Kinetics of Rhodopsin Deactivation and Its Role in Regulating Recovery and Reproducibility of Rod Photoresponse

The single photon response (SPR) in vertebrate phototransduction is regulated by the dynamics of R* during its lifetime, including the random number of phosphorylations, the catalytic activity and the random sojourn time at each phosphorylation level. Because of this randomness the electrical responses are expected to be inherently variable. However the SPR is highly reproducible. The mechanisms that confer to the SPR such a low variability are not completely understood. The kinetics of rhodopsin deactivation is investigated by a Continuous Time Markov Chain (CTMC) based on the biochemistry of rhodopsin activation and deactivation, interfaced with a spatio-temporal model of phototransduction. The model parameters are extracted from the photoresponse data of both wild type and mutant mice, having variable numbers of phosphorylation sites and, with the same set of parameters, the model reproduces both WT and mutant responses. The sources of variability are dissected into its components, by asking whether a random number of turnoff steps, a random sojourn time between steps, or both, give rise to the known variability. The model shows that only the randomness of the sojourn times in each of the phosphorylated states contributes to the Coefficient of Variation (CV) of the response, whereas the randomness of the number of R* turnoff steps has a negligible effect. These results counter the view that the larger the number of decay steps of R*, the more stable the photoresponse is. Our results indicate that R* shutoff is responsible for the variability of the photoresponse, while the diffusion of the second messengers acts as a variability suppressor

Earth-Moon Lagrangian points as a testbed for general relativity and effective field theories of gravity

We first analyse the restricted four-body problem consisting of the Earth, the Moon and the Sun as the primaries and a spacecraft as the planetoid. This scheme allows us to take into account the solar perturbation in the description of the motion of a spacecraft in the vicinity of the stable Earth-Moon libration points L4 and L5 both in the classical regime and in the context of effective field theories of gravity. A vehicle initially placed at L4 or L5 will not remain near the respective points. In particular, in the classical case the vehicle moves on a trajectory about the libration points for at least 700 days before escaping away. We show that this is true also if the modified long-distance Newtonian potential of effective gravity is employed. We also evaluate the impulse required to cancel out the perturbing force due to the Sun in order to force the spacecraft to stay precisely at L4 or L5. It turns out that this value is slightly modified with respect to the corresponding Newtonian one. In the second part of the paper, we first evaluate the location of all Lagrangian points in the Earth-Moon system within the framework of general relativity. For the points L4 and L5, the corrections of coordinates are of order a few millimeters and describe a tiny departure from the equilateral triangle. After that, we set up a scheme where the theory which is quantum corrected has as its classical counterpart the Einstein theory, instead of the Newtonian one. In other words, we deal with a theory involving quantum corrections to Einstein gravity, rather than to Newtonian gravity. By virtue of the effective-gravity correction to the long-distance form of the potential among two point masses, all terms involving the ratio between the gravitational radius of the primary and its separation from the planetoid get modified. Within this framework, for the Lagrangian points of stable equilibrium, we find quantum corrections of order two millimeters, whereas for Lagrangian points of unstable equilibrium we find quantum corrections below a millimeter. In the latter case, for the point L1, general relativity corrects Newtonian theory by 7.61 meters, comparable, as an order of magnitude, with the lunar geodesic precession of about 3 meters per orbit. The latter is a cumulative effect accurately measured at the centimeter level through the lunar laser ranging positioning technique. Thus, it is possible to study a new laser ranging test of general relativity to measure the 7.61-meter correction to the L1 Lagrangian point, an observable never used before in the Sun-Earth-Moon system. Performing such an experiment requires controlling the propulsion to precisely reach L1, an instrumental accuracy comparable to the measurement of the lunar geodesic precession, understanding systematic effects resulting from thermal radiation and multi-body gravitational perturbations. This will then be the basis to consider a second-generation experiment to study deviations of effective field theories of gravity from general relativity in the Sun-Earth-Moon system

Quantum effects on Lagrangian points and displaced periodic orbits in the Earth-Moon system

Recent work in the literature has shown that the one-loop long distance quantum corrections to the Newtonian potential imply tiny but observable effects in the restricted three-body problem of celestial mechanics, i.e., at the Lagrangian libration points of stable equilibrium the planetoid is not exactly at equal distance from the two bodies of large mass, but the Newtonian values of its coordinates are changed by a few millimeters in the Earth-Moon system. First, we assess such a theoretical calculation by exploiting the full theory of the quintic equation, i.e., its reduction to Bring-Jerrard form and the resulting expression of roots in terms of generalized hypergeometric functions. By performing the numerical analysis of the exact formulas for the roots, we confirm and slightly improve the theoretical evaluation of quantum corrected coordinates of Lagrangian libration points of stable equilibrium. Second, we prove in detail that also for collinear Lagrangian points the quantum corrections are of the same order of magnitude in the Earth-Moon system. Third, we discuss the prospects to measure, with the help of laser ranging, the above departure from the equilateral triangle picture, which is a challenging task. On the other hand, a modern version of the planetoid is the solar sail, and much progress has been made, in recent years, on the displaced periodic orbits of solar sails at all libration points, both stable and unstable. The present paper investigates therefore, eventually, a restricted three-body problem involving Earth, Moon and a solar sail. By taking into account the one-loop quantum corrections to the Newtonian potential, displaced periodic orbits of the solar sail at libration points are again found to exist

X-ray holography with a customizable reference

In X-ray Fourier-transform holography, images are formed by exploiting the interference pattern between the X-rays scattered from the sample and a known reference wave. To date, this technique has only been possible with a limited set of special reference waves. We demonstrate X-ray Fourier-transform holography with an almost unrestricted choice for the reference wave, permitting experimental geometries to be designed according to the needs of each experiment and opening up new avenues to optimize signal-to-noise and resolution. The optimization of holographic references can aid the development of holographic techniques to meet the demands of resolution and fidelity required for single-shot imaging applications with X-ray lasers

Coenzyme Q10 Levels Are Decreased in the Cerebellum of Multiple-System Atrophy Patients

Background: The objective of this study was to evaluate whether the levels of coenzyme Q10 (CoQ10) in brain tissue of multiple system atrophy (MSA) patients differ from those in elderly controls and in patients with other neurodegenerative diseases. Methods: Flash frozen brain tissue of a series of 20 pathologically confirmed MSA patients [9 olivopontocerebellar atrophy (OPCA) type, 6 striatonigral degeneration (SND) type, and 5 mixed type] was used for this study. Elderly controls (n = 37) as well as idiopathic Parkinson's disease (n = 7), dementia with Lewy bodies (n = 20), corticobasal degeneration (n = 15) and cerebellar ataxia (n = 18) patients were used as comparison groups. CoQ10 was measured in cerebellar and frontal cortex tissue by high performance liquid chromatography. Results: We detected a statistically significant decrease (by 3–5%) in the level of CoQ10 in the cerebellum of MSA cases (P = 0.001), specifically in OPCA (P = 0.001) and mixed cases (P = 0.005), when compared to controls as well as to other neurodegenerative diseases [dementia with Lewy bodies (P<0.001), idiopathic Parkinson's disease (P<0.001), corticobasal degeneration (P<0.001), and cerebellar ataxia (P = 0.001)]. Conclusion: Our results suggest that a perturbation in the CoQ10 biosynthetic pathway is associated with the pathogenesis of MSA but the mechanism behind this finding remains to be elucidated

Effects of Inhibiting CoQ10 Biosynthesis with 4-nitrobenzoate in Human Fibroblasts

Coenzyme Q10 (CoQ10) is a potent lipophilic antioxidant in cell membranes and a carrier of electrons in the mitochondrial respiratory chain. We previously characterized the effects of varying severities of CoQ10 deficiency on ROS production and mitochondrial bioenergetics in cells harboring genetic defects of CoQ10 biosynthesis. We observed a unimodal distribution of ROS production with CoQ10 deficiency: cells with <20% of CoQ10 and 50–70% of CoQ10 did not generate excess ROS while cells with 30–45% of CoQ10 showed increased ROS production and lipid peroxidation. Because our previous studies were limited to a small number of mutant cell lines with heterogeneous molecular defects, here, we treated 5 control and 2 mildly CoQ10 deficient fibroblasts with varying doses of 4-nitrobenzoate (4-NB), an analog of 4-hydroxybenzoate (4-HB) and inhibitor of 4-para-hydroxybenzoate:polyprenyl transferase (COQ2) to induce a range of CoQ10 deficiencies. Our results support the concept that the degree of CoQ10 deficiency in cells dictates the extent of ATP synthesis defects and ROS production and that 40–50% residual CoQ10 produces maximal oxidative stress and cell death

Dielectric Screening in Atomically Thin Boron Nitride Nanosheets

Two-dimensional (2D) hexagonal boron nitride (BN) nanosheets are excellent dielectric substrate for graphene, molybdenum disulfide and many other 2D nanomaterials based electronic and photonic devices. To optimize the performance of these 2D devices, it is essential to understand the dielectric screening properties of BN nanosheets as a function of the thickness. Here, electric force microscopy along with theoretical calculations based on both state-of-the-art first-principles calculations with van der Waals interactions under consideration and non-linear Thomas-Fermi theory models are used to investigate the dielectric screening in high-quality BN nanosheets of different thicknesses. It is found that atomically thin BN nanosheets are less effective in electric field screening, but the screening capability of BN shows a relatively weak dependence on the layer thickness

Lista bibliografica

Questa lista bibliografica contiene il secondo aggiornamento della bibliografia della Lisy e deriva dall’assemblaggio da parte della redazione (M. Serdoz ed E. Panfili) dei contributi parziali stilati dai gruppi regionali

Gene Therapy Corrects Mitochondrial Dysfunction in Hematopoietic Progenitor Cells and Fibroblasts from Coq9R239X Mice

This study has been submitted to the patent's offices at the "University of Granada" and "Fundación Progreso y Salud". Please note that the results of this manuscript have been submitted to patent protection (application number P201630630; title: “Uses of Coenzyme Q biosynthetic proteins”; date:05/16/2016).Recent clinical trials have shown that in vivo and ex vivo gene therapy strategies can be an option for the treatment of several neurological disorders. Both strategies require efficient and safe vectors to 1) deliver the therapeutic gene directly into the CNS or 2) to genetically modify stem cells that will be used as Trojan horses for the systemic delivery of the therapeutic protein. A group of target diseases for these therapeutic strategies are mitochondrial encephalopathies due to mutations in nuclear DNA genes. In this study, we have developed a lentiviral vector (CCoq9WP) able to overexpress Coq9 mRNA and COQ9 protein in mouse embryonic fibroblasts (MEFs) and hematopoietic progenitor cells (HPCs) from Coq9R239X mice, an animal model of mitochondrial encephalopathy due to primary Coenzyme Q (CoQ) deficiency. Ectopic over-expression of Coq9 in both cell types restored the CoQ biosynthetic pathway and mitochondrial function, improving the fitness of the transduced cells. These results show the potential of the CCoq9WP lentiviral vector as a tool for gene therapy to treat mitochondrial encephalopathies.This work was supported by grants from Ministerio de Economía y Competitividad (Spain) and the European Regional Development Fund (ERDF) from the European Union, to LCL through the research grants SAF2013-47761-R and SAF2015-65786-R; by Fondo de Investigaciones Sanitarias ISCIII (Spain) and the European Regional Development Fund (ERDF) from the European Union through the research grants PI12/01097 and ISCIII Red de Terapia Celular TerCel RD12/0019/0006 to FM; by the Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía-FEDER/Fondo de Cohesion Europeo (FSE) de Andalucía through the research grants P10-CTS-6133 to LCL; P09-CTS-04532, PI-57069, PI-0001/2009 and PAIDI-Bio-326 to F.M.; PI-0160/2012 to KB and PI-0407/2012 to MC; by the NIH through the research P01HD080642 to LCL and by the foundation “todos somos raros, todos somos únicos” to LCL. LCL is supported by the ‘Ramón y Cajal’ National Programme, Ministerio de Economía y Competitividad, Spain (RYC-2011-07643)