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A complete census of Active Galactic Nuclei (AGN) is a prerequisite for understanding the growth of supermassive black holes across cosmic time. A significant challenge toward this goal is the whereabouts of heavily obscured AGN that remain uncertain. This paper sets new constraints on the demographics of this population by developing a methodology that combines X-ray spectral information with priors derived from multiwavelength observations. We select X-ray AGN in the Chandra COSMOS Legacy survey and fit their $2.2-500\mu m$ spectral energy distributions with galaxy and AGN templates to determine the mid-infrared ($6\mu m$) luminosity of the AGN component. Empirical correlations between X-ray and $6\mu m$ luminosities are then adopted to infer the intrinsic accretion luminosity at X-rays for individual AGN. This is used as prior information in our Bayesian X-ray spectral analysis to estimate physical properties, such as line-of-sight obscuration. Our approach breaks the degeneracies between accretion luminosity and obscuration that affect X-ray spectral analysis, particularly for the most heavily obscured (Compton-Thick) AGN with low photon counts X-ray spectra. The X-ray spectral results are then combined with the selection function of the Chandra COSMOS Legacy survey to derive the AGN space density and a Compton-Thick fraction of $21.0^{+16.1}_{-9.9}\%$ at redshifts $z, Comment: Accepted for publication at MNRAS, 21 pages, 20 figures, 6 tables

The angiotensin-converting enzyme 2 (ACE2) is a viral receptor used by sarbecoviruses to infect cells. Fusion proteins comprising extracellular ACE2 domains and the Fc part of immunoglobulins exhibit high virus neutralization efficiency, but the structure and stability of these molecules are poorly understood. We show that although the hinge between the ACE2 and the IgG4-Fc is highly flexible, the conformational dynamics of the two ACE2 domains is restricted by their association. Interestingly, the conformational stability of the ACE2 moiety is much lower than that of the Fc part. We found that chemical compounds binding to ACE2, such as DX600 and MLN4760, can be used to strongly increase the thermal stability of the ACE2 by different mechanisms. Together, our findings reveal a general concept for stabilizing the labile receptor segments of therapeutic antiviral fusion proteins by chemical compounds.

Light chain (AL) amyloidosis is a debilitating disease in which mutant antibody light chains (LC), secreted by aberrant plasma cell clones, misfold and form insoluble fibrils, which can be deposited in various organs. In the majority of cases, the fibrillar deposits consist of LC variable domains (VL) containing destabilizing mutations compared to their germline counterparts. This is also true for the patient LC FOR005. However, this pathogenic LC sequence contains an additional mutation in the constant domain (CL). The mechanistic impact of CL mutations is not yet understood in the context of AL amyloidosis. Our analysis reveals that the FOR005 CL mutation influences the amyloid pathway in specific ways: (1) folding and stability of the patient CL domain are strongly impaired; (2) the mutation disrupts the LC dimer interface and weakens dimerization; (3) the CL mutation promotes proteolytic cleavage of the LC monomers resulting in an isolated, amyloidogenic VL domain while dimeric LCs are not cleaved. The enhanced proteolysis rates and the inability of full-length LCs to form amyloid fibrils even in the presence of a destabilized CL domain support a model for AL amyloidosis in which the CL domain plays a protective role and in which proteolytic cleavage precedes amyloid formation.

Hsp90 is a conserved molecular chaperone regulating the folding and activation of a diverse array of several hundreds of client proteins. The function of Hsp90 in client processing is fine-tuned by a cohort of co-chaperones that modulate client activation in a client-specific manner. They affect the Hsp90 ATPase activity and the recruitment of client proteins and can in addition affect chaperoning in an Hsp90-independent way. p23 and Aha1 are central Hsp90 co-chaperones that regulate Hsp90 in opposing ways. While p23 inhibits the Hsp90 ATPase and stabilizes a client-bound Hsp90 state, Aha1 accelerates ATP hydrolysis and competes with client binding to Hsp90. Even though both proteins have been intensively studied for decades, research of the last few years has revealed intriguing new aspects of these co-chaperones that expanded our perception of how they regulate client activation. Here, we review the progress in understanding p23 and Aha1 as promoters of client processing. We highlight the structures of Aha1 and p23, their interaction with Hsp90, and how their association with Hsp90 affects the conformational cycle of Hsp90 in the context of client maturation.

Fusion of ACE2 to IgM-Fc results in hexameric ACE2-IgM-Fc proteins with potent virus neutralization efficiency of patient-isolated SARS-CoV and SARS-CoV-2 variants. Coronavirus infections are a world-wide threat to human health. A promising strategy to develop a broadly active antiviral is the use of fusion proteins consisting of an antibody IgG Fc region and a human ACE2 domain to which the viral spike proteins bind. Here we create antiviral fusion proteins based on IgM scaffolds. The hexameric ACE2-IgM-Fc fusions can be efficiently produced in mammalian cells and they neutralize the infectious virus with picomolar affinity thus surpassing monomeric ACE2-IgM-Fc by up to 96-fold in potency. In addition, the ACE2-IgM fusion shows increased neutralization efficiency for the highly infectious SARS-CoV-2 omicron variant in comparison to prototypic SARS-CoV-2. Taken together, these multimeric IgM fusions proteins are a powerful weapon to fight coronavirus infections.

Binary black hole systems in close orbits are thought to be the precursors of gravitational wave events and their identification has fundamental implications for our understanding of black hole growth and evolution. However, a gravitationally bound companion orbiting closer than about a milli-parsec to an accreting supermassive black hole (SMBH, mass ≥106 solar masses) in an external galaxy cannot be spatially resolved with present-day instruments. Instead, its detection requires a combination of indirect observational methods and advanced modelling. Here we report the detection of quasi-periodic variability in X-ray spectral features after an outburst from a previously low-luminosity Active Galactic Nucleus (AGN) in a galaxy at redshift z=0.056. We interpret this variability as due to Quasi-Periodic Outflows (QPOuts) from the SMBH. The puzzling phenomenon repeats roughly once every 8.5 days and photo-ionization modeling of the energy spectra implies that the outflowing material moves with a high velocity of about a third of the speed of light. The mass of the central black hole, roughly 30 million solar masses, as derived from the optical broad line--SMBH mass scaling relation, implies that the outflows are launched from a few tens of gravitational radii from the SMBH event horizon. By performing 2D and 3D general relativistic magnetohydrodynamic (GRMHD) simulations and by comparing their results over a broad range of the system parameters we show that these QPOuts can be explained with an orbiting intermediate-mass black hole (IMBH) secondary (mass range of 100--10,000 solar masses) at a distance of about 100 gravitational radii (less than a milli-parsec) from the primary SMBH. Outflows are naturally enhanced when the secondary object punches through the SMBH's inner accretion disc during each orbital period and this is revealed as regular increases in X-ray absorption along our line of sight. The overall optical, UV and X-ray outburst properties indicate that a major accretion episode -- perhaps from a stellar tidal disruption by the SMBH -- could have provided the gas to illuminate the presence of the pre-existing IMBH secondary. Our work highlights the new astrophysical phenomenon of QPOuts and the importance of high cadence X-ray monitoring observations to potentially uncover electromagnetic signatures of such tight binary black hole systems.

Small Heat shock proteins (sHsps) are a family of molecular chaperones that bind nonnative proteins in an ATP-independent manner. Caenorhabditis elegans encodes 16 different sHsps, among them Hsp17, which is evolutionarily distinct from other sHsps in the nematode. The structure and mechanism of Hsp17 and how these may differ from other sHsps remain unclear. Here, we find that Hsp17 has a distinct expression pattern, structural organization, and chaperone function. Consistent with its presence under nonstress conditions, and in contrast to many other sHsps, we determined that Hsp17 is a mono-disperse, permanently active chaperone in vitro, which interacts with hundreds of different C. elegans proteins under physiological conditions. Additionally, our cryo-EM structure of Hsp17 reveals that in the 24-mer complex, 12 N-terminal regions are involved in its chaperone function. These flexible regions are located on the outside of the spherical oligomer, whereas the other 12 N-terminal regions are engaged in stabilizing interactions in its interior. This allows the same region in Hsp17 to perform different functions depending on the topological context. Taken together, our results reveal structural and functional features that further define the structural basis of permanently active sHsps.

The glucocorticoid receptor (GR) is an important transcription factor and drug target linked to a variety of biological functions and diseases. It is one of the most stringent physiological clients of the Hsp90/Hsp70/Hsp40 chaperone system. In this study, we used single-molecule force spectroscopy by optical tweezers to observe the interaction of the GR’s ligand-binding domain (GR-LBD) with the Hsp70/Hsp40 chaperone system (Hsp70/40). We show in real time that Hsp70/40 can unfold the complete GR-LBD in a stepwise manner. Each unfolding step involves binding of an Hsp70 to the GR-LBD and subsequent adenosine triphosphate (ATP) hydrolysis, stimulated by Hsp40. The kinetics of chaperone-mediated unfolding depend on chaperone concentrations as well as the presence of the nucleotide exchange factor BAG1. We find that Hsp70/40 can stabilize new unfolding intermediates, showing that Hsp70/40 can directly interact with the folded core of the protein when working as an unfoldase. Our results support an unfolding mechanism where Hsp70 can directly bind to folded protein structures and unfold them upon ATP hydrolysis. These results provide important insights into the regulation of GR by Hsp70/40.

Signal-anchored (SA) proteins are anchored into the mitochondrial outer membrane (OM) via a single transmembrane segment at their N-terminus while the bulk of the proteins is facing the cytosol. These proteins are encoded by nuclear DNA, translated on cytosolic ribosomes, and are then targeted to the organelle and inserted into its OM by import factors. Recently, research on the insertion mechanisms of these proteins into the mitochondrial OM have gained a lot of attention. In contrast, the early cytosolic steps of their biogenesis are unresolved. Using various proteins from this category and a broad set of in vivo, in organello, and in vitro assays, we reconstituted the early steps of their biogenesis. We identified a subset of molecular (co)chaperones that interact with newly synthesized SA proteins, namely, Hsp70 and Hsp90 chaperones and co-chaperones from the Hsp40 family like Ydj1 and Sis1. These interactions were mediated by the hydrophobic transmembrane segments of the SA proteins. We further demonstrate that interfering with these interactions inhibits the biogenesis of SA proteins to varying extents. Finally, we could demonstrate direct interaction of peptides corresponding to the transmembrane segments of SA proteins with the (co)chaperones and reconstitute in vitro the transfer of such peptides from the Hsp70 chaperone to the mitochondrial Tom70 receptor. Collectively, this study unravels an array of cytosolic chaperones and mitochondrial import factors that facilitates the targeting and membrane integration of mitochondrial SA proteins.

How much one has learned from an experiment is quantifiable by the information gain, also known as the Kullback-Leibler divergence. The narrowing of the posterior parameter distribution $P(\theta|D)$ compared with the prior parameter distribution $\pi(\theta)$, is quantified in units of bits, as: $ D_{\mathrm{KL}}(P|\pi)=\int\log_{2}\left(\frac{P(\theta|D)}{\pi(\theta)}\right)\,P(\theta|D)\,d\theta $. This research note gives an intuition what one bit of information gain means. It corresponds to a Gaussian shrinking its standard deviation by a factor of three., Comment: Accepted to RNAAS; Corrected typos (Thanks to Tariq Yasin and Torsten En{\ss}lin)

We review Skilling's nested sampling (NS) algorithm for Bayesian inference and more broadly multi-dimensional integration. After recapitulating the principles of NS, we survey developments in implementing efficient NS algorithms in practice in high-dimensions, including methods for sampling from the so-called constrained prior. We outline the ways in which NS may be applied and describe the application of NS in three scientific fields in which the algorithm has proved to be useful: cosmology, gravitational-wave astronomy, and materials science. We close by making recommendations for best practice when using NS and by summarizing potential limitations and optimizations of NS., Comment: 20 pages + supplementary information, 5 figures. preprint version; published version at https://www.nature.com/articles/s43586-022-00121-x

Description, ATP-driven conformational selection of Hsp90 conformations modulates the binding of clients and co-chaperones., Hsp90 is a molecular chaperone that interacts with a specific set of client proteins and assists their folding. The underlying molecular mechanisms, involving dynamic transitions between open and closed conformations, are still enigmatic. Combining nuclear magnetic resonance, small-angle x-ray scattering, and biochemical experiments, we have identified a key intermediate state of Hsp90 induced by adenosine triphosphate (ATP) binding, in which rotation of the Hsp90 N-terminal domain (NTD) yields a domain arrangement poised for closing. This ATP-stabilized NTD rotation is allosterically communicated across the full Hsp90 dimer, affecting distant client sites. By analyzing the interactions of four distinct clients, i.e., steroid hormone receptors (glucocorticoid receptor and mineralocorticoid receptor), p53, and Tau, we show that client-specific interactions with Hsp90 select and enhance the NTD-rotated state and promote closing of the full-length Hsp90 dimer. The p23 co-chaperone shifts the population of Hsp90 toward the closed state, thereby enhancing client interaction and processing.

Light chain amyloidosis (AL) is a systemic disease in which abnormally proliferating plasma cells secrete large amounts of mutated antibody light chains (LCs) that eventually form fibrils. The fibrils are deposited in various organs, most often in the heart and kidney, and impair their function. The prognosis for patients diagnosed with AL is generally poor. The disease is set apart from other amyloidoses by the huge number of patient-specific mutations in the disease-causing and fibril-forming protein. The molecular mechanisms that drive the aggregation of mutated LCs into fibrils have been enigmatic, which hindered the development of efficient diagnostics and therapies. In this review, we summarize our current knowledge on AL amyloidosis and discuss open issues.

Abdurro’uf et al., This paper documents the seventeenth data release (DR17) from the Sloan Digital Sky Surveys; the fifth and final release from the fourth phase (SDSS-IV). DR17 contains the complete release of the Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) survey, which reached its goal of surveying over 10,000 nearby galaxies. The complete release of the MaNGA Stellar Library accompanies this data, providing observations of almost 30,000 stars through the MaNGA instrument during bright time. DR17 also contains the complete release of the Apache Point Observatory Galactic Evolution Experiment 2 survey that publicly releases infrared spectra of over 650,000 stars. The main sample from the Extended Baryon Oscillation Spectroscopic Survey (eBOSS), as well as the subsurvey Time Domain Spectroscopic Survey data were fully released in DR16. New single-fiber optical spectroscopy released in DR17 is from the SPectroscipic IDentification of ERosita Survey subsurvey and the eBOSS-RM program. Along with the primary data sets, DR17 includes 25 new or updated value-added catalogs. This paper concludes the release of SDSS-IV survey data. SDSS continues into its fifth phase with observations already underway for the Milky Way Mapper, Local Volume Mapper, and Black Hole Mapper surveys., This publication uses data generated via the Zooniverse.org platform, development of which is funded by generous support, including a Global Impact Award from Google, and by a grant from the Alfred P. Sloan Foundation. This publication makes use of data products from the Two Micron All Sky Survey, which is a joint project of the University of Massachusetts and the Infrared Processing and Analysis Center/California Institute of Technology, funded by the National Aeronautics and Space Administration and the National Science Foundation. This work has made use of data from the European Space Agency (ESA) mission Gaia (https://www.cosmos.esa.int/gaia), processed by the Gaia Data Processing and Analysis Consortium (DPAC; https://www.cosmos.esa.int/web/gaia/dpac/consortium). Funding for the DPAC has been provided by national institutions, in particular the institutions participating in the Gaia Multilateral Agreement.

We have computed obscured active galactic nuclei (AGN) redshifts using the XZ method, adopting a broad treatment in which we employed a wide-ranging data set and worked primarily at the XZ counts sensitivity threshold, culminating with a redshift catalog containing 121 sources that lack documented redshifts. We considered 363 obscured AGN from the Chandra Source Catalog Release 2.0, 59 of which were selected using multiwavelength criteria while 304 were X-ray selected. One third of the data set had crossmatched spectroscopic or photometric redshifts. These sources, dominated by low-z and low-N H AGN, were supplemented by 1000 simulations to form a data set for testing the XZ method. We used a multilayer perceptron neural network to examine and predict cases in which XZ fails to reproduce the known redshift, yielding a classifier that can identify and discard poor redshift estimates. This classifier demonstrated a statistically significant ∼3σ improvement over the existing XZ redshift information gain filter. We applied the machine-learning model to sources with no documented redshifts, resulting in the 121 source new redshift catalog, all of which were X-ray selected. Our neural network’s performance suggests that nearly 90% of these redshift estimates are consistent with hypothetical spectroscopic or photometric measurements, strengthening the notion that redshifts can be reliably estimated using only X-rays, which is valuable to current and future missions such as Athena. We have also identified a possible Compton-thick candidate that warrants further investigation.

Context.The 6.4 keV Fe Kαemission line is a ubiquitous feature in X-ray spectra of active galactic nuclei (AGN), and its properties track the interaction between the variable primary X-ray continuum and the surrounding structure from which it arises.Aims.We clarify the nature and origin of the narrow Fe Kαemission using X-ray spectral, timing, and imaging constraints, plus possible correlations to AGN and host galaxy properties, for 38 bright nearby AGN (z Methods.ModelingChandraandXMM-Newtonspectra, we computed line full-width half-maxima (FWHMs) and constructed Fe Kαline and 2–10 keV continuum light curves. The FWHM provides one estimate of the Fe Kαemitting region size,RFeKα, assuming virial motion. A second estimate comes from comparing the degree of correlation between the variability of the continuum and line-only light curves, compared to simulated light curves. Finally, we extractedChandraradial profiles to place upper limits onRFeKα.Results.For 90% (21/24) of AGN with FWHM measurements,RFeKαis smaller than the fiducial dust sublimation radius,Rsub. From timing analysis, 37 and 18 AGN show significant continuum and Fe Kαvariability, respectively. Despite a wide range of variability properties, the constraints on the Fe Kαphoton reprocessor size independently confirm thatRFeKαis smaller thanRsubin 83% of AGN. Finally, the imaging analysis yields loose upper limits for all but two sources; notably, the Circinus Galaxy and NGC 1068 show significant but subdominant extended Fe Kαemission out to ∼100 and ∼800 pc, respectively.Conclusions.Based on independent constraints, we conclude that the majority of the narrow Fe Kαemission in typical AGN predominantly arises from regions smaller than and presumably insideRsub, and thus it is associated either with the outer broad line region or outer accretion disk. However, the large diversity of continuum and narrow Fe Kαvariability properties are not easily accommodated by a universal scenario.

SARS-CoV-2 enters host cells after binding through its spike glycoprotein to the angiotensin-converting enzyme 2 (ACE2) receptor. Soluble ACE2 ectodomains bind and neutralize the virus, yet their short in vivo half-live limits their therapeutic use. This limitation can be overcome by fusing the fragment crystallizable (Fc) part of human immunoglobulin G (IgG) to the ACE2 ectodomain, but this bears the risk of unwanted Fc-receptor activation and antibody-dependent disease enhancement. Here, we describe optimized ACE2-IgG4-Fc fusion constructs that avoid Fc-receptor activation, preserve the desired ACE-2 enzymatic activity and show promising pharmaceutical properties. The engineered ACE2-IgG4-Fc fusion proteins neutralize the original SARS-CoV, pandemic SARS-CoV-2 as well as the rapidly spreading SARS-CoV-2 variants-of-concern, B.1.17 and B.1.351. Importantly, these variants-of-concern are inhibited at picomolar concentrations proving that ACE-2-IgG4 maintains – in contrast to therapeutic antibodies - its full antiviral potential. Thus, ACE2-IgG4-Fc fusion proteins are promising candidate anti-antivirals to combat the current and future pandemics.

We investigate the physical properties--such as the stellar mass, SFR, IR luminosity, X-ray luminosity, and hydrogen column density--of MIR galaxies and AGN at $z < 4$ in the 140 deg$^2$ field observed by SRG/eROSITA through the eFEDS survey. By cross-matching the WISE 22 $μ$m (W4)-detected sample and the eFEDS X-ray point-source catalog, we find that 692 extragalactic objects are detected by eROSITA. We have compiled a multiwavelength dataset. We have also performed (i) an X-ray spectral analysis, (ii) SED fitting using X-CIGALE, (iii) 2D image-decomposition analysis using Subaru HSC images, and (iv) optical spectral fitting with QSFit to investigate the AGN and host-galaxy properties. For 7,088 WISE W4 objects that are undetected by eROSITA, we have performed an X-ray stacking analysis to examine the typical physical properties of these X-ray faint and/or probably obscured objects. We find that (i) 82% of the eFEDS-W4 sources are classified as X-ray AGN with $\log\,L_{\rm X} >$ 42 erg s$^{-1}$; (ii) 67% and 24% of the objects have $\log\,(L_{\rm IR}/L_{\odot}) > 12$ and 13, respectively; (iii) the relationship between $L_{\rm X}$ and the 6 $μ$m luminosity is consistent with that reported in previous works; and (iv) the relationship between the Eddington ratio and $N_{\rm H}$ for the eFEDS-W4 sample and a comparison with a model prediction from a galaxy-merger simulation indicates that approximately 5% of the eFEDS-W4 sources in our sample are likely to be in an AGN-feedback phase, in which strong radiation pressure from the AGN blows out the surrounding material from the nuclear region. Thanks to the wide area coverage of eFEDS, we have been able to constrain the ranges of the physical properties of the WISE W4 sample of AGNs at $z < 4$, providing a benchmark for forthcoming studies on a complete census of MIR galaxies selected from the full-depth eROSITA all-sky survey., 18 pages, 19 figures, and 3 tables, accepted to appear on A&A, Special Issue: The Early Data Release of eROSITA and Mikhail Pavlinsky ART-XC on the SRG Mission

The eROSITA X-ray telescope on board the Spectrum-Roentgen-Gamma (SRG) satellite has started to detect new X-ray sources over the full sky at an unprecedented rate. Understanding the performance and selection function of the source detection is important for the subsequent scientific analysis of the eROSITA catalogs. Through simulations, we test and optimize the eROSITA source detection procedures, and we characterize the detected catalog quantitatively. Taking the eROSITA Final Equatorial-Depth Survey (eFEDS) as an example, we ran extensive photon-event simulations based on our best knowledge of the instrument characteristics, the background spectrum, and the population of astronomical X-ray sources. We introduce a method of analyzing source detection completeness, purity, and efficiency based on the origin of each photon. According to the source detection efficiency measured in the simulation, we chose a two-pronged strategy to build eROSITA X-ray catalogs, creating a main catalog using only the most sensitive band (0.2-2.3 keV) and an independent hard-band-selected catalog using multiband detection in a range up to 5 keV. Because our mock data are highly representative of the real eFEDS data, we used the mock catalogs to measure the completeness and purity of the eFEDS catalogs as a function of multiple parameters, such as detection likelihood, flux, and luminosity. These measurements provide a basis for choosing the eFEDS catalog selection thresholds. The mock catalogs (available with this paper) can be used to construct the selection function of active galactic nuclei and galaxy clusters. A direct comparison of the output and input mock catalogs also gives rise to a correction curve that converts the raw point-source flux distribution into the intrinsic number counts distribution., Comment: Accepted by A&A for the Special Issue: The Early Data Release of eROSITA and Mikhail Pavlinsky ART-XC on the SRG Mission

Context. High-redshift quasars signpost the early accretion history of the Universe. The penetrating nature of X-rays enables a less absorption-biased census of the population of these luminous and persistent sources compared to optical/near-infrared colour selection. The ongoing SRG/eROSITA X-ray all-sky survey offers a unique opportunity to uncover the bright end of the high-z quasar population and probe new regions of colour parameter space. Aims. We searched for high-z quasars within the X-ray source population detected in the contiguous ~140 deg2 field observed by eROSITA during the performance verification phase. With the purpose of demonstrating the unique survey science capabilities of eROSITA, this field was observed at the depth of the final all-sky survey. The blind X-ray selection of high-redshift sources in a large contiguous, near-uniform survey with a well-understood selection function can be directly translated into constraints on the X-ray luminosity function (XLF), which encodes the luminosity-dependent evolution of accretion through cosmic time. Methods. We collected the available spectroscopic information in the eFEDS field, including the sample of all currently known optically selected z > 5.5 quasars and cross-matched secure Legacy DR8 counterparts of eROSITA-detected X-ray point-like sources with this spectroscopic sample. Results. We report the X-ray detection of eFEDSU J083644.0+005459, an eROSITA source securely matched to the well-known quasar SDSS J083643.85+005453.3 (z = 5.81). The soft X-ray flux of the source derived from eROSITA is consistent with previous Chandra observations. The detection of SDSS J083643.85+005453.3 allows us to place the first constraints on the XLF at z > 5.5 based on a secure spectroscopic redshift. Compared to extrapolations from lower-redshift observations, this favours a relatively flat slope for the XLF at z ~ 6 beyond L*, the knee in the luminosity function. In addition, we report the detection of the quasar with LOFAR at 145 MHz and ASKAP at 888 MHz. The reported flux densities confirm a spectral flattening at lower frequencies in the emission of the radio core, indicating that SDSS J083643.85+005453.3 could be a (sub-) gigahertz peaked spectrum source. The inferred spectral shape and the parsec-scale radio morphology of SDSS J083643.85+005453.3 indicate that it is in an early stage of its evolution into a large-scale radio source or confined in a dense environment. We find no indications for a strong jet contribution to the X-ray emission of the quasar, which is therefore likely to be linked to accretion processes. Conclusions. Our results indicate that the population of X-ray luminous AGNs at high redshift may be larger than previously thought. From our XLF constraints, we make the conservative prediction that eROSITA will detect ~90 X-ray luminous AGNs at redshifts 5.7 < z < 6.4 in the full-sky survey (De+RU). While subject to different jet physics, both high-redshift quasars detected by eROSITA so far are radio-loud; a hint at the great potential of combined X-ray and radio surveys for the search of luminous high-redshift quasars.

The 140 square degree Final Equatorial-Depth Survey (eFEDS) field, observed with the extended ROentgen Survey with an Imaging Telescope Array (eROSITA) aboard the Spectrum-Roentgen-Gamma (SRG) mission, provides a first look at the variable eROSITA sky. We analyze the intrinsic X-ray variability of the eFEDS sources, provide X-ray light curves and tables with variability test results in the 0.2-2.3 keV (soft) and 2.3-5.0 keV (hard) bands. respectively. We perform variability tests using the normalized excess variance and maximum amplitude variability methods as performed for the 2RXS catalogue and add results from the Bayesian excess variance and the Bayesian block methods. In total 65 sources have been identified as being significantly variable in the soft band. In the hard band only one source is found to vary significantly. For the most variable sources fits to stellar flare events reveal extreme flare properties. A few highly variable AGN have also been detected. About half of the variable eFEDS sources have been detected at X-rays with eROSITA for the first time. Comparison with 2RXS and XMM observations provide variability information on timescales of years to decades., Comment: To appear on A&A, Special Issue: The Early Data Release of eROSITA and Mikhail Pavlinsky ART-XC on the SRG Mission; 13 pages, 10 figures, accepted June 21, 2021

The novel severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2) enters its host cells after binding to the angiotensin-converting enzyme 2 (ACE2)viaits spike glycoprotein. This interaction is critical for virus entry and virus-host membrane fusion. Soluble ACE2 ectodomains bind and neutralize the virus but the shortin vivohalf-lives of soluble ACE2 limits its therapeutic use. Fusion of the fragment crystallizable (Fc) part of human immunoglobulin G (IgG) to the ACE2 ectodomain can prolong thein vivohalf-life but bears the risk of unwanted Fc-receptor activation and antibody-dependent disease enhancement. Here, we describe optimized ACE2-Fc fusion constructs that avoid Fc-receptor binding by using IgG4-Fc as a fusion partner. The engineered ACE2-IgG4-Fc fusion proteins described herein exhibit promising pharmaceutical properties and a broad antiviral activity at single-digit nanomolar concentration. In addition, they allow to maintain the beneficial enzymatic activity of ACE2 and thus are very promising candidate antivirals broadly acting against coronaviruses.

Methylation of a conserved lysine in C-terminal domain of the molecular chaperone Hsp90 was shown previously to affect its in vivo function. However, the underlying mechanism remained elusive. Through a combined experimental and computational approach, this study shows that this site is very sensitive to sidechain modifications and crucial for Hsp90 activity in vitro and in vivo. Our results demonstrate that this particular lysine serves as a switch point for the regulation of Hsp90 functions by influencing its conformational cycle, ATPase activity, co-chaperone regulation, and client activation of yeast and human Hsp90. Incorporation of the methylated lysine via genetic code expansion specifically shows that upon modification, the conformational cycle of Hsp90 is altered. Molecular dynamics simulations including the methylated lysine suggest specific conformational changes that are propagated through Hsp90. Thus, methylation of the C-terminal lysine allows a precise allosteric tuning of Hsp90 activity via long distances.

The XMM-RM project was designed to provide X-ray coverage of the Sloan Digital Sky Survey Reverberation Mapping (SDSS-RM) field. 41 XMM-Newton exposures, placed surrounding the Chandra AEGIS field, were taken, covering an area of 6.13 deg^2 and reaching a nominal exposure depth of ~15 ks. We present an X-ray catalog of 3553 sources detected in these data, using a PSF-fitting algorithm and a sample selection threshold that produces a ~5% fraction of spurious sources. In addition to the PSF-fitting likelihood, we calculate a second source reliability measure based on Poisson theory using source and background counts within an aperture. Using the Poissonian likelihood, we select a sub-sample with a high purity and find that it has similar number count profiles to previous X-ray surveys. The Bayesian method "NWAY" was employed to identify counterparts of the X-ray sources from the optical Legacy and the IR unWISE catalogs, using a 2-dimensional unWISE magnitude-color prior created from optical/IR counterparts of Chandra X-ray sources. A significant number of the optical/IR counterparts correspond to sources with low detection likelihoods, proving the value of retaining the low-likelihood detections in the catalog. 932 of the XMM-RM sources are covered by SDSS spectroscopic observations. 89% of them are classified as AGN, and 71% of these AGN are in the SDSS-RM quasar catalog. Among the SDSS-RM quasars, 80% are detectable at the depth of the XMM observations., Comment: ApJS accepted. 20 pages, 16 figures

Despite their importance for antibody architecture and design, the principles governing antibody domain stability are still not understood in sufficient detail. Here, to address this question, we chose a domain from the invariant part of IgG, the C(H)2 domain. We found that compared with other Ig domains, the isolated C(H)2 domain is a surprisingly unstable monomer, exhibiting a melting temperature of ∼44 °C. We further show that the presence of an additional C-terminal lysine in a C(H)2 variant substantially increases the melting temperature by ∼14 °C relative to C(H)2 WT. To explore the molecular mechanism of this effect, we employed biophysical approaches to probe structural features of C(H)2. The results revealed that Lys(101) is key for the formation of three secondary structure elements: the very C-terminal β-strand and two adjacent α-helices. We also noted that a dipole interaction between Lys(101) and the nearby α-helix, is important for stabilizing the C(H)2 architecture by protecting the hydrophobic core. Interestingly, this interaction between the α-helix and C-terminal charged residues is highly conserved in antibody domains, suggesting that it represents a general mechanism for maintaining their integrity. We conclude that the observed interactions involving terminal residues have practical applications for defining domain boundaries in the development of antibody therapeutics and diagnostics.

Mitochondrial β-barrel proteins are imported from the cytosol into the organelle. Jores et al. provide new insights into the early events of this process by describing an array of cytosolic chaperones and cochaperones that associate with newly synthesized β-barrel proteins and assure their optimal biogenesis., Mitochondrial β-barrel proteins are encoded in the nucleus, translated by cytosolic ribosomes, and then imported into the organelle. Recently, a detailed understanding of the intramitochondrial import pathway of β-barrel proteins was obtained. In contrast, it is still completely unclear how newly synthesized β-barrel proteins reach the mitochondrial surface in an import-competent conformation. In this study, we show that cytosolic Hsp70 chaperones and their Hsp40 cochaperones Ydj1 and Sis1 interact with newly synthesized β-barrel proteins. These interactions are highly relevant for proper biogenesis, as inhibiting the activity of the cytosolic Hsp70, preventing its docking to the mitochondrial receptor Tom70, or depleting both Ydj1 and Sis1 resulted in a significant reduction in the import of such substrates into mitochondria. Further experiments demonstrate that the interactions between β-barrel proteins and Hsp70 chaperones and their importance are conserved also in mammalian cells. Collectively, this study outlines a novel mechanism in the early events of the biogenesis of mitochondrial outer membrane β-barrel proteins.

Genetic and epigenetic alterations in FK506-binding protein 5 (FKBP5) have been associated with increased risk for psychiatric disorders, including post-traumatic stress disorder (PTSD). Some of these common variants can increase the expression of FKBP5, the gene that encodes FKBP51. Excess FKBP51 promotes hypothalamic-pituitary-adrenal (HPA) axis dysregulation through altered glucocorticoid receptor (GR) signaling. Thus, we hypothesized that GR activity could be restored by perturbing FKBP51. Here, we screened 1280 pharmacologically active compounds and identified three compounds that rescued FKBP51-mediated suppression of GR activity without directly activating GR. One of the three compounds, benztropine mesylate, disrupted the association of FKBP51 with the GR/Hsp90 complex in vitro. Moreover, we show that removal of FKBP51 from this complex by benztropine restored GR localization in ex vivo brain slices and primary neurons from mice. In conclusion, we have identified a novel disruptor of the FKBP51/GR/Hsp90 complex. Targeting this complex may be a viable approach to developing treatments for disorders related to aberrant FKBP51 expression. [Image: see text]

Multiple channels have been proposed to produce Type Ia supernovae, with many scenarios suggesting that the exploding white dwarf accretes from a binary companion pre-explosion. In almost all cases, theory suggests that this companion will survive. However, no such companion has been unambiguously identified in ancient supernova remnants -- possibly falsifying the accretion scenario. Existing surveys, however, have only looked for stars as faint as $\approx 0.1 L_\odot$ and thus would have missed a surviving white dwarf companion. In this work, we present very deep DECAM imaging $(u, g, r, z)$ of the Type Ia supernova remnant SN 1006 specifically to search for a potential surviving white dwarf companion. We find no object within the inner third of the SN 1006 remnant that is consistent with a relatively young cooling white dwarf. We find that if there is a companion white dwarf, it must have formed long ago and cooled undisturbed for $> 10^8$ yr to be consistent with the redder objects in our sample. We conclude that our findings are consistent with the complete destruction of the secondary (such as in a merger) or an unexpectedly cool and thus very dim surviving companion white dwarf.

THALES - European Union [383549]; Greek Government of the programme 'Education and lifelong learning'; FONDECYT Postdoctorados [3160439]; Ministry of Economy, Development, and Tourism's Millennium Science Initiative [IC120009]; Millennium Institute of Astro-physics MAS; Alfred P. Sloan Foundation; National Science Foundation; U.S. Department of Energy Office of Science; University of Arizona; Brazilian Participation Group; Brookhaven National Laboratory; Carnegie Mellon University; University of Florida; French Participation Group; German Participation Group; Harvard University; Instituto de Astrofisica de Canarias; Michigan State/Notre Dame/JINA Participation Group; Johns Hopkins University; Lawrence Berkeley National Laboratory; Max Planck Institute for Astrophysics; Max Planck Institute for Extraterrestrial Physics; New Mexico State University; New York University; Ohio State University; Pennsylvania State University; University of Portsmouth; Princeton University; Spanish Participation Group; University of Tokyo; University of Utah; Vanderbilt University; University of Virginia; University of Washington; Yale University

The heat shock protein 90 (HSP90) chaperone machinery is a key regulator of proteostasis under both physiological and stress conditions in eukaryotic cells. As HSP90 has several hundred protein substrates (or 'clients'), it is involved in many cellular processes beyond protein folding, which include DNA repair, development, the immune response and neurodegenerative disease. A large number of co-chaperones interact with HSP90 and regulate the ATPase-associated conformational changes of the HSP90 dimer that occur during the processing of clients. Recent progress has allowed the interactions of clients with HSP90 and its co-chaperones to be defined. Owing to the importance of HSP90 in the regulation of many cellular proteins, it has become a promising drug target for the treatment of several diseases, which include cancer and diseases associated with protein misfolding.

Small heat shock proteins (sHsps) are a ubiquitous family of molecular chaperones that suppress the unspecific aggregation of miscellaneous proteins. Multicellular organisms contain a large number of different sHsps, raising questions as to whether they function redundantly or are specialized in terms of substrates and mechanism. To gain insight into this issue, we undertook a comparative analysis of the eight major human sHsps on the aggregation of both model proteins and cytosolic lysates under standardized conditions. We discovered that sHsps, which form large oligomers (HspB1/Hsp27, HspB3, HspB4/αA-crystallin, and HspB5/αB-crystallin) are promiscuous chaperones, whereas the chaperone activity of the other sHsps is more substrate-dependent. However, all human sHsps analyzed except HspB7 suppressed the aggregation of cytosolic proteins of HEK293 cells. We identified ∼1100 heat-sensitive HEK293 proteins, 12% of which could be isolated in complexes with sHsps. Analysis of their biochemical properties revealed that most of the sHsp substrates have a molecular mass from 50 to 100 kDa and a slightly acidic pI (5.4–6.8). The potency of the sHsps to suppress aggregation of model substrates is correlated with their ability to form stable substrate complexes; especially HspB1 and HspB5, but also B3, bind tightly to a variety of proteins, whereas fewer substrates were detected in complex with the other sHsps, although these were also efficient in preventing the aggregation of cytosolic proteins.

During evolution C-terminal peptide extensions were added to proteins on the gene level. These convey additional functions such as interaction with partner proteins or oligomerisation. IgM antibodies and molecular chaperones are two prominent examples discussed.The protein universe as we know is composed of folded structures and intrinsic disordered regions. The latter may adopt structures upon interaction with binding partners. In addition, some proteins contain C-terminal extensions which act as independent functional units in the context of the protein. Since their activity does not depend on the protein context they can be considered as peptides in proteins. To illustrate this principle, we here discuss the C-terminal extensions of IgM antibodies which dictate their assembly and the molecular chaperones Hsp90, Hsp70, and Hsp104 which use C-terminal peptide extensions as a docking site for interaction with different co-chaperones.

Small heat-shock proteins (sHsps) compose the most widespread family of molecular chaperones. The human genome encodes 10 different sHsps (HspB1–10). It has been shown that HspB1 (Hsp27), HspB5 (αB-crystallin), and HspB6 (Hsp20) can form hetero-oligomers in vivo. However, the impact of hetero-oligomerization on their structure and chaperone mechanism remains enigmatic. Here, we analyzed hetero-oligomer formation in human cells and in vitro using purified proteins. Our results show that the effect of hetero-oligomer formation on the composition of the sHsp ensembles and their chaperone activities depends strongly on the respective sHsps involved. We observed that hetero-oligomer formation between HspB1 and HspB5 leads to an ensemble that is dominated by species larger than the individual homo-oligomers. In contrast, the interaction of dimeric HspB6 with either HspB1 or HspB5 oligomers shifted the ensemble toward smaller oligomers. We noted that the larger HspB1–HspB5 hetero-oligomers are less active and that HspB6 activates HspB5 by dissociation to smaller oligomer complexes. The chaperone activity of HspB1–HspB6 hetero-oligomers, however, was modulated in a substrate-specific manner, presumably due to the specific enrichment of an HspB1–HspB6 heterodimer. These heterodimeric species may allow the tuning of the chaperone properties toward specific substrates. We conclude that sHsp hetero-oligomerization exerts distinct regulatory effects depending on the sHsps involved.

Summary: Life is resilient because living systems are able to respond to elevated temperatures with an ancient gene expression program called the heat shock response (HSR). In yeast, the transcription of hundreds of genes is upregulated at stress temperatures. Besides stress protection conferred by chaperones, the function of the majority of the upregulated genes under stress has remained enigmatic. We show that those genes are required to directly counterbalance increased protein turnover at stress temperatures and to maintain the metabolism. This anaplerotic reaction together with molecular chaperones allows yeast to efficiently buffer proteotoxic stress. When the capacity of this system is exhausted at extreme temperatures, aggregation processes stop translation and growth pauses. The emerging concept is that the HSR is modular with distinct programs dependent on the severity of the stress. : Mühlhofer et al. show that under mild and severe heat stress, proteins lost due to increased aggregation and degradation are replenished by increased protein synthesis to ensure a constant pool of proteins, together with the molecular chaperones. The heat shock response is activated in modules by transcriptional regulation. Keywords: heat shock response, protein aggregation, chaperones, transcriptome, translatome, proteome, S. cerevisiae, ribosome profiling, mass spectrometry

On 17th August 2017, Gravitational Wave (GW) detector network AdvLIGO/VIRGO reported the first ever detection of a merging neutron star binary, GW170817 [1]. A spatially and temporally coincident gamma-ray signal, short Gamma Ray Burst (GRB) 170817A, was observed by the Fermi space telescope, kickstarting the era of multi-messenger astronomy [2]. Further electromagnetic follow-up observations revealed associated emission in X-ray, UV/Optical/IR, and radio wavelengths [3]. Our collaboration has used the Atacama Large Millimeter Array (ALMA) and the Giant Metrewave Radio Telescope (GMRT) to follow-up the event and made several successful detections of the low-frequency radio transient with the GMRT [4,5]. Multi-wavelength electromagnetic observations of the GW event corroborated the hypothesis that short GRBs originate from neutron star mergers. Yet some puzzles remained. The prompt gamma-ray signal was exceptionally under-luminous compared to the classical short GRB population. In addition, the non-thermal X-ray and radio emission had a distinctly unique time evolution in comparison to typical short GRB afterglows. Currently there are two competing models capable of explaining all the electromagnetic observations: (i) a relativistic jet viewed away from its axis (off-axis jet) or (ii) a quasi-spherical cocoon of sub-relativistically moving material. Both models are motivated from numerical general relativistic hydrodynamical simulations of neutron star mergers.

The prototypical kinase c-Src plays an important role in numerous signal transduction pathways, where its activity is tightly regulated by two phosphorylation events. Phosphorylation at a specific tyrosine by C-terminal Src kinase inactivates c-Src, whereas autophosphorylation is essential for the c-Src activation process. However, the structural consequences of the autophosphorylation process still remain elusive. Here we investigate how the structural landscape of c-Src is shaped by nucleotide binding and phosphorylation of Tyr(416) using biochemical experiments, hydrogen/deuterium exchange MS, and atomistic molecular simulations. We show that the initial steps of kinase activation involve large rearrangements in domain orientation. The kinase domain is highly dynamic and has strong cross-talk with the regulatory domains, which are displaced by autophosphorylation. Although the regulatory domains become more flexible and detach from the kinase domain because of autophosphorylation, the kinase domain gains rigidity, leading to stabilization of the ATP binding site and a 4-fold increase in enzymatic activity. Our combined results provide a molecular framework of the central steps in c-Src kinase regulation process with possible implications for understanding general kinase activation mechanisms.

The molecular chaperone Hsp90 is an important regulator of proteostasis. It has remained unclear why S. cerevisiae possesses two Hsp90 isoforms, the constitutively expressed Hsc82 and the stress-inducible Hsp82. Here, we report distinct differences despite a sequence identity of 97%. Consistent with its function under stress conditions, Hsp82 is more stable and refolds more efficiently than Hsc82. The two isoforms also differ in their ATPases and conformational cycles. Hsc82 is more processive and populates closed states to a greater extent. Variations in the N-terminal ATP-binding domain modulate its dynamics and conformational cycle. Despite these differences, the client interactomes are largely identical, but isoform-specific interactors exist both under physiological and heat shock conditions. Taken together, changes mainly in the N-domain create a stress-specific, more resilient protein with a shifted activity profile. Thus, the precise tuning of the Hsp90 isoforms preserves the basic mechanism but adapts it to specific needs., S. cerevisiae encodes two Hsp90 isoforms, the constitutively expressed Hsc82 and stress-inducible Hsp82 that are 97% identical. Here, the authors combine a range of biophysical methods and show that they differ in their enzymatic properties, resilience to stress and client range, which suggests that they evolved to provide fine-tuned chaperone assistance under physiological and stress conditions.

To be able to perform their biological function, a protein needs to be correctly folded into its three dimensional structure. The protein folding process is spontaneous and does not require the input of energy. However, in the crowded cellular environment where there is high risk of inter-molecular interactions that may lead to protein molecules sticking to each other, hence forming aggregates, protein folding is assisted. Cells have evolved robust machinery called molecular chaperones to deal with the protein folding problem and to maintain proteins in their functional state. Molecular chaperones promote efficient folding of newly synthesized proteins, prevent their aggregation and ensure protein homeostasis in cells. There are different classes of molecular chaperones functioning in a complex interplay. In this review, we discuss the principal characteristics of different classes of molecular chaperones, their structure-function relationships, their mode of regulation and their involvement in human disorders.

We present a unification model for a clumpy obscurer in active galactic nuclei (AGN) and investigate the properties of the resulting X-ray spectrum. Our model is constructed to reproduce the column density distribution of the AGN population and cloud eclipse events in terms of their angular sizes and frequency. We developed and release a generalised Monte Carlo X-ray radiative transfer code, XARS, to compute X-ray spectra of obscurer models. The geometry results in strong Compton scattering, causing soft photons to escape also along Compton-thick sight lines. This makes our model spectra very similar to the Brightman & Nandra TORUS model. However, only if we introduce an additional Compton-thick reflector near the corona, we achieve good fits to NuSTAR spectra. This additional component in our model can be interpreted as part of the dust-free broad-line region, an inner wall or rim, or a warped disk. It cannot be attributed to a simple disk because the reflector must simultaneously block the line of sight to the corona and reflect its radiation. We release our model as an Xspec table model and present corresponding CLUMPY infrared spectra, paving the way for self-consistent multi-wavelength analyses., Published in A&A. Xspec tables and VR videos of the UXClumpy model can be found at https://github.com/JohannesBuchner/xars/blob/master/doc/README.rst , among other geometries. The X-ray ray tracing code XARS is open source and available at https://github.com/JohannesBuchner/xars . Contributions and collaborations are welcome

We present a statistical analysis of the optical properties of an X-ray-selected Type 1 active galactic nucleus (AGN) sample, using high signal-to-noise ratio (S/N>20) spectra of the counterparts of the ROSAT/2RXS sources in the footprint of the SDSS-IV/SPIDERS (Spectroscopic IDentification of eROSITA Sources) programme. The final sample contains 2100 sources. It significantly extends the redshift and luminosity ranges (z ∼ 0.01–0.80 and L0.1−2.4keV∼2.0×1041−1.0×1046ergs−1⁠) used so far in this kind of analysis. By means of a principal component analysis, we derive eigenvector (EV) 1 and 2 in an eleven-dimensional optical and X-ray parameter space, which are consistent with previous results. The validity of the correlations of the Eddington ratio L/LEdd with EV1 and the black hole mass with EV2 is strongly confirmed. These results imply that L/LEdd and black hole mass are related to the diversity of the optical properties of Type 1 AGNs. Investigating the relation of the width and asymmetry of H β and the relative strength of the iron emission rFeII⁠, we show that our analysis supports the presence of a distinct kinematic region: the very broad line region. Furthermore, comparing sources with a red-asymmetric broad H β emission line to sources for which it is blue asymmetric, we find an intriguing difference in the correlation of the FeII and the continuum emission strengths. We show that this contrasting behaviour is consistent with a flattened, stratified model of the broad-line region, in which the FeII-emitting region is shielded from the central source., FJC acknowledges financial support through grant AYA2015-64346-C2-1P (MINECO/FEDER)., Funded by the Deutsche Forschungsgemeinschaft (DFG; German Research Foundation) under Germany’s Excellence Strategy – EXC-2094 – 390783311.

In the context of the upcoming SRG/eROSITA survey, we present an N-body simulation-based mock catalogue for X-ray-selected active galactic nucleus (AGN) samples. The model reproduces the observed hard X-ray AGN luminosity function (XLF) and the soft X-ray logN-logS from redshift 0 to 6. The XLF is reproduced to within +/- 5 per cent and the logN-logS to within +/- 20 per cent. We develop a joint X-ray - optical extinction and classification model. We adopt a set of empirical spectral energy distributions to predict observed magnitudes in the UV, optical, and NIR. With the latest eROSITA all sky survey sensitivity model, we create a high-fidelity full-sky mock catalogue of X-ray AGN. It predicts their distributions in right ascension, declination, redshift, and fluxes. Using empirical medium resolution optical spectral templates and an exposure time calculator, we find that 1.1 x 10(6) (4 x 10(5)) fibre-hours are needed to follow-up spectroscopically from the ground the detected X-ray AGN with an optical magnitude 21 < r < 22.8 (22.8 < r < 25) with a 4-m (8-m) class multiobject spectroscopic facility. We find that future clustering studies will measure the AGN bias to the per cent level at redshift z < 1.2 and should discriminate possible scenarios of galaxy-AGN co-evolution. We predict the accuracy to which the baryon acoustic oscillation standard ruler will be measured using X-ray AGN: better than 3 per cent for AGN between redshift 0.5 to 3 and better than 1 per cent using the Ly alpha forest of X-ray QSOs discovered between redshift 2 and 3. eROSITA will provide an outstanding set of targets for future galaxy evolution and cosmological studies.© 2019 The Author(s).Published by Oxford University Press on behalf of the Royal Astronomical Society, JB acknowledges support from the CONICYT-Chile grants Basal-CATA PFB-06/2007 & AFB-170002, FONDECYT Postdoctorados 3160439 and the Ministry of Economy, Development, and Tourism's Millennium Science Initiative through grant IC120009, awarded to The Millennium Institute of Astrophysics, MAS. This research was supported by the DFG cluster of excellence 'Origin and Structure of the Universe'. GY would like to thank MINECO/FEDER for financial support under project grant AYA2015-63810-P. MK acknowledges support from DLR grant 50OR1802. The CosmoSim data base is a service of the Leibniz-Institute for Astrophysics Potsdam (AIP). The MultiDark data base was developed in cooperation with the Spanish MultiDark Consolider Project CSD2009-00064.

To be able to perform their biological function, a protein needs to be correctly folded into its three dimensional structure. The protein folding process is spontaneous and does not require the input of energy. However, in the crowded cellular environment where there is high risk of inter-molecular interactions that may lead to protein molecules sticking to each other, hence forming aggregates, protein folding is assisted. Cells have evolved robust machinery called molecular chaperones to deal with the protein folding problem and to maintain proteins in their functional state. Molecular chaperones promote efficient folding of newly synthesized proteins, prevent their aggregation and ensure protein homeostasis in cells. There are different classes of molecular chaperones functioning in a complex interplay. In this review, we discuss the principal characteristics of different classes of molecular chaperones, their structure-function relationships, their mode of regulation and their involvement in human disorders.

Low-frequency radio selection finds radio-bright galaxies regardless of the amount of obscuration by gas and dust. We report Chandra observations of a complete 178 MHz–selected, and so orientation-unbiased, sample of 44 0.5 < z < 1 3CRR sources. The sample is comprised of quasars and narrow-line radio galaxies (NLRGs) with similar radio luminosities, and the radio structure serves as both an age and an orientation indicator. Consistent with unification, intrinsic obscuration (measured by N H, X-ray hardness ratio, and X-ray luminosity) generally increases with inclination. However, the sample includes a population not seen in high-z 3CRR sources: NLRGs viewed at intermediate inclination angles with N H < 1022 cm−2. Multiwavelength analysis suggests that these objects have lower L/L Edd than typical NLRGs at similar orientation. Thus, both orientation and L/L Edd are important, and a “radiation-regulated unification” provides a better explanation of the sample’s observed properties. In comparison with the 3CRR sample at 1 < z < 2, our lower-redshift sample shows a higher fraction of Compton-thin NLRGs (45% versus 29%) but a similar Compton-thick fraction (20%), implying a larger covering factor of Compton-thin material at intermediate viewing angles and thus a more “puffed-up” torus atmosphere. We posit that this is due to a range of L/L Edd extending to lower values in this sample. In contrast, at high redshifts, the narrower range and high L/L Edd values allowed orientation (and so simple unification) to dominate the sample’s observed properties.