Bayesian Markov chain Monte Carlo inversion of geophysical data for the purpose of estimating the hydraulic properties of the unsaturated zone

Ground-penetrating radar (GPR) has the potential to provide valuable information on hydrological properties of the vadose zone because of their strong sensitivity to soil water content. In particular, recent evidence has suggested that the stochastic inversion of crosshole GPR data within a coupled geophysical-hydrological framework may allow for effective estimation of subsurface van-Genuchten-Mualem (VGM) parameters and their corresponding uncertainties. An important and still unresolved issue, however, is how to best integrate GPR data into a stochastic inversion in order to estimate the VGM parameters and their uncertainties, thus improving hydrological predictions. Recognizing the importance of this issue, the aim of the research presented in this thesis was to first introduce a fully Bayesian inversion called Markov-chain-Monte-carlo (MCMC) strategy to perform the stochastic inversion of steady-state GPR data to estimate the VGM parameters and their uncertainties. Within this study, the choice of the prior parameter probability distributions from which potential model configurations are drawn and tested against observed data was also investigated. Analysis of both synthetic and field data collected at the Eggborough (UK) site indicates that the geophysical data alone contain valuable information regarding the VGM parameters. However, significantly better results are obtained when these data are combined with a realistic, informative prior. A subsequent study explore in detail the dynamic infiltration case, specifically to what extent time-lapse ZOP GPR data, collected during a forced infiltration experiment at the Arrenaes field site (Denmark), can help to quantify VGM parameters and their uncertainties using the MCMC inversion strategy. The findings indicate that the stochastic inversion of time-lapse GPR data does indeed allow for a substantial refinement in the inferred posterior VGM parameter distributions. In turn, this significantly improves knowledge of the hydraulic properties, which are required to predict hydraulic behaviour. Finally, another aspect that needed to be addressed involved the comparison of time-lapse GPR data collected under different infiltration conditions (i.e., natural loading and forced infiltration conditions) to estimate the VGM parameters using the MCMC inversion strategy. The results show that for the synthetic example, considering data collected during a forced infiltration test helps to better refine soil hydraulic properties compared to data collected under natural infiltration conditions. When investigating data collected at the Arrenaes field site, further complications arised due to model error and showed the importance of also including a rigorous analysis of the propagation of model error with time and depth when considering time-lapse data. Although the efforts in this thesis were focused on GPR data, the corresponding findings are likely to have general applicability to other types of geophysical data and field environments. Moreover, the obtained results allow to have confidence for future developments in integration of geophysical data with stochastic inversions to improve the characterization of the unsaturated zone but also reveal important issues linked with stochastic inversions, namely model errors, that should definitely be addressed in future research.

Stochastic stability and the evolution of coordination in spatially structured populations.

Animals can often coordinate their actions to achieve mutually beneficial outcomes. However, this can result in a social dilemma when uncertainty about the behavior of partners creates multiple fitness peaks. Strategies that minimize risk ("risk dominant") instead of maximizing reward ("payoff dominant") are favored in economic models when individuals learn behaviors that increase their payoffs. Specifically, such strategies are shown to be "stochastically stable" (a refinement of evolutionary stability). Here, we extend the notion of stochastic stability to biological models of continuous phenotypes at a mutation-selection-drift balance. This allows us to make a unique prediction for long-term evolution in games with multiple equilibria. We show how genetic relatedness due to limited dispersal and scaled to account for local competition can crucially affect the stochastically-stable outcome of coordination games. We find that positive relatedness (weak local competition) increases the chance the payoff dominant strategy is stochastically stable, even when it is not risk dominant. Conversely, negative relatedness (strong local competition) increases the chance that strategies evolve that are neither payoff nor risk dominant. Extending our results to large multiplayer coordination games we find that negative relatedness can create competition so extreme that the game effectively changes to a hawk-dove game and a stochastically stable polymorphism between the alternative strategies evolves. These results demonstrate the usefulness of stochastic stability in characterizing long-term evolution of continuous phenotypes: the outcomes of multiplayer games can be reduced to the generic equilibria of two-player games and the effect of spatial structure can be analyzed readily.

Feasibility and clinical outcomes when using practice guidelines for evaluation of fever in returning travelers and migrants : a validation study.

BACKGROUND: Practice guidelines for examining febrile patients presenting upon returning from the tropics were developed to assist primary care physicians in decision making. Because of the low level of evidence available in this field, there was a need to validate them and assess their feasibility in the context they have been designed for. OBJECTIVES: The objectives of the study were to (1) evaluate physicians' adherence to recommendations; (2) investigate reasons for non-adherence; and (3) ensure good clinical outcome of patients, the ultimate goal being to improve the quality of the guidelines, in particular to tailor them for the needs of the target audience and population. METHODS: Physicians consulting the guidelines on the Internet (www.fevertravel.ch) were invited to participate in the study. Navigation through the decision chart was automatically recorded, including diagnostic tests performed, initial and final diagnoses, and clinical outcomes. The reasons for non-adherence were investigated and qualitative feedback was collected. RESULTS: A total of 539 physician/patient pairs were included in this study. Full adherence to guidelines was observed in 29% of the cases. Figure-specific adherence rate was 54.8%. The main reasons for non-adherence were as follows: no repetition of malaria tests (111/352) and no presumptive antibiotic treatment for febrile diarrhea (64/153) or abdominal pain without leukocytosis (46/101). Overall, 20% of diversions from guidelines were considered reasonable because there was an alternative presumptive diagnosis or the symptoms were mild, which means that the corrected adherence rate per case was 40.6% and corrected adherence per figure was 61.7%. No death was recorded and all complications could be attributed to the underlying illness rather than to adherence to guidelines. CONCLUSIONS: These guidelines proved to be feasible, useful, and leading to good clinical outcomes. Almost one third of physicians strictly adhered to the guidelines. Other physicians used the guidelines not to forget specific diagnoses but finally diverged from the proposed attitudes. These diversions should be scrutinized for further refinement of the guidelines to better fit to physician and patient needs.

GENCODE: producing a reference annotation for ENCODE

Background: The GENCODE consortium was formed to identify and map all protein-coding genes within the ENCODE regions. This was achieved by a combination of initial manualannotation by the HAVANA team, experimental validation by the GENCODE consortium and a refinement of the annotation based on these experimental results.Results: The GENCODE gene features are divided into eight different categories of which onlythe first two (known and novel coding sequence) are confidently predicted to be protein-codinggenes. 5’ rapid amplification of cDNA ends (RACE) and RT-PCR were used to experimentallyverify the initial annotation. Of the 420 coding loci tested, 229 RACE products have beensequenced. They supported 5’ extensions of 30 loci and new splice variants in 50 loci. In addition,46 loci without evidence for a coding sequence were validated, consisting of 31 novel and 15putative transcripts. We assessed the comprehensiveness of the GENCODE annotation byattempting to validate all the predicted exon boundaries outside the GENCODE annotation. Outof 1,215 tested in a subset of the ENCODE regions, 14 novel exon pairs were validated, only twoof them in intergenic regions.Conclusions: In total, 487 loci, of which 434 are coding, have been annotated as part of theGENCODE reference set available from the UCSC browser. Comparison of GENCODEannotation with RefSeq and ENSEMBL show only 40% of GENCODE exons are contained withinthe two sets, which is a reflection of the high number of alternative splice forms with uniqueexons annotated. Over 50% of coding loci have been experimentally verified by 5’ RACE forEGASP and the GENCODE collaboration is continuing to refine its annotation of 1% humangenome with the aid of experimental validation.

FGF signaling controls caudal hindbrain specification through Ras-ERK1/2 pathway

Background: During early steps of embryonic development the hindbrain undergoes a regionalization process along the anterior-posterior (AP) axis that leads to a metameric organization in a series of rhombomeres (r). Refinement of the AP identities within the hindbrain requires the establishment of local signaling centers, which emit signals that pattern territories in their vicinity. Previous results demonstrated that the transcription factor vHnf1 confers caudal identity to the hindbrain inducing Krox20 in r5 and MafB/Kreisler in r5 and r6, through FGF signaling [1].Results: We show that in the chick hindbrain, Fgf3 is transcriptionally activated as early as 30 min after mvHnf1 electroporation, suggesting that it is a direct target of this transcription factor. We also analyzed the expression profiles of FGF activity readouts, such as MKP3 and Pea3, and showed that both are expressed within the hindbrain at early stages of embryonic development. In addition, MKP3 is induced upon overexpression of mFgf3 or mvHnf1 in the hindbrain, confirming vHnf1 is upstream FGF signaling. Finally, we addressed the question of which of the FGF-responding intracellular pathways were active and involved in the regulation of Krox20 and MafB in the hindbrain. While Ras-ERK1/2 activity is necessary for MKP3, Krox20 and MafB induction, PI3K-Akt is not involved in that process.Conclusion: Based on these observations we propose that vHnf1 acts directly through FGF3, and promotes caudal hindbrain identity by activating MafB and Krox20 via the Ras-ERK1/2 intracellular pathway.

Federalism and democracy. The case of minority nations: a federalist deficit

In this chapter, after pointing out the different logics that lie behind the familiar ideas of democracy and federalism, I have dealt with the case of plurinational federal democracies. Having put forward a double criterion of an empirical nature with which to differentiate between the existence of minority nations within plurinational democracies (section 2), I suggest three theoretical criteria for the political accommodation of these democracies. In the following section, I show the agonistic nature of the normative discussion of the political accommodation of this kind of democracies, which bring monist and pluralist versions of the demos of the polity into conflict (section 3.1), as well as a number of conclusions which are the result of a comparative study of 19 federal and regional democracies using four analytical axes: the uninational/plurinational axis; the unitarianism-federalism axis; the centralisation-decentralisation axis; and the symmetry-asymmetry axis (section 3.2). This analysis reveals shortcomings in the constitutional recognition of national pluralism in federal and regional cases with a large number of federated units/regions with political autonomy; a lower degree of constitutional federalism and a greater asymmetry in the federated entities or regions of plurinational democracies. It also reveals difficulties to establish clear formulas in these democracies in order to encourage a “federalism of trust” based on the participation and protection of national minorities in the shared government of plurinational federations/regional states. Actually, there is a federal deficit in this kind polities according to normative liberal-democratic patterns and to what comparative analysis show. Finally, this chapter advocates the need for a greater normative and institutional refinement in plurinational federal democracies. In order to achieve this, it is necessary to introduce a deeper form of “ethical” pluralism -which displays normative agonistic trends, as well as a more “confederal/asymmetrical” perspective, congruent with the national pluralism of these kind of polities.

Three theories of liberalism for the three theories of federalism. A Hegelian turn

This paper links different political liberal theories, considered from the perspective of their moral ontology, with federal democracies. After giving a brief description of these theories, I discuss their relationship with the theoretical and institutional models of federalism. As methodological tools, the paper introduces some Hegel’s political concepts and deals with their potential application to the analysis of federalism, taken into account the case of minorities in multinational democracies. I postulate the need for a moral and institutional refinement of liberal-democratic patterns that is better able to accommodate national pluralism than has so far been achieved by traditional constitutionalism.

Cosmopolitan justice and minority rights: the case of minority nations (or Kant again, but different)

Global Justice has usually been understood to mean institutional and social justice (political and redistributive issues on a global scale). In contrast, issues involving different national and cultural identities, are usually marginal in reflections on global justice. This occurs despite the fact that human rights include political social and cultural rights. This paper links a conception of global justice, moral cosmopolitanism, with plurinational democracies. After giving a brief description of moral cosmopolitanism I go on to analyse notions of cosmopolitanism and patriotism in Kant's work and the political significance that the notion of "unsocial sociability" and the "Ideas of Pure Reason" of Kant's first Critique have for cosmopolitanism. Finally, I analyse the relationship between cosmopolitanism and minority nations based on the preceding sections. I postulate the need for a moral and institutional refinement of democracies and international society that is better able to accommodate national pluralism than has so far been achieved by traditional liberal constitutionalism and cosmopolitanism

Motive-oriented therapeutic relationship in brief psychodynamic intervention for patients with depression and personality disorders.

Motive-Oriented Therapeutic Relationship (MOTR, also called Complementary Therapeutic Relationship) has already shown itself to be related to therapeutic outcome in several studies. The present study aims to test MOTR in a 4-session Brief Psychodynamic Intervention for patients presenting with major depressive disorder (MDD) and comorbid personality disorder (PD). In total, N = 20 patients were selected; n = 10 had MDD, n = 10 had MDD with comorbid PD. The first therapy session was videotaped and analyzed by means of Plan Analysis and the MOTR scale. Results suggest a differential effect on outcome: only the nonverbal component of MOTR is related to symptomatic change in patients presenting with MDD and comorbid PD; no such effect was found for patients with MDD alone. These results are discussed in line with the generalization and refinement of the conclusions of previous findings on the MOTR. © 2011 Wiley Periodicals, Inc. J Clin Psychol 67:1-11, 2011.

Choice by sequential procedures

We propose a rule of decision-making, the sequential procedure guided byroutes, and show that three influential boundedly rational choice models can be equivalentlyunderstood as special cases of this rule. In addition, the sequential procedure guidedby routes is instrumental in showing that the three models are intimately related. We showthat choice with a status-quo bias is a refinement of rationalizability by game trees, which, inturn, is also a refinement of sequential rationalizability. Thus, we provide a sharp taxonomyof these choice models, and show that they all can be understood as choice by sequentialprocedures.

Definition of clinically distinct molecular subtypes in estrogen receptor-positive breast carcinomas through genomic grade.

PURPOSE: A number of microarray studies have reported distinct molecular profiles of breast cancers (BC), such as basal-like, ErbB2-like, and two to three luminal-like subtypes. These were associated with different clinical outcomes. However, although the basal and the ErbB2 subtypes are repeatedly recognized, identification of estrogen receptor (ER) -positive subtypes has been inconsistent. Therefore, refinement of their molecular definition is needed. MATERIALS AND METHODS: We have previously reported a gene expression grade index (GGI), which defines histologic grade based on gene expression profiles. Using this algorithm, we assigned ER-positive BC to either high-or low-genomic grade subgroups and compared these with previously reported ER-positive molecular classifications. As further validation, we classified 666 ER-positive samples into subtypes and assessed their clinical outcome. RESULTS: Two ER-positive molecular subgroups (high and low genomic grade) could be defined using the GGI. Despite tracking a single biologic pathway, these were highly comparable to the previously described luminal A and B classification and significantly correlated to the risk groups produced using the 21-gene recurrence score. The two subtypes were associated with statistically distinct clinical outcome in both systemically untreated and tamoxifen-treated populations. CONCLUSION: The use of genomic grade can identify two clinically distinct ER-positive molecular subtypes in a simple and highly reproducible manner across multiple data sets. This study emphasizes the important role of proliferation-related genes in predicting prognosis in ER-positive BC.

A characterization of sequential rationalizability

A choice function is sequentially rationalizable if there is an ordered collection of asymmetric binary relations that identifies the selected alternative in every choice problem. We propose a property, F-consistency, and show that it characterizes the notion of sequential rationalizability. F-consistency is a testable property that highlights the behavioral aspects implicit in sequentially rationalizable choice. Further, our characterization result provides a novel tool with which to study how other behavioral concepts are related to sequential rationalizability, and establish a priori unexpected implications. In particular, we show that the concept of rationalizability by game trees, which, in principle, had little to do with sequential rationalizability, is a refinement of the latter. Every choice function that is rationalizable by a game tree is also sequentially rationalizable. Finally, we show that some prominent voting mechanisms are also sequentially rationalizable.

Auctions of licences and market structure

This paper studies sequential auctions of licences to operate in amarket where those firms that obtain at least one licence then engage ina symmetric market game. I employ a new refinement of Nash equilibrium,the concept of {\sl Markovian recursively undominated equilibrium}.The unique solution satisfies the following properties: (i) when severalfirms own licences before the auction (incumbents), new entrants buylicences in each stage, and (ii) when there is no more than one incumbent,either the single firm preempts entry altogether or entry occurs inevery stage, depending on the parameter configuration.

2007 Greenhouse Gas Emissions from Selected Iowa Source Categories

The Department’s 2007 Greenhouse Gas Inventory is a refinement of previous statewide inventories. It is a bottom-up inventory of two sectors – fossil fuel combustion at federally-recognized major sources of air pollution and fossil fuel combustion and ethanol fermentation at dry mill ethanol plants. This is the first bottomup greenhouse gas inventory conducted for Iowa and the first bottom-up greenhouse gas inventory of ethanol plants in the nation that the Department is aware of. In a bottom-up inventory, facility-specific activity data is used to calculate emissions. In a top-down inventory, aggregate activity data is used to calculate emissions. For example, this bottom-up inventory calculates greenhouse gas emissions from the fossil fuel combustion at each individual facility instead of using the total amount of fossil fuel combusted state-wide, which would be a top-down inventory method. The advantage to a bottom-up inventory is that the calculations are more accurate than a top-down inventory. However, because the two methods differ, the results from a bottom-up inventory are not directly comparable to a top-down inventory.

Lats2, a novel regulator of Elongin BC ubiquitin ligase

Résumé : Le Large tumor suppressor, Lats2, est une protéine humaine homologue au suppresseur de tumeur Warts (Lats) de Drosophila melanogaster, qui réprime la prolifération des cellules en altérant leur cycle au niveau des transitions Gl/S et G2/M, et en induisant l'apoptose. Pourtant, la voie moléculaire par laquelle Lats2, une sériase-thréonine kinase, déclenche l'arrêt du cycle cellulaire, est toujours inconnue. Notre équipe a d'abord déterminé que Lats2 était un gène de réponse à la protéine p53 (Kostic et al., 2000). Par la suite, nous avons identifié des protéines interagissant avec Lats2, notamment les modules de reconnaissance du substrat des ligases Colline E3 (des protéines contenant Socs box ou F box) ainsi que deux Bous-unités du Signalosome CSN: CSN4 et CSNS. En outre, Lats2 est connue pour s'associer au Super-complexe composé de CSN et des ligases Colline E3 (Rongere, thesis, 2004; Rongere, unpublished results, 2005). Le travail présenté ici sur Lats2 a confirmé que cette protéine est une kinase associée à CSN. Nous avons caractérisé les interactions spécifiques de domaines de Lats2 avec hSocs3, hWsb 1 (des protéines Socs box) et hFBX-7 (une protéine F box), ainsi que les conséquences physiologiques des interactions avec hSocs3, hWsb1 et hSocs1. Des expériences de GST pull-down ont montré que les deux domaines, N-terminal et kinase, de Lats2 interagissent avec hSocs3, hWsb1 et hFBX-7, ce qui suggère aussi que l'ensemble de la protéine Lats2 est impliqué dans ces interactions. Une étude approfondie des interactions entre Lats2 et hSocs3 indique que le domaine kinase de Lats2 interagit avec la région de hSocs3 contenant un domaine SH2, situé en amont du domaine Socs box de hSocs3. Par ailleurs, Lats2 phosphoryle des régions spécifiques entre les domaines N-terminal et SH2 (Sl), et, entre les domaines SH2 et Socs box (S3) de la protéine hSocs3. Ces résultats révèlent que hSocs3 est un.nouveau substrat de Lats2. Des modifications de l'activité kinase ont aussi révélé que la protéine sauvage Lats2 (wt Lats2) était capable de phosphoryler hSocs3, alors qu'un mutant dead du domaine kinase Lats (poche ATP délétée, Lats2OATP) non. L'analyse des mutations a permis d'identifier deux résidus sériase situés aux positions 1441145 (S3), spécifiquement phosphorylés par wt Lats2. La phosphorylation des protéines représentant un signal de dégradation protéolytique, nous avons envisagé que Lats2 pouvait cibler hSocs3 pour une dégradation protéasomale. Lorsque wt Lats2 est surexprimée dans des cellules HEK293T et COS7, la demi-vie de hSocs3, un élément de la ligase Elongine BC-Colline É3 (ligase EBC), diminue significativement, effet que n'a pas la surexpression de Lats2OATP. De plus, la stabilité de hSocs3 dépend de la phosphorylation des résidus sériase aux positions 144/145 par wt Lats2. Bien que les sites de phosphorylation ne soient pas définis pour les deux autres modules de reconnaissance du substrat de la ligase EBC: hWsb 1 et hSocsl, leurs demi-vies diminuent également quand wt Lats2 est surexprimée. Pour les tests in vivo, nous avons synthétisé des esiRNA pour diminuer l'expression du gène endogène lats2, ce qui a entraîné une augmentation d'un facteur 2 de la demi-vie de hSocs3 et de hWsbl dans les cellules HEK293T. En conclusion, nos résultats suggérent que Lats2, une kinase associée au CSN, est un nouveau régulateur de la fonction des ligases EBC, agissant sur le renouvellement des protéines hSocs3, hSocs1 et hWsb1. Ainsi, Lats2 altère la spécificité et la capacité des ligases EBC, régulant par là même la stabilité de nombreuses protéines, ciblées par les ligases EBC pour une dégradation protéasomale. D'autres études devraient révéler si la modification observée de la fonction de la ligase EBC par Lats2, associée au Super-complexe, est également responsable du renouvellement des régulateurs du cycle cellulaire et des changements dans ce même cycle observés lors de la surexpression de Lats2. Summary : The Large tumor suppressor 2 (Lats2) is a human homologue of the Drosophila melanogaster tumor suppressor Warts (Cats) who negatively regulates cell proliferation by altering cell cycle Gl/S and G2/M transition and inducing apoptosis. However, the molecular pathway by which Lats2, a serine-threonine kinase, mediates cell cycle arrest is still unknown. Lats2 was initially identified to be a p53 response gene by our group (Kostic et al., 2000). Subsequently, our group identified interacting candidates of Lats2, including substrate recognition modules of Cullin-based E3 ligases (Socs box or F-box containing proteins) as well as two subunits of the Signalosome (CSN), CSN4 and CSNS. Additionally, Lats2 was shown to associate with a Super-complex, composed of CSN and Cullin-based E3 ligases (Rongere, thesis, 2004; Rongere, unpublished results, 2005) We hypothesized that Lats2 may perform its physiological function through interaction with CSN and Cullin-based E3 ligases. The present work on Lats2 has confirmed that Lats2 is a CSN associated kinase. We defined the domain specific interactions of Lats2 with hSocs3, hWsb1 (Sots box proteins) and hFBX-7 (F box protein), as well as the physiological consequences of interaction with hSocs3, hWsb1 and hSocs1. Both the N-terminal and the kinase domains of Lats2 interact with full-length hSocs3, hWsb1 and hFBX-7, determined in GST pull-down assays suggesting that full-length Lats2 protein is involved in interactions. Refinement of the Lats2 interaction with hSocs3 indicated that the kinase domain of Lats2 interacts with a region of hSocs3 containing a SH2 domain located upstream of the Socs box domain of the hSocs3. Moreover, Lats2 phosphorylated specific regions between the N-terminal and SH2 domain (S l) as well as between the SH2 domain and Socs box domain of hSocs3 (S3).These results indicate that hSocs3 is a novel Lats2 substrate. The kinase assay has also demonstrated that wt Lats2 was able to phosphorylate hSocs3, but not Lats2 kinase dead mutant (deleted ATP pocket, Lats20ATP). Mutational analysis identified two serine residues located at positions 144/145 (S3) to be specifically phosphorylated by wt Lats2. Phosphorylation of proteins has been shown to be a signal for proteolytic degradation of many characterized proteins. Thus we hypothesized that Lats2 could target hSocs3 for proteasomal degradation. When wt Lats2 was over-expressed in HEK293T cells and COST cells, the half-life of hSocs3, as a component of Elongin BC Cullin-based E3 ubiquitin ligase (EBC ligase), decreased significantly. In contrast, aver-expression of the Lats2OATP did not alter the half-life of hSocs3. Furthermore, the stability of hSocs3 depended on phosphorylation of serine residues at positions 144/145 by wt Lats2. Although the sites of phosphorylation were not defined for two other substrate recognition modules of EBC ligasehWsbl and hSocsl, their half-lives also decreased when wt Lats2 was over-expressed. To test in vivo, we synthesized esiRNA to knock-down endogenous Lats2 and subsequently we measured the half-lives of hSocs3 and hVVsb l . Here we demonstrated that the half-lives of hSocs3 and hWsbl were increased by the factor of two in Lats2-depleted HEK293T cells. In conclusion, our findings suggest that Lats2, a CSN associated kinase, is a novel regulator of EBC ligase function by regulating the turn-over of hSocs3, hSocs1 and hWsb1. Thus, Lats2 alters the specificity and capacity of EBC ligases regulating thereby the stability of numerous proteins which are targeted by EBC ligases for proteasomal degradation. Further studies should reveal whether the observed modulation of EBC ligase function by Lats2 associated with a Super-complex is also responsible for the turn-over of cell cycle regulators and the observed alteration in cell cycle by Lats2 over-expression.