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The ALICE Zero Degree Calorimeters (ZDC) provide information about event geometry in heavy-ion collisions through the detection of spectator nucleons and allow to estimate the delivered luminosity. They are also very useful in p–A collisions, allowing an unbiased estimation of collision centrality. The Run 3 operating conditions will involve a tenfold increase in instantaneous luminosity in heavy-ion collisions, with event rates that, taking into account the different processes, could reach 5 MHz in the ZDCs. The challenges posed by this demanding environment lead to a redesign of the readout system and to the transition to a continuous acquisition. The new system is based on 12 bit, 1 Gsps FMC digitizers that will continuously sample the 26 ZDC channels. Triggering, pedestal estimation and luminosity measurements will be performed on FPGA directly connected to the front-end. The new readout system and the performances foreseen in Run 3 are presented.

Endothelial cells (EC) are the first elements exposed to mediators circulating in the bloodstream, and react to stimulation with finely tuned responses mediated by different signal transduction pathways, leading the endothelium to adapt. Neuropeptide Y (NPY), the most abundant peptide in heart and brain, is mainly involved in the neuroendocrine regulation of the stress response. The regulatory roles of NPY depend on many factors, including its enzymatic processing, receptor subtypes and related signal transduction systems, including the phosphoinositide (PI) pathway and related phospholipase C (PI-PLC) family of enzymes. The panel of expression of PI-PLC enzymes differs comparing quiescent versus differently stimulated human EC. Growing evidences indicate that the regulation of the expression of PLC genes, which codify for PI-PLC enzymes, might act as an additional mechanism of control of the PI signal transduction pathway. NPY was described to potentiate the activation of PI-PLC enzymes in different cell types, including EC. In the present experiments, we stimulated human umbilical vein EC using different doses of NPY in order to investigate a possible role upon the expression PLC genes. NPY reduced the overall transcription of PLC genes, excepting for PLCE . The most significant effects were observed for PLCB2 and PLCD1 , both isoforms recruited by means of G-proteins and G-protein-coupled receptors. NPY behavior was comparable with other PI-PLC interacting molecules that, beside the stimulation of phospholipase activity, also affect the upcoming enzymes’ production acting upon gene expression. That might represent a mode to regulate the activity of PI-PLC enzymes after activation.

Ezrin, a protein belonging to the Ezrin, radixin and moesin (ERM) family, was engaged in the metastatic spread of osteosarcoma. The Protein 4.1, Ezrin, radixin, moesin (FERM) domain of Ezrin binds the membrane Phosphatydil inositol (4,5) bisphosphate (PIP2), a crucial molecule belonging to the Phosphoinositide (PI) signal transduction pathway. The cytoskeleton cross-linker function of Ezrin largely depends on membrane PIP2 levels, and thus upon the activity of related enzymes belonging to the PI-specific phospholipase C (PI-PLC) family. Based on the role of Ezrin in tumour progression and metastasis, we silenced the expression of Vil2 (OMIM *123900), the gene which codifies for Ezrin, in cultured human osteosarcoma 143B and Hs888 cell lines. After Ezrin silencing, the growth rate of both cell lines was significantly reduced and morphogical changes were observed. We also observed moderate variations both of selected PI-PLC enzymes within the cell and of expression of the corresponding PLC genes. In 143B cell line the transcription of PLCB1 decreased, of PLCG2 increased and of PLCE differed in a time-dependent manner. In Hs888, the expression of PLCB1 and of PLCD4 significantly increased, of PLCE moderately increased in a time dependent manner; the expression of PLCG2 was up-regulated. These observations indicate that Ezrin silencing affects the transcription of selected PLC genes, suggesting that Ezrin might influence the expression regulation of PI-PLC enzymes.

The signaling system of phosphoinositides (PI) is involved in a variety of cell and tissue functions, including membrane trafficking, ion channel activity, cell cycle, apoptosis, differentiation, and cell and tissue polarity. Recently, PI and related molecules, such as the phosphoinositide-specific phospholipases C (PI-PLCs), main players in PI signaling were supposed to be involved in inflammation. Besides the control of calcium levels, PI-PLCs contribute to the regulation of phosphatydil-inositol bisphosphate metabolism, crucial in cytoskeletal organization. The expression of PI-PLCs is strictly tissue specific and evidences suggest that it varies under different conditions, such as tumor progression or cell activation. In a previous study, we obtained a complete panel of expression of PI-PLC isoforms in human umbilical vein endothelial cells (HUVEC), a widely used experimental model for endothelial cells. In the present study, we analyzed the mRNA concentration of PI-PLCs in lipopolysaccharide (LPS)-treated HUVEC by using the multiliquid bioanalyzer methodology after 3, 6, 24, 48, and 72 h from LPS administration. Marked differences in the expression of most PI-PLC codifying genes were evident.

We propose a new fixed-target experiment for the study of electromagnetic and hard probes of the Quark-Gluon Plasma (QGP) in heavy-ion collisions at the CERN SPS. The experiment aims at performing measurements of the dimuon spectrum from threshold up to the charmonium region, and of hadronic decays of charm and strange hadrons. It is based on a muon spectrometer, which includes a toroidal magnet and six planes of tracking detectors, coupled to a vertex spectrometer, equipped with Si MAPS immersed in a dipole field. High luminosity is an essential requirement for the experiment, with the goal of taking data with 10\\(^6\\) incident ions/s, at collision energies ranging from \\(\\sqrt{s_{\\rm NN}} = 6.3\\) GeV (\\(E_{\\rm lab}= 20\\) A GeV) to top SPS energy (\\(\\sqrt{s_{\\rm NN}} = 17.3\\) GeV, \\(E_{\\rm lab}= 158\\) A GeV). This document presents the physics motivation, the foreseen experimental set-up including integration and radioprotection studies, the current detector choices together with the status of the corresponding R&D, and the outcome of physics performance studies. A preliminary cost evaluation is also carried out.

Significant shifts in the phenology of life-cycle events have been observed in diverse taxa throughout the global oceans. While the migration phenology of marine fish and invertebrates is expected to be sensitive to climate change, the complex nature of these patterns has made measurement difficult and studies rare. With continuous weekly observations spanning 7 decades in Narragansett Bay, Rhode Island (USA), the University of Rhode Island Graduate School of Oceanography trawl survey provides an unprecedented opportunity to investigate the influence of climate on the migrations of marine species in the northwest Atlantic. Analyses of the survey observations of 12 species indicated that residence periods have changed by as much as 118 d, with shifts in the timing of both ingress to and egress from the coastal zone. The residence periods of warm-water species expanded while those of cold-water species contracted. Dirichlet regressions fit to the annual presence–absence patterns of each species identified interannual temperature variations, fluctuations in ocean circulation, and long-term warming all as having a significant effect on migration phenology. Additionally, temperature gradients within Narragansett Bay were shown by generalized additive models to cause detectable shifts in local spatial distributions during coastal residency. These novel findings mirror results found in the spatial domain and therefore suggest that the studied species are adapting their spatiotemporal distributions to track their thermal niche in a changing climate. If so, characterizing the spatial and temporal aspects of climate responses across species will be critical to understanding ongoing changes in marine ecosystems and successfully managing the fisheries they support.

Ab initio calculations are used to identify the structural conditions under which a polar state in metals might be stabilized; this information is used to guide the experimental realization of new room-temperature polar metals. A new polar metal from theory to synthesis The ordered electric dipoles that characterize, for example, ferroelectric materials, are not something generally associated with a metal. Indeed, the free carriers responsible for metallic behaviour will typically eliminate polar ordering, to achieve an equilibrium state of zero net internal electric field (Gauss's law). But the possible existence of a polar state in metals is not fundamentally excluded, and some rare examples exist. Tae Heon Kim and colleagues now use ab initio calculations to identify the structural conditions under which such an exotic state might be stabilized, and then use this information to guide the experimental realization of new room-temperature polar metals. Gauss’s law dictates that the net electric field inside a conductor in electrostatic equilibrium is zero by effective charge screening; free carriers within a metal eliminate internal dipoles that may arise owing to asymmetric charge distributions 1 . Quantum physics supports this view 2 , demonstrating that delocalized electrons make a static macroscopic polarization, an ill-defined quantity in metals 3 —it is exceedingly unusual to find a polar metal that exhibits long-range ordered dipoles owing to cooperative atomic displacements aligned from dipolar interactions as in insulating phases 4 . Here we describe the quantum mechanical design and experimental realization of room-temperature polar metals in thin-film A NiO 3 perovskite nickelates using a strategy based on atomic-scale control of inversion-preserving (centric) displacements 5 . We predict with ab initio calculations that cooperative polar A cation displacements are geometrically stabilized with a non-equilibrium amplitude and tilt pattern of the corner-connected NiO 6 octahedra—the structural signatures of perovskites—owing to geometric constraints imposed by the underlying substrate. Heteroepitaxial thin-films grown on LaAlO 3 (111) substrates fulfil the design principles. We achieve both a conducting polar monoclinic oxide that is inaccessible in compositionally identical films grown on (001) substrates, and observe a hidden, previously unreported 6 , 7 , 8 , 9 , 10 , non-equilibrium structure in thin-film geometries. We expect that the geometric stabilization approach will provide novel avenues for realizing new multifunctional materials with unusual coexisting properties.

The mechanisms underlying virus emergence are rarely well understood, making the appearance of outbreaks largely unpredictable. Bluetongue virus serotype 8 (BTV-8), an arthropod-borne virus of ruminants, emerged in livestock in northern Europe in 2006, spreading to most European countries by 2009 and causing losses of billions of euros. Although the outbreak was successfully controlled through vaccination by early 2010, puzzlingly, a closely related BTV-8 strain re-emerged in France in 2015, triggering a second outbreak that is still ongoing. The origin of this virus and the mechanisms underlying its re-emergence are unknown. Here, we performed phylogenetic analyses of 164 whole BTV-8 genomes sampled throughout the two outbreaks. We demonstrate consistent clock-like virus evolution during both epizootics but found negligible evolutionary change between them. We estimate that the ancestor of the second outbreak dates from the height of the first outbreak in 2008. This implies that the virus had not been replicating for multiple years prior to its re-emergence in 2015. Given the absence of any known natural mechanism that could explain BTV-8 persistence over this long period without replication, we hypothesise that the second outbreak could have been initiated by accidental exposure of livestock to frozen material contaminated with virus from approximately 2008. Our work highlights new targets for pathogen surveillance programmes in livestock and illustrates the power of genomic epidemiology to identify pathways of infectious disease emergence.

PurposeTo explore whether topical antibiotic prophylaxis in patients scheduled for intravitreal injections achieves surface sterility in a greater proportion of subjects as compared to povidone-iodine alone.Material and methodsA randomized, triple-blind clinical trial. Population: patients scheduled for intravitreal injections for maculopathy. Inclusion criteria: any sex and race, age 18 years and above. Subjects were randomized into 4 groups: the first group applied chloramphenicol (CHLORAM), the second netilmicin (NETILM), the third a commercial ozonized antiseptic solution (OZONE), and the fourth applied no drops (CONTROL). Outcome variable: percentage of non-sterile conjunctival swabs. Specimens were collected before and after the application of 5% povidone-iodine moments before the injection.ResultsNinety-eight subjects (33.7% females, 64.3% males), mean age: 70.2 ± 9.3 years (54–91). Before povidone-iodine, both the CHLORAM and NETILM group showed a lower percentage of non-sterile swabs (61.1% and 31.3% respectively), as compared to the OZONE (83.3%) and CONTROL (86.5%) groups (p < .04). However, this statistical difference was lost after the application of povidone-iodine for 3 min. Percentage of non-sterile swabs in each group after applying 5% povidone-iodine: CHLORAM 11.1%, NETILM 12.5%, CONTROL 15.4%, OZONE 25.0%. This was not statistically significant (p > .05).ConclusionsTopical antibiotic prophylaxis with chloramphenicol or netilmicin drops decreases the bacterial load on the conjunctiva. However, after the application of povidone-iodine, all groups showed a significant reduction in the percentage of non-sterile swabs, and this value was comparable among all groups. For this reason, authors conclude that povidone-iodine alone is sufficient and prior topical antibiotic prophylaxis is not indicated.

DNA single-strand breaks (SSB) formation coordinates the myogenic program, and defects in SSB repair in post-mitotic cells have been associated with human diseases. However, the DNA damage response by SSB in terminally differentiated cells has not been explored yet. Here we show that mouse post-mitotic muscle cells accumulate SSB after alkylation damage, but they are extraordinarily resistant to the killing effects of a variety of SSB-inducers. We demonstrate that, upon SSB induction, phosphorylation of H2AX occurs in myotubes and is largely ataxia telangiectasia mutated (ATM)-dependent. However, the DNA damage signaling cascade downstream of ATM is defective as shown by lack of p53 increase and phosphorylation at serine 18 (human serine 15). The stabilization of p53 by nutlin-3 was ineffective in activating the cell death pathway, indicating that the resistance to SSB inducers is due to defective p53 downstream signaling. The induction of specific types of damage is required to activate the cell death program in myotubes. Besides the topoisomerase inhibitor doxorubicin known for its cardiotoxicity, we show that the mitochondria-specific inhibitor menadione is able to activate p53 and to kill effectively myotubes. Cell killing is p53-dependent as demonstrated by full protection of myotubes lacking p53, but there is a restriction of p53-activated genes. This new information may have important therapeutic implications in the prevention of muscle cell toxicity.