Le sarcome de Ewing est la seconde tumeur pédiatrique de l’os la plus fréquente. Elle est caractérisée par une translocation chromosomique résultant à la fusion de EWSR1 avec un membre de la famille ETS. Chez 85% des patients, cette fusion conduit à l’expression de la protéine chimérique EWS-FLI1 qui est l’oncogène majeur de ce sarcome. Ce dernier agit principalement par son action transcriptionelle sur des cibles qui lui sont propres. Au niveau thérapeutique, le sarcome d’Ewing est traité par chimiothérapie, chirurgie locale et par radiothérapie. La survie à long terme des patients est de l’ordre de 70%, mais beaucoup plus basse pour les patients métastatiques et quasi nulle lors d’une récidive. Parmi maintes caractéristiques, certains cancers présentent une dérégulation énergétique. L’influence d’EWS-FLI1 sur cet aspect n’a fait l’objet d’aucune étude dans le contexte du sarcome d’Ewing. Nous avons donc étudié par profilage métabolomique des cellules de sarcome d’Ewing en présence ou en absence d’EWS-FLI1. En comparant ces deux conditions, des modulations du profil énergétique relatif au cycle de Krebs, des précurseurs de le glycosylation ainsi que des métabolites de la voie de la méthionine et du tryptophane ont été observés. En parallèle, grâce à un crible de banque de shRNAs réalisé dans des conditions expérimentales similaires à l’étude métabolomique (lignée d’Ewing avec ou sans EWS-FLI1), nous avons pu identifier des gènes présentant des caractéristiques « synthétique létales », c'est-à-dire tuant uniquement les cellules du sarcome d’Ewing en présence de son oncogène. / Ewing sarcoma, the second most commonly occurring pediatric bone tumor, is most often characterized by a chromosomal translocation between EWSR1 and FLI1. The gene fusion EWS-FLI1 accounts for 85% of all Ewing sarcoma and is considered the major oncogene and master regulator of Ewing sarcoma. EWS-FLI1 is a transcriptional modulator of targets, both directly and indirectly. Ewing sarcoma is aggressively treated with chemotherapy, localized surgery and radiation and has an overall survival of about 70%, however, survival for metastasis or relapsed cases remains low. One of the cancer hallmarks, metabolic deregulation, is most likely partly dependent on EWS-FLI1 in Ewing sarcoma cells. In order to get a better understanding of Ewing sarcoma biology and oncogenesis, it might be of high interest to investigate the influence of EWS-FLI1 in Ewing sarcoma cells. We therefore performed a global metabolic profiling of Ewing sarcoma cells with or without inhibition of EWS-FLI1. Several changes in the energy metabolism were observed throughout this study; the observed changes were consistent with an energy profile that moved from a cancer cell energy metabolism towards the energy metabolism of a more normal cell upon EWS-FLI1 inhibition, primarily based on the TCA cycle. Levels of TCA intermediates, glycosylation precursors, methionine pathway metabolites and amino acids, especially changes in the tryptophan metabolic pathway, were altered upon EWS-FLI1 inhibition. Parallel to this study, we performed a high-throughput synthetic lethality screen, in order to not only identify essential genes for cell survival and proliferation, but also to identify new synthetic lethal targets that could specifically target Ewing sarcoma cells carrying the EWS-FLI1 fusion gene.

No description available.

自1980年代各國推行金融自由化後，為穩定金融秩序，建立風險導向金融監理制度更顯重要。一般來說，金融監理工具可分為實地檢查及場外監控兩種，過去以行業別進行之監理，在金融控股公司的發展下，亦發展出對應之監控機制，然而僅止於實地檢查機制，以金融集團為預警對象之場外監控預警系統仍有待建立。 本研究遂在探討如何建立適合我國之以金融集團為預警對象的場外監控預警系統，挑選2003、2004年兩年之本國銀行、票券、證券、壽險、產險公司財務業務比率為樣本，以區別分析法建立預警模型，再以各金融控股公司之子產業公司結果建立各年度金融控股公司之預警模型。 本研究僅嘗試以財務比率建立量化場外監控預警模型，研究結果僅供學術上研究參考，並非運用於真實狀況之評斷，因此，依研究結果提出之結論及建議，僅供參考。此外，(1)模型並未加入質化指標，(2)資料有限的情況下，亦無做樣本外測試，(3)無實際破產金融機構資料，僅能以模擬方法分類，皆是本研究不足之處，仍須修正及改進。

In the context of energy transition, geothermics play an important role for the heating and cooling supply of both residential and commercial buildings. Thereby, the increasingly and intensive utilisation of shallow geothermal resources bears the risk of over-exploitation and thus poses a future challenge to ensure the sustainability and safety of such systems. Particularly, the well-established technology of borehole heat exchanger-coupled ground source heat pumps is applied for the thermal exploitation of the shallow subsurface. Due to the complexity of the involved physical processes, numerical modelling proves to be a powerful tool to enhance process understanding as well as to aid the planning and design processes. Simulations can also support the management of thermal subsurface resources, planning and decision-making on city and regional scales. In this work, the so-called dual-continuum approach was adopted and enhanced to develop a coupled numerical model considering flow and heat transport processes in both the subsurface and borehole heat exchangers as well as the heat pumps’ performance characteristics, and including the relevant phenomena influencing the underlying processes. Beside the temperature fields, the efficiency and thus the consumption of electrical energy by the heat pump is computed, allowing for the quantification of operational costs and equivalent carbon-dioxide emissions. The model is validated and applied to a number of numerical studies. First, a comprehensive sensitivity analysis on the efficiency and sustainability of such systems is performed. Second, a method for the quantification of technically extractable shallow geothermal energy is proposed. This procedure is demonstrated by means of a case study for the city of Cologne, Germany and its implications are discussed. / Im Rahmen der Energiewende nimmt die Geothermie eine besondere Rolle in der thermische Gebäudeversorgung ein. Die zunehmende, intensive Nutzung oberflächennaher geothermischer Ressourcen erhöht die Gefahr der übermäßigen thermischen Ausbeutung des Untergrundes und stellt damit eine wachsende Herausforderung für die Nachhaltigkeit und Sicherheit solcher Systeme dar. Zur Erschließung oberflächennaher geothermischer Energie wird insbesondere die etablierte Technologie Erdwärmesonden-gekoppelter Wärmepumpen eingesetzt. Aufgrund der daran beteiligten komplexen physikalischen Prozesse erweisen sich numerische Modelle als leistungsfähiges Werkzeug zur Erweiterung des Prozessverständnisses und Unterstützung des Planungs- und Auslegungsprozesses. Zudem können Simulationen zum Management thermischer Ressourcen im Untergrund sowie zur Planung und politischen Entscheidungsfindung auf städtischen und regionalen Maßstäben beitragen. Im Rahmen dieser Arbeit wurde, basierend auf dem sogenannten ”dual-continuum approach” und unter Berücksichtigung des Einflusses der Wärmepumpe, ein erweitertes gekoppeltes numerisches Modell zur Abbildung der in Erdwärmesonden und dem Untergrund stattfindenden Strömungs- und Wärmetransportprozesse entwickelt. Das Modell ist in der Lage, alle relevanten Einflussfaktoren zu berücksichtigen. Neben den Temperaturfeldern im Untergrund und der Erdwärmesonde werden die Effizienz und damit der Stromverbrauch der Wärmepumpe simuliert. Damit können sowohl die Betriebskosten als auch der äquivalente CO 2 -Ausstoß abgeschätzt werden. Das Modell wurde validiert und in einer Reihe numerischer Studien eingesetzt. Zuerst wurde eine umfassende Sensitivitätsanalyse zur Effizienz und Nachhaltigkeit entsprechender Anlagen durchgeführt. Weiterhin wird ein Verfahren zur Quantifizierung des technisch nutzbaren, oberflächennahen geothermischen Potentials vorgestellt und anhand einer Fallstudie für die Stadt Köln demonstriert, gefolgt von einer Diskussion der Ergebnisse.

Introduction: Genetic rearrangements in Ewing sarcoma, prostate, and leukemia cells result in activation of oncogenic ETS transcription factor fusions. Mithramycin (MTM) has been identified as an inhibitor of EWS-FLI1 transcription factor, a gene fusion product responsible for oncogenesis in Ewing sarcoma. Despite preclinical success, a phase I/II clinical trial testing MTM therapy in refractory Ewing sarcoma was terminated. Liver and blood toxicities resulted in dose de-escalation and sub-therapeutic exposures. However, the promise of selectively targeting oncogenic ETS transcription factors like EWS-FLI1 prompted us to undertake the discovery of more selective, less toxic analogues of MTM. MTM is a potent inhibitor of ubiquitous SP1 transcription factor, likely inducing non-specific toxicity. In collaboration with two medicinal chemistry groups, two semi-synthetic efforts were implemented to develop novel analogues of MTM. The first effort utilized the biosynthetic product mithramycin SA (MTMSA) to modify C3-side chain. The second effort utilized an oxime linker directly formed on MTM’s C3-side chain (MTM-oxime; MTMox). Here I present the pharmacological assessment of over 75 novel MTM analogues towards selectively targeting oncogenic ETS transcription factors, like EWS-FLI1, over ubiquitous transcription factors, like SP1. Methods: Novel MTM analogues were evaluated for selective cytotoxicity against ETS fusion-dependent cell lines. Selectively cytotoxic analogues were evaluated for inhibitory effects on several gene promoters in TC-32 reporter cell lines, a Ewing sarcoma cell line dependent on EWS-FLI1, transfected with luciferase reporter vector. Cloned reporter vectors incorporated NR0B1 (EWS-FLI1 binding), β-actin (SP1 binding) and CMV (non-specific) gene promoters. Furthermore, gene (mRNA) and protein expression changes of EWS-FLI1 and SP1, as well as regulated target genes, namely NR0B1, VEGFA and BCL-2 were evaluated with MTM analogue treatments. The MTM analogues with most selective activity in vitro were administered to mice by intravenous bolus dose for pharmacokinetic analysis. The MTM analogues with highest systemic exposure from each semi-synthetic effort, namely MTMSA-Trp-A10 and MTMox-24, were further evaluated. Metabolic stabilities in whole blood, plasma, and tumor cell matrices, and across multiple species were compared with MTM. Moreover, intrinsic hepatic clearances were estimated using mouse liver microsomes. Tumor and liver distributions were estimated in tumor bearing mice. Additionally, the effect of organic anionic transporter polypeptides (OATP) on distribution of MTM was investigated. Maximum tolerated doses were evaluated for lead MTM analogues, having both selective activities in vitro and high systemic exposure, compared to MTM. Complete blood cell counts and plasma alanine aminotransferase activity were measured to evaluate dose-dependent blood and liver toxicities, respectively. ETS fusion-dependent and non-dependent cell lines were implanted subcutaneously into immunocompromised mice for efficacy studies. Average tumor volumes and survival were tracked for mice receiving treatment, compared to MTM and vehicle treatment. Results: Evaluation of MTM analogues from both semi-synthetic efforts revealed that conjugation of MTM C3-side chain with tryptophan (Trp) and/or phenylalanine (Phe) improved selective cytotoxicity against ETS fusion-dependent cell lines. This was highlighted by MTMSA-Trp-A2 (also refer to as MTMSA-Phe-Trp) and MTMSA-Trp-A10 (also refer to as MTMSA-Trp-Trp), with selective indices of 19.1 and 15.6, respectively, compared to MTM (1.5). Similarly, MTMox-23 (also refer to as MTMox-Phe-Trp) and MTMox-20 (also refer to as MTMox-Trp) had selectivity indices of 4.6 and 4.5, respectively. These selectively cytotoxic MTM analogues inhibited EWS-FLI1-mediated transcription 10-fold more effectively than both non-specific CMV-mediated and SP1-mediated (via β-actin promoter) transcription in TC-32 reporter cell lines. Moreover, gene (mRNA) and protein expression of EWS-FLI1 and regulated gene, NR0B1, were inhibited with MTM analogue treatment (GI50, 6-hour) in TC-32 cells. Similarly, SP1 and target genes, VEGFA and BCL-2, gene (mRNA) and protein expressions were also inhibited with MTM analogue treatment (GI50, 6-hour) in TC-32 cells. Conjugation of Trp and/or Phe to C3-side chain of MTM increased systemic exposure in vivo. Most impressively, the addition of two Trp residues, namely MTMSA-Trp-A10 and MTMox-24 (also refer to as MTMox-Trp-Trp), resulted in systemic exposure increases of 218- and 42-fold, respectively, after intravenous (IV) bolus dose. Metabolically, tryptophan/phenylalanine conjugated MTM analogues are liable to esterase activity on carboxy-methyl functional group. Very rapid de-methylation in biological matrix was observed with MTMox-24, compared to MTMSA-Trp-A10, suggesting a regiospecific effect. However, esterase activity was limited to rodent matrices and demethylation occurred at significantly diminished rates in non-human primate and human plasma. MTM analogues were not susceptible to p450-mediated metabolism, with negligible loss in mouse liver microsome assay compared to verapamil control. MTM (1mg/kg) and MTMox-24 (6mg/kg) were detected in subcutaneously implanted (flank) LL2 tumors and liver homogenates after IV bolus dose. Interestingly, MTMSA-Trp-A10 (2mg/kg) was not. Despite a 3-fold increase in systemic exposure with rifampin oral pretreatment, an OATP inhibitor, exposure of MTM was unaffected in Oatp knockout mouse model. Exposure of MTM in liver tissue was 8.4-fold higher compared to tumor tissue with low tissue clearance. This agrees with the lack of metabolism observed in liver microsomes and may provide a mechanism for clinically observed liver toxicity. MTMSATrp-A10 had a single maximum tolerated dose (MTD) of 0.75mg/kg, compared to 1mg/kg for MTM, administered by IV bolus. In contrast, MTM-oxime analogues (MTMox-20, -23, -24 and -25) had single maximum tolerated doses of 20 – 25mg/kg. These increased tolerances are the result of additive differences in whole blood stability, cytotoxicity and systemic exposure. At a dose of 0.75mg/kg, administered every 3 days, MTMSA-Trp-A10 did not result in an efficacious result in tumor xenograft studies. These studies remain under further investigation, but the result may indicate high plasma protein binding of MTMSA-Trp-A10 and lack of free fraction available within tumor. The most selective MTM-oxime analogue in vitro, MTMox-23, significantly inhibited TC-32 (EWS-FLI1+) tumor xenograft growth (p=0.0025, day 16, one-way ANOVA multiple comparisons test) compared to MTM (p=0.1174, day 16) and extending survival for 17 days out of 48 days on study (p=0.0003, Log Rank (Mantel-Cox) single comparison test) with treatment at MTD every 3 days, compared to vehicle. Additionally, the MTM-oxime analogue with highest systemic exposure, MTMox-24, also significantly inhibited TC-32 (EWS-FLI1+) tumor xenograft growth (p=0.0003, day 21, one-way ANOVA multiple comparisons test) compared to MTM (p=0.032, day 21) and extending survival for 12 days out of 37 days on study (p=0.0004, Log Rank (Mantel-Cox) single comparison test) with treatment, compared to vehicle. Conclusion: These studies in whole highlight the importance of exposure (pharmacokinetics; PK), toxicity and efficacy (pharmacodynamics; PD) relationships. The cytotoxicity and high systemic exposure of MTMSA-Trp-A10 directly contributes to its lower tolerated dose. However, despite a similar tolerated dose to MTM, systemic exposure remains 163-fold higher at the MTD. High systemic exposure may be attributed to high plasma protein binding, but also reduces the exposure of free MTMSA-Trp-A10 within the tumor tissue, which drives the efficacious response. In contrast, the less cytotoxic and rapidly de-methylated MTM-oxime analogues allow for 25-fold higher tolerances in mice. This unique metabolism and clearance may prevent exposures required to induced systemic blood and liver toxicities induced by MTM. Moreover, at these highly tolerated doses, the initial systemic exposure at MTD is highest among analogues tested, which resulted in an efficacious response with MTMox-23 and MTMox-24 treatment in tumor xenograft models. It remains to be determined if these PK/PD relationships can be reproduced in additional animal models, including human, without inducing toxicity. Nonetheless, these initial studies in mice demonstrate that a more selective, more tolerated analogue of MTM has potential for clinical success in treating ETS fusion-dependent tumors.

Connus sous le nom de Systèmes d’Alerte Avancés, ou Early Warning Systems (EWS), les modèles de prévision des crises financières sont appelés à jouer un rôle déterminant dans l’orientation des politiques économiques tant au niveau microéconomique qu’au niveau macroéconomique et international. Or,dans le sillage de la crise financière mondiale, des questions majeures se posent sur leur réelle capacité prédictive. Deux principales problématiques émergent dans le cadre de cette littérature : comment évaluer les capacités prédictives des EWS et comment les améliorer ?Cette thèse d’économétrie appliquée vise à proposer (i) une méthode d’évaluation systématique des capacités prédictives des EWS et (ii) de nouvelles spécifications d’EWS visant à améliorer leurs performances. Ce travail comporte quatre chapitres. Le premier propose un test original d’évaluation des prévisions par intervalles de confiance fondé sur l’hypothèse de distribution binomiale du processus de violations. Le deuxième chapitre propose une stratégie d’évaluation économétrique des capacités prédictives des EWS. Nous montrons que cette évaluation doit être fondée sur la détermination d’un seuil optimal sur les probabilités prévues d’apparition des crises ainsi que sur la comparaison des modèles.Le troisième chapitre révèle que la dynamique des crises (la persistance) est un élément essentiel de la spécification économétrique des EWS. Les résultats montrent en particulier que les modèles de type logit dynamiques présentent de bien meilleurs capacités prédictives que les modèles statiques et que les modèles de type Markoviens. Enfin, dans le quatrième chapitre nous proposons un modèle original de type probit dynamique multivarié qui permet d’analyser les schémas de causalité intervenant entre différents types crises (bancaires, de change et de dette). L’illustration empirique montre clairement que le passage à une modélisation trivariée améliore sensiblement les prévisions pour les pays qui connaissent les trois types de crises. / Known as Early Warning Systems (EWS), financial crises forecasting models play a key role in definingeconomic policies at microeconomic, macroeconomic and international level. However, in the wake ofthe global financial crisis, numerous questions with respect to their forecasting abilities have been raised,as very few signals were drawn prior to the starting of the turmoil. Two questions arise in this context:how to evaluate EWS forecasting abilities and how to improve them?The broad goal of this applied econometrics dissertation is hence (i) to propose a systematic model-free evaluation methodology for the forecasting abilities of EWS as well as (ii) to introduce new EWSspecifications with improved out-of-sample performance. This work has been concretized in four chapters.The first chapter introduces a new approach to evaluate interval forecasts which relies on the binomialdistributional assumption of the violations series. The second chapter proposes an econometric evaluationmethodology of the forecasting abilities of an EWS. We show that adequate evaluation must take intoaccount the cut-off both in the optimal crisis forecast step and in the model comparison step. The thirdchapter points out that crisis dynamics (persistence) is essential for the econometric specification of anEWS. Indeed, dynamic logit models lead to better out-of-sample forecasting probabilities than those oftheir main competitors (static model and Markov-switching one). Finally, a multivariate dynamic probitEWS is proposed in the fourth chapter to take into account the causality between different types of crises(banking, currency, sovereign debt). The empirical application shows that the trivariate model improvesforecasts for countries that underwent the three types of crises.

In the context of energy transition, geothermics play an important role for the heating and cooling supply of both residential and commercial buildings. Thereby, the increasingly and intensive utilisation of shallow geothermal resources bears the risk of over-exploitation and thus poses a future challenge to ensure the sustainability and safety of such systems. Particularly, the well-established technology of borehole heat exchanger-coupled ground source heat pumps is applied for the thermal exploitation of the shallow subsurface. Due to the complexity of the involved physical processes, numerical modelling proves to be a powerful tool to enhance process understanding as well as to aid the planning and design processes. Simulations can also support the management of thermal subsurface resources, planning and decision-making on city and regional scales. In this work, the so-called dual-continuum approach was adopted and enhanced to develop a coupled numerical model considering flow and heat transport processes in both the subsurface and borehole heat exchangers as well as the heat pumps’ performance characteristics, and including the relevant phenomena influencing the underlying processes. Beside the temperature fields, the efficiency and thus the consumption of electrical energy by the heat pump is computed, allowing for the quantification of operational costs and equivalent carbon-dioxide emissions. The model is validated and applied to a number of numerical studies. First, a comprehensive sensitivity analysis on the efficiency and sustainability of such systems is performed. Second, a method for the quantification of technically extractable shallow geothermal energy is proposed. This procedure is demonstrated by means of a case study for the city of Cologne, Germany and its implications are discussed. / Im Rahmen der Energiewende nimmt die Geothermie eine besondere Rolle in der thermische Gebäudeversorgung ein. Die zunehmende, intensive Nutzung oberflächennaher geothermischer Ressourcen erhöht die Gefahr der übermäßigen thermischen Ausbeutung des Untergrundes und stellt damit eine wachsende Herausforderung für die Nachhaltigkeit und Sicherheit solcher Systeme dar. Zur Erschließung oberflächennaher geothermischer Energie wird insbesondere die etablierte Technologie Erdwärmesonden-gekoppelter Wärmepumpen eingesetzt. Aufgrund der daran beteiligten komplexen physikalischen Prozesse erweisen sich numerische Modelle als leistungsfähiges Werkzeug zur Erweiterung des Prozessverständnisses und Unterstützung des Planungs- und Auslegungsprozesses. Zudem können Simulationen zum Management thermischer Ressourcen im Untergrund sowie zur Planung und politischen Entscheidungsfindung auf städtischen und regionalen Maßstäben beitragen. Im Rahmen dieser Arbeit wurde, basierend auf dem sogenannten ”dual-continuum approach” und unter Berücksichtigung des Einflusses der Wärmepumpe, ein erweitertes gekoppeltes numerisches Modell zur Abbildung der in Erdwärmesonden und dem Untergrund stattfindenden Strömungs- und Wärmetransportprozesse entwickelt. Das Modell ist in der Lage, alle relevanten Einflussfaktoren zu berücksichtigen. Neben den Temperaturfeldern im Untergrund und der Erdwärmesonde werden die Effizienz und damit der Stromverbrauch der Wärmepumpe simuliert. Damit können sowohl die Betriebskosten als auch der äquivalente CO 2 -Ausstoß abgeschätzt werden. Das Modell wurde validiert und in einer Reihe numerischer Studien eingesetzt. Zuerst wurde eine umfassende Sensitivitätsanalyse zur Effizienz und Nachhaltigkeit entsprechender Anlagen durchgeführt. Weiterhin wird ein Verfahren zur Quantifizierung des technisch nutzbaren, oberflächennahen geothermischen Potentials vorgestellt und anhand einer Fallstudie für die Stadt Köln demonstriert, gefolgt von einer Diskussion der Ergebnisse.

Die verlässliche Vorhersage der Wärmeentzugsleistungen als auch der Soletemperaturen in den Sonden sind wichtig für deren Auslegung und Betriebsoptimierung. Es ist ebenso wichtig für die Auslegung und Optimierung der Anlagen im versorgten Gebäude. In der vorliegenden Dissertation wurde versucht, durch eine mathematische Weiterentwicklung von Greenschen Funktionen (g-Funktionen) eine präzisere Lösung für Temperaturverteilung im Erdreich infolge des von einer oder mehreren Sonden verursachten Wärmeentzuges mit verschiedenen Randbedingungen im geologischen Untergrund zu erreichen. Hierzu wurden sechs „neue“ g-Funktionen entwickelt, die vertikal variable Wärmeentzüge einzelner Sonden und Sondenfelder, eine Asymmetrie des Wärmeentzuges der Sonde, den Einfluss einer zusätzlichen Grundwasserströmung und den realen, geschichteten Untergrund berücksichtigen. Die mathematischen Modelle des Erdreichs wurden mit Modellen für die Soleströmung und Wärmeübergabe in der Hinterfüllung der Sonde gekoppelt und anschließend auf ein praktisches Betriebsbeispiel angewendet. Die Arbeit enthält ebenfalls umfangreiche Sichtung existierender Modelle sowie deren Anwendung und vergleichende Bewertung der teilweise komplexen Modellansätze.:Formelzeichen und Abkürzungen 1 Einführung 2 Energiequellen und Aufbau der Erdwärmeübertrager 2.1 Quellen der geothermalen Energie 2.2 Aufbau der Erdwärmeübertrager 2.3 Betriebsverhalten von Erdwärmesonden 2.4 Auslegung der Sonden 3 Vorhandene Modelle 3.1 Soleströmung 3.2 Wärmeübergang in den Rohren der Sonde 3.3 Wärmeleitung in der Hinterfüllung 3.4 Erdreichmodellierung – numerisch 3.5 Erdreichmodellierung mit g-Funktionen 4 Weiterentwicklung der analytischen Modelle 5 Anwendungsbeispiele 185 5.1 Ein praktisches Beispiel 5.2 Auswirkung auf die Jahresarbeitszahl 6 Zusammenfassung Literatur A Ableitung der Bohrlochwiderstände B Ableitung der Funktionen für Randbedingungen C Eidesstattliche Erklärung / The design of the ground heat exchangers (GHE) systems demands the precise prediction of their heat output and the brine temperature. The same information is needed for design and optimization of the HVAC systems coupled to GHEs. In the thesis at hand the Green’s functions (g-Functions) have been used to develop the more accurate solutions for the temperature distribution in soil resulting from the heat extraction from one GHE or a field of GHEs. These solutions consist of six novel g-functions that take account of the vertical variation of the extracted heat flux in one GHE or field of GHEs, of the horizontal ground water flow and of the horizontal variation of the soil properties. The models for prediction of the soil temperature have been coupled with models for brine flow and heat transfer in the GHE’s grout and eventually applied to the simulation of the real world object. Additionally, the thesis contains broad review of the known models and their applications as well as the comparative analysis of the complex modelling assumptions.:Formelzeichen und Abkürzungen 1 Einführung 2 Energiequellen und Aufbau der Erdwärmeübertrager 2.1 Quellen der geothermalen Energie 2.2 Aufbau der Erdwärmeübertrager 2.3 Betriebsverhalten von Erdwärmesonden 2.4 Auslegung der Sonden 3 Vorhandene Modelle 3.1 Soleströmung 3.2 Wärmeübergang in den Rohren der Sonde 3.3 Wärmeleitung in der Hinterfüllung 3.4 Erdreichmodellierung – numerisch 3.5 Erdreichmodellierung mit g-Funktionen 4 Weiterentwicklung der analytischen Modelle 5 Anwendungsbeispiele 185 5.1 Ein praktisches Beispiel 5.2 Auswirkung auf die Jahresarbeitszahl 6 Zusammenfassung Literatur A Ableitung der Bohrlochwiderstände B Ableitung der Funktionen für Randbedingungen C Eidesstattliche Erklärung

Practitioners of Forecast-based Action (FbA) argue that a humanitarian response able to utilize forecasts to accurately predict disaster, secure funding, and take action before the onset of a crisis will benefit donors and beneficiaries alike. In search of effective and efficient early-action regimes, a number of major humanitarian actors are developing FbA projects of various designs, predominantly in response to natural disaster and famine. While numerous organizations and institutions have expressed interest in developing FbA mechanisms, the tool has only been applied in a limited capacity to the humanitarian needs generated by armed conflict. This research seeks to understand whether a scalable FbA approach can be developed to stage principled, anticipatory humanitarian action in response to situations in which rigorous evaluations predict the likelihood of imminent armed conflict. The hypothesis is that the application of FbA to armed conflict is possible, but due to the complex political nature of conflict, implementing organizations should try to focus on creating mechanisms managed by humanitarian actors and, in so far as possible, be insulated from outside influence. This research is the first academic work to specifically investigate the application of FbA to armed conflict. Following an extensive review of current FbA mechanisms and conflict early warning practices, this research concludes that a conflict-centered FbA system akin to the automated FbA systems in use today to respond to natural disaster and famine is possible, but that the endeavor presents many practical and conceptual barriers to implementation. In particular, diffuse models such as the Start Fund offer a hopeful glimpse at a type of horizontal, member-driven FbA mechanism that is both highly context-sensitive and relatively insulated from outside influence. Such a design, however, features notable and inherent limitations in its ability to reliably and accurately predict the outbreak of conflict and respond in a manner that minimizes regretful actions.