The bulk of the X-ray emission in Active Galactic Nuclei (AGN) is produced very close to the accreting supermassive black hole (SMBH), in a corona of hot electrons which up scatters optical and ...ultraviolet photons from the accretion flow. The cutoff energy (\(E_{\rm C}\)) of the primary X-ray continuum emission carries important information on the physical characteristics of the X-ray emitting plasma, but little is currently known about its potential relation with the properties of accreting SMBHs. Using the largest broad-band (0.3-150 keV) X-ray spectroscopic study available to date, we investigate how the corona is related to the AGN luminosity, black hole mass and Eddington ratio (\(\lambda_{\rm Edd}\)). Assuming a slab corona the median values of the temperature and optical depth of the Comptonizing plasma are \(kT_{\rm e}=105 \pm 18\) keV and \(\tau=0.25\pm0.06\), respectively. When we properly account for the large number of \(E_{\rm C}\) lower limits, we find a statistically significant dependence of the cutoff energy on the Eddington ratio. In particular, objects with \( \lambda_{\rm Edd}>0.1\) have a significantly lower median cutoff energy (\(E_{\rm C}=160\pm41\) keV) than those with \(\lambda_{\rm Edd}\leq 0.1\) (\(E_{\rm C}=370\pm51\) keV). This is consistent with the idea that radiatively compact coronae are also cooler, because they tend to avoid the region in the temperature-compactness parameter space where runaway pair production would dominate. We show that this behaviour could also straightforwardly explain the suggested positive correlation between the photon index (\(\Gamma\)) and the Eddington ratio, being able to reproduce the observed slope of the \(\Gamma-\lambda_{\rm Edd}\) trend.
Ligand-induced protein degradation has emerged as a compelling approach to promote the targeted elimination of proteins from cells by directing these proteins to the ubiquitin-proteasome machinery. ...So far, only a limited number of E3 ligases have been found to support ligand-induced protein degradation, reflecting a dearth of E3-binding compounds for proteolysis-targeting chimera (PROTAC) design. Here, we describe a functional screening strategy performed with a focused library of candidate electrophilic PROTACs to discover bifunctional compounds that degrade proteins in human cells by covalently engaging E3 ligases. Mechanistic studies revealed that the electrophilic PROTACs act through modifying specific cysteines in DCAF11, a poorly characterized E3 ligase substrate adaptor. We further show that DCAF11-directed electrophilic PROTACs can degrade multiple endogenous proteins, including FBKP12 and the androgen receptor, in human prostate cancer cells. Our findings designate DCAF11 as an E3 ligase capable of supporting ligand-induced protein degradation via electrophilic PROTACs.
Galanin was measured by radioimmunoassay in whole thickness extracts of the gastrointestinal wall from four species and in extracts from separate layers of human small intestine. The immunoreactivity ...was characterized using gel chromatography and high-pressure liquid chromatography. Two antibodies were employed, which were characterized as non-C-terminal (Gal 8) and C-terminal (Gal 9) using a C-terminal galanin 10-29 fragment. Substantial quantities of galanin immunoreactivity were found, mainly localized at the muscle layer. Both intramolecular and intermolecular heterogeneity was apparent. Two molecular forms exist in humans (Kav 0.58, 0.69). The molecular heterogeneity in humans, rats, and guinea pigs may be localized near the C-terminus of the galanin molecule. A C-terminal extension of one human galanin form is likely (Kav 0.58). These findings give radioimmunologic evidence for a neurocrine origin of galanin. The chromatographic variations suggest that extrapolation of experimental results between species should be treated with caution.
Recent independent results from numerical simulations and observations have shown that brightest cluster galaxies (BCGs) have increased their stellar mass by a factor of almost 2 between z ∼ 0.9 and ...z ∼ 0.2. The numerical simulations further suggest that more than half this mass is accreted through major mergers. Using a sample of 18 distant galaxy clusters with over 600 spectroscopically confirmed cluster members between them, we search for observational evidence that major mergers do play a significant role. We find a major merger rate of 0.38 ± 0.14 mergers per Gyr at z ∼ 1. While the uncertainties, which stem from the small size of our sample, are relatively large, our rate is consistent with the results that are derived from numerical simulations. If we assume that this rate continues to the present day and that half of the mass of the companion is accreted on to the BCG during these mergers, then we find that this rate can explain the growth in the stellar mass of the BCGs that is observed and predicted by simulations. Major mergers therefore appear to be playing an important role, perhaps even the dominant one, in the build up of stellar mass in these extraordinary galaxies.
(1) The blood-brain barrier (BBB) is formed by brain capillary endothelial cells (ECs). There are various cell types, in particular astrocytes, but also pericytes and neurons, located in close ...vicinity to the capillary ECs which may influence formation and function of the BBB. Based on this consideration, this paper discusses various aspects of the influence of the surrounding cells on brain capillary ECs with special focus on the role of astrocytes. (2) Based on the morphology of the BBB, important aspects of brain EC functions are summarized, such as transport functions and maintenance of low paracellular permeability. Moreover, various facets are discussed with respect to the influence of astrocytes, pericytes, microglia, and neurons on the BBB. Data on the role of glial cells in the ontogenesis of the BBB are presented subsequently. The knowledge on this subject is far from being complete, however, these data imply that the neural/neuronal environment rather than glial cells may be of importance in the maturation of the barrier. (3) The role of glial cells in the induction and maintenance of the BBB is discussed under physiological as well as pathological conditions. Although the literature presents manifold evidence for a great variety of effects induced by astroglia, there are also many controversies, which may result from different cellular models and experimental conditions used in the respective studies. Numerous factors secreted by astrocytes have been shown to induce a BBB phenotype. On the molecular level, increased expression of barrier-relevant proteins (e.g., tight junction proteins) is documented in the presence of astrocyte-derived factors, and many studies demonstrate the improvement of physiological parameters, such as increased transendothelial resistance and decreased paracellular permeability, in different in vitro models of the BBB. Moreover, one has to take into account that the interaction of brain ECs and astrocytes is bi-directional, and that the other cell types surrounding the brain microvasculature also contribute to BBB function or dysfunction, respectively. (4) In conclusion, it is expected that the present and future research focused on molecular mechanisms and signaling pathways will produce new and exciting insights into the complex network of BBB regulation: the cornerstone is laid.
Abstract We present new central stellar velocity dispersions for 484 Sy 1.9 and Sy 2 from the second data release of the Swift/BAT AGN Spectroscopic Survey (BASS DR2). This constitutes the largest ...study of velocity dispersion measurements in X-ray-selected obscured active galactic nuclei (AGN) with 956 independent measurements of the Ca ii H and K λ 3969, 3934 and Mg I λ 5175 region (3880–5550 Å) and the calcium triplet region (8350–8730 Å) from 642 spectra mainly from VLT/X-Shooter or Palomar/DoubleSpec. Our sample spans velocity dispersions of 40–360 km s 1 , corresponding to 4–5 orders of magnitude in black hole mass ( M BH = 10 5.5−9.6 M ⊙ ), bolometric luminosity ( L bol ∼ 10 42–46 erg s −1 ), and Eddington ratio ( L / L Edd ∼ 10 −5 to 2). For 281 AGN, our data and analysis provide the first published central velocity dispersions, including six AGN with low-mass black holes ( M BH = 10 5.5−6.5 M ⊙ ), discovered thanks to high spectral resolution observations ( σ inst ∼ 25 km s −1 ). The survey represents a significant advance with a nearly complete census of velocity dispersions of hard X-ray–selected obscured AGN with measurements for 99% of nearby AGN ( z < 0.1) outside the Galactic plane (∣ b ∣ > 10°). The BASS AGN have much higher velocity dispersions than the more numerous optically selected narrow-line AGN (i.e., ∼150 versus ∼100 km s −1 ) but are not biased toward the highest velocity dispersions of massive ellipticals (i.e., >250 km s −1 ). Despite sufficient spectral resolution to resolve the velocity dispersions associated with the bulges of small black holes (∼10 4–5 M ⊙ ), we do not find a significant population of super-Eddington AGN. Using estimates of the black hole sphere of influence from velocity dispersion, direct stellar and gas black hole mass measurements could be obtained with existing facilities for more than ∼100 BASS AGN.
A repeat expansion in C9ORF72 causes frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). RNA of the expanded repeat (r(GGGGCC)exp) forms nuclear foci or undergoes repeat-associated ...non-ATG (RAN) translation, producing “c9RAN proteins.” Since neutralizing r(GGGGCC)exp could inhibit these potentially toxic events, we sought to identify small-molecule binders of r(GGGGCC)exp. Chemical and enzymatic probing of r(GGGGCC)8 indicate that it adopts a hairpin structure in equilibrium with a quadruplex structure. Using this model, bioactive small molecules targeting r(GGGGCC)exp were designed and found to significantly inhibit RAN translation and foci formation in cultured cells expressing r(GGGGCC)66 and neurons transdifferentiated from fibroblasts of repeat expansion carriers. Finally, we show that poly(GP) c9RAN proteins are specifically detected in c9ALS patient cerebrospinal fluid. Our findings highlight r(GGGGCC)exp-binding small molecules as a possible c9FTD/ALS therapeutic and suggest that c9RAN proteins could potentially serve as a pharmacodynamic biomarker to assess efficacy of therapies that target r(GGGGCC)exp.
•(GGGGCC) RNA forms a hairpin structure in equilibrium with a G-quadruplex structure•Neurons directly converted from C9ORF72+ fibroblasts express c9RAN proteins and foci•Small-molecule binders of (GGGGCC)exp RNA ameliorate c9FTD/ALS-associated defects•c9RAN proteins are detected in c9ALS patient cerebrospinal fluid
A repeat expansion in C9ORF72 causes frontotemporal dementia and amyotrophic lateral sclerosis, presumably via the expression of repeat-containing RNA (r(GGGGCC)exp). Su et al. find that small molecules targeting r(GGGGCC)exp can block c9FTD/ALS-associated defects and reveal a potential biomarker for c9FTD/ALS.
Abstract
Electrons at the border of localization generate exotic states of matter across all classes of strongly correlated electron materials and many other quantum materials with emergent ...functionality. Heavy electron metals are a model example, in which magnetic interactions arise from the opposing limits of localized and itinerant electrons. This remarkable duality is intimately related to the emergence of a plethora of novel quantum matter states such as unconventional superconductivity, electronic-nematic states, hidden order and most recently topological states of matter such as topological Kondo insulators and Kondo semimetals and putative chiral superconductors. The outstanding challenge is that the archetypal Kondo lattice model that captures the underlying electronic dichotomy is notoriously difficult to solve for real materials. Here we show, using the prototypical strongly-correlated antiferromagnet CeIn
3
, that a multi-orbital periodic Anderson model embedded with input from ab initio bandstructure calculations can be reduced to a simple Kondo-Heisenberg model, which captures the magnetic interactions quantitatively. We validate this tractable Hamiltonian via high-resolution neutron spectroscopy that reproduces accurately the magnetic soft modes in CeIn
3
, which are believed to mediate unconventional superconductivity. Our study paves the way for a quantitative understanding of metallic quantum states such as unconventional superconductivity.
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