.g. lime and/or cement is an alternative method to seize the volume change of swelling clays. The use of lime as a binding agent is becoming a popular method due to its abundant availability and cost-effectiveness. When mixed with swelling clays, lime enhances the mechanical properties, workability and reduces sensitivity to absorption and release of water. There is a consensus in the literature about the primary mechanisms, namely cation exchange, flocculation and pozzolanic reaction, which cause the changes in the soil characteristics after adding lime in the presence of water. The dispute is about whether these mechanisms occur in a sequential or synchronous manner. More precisely, the controversy concerns the formation of cementitious compounds in the pozzolanic reaction, whether it starts directly or after the cation exchange and flocculation are completed. The current study aims to monitor the signs of the formation of such compounds using a geotechnical approach. In this context, the effect of delayed compaction, lime content, mineralogy composition, curing time and environmental temperature on the properties of lime-treated clays were investigated. The compaction, swelling and permeability, and unconfind compression strength tests were chosen to evaluate such effect. In general, the results of the geotechnical approach have been characterised by their scattering. The sources of this dispersion are numerous and include sampling methods, pulverisation degree, mixing times and delay of compaction process, a pre-test temperature and humidity, differences in dry unit weight values, and testing methods. Therefore, in the current study, several precautions have been set to reduce the scattering in the results of such tests so that they can be used efficiently to monitor the evolution in the properties that are directly related to the formation and development of cementitious compounds. Four clays with different mineralogy compositions, covering a wide range of liquid limits, were chosen. The mechanical and hydraulic behaviour of such clays that had been treated by various concentrations of lime up to 25% at two ambient temperatures of 20 and 40oC were monitored for various curing times. The results indicated that the timing of the onset of changes in mechanical and hydraulic properties that are related to the formation of cementitious compounds depends on the mineralogy composition of treated clay and ambient temperature. Moreover, at a given temperature, the continuity of such changes in the characteristics of a given lime-treated clay depends on the lime availability.

In this investigation, the flow friction associated with laminar pulsating flows through porous media was numerically studied. The problem is of interest for understanding the regenerators of Stirling and pulse tube cryocoolers. Two-dimensional flow in a system composed of a number of unit cells of generic porous structures was simulated using a CFD tool, with sinusoidal variations of flow with time. Detailed numerical data representing the oscillating velocity and pressure variations for five different generic porous structure geometries in the porosity range of 0.64 to 0.84, with flow pulsation frequency of 40 Hz were obtained, and special attention was paid to the phase shift characteristics between the velocity and pressure waves. Based on these detailed numerical data, the standard unsteady volume-averaged momentum conservation equation for porous media was then applied in order to obtain the instantaneous as well as cycle-averaged permeability and Forchheimer coefficients. It was found that the cycle-averaged permeability coefficients were nearly the same as those for steady flow, but the cycle-averaged Forchheimer coefficients were about two times larger than those for steady flow. Significant phase lags were observed with respect to the volume-averaged velocity and pressure waves. The parametric trends representing the dependence of these phase lags on porosity and flow Reynolds number were discussed. The phase difference between pressure and velocity waves, which is important for pulse tube cryocooling, depended strongly on porosity and flow Reynolds number.

Bovine milk-derived extracellular vesicles (EVs) hold promises as oral drug delivery systems. Since EV bioavailability studies are difficult to compare, key factors regarding EV uptake and intestinal permeability remain little understood. This work aims to critically study uptake and transport properties of milk-derived EVs across the intestinal barrier in vitro by standardization approaches. Therefore, uptake properties were directly compared to liposomes in intestinal Caco-2 cells. Reliable staining results were obtained by the choice of three distinct EV labeling sites, while non-specific dye transfer and excess dye removal were carefully controlled. A novel fluorescence correction factor was implemented to account for different labelling efficiencies. Both EV and liposome uptake occurred mainly energy dependent with the neonatal Fc receptor (FcRn) providing an exclusive active pathway for EVs. Confocal microscopy revealed higher internalization of EVs whereas liposomes rather remained attached to the cell surface. Internalization could be improved when changing the liposomal formulation to resemble the EV lipid composition. In a Caco-2/HT29-MTX co-culture liposomes and EVs showed partial mucus penetration. For transport studies across Caco-2 monolayers we further established a standardized protocol considering the distinct requirements for EVs. Especially insert pore sizes were systematically compared with 3 µm inserts found obligatory. Obtained apparent permeability coefficients (Papp) reflecting the transport rate will allow for better comparison of future bioavailability testing.