FK506 and Cyclosporin A Enhance IL-6 Production in Monocytes: A single-Cell Assay

The effect of FK506 and cyclosporin A (CsA) on the production of interleukin 6 (IL-6) in adherent monocytes was studied at a single-cell level by the avidinbiotin- peroxidase complex methods. The percentage of IL-6-producing monocytes increased when stimulated with lipopolysaccharide (LPS) at concentrations between 10 ng/ml and 10 μg/ml, in a dose dependent manner. Both FK506 and CsA enhanced the percentage of IL-6- producing monocytes stimulated with 100 pg/ml-1 μg/ml of LPS up to values near those obtained with 10 μg/ml of LPS. The enhancement by FK506 and CsA was not seen when monocytes were stimulated with a high concentration of LPS (10 μg/ml). When monocytes were stimulated with a low concentration of LPS (10 ng/ml), FK506 and CsA enhanced IL-6 production in a dose dependent manner, at a drug concentration of 0.12 nM–1.2 μM (0.1–1 000 ng/ml) for FK506 and 0.83 nM–8.3 μM (1–10 000 ng/ml) for CsA. The optimal effect of FK506 was achieved at a concentration 7-fold lower than that of CsA. In contrast, production of turnout necrosis factor-α (TNFα and interleukin 1β (IL-1β) was slightly suppressed by FK506 and CsA at the concentrations tested. Moreover, pretreatment of monocytes with FK506 and CsA had a significant enhancing effect on LPS-induced IL-6 production, while treatment with FK506 or CsA after LPS stimulation had no effects on IL-6 production, suggesting that the enhancing effect of each drug is exerted before LPS stimulation or at an early stage of the post-receptor pathway after LPS stimulation. These experiments demonstrate that FK506 and CsA can selectively enhance IL-6 production in monocytes under certain conditions in vitro and, possibly, also in vivo

Autoimmune rheumatic diseases : An update on the role of atherogenic electronegative ldl and potential therapeutic strategies

Altres ajuts: Vascular and Medicinal Research Fund, Texas Heart Institute (#765-64050), Houston, TX, USA; Ministry of Science and Technology (Taiwana grant MOST 107-2314-B-039-053-MY3); Ministerio de Sanidad, Spain (co-financed by Fondo Europeo de Desarrollo Regional (FEDER)).Atherosclerosis has been linked with an increased risk of atherosclerotic cardiovascular disease (ASCVD). Autoimmune rheumatic diseases (AIRDs) are associated with accelerated atherosclerosis and ASCVD. However, the mechanisms underlying the high ASCVD burden in patients with AIRDs cannot be explained only by conventional risk factors despite disease-specific factors and chronic inflammation. Nevertheless, the normal levels of plasma low-density lipoprotein (LDL) cholesterol observed in most patients with AIRDs do not exclude the possibility of increased LDL atherogenicity. By using anion-exchange chromatography, human LDL can be divided into five increasingly electronegative subfractions, L1 to L5, or into electropositive and electronegative counterparts, LDL (+) and LDL (−). Electronegative L5 and LDL (−) have similar chemical composi-tions and can induce adverse inflammatory reactions in vascular cells. Notably, the percentage of L5 or LDL (−) in total LDL is increased in normolipidemic patients with AIRDs. Electronegative L5 and LDL (−) are not recognized by the normal LDL receptor but instead signal through the lectin-like oxidized LDL receptor 1 (LOX-1) to activate inflammasomes involving interleukin 1β (IL-1β). Here, we describe the detailed mechanisms of AIRD-related ASCVD mediated by L5 or LDL (−) and discuss the potential targeting of LOX-1 or IL-1β signaling as new therapeutic modalities for these diseases

A comparison study of regional atmospheric simulations with an elastic backscattering Lidar and sunphotometry in an urban area

We describe a comparison study of Aerosol Optical Thickness (AOT) from numerical simulations using a regional atmospheric model with an elastic backscattering lidar operating at 532 nm and a sunphotometer belonging to the AERONET network at São Paulo (23° S 46° W) city, Brazil, a very populated urban area. The atmospheric model includes an aerosol emission, transport and deposition module coupled to a radiative transfer parameterization, which takes the interaction between aerosol particles and short and long wave radiation into account. A period of one week was taken as case study during the dry season (late August) when intense biomass burning activities occur at remote areas in South America, and meteorological conditions disfavor the pollution dispersion in the city of São Paulo. The situation presented here showed how smoke from biomass burning in remote areas is transported to the south-east part of Brazil and affects the optical atmospheric conditions in São Paulo. The numerical simulations are corroborated by in situ measurements of AOT obtained by lidar and sun photometry

Tunable terahertz emission from the intrinsic Josephson junctions in acute isosceles triangular Bi2Sr2CaCu2O8+delta mesas

In order to determine if the mesa geometry might affect the properties of the coherent terahertz (THz) radiation emitted from the intrinsic Josephson junctions in mesas constructed from single crystals of the high-temperature superconductor, Bi2Sr2CaCu2O8+delta, we studied triangular mesas. For equilateral triangular mesas, the observed emission was found to be limited to the single mesa TM(1,0) mode. However, tunable radiation over the range from 0.495 to 0.934 THz was found to arise from an acute isosceles triangular mesa. This 47% tunability is the widest yet observed from the outer current-voltage characteristic branch of such mesas of any geometry. Although the radiation at a few of the frequencies in the tunable range appear to have been enhanced by cavity resonances, most frequencies are far from such resonance frequencies, and can only be attributed to the ac-Josephson effect

Oxidized low density lipoprotein (LDL) affects hyaluronan synthesis in human aortic smooth muscle cells

Thickening of the vessel in response to high low density lipoprotein(s) (LDL) levels is a hallmark of atherosclerosis, characterized by increased hyaluronan (HA) deposition in the neointima. Human native LDL trapped within the arterial wall undergoes modifications such as oxidation (oxLDL). The aim of our study is to elucidate the link between internalization of oxLDL and HA production in vitro, using human aortic smooth muscle cells. LDL were used at an effective protein concentration of 20-50 \u3bcg/ml, which allowed 80% cell viability. HA content in the medium of untreated cells was 28.9 \ub1 3.7 nmol HA-disaccharide/cell and increased after oxLDL treatment to 53.9 \ub1 5.6. OxLDL treatments doubled the transcripts of HA synthase HAS2 and HAS3. Accumulated HA stimulated migration of aortic smooth muscle cells and monocyte adhesiveness to extracellular matrix. The effects induced by oxLDL were inhibited by blocking LOX-1 scavenger receptor with a specific antibody (10 \u3bcg/ml). The cholesterol moiety of LDL has an important role in HA accumulation because cholesterol-free oxLDL failed to induce HA synthesis. Nevertheless, cholesterol-free oxLDL and unmodified cholesterol (20 \u3bcg/ml) induce only HAS3 transcription, whereas 22,oxysterol affects both HAS2 and HAS3. Moreover, HA deposition was associated with higher expression of endoplasmic reticulum stress markers (CHOP and GRP78). Our data suggest that HA synthesis can be induced in response to specific oxidized sterol-related species delivered through oxLDL

Beam-Breakup Instability Theory for Energy Recovery Linacs

Here we will derive the general theory of the beam-breakup instability in recirculating linear accelerators, in which the bunches do not have to be at the same RF phase during each recirculation turn. This is important for the description of energy recovery linacs (ERLs) where bunches are recirculated at a decelerating phase of the RF wave and for other recirculator arrangements where different RF phases are of an advantage. Furthermore it can be used for the analysis of phase errors of recirculated bunches. It is shown how the threshold current for a given linac can be computed and a remarkable agreement with tracking data is demonstrated. The general formulas are then analyzed for several analytically solvable cases, which show: (a) Why different higher order modes (HOM) in one cavity do not couple so that the most dangerous modes can be considered individually. (b) How different HOM frequencies have to be in order to consider them separately. (c) That no optics can cause the HOMs of two cavities to cancel. (d) How an optics can avoid the addition of the instabilities of two cavities. (e) How a HOM in a multiple-turn recirculator interferes with itself. Furthermore, a simple method to compute the orbit deviations produced by cavity misalignments has also been introduced. It is shown that the BBU instability always occurs before the orbit excursion becomes very large.Comment: 12 pages, 6 figure

Bosonic t-J Model in a stacked triangular lattice and its phase diagram

In this paper, we study phase diagram of a system of two-component hard-core bosons with nearest-neighbor (NN) pseudo-spin antiferromagnetic (AF) interactions in a stacked triangular lattice. Hamiltonian of the system contains three parameters one of which is the hopping amplitude $t$ between NN sites, and the other two are the NN pseudo-spin exchange interaction $J$ and the one that measures anisotropy of pseudo-spin interactions. We investigate the system by means of the Monte-Carlo simulations and clarify the low-temperature phase diagram. In particular, we are interested in how the competing orders, i.e., AF order and superfluidity, are realized, and also whether supersolid forms as a result of hole doping into the state of the $\sqrt{3}\times \sqrt{3}$ pseudo-spin pattern with the $120^o$ structure.Comment: 18 pages, 17 figures, Version to appear in J.Phys.Soc.Jp

The asialoglycoprotein receptor in human hepatocellular carcinomas: its expression on proliferating cells

The expression of the asialoglycoprotein receptor (ASGP-R) on human hepatocellular carcinoma (HCC) cells might be exploited to reduce the extrahepatic toxicity of DNA synthesis inhibitors by their conjugation with galactosyl-terminating peptides. In the present study we first assessed the frequency of ASGP-R expression in 60 HCCs. Secondly, we investigated whether the receptor was maintained on the plasma membranes of DNA synthesizing cancer cells. Needle biopsies of HCC were evaluated. Diagnosis and grading of HCC were performed on routine haematoxylin and eosin-stained sections according to Edmondson and Steiner (1953). Thirty-five tumours were grade I and II and were classified as well differentiated, while 25 tumours were grade III and IV and were classified as poorly differentiated. Sections from formalin-fixed, paraffin-embedded samples were incubated, after antigen retrieval, with an anti-ASGP-R monoclonal antibody revealed by secondary biotinylated antibody and streptavidin–biotin–peroxidase–diaminobenzidine reaction. A clear immunolabelling of plasma membranes of HCC cells was observed in 28 out of 35 (80%) well differentiated (grade I and II) and in five out of 25 (20%) poorly differentiated (grade III and IV) HCCs. The presence of the ASGP-R on the surface of DNA synthesizing cancer cells was also investigated after in vitro bromodeoxyuridine (BrdU) labelling of HCC samples by immunohistochemical visualization of both the ASGP-R and incorporated BrdU on the same section. The results obtained clearly demonstrated that DNA synthesizing cancer cells expressed the ASGP-R on their surface. The presence of ASGP-R on cell plasma membrane in the majority of differentiated HCCs and its maintenance on proliferating cells encourages studies in order to restrict the action of the inhibitors of DNA synthesis of HCC cells by their conjugation with galactosyl-terminating carriers internalized through this receptor. © 1999 Cancer Research Campaig

A habituation account of change detection in same/different judgments

We investigated the basis of change detection in a short-term priming task. In two experiments, participants were asked to indicate whether or not a target word was the same as a previously presented cue. Data from an experiment measuring magnetoencephalography failed to find different patterns for “same” and “different” responses, consistent with the claim that both arise from a common neural source, with response magnitude defining the difference between immediate novelty versus familiarity. In a behavioral experiment, we tested and confirmed the predictions of a habituation account of these judgments by comparing conditions in which the target, the cue, or neither was primed by its presentation in the previous trial. As predicted, cue-primed trials had faster response times, and target-primed trials had slower response times relative to the neither-primed baseline. These results were obtained irrespective of response repetition and stimulus–response contingencies. The behavioral and brain activity data support the view that detection of change drives performance in these tasks and that the underlying mechanism is neuronal habituation