Gain-of-function mutations in the EPAS1/HIF2A gene have been identified in patients with hereditary erythrocytosis that can be associated with the development of paraganglioma, pheochromocytoma and ...somatostatinoma. In the present study, we describe a unique European collection of 41 patients and 28 relatives diagnosed with an erythrocytosis associated with a germline genetic variant in EPAS1. In addition we identified two infants with severe erythrocytosis associated with a mosaic mutation present in less than 2% of the blood, one of whom later developed a paraganglioma. The aim of this study was to determine the causal role of these genetic variants, to establish pathogenicity, and to identify potential candidates eligible for the new hypoxia-inducible factor-2 α (HIF-2α) inhibitor treatment. Pathogenicity was predicted with in silico tools and the impact of 13 HIF-2b variants has been studied by using canonical and real-time reporter luciferase assays. These functional assays consisted of a novel edited vector containing an expanded region of the erythropoietin promoter combined with distal regulatory elements which substantially enhanced the HIF-2α-dependent induction. Altogether, our studies allowed the classification of 11 mutations as pathogenic in 17 patients and 23 relatives. We described four new mutations (D525G, L526F, G527K, A530S) close to the key proline P531, which broadens the spectrum of mutations involved in erythrocytosis. Notably, we identified patients with only erythrocytosis associated with germline mutations A530S and Y532C previously identified at somatic state in tumors, thereby raising the complexity of the genotype/phenotype correlations. Altogether, this study allows accurate clinical follow-up of patients and opens the possibility of benefiting from HIF-2α inhibitor treatment, so far the only targeted treatment in hypoxia-related erythrocytosis disease.
The oncogenic G-protein-coupled receptor (GPCR) Smoothened (SMO) is a key transducer of the hedgehog (HH) morphogen, which plays an essential role in the patterning of epithelial structures. Here, we ...examine how HH controls SMO subcellular localization and activity in a polarized epithelium using the
Drosophila
wing imaginal disc as a model. We provide evidence that HH promotes the stabilization of SMO by switching its fate after endocytosis toward recycling. This effect involves the sequential and additive action of protein kinase A, casein kinase I, and the Fused (FU) kinase. Moreover, in the presence of very high levels of HH, the second effect of FU leads to the local enrichment of SMO in the most basal domain of the cell membrane. Together, these results link the morphogenetic effects of HH to the apico-basal distribution of SMO and provide a novel mechanism for the regulation of a GPCR.
•Simple model provides an intuitive understanding of the vibro-acoustic phenomena.•Coupling dynamics dependent on three dimensionless parameters.•Resonators catalyze the conversion of vibrational ...energy into audible sound.•Proposed model enables the design of instruments with multi-modal coupling.•Experiments validate realism of the model, both qualitatively and quantitatively.
In some mallet percussion instruments, like vibraphones and marimbas, acoustical resonators are placed under the tuned bars to enhance acoustic radiation. Despite its wide use in commercial instruments, the vibro-acoustic interaction between the tuned bars and their acoustic resonators has not been studied extensively, and previous modeling attempts often neglect important aspects of the coupling dynamics. This work presents a physical model describing the two-way vibro-acoustic interaction between a vibrating beam and an acoustic resonator. The proposed formulation leads to a system composed of a set of mechanical oscillators coupled to a set of acoustical oscillators, representing bar and resonator modes, respectively. The simplicity of the proposed model provides an intuitive understanding of the physics occurring in real instruments and show how specific design parameters will affect their behavior. The dynamics of the system are analyzed through energy balance, time-domain simulations and eigenvalue analysis, revealing a number of interesting features and highlighting three dimensionless parameters: the ratio of frequencies and quality factors, as well as a coupling “strength” coefficient, dependent on the bar-resonator distance, the placement of the resonator along the bar length, bar and resonator mode shapes, amongst others. The proposed model is also shown to be a useful tool for the design of instruments optimized for multi-modal coupling, where several resonator modes are tuned to bar frequencies. Finally, experimental results are presented to validate various aspects of the proposed model and demonstrate its capacity to emulate real instruments, both qualitatively and quantitatively.
The semicircular canal (SC) system of the inner ear detects head angular accelerations and is essential for navigation and spatial awareness in vertebrates. Because the bony labyrinth encloses the ...membranous labyrinth SCs, it can be used as a proxy for animal behavior. The bony labyrinth of dicynodonts, a clade of herbivorous non-mammalian synapsids, has only been described in a handful of individuals and remains particularly obscure. Here we describe the bony labyrinth anatomy of three Endothiodon cf. bathystoma specimens from Mozambique based on digital reconstructions from propagation phase-contrast synchrotron micro-computed tomography. We compare these findings with the bony labyrinth anatomy of their close relative Niassodon. The bony labyrinths of Endothiodon and Niassodon are relatively similar and show only differences in the shape of the horizontal SCs and the orientation of the vertical SCs. When compared to extant mammals, Endothiodon and Niassodon have highly eccentric SCs. In addition, the Endothiodon SCs are nearly orthogonal. An eccentric and orthogonal SC morphology is consistent with a specialization in rapid head movements, which are typical of foraging or feeding behaviors. Furthermore, we estimate the body mass of these Endothiodon specimens at ~116 to 182 kg, based on the average SC radii calculated using a linear regression model optimized by the Amemiya Prediction Criterion. Our findings provide novel insights into the paleobiology of Endothiodon which are consistent with the peculiar feeding mechanism among dicynodonts presumed from their multiple postcanine toothrows.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We present a method to tune the natural frequencies of a generic bar of mallet percussion instruments (e.g. marimba, vibraphone), for a set of predefined target frequencies, using a global ...optimization algorithm. The bar is modelled as a one-dimensional Timoshenko beam and its natural frequencies are calculated via 1-D finite elements. The undercut is made up of a series of rectangular cuts, which aside from reducing the dimension of the optimization problem to a few pairs of variables (height and length of each cut) also generates shapes that are easy to manufacture. Moreover, two penalty terms are added to the objective function, in a weighted manner, to (1) minimize the amount of extracted material and (2) minimize abrupt changes in profile height, aimed to alleviate the complexity and accelerate the manufacturing process.
An evolutionary optimization algorithm is developed and extensive computational experiments are carried out to assess the algorithm’s performance and find appropriate parameter values for a faster convergence.
The results illustrate the effect of the different penalties on the solutions obtained. Additionally, optimized shapes for various unorthodox and demanding tuning targets are presented and compared to previously published results, illustrating the benefits of the simplified undercut model.
In some mallet percussion instruments, such as vibraphones and marimbas, tubular acoustic resonators are placed beneath the tuned bars to enhance acoustic radiation at their fundamental frequency. ...This work deals with the formulation of a minimal physical model describing the vibro-acoustic interaction occurring in these instruments. The fundamental bar mode is modelled as a disk-shaped oscillator and the resonator as a cylindrical acoustic waveguide, described in terms of its acoustic modes. The three-dimensional effects associated with sound radiation and the interaction between the two elements are calculated using a 2-D axisymmetric finite element (FE) model, whose numerical results are then fitted to dimensionless analytical expressions, which encapsulate the complex physics of the vibro-acoustic interaction in a simplified manner. This can pragmatically be used to formulate a lumped-parameter model of the coupled system. Illustrative numerical results are presented and qualitatively validated, demonstrating the ability of the proposed modelling approach to capture the essential features of the coupled dynamics occurring in real instruments.
Capable of maintaining characteristics practically intact over the centuries, bells are musical instruments able to provide important and unique data for the study of musicology and archaeology ...essential to understand past manufacturing and tuning techniques. In this research we present a multidisciplinary approach based on both direct and reverse engineering processes for the dynamical characterization and sound synthesis of historical bells which proven particularly useful to extract and preserve important information for Cultural Heritage. It allows the assessment of the bell’s 3D morphology, sound properties and casting and tuning techniques over time. The accuracy and usefulness of the developed techniques are illustrated for three historical bells, including the oldest recognized bell in Portugal, dated 1287, and two eighteenth century bells from the Mafra National Palace carillons (Portugal). The proposed approach combines non-invasive up-to-date imaging technology with modelling and computational techniques from vibration analysis, and can be summarized in the following steps: (1) For the diagnosis of existing bells, a precise assessment of the bell geometry is achieved through 3D scanning technologies, used for the field measurement and reconstruction of a 3D geometry model of each bell; (2) To access the modal properties of the bells, for any given (at the design stage) or measured geometry, a finite element model is built to compute the significant frequencies of the bell partials, and the corresponding modal masses and modeshapes. In the case of existing bells, comparison of the computed modes with those obtained from vibrational data, through experimental modal identification, enables the validation (or otherwise correction) of the finite element model; (3) Using the computed or experimentally identified modes, time-domain dynamical responses can be synthesized for any conceivable bell, providing realistic sounds for any given clapper and impact location. Although this study primarily aimed to better understand the morphology and sounds of historical bells to inform their conservation/preservation, this technique can be also applied to modern instruments, either existing or at design stages. To a larger extent, it presents strong potential for applications in the bell industry, namely for restoration and re-tuning, as well as in virtual museology.
•Continuation and bifurcation analysis of beams in confined axial flow.•Flutter instabilities can have both sub- and super-critical character.•Flow nonlinear effects are the root cause for ...sub-critical hopf bifurcations.•Proposed method for an “augmented” linear stability analysis.•Nonlinear dynamics include hysteresis, internal resonances and quasi-periodicity.
The flutter of cantilevered beams in channel flow is a benchmark example of flow-induced vibrations and its fundamental behaviour is found in numerous practical applications. Experiments have shown that such systems present a wide variety of complex nonlinear behaviour. However, the plethora of previous studies is mostly concerned with linear stability analysis. In this work, we provide an initial impulse for a comprehensive nonlinear study of these systems through bifurcation analysis. We consider a one-dimensional problem, where a cantilevered beam is treated in a modal framework and the surrounding flow is modelled by bulk-flow equations. The system is discretized in space and time via Galerkin procedures (modal, Tau and harmonic balance) and the continuation of periodic solutions is achieved using the asymptotic numerical method. Additionally, a numerical method for an “augmented” linear stability analysis is proposed, allowing the continuation of Hopf bifurcation branches, including their sub- or super-critical nature. The nonlinear dynamics are explored with respect to various dimensionless parameters. Results illustrate a number of behavioural trends: sub-critical bifurcations and hysteresis loops, internal resonances, grazing boundaries (separation between limit cycles with and without intermittent beam-wall impacts) as well as torus bifurcations and quasi-periodic oscillations.
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