Toward the quantification of α-synuclein aggregates with digital seed amplification assays.

The quantification and characterization of aggregated α-synuclein in clinical samples offer immense potential toward diagnosing, treating, and better understanding neurodegenerative synucleinopathies. Here, we developed digital seed amplification assays to detect single α-synuclein aggregates by partitioning the reaction into microcompartments. Using pre-formed α-synuclein fibrils as reaction seeds, we measured aggregate concentrations as low as 4 pg/mL.

Correlates of a caregiver-reported child sleep problem and variation by community disadvantage.

Background: Previous studies of sleep patterns and perceived problems in early childhood indicate variation by family socioeconomic status. The purpose of this study was to examine variation in correlates of a caregiver-perceived child sleep problem across and within levels of community disadvantage in a large US sample.

Methods: Caregivers of 14,980 young children (ages 0-35.

Effect of left atrial ligation-driven altered inflow hemodynamics on embryonic heart development: clues for prenatal progression of hypoplastic left heart syndrome.

Congenital heart defects (CHDs) are abnormalities in the heart structure present at birth. One important condition is hypoplastic left heart syndrome (HLHS) where severely underdeveloped left ventricle (LV) cannot support systemic circulation. HLHS usually initiates as localized tissue malformations with no underlying genetic cause, suggesting that disturbed hemodynamics contribute to the embryonic development of these defects.

Effectiveness of an mHealth Intervention for Infant Sleep Disturbances.

Bedtime problems and night wakings are highly prevalent in infants. This study assessed the real-world effectiveness of an mHealth behavioral sleep intervention (Customized Sleep Profile; CSP). Caregivers (83.

Norm-referenced scoring system for the Brief Infant Sleep Questionnaire - Revised (BISQ-R).

Objectives: To develop an age-based norm-referenced scoring system for the Brief Infant Sleep Questionnaire - Revised (BISQ-R).

Methods: In sum, 33,835 submissions (data sample 1) of the expanded and revised BISQ-R by caregivers of infants and toddlers (1-36 months) were analyzed in the US via a publicly-available smartphone application, Johnson's® Bedtime®. Three subscales were created: Infant Sleep (IS; 5 items), Parent Perception (PP; 3 items), and Parent Behavior (PB; 11 items).

Calpain 9 as a therapeutic target in TGFβ-induced mesenchymal transition and fibrosis.

Fibrosis is a common pathologic outcome of chronic disease resulting in the replacement of normal tissue parenchyma with a collagen-rich extracellular matrix produced by myofibroblasts. Although the progenitor cell types and cellular programs giving rise to myofibroblasts through mesenchymal transition can vary between tissues and diseases, their contribution to fibrosis initiation, maintenance, and progression is thought to be pervasive. Here, we showed that the ability of transforming growth factor-β (TGFβ) to efficiently induce myofibroblast differentiation of cultured epithelial cells, endothelial cells, or quiescent fibroblasts is dependent on the induced expression and activity of dimeric calpains, a family of non-lysosomal cysteine proteases that regulate a variety of cellular events through posttranslational modification of diverse substrates.

ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm.

Bicuspid aortic valve (BAV) is a common congenital heart defect (population incidence, 1-2%) that frequently presents with ascending aortic aneurysm (AscAA). BAV/AscAA shows autosomal dominant inheritance with incomplete penetrance and male predominance. Causative gene mutations (for example, NOTCH1, SMAD6) are known for ≤1% of nonsyndromic BAV cases with and without AscAA, impeding mechanistic insight and development of therapeutic strategies.

Corrigendum: Candidate Gene Resequencing in a Large Bicuspid Aortic Valve-Associated Thoracic Aortic Aneurysm Cohort: as an Important Contributor.

[This corrects the article on p. 400 in vol. 8, PMID: 28659821.

Pathophysiology of aortic aneurysm: insights from human genetics and mouse models.

Aneurysms are local dilations of an artery that predispose the vessel to sudden rupture. They are often asymptomatic and undiagnosed, resulting in a high mortality rate. The predisposition to develop thoracic aortic aneurysms is often genetically inherited and associated with syndromes affecting connective tissue homeostasis.

Cyclic Mechanical Loading Is Essential for Rac1-Mediated Elongation and Remodeling of the Embryonic Mitral Valve.

During valvulogenesis, globular endocardial cushions elongate and remodel into highly organized thin fibrous leaflets. Proper regulation of this dynamic process is essential to maintain unidirectional blood flow as the embryonic heart matures. In this study, we tested how mechanosensitive small GTPases, RhoA and Rac1, coordinate atrioventricular valve (AV) differentiation and morphogenesis.

Method for non-optical quantification of in situ local soft tissue biomechanics.

Soft tissues exhibit significant biomechanical changes as they grow, adapt, and remodel under a variety of normal and pathogenic stimuli. Biomechanical measurement of intact soft tissues is challenging because of its large strain and nonlinear behavior. Tissue distention through applied vacuum pressure is an attractive method for acquiring local biomechanical information minimally invasive and non-destructive, but the current requirement for optical strain measurement limits its use.

Hierarchical approaches for systems modeling in cardiac development.

Ordered cardiac morphogenesis and function are essential for all vertebrate life. The heart begins as a simple contractile tube, but quickly grows and morphs into a multichambered pumping organ complete with valves, while maintaining regulation of blood flow and nutrient distribution. Though not identical, cardiac morphogenesis shares many molecular and morphological processes across vertebrate species.

Multi-scale biomechanical remodeling in aging and genetic mutant murine mitral valve leaflets: insights into Marfan syndrome.

Mitral valve degeneration is a key component of the pathophysiology of Marfan syndrome. The biomechanical consequences of aging and genetic mutation in mitral valves are poorly understood because of limited tools to study this in mouse models. Our aim was to determine the global biomechanical and local cell-matrix deformation relationships in the aging and Marfan related Fbn1 mutated murine mitral valve.

Interactions between TGFβ1 and cyclic strain in modulation of myofibroblastic differentiation of canine mitral valve interstitial cells in 3D culture.

Objectives: The mechanisms of myxomatous valve degeneration (MVD) are poorly understood. Transforming growth factor-beta1 (TGFβ1) induces myofibroblastic activation in mitral valve interstitial cells (MVIC) in static 2D culture, but the roles of more physiological 3D matrix and cyclic mechanical strain are unclear. In this paper, we test the hypothesis that cyclic strain and TGFβ1 interact to modify MVIC phenotype in 3D culture.

Cyclic strain anisotropy regulates valvular interstitial cell phenotype and tissue remodeling in three-dimensional culture.

Many planar connective tissues exhibit complex anisotropic matrix fiber arrangements that are critical to their biomechanical function. This organized structure is created and modified by resident fibroblasts in response to mechanical forces in their environment. The directionality of applied strain fields changes dramatically during development, aging, and disease, but the specific effect of strain direction on matrix remodeling is less clear.

Quantification of embryonic atrioventricular valve biomechanics during morphogenesis.

Tissue assembly in the developing embryo is a rapid and complex process. While much research has focused on genetic regulatory machinery, understanding tissue level changes such as biomechanical remodeling remains a challenging experimental enigma. In the particular case of embryonic atrioventricular valves, micro-scale, amorphous cushions rapidly remodel into fibrous leaflets while simultaneously interacting with a demanding mechanical environment.

Isolation of valvular endothelial cells.

Heart valves are solely responsible for maintaining unidirectional blood flow through the cardiovascular system. These thin, fibrous tissues are subjected to significant mechanical stresses as they open and close several billion times over a lifespan. The incredible endurance of these tissues is due to the resident valvular endothelial (VEC) and interstitial cells (VIC) that constantly repair and remodel in response to local mechanical and biological signals.