6,356 research outputs found

    Rab8 binding to immune cell-specific adaptor LAX facilitates formation of trans-Golgi network-proximal CTLA-4 vesicles for surface expression.

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    Despite playing a central role in tolerance, little is known regarding the mechanism by which intracellular CTLA-4 is shuttled from the trans-Golgi network to the surfaces of T cells. In this context, Ras-related GTPase Rab8 plays an important role in the intracellular transport, while we have previously shown that CTLA-4 binds to the immune cell adaptor TRIM in T cells. In this study, we demonstrate that CTLA-4 forms a multimeric complex comprised of TRIM and related LAX that in turn binds to GTP bound Rab8 for post-Golgi transport to the cell surface. LAX bound via its N terminus to active GTP-Rab8, as well as the cytoplasmic tail of CTLA-4. TRIM required LAX for binding to Rab8 in a complex. Wild-type LAX or its N terminus (residues 1 to 77) increased CTLA-4 surface expression, whereas small interfering RNAs of Rab8 or LAX or disruption of LAX/Rab8 binding reduced numbers of CTLA-4-containing vesicles and its coreceptor surface expression. LAX also promoted the polarization of CTLA-4 and the reorientation of the microtubule-organizing center to the site of T-cell receptor engagement. Our results identify a novel CTLA-4/TRIM/LAX/Rab8 effector complex in the transport of CTLA-4 to the surfaces of T cells

    Effects of Vegetarian Nutrition–A Nutrition Ecological Perspective

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    Although vegetarian nutrition is a complex issue, the multidimensionality and interrelatedness of its effects are rarely explored. This article aims to demonstrate the complexity of vegetarian nutrition by means of the nutrition ecological modeling technique NutriMod. The integrative qualitative cause-effect model, which is based on scientific literature, provides a comprehensive picture of vegetarian nutrition. The nutrition ecological perspective offers a basis for the assessment of the effects of worldwide developments concerning shifts in diets and the effects of vegetarian nutrition on global problems like climate change. Furthermore, new research areas on the complexity of vegetarian nutrition can be identified

    Distinct Binding and Immunogenic Properties of the Gonococcal Homologue of Meningococcal Factor H Binding Protein

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    Neisseria meningitidis is a leading cause of sepsis and meningitis. The bacterium recruits factor H (fH), a negative regulator of the complement system, to its surface via fH binding protein (fHbp), providing a mechanism to avoid complement-mediated killing. fHbp is an important antigen that elicits protective immunity against the meningococcus and has been divided into three different variant groups, V1, V2 and V3, or families A and B. However, immunisation with fHbp V1 does not result in cross-protection against V2 and V3 and vice versa. Furthermore, high affinity binding of fH could impair immune responses against fHbp. Here, we investigate a homologue of fHbp in Neisseria gonorrhoeae, designated as Gonococcal homologue of fHbp (Ghfp) which we show is a promising vaccine candidate for N. meningitidis. We demonstrate that Gfhp is not expressed on the surface of the gonococcus and, despite its high level of identity with fHbp, does not bind fH. Substitution of only two amino acids in Ghfp is sufficient to confer fH binding, while the corresponding residues in V3 fHbp are essential for high affinity fH binding. Furthermore, immune responses against Ghfp recognise V1, V2 and V3 fHbps expressed by a range of clinical isolates, and have serum bactericidal activity against N. meningitidis expressing fHbps from all variant groups

    Detection of correlated galaxy ellipticities on CFHT data: first evidence for gravitational lensing by large-scale structures

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    We report the detection of a significant (5.5 sigma) excess of correlations between galaxy ellipticities at scales ranging from 0.5 to 3.5 arc-minutes. This detection of a gravitational lensing signal by large-scale structure was made using a composite high quality imaging survey of 6300 arcmin^2 obtained at the Canada France Hawaii Telescope (CFHT) with the UH8K and CFH12K panoramic CCD cameras. The amplitude of the excess correlation is 2.2\pm 0.2 % at 1 arcmin scale, in agreement with theoretical predictions of the lensing effect induced by large-scale structure.We provide a quantitative analysis of systematics which could contribute to the signal and show that the net effect is small and can be corrected for. We show that the measured ellipticity correlations behave as expected for a gravitational shear signal. The relatively small size of our survey precludes tight constraints on cosmological models. However the data are in favor of cluster normalized cosmological models, and marginally reject Cold Dark Matter models with (Omega=0.3, sigma_8<0.6) or (Omega=1, sigma_8=1). The detection of cosmic shear demonstrates the technical feasibility of using weak lensing surveys to measure dark matter clustering and the potential for cosmological parameter measurements, in particular with upcoming wide field CCD cameras.Comment: 19 pages. 19 Figures. Revised version accepted in A&

    Electrode material release during high voltage breakdown Final technical report

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    Electrode material release during high voltage breakdow

    Towards designing robust coupled networks

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    Natural and technological interdependent systems have been shown to be highly vulnerable due to cascading failures and an abrupt collapse of global connectivity under initial failure. Mitigating the risk by partial disconnection endangers their functionality. Here we propose a systematic strategy of selecting a minimum number of autonomous nodes that guarantee a smooth transition in robustness. Our method which is based on betweenness is tested on various examples including the famous 2003 electrical blackout of Italy. We show that, with this strategy, the necessary number of autonomous nodes can be reduced by a factor of five compared to a random choice. We also find that the transition to abrupt collapse follows tricritical scaling characterized by a set of exponents which is independent on the protection strategy

    Effects of fluoroquinolones and tetracyclines on mitochondria of human retinal MIO-M1 cells

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    Our goal was to explore the detrimental impacts of ciprofloxacin (CPFX) and tetracycline (TETRA) on human retinal Müller (MIO-M1) cells in vitro. Cells were exposed to 30, 60 and 120 μg/ml of CPFX and TETRA. The cellular metabolism was measured with the MTT assay. The JC-1 and CM-H2DCFDA assays were used to evaluate the levels of mitochondrial membrane potential (MMP) and ROS (reactive oxygen species), respectively. Mitochondrial DNA (mtDNA) copy number, along with gene expression levels associated with apoptotic (BAX, BCL2-L13, BCL2, CASP-3 and CASP-9), inflammatory (IL-6, IL-1β, TGF-α, TGF-β1 and TGF-β2) and antioxidant pathways (SOD2, SOD3, GPX3 and NOX4) were analyzed via Quantitative Real-Time PCR (qRT-PCR). Bioenergetic profiles were measured using the Seahorse® XF Flux Analyzer. Cells exposed 24 h to 120 μg/ml TETRA demonstrated higher cellular metabolism compared to vehicle-treated cells. At each time points, (i) all TETRA concentrations reduced MMP levels and (ii) ROS levels were reduced by TETRA 120 μg/ml treatment. TETRA caused (i) higher expression of CASP-3, CASP-9, TGF-α, IL-1B, GPX3 and SOD3 but (ii) decreased levels of TGF-B2 and SOD2. ATP production and spare respiratory capacity declined with TETRA treatment. Cellular metabolism was reduced with CPFX 120 μg/ml in all cultures and 60 μg/ml after 72 h. The CPFX 120 μg/ml reduced MMP in all cultures and ROS levels (72 h). CPFX treatment (i) increased expression of CASP-3, CASP-9, and BCL2-L13, (ii) elevated the basal oxygen consumption rate, and (iii) lowered the mtDNA copy numbers and expression levels of TGF-B2, IL-6 and IL-1B compared to vehicle-control cells. We conclude that clinically relevant dosages of bactericidal and bacteriostatic antibiotics can have negative effects on the cellular metabolism and mitochondrial membrane potential of the retinal MIO-M1 cells in vitro. It is noteworthy to mention that apoptotic and inflammatory pathways in exposed cells were affected significantly This is the first study showing the negative impact of fluoroquinolones and tetracyclines on mitochondrial behavior of human retinal MIO-M1 cells
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