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Cytochrome b5 reductase 3 (CYB5R3) is a membrane-bound NADH-dependent redox enzyme anchored to the mitochondrial outer membrane, endoplasmic reticulum, and plasma membrane. Recessive hereditary methaemoglobinaemia (RHM) type II is caused by CYB5R3 deficiency and is an incurable disease characterized by severe encephalopathy with mental retardation, microcephaly, generalized dystonia, and movement disorders. Currently, the etiology of type II RHM is poorly understood and there is no treatment for encephalopathy associated with this disease. Defective CYB5R3 leads to defects in the elongation and desaturation of fatty acids and cholesterol biosynthesis, which are conventionally linked with neurological disorders of type II RHM. Nevertheless, this abnormal lipid metabolism cannot explain all manifestations observed in patients. Current molecular and cellular studies indicate that CYB5R3 deficiency has pleiotropic tissue effects. Its localization in lipid rafts of neurons indicates its role in interneuronal contacts and its presence in caveolae of the vascular endothelial membrane suggests a role in the modulation of nitric oxide diffusion. Its role in aerobic metabolism and oxidative stress in fibroblasts, neurons, and cardiomyocytes has been reported to be due to its ability to modulate the intracellular ratio of NAD+/NADH. Based on the new molecular and cellular functions discovered for CYB5R3 linked to the plasma membrane and mitochondria, the conventional conception that the cause of type II RHM is a lipid metabolism disorder should be revised. We hypothesized that neurological symptoms of the disease could be caused by disorders in the synapse, aerobic metabolism, and/or vascular homeostasis rather than in disturbances of lipid metabolism. ; This work has been funded by the Instituto de Salud Carlos III FIS PI17-01286 grant. Authors were also funded by the Andalusian Government BIO177 research group.

Cytochrome b5 reductase 3 (CYB5R3) is a membrane-bound NADH-dependent redox enzyme anchored to the mitochondrial outer membrane, endoplasmic reticulum, and plasma membrane. Recessive hereditary methaemoglobinaemia (RHM) type II is caused by CYB5R3 deficiency and is an incurable disease characterized by severe encephalopathy with mental retardation, microcephaly, generalized dystonia, and movement disorders. Currently, the etiology of type II RHM is poorly understood and there is no treatment for encephalopathy associated with this disease. Defective CYB5R3 leads to defects in the elongation and desaturation of fatty acids and cholesterol biosynthesis, which are conventionally linked with neurological disorders of type II RHM. Nevertheless, this abnormal lipid metabolism cannot explain all manifestations observed in patients. Current molecular and cellular studies indicate that CYB5R3 deficiency has pleiotropic tissue effects. Its localization in lipid rafts of neurons indicates its role in interneuronal contacts and its presence in caveolae of the vascular endothelial membrane suggests a role in the modulation of nitric oxide diffusion. Its role in aerobic metabolism and oxidative stress in fibroblasts, neurons, and cardiomyocytes has been reported to be due to its ability to modulate the intracellular ratio of NAD+/NADH. Based on the new molecular and cellular functions discovered for CYB5R3 linked to the plasma membrane and mitochondria, the conventional conception that the cause of type II RHM is a lipid metabolism disorder should be revised. We hypothesized that neurological symptoms of the disease could be caused by disorders in the synapse, aerobic metabolism, and/or vascular homeostasis rather than in disturbances of lipid metabolism. ; This work has been funded by the Instituto de Salud Carlos III FIS PI17-01286 grant. Authors were also funded by the Andalusian Government BIO177 research group.

Changes in the Earth's water cycle can be estimated by analyzing sea surface salinity. This variable refects the balance between precipitation and evaporation over the ocean, since the upper layers of the ocean are the most sensitive to atmosphere–ocean interactions. In situ measurements lack spatial and temporal synopticity and are typically acquired at few meters below the surface. Satellite measurements, on the contrary, are synoptic, repetitive and acquired at the surface. Here we show that the satellite-derived sea surface salinity measurements evidence an intensifcation of the water cycle (the freshest waters become fresher and vice-versa) which is not observed at the in-situ nearsurface salinity measurements. The largest positive diferences between surface and near-surface salinity trends are located over regions characterized by a decrease in the mixed layer depth and the sea surface wind speed, and an increase in sea surface temperature, which is consistent with an increased stratifcation of the water column due to global warming. These results highlight the crucial importance of using satellites to unveil critical changes on ocean–atmosphere fuxes. ; This work was supported in part by the Spanish R&D project L-BAND (ESP2017-89463-C3-1-R), which is funded by MCIN/AEI/10.13039/501100011033 and "ERDF A way of making Europe", and project INTERACT (PID2020-114623RB-C31), which is funded by MCIN/AEI/10.13039/501100011033. , and in part by the Euro-pean Space Agency by means of the Contract SMOS ESL L2OS. We also acknowledge funding from the Spanish government through the 'Severo Ochoa Centre of Excellence' accreditation (CEX2019-000928-S). This work is a contribution to CSIC PTI Teledetect. ; Peer Reviewed ; Postprint (published version)