Mendelian randomization reveals interactions of the blood proteome and immunome in mitral valve prolapse.

Background: Mitral valve prolapse (MVP) is a common heart disorder characterized by an excessive production of proteoglycans and extracellular matrix in mitral valve leaflets. Large-scale genome-wide association study (GWAS) underlined that MVP is heritable. The molecular underpinnings of the disease remain largely unknown.

Experiencing accessibility of historical heritage places with individuals living with visible and invisible disabilities.

Introduction: Around 16% of world's population lives with visible and invisible disabilities. People with disabilities' participation may be limited because of the environmental obstacles. Moreover, historic heritage places were built before the development of accessibility standards and the rights of people living with disabilities and the majority were not designed to be accessible.

Connectome and regulatory hubs of CAGE highly active enhancers.

Evidence indicates that enhancers are transcriptionally active. Herein, we investigated transcriptionally active enhancers by using cap analysis of gene expression (CAGE) combined with epigenetic marks and chromatin interactions. We identified CAGE-tag highly active (CHA) enhancers as distant regulatory elements with CAGE-tag ≥ 90th percentile and overlapping with H3K27ac peaks (4.

Angiopoietin-like 2 is essential to aortic valve development in mice.

Aortic valve (AoV) abnormalities during embryogenesis are a major risk for the development of aortic valve stenosis (AVS) and cardiac events later in life. Here, we identify an unexpected role for Angiopoietin-like 2 (ANGPTL2), a pro-inflammatory protein secreted by senescent cells, in valvulogenesis. At late embryonic stage, mice knocked-down for Angptl2 (Angptl2-KD) exhibit a premature thickening of AoV leaflets associated with a dysregulation of the fine balance between cell apoptosis, senescence and proliferation during AoV remodeling and a decrease in the crucial Notch signalling.

Genetic association and Mendelian randomization for hypothyroidism highlight immune molecular mechanisms.

We carried out a genome-wide association analysis including 51,194 cases of hypothyroidism and 443,383 controls. In total, 139 risk loci were associated to hypothyroidism with genes involved in lymphocyte function. Candidate genes associated with hypothyroidism were identified by using molecular quantitative trait loci, colocalization, and enhancer-promoter chromatin looping.

Mendelian randomization of circulating proteome identifies actionable targets in heart failure.

Background: Heart failure (HF) is a prevalent cause of mortality and morbidity. The molecular drivers of HF are still largely unknown.

Results: We aimed to identify circulating proteins causally associated with HF by leveraging genome-wide genetic association data for HF including 47,309 cases and 930,014 controls.

Enhancer promoter interactome and Mendelian randomization identify network of druggable vascular genes in coronary artery disease.

Coronary artery disease (CAD) is a multifactorial disorder, which is partly heritable. Herein, we implemented a mapping of CAD-associated candidate genes by using genome-wide enhancer-promoter conformation (H3K27ac-HiChIP) and expression quantitative trait loci (eQTL). Enhancer-promoter anchor loops from human coronary artery smooth muscle cells (HCASMC) explained 22% of the heritability for CAD.

aPKCi triggers basal extrusion of luminal mammary epithelial cells by tuning contractility and vinculin localization at cell junctions.

Metastasis is the main cause of cancer-related deaths. How a single oncogenic cell evolves within highly organized epithelium is still unknown. Here, we found that the overexpression of the protein kinase atypical protein kinase C ι (aPKCi), an oncogene, triggers basally oriented epithelial cell extrusion in vivo as a potential mechanism for early breast tumor cell invasion.

Role of a Kinesin Motor in Cancer Cell Mechanics.

Molecular motors play important roles in force generation, migration, and intracellular trafficking. Changes in specific motor activities are altered in numerous diseases. KIF20A, a motor protein of the kinesin-6 family, is overexpressed in bladder cancer, and KIF20A levels correlate negatively with clinical outcomes.

Extracellular matrix mechanical cues regulate lipid metabolism through Lipin-1 and SREBP.

Extracellular matrix (ECM) mechanical cues have powerful effects on cell proliferation, differentiation and death. Here, starting from an unbiased metabolomics approach, we identify synthesis of neutral lipids as a general response to mechanical signals delivered by cell-matrix adhesions. Extracellular physical cues reverberate on the mechanical properties of the Golgi apparatus and regulate the Lipin-1 phosphatidate phosphatase.

Intracellular mechanics: connecting rheology and mechanotransduction.

Cell mechanics is crucial for a wide range of cell functions, including proliferation, polarity, migration and differentiation. Cells sense external physical cues and translate them into a cellular response. While force sensing occurs in the vicinity of the plasma membrane, forces can reach deep in the cell interior and to the nucleus.

Forced- and Self-Rotation of Magnetic Nanorods Assembly at the Cell Membrane: A Biomagnetic Torsion Pendulum.

In order to provide insight into how anisotropic nano-objects interact with living cell membranes, and possibly self-assemble, magnetic nanorods with an average size of around 100 nm × 1 µm are designed by assembling iron oxide nanocubes within a polymeric matrix under a magnetic field. The nano-bio interface at the cell membrane under the influence of a rotating magnetic field is then explored. A complex structuration of the nanorods intertwined with the membranes is observed.