The human cytomegalovirus (HCMV) viral chemokine gene, UL146, shows a high degree of variability in clinical isolates. The UL146-produced viral chemokine, vCXCL-1, has homology to CXC chemokines and is predicted to be an immune modulator that may contribute to the pathogenesis of HCMV infections. In the analysis of clinical isolates from congenitally infected infants, we found 11 distinct vCXCL-1 clades. Although the four cysteine residues that create two disulfide bonds providing the essential structure for CXC chemokines,are conserved, the N-loop region, which is important for receptor binding and activation, was hypervariable. One clade also contained a modified glutamic acid-leucine-arginine (ELR) motif (asparagine-glycine-arginine / NGR), which regulates binding to CXCR1 and CXCR2 receptors. Based on this sequence information, we hypothesize that these proteins differentially activate neutrophils, which may have a role in HCMV pathogenesis. To address these functional differences, we produced representative vCXCL-1 proteins from each of the 11 clades using a baculovirus protein expression system. Using competition binding assays, we have examined their binding affinities to either CXCR1 or CXCR2 expressed on HEK293 cells. All vCXCL-1s bound to CXCR2 with different binding affinities. Interestingly, only three vCXCL-1s bound to CXCR1 while the others demonstrated did not. We analyzed functional differences between the vCXCL-1s in calcium mobilization, adhesion molecule induction, and chemotaxis on human peripheral blood neutrophils (PBNs). Although the binding affinities to CXCR2 and/or CXCR1 were variable, all vCXCL-1s were capable of inducing intracellular calcium mobilization in PBNs and upregulating adhesion molecules on the surface of PBNs to similar levels as human CXCL1. However, the potency of the vCXCL-1s in the chemotaxis of neutrophils varied and was affinity independent. We also examined secondary chemokine production upon vCXCL-1 treatment on neutrophil-like HL60 T2 cells using real-time PCR. The results showed CCL22 induction was affinity dependent. Taken together, these results provide insights into the potential role of vCXCL-1 in HCMV pathogenesis and how the variability in these chemokines can affect neutrophil function.

The Wind-Evaporation-Sea Surface Temperature (WES) feedback is believedto play an important role in the tropics, where climate variability is governed byatmosphere-ocean coupled interactions. This dissertation reports on studies to distinctlyisolate the WES feedback mechanism over tropical oceans using a modiedversion of an NCAR-Community Climate Model (CCM3) thermodynamically coupledto a slab ocean model, where the WES feedback is deliberately suppressed inthe bulk aerodynamic formulation for surface heat uxes. A comparison of coupledintegrations using the modified WES-off CCM3 to those carried out using the standardCCM3 conclusively identifies the role of the WES feedback in enhancing theinter-annual variability over deep tropical oceans and the westward propagation ofthe equatorial annual cycle. An important role for near surface humidity in tropicalclimate variability in enhancing inter-annual variability and in sustaining the equatorialannual cycle is also suggested. Statistical analyses over the tropical Atlanticreveal that the free coupled meridional mode of the Atlantic Ocean is amplified in thepresence of the WES feedback. Similar analyses of coupled model integrations, whenforced with an articial El Ni~no Southern Oscillation (ENSO)-like SST cycle in tropicalPacific, reveal that only in the presence of the WES feedback is the meridionalmode the preferred mode of response of the Atlantic to ENSO forcings. It is also foundthat WES feedback reinforces the tendency of the ITCZ to stay north of the equator over the Atlantic during El-Nino events. Comparative studies between Last GlacialMaximum (LGM) equivalent imposed northern hemispheric sea-ice experiments withthe WES-off model and the standard model indicate a dominant role for the WESfeedback in the southward shift of the ITCZ as indicated by paleo-climate records.However, it is found not to be the sole thermodynamic mechanism responsible for thepropagation of high latitude cold SST anomalies to the tropics, suggesting significantroles for other mechanisms in the tropical response to high latitude changes.

Le principal objectif de ce travail est l’étude de l’influence de la pesanteur sur la mécanique respiratoire et le contrôle de la respiration, ainsi que sur les interactions cardio-respiratoires pendant les différents stades du sommeil. Le chapitre introductif présente le contexte général et les objectifs de la thèse. Des sections abordant le sommeil, la respiration, et l’interaction cardio-respiratoire y sont présentées, résumant l’état actuel des connaissances sur les effets de la pesanteur sur chacun de ces systèmes. Dans le deuxième chapitre, l’expérience “Sleep and Breathing in microgravity”, qui constitue la source des données à la base de ce travail, est présentée en détail. L’étude des signaux de longue durée requiert avant tout de disposer d’outils performants d’analyse des signaux. La première partie de la thèse présente en détail deux algorithmes : un algorithme de détection automatique d’événements respiratoires (inspiration / expiration) basé sur des réseaux neuronaux artificiels, et un algorithme de quantification de l’amplitude et de la phase de l’arythmie sinusale pendant le sommeil, utilisant la méthode des ondelettes. La validation de chaque algorithme est présentée, et leur performance évaluée. Cette partie inclut aussi des courtes introductions théoriques aux réseaux de neurones artificiels ainsi qu’aux méthodes d’analyse temps–fréquence (Fourier et ondelettes). Une approche similaire à celle utilisée pour la détection automatique d’événements respiratoires a été appliquée à la détection d’événements dans des signaux de vitesse du sang dans l’artère cérébrale moyenne, mesures obtenues par Doppler transcrânien. Ceci est le sujet de la thèse annexe. Ces deux algorithmes ont été appliqués aux données expérimentales pour extraire des informations physiologiques quant à l’impact de la pesanteur sur la mécanique respiratoire et l’interaction cardio-respiratoire. Ceci constitue la deuxième partie de la thèse. Un chapitre est consacré aux effets de l’apesanteur sur la mécanique respiratoire pendant le sommeil. Ce chapitre a mis en évidence, pour tous les stades de sommeil, une augmentation de la contribution abdominale en microgravité, suivi d’un retour progressif vers des valeurs observées avant le vol. L’augmentation initiale était attendue, mais l’adaptation progressive observée ne peut pas être expliquée par un effet purement mécanique, et nous suggère la présence d’un mécanisme d’adaptation central. Un deuxième chapitre présente les résultats comparant l’arythmie sinusale pendant le sommeil avant le vol, en apesanteur et après le retour sur terre. Le rythme cardiaque pendant le sommeil dans l’espace présente une moindre variabilité. Les différences NREM–REM observées sur terre pour les influences vagales et sympathiques sont accentuées dans l’espace. Aucun changement significatif n’est présent pour le gain et la différence de phase entre les les signaux cardiaque et respiratoire en comparant le sommeil sur terre et en apesanteur. La dissertation termine par une discussion générale du travail effectué, incluant les prin- cipales conclusions ainsi que les perspectives qui en découlent.

We argue that there is a crucial difference between determiner and adverbial quantification. Following Herburger [2000] and von Fintel [1994], we assume that determiner quantifiers quantify over individuals and adverbial quantifiers over eventualities. While it is usually assumed that the semantics of sentences with determiner quantifiers and those with adverbial quantifiers basically come out the same, we will show by way of new data that quantification over events is more restricted than quantification over individuals. This is because eventualities in contrast to individuals have to be located in time which is done using contextual information according to a pragmatic resolution strategy. If the contextual information and the tense information given in the respective sentence contradict each other, the sentence is uninterpretable. We conclude that this is the reason why in these cases adverbial quantification, i.e. quantification over eventualities, is impossible whereas quantification over individuals is fine.

Many organizations have transitioned from single-systems development to product-line development with the goal of increasing productivity and facilitating mass customization. Variability modelling is a key activity in software product-line development that deals with the explicit representation of variability using dedicated models. Variability models specify points of variability and their variants in a product line. Although many variability-modelling notations and tools have been designed by researchers and practitioners, very little is known about their usage, actual benefits or challenges. Existing studies mostly describe product-line practices in general, with little focus on variability modelling. We address this gap through a qualitative study on variability-modelling practices in medium- and large-scale companies using two empirical methods: surveys and interviews. We investigated companies' variability-modelling practices and experiences with the aim to gather information on 1) the methods and strategies used to create and manage variability models, 2) the tools and notations used for variability modelling, 3) the perceived values and challenges of variability modelling, and 4) the core characteristics of their variability models. Our results show that variability models are often created by re-engineering existing products into a product line. All of the interviewees and the majority of survey participants indicated that they represent variability using separate variability models rather than annotative approaches. We found that developers use variability models for many purposes, such as the visualization of variabilities, configuration of products, and scoping of products. Although we observed that high degree of heterogeneity exists in the variability-modelling notations and tools used by organizations, feature-based notations and tools are the most common. We saw huge differences in the sizes of variability models and their contents, which indicate that variability models can have different use cases depending on the organization. Most of our study participants reported complexity challenges that were related mainly to the visualization and evolution of variability models, and dependency management. In addition, reports from interviews suggest that product-line adoption and variability modelling have forced developers to think in terms of a product-line scenario rather than a product-based scenario.

The world population is growing and becoming more connected whereby disease transmission is becoming an increasingly important issue. To learn more about disease spread, honey bees (Apis mellifera) could provide an animal-model system for network transmission. The honey bees have both an individual and a social defense against pathogens, their diseases are well studied and they enable studies on hundreds of individuals. The genetic relatedness is believed to be one of many important factors for disease transmission. A hypothesis is that the more closely related the honey bees are the more interactions will occur. In this study, the genetic relatedness in honey bees was analyzed by the use of microsatellite-DNA primers, in a multiplex PCR. Of the 18 microsatellite-DNA primers that were evaluated, the loci HB-C16-05, A007, AC006, HB-C16-02, AP043 and UN351 showed the highest variation. However, when applied on a larger material, the PCR-products did not yield any chromatograms that were possible to score. Many factors possibly affecting the result are discussed and further efforts will be made to improve the method and thereby determine genetic relatedness.

There have been reports that rainfall in East Africa is changing or becoming more variable. This can have significant implications for conservation initiatives and the food security of this populace region that is heavily reliant on the rain fed agricultural system. The perceptions of farmers regarding rainfall along with 30 years of satellite data and 16 years of ground level observations were analyzed in order to characterize rainfall in and around Kibale National Park, a protected area in the Ugandan portion of the Albertine Rift. Two homogenous rainfall regions exist in the area, and the onset, cessation, and amount of rainfall during seasons is highly variable. The perceptions of farmers align with the analysis of rainfall data, indicating that the season beginning in March shows the highest degree of variability. Decreases in the amount of rainfall are found for both rainy seasons.

Ankylosing spondylitis (AS) is a chronic, inflammatory rheumatic disease that has a highly variable disease course. Three biologic agents, adalimumab, etanercept, and infliximab, have been developed for the treatment of AS. We conducted three studies: 1) an exploratory analysis of a year-long longitudinal dataset to gain insight into the variability of disease activity, physical function, and well-being and to explore the relationship between these outcome measures; 2) a systematic review of the available evidence for the efficacy of biologic treatment; 3) a systematic review of potential adverse effects of this treatment. We found that repeated measures of disease activity, function and well-being fluctuate considerably between patients, with complex patterns occurring over time within patients. There was mostly high quality evidence that these biologics are efficacious against placebo. We did not find evidence of an increase in serious adverse events or serious infections from short-term randomized controlled trials.

This study investigated the effect of palate morphology and anthropometric measures of the head and face on lingual consonant target (positional) variability of twenty one adult speakers (eleven male, ten female). An electromagnetic tracking system (WAVE, NDI, Canada) was used to collect tongue movements while each speaker produced a series of VCV syllables containing a combination of consonants /t, d, s, z, ʃ, tʃ, k, g, j/ and three corner vowel /i, ɑ, u/. Distributions of x, y, and z coordinates representing maximum tongue elevation during the consonants were used to represent target variability across contexts. Palate and anthropometric measures were obtained for each participant. A correlational analysis showed that target variability of the consonants produced in the front of the mouth (e.g. alveolar and palatal) was explained, to a degree, by palate morphology. The variability of velar consonants was not explained by the structural measures.

This study investigated the effect of palate morphology and anthropometric measures of the head and face on lingual consonant target (positional) variability of twenty one adult speakers (eleven male, ten female). An electromagnetic tracking system (WAVE, NDI, Canada) was used to collect tongue movements while each speaker produced a series of VCV syllables containing a combination of consonants /t, d, s, z, ʃ, tʃ, k, g, j/ and three corner vowel /i, ɑ, u/. Distributions of x, y, and z coordinates representing maximum tongue elevation during the consonants were used to represent target variability across contexts. Palate and anthropometric measures were obtained for each participant. A correlational analysis showed that target variability of the consonants produced in the front of the mouth (e.g. alveolar and palatal) was explained, to a degree, by palate morphology. The variability of velar consonants was not explained by the structural measures.