Quantitative proteomic analysis of Parkin substrates in Drosophila neurons.

Parkin (PARK2) is an E3 ubiquitin ligase that is commonly mutated in Familial Parkinson's Disease (PD). In cell culture models, Parkin is recruited to acutely depolarised mitochondria by PINK1. PINK1 activates Parkin activity leading to ubiquitination of multiple proteins, which in turn promotes clearance of mitochondria by mitophagy. Many substrates have been identified using cell culture models in combination with depolarising drugs or proteasome inhibitors, but not in more physiological settings.Here we utilized the recently introduced BioUb strategy to isolate ubiquitinated proteins in flies. Following Parkin Wild-Type (WT) and Parkin Ligase dead (LD) expression we analysed by mass spectrometry and stringent bioinformatics analysis those proteins differentially ubiquitinated to provide the first survey of steady state Parkin substrates using an in vivo model. We further used an in vivo ubiquitination assay to validate one of those substrates in SH-SY5Y cells.We identified 35 proteins that are more prominently ubiquitinated following Parkin over-expression. These include several mitochondrial proteins and a number of endosomal trafficking regulators such as v-ATPase sub-units, Syx5/STX5, ALiX/PDCD6IP and Vps4. We also identified the retromer component, Vps35, another PD-associated gene that has recently been shown to interact genetically with parkin. Importantly, we validated Parkin-dependent ubiquitination of VPS35 in human neuroblastoma cells.Collectively our results provide new leads to the possible physiological functions of Parkin activity that are not overtly biased by acute mitochondrial depolarisation

Vibrational spectrum of topologically disordered systems

The topological nature of the disorder of glasses and supercooled liquids strongly affects their high-frequency dynamics. In order to understand its main features, we analytically studied a simple topologically disordered model, where the particles oscillate around randomly distributed centers, interacting through a generic pair potential. We present results of a resummation of the perturbative expansion in the inverse particle density for the dynamic structure factor and density of states. This gives accurate results for the range of densities found in real systems.Comment: Completely rewritten version, accepted in Physical Review Letter

Nonequilibrium functional RG with frequency dependent vertex function: A study of the single impurity Anderson model

We investigate nonequilibrium properties of the single impurity Anderson model by means of the functional renormalization group (fRG) within Keldysh formalism. We present how the level broadening Gamma/2 can be used as flow parameter for the fRG. This choice preserves important aspects of the Fermi liquid behaviour that the model exhibits in case of particle-hole symmetry. An approximation scheme for the Keldysh fRG is developed which accounts for the frequency dependence of the two-particle vertex in a way similar but not equivalent to a recently published approximation to the equilibrium Matsubara fRG. Our method turns out to be a flexible tool for the study of weak to intermediate on-site interactions U <= 3 Gamma. In equilibrium we find excellent agreement with NRG results for the linear conductance at finite gate voltage, magnetic field, and temperature. In nonequilibrium, our results for the current agree well with TD-DMRG. For the nonlinear conductance as function of the bias voltage, we propose reliable results at finite magnetic field and finite temperature. Furthermore, we demonstrate the exponentially small scale of the Kondo temperature to appear in the second order derivative of the self-energy. We show that the approximation is, however, not able to reproduce the scaling of the effective mass at large interactions.Comment: [v2] - minor changes throughout the text; added new Fig. 3; corrected pert.-theory data in Figs. 10, 11; published versio

Dynamic structure factor of the Ising model with purely relaxational dynamics

We compute the dynamic structure factor for the Ising model with a purely relaxational dynamics (model A). We perform a perturbative calculation in the $\epsilon$ expansion, at two loops in the high-temperature phase and at one loop in the temperature magnetic-field plane, and a Monte Carlo simulation in the high-temperature phase. We find that the dynamic structure factor is very well approximated by its mean-field Gaussian form up to moderately large values of the frequency $\omega$ and momentum $k$. In the region we can investigate, $k\xi \lesssim 5$, $\omega \tau \lesssim 10$, where $\xi$ is the correlation length and $\tau$ the zero-momentum autocorrelation time, deviations are at most of a few percent.Comment: 21 pages, 3 figure

A new test for random number generators: Schwinger-Dyson equations for the Ising model

We use a set of Schwinger-Dyson equations for the Ising Model to check several random number generators. For the model in two and three dimensions, it is shown that the equations are sensitive tests of bias originated by the random numbers. The method is almost costless in computer time when added to any simulation.Comment: 6 pages, 3 figure

Driving current through single organic molecules

We investigate electronic transport through two types of conjugated molecules. Mechanically controlled break-junctions are used to couple thiol endgroups of single molecules to two gold electrodes. Current-voltage characteristics (IVs) of the metal-molecule-metal system are observed. These IVs reproduce the spatial symmetry of the molecules with respect to the direction of current flow. We hereby unambigously detect an intrinsic property of the molecule, and are able to distinguish the influence of both the molecule and the contact to the metal electrodes on the transport properties of the compound system.Comment: 4 pages, 5 figure