Pharmacological inhibition of fibroblast growth factor (FGF) receptor signaling ameliorates FGF23-mediated hypophosphatemic rickets.

Fibroblast growth factor 23 (FGF23) is a circulating factor secreted by osteocytes that is essential for phosphate homeostasis. In kidney proximal tubular cells FGF23 inhibits phosphate reabsorption and leads to decreased synthesis and enhanced catabolism of 1,25-dihydroxyvitamin D3 (1,25[OH]2 D3 ). Excess levels of FGF23 cause renal phosphate wasting and suppression of circulating 1,25(OH)2 D3 levels and are associated with several hereditary hypophosphatemic disorders with skeletal abnormalities, including X-linked hypophosphatemic rickets (XLH) and autosomal recessive hypophosphatemic rickets (ARHR). Currently, therapeutic approaches to these diseases are limited to treatment with activated vitamin D analogues and phosphate supplementation, often merely resulting in partial correction of the skeletal aberrations. In this study, we evaluate the use of FGFR inhibitors for the treatment of FGF23-mediated hypophosphatemic disorders using NVP-BGJ398, a novel selective, pan-specific FGFR inhibitor currently in Phase I clinical trials for cancer therapy. In two different hypophosphatemic mouse models, Hyp and Dmp1-null mice, resembling the human diseases XLH and ARHR, we find that pharmacological inhibition of FGFRs efficiently abrogates aberrant FGF23 signaling and normalizes the hypophosphatemic and hypocalcemic conditions of these mice. Correspondingly, long-term FGFR inhibition in Hyp mice leads to enhanced bone growth, increased mineralization, and reorganization of the disturbed growth plate structure. We therefore propose NVP-BGJ398 treatment as a novel approach for the therapy of FGF23-mediated hypophosphatemic diseases.

Ilmakuivaimen konstruktion modernisointi valmistustekniikan näkökul-masta

Diplomityössä tutkittiin päällystetyn paperin kuivatukseen käytettävän ilmakuivaimen rakennetta ja kustannuksia. Selvitysten perusteella modernisoinnin kohteeksi valittiin kuivaimen runko ja kääntöosa. Niiden modernisoinnissa huomioitiin nykyaikaisten valmistusmenetelmien mukanaan tuomia etuja ja mahdollisuuksia. Työn perusteella ehdotetaan nykyisen putkipalkkirakenteen korvaamista levyrakenteisella konstruktiolla. Tämä edellyttää särmäyksen tarkkaa hallintaa sekä laserleikkauksen hyväksikäyttöä levyosien valmistuksessa. Laser-leikkauksella vähennetään lisäksi leikkauksen jälkeisiä työvaiheita sekä mahdollistetaan osien vapaampi muotoilu. Uuden konstruktion myötä osien, nimikkeiden, hitsimetrien ja kustannusten määrät vähenevät sekä tuotantoketju ja kokoonpano yksinkertaistuvat. Lisäksi levyrakenteen ansiosta teollinen muotoilu kyetään ottamaan entistä paremmin huomioon tuotteen suunnittelussa. Jatkotoimenpiteenä levykonstruktiota kehitetään sekä sen mahdollisuuksia analysoidaan eri menetelmillä.

Suurnopeuskompressorin modulaarisen runkosarjan suunnittelu

Tässä diplomityössä suunniteltiin parametrisesti modulaarinen koneen runko. Pyrkimyksenä oli suunnitella kokonaiskustannuksiltaan alhaisempi runkosarja jo olemassa oleviin suurnopeuskompressoreihin. Raportissa kerrotaan ensin modulaaristen tuoterakenteiden suunnittelusta ja käytettävästä suunnitteluohjelmistosta (SolidWorks). Sen jälkeen keskitytään suurnopeuskompressorin runkosarjan suunnitteluun esimerkkitapauksena. Aluksi keskitytään selvittämään rungolle asetettuja vaatimuksia ja ideoimaan erilaisia runkokonsepteja. Työ etenee ideoiden vertailun kautta modulaaristen konseptien luomiseen ja kahden moduulin moduulikohtaiseen suunnitteluun. Suunnitteluprosessissa käytetään rakenteen käyttäytymisen arviointiin äärellisten elementtien menetelmää (FEM). Työssä kehitettiin alkuperäisiin runkorakenteisiin verrattuna 10 % kustannuksiltaan edullisempi runkorakenneratkaisu, jonka purettavuus lisäksi alentaa rakenteen kuljetus- ja varastointikustannuksia.

Hitsatun kerrossihtilevyrakenteen soveltuvuus sellutehtaan laitteiden suodatinpinnaksi

Tässä diplomityössä tutkittiin hitsaamalla valmistettavan kerrossihtilevyn soveltuvuutta eri sellutehtaan laitteisiin mekaanisen kuormituskokeen, korroosiokokeen ja syrjäytyskokeiden avulla. Tutkimusympäristönä käytettiin puukuitupesuria, sillä kerrossihtilevyrakenteen todennäköisimpiä käyttökohteita ovat erilaiset massan pesuun tarkoitetut laitteet. Mekaanisen kuormituksen kokeessa tarkasteltiin kerrossihtilevyn staattista ja dynaamista kuormituksen kestoa painevaihteluiden avulla pesurin koelokerossa ja verrattiin sitä porattuun reikälevyyn. Kokeessa käytetyn kerrossihtilevyversion todettiin olevan huomattavasti porattua saman paksuista reikälevyä heikompi dynaamisen kuormituksen alaisena. Syrjäytyskokeilla määritettiin syrjäytysnopeus erilaisilla reiänhalkaisijoilla ja –jaoilla sekä tutkittiin väriaineen avulla sokeiden tukikannasten vaikutusta syrjäytyspesun homogeenisuuteen levyn pinnassa. Syrjäytysnopeuden todettiin heikentyvän vapaan reikäpinta-alan pienentyessä. Väriaineellisissa kokeissa ei havaittu tukikannasten merkittävästi alentavan syrjäytysnopeutta. Korroosiokokeilla tutkittiin ja vertailtiin laser- ja vastuspistehitsien korroosionkestokykyä kloridipitoisissa olosuhteissa lämpötilan säätelyn mahdollistavan olosuhdekaapin avulla. Laserhitsauksessa parametrien ei havaittu vaikuttavan merkittävästi hitsin herkistymislämpötilaan. Vastuspistehitsaamalla on mahdollista saavuttaa laserhitsien korroosionkesto.

Distortion and internal warping torsion of a double symmetric hollow section

This thesis is made in cooperation with Laboratory of Steel Structures and the steel company SSAB. Maximization of the benefits of high-strength steel usually requires the usage of thin wall thicknesses. This means the failures related to buckling, distortion and warping stand out. One must be aware of these phenomena to design thin-walled structures stressed with forces such as torsional loading. It is also important to take into account small stress ranges when evaluating the accurate fatigue strength of structures. The objective of this thesis is to clarify the theory of the uniform and non-uniform torsion. This paper focuses on warping due to the non-uniform torsion in double symmetric box girder and structural hollow section. The arisen stress states are explained and researched using the finite element method. Another research target is the distortion in double symmetric box girder due to torsion, and the restraining effect of transverse diaphragms at the load end. Multiple transverse diaphragms are used to study more efficient restraining against warping and distortion than a common one end plate structure.

Análisis del acoplamiento vibro-acústico en resonadores de membrana

El presente Trabajo Fin de Máster pretende llevar a cabo el análisis del comportamiento vibratorio de resonadores de membrana, consistentes en un panel delgado y ligero montado a cierta distancia de un elemento constructivo rígido y pesado. Este tipo de sistemas resonantes son empleados habitualmente como absorbentes de media-baja frecuencia en aplicaciones de acondicionamiento acústico de salas. El análisis hará especial hincapié en la influencia del acoplamiento mecánico-acústico entre la placa vibrante (estructura) y el colchón de aire (fluido) encerrado entre la misma y la pared rígida. En primer lugar, realizaremos el análisis modal experimental del resonador objeto de ensayo a partir de las mediciones de su respuesta vibratoria, con el fin de caracterizar su comportamiento en base a sus primeros modos propios acoplados de flexión. El análisis de las señales vibratorias en el dominio de la frecuencia para la identificación de dicho modos se realizará en el entorno de programación MATLAB, haciendo uso de una herramienta propia que implementa los métodos de cálculo y los algoritmos necesarios para tal fin. Asimismo, simularemos el comportamiento del resonador mediante el método de elementos finitos (FEM), utilizando las aplicaciones ANSYS y SYSNOISE, considerando diferentes condiciones frontera en el modelo generado. Los resultados aquí obtenidos serán de utilidad para complementar aquellos obtenidos de forma experimental a la hora de extraer conclusiones prácticas del análisis realizado. SUMMARY. This Master's Thesis intends to carry out the analysis of the vibratory behaviour of resonance absorbers, consisting of a thin and lightweight panel mounted at a distance from a rigid wall. Such systems are commonly used as sound absorption systems for mid-low frequency in room acoustics applications. The analysis will emphasize the influence of mechanical-acoustic coupling between the vibrating plate (structure) and the air cushion (acoustic element) enclosed behind it. First of all, we are performing the experimental modal analysis of the resonance absorber under test from the vibrational response measurements, in order to characterize its behaviour based on its first bending coupled-modes. The analysis of vibration signals in the frequency domain for the identification of such modes will be made in MATLAB programming environment, using a proprietary tool that implements the calculation methods and algorithms needed for this purpose. Furthermore, we are simulating the behaviour of the resonance absorber applying the Finite Element Method (FEM) – using ANSYS and SYSNOISE applications - considering different boundary conditions in the model created. The results from the simulation will be useful to complement those obtained experimentally when drawing practical conclusions from this analysis.

An investigation of the effect of powder on the impact characteristics between a ball and a plate using free falling experiments

The study of the mechanisms of mechanical alloying requires knowledge of the impact characteristics between the ball and vial in the presence of milling powders. In this paper, foe falling experiments have br cn used to investigate the characteristics of impact events involved in mechanical milling. The effects of milling conditions, including impact velocity, ball size and powder thickness. on the coefficient of restitution and impact force are studied. It is found that the powder has a significant influence on the impact process due to its porous structure. This effect can be demonstrated using a modified Kelvin model. This study also confirms that the impact force is a relevant parameter for characterising the impact event due to its sensitivity to the milling conditions. (C) 1998 Elsevier Science S.A.

Structure development in octadecyl trimethylammonium templated silicate films grown at the air/water interface

The mechanism of growth of silicate films at the air/liquid interface has been investigated in situ by a series of grazing incidence diffraction experiments using a 20 x 25 cm(2) imaging plate as the detector. C(18)TAX (X = Br- or Cl-) has been used as the film templating surfactant. The formation of a layered phase, prior to growth of the hexagonal mesophase in C(18)TABr templated films. has been seen. This layered structure has a significantly shorter d spacing compared to the final hexagonal film (43 versus 48 Angstrom, respectively). The correlation lengths associated with the development of the hexagonal in-plane diffraction spots are much longer in-plane than perpendicular to the air/liquid interface (300 Angstrom versus 50 Angstrom). This implies that the film forms via the growth or aggregation of islands that are initially only a micelle or two thick. which then grow down into the solution.

Analysis of a circular patch antenna radiating in a parallel-plate radial guide

A field matching method is described to analyze a recessed circular cavity radiating into a radial waveguide. Using the wall impedance approach, the analysis is divided into two separate problems of the cavity and its external environment. Based on this analysis, a computer algorithm is developed for determining wall admittances as seen at the edge of the patch in the cavity, the radial admittance matrix for the two-probe feed arrangement, and the input impedance as observed from the coaxial line feeding the cavity. This algorithm is tested against the general-purpose Hewlett-Packard finite-element High Frequency Structure Simulator as well as against measured results. Good agreement in all considered cases is noted.

Paleomagnetic study of the Messejana Plasencia dyke (Portugal and Spain): A lower Jurassic paleopole for the Iberian plate

The only Iberian lower Jurassic palcomagnetic pole come from the "Central Atlantic Magmatic Province"-related Messejana Plasencia dyke, but the age and origin of its remanence have been a matter of discussion. With the aim of solving this uncertainty, and to go further into a better understanding of its emplacement and other possible tectonic features, a systematic paleomagnetic investigation of 40 sites (625 specimens) distributed all along the 530 kin of the Messejana Plasencia dyke has been carried out. Rock magnetic experiments indicate PSD low Ti-titanomagnetite and magnetite as the minerals carrying the NRM. The samples were mostly thermally demagnetized. Most sites exhibit a characteristic remanent component of normal polarity with the exception of two sites, where samples with reversed polarities have been observed. The paleomagnetic pole derived from a total of 35 valid sites is representative of the whole structure of the dyke, and statistically well defined, with values of PLa = 70.4 degrees N, PLo = 237.6 degrees E, K= 47.9 and A(95) = 3.5 degrees. Paleomagnetic data indicates that: (i) there is no evidence of a Cretaceous remagnetization in the dyke, as it was suggested; (ii) most of the dyke had a brief emplacement time; furthermore, two dyke intrusion events separated in time from it by at least 10,000 y have been detected; (iii) the high grouping of the VGPs directions suggests no important tectonic perturbations of the whole structure of the dyke since its intrusion time; (iv) the pole derived from this study is a good quality lower Jurassic paleopole for the Iberian plate; and (v) the Messejana Plasencia dyke paleopole for the Iberian plate is also in agreement with quality-selected European and North American lower Jurassic paleopoles and the magnetic anomalies data sets that are available for rotate them to Iberia.

The Maggia cross-fold: An enigmatic structure of the lower Penninic nappes of the Lepontine Alps

The geometry and kinematics of the map scale Maggia cross-fold structure has been studied by several generations of geologists over seventy years and different models have been proposed for its formation. New observations indicate that the Maggia structure is a SW-verging cross-fold created after earlier NW-directed overthrusting of the Maggia nappe onto the deeper Simano and Antigorio recumbent fold nappes. The nappe emplacement and later cross-folding occurred under amphibolite facies conditions by detachment of the upper European crust during its SE-directed underthrusting below the Adriatic plate.

Structure and kinematics of the Jungfrau syncline, Faflertal (Valais, Alps), and its regional significance

The formation and structural evolution of the jungrau syncline is described, based on excellent outcrops occurring in the lotschental, in the central alps of switzerland. the quality of the outcrops allows us to demonstrate that the external massifs of the swiss alps have developed due to internal folding. The jungfrau suncline, which separates the autochtonous gastern dome from the aar massif basement gneiss folds, is composed of slivers of basement rocks with their mesozoic sedimentary cover. in the inner faflertal, a side valley of the lotschental, the 200 m thick syncline cp, roses fpir imots, the gastern massif with a reduced mesozoic sedimentary cover in a normal stratigraphic succession, two units of overturned basement rocks with their mesozoic sedimentary cover, and the overturned lower limn of the tschingelhorn gneiss fold of the aar massif with lenses of its sedimentary cover. stratigraphy shows that the lower units, related to the gastern massis, are condensed and that the upper units, deposited farther away from a gastern paleo-high, form a more complete sequence, linked to the doldenhorn meso-cneozoic basin fill. the integration of these local observations with published regional data leads to the following model. on the northern margin of the doldenhorn hbasin, at the northern fringe of the alpine tethuys, the pre-triassic crystalline basement and its mesozoic sedimentary cover were folded by ductile deformation at temperatures above 300 degrees C and in the presence of high fluid pressures, as the helveti c and penninic nappes were overthrusted towards the northwest during the main alpine deformation phase, the visosity contrast between the basement gneisses and the sediments caused the formation of large basement anticlines and tight sedimentary sunclines (mullion-type structures). The edges of basement blocks bounded buy pre-cursor se-dipping normal faults at the northwestern border of the doldenhorn basin were deformed bu simple shear, creating overturned slices of crystalline rocks with their sedimentary cover in what now forms the hungfrau syncline. the localisation of ductile deformation in the vicinity of pre-existing se-dipping faults is thought to have been helped by the circulation of fluids along the faults; these fluids would have been released from the mesozoic sediments by metamorphic dehydration reactions accompanied by creep and dynamic recrystallisation of quartz at temperatures above 300 degrees C. Quantification of the deformation suggests an strain ellipsoid with a ratio (1 + e(1)/+ e(3)) of approximately 1000. The jungfrau suncline was deformed bu more brittle nw-directed shear creating well-developed shear band cleavages at a late stage, after cooling by uplift and erosion. It is suggested that the external massifs of the apls are basement gneiss folds created at temperatures of 300 degrees C by detachment through ductile deformation of the upper crust of the european plate as it was underthrusted below the adriatic plate.

The Hercynian structure of the Catalonian Coastal Ranges (NE Spain)

In the Catalonian Coastal Ranges, Paleozoic sedimentary and meta-sedimentary rocks crop out in severa1 areas, intruded by late tectonic Hercynian granitoids and separated by Mesozoic and Tertiary cover sediments. Large structures are often difficult to recognize, although a general east-west trend can be observed on the geological map. Deformation was accompanied by the development of cleavages and regional metamorphism. Green-schist facies rocks are prominent throughout the Ranges, while amphibolite facies are restricted to small areas. In low-grade areas, the main deformation phase generated south-facing folds with an axial plane cleavage (slaty cleavage in metapelitic rocks). The intersection lineation (Ss/Sl) and the axes of minor folds trend cast-west, as do all mapable structures. Late deformations generated coarse crenulations, small chevrons and kink-bands, all intersecting the slaty cleavage at high angles. In medium- to high-grade areas no major folds have been observed. In these areas, the main foliation is a schistosity and is often folded, giving centimetric to decimetric, nearly isoclinal intrafolial folds. In schists, these folds aremuchmore common than inother lithologies, and can be associated with a crenulation cleavage. All these planar structures in high-grade rocks are roughly parallel. The late Hercynian deformational events, which gave rise to the crenulations and small chevrons, also produced large (often kilometric) open folds which fold the slaty cleavage and schistosity. As aconsequence, alternating belts with opposite dip (north and south) of the main foliation were formed. With respect to the Hercynian orogenic belt, the Paleozoic outcrops of the Catalonian Coastal Ranges are located within the northern branch of the Ibero-Armorican arc, and have a relatively frontal position within the belt. The Carboniferous of the Priorat-Prades area, together with other outcrops in the Castellón Province, the Montalbán massif (Iberian Chain) and the Cantabrian zone (specially the Pisuerga-Carrión Province) probably form part of a wide area of foreland Carboniferous deposition placed at the core of the arc.