Mechanism and determinants of nanoparticle penetration through human skin

The ability of nanoparticles to penetrate the stratum corneum was the focus of several studies. Yet, there are controversial issues available for particle penetration due to different experimental setups. Meanwhile, there is little known about the mechanism and determinants of their penetration. In this paper the penetration of four model gold nanoparticles of diameter 6 and 15 nm, differing in surface polarity and the nature of the vehicle, through human skin was studied using multiphoton microscopy. This is in an attempt to profoundly investigate the parameters governing particle penetration through human skin. Our results imply that nanoparticles at this size range permeate the stratum corneum in a similar manner to drug molecules, mainly through the intercellular pathways. However, due to their particulate nature, permeation is also dependent on the complex microstructure of the stratum corneum with its tortuous aqueous and lipidic channels, as shown from our experiments performed using skin of different grades of barrier integrity. The vehicle (toluene-versus-water) had a minimal effect on skin penetration of gold nanoparticles. Other considerations in setting up a penetration experiment for nanoparticles were also studied. The results obtained are important for designing a new transdermal carrier and for a basic understanding of skin–nanoparticle interaction

The Measurement Problem and two Dogmas about Quantum Mechanics

According to a nowadays widely discussed analysis by Itamar Pitowsky, the theoretical problems of QT are originated from two ‘dogmas’: the first forbidding the use of the notion of measurement in the fundamental axioms of the theory; the second imposing an interpretation of the quantum state as representing a system’s objectively possessed properties and evolution. In this paper I argue that, contrarily to Pitowsky analysis, depriving the quantum state of its ontological commitment is not sufficient to solve the conceptual issues that affect the foundations of QT. In order to test Pitowsky’s analysis I make use of an argument elaborated by Amit Hagar and Meir Hemmo, showing how some probabilistic interpretations of QT fail at dictating coherent predictions in Wigner’s Friend situations. More specifically, I evaluate three different probabilistic approaches: qBism, as a representative of the epistemic subjective interpretation of the quantum state; Jeff Bub’s information-theoretic interpretation of QT, as an example of the ontic approach to the quantum state; Itamar Pitowsky’s probabilistic interpretation, as an epistemic but objective interpretation. I argue that qBism succeeds in providing a formal solution to the problem that does not lead to a self-contradictory picture, although the resulting interpretation leads to an interpretation where the real subject matter of QT clashes alarmingly with scientific practice. The other two approaches, instead, strictly fail in Wigner’s Friend scenarios, showing in such a way that they don’t provide a genuine solution to the problem

Thrombocytopenia in systemic lupus erythematosus patients and its association with antiphospholipid antibodies

Introduction: Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease, characterized by immune-mediated inflammation in different organs. The course of the disease is characterized by relapses and remissions, and the degree of severity of the clinical manifestations is greatly affected by the number and nature of the various organ affection. The death rate in patients with SLE is still significant, and it may be due to lupus activity, when vital organs are affected, the complications of treatment especially infections or long-term complications, such as cardiovascular disorders. Objective: To detect the relation between thrombocytopenia in SLE patients and presence antiphospholipid antibodies.Patients and methods: This study was a cross-sectional study included 100 SLE patients who attended to Sohag University Hospitals. Patients included in this study were classified as SLE patients according to either the 2012 SLICC criteria or the new 2017 ACR/EULAR SLE classification criteria. All of the participants were subjected to the following: Full history, full clinical examination, routine investigations, ANA by immunofluorescence, and ANA profile for the most common 19 autoantibodies by immunoblot. All of the participants were subjected to detection of serum titers of all antiphospholipid antibodies (aPLs) including lupus anticoagulant (LA), anti-cardiolipin (aCL) and anti-beta2-glycoprotein I (ab2GPI).Results: In this study, we demonstrated that aPLs are strongly associated with increased risk of thrombocytopenia in SLE patients. We identified aPL profiles, especially LA and IgM isotypes, as biomarkers for the risk stratification of thrombocytopenia in SLE patients.Conclusions: We concluded that aPLs are strongly associated with increased risk of thrombocytopenia in SLE patients

RELATING CELLULAR ASSOCIATION WITH LIPOSOME CYTOTOXICITY IN HUMAN ENDOTHELIAL CELLS

INTRODUCTION Interactions with the endothelium play a key role in the behaviour of intravenously administered nanoparticle drug carriers[1]. Hence, quantifying cellular association (membrane adhesion and cell internalization) of liposomes with endothelial cells is an effective screening method of biocompatibility and success of new drug carriers. Current methods are inaccurate as concentration does not necessarily equate to local cellular association. The focus of this experiment is to quantify the cellular association between liposomes and two types of human endothelial cells and compare the associations with cells’ cytotoxic response. Cellular association of liposomes as well as cell viability were quantified on cellular level at different concentrations of liposomes. METHODS Two different types of cells, Human Umbilical Vein Endothelial cell, which is a common cell type used in vitro studies, and Human MicroVascular Cell, which is more accurate representation of in vivo, were used[2]. HUVEC and HMVEC were cultured and passaged onto chamber slides using standard cell culture techniques. The confluent cells were exposed to fluorescent liposomes with hydrodynamic diameter of 90.4 nm at concentrations ranging from 0.08nM to 8nM for 24 hours, membrane stained with CellMask Deep Red and fixed with paraformaldehyde, following same protocols for both types of cells. Cell viability on exposure to the same concentration range of liposomes was determined using Vialight assay using manufacturer protocols. Z-stacks of the treated cells were obtained using Olympus Fluoview FV1000 confocal microscope. Region of interest, limited by cell membranes, was set using the membrane stain channel using ImageJ. The region of interest was superimposed onto the fluorescent liposome channel to determine exclusively the fluorescence of cell adhered and cell internalized liposomes RESULTS Compared to HUVECs, higher cellular association of liposomes was observed for HMVC as shown in Figure 1.While cellular association of liposomes increased with concentration, cell viability was in the range of 85 to nearly 100% for the concentration range of 0.08-4 nM with no significant difference. Only at 8 nM, cell viability decreased significantly to approximately 62 %. DISCUSSION AND CONCLUSIONS Liposome cellular association provide insight into the cytotoxicity and the endothelial cytotoxicity of the liposomes at low concentration of 8nM raises cautions on documented innocuous properties of liposomes. Cytotoxicity and cellular association upon comparison showed exponential relationship. Because the cytotoxicity and cellular association relationship is exponential, slight over-administration can cause severe toxicity. 8nM is lower than concentration of current intravenous liposome-based drug doxorubicin[3]. High toxicity and exponential relationship raise caution on the importance of proper safe dosage

Effect of Dual-fuelled CNG and Gasoline on Spark Ignition engine performance and Emissions behaviors at different loads

Engine emissions are one of numerous factors that have detrimentally affected the environment, such as global warming, which is the result of growing exhaust gases, practically carbon dioxide (CO2). These emissions have substantially influenced researchers to develop strategic initiatives to minimize the carbon contents of fuels. The purpose of this research is to investigate the characteristics of internal combustion (SI) engines fueled by gasoline and compressed natural gas (CNG) blends. The experiments are performed using a HONDA 4-stroke, single-cylinder, and air-cooled SI engine. Five CNG concentrations are evaluated, the concentrations range from 0.5 to 2.5 L/min with a 0.5 L/min step increase. In addition, an electrical loading board contains ten lamps of 0.5 KW power and 8 KVA Variac is used to generate and control the load. The exhaust emission factor, exhaust Gases temperature (Tex), brake thermal efficiency (BTE), and brake specific fuel combustion (BSFC) are parametric indicators of engine efficiency. The best blend ratio was 1.0 L/min, which improved the average thermal efficiency to 22.1% compared to gasoline at 17.77%, resulting in a 24.42% improvement

Modelling of the effect of ELMs on fuel retention at the bulk W divertor of JET

Effect of ELMs on fuel retention at the bulk W target of JET ITER-Like Wall was studied with multi-scale calculations. Plasma input parameters were taken from ELMy H-mode plasma experiment. The energetic intra-ELM fuel particles get implanted and create near-surface defects up to depths of few tens of nm, which act as the main fuel trapping sites during ELMs. Clustering of implantation-induced vacancies were found to take place. The incoming flux of inter-ELM plasma particles increases the different filling levels of trapped fuel in defects. The temperature increase of the W target during the pulse increases the fuel detrapping rate. The inter-ELM fuel particle flux refills the partially emptied trapping sites and fills new sites. This leads to a competing effect on the retention and release rates of the implanted particles. At high temperatures the main retention appeared in larger vacancy clusters due to increased clustering rate

On the mechanisms governing gas penetration into a tokamak plasma during a massive gas injection

A new 1D radial fluid code, IMAGINE, is used to simulate the penetration of gas into a tokamak plasma during a massive gas injection (MGI). The main result is that the gas is in general strongly braked as it reaches the plasma, due to mechanisms related to charge exchange and (to a smaller extent) recombination. As a result, only a fraction of the gas penetrates into the plasma. Also, a shock wave is created in the gas which propagates away from the plasma, braking and compressing the incoming gas. Simulation results are quantitatively consistent, at least in terms of orders of magnitude, with experimental data for a D 2 MGI into a JET Ohmic plasma. Simulations of MGI into the background plasma surrounding a runaway electron beam show that if the background electron density is too high, the gas may not penetrate, suggesting a possible explanation for the recent results of Reux et al in JET (2015 Nucl. Fusion 55 093013)

RELATING QUANTUM DOT ASSOCIATION WITH HUMAN ENDOTHELIAL CELLS WITH THEIR CYTOTOXIC EFFECTS

INTRODUCTION Advances in the field of nanotechnology have enabled researchers to pursue biomedical applications of nanoparticles. Quantum dots are commonly used fluorescent probes because they are brighter and less prone to photobleaching than other fluorophores [1]. However, despite the advantages, potential for toxicity must be acknowledged. Quantum dots are commonly made with toxic metal elements, which can cause oxidative stress [2]. Cadmium ions have been shown to disrupt mitochondria activity, leading to cell death [2]. Quantum dots have been shown to attach to the cell membrane as well as be internalized through endocytic mechanisms [3]. In this study, we aim to quantify quantum dot association and compare results from cytotoxicity assays for identical conditions, relating cellular association with cytotoxicity. METHODS Human Umbilical Vein Endothelial Cells (HUVECs) and Human Micro-vascular Endothelial Cells (HMVECs) were cultured in static conditions in 8-well chamber slides then exposed to amino-PEG quantum dots at a concentration of 0.2nM to 200nM. After exposure for 24 hours, the cells were washed, fixed, and stained. Z-stacks were obtained using an Olympus Fluoview FV1000 confocal microscope. Images were analyzed using ImageJ software to quantify mean fluorescence intensity within the defined region of interest, selected from the boundaries of stained cell membranes. Statistical analysis using one-way Analysis of Variance (ANOVA) and post-hoc Tukey HSD test was performed. Finally, Vialight assay was used to test cell viability after exposure to quantum dots under the same experimental conditions used for association experiments. RESULTS Exposure to different concentrations of quantum dots results in significant changes in the observed fluorescence intensity per area. Non-linear dependence of cellular association of quantum dots on exposure concentration was observed. A representative example of mean fluorescence intensity of quantum dots associated with HUVECs is shown in Figure 1.A significant decrease in the viability of HUVECs was observed on exposure to quantum dots (30-50% cell viability relative to 100% for non-exposed cells). However, no significant difference in cell viability was observed between 0.2nM to 200nM concentrations. DISCUSSION AND CONCLUSIONS Nanoparticle association studies play a vital role in predicting cell viability in nanoparticle cytotoxicity studies. The non-linear trend observed suggests that for the range of concentrations examined, cellular association does not increase linearly with exposure concentration, and that cytotoxicity can be related to association, rather than just to exposure concentration. This experiment provides an approach to advance future studies relating cellular association to cytotoxicity

EFFECT OF PEG COATING ON NANOPARTICLE DIFFUSION THROUGH TUMOUR EXTRACELLULAR MATRIX

INTRODUCTION Nanoparticle drug delivery systems have the potential to improve current cancer treatments through encapsulating cytotoxic agents and delivering them to specific sites in the body. One such class of particle, liposomes, has already found some commercial success [1]. Liposomes are vesicles composed of a lipid bi-layer surrounding an aqueous solution. Poly(ethylene) glycol (PEG) surface coating is commonly used to improve the hydrophilicity of liposomes, thereby increasing their stability in aqueous solutions. Furthermore, PEG limits the binding of blood antigens, which minimizes opsonisation and phagocytosis, extending circulation time in the blood stream. When applied to the surface of liposomes at lower molecular weights and surface densities, PEG adopts a “mushroom” conformation, in which adjacent chains of PEG do not interact laterally, therefore portions of the bi-layer remain exposed [2]. However, at higher molecular weights and surface densities, the “brush” conformation is adopted; where lateral interactions occur between neighbouring PEG strands and provide complete coverage of the lipid bi-layer [2]. This study will investigate the effect of varying PEG molecular weight and surface density on liposome transport through tumour extracellular matrix. METHODS Seven different formulations of liposomes were synthesized using a modification of the lipid extrusion method described in [1]. Molecular weight and surface density values were chosen to include both PEG conformations. The Type I collagen hydrogel was prepared with a collagen concentration of 2.5mg/mL. Confocal Microscopy was used to track the liposome transport into the gels via the bilayer incorporated Rhodamine dye. While simple collagen hydrogels may not capture all of the complexity of native tumour ECM, they allow for more carefully controlled conditions than in vivo models. Images were taken every 30 minutes until the 900 minute mark. RESULTS As shown in Figure 1, the liposomes with a lower PEG loading (DOPC, 5, 10% PEG 1000, 5, 10% PEG 2000), all accumulated at the interface of the hydrogel, and had identical diffusion coefficients. The 5% and 10% PEG 5000 however, accumulated significantly less and therefore had a much greater diffusion coefficient.DISCUSSION AND CONCLUSIONS The liposomes with low PEG surface density, and DOPC control liposomes shown in Figure 1, are all within the “mushroom” conformation of PEG [2] and therefore would all have exposed bilayer which is not shielded by the PEG strands. The formulations that penetrated deeply were notably only higher PEG surface densities (5 and 10% PEG 5000) which literature suggests would have been in the “brush” conformation [2]. This suggests that the high PEG surface densities sterically shielded the liposomes, and reduced the electrostatic interactions between the hydrogels and the liposomes, allowing increased diffusion

Measurement of the Production Rate of Charm Quark Pairs from Gluons in Hadronic Z0Z^{0} Decays

The rate of secondary charm-quark-pair production has been measured in 4.4 million hadronic Z0 decays collected by OPAL. By selecting events with three jets and tagging charmed hadrons in the gluon jet candidate using leptons and charged D* mesons, the average number of secondary charm-quark pairs per hadronic event is found to be (3.20+-0.21+-0.38)x10-2