Brimonidine prevents axonal and somatic degeneration of retinal ganglion cell neurons

<p>Abstract</p> <p>Background</p> <p>Brimonidine is a common drug for lowering ocular pressure and may directly protect retinal ganglion cells in glaucoma. The disease involves early loss of retinal ganglion cell transport to brain targets followed by axonal and somatic degeneration. We examined whether brimonidine preserves ganglion cell axonal transport and abates degeneration in rats with elevated ocular pressure induced by laser cauterization of the episcleral veins.</p> <p>Results</p> <p>Ocular pressure was elevated unilaterally by 90% for a period of 8 weeks post- cauterization. During this time, brimonidine (1mg/kg/day) or vehicle (phosphate-buffered saline) was delivered systemically and continuously via subcutaneous pump. Animals received bilateral intravitreal injections of fluorescent cholera toxin subunit β (CTB) two days before sacrifice to assess anterograde transport. In retinas from the vehicle group, elevated pressure induced a 44% decrease in the fraction of ganglion cells with intact uptake of CTB and a 14-42% reduction in the number of immuno-labelled ganglion cell bodies, with the worst loss occurring nasally. Elevated pressure also caused a 33% loss of ganglion cell axons in vehicle optic nerves and a 70% decrease in CTB transport to the superior colliculus. Each of these components of ganglion cell degeneration was either prevented or significantly reduced in the brimonidine treatment group.</p> <p>Conclusions</p> <p>Continuous and systemic treatment with brimonidine by subcutaneous injection significantly improved retinal ganglion cell survival with exposure to elevated ocular pressure. This effect was most striking in the nasal region of the retina. Brimonidine treatment also preserved ganglion cell axon morphology, sampling density and total number in the optic nerve with elevated pressure. Consistent with improved outcome in the optic projection, brimonidine also significantly reduced the deficits in axonal transport to the superior colliculus associated with elevated ocular pressure. As transport deficits to and from retinal ganglion cell projection targets in the brain are relevant to the progression of glaucoma, the ability of brimonidine to preserve optic nerve axons and active transport suggests its neuroprotective effects are relevant not only at the cell body, but throughout the entire optic projection.</p

The burden of proof: the current state of atrial fibrillation prevention and treatment trials

Atrial fibrillation (AF) is an age-related arrhythmia of enormous socioeconomic significance. In recent years, our understanding of the basic mechanisms that initiate and perpetuate AF has evolved rapidly, catheter ablation of AF has progressed from concept to reality, and recent studies suggest lifestyle modification may help prevent AF recurrence. Emerging developments in genetics, imaging, and informatics also present new opportunities for personalized care. However, considerable challenges remain. These include a paucity of studies examining AF prevention, modest efficacy of existing antiarrhythmic therapies, diverse ablation technologies and practice, and limited evidence to guide management of high-risk patients with multiple comorbidities. Studies examining the long-term effects of AF catheter ablation on morbidity and mortality outcomes are not yet completed. In many ways, further progress in the field is heavily contingent on the feasibility, capacity, and efficiency of clinical trials to incorporate the rapidly evolving knowledge base and to provide substantive evidence for novel AF therapeutic strategies. This review outlines the current state of AF prevention and treatment trials, including the foreseeable challenges, as discussed by a unique forum of clinical trialists, scientists, and regulatory representatives in a session endorsed by the Heart Rhythm Society at the 12th Global CardioVascular Clinical Trialists Forum in Washington, DC, December 3–5, 2015

Monitoring Repair of UV-Induced 6-4-Photoproducts with a Purified DDB2 Protein Complex

Because cells are constantly subjected to DNA damaging insults, DNA repair pathways are critical for genome integrity [1]. DNA damage recognition protein complexes (DRCs) recognize DNA damage and initiate DNA repair. The DNA-Damage Binding protein 2 (DDB2) complex is a DRC that initiates nucleotide excision repair (NER) of DNA damage caused by ultraviolet light (UV) [2]-[4]. Using a purified DDB2 DRC, we created a probe ("DDB2 proteo-probe") that hybridizes to nuclei of cells irradiated with UV and not to cells exposed to other genotoxins. The DDB2 proteo-probe recognized UV-irradiated DNA in classical laboratory assays, including cyto- and histo-chemistry, flow cytometry, and slot-blotting. When immobilized, the proteo-probe also bound soluble UV-irradiated DNA in ELISA-like and DNA pull-down assays. In vitro, the DDB2 proteo-probe preferentially bound 6-4-photoproducts [(6-4)PPs] rather than cyclobutane pyrimidine dimers (CPDs). We followed UV-damage repair by cyto-chemistry in cells fixed at different time after UV irradiation, using either the DDB2 proteo-probe or antibodies against CPDs, or (6-4)PPs. The signals obtained with the DDB2 proteo-probe and with the antibody against (6-4)PPs decreased in a nearly identical manner. Since (6-4)PPs are repaired only by nucleotide excision repair (NER), our results strongly suggest the DDB2 proteo-probe hybridizes to DNA containing (6-4)PPs and allows monitoring of their removal during NER. We discuss the general use of purified DRCs as probes, in lieu of antibodies, to recognize and monitor DNA damage and repair

Biodistribution of intravitreal lenadogene nolparvovec gene therapy in nonhuman primates.

Lenadogene nolparvovec (Lumevoq) gene therapy was developed to treat Leber hereditary optic neuropathy (LHON) caused by the m.11778G > A in MT-ND4 that affects complex I of the mitochondrial respiratory chain. Lenadogene nolparvovec is a replication-defective, single-stranded DNA recombinant adeno-associated virus vector 2 serotype 2, containing a codon-optimized complementary DNA encoding the human wild-type MT-ND4 subunit protein. Lenadogene nolparvovec was administered by unilateral intravitreal injection in MT-ND4 LHON patients in two randomized, double-masked, and sham-controlled phase III clinical trials (REVERSE and RESCUE), resulting in bilateral improvement of visual acuity. These and other earlier results suggest that lenadogene nolparvovec may travel from the treated to the untreated eye. To investigate this possibility further, lenadogene nolparvovec was unilaterally injected into the vitreous body of the right eye of healthy, nonhuman primates. Viral vector DNA was quantifiable in all eye and optic nerve tissues of the injected eye and was detected at lower levels in some tissues of the contralateral, noninjected eye, and optic projections, at 3 and 6 months after injection. The results suggest that lenadogene nolparvovec transfers from the injected to the noninjected eye, thus providing a potential explanation for the bilateral improvement of visual function observed in the LHON patients

Kepler-432: a red giant interacting with one of its two long period giant planets

We report the discovery of Kepler-432b, a giant planet ($M_b = 5.41^{+0.32}_{-0.18} M_{\rm Jup}, R_b = 1.145^{+0.036}_{-0.039} R_{\rm Jup}$) transiting an evolved star $(M_\star = 1.32^{+0.10}_{-0.07} M_\odot, R_\star = 4.06^{+0.12}_{-0.08} R_\odot)$ with an orbital period of $P_b = 52.501129^{+0.000067}_{-0.000053}$ days. Radial velocities (RVs) reveal that Kepler-432b orbits its parent star with an eccentricity of $e = 0.5134^{+0.0098}_{-0.0089}$, which we also measure independently with asterodensity profiling (AP; $e=0.507^{+0.039}_{-0.114}$), thereby confirming the validity of AP on this particular evolved star. The well-determined planetary properties and unusually large mass also make this planet an important benchmark for theoretical models of super-Jupiter formation. Long-term RV monitoring detected the presence of a non-transiting outer planet (Kepler-432c; $M_c \sin{i_c} = 2.43^{+0.22}_{-0.24} M_{\rm Jup}, P_c = 406.2^{+3.9}_{-2.5}$ days), and adaptive optics imaging revealed a nearby (0\farcs87), faint companion (Kepler-432B) that is a physically bound M dwarf. The host star exhibits high signal-to-noise asteroseismic oscillations, which enable precise measurements of the stellar mass, radius and age. Analysis of the rotational splitting of the oscillation modes additionally reveals the stellar spin axis to be nearly edge-on, which suggests that the stellar spin is likely well-aligned with the orbit of the transiting planet. Despite its long period, the obliquity of the 52.5-day orbit may have been shaped by star-planet interaction in a manner similar to hot Jupiter systems, and we present observational and theoretical evidence to support this scenario. Finally, as a short-period outlier among giant planets orbiting giant stars, study of Kepler-432b may help explain the distribution of massive planets orbiting giant stars interior to 1 AU.Comment: 22 pages, 19 figures, 5 tables. Accepted to ApJ on Jan 24, 2015 (submitted Nov 11, 2014). Updated with minor changes to match published versio

SN~2012cg: Evidence for Interaction Between a Normal Type Ia Supernova and a Non-Degenerate Binary Companion

We report evidence for excess blue light from the Type Ia supernova SN 2012cg at fifteen and sixteen days before maximum B-band brightness. The emission is consistent with predictions for the impact of the supernova on a non-degenerate binary companion. This is the first evidence for emission from a companion to a SN Ia. Sixteen days before maximum light, the B-V color of SN 2012cg is 0.2 mag bluer than for other normal SN~Ia. At later times, this supernova has a typical SN Ia light curve, with extinction-corrected M_B = -19.62 +/- 0.02 mag and Delta m_{15}(B) = 0.86 +/- 0.02. Our data set is extensive, with photometry in 7 filters from 5 independent sources. Early spectra also show the effects of blue light, and high-velocity features are observed at early times. Near maximum, the spectra are normal with a silicon velocity v_{Si} = -10,500$ km s^{-1}. Comparing the early data with models by Kasen (2010) favors a main-sequence companion of about 6 solar masses. It is possible that many other SN Ia have main-sequence companions that have eluded detection because the emission from the impact is fleeting and faint.Comment: accepted to Ap

NLTT 41135: a field M-dwarf + brown dwarf eclipsing binary in a triple system, discovered by the MEarth observatory

We report the discovery of an eclipsing companion to NLTT 41135, a nearby M5 dwarf that was already known to have a wider, slightly more massive common proper motion companion, NLTT 41136, at 2.4 arcsec separation. Analysis of combined-light and radial velocity curves of the system indicates that NLTT 41135B is a 31-34 +/- 3 MJup brown dwarf (where the range depends on the unknown metallicity of the host star) on a circular orbit. The visual M-dwarf pair appears to be physically bound, so the system forms a hierarchical triple, with masses approximately in the ratio 8:6:1. The eclipses are grazing, preventing an unambiguous measurement of the secondary radius, but follow-up observations of the secondary eclipse (e.g. with the James Webb Space Telescope) could permit measurements of the surface brightness ratio between the two objects, and thus place constraints on models of brown dwarfs.Comment: 15 pages, 6 figures, 10 tables, emulateapj format. Accepted for publication in Ap

Radar-cross-section reduction of wind turbines. part 1.

In recent years, increasing deployment of large wind-turbine farms has become an issue of growing concern for the radar community. The large radar cross section (RCS) presented by wind turbines interferes with radar operation, and the Doppler shift caused by blade rotation causes problems identifying and tracking moving targets. Each new wind-turbine farm installation must be carefully evaluated for potential disruption of radar operation for air defense, air traffic control, weather sensing, and other applications. Several approaches currently exist to minimize conflict between wind-turbine farms and radar installations, including procedural adjustments, radar upgrades, and proper choice of low-impact wind-farm sites, but each has problems with limited effectiveness or prohibitive cost. An alternative approach, heretofore not technically feasible, is to reduce the RCS of wind turbines to the extent that they can be installed near existing radar installations. This report summarizes efforts to reduce wind-turbine RCS, with a particular emphasis on the blades. The report begins with a survey of the wind-turbine RCS-reduction literature to establish a baseline for comparison. The following topics are then addressed: electromagnetic model development and validation, novel material development, integration into wind-turbine fabrication processes, integrated-absorber design, and wind-turbine RCS modeling. Related topics of interest, including alternative mitigation techniques (procedural, at-the-radar, etc.), an introduction to RCS and electromagnetic scattering, and RCS-reduction modeling techniques, can be found in a previous report

GJ 3236: a new bright, very low-mass eclipsing binary system discovered by the MEarth observatory

We report the detection of eclipses in GJ 3236, a bright (I = 11.6) very low mass binary system with an orbital period of 0.77 days. Analysis of light- and radial velocity curves of the system yielded component masses of 0.38 +/- 0.02 and 0.28 +/- 0.02 Msol. The central values for the stellar radii are larger than the theoretical models predict for these masses, in agreement with the results for existing eclipsing binaries, although the present 5% observational uncertainties limit the significance of the larger radii to approximately 1 sigma. Degeneracies in the light curve models resulting from the unknown configuration of surface spots on the components of GJ 3236 currently dominate the uncertainties in the radii, and could be reduced by obtaining precise, multi-band photometry covering the full orbital period. The system appears to be tidally synchronized and shows signs of high activity levels as expected for such a short orbital period, evidenced by strong Halpha emission lines in the spectra of both components. These observations probe an important region of mass-radius parameter space around the predicted transition to fully-convective stellar interiors, where there are a limited number of precise measurements available in the literature.Comment: 14 pages, 5 figures, 10 tables, emulateapj format. Accepted for publication in Ap