L'étude porte sur les propriétés spectrales et spatiales de structures à réseaux résonants. Les réseaux résonants en cavité sont identifiés comme des structures permettant la réalisation de réflecteurs et de coupleurs efficaces sur de petites dimensions. Un modèle basé sur la théorie des modes couplés a été développé permettant la modélisation et la conception rapide de ce type de structures. La modélisation a contribué à la compréhension des propriétés spectrales et spatiales de réseaux résonants en cavité. Elle permet notamment de faire le lien entre les propriétés spectrales et spatiales des modes pouvant interagir efficacement avec les structures utilisées comme réflecteurs ou coupleurs. La conception de structures couplantes à fort facteur de qualité et aux profils spatiaux contrôlés sur des surfaces de l'ordre du cm a été étudiée. Deux axes de recherches sont présentés: des structures composées de plusieurs cavités et des structures possédant une seule grande cavité. Ce dernier axe permet une plus grande maîtrise des propriétés spatiales en intensité et en phase. Il est démontré que ces structures ont un fort potentiel en holographie. La conception de telles structures avec des matériaux de bas indice est également abordée, en particulier la conception et la réalisation de guides d'onde en polymères qui sont la base de ces structures. Les dimensionnements déterminés par la modélisation sont compatibles avec des matériaux présentant de faibles sauts d'indice. / The study is focused on the spectral and spatial properties of resonant grating structures. Resonant gratings in cavity are identified as structures allowing the fabrication of small-area and efficient reflectors and couplers. A model based on coupled mode theory has been developped, enabling fast modeling and design of this kind of structures. Thanks to this model we improved our understanding of the spectral and spatial properties of resonant gratings in cavity. In particular, we have established the relationship between the structure's geometry and the spectral and spatial properties of the modes which efficiently interact with the structures when used as reflectors or as couplers. The design of coupling structures with high-quality factor and controlled spatial profiles on cm-sized surfaces has been studied. Two axis of research are presented: structures composed of several cavities and structures composed by one large cavity. The later ones allow a better control of the spatial properties both in intensity and phase. We demonstrate that these structures have a high potential for holography. Design of such structures with low contrast index is also considered, particularly the design and fabrication of polymer-based waveguiding structures.

The apelin system is an evolving transmitter system consisting of the G protein coupled apelin receptor and two endogenous peptide ligands, apelin and elabela. It is implicated as a potential therapeutic for a number of diseases; however, the endogenous peptides are limited by half-life and bioavailability. This study aims to identify and pharmacologically characterise apelin agonists in vitro and in vivo and to evaluate their therapeutic potential in pulmonary arterial hypertension as a model disease. CMF-019 was identified as the first G protein biased apelin agonist. To date, suitable small molecule apelin agonists as experimental tool compounds have been limited and CMF-019 represents an important advance. CMF-019 was active in vivo, producing an increase in cardiac contractility and vasodilatation, similar to apelin. These effects were achieved without receptor desensitisation, supporting the remarkable G protein bias observed in vitro. Furthermore, it was disease-modifying in vitro in an endothelial cell apoptosis assay but despite this, did not prevent pulmonary arterial hypertension in a monocrotaline rat model of the disease. An apelin mimetic peptide possessing an unnatural amino acid, MM202, conjugated chemically via a polyethylene glycol linker to an anti-serum domain antibody (AlbudAb) was also characterised. The product MM202-AlbudAb represents the first time an AlbudAb has been conjugated chemically to an unnatural peptide mimetic, providing protection from proteolysis and glomerular filtration. Importantly, it retained binding to albumin and demonstrated in vitro and in vivo activity at the apelin receptor. In conclusion, this thesis has identified and pharmacologically characterised two novel apelin agonists that possess significant advantages over the endogenous peptides. CMF-019 is suitable as an experimental tool compound and, as the first G protein biased small molecule, provides a starting point for more suitable therapeutics. In addition, MM202-AlbudAb proves that unnatural peptides can be conjugated to AlbudAb, supporting use of this technology in other small-peptide ligand transmitter systems.

abstract: Our daily life is becoming more and more reliant on services provided by the infrastructures power, gas , communication networks. Ensuring the security of these infrastructures is of utmost importance. This task becomes ever more challenging as the inter-dependence among these infrastructures grows and a security breach in one infrastructure can spill over to the others. The implication is that the security practices/ analysis recommended for these infrastructures should be done in coordination. This thesis, focusing on the power grid, explores strategies to secure the system that look into the coupling of the power grid to the cyber infrastructure, used to manage and control it, and to the gas grid, that supplies an increasing amount of reserves to overcome contingencies. The first part (Part I) of the thesis, including chapters 2 through 4, focuses on the coupling of the power and the cyber infrastructure that is used for its control and operations. The goal is to detect malicious attacks gaining information about the operation of the power grid to later attack the system. In chapter 2, we propose a hierarchical architecture that correlates the analysis of high resolution Micro-Phasor Measurement Unit (microPMU) data and traffic analysis on the Supervisory Control and Data Acquisition (SCADA) packets, to infer the security status of the grid and detect the presence of possible intruders. An essential part of this architecture is tied to the analysis on the microPMU data. In chapter 3 we establish a set of anomaly detection rules on microPMU data that flag "abnormal behavior". A placement strategy of microPMU sensors is also proposed to maximize the sensitivity in detecting anomalies. In chapter 4, we focus on developing rules that can localize the source of an events using microPMU to further check whether a cyber attack is causing the anomaly, by correlating SCADA traffic with the microPMU data analysis results. The thread that unies the data analysis in this chapter is the fact that decision are made without fully estimating the state of the system; on the contrary, decisions are made using a set of physical measurements that falls short by orders of magnitude to meet the needs for observability. More specifically, in the first part of this chapter (sections 4.1- 4.2), using microPMU data in the substation, methodologies for online identification of the source Thevenin parameters are presented. This methodology is used to identify reconnaissance activity on the normally-open switches in the substation, initiated by attackers to gauge its controllability over the cyber network. The applications of this methodology in monitoring the voltage stability of the grid is also discussed. In the second part of this chapter (sections 4.3-4.5), we investigate the localization of faults. Since the number of PMU sensors available to carry out the inference is insufficient to ensure observability, the problem can be viewed as that of under-sampling a "graph signal"; the analysis leads to a PMU placement strategy that can achieve the highest resolution in localizing the fault, for a given number of sensors. In both cases, the results of the analysis are leveraged in the detection of cyber-physical attacks, where microPMU data and relevant SCADA network traffic information are compared to determine if a network breach has affected the integrity of the system information and/or operations. In second part of this thesis (Part II), the security analysis considers the adequacy and reliability of schedules for the gas and power network. The motivation for scheduling jointly supply in gas and power networks is motivated by the increasing reliance of power grids on natural gas generators (and, indirectly, on gas pipelines) as providing critical reserves. Chapter 5 focuses on unveiling the challenges and providing solution to this problem. / Dissertation/Thesis / Doctoral Dissertation Electrical Engineering 2018

Delaminations in concrete bridge decks result primarily from corrosion of the reinforcing bars (or rebar). This corrosion leads to volumetric expansion of the rebar. When the rebar expands, concrete cracks, and there is a localized separation of the concrete cover from the underlying concrete. Impact-echo testing is an effective technique to map delaminations on concrete bridge decks. However, mapping speed is limited by necessary retrieval of the impactor for traditional tests. To achieve higher scanning speeds, it is advantageous to use both a non-contact measurement (air-coupled impact-echo) and disposable-impactor excitation. Disposable impactors have the potential advantage of achieving greater deck scanning speeds because they do not need to be retrieved, and they can also be used with air-coupled measurement systems. This thesis reports impact excitation of concrete using disposable impactors such as water droplets and ice balls. The impact characteristics of these impactors are compared with those of steel balls and chain links. Comparing the acoustic recordings on intact and delaminated concrete surface shows that water droplets and ice balls are able to excite flexural resonant modes associated with delamination defects. The use of water droplets and ice balls for shallow delamination detection in concrete is thus demonstrated.

Ultracold neutral plasmas (UNP) are laboratory plasmas formed by the photoionization of a magneto-optically trapped and cooled gas. Because of their unusually low temperatures, UNPs are an example of a strongly coupled plasma, meaning that the potential energy of Coulomb interactions between particles is comparable to or greater than their thermal kinetic energy. In the field of strongly coupled plasmas, which also includes dense plasmas found in astrophysics and inertial confinement fusion experiments, there is a pressing need to better understand the collisional transport of matter, momentum, and energy between electrons and ions. The main result of this thesis is to demonstrate the existence of a new physical effect that significantly influences the electron-ion collision rates of strongly coupled plasmas. The essence of the effect is that the electron-ion collision rate depends explicitly on the sign of the colliding charges. This runs counter to both traditional plasma kinetic theory and modern extensions to strong coupling, all of which predict collision rates that do not depend on the sign of the electron-ion interaction. The effect is similar to a phenomenon observed charged-particle stopping known as the Barkas effect. The existence of the Barkas effect in the electron-ion collision rate of strongly coupled plasmas is first demonstrated using molecular dynamics (MD) simulations. A non-equilibrium simulation methodology is developed to extract the electron-ion collision frequency from the relaxation of an induced electron drift velocity. The simulations are carefully designed to ensure that the relaxation process can be modeled with a constant relaxation rate, which facilitates comparison with theoretical predictions developed later in the thesis. The Barkas effect becomes apparent when these simulations are repeated with positrons in place of electrons. It is seen that the positron-ion collision rate is always lower than the equivalent electron-ion one, and that this charge-sign asymmetry widens rapidly with increasing electron (or positron) coupling strength. It is hypothesized that the observed Barkas effect can be explained by accounting for plasma screening in the kinematics of binary electron-ion collisions. This is the main tenet of Effective Potential Theory (EPT), which assumes transport occurs through binary collisions governed by the potential of mean force. In order to apply EPT to electron-ion transport in UNPs, several new theoretical developments are made. First, it is demonstrated that EPT is able to accurately predict near-equilibrium transport in ionic mixtures as compared with equilibrium MD simulations. Next, a previously proposed model for the potentials of mean force in two-temperature positron-ion plasma is validated using a new two-thermostat MD methodology. Finally, EPT is applied to electron-ion transport in UNPs using a semi-analytic mapping between a two-component plasma and a screened one-component plasma system, which alleviates numerical difficulties in the theory associated with attractive interactions. The EPT predictions for the electron-ion and positron-ion relaxation rates are in excellent agreement with the MD simulations over the range of coupling strengths attained in present-day UNP experiments. EPT is thus shown to be the first transport theory for strongly coupled plasmas that accounts for the close-interaction physics that give rise to the Barkas effect in electron-ion transport.

Le thème central de la thèse est l'interférométrie atomique et la réduction du bruit de phase lié aux vibrations de l'environnement. Les interféromètres atomiques sont des instruments pouvant permettre des mesures fondamentales de grande précision et cette précision est fortement liée à la vitesse des atomes. L'interféromètre qui était utilisé à Toulouse travaillait alors avec des atomes de lithium aux énergies thermiques et le projet était de pouvoir utiliser des atomes fortement ralentis. Les vibrations du sol (bruit sismique) deviennent alors un inconvénient majeur et il est indispensable de s'en affranchir le plus possible. La première partie du travail fut de prévoir une isolation vis à vis du bruit sismique. Un premier filtre est réalisé en plaçant l'ensemble de la manipulation sur un pendule suspendu par 3 fils. Celui ci atténue les vibrations de fréquence supérieure à sa fréquence propre mais amplifie celles de fréquences voisines de celle-ci. Il faut donc un pendule asservi et cela implique un sismomètre sensible pouvant fonctionner sous ultravide. Nous avons développé une stabilisation des mouvements horizontaux en nous appuyant tout d'abord sur des sismomètres simples mais peu sensibles, puis nous avons cherché à améliorer les performances en réalisant un capteur de déplacement basé sur un interféromètre de Michelson à coins de cube. Nous avons suivi en cela les travaux de l'équipe de M.Zumberge qui utilise une détection de deux signaux en quadrature ce qui permet une mesure de déplacement avec une sensibilité meilleure que 4.10-13 m/vHz à 1 Hz et entrepris d'adapter cette technologie à un fonctionnement sous ultravide. Mais les difficultés rencontrées et l'abandon de l'interféromètre tel qu'il était pour en developper un nouveau ne nous ont pas permis d'atteindre complètement notre but et de pouvoir tester le sismomètre in-situ.Cependant, la mise au point et l'optimisation du sismomètre nous a amené à nous pencher sur la théorie des pendules à lame élastique, lesquels sont largement utilisés dans ce genre de capteurs. Il nous est apparu que cette théorie était très incomplète et nous avons entrepris une étude plus systématique de tels pendules ce qui a donné lieu à une publication et fait l'objet de la seconde partie de la thèse. [...] / The main theme of my thesis is atomic interferometry and in particular the reduction of the phase noise induced by vibrations. Atomic interferometers are good devices to achieve accurate and fundamental measuring. The sensibility of these devices is related to the flying time of the atoms inside the apparatus. At Toulouse, our interferometer worked with atoms at thermal velocity and to increase the sensibility we wanted slower atoms. However, this will at the same time increase the effect of vibrations, witch result in a larger phase noise and a jamming of the fringes. In order to reduce this effect, I've put the core of the interferometer on a 3 wires pendulum. A pendulum attenuates the vibrations of frequencies much higher than its resonant frequencies but amplifies those with frequencies close to its resonances. To avoid this phenomenom, we have to enslave the pendulum on the signal given by seismometers. With a first realisation, I was able to stabilize 2 horizontal movements with 2 low sensibility seismometers. To increase the performances, I needed high sensibility seismometer and the possibility to operate under ultra vacuum. I've made a deplacement sensor based on the Michelson interferometer with cube corners, following the works of Zumberge's team. By choosing cleverly the polarisation of the laser beam, we can detect 2 signals in quadrature and the sensibility achieved is better than 4x10-13 m/vHz at 1 Hz. The next step was to migrate this seismometer in ultra vacuum but the retirement of the interferometer using slow down lithium atoms at the benefit of an atomic fountain of rubidium stopped this project. However, this work on the seismometer led me to think about elastic blade pendulums, widely used in such sensors. I've complete the theory, showing the presence of 2 resonance frequencies and, as a test, I've build a such pendulum, for witch I've measured the caracteristics with some position and velocity sensors I've developped for this purpose. I was able to measure precisely the damping of the oscillations of the pendulum and study more precisely the different origins of the damping. Two of them have given some additionnal work : a)the coupling with the resonances of the frame witch support the pendulum may have an effect on the quality factor of the pendulum. [...]

The concern of this thesis was to investigate the nonlinear dynamics inherent in oscillating waterfalls.

Medulloblastoma is the most common malignant brain tumor in children. Genetic profiling has identified four principle tumor subgroups; each subgroup is characterized by different initiating mutations, genetic and clinical profiles, and prognoses. The two most well-defined subgroups are caused by overactive signaling in the WNT and SHH mitogenic pathways; less is known about Groups 3 and 4 medulloblastomas. Identification of tumor subgroup using molecular classification is poised to become an important component of the medulloblastoma diagnosis and staging and will likely guide therapeutic options. G-protein coupled receptors (GPCR) possess characteristics that make them ideal targets for molecular imaging and therapeutics. While expression patterns of many proteins in human medulloblastoma subgroups have been discerned, the expression pattern of GPCRs in medulloblastoma has not been investigated. We have found that clusters of medulloblastoma tumors arise based solely on differential GPCR expression patterns. Further, two of these clusters correspond with high fidelity to the WNT and SHH subgroups. Distinct over-expressed GPCRs emerge; for example, LGR5 and GPR64 are significantly and uniquely over-expressed in the WNT subgroup of tumors, while PTGER4 is over-expressed in the SHH subgroup. Uniquely under-expressed GPCRs were also observed. Our results identify GPCRs with potential to act as imaging and therapeutic targets; elucidating tumorigenic mechanisms is a secondary benefit to identifying differential GPCR expression patterns in medulloblastoma tumors. Current imaging for diagnosis, staging, and measuring response to therapy for medulloblastoma patients relies heavily on MRI; single photon emission tomography (SPECT) using 111In-DTPA-Octreotide targeting the somatostatin type 2 receptor (SSTR2) is also available. Positron emission tomography (PET) affords a more sensitive and specific imaging modality than SPECT; however, the most common tracer 18FDG, is of limited usefulness for the delineation of brain tumors. Smoothened (SMO) is a GPCR that is overexpressed in a subset of medulloblastoma; we hypothesized that SMO overexpression could be exploited as a specific PET target in these tumors. Genentech generously provided the synthetically-derived small-molecule SMO ligand, GDC-0449, for use as the lead compound for development of a PET tracer. GDC-0449 has already been demonstrated to localize in brain tumors and has Cl- atoms incorporated in positions that are predicted to readily exchange with fluorine-18 to generate a fluorinated analog of the compound. We have successfully fluorinated GDC-0449, with very high radiochemical purity. Binding assays reveal affinities of the fluorinated analog of GDC-0449 for SMO to be comparable to precursor GDC-0449, and biodistribution experiments demonstrate accumulation of the fluorinated compound in tumors. The fluorinated analog of GDC-0449 holds promise as a novel PET imaging agent in medulloblastoma, providing highly specific and sensitive imaging for use in diagnosis, staging and measurement of response-to-treatment.

G–Protein Coupled Receptors are one of the most important targets in drug development, making up over 60% of drug targets. Recent studies have implicated a role of Regulator of G–Protein Signaling (RGS) proteins in the development and progression of pathologies, including some cancers. RGS17, the most–recently identified family member of the RZ family of RGS proteins, has been implicated in the growth, proliferation, metastasis and migration of prostate tumors as well as small–cell and non–small cell lung cancers. In neoplastic tumor tissues RGS17 is up–regulated 13 fold over patient–matched normal tissues in prostate cancer. Studies have shown that RGS17 RNAi knockdown inhibits colony formation and decreases tumorigenesis in nude mice. Based on these findings, this thesis explores the research undertaken to develop small molecule inhibitors of the RGS17: Gαo protein: protein interaction. In this thesis, we implemented AlphaScreen® technology to develop a high–throughput screening method for interrogating small molecule libraries for inhibitors of RGS17. Chapter 3 focuses on the initial results of the AlphaScreen® in 384–well format. The screen utilizes a measurement of the Gα: RGS17 protein: protein interaction (PPI) and with an excellent Z–score exceeding 0.73, a signal to noise ratio >70 and a screening time of 1,100 compounds per hour. Chapter 3 presents the development, validation and initial high–throughput screening for inhibitors of Gα: RGS17 interaction as well as preliminary characterization of the RL series of hits. In this pilot screen the NCI Diversity Set II was interrogated, yielding 35 initial hits of which 16 were confirmed after screening against controls. The 16 compounds exhibited IC50 <10 ΜM in dose–response experiments for inhibiting the Gα: RGS17 interaction. Four exhibited IC50 values <6 ΜM while inhibiting the Gα: RGS17 interaction >50% when compared to a biotinylated GST control (TrueHits). Compounds RL–1 and RL–2 were confirmed by flow cytometry protein interaction assay (FCPIA) while RL–3 and RL–4 were unable to disrupt this PPI in FCPIA. All four compounds were tested using the differential scanning fluorimetry (DSF) method, which is based on energetic coupling between ligand binding and protein unfolding and found compounds RL–1 to RL–4 all slightly increased protein stability upon ligand binding. Chapter 4 focuses on the miniaturization and optimization of AlphaScreen® to a 1536–well format and screening of the MicroSource SPECTRUM and NDL3000 small molecule libraries. This increased throughput 11–fold and decreased our working volumes from 45 ΜL to 10 ΜL, which reduced reagent cost. After optimization, we retained in an excellent Z–factor ≥0.70 with S/N>5.77 and increased the screening rate to more than 12,000 compounds per hour. In this format, the initial screening of the SPECTRUM and NDL3000 libraries was completed and filtered the initial hits by counter screening and PAINs filtering as well as developing four powerful orthogonal assays for the characterization of potential lead molecules. Chapter 6 focuses on the future directions, which include the screening the in–house 50,000 compound library in the University of Iowa HTS Core facility as well as the development of cell based assays to determine the activity of these leads in the cellular milieu. These screens are the first step to developing novel pharmacophores for further optimization of structure with the focus on RGS17 activity in enzymatic, whole cell, xenograft and whole animal models as well as providing new avenues for the development of anticancer therapies.

The endogenous neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) exerts various neuromodulatory functions in mammalian brain. Enhancement of synaptic activity, mediation of chronic inflammatory and neuropathic pain, and neuroprotection in cerebral ischemia reperfusion injury constitute some of the exemplary functions of PACAP. However, it remains unclear whether PACAP signaling can directly influence the function of critical voltage-gated ion channels, which could profoundly alter the excitability of neurons. Voltage-gated K+ (Kv) channels are critical regulators of neuronal excitability. The major Kv channel in the dendrites of mammalian neurons, Kv4.2, contributes most of the fast-activating and rapidly-inactivating K+ currents (IA), and is a key regulator of dendritic excitability, as well as modulation of synaptic inputs. In addition, the major somatic Kv channel Kv2.1 that contributes the bulk of slow-activating and non-inactivating K+ currents (IK), acts as an integrator of neuronal inputs and limits high frequency firing in neurons. As such, it provides homeostatic control of excitability under hyperexcitable and ischemic conditions. Both these Kv channels are known to undergo extensive post-translational modifications mainly by phosphorylation that alters their localization and biophysical properties. PACAP can activate its specific receptor PAC1 that could result in downstream activation of various kinases including protein kinase A (PKA), protein kinase C (PKC), extracellular signal-regulated kinase (ERK1/2). Therefore, I hypothesize that PACAP activation of PAC1 receptor can cause phosphorylation-dependent modulation of somatodendritic Kv4.2 and Kv2.1 channels, resulting in altered neuronal excitability. First, I identified the various PAC1 receptor isoforms expressed in rat and mouse brain and elucidated that their activation by PACAP caused downstream PKA- and PKC-dependent signaling pathways, ultimately converging on ERK1/2 activation. Further, PACAP caused reduction in IA that was mediated by phosphorylation-dependent internalization of the channel protein from the plasma membrane. These effects were mediated by direct phosphorylation of the channel by ERK1/2 at the cytoplasmic C-terminus of the channel. Although PACAP did not significantly alter the voltage-dependence of Kv4.2 channel activation/inactivation, I observed distinct ERK1/2- and PKA-dependent changes in the extent and kinetics of channel inactivation. Next, I observed that PACAP induced dephosphorylation of the Kv2.1 channel in CHN that was mediated by protein phosphatase 2A (PP2A), and was dependent on PKC activation but was independent of the effects of PACAP on Kv4.2 currents. Rapid but reversible dephosphorylation of Kv2.1 was also observed following induction of ischemia in neurons by oxygen-glucose deprivation (OGD). PACAP prolonged the dephosphorylation of Kv2.1 following in vitro ischemia-reperfusion and also reduced neuronal death. My results therefore suggest a novel PACAP/PAC1-PKC-PP2A-Kv2.1 signaling axis that provides neuroprotection during ischemia reperfusion injury. In summary, my results suggest that PACAP can induce direct phosphorylation-dependent modulation of the Kv4.2 and Kv2.1 channel localization and function in mammalian brain neurons. The effect of PACAP on these two critical somatodendritic ion channels occurs via distinct signaling - convergent PKA-PKC-ERK-mediated phosphorylation of Kv4.2 channel, and PKC-PP2A-mediated dephosphorylation of the Kv2.1 channel. Such distinct modulations of these ion channels are presumably responsible for the multifarious roles of PACAP in the central nervous system.