PMI: A Delta Psi(m) Independent Pharmacological Regulator of Mitophagy

Mitophagy is central to mitochondrial and cellular homeostasis and operates via the PINK1/Parkin pathway targeting mitochondria devoid of membrane potential (ΔΨm) to autophagosomes. Although mitophagy is recognized as a fundamental cellular process, selective pharmacologic modulators of mitophagy are almost nonexistent. We developed a compound that increases the expression and signaling of the autophagic adaptor molecule P62/SQSTM1 and forces mitochondria into autophagy. The compound, P62-mediated mitophagy inducer (PMI), activates mitophagy without recruiting Parkin or collapsing ΔΨm and retains activity in cells devoid of a fully functional PINK1/Parkin pathway. PMI drives mitochondria to a process of quality control without compromising the bio-energetic competence of the whole network while exposing just those organelles to be recycled. Thus, PMI circumvents the toxicity and some of the nonspecific effects associated with the abrupt dissipation of ΔΨm by ionophores routinely used to induce mitophagy and represents a prototype pharmacological tool to investigate the molecular mechanisms of mitophagy

Ozone concentrations and damage for realistic future European climate and air quality scenarios

Ground level ozone poses a significant threat to human health from air pollution in the European Union. While anthropogenic emissions of precursor substances (NOx, NMVOC, CH4) are regulated by EU air quality legislation and will decrease further in the future, the emissions of biogenic NMVOC (mainly isoprene) may increase significantly in the coming decades if short-rotation coppice plantations are expanded strongly to meet the increased biofuel demand resulting from the EU decarbonisation targets. This study investigates the competing effects of anticipated trends in land use change, anthropogenic ozone precursor emissions and climate change on European ground level ozone concentrations and related health and environmental impacts until 2050. The work is based on a consistent set of energy consumption scenarios that underlie current EU climate and air quality policy proposals: a current legislation case, and an ambitious decarbonisation case. The Greenhouse Gas-Air Pollution Interactions and Synergies (GAINS) integrated assessment model was used to calculate air pollutant emissions for these scenarios, while land use change because of bioenergy demand was calculated by the Global Biosphere Model (GLOBIOM). These datasets were fed into the chemistry transport model LOTOS-EUROS to calculate the impact on ground level ozone concentrations. Health damage because of high ground level ozone concentrations is projected to decline significantly towards 2030 and 2050 under current climate conditions for both energy scenarios. Damage to plants is also expected to decrease but to a smaller extent. The projected change in anthropogenic ozone precursor emissions is found to have a larger impact on ozone damage than land use change. The increasing effect of a warming climate (+2–5 °C across Europe in summer) on ozone concentrations and associated health damage, however, might be higher than the reduction achieved by cutting back European ozone precursor emissions. Global action to reduce air pollutant emissions is needed to make sure that ozone damage in Europe decreases towards the middle of this century

Localization of Chemoattractant Receptors on Dictyostelium discoideum Cells during Aggregation and Down-regulation

cAMP chemoattractant receptors on the surface of Dictyostelium discoideum cells are visualized by means of immunocytochemistry. Receptor antigen is virtually absent from growing cells and begins to accumulate after about 6 hr of starvation, concomitant with the increase in surface cAMP binding activity. In aggregating cells, the antigen is uniformly distributed over the cell surface. Persistent cAMP stimulation, which leads to down-regulation of cAMP binding activity, induces a striking rearrangement of receptor antigen into patches or internal vesicles. A similar patching of receptor antigen is observed during tight aggregate formation, when surface cAMP binding activity decreases. These observations indicate that receptor down-regulation involves receptor agglomeration and suggest that receptor down-regulation takes place in vivo, when tight aggregates are being formed

Generation of Vorticity and Velocity Dispersion by Orbit Crossing

We study the generation of vorticity and velocity dispersion by orbit crossing using cosmological numerical simulations, and calculate the backreaction of these effects on the evolution of large-scale density and velocity divergence power spectra. We use Delaunay tessellations to define the velocity field, showing that the power spectra of velocity divergence and vorticity measured in this way are unbiased and have better noise properties than for standard interpolation methods that deal with mass weighted velocities. We show that high resolution simulations are required to recover the correct large-scale vorticity power spectrum, while poor resolution can spuriously amplify its amplitude by more than one order of magnitude. We measure the scalar and vector modes of the stress tensor induced by orbit crossing using an adaptive technique, showing that its vector modes lead, when input into the vorticity evolution equation, to the same vorticity power spectrum obtained from the Delaunay method. We incorporate orbit crossing corrections to the evolution of large scale density and velocity fields in perturbation theory by using the measured stress tensor modes. We find that at large scales (k~0.1 h/Mpc) vector modes have very little effect in the density power spectrum, while scalar modes (velocity dispersion) can induce percent level corrections at z=0, particularly in the velocity divergence power spectrum. In addition, we show that the velocity power spectrum is smaller than predicted by linear theory until well into the nonlinear regime, with little contribution from virial velocities.Comment: 27 pages, 14 figures. v2: reorganization of the material, new appendix. Accepted by PR

Spin alignment of dark matter haloes in filaments and walls

The MMF technique is used to segment the cosmic web as seen in a cosmological N-body simulation into wall-like and filament-like structures. We find that the spins and shapes of dark matter haloes are significantly correlated with each other and with the orientation of their host structures. The shape orientation is such that the halo minor axes tend to lie perpendicular to the host structure, be it a wall or filament. The orientation of the halo spin vector is mass dependent. Low mass haloes in walls and filaments have a tendency to have their spins oriented within the parent structure, while higher mass haloes in filaments have spins that tend to lie perpendicular to the parent structure.Comment: 4 pages, 2 figure

ZOBOV: a parameter-free void-finding algorithm

ZOBOV (ZOnes Bordering On Voidness) is an algorithm that finds density depressions in a set of points, without any free parameters, or assumptions about shape. It uses the Voronoi tessellation to estimate densities, which it uses to find both voids and subvoids. It also measures probabilities that each void or subvoid arises from Poisson fluctuations. This paper describes the ZOBOV algorithm, and the results from its application to the dark-matter particles in a region of the Millennium Simulation. Additionally, the paper points out an interesting high-density peak in the probability distribution of dark-matter particle densities.Comment: 10 pages, 8 figures, MNRAS, accepted. Added explanatory figures, and better edge-detection methods. ZOBOV code available at http://www.ifa.hawaii.edu/~neyrinck/vobo

Preclinical validation of the advection diffusion flow estimation method using computational patient specific coronary tree phantoms

Coronary computed tomography angiography (CCTA) does not allow the quantification of reduced blood flow due to coronary artery disease (CAD). In response, numerical methods based on the CCTA image have been developed to compute coronary blood flow and assess the impact of disease. However to compute blood flow in the coronary arteries, numerical methods require specification of boundary conditions that are difficult to estimate accurately in a patient-specific manner. We describe herein a new noninvasive flow estimation method, called Advection Diffusion Flow Estimation (ADFE), to compute coronary artery flow from CCTA to use as boundary conditions for numerical models of coronary blood flow. ADFE uses image contrast variation along the tree-like structure to estimate flow in each vessel. For validating this method we used patient specific software phantoms on which the transport of contrast was simulated. This controlled validation setting enables a direct comparison between estimated flow and actual flow and a detailed investigation of factors affecting accuracy. A total of 10 CCTA image data sets were processed to extract all necessary information for simulating contrast transport. A spectral element method solver was used for computing the ground truth simulations with high accuracy. On this data set, the ADFE method showed a high correlation coefficient of 0.998 between estimated flow and the ground truth flow together with an average relative error of only 1 % . Comparing the ADFE method with the best method currently available (TAFE) for image-based blood flow estimation, which showed a correlation coefficient of 0.752 and average error of 20 % , it can be concluded that the ADFE method has the potential to significantly improve the quantification of coronary artery blood flow derived from contrast gradients in CCTA images. </p