CSF1R blockade slows the progression of amyotrophic lateral sclerosis by reducing microgliosis and invasion of macrophages into peripheral nerves

Inflammation is a common neuropathological feature in several neurological disorders, including amyotrophic lateral sclerosis (ALS). We have studied the contribution of CSF1R signalling to inflammation in ALS, as a pathway previously reported to control the expansion and activation of microglial cells. We found that microglial cell proliferation in the spinal cord of SOD1G93A transgenic mice correlates with the expression of CSF1R and its ligand CSF1. Administration of GW2580, a selective CSF1R inhibitor, reduced microglial cell proliferation in SOD1G93A mice, indicating the importance of CSF1-CSF1R signalling in microgliosis in ALS. Moreover, GW2580 treatment slowed disease progression, attenuated motoneuron cell death and extended survival of SOD1G93A mice. Electrophysiological assessment revealed that GW2580 treatment protected skeletal muscle from denervation prior to its effects on microglial cells. We found that macrophages invaded the peripheral nerve of ALS mice before CSF1R-induced microgliosis occurred. Interestingly, treatment with GW2580 attenuated the influx of macrophages into the nerve, which was partly caused by the monocytopenia induced by CSF1R inhibition. Overall, our findings provide evidence that CSF1R signalling regulates inflammation in the central and peripheral nervous system in ALS, supporting therapeutic targeting of CSF1R in this disease

Forward-central two-particle correlations in p-Pb collisions at root s(NN)=5.02 TeV

Two-particle angular correlations between trigger particles in the forward pseudorapidity range (2.5 2GeV/c. (C) 2015 CERN for the benefit of the ALICE Collaboration. Published by Elsevier B. V.Peer reviewe

Event-shape engineering for inclusive spectra and elliptic flow in Pb-Pb collisions at root(NN)-N-S=2.76 TeV

Peer reviewe

Elliptic flow of muons from heavy-flavour hadron decays at forward rapidity in Pb-Pb collisions at root s(NN)=2.76TeV

The elliptic flow, v(2), of muons from heavy-flavour hadron decays at forward rapidity (2.5 <y <4) is measured in Pb-Pb collisions at root s(NN)= 2.76TeVwith the ALICE detector at the LHC. The scalar product, two- and four-particle Q cumulants and Lee-Yang zeros methods are used. The dependence of the v(2) of muons from heavy-flavour hadron decays on the collision centrality, in the range 0-40%, and on transverse momentum, p(T), is studied in the interval 3 <p(T)<10 GeV/c. A positive v(2) is observed with the scalar product and two-particle Q cumulants in semi-central collisions (10-20% and 20-40% centrality classes) for the p(T) interval from 3 to about 5GeV/c with a significance larger than 3 sigma, based on the combination of statistical and systematic uncertainties. The v(2) magnitude tends to decrease towards more central collisions and with increasing pT. It becomes compatible with zero in the interval 6 <p(T)<10 GeV/c. The results are compared to models describing the interaction of heavy quarks and open heavy-flavour hadrons with the high-density medium formed in high-energy heavy-ion collisions. (C) 2015 CERN for the benefit of the ALICE Collaboration. Published by Elsevier B.V.Peer reviewe

Interleukin-4 and interleukin-13 induce different metabolic profiles in microglia and macrophages that relate with divergent outcomes after spinal cord injury

Background: Microglia and macrophages adopt a pro-inflammatory phenotype after spinal cord injury (SCI), what is thought to contribute to secondary tissue degeneration. We previously reported that this is due, in part, to the low levels of anti-inflammatory cytokines, such as IL-4. Since IL-13 and IL-4 share receptors and both cytokines drive microglia and macrophages towards an anti-inflammatory phenotype in vitro, here we studied whether administration of IL-13 and IL-4 after SCI leads to beneficial effects. Methods: We injected mice with recombinant IL-13 or IL-4 at 48 h after SCI and assessed their effects on microglia and macrophage phenotype and functional outcomes. We also performed RNA sequencing analysis of macrophages and microglia sorted from the injured spinal cords of mice treated with IL-13 or IL-4 and evaluated the metabolic state of these cells by using Seahorse technology. Results: We observed that IL-13 induced the expression of anti-inflammatory markers in microglia and macrophages after SCI but, in contrast to IL-4, it failed to mediate functional recovery. We found that these two cytokines induced different gene signatures in microglia and macrophages after SCI and that IL-4, in contrast to IL-13, shifted microglia and macrophage metabolism from glycolytic to oxidative phosphorylation. These findings were further confirmed by measuring the metabolic profile of these cells. Importantly, we also revealed that macrophages stimulated with IL-4 or IL-13 are not deleterious to neurons, but they become cytotoxic when oxidative metabolism is blocked. This suggests that the metabolic shift, from glycolysis to oxidative phosphorylation, is required to minimize the cytotoxic responses of microglia and macrophages. Conclusions: These results reveal that the metabolic fitness of microglia and macrophages after SCI contributes to secondary damage and that strategies aimed at boosting oxidative phosphorylation might be a novel approach to minimize the deleterious actions of microglia and macrophages in neurotrauma.This work was supported by the Spanish Ministry of Economy and Competitiveness (MINECO, SAF2016-79774-R), Wings for Life International Foundation, Red de Terapia Celular (TERCEL) and, funds from ''la Caixa” Foundation under agreement LCF/TR/CI17/10020018 and LCF/PR/HA17/52170001 to RL-V, and by NIH Grant AI 15614 to CD and the Interleukin Foundation to C

燒津鰹漁業に於ける船仲組織(上) - 本邦漁業に特異なる勞働組織の一例 -

We report on the measurement of freeze-out radii for pairs of identical-charge pions measured in Pb-Pb collisions at √sNN = 2.76 TeV as a function of collision centrality and the average transverse momentum of the pair kT. Three-dimensional sizes of the system (femtoscopic radii), as well as direction-averaged onedimensional radii are extracted. The radii decrease with kT, following a power-law behavior. This is qualitatively consistent with expectations from a collectively expanding system, produced in hydrodynamic calculations. The radii also scale linearly with _dNch/dη_1/3. This behavior is compared to world data on femtoscopic radii in heavy-ion collisions. While the dependence is qualitatively similar to results at smaller √sNN, a decrease in the ratio Rout/Rside is seen, which is in qualitative agreement with a specific prediction from hydrodynamic models: a change from inside-out to outside-in freeze-out configuration. The results provide further evidence for the production of a collective, strongly coupled system in heavy-ion collisions at the CERN Large Hadron Collider

Centrality dependence of the nuclear modification factor of charged pions, kaons, and protons in Pb-Pb collisions at sNN=2.76\sqrt{s_{\rm NN}}=2.76 TeV

Transverse momentum (pT) spectra of pions, kaons, and protons up to pT=20GeV/c have been measured in Pb-Pb collisions at sNN=2.76TeV using the ALICE detector for six different centrality classes covering 0%–80%. The proton-to-pion and the kaon-to-pion ratios both show a distinct peak at pT≈3GeV/c in central Pb-Pb collisions that decreases for more peripheral collisions. For pT>10GeV/c, the nuclear modification factor is found to be the same for all three particle species in each centrality interval within systematic uncertainties of 10%–20%. This suggests there is no direct interplay between the energy loss in the medium and the particle species composition in the hard core of the quenched jet. For pT<10GeV/c, the data provide important constraints for models aimed at describing the transition from soft to hard physics

Two-pion femtoscopy in p-Pb collisions at sNN=5.02\sqrt{s_{\rm NN}}=5.02 TeV

We report the results of the femtoscopic analysis of pairs of identical pions measured in p-Pb collisions at $\sqrt{s_{\mathrm{NN}}}=5.02$ TeV. Femtoscopic radii are determined as a function of event multiplicity and pair momentum in three spatial dimensions. As in the pp collision system, the analysis is complicated by the presence of sizable background correlation structures in addition to the femtoscopic signal. The radii increase with event multiplicity and decrease with pair transverse momentum. When taken at comparable multiplicity, the radii measured in p-Pb collisions, at high multiplicity and low pair transverse momentum, are 10-20% higher than those observed in pp collisions but below those observed in A-A collisions. The results are compared to hydrodynamic predictions at large event multiplicity as well as discussed in the context of calculations based on gluon saturation

Inclusive, prompt and non-prompt J/ψ\psi production at mid-rapidity in Pb-Pb collisions at sNN\sqrt{s_{\rm NN}} = 2.76 TeV

The transverse momentum ($p_{\rm T}$) dependence of the nuclear modification factor $R_{\rm AA}$ and the centrality dependence of the average transverse momentum $\langle p_{\rm T}\rangle$ for inclusive J/$\psi$ have been measured with ALICE for Pb-Pb collisions at $\sqrt{s_{\rm NN}}$ = 2.76 TeV in the e$^+$e$^-$ decay channel at mid-rapidity ($|y|<0.8$). The $\langle p_{\rm T}\rangle$ is significantly smaller than the one observed for pp collisions at the same centre-of-mass energy. Consistently, an increase of $R_{\rm AA}$ is observed towards low $p_{\rm T}$. These observations might be indicative of a sizable contribution of charm quark coalescence to the J/$\psi$ production. Additionally, the fraction of non-prompt J/$\psi$ from beauty hadron decays, $f_{\rm B}$, has been determined in the region $1.5 < p_{\rm T} < 10$ GeV/c in three centrality intervals. No significant centrality dependence of $f_{\rm B}$ is observed. Finally, the $R_{\rm AA}$ of non-prompt J/$\psi$ is discussed and compared with model predictions. The nuclear modification in the region $4.5 < p_{\rm T} < 10$ GeV/c is found to be stronger than predicted by most models.The transverse momentum (p$_{T}$) dependence of the nuclear modification factor R$_{AA}$ and the centrality dependence of the average transverse momentum 〈p$_{T}$〉 for inclusive J/ψ have been measured with ALICE for Pb-Pb collisions at $\sqrt{s_{\mathrm{NN}}}=2.76$ TeV in the e+e$^{−}$ decay channel at mid-rapidity (|y| < 0.8). The 〈p$_{T}$〉 is significantly smaller than the one observed for pp collisions at the same centre-of-mass energy. Consistently, an increase of R$_{AA}$ is observed towards low p$_{T}$. These observations might be indicative of a sizable contribution of charm quark coalescence to the J/ψ production. Additionally, the fraction of non-prompt J/ψ from beauty hadron decays, f$_{B}$, has been determined in the region 1.5 < p$_{T}$ < 10 GeV/c in three centrality intervals. No significant centrality dependence of f$_{B}$ is observed. Finally, the R$_{AA}$ of non-prompt J/ψ is discussed and compared with model predictions. The nuclear modification in the region 4.5 < p$_{T}$ < 10 GeV/c is found to be stronger than predicted by most models.The transverse momentum ($p_{\rm T}$) dependence of the nuclear modification factor $R_{\rm AA}$ and the centrality dependence of the average transverse momentum $\langle p_{\rm T}\rangle$ for inclusive J/$\psi$ have been measured with ALICE for Pb-Pb collisions at $\sqrt{s_{\rm NN}}$ = 2.76 TeV in the e$^+$e$^-$ decay channel at mid-rapidity ($|y|<0.8$). The $\langle p_{\rm T}\rangle$ is significantly smaller than the one observed for pp collisions at the same centre-of-mass energy. Consistently, an increase of $R_{\rm AA}$ is observed towards low $p_{\rm T}$. These observations might be indicative of a sizable contribution of charm quark coalescence to the J/$\psi$ production. Additionally, the fraction of non-prompt J/$\psi$ from beauty hadron decays, $f_{\rm B}$, has been determined in the region $1.5 < p_{\rm T} < 10$ GeV/c in three centrality intervals. No significant centrality dependence of $f_{\rm B}$ is observed. Finally, the $R_{\rm AA}$ of non-prompt J/$\psi$ is discussed and compared with model predictions. The nuclear modification in the region $4.5 < p_{\rm T} < 10$ GeV/c is found to be stronger than predicted by most models