Title Page Sildenafil does not prevent heart hypertrophy and fibrosis induced by cardiomyocyte AT 1 R signaling

List of non-standard abbreviations: cGMP-dependent protein kinase type I (cGKI); protein kinase G (PKG); natriuretic peptides (NPs), cyclic guanosine-3´,5´-monophosphate (cGMP); nitric oxide (NO); cyclic adenosine-3´,5´-monophosphate (cAMP); Angiotensin II (AngII); Angiotensin II receptor type 1 (AT 1 R); sildenafil (SIL); cardiomyocyte (CM), smooth muscle cell (SMC); angiotensin converting enzyme (ACE), cGKIβ rescue mice (βRM), phosphodiesterase (PDE); Förster resonance energy transfer (FRET); 3-isobutyl-1-methylxanthine (IBMX), C-type natriuretic peptide (CNP). Section assignment: Cardiovascular Number of words: 4141 (excluding abstract, material and methods, reference list and figure legends) Number of words (abstract): 250 Number of references: 67 Page count: 37 JPET#226092 3 Abstract Analyses of several mouse models imply that the phosphodiesterase 5 (PDE5) inhibitor sildenafil (SIL), via increasing cyclic guanosine-3',5'-monophosphate (cGMP), affords protection against angiotensin II (AngII) stimulated cardiac remodeling. However, it is unclear which cell types are involved in these beneficial effects, because AngII may exert its adverse effects by modulating multiple reno-vascular and cardiac functions via AngII type 1 receptors (AT 1 R). To test the hypothesis that SIL/cGMP oppose cardiac stress provoked by amplified AngII/AT 1 R directly in cardiomyocytes (CMs), we studied transgenic mice with CM-specific overexpression of the AT 1 R under the control of the α -myosin-heavy chain promoter (αMHC-AT 1 R tg/+ ). The extent of cardiac growth was assessed in absence or presence of SIL and defined by referring changes in heart-weight to body-weight or tibia length. Hypertrophic marker genes, extracellular matrix-regulating factors and expression patterns of fibrosis markers were examined in α MHC-AT 1 R tg/+ ventricles (±SIL) and corroborated by investigating different components of the natriuretic peptide (NP)/PDE5/cGMP pathway as well as cardiac functions. cGMP levels in heart lysates and intact CMs were measured by competitive immunoassays and FRET. We find higher cardiac and CM cGMP levels and up-regulation of the cGMP-dependent protein kinase I (cGKI) with AT 1 R over-expression. However, even a prolonged SIL treatment regimen did not limit the progressive CM growth, fibrosis or decline in cardiac functions in the αMHC-AT 1 R tg/+ model suggesting that SIL does not interfere with the pathogenic actions of amplified AT 1 R signaling in CMs. Hence, the cardiac/non-cardiac cells involved in the cross-talk between SIL-sensitive PDE activity and AngII/AT 1 R need to be identified

Multiplicity Distributions and Charged-neutral Fluctuations

Results from the multiplicity distributions of inclusive photons and charged particles, scaling of particle multiplicities, event-by-event multiplicity fluctuations, and charged-neutral fluctuations in 158$\cdot A$ GeV Pb+Pb collisions are presented and discussed. A scaling of charged particle multiplicity as $N_{part}^{1.07\pm 0.05}$ and photons as $N_{part}^{1.12\pm 0.03}$ have been observed, indicating violation of naive wounded nucleon model. The analysis of localized charged-neutral fluctuation indicates a model-independent demonstration of non-statistical fluctuations in both charged particles and photons in limited azimuthal regions. However, no correlated charged-neutral fluctuations are observed.Comment: Talk given at the International Symposium on Nuclear Physics (ISNP-2000), Mumbai, India, 18-22 Dec 2000, Proceedings to be published in Pramana, Journal of Physic

Azimuthal Anisotropy of Photon and Charged Particle Emission in Pb+Pb Collisions at 158 A GeV/c

The azimuthal distributions of photons and charged particles with respect to the event plane are investigated as a function of centrality in Pb + Pb collisions at 158 A GeV/c in the WA98 experiment at the CERN SPS. The anisotropy of the azimuthal distributions is characterized using a Fourier analysis. For both the photon and charged particle distributions the first two Fourier coefficients are observed to decrease with increasing centrality. The observed anisotropies of the photon distributions compare well with the expectations from the charged particle measurements for all centralities.Comment: 8 pages and 6 figures. The manuscript has undergone a major revision. The unwanted correlations were enhanced in the random subdivision method used in the earlier version. The present version uses the more established method of division into subevents separated in rapidity to minimise short range correlations. The observed results for charged particles are in agreement with results from the other experiments. The observed anisotropy in photons is explained using flow results of pions and the correlations arising due to the decay of the neutral pion

HERAFitter

HERAFitter is an open-source package that provides a framework for the determination of the parton distribution functions (PDFs) of the proton and for many different kinds of analyses in Quantum Chromodynamics (QCD). It encodes results from a wide range of experimental measurements in lepton–proton deep inelastic scattering and proton–proton (proton–antiproton) collisions at hadron colliders. These are complemented with a variety of theoretical options for calculating PDF-dependent cross section predictions corresponding to the measurements. The framework covers a large number of the existing methods and schemes used for PDF determination. The data and theoretical predictions are brought together through numerous methodological options for carrying out PDF fits and plotting tools to help to visualise the results. While primarily based on the approach of collinear factorisation, HERAFitter also provides facilities for fits of dipole models and transverse-momentum dependent PDFs. The package can be used to study the impact of new precise measurements from hadron colliders. This paper describes the general structure of HERAFitter and its wide choice of options

Redox regulation of mitochondrial fission, protein misfolding, synaptic damage, and neuronal cell death: potential implications for Alzheimer’s and Parkinson’s diseases

Normal mitochondrial dynamics consist of fission and fusion events giving rise to new mitochondria, a process termed mitochondrial biogenesis. However, several neurodegenerative disorders manifest aberrant mitochondrial dynamics, resulting in morphological abnormalities often associated with deficits in mitochondrial mobility and cell bioenergetics. Rarely, dysfunctional mitochondrial occur in a familial pattern due to genetic mutations, but much more commonly patients manifest sporadic forms of mitochondrial disability presumably related to a complex set of interactions of multiple genes (or their products) with environmental factors (G × E). Recent studies have shown that generation of excessive nitric oxide (NO), in part due to generation of oligomers of amyloid-β (Aβ) protein or overactivity of the NMDA-subtype of glutamate receptor, can augment mitochondrial fission, leading to frank fragmentation of the mitochondria. S-Nitrosylation, a covalent redox reaction of NO with specific protein thiol groups, represents one mechanism contributing to NO-induced mitochondrial fragmentation, bioenergetic failure, synaptic damage, and eventually neuronal apoptosis. Here, we summarize our evidence in Alzheimer’s disease (AD) patients and animal models showing that NO contributes to mitochondrial fragmentation via S-nitrosylation of dynamin-related protein 1 (Drp1), a protein involved in mitochondrial fission. These findings may provide a new target for drug development in AD. Additionally, we review emerging evidence that redox reactions triggered by excessive levels of NO can contribute to protein misfolding, the hallmark of a number of neurodegenerative disorders, including AD and Parkinson’s disease. For example, S-nitrosylation of parkin disrupts its E3 ubiquitin ligase activity, and thereby affects Lewy body formation and neuronal cell death

Azimuthal anisotropy in S+Au reactions at 200 A GeV

Azimuthal correlations of photons produced at mid-rapidity in 200 A GeV S + Au collisions have been studied using a preshower photon multiplicity detector in the WA93 experiment. The Fourier expansion method has been employed to estimate the event plane via the anisotropy of the event as a function of centrality. The event plane correlation technique has been used to determine the true event anisotropy, beyond the anisotropy which arises due to finite multiplicity. The VENUS event generator with rescattering and proper simulation of the detector response can explain only a portion of the observed anisotropy. The residual anisotropy is found to be of the order of 5% for semi-central collisions. This suggests that directed collective flow of the produced particles is present at SPS energies. (C) 1997 Published by Elsevier Science B.V