Ucma/GRP inhibits phosphate-induced vascular smooth muscle cell calcification via SMAD-dependent BMP signalling

Vascular calcification (VC) is the process of deposition of calcium phosphate crystals in the blood vessel wall, with a central role for vascular smooth muscle cells (VSMCs). VC is highly prevalent in chronic kidney disease (CKD) patients and thought, in part, to be induced by phosphate imbalance. The molecular mechanisms that regulate VC are not fully known. Here we propose a novel role for the mineralisation regulator Ucma/GRP (Upper zone of growth plate and Cartilage Matrix Associated protein/Gla Rich Protein) in phosphate-induced VSMC calcification. We show that Ucma/GRP is present in calcified atherosclerotic plaques and highly expressed in calcifying VSMCs in vitro. VSMCs from Ucma/GRP(-/-) mice showed increased mineralisation and expression of osteo/chondrogenic markers (BMP-2, Runx2, beta-catenin, p-SMAD1/5/8, ALP, OCN), and decreased expression of mineralisation inhibitor MGP, suggesting that Ucma/GRP is an inhibitor of mineralisation. Using BMP signalling inhibitor noggin and SMAD1/5/8 signalling inhibitor dorsomorphin we showed that Ucma/GRP is involved in inhibiting the BMP-2-SMAD1/5/8 osteo/chondrogenic signalling pathway in VSMCs treated with elevated phosphate concentrations. Additionally, we showed for the first time evidence of a direct interaction between Ucma/GRP and BMP-2. These results demonstrate an important role of Ucma/GRP in regulating osteo/chondrogenic differentiation and phosphate-induced mineralisation of VSMCs.NWO ZonMw [MKMD 40-42600-98-13007]; FCT [SFRH/BPD/70277/2010]info:eu-repo/semantics/publishedVersio

Extracellular Matrix Proteomics Reveals Interplay of Aggrecan and Aggrecanases in Vascular Remodeling of Stented Coronary Arteries.

BACKGROUND: Extracellular matrix (ECM) remodeling contributes to in-stent restenosis and thrombosis. Despite its important clinical implications, little is known about ECM changes post-stent implantation. METHODS: Bare-metal and drug-eluting stents were implanted in pig coronary arteries with an overstretch under optical coherence tomography guidance. Stented segments were harvested 1, 3, 7, 14, and 28 days post-stenting for proteomics analysis of the media and neointima. RESULTS: A total of 151 ECM and ECM-associated proteins were identified by mass spectrometry. After stent implantation, proteins involved in regulating calcification were upregulated in the neointima of drug-eluting stents. The earliest changes in the media were proteins involved in inflammation and thrombosis, followed by changes in regulatory ECM proteins. By day 28, basement membrane proteins were reduced in drug-eluting stents in comparison with bare-metal stents. In contrast, the large aggregating proteoglycan aggrecan was increased. Aggrecanases of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family contribute to the catabolism of vascular proteoglycans. An increase in ADAMTS-specific aggrecan fragments was accompanied by a notable shift from ADAMTS1 and ADAMTS5 to ADAMTS4 gene expression after stent implantation. Immunostaining in human stented coronary arteries confirmed the presence of aggrecan and aggrecan fragments, in particular, at the contacts of the stent struts with the artery. Further investigation of aggrecan presence in the human vasculature revealed that aggrecan and aggrecan cleavage were more abundant in human arteries than in human veins. In addition, aggrecan synthesis was induced on grafting a vein into the arterial circulation, suggesting an important role for aggrecan in vascular plasticity. Finally, lack of ADAMTS-5 activity in mice resulted in an accumulation of aggrecan and a dilation of the thoracic aorta, confirming that aggrecanase activity regulates aggrecan abundance in the arterial wall and contributes to vascular remodeling. CONCLUSIONS: Significant differences were identified by proteomics in the ECM of coronary arteries after bare-metal and drug-eluting stent implantation, most notably an upregulation of aggrecan, a major ECM component of cartilaginous tissues that confers resistance to compression. The accumulation of aggrecan coincided with a shift in ADAMTS gene expression. This study provides the first evidence implicating aggrecan and aggrecanases in the vascular injury response after stenting

Complexity of multi-dimensional spontaneous EEG decreases during propofol induced general anaesthesia

Emerging neural theories of consciousness suggest a correlation between a specific type of neural dynamical complexity and the level of consciousness: When awake and aware, causal interactions between brain regions are both integrated (all regions are to a certain extent connected) and differentiated (there is inhomogeneity and variety in the interactions). In support of this, recent work by Casali et al (2013) has shown that Lempel-Ziv complexity correlates strongly with conscious level, when computed on the EEG response to transcranial magnetic stimulation. Here we investigated complexity of spontaneous high-density EEG data during propofol-induced general anaesthesia. We consider three distinct measures: (i) Lempel-Ziv complexity, which is derived from how compressible the data are; (ii) amplitude coalition entropy, which measures the variability in the constitution of the set of active channels; and (iii) the novel synchrony coalition entropy (SCE), which measures the variability in the constitution of the set of synchronous channels. After some simulations on Kuramoto oscillator models which demonstrate that these measures capture distinct ‘flavours’ of complexity, we show that there is a robustly measurable decrease in the complexity of spontaneous EEG during general anaesthesia

Explicit de Sitter Flux Vacua for Global String Models with Chiral Matter

We address the open question of performing an explicit stabilisation of all closed string moduli (including dilaton, complex structure and Kaehler moduli) in fluxed type IIB Calabi-Yau compactifications with chiral matter. Using toric geometry we construct Calabi-Yau manifolds with del Pezzo singularities. D-branes located at such singularities can support the Standard Model gauge group and matter content. In order to control complex structure moduli stabilisation we consider Calabi-Yau manifolds which exhibit a discrete symmetry that reduces the effective number of complex structure moduli. We calculate the corresponding periods in the symplectic basis of invariant three-cycles and find explicit flux vacua for concrete examples. We compute the values of the flux superpotential and the string coupling at these vacua. Starting from these explicit complex structure solutions, we obtain AdS and dS minima where the Kaehler moduli are stabilised by a mixture of D-terms, non-perturbative and perturbative alpha'-corrections as in the LARGE Volume Scenario. In the considered example the visible sector lives at a dP_6 singularity which can be higgsed to the phenomenologically interesting class of models at the dP_3 singularity.Comment: 49 pages, 5 figures; v2: references adde

Light Hadron Spectrum and Quark Masses from Quenched Lattice QCD

We present details of simulations for the light hadron spectrum in quenched QCD carried out on the CP-PACS parallel computer. Simulations are made with the Wilson quark action and the plaquette gauge action on 32^3x56 - 64^3x112 lattices at four lattice spacings (a \approx 0.1-0.05 fm) and the spatial extent of 3 fm. Hadronic observables are calculated at five quark masses (m_{PS}/m_V \approx 0.75 - 0.4), assuming the u and d quarks being degenerate but treating the s quark separately. We find that the presence of quenched chiral singularities is supported from an analysis of the pseudoscalar meson data. We take m_\pi, m_\rho and m_K (or m_\phi) as input. After chiral and continuum extrapolations, the agreement of the calculated mass spectrum with experiment is at a 10% level. In comparison with the statistical accuracy of 1-3% and systematic errors of at most 1.7% we have achieved, this demonstrates a failure of the quenched approximation for the hadron spectrum: the meson hyperfine splitting is too small, and the octet masses and the decuplet mass splittings are both smaller than experiment. Light quark masses are calculated using two definitions: the conventional one and the one based on the axial-vector Ward identity. The two results converge toward the continuum limit, yielding m_{ud}=4.29(14)^{+0.51}_{-0.79} MeV. The s quark mass depends on the strange hadron mass chosen for input: m_s = 113.8(2.3)^{+5.8}_{-2.9} MeV from m_K and m_s = 142.3(5.8)^{+22.0}_{-0} MeV from m_\phi, indicating again a failure of the quenched approximation. We obtain \Lambda_{\bar{MS}}^{(0)}= 219.5(5.4) MeV. An O(10%) deviation from experiment is observed in the pseudoscalar meson decay constants.Comment: 60 pages, 49 figure

Precise Measurements of Direct CP Violation, CPT Symmetry, and Other Parameters in the Neutral Kaon System

We present precise tests of CP and CPT symmetry based on the full dataset of K to pipi decays collected by the KTeV experiment at Fermi National Accelerator Laboratory during 1996, 1997, and 1999. This dataset contains 16 million K to 2pi0 and 69 million K to pi+pi- decays. We measure the direct CP violation parameter Re(epsilon'/epsilon) = (19.2 pm 2.1)x10-4. We find the KL-KS mass difference Deltam = (5270 pm 12)x10^6 hbar/s and the KS lifetime tauS = (89.62 pm 0.05)x10-12 s. We also measure several parameters that test CPT invariance. We find the difference between the phase of the indirect CP violation parameter, epsilon, and the superweak phase, phi_epsilon - phi_SW = (0.40 pm 0.56) degrees. We measure the difference of the relative phases between the CP violating and CP conserving decay amplitudes for K to pi+pi- (phi+-) and for K to 2pi0 (phi00), Delta phi = (0.30 pm 0.35) degrees. From these phase measurements, we place a limit on the mass difference between K0 and K0bar, DeltaM < 4.8 x 10-19 GeV/c^2 at 95% C.L. These results are consistent with those of other experiments, our own earlier measurements, and CPT symmetry.Comment: 28 pages, 30 figures; removed extra figur

Measurements of KL Branching Fractions and the CP Violation Parameter |eta+-|

We present new measurements of the six largest branching fractions of the KL using data collected in 1997 by the KTeV experiment (E832) at Fermilab. The results are B(KL -> pi e nu) = 0.4067 +- 0.0011 B(KL -> pi mu nu) = 0.2701 +- 0.0009 B(KL -> pi+ pi- pi0) = 0.1252 +- 0.0007 B(KL -> pi0 pi0 pi0) = 0.1945 +- 0.0018 B(KL -> pi+ pi-) = (1.975 +- 0.012)E-3, and B(KL -> pi0 pi0) = (0.865 +- 0.010)E-3, where statistical and systematic errors have been summed in quadrature. We also determine the CP violation parameter |eta+-| to be (2.228 +- 0.010)E-3. Several of these results are not in good agreement with averages of previous measurements.Comment: Submitted to Phys. Rev. D; 20 pages, 22 figure

Plasma filaments in the scrape-off layer of Wendelstein 7-X

Plasma filaments have been observed by reciprocating electric probes in the Scrape-Off Layer (SOL) of the Wendelstein 7-X stellarator. Comparison with target probes indicates that a filament observed in the W7-X SOL extends to the sheath. Two-dimensional simulations of seeded filaments exhibit good quantitative agreement with experimental measurements in filament velocity scalings, despite an assumption of constant field line curvature. Both experiment and simulation show a slow radial propagation of filaments, indicating that filaments are essentially bound to their flux surface and do not perform ballistic radial motion. In contrast, the poloidal propagation along flux surfaces is much faster than the radial motion

Improved Search for Muon-Neutrino to Electron-Neutrino Oscillations in MINOS

We report the results of a search for ν_e appearance in a ν_μ beam in the MINOS long-baseline neutrino experiment. With an improved analysis and an increased exposure of 8.2×10^(20) protons on the NuMI target at Fermilab, we find 2sin^2(θ_(23))sin^2(2θ_(13))<0.12(0.20) at 90% confidence level for δ=0 and the normal (inverted) neutrino mass hierarchy, with a best-fit of 2sin^2(θ_(23))sin^2(2θ_(13))=0.041^(+0.047)_(-0.031)(0.079^(+0.071)_(-0.053). The θ_(13)= 0 hypothesis is disfavored by the MINOS data at the 89% confidence level

A Measurement of the KL Charge Asymmetry

We present a measurement of the charge asymmetry $\delta_L$ in the mode $K_L \to \pi^{\pm}e^{\mp}\nu$ based on 298 million analyzed decays. We measure a value of $\delta_L = (3322 \pm 58(stat) \pm 47(sys))\cdot 10^{-6}$, in good agreement with previous measurements and 2.4 times more precise than the current best published result. The result is used to place more stringent limits on CPT and $\Delta S = \Delta Q$ violation in the neutral kaon system.Comment: Submitted to Physical Review Letters, Dec 31, 2001. 4 pages, 4 figure