Detection and Modeling of Boundary Layer Height

This thesis tackles the problem of the automated detection of the atmospheric boundary layer (BL) height, h, from aerosol lidar/ceilometer observations. A new method, the Bayesian Selective Method (BSM), is presented. It implements a Bayesian statistical inference procedure which combines in an statistically optimal way different sources of information. Firstly atmospheric stratification boundaries are located from discontinuities in the ceilometer back-scattered signal. The BSM then identifies the discontinuity edge that has the highest probability to effectively mark the BL height. Information from the contemporaneus physical boundary layer model simulations and a climatological dataset of BL height evolution are combined in the assimilation framework to assist this choice. The BSM algorithm has been tested for four months of continuous ceilometer measurements collected during the BASE:ALFA project and is shown to realistically diagnose the BL depth evolution in many different weather conditions. Then the BASE:ALFA dataset is used to investigate the boundary layer structure in stable conditions. Functions from the Obukhov similarity theory are used as regression curves to fit observed velocity and temperature profiles in the lower half of the stable boundary layer. Surface fluxes of heat and momentum are best-fitting parameters in this exercise and are compared with what measured by a sonic anemometer. The comparison shows remarkable discrepancies, more evident in cases for which the bulk Richardson number turns out to be quite large. This analysis supports earlier results, that surface turbulent fluxes are not the appropriate scaling parameters for profiles of mean quantities in very stable conditions. One of the practical consequences is that boundary layer height diagnostic formulations which mainly rely on surface fluxes are in disagreement to what obtained by inspecting co-located radiosounding profiles.

Generation and characterization of mouse models of Small cell lung cancer and Basal cell carcinoma for the preclinical evaluation of new therapies

Background. Human small cell lung cancer (SCLC) accounting for approximately 15-20% of all lung cancers, is an aggressive tumor with high propensity for early regional and distant metastases. Although the initial tumor rate response to chemotherapy is very high, SCLC relapses after approximately 4 months in ED and 12 months in LD. Basal cell carcinoma (BCC) is the most prevalent cancer in the western world, and its incidence is increasing worldwide. This type of cancer rarely metastasizes and the death rate is extraordinary low. Surgery is curative for most of the patients, but for those that develop locally advanced or metastatic BCC there is currently no effective treatment. Both types of cancer have been deeply investigated and genetic alterations, MYCN amplification (MA) among the most interesting, have been found. These could become targets of new pharmacological therapies. Procedures. We created and characterized novel BLI xenograft orthotopic mouse models of SCLC to evaluate the tumor onset and progression and the efficacy of new pharmacological strategies. We compared an in vitro model with a transgenic mouse model of BCC, to investigate and delineate the canonical HH signalling pathway and its connections with other molecular pathways. Results and conclusions. The orthotopic models showed latency and progression patterns similar to human disease. Chemotherapy treatments improved survival rates and validated the in vivo model. The presence of MA and overexpression were confirmed in each model and we tested the efficacy of a new MYCN inhibitor in vitro. Preliminar data of BCC models highlighted Hedgehog pathway role and underlined the importance of both in vitro and in vivo strategies to achieve a better understanding of the pathology and to evaluate the applicability of new therapeutic compounds

The search for Multiple Myeloma Stem cells: molecular characterization and self-renewal mechanisms involved in the disease persistence

The existence of Multiple Myeloma Stem cells (MMSCs)is supposed to be one of the major causes of MM drug-resistance. However, very little is known about the molecular characteristics of MMSCs, even if some studies suggested that these cells resembles the memory B cells. In order to molecularly characterize MMSCs, we isolated the 138+138- population. For each cell fraction we performed a VDJ rearrangement analysis. The complete set of aberrations were performed by SNP Array 6.0 and HG-U133 Plus 2.0 microarray analyses (Affymetrix). The VDJ rearrangement analyses confirmed the clonal relationship between the 138+ clone and the immature clone. Both BM and PBL 138+ clones showed exactly the same genomic macroalterations. In the BM and PBL 138-19+27+ cell fractions several micro-alterations (range: 1-350 Kb) unique of the memory B cells clone were highlighted. Any micro-alterations detected were located out of any genomic variants region and are presumably associated to the MM pathogenesis, as confirmed by the presence of KRAS, WWOX and XIAP genes among the amplified regions. To get insight into the biology of the clonotypic B cell population, we compared the gene expression profile of 8 MM B cells samples 5 donor B cells vs, thus showing a differential expression of 11480 probes (p-value: <0,05). Among the self-renewal mechanisms, we observed the down-regulation of Hedgehog pathway and the iperactivation of Notch and Wnt signaling. Moreover, these immature cells showed a particular phenotype correlated to resistance to proteasome inhibitors (IRE1α-XBP1: -18.0; -19.96. P<0,05). Data suggested that the MM 138+ clone might resume the end of the complex process of myelomagenesis, whereas the memory B cells have some intriguing micro-alterations and a specific transcriptional program, supporting the idea that these post germinal center cells might be involved in the transforming event that originate and sustain the neoplastic clone.

A SMO inhibitor drug reduces the progenitor cell's maintenance in the Drosophila hematopoietic organ: a novel model to study Chronic Myelogenous Leukemia relapse

The chronic myeloid leukemia complexity and the difficulties of disease eradication have recently led to the development of drugs which, together with the inhibitors of TK, could eliminate leukemia stem cells preventing the occurrence of relapses in patients undergoing transplantation. The Hedgehog (Hh) signaling pathway positively regulates the self-renewal and the maintenance of leukemic stem cells and not, and this function is evolutionarily conserved. Using Drosophila as a model, we studied the efficacy of the SMO inhibitor drug that inhibit the human protein Smoothened (SMO). SMO is a crucial component in the signal transduction of Hh and its blockade in mammals leads to a reduction in the disease induction. Here we show that administration of the SMO inhibitor to animals has a specific effect directed against the Drosophila ortholog protein, causing loss of quiescence and hematopoietic precursors mobilization. The SMO inhibitor induces in L3 larvae the appearance of melanotic nodules generated as response by Drosophila immune system to the increase of its hemocytes. The same phenotype is induced even by the dsRNA:SMO specific expression in hematopoietic precursors of the lymph gland. The drug action is also confirmed at cellular level. The study of molecular markers has allowed us to demonstrate that SMO inhibitor leads to a reduction of the quiescent precursors and to an increase of the differentiated cells. Moreover administering the inhibitor to heterozygous for a null allele of Smo, we observe a significant increase in the phenotype penetrance compared to administration to wild type animals. This helps to confirm the specific effect of the drug itself. These data taken together indicate that the study of inhibitors of Smo in Drosophila can represent a useful way to dissect their action mechanism at the molecular-genetic level in order to collect information applicable to the studies of the disease in humans.

Behaviour and applications of elastic waves in structures and metamaterials

The present thesis focuses on elastic waves behaviour in ordinary structures as well as in acousto-elastic metamaterials via numerical and experimental applications. After a brief introduction on the behaviour of elastic guided waves in the framework of non-destructive evaluation (NDE) and structural health monitoring (SHM) and on the study of elastic waves propagation in acousto-elastic metamaterials, dispersion curves for thin-walled beams and arbitrary cross-section waveguides are extracted via Semi-Analytical Finite Element (SAFE) methods. Thus, a novel strategy tackling signal dispersion to locate defects in irregular waveguides is proposed and numerically validated. Finally, a time-reversal and laser-vibrometry based procedure for impact location is numerically and experimentally tested. In the second part, an introduction and a brief review of the basic definitions necessary to describe acousto-elastic metamaterials is provided. A numerical approach to extract dispersion properties in such structures is highlighted. Afterwards, solid-solid and solid-fluid phononic systems are discussed via numerical applications. In particular, band structures and transmission power spectra are predicted for 1P-2D, 2P-2D and 2P-3D phononic systems. In addition, attenuation bands in the ultrasonic as well as in the sonic frequency regimes are experimentally investigated. In the experimental validation, PZTs in a pitch-catch configuration and laser vibrometric measurements are performed on a PVC phononic plate in the ultrasonic frequency range and sound insulation index is computed for a 2P-3D phononic barrier in the sonic frequency range. In both cases the numerical-experimental results comparison confirms the existence of the numerical predicted band-gaps. Finally, the feasibility of an innovative passive isolation strategy based on giant elastic metamaterials is numerically proved to be practical for civil structures. In particular, attenuation of seismic waves is demonstrated via finite elements analyses. Further, a parametric study shows that depending on the soil properties, such an earthquake-proof barrier could lead to significant reduction of the superstructure displacement.

cis-Regulation des Drosophila-melanogaster-Gens optomotor-blind

Die zeitliche und räumliche Expression von Genen trägt zu einem entscheidenden Ausmaß zu der Entwicklung eines Organismus bei. Unter vielen Faktoren spielt dabei die transkriptionelle Regulation eine wichtige Rolle. Diese basiert auf Anwesenheit und Binden von regulatorischen Proteinen an cis-regulatorischen Sequenzen (CRMs) und deren Einfluss auf die Transkriptionsmaschinerie am Promotor. Veränderungen der CRMs können zu Veränderungen der Genexpression führen, und somit einen Beitrag zur morphologischen Evolution leisten. rnIn dieser Arbeit wurde die transkriptionelle Regulation des Drosophila melanogaster Gens optomotor-blind insbesondere in den pupalen Tergiten untersucht. In einem Enhancer-Reporter screen wurde eine regulatorische Region in Intron IV, die Reportergen-Expression in den pupalen Tergiten treibt, identifiziert. Große Teile dieser Region (ombTU10 und ombTU11) trieben Reportergen-Expression in einem omb-ähnlichen Muster. Eine weitere Region (ombTU12) trieb Expression in einem für Hh-Zielgene typischen Expressionsmuster. Für ombTU12 konnte eine Hh-Abhängigkeit nachgewiesen werden. Die für Hh-Zielgene typische Enhanceraktivität konnte in dem Subfragment ombTU12Amin lokalisiert werden, welches zwei konservierte Bindestellen des Effektors der Hh-Signaltransduktionskaskase, Cubitus interruptus (Ci), enthält. Eine deutliche Abhängigkeit der Expression dieses Fragments von den Ci-Bindestellen konnte bisher aber noch nicht nachgewiesen werden.rnDeletionen verschiedener Bereiche dieser Tergitenenhancer-Region aus dem endogenen Gen sollten Aufschluss über deren Notwendigkeit in der Regulation von omb geben. Die Deletion des Fragments ombTU10 (ΔombTU10-2) führte zu einer Variabilität in der Pigmentierung der Abdominalsegmente A5 und A6 der Weibchen. Eine Deletion von Teilen des hh-responsiven Fragments ombTU12 (ΔombTU12A) zeigte keinen abdominalen Phänotyp. Dies deutet auf eine redundante Wirkung der Fragmente untereinander, oder mit einem weiteren bisher nicht identifizierten Tergitenenhancer im omb-Locus hin.rnFragmente, die in den pupalen Tergiten Reportergen-Expression trieben, waren zum Teil auch in Imaginalscheiben von Larven aktiv. Desweiteren wurde gezeigt, dass Fragmente, die in Isolation Reportergen-Expression trieben, als Fusionskonstrukt mit benachbarten genomischen Sequenzen keine Expression zeigten und somit im genomischen Kontext inaktiv sein können. Demzufolge sind nicht nur Aktivator- sondern auch Repressorregionen für die korrekte Expression eines Gens von Bedeutung.rnDie Analyse von omb Enhancer-Trap Insertionen zeigte, dass von drei untersuchten Typen (PlacW, PGalW und PGawB) nur Insertionen vom letzteren in den pupalen Tergiten aktiv waren. Von vier PGawB Insertionen waren nur drei aktiv. Es ist denkbar, dass die Orientierung der inaktiven Insertion für die mangelnde Responsivität verantwortlich ist.rn

Clinical results with two different methods of root-end preparation and filling in apical surgery: mineral trioxide aggregate and adhesive resin composite

INTRODUCTION: The aim of apical surgery is to hermetically seal the root canal system after root-end resection, thereby enabling periradicular healing. The objective of this nonrandomized prospective clinical study was to report results of 2 different root-end preparation and filling methods, ie, mineral trioxide aggregate (MTA) and an adhesive resin composite (Retroplast). METHODS: The study included 353 consecutive cases with endodontic lesions limited to the periapical area. Root-end cavities were prepared with sonic microtips and filled with MTA (n = 178), or alternatively, a shallow concavity was prepared in the cut root face, with subsequent placement of an adhesive resin composite (Retroplast) (n = 175). Patients were recalled after 1 year. Cases were defined as healed when no clinical signs or symptoms were present and radiographs demonstrated complete or incomplete (scar tissue) healing of previous radiolucencies. RESULTS: The overall rate of healed cases was 85.5%. MTA-treated teeth demonstrated a significantly (P = .003) higher rate of healed cases (91.3%) compared with Retroplast-treated teeth (79.5%). Within the MTA group, 89.5%-100% of cases were classified as healed, depending on the type of treated tooth. In contrast, more variable rates ranging from 66.7%-100% were found in the Retroplast group. In particular, mandibular premolars and molars demonstrated considerably lower rates of healed cases when treated with Retroplast. CONCLUSIONS: MTA can be recommended for root-end filling in apical surgery, irrespective of the type of treated tooth. Retroplast should be used with caution for root-end sealing in apical surgery of mandibular premolars and molars.

Hand and ultrasonic instrumentation for orthograde root canal treatment of permanent teeth

Root canal treatment is a frequently performed dental procedure and is carried out on teeth in which irreversible pulpitis has led to necrosis of the dental pulp. Removal of the necrotic tissue remnants and cleaning and shaping of the root canal are important phases of root canal treatment. Treatment options include the use of hand and rotary instruments and methods using ultrasonic or sonic equipment. OBJECTIVES: The objectives of this systematic review of randomized controlled trials were to determine the relative clinical effectiveness of hand instrumentation versus ultrasonic instrumentation alone or in conjunction with hand instrumentation for orthograde root canal treatment of permanent teeth. MATERIAL AND METHODS: The search strategy retrieved 226 references from the Cochrane Oral Health Group Trials Register (7), the Cochrane Central Register of Controlled Trials (CENTRAL) (12), MEDLINE (192), EMBASE (8) and LILACS (7). No language restriction was applied. The last electronic search was conducted on December 13th, 2007. Screening of eligible studies was conducted in duplicate and independently. RESULTS: Results were to be expressed as fixed-effect or random-effects models using mean differences for continuous outcomes and risk ratios for dichotomous outcomes with 95% confidence intervals. Heterogeneity was to be investigated including both clinical and methodological factors. No eligible randomized controlled trials were identified. CONCLUSIONS: This review illustrates the current lack of published or ongoing randomized controlled trials and the unavailability of high-level evidence based on clinically relevant outcomes referring to the effectiveness of ultrasonic instrumentation used alone or as an adjunct to hand instrumentation for orthograde root canal treatment. In the absence of reliable research-based evidence, clinicians should base their decisions on clinical experience, individual circumstances and in conjunction with patients' preferences where appropriate. Future randomized controlled trials might focus more closely on evaluating the effectiveness of combinations of these interventions with an emphasis on not only clinically relevant, but also patient-centered outcomes.

Er:YAG laser treatment in supportive periodontal therapy

To assess clinical and microbiological outcomes of an Er:YAG laser in comparison with sonic debridement in the treatment of persistent periodontal pockets in a prospective randomized controlled multicentre study design.

Prediction of hip fracture risk by quantitative ultrasound in more than 7000 Swiss women > or =70 years of age: comparison of three technologically different bone ultrasound devices in the SEMOF study

To compare the prediction of hip fracture risk of several bone ultrasounds (QUS), 7062 Swiss women > or =70 years of age were measured with three QUSs (two of the heel, one of the phalanges). Heel QUSs were both predictive of hip fracture risk, whereas the phalanges QUS was not. INTRODUCTION: As the number of hip fracture is expected to increase during these next decades, it is important to develop strategies to detect subjects at risk. Quantitative bone ultrasound (QUS), an ionizing radiation-free method, which is transportable, could be interesting for this purpose. MATERIALS AND METHODS: The Swiss Evaluation of the Methods of Measurement of Osteoporotic Fracture Risk (SEMOF) study is a multicenter cohort study, which compared three QUSs for the assessment of hip fracture risk in a sample of 7609 elderly ambulatory women > or =70 years of age. Two QUSs measured the heel (Achilles+; GE-Lunar and Sahara; Hologic), and one measured the heel (DBM Sonic 1200; IGEA). The Cox proportional hazards regression was used to estimate the hazard of the first hip fracture, adjusted for age, BMI, and center, and the area under the ROC curves were calculated to compare the devices and their parameters. RESULTS: From the 7609 women who were included in the study, 7062 women 75.2 +/- 3.1 (SD) years of age were prospectively followed for 2.9 +/- 0.8 years. Eighty women reported a hip fracture. A decrease by 1 SD of the QUS variables corresponded to an increase of the hip fracture risk from 2.3 (95% CI, 1.7, 3.1) to 2.6 (95% CI, 1.9, 3.4) for the three variables of Achilles+ and from 2.2 (95% CI, 1.7, 3.0) to 2.4 (95% CI, 1.8, 3.2) for the three variables of Sahara. Risk gradients did not differ significantly among the variables of the two heel QUS devices. On the other hand, the phalanges QUS (DBM Sonic 1200) was not predictive of hip fracture risk, with an adjusted hazard risk of 1.2 (95% CI, 0.9, 1.5), even after reanalysis of the digitalized data and using different cut-off levels (1700 or 1570 m/s). CONCLUSIONS: In this elderly women population, heel QUS devices were both predictive of hip fracture risk, whereas the phalanges QUS device was not.

Tumour suppressors in liver carcinogenesis

The circuitous cell signalling pathways of hepatocytes comprise several factors that operate to downgrade or even interrupt the transmission of a given signal. These down-regulating influences are essential to keep cell proliferation and cell survival in check and if impaired, can alter a delicate balance in favour of cell proliferation. Each signalling pathway that has been implicated in carcinogenesis is influenced by both oncogenic factors that promote tumour growth when activated as well as tumour suppressor proteins that have to be impaired to favour tumour growth. This summary of the Tumour Suppressors in Liver Carcinogenesis Symposium held at the 2007 EASL Annual Meeting discusses four pathways with pre-eminent tumour suppressor activity, each involved in hepatocarcinogenesis: p53, mTOR, beta-catenin and hedgehog.

Site-1 protease is essential for endochondral bone formation in mice

Site-1 protease (S1P) has an essential function in the conversion of latent, membrane-bound transcription factors to their free, active form. In mammals, abundant expression of S1P in chondrocytes suggests an involvement in chondrocyte function. To determine the requirement of S1P in cartilage and bone development, we have created cartilage-specific S1P knockout mice (S1P(cko)). S1P(cko) mice exhibit chondrodysplasia and a complete lack of endochondral ossification even though Runx2 expression, Indian hedgehog signaling, and osteoblastogenesis is intact. However, there is a substantial increase in chondrocyte apoptosis in the cartilage of S1P(cko) mice. Extraction of type II collagen is substantially lower from S1P(cko) cartilage. In S1P(cko) mice, the collagen network is disorganized and collagen becomes entrapped in chondrocytes. Ultrastructural analysis reveals that the endoplasmic reticulum (ER) in S1P(cko) chondrocytes is engorged and fragmented in a manner characteristic of severe ER stress. These data suggest that S1P activity is necessary for a specialized ER stress response required by chondrocytes for the genesis of normal cartilage and thus endochondral ossification.

A PETROPHYSICAL EVALUATION OF THE TRENTON-BLACK RIVER FORMATION OF THE MICHIGAN BASIN

This work is conducted to study the geological and petrophysical features of the Trenton- Black River limestone formation. Log curves, crossplots and mineral identification methods using well-log data are used to determine the components and analyze changes in lithology. Thirty-five wells from the Michigan Basin are used to define the mineralogy of Trenton-Black River limestone. Using the different responses of a few log curves, especially gamma-ray, resistivity and neutron porosity, the formation tops for the Utica shale, the Trenton limestone, the Black River limestone and the Prairie du Chien sandstone are identified to confirm earlier authors’ work and provide a basis for my further work. From these, an isopach map showing the thickness of Trenton-Black River formation is created, indicating that its maximum thickness lies in the eastern basin and decreases gradually to the west. In order to obtain more detailed lithological information about the limestone formations at the thirty-five wells, (a) neutron-density and neutron-sonic crossplots, (b) mineral identification methods, including the M-N plot, MID plot, ϱmaa vs. Umaa MID plot, and the PEF plot, and (c) a modified mineral identification technique are applied to these wells. From this, compositions of the Trenton-Black River formation can be divided into three different rock types: pure limestone, partially dolomitized limestone, and shaly limestone. Maps showing the fraction of dolomite and shale indicate their geographic distribution, with dolomite present more in the western and southwestern basin, and shale more common in the north-central basin. Mineral identification is an independent check on the distribution found from other authors, who found similar distributions based on core descriptions. The Thomas Stieber method of analysis is best suited to sand-shale sequences, interpreting hree different distributions of shale within sand, including dispersed, laminated and structural. Since this method is commonly applied in clastic rocks, my work using the Thomas Stieber method is new, as an attempt to apply this technique, developed for clastics, to carbonate rocks. Based on the original assumption and equations with a corresponding change to the Trenton-Black River formation, feasibility of using the Thomas Stieber method in carbonates is tested. A graphical display of gamma-ray versus density porosity, using the properties of clean carbonate and pure shale, suggests the presence of laminated shale in fourteen wells in this study. Combined with Wilson’s study (2001), it is safe to conclude that when shale occurs in the Trenton-Black River formation, it tends to be laminated shale.

Sound As Artifact

A distinguishing feature of the discipline of archaeology is its reliance upon sensory dependant investigation. As perceived by all of the senses, the felt environment is a unique area of archaeological knowledge. It is generally accepted that the emergence of industrial processes in the recent past has been accompanied by unprecedented sonic extremes. The work of environmental historians has provided ample evidence that the introduction of much of this unwanted sound, or "noise" was an area of contestation. More recent research in the history of sound has called for more nuanced distinctions than the noisy/quiet dichotomy. Acoustic archaeology tends to focus upon a reconstruction of sound producing instruments and spaces with a primary goal of ascertaining intentionality. Most archaeoacoustic research is focused on learning more about the sonic world of people within prehistoric timeframes while some research has been done on historic sites. In this thesis, by way of a meditation on industrial sound and the physical remains of the Quincy Mining Company blacksmith shop (Hancock, MI) in particular, I argue for an acceptance and inclusion of sound as artifact in and of itself. I am introducing the concept of an individual sound-form, or sonifact, as a reproducible, repeatable, representable physical entity, created by tangible, perhaps even visible, host-artifacts. A sonifact is a sound that endures through time, with negligible variability. Through the piecing together of historical and archaeological evidence, in this thesis I present a plausible sonifactual assemblage at the blacksmith shop in April 1916 as it may have been experienced by an individual traversing the vicinity on foot: an 'historic soundwalk.' The sensory apprehension of abandoned industrial sites is multi-faceted. In this thesis I hope to make the case for an acceptance of sound as a primary heritage value when thinking about the industrial past, and also for an increased awareness and acceptance of sound and listening as a primary mode of perception.

IL26 gene inactivation in Equidae

Interleukin-26 (IL26) is a member of the IL10 cytokine family. The IL26 gene is located between two other well-known cytokines genes of this family encoding interferon-gamma (IFNG) and IL22 in an evolutionary conserved gene cluster. In contrast to humans and most other mammals, mice lack a functional Il26 gene. We analyzed the genome sequences of other vertebrates for the presence or absence of functional IL26 orthologs and found that the IL26 gene has also become inactivated in several equid species. We detected a one-base pair frameshift deletion in exon 2 of the IL26 gene in the domestic horse (Equus caballus), Przewalski horse (Equus przewalskii) and donkey (Equus asinus). The remnant IL26 gene in the horse is still transcribed and gives rise to at least five alternative transcripts. None of these transcripts share a conserved open reading frame with the human IL26 gene. A comparative analysis across diverse vertebrates revealed that the IL26 gene has also independently been inactivated in a few other mammals, including the African elephant and the European hedgehog. The IL26 gene thus appears to be highly variable, and the conserved open reading frame has been lost several times during mammalian evolution.