The hERG channel is dependent upon the Hsp90α isoform for maturation and trafficking

Heat shock protein 90 (Hsp90) has emerged as a promising therapeutic target for the treatment of cancer. Several Hsp90 inhibitors have entered clinical trials. However, some toxicological detriments have arisen, such as cardiotoxicity resulting from hERG inhibition following the administration of Hsp90 inhibitors. We sought to investigate this toxicity as hERG has been previously reported as a client protein that depends upon Hsp90 for its maturation and functional trafficking. In this study we show that hERG depends upon a single Hsp90 isoform. hERG preferentially co-immunoprecipitated with Hsp90α and genetic knockdown of Hsp90α, but not Hsp90β, resulted in a trafficking-defective hERG channel. This study demonstrates the importance of delineating the isoform dependence of Hsp90 client proteins and provides rationale for the design of isoform-selective Hsp90 inhibitors that avoid detrimental effect

The oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway

The identification of cancer-associated mutations in the tricarboxylic acid (TCA) cycle enzymes isocitrate dehydrogenases 1 and 2 (IDH1/2) highlights the prevailing notion that aberrant metabolic function can contribute to carcinogenesis. IDH1/2 normally catalyse the oxidative decarboxylation of isocitrate into α-ketoglutarate (αKG). In gliomas and acute myeloid leukaemias, IDH1/2 mutations confer gain-of-function leading to production of the oncometabolite R-2-hydroxyglutarate (2HG) from αKG. Here we show that generation of 2HG by mutated IDH1/2 leads to the activation of mTOR by inhibiting KDM4A, an αKG-dependent enzyme of the Jumonji family of lysine demethylases. Furthermore, KDM4A associates with the DEP domain-containing mTOR-interacting protein (DEPTOR), a negative regulator of mTORC1/2. Depletion of KDM4A decreases DEPTOR protein stability. Our results provide an additional molecular mechanism for the oncogenic activity of mutant IDH1/2 by revealing an unprecedented link between TCA cycle defects and positive modulation of mTOR function downstream of the canonical PI3K/AKT/TSC1-2 pathway

Filamin A Binds to CCR2B and Regulates Its Internalization

The chemokine (C-C motif) receptor 2B (CCR2B) is one of the two isoforms of the receptor for monocyte chemoattractant protein-1 (CCL2), the major chemoattractant for monocytes, involved in an array of chronic inflammatory diseases. Employing the yeast two-hybrid system, we identified the actin-binding protein filamin A (FLNa) as a protein that associates with the carboxyl-terminal tail of CCR2B. Co-immunoprecipitation experiments and in vitro pull down assays demonstrated that FLNa binds constitutively to CCR2B. The colocalization of endogenous CCR2B and filamin A was detected at the surface and in internalized vesicles of THP-1 cells. In addition, CCR2B and FLNa were colocalized in lamellipodia structures of CCR2B-expressing A7 cells. Expression of the receptor in filamin-deficient M2 cells together with siRNA experiments knocking down FLNa in HEK293 cells, demonstrated that lack of FLNa delays the internalization of the receptor. Furthermore, depletion of FLNa in THP-1 monocytes by RNA interference reduced the migration of cells in response to MCP-1. Therefore, FLNa emerges as an important protein for controlling the internalization and spatial localization of the CCR2B receptor in different dynamic membrane structures

Recovered SN Ia rate from simulated LSST images

International audienceThe Legacy Survey of Space and Time (LSST) will revolutionize Time Domain Astronomy by detecting millions of transients. In particular, it is expected to increment the number of type Ia supernovae (SNIa) of a factor of 100 compared to existing samples up to z~1.2. Such a high number of events will dramatically reduce statistical uncertainties in the analysis of SNIa properties and rates. However, the impact of all other sources of uncertainty on the measurement must still be evaluated. The comprehension and reduction of such uncertainties will be fundamental both for cosmology and stellar evolution studies, as measuring the SNIa rate can put constraints on the evolutionary scenarios of different SNIa progenitors. We use simulated data from the DESC Data Challenge 2 (DC2) and LSST Data Preview 0 (DP0) to measure the SNIa rate on a 15 deg2 region of the Wide-Fast-Deep area. We select a sample of SN candidates detected on difference images, associate them to the host galaxy, and retrieve their photometric redshifts (z-phot). Then, we test different light curves classification methods, with and without redshift priors. We discuss how the distribution in redshift measured for the SN candidates changes according to the selected host galaxy and redshift estimate. We measure the SNIa rate analyzing the impact of uncertainties due to z-phot, host galaxy association and classification on the distribution in redshift of the starting sample. We found a 17% average lost fraction of SNIa with respect to the simulated sample. As 10% of the bias is due to the uncertainty on the z-phot alone (which also affects classification when used as a prior), it results to be the major source of uncertainty. We discuss possible reduction of the errors in the measurement of the SNIa rate, including synergies with other surveys, which may help using the rate to discriminate different progenitor models

Size-dependent spatial magnetization profile of Manganese-Zinc ferrite Mn0.2Zn0.2Fe2.6O4 nanoparticles

[EN] We report the results of an unpolarized small-angle neutron-scattering (SANS) study on Mn-Zn ferrite (MZFO) magnetic nanoparticles with the aim to elucidate the interplay between their particle size and the magnetization configuration. We study different samples of single-crystalline MZFO nanoparticles with average diameters ranging between 8 to 80 nm, and demonstrate that the smallest particles are homogeneously magnetized. However, with increasing nanoparticle size, we observe the transition from a uniform to a nonuniform magnetization state. Field-dependent results for the correlation function confirm that the internal spin disorder is suppressed with increasing field strength. The experimental SANS data are supported by the results of micromagnetic simulations, which confirm an increasing inhomogeneity of the magnetization profile of the nanoparticle with increasing size. The results presented demonstrate the unique ability of SANS to detect even very small deviations of the magnetization state from the homogeneous one.The authors acknowledge the Heinz Maier-Leibnitz Zentrum for provision of neutron beamtime. We thank Jörg Schwarz and Jörg Schmauch (Universität des Saarlandes) for the technical support with the hydraulic press and for the SEM investigations. It is also a pleasure to thank Dirk Honecker for fruitful discussions. This research was supported by the EU-H2020 AMPHIBIAN Project No. 720853. P.B. and A.M.thank the Fonds National de la Recherche of Luxembourg for financial support (CORE ANS4NCC grant).Peer reviewe

Size-dependent spatial magnetization profile of manganese-zinc ferrite Mn0.2Zn0.2Fe2.6O4 nanoparticles

[EN] We report the results of an unpolarized small-angle neutron-scattering (SANS) study on Mn-Zn ferrite (MZFO) magnetic nanoparticles with the aim to elucidate the interplay between their particle size and the magnetization configuration. We study different samples of single-crystalline MZFO nanoparticles with average diameters ranging between 8 to 80 nm, and demonstrate that the smallest particles are homogeneously magnetized. However, with increasing nanoparticle size, we observe the transition from a uniform to a nonuniform magnetization state. Field-dependent results for the correlation function confirm that the internal spin disorder is suppressed with increasing field strength. The experimental SANS data are supported by the results of micromagnetic simulations, which confirm an increasing inhomogeneity of the magnetization profile of the nanoparticle with increasing size. The results presented demonstrate the unique ability of SANS to detect even very small deviations of the magnetization state from the homogeneous one.The authors acknowledge the Heinz Maier-Leibnitz Zentrum for provision of neutron beamtime. We thank Jörg Schwarz and Jörg Schmauch (Universität des Saarlandes) for the technical support with the hydraulic press and for the SEM investigations. It is also a pleasure to thank Dirk Honecker for fruitful discussions. This research was supported by the EU-H2020 AMPHIBIAN Project No. 720853. P.B. and A.M.thank the Fonds National de la Recherche of Luxembourg for financial support (CORE ANS4NCC grant).Peer reviewe

AMPHIBIAN CNR experimental data MnZn-ferrite-SANS PhysRevB2019. AMPHIBIAN GNRL simulated data MnZn-ferrite-SANS PhysRevB2019 [Dataset]

Dataset description: EXPERIMENTAL DATA folder "XRD data" containes the XRD patterns of all the samples presented in the manuscript folder "Magnetic data" containes the M(H) curves of all the samples presented in the manuscript measured at room temperature in a field range of � 5 T folder "TEM data" containes the TEM images of all the samples presented in the manuscript SIMULATED DATA prb_mzfo_fig10.png Microstructures used in the micromagnetic simulations. The volume fraction of the particle phase was set to 80% in all computations. The simulation volume approximately 300 � 300 � 300 nm^3 is constant in the simulations (mesh size: 4 nm). prb_mzfo_fig11.png Applied field dependence of the quantity |M|/M_s for different average particle sizes. ASCII data file for this data set is in "prb_mzfo_absm.dat", where the first column mu0H (mT) and the following ones are |M|/M_S for 14, 26, 38, 50, 62 and 74 nm crystallites systems correspondingly. Inset: Corresponding normalized magnetization curves. ASCII data file for this data set is in "prb_mzfo_mz.dat", where the first column mu0H (mT) and the following ones are M_z/M_s for 14, 26, 38, 50, 62 and 74 nm crystallites systems correspondingly. prb_mzfo_fig12.png Particle-size-dependent evolution of the parameter |M|/M_s for each magnetic particle as a function of the applied magnetic field. ASCII data file for this data set is in "prb_mzfo_absm14nmALLstep100.dat", "prb_mzfo_absm38nmALLstep5.dat" and "prb_mzfo_absm74nmALLstep1.dat" for for 14, 38, and 74 nm crystallites systems correspondingly. The first column mu0H (mT) and the following ones are |M|/M_s for every crystallite. Snapshots of spin structures at selected fields, where the largest deviations from the uniform magnetization state are observed.[EN] We report the results of an unpolarized small-angle neutron-scattering (SANS) study on Mn-Zn ferrite (MZFO) magnetic nanoparticles with the aim to elucidate the interplay between their particle size and the magnetization configuration. We study different samples of single-crystalline MZFO nanoparticles with average diameters ranging between 8 to 80 nm, and demonstrate that the smallest particles are homogeneously magnetized. However, with increasing nanoparticle size, we observe the transition from a uniform to a nonuniform magnetization state. Field-dependent results for the correlation function confirm that the internal spin disorder is suppressed with increasing field strength. The experimental SANS data are supported by the results of micromagnetic simulations, which confirm an increasing inhomogeneity of the magnetization profile of the nanoparticle with increasing size. The results presented demonstrate the unique ability of SANS to detect even very small deviations of the magnetization state from the homogeneous one.UE, programa H2020, Proyecto AMPHIBIAN n º 720853.Dataset description: >>> EXPERIMENTAL DATA folder "XRD data" containes the XRD patterns of all the samples presented in the manuscript folder "Magnetic data" containes the M(H) curves of all the samples presented in the manuscript measured at room temperature in a field range of � 5 T folder "TEM data" containes the TEM images of all the samples presented in the manuscript >>> SIMULATED DATA prb_mzfo_fig10.png Microstructures used in the micromagnetic simulations. The volume fraction of the particle phase was set to 80% in all computations. The simulation volume approximately 300 � 300 � 300 nm^3 is constant in the simulations (mesh size: 4 nm). prb_mzfo_fig11.png Applied field dependence of the quantity |M|/M_s for different average particle sizes. ASCII data file for this data set is in "prb_mzfo_absm.dat", where the first column mu0H (mT) and the following ones are |M|/M_S for 14, 26, 38, 50, 62 and 74 nm crystallites systems correspondingly. Inset: Corresponding normalized magnetization curves. ASCII data file for this data set is in "prb_mzfo_mz.dat", where the first column mu0H (mT) and the following ones are M_z/M_s for 14, 26, 38, 50, 62 and 74 nm crystallites systems correspondingly. prb_mzfo_fig12.png Particle-size-dependent evolution of the parameter |M|/M_s for each magnetic particle as a function of the applied magnetic field. ASCII data file for this data set is in "prb_mzfo_absm14nmALLstep100.dat", "prb_mzfo_absm38nmALLstep5.dat" and "prb_mzfo_absm74nmALLstep1.dat" for for 14, 38, and 74 nm crystallites systems correspondingly. The first column mu0H (mT) and the following ones are |M|/M_s for every crystallite. Snapshots of spin structures at selected fields, where the largest deviations from the uniform magnetization state are observed.Peer reviewe