Identification of Protein Networks Involved in the Disease Course of Experimental Autoimmune Encephalomyelitis, an Animal Model of Multiple Sclerosis

A more detailed insight into disease mechanisms of multiple sclerosis (MS) is crucial for the development of new and more effective therapies. MS is a chronic inflammatory autoimmune disease of the central nervous system. The aim of this study is to identify novel disease associated proteins involved in the development of inflammatory brain lesions, to help unravel underlying disease processes. Brainstem proteins were obtained from rats with MBP induced acute experimental autoimmune encephalomyelitis (EAE), a well characterized disease model of MS. Samples were collected at different time points: just before onset of symptoms, at the top of the disease and following recovery. To analyze changes in the brainstem proteome during the disease course, a quantitative proteomics study was performed using two-dimensional difference in-gel electrophoresis (2D-DIGE) followed by mass spectrometry. We identified 75 unique proteins in 92 spots with a significant abundance difference between the experimental groups. To find disease-related networks, these regulated proteins were mapped to existing biological networks by Ingenuity Pathway Analysis (IPA). The analysis revealed that 70% of these proteins have been described to take part in neurological disease. Furthermore, some focus networks were created by IPA. These networks suggest an integrated regulation of the identified proteins with the addition of some putative regulators. Post-synaptic density protein 95 (DLG4), a key player in neuronal signalling and calcium-activated potassium channel alpha 1 (KCNMA1), involved in neurotransmitter release, are 2 putative regulators connecting 64% of the identified proteins. Functional blocking of the KCNMA1 in macrophages was able to alter myelin phagocytosis, a disease mechanism highly involved in EAE and MS pathology. Quantitative analysis of differentially expressed brainstem proteins in an animal model of MS is a first step to identify disease-associated proteins and networks that warrant further research to study their actual contribution to disease pathology

Signaling Signatures and Functional Properties of Anti-Human CD28 Superagonistic Antibodies

Superagonistic CD28 antibodies (CD28SAs) activate T lymphocytes without concomitant perturbation of the TCR/CD3-complex. In rodents these reagents induce the preferential expansion of regulatory T cells and can be used for the treatment of autoimmune diseases. Unexpectedly, the humanized CD28 superagonist TGN1412 caused severe and life threatening adverse effects during a recently conducted phase I clinical trail. The underlying molecular mechanisms are as yet unclear. We show that TGN1412 as well as the commercially available CD28 superagonist ANC28.1 induce a delayed but extremely sustained calcium response in human naïve and memory CD4+ T cells but not in cynomolgus T lymphocytes. The sustained Ca++-signal was associated with the activation of multiple intracellular signaling pathways and together these events culminated in the rapid de novo synthesis of high amounts of pro-inflammatory cytokines, most notably IFN-γ and TNF-α. Importantly, sustained transmembranous calcium flux, activation of Src-kinases as well as activation of PI3K were found to be absolutely required for CD28SA-mediated production of IFN-γ and IL-2. Collectively, our data suggest a molecular basis for the severe side effects caused by TGN1412 and impinge upon the relevance of non-human primates as preclinical models for reagents that are supposed to modify the function of human T cells

Long- and short-range correlations and their event-scale dependence in high-multiplicity pp collisions at 1as = 13 TeV

Two-particle angular correlations are measured in high-multiplicity proton-proton collisions at s = 13 TeV by the ALICE Collaboration. The yields of particle pairs at short-( 06\u3b7 3c 0) and long-range (1.6 < | 06\u3b7| < 1.8) in pseudorapidity are extracted on the near-side ( 06\u3c6 3c 0). They are reported as a function of transverse momentum (pT) in the range 1 < pT< 4 GeV/c. Furthermore, the event-scale dependence is studied for the first time by requiring the presence of high-pT leading particles or jets for varying pT thresholds. The results demonstrate that the long-range \u201cridge\u201d yield, possibly related to the collective behavior of the system, is present in events with high-pT processes as well. The magnitudes of the short- and long-range yields are found to grow with the event scale. The results are compared to EPOS LHC and PYTHIA 8 calculations, with and without string-shoving interactions. It is found that while both models describe the qualitative trends in the data, calculations from EPOS LHC show a better quantitative agreement for the pT dependency, while overestimating the event-scale dependency. [Figure not available: see fulltext.

Search for a common baryon source in high-multiplicity pp collisions at the LHC

We report on the measurement of the size of the particle-emitting source from two-baryon correlations with ALICE in high-multiplicity pp collisions at s=13 TeV. The source radius is studied with low relative momentum p–p, p‾–p‾, p–Λ, and p‾–Λ‾ pairs as a function of the pair transverse mass mT considering for the first time in a quantitative way the effect of strong resonance decays. After correcting for this effect, the radii extracted for pairs of different particle species agree. This indicates that protons, antiprotons, Λ s, and Λ‾ s originate from the same source. Within the measured mT range (1.1–2.2) GeV/c2the invariant radius of this common source varies between 1.3 and 0.85 fm. These results provide a precise reference for studies of the strong hadron–hadron interactions and for the investigation of collective properties in small colliding systems. © 2020 CERN for the benefit of the ALICE CollaborationPeer reviewe

Inclusive J/ψ production at forward and backward rapidity in p-Pb collisions at √sNN=8.16 TeV

Inclusive J/psi production is studied in p-Pb interactions at a centre-of-mass energy per nucleon-nucleon collision sqrt(s_NN) = 8.16TeV, using the ALICE detector at the CERN LHC. The J/psi meson is reconstructed, via its decay to a muon pair, in the centre-of-mass rapidity intervals 2.03 < ycms < 3.53 and -4.46 < ycms < -2.96, where positive and negative ycms refer to the p-going and Pb-going direction, respectively. The transverse momentum coverage is pT < 20 GeV/c. In this paper, ycms- and pT-differential cross sections for inclusive J/psi production are presented, and the corresponding nuclear modification factors RpPb are shown. Forward results show a suppression of the J/psi yield with respect to pp collisions, concentrated in the region pT < 5 GeV/c. At backward rapidity no significant suppression is observed. The results are compared to previous measurements by ALICE in p-Pb collisions at sqrt(s_NN) = 5.02TeV and to theoretical calculations. Finally, the ratios RFB between forward- and backward-ycms RpPb values are shown and discussed

Constraints on jet quenching in p-Pb collisions at root s(NN)=5.02 TeV measured by the event-activity dependence of semi-inclusive hadron-jet distributions

CNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFINEP - FINANCIADORA DE ESTUDOS E PROJETOSFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOThe ALICE Collaboration reports the measurement of semi-inclusive distributions of charged-particle jets recoiling from a high-transverse momentum trigger hadron in p-Pb collisions at root s(NN) = 5.02TeV. Jets are reconstructed from charged-particle tracks using the anti-k(T) algorithm with resolution parameter R = 0.2 and 0.4. A data-driven statistical approach is used to correct the uncorrelated background jet yield. Recoil jet distributions are reported for jet transverse momentum 15 < p(T,jet)(ch) < 50 GeV/c and are compared in various intervals of p-Pb event activity, based on charged-particle multiplicity and zero-degree neutral energy in the forward (Pb-going) direction. The semi-inclusive observable is self-normalized and such comparisons do not require the interpretation of p-Pb event activity in terms of collision geometry, in contrast to inclusive jet observables. These measurements provide new constraints on the magnitude of jet quenching in small systems at the LHC. In p-Pb collisions with high event activity, the average medium-induced out-of-cone energy transport for jets with R = 0.4 and 15 < p(T,jet)(ch) < 50 GeV/c is measured to be less than 0.4 GeV/c at 90% confidence, which is over an order of magnitude smaller than a similar measurement for central Pb-Pb collisions at root s(NN) = 2.76 TeV. Comparison is made to theoretical calculations of jet quenching in small systems, and to inclusive jet measurements in p-Pb collisions selected by event activity at the LHC and in d-Au collisions at RHIC.78395113CNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFINEP - FINANCIADORA DE ESTUDOS E PROJETOSFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFINEP - FINANCIADORA DE ESTUDOS E PROJETOSFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOSem informaçãoSem informaçãoSem informaçãoAgências de fomento estrangeiras apoiaram essa pesquisa, mais informações acesse artig

Charged-particle multiplicity fluctuations in Pb–Pb collisions at √sNN = 2.76 TeV

Measurements of event-by-event fluctuations of charged-particle multiplicities in Pb–Pb collisions at √sNN = 2.76 TeV using the ALICE detector at the CERN Large Hadron Collider (LHC) are presented in the pseudorapidity range |η|<0.8 and transverse momentum 0.2<pT<2.0 GeV/c. The amplitude of the fluctuations is expressed in terms of the variance normalized by the mean of the multiplicity distribution. The η and pT dependences of the fluctuations and their evolution with respect to collision centrality are investigated. The multiplicity fluctuations tend to decrease from peripheral to central collisions. The results are compared to those obtained from HIJING and AMPT Monte Carlo event generators as well as to experimental data at lower collision energies. Additionally, the measured multiplicity fluctuations are discussed in the context of the isothermal compressibility of the high-density strongly-interacting system formed in central Pb–Pb collisions.publishedVersio

First measurement of Ωc 0 production in pp collisions at s=13 TeV

The inclusive production of the charm–strange baryon Omega_c^0 is measured for the first time via its hadronic decay into Omega-pi+ at midrapidity (|y|<0.5) in proton–proton (pp) collisions at the centre-of-mass energy sqrt(s) = 13 TeV with the ALICE detector at the LHC. The transverse momentum (pT) differential cross section multiplied by the branching ratio is presented in the interval 2 < pT < 12 GeV/c . The pT dependence of the Omega_C^0-baryon production relative to the prompt D^0-meson and to the prompt Csi_C^0-baryon production is compared to various models that take different hadronisation mechanisms into consideration. In the measured pT interval, the ratio of the pT-integrated cross sections of Omega_c^0 and prompt Lambda_c^+ baryons multiplied by the Omega- pi+ branching ratio is found to be larger by a factor of about 20 with a significance of about 4σ when compared to e+e- collisions

Measurement of electrons from beauty-hadron decays in pp and Pb-Pb collisions at sNN=5.02 TeV

The production of electrons from beauty-hadron decays was measured at midrapidity in proton-proton (pp) and central Pb-Pb collisions at center-of-mass energy per nucleon-nucleon pair √s NN = 5.02 TeV, using the ALICE detector at the LHC. The cross section measured in pp collisions in the transverse momentum interval 2 < pT < 8 GeV/c was compared with models based on perturbative quantum chromodynamics calculations. The yield in the 10% most central Pb-Pb collisions, measured in the interval 2 < pT < 26 GeV/c, was used to compute the nuclear modification factor RAA, extrapolating the pp reference cross section to pT larger than 8 GeV/c. The measured R AA shows significant suppression of the yield of electrons from beauty-hadron decays at high pT and does not show a significant dependence above 8 GeV/c within uncertainties. The results are de- scribed by several theoretical models based on different implementations of the interaction of heavy quarks with a quark-gluon plasma, which predict a smaller energy loss for beauty quarks compared to light and charm quark