The therapeutic potential of stem cell-based therapies may be largely dependent on the ability of stem cells to modulate host cells rather than on their differentiation into host tissues. Within the ...last decade, there has been considerable interest in the intercellular communication mediated by the transfer of cytoplasmic material and organelles between cells. Numerous studies have shown that mitochondria and lysosomes are transported between cells by various mechanisms, such as tunneling nanotubes, microvesicles, and cellular fusion. This review will focus on the known instances of organelle transfer between stem cells and differentiated cells, what effects it has on recipient cells and how organelle transfer is regulated. Stem Cells 2019;37:14-25.
Dysfunction in Ataxia-telangiectasia mutated (ATM), a central component of the DNA repair machinery, results in Ataxia Telangiectasia (AT), a cancer-prone disease with a variety of inflammatory ...manifestations. By analyzing AT patient samples and Atm(-/-) mice, we found that unrepaired DNA lesions induce type I interferons (IFNs), resulting in enhanced anti-viral and anti-bacterial responses in Atm(-/-) mice. Priming of the type I interferon system by DNA damage involved release of DNA into the cytoplasm where it activated the cytosolic DNA sensing STING-mediated pathway, which in turn enhanced responses to innate stimuli by activating the expression of Toll-like receptors, RIG-I-like receptors, cytoplasmic DNA sensors, and their downstream signaling partners. This study provides a potential explanation for the inflammatory phenotype of AT patients and establishes damaged DNA as a cell intrinsic danger signal that primes the innate immune system for a rapid and amplified response to microbial and environmental threats.
Glucocorticoids are powerful modulators of brain function. They act via mineralocorticoid and glucocorticoid receptors (MR and GR). These are best understood as transcription factors. Although many ...glucocorticoid effects depend on the modulation of gene transcription, it is a major challenge to link gene expression to function given the large‐scale, apparently pleiotropic genomic responses. The extensive sets of MR and GR target genes are highly specific per cell type, and the brain contains many different (neuronal and non‐neuronal) cell types. Next to the set “trait” of cellular context, the “state” of other active signaling pathways will affect MR and GR transcriptional activity. Here, we discuss receptor specificity and contextual factors that determine the transcriptional outcome of MR/GR signaling, experimental possibilities offered by single‐cell transcriptomics approaches, and reflect on how to make sense of lists of target genes in relation to understanding the functional effects of steroid receptor activation.
Glucocorticoid hormones affect the brain in the context of stress, medical treatment and disease. They have massive effects on gene expression in many different neuronal and non‐neuronal cell types in the brain. We discuss challenges and possible solutions in identifying those target genes that are responsible for particular adaptive, pathogenic of therapeutic effects.
Introduction Respiratory Distress Syndrome (RDS) is a common cause of neonatal morbidity and mortality in premature newborns. In this study, we aim to compare the reintubation rate in preterm babies ...with RDS who were extubated to Nasal Continuous Positive Airway Pressure (NCPAP) versus those extubated to Nasal Intermittent Positive Pressure Ventilation (NIPPV). Methods This is a retrospective study conducted in the Neonatal Intensive Care Unit (NICU) of Women's Wellness and Research Center (WWRC), Doha, Qatar. The medical files (n = 220) of ventilated preterm infants with gestational age ranging between 28 weeks 0 days and 36 weeks + 6 days gestation and extubated to non-invasive respiratory support (whether NCPAP, NIPPV, or Nasal Cannula) during the period from January 2016 to December 2017 were reviewed. Results From the study group of 220 babies, n = 97 (44%) babies were extubated to CPAP, n = 77 (35%) were extubated to NIPPV, and n = 46 (21%) babies were extubated to Nasal Cannula (NC). Out of the n = 220 babies, 18 (8.2%) were reintubated within 1 week after extubation. 14 of the 18 (77.8%) were reintubated within 48 h of extubation. Eleven babies needed reintubation after being extubated to NCPAP (11.2%) and seven were reintubated after extubation to NIPPV (9.2%), none of those who were extubated to NC required reintubation (P = 0.203). The reintubation rate was not affected by extubation to any form of non-invasive ventilation (P = 0.625). The mode of ventilation before extubation does not affect the reintubation rate (P = 0.877). The presence of PDA and NEC was strongly associated with reintubation which increased by two and four-folds respectively in those morbidities. There is an increased risk of reintubation with babies suffering from NEC and BPD and this was associated with an increased risk of hospital stay with a P-value ranging (from 0.02-0.003). Using multivariate logistic regression, NEC the NEC (OR = 5.52, 95% CI 1.26, 24.11, P = 0.023) and the vaginal delivery (OR = 0.23, 95% CI 0.07, 0.78, P = 0.018) remained significantly associated with reintubation. Conclusion Reintubation rates were less with NIPPV when compared with NCPAP, however, this difference was not statistically significant. This study highlights the need for further research studies with a larger number of neonates in different gestational ages birth weight categories. Ascertaining this information will provide valuable data for the factors that contribute to re-intubation rates and influence the decision-making and management of RDS patients in the future. Keywords: Nasal intermittent positive pressure ventilation, Nasal continuous positive airway pressure, Respiratory distress syndrome, Reintubation, Newborn
Abstract
We analyse the radial pressure profiles, the intracluster medium (ICM) clumping factor and the Sunyaev–Zel'dovich (SZ) scaling relations of a sample of simulated galaxy clusters and groups ...identified in a set of hydrodynamical simulations based on an updated version of the treepm–SPH GADGET-3 code. Three different sets of simulations are performed: the first assumes non-radiative physics, the others include, among other processes, active galactic nucleus (AGN) and/or stellar feedback. Our results are analysed as a function of redshift, ICM physics, cluster mass and cluster cool-coreness or dynamical state. In general, the mean pressure profiles obtained for our sample of groups and clusters show a good agreement with X-ray and SZ observations. Simulated cool-core (CC) and non-cool-core (NCC) clusters also show a good match with real data. We obtain in all cases a small (if any) redshift evolution of the pressure profiles of massive clusters, at least back to z = 1. We find that the clumpiness of gas density and pressure increases with the distance from the cluster centre and with the dynamical activity. The inclusion of AGN feedback in our simulations generates values for the gas clumping ($\sqrt{C}_{\rho }\sim 1.2$ at R200) in good agreement with recent observational estimates. The simulated YSZ–M scaling relations are in good accordance with several observed samples, especially for massive clusters. As for the scatter of these relations, we obtain a clear dependence on the cluster dynamical state, whereas this distinction is not so evident when looking at the subsamples of CC and NCC clusters.
Heterogeneity of major depressive disorder (MDD) illness course complicates clinical decision-making. Although efforts to use symptom profiles or biomarkers to develop clinically useful prognostic ...subtypes have had limited success, a recent report showed that machine-learning (ML) models developed from self-reports about incident episode characteristics and comorbidities among respondents with lifetime MDD in the World Health Organization World Mental Health (WMH) Surveys predicted MDD persistence, chronicity and severity with good accuracy. We report results of model validation in an independent prospective national household sample of 1056 respondents with lifetime MDD at baseline. The WMH ML models were applied to these baseline data to generate predicted outcome scores that were compared with observed scores assessed 10-12 years after baseline. ML model prediction accuracy was also compared with that of conventional logistic regression models. Area under the receiver operating characteristic curve based on ML (0.63 for high chronicity and 0.71-0.76 for the other prospective outcomes) was consistently higher than for the logistic models (0.62-0.70) despite the latter models including more predictors. A total of 34.6-38.1% of respondents with subsequent high persistence chronicity and 40.8-55.8% with the severity indicators were in the top 20% of the baseline ML-predicted risk distribution, while only 0.9% of respondents with subsequent hospitalizations and 1.5% with suicide attempts were in the lowest 20% of the ML-predicted risk distribution. These results confirm that clinically useful MDD risk-stratification models can be generated from baseline patient self-reports and that ML methods improve on conventional methods in developing such models.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic that is a serious global health problem. Evasion of ...IFN-mediated antiviral signaling is a common defense strategy that pathogenic viruses use to replicate and propagate in their host. In this study, we show that SARS-CoV-2 is able to efficiently block STAT1 and STAT2 nuclear translocation in order to impair transcriptional induction of IFN-stimulated genes (ISGs). Our results demonstrate that the viral accessory protein Orf6 exerts this anti-IFN activity. We found that SARS-CoV-2 Orf6 localizes at the nuclear pore complex (NPC) and directly interacts with Nup98-Rae1 via its C-terminal domain to impair docking of cargo-receptor (karyopherin/importin) complex and disrupt nuclear import. In addition, we show that a methionine-to-arginine substitution at residue 58 impairs Orf6 binding to the Nup98-Rae1 complex and abolishes its IFN antagonistic function. All together our data unravel a mechanism of viral antagonism in which a virus hijacks the Nup98-Rae1 complex to overcome the antiviral action of IFN.
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