Monoklonale Antikörper (mAk) werden bereits erfolgreich zur therapeutischen Depletion verschiedener Zellpopulationen in vivo verwendet, die Mechanismen der Depletion sind jedoch unklar geblieben. In dieser Arbeit wurden im Mausmodell die molekularen Grundlagen der CD4+ T-Zelldepletion (CD4 TZD) nach einmaliger Gabe (i.p.) von 100 µg des anti-CD4-mAk YTS191.1 untersucht. Dabei konnte eine starke Korrelation zwischen Depletion und der Modulation des CD4-Moleküls von der Oberfläche beobachtet werden. Gleichzeitig zeigten sich organabhängige Unterschiede, sowohl im zeitlichen Verlauf, als auch in der Effizienz der Depletion. Im Thymus konnten weder Depletion noch Modulation detektiert werden, in Milz und Lymphknoten (Lk) war die CD4 TZD nach starker CD4-Modulation bereits nach 48 h mit 80-90 % maximal, in den Peyer-Plaques jedoch niedriger und verzögert (50-60 % nach 72 h). Anhand C3-defizienter Mäuse konnte ferner kein wesentlicher Beitrag von Komplement an der CD4 TZD beobachtet werden. Im Gegensatz dazu konnte durch die Verwendung verschiedener FcGamma-Rezeptor (FcGammaR)-defizienter Mäuse (FcGammaRI, FcGammaRII, FcGammaRIII, FcGammaRI/III und FcRGamma) wie auch durch die Blockade des FcGammaRIV eine starke, zudem organabhängige Beteiligung von FcGammaR an der CD4 TZD gezeigt werden. Während in der Milz die CD4 TZD von FcGammaRIV vermittelt wurde, waren in den Lk und Peyer-Plaques FcGammaRI/III involviert. Diese Befunde korrelierten mit der starken Expression von FcGammaRIV in Milz, Lunge, Darm, Niere und Leber, während in den Lk nur eine schwache und in Thymus und Peyer-Plaques keine Expression detektiert werden konnte. Innerhalb der Milz konnten erstmalig F4/80hoch Makrophagen als FcGammaRIV+ identifiziert und somit als potenzielle Effektorzellen der CD4 TZD bestimmt werden. Der direkte Vergleich der Depletion von CD4+ T-Zellen mit der Depletion von ICOS+ T-Zellen verdeutlichte darüber hinaus, dass die Effizienz der Zelldepletion nicht nur von den Eigenschaften des verwendeten mAk, sondern auch von denen des Zielmoleküls abhängig ist. / Monoclonal antibodies (mAb) are efficiently used for the therapeutic depletion of various cells in vivo yet the mechanisms of depletion are still unclear. In this work, the molecular principles of CD4+ T cell depletion (CD4 Tcd) by a single application of 100 µg of the anti-CD4 mAb YTS191.1.1 were investigated in the mouse. A strong correlation between the depletion and the surface modulation of the CD4 molecule could be observed. At the same time, organ-dependent differences in the kinetics as well as in the efficiency of depletion could be detected. In the thymus, neither modulation nor depletion were detectable. In the spleen and the lymph nodes (Ln), the modulation was strong and the depletion was maximal (80-90%) 48 h after mAb treatment. Interestingly, both modulation and depletion were decreased and delayed (50-60% after 72 h) in the Peyer`s patches. By using C3-deficient mice, no major contribution of complement to the CD4 Tcd was seen. On the contrary, with the help of different FcGamma-receptor (FcGammaR)-deficient mice (FcGammaRI, FcGammaRII, FcGammaRIII, FcGammaRI/III, and FcRGamma) and through the blockade of FcGammaRIV, a strong organ dependent involvement of FcGammaR could be shown. While the depletion in the spleen was clearly dependent on FcGammaRIV, in the Ln and the Peyer`s patches, FcGammaRI/III were involved. These findings correlated with the strong expression of FcGammaRIV in the spleen, the lung, the colon, the kidney, and the liver, while in the Ln the expression was weak and undetectable in the thymus and the Peyer`s patches. For the first time, F4/80high macrophages in the spleen could be identified as also being FcGammaRIV+, and are therfore considered as the potential effector cells of the CD4 Tcd. The direct comparison of the depletion of T cells via CD4 or ICOS pointed out that the target cell depletion is not only dependent on the properties of the mAb used, but also on those of the target molecule.

[pt] Esta dissertação revisita quatro modelos multiaxiais de dano por fadiga (SWTD, SWT, Findley e Crossland) e discute a sua aplicação na previsão do risco de nucleação de trinca sob solicitações de fadiga por fretting segundo as abordagens local e não-local. As previsões do risco de nucleação de trinca obtidas através dos modelos estudados foram confrontadas com dados experimentais disponíveis na literatura para o contato cilindro/plano em aços AISI 52100 e AISI 1034 respectivamente. As melhores previsões foram obtidas através da versão desviadora SWTD. Segundo a abordagem local, o modelo SWTD fez previsões menos conservativas que os demais, sendo estas com erros conservativos inferiores a 15 porcento. Segundo a abordagem não-local, os quatro modelos geram previsões com erros inferiores a 15 porcento se os mesmos forem calibrados de forma independente. É importante mencionar que as melhores previsões obtidas através da abordagem não-local (que requer a calibração de um parâmetro adicional) são similares àquelas obtidas por SWTD local. Especificamente para os testes de fadiga por fretting com carga remota, o modelo SWTD não-local gerou previsões com 100 porcento de acertos (13 testes). Segundo a abordagem não-local, foi verificado que, para o conjunto de testes estudado, a precisão nas previsões é mais influenciada pela dimensão característica (que deve ser calibrada) que pelo modelo de fadiga multiaxial ou método de integração considerado. Por fim, verificou-se que previsões não conservativas podem ser obtidas ao se considerar uma dimensão característica assumida como parâmetro material (sem calibração) tal qual a distância crítica proposta por Taylor, definida em termos do método do ponto. / [en] This work presents and discusses four multiaxial fatigue damage models (SWTD, SWT, Findley and Crossland) applied to crack nucleation prediction under fretting fatigue loadings according to the local and the non-local approaches. The predictions have been compared with experimental data available in the literature for the cylinder on flat configuration made of 52100 and 1034 AISI steel s respectively. In particular, for the data set analyzed, SWTD parameter (deviatoric version of SWT model) predictions were less conservative than the ones made by the other three models and have better correlated the experimental results. Considering the local approach, the error observed on the SWTD predictions was lower than 15 percent. On the other hand, for the non-local approach, it has been demonstrated that the four multiaxial fatigue models can provide crack nucleation predictions with similar level of accuracy (error lower than 15 percent) if the characteristic dimension is calibrated model-by-model. Note that this same level of accuracy was obtained with SWTD parameter defined in terms of the local approach, which requires one less parameter to be calibrated (characteristic dimension). In particular, considering only the fretting fatigue tests with bulk stresses, SWTD non-local (area method) prediction accuracy was 100 percent (13 tests). For the material studied, it has also been concluded that the non-local predictions accuracy depends more on the calibrated characteristic dimension than on the multiaxial model or integration method considered. Moreover, it has been verified that non-conservative predictions can be made if the characteristic dimension is assumed as a material property as proposed by Taylor on the critical distances theory (point method).

Measures of workload have been developed on the basis of the various definitions, some are designed to capture the multi-dimensional aspects of a unitary resource pool (Kahneman, 1973) while others are developed on the basis of multiple resource theory (Wickens, 2002). Although many theory based workload measures exist, others have often been constructed to serve the purpose of specific experimental tasks. As a result, it is likely that not every workload measure is reliable and valid for all tasks, much less each domain. To date, no single measure, systematically tested across experimental tasks, domains, and other measures is considered a universal measure of workload. Most researchers would argue that multiple measures from various categories should be applied to a given task to comprehensively assess workload. The goal for Study 1 to establish task load manipulations for two theoretically different tasks that induce distinct levels of workload assessed by both subjective and performance measures was successful. The results of the subjective responses support standardization and validation of the tasks and demands of that task for investigating workload. After investigating the use of subjective and objective measures of workload to identify a universal and comprehensive measure or set of measures, based on Study 2, it can only be concluded that not one or a set of measures exists. Arguably, it is not to say that one will never be conceived and developed, but at this time, one does not reside in the psychometric catalog. Instead, it appears that a more suitable approach is to customize a set of workload measures based on the task. The novel approach of assessing the sensitivity and comprehensive ability of conjointly utilizing subjective, performance, and physiological workload measures for theoretically different tasks within the same domain contributes to the theory by laying the foundation for improving methodology for researching workload. The applicable contribution of this project is a stepping-stone towards developing complex profiles of workload for use in closed-loop systems, such as human-robot team iv interaction. Identifying the best combination of workload measures enables human factors practitioners, trainers, and task designers to improve methodology and evaluation of system designs, training requirements, and personnel selection