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Les systèmes de contrôle des événements discrets ont la possibilité de résoudre les défis importants de la société moderne. En particulier, cela représente une solution fondamentale pour gérer et contrôler les nouvelles avancées technologiques en conformité avec la requis du développement durable. Le paramétrage, la configuration et la prise de décision de ces systèmes de contrôle sont des aspects critiques qui influent sur les performances et la productivité. Les approches d'architecture de contrôle dynamique, telles que les systèmes de contrôle reconfigurables, ont été proposées pour la modélisation de ces systèmes. Cependant, ils n'ont pas réussi à optimiser le processus de reconfiguration car celles-ci se concentrent sur la continuité de l'exécution plutôt que sur l'optimisation de la reconfiguration. Cette dissertation propose une architecture de référence pour un système de contrôle reconfigurable, nommé Pollux, conçu pour gérer et ajuster de manière optimale et en temps réel l'architecture d'un système de contrôle, soit pour guider l'exécution opérationnelle ou répondre à une perturbation du système. En considérant une proposition d'une configuration optimale des architectures de contrôle basées sur la gouvernance partagée, cette approche proposée un système de contrôle reconfigurable compose d’une entité décisionnelle flexible et personnalisable, d’une représentation qui caractérise la configuration unique et la solution de contrôle de l'architecture de contrôle et d’un mécanisme de reconfiguration à trois modules qui intègre les principes basés sur l'optimalité dans la reconfiguration. Notre approche est appliquée dans le domaine de la fabrication et est validée dans une simulation et une cellule réelle de fabrication située à l'Université de Valenciennes, en France. La validation effectuée dans trois scénarios expérimentaux a permis de vérifier les avantages de notre approche et de nous encourager à continuer la recherche. / Discrete-event control systems have the opportunity to resolve significant challenges of modern society. In particular, these represent a fundamental solution to manage and control the new technological advances in compliance to the increased consciousness of sustainable development. The parameterization, configuration and decision-making of these control systems are critical aspects that impact the performance and productivity required. Dynamic control architecture approaches, such as reconfigurable control systems, have been proposed for modelling such systems. However, such approaches have failed to address the recovery of the reconfiguration process as these focus on the continuity of execution rather than on the optimisation of the reconfiguration. This dissertation proposes a reference architecture for a reconfigurable control system, named Pollux, designed to manage and adjust optimally and in real time the architecture of a control system, either to guide operational execution or to respond to a system perturbation. Considering a proposed framework of an optimal configuration of control architectures based on shared governance, this proposed approach aims to orchestrate a flexible and customizable decisional entity, a representation that characterize the unique configuration and control solution of the control architecture, and a three-module reconfiguration mechanism that integrates the optimality-based principles into the reconfiguration process, to ensure a recovery of global performance and/or minimise the degradation caused by perturbations. Our approach is applied in the manufacturing domain and is validated in a simulation and a real flexible manufacturing system cell located at the University of Valenciennes, France. The validation conducted in three experimental scenarios verified the benefits of our approach and encourage us to continue research in this direction.

Tese de mestrado integrado. Engenharia Civil (Área de Especialização de Vias de Comunicação). Faculdade de Engenharia. Universidade do Porto. 2012

Le contrôle hétérarchique des systèmes de production flexibles (FMS) préconise un contrôle peu complexe et hautement réactif supporté par des entités décisionnelles locales (DEs). En dépit d'avancées prometteuses, ces architectures présentent un comportement myope car les DEs ont une visibilité informationnelle limitée sue les autres DEs, ce qui rend difficile la garantie d'une performance globale minimum. Cette thèse se concentre sur les approches permettant de réduire cette myopie. D'abord, une définition et une typologie de cette myopie dans les FMS sont proposées. Ensuite, nous proposons de traiter explicitement le comportement myope avec une architecture semihétérarchique. Dans celle-ci, une entité décisionnelle globale (GDE) traite différents types de décisions myopes à l'aide des différentes techniques d'optimisation basée sur la simulation (SbO). De plus, les SbO peuvent adopter plusieurs rôles, permettant de réduire le comportement myope de plusieurs façons. Il est également possible d'avoir plusieurs niveaux d'autonomie en appliquant différents modes d'interaction. Ainsi, notre approche accepte des configurations dans lesquelles certains comportements myopes sont réduits et d'autres sont acceptés. Notre approche a été instanciée pour contrôler la cellule flexible AIP- PRIMECA de l'Université de Valenciennes. Les résultats des simulations ont montré que l'architecture proposée peut réduire les comportements myopes en établissant un équilibre entre la réactivité et la performance globale. Des expérimentations réelles ont été réalisées sur la cellule AIP-PRIMECA pour des scenarios dynamiques et des résultats prometteurs ont été obtenus.

Ce projet industriel porte sur la production de biopesticides actifs sur les nématodes à galles des cultures intensives de tomates sous abris au Maroc. Les travaux portent sur (i) l’isolement de souches de champignons filamenteux nématophages provenant des sols des cultures infectées par les nématodes, (ii) la réalisation de cultures de ces souches sur un milieu adapté à la Fermentation en Milieu Solide, technique optimale à la biologie des champignons filamenteux et présentant des avantages technologiques et économiques exploitables à une échelle industrielle, (iii) la production de biomasse et de molécules actives extrapolable à une échelle semi-industrielle, (iv) la mise en œuvre d’essais agronomiques pour valider l’efficacité d’un biopesticide produit par FMS dans des dispositifs innovants.24 souches de champignons filamenteux nématophages ont été isolées à partir des sols des cultures intensives de tomate sous serre au Maroc, mais également à partir de produits commerciaux. Le milieu FMS composé de sous-produits agro-industriels permettant une production de l’ordre de 1010 spores par gramme de substrat PS a été validé, et les conditions de cultures des souches établies. 4 dispositifs de Fermentation en Milieu Solide dont un à usage unique, de 300 à 5 000 g ont été mis au point, et ont été protégés par 3 brevets. Enfin, des essais agronomiques de différentes tailles (quelques billons à plusieurs hectares de tomates) ont été mis en place au Maroc de manière à valider l’utilisation de champignons filamenteux actifs contre les nématodes à galles comme étant une alternative écologique à l’utilisation de produits chimiques. / This industrial project involves the production of biopesticides active against root knot nematodes of intensive greenhouse tomato cultures in Morocco. This work focuses on (i) the isolement of nematophagous filamentous fungi from agricultural soils infected with nematodes, (ii) the cultures of these strains on a suitable medium for Solid State Fermentation (SSF), which is the optimal cultural technique for filamentous fungi, presenting technological and economical benefits at an industrial scale, (iii) the production of biomass and active molecules at a semi-industrial scale, (iv) the installation of agronomic assays to validate the effectiveness of a biopesticide production by SSF in innovative devices.24 nematophagous filamentous fungi strains were isolated from intensive greenhouse tomato culture soils, but also from commercial products. The SSF medium composed of agro-industrial by-products allowing a production of about 1010 spores per gram of DW substrate was validated, and the culture conditions of these strains were established. 4 SSF devices including one at single use, from 300 to 5 000 g DW substrate were developed, and were protected by 3 patents. Finally, agronomic assays of different sizes (from few lines to several hectares of tomatoes) were carried out in Morocco in order to validate the use of active filamentous fungi against root-knot nematodes as an ecological alternative to the use of chemical products.

Tento projekt se podrobně zaměřuje na data z avioniky a může být chápán jako horní vrstva nad systémy monitorujícími poruchy, která poskytuje dodatečné informace o letu. Pro konkrétní návrh byly vybrány Airbus A320 a A340 jako zástupci moderních a rozšířených dopravních letadel. Vyvíjená aplikace analyzuje dvě vybrané komplexní situace z toku dat palubní avioniky a hledá podmínky, které vedou k abnormálnímu chování letadla (nikoliv poruchám). Práce je primárně zaměřena na letové fáze, strukturu dat (a jejich kategorizaci) a na vývoj aplikace na bázi fuzzy systému s expertní znalostí uloženou v jeho pravidlech.

Fibromyalgia syndrome (FMS) is a debilitating and chronic condition with an array of symptoms, the most distinguishable being widespread pain. FMS patients experience a marked decrease in quality of life related to intensity of symptoms. Current treatment options and pharmaceuticals do not provide adequate relief. This thesis examines integrative and complementary therapy options for symptom management and improvement of quality of life for FMS patients. A literature review was conducted of English current research using multiple databases. Findings indicate mindful movement therapies (MMT) such as yoga and tai chi, mindfulness, sensory-related relaxation techniques with guided imagery, and cognitive behavioral therapy (CBT) provided some relief and increased in perceived quality of life (QoL).

Adoptive immunotherapy using chimeric antigen receptor (CAR)-modified T cells targeting CD19 has shown remarkable therapeutic efficacy against B cell leukemia and lymphoma, and provided proof of concept for therapeutic potential in other hematologic malignancies. Acute myeloid leukemia (AML) is an entity with an unmet medical need for effective and curative treatments. Therefore, there is a strong desire for development of potentially curative CAR-T cell immunotherapy for AML treatment. FMS-like tyrosine kinase 3 (FLT3) is a homodimeric transmembrane protein expressed uniformly by AML blasts. FLT3 plays a vital role in the survival of AML blasts and is a key driver of leukemia-genesis in AML cases with internal tandem duplication (FLT3ITD) and tyrosine kinase domain (TKD) mutations. These attributes suggest that FLT3 could be an excellent target for CAR-T cell immunotherapy. Here, we engineered human CD4+ and CD8+ T cells to express FLT3-specific CARs and demonstrate that they confer potent reactivity against AML cell lines and primary AML blasts that express either wild-type FLT3 or FLT3-ITD. Further, we show that FLT3 CAR-T cells exert potent antileukemia activity in xenograft models of AML and induce complete remissions. We also demonstrate that FLT3-expression on FLT3-ITD+ AML cells can be augmented by FLT3 inhibitors, which lead to increased recognition by CARs and improved efficacy of FLT3 CAR-T cells. We confirmed this principle with three different FLT3 inhibitors which are at distinct stages of clinical development i.e. Phase II/III clinical trial (crenolanib, quizartinib) and clinically approved (midostaurin). Further, we observed the strongest anti-leukemia activity of FLT3 CAR-T cells in combination with crenolanib in vivo. FLT3 is known to be expressed by normal hematopoietic stem and progenitor cells. We evaluated FLT3-expression on normal hematopoietic stem cells (HSCs) using flow cytometry and confirmed lower level of FLT3-expression on HSCs and progenitors compared to AML cells. As anticipated, we found that FLT3 CAR-T cells recognize normal HSCs in vitro and in vivo, and compromise normal hematopoiesis, suggesting that adoptive therapy with FLT3 CAR-T cells will require successive CAR-T cell depletion and allogeneic HSC transplantation (HSCT) to reconstitute the hematopoietic system. Moreover, an FLT3 inhibitor treatment does not increase FLT3-expression on HSCs. Accordingly, we demonstrate that the depletion of FLT3 CAR-T cells is possible with inducible Caspase 9 (iCasp9) safety switch. Collectively, our data establish FLT3 as a novel CAR target in AML with particular relevance in high-risk FLT3-ITD+ AML. Our data demonstrate that FLT3 CAR-T cells act synergistically with FLT3 inhibitors in FLT3-ITD+ AML. i.e. FLT3 inhibitors-induced upregulation of FLT3 in FLT3-ITD+ AML cells enhances their recognition and elimination by FLT3 CAR-T cells. Due to recognition of normal HSCs, the clinical use of FLT3 CART cells is likely restricted to a defined therapeutic window and must be followed by CART cell depletion and allogeneic HSCT for hematopoietic reconstitution. The data provide rational to use FLT3 CAR-T cells in combination with FLT3 inhibitors to augment the anti-leukemia efficacy of FLT3 CAR-T cells in high-risk FLT3-ITD+ AML patients, and to mitigate the risk of relapse with FLT3-negative AML variants, which could otherwise develop under therapeutic pressure. The data provide proof of concept for synergistic use of CAR-T cell immunotherapy and small molecule targeted therapy and encourage the clinical evaluation of this combination treatment in high-risk patients with FLT3-ITD+ AML. / Adoptive Immuntherapie, die Chimäre- Antigenrezeptor (CAR) –modifizierte, gegen CD19 gerichtet T-Zellen verwendet, hat eine bemerkenswerte therapeutische Wirksamkeit gegen B-Zell-Leukämien und -Lymphome und großes therapeutisches Potenzial für die Behandlung anderer hämatologischer Erkrankungen gezeigt. Die Akute Myeloische Leukämie (AML) ist hierbei eine Entität, für die es bisher an wirksamen und kurativen Therapien fehlt und für die die Entwicklung einer potentiell kurativen CAR-T-Zellimmuntherapie von großer Bedeutung ist. FMS-like tyrosine kinase 3 (FLT3) ist ein homodimeres Transmembranprotein, das von AML-Blasten uniform exprimiert wird. FLT3 spielt eine wichtige Rolle beim Überleben von AML-Blasten und ist ein Schlüsselfaktor in der Leukämie-Genese bei AML-Fällen mit interner Tandem-Duplikation (FLT3-ITD) und Tyrosinkinase-Domänen (TKD)-Mutationen. Diese Eigenschaften legen die Vermutung nahe, dass FLT3 ein ausgezeichnetes Target für die CAR-T-Zell-Immuntherapie darstellen könnte. Daher setzten wir dort an und modifizierten humane CD4+ und CD8+ T-Zellen, um FLT3-spezifische CARs zu exprimieren, und konnten nachweisen, dass diese eine starke Reaktivität gegen AML-Zelllinien und primäre AML-Blasten besitzen, die entweder den FLT3-Wildtyp oder FLT3-ITD exprimieren. Weiterhin konnten wir zeigen, dass FLT3 CAR-T-Zellen in AML-Xenograft-Modellen eine starke anti-Leukämie-Aktivität besitzen und vollständige Remissionen hervorrufen können. Zudem gelang der Nachweis, dass die FLT3-Expression auf FLT3-ITD+ AML-Zellen durch FLT3-Inhibitoren verstärkt werden kann, was zu einer erhöhten Erkennung durch die CARs und einer verbesserten Wirksamkeit von FLT3-CAR-T-Zellen führt. Wir konnten dieses Prinzip mit drei verschiedenen FLT3-Inhibitoren belegen, die sich in unterschiedlichen Stadien der klinischen Entwicklung befinden, d. h. aus einer Klinischen Phase II / III-Studie (Crenolanib, Quizartinib) und einem klinisch zugelassenen Inhibitor (Midostaurin). Darüber hinaus beobachteten wir die stärkste anti-Leukämie-Aktivität von FLT3 CAR-T-Zellen in einer Kombination mit Crenolanib in vivo. Es ist bekannt, dass FLT3 von normalen hämatopoetischen Stamm- und Vorläuferzellen exprimiert wird. Wir untersuchten die FLT3-Expression in normalen hämatopoetischen Stammzellen (HSCs) mittels Durchflusszytometrie und bestätigten im Vergleich zu AML-Zellen eine niedrigere FLT3-Expression auf HSCs und Vorläuferzellen. Wie erwartet, zeigte sich, dass FLT3 CAR-T-Zellen normale HSCs in vitro und in vivo erkennen und die normale Hämatopoese beeinträchtigen, was darauf hindeutet, dass eine adoptive Therapie mit FLT3 CAR-T-Zellen eine sukzessive CAR-T-Zell-Depletion und allogene HSC-Transplantation erfordert, um das hämatopoetische System wiederaufzubauen. Darüber hinaus erhöht die Behandlung mit einem FLT3-Inhibitor nicht die FLT3-Expression auf den HSCs. Dementsprechend konnten wir aufzeigen, dass die Depletion von FLT3 CAR-T Zellen mit einer induzierbaren Caspase 9 (iCasp9) als „Sicherheitsschalter“ möglich ist. Zusammenfassend etablieren unsere Daten FLT3 als ein neuartiges CAR-Target in der Behandlung von AML mit besonderer Relevanz für die Hochrisiko-FLT3-ITD+ AML. Unsere Daten zeigen, dass FLT3 CAR-T-Zellen synergistisch mit FLT3-Inhibitoren in FLT3-ITD+ AML wirken, d.h. eine FLT3-Inhibitoren-induzierte Hochregulation von FLT3 in FLT3-ITD+ AML-Zellen bewirkt und dies die Erkennung und Eliminierung durch FLT3-CAR-T-Zellen verstärkt. Durch ihre Eigenschaft der Erkennung von normalen HSCs ist die klinische Verwendung von FLT3 CAR-T-Zellen wahrscheinlich auf ein definiertes therapeutisches Fenster beschränkt und muss durch eine anschließende CAR-T-Zell-Depletion und eine allogene HSCT zur Rekonstitution des hämatopoetischen Systems ergänzt werden. In Anbetracht der Daten scheint es sinnvoll, FLT3-CAR-T-Zellen in Kombination mit FLT3-Inhibitoren zu verwenden, um die anti-leukämische Wirksamkeit von FLT3-CAR-T-Zellen bei Hochrisiko-FLT3-ITD+ AML-Patienten zu erhöhen und das Risiko eines Rückfalls mit FLT3-negativen AML-Varianten zu verringern, die sich sonst therapiebedingt entwickeln könnten. Die Daten stellen ein Proof-of-Concept für den synergistischen Einsatz von CAR-T-Zell-Immuntherapie und niedermolekularen Inhibitoren dar, der eine klinische Evaluation dieser Kombinationsbehandlung bei Hochrisikopatienten mit FLT3-ITD+ AML erstrebenswert macht.

The thesis documents findings of a study conducted to develop a project based financial management system (PBFMS) whose role was viewed as a contributor to the successful delivery of projects leading to improved financial performance of small and medium construction enterprise (SMCEs). In particular, the PBFMS was viewed as a facilitator {function) for the efficient and effective conduction of the strategic management, project planning and control processes. Thus an adequate PBFMS was seen as one which, facilitates the efficient and effective delivery of projects with a view to provide enhanced enterprise performance. In pursuit of this aim, theory and practices relating to the development, operation and use of a PBFMS were investigated and analysed from both literature and field work leading to findings being reported in the thesis. In addition, the actual financial management systems of SMCEs were investigated to determine the extent to which their attributes match those of the proposed PBFMS model. The motivation for embarking on the study was brought about by three aspects observed in Botswana. Firstly, was the frequently documented poor delivery of projects, that is, for a sustained period of time, projects were being delivered beyond stipulated times, above agreed cost, and below specified quality. In some worst scenarios, projects were being abandoned at various stages execution but before completion. Secondly, the investigation was also prompted by the frequent financial failures of enterprises that were being recorded in the construction industry. Thirdly, the conduct of the proprietors of the construction enterprises was also frequently circumspect, particularly in matters relating to financial management. Thus in pursuing the study, a number of premises were made. Firstly, the financial management systems of the SMCEs were considered inadequate to fulfil their functions, that is, they were incapable of facilitating the strategic management, project planning and control process. It was also speculated that management of SMCEs were not committed to the PBFMS i.e. they did not participate, get involved and did not comply with the policies regarding the planning, developing, and operation of financial management systems. As a result, PBFMS were unable to play their role of facilitating to the successful delivery of projects for improved contribution to the financial performance of SMCEs. The second premise was that financial models available are either too generic to guide SMCEs in financial management matters or the strategic component is not linked to the operational plans to execute the strategy. For those which are meant for construction enterprises, they normally prescribe practices for project planning and control without including the strategic element and vice versa. In essence there is a gap in each of the models available for use by the SMCEs. It is the closing of this perceived gap in knowledge that the results of the thesis contribute in finding a solution to the mentioned problem. Thus the study aimed at answering two research questions: (i) Do SMCEs have adequate PBFMS that facilitate the effective delivery of projects for enhanced financial performance? and (ii) Is there a relationship between the adequacy PBFMS and poor performance of SMCEs? To facilitate the answering of these two question two hypothesis were formulated namely: Hoi: The PBFMS of SMCEs are adequate to facilitate the delivery of projects; and Ho2: The adequacy of the PBFMS is positively correlated with the performance of SMCEs. To test the two questions a research process was planned and executed in several steps. Firstly, a survey strategy using the questionnaire was selected as the most appropriate method to provide a snap shot of the existence of attributes of PBFMS and to investigate associated practices relating to their development and operation. The method was considered more appropriate and effective in gathering large data in a short space of time in line with the doctoral time framework. Construction enterprises registered with Public Procurement and Asset Disposal Board (PPADB) for building and civil work in classes A, B, C and D were surveyed. The internal quantity surveyor, estimator or accountant were requested to respond on matters relating PBFMS on behalf of the SMCEs. The sampling frame from which the SMCEs considered for study were obtained from the two government departments which work closely with PPADB, the Department of Building and Engineering Services (DBES) and Department of Roads (DR). The sample sizes for each group category (small and medium) were determined using Krajcie and Morgan (1970) table. Stratified and systematic random sampling was used to select the identity of the members to form a sample fro study from the sampling frame. The second step was to design the questionnaire to probe the three aspects identified as constituting the PBFMS namely the strategic management; project planning and control; and management commitment. Essentially the questionnaire sought to investigate the knowledge, tools, techniques, practices, opinions and attitudes of those who design, develop, operate and use the PBFMS in the SMCEs. To ensure a high quality design, the questionnaire was given to experts in the subject area to provide some comments on its suitability and was also piloted on four enterprises. Data collected was analysed using mainly the SPSS software and involved application of various statistical techniques including cross-tabs, ratio analysis, ttests and correlational tests. A total of 101 completed questionnaires were received, made up of 55% and 46% small and medium enterprises, respectively. The demographic profile of SMCEs confirmed some of the expected results, for example, majority (59%) of the respondents were owner/managers confirming the dominance of the owner in SMCEs. Majority of SMCEs (59%) were more than 9 years old, with medium enterprises being more mature (60% older than 9 years) than the small sized enterprises (49% older than 9 years). Majority (56%) of SMCEs had 10 or more employees, with medium sized enterprises having more employees (75% with 10 or more) than the small sized enterprises (42% with 10 or more). SMCEs performed more of building work alone (48%) than both building and civil work (48%) or maintenance (11%) and no enterprise performed civil work (0%) alone. Majority of SMCEs (65%) acted as main contractors as opposed to sub-contractors, though as expected sub-contracting was seen more in small (20%) than medium (10%) enterprises. Lastly, the public sector (central and local authorities) provided majority (65%) of the SMCEs jobs. However, if parastatals which are wholly owned by government were added, the public sector job market adds up to 73% (65%+8%). The testing of the major two major hypothesis resulted in the following conclusion. The results indicated that the first hypothesis was supported, that is, in a majority of SMCEs operating in Botswana the PBFMS were found to be adequate in facilitating the delivery of projects. The results were therefore not in agreement with the basic premise made at the commencement of the study. In view of the finding, it suggests that SMCEs in Botswana have adequate systems that support the efficient and effective project planning and control. Secondly, management is committed to the 'welfare' of the PBFMS in terms of complying and supporting their development and operation. However, like any human endeavour, there are weaknesses in the PBFMS, for example, they were found inadequate in facilitating the strategic management process, including lack of linking the process to the operational process in order to execute the strategy. They were also found weak in one of the most crucial process of project management; that of project control. The second major investigation showed a weak link between the adequacy of a PBFMS and performance. Secondly, the results also indicated that the SMCEs which had adequate PBFMS performed better than their counterparts. The first results were not surprising since the cause of poor performance were shown as three pillars (business environment, client/representatives and enterprise factors). However, the second results emphasise that SMCEs with adequate PBFMS posted better performance than their counterparts with inadequate systems. In this way the role of PBFMS in contributing to better performance was illustrated by the results. Some recommendations are proposed resulting from the findings and how to achieve a deeper understanding of the subject. Firstly, SMCEs should pay more attention to matters pertaining to strategic management to ensure a long-term view of their enterprises. Secondly, when a strategic plan is developed, it must be implemented through operational plans as a means of executing the strategy. Thirdly, concerted effort should made in ensuring that the projects are controlled as it is the only way to achieve sustained profitability and satisfied customers. Fourthly, as a way of providing a deeper understanding of the subject, it is suggested a longitudinal study could be undertaken to yield a more encompassing investigation than a cross sectional study which captured only one business cycle of the industry (down turn). Lastly, the study could be replicated in another industry with a similar profile like the construction industry in Botswana, for example, Namibia or/and the study could include large enterprises to provide means of comparing the different profiles of enterprises. / Business Management / D. B. L.

There is a need for a fuel-optimal required time of arrival (RTA) mode for aircraft flight management systems capable of enabling controlled time of arrival functionality in the presence of wind speed forecast uncertainty. A computationally tractable two-stage stochastic algorithm utilizing a data-driven, location-specific forecast uncertainty model to generate forecast uncertainty scenarios is proposed as a solution. Three years of Aircraft Communications Addressing and Reporting Systems (ACARS) wind speed reports are used in conjunction with corresponding wind speed forecasts from the Rapid Update Cycle (RUC) forecast product to construct an inhomogeneous Markov model quantifying forecast uncertainty characteristics along specific route through the national airspace system. The forecast uncertainty modeling methodology addresses previously unanswered questions regarding the regional uncertainty characteristics of the RUC model, and realizations of the model demonstrate a clear tendency of the RUC product to be positively biased along routes following the normal contours of the jet stream. A two-stage stochastic algorithm is then developed to calculate the fuel optimal stage one cruise speed given a required time of arrival at a destination waypoint and wind forecast uncertainty scenarios generated using the inhomogeneous Markov model. The algorithm utilizes a quadratic approximation of aircraft fuel flow rate as a function of cruising Mach number to quickly search for the fuel-minimum stage one cruise speed while keeping computational footprint small and ensuring RTA adherence. Compared to standard approaches to the problem utilizing large scale linear programming approximations, the algorithm performs significantly better from a computational complexity standpoint, providing solutions in fractional power time while maintaining computational tractability in on-board systems.