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

Microbiology and atmospheric processes: Biological, physical and chemical characterization of aerosol particles

The interest in bioaerosols has traditionally been linked to health hazards for humans, animals and plants. However, several components of bioaerosols exhibit physical properties of great significance for cloud processes, such as ice nucleation and cloud condensation. To gain a better understanding of their influence on climate, it is therefore important to determine the composition, concentration, seasonal fluctuation, regional diversity and evolution of bioaerosols. In this paper, we will review briefly the existing techniques for detection, quantification, physical and chemical analysis of biological particles, attempting to bridge physical, chemical and biological methods for analysis of biological particles and integrate them with aerosol sampling techniques. We will also explore some emerging spectroscopy techniques for bulk and single-particle analysis that have potential for in-situ physical and chemical analysis. Lastly, we will outline open questions and further desired capabilities (e. g., in-situ, sensitive, both broad and selective, on-line, time-resolved, rapid, versatile, cost-effective techniques) required prior to comprehensive understanding of chemical and physical characterization of bioaerosols

Heterogeneous ice nucleation activity of bacteria: new laboratory experiments at simulated cloud conditions

The ice nucleation activities of five different <i>Pseudomonas syringae</i>, <i>Pseudomonas viridiflava</i> and <i>Erwinia herbicola</i> bacterial species and of Snomax™ were investigated in the temperature range between −5 and −15°C. Water suspensions of these bacteria were directly sprayed into the cloud chamber of the AIDA facility of Forschungszentrum Karlsruhe at a temperature of −5.7°C. At this temperature, about 1% of the Snomax™ cells induced immersion freezing of the spray droplets before the droplets evaporated in the cloud chamber. The living cells didn't induce any detectable immersion freezing in the spray droplets at −5.7°C. After evaporation of the spray droplets the bacterial cells remained as aerosol particles in the cloud chamber and were exposed to typical cloud formation conditions in experiments with expansion cooling to about −11°C. During these experiments, the bacterial cells first acted as cloud condensation nuclei to form cloud droplets. Then, only a minor fraction of the cells acted as heterogeneous ice nuclei either in the condensation or the immersion mode. The results indicate that the bacteria investigated in the present study are mainly ice active in the temperature range between −7 and −11°C with an ice nucleation (IN) active fraction of the order of 10<sup>−4</sup>. In agreement to previous literature results, the ice nucleation efficiency of Snomax™ cells was much larger with an IN active fraction of 0.2 at temperatures around −8°C

Recoil Polarization Measurements for Neutral Pion Electroproduction at Q^2=1 (GeV/c)^2 Near the Delta Resonance

We measured angular distributions of differential cross section, beam analyzing power, and recoil polarization for neutral pion electroproduction at Q^2 = 1.0 (GeV/c)^2 in 10 bins of W across the Delta resonance. A total of 16 independent response functions were extracted, of which 12 were observed for the first time. Comparisons with recent model calculations show that response functions governed by real parts of interference products are determined relatively well near 1.232 GeV, but variations among models is large for response functions governed by imaginary parts and for both increases rapidly with W. We performed a nearly model-independent multipole analysis that adjusts complex multipoles with high partial waves constrained by baseline models. Parabolic fits to the W dependence of the multipole analysis around the Delta mass gives values for SMR = (-6.61 +/- 0.18)% and EMR = (-2.87 +/- 0.19)% that are distinctly larger than those from Legendre analysis of the same data. Similarly, the multipole analysis gives Re(S0+/M1+) = (+7.1 +/- 0.8)% at W=1.232 GeV, consistent with recent models, while the traditional Legendre analysis gives the opposite sign because its truncation errors are quite severe. Finally, using a unitary isobar model (UIM), we find that excitation of the Roper resonance is dominantly longitudinal with S1/2 = (0.05 +/- 0.01) GeV^(-1/2) at Q^2=1. The ReS0+ and ReE0+ multipoles favor pseudovector coupling over pseudoscalar coupling or a recently proposed mixed-coupling scheme, but the UIM does not reproduce the imaginary parts of 0+ multipoles well.Comment: 60 pages, 54 figure

Measurement of the Transverse-Longitudinal Cross Sections in the p (e,e'p)pi0 Reaction in the Delta Region

Accurate measurements of the p(e,e?p)pi0 reaction were performed at Q^2=0.127(GeV/c)^2 in the Delta resonance energy region. The experiments at the MIT-Bates Linear Accelerator used an 820 MeV polarized electron beam with the out of plane magnetic spectrometer system (OOPS). In this paper we report the first simultaneous determination of both the TL and TL? (``fifth" or polarized) cross sections at low Q^{2} where the pion cloud contribution dominates the quadrupole amplitudes (E2 and C2). The real and imaginary parts of the transverse-longitudinal cross section provide both a sensitive determination of the Coulomb quadrupole amplitude and a test of reaction calculations. Comparisons with model calculations are presented. The empirical MAID calculation gives the best overall agreement with this accurate data. The parameters of this model for the values of the resonant multipoles are |M_{1+}(I=3/2)|= (40.9 \pm 0.3)10^{-3}/m_pi, CMR= C2/M1= -6.5 \pm 0.3%, EMR=E2/M1=-2.2 \pm 0.9%, where the errors are due to the experimental uncertainties.Comment: 10 pages, 3 figures, minor corrections and addition

The pharmacological regulation of cellular mitophagy

Small molecules are pharmacological tools of considerable value for dissecting complex biological processes and identifying potential therapeutic interventions. Recently, the cellular quality-control process of mitophagy has attracted considerable research interest; however, the limited availability of suitable chemical probes has restricted our understanding of the molecular mechanisms involved. Current approaches to initiate mitophagy include acute dissipation of the mitochondrial membrane potential (ΔΨm) by mitochondrial uncouplers (for example, FCCP/CCCP) and the use of antimycin A and oligomycin to impair respiration. Both approaches impair mitochondrial homeostasis and therefore limit the scope for dissection of subtle, bioenergy-related regulatory phenomena. Recently, novel mitophagy activators acting independently of the respiration collapse have been reported, offering new opportunities to understand the process and potential for therapeutic exploitation. We have summarized the current status of mitophagy modulators and analyzed the available chemical tools, commenting on their advantages, limitations and current applications