Can two wrongs make a right?:F508del-CFTR ion channel rescue by second-site mutations in its transmembrane domains

Deletion of phenylalanine 508 (F508del) in the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel is the most common cause of cystic fibrosis. The F508 residue is located on nucleotide-binding domain 1 (NBD1) in contact with the cytosolic extensions of the transmembrane helices, in particular intracellular loop 4 (ICL4). To investigate how absence of F508 at this interface impacts the CFTR protein, we carried out a mutagenesis scan of ICL4 by introducing second-site mutations at 11 positions in cis with F508del. Using an image-based fluorescence assay, we measured how each mutation affected membrane proximity and ion-channel function. The scan strongly validated the effectiveness of R1070W at rescuing F508del defects. Molecular dynamics simulations highlighted two features characterizing the ICL4/NBD1 interface of F508del/R1070W-CFTR: flexibility, with frequent transient formation of interdomain hydrogen bonds, and loosely stacked aromatic sidechains (F1068, R1070W, and F1074, mimicking F1068, F508, and F1074 in WT CFTR). F508del-CFTR displayed a distorted aromatic stack, with F1068 displaced toward the space vacated by F508, while in F508del/R1070F-CFTR, which largely retained F508del defects, R1070F could not form hydrogen bonds and the interface was less flexible. Other ICL4 second-site mutations which partially rescued F508del-CFTR included F1068M and F1074M. Methionine side chains allow hydrophobic interactions without the steric rigidity of aromatic rings, possibly conferring flexibility to accommodate the absence of F508 and retain a dynamic interface. These studies highlight how both hydrophobic interactions and conformational flexibility might be important at the ICL4/NBD1 interface, suggesting possible structural underpinnings of F508del-induced dysfunction

Massive black hole binaries in LISA: multimessenger prospects and electromagnetic counterparts

In the next decade, the Laser Interferometer Space Antenna (LISA) will detect the coalescence of massive black hole binaries (MBHBs) in the range $[10^4, 10^8] \, \rm M_{\odot}$, up to $z\sim10$. Their gravitational wave (GW) signal is expected to be accompanied by an electromagnetic counterpart (EMcp), generated by the gas accreting on the binary or on the remnant BH. In this work, we present the number and characteristics (such as redshift and mass distribution, apparent magnitudes or fluxes) of EMcps detectable jointly by LISA and some representative EM telescopes. We combine state-of-the-art astrophysical models for the galaxies formation and evolution to build the MBHBs catalogues, with Bayesian tools to estimate the binary sky position uncertainty from the GW signal. Exploiting additional information from the astrophysical models, such as the amount of accreted gas and the BH spins, we evaluate the expected EM emission in the soft X-ray, optical and radio bands. Overall, we predict between 7 and 21 EMcps in 4 yrs of joint observations by LISA and the considered EM facilities, depending on the astrophysical model. We also explore the impact of the hydrogen and dust obscuration of the optical and X-ray emissions, as well as of the collimation of the radio emission: these effects reduce the number to EMcps to 2 or 3, depending on the astrophysical model, again in 4 yrs of observations. Most of the EMcps are characterised by faint EM emission, challenging the observational capabilities of future telescopes. Finally, we also find that systems with multi-modal sky position posterior distributions represent only a minority of cases and do not affect significantly the number of EMcps.Comment: 28 pages, 18 figures. Submitted to PR

Epoxy Resins for Flooring Applications, an Optimal Host for Recycling Deactivated Cement Asbestos

Cement asbestos slates, commonly known as Eternit((R)) and still abundant in private and public buildings, were deactivated through a thermal process. The resulting deactivated cement asbestos powder (DCAP), a mixture of Ca-Mg-Al silicates and glass, was compounded with Pavatekno Gold 200 (PT) and Pavafloor H200/E (PF), two different epoxy resins (bisphenol A epichlorohydrin) for flooring applications. The addition of the DCAP filler to the PF samples causes a slight but acceptable decrease in the relevant mechanical properties (compressive, tensile, and flexural strengths) upon increasing DCAP content. The addition of the DCAP filler to pure epoxy (PT resin) causes a slight decrease in the tensile and flexural strengths with increasing DCAP content, while the compressive strength is almost unaffected, and the Shore hardness increases. The main mechanical properties of the PT samples are significantly better than those of the filler-bearing sample of normal production. Overall, these results suggest that DCAP can be advantageously used as filler in addition to, or in substitution for, commercial barite. In particular, the sample with 20 wt% of DCAP is the best performing in terms of compressive, tensile, and flexural strengths, whereas the sample with 30 wt% of DCAP shows the highest Shore hardness, which is an important property to be considered in flooring applications

A method for quantifying the gamma-ray burst bias. Application in the redshift range of 0–1.1

International audienceContext. Long gamma-ray bursts (LGRBs) are related to the final stages of evolution of very massive stars. As such, they should follow the star formation rate (SFR) of galaxies. We can use them to probe for star-forming galaxies in the distant universe following this assumption. The relation between the rate of LGRBs in a given galaxy and its SFR (which we call the LGRB bias) may however be complex, as we have good indications that the LGRB hosts are not perfect analogues to the general population of star-forming galaxies. Aims. In this work, we try to quantify how the LGRB bias depends on physical parameters of their host galaxy, such as SFR or stellar mass. These trends may reveal more fundamental properties such as the role of the metallicity of LGRBs and of their progenitors .Methods. We propose an empirical method based on the comparison of stellar mass functions (and SFR distributions) of LGRB hosts and of star-forming galaxies to find how the bias depends on the stellar mass or the SFR.Results. By applying this method to a sample of LGRB hosts at redshifts lower than 1.1, where the properties of star-forming galaxies are fairly well established and where the properties of LGRB host galaxies can be deduced from observations (limiting ourselves to stellar masses higher than 109.25M⊙ and SFR higher than ~1.8 M⊙ yr-1), we find that the LGRB bias depends on both the stellar mass and SFR. We find that the bias decreases with the SFR; that is, we see no preference for highly star-forming galaxies, once we account for the higher number of massive stars in galaxies with larger SFR. We do not find any trend with the specific star formation rate (SSFR), but the dynamical range in SSFR in our study is narrow. Through an indirect method, we relate these trends to a possible decrease in the LGRBs rate / SFR ratio with the metallicity.Conclusions. The method we propose suggests trends that may be useful to constrain models of LGRB progenitors, showing a clear decrease in the LGRB bias with the metallicity. This is promising for the future as the number of LGRB hosts studied will increase

Multimessenger study of merging massive black holes in the Obelisk simulation: gravitational waves, electromagnetic counterparts, and their link to galaxy and black hole populations

Massive black hole (BH) mergers are predicted to be powerful sources of low-frequency gravitational waves (GWs). Coupling the detection of GWs with electromagnetic (EM) detection can provide key information about merging BHs and their environments. We study the high-resolution cosmological radiation-hydrodynamics simulation Obelisk, run to redshift $z=3.5$, to assess the GW and EM detectability of high-redshift BH mergers, modelling spectral energy distribution and obscuration. For EM detectability we further consider sub-grid dynamical delays in postprocessing. We find that most of the merger events can be detected by LISA, except for high-mass mergers with very unequal mass ratios. Intrinsic binary parameters are accurately measured, but the sky localisation is poor generally. Only $\sim 40\%$ of these high-redshift sources have sky localisation better than $10\,\mathrm{deg}^2$. Merging BHs are hard to detect in the restframe UV since they are fainter than the host galaxies, which at high $z$ are star-forming. A significant fraction, $15-35\%$, of BH mergers instead outshines the galaxy in X-rays, and about $5-15\%$ are sufficiently bright to be detected with sensitive X-ray instruments. If mergers induce an Eddington-limited brightening, up to $30\%$ of sources can become observable. The transient flux change originating from such a brightening is often large, allowing $4-20\%$ of mergers to be detected as EM counterparts. A fraction $1-30\%$ of mergers is also detectable at radio frequencies. Observable merging BHs tend to have higher accretion rates and masses and are overmassive at fixed galaxy mass with respect to the full population. Most EM-observable mergers can also be GW-detected with LISA, but their sky localisation is generally poorer. This has to be considered when using EM counterparts to obtain information about the properties of merging BHs and their environment.Comment: 17 pages, 11 figures, submitted to A&

Probing the complex environments of GRB host galaxies and intervening systems: high resolution spectroscopy of GRB050922C

The aim of this paper is to investigate the environment of gamma ray bursts (GRBs) and the interstellar matter of their host galaxies. We use to this purpose high resolution spectroscopic observations of the afterglow of GRB050922C, obtained with UVES/VLT 3.5 hours after the GRB event. We found that, as for most high resolution spectra of GRBs, the spectrum of the afterglow of GRB050922C is complex. At least seven components contribute to the main absorption system at z=2.1992. The detection of lines of neutral elements like MgI and the detection of fine-structure levels of the ions FeII, SiII and CII allows us to separate components in the GRB ISM along the line of sight. Moreover, in addition to the main system, we have analyzed the five intervening systems between z = 2.077 and z = 1.5664 identified along the GRB line of sight. GRB afterglow spectra are very complex, but full of information. This can be used to disentangle the contribution of the different parts of the GRB host galaxy and to study their properties. Our metallicity estimates agree with the scenario of GRBs exploding in low metallicity galaxiesComment: 11 pages, 12 figures, accepted by A&

Alix protein is substrate of Ozz-E3 ligase and modulates actin remodeling in skeletal muscle

Alix/AIP1 is a multifunctional adaptor protein that participates in basic cellular processes, including membrane trafficking and actin cytoskeleton assembly, by binding selectively to a variety of partner proteins. However, the mechanisms regulating Alix turnover, subcellular distribution, and function in muscle cells are unknown. We now report that Alix is expressed in skeletal muscle throughout myogenic differentiation. In myotubes, a specific pool of Alix colocalizes with Ozz, the substrate-binding component of the muscle-specific ubiquitin ligase complex Ozz-E3. We found that interaction of the two endogenous proteins in the differentiated muscle fibers changes Alix conformation and promotes its ubiquitination. This in turn regulates the levels of the protein in specific subcompartments, in particular the one containing the actin polymerization factor cortactin. In Ozz(−/−) myotubes, the levels of filamentous (F)-actin is perturbed, and Alix accumulates in large puncta positive for cortactin. In line with this observation, we show that the knockdown of Alix expression in C2C12 muscle cells affects the amount and distribution of F-actin, which consequently leads to changes in cell morphology, impaired formation of sarcolemmal protrusions, and defective cell motility. These findings suggest that the Ozz-E3 ligase regulates Alix at sites where the actin cytoskeleton undergoes remodeling