CXCL5 limits macrophage foam cell formation in atherosclerosis

The ELR+-CXCL chemokines have been described typically as potent chemoattractants and activators of neutrophils during the acute phase of inflammation. Their role in atherosclerosis, a chronic inflammatory vascular disease, has been largely unexplored. Using a mouse model of atherosclerosis, we found that CXCL5 expression was upregulated during disease progression, both locally and systemically, but was not associated with neutrophil infiltration. Unexpectedly, inhibition of CXCL5 was not beneficial but rather induced a significant macrophage foam cell accumulation in murine atherosclerotic plaques. Additionally, we demonstrated that CXCL5 modulated macrophage activation, increased expression of the cholesterol efflux regulatory protein ABCA1, and enhanced cholesterol efflux activity in macrophages. These findings reveal a protective role for CXCL5, in the context of atherosclerosis, centered on the regulation of macrophage foam cell formation

The Role of Visual Information in Numerosity Estimation

Mainstream theory suggests that the approximate number system supports our non-symbolic number abilities (e.g. estimating or comparing different sets of items). It is argued that this system can extract number independently of the visual cues present in the stimulus (diameter, aggregate surface, etc.). However, in a recent report we argue that this might not be the case. We showed that participants combined information from different visual cues to derive their answers. While numerosity comparison requires a rough comparison of two sets of items (smaller versus larger), numerosity estimation requires a more precise mechanism. It could therefore be that numerosity estimation, in contrast to numerosity comparison, might rely on the approximate number system. To test this hypothesis, we conducted a numerosity estimation experiment. We controlled for the visual cues according to current standards: each single visual property was not informative about numerosity. Nevertheless, the results reveal that participants were influenced by the visual properties of the dot arrays. They gave a larger estimate when the dot arrays consisted of dots with, on average, a smaller diameter, aggregate surface or density but a larger convex hull. The reliance on visual cues to estimate numerosity suggests that the existence of an approximate number system that can extract numerosity independently of the visual cues is unlikely. Instead, we propose that humans estimate numerosity by weighing the different visual cues present in the stimuli

The role of short-term memory and visuo-spatial skills in numerical magnitude processing: evidence from Turner syndrome

Peer reviewe

Ubiquinone Analogs: A Mitochondrial Permeability Transition Pore-Dependent Pathway to Selective Cell Death

International audienceBACKGROUND: Prolonged opening of the mitochondrial permeability transition pore (PTP) leads to cell death. Various ubiquinone analogs have been shown to regulate PTP opening but the outcome of PTP regulation by ubiquinone analogs on cell fate has not been studied yet. METHODOLOGY/PRINCIPAL FINDINGS: The effects of ubiquinone 0 (Ub(0)), ubiquinone 5 (Ub(5)), ubiquinone 10 (Ub(10)) and decyl-ubiquinone (DUb) were studied in freshly isolated rat hepatocytes, cultured rat liver Clone-9 cells and cancerous rat liver MH1C1 cells. PTP regulation by ubiquinones differed significantly in permeabilized Clone-9 and MH1C1 cells from that previously reported in liver mitochondria. Ub(0) inhibited PTP opening in isolated hepatocytes and Clone-9 cells, whereas it induced PTP opening in MH1C1 cells. Ub(5) did not affect PTP opening in isolated hepatocytes and MH1C1 cells, but it induced PTP opening in Clone-9 cells. Ub(10) regulated PTP in isolated hepatocytes, whereas it did not affect PTP opening in Clone-9 and MH1C1 cells. Only DUb displayed the same effect on PTP regulation in the three hepatocyte lines tested. Despite such modifications in PTP regulation, competition between ubiquinones still occurred in Clone-9 and MH1C1 cells. As expected, Ub(5) induced a PTP-dependent cell death in Clone-9, while it did not affect MH1C1 cell viability. Ub(0) induced a PTP-dependent cell death in MH1C1 cells, but was also slightly cytotoxic in Clone-9 by an oxidative stress-dependent mechanism. CONCLUSIONS/SIGNIFICANCE: We found that various ubiquinone analogs regulate PTP in different ways depending on the cell studied. We took advantage of this unique property to develop a PTP opening-targeted strategy that leads to cell death specifically in cells where the ubiquinone analog used induces PTP opening, while sparing the cells in which it does not induce PTP opening

Investigating the TeV Morphology of MGRO J1908+06 with VERITAS

We report on deep observations of the extended TeV gamma-ray source MGRO J1908+06 made with the VERITAS very high energy (VHE) gamma-ray observatory. Previously, the TeV emission has been attributed to the pulsar wind nebula (PWN) of the Fermi-LAT pulsar PSR J1907+0602. We detect MGRO J1908+06 at a significance level of 14 standard deviations (14 sigma) and measure a photon index of 2.20 +/- 0.10_stat +/- 0.20_sys. The TeV emission is extended, covering the region near PSR J1907+0602 and also extending towards SNR G40.5--0.5. When fitted with a 2-dimensional Gaussian, the intrinsic extension has a standard deviation of sigma_src = 0.44 +/- 0.02 degrees. In contrast to other TeV PWNe of similar age in which the TeV spectrum softens with distance from the pulsar, the TeV spectrum measured near the pulsar location is consistent with that measured at a position near the rim of G40.5--0.5, 0.33 degrees away.Comment: To appear in ApJ, 8 page

Very-high-energy observations of the binaries V 404 Cyg and 4U 0115+634 during giant X-ray outbursts

Transient X-ray binaries produce major outbursts in which the X-ray flux can increase over the quiescent level by factors as large as $10^7$. The low-mass X-ray binary V 404 Cyg and the high-mass system 4U 0115+634 underwent such major outbursts in June and October 2015, respectively. We present here observations at energies above hundreds of GeV with the VERITAS observatory taken during some of the brightest X-ray activity ever observed from these systems. No gamma-ray emission has been detected by VERITAS in 2.5 hours of observations of the microquasar V 404 Cyg from 2015, June 20-21. The upper flux limits derived from these observations on the gamma-ray flux above 200 GeV of F $< 4.4\times 10^{-12}$ cm$^{-2}$ s$^{-1}$ correspond to a tiny fraction (about $10^{-6}$) of the Eddington luminosity of the system, in stark contrast to that seen in the X-ray band. No gamma rays have been detected during observations of 4U 0115+634 in the period of major X-ray activity in October 2015. The flux upper limit derived from our observations is F $< 2.1\times 10^{-12}$ cm$^{-2}$ s$^{-1}$ for gamma rays above 300 GeV, setting an upper limit on the ratio of gamma-ray to X-ray luminosity of less than 4%.Comment: Accepted for publication in the Astrophysical Journa

CSF2-dependent monocyte education in the pathogenesis of ANCA-induced glomerulonephritis

OBJECTIVES: Myeloid cell activation by antineutrophil cytoplasmic antibody (ANCA) is pivotal for necrotising vasculitis, including necrotising crescentic glomerulonephritis (NCGN). In contrast to neutrophils, the contribution of classical monocyte (CM) and non-classical monocyte (NCM) remains poorly defined. We tested the hypothesis that CMs contribute to antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and that colony-stimulating factor-2 (CSF2, granulocyte-macrophage colony-stimulating factor (GM-CSF)) is an important monocyte-directed disease modifier.METHODS: Myeloperoxidase (MPO)-immunised MPO(-/-) mice were transplanted with haematopoietic cells from wild-type (WT) mice, C-C chemokine receptor 2 (CCR2)(-/-) mice to abrogate CM, or transcription factor CCAAT-enhancer-binding protein beta (C/EBPß)(-/-) mice to reduce NCM, respectively. Monocytes were stimulated with CSF2, and CSF2 receptor subunit beta (CSF2rb)-deficient mice were used. Urinary monocytes and CSF2 were quantified and kidney expression was analysed. CSF2-blocking antibody was used in the nephrotoxic nephritis (NTN) model. RESULTS: Compared with WT mice, CCR2(-/-) chimeric mice showed reduced circulating CM and were protected from NCGN. C/EBPß(-/-) chimeric mice lacked NCM but developed NCGN similar to WT chimeric mice. Kidney and urinary CSF2 were upregulated in AAV mice. CSF2 increased the ability of ANCA-stimulated monocytes to generate interleukin-1ß and to promote T17(H) effector cell polarisation. CSF2rb(-/-) chimeric mice harboured reduced numbers of kidney T17(H) cells and were protected from NCGN. CSF2 neutralisation reduced renal damage in the NTN model. Finally, patients with active AAV displayed increased urinary CM numbers, CSF2 levels and expression of GM-CSF in infiltrating renal cells. CONCLUSIONS: CMs but not NCMs are important for inducing kidney damage in AAV. CSF2 is a crucial pathological factor by modulating monocyte proinflammatory functions and thereby T17(H) cell polarisation

Distribution of laminin and fibronectin isoforms in oral mucosa and oral squamous cell carcinoma

The expression of laminin and fibronectin isoforms varies with cellular maturation and differentiation and these differences may well influence cellular processes such as adhesion and motility. The basement membrane (BM) of fetal oral squamous epithelium contains the laminin chains, α2, α3, α5, β1, β2, β3, γ1 and γ2. The BM of adult normal oral squamous epithelium comprises the laminin chains, α3, α5, β1, β3, γ1 and γ2. A re-expression of the laminin α2 and β2 chains could be shown in adult hyperproliferative, dysplastic and carcinomatous lesions. In dysplasia and oral squamous cell carcinoma (OSCC), multifocal breaks of the BM are present as indicated by laminin chain antibodies. These breaks correlate to malignancy grade in their extent. Moreover, in the invasion front the α3 and γ2 chain of laminin-5 can immunohistochemically be found outside the BM within the cytoplasm of budding carcinoma cells and in the adjacent stroma. The correlation between the morphological pattern of invasive tumour clusters and a laminin-5 immunostaining in the adjacent stroma may suggest, first, that a laminin-5 deposition outside the BM is an immunohistochemical marker for invasion and second, that OSCC invasion is guided by the laminin-5 matrix. Expression of oncofetal fibronectins (IIICS de novo glycosylated fibronectin and ED-B fibronectin) could be demonstrated throughout the stromal compartment. However, the ED-B fibronectin synthesizing cells (RNA/RNA in situ hybridization) are confined to small stroma areas and to single stroma and inflammatory cells in the invasion front. A correlation of the number of ED-B fibronectin synthesizing cells to malignancy grade could not be seen. ED-B fibronectin mRNA-positive cells seem to be concentrated in areas of fibrous stroma recruitment with a linear alignment of stromal fibro-/myofibroblasts (desmoplasia). Double staining experiments (ED-B fibronectin in situ hybridization and α-smooth muscle actin immunohistochemistry) indicated that the stroma myofibroblasts are a preferential source of ED-B fibronectin. In conclusion, in OSCC, a fetal extracellular matrix conversion is demonstrable. Tumour cells (laminin α2 and β2 chain) and recruited stromal myofibroblasts (oncofetal ED-B fibronectin) contribute to the fetal extracellular matrix milieu. © 1999 Cancer Research Campaig