Huntington's disease (HD) is a neurodegenerative disease caused by a CAG repeat expansion in the Huntingtin gene (HTT), translated into a Huntingtin protein with a polyglutamine expansion. There is ...preferential loss of medium spiny neurons within the striatum and cortical pyramidal neurons. Pridopidine is a small molecule showing therapeutic potential in HD preclinical and clinical studies. Pridopidine has nanomolar affinity to the sigma-1 receptor (sigma-1R), which is located predominantly at the endoplasmic reticulum (ER) and mitochondrial associated ER membrane, and activates neuroprotective pathways. Here we evaluate the neuroprotective effects of pridopidine against mutant Huntingtin toxicity in mouse and human derived in vitro cell models. We also investigate the involvement of the sigma-1 receptor in the mechanism of pridopidine. Pridopidine protects mutant Huntingtin transfected mouse primary striatal and cortical neurons, with an EC50 in the mid nanomolar range, as well as HD patient-derived induced pluripotent stem cells (iPSCs). This protection by pridopidine is blocked by NE-100, a purported sigma-1 receptor antagonist, and not blocked by ANA-12, a reported TrkB receptor antagonist. 3PPP, a documented sigma-1 receptor agonist, shows similar neuroprotective effects. Genetic knock out of the sigma-1 receptor dramatically decreases protection from pridopidine and 3PPP, but not protection via brain derived neurotrophic factor (BDNF). The neuroprotection afforded by pridopidine in our HD cell models is robust and sigma-1 receptor dependent. These studies support the further development of pridopidine, and other sigma-1 receptor agonists as neuroprotective agents for HD and perhaps for other disorders.
•Pridopidine protects against mutant Huntingtin toxicity in mouse primary neurons.•Protection is blocked by sigma-1R antagonist, but not by TrkB receptor antagonist.•Pridopidine shows similar protection of HD patient iPSCs.•Sigma-1R knockout specifically blocks pridopidine neuroprotection.
ABSTRACT
In order to accurately determine stellar properties, knowledge of the effective temperature of stars is vital. We implement Gaia and 2MASS photometry in the InfraRed Flux Method and apply it ...to over 360 000 stars across different evolutionary stages in the GALAH DR3 survey. We derive colour-effective temperature relations that take into account the effect of metallicity and surface gravity over the range $4000\, \rm {K}\lesssim T_{\rm {eff}}\lesssim 8000\, \rm {K}$, from very metal-poor stars to supersolar metallicities. The internal uncertainty of these calibrations is of order 40–80 K depending on the colour combination used. Comparison against solar-twins, Gaia benchmark stars, and the latest interferometric measurements validates the precision and accuracy of these calibrations from F to early M spectral types. We assess the impact of various sources of uncertainties, including the assumed extinction law, and provide guidelines to use our relations. Robust solar colours are also derived.
Doxorubicin is a highly efficacious anti-cancer drug but causes cardiotoxicity in many patients. The mechanisms of doxorubicin-induced cardiotoxicity (DIC) remain incompletely understood. We ...investigated the characteristics and molecular mechanisms of DIC in human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs). We found that doxorubicin causes dose-dependent increases in apoptotic and necrotic cell death, reactive oxygen species production, mitochondrial dysfunction and increased intracellular calcium concentration. We characterized genome-wide changes in gene expression caused by doxorubicin using RNA-seq, as well as electrophysiological abnormalities caused by doxorubicin with multi-electrode array technology. Finally, we show that CRISPR-Cas9-mediated disruption of TOP2B, a gene implicated in DIC in mouse studies, significantly reduces the sensitivity of hPSC-CMs to doxorubicin-induced double stranded DNA breaks and cell death. These data establish a human cellular model of DIC that recapitulates many of the cardinal features of this adverse drug reaction and could enable screening for protective agents against DIC as well as assessment of genetic variants involved in doxorubicin response.
The sigma-1 receptor (S1R) is a 223 amino acid-long transmembrane endoplasmic reticulum (ER) protein. The S1R modulates the activity of multiple effector proteins, but its signaling functions are ...poorly understood. S1R is associated with cholesterol, and in our recent studies we demonstrated that S1R association with cholesterol induces the formation of S1R clusters. We propose that these S1R-cholesterol interactions enable the formation of cholesterol-enriched microdomains in the ER membrane. We hypothesize that a number of secreted and signaling proteins are recruited and retained in these microdomains. This hypothesis is consistent with the results of an unbiased screen for S1R-interacting partners, which we performed using the engineered ascorbate peroxidase 2 (APEX2) technology. We further propose that S1R agonists enable the disassembly of these cholesterol-enriched microdomains and the release of accumulated proteins such as ion channels, signaling receptors, and trophic factors from the ER. This hypothesis may explain the pleotropic signaling functions of the S1R, consistent with previously observed effects of S1R agonists in various experimental systems.
Abstract
We use the second data releases of the European Space AgencyGaia astrometric survey and the high-resolution Galactic Archaeology with HERMES (GALAH) spectroscopic survey to analyse the ...structure of our Galaxy’s disc components. With GALAH, we separate the α-rich and α-poor discs (with respect to Fe), which are superposed in both position and velocity space, and examine their distributions in action space. We study the distribution of stars in the zV$\mathrm{ z}$ phase plane, for both Vϕ and VR, and recover the remarkable ‘phase spiral’ discovered by Gaia. We identify the anticipated quadrupole signature in zV$\mathrm{ z}$ of a tilted velocity ellipsoid for stars above and below the Galactic plane. By connecting our work with earlier studies, we show that the phase spiral is likely to extend well beyond the narrow solar neighbourhood cylinder in which it was found. The phase spiral is a signature of corrugated waves that propagate through the disc, and the associated non-equilibrium phase mixing. The radially asymmetric distribution of stars involved in the phase spiral reveals that the corrugation, which is mostly confined to the α-poor disc, grows in z-amplitude with increasing radius. We present new simulations of tidal disturbance of the Galactic disc by the Sagittarius (Sgr) dwarf. The effect on the zV$\mathrm{ z}$ phase plane lasts ${\gtrsim } 2\, \mathrm{Gyr}$, but a subsequent disc crossing wipes out the coherent structure. We find that the phase spiral was excited ${\lesssim } 0.5\, \mathrm{Gyr}$ ago by an object like Sgr with total mass ∼3 × 1010 M⊙ (stripped down from ∼5 × 1010 M⊙ when it first entered the halo) passing through the plane.
Huntington's disease is an inherited and incurable neurodegenerative disorder caused by an abnormal polyglutamine (polyQ) expansion in huntingtin (encoded by HTT). PolyQ length determines disease ...onset and severity, with a longer expansion causing earlier onset. The mechanisms of mutant huntingtin-mediated neurotoxicity remain unclear; however, mitochondrial dysfunction is a key event in Huntington's disease pathogenesis. Here we tested whether mutant huntingtin impairs the mitochondrial fission-fusion balance and thereby causes neuronal injury. We show that mutant huntingtin triggers mitochondrial fragmentation in rat neurons and fibroblasts of individuals with Huntington's disease in vitro and in a mouse model of Huntington's disease in vivo before the presence of neurological deficits and huntingtin aggregates. Mutant huntingtin abnormally interacts with the mitochondrial fission GTPase dynamin-related protein-1 (DRP1) in mice and humans with Huntington's disease, which, in turn, stimulates its enzymatic activity. Mutant huntingtin-mediated mitochondrial fragmentation, defects in anterograde and retrograde mitochondrial transport and neuronal cell death are all rescued by reducing DRP1 GTPase activity with the dominant-negative DRP1 K38A mutant. Thus, DRP1 might represent a new therapeutic target to combat neurodegeneration in Huntington's disease.
Early diagnosis of invasive mucormycosis is important for timely therapeutic intervention, improved survival, and reduced morbidity. Given the importance of an accurate and rapid diagnosis of ...invasive mucormycosis to guide the timely initiation of amphotericin B and possible surgical intervention, a coordinated multidisciplinary approach of clinical assessment, diagnostic imaging, and laboratory assessment is necessary. Laboratory assessment for mucormycosis includes the conventional methods of direct examination and culture of tissue, respiratory secretions, bronchoalveolar lavage fluid, and other fluids. However, because conventional diagnostic tools are limited in their sensitivity, advanced molecular amplification systems, antigen detection assays, proteomic profiles, and metabolite detection may complement existing approaches to improve the rate of early diagnosis of invasive mucormycosis.
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