Tauroursodeoxycholic acid prevents retinal degeneration in transgenic P23H rats

Purpose. To evaluate the preventive effect of tauroursodeoxycholic acid (TUDCA) on photoreceptor degeneration, synaptic connectivity and functional activity of the retina in the transgenic P23H rat, an animal model of autosomal dominant retinitis pigmentosa (RP). Methods. P23H line-3 rats were injected with TUDCA once a week from postnatal day (P)21 to P120, in parallel with vehicle-administered controls. At P120, functional activity of the retina was evaluated by electroretinographic (ERG) recording. The effects of TUDCA on the number, morphology, integrity, and synaptic connectivity of retinal cells were characterized by immunofluorescence confocal microscopy. Results. The amplitude of ERG a- and b-waves was significantly higher in TUDCA-treated animals under both scotopic and photopic conditions than in control animals. In the central area of the retina, TUDCA-treated P23H rats showed threefold more photoreceptors than control animals. The number of TUNEL-positive cells was significantly smaller in TUDCA-treated rats, in which photoreceptor morphology was preserved. Presynaptic and postsynaptic elements, as well as the synaptic contacts between photoreceptors and bipolar or horizontal cells, were preserved in TUDCA-treated P23H rats. Furthermore, in TUDCA-treated rat retinas, the number of both rod bipolar and horizontal cell bodies, as well as the density of their synaptic terminals in the outer plexiform layer, was greater than in control rats. Conclusions. TUDCA treatment was capable of preserving cone and rod structure and function, together with their contacts with their postsynaptic neurons. The neuroprotective effects of TUDCA make this compound potentially useful for delaying retinal degeneration in RP.

Partial rescue of retinal function in chronically hypoglycemic mice

Purpose. Mice rendered hypoglycemic by a null mutation in the glucagon receptor gene Gcgr display late-onset retinal degeneration and loss of retinal sensitivity. Acute hyperglycemia induced by dextrose ingestion does not restore their retinal function, which is consistent with irreversible loss of vision. The goal of this study was to establish whether long-term administration of high dietary glucose rescues retinal function and circuit connectivity in aged Gcgr−/− mice. Methods. Gcgr−/− mice were administered a carbohydrate-rich diet starting at 12 months of age. After 1 month of treatment, retinal function and structure were evaluated using electroretinographic (ERG) recordings and immunohistochemistry. Results. Treatment with a carbohydrate-rich diet raised blood glucose levels and improved retinal function in Gcgr−/− mice. Blood glucose increased from moderate hypoglycemia to euglycemic levels, whereas ERG b-wave sensitivity improved approximately 10-fold. Because the b-wave reflects the electrical activity of second-order cells, we examined for changes in rod-to-bipolar cell synapses. Gcgr−/− retinas have 20% fewer synaptic pairings than Gcgr+/− retinas. Remarkably, most of the lost synapses were located farthest from the bipolar cell body, near the distal boundary of the outer plexiform layer (OPL), suggesting that apical synapses are most vulnerable to chronic hypoglycemia. Although treatment with the carbohydrate-rich diet restored retinal function, it did not restore these synaptic contacts. Conclusions. Prolonged exposure to diet-induced euglycemia improves retinal function but does not reestablish synaptic contacts lost by chronic hypoglycemia. These results suggest that retinal neurons have a homeostatic mechanism that integrates energetic status over prolonged periods of time and allows them to recover functionality despite synaptic loss.

Age-related functional and structural retinal modifications in the Igf1−/− null mouse

Background. Mutations in the gene encoding human insulin-like growth factor-I (IGF-I) cause syndromic neurosensorial deafness. To understand the precise role of IGF-I in retinal physiology, we have studied the morphology and electrophysiology of the retina of the Igf1−/− mice in comparison with that of the Igf1+/− and Igf1+/+ animals during aging. Methods. Serological concentrations of IGF-I, glycemia and body weight were determined in Igf1+/+, Igf1+/− and Igf1−/− mice at different times up to 360 days of age. We have analyzed hearing by recording the auditory brainstem responses (ABR), the retinal function by electroretinographic (ERG) responses and the retinal morphology by immunohistochemical labeling on retinal preparations at different ages. Results. IGF-I levels are gradually reduced with aging in the mouse. Deaf Igf1−/− mice had an almost flat scotopic ERG response and a photopic ERG response of very small amplitude at postnatal age 360 days (P360). At the same age, Igf1+/− mice still showed both scotopic and photopic ERG responses, but a significant decrease in the ERG wave amplitudes was observed when compared with those of Igf1+/+ mice. Immunohistochemical analysis showed that P360 Igf1−/− mice suffered important structural modifications in the first synapse of the retinal pathway, that affected mainly the postsynaptic processes from horizontal and bipolar cells. A decrease in bassoon and synaptophysin staining in both rod and cone synaptic terminals suggested a reduced photoreceptor output to the inner retina. Retinal morphology of the P360 Igf1+/− mice showed only small alterations in the horizontal and bipolar cell processes, when compared with Igf1+/+ mice of matched age. Conclusions. In the mouse, IGF-I deficit causes an age-related visual loss, besides a congenital deafness. The present results support the use of the Igf1−/− mouse as a new model for the study of human syndromic deaf-blindness.

Proinsulin slows retinal degeneration and vision loss in the P23H rat model of retinitis pigmentosa

Proinsulin has been characterized as a neuroprotective molecule. In this work we assess the therapeutic potential of proinsulin on photoreceptor degeneration, synaptic connectivity, and functional activity of the retina in the transgenic P23H rat, an animal model of autosomal dominant retinitis pigmentosa (RP). P23H homozygous rats received an intramuscular injection of an adeno-associated viral vector serotype 1 (AAV1) expressing human proinsulin (hPi+) or AAV1-null vector (hPi−) at P20. Levels of hPi in serum were determined by enzyme-linked immunosorbent assay (ELISA), and visual function was evaluated by electroretinographic (ERG) recording at P30, P60, P90, and P120. Preservation of retinal structure was assessed by immunohistochemistry at P120. Human proinsulin was detected in serum from rats injected with hPi+ at all times tested, with average hPi levels ranging from 1.1 nM (P30) to 1.4 nM (P120). ERG recordings showed an amelioration of vision loss in hPi+ animals. The scotopic b-waves were significantly higher in hPi+ animals than in control rats at P90 and P120. This attenuation of visual deterioration correlated with a delay in photoreceptor degeneration and the preservation of retinal cytoarchitecture. hPi+ animals had 48.7% more photoreceptors than control animals. Presynaptic and postsynaptic elements, as well as the synaptic contacts between photoreceptors and bipolar or horizontal cells, were preserved in hPi+ P23H rats. Furthermore, in hPi+ rat retinas the number of rod bipolar cell bodies was greater than in control rats. Our data demonstrate that hPi expression preserves cone and rod structure and function, together with their contacts with postsynaptic neurons, in the P23H rat. These data strongly support the further development of proinsulin-based therapy to counteract retinitis pigmentosa.

The outburst decay of the low magnetic field magnetar SGR 0418+5729

We report on the long-term X-ray monitoring of the outburst decay of the low magnetic field magnetar SGR 0418+5729 using all the available X-ray data obtained with RXTE, Swift, Chandra, and XMM-Newton observations from the discovery of the source in 2009 June up to 2012 August. The timing analysis allowed us to obtain the first measurement of the period derivative of SGR 0418+5729: ˙ P = 4(1) × 10−15 s s−1, significant at a ∼3.5σ confidence level. This leads to a surface dipolar magnetic field of Bdip 6 × 1012 G. This measurement confirms SGR 0418+5729 as the lowest magnetic field magnetar. Following the flux and spectral evolution from the beginning of the outburst up to ∼1200 days, we observe a gradual cooling of the tiny hot spot responsible for the X-ray emission, from a temperature of ∼0.9 to 0.3 keV. Simultaneously, the X-ray flux decreased by about three orders of magnitude: from about 1.4 × 10−11 to 1.2 × 10−14 erg s−1 cm−2. Deep radio, millimeter, optical, and gamma-ray observations did not detect the source counterpart, implying stringent limits on its multi-band emission, as well as constraints on the presence of a fossil disk. By modeling the magneto-thermal secular evolution of SGR 0418+5729, we infer a realistic age of ∼550 kyr, and a dipolar magnetic field at birth of ∼1014 G. The outburst characteristics suggest the presence of a thin twisted bundle with a small heated spot at its base. The bundle untwisted in the first few months following the outburst, while the hot spot decreases in temperature and size. We estimate the outburst rate of low magnetic field magnetars to be about one per year per galaxy, and we briefly discuss the consequences of such a result in several other astrophysical contexts.

3XMM J185246.6+003317: another low magnetic field magnetar

We study the outburst of the newly discovered X-ray transient 3XMMJ185246.6+003317, re-analyzing all available XMM-Newton observations of the source to perform a phase-coherent timing analysis, and derive updated values of the period and period derivative. We find the source rotating at P = 11.55871346(6) s (90% confidence level; at epoch MJD 54728.7) but no evidence for a period derivative in the seven months of outburst decay spanned by the observations. This translates to a 3σ upper limit for the period derivative of ˙ P <1.4×10−13 s s−1, which, assuming the classical magneto-dipolar braking model, gives a limit on the dipolar magnetic field of Bdip < 4.1×1013 G. The X-ray outburst and spectral characteristics of 3XMM J185246.6+003317 confirm its identification as a magnetar, but the magnetic field upper limit we derive defines it as the third “low-B” magnetar discovered in the past 3 yr, after SGR 0418+5729 and Swift J1822.3−1606. We have also obtained an upper limit to the quiescent luminosity (<4×1033 erg s−1), in line with the expectations for an old magnetar. The discovery of this new low field magnetar reaffirms the prediction of about one outburst per year from the hidden population of aged magnetars.

The accretion environment in Vela X-1 during a flaring period using XMM-Newton

We present analysis of 100 ks contiguous XMM-Newton data of the prototypical wind accretor Vela X-1. The observation covered eclipse egress between orbital phases 0.134 and 0.265, during which a giant flare took place, enabling us to study the spectral properties both outside and during the flare. This giant flare with a peak luminosity of 3.92+0.42-0.09 × 1037 erg s-1 allows estimates of the physical parameters of the accreted structure with a mass of ~1021 g. We have been able to model several contributions to the observed spectrum with a phenomenological model formed by three absorbed power laws plus three emission lines. After analysing the variations with orbital phase of the column density of each component, as well as those in the Fe and Ni fluorescence lines, we provide a physical interpretation for each spectral component. Meanwhile, the first two components are two aspects of the principal accretion component from the surface of the neutron star, the third component seems to be the X-ray light echo formed in the stellar wind of the companion.

Neuroprotective effects of the cannabinoid agonist HU210 on retinal degeneration

Cannabinoids have been demonstrated to exert neuroprotective effects on different types of neuronal insults. Here we have addressed the therapeutic potential of the synthetic cannabinoid HU210 on photoreceptor degeneration, synaptic connectivity and functional activity of the retina in the transgenic P23H rat, an animal model for autosomal dominant retinitis pigmentosa (RP). In P23H rats administered with HU210 (100 μg/kg, i.p.) from P24 to P90, ERG recordings showed an amelioration of vision loss, as compared to vehicle-administered animals. Under scotopic conditions, the maximum a-wave amplitudes recorded at P60 and P90 were higher in HU210-treated animals, as compared to the values obtained in untreated animals. The scotopic b-waves were significantly higher in treated animals than in untreated rats at P30, P60 and P90. This attenuation of visual deterioration correlated with a delay in photoreceptor degeneration and the preservation of retinal cytoarchitecture. HU210-treated animals had 40% more photoreceptors than untreated animals. Presynaptic and postsynaptic elements, as well as the synaptic contacts between photoreceptors and bipolar or horizontal cells, were also preserved in HU210-treated P23H rats. These results indicate that HU210 preserves cone and rod structure and function, together with their contacts with postsynaptic neurons, in P23H rats. These data suggest that cannabinoids are potentially useful to delay retinal degeneration in RP patients.

Deriving the Dynamical Masses of Ultra-Luminous X-ray Sources with OSIRIS

Ultra Luminous X-ray Sources (ULXs) are extragalactic X-ray point sources with LX ∼ 1039 − 1041 erg s−1 discovered in the 80s with the Einstein satellite and confirmed as black hole X-ray binaries during the last decade. The nature of the compact object is highly controversial. They could be super-Eddington stellar-mass black holes or intermediate mass black holes. Deriving dynamical masses of the brightest ULXs, which can be done with OSIRIS, is the only way to find out the nature of the compact object.

Physiological and Morphological Similarities between the Octodon Degus Retina and the Human Retina

Octodon degus is a rodent with diurnal crepuscular activity. Here we compare the function and morphology of the retina of this diurnal rodent with the retinas of nocturnal rodents and humans.

Probing large-scale wind structures in Vela X–1 using off-states with INTEGRAL

Vela X–1 is the prototype of the class of wind-fed accreting pulsars in high-mass X-ray binaries hosting a supergiant donor. We have analysed in a systematic way 10 years of INTEGRAL data of Vela X–1 (22–50 keV) and we found that when outside the X-ray eclipse, the source undergoes several luminosity drops where the hard X-rays luminosity goes below ∼3 × 1035 erg s−1, becoming undetected by INTEGRAL. These drops in the X-ray flux are usually referred to as ‘off-states’ in the literature. We have investigated the distribution of these off-states along the Vela X–1 ∼ 8.9 d orbit, finding that their orbital occurrence displays an asymmetric distribution, with a higher probability to observe an off-state near the pre-eclipse than during the post-eclipse. This asymmetry can be explained by scattering of hard X-rays in a region of ionized wind, able to reduce the source hard X-ray brightness preferentially near eclipse ingress. We associate this ionized large-scale wind structure with the photoionization wake produced by the interaction of the supergiant wind with the X-ray emission from the neutron star. We emphasize that this observational result could be obtained thanks to the accumulation of a decade of INTEGRAL data, with observations covering the whole orbit several times, allowing us to detect an asymmetric pattern in the orbital distribution of off-states in Vela X–1.

The X-ray outburst of the Galactic Centre magnetar SGR J1745−2900 during the first 1.5 year

In 2013 April a new magnetar, SGR 1745−2900, was discovered as it entered an outburst, at only 2.4 arcsec angular distance from the supermassive black hole at the centre of the Milky Way, Sagittarius A*. SGR 1745−2900 has a surface dipolar magnetic field of ∼2 × 1014 G, and it is the neutron star closest to a black hole ever observed. The new source was detected both in the radio and X-ray bands, with a peak X-ray luminosity LX ∼ 5 × 1035 erg s−1. Here we report on the long-term Chandra (25 observations) and XMM–Newton (eight observations) X-ray monitoring campaign of SGR 1745−2900 from the onset of the outburst in 2013 April until 2014 September. This unprecedented data set allows us to refine the timing properties of the source, as well as to study the outburst spectral evolution as a function of time and rotational phase. Our timing analysis confirms the increase in the spin period derivative by a factor of ∼2 around 2013 June, and reveals that a further increase occurred between 2013 October 30 and 2014 February 21. We find that the period derivative changed from 6.6 × 10−12 to 3.3 × 10−11 s s−1 in 1.5 yr. On the other hand, this magnetar shows a slow flux decay compared to other magnetars and a rather inefficient surface cooling. In particular, starquake-induced crustal cooling models alone have difficulty in explaining the high luminosity of the source for the first ∼200 d of its outburst, and additional heating of the star surface from currents flowing in a twisted magnetic bundle is probably playing an important role in the outburst evolution.

Ultraluminous X-ray sources with the SKA

The discovery almost three decades ago of non-nuclear, point-like X-ray sources with X-ray luminosities LX ≥ 3 × 1039 erg s−1 revolutionized the physics of black hole accretion. If of stellar origin, such Ultraluminous X-ray sources (ULXs) would have to accrete at super-Eddington rates in order to reach the observed high X-ray luminosities. Alternatively, ULXs could host sub-Eddington accreting intermediate-mass black holes, which are the long-time sought missing link between stellar and supermassive black holes and the possible seeds of the supermassive black holes that formed in the early Universe. The nature of ULXs can be better investigated in those cases for which a radio counterpart is detected. Radio observations of ULXs have revealed a wide variety of morphologies and source types, from compact and extended jets to radio nebulae and transient behaviours, providing the best observational evidence for the presence of an intermediate-mass black hole in some of them. The high sensitivity of the SKA will allow us to study the faintest ULX radio counterparts in the Local Universe as well as to detect new sources at much larger distances. It will thus perform a leap step in understanding ULXs, their accretion physics, and their possible role as seed black holes in supermassive black hole and galaxy growth.

The discovery, monitoring and environment of SGR J1935+2154

We report on the discovery of a new member of the magnetar class, SGR J1935+2154, and on its timing and spectral properties measured by an extensive observational campaign carried out between 2014 July and 2015 March with Chandra and XMM–Newton (11 pointings). We discovered the spin period of SGR J1935+2154 through the detection of coherent pulsations at a period of about 3.24 s. The magnetar is slowing down at a rate of P˙=1.43(1)×10−11 s s−1 and with a decreasing trend due to a negative P¨ of −3.5(7) × 10−19 s s−2. This implies a surface dipolar magnetic field strength of ∼2.2 × 1014 G, a characteristic age of about 3.6 kyr and a spin-down luminosity Lsd ∼1.7 × 1034 erg s−1. The source spectrum is well modelled by a blackbody with temperature of about 500 eV plus a power-law component with photon index of about 2. The source showed a moderate long-term variability, with a flux decay of about 25 per cent during the first four months since its discovery, and a re-brightening of the same amount during the second four months. The X-ray data were also used to study the source environment. In particular, we discovered a diffuse emission extending on spatial scales from about 1 arcsec up to at least 1 arcmin around SGR J1935+2154 both in Chandra and XMM–Newton data. This component is constant in flux (at least within uncertainties) and its spectrum is well modelled by a power-law spectrum steeper than that of the pulsar. Though a scattering halo origin seems to be more probable we cannot exclude that part, or all, of the diffuse emission is due to a pulsar wind nebula.