Natural product P57 induces hypothermia through targeting pyridoxal kinase.

Induction of hypothermia during hibernation/torpor enables certain mammals to survive under extreme environmental conditions. However, pharmacological induction of hypothermia in most mammals remains a huge challenge. Here we show that a natural product P57 promptly induces hypothermia and decreases energy expenditure in mice. Mechanistically, P57 inhibits the kinase activity of pyridoxal kinase (PDXK), a key metabolic enzyme of vitamin B6 catalyzing phosphorylation of pyridoxal (PL), resulting in the accumulation of PL in hypothalamus to cause hypothermia. The hypothermia induced by P57 is significantly blunted in the mice with knockout of PDXK in the preoptic area (POA) of hypothalamus. We further found that P57 and PL have consistent effects on gene expression regulation in hypothalamus, and they may activate medial preoptic area (MPA) neurons in POA to induce hypothermia. Taken together, our findings demonstrate that P57 has a potential application in therapeutic hypothermia through regulation of vitamin B6 metabolism and PDXK serves as a previously unknown target of P57 in thermoregulation. In addition, P57 may serve as a chemical probe for exploring the neuron circuitry related to hypothermia state in mice

Natural product P57 induces hypothermia through targeting pyridoxal kinase

Abstract Induction of hypothermia during hibernation/torpor enables certain mammals to survive under extreme environmental conditions. However, pharmacological induction of hypothermia in most mammals remains a huge challenge. Here we show that a natural product P57 promptly induces hypothermia and decreases energy expenditure in mice. Mechanistically, P57 inhibits the kinase activity of pyridoxal kinase (PDXK), a key metabolic enzyme of vitamin B6 catalyzing phosphorylation of pyridoxal (PL), resulting in the accumulation of PL in hypothalamus to cause hypothermia. The hypothermia induced by P57 is significantly blunted in the mice with knockout of PDXK in the preoptic area (POA) of hypothalamus. We further found that P57 and PL have consistent effects on gene expression regulation in hypothalamus, and they may activate medial preoptic area (MPA) neurons in POA to induce hypothermia. Taken together, our findings demonstrate that P57 has a potential application in therapeutic hypothermia through regulation of vitamin B6 metabolism and PDXK serves as a previously unknown target of P57 in thermoregulation. In addition, P57 may serve as a chemical probe for exploring the neuron circuitry related to hypothermia state in mice

Long-range angular correlations of π, K and p in p–Pb collisions at sNN\sqrt{s_{NN}} = 5.02 TeV

Angular correlations between unidentified charged trigger particles and various species of charged associated particles (unidentified particles, pions, kaons, protons and antiprotons) are measured by the ALICE detector in p-Pb collisions at a nucleon--nucleon centre-of-mass energy of 5.02 TeV in the transverse-momentum range 0.3 < $p_T$ < 4 GeV/c. The correlations expressed as associated yield per trigger particle are obtained in the pseudorapidity range |$\eta_{lab}$| < 0.8. Fourier coefficients are extracted from the long-range correlations projected onto the azimuthal angle difference and studied as a function of $p_T$ and in intervals of event multiplicity. In high-multiplicity events, the second-order coefficient for protons, $v_2^p$, is observed to be smaller than that for pions, $v_2^\pi$, up to about $p_T$ = 2 GeV/c. To reduce correlations due to jets, the per-trigger yield measured in low-multiplicity events is subtracted from that in high-multiplicity events. A two-ridge structure is obtained for all particle species. The Fourier decomposition of this structure shows that the second-order coefficients for pions and kaons are similar. The $v_2^p$ is found to be smaller at low $p_T$ and larger at higher $p_T$ than $v_2^\pi$, with a crossing occurring at about 2 GeV. This is qualitatively similar to the elliptic-flow pattern observed in heavy-ion collisions. A mass ordering effect at low transverse momenta is consistent with expectations from hydrodynamic model calculations assuming a collectively expanding system.Angular correlations between unidentified charged trigger particles and various species of charged associated particles (unidentified particles, pions, kaons, protons and antiprotons) are measured by the ALICE detector in p-Pb collisions at a nucleon-nucleon centre-of-mass energy of 5.02 TeV in the transverse-momentum range $0.3 < p_{\rm T} < 4$ GeV/$c$. The correlations expressed as associated yield per trigger particle are obtained in the pseudorapidity range $|\eta_{\rm lab}|<0.8$. Fourier coefficients are extracted from the long-range correlations projected onto the azimuthal angle difference and studied as a function of $p_{\rm T}$ and in intervals of event multiplicity. In high-multiplicity events, the second-order coefficient for protons, $v_2^p$, is observed to be smaller than that for pions, $v_2^\pi$, up to about $p_{\rm T} = 2$ GeV/$c$. To reduce correlations due to jets, the per-trigger yield measured in low-multiplicity events is subtracted from that in high-multiplicity events. A two-ridge structure is obtained for all particle species. The Fourier decomposition of this structure shows that the second-order coefficients for pions and kaons are similar. The $v_2^p$ is found to be smaller at low $p_{\rm T}$ and larger at higher $p_{\rm T}$ than $v_2^pi$, with a crossing occurring at about 2 GeV. This is qualitatively similar to the elliptic-flow pattern observed in heavy-ion collisions. A mass ordering effect at low transverse momenta is consistent with expectations from hydrodynamic model calculations assuming a collectively expanding system.Angular correlations between unidentified charged trigger particles and various species of charged associated particles (unidentified particles, pions, kaons, protons and antiprotons) are measured by the ALICE detector in p–Pb collisions at a nucleon–nucleon centre-of-mass energy of 5.02 TeV in the transverse-momentum range 0.3<pT<4 GeV/c . The correlations expressed as associated yield per trigger particle are obtained in the pseudorapidity range |ηlab|<0.8 . Fourier coefficients are extracted from the long-range correlations projected onto the azimuthal angle difference and studied as a function of pT and in intervals of event multiplicity. In high-multiplicity events, the second-order coefficient for protons, v2p , is observed to be smaller than that for pions, v2π , up to about pT=2 GeV/c . To reduce correlations due to jets, the per-trigger yield measured in low-multiplicity events is subtracted from that in high-multiplicity events. A two-ridge structure is obtained for all particle species. The Fourier decomposition of this structure shows that the second-order coefficients for pions and kaons are similar. The v2p is found to be smaller at low pT and larger at higher pT than v2π , with a crossing occurring at about 2 GeV/c . This is qualitatively similar to the elliptic-flow pattern observed in heavy-ion collisions. A mass ordering effect at low transverse momenta is consistent with expectations from hydrodynamic model calculations assuming a collectively expanding system

Performance of the ALICE Experiment at the CERN LHC

ALICE is the heavy-ion experiment at the CERN Large Hadron Collider. The experiment continuously took data during the first physics campaign of the machine from fall 2009 until early 2013, using proton and lead-ion beams. In this paper we describe the running environment and the data handling procedures, and discuss the performance of the ALICE detectors and analysis methods for various physics observables.ALICE is the heavy-ion experiment at the CERN Large Hadron Collider. The experiment continuously took data during the first physics campaign of the machine from fall 2009 until early 2013, using proton and lead-ion beams. In this paper we describe the running environment and the data handling procedures, and discuss the performance of the ALICE detectors and analysis methods for various physics observables.ALICE is the heavy-ion experiment at the CERN Large Hadron Collider. The experiment continuously took data during the first physics campaign of the machine from fall 2009 until early 2013, using proton and lead-ion beams. In this paper we describe the running environment and the data handling procedures, and discuss the performance of the ALICE detectors and analysis methods for various physics observables

J/ψJ/\psi production and nuclear effects in p-Pb collisions at SNN\sqrt{S_{NN}} = 5.02 TeV

Inclusive J/$\psi$ production has been studied with the ALICE detector in p-Pb collisions at $\sqrt{s_{NN}}$ = 5.02 TeV at the CERN LHC, in the rapidity domains 2.03 < y$_{cms}$ < 3.53 and −4.46 < y$_{cms}$ < −2.96, down to zero transverse momentum. The J/$\psi$ measurement is performed in the Muon Spectrometer through the $\mu^+\mu^−$ decay mode. In this Letter, the J/$\psi$ production cross section and the nuclear modification factor R$_{pPb}$ for the rapidities under study are presented. While at forward rapidity a suppression of the J/$\psi$ yield with respect to binary-scaled pp collisions is observed, in the backward region no suppression is present. The ratio of the forward and backward yields is also shown differentially in rapidity and transverse momentum. Theoretical predictions based on nuclear shadowing, as well as on models including, in addition, a contribution from partonic energy loss, are in fair agreement with the experimental results.Inclusive J/$\psi$ production has been studied with the ALICE detector in p-Pb collisions at the nucleon-nucleon center of mass energy $\sqrt{s_{\rm NN}}$ = 5.02 TeV at the CERN LHC. The measurement is performed in the center of mass rapidity domains $2.03<y_{\rm cms}<3.53$ and $-4.46<y_{\rm cms}<-2.96$, down to zero transverse momentum, studying the $\mu^+\mu^-$ decay mode. In this paper, the J/$\psi$ production cross section and the nuclear modification factor $R_{\rm pPb}$ for the rapidities under study are presented. While at forward rapidity, corresponding to the proton direction, a suppression of the J/$\psi$ yield with respect to binary-scaled pp collisions is observed, in the backward region no suppression is present. The ratio of the forward and backward yields is also measured differentially in rapidity and transverse momentum. Theoretical predictions based on nuclear shadowing, as well as on models including, in addition, a contribution from partonic energy loss, are in fair agreement with the experimental results