The RNA-binding protein quaking maintains endothelial barrier function and affects VE-cadherin and beta-catenin protein expression

Vascular nephrologyNephrolog

Prediction Power on Cardiovascular Disease of Neuroimmune Guidance Cues Expression by Peripheral Blood Monocytes Determined by Machine-Learning Methods

Atherosclerosis is the underlying pathology in a major part of cardiovascular disease, the leading cause of mortality in developed countries. The infiltration of monocytes into the vessel walls of large arteries is a key denominator of atherogenesis, making monocytes accountable for the development of atherosclerosis. With the development of high-throughput transcriptome profiling platforms and cytometric methods for circulating cells, it is now feasible to study in-depth the predicted functional change of circulating monocytes reflected by changes of gene expression in certain pathways and correlate the changes to disease outcome. Neuroimmune guidance cues comprise a group of circulating- and cell membrane-associated signaling proteins that are progressively involved in monocyte functions. Here, we employed the CIRCULATING CELLS study cohort to classify cardiovascular disease patients and healthy individuals in relation to their expression of neuroimmune guidance cues in circulating monocytes. To cope with the complexity of human datasets featured by noisy data, nonlinearity and multidimensionality, we assessed various machine-learning methods. Of these, the linear discriminant analysis, Naive Bayesian model and stochastic gradient boost model yielded perfect or near-perfect sensibility and specificity and revealed that expression levels of the neuroimmune guidance cues SEMA6B, SEMA6D and EPHA2 in circulating monocytes were of predictive values for cardiovascular disease outcome.Cardiolog

Targeting the RNA-Binding Protein QKI in Myeloid Cells Ameliorates Macrophage-Induced Renal Interstitial Fibrosis

In the pathophysiologic setting of acute and chronic kidney injury, the excessive activation and recruitment of blood-borne monocytes prompts their differentiation into inflammatory macrophages, a process that leads to progressive glomerulosclerosis and interstitial fibrosis. Importantly, this differentiation of monocytes into macrophages requires the meticulous coordination of gene expression at both the transcriptional and post-transcriptional level. The transcriptomes of these cells are ultimately determined by RNA-binding proteins such as QUAKING (QKI), that define their pre-mRNA splicing and mRNA transcript patterns. Using two mouse models, namely (1) quaking viable mice (qk(v)) and (2) the conditional deletion in the myeloid cell lineage using the lysozyme 2-Cre (QKI(FL/FL;LysM-Cre) mice), we demonstrate that the abrogation of QKI expression in the myeloid cell lineage reduces macrophage infiltration following kidney injury induced by unilateral urethral obstruction (UUO). The qk(v) and QKI(FL/FL;LysM-Cre) mice both showed significant diminished interstitial collagen deposition and fibrosis in the UUO-damaged kidney, as compared to wild-type littermates. We show that macrophages isolated from QKI(FL/FL;LysM-Cre) mice are associated with defects in pre-mRNA splicing. Our findings demonstrate that reduced expression of the alternative splice regulator QKI in the cells of myeloid lineage attenuates renal interstitial fibrosis, suggesting that inhibition of this splice regulator may be of therapeutic value for certain kidney diseases.Nephrolog

Reasons for (non)participation in supplemental population-based MRI breast screening for women with extremely dense breasts

Aim: To determine the willingness of women with extremely dense breasts to undergo breast cancer screening with magnetic resonance imaging (MRI) in a research setting, and to examine reasons for women to participate or not. Materials and methods: Between 2011 and 2015, 8,061 women (50–75 years) were invited for supplemental MRI as part of the Dense Tissue and Early Breast Neoplasm Screening (DENSE) trial (ClinicalTrials.gov Identifier: NCT01315015), after a negative screening mammography in the national population-based mammography screening programme. Demographics of participants and non-participants were compared. All invitees were asked to report reasons for (non)participation. Ethical approval was obtained. Participants provided written informed consent. Results: Of the 8,061 invitees, 66% answered that they were interested, and 59% eventually participated. Participants were on average 54-years old (interquartile range: 51–59 years), comparable to women with extremely dense breasts in the population-based screening programme (55 years). Women with higher socio-economic status (SES) were more often interested in participation than women with lower SES (68% versus 59%, p<0.001). The most frequently stated reasons for non-participation were “MRI-related inconveniences and/or self-reported contraindications to MRI” (27%) and “anxiety regarding the result of supplemental screening” (21%). “Expected personal health benefit” (68%) and “contribution to science” (43%) were the most frequent reasons for participation. Conclusion: Of women invited for MRI because of extremely dense breasts, 59% participated. Common reasons for non-participation were “MRI-related inconveniences” and “anxiety regarding the result of supplemental screening”. In case of future implementation, availability of precise evidence on benefits and harms might reduce this anxiety

Quaking promotes monocyte differentiation into pro-atherogenic macrophages by controlling pre-mRNA splicing and gene expression

Nephrolog

Quaking, an RNA-Binding Protein, Is a Critical Regulator of Vascular Smooth Muscle Cell Phenotype

Pathogenesis and treatment of chronic pulmonary disease