Tumor-derived exosomes confer antigen-specific immunosuppression in a murine delayed-type hypersensitivity model

Exosomes are endosome-derived small membrane vesicles that are secreted by most cell types including tumor cells. Tumor-derived exosomes usually contain tumor antigens and have been used as a source of tumor antigens to stimulate anti-tumor immune responses. However, many reports also suggest that tumor-derived exosomes can facilitate tumor immune evasion through different mechanisms, most of which are antigen-independent. In the present study we used a mouse model of delayed-type hypersensitivity (DTH) and demonstrated that local administration of tumor-derived exosomes carrying the model antigen chicken ovalbumin (OVA) resulted in the suppression of DTH response in an antigen-specific manner. Analysis of exosome trafficking demonstrated that following local injection, tumor-derived exosomes were internalized by CD11c+ cells and transported to the draining LN. Exosome-mediated DTH suppression is associated with increased mRNA levels of TGF-β1 and IL-4 in the draining LN. The tumor-derived exosomes examined were also found to inhibit DC maturation. Taken together, our results suggest a role for tumor-derived exosomes in inducing tumor antigen-specific immunosuppression, possibly by modulating the function of APCs. © 2011 Yang et al

Holographic three-point functions of giant gravitons

Working within the AdS/CFT correspondence we calculate the three-point function of two giant gravitons and one pointlike graviton using methods of semiclassical string theory and considering both the case where the giant gravitons wrap an S^3 in S^5 and the case where the giant gravitons wrap an S^3 in AdS_5. We likewise calculate the correlation function in N=4 SYM using two Schur polynomials and a single trace chiral primary. We find that the gauge and string theory results have structural similarities but do not match perfectly, and interpret this in terms of the Schur polynomials' inability to interpolate between dual giant and pointlike gravitons.Comment: 21 page

Drosophila TRPN( = NOMPC) Channel Localizes to the Distal End of Mechanosensory Cilia

BACKGROUND: A TRPN channel protein is essential for sensory transduction in insect mechanosensory neurons and in vertebrate hair cells. The Drosophila TRPN homolog, NOMPC, is required to generate mechanoreceptor potentials and currents in tactile bristles. NOMPC is also required, together with a TRPV channel, for transduction by chordotonal neurons of the fly's antennal ear, but the TRPN or TRPV channels have distinct roles in transduction and in regulating active antennal mechanics. The evidence suggests that NOMPC is a primary mechanotransducer channel, but its subcellular location-key for understanding its exact role in transduction-has not yet been established. METHODOLOGY/PRINCIPAL FINDINGS: Here, by immunostaining, we locate NOMPC at the tips of mechanosensory cilia in both external and chordotonal sensory neurons, as predicted for a mechanotransducer channel. In chordotonal neurons, the TRPN and TRPV channels are respectively segregated into distal and proximal ciliary zones. This zonal separation is demarcated by and requires the ciliary dilation, an intraciliary assembly of intraflagellar transport (IFT) proteins. CONCLUSIONS: Our results provide a strong evidence for NOMPC as a primary transduction channel in Drosophila mechansensory organs. The data also reveals a structural basis for the model of auditory chordotonal transduction in which the TRPN and TRPV channels play sequential roles in generating and amplifying the receptor potential, but have opposing roles in regulating active ciliary motility

<i>C-elegans</i> model identifies genetic modifiers of alpha-synuclein inclusion formation during aging

Inclusions in the brain containing alpha-synuclein are the pathological hallmark of Parkinson's disease, but how these inclusions are formed and how this links to disease is poorly understood. We have developed a &lt;i&gt;C-elegans&lt;/i&gt; model that makes it possible to monitor, in living animals, the formation of alpha-synuclein inclusions. In worms of old age, inclusions contain aggregated alpha-synuclein, resembling a critical pathological feature. We used genome-wide RNA interference to identify processes involved in inclusion formation, and identified 80 genes that, when knocked down, resulted in a premature increase in the number of inclusions. Quality control and vesicle-trafficking genes expressed in the ER/Golgi complex and vesicular compartments were overrepresented, indicating a specific role for these processes in alpha-synuclein inclusion formation. Suppressors include aging-associated genes, such as sir-2.1/SIRT1 and lagr-1/LASS2. Altogether, our data suggest a link between alpha-synuclein inclusion formation and cellular aging, likely through an endomembrane-related mechanism. The processes and genes identified here present a framework for further study of the disease mechanism and provide candidate susceptibility genes and drug targets for Parkinson's disease and other alpha-synuclein related disorders

Activation of Human Stearoyl-Coenzyme A Desaturase 1 Contributes to the Lipogenic Effect of PXR in HepG2 Cells

The pregnane X receptor (PXR) was previously known as a xenobiotic receptor. Several recent studies suggested that PXR also played an important role in lipid homeostasis but the underlying mechanism remains to be clearly defined. In this study, we found that rifampicin, an agonist of human PXR, induced lipid accumulation in HepG2 cells. Lipid analysis showed the total cholesterol level increased. However, the free cholesterol and triglyceride levels were not changed. Treatment of HepG2 cells with rifampicin induced the expression of the free fatty acid transporter CD36 and ABCG1, as well as several lipogenic enzymes, including stearoyl-CoA desaturase-1 (SCD1), long chain free fatty acid elongase (FAE), and lecithin-cholesterol acyltransferase (LCAT), while the expression of acyl:cholesterol acetyltransferase(ACAT1) was not affected. Moreover, in PXR over-expressing HepG2 cells (HepG2-PXR), the SCD1 expression was significantly higher than in HepG2-Vector cells, even in the absence of rifampicin. Down-regulation of PXR by shRNA abolished the rifampicin-induced SCD1 gene expression in HepG2 cells. Promoter analysis showed that the human SCD1 gene promoter is activated by PXR and a novel DR-7 type PXR response element (PXRE) response element was located at -338 bp of the SCD1 gene promoter. Taken together, these results indicated that PXR activation promoted lipid synthesis in HepG2 cells and SCD1 is a novel PXR target gene. © 2013 Zhang et al

Synthesis of titanate nanostructures using amorphous precursor material and their adsorption/photocatalytic properties

This paper reports on a new and swift hydrothermal chemical route to prepare titanate nanostructures (TNS) avoiding the use of crystalline TiO2 as starting material. The synthesis approach uses a commercial solution of TiCl3 as titanium source to prepare an amorphous precursor, circumventing the use of hazardous chemical compounds. The influence of the reaction temperature and dwell autoclave time on the structure and morphology of the synthesised materials was studied. Homogeneous titanate nanotubes with a high length/diameter aspect ratio were synthesised at 160^{\circ}C and 24 h. A band gap of 3.06\pm0.03 eV was determined for the TNS samples prepared in these experimental conditions. This value is red shifted by 0.14 eV compared to the band gap value usually reported for the TiO2 anatase. Moreover, such samples show better adsorption capacity and photocatalytic performance on the dye rhodamine 6G (R6G) photodegradation process than TiO2 nanoparticles. A 98% reduction of the R6G concentration was achieved after 45 minutes of irradiation of a 10 ppm dye aqueous solution and 1 g/L of TNS catalyst.Comment: 29 pages, 10 figures, accepted for publication in Journal of Materials Scienc

Associations of sitting accumulation patterns with cardio-metabolic risk biomarkers in Australian adults

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Photoconductivity of biased graphene

Graphene is a promising candidate for optoelectronic applications such as photodetectors, terahertz imagers, and plasmonic devices. The origin of photoresponse in graphene junctions has been studied extensively and is attributed to either thermoelectric or photovoltaic effects. In addition, hot carrier transport and carrier multiplication are thought to play an important role. Here we report the intrinsic photoresponse in biased but otherwise homogeneous graphene. In this classic photoconductivity experiment, the thermoelectric effects are insignificant. Instead, the photovoltaic and a photo-induced bolometric effect dominate the photoresponse due to hot photocarrier generation and subsequent lattice heating through electron-phonon cooling channels respectively. The measured photocurrent displays polarity reversal as it alternates between these two mechanisms in a backgate voltage sweep. Our analysis yields elevated electron and phonon temperatures, with the former an order higher than the latter, confirming that hot electrons drive the photovoltaic response of homogeneous graphene near the Dirac point

Sphingosine 1-phosphate modulates antigen capture by murine langerhans cells via the S1P2 receptor subtype

Dendritic cells (DCs) play a pivotal role in the development of cutaneous contact hypersensitivity (CHS) and atopic dermatitis as they capture and process antigen and present it to T lymphocytes in the lymphoid organs. Recently, it has been indicated that a topical application of the sphingolipid sphingosine 1-phosphate (S1P) prevents the inflammatory response in CHS, but the molecular mechanism is not fully elucidated. Here we indicate that treatment of mice with S1P is connected with an impaired antigen uptake by Langerhans cells (LCs), the initial step of CHS. Most of the known actions of S1P are mediated by a family of five specific G protein-coupled receptors. Our results indicate that S1P inhibits macropinocytosis of the murine LC line XS52 via S1P2 receptor stimulation followed by a reduced phosphatidylinositol 3-kinase (PI3K) activity. As down-regulation of S1P2 not only diminished S1P-mediated action but also enhanced the basal activity of LCs on antigen capture, an autocrine action of S1P has been assumed. Actually, S1P is continuously produced by LCs and secreted via the ATP binding cassette transporter ABCC1 to the extracellular environment. Consequently, inhibition of ABCC1, which decreased extracellular S1P levels, markedly increased the antigen uptake by LCs. Moreover, stimulation of sphingosine kinase activity, the crucial enzyme for S1P formation, is connected not only with enhanced S1P levels but also with diminished antigen capture. These results indicate that S1P is essential in LC homeostasis and influences skin immunity. This is of importance as previous reports suggested an alteration of S1P levels in atopic skin lesions