Frequency of the allelic variant c.1150T > C in exon 10 of the fibroblast growth factor receptor 3 (FGFR3) gene is not increased in patients with pathogenic mutations and related chondrodysplasia phenotypes

Mutations in the FGFR3 gene cause the phenotypic spectrum of FGFR3 chondrodysplasias ranging from lethal forms to the milder phenotype seen in hypochondroplasia (Hch). The p.N540K mutation in theFGFR3 gene occurs in ∼70% of individuals with Hch, and nearly 30% of individuals with the Hch phenotype have no mutations in the FGFR3, which suggests genetic heterogeneity. The identification of a severe case of Hch associated with the typical mutation c.1620C > A and the occurrence of a c.1150T > C change that resulted in a p.F384L in exon 10, together with the suspicion that this second change could be a modulator of the phenotype, prompted us to investigate this hypothesis in a cohort of patients. An analysis of 48 patients with FGFR3 chondrodysplasia phenotypes and 330 healthy (control) individuals revealed no significant difference in the frequency of the C allele at the c.1150 position (p = 0.34). One patient carrying the combination ‘pathogenic mutation plus the allelic variant c.1150T > C’ had a typical achondroplasia (Ach) phenotype. In addition, three other patients with atypical phenotypes showed no association with the allelic variant. Together, these results do not support the hypothesis of a modulatory role for the c.1150T > C change in the FGFR3 gene.Mutations in the FGFR3 gene cause the phenotypic spectrum of FGFR3 chondrodysplasias ranging from lethal forms to the milder phenotype seen in hypochondroplasia (Hch). The p.N540K mutation in the FGFR3 gene occurs in ~70% of individuals with Hch, and ne374622624CNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTIFICO E TECNOLOGICO402008/2010-3; 590148/2011-7; 132270/2012-9Adzhubei, I.A., Schmidt, S., Peshkin, L., Ramensky, V.E., Gerasimova, A., Bork, P., Kondrashov, A.S., Sunyaev, S.R., A method and server for predicting damaging missense mutations (2010) Nat Methods, 7, pp. 248-249Bellus, G.A., Spector, E.B., Speiser, P.W., Weaver, C.A., Garber, A.T., Bryke, C.R., Israel, J., Donoghue, D.J., Distinct missense mutations of the FGFR3 Lys650 codon modulate receptor kinase activation and the severity of the skeletal dysplasia phenotype (2000) Am J Hum Genet, 67, pp. 1411-1421Bonaventure, J., Rousseau, F., Legeai-Mallet, L., Le Merrer, M., Munnich, A., Maroteaux, P., Common mutations in the fibroblast growth factor receptor 3 (FGFR3) gene account for achondroplasia, hypochondroplasia, and thanatophoric dwarfism (1996) Am J Med Genet, 63, pp. 148-154Castro-Feijóo, L., Loidi, L., Vidal, A., Parajes, S., Rosón, E., Álvarez, A., Cabanas, P., Domínguez, F., Hypochondroplasia and acanthosis nigricans: A new syndrome due to the p.Lys650Thr mutation in the fibroblast growth factor receptor 3 gene? (2008) Eur J Endocrinol 159:243-, p. 249Golla, A., Lichtner, P., Von Gernet, S., Winterpacht, A., Fairley, J., Murken, J., Schuffenhauer, S., Phenotypic expression of the fibroblast growth factor receptor 3 (FGFR3) mutation P250R in a large craniosynostosis family (1997) J Med Genet, 34, pp. 683-684Karadimas, C., Sifakis, S., Valsamopoulos, P., Makatsoris, C., Velissariou, V., Nasioulas, G., Petersen, M.B., Hatzaki, A., Prenatal diagnosis of hypochondroplasia: Report of two cases (2006) Am J Med Genet, 1003, pp. 998-1003Spranger, J.W., Brill, P.W., Nishimura, G., Superti-Furga, A., Unger, S., Bone Dysplasias -An Atlas of Genetic Disorders of Skeletal Development (2012) Nature, 491, pp. 56-65. , Oxford University Press, Oxford, 11 pp. The 1000 Genomes Project Consortium (2012) An integrated map of genetic variation from 1,092 human genomesTrujillo-Tiebas, M.J., Riveiro, R., Queipo, A., Vallespin, E., Cantalapiedra, D., Lorda-Sanchez, I., Ayuso, C., Human gene mutations. Gene symbol: FGFR3. Disease: Skeletal dysplasia (2004) Hum Genet, 115, pp. 347-356Trujillo-Tiebas, M.J., Fenollar-Cortés, M., Lorda-Sánchez, I., DíAz- Recasens, J., Redondo, A.C., Ramos-Corrales, C., Ayuso, C., Prenatal diagnosis of skeletal dysplasia due to FGFR3 gene mutations: A 9-year experience: Prenatal diagnosis in FGFR3 gene (2009) J Assist Reprod Genet, 26, pp. 455-460Warman, M., Cormier-Daire, V., Hall, C., Krakow, D., Lachman, R., Lemerrer, M., Mortier, G., Rimoin, D., Nosology and classification of genetic skeletal disorders: 2010 revision (2011) Am J Med Genet A 155A:943-, p. 96

Downregulation Of 14q32 Micrornas In Primary Human Desmoplastic Medulloblastoma

Medulloblastoma (MB) is one of the most common pediatric cancers, likely originating from abnormal development of cerebellar progenitor neurons. MicroRNA (miRNA) has been shown to play an important role in the development of the central nervous system. Microarray analysis was used to investigate miRNA expression in desmoplastic MB from patients diagnosed at a young age (1 or 2 years old). Normal fetal or newborn cerebellum was used as control. A total of 84 differentially expressed miRNAs (64 downregulated and 20 upregulated) were found. Most downregulated miRNAs (32/64) were found to belong to the cluster of miRNAs at the 14q32 locus, suggesting that this miRNA locus is regulated as a module in MB. Possible mechanisms of 14q32 miRNAs downregulation were investigated by the analysis of publicly available gene expression data sets. First, expression of estrogen-related receptor-γ (ESRRG), a reported positive transcriptional regulator of some 14q32 miRNAs, was found downregulated in desmoplastic MB. Second, expression of the parentally imprinted gene MEG3 was lower in MB in comparison to normal cerebellum, suggesting a possible epigenetic silencing of the 14q32 locus. miR-129-5p (11p11.2/7q32.1), miR-206 (6p12.2), and miR-323-3p (14q32.2), were chosen for functional studies in DAOY cells. Overexpression of miR-129-5p using mimics decreased DAOY proliferation. 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Cultura e desenvolvimento humano sustentável

A cultura é cada vez mais o centro das políticas locais, pela importância que vem revelando no contexto de um paradigma de desenvolvimento humano integral. Para além da atenção que lhe é dirigida graças à sua intima conexão a fatores de índole económica, social e urbana; a sua relevância deve-se essencialmente às relações intrínsecas que mantém com as questões da identidade, da memória, da criatividade, da ciência e do pensamento e conhecimento crítico. Optámos por dividir este livro em três capítulos de modo a permitir uma sequência de leitura, desde as temáticas gerais de grande escala – da União Europeia e da Globalização, até ao cerne do problema que em nosso entendimento urge solucionar nas cidades: a efetiva e definitiva integração da dimensão cultural nas estratégias territoriais de desenvolvimento humano sustentável.N/

Search for direct production of charginos and neutralinos in events with three leptons and missing transverse momentum in √s = 7 TeV pp collisions with the ATLAS detector

A search for the direct production of charginos and neutralinos in final states with three electrons or muons and missing transverse momentum is presented. The analysis is based on 4.7 fb−1 of proton–proton collision data delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in three signal regions that are either depleted or enriched in Z-boson decays. Upper limits at 95% confidence level are set in R-parity conserving phenomenological minimal supersymmetric models and in simplified models, significantly extending previous results

Jet size dependence of single jet suppression in lead-lead collisions at sqrt(s(NN)) = 2.76 TeV with the ATLAS detector at the LHC

Measurements of inclusive jet suppression in heavy ion collisions at the LHC provide direct sensitivity to the physics of jet quenching. In a sample of lead-lead collisions at sqrt(s) = 2.76 TeV corresponding to an integrated luminosity of approximately 7 inverse microbarns, ATLAS has measured jets with a calorimeter over the pseudorapidity interval |eta| < 2.1 and over the transverse momentum range 38 < pT < 210 GeV. Jets were reconstructed using the anti-kt algorithm with values for the distance parameter that determines the nominal jet radius of R = 0.2, 0.3, 0.4 and 0.5. The centrality dependence of the jet yield is characterized by the jet "central-to-peripheral ratio," Rcp. Jet production is found to be suppressed by approximately a factor of two in the 10% most central collisions relative to peripheral collisions. Rcp varies smoothly with centrality as characterized by the number of participating nucleons. The observed suppression is only weakly dependent on jet radius and transverse momentum. These results provide the first direct measurement of inclusive jet suppression in heavy ion collisions and complement previous measurements of dijet transverse energy imbalance at the LHC.Comment: 15 pages plus author list (30 pages total), 8 figures, 2 tables, submitted to Physics Letters B. All figures including auxiliary figures are available at http://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/HION-2011-02

Measurement of event-shape observables in Z→ℓ+ℓ− events in pp collisions at √ s=7 TeV with the ATLAS detector at the LHC

Event-shape observables measured using charged particles in inclusive $Z$-boson events are presented, using the electron and muon decay modes of the $Z$ bosons. The measurements are based on an integrated luminosity of $1.1 {\rm fb}^{-1}$ of proton--proton collisions recorded by the ATLAS detector at the LHC at a centre-of-mass energy $\sqrt{s}=7$ TeV. Charged-particle distributions, excluding the lepton--antilepton pair from the $Z$-boson decay, are measured in different ranges of transverse momentum of the $Z$ boson. Distributions include multiplicity, scalar sum of transverse momenta, beam thrust, transverse thrust, spherocity, and $\mathcal{F}$-parameter, which are in particular sensitive to properties of the underlying event at small values of the $Z$-boson transverse momentum. The Sherpa event generator shows larger deviations from the measured observables than Pythia8 and Herwig7. Typically, all three Monte Carlo generators provide predictions that are in better agreement with the data at high $Z$-boson transverse momenta than at low $Z$-boson transverse momenta and for the observables that are less sensitive to the number of charged particles in the event.Comment: 36 pages plus author list + cover page (54 pages total), 14 figures, 4 tables, submitted to EPJC, All figures including auxiliary figures are available at http://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/STDM-2014-0