Melanoma, a malignant neoplasm of melanocytes, is the most lethal form of skin cancer. A majority of melanomas are driven by activating mutations in the kinase BRAF, which drives cellular proliferation through constitutive stimulation of the mitogen-activated protein kinase (MAPK) signaling pathway. Intriguingly, expression of oncogenic BRAF alone in vivo is insufficient to promote melanoma; rather, its expression leads to the development of benign nevi (moles) comprised of growth-arrested melanocytes. The acquisition of additional genetic or epigenetic changes is therefore critical for melanocytes to evade arrest and drive melanomagenesis, however the identity of these changes remains incompletely understood. Here we demonstrate that expression of oncogenic BRAF leads to activation of the Hippo tumor suppressor pathway in vitro, which acts to limit melanocyte proliferation through the inhibition of the pro-growth transcriptional co-activators YAP and TAZ. Melanocyte-specific inactivation of Hippo signaling in vivo, via deletion of the Hippo kinases Lats1/2 alone, or in conjunction with oncogenic Braf expression, potently induces melanoma development in mice. Collectively, our data reveal that the Hippo tumor suppressor pathway represents an important barrier to melanoma development, and implicates YAP and TAZ as new therapeutic targets for the treatment of human melanoma.

There is currently a great deal of information available to euphonium players who double on trombone, but far less for euphonium players who double on tuba. This dissertation takes information gathered from many top euphonium/tuba doublers, including: Benjamin Pierce, D.M.A., Aaron Tindall, D.M.A., Gail Robertson, D.M.A., Gretchen Renshaw James, D.M.A., Matthew Murchison, D.M.A., Matthew Shipes, D.M.A., Matthew Tropman, D.M.A., and Keith Kile, and presents a synopsis of their thoughts/reflections on tuba doubling. This dissertation is designed to aide euphonium players in the process of learning tuba, enabling them to be as efficient as possible with both their time and money throughout the process. Topics covered include: difficulties unique to the euphonium/tuba double and approaches to overcome them, similarities and differences between euphonium and tuba playing (from the perspective of euphonium/tuba doublers), "reverse" benefits of euphonium/tuba doubling on the primary instrument, literature recommendations for euphonium/tuba doublers, and equipment considerations for euphonium/tuba doublers.

There is a high degree of morphosyntactic microvariation with respect to the number and position of object markers found across Bantu languages. This paper examines variation in object marking in Swahili, against the backdrop of variation in object marking in Bantu more broadly. Verb forms in Standard Swahili are well-known to typically only permit one pre-stem object marker. However, here we show that there are isolated cases of post-verbal marking of objects from both a synchronic and diachronic perspective. The paper focuses on two case studies. Firstly, ‘Old Swahili’ – that is, the language of classical Swahili poetry – where examples of typologically unusual emphatic object marker doubling are found. Secondly, we show that post-verbal object marking is in fact also found in Standard (Modern) Swahili, namely in second person plural marking, in post-verbal locative markers and with non-verbal predication. However, we also show that the relationship between these forms, the Old Swahili paradigm of object marker doubling, and post-verbal object marking in Bantu more widely – in particular post-verbal plural addressee marking – is complex.

No description available.

No description available.

Mathematical models, that depict the dynamics of a cancer cell population growing out of the human body (in vitro) in unconstrained microenvironment conditions, are considered in this thesis. Cancer cells in vitro grow and divide much faster than cancer cells in the human body, therefore, the effects of various cancer treatments applied to them can be identified much faster. These cell populations, when not exposed to any cancer treatment, exhibit exponential growth that we refer to as the balanced exponential growth (BEG) state. This observation has led to several effective methods of estimating parameters that thereafter are not required to be determined experimentally. We present derivation of the age-structured model and its theoretical analysis of the existence of the solution. Furthermore, we have obtained the condition for BEG existence using the Perron-Frobenius theorem. A mathematical description of the cell-cycle control is shown for one-compartment and two-compartment populations, where a compartment refers to a cell population consisting of cells that exhibit similar kinetic properties. We have incorporated into our mathematical model the required growing/aging times in each phase of the cell cycle for the biological viability. Moreover, we have derived analytical formulae for vital parameters in cancer research, such as population doubling time, the average cell-cycle age, and the average removal age from all phases, which we argue is the average cell-cycle time of the population. An estimate of the average cell-cycle time is of a particular interest for biologists and clinicians, and for patient survival prognoses as it is considered that short cell-cycle times correlate with poor survival prognoses for patients. Applications of our mathematical model to experimental data have been shown. First, we have derived algebraic expressions to determine the population doubling time from single experimental observation as an alternative to empirically constructed growth curve. This result is applicable to various types of cancer cell lines. One option to extend this model would be to derive the cell cycle time from a single experimental measurement. Second, we have applied our mathematical model to interpret and derive dynamic-depicting parameters of five melanoma cell lines exposed to radiotherapy. The mathematical result suggests there are shortcomings in the experimental methods and provides an insight into the cancer cell population dynamics during post radiotherapy. Finally, a mathematical model depicting a theoretical cancer cell population that comprises two sub-populations with different kinetic properties is presented to describe the transition of a primary culture to a cell line cell population.

Ce mémoire consiste en l’étude du comportement dynamique de deux oscillateurs FitzHugh-Nagumo identiques couplés. Les paramètres considérés sont l’intensité du courant injecté et la force du couplage. Juqu’à cinq solutions stationnaires, dont on analyse la stabilité asymptotique, peuvent co-exister selon les valeurs de ces paramètres. Une analyse de bifurcation, effectuée grâce à des méthodes tant analytiques que numériques, a permis de détecter différents types de bifurcations (point de selle, Hopf, doublement de période, hétéroclinique) émergeant surtout de la variation du paramètre de couplage. Une attention particulière est portée aux conséquences de la symétrie présente dans le système. / We study the dynamical behaviour of a pair of identical, coupled FitzHugh-Nagumo oscillators. We determine the parameter values leading to the existence of up to five equilibrium solutions, and analyze the asymptotic stability of each one. A combination of analytical and numerical techniques is used to analyze the numerous bifurcations (saddle-node, Hopf, period-doubling, heteroclinic) occurring as parameters, most notably the coupling strength, are varied, attention being paid to the rôle played by symmetries in the system.

In this thesis the development of a high efficiency harmonic re-radiator, consisting of a diode doubler and conjugate-matched receive and transmit antennas, is described. Diode-based frequency multipliers and rectifiers, coupled with antennas, are of interest for quasi-optical applications, for energy-scavenging and for sensing applications. The device studied operates by receiving an interrogating signal at a frequency of 1.3 GHz and re-radiating a signal at 2.6 GHz. The primary goal of this research was to develop a passive, miniature and effective frequency doubler integrated with planar antennas. The system is referred to as a frequency doubling reflectenna, (FDR). Prediction of accurate performance was achieved by employing precise modeling and measurement methods. The FDR can be utilized in data collection applications. The footprint of the FDR is occupied primarily by the receive and transmit antennas. Therefore, a significant portion of the research focused on the development of compact and efficient planar antennas, which would provide for a miniature FDR. A first-generation FDR design was designed, which utilized quarter-wavelength shorted microstrip patch antennas. The choice of antennas provided a small prototype with dimensions equal to 44 mm by 17 mm. In order to further reduce the size of the harmonic re-radiator, meandered planar antennas were investigated and optimized for efficient operation. A second-generation FDR design, which utilized meandered microstrip patch antennas, was produced and a size reduction of 75% was achieved. Both first- and second-generation harmonic re-radiator designs were designed for low input power operation and provided maximum measured conversion efficiencies of approximately 4.5% and 1.8%, with the input to the diode doubler at -14.5 and -17.5 dBm, respectively. Re-configurable microwave devices, which dynamically operate at different frequencies, are often desirable for sensing applications. Therefore, to conclude this research, a tunable FDR was realized using a semiconductor varactor that provided the dynamic capacitance required for the tunability.

<p>The determination of the optical properties of biological tissue is an important issue in laser medicine. The optical properties define the tissue´s absorption and scattering behaviour, and can be expressed by quantities such as the albedo, the optical thickness and the anisotropy coefficient. During this project, a measurement system for the determination of the optical properties was built up. The system consists of a double integrating sphere set-up to perform the necessary reflection and transmission measurements, and a computer algorithm to calculate the optical properties from the measured data. This algorithm is called Inverse Adding Doubling method, and is based on a one-dimensional transport model. First measurements were conducted with the system, including measurements with phantom media (Intralipid-ink solutions) and with cartilage samples taken from the human knee joint. This work also includes an investigation about the preparation of tissue samples for optical measurements.</p>

The fully quantum mechanical 'direct-potential-fit' (DPF) method has become increasingly widely used in the reduction of diatomic spectra. The central problem of this method is the representation of the potential energy and Born-Oppenheimer breakdown (BOB) correction functions. There are a number of problems associated with the existing method and potential forms. This thesis delineates these problems and finds solutions to some of them. In particular, it is shown that use of a different expansion variable and a new treatment of some of the expansions resolves most of the problems. These techniques have been successfully tested on the ground electronic states of the coinage metal hydrides and the Rb2 molecule. To address the problem of representing 'barrier' potential curves, a flexible new functional form, the 'double-exponential long-range' (DELR) potential function, is introduced and applied to the B barrier state of Li2. In addition, the Lambda-doubling level splitting which occurs for singlet Pi electronic states has been taken into account by extending the effective Schrodinger equation. The computer program DSPotFit developed in our laboratory for performing DPF analyses has been extended to incorporate the ability to fit the analytical potential energy functions to tunneling predissociation line widths for quasibound levels. Finally, an attempt is made to investigate whether there exists a hump in the ground state rotationless potential curve of beryllium hydride.