Dissertation (Ph.D.)--University of Toledo, 2009. / "In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Sciences." Title from title page of PDF document. Bibliography: p. 138-150.

Adhesion signaling is a field of cell biology studied mostly on adherent cell types. However, hematopoietic cells grow in suspension, and use adhesion to the extracellular matrix (ECM) only in their early development, or - in case of differentiated cells - to perform the tasks they are specialized for. Peripheral leukemic cells are derived from more or less immature hematopoietic precursors that have, among other alterations, defects in adhesion to the bone marrow microenvironment. On the other hand, leukemic stem cells (LSC) use adhesion to the bone marrow ECM as a mean to evade chemotherapy, and are a source of the minimal residual disease, and of the disease relapses. Kinases of the Src family (SFK) are known regulators of adhesion signaling in adherent cell types, and their overexpression and/or hyperactivation is often seen in malignant diseases. They are also involved in hematooncologic disease progression and resistance to therapy, particularly in several types of leukemias. In the present work, we used a variety of methods including microimpedance measurement, fluorimetric measurement of adhered cell fraction, immunoblotting, confocal microscopy, and interference reflection microscopy. Our results indicate that active Lyn kinase, a hematopoietic SFK, is present in adhesion structures of...

The interaction between CD40 ligand (CD154) expressed on activated T cells and its receptor, CD40, has been shown to play a role in the onset and maintenance of autoimmune inflammation. Recent studies suggest that CD154+T cells also contribute to the regulation of atherogenesis due to their capacity to activate CD40+cells of the vasculature, including vascular smooth muscle cells (VSMC). The present study evaluated the signalling events initiated through CD40 ligation which culminate in VSMC chemokine production. CD40 ligation resulted in the phosphorylation/activation of mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinases 1 and 2 (ERK1/2), and p38, but not c-jun N-terminal kinase. Inhibition of both ERK1/2 and p38 activity abrogated CD40 stimulation of IL-8 and MCP-1 production. CD40-mediated induction of chemokines also showed dependence on the Src family kinase activity. The Src kinase inhibitor, PP2, was found to inhibit CD40-induced phosphorylation of ERK1/2 as well as activation of IκB kinase. An evaluation of Src kinases that may be important in CD40 signalling identified Lyn as a potential candidate. These data indicate that CD40 signalling in VSMC activates a Src family kinase-initiated pathway that results in the induction of MAPK activities required for successful induction of chemokine synthesis.

Tableau d'honneur de la Faculté des études supérieures et postdorales, 2015-2016 / Src régule le remodelage du cytosquelette d’actine et les propriétés invasives des cellules. Une régulation spatio-temporelle du transport endosomal polarisé est nécessaire pour ces fonctions et le rétromère, un substrat de Src, est un élément crucial de ce trafic. Nous avons postulé que le rétromère pourrait moduler le transport requis pour le remodelage cellulaire et la migration induits par Src. Nous montrons qu’une perte de fonction du rétromère dans des cellules épithéliales exprimant v-Src mène à la formation d’invadosomes désorganisés et anormalement stables, mais toujours aptes à dégrader la matrice extracellulaire. Dans un modèle de cellules cancéreuses, une perte de fonction du rétromère diminue la migration en affectant la polarisation et la directionalité des cellules, mais augmente la migration trans-endothéliale. Nos résultats suggèrent un rôle pour le rétromère en aval de Src dans le remodelage de l’actine, la polarité, la migration cellulaire et l’invasion, possiblement par la phosphorylation du rétromère. / Src-family kinases (Src) modulate actin cytoskeleton remodeling and tumor cell invasive properties. Directional endosomal trafficking needs to be regulated in time and space to support these processes, but little is known on the mechanisms involved. The retromer, a Src kinase target, is emerging as a key player of endosomal recycling. We postulated that the retromer could modulate the polarized trafficking of endosomes required to support Src-induced cell remodeling and migration. We show that retromer loss of function caused the assembly of disorganized, more stable invadosomes in epithelial cells expressing v-Src, which were nevertheless able to degrade extracellular matrix. In a cancer cell model, inhibition of retromer function reduced cell migration by affecting polarization and directionality of cells, but promoted transendothelial cancer cell migration. The results thus suggest the existence of a phosphorylation-regulated function for the retromer downstream of Src in actin remodeling, cell polarity, cell migration and invasion.

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Distributed power system (DPS) is widely adopted in Power supplies for the telecom, computer and network applications. Constant on-time current mode control and V2 control are widely used as point-of-load (POL) converters and voltage regulators (VR) in DPS systems. Series resonant converters (SRC) are widely used in aerospace systems and LLC resonant converters are widely used as Front-end converters in DPS systems. The technological innovations bring increasing demand for optimizing the dynamic performance of the switching regulators in these applications. There has been a strong desire to develop simple and accurate equivalent circuit models to facilitate the design of these converters. Constant on-time current-mode control has been widely used in POL and VRM converters. For multi-phase application, external ramp is required to improve jittering performance using pulse distribution method. Chapter II analyzes the effect of external ramp on small-signal model of constant on-time current mode control. It is found that external ramp brings additional dynamics by introducing a moving pole and a static zero. Next, a three-terminal switch model is proposed based on non-ideal current source concept, where the non-idealness of the current source is presented by a Re2-Le2 branch. Based on the proposed model, design guidelines are proposed based on either worst case design strategy or auto-tuning strategy. V2 control has advantages of simple implementation and fast transient response and is widely used in industry for POL and VR applications. However, the capacitor voltage sideband effect, which casues the instability problem when ceramic capacitors are employed, also needs to be taken into consideration in modeling. Chapter III proposed a unified equivalent circuit model of V2 control, the model is built based on non-ideal voltage source concept. The model represents capacitor voltage sideband effect with a Re2-Le2 branch, which forms the double pole by resonating with power stage output capacitor. The equivalent circuit model is a complete model and can be used to examine all the transfer functions. Bsed on the unified equivalent circuit model, design guidelines for VR applications and general POL applications are provided in Chapter IV, for both constant on-time V2 control and constant frequency V2 control. For resonant converters, the small-sginal modelling is very challenging as some of the state variables do not have dc components but contain strong switching frequency component and therefore the average concept breaks down. For SRC, the equivalent circuit model proposed by E. Yang in [E26] based on the results by the extended describing function concept is the most successful model. However, the order of the equivalent circuit model is too high and the transfer functions are still derived based on numerical solution instead of analytical solutions. Chapter V proposes a methodology to simplify the fifth-order equivalent circuit of SRC to a third-order equivalent circuit. The proposed equivalent circuit model can be used to explain the beat frequency dynamics: when switching frequency is far away from resonant frequency, beat frequency will occur; when the two frequencies are close, beat frequency will disappear and another double pole which is determined by equivalent inductor and output capacitor will be formed. For the first time, analytical solutions are provided for all the transfer functions which are very helpful for feedback design. LLC resonant converters are widely adopted as front-end converter in distributed power system for the telecom, computer and network applications [F2]. Besides, LLC resonant converters are also very popular in other applications, such as LCD, LED and plasma display in TV and flat panels [F3]-[F6]; iron implanter arc power supply[F7]; solar array simulator in photovoltaic application[F8]; fuel cell applications[F9],and so on. For LLC, no simple equivalent circuit model is available and no analytical expressions of transfer functions are presented. Chapter VI proposes an equivalent circuit model for LLC resonant converter. When Fs ≥ Fo, Lm is clamped by the output voltage and LLC behaves very similar as SRC. As a result, the dynamic behavior is similar as SRC: when switching frequency is larger than resonant frequency, the beat frequency double pole show up and the circuit is third-order; when switching frequency is close to resonant frequency, beat frequency double pole disappear and a new double pole formed by equivalent inductor Le and equivalent output capacitor Cf show up. The circuit reduces to second order. When Fs<Fo, Lm participates in resonance during some time periods and the circuit is essentially a multiresonant structure. An approximated model is proposed where the equivalent resonant inductor is modified to include the effect of Lm. As a result, the double pole will move to a little lower frequency. For the first time, analytical solutions are provided for all the transfer functions which are very helpful for feedback design. In conclusion, the works shown in this dissertation focus on small-signal equivalent circuit modeling for Buck converters with advanced control schemes and also resonant converters. The models are simple and accurate up to very high frequency range (1/2 fsw). / Ph. D.

No / BACKGROUND AND PURPOSE: Hypoxia in tumours is known to cause resistance to conventional chemotherapeutic drugs. In contrast, little is known about the effects of hypoxia on targeted anti-cancer drugs. This study evaluated the effect of hypoxia on a series of clinically approved tyrosine kinase inhibitors (TKIs). EXPERIMENTAL APPROACH: The effect of hypoxia (0.1% oxygen) on the activity of conventional cytotoxic drugs (5-fluorouracil, doxorubicin and vinblastine), the hypoxia-activated prodrug tirapazamine and 9 TKIs was determined in a panel of cell lines. Where hypoxia had a marked effect on chemosensitivity, Western blot analysis was conducted to determine the effect of hypoxia on target expression and the effect of TKIs on cell signalling response under aerobic and hypoxic conditions. KEY RESULTS: Three patterns of chemosensitivity were observed: resistance under hypoxia, equitoxic activity against hypoxic and aerobic cells, and preferential cytotoxicity to hypoxic cells. Significant hypoxia selectivity (independent of HIF1) was observed in the case of dasatinib and this correlated with the ability of dasatinib to inhibit phosphorylation of Src at tyrosine 530. Sorafenib was significantly less effective under hypoxic conditions but resistance did not correlate with hypoxia-induced changes in Raf/MEK/ERK signalling. CONCLUSIONS AND IMPLICATIONS: Hypoxia influences the activity of TKIs but in contrast to conventional cytotoxic drugs, preferential activity against hypoxic cells can occur. The search for hypoxia-targeted therapies has been long and fruitless and this study suggests that some clinically approved TKIs could preferentially target the hypoxic fraction of some tumour types.

Yes / ... Sustaining a sport-related concussion (SRC) has been associated with negative consequences to emotion and cognition in recent years,4,5 and head impacts are no different.1 Moreover, there is a consistent link reported with neurodegenerative diseases such as motor-neuron disease, Parkinson’s disease, and dementia. Although this is well-known within the scientific community, and becoming so in the general population, we still place children at risk. Promoting attitude change toward SRC and head impacts in sport is difficult enough with adults as many are accustomed to the way their contact sports are played and spectated. However, a redeeming feature for many researchers is that the evidence is there, and the rhetoric is being discussed in the mainstream media across the world.

Approved for public release, distribution is unlimited / A hardware interface is designed, developed, constructed, and tested to interface a naval radar to the SRC 6E reconfigurable computer. The U.S. Navy AN/SPS 65 radar provides in-phase (I) and quadrature (Q) channels along with the AGC voltage to the hardware interface in analog form. The hardware interface receives a sampling clock from the SRC 6E and in turn performs the requisite attenuation and digital conversion before presenting the signals to the SRC 6E through its CHAIN port. The results show that the SRC 6E can effectively generate a sampling clock to drive the analog-to-digital converters and that real- time radar data can be brought into the SRC 6E via its high speed CHAIN port for performing high speed digital signal processing. / Lieutenant, United States Naval Reserve