A growing number of proteins devoid of signal peptides have been demonstrated to be released through the non-classical pathways independent of endoplasmic reticulum and Golgi. Among them are two potent proangiogenic cytokines FGF1 and IL1α. Stress-induced transmembrane translocation of these proteins requires the assembly of copper-dependent multiprotein release complexes. It involves the interaction of exported proteins with the acidic phospholipids of the inner leaflet of the cell membrane and membrane destabilization. Not only stress, but also thrombin treatment and inhibition of Notch signaling stimulate the export of FGF1. Non-classical release of FGF1 and IL1α presents a promising target for treatment of cardiovascular, oncologic, and inflammatory disorders. Keywords non-classical secretion; FGF1; IL1α VARIETY OF NON-CLASSICALLY RELEASED PROTEINSThe familiar textbook scheme of protein secretion starts with the cotranslational protein translocation into the endoplasmic reticulum (ER). This translocation requires a molecular exit visa, a hydrophobic signal peptide located usually at the N-terminus of a secretable protein [Blobel, 1995]. After the protein is translocated through the ER membrane, its folding, transport, sorting, and covalent modifications occur in the ER and Golgi. Finally, the protein is released from the cell as a result of the fusion of an exocytotic vesicle with the cell membrane.
A theoretical model has been developed to describe the generation of Sum Frequency (SF) light from a monolayer film adsorbed to the surface of a dielectric and metal composite substrate. This type of substrate provides enhanced SF signals from the monolayer without modifying the intrinsic (hydrophilic) properties of the dielectric surface. The fundamental equations of both resonant and nonresonant SF generation have been extended from a single interface to encompass the two displaced sources, the air/dielectric interface at which the monolayer film is located, and the dielectric/metal interface. The model describes the coherent addition of three separate SF signals which coherently interfere with each other, thereby affecting the line-shape observed in the net SF spectrum. Representative calculations have been made for a highly ordered monolayer of an aliphatic hydrocarbon molecule, adsorbed on a dielectric with the optical properties of mica, which is itself in contact with a metal modeled to resemble gold. The SF spectral line-shapes are predicted as a function of the thickness of the dielectric material for the methyl terminal groups of the hydrocarbon chain. The model can be applied to any dielectric/metal composite by modifying the optical properties appropriately.
Sum frequency generation (SFG) vibrational spectra of cadmium arachidate multilayer films adsorbed on a substrate with high nonresonant susceptibility, i.e., gold, and on a low nonresonant susceptibility substrate, i.e., fused quartz, have been investigated in the C-H stretching region in air. The films were formed by Langmuir-Blodgett (LB) deposition and their spectra recorded using SFG spectrometers employing both 532-nm nanosecond and 800-nm femtosecond lasers, with counter-propagating and co-propagating beam geometries, respectively. Both kinds of substrate were rendered hydrophobic by coating them with per-deuterated octadecanethiol (gold) or per-deuterated cadmium arachidate (fused quartz) monolayers. Single per-protonated arachidate layers in otherwise per-deuterated 10-layer films were used to show that the SFG resonances arise only from the topmost and lowermost layers in a LB film comprised of an even number of per-protonated layers, although the SFG spectra from the two hydrophobic substrates are different from each other. The differences in the spectra from the same ten-layer per-protonated films deposited on the two types of hydrophobic substrate have been explained in terms of a simple model that accounts for resonant and nonresonant contributions.
Sum frequency (SF) vibrational spectra in the C-H stretching region of polydimethyl siloxane (PDMS) and of the comb copolymer cetyl dimethicone copolyol (CDC), consisting of a PDMS backbone with grafted poly(ethylene oxide) and cetyl side chains, have been recorded in air after deposition onto a gold-coated substrate. The polymers were deposited over a range of thicknesses (up to 70 nm) by spin coating from chloroform solutions of different polymer concentrations. Film thicknesses were determined by ellipsometry. The methyl symmetric (r + ) stretching modes appeared as peaks in the SF spectra of both polymers at all film thicknesses investigated, indicating that the constituent methyl groups have a net orientation toward the air. However, the phase of the methyl anti-symmetric (r -) stretching mode displayed a dependence upon film thickness, changing from a peak (positive phase) to a dip (negative phase) as film thickness was increased. The phase behavior of the rmethyl resonance has been successfully modeled by the extension of a previously developed interference theory to include multiple reflections and a resonant contribution from the polymer/ gold interface.
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