The pathogenic role of c‑Kit+ mast cells in the spinal motor neuron‑vascular niche in ALS

Degeneration of motor neurons, glial cell reactivity, and vascular alterations in the CNS are important neuropathological features of amyotrophic lateral sclerosis (ALS). Immune cells trafficking from the blood also infiltrate the affected CNS parenchyma and contribute to neuroinflammation. Mast cells (MCs) are hematopoietic-derived immune cells whose precursors differentiate upon migration into tissues. Upon activation, MCs undergo degranulation with the ability to increase vascular permeability, orchestrate neuroinflammation and modulate the neuroimmune response. However, the prevalence, pathological significance, and pharmacology of MCs in the CNS of ALS patients remain largely unknown. In autopsy ALS spinal cords, we identified for the first time that MCs express c-Kit together with chymase, tryptase, and Cox-2 and display granular or degranulating morphology, as compared with scarce MCs in control cords. In ALS, MCs were mainly found in the niche between spinal motor neuron somas and nearby microvascular elements, and they displayed remarkable pathological abnormalities. Similarly, MCs accumulated in the motor neuron-vascular niche of ALS murine models, in the vicinity of astrocytes and motor neurons expressing the c-Kit ligand stem cell factor (SCF), suggesting an SCF/c-Kit-dependent mechanism of MC differentiation from precursors. Mechanistically, we provide evidence that fully differentiated MCs in cell cultures can be generated from the murine ALS spinal cord tissue, further supporting the presence of c-Kit+ MC precursors. Moreover, intravenous administration of bone marrow-derived c-Kit+ MC precursors infiltrated the spinal cord in ALS mice but not in controls, consistent with aberrant trafficking through a defective microvasculature. Pharmacological inhibition of c-Kit with masitinib in ALS mice reduced the MC number and the influx of MC precursors from the periphery. Our results suggest a previously unknown pathogenic mechanism triggered by MCs in the ALS motor neuron-vascular niche that might be targeted pharmacologically

First archaeointensity reference paleosecular variation curve for South America and its implications for geomagnetism and archaeology

We report comprehensive rock-magnetic and archaeointensity investigations from 21 well-constrained pottery fragments from the Catamarca province of northwest Argentina. The absolute ages of the studied sites are ascertained by several high-quality radiometric ages and range between 1940 to 114014C yr BP. Magnetic mineralogy experiments indicates that the remanence is carried by thermally stable Ti-poor titanomagnetites. Forty-seven samples belonging to 11 out of 98 studied potsherds yielded reliable absolute intensity determinations judging from the quality parameters associated with the Thellier double-heating experiments. Moreover, we analyzed the available absolute geomagnetic intensities associated with the radiometric ages to construct the first intensity paleosecular variation curve (PSVC) for South America using thermoremanent magnetization carried by burned archaeological artifacts obtained in the present investigation and 79 other selected archaeointensities (out of 213 published in the literature). The dataset is used to build the PSVC reference curve by combined bootstrap and temporal P-spline methods. The variation curve shows significant differences with the global prediction model SHA.DIF.14k mainly based on the GEOMAGIA database. This intensity PSVC curve shows reasonably good agreement with paleosecular variation curves for Europe between 850 through 1150 BC and for Asia between 1000 and 1500 BC. This regional curve may be used as most reliable archaeomagnetic dating tool for the major part of South America (Peru, Brazil, Argentina, Chile, and Bolivia) for the last two millennia.Fil: Goguitchaichvili, Avto. Universidad Nacional Autónoma de México. Instituto de Geofísica; MéxicoFil: Greco Mainero, Mariano Catriel. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Departamento de Geología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: García Ruíz, Rafael. Universidad Nacional Autónoma de México. Instituto de Geofísica; MéxicoFil: Pereyra Domingorena, Lucas. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Saavedra 15. Instituto de las Culturas. Universidad de Buenos Aires. Instituto de las Culturas; ArgentinaFil: Cejudo, Ruben. Universidad Nacional Autónoma de México. Instituto de Geofísica; MéxicoFil: Morales, Juan. Laboratorio Interinstitucional de Magnetismo Natural; MéxicoFil: Gogorza, Claudia Susana. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigaciones en Física e Ingeniería del Centro de la Provincia de Buenos Aires. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigaciones en Física e Ingeniería del Centro de la Provincia de Buenos Aires. - Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Centro de Investigaciones en Física e Ingeniería del Centro de la Provincia de Buenos Aires; ArgentinaFil: Scattolin, Maria Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Saavedra 15. Instituto de las Culturas. Universidad de Buenos Aires. Instituto de las Culturas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Tarrago, Myriam Noemi. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Saavedra 15. Instituto de las Culturas. Universidad de Buenos Aires. Instituto de las Culturas; Argentin