45 research outputs found
Numerical simulation of impact noise generated at the railway insulated joint
No full textThis paper presents a full finite element (FE) model of wheel-track interaction to study the wheel-rail impact noise excited by an insulated joint (IJ). The integration is performed in the time domain with an explicit central difference scheme. The vibratory behaviour of the track and wheel model are respectively validated with hammer test and Axle Box Acceleration (ABA) measurement. By making use of the calculated velocities and pressures on the vibrating surfaces, the boundary element method (BEM) based on Helmholtz equation is adopted to transform the vibrations of the wheel-track into acoustic signals. The decay rate of impact noise at different frequency bands during propagation are analysed. The predictions of total impact noise radiation and the noise contributions of different track components are in good agreement with results reported in the literature, while the effective frequency range is successfully extended from 5 kHz to 10 kHz.Accepted Author ManuscriptRailway Engineerin
Acoustic liners for jet-installation noise reduction
No full textsponsorship: This work is part of the IPER-MAN project (Innovative PERmeable Materials for Airfoil Noise Reduction) , project number 15452, funded by the Netherlands Organization for Scientific Research (NWO) . The authors would like to thank Dr. Mirjam Snellen and Prof. Sybrand van der Zwaag from the Delft University of Technology, for collaboration in the project. (Netherlands Organization for Scientific Research (NWO)|15452)status: Published onlin
De NCFC syndromen: klinische, moleculaire en cognitieve aspecten in geselecteerde syndromen
No full textDe neuro-cardio-facio-cutane (NCFC) syndromen vormen een groep fenotypis ch overlappende aandoeningen die zich presenteren met een variabele graa d van cognitieve beperkingen, hartafwijkingen, gelaatsdysmorfieën en hui dproblemen. De meeste van deze syndromen gaan gepaard met een verhoogd r isico op kanker. De laatste jaren is het duidelijk geworden dat deze syn dromen veroorzaakt worden door mutaties in genen van de RAS-MAPKinase si gnaaltransductiecascade. Deze cascade speelt een rol in celgroei en -dif ferentiatie en is gekend voor zijn rol in kanker en meer recent ook in c ognitie. In deze thesis werd geprobeerd het gekende mutatie- en fenotypisch spect rum van enkele van deze syndromen, namelijk Costello, Noonan en CFC synd room uit te breiden. We beschrijven een nieuwe HRAS mutatie in een pa tiënt met Costello syndroom die geen effect heeft op enzymatische activi teit, maar wel op guanine-nucleotide dissociatie. Ook beschrijven we het fenotype in patiënten met Noonan syndroom en SOS1, RAF1, KRAS en NRAS mutaties en in patiënten met CFC syndroom en BRAF en MEK2 mutaties. Niet eerder gerapporteerde mutaties in SOS1, KRAS, NR AS, BRAF en MEK2 werden gevonden. Daarnaast beschrijven we het fenotype in Legius syndroom, aanvankelijk neurofibromatose type1-achtig syndroom genoemd, een nieuw lid van deze groep van NCFC syndromen. Legius syndroom wordt veroorzaakt door mutatie s in SPRED1, een negatieve regulator van de RAS-MAPKinase cascade, en patiënten presenteren zich met café-au-lait vlekken met of zonder freck ling, doch zonder de andere typische symptomen van neurofibromatose type 1. Leerproblemen werden meermaals gerapporteerd in patiënten met Legius syndroom. We bestudeerden het leergedrag in een Spred1 knockout muiz enmodel en stelden vast dat deze muizen een verrassend gelijkaardig feno type vertonen met Nf1 heterozygote muizen zowel wat betreft leren als synaptische plasticiteit. Tenslotte bestudeerden we de intelligentie en het gedrag in een groep patiënten met Legius syndroom en niet-aangetast e siblings. Patiënten met Legius syndroom hebben een normaal totaal IQ, wat niet verschilt van de siblings, maar wel een lager performaal IQ. In de toekomst willen we proberen de leerproblemen in het Spred1 muiz enmodel om te keren door behandeling met statines, een behandeling die r eeds effectief gebleken is bij het Nf1 muizenmodel. Indien we een pos itief effect van statines op het leergedrag van Spred1 muizen kunnen aantonen, versterkt dit de theoretische basis voor klinische studies met deze medicatie in kinderen met neurofibromatose type 1 en misschien bij uitbreiding de andere NCFC syndromen.status: Publishe
What’s new in the neuro-cardio-facial-cutaneous syndromes?
No full textThe RAS-MAPKinase pathway is a signal transduction cascade which has been studied extensively during the last decades for its role in human oncogenesis. Activation of this cascade is controlled by cycling of the RAS protein between an inactive and an active state and by phosphorylation of downstream proteins. The signalling cascade regulates cell proliferation, differentiation and survival. Disturbed RAS signalling in malignancies is caused by acquired somatic mutations in RAS genes or other components of this pathway. Recently, germline mutations in genes coding for different components of the RAS signalling cascade have been recognized as the cause of several phenotypically overlapping disorders, recently referred to as the neuro-cardio-facial-cutaneous syndromes. Neurofibromatosis type 1, Noonan, LEOPARD, Costello and cardiofaciocutaneous syndromes all present with variable degrees of psychomotor delay, congenital heart defects, facial dysmorphism, short stature, skin abnormalities and a predisposition for malignancy. These findings point to important roles for this evolutionary conserved pathway in oncogenesis, development, cognition and growth. Conclusion: it has become obvious in recent years that the neuro-cardio-facial-cutaneous syndromes all share a common genetic and pathophysiologic basis. Dysregulation of the RAS-MAPKinase pathway is caused by germline mutations in genes involved in this pathway. Undoubtedly more genes causing related syndromes will be discovered in the near future since there are still a substantial number of genes in the pathway that are not yet associated with a known syndrome.status: Publishe
Legius Syndrome and its Relationship with Neurofibromatosis Type 1
No full textNeurofibromatosis type 1 (NF1) is the most common disorder characterized by multiple café-au-lait macules. Most individuals with this autosomal dominant disorder also have other features, such as skinfold freckling, iris Lisch nodules and benign or malignant peripheral nerve sheath tumours. Legius syndrome is a less frequent autosomal dominant disorder with similar multiple café-au-lait macules and skinfold freckling. Legius syndrome is not characterized by an increased risk of tumours, and a correct diagnosis is important. In young children with a sporadic form of multiple café-au-lait macules with or without freckling and no other manifestations of NF1 these 2 conditions cannot be differentiated based on clinical examination. Molecular analysis of the NF1 and SPRED1 genes is usually needed to differentiate the 2 conditions. Other less frequent conditions with café-au-lait macules are Noonan syndrome with multiple lentigines, constitutional mismatch repair deficiency and McCune-Albright syndrome.status: Publishe
Clinical and molecular aspects of RAS related disorders
No full textRAS proteins play key roles in normal cell growth, malignant transformation and learning and memory. Somatic mutations in RAS genes and several of their upstream and downstream molecules result in different human malignancies. In recent years germline mutations in genes coding for components of the RAS signalling cascade have been recognised in a group of phenotypically overlapping disorders, referred to as the neuro-cardio-facial-cutaneous syndromes. These present with variable degrees of psychomotor delay, cardiac abnormalities, facial dysmorphism, short stature, skin defects and increased cancer risk. These findings point to important roles for this evolutionary conserved pathway not only in oncogenesis, but also in cognition, growth and development. Other constitutional disorders caused by mutated RAS pathway genes point to involvement of the RAS-MAPK pathway in immune modulation and vascular development.sponsorship: Funding: This work is supported by research grants from the Fonds voor Wetenschappelijk Onderzoek Vlaanderen (G.0578.06 and G.O551.08 to EL); the Interuniversity Attraction Poles (IAP) granted by the Federal Office for Scientific, Technical and Cultural Affairs, Belgium (2007-2011; P6/05) (EL) and by a Concerted Action Grant from the K U Leuven (EL). (Fonds voor Wetenschappelijk Onderzoek Vlaanderen|G.0578.06, Fonds voor Wetenschappelijk Onderzoek Vlaanderen|G.O551.08, Federal Office for Scientific, Technical and Cultural Affairs, Belgium|P6/05)status: Publishe
Legius syndrome in fourteen families
No full textLegius syndrome presents as an autosomal dominant condition characterized by café-au-lait macules with or without freckling and sometimes a Noonan-like appearance and/or learning difficulties. It is caused by germline loss-of-function SPRED1 mutations and is a member of the RAS-MAPK pathway syndromes. Most mutations result in a truncated protein and only a few inactivating missense mutations have been reported. Since only a limited number of patients has been reported up until now, the full clinical and mutational spectrum is still unknown. We report mutation data and clinical details in fourteen new families with Legius syndrome. Six novel germline mutations are described. The Trp31Cys mutation is a new pathogenic SPRED1 missense mutation. Clinical details in the 14 families confirmed the absence of neurofibromas, and Lisch nodules, and the absence of a high prevalence of central nervous system tumors. We report white matter T2 hyperintensities on brain MRI scans in 2 patients and a potential association between postaxial polydactyly and Legius syndrom
Canonical Wnt signaling controls proliferation of retinal stem/progenitor cells in postembryonic Xenopus eyes
No full textInternational audienceVertebrate retinal stem cells, which reside quiescently within the ciliary margin, may offer a possibility for treatment of degenerative retinopathies. The highly proliferative retinal precursor cells in Xenopus eyes are confined to the most peripheral region, called the ciliary marginal zone (CMZ). While the canonical Wnt pathway has been implicated in the developing retina of different species, little is known about its involvement in post-embryonic retinas. Using a GFP-based Wnt-responsive reporter, we show that in transgenic Xenopus tadpoles the canonical Wnt signaling is activated in the post-embryonic CMZ. To further investigate the functional implications of this, we generated transgenic, hormone-inducible canonical Wnt pathway activating and repressing systems, which are directed to specifically intersect at the nuclear endpoint of transcriptional Wnt target gene activation. We found that post-embryonic induction of the canonical Wnt pathway in transgenic retinas resulted in increased proliferation in the CMZ compartment. This is most likely due to delayed cell cycle exit, as inferred from a pulse chase experiment on BrdU labeled retinal precursors. Conversely, repression of the canonical Wnt pathway inhibited proliferation of CMZ cells. Neither activation nor repression of the Wnt pathway affected the differentiated cells in the central retina. We conclude that even at post-embryonic stages the canonical Wnt signaling pathway continues to have a major function in promoting proliferation and maintaining retinal stem cells. These findings may contribute to the eventual design of vertebrate, stem cell-based retinal therapies. ______________________________________________________________________________ Author contributions: T.Denayer: Conception and design, manuscript writing, collection and/or assembly of data, data analysis and interpretation; M.L.: Conception and design, collection and/or assembly of data, data analysis and interpretation; C.B.: Collection and/or assembly of data, data analysis and interpretation; T.Deroo: Generation of specific plasmid constructs; S.J.: Collection and/or assembly of data; A.H.: Generation of specific plasmid constructs; F.V.R.: Financial support; M.P.: Conception and design, manuscript writing, collection and/or assembly of data, data analysis and interpretation, final approval of manuscript, financial support; K.V.: Conception and design, manuscript writing, data analysis and interpretation, final approval of manuscript, financial support. Tinneke Denayer and Morgane Locker contributed equally to this work
