Inhibition of YAP/TAZ-driven TEAD activity prevents growth of NF2-null schwannoma and meningioma.

Schwannoma tumours typically arise on the 8th cranial nerve and are mostly caused by loss of the tumour suppressor Merlin (NF2). There are no approved chemotherapies for these tumours and the surgical removal of the tumour carries a high risk of damage to the 8th or other close cranial nerve tissue. New treatments for schwannoma and other NF2-null tumours such as meningioma are urgently required. Using a combination of human primary tumour cells and mouse models of schwannoma, we have examined the role of the Hippo signalling pathway in driving tumour cell growth. Using both genetic ablation of the Hippo effectors YAP and TAZ as well as novel TEAD palmitoylation inhibitors, we show that Hippo signalling may be successfully targeted in vitro and in vivo to both block and, remarkably, regress schwannoma tumour growth. In particular, successful use of TEAD palmitoylation inhibitors in a pre-clinical mouse model of schwannoma points to their potential future clinical use. We also identify the cancer stem cell marker aldehyde dehydrogenase 1A1 (ALDH1A1) as a Hippo signalling target, driven by the TAZ protein in human and mouse NF2-null schwannoma cells, as well as in NF2-null meningioma cells, and examine the potential future role of this new target in halting schwannoma and meningioma tumour growth

Inheritance analysis and identification of SNP markers associated with ZYMV resistance in Cucurbita pepo

[EN] Cucurbit crops are economically important worldwide. One of the most serious threats to cucurbit production is Zucchini yellow mosaic virus (ZYMV). Several resistant accessions were identified in Cucurbita moschata and their resistance was introgressed into Cucurbita pepo. However, the mode of inheritance of ZYMV resistance in C. pepo presents a great challenge to attempts at introgressing resistance into elite germplasm. The main goal of this work was to analyze the inheritance of ZYMV resistance and to identify markers associated with genes conferring resistance. An Illumina GoldenGate assay allowed us to assess polymorphism among nine squash genotypes and to discover six polymorphic single-nucleotide polymorphisms (SNPs) between two near-isogenic lines, "True French" (susceptible to ZYMV) and Accession 381e (resistant to ZYMV). Two F-2 and three BC1 populations obtained from crossing the ZYMV-resistant Accession 381e with two susceptible ones, the zucchini True French and the cocozelle "San Pasquale," were assayed for ZYMV resistance. Molecular analysis revealed an approximately 90% association between SNP1 and resistance, which was confirmed using High Resolution Melt (HRM) and a CAPS marker. Co-segregation up to 72% in populations segregating for resistance was observed for two other SNP markers that could be potentially linked to genes involved in resistance expression. A functional prediction of proteins involved in the resistance response was performed on genome scaffolds containing the three SNPs of interest. Indeed, 16 full-length pathogen recognition genes (PRGs) were identified around the three SNP markers. In particular, we discovered that two nucleotide-binding site leucine-rich repeat (NBS-LRR) protein-encoding genes were located near the SNP1 marker. The investigation of ZYMV resistance in squash populations and the genomic analysis performed in this work could be useful for better directing the introgression of disease resistance into elite C. pepo germplasm.This work was supported by the Ministry of University and Research (GenHORT project).Capuozzo, C.; Formisano, G.; Iovieno, P.; Andolfo, G.; Tomassoli, L.; Barbella, M.; Picó Sirvent, MB.... (2017). Inheritance analysis and identification of SNP markers associated with ZYMV resistance in Cucurbita pepo. Molecular Breeding. 37(8). https://doi.org/10.1007/s11032-017-0698-5S378Addinsoft (2007) XLSTAT, Analyse de données et statistique avec MS Excel. Addinsoft, NYAndolfo G, Ercolano MR (2015) Plant innate immunity multicomponent model. Front Plant Sci 6:987Andolfo G, Sanseverino W, Rombauts S et al (2013) Overview of tomato (Solanum lycopersicum) candidate pathogen recognition genes reveals important Solanum R locus dynamics. New Phytol 197:223–237Andolfo G, Ferriello F, Tardella L et al (2014) Tomato genome-wide transcriptional responses to fusarium wilt, and tomato mosaic virus. PLoS One 9:e94963Blanca J, Cañizares J, Roig C, Ziarsolo P, Nuez F, Picó B (2011) Transcriptome characterization and high throughput SSRs and SNPs discovery in Cucurbita pepo (Cucurbitaceae). BMC Genomics 12:104Brown RN, Bolanos-Herrera A, Myers JR, Jahn MM (2003) Inheritance of resistance to four cucurbit viruses in Cucurbita moschata. Euphytica 129:253–258Burge CB, Karlin S (1998) Finding the genes in genomic DNA. Curr Opin Struct Biol 8:346–354Cipollini D (2008) Constitutive expression of methyl jasmonate-inducible responses delays reproduction and constrains fitness responses to nutrients in Arabidopsis thaliana. Evol Ecol 24:59–68Cohen R, Hanan A, Paris HS (2003) Single-gene resistance to powdery mildew in zucchini squash (Cucurbita pepo). Euphytica 130:433–441Collum TD, Padmanabhan MS, Hsieh YC, Culver JN (2016) Tobacco mosaic virus-directed reprogramming of auxin/indole acetic acid protein transcriptional responses enhances virus phloem loading. Proc Natl Acad Sci U S A 113:E2740–E2749Desbiez C, Lecoq H (1997) Zucchini yellow mosaic virus. Plant Pathol 46:809–829Ercolano MR, Sanseverino W, Carli P, Ferriello F, Frusciante L (2012) Genetic and genomic approaches for R-gene mediated disease resistance in tomato: retrospects and prospects. Plant Cell Rep 31:973–985Esteras C, Gómez P, Monforte AJ, Blanca J, Vicente-Dólera N, Roig C, Nuez F, Picó B (2012) High-throughput SNP genotyping in Cucurbita pepo for map construction and quantitative trait loci mapping. BMC Genomics 13:80Formisano G, Paris HS, Frusciante L, Ercolano MR (2010) Commercial Cucurbita pepo squash hybrids carrying disease resistance introgressed from Cucurbita moschata have high genetic similarity. Plant Genet Resour 8:198–203Fulton TM, Chunwongse J, Tanksley SD (1995) Microprep protocol for extraction of DNA from tomato and other herbaceous plants. Plant Mol Biol Report 13:207–209Gal-On A (2007) Zucchini yellow mosaic virus: insect transmission and pathogenicity—the tails of two proteins. Mol Plant Pathol 8:139–150Gilbert-Albertini F, Lecoq H, Pitrat M, Nicolet JL (1993) Resistance of Cucurbita moschata to watermelon mosaic virus type 2 and its genetic relation to resistance to zucchini yellow mosaic virus. Euphytica 69:231–237Gómez P, Rodríguez-Hernández AM, Moury B, Aranda MA (2009) Genetic resistance for the sustainable control of plant virus diseases: breeding, mechanisms and durability. Eur J Plant Pathol 125:1–22Gong L, Stift G, Kofler R, Pachner M, Lelley T (2008a) Microsatellites for the genus Cucurbita and an SSR-based genetic linkage map of Cucurbita pepo L. Theor Appl Genet 117:37–48Gong L, Pachner M, Kalai K, Lelley T (2008b) SSR-based genetic linkage map of Cucurbita moschata and its synteny with Cucurbita pepo. Genome 51:878–887Iovieno P, Andolfo G, Schiavulli A, Catalano D, Ricciardi L, Frusciante L et al. (2015) Structure, evolution and functional inference on the MildewLocusO (MLO) gene family in three cultivated Cucurbitaceae. BMC Genomics 16:1112. doi: 10.1186/s12864-015-2325-3Ishibashi K, Kezuka Y, Kobayashi C, Kato M, Inoue T, Nonaka T et al (2014) Structural basis for the recognition–evasion arms race between Tomato mosaic virus and the resistance gene Tm-1. PNAS 111:E3486–E3495Lecoq H, Pitrat M, Clément M (1981) Identification et caractérisation d’un potyvirus provoquant la maladie du rabougrissement jaune du melon. Agronomie 1:827–834Lefebvre V, Palloix A (1996) Both epistatic and additive effects of QTLs are involved in polygenic induced resistance to disease: a case study, the interaction pepper—Phytophthora capsici Leonian. Theor Appl Genet 93:503–511Levi A, Thomas CE, Newman M, Zhan X, Xu Y, Wehner TC (2003) Massive preferential segregation and nonrandom assortment of linkage-groups produce quasi-linkage in an F2 mapping population of watermelon. Hortscience 38:782Lisa V, Lecoq H (1984) Zucchini yellow mosaic virus. Descriptions of Plant Viruses, Commonwealth Mycological Institute and Association of Applied Biologists 282Lisa V, Boccardo G, D'Agostino G, Dellavalle G, d’Aquilio M (1981) Characterization of a potyvirus that causes zucchini yellow mosaic. Phytopathology 71:667–672MacQueen A, Bergelson J (2016) Modulation of R-gene expression across environments. J Exp Bot 67:2093–2105Mantel N (1967) The detection of disease clustering and a generalized regression approach. Cancer Res 27:209–220Munger HM, Provvidenti R (1987) Inheritance of resistance to zucchini yellow mosaic virus in Cucurbita moschata. Cucurbit Genet Coop Rep 10:8–81Nameth ST, Dodds JA, Paulus AO, Laemmlen FF (1986) Cucurbit viruses of California: an ever-changing problem. Plant Dis 70:8–12Ott J, Wang J, Leal SM (2015) Genetic linkage analysis in the age of whole-genome sequencing. Nat Rev Genet 16(5):275–284Pachner M, Lelley T (2004) Different genes for resistance to zucchini yellow mosaic virus (ZYMV) in Cucurbita moschata. In: Lebeda A, Paris HS (eds) Progress in cucurbit genetics and breeding research: Proceedings of Cucurbitaceae 2004. Palacky University, Olomouc (Czech Republic), pp 237–243Pachner M, Paris HS, Lelley T (2011) Genes for resistance to zucchini yellow mosaic in tropical pumpkin. J Hered 102:330–335Pachner M, Paris HS, Winkler J, Lelley T (2015) Phenotypic and marker-assisted pyramiding of genes for resistance to zucchini yellow mosaic virus in oilseed pumpkin (Cucurbita pepo). Plant Breed 134:121–128Paris HS (1986) A proposed subspecific classification for Cucurbita pepo. Phytologia 61:133–138Paris HS (2001) Characterization of the Cucurbita pepo collection at the Newe Ya‘ar Research Center, Israel. Plant Genet Resour Newsl 126:41–45Paris HS (2008) Summer squash. In: Prohens J, Nuez F (eds) Handbook of plant breeding, Vegetables I: 351–379Paris HS, Cohen S (2000) Oligogenic inheritance for resistance to zucchini yellow mosaic virus in Cucurbita pepo. Ann Appl Biol 136:209–214Paris HS, Cohen S, Burger Y, Joseph R (1988) Single-gene resistance to zucchini yellow mosaic virus in Cucurbita moschata. Euphytica 37:27–29Peakall PE, Smouse R (2012) GenAlEx 6.5: genetic analysis in Excel. Population genetic software for teaching and research—an update. Bioinformatics 28:2537–2539Sakamoto T, Deguchi M, Brustolini OJ, Santos AA, Silva FF, Fontes EP (2012) The tomato RLK superfamily: phylogeny and functional predictions about the role of the LRRII-RLK subfamily in antiviral defense. BMC Plant Biol 12:229Sanseverino W, Ercolano MR (2012) In silico approach to predict candidate R proteins and to define their domain architecture. BMC Res Notes 5:678Tamura K, Peterson D, Peterson N, Stecher G, Nei M, Kumar S (2011) MEGA5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Mol Biol Evol 28:2731–2739Teare MD, Santibanez Koref MF (2014) Linkage analysis and the study of Mendelian disease in the era of whole exome and genome sequencing. Brief Funct Genomics 13(5):378–383Valkonen JPT, Wiegmann K, Hämäläinen JH, Marczewski W, Watanabe KN (2008) Evidence for utility of the same PCR-based markers for selection of extreme resistance to Potato virus Y controlled by Rysto of Solanum stoloniferum derived from different sources. Ann Appl Biol 152:121–130Wessel-Beaver L (2005) Cultivar and germplasm release. Release of ‘Soler’ tropical pumpkin. J Agric Univ P R 89:263–266Whitaker TW, Davis GN (1962) Cucurbits: botany, cultivation and utilization. Interscience, New York, pp 105–116Whitaker TW, Robinson RW (1986) Squash breeding. In: Bassett MJ (ed) Breeding vegetable crops. Avi, Westport, pp 209–242Xu Y, Crouch JH (2008) Marker-assisted selection in plant breeding: from publications to practice. Crop Sci 48:391–407Xu R, Zhang S, Huang J, Zheng C (2013) Genome-wide comparative in silico analysis of the RNA helicase gene family in Zea mays and Glycine max: a comparison with Arabidopsis and Oryza sativa. PLoS One 8:e78982Ye G, Smith KF (2008) Marker-assisted gene pyramiding for inbred line development: basic principles and practical guidelines. Int J Plant Breed 2:1–10Zdobnov EM, Apweiler R (2001) InterProScan—an integration platform for the signature-recognition methods in InterPro. Bioinformatics 17:847–848Zraidi A, Stift G, Pachner M, Shojaeiyan A, Gong L, Lelley T (2007) A consensus map for Cucurbita pepo. Mol Breed 20:375–38

Circumstellar discs: What will be next?

This prospective chapter gives our view on the evolution of the study of circumstellar discs within the next 20 years from both observational and theoretical sides. We first present the expected improvements in our knowledge of protoplanetary discs as for their masses, sizes, chemistry, the presence of planets as well as the evolutionary processes shaping these discs. We then explore the older debris disc stage and explain what will be learnt concerning their birth, the intrinsic links between these discs and planets, the hot dust and the gas detected around main sequence stars as well as discs around white dwarfs.Comment: invited review; comments welcome (32 pages

Circumstellar disks and planets. Science cases for next-generation optical/infrared long-baseline interferometers

We present a review of the interplay between the evolution of circumstellar disks and the formation of planets, both from the perspective of theoretical models and dedicated observations. Based on this, we identify and discuss fundamental questions concerning the formation and evolution of circumstellar disks and planets which can be addressed in the near future with optical and infrared long-baseline interferometers. Furthermore, the importance of complementary observations with long-baseline (sub)millimeter interferometers and high-sensitivity infrared observatories is outlined.Comment: 83 pages; Accepted for publication in "Astronomy and Astrophysics Review"; The final publication is available at http://www.springerlink.co

Genome Physical Mapping of Polyploids: A BIBAC Physical Map of Cultivated Tetraploid Cotton, Gossypium hirsutum L

Polyploids account for approximately 70% of flowering plants, including many field, horticulture and forage crops. Cottons are a world-leading fiber and important oilseed crop, and a model species for study of plant polyploidization, cellulose biosynthesis and cell wall biogenesis. This study has addressed the concerns of physical mapping of polyploids with BACs and/or BIBACs by constructing a physical map of the tetraploid cotton, Gossypium hirsutum L. The physical map consists of 3,450 BIBAC contigs with an N50 contig size of 863 kb, collectively spanning 2,244 Mb. We sorted the map contigs according to their origin of subgenome, showing that we assembled physical maps for the A- and D-subgenomes of the tetraploid cotton, separately. We also identified the BIBACs in the map minimal tilling path, which consists of 15,277 clones. Moreover, we have marked the physical map with nearly 10,000 BIBAC ends (BESs), making one BES in approximately 250 kb. This physical map provides a line of evidence and a strategy for physical mapping of polyploids, and a platform for advanced research of the tetraploid cotton genome, particularly fine mapping and cloning the cotton agronomic genes and QTLs, and sequencing and assembling the cotton genome using the modern next-generation sequencing technology

Guidance to 2018 good practice : ARIA digitally-enabled, integrated, person-centred care for rhinitis and asthma

AimsMobile Airways Sentinel NetworK (MASK) belongs to the Fondation Partenariale MACVIA-LR of Montpellier, France and aims to provide an active and healthy life to rhinitis sufferers and to those with asthma multimorbidity across the life cycle, whatever their gender or socio-economic status, in order to reduce health and social inequities incurred by the disease and to improve the digital transformation of health and care. The ultimate goal is to change the management strategy in chronic diseases.MethodsMASK implements ICT technologies for individualized and predictive medicine to develop novel care pathways by a multi-disciplinary group centred around the patients.StakeholdersInclude patients, health care professionals (pharmacists and physicians), authorities, patient's associations, private and public sectors.ResultsMASK is deployed in 23 countries and 17 languages. 26,000 users have registered.EU grants (2018)MASK is participating in EU projects (POLLAR: impact of air POLLution in Asthma and Rhinitis, EIT Health, DigitalHealthEurope, Euriphi and Vigour).Lessons learnt(i) Adherence to treatment is the major problem of allergic disease, (ii) Self-management strategies should be considerably expanded (behavioural), (iii) Change management is essential in allergic diseases, (iv) Education strategies should be reconsidered using a patient-centred approach and (v) Lessons learnt for allergic diseases can be expanded to chronic diseases.Peer reviewe

Correlation between work impairment, scores of rhinitis severity and asthma using the MASK-air (R) App

Background In allergic rhinitis, a relevant outcome providing information on the effectiveness of interventions is needed. In MASK-air (Mobile Airways Sentinel Network), a visual analogue scale (VAS) for work is used as a relevant outcome. This study aimed to assess the performance of the work VAS work by comparing VAS work with other VAS measurements and symptom-medication scores obtained concurrently. Methods All consecutive MASK-air users in 23 countries from 1 June 2016 to 31 October 2018 were included (14 189 users; 205 904 days). Geolocalized users self-assessed daily symptom control using the touchscreen functionality on their smart phone to click on VAS scores (ranging from 0 to 100) for overall symptoms (global), nose, eyes, asthma and work. Two symptom-medication scores were used: the modified EAACI CSMS score and the MASK control score for rhinitis. To assess data quality, the intra-individual response variability (IRV) index was calculated. Results A strong correlation was observed between VAS work and other VAS. The highest levels for correlation with VAS work and variance explained in VAS work were found with VAS global, followed by VAS nose, eye and asthma. In comparison with VAS global, the mCSMS and MASK control score showed a lower correlation with VAS work. Results are unlikely to be explained by a low quality of data arising from repeated VAS measures. Conclusions VAS work correlates with other outcomes (VAS global, nose, eye and asthma) but less well with a symptom-medication score. VAS work should be considered as a potentially useful AR outcome in intervention studies.Peer reviewe

Production of dust by massive stars at high redshift

The large amounts of dust detected in sub-millimeter galaxies and quasars at high redshift pose a challenge to galaxy formation models and theories of cosmic dust formation. At z > 6 only stars of relatively high mass (> 3 Msun) are sufficiently short-lived to be potential stellar sources of dust. This review is devoted to identifying and quantifying the most important stellar channels of rapid dust formation. We ascertain the dust production efficiency of stars in the mass range 3-40 Msun using both observed and theoretical dust yields of evolved massive stars and supernovae (SNe) and provide analytical expressions for the dust production efficiencies in various scenarios. We also address the strong sensitivity of the total dust productivity to the initial mass function. From simple considerations, we find that, in the early Universe, high-mass (> 3 Msun) asymptotic giant branch stars can only be dominant dust producers if SNe generate <~ 3 x 10^-3 Msun of dust whereas SNe prevail if they are more efficient. We address the challenges in inferring dust masses and star-formation rates from observations of high-redshift galaxies. We conclude that significant SN dust production at high redshift is likely required to reproduce current dust mass estimates, possibly coupled with rapid dust grain growth in the interstellar medium.Comment: 72 pages, 9 figures, 5 tables; to be published in The Astronomy and Astrophysics Revie

Allergic Rhinitis and its Impact on Asthma (ARIA) Phase 4 (2018): Change management in allergic rhinitis and asthma multimorbidity using mobile technology

Allergic Rhinitis and its Impact on Asthma (ARIA) has evolved from a guideline by using the best approach to integrated care pathways using mobile technology in patients with allergic rhinitis (AR) and asthma multimorbidity. The proposed next phase of ARIA is change management, with the aim of providing an active and healthy life to patients with rhinitis and to those with asthma multimorbidity across the lifecycle irrespective of their sex or socioeconomic status to reduce health and social inequities incurred by the disease. ARIA has followed the 8-step model of Kotter to assess and implement the effect of rhinitis on asthma multimorbidity and to propose multimorbid guidelines. A second change management strategy is proposed by ARIA Phase 4 to increase self-medication and shared decision making in rhinitis and asthma multimorbidity. An innovation of ARIA has been the development and validation of information technology evidence-based tools (Mobile Airways Sentinel Network [MASK]) that can inform patient decisions on the basis of a self-care plan proposed by the health care professional