MicroRNA9 regulates neural stem cell differentiation by controlling Hes1 expression dynamics in the developing brain

Earlier studies show that Hes1 expression is oscillatory in neural stem cells but sustained and high in the roof plate and the floor plate, and that such different dynamics of Hes1 expression (oscillatory versus sustained) regulate different proliferation and differentiation characteristics of these cells (active in neural stem cells but rather dormant in roof/floor plate cells). The mechanism of how different dynamics of Hes1 expression is controlled remains to be determined. Here, we found that the seed sequence of microRNA‐9 (miR‐9) is complementary to the 3′‐UTR sequence of Hes1 mRNA. MiR‐9 is highly expressed in the ventricular zone of the developing brain, which contains neural stem cells, but it is not expressed in the roof plate or the floor plate. Over‐expression of miR‐9 negatively regulates the Hes1 protein expression by interacting with the 3′‐UTR of Hes1 mRNA, thereby inducing cell cycle exit and neuronal differentiation. Conversely, knockdown of miR‐9 inhibits neuronal differentiation. Furthermore, knockdown of miR‐9 inhibits the oscillatory expression of Hes1 mRNA in neural stem cells. These results indicate that miR‐9 regulates the proliferation and differentiation of neural stem cells by controlling the dynamics of Hes1 expression in the developing brain.     

The adaptor Grb7 is a novel calmodulin-binding protein: functional implications of the interaction of calmodulin with Grb7

We demonstrate using Ca2+-dependent calmodulin (CaM)-affinity chromatography and overlay with biotinylated CaM that the adaptor proteins growth factor receptor bound (Grb)7 and Grb7V (a naturally occurring variant lacking the Src homology 2 (SH2) domain) are CaM-binding proteins. Deletion of an amphiphilic basic amino-acid sequence (residues 243-256) predicted to form an alpha-helix located in the proximal region of its pleckstrin homology (PH) domain demonstrates the location of the CaM-binding domain. This site is identical in human and rodents Grb7, and shares great homology with similar regions of Grb10 and Grb14, and the Mig10 protein from Caenorhabditis elegans. We show that Grb7 and Grb7V are present in the cytosol and bound to membranes, while the deletion mutants (Grb7Delta and Grb7VDelta) have less capacity to be associated to membranes. Grb7Delta maintains in part the capacity to bind phosphoinositides, and CaM competes for phosphoinositide binding. Activation of ErbB2 by heregulin beta1 decreases the pool of Grb7 associated to membranes. The cell-permeable CaM antagonist W7 (N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide), but not the CaM-dependent protein kinase II inhibitor KN93, prevents this effect. Highly specific cell-permeable CaM inhibitory peptides decrease the association of Grb7 to membranes. This suggests that CaM regulates the intracellular mobilization of Grb7 in living cells. Direct interaction between enhanced yellow fluorescent protein (EYFP)-Grb7 and enhanced cyan fluorescent protein (ECFP)-CaM chimeras at the plasma membrane of living cells was demonstrated by fluorescence resonance energy transfer (FRET). The FRET signal dramatically decreased in cells loaded with a cell-permeable Ca2+ chelator, and was significantly attenuated when enhanced yellow fluorescent protein-Grb7 chimera (EYFP-Grb7)Delta instead of EYFP-Grb7 was used. Finally, we show that conditioned media from cells transiently transfected with Grb7Delta and Grb7VDelta lost its angiogenic activity, in contrast to those from cells transiently transfected with their wild-type counterparts.     

Non-alcoholic Steatohepatitis (NASH) and Hepatocellular Carcinoma

Non-alcoholic fatty liver disease (NAFLD) is characterized by an excessive accumulation of fatty acids and triglycerides within the cytoplasm of the hepatocytes of non-alcohol users. The natural history varies according to the initial histological diagnosis. A current consideration is that cryptogenic cirrhosis may be representative of a late stage of non-alcoholic steatohepatitis (NASH), which has lost its features of necroinflammatory activity and steatosis in up to 80% of patients. Since NASH is able to progress to cirrhosis, hepatocellular carcinoma (HCC) development may be an end-stage of this disease. We report below two clinical cases of patients diagnosed with NASH who developed HCC. The relationship between NAFLD and HCC is reviewed.     

Fibrilación auricular en pacientes con COVID-19. Utilidad de la puntuación CHA2DS2-VASc: un análisis del registro internacional HOPE COVID-19

Introduction and objectivesCoronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2. Atrial fibrillation (AF) is common in acute situations, where it is associated with more complications and higher mortality.MethodsAnalysis of the international HOPE registry (NCT04334291). The objective was to assess the prognostic information of AF in COVID-19 patients. A multivariate analysis and propensity score matching were performed to assess the relationship between AF and mortality. We also evaluated the impact on mortality and embolic events of the CHA₂DS₂-VASc score in these patients.ResultsAmong 6217 patients enrolled in the HOPE registry, 250 had AF (4.5%). AF patients had a higher prevalence of cardiovascular risk factors and comorbidities. After propensity score matching, these differences were attenuated. Despite this, patients with AF had a higher incidence of in-hospital complications such as heart failure (19.3% vs 11.6%, P = .021) and respiratory insufficiency (75.9% vs 62.3%, P = .002), as well as a higher 60-day mortality rate (43.4% vs 30.9%, P = .005). On multivariate analysis, AF was independently associated with higher 60-day mortality (hazard ratio, 1.234; 95%CI, 1.003-1.519). CHA₂DS₂-VASc score acceptably predicts 60-day mortality in COVID-19 patients (area ROC, 0.748; 95%CI, 0.733-0.764), but not its embolic risk (area ROC, 0.411; 95%CI, 0.147-0.675).ConclusionsAF in COVID-19 patients is associated with a higher number of complications and 60-day mortality. The CHA₂DS₂-VASc score may be a good risk marker in COVID patients but does not predict their embolic risk.     

Accelerated phase of idiopathic pulmonary fibrosis

The natural history of idiopathic pulmonary fibrosis is characterized by a slow progression resulting in respiratory failure and death. The progression to the fulminant form is rapid in a small percentage of cases, however. Within weeks or months, patients develop respiratory distress, and extensive ground-glass patterns can be seen in computed tomography scans and hyaline membranes in biopsy samples. This is described as an accelerated phase of idiopathic pulmonary fibrosis, in which elevated levels of acute-phase reactants and tumor markers have been reported. To date, the monoclonal tumor marker, CA 15/3 has not been associated with the accelerated phase.     

The capsid protein of infectious bursal disease virus contains a functional α4β1 integrin ligand motif

Infectious bursal disease virus (IBDV), a member of the dsRNA Birnaviridae family, is an important immunosuppressive avian pathogen. We have identified a strictly conserved amino acid triplet matching the consensus sequence used by fibronectin to bind the α4β1 integrin within the protruding domain of the IBDV capsid polypeptide. We show that a single point mutation on this triplet abolishes the cell-binding activity of IBDV-derived subviral particles (SVP), and abrogates the recovering of infectious IBDV by reverse genetics without affecting the overall SVP architecture. Additionally, we demonstrate that the presence of the α4β1 heterodimer is a critical determinant for the susceptibility of murine BALB/c 3T3 cells to IBDV binding and infectivity. Our data suggests that the IBDV might also use the α4β1 integrin as a specific binding receptor in avian cells.     

Multifocal lymphangioendotheliomatosis without thrombocytopenia or clinical signs of systemic bleeding

Multifocal lymphangioendotheliomatosis with thrombocytopenia (MLT) is an extremely rare recently described disorder characterized by diffuse congenital skin and gastrointestinal vascular lesions that may be associated with gastrointestinal bleeding and thrombocytopenia. We herein present a case report of multifocal lymphangioendotheliomatosis without thrombocytopenia or extensive extracutaneous involvement (gastrointestinal bleeding). Given the high morbidity and mortality associated with this disease, it is important for clinicians to recognize this disorder in order to select the most appropriate therapeutic approach.     

Analysis of KCNH2 and CACNA1C schizophrenia risk genes on EEG functional network modulation during an auditory odd-ball task

European Archives of Psychiatry and Clinical Neuroscience - A deficit in task-related functional connectivity modulation from electroencephalogram (EEG) has been described in schizophrenia. The use...