Cordon-Bleu Is an Actin Nucleation Factor and Controls Neuronal Morphology

SummaryDespite the wealth of different actin structures formed, only two actin nucleation factors are well established in vertebrates: the Arp2/3 complex and formins. Here, we describe a further nucleator, cordon-bleu (Cobl). Cobl is a brain-enriched protein using three Wiskott-Aldrich syndrome protein homology 2 (WH2) domains for actin binding. Cobl promotes nonbundled, unbranched filaments. Filament formation relies on barbed-end growth and requires all three Cobl WH2 domains and the extended linker L2. We suggest that the nucleation power of Cobl is based on the assembly of three actin monomers in cross-filament orientation. Cobl localizes to sites of high actin dynamics and modulates cell morphology. In neurons, induction of both neurites and neurite branching is dramatically increased by Cobl expression—effects that critically depend on Cobl's actin nucleation ability. Correspondingly, Cobl depletion results in decreased dendritic arborization. Thus, Cobl is an actin nucleator controlling neuronal morphology and development

Recent debris flows in the Portainé catchment (Eastern Pyrenees, Spain): analysis of monitoring and field data focussing on the 2015 event

The final publication is available at Springer via http://dx.doi.org/10.1007/s10346-017-0832-9During the night of the 21 August 2015, a debris flow took place in one of the presently most active ravines of the Pyrenees, the Portainé torrent (Eastern Pyrenees, Spain), and caused considerable damage to the road. Detailed information was gathered from the debris flow monitoring system recently installed in the torrent and field surveys. The monitoring system measures ground vibration at geophones and flow height at an ultrasonic sensor. Meteorological data showed that the debris flow was triggered by a convective rainstorm with a total rainfall amount of 29 mm. All these data provide information on the debris flow occurrence and dynamics. The analysis of the data showed that the debris flow had three different surges and mobilised a total volume of about 2130 m3. The front velocity in the monitoring reach was somewhat small (about 2 m/s) and the peak flow discharge comparatively low (about 13 m3/s). In addition, the debris flow was back-analysed by a numerical model calibrated by the observed event. The results of the simulation showed that a Voellmy fluid rheological model can represent considerably well the recorded and observed measurements, and the best-fit values were µ = 0.28 and C = 8 m0.5/s.Peer ReviewedPostprint (author's final draft

Notorious places: image, reputation, stigma: the role of newspapers in area reputations for social housing estates

This paper reviews work in several disciplines to distinguish between image, reputation and stigma. It also shows that there has been little research on the process by which area reputations are established and sustained through transmission processes. This paper reports on research into the portrayal of two social housing estates in the printed media over an extended period of time (14 years). It was found that negative and mixed coverage of the estates dominated, with the amount of positive coverage being very small. By examining the way in which dominant themes were used by newspapers in respect of each estate, questions are raised about the mode of operation of the press and the communities' collective right to challenge this. By identifying the way regeneration stories are covered and the nature of the content of positive stories, lessons are drawn for programmes of area transformation. The need for social regeneration activities is identified as an important ingredient for changing deprived-area reputations

MPM developments in soil-water-structure interaction implemented in Anura3D

Many geotechnical problems involve large deformations, non-linear material behaviour, soil-structure interactions, and multiphase (solid, liquid, gas) interactions, which poses significant challenges for numerical simulations. The material point method (MPM) showed to be well suited to study slope instabilities, such as landslides, earth embankment and levee failures, underground excavations, explosions, soil-penetration problems, such as pile installation, Cone Penetration Testing, Free Fall Penetrometer testing, etc. Moreover, erosion and sedimentation problems require considering phase transitions (from solid-like to fluid-like), and This contribution will show the latest numerical developments of MPM with respect to the above-mentioned aspects as implemented in the open-source software Anura3D. Particular attention is given to some geotechnical applications, such as the simulation of slope collapse due to earthquake or water pressure changes, erosion problems, porous sea defences, installation problems, and many more

El barranco de Portainé (Pirineo central): un laboratorio in situ completo para el estudio de la actividad torrencial

Entre 2006 y 2015, el barranco de Portainé y su afluente, el barranco de Reguerals (comarca del Pallars Sobirà, Pirineos de Lleida), han presentado una intensa actividad torrencial. Durante este periodo se han producido diez avenidas, nueve de las cuales han provocado daños importantes en la carretera de acceso a las pistas de esquí de Port Ainé e importantes pérdidas económicas asociadas no sólo a la reparación de las infraestructuras, sino también a la interrupción de la actividad turística después de cada episodio y a las inversiones realizadas para proteger la zona, como la instalación de barreras dinámicas para la retención de sedimentos. En este artículo se presenta una síntesis de los trabajos realizados desde dos ópticas diferentes, el de la gestión del territorio, al ser la estación de esquí uno de los motores socioeconómicos de la zona, y el científico, dado su interés para el estudio de la dinámica torrencial.Postprint (published version

An Immune Gene Expression Signature Associated With Development of Human Hepatocellular Carcinoma Identifies Mice That Respond to Chemopreventive Agents

Program (HEPCAR, reference no. 667273-2); US Department of Defense(CA150272P3); an Accelerator Award (CRUCK, AECC, AIRC) (HUNTER,reference no. C9380/A26813), NCI Cancer Center Support Grant, National Cancer Institute; Tisch Cancer Institute (P30-CA196521); Samuel Waxman Cancer Research Foundation; Spanish National Health Institute (SAF2016-76390); and the Generalitat de Catalunya/AGAUR (SGR-1358). Agrin Moeini is supported by Spanish National Health Institute. Sara Torrecilla and Judit Peix are funded by Centro de Investigación Biomedica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd-ISCIII). Carla Montironi is a recipient of Josep Font grant. Carmen Andreu-Oller is supported by "la Caixa" INPhINIT Fellowship Grant (LCF/BQ/IN17/11620024). Roser Pinyol is supported by HEPCAR and AECC. Daniela Sia is supported by the Gilead Sciences Research Scholar Program in Liver Disease. Scott L. Friedman is supported by the National Institutes of Health Research project grant (R01,DK5662) and US Department of Defense (CA150272P3). Mathias Heikenwälder was supported by an ERC Consolidator grant (HepatoMetaboPath), the SFBTR 209, 1335 and SFBTR179.Background & Aims: Cirrhosis and chronic inflammation precede development of hepatocellular carcinoma (HCC) in approximately 80% of cases. We investigated immune-related gene expression patterns in liver tissues surrounding early-stage HCCs and chemopreventive agents that might alter these patterns to prevent liver tumorigenesis. Methods: We analyzed gene expression profiles of nontumor liver tissues from 392 patients with early-stage HCC (training set, N = 167 and validation set, N = 225) and liver tissue from patients with cirrhosis without HCC (N = 216, controls) to identify changes in expression of genes that regulate the immune response that could contribute to hepatocarcinogenesis. We defined 172 genes as markers for this deregulated immune response, which we called the immune-mediated cancer field (ICF). We analyzed the expression data of liver tissues from 216 patients with cirrhosis without HCC and investigated the association between this gene expression signature and development of HCC and outcomes of patients (median follow-up, 10 years). Human liver tissues were also analyzed by histology. C57BL/6J mice were given a single injection of diethylnitrosamine (DEN) followed by weekly doses of carbon tetrachloride to induce liver fibrosis and tumorigenesis. Mice were then orally given the multiple tyrosine inhibitor nintedanib or vehicle (controls); liver tissues were collected and histology, transcriptome, and protein analyses were performed. We also analyzed transcriptomes of liver tissues collected from mice on a choline-deficient high-fat diet, which developed chronic liver inflammation and tumors, orally given aspirin and clopidogrel or the anti-inflammatory agent sulindac vs mice on a chow (control) diet. Results: We found the ICF gene expression pattern in 50% of liver tissues from patients with cirrhosis without HCC and in 60% of nontumor liver tissues from patients with early-stage HCC. The liver tissues with the ICF gene expression pattern had 3 different features: increased numbers of effector T cells; increased expression of genes that suppress the immune response and activation of transforming growth factor β signaling; or expression of genes that promote inflammation and activation of interferon gamma signaling. Patients with cirrhosis and liver tissues with the immunosuppressive profile (10% of cases) had a higher risk of HCC (hazard ratio, 2.41; 95% confidence interval, 1.21-4.80). Mice with chemically induced fibrosis or diet-induced steatohepatitis given nintedanib or aspirin and clopidogrel down-regulated the ICF gene expression pattern in liver and developed fewer and smaller tumors than mice given vehicle. Conclusions: We identified an immune-related gene expression pattern in liver tissues of patients with early-stage HCC, called the ICF, that is associated with risk of HCC development in patients with cirrhosis. Administration of nintedanib or aspirin and clopidogrel to mice with chronic liver inflammation caused loss of this gene expression pattern and development of fewer and smaller liver tumors. Agents that alter immune regulatory gene expression patterns associated with carcinogenesis might be tested as chemopreventive agents in patients with cirrhosis

Molecular portrait of high alpha-fetoprotein in hepatocellular carcinoma: implications for biomarker-driven clinical trials

The clinical utility of serum alpha-fetoprotein (AFP) in patients with hepatocellular carcinoma (HCC) is widely recognised. However, a clear understanding of the mechanisms of AFP overexpression and the molecular traits of patients with AFP-high tumours are not known. We assessed transcriptome data, whole-exome sequencing data and DNA methylome profiling of 520 HCC patients from two independent cohorts to identify distinct molecular traits of patients with AFP-high tumours (serum concentration?>?400?ng/ml), which represents an accepted prognostic cut-off and a predictor of response to ramucirumab. Those AFP-high tumours (18% of resected cases) were characterised by significantly lower AFP promoter methylation (p?<?0.001), significant enrichment of progenitor-cell features (CK19, EPCAM), higher incidence of BAP1 oncogene mutations (8.5% vs 1.6%) and lower mutational rates of CTNNB1 (14% vs 30%). Specifically, AFP-high tumours displayed significant activation of VEGF signalling (p?<?0.001), which might provide the rationale for the reported benefit of ramucirumab in this subgroup of patients