The Role of the Selective Adaptor p62 and Ubiquitin-Like Proteins in Autophagy.

The ubiquitin-proteasome system and autophagy were long viewed as independent, parallel degradation systems with no point of intersection. By now we know that these degradation pathways share certain substrates and regulatory molecules and show coordinated and compensatory function. Two ubiquitin-like protein conjugation pathways were discovered that are required for autophagosome biogenesis: the Atg12-Atg5-Atg16 and Atg8 systems. Autophagy has been considered to be essentially a nonselective process, but it turned out to be at least partially selective. Selective substrates of autophagy include damaged mitochondria, intracellular pathogens, and even a subset of cytosolic proteins with the help of ubiquitin-binding autophagic adaptors, such as p62/SQSTM1, NBR1, NDP52, and Optineurin. These proteins selectively recognize autophagic cargo and mediate its engulfment into autophagosomes by binding to the small ubiquitin-like modifiers that belong to the Atg8/LC3 family

Reducing the weak lensing noise for the gravitational wave Hubble diagram using the non-Gaussianity of the magnification distribution

Gravitational wave sources are a promising cosmological standard candle because their intrinsic luminosities are determined by fundamental physics (and are insensitive to dust extinction). They are, however, affected by weak lensing magnification due to the gravitational lensing from structures along the line of sight. This lensing is a source of uncertainty in the distance determination, even in the limit of perfect standard candle measurements. It is commonly believed that the uncertainty in the distance to an ensemble of gravitational wave sources is limited by the standard deviation of the lensing magnification distribution divided by the square root of the number of sources. Here we show that by exploiting the non-Gaussian nature of the lensing magnification distribution, we can improve this distance determination, typically by a factor of 2--3; we provide a fitting formula for the effective distance accuracy as a function of redshift for sources where the lensing noise dominates.Comment: matches PRD accepted version (expanded description of the cosmological parameter space + minor changes

Gravity map of the isla Grande de Tierra de Fuego, and morphology of Lago Fagnano

A complete Bouguer gravity map of the central-eastern part of the Isla Grande de Tierra del Fuego, and a general bathymetric chart of the Lago Fagnano have been realized, on the basis of a series of field geophysical surveys carried out on the Island since 1998. The regional gravity anomaly trend onshore shows a progressive negative gradient from N to S. Distinct, broadly E-W-trending gravity minima are superimposed on this regional negative gradient. They follow the main trace of the Magallanes-Fagnano fault system, which represents the western segment of the left-lateral South America-Scotia transform plate boundary. The gravity minima reflect the presence in the subsurface of restricted and elongated basins developed within the principal displacement zone of the fault system. A relative positive gravity maximum is located just at the SE corner of the Lago Fagnano, and represents the response of a partially exposed crystalline body, occupying an area 3 x 3 km wide. A 2D vertical crustal model has been constructed, combining gravity data inversion and geological information available for the central-eastern region of Lago Fagnano. The bathymetric map of the Lago Fagnano delineates the main morphological features of this 110-km-long, 7-km-wide lake, the largest of Isla Grande. The floor is divided into distinct parts, which suggests that the basin is composed of different sub-basins. In most areas, the basin floor is highly asymmetric in shape, with flat depocentral areas. The most pronounced asymmetry of the basin is seen in the eastern end of the lake, where there is also the deepest depression. The steeper slope of the basin, along the northern shore of the Lago Fagnano, also coincides with the most pronounced regional topographic gradient. The general gravimetric and morphological features of the investigated region are here discussed

Dual black holes in merger remnants. I: linking accretion to dynamics

We study the orbital evolution and accretion history of massive black hole (MBH) pairs in rotationally supported circumnuclear discs up to the point where MBHs form binary systems. Our simulations have high resolution in mass and space which, for the first time, makes it feasible to follow the orbital decay of a MBH either counter- or co-rotating with respect to the circumnuclear disc. We show that a moving MBH on an initially counter-rotating orbit experiences an "orbital angular momentum flip" due to the gas-dynamical friction, i.e., it starts to corotate with the disc before a MBH binary forms. We stress that this effect can only be captured in very high resolution simulations. Given the extremely large number of gas particles used, the dynamical range is sufficiently large to resolve the Bondi-Hoyle-Lyttleton radii of individual MBHs. As a consequence, we are able to link the accretion processes to the orbital evolution of the MBH pairs. We predict that the accretion rate is significantly suppressed and extremely variable when the MBH is moving on a retrograde orbit. It is only after the orbital angular momentum flip has taken place that the secondary rapidly "lights up" at which point both MBHs can accrete near the Eddington rate for a few Myr. The separation of the double nucleus is expected to be around ~10 pc at this stage. We show that the accretion rate can be highly variable also when the MBH is co-rotating with the disc (albeit to a lesser extent) provided that its orbit is eccentric. Our results have significant consequences for the expected number of observable double AGNs at separations of <100 pc.Comment: 8 pages, 4 figures, revised version accepted to MNRA

Black hole mergers: the first light

The coalescence of supermassive black hole binaries occurs via the emission of gravitational waves, that can impart a substantial recoil to the merged black hole. We consider the energy dissipation, that results if the recoiling black hole is surrounded by a thin circumbinary disc. Our results differ significantly from those of previous investigations. We show analytically that the dominant source of energy is often potential energy, released as gas in the outer disc attempts to circularize at smaller radii. Thus, dimensional estimates, that include only the kinetic energy gained by the disc gas, underestimate the real energy loss. This underestimate can exceed an order of magnitude, if the recoil is directed close to the disc plane. We use three dimensional Smooth Particle Hydrodynamics (SPH) simulations and two dimensional finite difference simulations to verify our analytic estimates. We also compute the bolometric light curve, which is found to vary strongly depending upon the kick angle. A prompt emission signature due to this mechanism may be observable for low mass (10^6 Solar mass) black holes whose recoil velocities exceed about 1000 km/s. Emission at earlier times can mainly result from the response of the disc to the loss of mass, as the black holes merge. We derive analytically the condition for this to happen.Comment: 16 pages, accepted by MNRAS. Animations of the simulations are available at http://jilawww.colorado.edu/~pja/recoil.htm

Microarray Analysis Reveals Increased Expression of Matrix Metalloproteases and Cytokines of Interleukin-20 Subfamily in the Kidneys of Neonate Rats Underwent Unilateral Ureteral Obstruction: A Potential Role of IL-24 in the Regulation of Inflammation and Tissue Remodeling

Background/Aims: Congenital obstructive nephropathy (CON) is the main cause of pediatric chronic kidney diseases leading to renal fibrosis. High morbidity and limited treatment opportunities of CON urge the better understanding of the underlying molecular mechanisms. Methods: To identify the differentially expressed genes, microarray analysis was performed on the kidney samples of neonatal rats underwent unilateral ureteral obstruction (UUO). Microarray results were then validated by real-time RT-PCR and bioinformatics analysis was carried out to identify the relevant genes, functional groups and pathways involved in the pathomechanism of CON. Renal expression of matrix metalloproteinase (MMP)-12 and interleukin (IL)-24 were evaluated by real-time RT-PCR, flow cytometry and immunohistochemical analysis. Effect of the main profibrotic factors on the expression of MMP-12 and IL-24 was investigated on HK-2 and HEK-293 cell lines. Finally, the effect of IL-24 treatment on the expression of pro-inflammatory cytokines and MMPs were tested in vitro. Results: Microarray analysis revealed 880 transcripts showing &#x3e;2.0-fold change following UUO, enriched mainly in immune response related processes. The most up-regulated genes were MMPs and members of IL-20 cytokine subfamily, including MMP-3, MMP-7, MMP-12, IL-19 and IL-24. We found that while TGF-β treatment inhibits the expression of MMP-12 and IL-24, H2O2 or PDGF-B treatment induce the epithelial expression of MMP-12. We demonstrated that IL-24 treatment decreases the expression of IL-6 and MMP-3 in the renal epithelial cells. Conclusions: This study provides an extensive view of UUO induced changes in the gene expression profile of the developing kidney and describes novel molecules, which may play significant role in the pathomechanism of CON

Dual black holes in merger remnants. II: spin evolution and gravitational recoil

Using high resolution hydrodynamical simulations, we explore the spin evolution of massive dual black holes orbiting inside a circumnuclear disc, relic of a gas-rich galaxy merger. The black holes spiral inwards from initially eccentric co or counter-rotating coplanar orbits relative to the disc's rotation, and accrete gas that is carrying a net angular momentum. As the black hole mass grows, its spin changes in strength and direction due to its gravito-magnetic coupling with the small-scale accretion disc. We find that the black hole spins loose memory of their initial orientation, as accretion torques suffice to align the spins with the angular momentum of their orbit on a short timescale (<1-2 Myr). A residual off-set in the spin direction relative to the orbital angular momentum remains, at the level of <10 degrees for the case of a cold disc, and <30 degrees for a warmer disc. Alignment in a cooler disc is more effective due to the higher coherence of the accretion flow near each black hole that reflects the large-scale coherence of the disc's rotation. If the massive black holes coalesce preserving the spin directions set after formation of a Keplerian binary, the relic black hole resulting from their coalescence receives a relatively small gravitational recoil. The distribution of recoil velocities inferred from a simulated sample of massive black hole binaries has median <70 km/s much smaller than the median resulting from an isotropic distribution of spins.Comment: 11 pages, 3 figures. Accepted for publication in MNRA

Gender, hyperandrogenism and vitamin D deficiency related functional and morphological alterations of rat cerebral arteries

Hyperandrogenism is a risk factor of cerebrovascular diseases as androgens can alter markedly the regulation of cerebrovascular tone. We examined the combined impact of androgen excess and vitamin D deficiency (VDD), a common co-morbidity in hyperandrogenic disorders, on remodeling and testosterone-induced vascular responses of anterior cerebral arteries (ACA) in order to evaluate the interplay between androgens and VDD in the cerebral vasculature. Male and female Wistar rats were either fed with vitamin D deficient or vitamin D supplemented diet. Half of the female animals from both groups received transdermal testosterone treatment. After 8 weeks, vessel lumen, wall thickness and testosterone-induced vascular tone of isolated ACA were determined using pressure microangiometry and histological examination. Androgen receptor protein expression in the wall of cerebral arteries was examined using immunohistochemistry. In female rats only combined VDD and testosterone treatment decreased the lumen and increased the wall thickness of ACA. In males, however VDD by itself was able to decrease the lumen and increase the wall thickness. Vascular reactivity showed similar alterations: in females, testosterone constricted the ACA only after combined VDD and hyperandrogenism, whereas in males VDD resulted in increased testosterone-induced contractions in spite of decreased androgen receptor expression. In conclusion, a marked interplay between hyperandrogenism and VDD results in inward remodeling and enhanced testosterone-induced constrictions of cerebral arteries, which might compromise the cerebral circulation and thus, increase the risk of stroke in the long term. In addition, the early cerebrovascular manifestation of VDD appears to require androgen excess and thus, depends on gender

Star Clusters Around Recoiled Black Holes in the Milky Way Halo

Gravitational wave emission by coalescing black holes (BHs) kicks the remnant BH with a typical velocity of hundreds of km/s. This velocity is sufficiently large to remove the remnant BH from a low-mass galaxy but is below the escape velocity from the Milky Way (MW) galaxy. If central BHs were common in the galactic building blocks that merged to make the MW, then numerous BHs that were kicked out of low-mass galaxies should be freely floating in the MW halo today. We use a large statistical sample of possible merger tree histories for the MW to estimate the expected number of recoiled BH remnants present in the MW halo today. We find that hundreds of BHs should remain bound to the MW halo after leaving their parent low-mass galaxies. Each BH carries a compact cluster of old stars that populated the core of its original host galaxy. Using the time-dependent Fokker-Planck equation, we find that present-day clusters are ~< 1 pc in size, and their central bright regions should be unresolved in most existing sky surveys. These compact systems are distinguishable from globular clusters by their internal (Keplerian) velocity dispersion greater than one hundred km/s and their high mass-to-light ratio owing to the central BH. An observational discovery of this relic population of star clusters in the MW halo, would constrain the formation history of the MW and the dynamics of BH mergers in the early Universe. A similar population should exist around other galaxies, and may potentially be detectable in M31 and M33.Comment: 7 Pages, 2 Figures. Discussion/references expanded. MNRAS accepted, in pres

Identifying Decaying Supermassive Black Hole Binaries from their Variable Electromagnetic Emission

Supermassive black hole binaries (SMBHBs) with masses in the range 10^4-10^7 M_sun/(1+z), produced in galaxy mergers, are thought to complete their coalescence due to the emission of gravitational waves (GWs). The anticipated detection of the GWs by the LISA will constitute a milestone for fundamental physics and astrophysics. While the GW signatures themselves will provide a treasure trove of information, if the source can be securely identified in electromagnetic (EM) bands, this would open up entirely new scientific opportunities, to probe fundamental physics, astrophysics, and cosmology. We discuss several ideas, involving wide-field telescopes, that may be useful in locating electromagnetic counterparts to SMBHBs detected by LISA. In particular, the binary may produce a variable electromagnetic flux, such as a roughly periodic signal due to the orbital motion prior to coalescence, or a prompt transient signal caused by shocks in the circumbinary disk when the SMBHB recoils and "shakes" the disk. We discuss whether these time-variable EM signatures may be detectable, and how they can help in identifying a unique counterpart within the localization errors provided by LISA. We also discuss a possibility of identifying a population of coalescing SMBHBs statistically, in a deep optical survey for periodically variable sources, before LISA detects the GWs directly. The discovery of such sources would confirm that gas is present in the vicinity and is being perturbed by the SMBHB - serving as a proof of concept for eventually finding actual LISA counterparts.Comment: 10 pages with 4 figures; submitted to Classical and Quantum Gravity (special issue for the proceedings of the 7th International LISA Symposium