Bcar1/p130Cas is essential for ventricular development and neural crest cell remodelling of the cardiac outflow tract.

AIM: The adapter protein p130Cas, encoded by the Bcar1 gene, is a key regulator of cell movement, adhesion, and cell cycle control in diverse cell types. Bcar1 constitutive knockout mice are embryonic lethal by embryonic days (E) 11.5-12.5, but the role of Bcar1 in embryonic development remains unclear. Here, we investigated the role of Bcar1 specifically in cardiovascular development and defined the cellular and molecular mechanisms disrupted following targeted Bcar1 deletions. METHODS AND RESULTS: We crossed Bcar1 floxed mice with Cre transgenic lines allowing for cell-specific knockout either in smooth muscle and early cardiac tissues (SM22-Cre), mature smooth muscle cells (smMHC-Cre), endothelial cells (Tie2-Cre), second heart field cells (Mef2c-Cre), or neural crest cells (NCC) (Pax3-Cre) and characterised these conditional knock outs using a combination of histological and molecular biology techniques.Conditional knockout of Bcar1 in SM22-expressing smooth muscle cells and cardiac tissues (Bcar1SM22KO) was embryonically lethal from E14.5-15.5 due to severe cardiovascular defects, including abnormal ventricular development and failure of outflow tract (OFT) septation leading to a single outflow vessel reminiscent of persistent truncus arteriosus. SM22-restricted loss of Bcar1 was associated with failure of OFT cushion cells to undergo differentiation to septal mesenchymal cells positive for SMC-specific α-actin, and disrupted expression of proteins and transcription factors involved in epithelial-to-mesenchymal transformation (EMT). Furthermore, knockout of Bcar1 specifically in NCC (Bcar1PAX3KO) recapitulated part of the OFT septation and aortic sac defects seen in the Bcar1SM22KO mutants, indicating a cell-specific requirement for Bcar1 in NCC essential for OFT septation. In contrast, conditional knockouts of Bcar1 in differentiated smooth muscle, endothelial cells, and second heart field cells survived to term and were phenotypically normal at birth and post-natally. CONCLUSIONS: Our work reveals a cell-specific requirement for Bcar1 in NCC, early myogenic and cardiac cells, essential for OFT septation, myocardialisation and EMT/cell cycle regulation and differentiation to myogenic lineages. TRANSLATIONAL PERSPECTIVE: The molecular pathways coordinating cardiogenesis and the remodelling of the OFT are complex, and dysregulation of these pathways causes human heart defects. Our findings highlight a specific requirement for Bcar1 essential for cardiogenesis. Furthermore, the failure of OFT septation in Bcar1SM22KO mice resembles persistent truncus arteriosus (PTA), a feature of several human congenital heart diseases, including DiGeorge Syndrome. Our findings have implications for the mechanisms underlying the pathogenesis of congenital heart disease, and suggest that mice with conditional Bcar1 deletions may be useful models for dissecting mechanisms involved in the pathogenesis of human heart defects

Arase Observation of the Source Region of Auroral Arcs and Diffuse Auroras in the Inner Magnetosphere

Auroral arcs and diffuse auroras are common phenomena at high latitudes, though characteristics of their source plasma and fields have not been well understood. We report the first observation of fields and particles including their pitch‐angle distributions in the source region of auroral arcs and diffuse auroras, using data from the Arase satellite at L ~ 6.0–6.5. The auroral arcs appeared and expanded both poleward and equatorward at local midnight from ~0308 UT on 11 September 2018 at Nain (magnetic latitude: 66°), Canada, during the expansion phase of a substorm, while diffuse auroras covered the whole sky after 0348 UT. The top part of auroral arcs was characterized by purple/blue emissions. Bidirectional field‐aligned electrons with structured energy‐time spectra were observed in the source region of auroral arcs, while source electrons became isotropic and less structured in the diffuse auroral region afterwards. We suggest that structured bidirectional electrons at energies below a few keV were caused by upward field‐aligned potential differences (upward electric field along geomagnetic field) reaching high altitudes (~30,000 km) above Arase. The bidirectional electrons above a few keV were probably caused by Fermi acceleration associated with the observed field dipolarization. Strong electric‐field fluctuations and earthward Poynting flux were observed at the arc crossing and are probably also caused by the field dipolarization. The ions showed time‐pitch‐angle dispersion caused by mirror reflection. These results indicate a clear contrast between auroral arcs and diffuse auroras in terms of source plasma and fields and generation mechanisms of auroral arcs in the inner magnetosphere

Life at high Deborah number

In many biological systems, microorganisms swim through complex polymeric fluids, and usually deform the medium at a rate faster than the inverse fluid relaxation time. We address the basic properties of such life at high Deborah number analytically by considering the small-amplitude swimming of a body in an arbitrary complex fluid. Using asymptotic analysis and differential geometry, we show that for a given swimming gait, the time-averaged leading-order swimming kinematics of the body can be expressed as an integral equation on the solution to a series of simpler Newtonian problems. We then use our results to demonstrate that Purcell's scallop theorem, which states that time-reversible body motion cannot be used for locomotion in a Newtonian fluid, breaks down in polymeric fluid environments

Persistence with Partial Survival

We introduce a parameter $p$, called partial survival, in the persistence of stochastic processes and show that for smooth processes the persistence exponent $\theta(p)$ changes continuously with $p$, $\theta(0)$ being the usual persistence exponent. We compute $\theta(p)$ exactly for a one-dimensional deterministic coarsening model, and approximately for the diffusion equation. Finally we develop an exact, systematic series expansion for $\theta(p)$, in powers of $\epsilon=1-p$, for a general Gaussian process with finite density of zero crossings.Comment: 5 pages, 2 figures, references added, to appear in Phys.Rev.Let

Characterization of the material response in the granular ratcheting

The existence of a very special ratcheting regime has recently been reported in a granular packing subjected to cyclic loading \cite{alonso04}. In this state, the system accumulates a small permanent deformation after each cycle. After a short transient regime, the value of this permanent strain accumulation becomes independent on the number of cycles. We show that a characterization of the material response in this peculiar state is possible in terms of three simple macroscopic variables. They are defined that, they can be easily measured both in the experiments and in the simulations. We have carried out a thorough investigation of the micro- and macro-mechanical factors affecting these variables, by means of Molecular Dynamics simulations of a polydisperse disk packing, as a simple model system for granular material. Biaxial test boundary conditions with a periodically cycling load were implemented. The effect on the plastic response of the confining pressure, the deviatoric stress and the number of cycles has been investigated. The stiffness of the contacts and friction has been shown to play an important role in the overall response of the system. Specially elucidating is the influence of the particular hysteretical behavior in the stress-strain space on the accumulation of permanent strain and the energy dissipation.Comment: 13 pages, 20 figures. Submitted to PR

Analytical results for random walk persistence

In this paper, we present the detailed calculation of the persistence exponent $\theta$ for a nearly-Markovian Gaussian process $X(t)$, a problem initially introduced in [Phys. Rev. Lett. 77, 1420 (1996)], describing the probability that the walker never crosses the origin. New resummed perturbative and non-perturbative expressions for $\theta$ are obtained, which suggest a connection with the result of the alternative independent interval approximation (IIA). The perturbation theory is extended to the calculation of $\theta$ for non-Gaussian processes, by making a strong connection between the problem of persistence and the calculation of the energy eigenfunctions of a quantum mechanical problem. Finally, we give perturbative and non-perturbative expressions for the persistence exponent $\theta(X_0)$, describing the probability that the process remains bigger than $X_0\sqrt{}$.Comment: 23 pages; accepted for publication to Phys. Rev. E (Dec. 98

Generalized persistence exponents: an exactly soluble model

It was recently realized that the persistence exponent appearing in the dynamics of nonequilibrium systems is a special member of a continuously varying family of exponents, describing generalized persistence properties. We propose and solve a simplified model of coarsening, where time intervals between spin flips are independent, and distributed according to a L\'evy law. Both the limit distribution of the mean magnetization and the generalized persistence exponents are obtained exactly.Comment: 4 pages, 3 figures Submitted to PR