A yeast-based screening unravels potential therapeutic molecules for mitochondrial diseases associated with dominant ant1 mutations

Mitochondrial diseases result from inherited or spontaneous mutations in mitochondrial or nuclear DNA, leading to an impairment of the oxidative phosphorylation responsible for the synthesis of ATP. To date, there are no effective pharmacological therapies for these pathologies. We performed a yeast-based screening to search for therapeutic drugs to be used for treating mito-chondrial diseases associated with dominant mutations in the nuclear ANT1 gene, which encodes for the mitochondrial ADP/ATP carrier. Dominant ANT1 mutations are involved in several degen-erative mitochondrial pathologies characterized by the presence of multiple deletions or depletion of mitochondrial DNA in tissues of affected patients. Thanks to the presence in yeast of the AAC2 gene, orthologue of human ANT1, a yeast mutant strain carrying the M114P substitution equivalent to adPEO-associated L98P mutation was created. Five molecules were identified for their ability to suppress the defective respiratory growth phenotype of the haploid aac2M114P . Furthermore, these molecules rescued the mtDNA mutability in the heteroallelic AAC2/aac2M114P strain, which mimics the human heterozygous condition of adPEO patients. The drugs were effective in reducing mtDNA instability also in the heteroallelic strain carrying the R96H mutation equivalent to the more severe de novo dominant missense mutation R80H, suggesting a general therapeutic effect on diseases associated with dominant ANT1 mutations

Photometry of cometary nuclei: Rotation rates, colours and a comparison with Kuiper Belt Objects

We present time-series data on Jupiter Family Comets (JFCs) 17P/Holmes, 47P/Ashbrook-Jackson and 137P/Shoemaker-Levy 2. In addition we also present results from `snap-shot' observations of comets 43P/Wolf-Harrington, 44P/Reinmuth 2, 103P/Hartley 2 and 104P/Kowal 2 taken during the same run. The comets were at heliocentric distances of between 3 and 7 AU at this time. We present measurements of size and activity levels for the snap-shot targets. The time-series data allow us to constrain rotation periods and shapes, and thus bulk densities. We also measure colour indices (V-R) and (R-I) and reliable radii for these comets. We compare all of our findings to date with similar results for other comets and Kuiper Belt Objects (KBOs). We find that the rotational properties of nuclei and KBOs are very similar, that there is evidence for a cut-off in bulk densities at ~ 0.6 g cm^{-3} in both populations, and the colours of the two populations show similar correlations. For JFCs there is no observational evidence for the optical colours being dependant on either position in the orbit or on orbital parameters.Comment: 15 pages, 19 figures, accepted for publication in MNRA

The nuclei of comets 7P/Pons-Winnecke, 14P/Wolf and 92P/Sanguin

Jupiter Family comets (JFCs) are short period comets which have recently entered the inner solar system, having previously orbited in the Kuiper Belt since the formation of the planets. We used two nights on the 3.6m New Technology Telescope (NTT) at the European Southern Observatory, to obtain VRI photometry of three JFCs; 7P/Pons-Winnecke, 14P/Wolf and 92P/Sanguin. These were observed to be stellar in appearance. We find mean effective radii of 2.24 \pm 0.02 km for 7P, 3.16 \pm 0.01 km for 14P and 2.08 \pm 0.01 km for 92P, assuming a geometric albedo of 0.04. From light-curves for each comet we find rotation periods of 7.53 \pm 0.10 and 6.22 \pm 0.05 hours for 14P and 92P respectively. 7P exhibits brightness variations which imply a rotation period of 6.8 \le P_rot \le 9.5 hours. Assuming the nuclei to be ellipsoidal the measured brightness variations imply minimum axial ratios a/b of 1.3 \pm 0.1 for 7P and 1.7 \pm 0.1 for both 14P and 92P. This in turn implies minimum densities of 0.23 \pm 0.08 g cm^{-3} for 7P, 0.32 \pm 0.02 g cm^{-3} for 14P and 0.49 \pm 0.06 g cm^{-3} for 92P. Finally, we measure colour indices of (V-R) = 0.40 \pm 0.05 and (R-I) = 0.41 \pm 0.06 for 7P/Pons-Winnecke, (V-R) = 0.57 \pm 0.07 and (R-I) = 0.51 \pm 0.06 for 14P/Wolf, and (V-R) = 0.54 \pm 0.04 and (R-I) = 0.54 \pm 0.04 for 92P/Sanguin.Comment: 12 pages, 14 figures, accepted for publication in A&

Implications of the Small Spin Changes Measured for Large Jupiter-Family Comet Nuclei

Rotational spin-up due to outgassing of comet nuclei has been identified as a possible mechanism for considerable mass-loss and splitting. We report a search for spin changes for three large Jupiter-family comets (JFCs): 14P/Wolf, 143P/Kowal-Mrkos, and 162P/Siding Spring. None of the three comets has detectable period changes, and we set conservative upper limits of 4.2 (14P), 6.6 (143P) and 25 (162P) minutes per orbit. Comparing these results with all eight other JFCs with measured rotational changes, we deduce that none of the observed large JFCs experiences significant spin changes. This suggests that large comet nuclei are less likely to undergo rotationally-driven splitting, and therefore more likely to survive more perihelion passages than smaller nuclei. We find supporting evidence for this hypothesis in the cumulative size distributions of JFCs and dormant comets, as well as in recent numerical studies of cometary orbital dynamics. We added 143P to the sample of 13 other JFCs with known albedos and phase-function slopes. This sample shows a possible correlation of increasing phase-function slopes for larger geometric albedos. Partly based on findings from recent space missions to JFCs, we hypothesise that this correlation corresponds to an evolutionary trend for JFCs. We propose that newly activated JFCs have larger albedos and steeper phase functions, which gradually decrease due to sublimation-driven erosion. If confirmed, this could be used to analyse surface erosion from ground and to distinguish between dormant comets and asteroids

Efficient clofilium tosylate-mediated rescue of POLG-related disease phenotypes in zebrafish

The DNA polymerase gamma (Polg) is a nuclear-encoded enzyme involved in DNA replication in animal mitochondria. In humans, mutations in the POLG gene underlie a set of mitochondrial diseases characterized by mitochondrial DNA (mtDNA) depletion or deletion and multiorgan defects, named POLG disorders, for which an effective therapy is still needed. By applying antisense strategies, ENU- and CRISPR/Cas9-based mutagenesis, we have generated embryonic, larval-lethal and adult-viable zebrafish Polg models. Morphological and functional characterizations detected a set of phenotypes remarkably associated to POLG disorders, including cardiac, skeletal muscle, hepatic and gonadal defects, as well as mitochondrial dysfunctions and, notably, a perturbed mitochondria-to-nucleus retrograde signaling (CREB and Hypoxia pathways). Next, taking advantage of preliminary evidence on the candidate molecule Clofilium tosylate (CLO), we tested CLO toxicity and then its efficacy in our zebrafish lines. Interestingly, at well tolerated doses, the CLO drug could successfully rescue mtDNA and Complex I respiratory activity to normal levels, even in mutant phenotypes worsened by treatment with Ethidium Bromide. In addition, the CLO drug could efficiently restore cardio-skeletal parameters and mitochondrial mass back to normal values. Altogether, these evidences point to zebrafish as a valuable vertebrate organism to faithfully phenocopy multiple defects detected in POLG patients. Moreover, this model represents an excellent platform to screen, at the whole-animal level, candidate molecules with therapeutic effects in POLG disorders

The size distribution of Jupiter Family comet nuclei

We present an updated cumulative size distribution (CSD) for Jupiter Family comet (JFC) nuclei, including a rigourous assessment of the uncertainty on the slope of the CSD. The CSD is expressed as a power law, N(>r_N) \propto r_N^{-q}, where r_N is the radius of the nuclei and q is the slope. We include a large number of optical observations published by ourselves and others since the comprehensive review in the "Comets II" book (Lamy et al. 2004), and make use of an improved fitting method. We assess the uncertainty on the CSD due to all of the unknowns and uncertainties involved (photometric uncertainty, assumed phase function, albedo and shape of the nucleus) by means of Monte Carlo simulations. In order to do this we also briefly review the current measurements of these parameters for JFCs. Our final CSD has a slope q=1.92\pm 0.20 for nuclei with radius r_N \ge 1.25 km.Comment: 13 pages, accepted for publication in MNRA

Broadband infrared photometry of comet Hale-Bopp with ISOPHOT

Comet Hale-Bopp was observed five times with ISOPHOT, the photometer on board ESA's Infrared Space Observatory (ISO) between 4.6 and 2.8 AU. Each time, broadband photometry was performed using 4 different detectors, 5 apertures and 10 filters covering the range between 3.6 and 170 μm. Background observations were performed with identical instrument settings at the same positions on the sky several days after the comet observations. The observation strategy and the data reduction steps are described in some detail, including the techniques to correct for variable detector responsivity. The resulting inband power values of the Hale-Bopp observations and their uncertainties are given. The mean uncertainty is 25%. The final fluxes were computed, taking into account the zodiacal background, possible offset of the comet's position from the center of the aperture, the brightness distribution within the coma, and the spectral energy distribution of the comet's emission. Strong thermal emission from a broad size distribution of dust particles was detected in all of the data sets, even at r = 4.6-4.9 AU pre-perihelion and 3.9 AU post-perihelion; the total thermal energy varied as r-3. The 7.3-12.8 μm color temperature was ~1.5 times the blackbody temperature, higher than that observed in any other comet. Silicate features at 10 and 25 μm were prominent in all 5 data sets, the largest heliocentric distances that silicate emission has been detected in a comet. The presence of crystalline water ice grains is suggested from the 60 μm excess emission at 4.6-4.9 AU, consistent with the observed QOH if the icy grains were slightly warmer than an equilibrium blackbody. The average albedo of the dust is higher than that of comet P/Halley, but lower than other albedo measurements for Hale-Bopp nearer perihelion. There is no evidence for a component of cold, bright icy grains enhancing the scattered light at 4.6 AU. Simple models for a mixture of silicate and absorbing grains were fit to the ISO spectra and photometry at 2.8 AU. The observed flux at λ >100 μm requires a size distribution in which most of the mass is concentrated in large particles. Dust production rates of order 1.5 x 105 kg s-1 at 2.8 AU and 3 x 104 kg s-1 at 4.6 AU have been found. They correspond to dust to gas mass ratios of 6 to 10