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Orbital-based methods for electronic-structure calculations are limited to atoms or molecules with up to about 50 electrons. This limitation comes from the requirement of a long expansion in basis functions to approximate correctly the wave function. Replacing the Coulomb interaction with a smooth model potential has two main consequences: first, the wave function becomes cuspless and the expansion in basis functions converges more rapidly, and second, the smooth potential describes a weaker interaction at the electronic coalescence point, which leads to the loss of accuracy. This work explores whether one can construct models with smooth, non-singular, potentials, but without compromising accuracy. The key idea is to use extrapolation procedures to predict the energy for the Coulomb interaction from a sequence of (cheaper) calculations for smooth potentials. By replacing the Coulomb electron-electron interaction with a smooth potential, using the semi-stochastic heat-bath configuration interaction method (SHCI) to select key configurations, and extrapolating to the limiting (non-smoothed) Coulomb potential, we were able to retain the accuracy of full configuration interaction (FCI) calculations, at reduced computational cost. / Thesis / Doctor of Philosophy (PhD)

Master of Science / Department of Chemistry / Christopher T. Culbertson / Circulating tumor cells (CTCs) have become a key component in the identification and treatment of cancer. Once dislodged from the main tumor, CTCs travel through the bloodstream and cause metastasis. Early detection and identification of these cells can help in the evaluation and prognosis of various types of cancer, as well as assisting in patient treatments by determining the spread of the disease. Here, a high-throughput microfluidic analysis technique is described that can efficiently detect and identify cells, with the specific identification of CTCs as a future application through fluorescent labeling in mind. As proof of principle, the device has been shown to detect and characterize individual human Jurkat (T-lymphocyte) cells at a rate of 100 cells/minute. The device employs micro-scale flow focusing to isolate individual cells. The cells are detected using both light scattering and laser-induced fluorescence to evaluate cell size and surface functionality.

Inositol phosphates (IPs) have important cellular functions from teleomere maintenance (IP7 and IP8) to Ca2+ signaling pathways (1, 4, 5-IP3). Yet there is no robust, quantitative method to separate all the inositol phosphate isomers from IP1 to IP8. Four findings contributed heavily towards the development of a robust, quantitative IP isomer separation and identification method on the EskpertTM MicroLC 200+ QTrap 6500 system with a SelexIonTM DMS attachment. 1) TCA from inositol phosphate algal extractions was removed by elution with 100 mM ammonium carbonate, ammonium formate, or ammonium bicarbonate or by immobilized metal affinity chromatography (Fe-NTA columns). 2) A 250 mM ammonium carbonate and 25% methanol gradient was run on a weak anion exchange column to separate all the inositol phosphates from each other (IP1 through IP8. 3) Using ten different inositol phosphate isomer standards and fluoro- IP3 as an internal standard for future quantitation and recovery studies, isomer separation was obtained using SelexIonTM DMS with a 2- propanol modifier. 4) Ion suppression of inositol phosphate signals caused by 250 mM ammonium carbonate can be alleviated with a post-column dilution. The final assembled EskpertTM MicroLC 200+ QTrap 6500 system with a SelexIonTM DMS attachment and post-column dilution method was able to separate out IP isomers from IP1 to IP6 and detect IP7 and IP8. Once further optimized using the full compensation voltage range and a more polar modifier such as methanol, this method will allow the lipid biosynthesis pathways of C. reinhardtii, a promising candidate for algal biofuels, to be better studied.

I denna uppsats undersöker vi Game/Media Jam, Hackathon och liknande koncept och försökerskapa en metod för att ta fram en modell för deras topologi. Vi ämnar att undersöka degemensamma punkterna Jams och Hackathons har via deras regler, samt jämföra detta med JamSessions. Vidare kommer vi försöka identifiera reglernas syften. Dessa syften sätter vi i entopologiskt mätbar intervall som sedan kan överföras på den topologisk modellen. Sedan användsdessa resultat för att jämföra regelrätta Jams/Hackathons, närliggande koncept och arrangemangsom endast har vissa gemensamma punkter med Jams, för att se om modellen kan påvisa om ettarrangemang har en känsla av Jam utan att faktiskt vara det. / In this thesis we will study Game/Media-Jams, Hackathons and similar concepts and try to establisha method to create a model for their topology. We intend to investigate what these concepts have incommon through their rules and compare that to Jam Sessions. Following this we will try to extractthe purpose of the rules. These purposes will then be put in topologically measurable intervals thatcan be transfered onto the topological model. The results will then be used to compareJams/Hackathons, similar concepts and events that only have a few things in common with Jams, tosee if the model can determine if an event is in the spirit of a Jam without actually being one.

In this thesis, I have developed a new methodology for the accurate determination of mass-dependent variations in nickel (Ni) isotope compositions. Nickel is initially separated in a three-column ion-exchange procedure, and the purified solutions are analysed by multi-collector inductively coupled plasma mass spectrometry (MCICPMS) using a double-spike technique. Using this methodology, I have measured the first Ni isotope ratios for a wide variety of natural geological samples. Significant Ni isotope variations were observed, with an overall spread in delta 60Ni-values of -0.9 to 2.5 permil. In igneous rocks Ni isotopes appear to be largely homogeneous, with only small variations (0.2 permil) between different rock types. Weathering of silicate rocks does on the other hand appear to cause significant fractionation of Ni isotopes, probably producing an isotopically heavy riverine input to the ocean. A heavy isotope signature is also visible in hydrogenetic ferromanganese crusts, with surface scrapings from globally distributed crusts show an average delta 60Ni-value of 1.65 permil. However, the variation in these samples is over 1.5 permil, likely reflecting local sources or biological processes, or alternatively indicating a heterogeneous Ni isotopic composition of the ocean. Organic-rich sediments also show heavy isotopic compositions, which are possibly transferred to the crude oils originating in these types of sediments. The only significant reservoir of light Ni isotopes found during this project are sulphides from magmatic systems. Overall, this thesis demonstrates the potential of this system as a powerful new tracer for a variety of geochemical processes.

Trimethylamine-n-oxide (TMAO) is a metabolite found in plasma/serum in humans. Elevated levels of TMAO have been associated with several types of heart disease. It’s therefore of interest to make a simple analytical method to analyse TMAO and other metabolites that are degraded to TMAO, including betaine. In this study, the goal was to develop a method for the sample preparation and analysis of these compounds in human plasma. Sample preparation was performed with an Ostro 96-well method for sample clean-up. The analysis was performed by ultraperformance liquid chromatography – hydrophilic interaction liquid chromatography – tandem masspectrometry (UPLC-HILIC-MS/MS) in multiple reaction monitoring (MRM)-mode using electrospray ionization in positive mode (ESI+)-mode as the ion source. The analytes eluted under five minutes and were all baseline separated in the chromatogram. TMAO and betaine were quantified in quality control (QC) plasma samples using external calibration. Concentration of TMAO ranged from 132 ng/mL – 253 ng/mL and 1025-2084 ng/mL for betaine. Due to the lack of isotopically labelled standards for TMAO and betaine, valine-d8 was tested as an internal standard for the extraction; however, it was not a suitable option due to the low recovery obtained (5-34%) and the low response in ESI+. The recovery needs to be investigated further using isotopically labelled TMAO or betaine. Overall, the developed UPLC-HILIC-MS/MS method was found to be suitable for analysis of TMAO and betaine in human plasma. Further development and validation is required before application to samples from clinical studies.

This thesis describes the development of liquid chromatography tandem mass spectrometry (LC-MS/MS) methods for the trace analysis of active pharmaceutical ingredients (APIs) and their metabolites in aqueous environmental matrices. The research was focused on the development of chiral LC-MS/MS methods for the analysis of fluoxetine and metoprolol, as well as their chiral metabolites in environmental water samples. A method was also developed for the achiral compounds, diazepam and nordiazepam. The LC-MS/MS methods were validated by the use of the isotope-labeled compounds. As these isotope-labeled compounds were not found in the wastewater samples, the validation could be assessed at trace level concentrations in the actual matrices in which the analytes were detected. The analytes were extracted from the water samples using solid phase extraction methods. Different types of solid phase extraction sorbents were evaluated. Fluoxetine and norfluoxetine were extracted through the use of a mixed mode polymeric based extraction sorbent. A hydrophilic and lipophilic balanced sorbent was employed for the simultaneous extraction of metoprolol and its metabolites, the base α-hydroxymetoprolol and the acidic metabolite deaminated metoprolol. Moreover, silica based C18 extraction discs were applied for the sample preparation of diazepam and nordiazepam. The chromatographic separations were conducted in reversed phase LC with MS compatible mobile phases. The enantiomers of fluoxetine and norfluoxetine were simultaneously separated using the chiral stationary phase (CSP), α1-acid glycoprotein (AGP). The Chiral AGP column was also applied for the separation of the enantiomers of deaminated metoprolol. For the simultaneous separation of the metoprolol enantiomers and the four stereoisomers of α-hydroxymetoprolol, the cellobiohydrolase (CBH) protein based CSP was used. An octadecyl silica based LC column was applied for the separation of diazepam and nordiazepam. The analytes were detected by the use of tandem quadrupole mass spectrometry operating in selective reactive monitoring mode. High resolution MS, employing a quadrupole time-of-flight (QqTOF) mass analyzer, was utilized for the identification of an unknown compound in wastewater samples. The APIs and their metabolites, as well as their respective enantiomers, were quantified in raw and treated wastewater from Uppsala, Sweden along with surface water from the River Fyris in Uppsala.

Aerospace systems are complex systems with interacting disciplines and technologies. As a result, the Decision Makers (DMs) dealing with such problems are involved in balancing the multiple, potentially conflicting attributes/criteria, transforming a large amount of customer supplied guidelines into a solidly defined set of requirement definitions. A variety of existing decision making methods are available to deal with this type of decision problems. The selection of a most appropriate decision making method is of particular importance since inappropriate decision methods are likely causes of misleading engineering design decisions. The research presented in this dissertation proposes a knowledge-based Multi-criteria Interactive Decision-making Advisor and Synthesis process (MIDAS), which can facilitate the selection of the most appropriate decision making method and which provides insight to the user for fulfilling different preferences. Once the most appropriate method is selected for the given problem, the advisor is also able to aid the DM to reach the final decision by following the rigorous problem solving procedure of the selected method. The MIDAS can also provide guidance as to the requirements needed to be fulfilled by a potentially new method for cases where no suitable method is found. In many other domains, such as complex system operation, decisions are often made in an environment with continuously changing situations. In addition, the decisions are usually completed based on uncertain or incomplete information due to the data availability and the environmental variation. This fact exacerbates the complexity of the decision making process because it results in the difficulties in perfectly and deterministically reasoning about the effects of the decisions and thus make it hard in determining the further decisions. In order to make proper decision and increase the system’s effectiveness, an advanced decision strategy is needed to capture the system’s dynamic characteristics and environmental uncertainty. An autonomous decision making advisor is developed to perform the real-time decision making under uncertainty. The development of the advisor system aims to solve a resource allocation problem to redistribute the limited resources to different agents under various scenarios and try to maximize the total rewards obtained from the resource allocation actions.