Fzd7 (Frizzled-7) Expressed by Endothelial Cells Controls Blood Vessel Formation Through Wnt/β-Catenin Canonical Signaling.

Abstract OBJECTIVE: Vessel formation requires precise orchestration of a series of morphometric and molecular events controlled by a multitude of angiogenic factors and morphogens. Wnt/frizzled signaling is required for proper vascular formation. In this study, we investigated the role of the Fzd7 (frizzled-7) receptor in retinal vascular development and its relationship with the Wnt/β-catenin canonical pathway and Notch signaling. APPROACH AND RESULTS: Using transgenic mice, we demonstrated that Fzd7 is required for postnatal vascular formation. Endothelial cell (EC) deletion of fzd7 (fzd7ECKO) delayed retinal plexus formation because of an impairment in tip cell phenotype and a decrease in stalk cell proliferation. Dvl (dishevelled) proteins are a main component of Wnt signaling and play a functionally redundant role. We found that Dvl3 depletion in dvl1-/- mice mimicked the fzd7ECKO vascular phenotype and demonstrated that Fzd7 acted via β-catenin activation by showing that LiCl treatment rescued impairment in tip and stalk cell phenotypes induced in fzd7 mutants. Deletion of fzd7 or Dvl1/3 induced a strong decrease in Wnt canonical genes and Notch partners' expression. Genetic and pharmacological rescue strategies demonstrated that Fzd7 acted via β-catenin activation, upstream of Notch signaling to control Dll4 and Jagged1 EC expression. CONCLUSIONS: Fzd7 expressed by EC drives postnatal angiogenesis via activation of Dvl/β-catenin signaling and can control the integrative interaction of Wnt and Notch signaling during postnatal angiogenesis

Experimental and numerical activities in support of the design of astrid sodium-gas heat exchanger

International audienceIn the framework of the development of the ASTRID Sodium-cooled Fast Reactor prototype, the CEA is studying the technical feasibility of adopting a Brayton power conversion cycle to eliminate the sodium-water interaction hazard. The sodium-gas (i.e. nitrogen) heat exchanger is the critical component to be designed, especially considering the fact that such a component has never been designed before for an operating nuclear power plant. Compact heat exchanger technologies are crucial to have reasonable dimensions of this component. The CEA is working on several design possibilities, especially in terms of heat transfer pattern and inlet/outlet header geometry, to find the optimal configuration. This paper aims to describe the experimental and numerical activities related to these topics. In particular, for the heat transfer patterns, traditional Printed Circuit Heat Exchangers (PCHE) as well as an innovative PCHE geometry are studied Laser Doppler and Particle Image Velocimetry facilities are described, together with a Validation of Heat Exchange in GAS (VHEGAS) facility, exploited to acquire a wide database to be used to validate the numerical model. The CFD model validation is detailed and a first set of heat transfer and pressure drop correlations is obtained. The comparison between traditional and innovative PCHE geometries is then shown, to demonstrate that the innovative PCHE is potentially more compact than traditional PCHEs. Regarding the inlet/outlet headers, the adopted calculation methodology is described. First characterizing maldistribution in large channel bundle and secondly adopting a porous media approach to be able to correctly represent the physical phenomena in a reasonably large computational domain

Status of the Sodium Gas Heat Exchanger (SGHE) development for the Nitrogen Power Conversion System planned for the ASTRID SFR prototype

International audienceIn the framework of the CEA RandD program developing the Advanced Sodium Technological Reactor for Industrial Demonstration (ASTRID), the present work describes the current status of an innovative compact heat exchanger and highlights the industrial challenges this technology raises. One of the main innovative options under investigation for ASTRID is the use of a Brayton cycle gas-power conversion system. This system permits to avoid the energetic sodium-water interaction, which can occur in steam generators in case of tube failure if a traditional Rankine cycle is used. In this novel concept, steam generators would be replaced by the Sodium Gas Heat Exchanger (SGHE). The first part of this paper presents the details of the original design of this heat exchanger which allows a high thermal compactness. The main studies supporting this development are described in the second part of the paper. The thermal hydraulic program demonstrates the potential of the technology used. An innovative geometry is also studied on the gas side improving the thermal compactness. Thermomechanical analyses show the good behavior of this exchanger under the ASTRID operating conditions. The manufacturing / welding process optimization is ongoing in order to produce a component with nuclear specifications. Specific sensors and control techniques are also being developed in order to assess the manufacturing process quality and to allow future in-service inspections. At last, the qualification program is presented and the first results obtained on an operating small scale SGHE mock up working under ASTRID conditions are described

Conceptual Designs Of Complementary Safety Devices For Astrid: From Selection Method To Selected Options

International audience– To comply with the GEN IV objectives set for it, the 600 MWe Advanced Sodium Technological Reactor for Industrial Demonstration (ASTRID) promises enhanced safety. The ability to shut the reactor down in any condition is one of the most important safety aspects. At the end of ASTRID preconceptual design phase (end of 2012), the need for additional safety devices that would complement ASTRID low void fraction (CFV) design core natural behavior in case of unprotected loss of flow (ULOF) and loss of heat sink (ULOHS) transients emerged from the transient studies in order to meet temperature criteria on coolant, core and primary circuit structures. The process from the selection method, on the basis of ASTRID functional specifications and safety requirements, to the selected options/designs, on the basis of itemization of these specifications/requirements and value engineering, of ASTRID Complementary Safety Devices (DCS) is presented. In this paper, only DCS dedicated to core melting Prevention (DCS-P) that would passively shutdown the reactor, i.e. whose actuation would be triggered by the sole physical effects induced by the transient, are dealt with regardless of whether they would depend on ASTRID first two distinct and independent fast-acting reactor shutdown systems (RBC and RBD) or not. Several concepts of such DCS-P were considered among which SEPIA (abbreviation for SEntinal for Passive Insertion of Antireactivity) concept of absorber subassembly specifically designed by CEA, (DCS-P)-H concept of hydraulically suspended absorber rod subassembly and (DCS-P)-RBD_Curie concept based on the exploitation of the Curie point of the RBD electromagnetic delatch system; they are listed and discussed with regard to whether and how they could effectively match each type of ULOF and ULOHS transient (some concepts that were abandoned are discussed as well). Concepts which are the most promising in ASTRID framework, resulting from the best way their combination could deal with all considered transients, are finally described; these will be further investigated and developed in the near future

Trait-related decision-making impairment in the three phases of bipolar disorder.

BACKGROUND: In bipolar disorder (BD), little is known about how deficits in neurocognitive functions such as decision-making are related to phase of illness. We predicted that manic, depressed, and euthymic bipolar patients (BPs) would display impaired decision-making, and we tested whether clinical characteristics could predict patients' decision-making performance. METHODS: Subjects (N = 317; age range: 18-65 years) including 167 BPs (45 manic and 32 depressed inpatients, and 90 euthymic outpatients) and 150 age-, IQ-, and gender-matched healthy control (HC) participants, were included within three university psychiatric hospitals using a cross-sectional design. The relationship between predictor variables and decision-making was assessed by one-step multivariate analysis. The main outcome measures were overall decision-making ability on the Iowa Gambling Task (IGT) and an index of sensitivity to punishment frequency. RESULTS: Manic, depressed, and euthymic BPs selected significantly more cards from the risky decks than HCs (p < .001, p < .01, and p < .05, respectively), with no significant differences between the three BD groups. However, like HCs, BPs preferred decks that yielded infrequent penalties over those yielding frequent penalties. In multivariate analysis, decision-making impairment was significantly (p < .001) predicted by low level of education, high depressive scores, family history of BD, use of benzodiazepines, and nonuse of serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressants. CONCLUSIONS: BPs have a trait-related impairment in decision-making that does not vary across illness phase. However, some subtle differences between the BD groups in the individual deck analyses may point to subtle state influences on reinforcement mechanisms, in addition to a more fundamental trait impairment in risk-sensitive decision making

Trait-related decision-making impairment in the three phases of bipolar disorder

Background: In bipolar disorder (BD), little is known about how deficits in neurocognitive functions such as decision-making are related to phase of illness. We predicted that manic, depressed, and euthymic bipolar patients (BPs) would display impaired decision-making, and we tested whether clinical characteristics could predict patients' decision-making performance. Methods: Subjects (N = 317; age range: 1865 years) including 167 BPs (45 manic and 32 depressed inpatients, and 90 euthymic outpatients) and 150 age-, IQ-, and gender-matched healthy control (HC) participants, were included within three university psychiatric hospitals using a cross-sectional design. The relationship between predictor variables and decision-making was assessed by one-step multivariate analysis. The main outcome measures were overall decision-making ability on the Iowa Gambling Task (IGT) and an index of sensitivity to punishment frequency. Results: Manic, depressed, and euthymic BPs selected significantly more cards from the risky decks than HCs (p <.001, p <.01, and p <.05, respectively), with no significant differences between the three BD groups. However, like HCs, BPs preferred decks that yielded infrequent penalties over those yielding frequent penalties. In multivariate analysis, decision-making impairment was significantly (p <.001) predicted by low level of education, high depressive scores, family history of BD, use of benzodiazepines, and nonuse of serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressants. Conclusions: BPs have a trait-related impairment in decision-making that does not vary across illness phase. However, some subtle differences between the BD groups in the individual deck analyses may point to subtle state influences on reinforcement mechanisms, in addition to a more fundamental trait impairment in risk-sensitive decision making. © 2011 Society of Biological Psychiatry

Sci signal

Endothelial cells serve as a barrier between blood and tissues. Maintenance of the endothelial cell barrier depends on the integrity of intercellular junctions, which is regulated by a polarity complex that includes the ζ isoform of atypical protein kinase C (PKCζ) and partitioning defective 3 (PAR3). We revealed that the E3 ubiquitin ligase PDZ domain-containing ring finger 3 (PDZRN3) regulated endothelial intercellular junction integrity. Endothelial cell-specific overexpression of Pdzrn3 led to early embryonic lethality with severe hemorrhaging and altered organization of endothelial intercellular junctions. Conversely, endothelial-specific loss of Pdzrn3 prevented vascular leakage in a mouse model of transient ischemic stroke, an effect that was mimicked by pharmacological inhibition of PKCζ. PDZRN3 regulated Wnt signaling and associated with a complex containing PAR3, PKCζ, and the multi-PDZ domain protein MUPP1 (Discs Lost-multi-PDZ domain protein 1) and targeted MUPP1 for proteasomal degradation in transfected cells. Transient ischemic stroke increased the ubiquitination of MUPP1, and deficiency of MUPP1 in endothelial cells was associated with decreased localization of PKCζ and PAR3 at intercellular junctions. In endothelial cells, Pdzrn3 overexpression increased permeability through a PKCζ-dependent pathway. In contrast, Pdzrn3 depletion enhanced PKCζ accumulation at cell-cell contacts and reinforced the cortical actin cytoskeleton under stress conditions. These findings reveal how PDZRN3 regulates vascular permeability through a PKCζ-containing complex

Therapies targeting Frizzled‐7/β‐catenin pathway prevent the development of pathological angiogenesis in an ischemic retinopathy model

Retinopathies remain major causes of visual impairment in diabetic patients and premature infants. Introduction of anti‐angiogenic drugs targeting vascular endothelial growth factor (VEGF) has transformed therapy for these proliferative retinopathies. However, limitations associated with anti‐VEGF medications require to unravel new pathways of vessel growth to identify potential drug targets. Here, we investigated the role of Wnt/Frizzled‐7 (Fzd7) pathway in a mouse model of oxygen‐induced retinopathy (OIR). Using transgenic mice, which enabled endothelium‐specific and time‐specific Fzd7 deletion, we demonstrated that Fzd7 controls both vaso‐obliteration and neovascular phases (NV). Deletion of Fzd7 at P12, after the ischemic phase of OIR, prevented formation of aberrant neovessels into the vitreous by suppressing proliferation of endothelial cells (EC) in tufts. Next we validated in vitro two Frd7 blocking strategies: a monoclonal antibody (mAbFzd7) against Fzd7 and a soluble Fzd7 receptor (CRD). In vivo a single intravitreal microinjection of mAbFzd7 or CRD significantly attenuated retinal neovascularization (NV) in mice with OIR. Molecular analysis revealed that Fzd7 may act through the activation of Wnt/β‐catenin and Jagged1 expression to control EC proliferation in extra‐retinal neovessels. We identified Fzd7/β‐catenin signaling as new regulator of pathological retinal NV. Fzd7 appears to be a potent pharmacological target to prevent or treat aberrant angiogenesis of ischemic retinopathies