JIP1 Regulates Axonal Transport of APP and Autophagosomes via Coordination of Kinesin and Dynein Motors

Neurons are specialized cells that extend polarized processes called dendrites and axons in order to maintain synaptic connections over long distances. Consequently, neuronal homeostasis requires axonal transport of organelles, such as mitochondria, synaptic vesicles, and autophagosomes. The microtubule-based motors responsible for long-distance fast axonal transport are the anterograde kinesin motors and the retrograde dynein motors. Two cargos that exhibit robust axonal transport characterized by high speeds with few directional switches are APP- (amyloid precursor protein) positive vesicles and autophagosomes. While APP-positive vesicles transport occurs in both anterograde and retrograde directions, autophagosomes move unidirectionally in the retrograde direction. Here, we demonstrate that processive transport of both these cargos requires coordination of opposing motor activity by the scaffolding protein JIP1 (c-jun N-terminal kinase- interacting protein). We identify novel interactions between JIP1 and kinesin heavy chain (KHC), which are sufficient to relieve KHC autoinhibition and activate motor function in single molecule assays. In addition, the direct binding of the dynactin subunit p150Glued to JIP1 competitively inhibits KHC activation in vitro and disrupts the transport of APP in neurons. Together with coimmunoprecipitation results, these experiments support a model whereby JIP1 coordinates transport by switching between anterograde and retrograde motile complexes. Furthermore, we find that mutations in the JNK-dependent phosphorylation site S421 in JIP1 alter both KHC activation in vitro and the directionality of APP and autophagosome transport in neurons. In knockdown and rescue experiments, the phosphomimetic JIP1-S421D promotes anterograde APP transport and disrupts retrograde autophagosome transport while the phosphodeficient JIP1-S421A promotes retrograde APP transport and rescues retrograde autophagosome transport. Thus, post-translational modification of a scaffolding protein can serve as a molecular switch that coordinates opposing motor activity in order to regulate the direction of vesicular transport of various organelles in the axon

Self-Learning Monte Carlo Method

Monte Carlo simulation is an unbiased numerical tool for studying classical and quantum many-body systems. One of its bottlenecks is the lack of general and efficient update algorithm for large size systems close to phase transition or with strong frustrations, for which local updates perform badly. In this work, we propose a new general-purpose Monte Carlo method, dubbed self-learning Monte Carlo (SLMC), in which an efficient update algorithm is first learned from the training data generated in trial simulations and then used to speed up the actual simulation. We demonstrate the efficiency of SLMC in a spin model at the phase transition point, achieving a 10-20 times speedup.Comment: add more refs and correct some typo

Criticality in quark-gluon systems far beyond thermal and chemical equilibrium

Experimental evidence and theoretical arguments for the existence of self-organized criticality in systems of gluons and quarks are presented. It is observed that the existing data for high-transverse-momentum jet-production exhibit striking regularities; and it is shown that, together with first-principle considerations, such regularities can be used, not only to probe the possible compositness of quarks, but also to obtain {\em direct evidence} for, or against, the existence of critical temperature and/or critical chemical potential in quark-gluon systems when hadrons are squeezed together.Comment: 13 pages, including 1 figure and 1 tabl

Anisotropic emission of thermal dielectrons from Au+Au collisions at sNN=200\sqrt{s_{NN}}=200~GeV with EPOS3

Dileptons, as an electromagnetic probe, are crucial to study the properties of a Quark-Gluon Plasma (QGP) created in heavy ion collisions. We calculated the invariant mass spectra and the anisotropic emission of thermal dielectrons from Au+Au collisions at the Relativistic Heavy Ion Collider (RHIC) energy $\sqrt{s_{NN}}=200$~GeV based on EPOS3. This approach provides a realistic (3+1)-dimensional event-by-event viscous hydrodynamic description of the expanding hot and dense matter with a very particular initial condition, and a large set of hadron data and direct photons (besides $v_{2}$ and $v_{3}$ !) can be successfully reproduced. Thermal dilepton emission from both the QGP phase and the hadronic gas are considered, with the emission rates based on Lattice QCD and a vector meson model, respectively. We find that the computed invariant mass spectra (thermal contribution + STAR cocktail) can reproduce the measured ones from STAR at different centralities. Different compared to other model predictions, the obtained elliptic flow of thermal dileptons is larger than the STAR measurement referring to all dileptons. We observe a clear centrality dependence of thermal dilepton not only for elliptic flow $v_{2}$ but also for higher orders. At a given centrality, $v_{n}$ of thermal dileptons decreases monotonically with $n$ for $2\leq n\leq5$.Comment: 10pages, 12fig