Caveolin-1 Modulates Mechanotransduction Responses to Substrate Stiffness through Actin-Dependent Control of YAP

The transcriptional regulator YAP orchestrates many cellular functions, including tissue homeostasis, organ growth control, and tumorigenesis. Mechanical stimuli are a key input to YAP activity, but the mechanisms controlling this regulation remain largely uncharacterized. We show that CAV1 positively modulates the YAP mechanoresponse to substrate stiffness through actin-cytoskeleton-dependent and Hippo-kinase-independent mechanisms. RHO activity is necessary, but not sufficient, for CAV1-dependent mechanoregulation of YAP activity. Systematic quantitative interactomic studies and image-based small interfering RNA (siRNA) screens provide evidence that this actin-dependent regulation is determined by YAP interaction with the 14-3-3 protein YWHAH. Constitutive YAP activation rescued phenotypes associated with CAV1 loss, including defective extracellular matrix (ECM) remodeling. CAV1-mediated control of YAP activity was validated in vivo in a model of pancreatitis-driven acinar-to-ductal metaplasia. We propose that this CAV1-YAP mechanotransduction system controls a significant share of cell programs linked to these two pivotal regulators, with potentially broad physiological and pathological implications. Moreno-Vicente et al. report that CAV1, a key component of PM mechanosensing caveolae, mediates adaptation to ECM rigidity by modulating YAP activity through the control of actin dynamics and phosphorylation-dependent interaction of YAP with the 14-3-3-domain protein YWHAH. Cav1-dependent YAP regulation drives two pathophysiological processes: ECM remodeling and pancreatic ADM. © 2018 The Author

Optimal streaks in a Falkner-Skan boundary layer

This paper deals with the optimal streaky perturbations (which maximize the perturbed energy growth) in a wedge flow boundary layer. These three dimensional perturbations are governed by a system of linearized boundary layer equations around the Falkner-Skan base flow. Based on an asymptotic analysis of this system near the free stream and the leading edge singularity, we show that for acute wedge semi-angle, all solutions converge after a streamwise transient to a single streamwise-growing solution of the linearized equations, whose initial condition near the leading edge is given by an eigenvalue problem first formulated in this context by Tumin (2001). Such a solution may be regarded as a streamwise evolving most unstable streaky mode, in analogy with the usual eigenmodes in strictly parallel flows, and shows an approximate self-similarity, which was partially known and is completed in this paper. An important consequence of this result is that the optimization procedure based on the adjoint equations heretofore used to define optimal streaks is not necessary. Instead, a simple low-dimensional optimization process is proposed and used to obtain optimal streaks. Comparison with previous results by Tumin and Ashpis (2003) shows an excellent agreement. The unstable streaky mode exhibits transient growth if the wedge semi-angle is smaller than a critical value that is slightly larger than $\pi/6$, and decays otherwise. Thus the cases of right and obtuse wedge semi-angles exhibit less practical interest, but they show a qualitatively different behavior, which is briefly described to complete the analysis

Synthesis, structure and reactivity of Pd and Ir complexes based on new lutidine-derived NHC/phosphine mixed pincer ligands

Coordination studies of new lutidine-derived hybrid NHC/phosphine ligands (CNP) to Pd and Ir have been performed. Treatment of the square-planar [Pd(CNP)Cl](AgCl2) complex 2a with KHMDS produces the selective deprotonation at the CH2P arm of the pincer to yield the pyridine-dearomatised complex 3a. A series of cationic [Ir(CNP)(cod)]+ complexes 4 has been prepared by reaction of the imidazolium salts 1 with Ir(acac)(cod). These derivatives exhibit in the solid state, and in solution, a distorted trigonal bipyramidal structure in which the CNP ligands adopt an unusual C(axial)–N(equatorial)–P(equatorial) coordination mode. Reactions of complexes 4 with CO and H2 yield the carbonyl species 5a(Cl) and 6a(Cl), and the dihydrido derivatives 7, respectively. Furthermore, upon reaction of complex 4b(Br) with base, selective deprotonation at the methylene CH2P arms is observed. The, thus formed, deprotonated Ir complex 8b reacts with H2 in a ligand-assisted process leading to the trihydrido complex 9b, which can also be obtained by reaction of 7b(Cl) with H2 in the presence of KOtBu. Finally, the catalytic activity of Ir–CNP complexes in the hydrogenation of ketones has been briefly assessed.CTQ2013-45011-P, CTQ2016-80814-R and CTQ2014 -51912-RE

Basement membrane-rich Organoids with functional human blood vessels are permissive niches for human breast cancer metastasis

Metastasic breast cancer is the leading cause of death by malignancy in women worldwide. Tumor metastasis is a multistep process encompassing local invasion of cancer cells at primary tumor site, intravasation into the blood vessel, survival in systemic circulation, and extravasation across the endothelium to metastasize at a secondary site. However, only a small percentage of circulating cancer cells initiate metastatic colonies. This fact, together with the inaccessibility and structural complexity of target tissues has hampered the study of the later steps in cancer metastasis. In addition, most data are derived from in vivo models where critical steps such as intravasation/extravasation of human cancer cells are mediated by murine endothelial cells. Here, we developed a new mouse model to study the molecular and cellular mechanisms underlying late steps of the metastatic cascade. We have shown that a network of functional human blood vessels can be formed by co-implantation of human endothelial cells and mesenchymal cells, embedded within a reconstituted basement membrane-like matrix and inoculated subcutaneously into immunodeficient mice. The ability of circulating cancer cells to colonize these human vascularized organoids was next assessed in an orthotopic model of human breast cancer by bioluminescent imaging, molecular techniques and immunohistological analysis. We demonstrate that disseminated human breast cancer cells efficiently colonize organoids containing a functional microvessel network composed of human endothelial cells, connected to the mouse circulatory system. Human breast cancer cells could be clearly detected at different stages of the metastatic process: initial arrest in the human microvasculature, extravasation, and growth into avascular micrometastases. This new mouse model may help us to map the extravasation process with unprecedented detail, opening the way for the identification of relevant targets for therapeutic intervention

Implementation of an autonomy support program during Physical Education lessons

El objetivo de este estudio es conocer los efectos de un programa basado en el soporte de autonomía a través de las clases de Educación Física sobre las necesidades psicológicas básicas, la regulación conductual y la percepción del estilo interpersonal del docente. Los participantes del estudio fueron 61 alumnos (25 chicos y 36 chicas) con edades comprendidas entre los 14 y los 17 años de edad (M = 14.97; DT = .85), pertenecientes a dos Centros Educativos españoles. Los estudiantes fueron divididos aleatoriamente en dos grupos (control y experimental). Los instrumentos utilizados fueron la Escala de Satisfacción de Necesidades Psicológicas Básicas, el Cuestionario de la Regulación Conductual en el Deporte y el Cuestionario de Estilo interpersonal del docente. Los profesores aplicaron en el grupo experimental el programa basado en el soporte de autonomía durante las clases de Educación Física en un total de ocho semanas. Los resultados indicaron diferencias estadísticamente significativas respecto a la relación con los demás (p<.01) y a la percepción del estilo autónomo del docente (p<.05), no encontrándose diferencias significativas respecto al resto de variables. Como conclusión principal indicar que un programa basado en el fomento de la autonomía, puede ser óptimo para el incremento de las relaciones entre los alumnos

On balancedness and D-Completeness of the space of Semi-lipschitz functions

Let (X, d) be a quasi-metric space and (Y, q) be a quasi-normed linear space. We show that the normed cone of semi-Lipschitz functions from (X, d) to (Y, q) that vanish at a point x0 E X, is balanced. Moreover, it is complete in the sense of D. Doitchinov whenever (Y, q) is a biBanach spac