Zebrafish mutants in vegfab can affect endothelial cell proliferation without altering ERK phosphorylation and are phenocopied by loss of PI3K signaling.

The formation of appropriately patterned blood vessel networks requires endothelial cell migration and proliferation. Signaling through the Vascular Endothelial Growth Factor A (VEGFA) pathway is instrumental in coordinating these processes. mRNA splicing generates short (diffusible) and long (extracellular matrix bound) Vegfa isoforms. The differences between these isoforms in controlling cellular functions are not understood. In zebrafish, vegfaa generates short and long isoforms, while vegfab only generates long isoforms. We found that mutations in vegfaa had an impact on endothelial cell (EC) migration and proliferation. Surprisingly, mutations in vegfab more strongly affected EC proliferation in distinct blood vessels, such as intersegmental blood vessels in the zebrafish trunk and central arteries in the head. Analysis of downstream signaling pathways revealed no change in MAPK (ERK) activation, while inhibiting PI3 kinase signaling phenocopied vegfab mutant phenotypes in affected blood vessels. Together, these results suggest that extracellular matrix bound Vegfa might act through PI3K signaling to control EC proliferation in a distinct set of blood vessels during angiogenesis.We would like to thank Reinhild Bussmann, Mona Finch Stephen, Nadine Greer and Bill Vought for excellent fish care. In addition, we would like to thank Roman Tsaryk and Zeenat Diwan for critically reading of the manuscript and Caitlyn Parker for excellent technical assistance. We are grateful to Federica Lunella for help with the mouse retina dissection and immunohistochemistry. We would like to thank William Jones and Mary Mullins for providing the pCS2þ β-galactosidase plasmid. This work was funded by the Max-Planck-Society (A.F.S.), the Deutsche Forschungsgemeinschaft (DFG SI-1374/4-1, DFG SI-1374/5-1 and DFG SI-1374/6-1; A.F.S.) and start-up funds from the Cardiovascular Institute and the Department of Cell and Developmental Biology of the University of Pennsylvania Perelman School of Medicine (A.F.S.). We further acknowledge support from the NIH R01HL152086 (A.F.S.). Work in R.B.’s lab was funded by the Ministerio de Economía, Industría y Competitividad (MEIC: SAF2017-89299-P and RYC-2013-13209) and the European Research Council (ERC-2014-StG – 638028 AngioGenesHD).S

Advantages and Challenges of Cardiovascular and Lymphatic Studies in Zebrafish Research

Since its introduction, the zebrafish has provided an important reference system to model and study cardiovascular development as well as lymphangiogenesis in vertebrates. A scientific workshop, held at the 2018 European Zebrafish Principal Investigators Meeting in Trento (Italy) and chaired by Massimo Santoro, focused on the most recent methods and studies on cardiac, vascular and lymphatic development. Daniela Panáková and Natascia Tiso described new molecular mechanisms and signaling pathways involved in cardiac differentiation and disease. Arndt Siekmann and Wiebke Herzog discussed novel roles for Wnt and VEGF signaling in brain angiogenesis. In addition, Brant Weinstein’s lab presented data concerning the discovery of endothelium-derived macrophage-like perivascular cells in the zebrafish brain, while Monica Beltrame’s studies refined the role of Sox transcription factors in vascular and lymphatic development. In this article, we will summarize the details of these recent discoveries in support of the overall value of the zebrafish model system not only to study normal development, but also associated disease states

Toward a better understanding of tool wear effect through a comparison between experiments and SPH numerical modelling of machining hard materials

The aim of this study is to improve the general understanding of tungsten carbide (WC–Co) tool wear under dry machining of the hard-to-cut titanium alloy Ti6Al4V. The chosen approach includes experimental and numerical tests. The experimental part is designed to identify wear mechanisms using cutting force measurements, scanning electron microscope observations and optical profilometer analysis. Machining tests were conducted in the orthogonal cutting framework and showed a strong evolution of the cutting forces and the chip profiles with tool wear. Then, a numerical method has been used in order to model the machining process with both new and worn tools. The use of smoothed particle hydrodynamics model (SPH model) as a numerical tool for a better understanding of the chip formation with worn tools is a key aspect of this work. The redicted chip morphology and the cutting force evolution with respect to the tool wear are qualitatively compared with experimental trends. The chip formation mechanisms during dry cutting process are shown to be quite dependent from the worn tool geometry. These mechanisms explain the high variation of the experimental and numerical feed force between new and worn tools

Chemokine Signaling Directs Trunk Lymphatic Network Formation along the Preexisting Blood Vasculature

SummaryThe lymphatic system is crucial for fluid homeostasis, immune responses, and numerous pathological processes. However, the molecular mechanisms responsible for establishing the anatomical form of the lymphatic vascular network remain largely unknown. Here, we show that chemokine signaling provides critical guidance cues directing early trunk lymphatic network assembly and patterning. The chemokine receptors Cxcr4a and Cxcr4b are expressed in lymphatic endothelium, whereas chemokine ligands Cxcl12a and Cxcl12b are expressed in adjacent tissues along which the developing lymphatics align. Loss- and gain-of-function studies in zebrafish demonstrate that chemokine signaling orchestrates the stepwise assembly of the trunk lymphatic network. In addition to providing evidence for a lymphatic vascular guidance mechanism, these results also suggest a molecular basis for the anatomical coalignment of lymphatic and blood vessels

Secondary organic aerosol formation from isoprene photooxidation during cloud condensation-evaporation cycles

Abstract. The impact of cloud events on isoprene secondary organic aerosol (SOA) formation has been studied from an isoprene ∕ NOx ∕ light system in an atmospheric simulation chamber. It was shown that the presence of a liquid water cloud leads to a faster and higher SOA formation than under dry conditions. When a cloud is generated early in the photooxidation reaction, before any SOA formation has occurred, a fast SOA formation is observed with mass yields ranging from 0.002 to 0.004. These yields are 2 and 4 times higher than those observed under dry conditions. When the cloud is generated at a later photooxidation stage, after isoprene SOA is stabilized at its maximum mass concentration, a rapid increase (by a factor of 2 or higher) of the SOA mass concentration is observed. The SOA chemical composition is influenced by cloud generation: the additional SOA formed during cloud events is composed of both organics and nitrate containing species. This SOA formation can be linked to the dissolution of water soluble volatile organic compounds (VOCs) in the aqueous phase and to further aqueous phase reactions. Cloud-induced SOA formation is experimentally demonstrated in this study, thus highlighting the importance of aqueous multiphase systems in atmospheric SOA formation estimations. The authors thank Arnaud Allanic, Sylvain Ravier, Pascal Renard and Pascal Zapf for their contributions in the experiments. The authors also acknowledge the institutions that have provided financial support: the French National Institute for Geophysical Research (CNRS-INSU) within the LEFE-CHAT program through the project “Impact de la chimie des nuages sur la formation d’aérosols organiques secondaires dans l’atmosphère” and the French National Agency for Research (ANR) project CUMULUS ANR-2010-BLAN-617-01. This work was also supported by the EC within the I3 project “Integrating of European Simulation Chambers for Investigating Atmospheric Processes” (EUROCHAMP-2, contract no. 228335). The authors thank the MASSALYA instrumental platform (Aix Marseille Université, lce.univ-amu.fr) for the analysis and measurements used in this paper.This is the final version of the article. It first appeared from Copernicus Publications via http://dx.doi.org/10.5194/acp-16-1747-201

MicroRNA 139-5p coordinates APLNR-CXCR4 crosstalk during vascular maturation

G protein-coupled receptor (GPCR) signalling, including that involving apelin (APLN) and its receptor APLNR, is known to be important in vascular development. How this ligand–receptor pair regulates the downstream signalling cascades in this context remains poorly understood. Here, we show that mice with Apln, Aplnr or endothelial-specific Aplnr deletion develop profound retinal vascular defects, which are at least in part due to dysregulated increase in endothelial CXCR4 expression. Endothelial CXCR4 is negatively regulated by miR-139-5p, whose transcription is in turn induced by laminar flow and APLN/APLNR signalling. Inhibition of miR-139-5p in vivo partially phenocopies the retinal vascular defects of APLN/APLNR deficiency. Pharmacological inhibition of CXCR4 signalling or augmentation of the miR-139-5p-CXCR4 axis can ameliorate the vascular phenotype of APLN/APLNR deficient state. Overall, we identify an important microRNA-mediated GPCR crosstalk, which plays a key role in vascular development

Acute Leriche syndrome due to the thrombus in the left ventricle.

Abstract. In this contribution we present a variant of a resolution theorem prover which selects resolution steps based on the proportion of models a newly generated clause satisfies compared to all models given in a reference class. This reference class is generated from a subset of the initial clause set. Since the empty clause does not satisfy any models, preference is given to such clauses which satisfy few models only. Because computing the number of models is computationally expensive on the one hand, but will remain almost unchanged after the application of one single resolution step on the other hand, we adapt Kowalski’s connection graph method to store the number of models at each link.