Influence of Inflammatory Mediators and Cytokines on Human Melanocyte Function

The fully differentiated human melanocyte functions as a necessary and integral part of the epidermis, synthesizing melanin in intracellular organelles and transferring these pigment-containing organelles to surrounding keratino-cytes. The epidermal environment contains multiple inflammatory mediators, cytokines, and growth factors that may alter constitutive melanocyte function. Constitutive melanocyte function can also be markedly altered by release of such mediators in inflammatory dermatoses. Many of the same factors can also be released by ultraviolet radiation and psoralen + ultraviolet A treatment. These inflammatory mediators and cytokines affect not only melanocyte pigment production, but also proliferation, differentiation, immunologic susceptibility and cytotoxicity, inflammatory mediator, cytokine and matrix protein production, and cell movement. The effect of inflammatory mediators and cytokines on melanocytes and the regulation of these effects are an active area of investigation. J Invest Dermatol 100:191S–195S, 199

Melanocyte Mitogens Induce Both Melanocyte Chemokinesis and Chemotaxis

It is believed that during repigmentation of vitiligo, inactive melanocytes in the outer root sheath of the hair follicle become activated, proliferate, and migrate into the depigmented skin. However, the mechanisms controlling melanocyte migration remain to be elucidated. In this study, we investigated the effects of well-described melanocyte growth factors on melanocyte migration. Using time-lapse photography, we demonstrated that melanocyte chemokinetic movement was induced by basic fibroblast growth factor, stem cell factor, and endothelin-1, with the greatest effect noted using 100 nM endothelin-1. Similar results were reported previously with leukotriene C4. When surrounded by these stimuli, melanocytes moved in a random, nonlinear fashion and showed no desensitization at the concentrations studied.In Boyden chamber checkerboard analysis, basic fibroblast growth factor, leukotriene C4 and endothelin-1 were chemotactic. They produced directional migration and showed desensitization at higher concentrations. The greatest effect again was seen with 100 nM endothelin-1. Stem cell factor showed no effect in this assay system at the concentrations tested.The four melanocyte mitogens-leukotriene C4, endothelin-1, basic fibroblast growth factor, and stem cell factor-stimulate melanocyte migration, and this migration may be either chemokinetic (activated random movement) or chemotactic (requiring a gradient, directional, and showing desensitization), depending on the conditions used. We believe that these factors may be effective in stimulating vitiligo repigmentation by inducing proliferation and migration of hair-follicle outer-root-sheath melanocytes into the depigmented epidermis

Full-Scale Prop-Rotor Stability Tests on the XV3 at High Advance Ratios

Tests in the 40-by-80 foot wind tunnel were made at airspeeds from 40 to 195 knots. The aircraft was mounted with and without roll freedom. Rotor pylon configuration variables included the following: swashplate stabilization by mechanically coupling the swashplate to the wing or fuselage; pylon restraint stiffness and damping; hub restraint; and delta-three combined with swashplate retardation. Time histories were recorded of pylon motions and rotor loads following pulse-type excitations of the pylon. It was found that damping of the low frequency whirl mode increased with swashplate stabilization, pylon stiffness, and hub restraint

Identification of Functional Platelet-Activating Factor Receptors on Human Keratinocytes

Platelet-activating factor (PAP) is a potent inflammatory mediator that has been shown to be produced by human keratinocytes and is thought to play a role in cutaneous inflammation, Immunofluorescence and radioligand binding studies were used to characterize PAP receptors (PAF-R) on human keratinocytes and the human epidermoid cell lines A-431 and HaCaT. Indirect immunofluorescence studies demonstrated anti-PAF-R staining of primary cultures of human keratinocytes, A-431 cells, and HaCaT cells, Primary cultures of human fibroblasts and the melanoma cell line SK-30 failed to show immunostaining above that seen with control antiserum. With indirect immunofluorescence studies of sections of normal human skin, a granular anti-PAF-R staining pattern was noted on the keratinocyte cell membranes. A-431 cells readily metabolized PAF by deacetylationreacylation at 37°C, but not at 4°C. Binding studies on crude membrane preparations of A-431 cells conducted at 4°C demonstrated specific binding that reached saturation by 120 min. Scatchard analysis of PAF binding data revealed a single class of high-affinity (KD = 6.3 ± 0.3 nM) PAP binding sites, The immunofluorescence and radioligand binding sites were shown to be functional PAF-Rs, as 10 pM to 1 μM PAF increased intracellular calcium in primary cultures of human keratinocytes, A-.431 cells, and HaCaT cells, whereas PAF treatment of primary cultures of human fibroblasts or the melanoma cell line SK-30 did not result in changes in the intracellular calcium concentration. The structurally dissimilar PAF-R antagonists CV-6209, Ro19-3704, and alprazolam all inhibited the PAF-induced calcium changes in A-431 cells, The CV-6209 inhibition was seen at doses that competed with the PAF binding to these cells. These studies provide the first evidence for the presence of a functional PAF-R expressed on human keratinocytes, suggesting that this lipid mediator may play an important role in normal keratinocytes or in inflammatory dermatology

Mendelian breeding units <i>versus</i> standard sampling strategies: mitochondrial DNA variation in southwest Sardinia

We report a sampling strategy based on Mendelian Breeding Units (MBUs), representing an interbreeding group of individuals sharing a common gene pool. The identification of MBUs is crucial for case-control experimental design in association studies. The aim of this work was to evaluate the possible existence of bias in terms of genetic variability and haplogroup frequencies in the MBU sample, due to severe sample selection. In order to reach this goal, the MBU sampling strategy was compared to a standard selection of individuals according to their surname and place of birth. We analysed mitochondrial DNA variation (first hypervariable segment and coding region) in unrelated healthy subjects from two different areas of Sardinia: the area around the town of Cabras and the western Campidano area. No statistically significant differences were observed when the two sampling methods were compared, indicating that the stringent sample selection needed to establish a MBU does not alter original genetic variability and haplogroup distribution. Therefore, the MBU sampling strategy can be considered a useful tool in association studies of complex traits

Mendelian breeding units versus standard sampling strategies: Mitochondrial DNA variation in southwest Sardinia

We report a sampling strategy based on Mendelian Breeding Units (MBUs), representing an interbreeding group of individuals sharing a common gene pool. The identification of MBUs is crucial for case-control experimental design in association studies. The aim of this work was to evaluate the possible existence of bias in terms of genetic variability and haplogroup frequencies in the MBU sample, due to severe sample selection. In order to reach this goal, the MBU sampling strategy was compared to a standard selection of individuals according to their surname and place of birth. We analysed mitochondrial DNA variation (first hypervariable segment and coding region) in unrelated healthy subjects from two different areas of Sardinia: the area around the town of Cabras and the western Campidano area. No statistically significant differences were observed when the two sampling methods were compared, indicating that the stringent sample selection needed to establish a MBU does not alter original genetic variability and haplogroup distribution. Therefore, the MBU sampling strategy can be considered a useful tool in association studies of complex traits

Decision-Directed Channel Estimation Implementation for Spectral Efficiency Improvement in Mobile MIMO-OFDM

Channel estimation algorithms and their implementations for mobile receivers are considered in this paper. The 3GPP long term evolution (LTE) based pilot structure is used as a benchmark in a multiple-input multiple-output (MIMO) orthogonal frequency division multiplexing (OFDM) receiver. The decision directed (DD) space alternating generalized expectation-maximization (SAGE) algorithm is used to improve the performance from that of the pilot symbol based least-squares (LS) channel estimator. The performance is improved with high user velocities, where the pilot symbol density is not sufficient. Minimum mean square error (MMSE) filtering is also used in estimating the channel in between pilot symbols. The pilot overhead can be reduced to a third of the LTE pilot overhead with DD channel estimation, obtaining a ten percent increase in data throughput. Complexity reduction and latency issues are considered in the architecture design. The pilot based LS, MMSE and the SAGE channel estimators are implemented with a high level synthesis tool, synthesized with the UMC 0.18 μm CMOS technology and the performance-complexity trade-offs are studied. The MMSE estimator improves the performance from the simple LS estimator with LTE pilot structure and has low power consumption. The SAGE estimator has high power consumption but can be used with reduced pilot density to increase the data rate.National Science FoundationTekesElektrobitRenesas Mobile EuropeAcademy of FinlandNokia Siemens NetworksXilin

Effectiveness of Simeprevir Plus Sofosbuvir, With or Without Ribavirin, in Real-World Patients With HCV Genotype 1 Infection

The interferon-free regimen of simeprevir plus sofosbuvir was recommended by professional guidelines for certain patients with hepatitis C virus (HCV) genotype 1 infection based on the findings of a phase 2 trial. We aimed to evaluate the safety and efficacy of this regimen in clinical practice settings in North America

Source Evaluation and Trace Metal Contamination in Benthic Sediments from Equatorial Ecosystems Using Multivariate Statistical Techniques

race metals (Cd, Cr, Cu, Ni and Pb) concentrations in benthic sediments were analyzed through multi-step fractionation scheme to assess the levels and sources of contamination in estuarine, riverine and freshwater ecosystems in Niger Delta (Nigeria). The degree of contamination was assessed using the individual contamination factors (ICF) and global contamination factor (GCF). Multivariate statistical approaches including principal component analysis (PCA), cluster analysis and correlation test were employed to evaluate the interrelationships and associated sources of contamination. The spatial distribution of metal concentrations followed the pattern Pb>Cu>Cr>Cd>Ni. Ecological risk index by ICF showed significant potential mobility and bioavailability for Cu, Cu and Ni. The ICF contamination trend in the benthic sediments at all studied sites was Cu>Cr>Ni>Cd>Pb. The principal component and agglomerative clustering analyses indicate that trace metals contamination in the ecosystems was influenced by multiple pollution sources

Mechanism of Neuronal versus Endothelial Cell Uptake of Alzheimer's Disease Amyloid β Protein

Alzheimer's disease (AD) is characterized by significant neurodegeneration in the cortex and hippocampus; intraneuronal tangles of hyperphosphorylated tau protein; and accumulation of β-amyloid (Aβ) proteins 40 and 42 in the brain parenchyma as well as in the cerebral vasculature. The current understanding that AD is initiated by the neuronal accumulation of Aβ proteins due to their inefficient clearance at the blood-brain-barrier (BBB), places the neurovascular unit at the epicenter of AD pathophysiology. The objective of this study is to investigate cellular mechanisms mediating the internalization of Aβ proteins in the principle constituents of the neurovascular unit, neurons and BBB endothelial cells. Laser confocal micrographs of wild type (WT) mouse brain slices treated with fluorescein labeled Aβ40 (F-Aβ40) demonstrated selective accumulation of the protein in a subpopulation of cortical and hippocampal neurons via nonsaturable, energy independent, and nonendocytotic pathways. This groundbreaking finding, which challenges the conventional belief that Aβ proteins are internalized by neurons via receptor mediated endocytosis, was verified in differentiated PC12 cells and rat primary hippocampal (RPH) neurons through laser confocal microscopy and flow cytometry studies. Microscopy studies have demonstrated that a significant proportion of F-Aβ40 or F-Aβ42 internalized by differentiated PC12 cells or RPH neurons is located outside of the endosomal or lysosomal compartments, which may accumulate without degradation. In contrast, BBME cells exhibit energy dependent uptake of F-Aβ40, and accumulate the protein in acidic cell organelle, indicative of endocytotic uptake. Such a phenomenal difference in the internalization of Aβ40 between neurons and BBB endothelial cells may provide essential clues to understanding how various cells can differentially regulate Aβ proteins and help explain the vulnerability of cortical and hippocampal neurons to Aβ toxicity