Nuclear Attenuation Research Articles

FBXW7 modulates cellular stress response and metastatic potential through ​HSF1 post-translational modification.

Heat-shock factor 1 (HSF1) orchestrates the heat-shock response in eukaryotes. Although this pathway has been evolved to help cells adapt in the presence of challenging conditions, it is co-opted in cancer to support malignancy. However, the mechanisms that regulate HSF1 and thus cellular stress response are poorly understood. Here we show that the ubiquitin ligase FBXW7 α interacts with HSF1 through a conserved motif phosphorylated by GSK3β and ERK1. FBXW7α ubiquitylates HSF1 and loss of FBXW7α results in impaired degradation of nuclear HSF1 and defective heat-shock response attenuation. FBXW7α is either mutated or transcriptionally downregulated in melanoma and HSF1 nuclear stabilization correlates with increased metastatic potential and disease progression. FBXW7α deficiency and subsequent HSF1 accumulation activates an invasion-supportive transcriptional program and enhances the metastatic potential of human melanoma cells. These findings identify a post-translational mechanism of regulation of the HSF1 transcriptional program both in the presence of exogenous stress and in cancer.

Latest LHCb results from the pA data

The J/ψ production cross-sections in proton-nucleus collisions at = 5 TeV are measured using the LHCb detector. A sizable suppression is observed in pA forward collisions, while only a slight suppression is seen in pA backward collisions. The nuclear attenuation factor RpA and the forward-backward production ratio rFB are determined.

Histone deacetylase inhibitor suberoylanilide hydroxamic acid attenuates Toll-like receptor 4 signaling in lipopolysaccharide-stimulated mouse macrophages

ObjectiveWe have previously demonstrated that pretreatment and posttreatment of animals with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, can improve survival in a mouse model of lipopolysaccharide (LPS)-induced severe shock. This study was designed to assess whether SAHA affects LPS/Toll-like receptor 4 signaling through acetylation of heat shock protein 90 (HSP90) and degradation of its client protein interleukin-1 receptor–associated kinase 1 (IRAK1). MethodsRAW264.7 cells were exposed to LPS (1 μg/mL) for 2 h, followed by treatment with SAHA (10 μM) or geldanamycin (3 μM), an inhibitor of HSP90. Sham (no SAHA, no LPS) macrophages served as a control. The cells were harvested at different time points, and time zero served as the reference point. ResultsLPS dramatically increased protein expression of myeloid differentiation factor 88 and IRAK1, and stimulated nuclear translocation of nuclear factor κB, leading to an increases of gene expression and protein production of tumor necrosis factor α and interleukin-6. Treatment with SAHA significantly attenuated these LPS-stimulated alterations. LPS or SAHA did not change the levels of HSP90 protein, but immunoprecipitation studies demonstrated that SAHA treatment enhanced acetylation of HSP90, and increased the dissociation of IRAK1, compared to the LPS control. ConclusionsSAHA suppresses LPS/Toll-like receptor 4 signaling in LPS-stimulated macrophages through multiple potential mechanisms. It inhibits the function of HSP90 through hyperacetylation of the chaperone protein, which results in dissociation and degradation of the client protein IRAK1 and, at least in part, leads to a decrease in nuclear translocation of nuclear factor κB and attenuation of key proinflammatory cytokine expression.

Nuclear attenuation at low energies

Nuclear attenuation of the single hadron at low energies of the virtual photon $\ensuremath{\nu}$ ($\ensuremath{\nu}l5\phantom{\rule{0.16em}{0ex}}\phantom{\rule{4.pt}{0ex}}\text{GeV}$) is considered in the framework of the improved two-scale model, which is one of the versions of the string model. The model is used for a description of the ratio of the multiplicities of pions electroproduced on nuclear and deuterium targets as a function of the energy of virtual photons and the fractional energy of the pions. The final state interactions, which are essential in this energy range, are taken into account. A comparison with two sets of the experimental data obtained at JLab is performed. A satisfactory agreement of the theoretical calculations with the first set of data for the ratio of the multiplicities of positively charged pions on carbon, iron, and lead targets to that on the deuterium one is obtained. However, agreement with the second set of data for the ratio of the multiplicities of positively and negatively charged pions on the aluminum target to those on the deuterium one is poor. Possible reasons for this situation are discussed.

Nuclear attenuation of high-energy multihadron systems in a string model

Nuclear attenuation of the multi-hadron systems in the string model is considered. The improved two-scale model with set of parameters obtained recently for the single hadron attenuation is used for calculation of the multiplicity ratios of the one-, two- and three-hadron systems electroproduced on nuclear and deuterium targets. The comparison of the features of the one-, two- and three-hadron systems is performed. The predictions of the model for multiplicity ratios of multi-hadron systems as functions of different convenient variables are presented.

A study of the double hadron neutrino production on nuclei

The nuclear medium influence on the dihadron neutrinoproduction is investigated for the first time, using the data obtained with SKAT bubble chamber. An indication is obtained that the nuclear attenuation of the dihadron is more expressed for kinematically closest hadron pairs. The experimental data on the dihadron attenuation and on the ratio of the dihadron to single-hadron yields are compared with predictions of the two-scale string fragmentation model.

Modeling Final-State Interactions with a Relativistic Multiple-Scattering Approximation

We address the issue of nuclear attenuation in nucleon and pion knockout reactions. A selection of results from a model based on a relativistic multiple-scattering approximation is presented. We show transparency calculations for pion electroproduction on several nuclei, where data are in very good agreement with calculations including color transparency. Secondly, we discuss the density dependence of reactions involving one or double proton knockout. The latter reaction succeeds in probing the high density regions in the deep interior of the nucleus.

Validation of a multi-layer Green’s function code for ion beam transport

To meet the challenge of future deep space programs, an accurate and efficient engineering code for analyzing the shielding requirements against high-energy galactic heavy ion radiation is needed. In consequence, a new version of the HZETRN code capable of simulating high charge and energy (HZE) ions with either laboratory or space boundary conditions is currently under development. This code, GRNTRN, is based on a Green’s function approach to the solution of the one-dimensional Boltzmann transport equation and like its predecessor is deterministic in nature. The computational model consists of the lowest order asymptotic approximation followed by a Neumann series expansion with non-perturbative corrections. The physical description includes energy loss with straggling, nuclear attenuation, nuclear fragmentation with energy dispersion and down shift. Code validation in the laboratory environment is addressed by showing that GRNTRN accurately predicts energy loss spectra as measured by solid-state detectors in ion beam experiments with multi-layer targets. In order to verify and benchmark the code with space boundary conditions, measured particle fluxes are propagated through several thicknesses of shielding using both GRNTRN and the current version of HZETRN. The favorable agreement obtained indicates that GRNTRN accurately models the propagation of HZE ions in laboratory settings. It also compares very well with the extensively validated space environment HZETRN code and thus provides verification of the HZETRN propagator.

W1713 8-Hydroxydeoxyguanosine (OH 8Dg) Paradoxically Attenuated Oxidative Stress Through Inactivation of Small GTP-Binding Protein RAC and Inhibition of NADPH Oxidases; Efficacy in Wirs Induced Gastritis

Background & Aims Guanine is easily attacked by ROS to yield oh8dG and oh8dG, the most common DNA adduct known to be mutagenic or carcinogenic, is used as a marker of oxidative stress. Fortunately, mammalian cells have multiple repair systems such as BER or NER to remove oh8dG formed by overwhelming stress. We performed the study to know whether exogenous oh8dG can ameliorate the degree of water immersion restraint stress (WIRS)-induced gastritis through anti-inflammatory and anti-oxidative actions, a novel action of synthetic oh8dG as gastroprotective agent. Methods Electron spin resonance (ESR, Joel) measurement based on Fenton reaction using DMPO as spin adductor was done to check antioxidative action of oh8dG. In Vivo animal model of WIRS were treated with several kinds of drug, PPI, rebamipide, vitamine E, and oh8dG, and we progressed to identify molecular mechanisms how oh8dG did impose anti-inflammatory actions in E. coli LPS (1μg/ml) stimulated Raw264.7 mouse macrophage cell. Results On ESR measurement, OH radical was detected with iron based Fenton reaction using DMPO adductor, but oh8dG in >50pg dose completely scavenged OH radicals, of which action was further confirmed by DCFDA spectroscopy and confocal measurement. oh8dG efficiently preventedWIRS-induced gastritis and ulceration, equivalent efficacy to PPI, for which mucosal levels of TNF-α and IL-1β were significantly attenuated. In a translational study to document the action mechanisms of anti-inflammatory and anti-oxidative action of oh8dG, we checked NOXs expression after oh8dG. oh8dG treatment was associated with marked attenuations of NOX1, NOXO1, and NOXA1 in addition to decreased expression of LPS-induced inflammatory mediators, iNOS, COX-2, IL-1β, and IL-6. These inhibitory actions of NOXs with oh8dG were associated with either plasma membrane or nuclear membrane attenuation of NOXs expression on confocal imaging study, coinciding with decreased levels of oxidized products. oh8dG inactivated p38 and inhibited nuclear translocation of NF-κB, but did not affect Akt activation. Instead of Akt regulation, oh8dG antagonized GTP toward Rac, a small GTP binding protein Conclusions oh8dG is not a simple byproduct, but a functional molecule regulating oxidative stressinduced gastritis through antagonizing small GTP-binding proteins like Rac and blocking the stream to stress-induced inflammatory and oxidative bursts.

Density dependence of single-proton and two-proton knockout reactions under quasifree conditions

We consider high-energy quasifree single- and two-proton knockout reactions induced by electrons and protons and address the question of what target-nucleus densities can be effectively probed after correcting for nuclear attenuation (initial- and final-state interactions). Our calculations refer to ejected proton kinetic energies of 1.5 GeV, the reactions $(e,{e}^{'}p)$, $(\ensuremath{\gamma},\mathit{pp})$, and $(p,2p)$, and a carbon target. It is shown that each of the three reactions is characterized by a distinctive sensitivity to the density of the target nucleus. The bulk of the $(\ensuremath{\gamma},\mathit{pp})$ strength stems from the high-density regions in the deep nuclear interior. Despite the strong attenuation, sizable densities can be probed by $(p,2p)$ reactions provided that the energy resolution allows one to pick nucleons from $s$ orbits. The effective mean densities that can be probed in high-energy $(e,{e}^{'}p)$ reactions is of the order of 30%--50% of the nuclear saturation density.

Akt-dependent NF-κB activation is required for bile acids to rescue colon cancer cells from stress-induced apoptosis

Conjugated secondary bile acids promote human colon cancer cell proliferation by activating EGF receptors (EGFR). We hypothesized that bile acid-induced EGFR activation also mediates cell survival by downstream Akt-regulated activation of NF-κB. Deoxycholyltaurine (DCT) treatment attenuated TNF-α-induced colon cancer cell apoptosis, and stimulated rapid and sustained NF-κB nuclear translocation and transcriptional activity (detected by NF-κB binding to an oligonucleotide consensus sequence and by activation of luciferase reporter gene constructs). Both DCT-induced NF-κB nuclear translocation and attenuation of TNF-α-stimulated apoptosis were dependent on EGFR activation. Inhibitors of nuclear translocation, proteosome activity, and IκBα kinase attenuated NF-κB transcriptional activity. Cell transfection with adenoviral vectors encoding a non-degradable IκBα ‘super-repressor’ blocked the actions of DCT on both NF-κB activation and TNF-α-induced apoptosis. Likewise, transfection with mutant akt and treatment with a chemical inhibitor of Akt attenuated effects of DCT on NF-κB transcriptional activity and TNF-α-induced apoptosis. Chemical inhibitors of Akt and NF-κB activation also attenuated DCT-induced rescue of H508 cells from ultraviolet radiation-induced apoptosis. Collectively, these observations indicate that, downstream of EGFR, bile acid-induced colon cancer cell survival is mediated by Akt-dependent NF-κB activation. These findings provide a mechanism whereby bile acids increase resistance of colon cancer to chemotherapy and radiation.

Nuclear attenuation and pt broadening in DIS at HERMES

The influence of the cold nuclear medium effects on hadron multiplicities in semiinclusive deepinelastic scattering was studied extensively. A series of measurements on deuterium, helium, neon, krypton and xenon target has been performed in order to study hadronization. Hadron multiplicities on nucleus A relative to those on deuteron are presented for various hadrons together with the first direct measurement of pt-broadening effects in lepto production. The data have been accumulated by the Hermes experiment at the Desy laboratory using a 27.6 GeV positron or electron beam. These analysis provide precious information concerning the spacetime evolution of hadronization.

Hadrons in nuclei from high (200 GeV) to low (1 GeV) energies

The study of the interaction of hadrons, produced by introducing elementary probes into a nucleus, with the surrounding nuclear medium can give insight into two important questions. Firstly, at high energies, the production process, the time-scales connected with it, and the prehadronic interactions can be studied by using the nuclear radius as a length-scale. We do this here by analyzing data from the EMC and HERMES experiments on nuclear attenuation. Secondly, at low energies the spectral function, and thus the selfenergy of the produced hadron, can be studied. Specifically, we analyze the CBELSA/TAPS data on ω production in nuclei and discuss the importance of understanding in-medium effects both on the primary production cross section and the final state branching ratio. In both of these studies, an excellent control of the final state interactions is essential.

Time dependent hadronization via HERMES and EMC data consistency

Using QCD-inspired time dependent cross sections for pre-hadrons we provide a combined analysis of available experimental data on hadron attenuation in DIS off nuclei as measured by HERMES with 12 and 27 GeV and by EMC with 100 and 280 GeV lepton beam energies. We extract the complete four-dimensional evolution of the pre-hadrons using the Jetset-part of Pythia. We find a remarkable sensitivity of nuclear attenuation data to the details of the time-evolution of cross sections. Only cross sections evolving linearly in time describe the available data in a wide kinematical regime. Predictions for experimental conditions at JLAB/CLAS (5 and 12 GeV beam energies) are included.

Open charm tomography of cold and hot nuclear matter

We identify the nuclear effects that modify the cross sections for open heavy flavor production in proton-nucleus and nucleus-nucleus collisions. In p+A reactions, we calculate and resum the coherent nuclear-enhanced power corrections from the final-state parton scattering in the medium. We find that single and double inclusive open charm production can be suppressed as much as the yield of neutral pions from dynamical high-twist shadowing. Effects of energy loss in p+A collisions are also investigated. These lead to significantly weaker transverse momentum dependence of the nuclear attenuation and give a sizable contribution to the forward rapidity hadron suppression. In A+A reactions we revisit the question of the measured large heavy flavor quenching at RHIC. We derive the collisional broadening of the heavy meson's transverse momentum and the distortion of its intrinsic light cone wave function. The medium-induced dissociation probability of heavy mesons is shown to be sensitive to the opacity of the quark-gluon plasma and the time dependence of its formation and evolution. In contrast to previous results on heavy quark modification, our approach predicts suppression of B-mesons comparable to that of D-mesons at transverse momenta as low as pT ~ 10 GeV. It allows for an improved description of the large attenuation of non-photonic electrons in central Au+Au reactions at RHIC. Preliminary results in the implementation of collisional and radiative energy loss in a Langevin simulation approach to heavy quark diffusion and attenuation are also presented.

Nuclear attenuation of high energy two-hadron system in the string model

Nuclear attenuation of the two-hadron system is considered in the string model. The two-scale model and its improved version, with two different choices of constituent formation time and sets of parameters obtained earlier for the single hadron attenuation, are used to describe the available experimental data for the z-dependence of the subleading hadron, whereas satisfactory agreement with the experimental data has been observed. A model prediction for the ν-dependence of the nuclear attenuation of the two-hadron system is also presented.

Recent pQCD calculations of heavy quark production

We summarize the results of a recent study of heavy quark production and attenuation in cold nuclear matter. In p+p collisions we investigate the relative contribution of partonic sub-processes to D meson production and D meson-triggered inclusive di-hadrons to lowest order in perturbative QCD. While gluon fusion dominates the creation of large angle pairs, charm on light parton scattering determines the yield of single inclusive D mesons. The distinctly different non-perturbative fragmentation of c quarks into D mesons versus the fragmentation of quarks and gluons into light hadrons results in a strong transverse momentum dependence of anticharm content of the away-side charm-triggered jet. In p+A reactions we calculate and resum the coherent nuclear-enhanced power corrections from the final-state partonic scattering in the medium. We find that single and double inclusive open charm production can be suppressed as much as the yield of neutral pions from dynamical high-twist shadowing. Effects of energy loss in p+A collisions are also investigated in the incoherent Bertsch–Gunion limit and may lead to significantly weaker transverse momentum dependence of the nuclear attenuation.

Open charm tomography of cold nuclear matter

We study the relative contribution of partonic subprocesses to $D$ meson production and $D$ meson-triggered inclusive di-hadrons to lowest order in perturbative QCD. While gluon fusion dominates the creation of large angle $D\overline{D}$ pairs, charm on light parton scattering determines the yield of single inclusive $D$ mesons. The distinctly different nonperturbative fragmentation of $c$ quarks into $D$ mesons versus the fragmentation of quarks and gluons into light hadrons results in a strong transverse momentum dependence of anticharm content of the away side charm-triggered jet. In $p+A$ reactions, we calculate and resum the coherent nuclear-enhanced power corrections from the final-state partonic scattering in the medium. We find that single and double inclusive open charm production can be suppressed as much as the yield of neutral pions from dynamical high-twist shadowing. Effects of energy loss in $p+A$ collisions are also investigated phenomenologically and may lead to significantly weaker transverse momentum dependence of the nuclear attenuation.

Color neutralization in deep inelastic scattering on nuclei

Particle production in deep inelastic scattering on nuclei is reduced due to absorption of the produced particles in the nucleus. The photon ejects a quark from a bound nuclon which propagates through the nucleus forming a prehadron before turning into a hadron. Prehadron formation occurs on a shorter length scale than hadron formation and is therefore very important. We explicitly derive aA 2/3 dependence of nuclear attenuation.

Coherent QCD multiple scattering in proton–nucleus collisions

We argue that high energy proton–nucleus (p + A) collisions provide an excellent laboratory for studying nuclear size enhanced parton multiple scattering where power corrections to the leading twist perturbative QCD factorization approach can be systematically computed. We identify and resum these corrections and calculate the centrality- and rapidity-dependent nuclear suppression of single and double inclusive hadron production at moderate transverse momenta. We demonstrate that both spectra and dihadron correlations in p + A reactions are sensitive measures of such dynamical nuclear attenuation effects.