Electrospray ionization (ESI) mass spectrometry (MS) in combination with liquid chromatography (LC) is an excellent tool for the identification of drug metabolites. Utilizing this hyphenated technique in combination with proper sample pretreatment, the metabolic pathways of the analgesic drug ketobemidone were investigated in human urine and rat microdialysate from blood and brain. Two novel phase I metabolites (ketobemidone N-oxide and meta-hydroxymethoxyketobemidone) and three novel phase II metabolites (glucuronic acid conjugates of ketobemidone, norketobemidone and hydroxymethoxyketobemidone) were identified in human urine. Further, norketobemidone and ketobemidone N-oxide were identified in rat microdialysate from brain after regional distribution of ketobemidone in striatum. This indicates that the brain itself has the possibility to metabolize ketobemidone. Synthetic ketobemidone metabolites were used for comparison of retention times and tandem MS spectra with the possible metabolites recovered from the biological samples. The conjugated metabolites were identified by accurate mass measurements and tandem MS spectra of the aglycones. The accuracy of the estimated masses was better than 2.1 ppm for two out of three conjugates in presence of internal standard. On-line micro-SPE was successfully used for trapping and desalting of the microdialysates. The small SPE pre-column made it possible to inject approximately 100 times more sample on the analytical column compared to injection without pre-column. Selective trapping was demonstrated for the polar catechol amine metabolite, dihydroxyketobemidone, which forms covalent complexes with phenylboronic acid (PBA). A fluorinated silica type stationary phase was the only column out of several tested that was able to separate ketobemidone and all relevant phase I metabolites. Liquid chromatography and mass spectrometry are independently valuable tools in the field of analytical pharmaceutical chemistry. The present study showed that the combination of LC-MS, with its excellent selectivity and sensitivity, offers an outstanding tool in the qualitative analysis of drugs and metabolites in biological fluids.

Many people use the train both as a daily means of transport as well as a working place to carry out activities such as reading or writing. There are, however, several important factors in this environment that will hamper good performance of such activities. Some of the main sources of disturbance, apart form other train passengers, are noise and vibrations generated from the train itself. Although there are standards available for evaluation of ride comfort in vehicles none of them consider the effects that vibrations have on particular passengers' activities. To address these issues, three different studies were conducted to investigate how low frequency lateral vibrations influence the passengers' ability to read and write onboard trains. The first study was conducted on three types of Inter-Regional trains during normal service and included both a questionnaire survey and vibration measurements. Two proceeding laboratory studies were conducted in a train mock-up where the perceived difficulty of reading and writing was evaluated for different frequencies and amplitudes. To model and clarify how vibrations influence the processes of reading and writing the fundamentals of Human Activity Theory was used as a framework in this thesis. In the field study about 80% of the passengers were found to be reading at some point during the journey, 25% were writing by hand, and 14% worked with portable computers. The passengers applied a wide range of seated postures for their different activities. According to the standardised measurements, even the trains running on poor tracks showed acceptable levels of vibration. However, when the passengers performed a short written test, over 60 % reported to be disturbed or affected by vibrations and noise in the train. In the laboratory studies it was found that the difficulty in reading and writing is strongly influenced by both vibration frequency and acceleration amplitude. The vibration spectra of real trains were found to correspond well to the frequency characteristics of the rated difficulty. It was also observed that moderate levels of difficulty begin at fairly low vibration levels. Contextual parameters like sitting posture and type of activity also showed strong influence on how vibrations cause difficulty.

Cette thèse décrit quelques développements dans les techniques de calcul des amplitudes de diffusion en théorie supersymétrique de champ de jauge . L'accent est mis sur les relations de récurrence on-shell et sur l'utilisation de méthodes d'unitarité pour des calculs de boucle. En particulier, la récurrence on-shell est liée aux règles BCFW pour calculer les amplitudes de jauge au niveau des arbres. Les combinaisons de techniques de coupe d'unitarité et la récurrence sont utilisées pour calculer les amplitudes de boucle, et finalement, à partir des amplitudes, pour obtenir la fonction de corrélation énergie-énergie en théorie de super-Yang-Mills N = 4 à l'aide de la représentation de Mellin-Barnes. Dans le dernier chapitre, nous tentons de trouver un contour convergent pour les intégrales de Mellin Barnes en multi-dimension obtenu par une certaine approximation d'un contour de phase stationnaire.

Brushless Direct Current (BLDC) motors are one of the motor types rapidly gaining popularity. BLDC motors are being increasingly used in critical high performance industries such as appliances, automotive, aerospace, consumer, medical, industrial automation equipment and instrumentation. Fault detection and condition monitoring of BLDC machines is therefore assuming a new importance. The objective of this research is to advance the field of rotor and load fault diagnosis in BLDC machines operating in a variety of operating conditions ranging from constant speed to continuous transient operation. This objective is addressed as three parts in this research. The first part experimentally characterizes the effects of rotor faults in the stator current and voltage of the BLDC motor. This helps in better understanding the behavior of rotor defects in BLDC motors. The second part develops methods to detect faults in loads coupled to BLDC motors by monitoring the stator current. As most BLDC applications involve non-stationary operating conditions, the diagnosis of rotor faults in non-stationary conditions forms the third and most important part of this research. Several signal processing techniques are reviewed to analyze non-stationary signals. Three new algorithms are proposed that can track and detect rotor faults in non-stationary or transient current signals.

The bgl operon of Escherichia coli, involved in the uptake and utilization of aromatic β-glucosides salicin and arbutin, is maintained in a silent state in the wild type organism by the presence of structural elements in the regulatory region. This operon can be activated by mutations that disrupt these negative elements. The fact that the silent bgl operon is retained without accumulating deleterious mutations seems paradoxical from an evolutionary view point. Although this operon appears to be silent, specific physiological conditions might be able to induce its expression and/or the operon might be carrying out function(s) apart from the utilization of aromatic β-glucosides. The experiments described in this thesis were carried out to test these possibilities. In cultures exposed to prolonged stationary phase, majority of the bacterial population dies and a few mutants that have the ability to scavenge the nutrients released by the dying cell mass survive. Bgl+ mutants were found to be enriched in twenty-eight-day-old Luria Broth grown cultures of E. coli that are wild type for bgl but carry the rpoS819 allele. Out of the five Bgl+ mutants that were isolated, four carried a mutation in the hns locus while one of them, ZK819-97, had an activating mutation linked to the bgl operon. Further analysis of ZK819-97 by DNA sequencing revealed the existence of a single C to T transition at the CAP binding site in the regulatory region. ZK819-97 was chosen for further analysis. Competition assays were carried out in which Bgl+ strain, ZK819-97 (Strr), and the parental Bgl- strain, ZK820 (Nalr), were grown independently for twenty-four hours in Luria Broth and then mixed in 1:1,000 (v/v) ratio reciprocally, without addition of fresh nutrients. ZK819-97, when present in minority, was found to increase in number and take over the parental strain, ZK820, i.e. ZK819-97 showed a Growth Advantage in Stationary Phase phenotype. To determine whether the GASP phenotype of ZK819-97 is associated with the bgl locus, the bgl allele from this strain was transferred by P1 transduction to its parental strain, ZK819. The resulting strain, ZK819-97T (Bgl+, Tetr), when competed with the parental strain, ZK819 Tn5 (Bgl-, Kanr), also showed a GASP phenotype when present in minority in the mixed cultures. To reconfirm this further, the bgl locus was deleted from ZK819-97T. The resulting strain, ZK819-97Δbgl, showed a loss of the GASP phenotype. When the bglB locus was disrupted in ZK819-97T, the resulting strain, ZK819-97ΔB, also failed to show a GASP phenotype, indicating that the phospho-β-glucosidase B activity is essential for this phenotype. The strain, ZK819-IS1, carrying an activating IS1 insertion within the bgl regulatory region also showed a GASP phenotype, confirming that this phenotype of the Bgl+ strain is independent of the nature of the activating mutation. All the above mentioned strains used in the competition assays carry a mutant allele of rpoS, rpoS819. Introduction of the wild type rpoS allele in these strains resulted in the loss of the GASP phenotype of the Bgl+ strain, suggesting that the two mutations work in a concerted manner. The Bgl+ strain was found to show the GASP phenotype only when present in minority of 1:1,000 or 1:10,000 in the mixed cultures and showed a slight disadvantage at higher ratios, indicating that the GASP phenotype of the Bgl+ strain is a frequency dependent phenomenon. In competition assays carried out between 24-hour-old cultures of Bgl+ and Bgl- strains resuspended in five-day-old spent medium prepared from a wild type E. coli strain, Bgl+ strain did not show any extra or early GASP phenotype. In addition, a reporter strain, which has a lacZ transcriptional fusion with the activated bgl promoter, was resuspended in spent medium prepared from a five-day-old culture of wild type strain of E. coli and bgl promoter activity was measured by β-galactosidase assay. The bgl promoter did not show any induction in this medium. These experiments suggest the absence of any β-glucoside like molecules in the spent medium within the sensitivity of these assays. A reporter strain that has a lacZ transcriptional fusion to the wild type bgl promoter was used to measure the expression level of this promoter during exponential and stationary phase of growth in LB. Expression of the wild type as well as various activated promoters of bgl was found to be enhanced in stationary phase. To investigate a possible role of the rpoS encoded stationary phase specific sigma factor, RpoS (σs), and another stationary phase factor, Crl, known to be important for the regulation of many genes of the σs regulon, the bgl promoter activity measurements were carried out in the presence or the absence of RpoS and/or Crl. RpoS along with Crl was found to negatively regulate the expression of wild type as well as activated promoters of bgl, both in exponential and stationary phase. In the absence of the negative regulation by RpoS and Crl, the increase in the bgl promoter activity was more pronounced as compared to that in its presence. rpoS and crl mutations are common in nature and it has been suggested that crl deletion gives a growth advantage to the strain in stationary phase. To test this possibility crl deletion was created in wild type as well as in attenuated rpoS allele background. The strain carrying the crl deletion was found to have a growth advantage in stationary phase over the wild type strain in the presence of wild type rpoS allele, while it shows a slight disadvantage in combination with mutant rpoS. Over expression of LeuO or BglJ is known to activate the bgl operon. To study a possible role of these factors in the regulation of the bgl expression in stationary phase, the bgl promoter activity was measured in strains that were deleted for leuO and/or bglJ, in the absence or presence of crl. These studies indicated that BglJ had a moderate effect on the bgl promoter activity in stationary phase in the absence of Crl but not in its presence. LeuO did not have a significant effect on the bgl promoter activity in either condition. Thus under the conditions tested, the physiological increase in the levels of LeuO and BglJ in stationary phase was insufficient to regulate the bgl expression. Preliminary results show that the bgl operon might be involved in the regulation of oppA, an oligopeptide transporter subunit, in stationary phase. Implications of these findings are discussed. The studies reported in this thesis highlight the involvement of the bgl operon of E. coli in stationary phase. This could be mediated by genetic as well as physiological mechanisms. This study also underscores the importance of observing organisms closer to their natural context and the need to reconsider the concept of ‘cryptic genes’.

The test facility ROCOM (Rossendorf Coolant Mixing Model) has been built for the investigation of coolant mixing processes in the reactor pressure vessel of pressurised water reactors (PWR). ROCOM is a 1:5 model of the German PWR KONVOI and has been designed for a wide range of different mixing scenarios. ROCOM disposes of four loops with fully controllable coolant pumps. The test facility is operated with demineralised water. For the investigation of mixing, tracer solution (water labelled with salt) is injected into the facility. The transient distribution of the electrical conductivity is is measured at different positions of the flow path by means of wire-mesh sensor technique with high resolution in space and time. The measured conductivity is transformed into a dimensionless mixing scalar. The mixing at quasi-stationary conditions (constant loop mass flow rates) has been investigated in the presented experiments. That concerned nominal operation conditions, the operation with a reduced number of loops and the investigation of cold-water transients with running pumps and conditions of developed natural circulation. In special experimental series, the reproducibility of the results at identicla boundary conditions within the confidence intervalls has been shown. Further, the influence of various factors on the mixing has been investigated. This included the pressure losses at the core bottom plate, the global coolant flow level and the influence of the loop flow rate on the perturbed sector at the core inlet. An analysis of the measurement error of the used measurement technique completes the report.

<p>The objectives of this doctoral thesis are to give a basisincluding methods for the development of stationary polymerelectrolyte fuel cell (PEFC) systems for combined heat andpower production. Moreover, the objectives include identifyingprerequisites, requirements and possibilities for PEFC systemsproducing heat and power for buildings in Sweden. The PEFCsystem is still in a pre-commercial state, but low emissionlevels, fast dynamics and high efficiencies are promisingcharacteristics.</p><p>A thermodynamic model to simulate stationary PEFC systemshas been constructed and pinch technology and exergy analysesare utilised to design and evaluate the system. The finalsystem configuration implies a high total efficiency ofapproximately 98 % (LHV).</p><p>A flexible test facility was built in connection with theresearch project to experimentally evaluate small-scalestationary PEFC systems at KTH. The research PEFC system hasextensive measurement equipment, a rigorous control system andallows fuel cell systems from approximately 0.2 to 4 kWel insize to be tested. The simulation models of the fuel processorand the fuel cell stack are verified with experimental datataken from the test facility. The initial evaluation andsimulation of the first residential installation of a PEFCsystem in Sweden is also reported. This PEFC system, fuelled bybiogas and hydrogen, is installed in an energy system alsoincluding a photovoltaic array, an electrolyser and hydrogenstorage.</p><p>Technical aspects of designing a fuel cell system-basedenergy system, including storages and grid connections, whichprovides heat and power to a building are presented in thisthesis. As a basis for the technical and economic evaluations,exemplifying energy systems are constructed and simulated. Fuelcell system installations are predicted to be economicallyunviable for probable near-term conditions in Sweden. The mainfactor in the economic evaluations is the fuel price. However,fuel cell system installations are shown to have a higher fuelutilisation than the conventional method of energy supply.</p><p>The methods presented in this thesis serve as a collectedbasis for continued research and development in the area.</p><p><b>Keywords:</b>Small-scale, stationary, fuel cell system,polymer electrolyte fuel cell, PEFC system, reformer,thermodynamic modelling, pinch technology, exergy analyses,system configuration, test facility, experiments, application,simulation, installation, energy system, energy storage, heatand power demand.</p>

Στο πρώτο κεφάλαιο εισάγουμε τις βασικές έννοιες της διπλωματικής εργασίας. Αναφέρουμε τους ορισμούς και τον σκοπό της ανάλυσης χρονολογικών σειρών. Επίσης εισάγονται ορισμένα βασικά χαρακτηριστικά των χρονολογικών σειρών όπως η έννοια της στασιμότητας και της συνάρτησης αυτοσυσχέτισης και αναφέρουμε τις τρεις βασικές κατηγορίες στοχαστικών υποδειγμάτων χρονολογικών σειρών που αφορούν στις στάσιμες στοχαστικές διαδικασίες, οι οποίες θα αναλυθούν στα επόμενα κεφάλαια. Στο δεύτερο κεφάλαιο αναλύουμε τα αυτοπαλίνδρομα υποδείγματα, πρώτης, δεύτερης και γενικά p τάξης. Αναφέρονται παραδείγματα. Στο τρίτο κεφάλαιο αναλύουμε τα υποδείγματα κινητού μέσου πρώτης και γενικά q τάξης καθώς και μεικτά υποδείγματα πρώτης και γενικά (p,q) τάξης. Αναφέρονται παραδείγματα. Στο τέταρτο κεφάλαιο αναλύουμε χρονολογικές σειρές που δεν έχουν τα χαρακτηριστικά στάσιμων στοχαστικών διαδικασιών. Επίσης αναλύουμε την μεθοδολογία Box-Jenkins, η οποία είναι μία μέθοδος εξεύρεσης ενός στατιστικού υποδείγματος (ARIMA). Τέλος εφαρμόζεται η παραπάνω μέθοδος σε ένα παράδειγμα με τη χρήση του SPSS. / At the first chapter we introduce the basic concepts. We present the main definitions and the objectives of the time series analysis. Furthermore, we introduce some basic characteristics of the time series such as the concepts of “stationary process” and “autocorrelation”. Finally we mention three basic categories of time series models that concern stationary stochastic processes. Following in the second chapter we analyze the autoregressive models of first, second and generally “p” order. We present various relative examples. At the third chapter we analyze the moving average models of first and generally “q” order. Additionally, we analyze the mixed models of first and generally (p,q) order. Various relative examples are presented. Finally, at the forth chapter we analyze time series that don’t have the characteristics of stationary stochastic proceedings. Also we analyze the method Box-Jenkins. Furthermore, the later method is studied using the statistic software package SPSS.

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La première augmentation de la longévité en laboratoire fût observée à la suite d’une intervention nutritionnelle consistant en une réduction de l’apport alimentaire chez le rat. Plus tard, ce phénomène a été reproduit dans de très nombreuses espèces et référé en tant que restriction calorique. Le développement des techniques de biologie moléculaire moderne a permis de montrer dans des organismes modèles simples que cette flexibilité du processus de vieillissement était régulée par des facteurs génétiques. De fait, plusieurs mécanismes cellulaires ont alors pu être identifiés comme responsables de ce contrôle du vieillissement. Ces voies de régulation ont révélées être conservées entre les espèces, depuis les levures jusqu’aux organismes multicellulaires tels que le nématode, la mouche ou la souris, suggérant l’existence d’un programme universel de vieillissement dans le vivant. La levure s’est avéré à plusieurs reprises être un modèle puissant et fiable pour la découverte de gènes impliqués dans ce phénomène. Mon étude a consisté au développement d’un nouveau modèle unicellulaire d’étude du vieillissement à travers l’espèce Schizosaccharomyces pombe appelée aussi levure à fission. La première étape de mon travail a montré que les voies de détection des nutriments gouvernées par la sérine/thréonine protéine kinase A (Pka1) et la sérine/thréonine kinase Sck2 contrôlent le vieillissement chronologique de ces cellules comme il était connu dans la levure Saccharomyces cerevisiae. Ceci permit de valider l’utilisation de la levure à fission pour l’étude du vieillissement. Ensuite, nous avons analysé plus en détail l’effet pro-vieillissement du glucose en étudiant le rôle de sa détection par le récepteur membranaire Git3 couplé à la protéine G (Gpa2) en amont de la kinase Pka1. La perte du signal du glucose par la délétion de Git3 imite partiellement l’effet d’augmentation de longévité obtenu par baisse de la concentration en glucose dans le milieu. De plus, l’effet néfaste du signal du glucose est maintenu en absence de tout métabolisme du glucose suite à la mutation des hexokinases, premières enzymes de la glycolyse. L’ensemble de ces résultats suggèrent que la signalisation du glucose est prédominante sur son métabolisme pour son effet pro-vieillissement. D’autre part, à la fois la suppression de cette signalisation et la baisse de niveau de glucose disponible allongent la durée de vie en corrélation avec une augmentation de la résistance au stress, une hausse d’activité mitochondriale et une baisse de production de radicaux libres. Finalement, le criblage d’une banque de surexpression d’ADNc a permis d’identifier plusieurs gènes candidats responsables de ces effets en aval de la voie de signalisation Git3/PKA. La recherche sur les mécanismes moléculaires du vieillissement propose une nouvelle approche, un nouvel angle de vue, pour la compréhension des fonctions cellulaires et promet d’apporter de précieuses clefs pour mieux comprendre certaines maladies. En effet, le vieillissement est la première cause d’apparition de nombreuses affections comme les cancers, les maladies cardiovasculaires et métaboliques ou les maladies neurodégénératives tels que les syndromes d’Alzheimer et de Parkinson. / The first increase in life span due to man’s intervention was obtained with rats subjected to a diet reduced in calorie intake. Later, this phenomenon was repeated with many other species and referred as diet restriction or calorie restriction. The development of modern Molecular Biology approaches and the use of simple model organisms demonstrated that the rate of aging was regulated by genetic traits. Indeed, several cellular mechanisms were identified as responsible for the control of aging. These regulatory pathways appear to be conserved throughout species, from yeast to multicellular organisms like nematode, fly and mice, thus suggesting the existence of a universal program of aging. Yeast proved several times to be a powerful and reliable model for discovering genes involved in the regulation of aging. My study consisted in developing Schizosaccharomyces pombe (also called fission yeast) as a new unicellular model to study aging. The first step of my work was to show that pathways of nutrient detection through kinases involving Pka1 and Sck2 control chronological aging in S. pombe, as it was previously demonstrated in Saccharomyces cerevisiae. This first work validated the use of fission yeast for the study of aging. Subsequently, we analysed in more detail the pro-aging effect of glucose focusing on the role of its signalling through the G-protein Gpa2-coupled membrane receptor Git3, which acts upstream of Pka1. The loss of the glucose signal due to deletion of Git3 mimics partially the effect of increasing longevity by reducing glucose in the medium. Moreover, detrimental effects of glucose signal are maintained in absence of sugar metabolism following loss of hexokinases, the first enzymes of glycolysis. Together, these results suggest that the pro-aging effects of glucose signalling are predominant over those due to metabolism of this sugar. Moreover, both obliteration of this signalling pathway and decrease of glucose availability extend life span, and correlate with an increase in stress resistance, in mitochondrial activity and a lower production of free radicals. Finally, screening a cDNA-overexpression library allowed us to identify several genes candidates responsible for the effects on longevity downstream of Git3/Pka1. Research in the molecular mechanisms of aging propose holds the promise to bring precious clues as to this mysterious processes affecting all living creatures, and paves the way to unravel the underlying causes of many human diseases. Indeed, aging is the first cause of numerous late-onset pathologies including cancers, cardiovascular diseases or neurodegenerative diseases like Alzheimer and Parkinson syndromes.