57 research outputs found

    Diffusion in Low-Dimensional Lipid Membranes

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    The diffusion behavior of biological components in cellular membranes is vital to the function of cells. By collapsing the complexity of planar 2D membranes down to one dimension, fundamental investigations of bimolecular behavior become possible in one dimension. Here we develop lipid nanolithography methods to produce membranes, under fluid, with widths as low as 6 nm but extending to microns in length. We find reduced lipid mobility, as the width is reduced below 50 nm, suggesting different lipid packing in the vicinity of boundaries. The insertion of a membrane protein, M2, into these systems, allowed characterization of protein diffusion using high-speed AFM to demonstrate the first membrane protein 1D random walk. These quasi-1D lipid bilayers are ideal for testing and understanding fundamental concepts about the roles of dimensionality and size on physical properties of membranes from energy transfer to lipid packing

    Sensitivity to change of MRP8/14 serum levels compared to DAS28 and CRP serum level.

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    <p>Standardized response mean (SRM) of the change in myeloid related protein 8/14 (MRP8/14), C-reactive protein (CRP) and disease activity score evaluated in 28 joints (DAS28-CRP) 4 weeks after treatment with infliximab (n = 34), adalimumab (n = 85), rituximab (n = 20) and treatment with placebo or ineffective therapy (n = 28). The solid line indicates the 0.2 SRM cut off point (low), the thick dotted line indicates the 0.5 SRM cut off point (moderate) and the thin dotted line indicates the 0.8 SRM cut off point (high).</p

    Baseline characteristics of patients enrolled in the effective and placebo/ineffective treatment groups.

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    <p>Median and interquartile range or percentages are shown. EULAR responder = good or moderate responder according to the European League Against Rheumatism Response, TJC68 =  tender joint count of 68 joints, SJC68 =  swollen joint count of 68 joints, ESR = erythrocyte sedimentation rate, CRP = C-reactive protein, DAS28-CRP = disease activity score based on CRP. P-value <0.05 was considered statistically significant. Significance of the comparison is determined by the chi-square test or the Mann-Whitney test.</p><p>Baseline characteristics of patients enrolled in the effective and placebo/ineffective treatment groups.</p

    An S100A9-binding small molecule inhibits EL4 lymphoma growth <i>in vivo</i>.

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    <p>A. Binding of S100A9 to immobilized TLR4/MD2 complex is blocked by ABR-215050. Sensorgrams obtained after injection (2 min at 30 µL/min) of 50 nM S100A9 ± ABR-215050 over amine coupled TLR4/MD2 (density ∼2.3 kRU). Sensorgrams from top to bottom: S100A9 without competitor and with 3.91, 31.25 and 1,000 µM ABR-215050. Arrows indicate injection of sample (1); sample buffer - i.e. HBS-P containing 1 mM Ca<sup>2+</sup> and 10 uM Zn<sup>2+</sup> (2); and regeneration of surface with 3 M EDTA (3). B. Anti-tumor effect of ABR-215050 in EL4 tumors inoculated (s.c.) into wild type mice. The ABR-215050 was administrated in the drinking water at 30 mg/kg/day seven days/week from day 0 throughout the experiment. Each data point represents mean ± SEM (n = 10; p<0.01, Mann Whitney U). Control animals received only normal drinking water. The water intake of the animals was not affected by the presence of ABR-215050 in the drinking water. C. ELISA measurements of TGFβ serum levels day 20 in C57BL/6 animals inoculated with EL4 tumors and animals treated with 30 mg/kg/day of ABR-215050, as indicated (p = 0.0037, Student t test).</p

    TRAMP tumor growth is delayed in S100A9<sup>−/−</sup> mice.

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    <p>Time to palpable tumor curves for C57BL/6 TRAMP mice (grey line; n = 42) and TRAMP S100A9<sup>−/−</sup> mice (black line; n = 34). The median time to palpable tumor (TM) was 26 and 29 weeks, respectively (p = 0.0008; Gehan-Breslow-Wilcoxon).</p

    TGFβ expression is reduced in S100A9<sup>−/−</sup> and TLR4<sup>−/−</sup> animals.

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    <p>A. Quantitative real time RT-PCR analysis (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0034207#s4" target="_blank">Materials and Methods</a>) of TGFβ RNA expression from CD11b<sup>+</sup> cells (>90% pure by FACS analysis) from the spleen of C57BL/6, S100A9<sup>−/−</sup> and TLR4<sup>−/−</sup> animals in the absence of, or 14 days after inoculation, with 50,000 EL4 lymphoma cells subcutaneously. The mean expression from 4 separate experiments is shown where the expression in the C57BL/6 controls have been set to 1. B. ELISA measurements of TGFβ serum levels of C57BL/6 (filled circles), RAGE<sup>−/−</sup> (filled triangles), S100A9<sup>−/−</sup> (filled squares) and TLR4<sup>−/−</sup> (filled diamonds) in the absence of, or 14 days after inoculation (open symbols), with 50,000 EL4 lymphoma cells subcutaneously. Statistical analysis using two-tailed t test *** p = 0.0008; * p = 0.039 and 0.0028, respectively. There was no statistical significant difference in TGFβ serum levels between EL4 inoculated C57BL/6 or RAGE<sup>−/−</sup> mice.</p

    TRAMP tumor growth is delayed in TLR4<sup>−/−</sup> mice and EL4 lymphoma growth in both S100A9<sup>−/−</sup> and TLR4<sup>−/−</sup> animals.

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    <p>A. Time to palpable tumor curves for C57BL/6 TRAMP mice (black line; n = 18) and TRAMP TLR4<sup>−/−</sup> mice (dashed line; n = 32). The median time to palpable tumor (TM) was 26 and 31 weeks, respectively (p = <0.0001; Gehan-Breslow-Wilcoxon). B. Tumor weight of EL4 lymphoma tumors scored 14 days after subcutaneous inoculation in C57BL/6, S100A9<sup>−/−</sup>, RAGE<sup>−/−</sup> and TLR4<sup>−/−</sup> animals. Statistical analysis using two-tailed t test *** p = 0.0008; * p = 0.039.</p

    The CD11b<sup>+</sup>Ly6G<sup>+</sup>Ly6C<sup>+</sup> cell population is reduced in spleens from S100A9<sup>−/−</sup> and TLR4<sup>−/−</sup> animals.

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    <p>FACS analysis of spleen cells from C57BL/6, S100A9<sup>−/−</sup>, TLR4<sup>−/−</sup> and RAGE<sup>−/−</sup> animals. Panel A: Left: The gate used for defining CD11b<sup>+</sup> cells is shown. Right: The Ly6C/Ly6G populations used for comparison and defined as indicated. Panel B: The ratio of CD11b<sup>+</sup>Ly6G<sup>+</sup>C<sup>+</sup>/CD11b<sup>+</sup>Ly6C<sup>++</sup> cells in the different mouse strains in the presence and absence of subcutaneous EL4 tumor, as indicated. Statistical analysis using two-tailed t test ** p = 0.0034.</p

    White blood cell composition and total white blood cell count in blood from WT and S100A9 KO mice.

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    <p>White blood cell composition and total cell count in blood from WT and S100A9 KO mice, 24 and 48 hours after instillation with 9×10<sup>8</sup> CFU uropathogenic <i>E. coli</i>/mouse or 4.5×10<sup>8</sup> CFU/mouse. Sham mice were sacrificed 24 hours after inoculation with sterile PBS. Monocytes (mono), lymphocytes (lympho) and granulocytes (gran) are expressed as percentage of white blood cells. Total cell count (TCC) is presented as amount of white blood cells per ml. Data are mean ± SEM. (N = 6–8 per group).</p

    Role of myeloid regulatory cells (MRCs) in maintaining tissue homeostasis and promoting tolerance in autoimmunity, inflammatory disease and transplantation

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    Myeloid cells play a pivotal role in regulating innate and adaptive immune responses. In inflammation, autoimmunity, and after transplantation, myeloid cells have contrasting roles: on the one hand they initiate the immune response, promoting activation and expansion of effector T-cells, and on the other, they counter-regulate inflammation, maintain tissue homeostasis, and promote tolerance. The latter activities are mediated by several myeloid cells including polymorphonuclear neutrophils, macrophages, myeloid-derived suppressor cells, and dendritic cells. Since these cells have been associated with immune suppression and tolerance, they will be further referred to as myeloid regulatory cells (MRCs). In recent years, MRCs have emerged as a therapeutic target or have been regarded as a potential cellular therapeutic product for tolerance induction. However, several open questions must be addressed to enable the therapeutic application of MRCs including: how do they function at the site of inflammation, how to best target these cells to modulate their activities, and how to isolate or to generate pure populations for adoptive cell therapies. In this review, we will give an overview of the current knowledge on MRCs in inflammation, autoimmunity, and transplantation. We will discuss current strategies to target MRCs and to exploit their tolerogenic potential as a cell-based therapy