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Propranolol and atenolol, current therapies for problematic infantile hemangioma (IH), are composed of R(+) and S(-) enantiomers: the R(+) enantiomer is largely devoid of beta blocker activity. We investigated the effect of R(+) enantiomers of propranolol and atenolol on the formation of IH-like blood vessels from hemangioma stem cells (HemSCs) in a murine xenograft model. Both R(+) enantiomers inhibited HemSC vessel formation in vivo. In vitro, similar to R(+) propranolol, both atenolol and its R(+) enantiomer inhibited HemSC to endothelial cell differentiation. As our previous work implicated the transcription factor sex-determining region Y (SRY) box transcription factor 18 (SOX18) in propranolol-mediated inhibition of HemSC to endothelial differentiation, we tested in parallel a known SOX18 small-molecule inhibitor (Sm4) and show that this compound inhibited HemSC vessel formation in vivo with efficacy similar to that seen with the R(+) enantiomers. We next examined how R(+) propranolol alters SOX18 transcriptional activity. Using a suite of biochemical, biophysical, and quantitative molecular imaging assays, we show that R(+) propranolol directly interfered with SOX18 target gene trans-activation, disrupted SOX18-chromatin binding dynamics, and reduced SOX18 dimer formation. We propose that the R(+) enantiomers of widely used beta blockers could be repurposed to increase the efficiency of current IH treatment and lower adverse associated side effects.

Few genetically dominant mutations involved in human disease have been fully explained at the molecular level. In cases where the mutant gene encodes a transcription factor, the dominant-negative mode of action of the mutant protein is particularly poorly understood. Here, we studied the genome-wide mechanism underlying a dominant-negative form of the SOX18 transcription factor (SOX18RaOp) responsible for both the classical mouse mutant Ragged Opossum and the human genetic disorder Hypotrichosis-lymphedema-telangiectasia-renal defect syndrome. Combining three single-molecule imaging assays in living cells together with genomics and proteomics analysis, we found that SOX18RaOp disrupts the system through an accumulation of molecular interferences which impair several functional properties of the wild-type SOX18 protein, including its target gene selection process. The dominant-negative effect is further amplified by poisoning the interactome of its wild-type counterpart, which perturbs regulatory nodes such as SOX7 and MEF2C. Our findings explain in unprecedented detail the multi-layered process that underpins the molecular aetiology of dominant-negative transcription factor function.

Breakthroughs in understanding the structure and dynamics of our planet will strongly depend upon instrumenting deep oceans. Progress has been made these last decades in ocean-bottom seismic observations, but ocean-bottom seismometer (OBS) temporary deployments are still challenging and face set-up limitations. Launched from oceanographic vessels, OBSs fall freely and may slightly drift laterally, dragged by currents. Therefore, their actual orientation and location on the landing sites are hard to assess precisely. Numerous techniques have been developed to retrieve this key information, but most of them are costly, time-consuming or inaccurate. In this work, we show how ship noise can be used as an acoustic source of opportunity to retrieve both the orientation and the location of OBSs on the ocean floor. To retrieve the OBS orientation, we developed a first method based on a combination of seismic and pressure data through the use of the acoustic intensity. This latter can be used to quantify the OBS orientation from the ship noise direction of arrival (DOA), which can then be compared with known ship trajectories obtained from the automatic identification system (AIS). To accurately relocate OBSs, we also developed a second method based on the hydrophone data which computes distances of acoustical sources by measuring time differences of arrival (TDOA) between direct and reverberated phases. The OBS location is then retrieved by fitting measured ship distances with known ship trajectories. In this study, a full network of OBSs deployed in the SW Indian Ocean was reoriented and a test station was relocated. We demonstrate that our new methods may quantify the OBS orientation with an accuracy of about one degree, and its location with an accuracy of a few tens of metres, depending on the number of ships used in the analysis.

Vitis vinifera is affected by many diseases every year, depending on causal agents, susceptibility of cultivars, and climate region. Some are caused by a single agent, such as gray mold caused by Botrytis cinerea or powdery mildew caused by Erysiphe necator. Others result from the actions of a complex of pathogens such as grapevine trunk diseases (GTDs). GTDs are presently among the most devastating diseases in viticulture worldwide because both the economic losses and the long-term sustainability of vineyards are strongly affected. The complexity of GTDs results from the diversity of associated fungi, the undetermined period of latency within the vine (asymptomatic status), the erratic foliar symptom expression from one year to the next, and, probably correlated with all of these points, the lack of efficient strategies to control them. Distinct methods can be beneficial to improve our knowledge of GTDs. In vitro bioassays with cell suspensions, calli, foliar discs, full leaves, or plantlets, and in vivo natural bioassays with cuttings, grafted plants in the greenhouse, or artificially infected ones in the vineyard, can be applied by using progressive integrative levels of in vitro and in vivo, depending on the information searched. In this review, the methods available to understand GTDs are described in terms of experimental procedures, main obtained results, and deliverable prospects. The advantages and disadvantages of each model are also discussed.

Species of Diaporthe are considered important plant pathogens, saprobes, and endophytes on a wide range of plant hosts. Several species are well-known on grapevines, either as agents of pre- or post-harvest infections, including Phomopsis cane and leaf spot, cane bleaching, swelling arm and trunk cankers. In this study we explore the occurrence, diversity and pathogenicity of Diaporthe spp. associated with Vitis vinifera in major grape production areas of Europe and Israel, focusing on nurseries and vineyards. Surveys were conducted in Croatia, Czech Republic, France, Hungary, Israel, Italy, Spain and the UK. A total of 175 Diaporthe strains were isolated from asymptomatic and symptomatic shoots, branches and trunks. A multi-locus phylogeny was established based on five genomic loci (ITS, tef1, cal, his3 and tub2), and the morphological characters of the isolates were determined. Preliminary pathogenicity tests were performed on green grapevine shoots with representative isolates. The most commonly isolated species were D. eres and D. ampelina. Four new Diaporthe species described here as D. bohemiae, D. celeris, D. hispaniae and D. hungariae were found associated with affected vines. Pathogenicity tests revealed D. baccae, D. celeris, D. hispaniae and D. hungariae as pathogens of grapevines. No symptoms were caused by D. bohemiae. This study represents the first report of D. ambigua and D. baccae on grapevines in Europe. The present study improves our understanding of the species associated with several disease symptoms on V. vinifera plants, and provides useful information for effective disease management.

This study aims at characterizing the subseafloor architecture of the Lucky Strike hydrothermal field (LSHF) based on an extensive chemical database of the various vents. Our analysis is motivated by the discovery in 2013 of a new active high‐temperature site, named Capelinhos, approximately 1.5 km east of the LSHF. Capelinhos fluids display particular chemical features with chloride and metals (Fe, Mn) concentrations two times lower and four times higher, respectively, compared to other vent sites. Trace element partitioning over the entire chlorinity range indicates a single deep fluid source feeding all the venting sites. Applying the Si‐Cl geothermobarometer at Capelinhos, we find phase separation conditions at 435–440°C, and 370‐390 bars (2500–2800 m below seafloor (mbsf)) consistent with former estimates for the LSHF, while temperatures of fluid‐rock last equilibrium are estimated at ~400°C for Capelinhos and 350‐375°C for the other sites based on the Fe‐Mn geothermometer. We interpret these discrepancies in thermodynamic conditions beneath the sites in terms of crustal residence time which are likely related to permeability variations across the hydrothermal upflow zone. We propose that conductive cooling of the up flowing fluids from the phase separation zone to the seafloor, beneath the main field vent sites, lowers the T conditions of last fluid‐rock equilibrium, enabling ~65% of Fe mobilized in the reaction zone to be stored. In comparison, Capelinhos fluids are transported more rapidly from the reaction zone to the seafloor along a high‐angle fracture system. The fluids venting at Capelinhos are more representative of the deeper part of the hydrothermal reaction zone.

[EN] Species of Diaporthe are considered important plant pathogens, saprobes, and endophytes on a wide range of plant hosts. Several species are well-known on grapevines, either as agents of pre-or post-harvest infections, including Phomopsis cane and leaf spot, cane bleaching, swelling arm and trunk cankers. In this study we explore the occurrence, diversity and pathogenicity of Diaporthe spp. associated with Vitis vinifera in major grape production areas of Europe and Israel, focusing on nurseries and vineyards. Surveys were conducted in Croatia, Czech Republic, France, Hungary, Israel, Italy, Spain and the UK. A total of 175 Diaporthe strains were isolated from asymptomatic and symptomatic shoots, branches and trunks. A multi-locus phylogeny was established based on five genomic loci (ITS, tef1, cal, his3 and tub2), and the morphological characters of the isolates were determined. Preliminary pathogenicity tests were performed on green grapevine shoots with representative isolates. The most commonly isolated species were D. eres and D. ampelina. Four new Diaporthe species described here as D. bohemiae, D. celeris, D. hispaniae and D. hungariae were found associated with affected vines. Pathogenicity tests revealed D. baccae, D. celeris, D. hispaniae and D. hungariae as pathogens of grapevines. No symptoms were caused by D. bohemiae. This study represents the first report of D. ambigua and D. baccae on grapevines in Europe. The present study improves our understanding of the species associated with several disease symptoms on V. vinifera plants, and provides useful information for effective disease management.

[EN] Since the early 1990s, grapevine trunk diseases (GTDs) have posed threats for viticulture. Esca complex, Eutypa- and Botryosphaeria-diebacks, mostly detected in adult vineyards, are currently responsible for considerable economic losses in the main vine-growing areas of the world. Other GTDs, such as Petri- (Esca complex) and Black-foot diseases, are emerging problems in grapevine nurseries (resulting in grafting failures and/or loss of saleable plants) and in young vineyards. The impacts of GTDs in modern viticulture depend on several factors, some related to their complexity, and others linked to host plant characteristics, changes in vineyard management and to the scarcity of simple tools for their control. For these reasons control of GTDs remains difficult, also depending on knowledge transfer from research to field and vice versa. This paper outlines the main preventive and curative techniques currently applied, scientifically tested or not that have resulted from the outcomes of "Winetwork", a European Union funded project with special emphasis on the promising and innovative approaches.

Species of Diaporthe are considered important plant pathogens, saprobes, and endophytes on a wide range of plant hosts. Several species are well-known on grapevines, either as agents of pre- or post-harvest infections, including Phomopsis cane and leaf spot, cane bleaching, swelling arm and trunk cankers. In this study we explore the occurrence, diversity and pathogenicity of Diaporthe spp. associated with Vitis vinifera in major grape production areas of Europe and Israel, focusing on nurseries and vineyards. Surveys were conducted in Croatia, Czech Republic, France, Hungary, Israel, Italy, Spain and the UK. A total of 175 Diaporthe strains were isolated from asymptomatic and symptomatic shoots, branches and trunks. A multi-locus phylogeny was established based on five genomic loci (ITS, tef1, cal, his3 and tub2), and the morphological characters of the isolates were determined. Preliminary pathogenicity tests were performed on green grapevine shoots with representative isolates. The most commonly isolated species were D. eres and D. ampelina. Four new Diaporthe species described here as D. bohemiae, D. celeris, D. hispaniae and D. hungariae were found associated with affected vines. Pathogenicity tests revealed D. baccae, D. celeris, D. hispaniae and D. hungariae as pathogens of grapevines. No symptoms were caused by D. bohemiae. This study represents the first report of D. ambigua and D. baccae on grapevines in Europe. The present study improves our understanding of the species associated with several disease symptoms on V. vinifera plants, and provides useful information for effective disease management.

© Overman et al. Pharmacological targeting of transcription factors holds great promise for the development of new therapeutics, but strategies based on blockade of DNA binding, nuclear shuttling, or individual protein partner recruitment have yielded limited success to date. Transcription factors typically engage in complex interaction networks, likely masking the effects of specifically inhibiting single protein-protein interactions. Here, we used a combination of genomic, proteomic and biophysical methods to discover a suite of protein-protein interactions involving the SOX18 transcription factor, a known regulator of vascular development and disease. We describe a small-molecule that is able to disrupt a discrete subset of SOX18-dependent interactions. This compound selectively suppressed SOX18 transcriptional outputs in vitro and interfered with vascular development in zebrafish larvae. In a mouse pre-clinical model of breast cancer, treatment with this inhibitor significantly improved survival by reducing tumour vascular density and metastatic spread. Our studies validate an interactome-based molecular strategy to interfere with transcription factor activity, for the development of novel disease therapeutics.

L. WAUTERS (1), F. SMETS (2), E. DE GREEF (3), I. HOFFMAN (4), P. BONTEMS (5), S. VAN BIERVLIET (6), E. VAN DE VIJVER (7), I. PAQUOT (8), P. ALLIET (9), W. ARTS (10), B. HAUSER (11), H. PEETERS (12), M. DE VOS (13), P. BOSSUYT (14), J. RAHIER (15), O. DEWIT (16), O. DEWIT (16), T. MOREELS (16), F. FONTAINE (17), E. LOUIS (17), D. FRANCHIMONT (18), V. MULS (18), J. COCHE (19), F. BAERT (20), S. VERMEIRE (1), G. VEEREMAN (11) / [1] University Hospitals Leuven, Leuven, Belgium, Gastroenterology and Hepatology, [2] Clin universitaires St-Luc, UCL, Brussels, Belgium, Paediatric Gastroenterology, [3] UZ Brussel, Jette, Belgium, Paediatric Gastroenterology, [4] University Hospitals Leuven, Leuven, Belgium, Paediatric Gastroenterology, [5] HUDERF, City of Brussels, Belgium, Paediatric Gastroenterology, [6] UZ Gent, Gent, Belgium, Paediatric Gastroenterology, [7] UZ Antwerpen, Antwerp, Belgium, , Belgium, Pediatric Gastroenterology, [8] CHC Clinique de l'Esperance, Liège, Belgium, Paediatric Gastroenterology, [9] Jessa Hospital, Hasselt, Belgium, Paediatric Gastroenterology, [10] ZOL, Genk, Belgium, Paediatric Gastroenterology, [11] UZ Brussel, Jette, Belgium, Pediatric Gastroenterology, [12] AZ St Lucas, Ghent, Belgium, Gastroenterology, [13] UZ Gent, Gent, Belgium, Gastroenterology, [14] Imelda Hospital, Bonheiden, Belgium, Gastroenterology, [15] UCL, Mont-Godinne, Belgium, Gastroenterology, [16] Clin universitaires St-Luc, UCL, Brussels, Belgium, Gastroenterology, [17] CHU Liege, Liège, Belgium, Gastroenterology, [18] ULB Hôpital Erasme, Brussels, Belgium, Gastroenterology, [19] Clinique St. Pierre, Ottignies, Belgium, Gastroenterology, [20] Heilig Hart Ziekenhuis, Roeselare, Belgium, Gastroenterology Introduction The prolonged use of biologic agents with or without immunomodulators (IM) remains controversial in the management of paediatric Crohn’s disease (CD). Aim The prolonged use of biologic agents with or without immunomodulators (IM) remains controversial in the man

Ocean waves activity is a major source of microvibrations that travel through the solid Earth, known as microseismic noise and recorded worldwide by broadband seismometers. Analysis of microseismic noise in continuous seismic records can be used to investigate noise sources in the oceans such as storms, and their variations in space and time, making possible the regional and global-scale monitoring of the wave climate. In order to complete the knowledge of the Atlantic and Pacific oceans microseismic noise sources, we analyse 1 yr of continuous data recorded by permanent seismic stations located in the Indian Ocean basin. We primarily focus on secondary microseisms (SM) that are dominated by Rayleigh waves between 6 and 11 s of period. Continuous polarization analyses in this frequency band at 15 individual seismic stations allow us to quantify the number of polarized signal corresponding to Rayleigh waves, and to retrieve their backazimuths (BAZ) in the time–frequency domain. We observe clear seasonal variations in the number of polarized signals and in their frequencies, but not in their BAZ that consistently point towards the Southern part of the basin throughout the year. This property is very peculiar to the Indian Ocean that is closed on its Northern side, and therefore not affected by large ocean storms during Northern Hemisphere winters. We show that the noise amplitude seasonal variations and the backazimuth directions are consistent with the source areas computed from ocean wave models.

Humans resist infection by the African parasite Trypanosoma brucei owing to the trypanolytic activity of the serum apolipoprotein L1 (APOL1). Following uptake by endocytosis in the parasite, APOL1 forms pores in endolysosomal membranes and triggers lysosome swelling. Here we show that APOL1 induces both lysosomal and mitochondrial membrane permeabilization (LMP and MMP). Trypanolysis coincides with MMP and consecutive release of the mitochondrial TbEndoG endonuclease to the nucleus. APOL1 is associated with the kinesin TbKIFC1, of which both the motor and vesicular trafficking VHS domains are required for MMP, but not for LMP. The presence of APOL1 in the mitochondrion is accompanied by mitochondrial membrane fenestration, which can be mimicked by knockdown of a mitochondrial mitofusin-like protein (TbMFNL). The BH3-like peptide of APOL1 is required for LMP, MMP and trypanolysis. Thus, trypanolysis by APOL1 is linked to apoptosis-like MMP occurring together with TbKIFC1-mediated transport of APOL1 from endolysosomal membranes to the mitochondrion.

Three major grapevine trunk diseases, esca, botryosphaeria dieback and eutypa dieback, pose important economic problems for vineyards worldwide, and currently, no efficient treatment is available to control these diseases. The different fungi associated with grapevine trunk diseases can be isolated in the necrotic wood, but not in the symptomatic leaves. Other factors seem to be responsible for the foliar symptoms and may represent the link between wood and foliar symptoms. One hypothesis is that the extracellular compounds produced by the fungi associated with grapevine trunk diseases are responsible for pathogenicity. In the present work, we used Vitis vinifera cv. Chardonnay cells to test the aggressiveness of total extracellular compounds produced by Diplodia seriata and Neofusicoccum parvum, two causal agents associated with botryosphaeria dieback. Additionally, the toxicity of purified mellein, a characteristic toxin present in the extracellular compounds of Botryosphaeriaceae, was assessed. Our results show that the total extracellular compounds produced by N. parvum induce more necrosis on Chardonnay calli and induce a different defence gene expression pattern than those of D. seriata. Mellein was produced by both fungi in amounts proportional to its aggressiveness. However, when purified mellein was added to the culture medium of calli, only a delayed necrosis and a lower-level expression of defence genes were observed. Extracellular compounds seem to be involved in the pathogenicity of the fungi associated with botryosphaeria dieback. However, the doses of mellein used in this study are 100 times higher than those found in the liquid fungal cultures: therefore, the possible function of this toxin is discussed.

AIM: A Belgian registry for pediatric Crohn's disease, BELCRO, was created. This first report aims at describing disease presentation and phenotype and determining associations between variables at diagnosis and registration in the database. METHODS: Through a collaborative network, children with previously established Crohn's disease and newly diagnosed children and adolescents (under 18 y of age) were recruited over a 2 year period. Data were collected by 23 centers and entered in a database. Statistical association tests analyzed relationships between variables of interest at diagnosis. RESULTS: Two hundred fifty-five patients were included. Median age at diagnosis was 12.5 y (range: 1.6-18 y); median duration of symptoms prior to diagnosis was 3 m (range: 1-12 m). Neonatal history and previous medical history did not influence disease onset nor disease behavior. Fifty three % of these patients presented with a BMI z-score < -1. CRP was an independent predictor of disease severity. Steroids were widely used as initial treatment in moderate to severe and extensive disease. Over time, immunomodulators and biological were prescribed more frequently, reflecting a lower prescription rate for steroids and 5-ASA. A positive family history was the sole significant determinant for earlier use of immunosuppression. CONCLUSION: In Belgium, the median age of children presenting with Crohn's disease is 12.5 y. Faltering growth, extensive disease and upper GI involvement are frequent. CRP is an independent predictive factor of disease activity. A positive family history appears to be the main determinant for initial treatment choice.