Adult autologous mesenchymal stem cells for the treatment of suspected non-infectious inflammatory diseases of the canine central nervous system: safety, feasibility and preliminary clinical findings

Non-infectious inflammatory diseases of the canine central nervous system (CNS) are common idiopathic disorders grouped under the term meningoencephalomyelitis of unknown origin (MUO). Ante mortem diagnosis is achieved via assessment of clinical signs, magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) analysis, but the definitive diagnosis needs histopathological examination. MUO are mostly considered as autoimmune CNS disorders, so that suppressing the immune reaction is the best management method for patients. Mesenchymal stem cells (MSCs) are under investigation to treat autoimmune and degenerative disorders due to their immunomodulatory and regenerative properties. This study aims to verify the safety, feasibility, and efficacy of MSCs treatment in canine idiopathic autoimmune inflammatory disorders of the CNS

Shedding light on the D1-like receptors : a fluorescence-based toolbox for visualization of the D1 and D5 receptors

Funding: Universitat de Barcelona; Fonds der Chemischen Industrie. Grant Number: 661688; University of Regensburg graduate school “Receptor Dynamics: Emerging Paradigms for Novel Drugs. Grant Number: K-BM-2013-247; Elite Network of Bavaria Deutsche Forschungsgemeinschaft. Grant Numbers: 421152132, SFB1423, SFB1470; Spanish MCIN/AEI/10.13039/501100011033. Grant Number: PID2021-126600OB−I00; European Union Next Generation EU/PRTR.Dopamine D1-like receptors are the most abundant type of dopamine receptors in the central nervous system and, even after decades of discovery, still highly interesting for the study of neurological diseases. We herein describe the synthesis of a new set of fluorescent ligands, structurally derived from D1R antagonist SCH-23390 and labeled with two different fluorescent dyes, as tool compounds for the visualization of D1-like receptors. Pharmacological characterization in radioligand binding studies identified UR-NR435 (25) as a high-affinity ligand for D1-like receptors (pKi (D1R) = 8.34, pKi (D5R) = 7.62) with excellent selectivity towards D2-like receptors. Compound 25 proved to be a neutral antagonist at the D1R and D5R in a Gs heterotrimer dissociation assay, an important feature to avoid receptor internalization and degradation when working with whole cells. The neutral antagonist 25 displayed rapid association and complete dissociation to the D1R in kinetic binding studies using confocal microscopy verifying its applicability for fluorescence microscopy. Moreover, molecular brightness studies determined a single-digit nanomolar binding affinity of the ligand, which was in good agreement with radioligand binding data. For this reason, this fluorescent ligand is a useful tool for a sophisticated characterization of native D1 receptors in a variety of experimental setups.Publisher PDFPeer reviewe

General analysis of signals with two leptons and missing energy at the Large Hadron Collider

A signal of two leptons and missing energy is challenging to analyze at the Large Hadron Collider (LHC) since it offers only few kinematical handles. This signature generally arises from pair production of heavy charged particles which each decay into a lepton and a weakly interacting stable particle. Here this class of processes is analyzed with minimal model assumptions by considering all possible combinations of spin 0, 1/2 or 1, and of weak iso-singlets, -doublets or -triplets for the new particles. Adding to existing work on mass and spin measurements, two new variables for spin determination and an asymmetry for the determination of the couplings of the new particles are introduced. It is shown that these observables allow one to independently determine the spin and the couplings of the new particles, except for a few cases that turn out to be indistinguishable at the LHC. These findings are corroborated by results of an alternative analysis strategy based on an automated likelihood test.Comment: 18 pages, 3 figures, LaTe

Climate and southern Africa's water-energy-food nexus

In southern Africa, the connections between climate and the water-energy-food nexus are strong. Physical and socioeconomic exposure to climate is high in many areas and in crucial economic sectors. Spatial interdependence is also high, driven for example, by the regional extent of many climate anomalies and river basins and aquifers that span national boundaries. There is now strong evidence of the effects of individual climate anomalies, but associations between national rainfall and Gross Domestic Product and crop production remain relatively weak. The majority of climate models project decreases in annual precipitation for southern Africa, typically by as much as 20% by the 2080s. Impact models suggest these changes would propagate into reduced water availability and crop yields. Recognition of spatial and sectoral interdependencies should inform policies, institutions and investments for enhancing water, energy and food security. Three key political and economic instruments could be strengthened for this purpose; the Southern African Development Community, the Southern African Power Pool, and trade of agricultural products amounting to significant transfers of embedded water

Shedding Light on the D1‐Like Receptors: A Fluorescence‐Based Toolbox for Visualization of the D1 and D5 Receptors

Dopamine D1-like receptors are the most abundant type of dopamine receptors in the central nervous system and, even after decades of discovery, still highly interesting for the study of neurological diseases. We herein describe the synthesis of a new set of fluorescent ligands, structurally derived from D1R antagonist SCH-23390 and labeled with two different fluorescent dyes, as tool compounds for the visualization of D1-like receptors. Pharmacological characterization in radioligand binding studies identified UR-NR435 (25) as a high-affinity ligand for D1-like receptors (pKi (D1R)=8.34, pKi (D5R)=7.62) with excellent selectivity towards D2-like receptors. Compound 25 proved to be a neutral antagonist at the D1R and D5R in a Gs heterotrimer dissociation assay, an important feature to avoid receptor internalization and degradation when working with whole cells. The neutral antagonist 25 displayed rapid association and complete dissociation to the D1R in kinetic binding studies using confocal microscopy verifying its applicability for fluorescence microscopy. Moreover, molecular brightness studies determined a single-digit nanomolar binding affinity of the ligand, which was in good agreement with radioligand binding data. For this reason, this fluorescent ligand is a useful tool for a sophisticated characterization of native D1 receptors in a variety of experimental setups

Fluorescent Tools for the Imaging of Dopamine D2‐Like Receptors

The family of dopamine D2-like receptors represents an interesting target for a variety of neurological diseases, e. g. Parkinson's disease (PD), addiction, or schizophrenia. In this study we describe the synthesis of a new set of fluorescent ligands as tools for visualization of dopamine D2-like receptors. Pharmacological characterization in radioligand binding studies identified UR-MN212 (20) as a high-affinity ligand for D2-like receptors (pKi (D2longR)=8.24, pKi (D3R)=8.58, pKi (D4R)=7.78) with decent selectivity towards D1-like receptors. Compound 20 is a neutral antagonist in a Go1 activation assay at the D2longR, D3R, and D4R, which is an important feature for studies using whole cells. The neutral antagonist 20, equipped with a 5-TAMRA dye, displayed rapid association to the D2longR in binding studies using confocal microscopy demonstrating its suitability for fluorescence microscopy. Furthermore, in molecular brightness studies, the ligand's binding affinity could be determined in a single-digit nanomolar range that was in good agreement with radioligand binding data. Therefore, the fluorescent compound can be used for quantitative characterization of native D2-like receptors in a broad variety of experimental setups

Gamma-ray spectroscopy of positron annihilation in the Milky Way

T. Siegert, et al., “Gamma-ray spectroscopy of positron annihilation in the Milky Way”, Astronomy & Astrophysics, Vol. 586, January 2016, https://doi.org/10.1051/0004-6361/201527510. Reproduced with permission from Astronomy & Astrophysics, © ESO”.Context. The annihilation of positrons in the Galaxy's interstellar medium produces characteristic gamma-rays with a line at 511 keV. This gamma-ray emission has been observed with the spectrometer SPI on ESA's INTEGRAL observatory, confirming a puzzling morphology with bright emission from an extended bulge-like region, while emission from the disk is faint. Most known or plausible sources of positrons are, however, believed to be distributed throughout the disk of the Milky Way. Aims: We aim to constrain characteristic spectral shapes for different spatial components in the disk and bulge using data with an exposure that has doubled since earlier reports. Methods: We exploit high-resolution gamma-ray spectroscopy with SPI on INTEGRAL based on a new instrumental background method and detailed multi-component sky model fitting. Results: We confirm the detection of the main extended components of characteristic annihilation gamma-ray signatures, altogether at 58σ significance in the 511 keV line. The total Galactic 511 keV line intensity amounts to (2.74 ± 0.25) × 10-3 ph cm-2 s-1 for our assumed model of the spatial distribution. We derive spectra for the bulge and disk, and a central source modelled as point-like and at the position of Sgr A*, and discuss spectral differences. The bulge (56σ) shows a 511 keV line intensity of (0.96 ± 0.07) × 10-3 ph cm-2 s-1 together with ortho-positronium continuum equivalent to a positronium fraction of (1.080 ± 0.029). The two-dimensional Gaussian that represents the disk emission (12σ) has an extent of 60+10-5 degrees in longitude and a rather large latitudinal extent of 10.5+2.5-1.5 degrees; the line intensity is (1.66 ± 0.35) × 10-3 ph cm-2 s-1 with a marginal detection of the annihilation continuum and an overall diffuse Galactic continuum of (5.85 ± 1.05) × 10-5 ph cm-2 s-1 keV-1 at 511 keV. The disk shows no flux asymmetry between positive and negative longitudes, although spectral details differ. The flux ratio between bulge and disk is (0.58 ± 0.13). The central source (5σ) has an intensity of (0.80 ± 0.19) × 10-4 ph cm-2 s-1.Peer reviewe