Le développement constant des systèmes de communication soulèvent des inquiétudes sur l’influence des ondes électromagnétique sur le corps humain. Une législation existante permet de rassurer la population, mais, l’exposition quotidienne, souvent multi sources implique des interrogations sur ces nouveaux types d’usages. La méthode des Différence Finies dans le Domaine Temporel (FDTD) permet d’évaluer avec précision le niveau d’exposition a été décrit dans ce manuscrit. Cependant, cette méthode présente des limites si on souhaite représenter des structures présentant des courbures du fait de l’usage de mailles orthogonales. Ce manuscrit est une contribution à la problématique en développant une méthode de FDTD conforme dont les mailles suivent la forme des objets à modéliser. Même si, quelques méthodes de FDTD conforme existantes dans la littérature seront au préalable présentées. Dans cette étude, un soin particulier sera porté sur la validation de la méthode développée à travers plusieurs types de maillages différents et en comparant les résultats obtenus avec HFSS et la FDTD classique. Le débit d’absorption spécifique (DAS) sera également calculé en homogénéisant les tissus humains par pondération volumique. Ce qui permettra de réduire les temps de calcul / The constant development of communication systems raises concerns about the influence of electromagnetic waves on human body. Existing legislation helps to reassure population, but daily exposure, often multi-source, involves questions about these new types of use. The Time Domain Finite Difference (FDTD) method allows accurate assessment of the level of exposure described in this manuscript. However, this method has limitations if it is desired to represent structures with curvatures due to the use of orthogonal meshes. This manuscript is a contribution to the problem by developing a conformal FDTD method whose meshes follow the shape of the objects to be modeled. Even so, some existing FDTD compliant methods in the literature will be presented beforehand. In this study, particular attention will be paid to the validation of the method developed through several different types of meshes and comparing results obtained with HFSS and conventional FDTD. The specific absorption rate (SAR) will also be calculated by homogenizing human tissues by volume weighting. This will reduce computing time

<p>The overall aim of this thesis is to increase our knowledge of relevant exposure parameters when discussing possible health implication from exposure to radiofrequency electromagnetic fields (RF), especially effects that might occur at non-thermal levels.</p><p>In this thesis an effort is made to broaden the exposure assessment and to take the exposure time into account and combine it with the Specific Absorption Rate (SAR) and the field parameters (electric and magnetic field strength) to approach a dose concept.</p><p>In the first part of the thesis self-reported subjective symptoms among mobile phone users were studied. As a basis for this an epidemiological study among mobile phone users was completed with the main hypothesis that users of the digital transmission system GSM experience more symptoms than users of the older analogue NMT transmission system.</p><p>The hypothesis was falsified, but an interesting side finding was that people with longer calling time per day experienced more symptoms than people with shorter calling time per day. The time-aspect (long duration phone call etc.) was also found to be relevant for the occurrence of symptoms in association with mobile phone use as well as duration of symptoms. The new suggested dosimetric quantity Specific Absorption per Day (SAD), in which both calling time per day as well as the measured SAR1g are included showed a stronger association to the prevalence of some of the symptoms, such as dizziness, discomfort and warmth behind the ear compared to both CT and SAR1g alone.</p><p>In the second part whole body exposure conditions were considered. Methods to measure the induced current were examined in an experimental study, where different techniques were compared in different grounding conditions. The results were used in a study of operators of RF plastic sealers (RF operators) where the health status as well as the exposure were studied. The results showed that RF operators are a highly exposed group, which was confirmed by the fact that 16 out of 46 measured work places exceeded the ICNIRP guidelines. Headaches were found to be associated with the mean value of the time integrated E-field during a weld (E-weld) and the warmth sensations in the hands (warm hands) with the time integrated E-field exposure during one day (E-day).</p><p>The general findings in this thesis indicated that time should be included in the exposure assessment when studying non-thermal effects such as subjective symptoms in connection with RF exposure. The thesis proposes two different methods for doing this, namely timeintegrated exposure [V/m x t and A/m x t] and dose [J/kg]. </p>

High Throughput Screening (HTS) is used in drug discovery to screen large numbers of compounds against a biological target. Data on activity against the target are collected for a representative sample of compounds selected from a large library. The goal of drug discovery is to relate the activity of a compound to its chemical structure, which is quantified by various explanatory variables, and hence to identify further active compounds. Often, this application has a very unbalanced class distribution, with a rare active class. <br /><br /> Classification methods are commonly proposed as solutions to this problem. However, regarding drug discovery, researchers are more interested in ranking compounds by predicted activity than in the classification itself. This feature makes my approach distinct from common classification techniques. <br /><br /> In this thesis, two AIDS data sets from the National Cancer Institute (NCI) are mainly used. Local methods, namely K-nearest neighbours (KNN) and classification and regression trees (CART), perform very well on these data in comparison with linear/logistic regression, neural networks, and Multivariate Adaptive Regression Splines (MARS) models, which assume more smoothness. One reason for the superiority of local methods is the local behaviour of the data. Indeed, I argue that conventional classification criteria such as misclassification rate or deviance tend to select too small a tree or too large a value of <em>k</em> (the number of nearest neighbours). A more local model (bigger tree or smaller <em>k</em>) gives a better performance in terms of drug discovery. <br /><br /> Because off-the-shelf KNN works relatively well, this thesis takes this promising method and makes several novel modifications, which further improve its performance. The choice of <em>k</em> is optimized for each test point to be predicted. The empirically observed superiority of allowing <em>k</em> to vary is investigated. The nature of the problem, ranking of objects rather than estimating the probability of activity, enables the <em>k</em>-varying algorithm to stand out. Similarly, KNN combined with a kernel weight function (weighted KNN) is proposed and demonstrated to be superior to the regular KNN method. <br /><br /> High dimensionality of the explanatory variables is known to cause problems for KNN and many other classifiers. I propose a novel method (subset KNN) of averaging across multiple classifiers based on building classifiers on subspaces (subsets of variables). It improves the performance of KNN for HTS data. When applied to CART, it also performs as well as or even better than the popular methods of bagging and boosting. Part of this improvement is due to the discovery that classifiers based on irrelevant subspaces (unimportant explanatory variables) do little damage when averaged with good classifiers based on relevant subspaces (important variables). This result is particular to the ranking of objects rather than estimating the probability of activity. A theoretical justification is proposed. The thesis also suggests diagnostics for identifying important subsets of variables and hence further reducing the impact of the curse of dimensionality. <br /><br /> In order to have a broader evaluation of these methods, subset KNN and weighted KNN are applied to three other data sets: the NCI AIDS data with Constitutional descriptors, Mutagenicity data with BCUT descriptors and Mutagenicity data with Constitutional descriptors. The <em>k</em>-varying algorithm as a method for unbalanced data is also applied to NCI AIDS data with Constitutional descriptors. As a baseline, the performance of KNN on such data sets is reported. Although different methods are best for the different data sets, some of the proposed methods are always amongst the best. <br /><br /> Finally, methods are described for estimating activity rates and error rates in HTS data. By combining auxiliary information about repeat tests of the same compound, likelihood methods can extract interesting information about the magnitudes of the measurement errors made in the assay process. These estimates can be used to assess model performance, which sheds new light on how various models handle the large random or systematic assay errors often present in HTS data.

Lysis of the host by bacteriophage 21 requires two proteins: the pinholin S21 (forms pinholes in the cytoplasmic membrane and controls lysis timing) and the endolysin (degrades the cell wall). S21 has a dual-start motif, encoding a holin, S2168, and a weak antiholin, S2171. Both proteins have two transmembrane domains (TMD) and adopt an N-in, C-in topology. The topology of S2168 is dynamic because TMD1 is a signal-anchor-release (SAR) domain which, while initially integrated into the cytoplasmic membrane, is eventually released into the periplasm. TMD1 is dispensable because the truncated protein, S2168?TMD1, retains the holin function. Adding two positive charges to N-terminus of S2168 by an irs tag (RYIRS) prevents the release of TMD1. The irsS2168 protein not only has lost its holin function, but is a potent antiholin and blocks the function of S2168. In this dissertation, the structure of S2168 was suggested by incorporating electron-microscopy, biochemical, and computational approaches. The results suggest that S2168 forms a symmetric heptamer, with the hydrophilic side of TMD2 lining the channel of ~ 15 A in diameter. This model also identifies two interacting surfaces, A and B, of TMD2. A model for the pinhole formation pathway was generated from analyzing phenotypes of an extensive collection of S21 mutants. In this model, the individually folded and inserted S21 molecules first form the inactive dimer, with the membrane-inserted TMD1 inhibiting the lethal function of TMD2 both inter- and intra-molecularly. A second inactive dimer may form, with one TMD1 released. When both TMD1s are released, the activated dimer is formed, with the homotypic interfaces A:A interaction of the TMD2s. However, this interaction might not be stable, which will shift to heterotypic A:B interactions, allowing TMD2 to oligomerize. Finally, the pinhole forms, possibly driven by the hydration of lumenal hydrophilic residues. In addition, the localization of pinholes was visualized by fusing the green fluorescent protein (GFP) to the C-terminus of pinholins. The results showed that pinholins form numerous small aggregates, designated as rafts, spread all over the cell body. The antiholin irsS2168 not only inhibits the triggering of S2168GFP, but inhibits the rafts formation as well.

SAR-ADCs are very popular and suitable for conversions up to few tens of MHz with 8 to 12 bits of resolution. A very popular type is the Charge Redistribution SAR-ADC which is based on a capacitive array. Higher speeds can be achieved by using the interleaving technique where a number of SAR-ADCs are working in parallel. These speeds, however, can only be achieved if the reference voltage can cope with the switching of the capacitive array. In this thesis the design of a programmable voltage reference generator for a Charge Redistribution SAR-ADC was studied. A number of architectures were studied and one based on a Current Steering DAC was chosen because of the settling time that could offer to the Charge Redistribution SAR-ADC switching operation. This architecture was further investigated in order to spot the weak points of the design and try to minimize the settling time. In the end, the final design was evaluated and possible trimming techniques were proposed that could further speed up the design.

SAR endolysins are a recently discovered class of muralytic enzymes that are regulated by dynamic membrane topology. They are synthesized as enzymatically inactive integral membrane proteins during the phage infection cycle and then are activated by conformational remodeling upon release from the membrane. This topological duality depends on N-terminal SAR (Signal-Anchor-Release) domains, which are enriched in weakly hydrophobic residues and require the proton motive force to be maintained in the bilayer. The first SAR endolysin to be characterized was P1 Lyz, of phage P1. Its activation requires a disulfide bond isomerization involving its catalytic Cys initiated by a free cysteine thiol from the newly-liberated SAR domain. A second mode of disulfide bond regulation, as typified by Lyz103 of the Erwinia Amylovora phage ERA103, has been demonstrated. In its membrane bound form, Lyz103 is inactivated by a disulfide that is formed between cysteine residues flanking a catalytic glutamate. A second class of SAR endolysins, typified by R21, the lysozyme of the lambdoid phage 21, does not require disulfide bond isomerization for activation. Rather, these proteins are dependent on the release of the SAR domain for proper folding of the catalytic cleft. Bioinformatic analysis indicates that the regulatory theme of R21 is common in the SAR endolysins of dsDNA phages. Furthermore, bioinformatic study of endolysins of dsDNA phage of Gram-negative hosts revealed two new classes of SAR endolysins that are not homologous to T4 gpe, as all SAR endolysins were once thought to be. SAR endolysins were found in nearly 25% of sequenced dsDNA phages of Gram- negative hosts including 933W, which is involved in the release of Shiga toxin from EHEC strain EDL933. An inhibitor study against the SAR endolysin of 933W, R933W, was performed using a custom compound library in a high through-put, in vivo lysis assay. Of nearly 8,000 compounds screened, one compound, designated 67-J8, inhibited lysis but not growth. In vivo and in vitro experiments show that the compound has no effect on R933W activity, accumulation, or secretion. In vivo experiments suggest that 67-J8 increases the proton motive force, thereby presumably retaining the SAR domain in the membrane.

Grasslands are the most important ecosystem to humanity, as they are responsible for feeding that majority of the human population. These are also very large ecosystems; they cover approximately 40% of the surface of the earth (Loveland et al., 1998), making ground-based surveys for monitoring grassland health and productivity extremely time consuming. Remote sensing has the advantage of providing reliable and repeatable observations over large swaths of land; however, optical sensors exploiting the visible and near infrared regions of electromagnetic (EM) spectrum will be unable to collect information from the ground if clouds are present (Wang et al., 2009). Imaging radar sensors, the most common being synthetic aperture radar (SAR), have the advantage of being able to image the ground even during cloudy conditions. The longer wavelengths of EM energy used by the SAR sensor are able to penetrate clouds while shorter wavelength used by optical sensors are scattered. A grassland monitoring tool based on SAR imagery would have many advantages over an optical imagery system, especially when SAR data becomes widely available. To demonstrate the feasibility of grassland monitoring using SAR, this study experimented with a set of dual-polarimetric SAR imagery to extract several grassland biophysical parameters such as soil moisture, canopy moisture, and green grass biomass over the mixed grassland in southwestern Saskatchewan. Soil moisture was derived from these images using the simple Delta Index (Thoma et al., 2006) first developed for a sparsely vegetated landscape. The Delta Index was found to explain 80% of the variation in soil moisture, in this vegetated landscape. Canopy moisture was modeled using the water cloud model (Attema and Ulaby, 1978). This model has a similar explanatory power of R2 = 0.80. This study found that only the photosynthesizing green grass biomass had a significant relationship with the canopy moisture model. However, only about 40% of the variation in green grass biomass can be explained by canopy moisture alone. The cross-polarized ratio developed from the dual polarimetric images was found to reflect the plant form diversity of the grassland. Biophysical parameters extracted from optical satellite imagery, Landsat-5 in the case of this study, were compared to those derived from the SAR images. This comparison revealed that the SAR images were superior in sensitivity to soil and canopy moisture. Optical imagery was found to be more sensitive to green canopy cover. An approach combining the results from both sensors showed an improvement in green grass biomass estimation (Adjusted R2 = 0.71).

An introduction, background and research progress in the areas of antifolates, receptor tyrosine kinase (RTK) inhbitors and antimitotic agents has been discussed. &lt;br&gt;Thymidylate synthase (TS), dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyltransferase (GARFTase) are important folate dependent enzymes that are targets for cancer chemotherapy and the treatment of infectious diseases. Classical antifolates, in most cases, are substrates for folypoly-g-glutamate synthase (FPGS) and rely on folate transporter systems to enter cells. As a part of this study, twenty-eight compounds were designed on the basis of existing clinically active compounds and crystal structures, synthesized and evaluated as single and/or muliple targeted classical and nonclassical antifolates to decrease toxicity and improve the activity and selectivity of existing therapeutic agents. In addition, these structures provides an extension to the structure activity relationship in the antifolate area. &lt;br&gt;RTK inhibitors and antimitotic agents are important antitumor agents and are extensively used in the clinic for the treament of various types of cancers. Pgp overexpression is one of the common reasons for drug resistance to existing antitumor agents and consequently the reason for some chemotherapeutic failures. A furo[2,3-d]pyrimidine compound was discovered to have dual RTK inhibitory activity along with antimitotic activity that circumvent pgp over expression. Antimitotic activity via the binding at the colchicine site is one of the mechanisms of action. Molecular modelling and biological evaluation suggest the importance of conformational restriction for activity. Fifty-seven furo[2,3-d]pyrimidines and six thieno[2,3-d]pyrimidines were designed on the basis of crustal structures and synthesized as potential RTK inhibitors with antimitotic antitumor activity. Four pyrrolo[2,3-d]pyrimidines were designed and synthesized as antimitotic anticancer agents that also reverse pgp action. / Mylan School of Pharmacy and the Graduate School of Pharmaceutical Sciences / Medicinal Chemistry / PhD / Dissertation

Imagens de radar de abertura sintética (SAR) são tipicamente corrompidas pelo ruído \"speckle\" que também degrada imagens geradas por ultra-som, laser, etc. Esta tese propõe algoritmos de filtragem baseados na abordagem \"maximum a posteriori\" (MAP) para redução de \"speckle\" em imagens SAR. Na derivação dos filtros MAP, para imagens obtidas por detecção linear, são utilizadas as distribuições (condicionais) Rayleigh e raiz quadrada de gama na regra de Bayes como modelos para o ruído \"speckle\" em imagens SAR obtidas em amplitudes com 1 e múltiplas visadas, respectivamente, e usadas várias distribuições para o modelo \"a priori\". Toda a formulação dos algoritmos tem por base o modelo multiplicativo que constitui o modelo mais adequado ao \"speckle\". Propõe-se ainda neste trabalho a combinação dos filtros MAP formulados com o algoritmo k-médias e com a técnica de crescimento de regiões, como forma de melhoria da abordagem de filtragem proposta. Os resultados de filtragem foram avaliados segundo critérios (medidas) de melhoria da relação sinal-ruído e perda de resolução. O primeiro critério avalia a redução da intensidade do ruído \"speckle\" sobre regiões homogêneas e para avaliar a perda de resolução decorrente da filtragem é proposta uma nova técnica baseada na transformada de Hough. Os algoritmos foram testados em imagens artificialmente contaminadas por ruído \"speckle\" e em imagens SAR reais apresentando estatísticas Rayleigh e raiz de gama. Os resultados obtidos mostram a melhoria que proporcionam os algoritmos de filtragem MAP, especialmente quando combinados com o classificador k-médias e com a técnica de crescimento de região. O uso da técnica de crescimento de região reforça a conclusão de que o uso de vizinhança estatisticamente mais semelhante ao pixel ruidoso melhora a estimação dos parâmetros de filtragem. As medidas de desempenho e validação dos algoritmos MAP permitiram concluir que os filtros com distribuições \"a priori\" Gaussiana, gama, chi-quadrado e beta apresentaram melhores resultados de filtragem em relação aos demais modelos \"a priori\" quando comparados ao filtro de Kuan e com a técnica de \"wavelets\" para a classe de imagens utilizadas / Synthetic aperture radar (SAR) images are typically corrupted by speckle noise, which also degrade images produced by laser beams, ultrasound, etc. This thesis proposes filtering algorithms based on the \"maximum a posteriori\" (MAP) approach, to reduce speckle in SAR images. To derive the MAP filters for linearly detected images we assumed the multiplicative model for the speckle and used the conditional density functions in the Bayes rule following a Rayleigh and square root of gamma for one-look and N-looks images, respectively, and several different \"a priori\" densities. The MAP filters are combined with the k-means classifier and region growing tools to improve the proposed filtering approach. Measures evaluating both the signal-to-noise improvement and resolution loss due to filtering are computed. To assess the improvement brought by the proposed algorithms we evaluate them with respect to signal to noise ratio and edge preservation. The former is a classical way to evaluate the speckle strenght reduction over homogeneous areas and the latter is a new proposed technique based on the Hough transform that measures distortions at the edges produced by the speckle MAP filtering algorithms. The qualitative analysis of the MAP proposed algorithms includes the methods based on the curvature and wavelets . The algorithms were applied to simulated noisy speckled images and real SAR images with statistics of linearly detected images with one-look and N-looks. The obtained results demonstrated the improvement brought by the speckle MAP filtering algorithms, specially when combined with the k-means clustering algorithm and with the region growing approach. This region growing approach reinforces the conclusion that the use of a neighborhood whose pixels have statistics similar to the noisy pixel provides a better estimation for filtering. The evaluating measures point out that the MAP filters whose \"a priori\" models are the Gaussian, gamma, chi-square and beta presented better results than the other \"a priori\" models proposed in this thesis, the Kuan filter and the wavelets filter, for the class of images that were tested

Although Malaria rates are on the decline due to the efforts of the World Health Organization and other organizations dedicated to the eradication of this disease, a relaxed attitude towards the development of new antimalarial entities would be flawed. Due to the emergence of resistance in the parasite, the almost 50% world-wide reduction in malarial death rates that have been produced over the past 15 years are threatening to be lost New drugs are urgently needed and our approach focuses on the re-evaluation and optimization of the historic antimalarial ICI 56,780. Due to its causal prophylactic activity, along with its ability to prevent transmission and potent blood schizonticidal activities, it was revisited with the hopes of first understanding which functionalities were responsible to the compound's activity. Secondly, we wanted to optimize the substituents in the 3, 6 and 7-positions. Finally and most importantly, we wanted to address the cross-resistance problem of the ICI 56,780 scaffold. Initial, analogues showed the importance of the ester in facilitating the convergence of the RI towards 1. Although those analogues lost activity in W2, TM90-C2B, and Pb, they were our first glimpse at this important trend that was later exploited in our 3-halo-6-butyl-7-(2-phenoxyethoxy)quinolin-4(1H)-one and 3-halo-6-butyl-2-methyl-7-(2-phenoxyethoxy)quinolin-4(1H)-ones which showed RI values of < 5 for our best analogues. Although our lead compound 3-bromo-6-butyl-2-methyl7-(2phenoxyethoxy)quinolin-4(1H) one possessed decreased activities as compared to ICI 56,780 at 2.60 nM for W2, 12.2 nM for TM90-C2B and 2.12 nM for Pb, it had 100% inhibition of parasite development on day 6 PE in our scouting assay and 61% inhibition on day 6in our Thompson model, increased from the < 2% value given by the ICI 56,780. Solubility and unfavorable in vivo stability were still major issues for this scaffold. Therefore, a series of piperazinyl 4(1H)-quinolones with greatly enhanced solubility were designed and tested in detailed structure activity relationships and structure property relationship studies. Initial results showed that 7-piperazinyl-4(1H)-quinolones possessed greatly increased solubilities when compared to ICI 56,780 analogues. Primarily, the linker length and the piperazine core was probed. This showed that compounds with a single carbon spacer were most active. Further testing of the 6-position gave methyl 6-methyl-4-oxo-7-((4-phenylpiperazin-1-yl)methyl)-1,4-dihydroquinoline-3-carboxylate with W2 and TM90-C2B values of 0.435 nM and 147 nM respectively. Substitution on the piperazinyl phenyl gave the most active compounds however the RI of >1500 was unacceptable. Because of this, 3-halo substituents were added to these quinolones with promising results. With RIs of < 3, the compounds were promising, however they were not active in vivo. However, methyl 6-methoxy-4-oxo-7-((4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)methyl)-1,4-dihydroquinoline-3-carboxylate and methyl 6-methyl-4-oxo-7-((4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)methyl)-1,4-dihydroquinoline-3-carboxylate both gave cures in our in vivo Thomson model. These studies highlight the potential in using detailed structural activity and structural property studies to re-evaluate and optimize historic antimalarials. These studies have introduced a new generation of soluble 4(1H)-quinolones with high potency against P. falciparum.