High incidence of Noonan syndrome features including short stature and pulmonic stenosis in patients carrying NF1 missense mutations affecting p.Arg1809: genotype-phenotype correlation

Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders, affecting 1:3,000 worldwide. Identification of genotype-phenotype correlations is challenging because of the wide range clinical variability, the progressive nature of the disorder, and extreme diversity of the mutational spectrum. We report 136 individuals with a distinct phenotype carrying one of five different NF1 missense mutations affecting p.Arg1809. Patients presented with multiple cafe-au-lait macules (CALM) with or without freckling and Lisch nodules, but no externally visible plexiform neurofibromas or clear cutaneous neurofibromas were found. About 25% of the individuals had Noonan-like features. Pulmonic stenosis and short stature were significantly more prevalent compared with classic cohorts (P<0.0001). Developmental delays and/or learning disabilities were reported in over 50% of patients. Melanocytes cultured from a CALM in a segmental NF1-patient showed two different somatic NF1 mutations, p.Arg1809Cys and a multi-exon deletion, providing genetic evidence that p.Arg1809Cys is a loss-of-function mutation in the melanocytes and causes a pigmentary phenotype. Constitutional missense mutations at p.Arg1809 affect 1.23% of unrelated NF1 probands in the UAB cohort, therefore this specific NF1 genotype-phenotype correlation will affect counseling and management of a significant number of patients

Dynamic soil-structure interaction analysis of a telescope at the Javalambre Astrophysical Observatory

This paper reports on the dynamic soil-structure analysis of a telescope pier of an astrophysical laboratory in the Sierra de Javalambre, Teruel (Spain). Vibration control in the design stage is of prime concern, since astrophysical observations may be hindered by mechanical vibration of the sensitive optics of the telescope. These vibrations may result from wind loading on the telescope dome, transferred through the foundation to the telescope. Therefore, the manufacturer of the telescope has imposed a minimal resonance frequency of 10 Hz for the supporting structure. For a massive construction such as a telescope pier, this resonance frequency may be significantly influenced by the effects of dynamic soil-structure interaction. The telescope is mounted on a concrete pier with a height of 15.25 m, founded on 73 reinforced concrete micro-piles with a diameter of 0.40 m. The dynamic soil characteristics at the site have been determined by means of a down-hole test. The effect of dynamic soil-structure interaction is studied using a coupled finite element - boundary element model of the telescope pier - foundation soil system. The response of the telescope is computed for harmonic loading at the top of the telescope pier. Results demonstrate that the effect of dynamic soil-structure interaction is significant. An analysis that disregards dynamic soil-structure interaction results a predicted resonance of 14.28 Hz while a fully coupled analysis predicts a resonance frequency of 11.2 Hz.status: publishe

Dynamic soil-structure interaction analysis of a telescope at the Javalambre Astrophysical Observatory

This paper presents the dynamic soil-structure analysis of the main telescope 1250 of the Observatorio Astroffsico de Javalambre (OAJ, Javalambre Astrophysical Observatory) on the Pico del Buitre. Vibration control has been of prime concern in the design, since astrophysical observations may be hindered by mechanical vibration of optical equipment due to wind loading. The telescope manufacturer therefore has imposed a minimal natural frequency of 10 Hz for the supporting telescope pier. Dynamic soilstructure interaction may significantly influence the lowest natural frequency of a massive construction as a telescope pier. The structure clamped at its base has a resonance frequency of 14.3 Hz. A coupled finite element-boundary element (FE-BE) model of the telescope pier that accounts for the dynamic interaction of the piled foundation and the soil predicts a resonance frequency of 11.2 Hz, demonstrating the significant effect of dynamic soil-structure interaction. It is further investigated to what extent the coupled FE-BE model can be simplified in order to reduce computation time. The assumption of a rigid pile cap allows us to account for dynamic soil-structure interaction in a simplified way. A coupled FE-BE analysis with a rigid pile cap predicts a resonance frequency of 11.7 Hz, demonstrating a minor effect of the pile cap flexibility on the resonance frequency of the telescope pier. The use of an analytical model for the pile group results in an overestimation of the dynamic soil stiffness. This error is due to the large difference between the actual geometry and the square pile cap model for which the parameters have been tuned. (C) 2014 Elsevier Ltd. All rights reserved.Francois, S.; Galvin, P.; Museros Romero, P.; Lombaert, G.; Degrande, G. (2014). Dynamic soil-structure interaction analysis of a telescope at the Javalambre Astrophysical Observatory. Soil Dynamics and Earthquake Engineering. 65:165-180. doi:10.1016/j.soildyn.2014.06.014S1651806

A 2.5D coupled FE-BE methodology for the dynamic interaction between longitudinally invariant structures and the soil

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A 2.5D coupled FE-BE methodology for the prediction of railway induced vibrations

Ground vibrations induced by railway traffic are often studied by means of two-and-half dimensional (2.5D) models that are based on the longitudinal invariance of the track geometry. In this paper, a 2.5D methodology is used where the finite element method is combined with a boundary element method, based on a regularized boundary integral equation. In the formulation of the boundary integral equation, the Green's functions of a layered elastic halfspace are used, so that no discretization of the free surface or the layer interfaces is required. The methodology is applied to two cases. In the first case, two alternative models for a ballasted track on an embankment are compared. In the first model, the ballast and the embankment are modelled as a continuum using 2.5D solid elements, whereas a simplified beam representation is adopted in the second model. A very large difference is found for the free field mobility of both models, which demonstrates the need for detailed 2.5D modelling of the embankement. In the second case, the efficiency of a vibration isolating screen is studied. A vibration isolating screen is a soft or stiff wave barrier. Due to the impedance contrast between the isolating screen and the soil, incident waves are reflected. As a result, the vibration levels behind the screen are effectively reduced. Both examples demonstrate that the use of detailed 2.5D models result in a better insight in the mechanical behavior of the coupled soil-track system.status: publishe

Regional Amyloid-β Load and White Matter Abnormalities Contribute to Hypometabolism in Alzheimer's Dementia

We investigated the association between amyloid-β deposition and white matter (WM) integrity as a determinant of brain glucose hypometabolism across the Alzheimer's disease (AD) spectrum. We assessed ninety-six subjects (27 cognitively normal, 49 mild cognitive impairment, and 20 AD dementia) who underwent [ F]FDG and [ F]Florbetapir positron emission tomography (PET) as well as magnetic resonance imaging (MRI) with diffusion tensor imaging. Among the regions with reduced fractional anisotropy (FA) in the AD group, we selected a voxel of interest in the angular bundle bilaterally for subsequent analyses. Using voxel-based interaction models at voxel level, we tested whether the regional hypometabolism is associated with FA in the angular bundle and regional amyloid-β deposition. In the AD patients, [ F]FDG hypometabolism in the striatum, mesiobasal temporal, orbitofrontal, precuneus, and cingulate cortices were associated with the interaction between high levels of [ F]Florbetapir standard uptake value ratios (SUVR) in these regions and low FA in the angular bundle. We found that the interaction between, rather than the independent effects of, high levels of amyloid-β deposition and WM integrity disruption determined limbic hypometabolism in patients with AD. This finding highlights a more integrative model for AD, where the interaction between partially independent processes determines the glucose hypometabolism

Signaling pathway screening platforms are an efficient approach to identify therapeutic targets in cancers that lack known driver mutations: a case report for a cancer of unknown primary origin

Precision medicine aims to tailor cancer therapies to target specific tumor-promoting aberrations. For tumors that lack actionable drivers, which occurs frequently in the clinic, extensive molecular characterization and pre-clinical drug efficacy studies will be required. A cell line maintained at low passage and a patient- derived xenograft model (PDX) were generated using a fresh biopsy from a patient with a poorly-differentiated neuroendocrine tumor of unknown primary origin. Next-generation sequencing, high throughput signaling network analysis, and drug efficacy trials were then conducted to identify actionable targets for therapeutic intervention. No actionable mutations were identified after whole exome sequencing of the patient’s DNA. However, whole genome sequencing revealed amplification of the 3q and 5p chromosomal arms, that include the PIK3CA and RICTOR genes, respectively. We then conducted pathway analysis, which revealed activation of the AKT pathway. Based on this analysis, efficacy of PIK3CA and AKT inhibitors were evaluated in the tumor biopsy-derived cell culture and PDX, and response to the AKT inhibitor AZD5363 was observed both in vitro and in vivo indicating the patient would benefit from targeted therapies directed against the serine/threonine kinase AKT. In conclusion, our study demonstrates that high throughput signaling pathway analysis will significantly aid in identifying actionable alterations in rare tumors and guide patient stratification into early-phase clinical trials