O carcinoma epidermóide de pênis (CEP) representa 95% das neoplasias penianas e afeta quase sempre pacientes não circuncidados estando muitas vezes associado à falta de higiene local adequada e à fimose. No Brasil a sua incidência é de 2,7 % porém em algumas áreas do país pode chegar a 17% dos casos diagnosticados por ano. O tumor pode ocorrer em qualquer parte do órgão sexual masculino e o tipo de estadiamento empregado é controverso. A classificação de Broders é a mais utilizada. Estudos sugerem a relação entre o desenvolvimento do carcinoma de pênis com a infecção por HPV (Papiloma Vírus Humano). O método de avaliação dos linfonodos inguinais permanece controverso sendo difícil a diferenciação entre linfadenomegalia inflamatória reacional e metastática. O exame físico não é um preditor confiável do comprometimento linfonodal pois pacientes com linfonodos palpáveis podem não apresentar metástases. Há poucas publicações sobre os mecanismos moleculares envolvidos na gênese e progressão do CEP. Apesar de vários marcadores terem sido avaliados, atualmente a aplicação clínica destes é limitada. A maior parte dos marcadores estudados requer procedimentos invasivos para obtenção do tecido tumoral. Existe a necessidade de encontrar através de uma técnica pouco invasiva marcadores tumorais circulantes capazes de diferenciar portadores de CEP com e sem envolvimento metastático. Neste tipo de neoplasia, a descoberta de biomarcadores que avaliem o prognóstico é relevante, pois o exame físico não é um indicador confiável do comprometimento linfonodal e da sobrevida.Os objetivos foram 1) revisar e discutir a epidemiologia, a etiologia, os diversos tipos de abordagem cirúrgica e as controvérsias no tratamento cirúrgico do câncer de pênis 2) investigar através da plataforma ClinProt/ MALDI / TOF a presença de marcadores plasmáticos capazes de discriminar indivíduos saudáveis de pacientes afetados por carcinoma epidermóide de pênis (CEP) 3) avaliar a importância destes marcadores na evolução da doença. Foram coletados e analisados pela plataforma ClinProt / MALDI / TOF o plasma de 36 indivíduos saudáveis e 25 pacientes com CEP invasivo, submetidos a tratamento cirúrgico entre junho de 2010 e junho de 2011, nos serviços de urologia do Instituto Nacional de Câncer e do Hospital Mário Kröeff (Rio de Janeiro). Nossos resultados apontaram para um conjunto de dois peptídeos (A = m / z 1897,22 + -9 Da e B = m / z 2021,99 + -9 Da) que foram capazes de diferenciar pacientes com CEP de indivíduos controles. Esses peptídeos foram posteriormente identificados como fragmentos C3 e C4 A/B do sistema complemento. A validação cruzada, utilizando toda casuística apresentou 62,5% e 86,76% de sensibilidade e de especificidade, respectivamente, com uma alta sensibilidade (100%) e especificidade (97%) nos pacientes que morreram pela doença. Além disso, os pacientes com envolvimento ganglionar obtiveram uma sensibilidade e uma especificidade de 80 % e 97%, respectivamente. Ficou demonstrado que à medida que a doença progride mais subexpressos está o conjunto de peptídeos quando comparados com indivíduos saudáveis. Estes resultados podem ser úteis como ferramentas para a avaliação do prognóstico destes pacientes. / Squamous cell carcinoma of the penis (SSCP) represents 95% of penile cancers. It affects mostly uncircumcised patients and is often associated with lack of adequate local hygiene and phimosis. In Brazil, the incidence is 2.7% but in some areas of the country can reach 17% of diagnosed cases of cancer per year. The tumor can occur in any part of the sexual organ and the type of staging to be used is controversial. The Broders classification is more often used to classify tumors. Studies suggest the relationship between the development of penile carcinoma and HPV infection (Human Papilloma Virus). The evaluation method of inguinal lymph nodes remains controversial and it is difficult to differentiate inflammatory reaction from metastatic lymphadenopathy. Physical examination is not a reliable predictor of lymph node involvement since patients with palpable lymph nodes can not present metastases. There are few publications about the molecular mechanisms involved in the genesis and progression of the SSCP. Although several markers have been evaluated, currently the clinical application of these is limited. Most of the markers studied require invasive procedures for obtaining tumor tissue. There is a need to find through a minimally invasive technique circulating tumor markers able to differentiate SSCP patients with and without metastatic involvement. In this type ofmalignancythediscovery of biomarkers that assessthe prognosisis relevant since physical examination is not a reliable predictor oflymph node involvementand survival. The objectives of this study were: 1) to review and discuss the epidemiology, etiology, different types of surgical approach and controversies in the surgical treatment of penile cancer 2)to investigate via the platform ClinProt / MALDI / TOF presence of plasma markers able to discriminate healthy subjects from patients affected by squamous cell carcinoma of the penis (SCCP) 3) to evaluate the importance of these markers in disease progression. Between June 2010 and June 2011, plasma samples from 36 healthy subjects and 25 patients with penile carcinoma who underwent surgical treatment in the UrologyServicesofNational Cancer InstituteandMarioKröeffHospital were collected and analyzed by the ClinProt/MALDI/TOF platform. Our results found a cluster of 2 peptides (A=m/z 1897.22 +-9 Da and B=m/z 2021.99 +-9 Da that was able to discriminate patients from controls subjects. These peptides were further identified as C3 and C4 A/B fragments from complement system. Cross validation analysis using the whole casuistic showed 62.5% and 86.76% of sensitivity and specificity, respectively with a very high sensitivity (100%) and specificity (97%) for SCCP patients that have died by disease. Moreover, patients with lymph node involvement present a sensitivity and specificity of 80% and 97%, respectively. The results showed that as the disease progresses more under express are the cluster comparing with healthy subjects. These results may be useful as prognostic toll.

L’allogreffe de cellules hématopoïétiques est une stratégie thérapeutique importante dans les hémopathies malignes. La maladie du greffon contre l’hôte (GvH) en est une complication majeure menaçant le pronostic vital. Elle est due à la reconnaissance des antigènes du receveur par les lymphocytes T du donneur et à l’activation de ceux-ci, à l’origine de dommages tissulaires. L’altération de la barrière intestinale joue un rôle critique dans la GvH. La famille des protéines de choc thermique (HSP)90 comporte cinq membres dont trois cytosoliques dénommés HSP90, et un localisé dans le réticulum endoplasmique (RE), Gp96, qui peut être sécrété en cas de stress. Nous montrons dans nos travaux de thèse que la 17AAG, un inhibiteur des HSP90, réduit la mortalité liée à la GvH dans un modèle murin. Cet effet est associé à une augmentation de la réponse au stress du RE dans les cellules épithéliales intestinales comme en atteste l’augmentation de l’épissage du facteur de transcription XBP-1, corrélée à une diminution du dommage tissulaire intestinal. Ces résultats permettent d’envisager une place pour la 17AAG ou d’autres inhibiteurs de HSP90 dans la prévention de la GvH chez l’homme. D’autre part, nous montrons que Gp96 est sécrétée dans le sérum de patients développant une GvH aiguë sévère avec atteinte intestinale. Nous suggérons de valider la pertinence de Gp96 comme biomarqueur de GvH intestinale dans une étude de plus grande ampleur. Enfin, nous trouvons que Gp96 s’associe avec le composant 3 du complément, une protéine impliquée dans l’immunité innée et adaptative, et inhibe certaines de ses fonctions. Les conséquences fonctionnelles de cette association sont discutées. / Allogeneic hematopoietic cell transplantation is a treatment for certain disorders including hematologic malignancies. Graft-versus-host-disease (GvHD) is a major, life-threatening complication. It is due to the recognition of recipient antigens by donor T cells, which activate and damage tissues. Intestinal barrier alteration plays a critical role in GvHD. Heat shock proteins (HSP)90 include five members, three cytosolic members named HSP90, and one member localized in endoplasmic reticulum (ER) called Gp96 and able to gain extracellular level in case of stress. We show in our thesis that 17AAG, a HSP90 inhibitor, reduces GvHD mortality in a mouse model. This effect is associated with an increase in ER stress pathway in intestinal epithelial cells as figured by transcription factor XBP-1 splicing, correlated to a decrease in intestinal tissue damage. These results suggest that 17AAG could be considered in GvHD prevention in human. Moreover, we show that Gp96 is secreted in serum of patients developing an acute GvHD with intestinal involvement. We propose to validate the relevance of Gp96 as an intestinal GvHD biomarker is a larger study. Finally, we find that Gp96 associate with complement component 3, a protein involved in innate and adaptive immunity, and inhibit some of its functions. Functional consequences of this association are discussed.

The current increased use of antifungal agents has resulted in the development of resistance to these drugs. Search for new antifungals with different mechanisms of action overcoming the multidrug resistance is thus underway. Surface-active antifungals have the advantages of minimizing host toxicity and the emergence of drug resistance. We have developed a fluorescence method based on the use of the potentiometric fluorescent probe diS-C3(3), substrate of two major S. cerevisiae MDR pumps, Pdr5p and Snq2p. It allows us to monitor with high sensitivity and in real time changes in the activities of both pumps and also in membrane potential. We present here an efficient strategy for identifying pump inhibitors with minimal side effects on membrane integrity, and compare the potencies of different inhibitors towards MDR pumps. New efficient inhibitors of MDR pumps could potentially be used in conjunction with current antimicrobials that are MDR pump substrates. The method can be also used to determine the mechanism of action of surface-active drugs and their lowest effective concentrations.

Sweden produced 215 kilotons of electronic waste in 2016. One way to reduce this amount is to repair electronic devices when they fail instead of replacing them. The company Mavenoid has a troubleshooting service in the form a web application to help troubleshoot machines like for example consumer electronics. The company desired a tool to visualize data about the usage of the troubleshooting models in their web app. The prospect was that the users who build the troubleshooting models would be able to analyse how their models are being used and how well they work with the tool. To implement the tool, a method with three phases was used. An initial preparation phase with requirements elicitation via a domain analysis and set-up of the development environment, a development phase with iterative development and requirements management with weekly meetings and an analysis phase with evaluation of the tool according to the requirements and the status of a pull request. The product met eight out of ten requirements and was of a sufficiently high quality that it could be integrated into the company’s system. The use of the library C3 resulted in a 21% increase of the web application’s build size. / Sverige producerade 2016 215 kiloton elektronikavfall. Ett sätt att minska denna mängd är att reparera elektronik när den fallerar istället för att byta ut den. Företaget Mavenoid erbjuder en tjänst i form av en React webapplikation för att underlätta felsökning av maskiner som t.ex. hemelektronik. Företaget eftersökte ett verktyg för att visualisera data om användningen av felsökningsmodellerna i sin webbapplikation. Förhoppningen var att de användare som bygger modellerna via det nya verktyget skulle kunna analysera hur deras modeller används och väl de fungerar. För att utveckla verktyget användes en metod med tre faser. En inledande förberedelsefas med kravinsamling via en domänundersökning och uppbyggnad av utvecklingsmiljö, en utvecklingsfas med iterativ utveckling och kravhantering med veckomöten och en analysfas med utvärdering av verktyget efter kraven och status på en pull-request. Produkten uppfyllde åtta utav tio av de insamlade kraven och var av tillräckligt hög kvalitet att integreras i företagets system. Användningen av biblioteket C3 medförde att webapplikationens transaktionsstorlek ökade med ca 21%

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

No description available.

Intercropping, defined as two or more crops grown on the same land area at the same time, is a sustainable alternative to sole crops. Intercropping has been associated with multiple benefits, such as increased nutrient and soil organic carbon (SOC) cycling, decreased soil erosion and increased carbon (C) sequestration. A common intercropping practice is to integrate cereal and legume crops such as maize (Zea mays L.), and soybean (Glycine max (L.) Merr.). Most studies on intercropping have focused on yield, weed control, and land use efficiency in the tropics. Few studies have researched C and nitrogen (N) dynamics in temperate intercrops, with respect to soybean and maize residue stabilization. Soil from Balcarce, Argentina, was incubated for 140 days with soybean, maize, or no residue. Throughout the incubation, results illustrated the effect of residue application upon the soil, specifically through significantly higher amounts of light fraction (LF) C and LFN concentrations, soil microbial biomass (SMB) C and SMBN concentrations, higher microbial diversity, lower N2O production rates, in addition to distinct isotopic values in soil fractions and CO2 (p<0.05). Furthermore, it was observed from δ15N-TN and δ15N-LF that treatments with soybean residues included had higher N cycling (p<0.05), emphasizing the importance of including N-fixing legumes in complex agroecosystems. Significant changes over time in SMB and SMCS characteristics, and isotope values (p<0.05) indicated the preferential utilization of relatively young and easily accessible litter. Furthermore, the loss of labile material over the incubation resulted in more recalcitrant forms (such as older C and lignin) to be utilized. Slightly higher SOC, TN, LFC and LFN concentrations, as well as lower CO2 production rates suggested 2:3 (rows of maize:rows of soybean) as a more desirable intercrop design for C sequestration. The 1:2 intercrop design was observed to be more beneficial for microbial community structure, furthering the idea that intercropping is a beneficial alternative to sole cropping. This study improves knowledge in residue stabilization and C sequestration in complex agroecosystems, providing encouragement for the implementation of more sustainable management practices.

For the astrophysically relevant molecules, C3 and C6, ab initio calculations are performed to study the geometries of different neutral isomers, the electronic structures of C3 in its ground and excited states, and possible pathways for the reaction C3 + C3 = C6. For C3 we present calculations for the potential energy surfaces of C3 in different electronic configurations, including the singlet ground state, the triplet ground state, and some higher excited states. The geometries studied include triangular shapes with two identical bond lengths, but different bond angles between them. For the singlet and triplet ground states in the linear geometry, the total energies resulting from the mixed density functional-Hartree-Fock and quadratic configuration interaction methods reproduce the experimental values, i.e. the triplet occurs 2.1 eV above the singlet. In the geometry of an equilateral triangle, we find a low-lying triplet state with an energy of only 0.8 eV above the energy of the singlet in the linear configuration, so that the triangular geometry yields the lowest excited state of C3. For the higher excited states up to about 12 eV above the ground state, we apply time-dependent density functional theory. Even though the systematic error produced by this approach is of the order of 0.4 eV, the results give new insight into the potential energy landscape for higher excitation energies. For C6 we consider the known linear states and the lowest state of monocyclic ring. The potential energy surfaces, were built for various pathways for the reaction C3 + C3 = C6. For this investigation we apply a mixed density functional-Hartree-Fock method which gives good results with respect to the experimental values and does not demand much computational time. We have considered collinear and symmetric non-linear as well as some non-symmetric collision schemes of two C3 subunits, producing the 1Ag states of a D2h isomer, one in a cyclic shape, the other in the form of two triangles connected by the corners, and for the non-symmetric scheme the 1A' state of a Cs isomer. To investigate the pathways for the creation of C6 from two C3 we emphasize the importance of the electron configuration for the reacting C3 subunits. As a result we have obtained the following rule: The stable linear as well as the cyclic C6 molecule can only be created in the case when at least one C3 has a partially filled orbital, requiring an excited state with respect to the singlet ground state of C3. / Für die astrophysikalisch bedeutenden Moleküle C3 und C6 werden ab initio Berechnungen von elektronischen Zuständen verschiedener Isomere durchgeführt. Basierend auf der Optimierung verschiedener neutraler Isomere von C3 im Grundzustand und mehreren angeregten Zuständen werden mögliche Wege für die Reaktion C3 + C3 = C6 studiert. Für C3 werden ab initio Berechnungen für die Flächen der potentiellen Energie in verschiedenen elektronischen Konfigurationen durchgeführt, einschließlich des Singulett-Grundzustands, des Triplett-Grundzustands, und einiger höherer Anregungszustände. Die untersuchten Geometrien schließen gleichschenklige Dreiecke mit zwei identischen Bindungslängen ein, wobei der Bindungswinkel dazwischen variiert wird. Die Gesamtenergien, die sich in einem gemischten Hartree-Fock-Dichtefunktional-Verfahren und unter Verwendung der quadratischen Konfigurationswechselwirkung ergeben, reproduzieren die experimentell beobachtete Energiedifferenz von 2.1 eV zwischen dem niedrigsten Triplett-Zustand und dem Singulett-Grundzustand. In der Geometrie des gleichseitigen Dreiecks ergibt sich ein niedrigerliegender Triplett-Zustand mit einer Energie von nur 0.8 eV über der Energie des Singuletts im linearen Isomer, so dass die dreieckige Geometrie den niedrigsten Anregungszustand von C3 ergibt. Für höhere Anregungsenergien bis zu 12 eV über dem Grundzustand wird zeitabhängige Dichtefunktional-Theorie zur Ermittlung der Energie angeregter elektronischer Konfigurationen eingesetzt. Obwohl der von dieser Methode produzierte systematische Fehler von der Größenordnung von 0.4 eV ist, ergeben sich interessante neue Einblicke in die Potentiallandschaft angeregter Zustände. Für C6 betrachten wir das bekannte lineare Isomer und das zyklische Isomer. Der Verlauf der Potentialoberflächen wird für verschiedene Reaktionspfade C3+C3 = C6 untersucht, wobei ein gemischtes Hartree-Fock-Dichtefunktional-Verfahren einesetzt wird. Im Mittelpunkt des Interesses stehen dabei kollineare Anordnungen linearer C3 Moleküle, symmetrische Kollisionen nichtlinearer Reaktanden, sowie einige nichtsymmetrische koplanare Geometrien des Zusammenstosses zweier linearer Moleküle. Als Ergebnis der Reaktionen mit symmetrischen Anordnungen ergibt sich lineares C6 oder zyklisches C6 mit D2h Symmetrie in einem elektronischen Zustand der höchsten Symmetrie 1Ag. Das nicht-symmetrische Reaktionsschema führt zu einem planaren Isomer Cs im Zustand 1A'. Um die Wege für die Bildung von C6 aus zwei C3 zu untersuchen, ist die elektronische Konfiguration der Reaktanden von entscheidender Bedeutung. Als Ergebnis erhält man die folgende Regel: sowohl ein stabiles lineares als auch ein zyklisches C6 Molekül können nur gebildet werden, wenn zumindest eines der C3 Moleküle ein teilweise gefülltes Orbital hat, wofür eine Anregung aus dem Singulett-Grundzustand heraus erforderlich ist.

Ce travail de thèse s'intéresse d'une part aux dimères rigides de tétrathiafulvalène (TTF) et à la modulation de la valence mixte intramoléculaire et, d'autre part, à des dérivés tris(TTF) possédant la capacité de conduire par auto-assemblage à des organogels et fibres, éventuellement présentant une chiralité supramoléculaire. Lors d'une première partie, des composés de type (TTF)2(XY) (X = PPh, Y = PPh ou SiMe2) ont été synthétisés et caractérisés par diffraction de rayons X sur monocristal. Leur réactivité et chimie de coordination ont été étudiées et l'état de valence mixte intramoléculaire dans les espèces oxydées a été caractérisé par des moyes spectroscopiques et théoriques. Dans la deuxième partie, une nouvelle famille de composés qui allient propriétés électroactives, grâce aux unités TTF, avec un haut degré d'organisation supramoléculaire hélicoïdale est introduite. Le composé Ph[CONH-bipy-NHCO-TTF(SEt)2]3 montre des bonne propriétés de gélation dans les solvants chlorés. Un xérogel, formé par deux types de fibres, est obtenu et devient conducteur à la suite du dopage à l'iode. Les composés (S)- et (R)-Ph[CONH-bipy-NHCO-TTF(S-2-méthylbutyle)2]3, possédant des groupes isopentyle chiraux, forment des fibres d'une seule hélicité, comme indiqué par des études de microscopie optique et électronique de balayage, de spectroscopie de dichroïsme circulaire et par calculs de mécanique moléculaire et de dynamique moléculaire.