周囲プラズマベースの周囲脱離/イオン化ソースにより、従来の大気圧イオン化では不可能な周囲条件下でのサンプルの直接分析が可能になります。これにより、面倒な準備と、多くの有害で複雑なサンプルの分析用質量分析計への導入が解消されます。既存のプラズマベースのアンビエント脱離/イオン化ソースは、通常、2つの電極間にキロヘルツから数メガヘルツの範囲の周波数で直流（DC）または交流（AC）電圧を印加することによって形成されます。この研究では、新しいプラズマベースの周囲脱離/イオン化は、13.56 MHz RFソースから供給される非常に低い電力密度で動作する誘導結合によって生成されたワイヤ安定化大気圧プラズマで構成されています。ワイヤ安定化大気圧プラズマの点火特性、安定性およびプラズマ特性を研究した。 / Ambient plasma-based ambient desorption/ionization source enables direct analysis of samples under ambient conditions that traditional atmospheric pressure ionization is incapable. It overcomes the tedious preprocessing and often detrimental and complicated sample introduction to the mass spectrometer for analysis. Existing plasma-based ambient desorption/ionization sources feature an electrical discharge typically formed between two electrodes by applying either a direct-current (DC) voltage or an alternating-current (AC) voltage with frequencies ranging from kilohertz to several megahertz. In this study, a novel plasma-based ambient desorption/ionization consists of a wire stabilized atmospheric pressure plasma produced by inductive coupling operated at very low power density supplied by a 13.56 MHz RF source. The ignition characteristics, stability and plasma properties of the wire stabilized atmospheric pressure plasma were studied. / 博士(工学) / Doctor of Philosophy in Engineering / 同志社大学 / Doshisha University

No description available.

The inductively coupled plasma mass spectrometer (ICP-MS) has been used in laboratories for many years. The majority of the improvements to the instrument have been done empirically through trial and error. A few fluid models have been made, which have given a general description of the flow through the mass spectrometer interface. However, due to long mean free path effects and other factors, it is very difficult to simulate the flow details well enough to predict how changing the interface design will change the formation of the ion beam. Towards this end, Spencer et al. developed FENIX, a direct simulation Monte Carlo algorithm capable of modeling this transitional flow through the mass spectrometer interface, the transitional flow from disorganized plasma to focused ion beam. Their previous work describes how FENIX simulates the neutral ion flow. While understanding the argon flow is essential to understanding the ICP-MS, the true goal is to improve its analyte detection capabilities. In this work, we develop a model for adding analyte to FENIX and compare it to previously collected experimental data. We also calculate how much ambipolar fields, plasma sheaths, and electron-ion recombination affect the ion beam formation. We find that behind the sampling interface there is no evidence of turbulent mixing. The behavior of the analyte seems to be described simply by convection and diffusion. Also, ambipolar field effects are small and do not significantly affect ion beam formation between the sampler and skimmer cones. We also find that the plasma sheath that forms around the sampling cone does not significantly affect the analyte flow downstream from the skimmer. However, it does thermally insulate the electrons from the sampling cone, which reduces ion-electron recombination. We also develop a model for electron-ion recombination. By comparing it to experimental data, we find that significant amounts of electron-ion recombination occurs just downstream from the sampling interface.

A Direct Simulation Monte Carlo fluid dynamics code named FENIX has been employed to study gas flow-through properties of the inductively coupled plasma mass spectrometer (ICP-MS). Simulation data have been tested against the Navier-Stokes and heat equations in order to see if FENIX functions properly. The Navier-Stokes and heat equations have been constructed from simulation data and are compared term by term. This comparison shows that FENIX is able to correctly reproduce fluid dynamics throughout the ICP-MS simulation, with an exception immediately behind the ICP-MS sampler cone, where the continuum criterion for the Navier-Stokes equation is not met. Testing the data produced by Fenix also shows that this DSMC method correctly produces momentum and thermal boundary layer phenomenon as well. FENIX output data produce statistical fluctuations of about 2%. Limitations occur from fitting data near surfaces, incurring a relative error of about 5%, and fitting data to take second derivatives where fluid velocity gradients are steep, introducing a relative error of about 10%.

<p>  </p> <p>Vector-borne diseases (VBDs) represent a significant health burden worldwide, threatening approximately 80% of the global population. Insecticide-based vector control is the most effective method to manage many VBDs, but its efficacy has been declining due to high levels of resistance in vector populations to the main insecticide classes which operate via limited modes of action. Therefore, the discovery of new chemistries from non-conventional chemical classes and with novel modes of action is a priority for the control of vectors and VBDs. Natural products (NPs) are diverse in chemical structures and, potentially, modes of action. They have been used as insecticides for many decades and have inspired the development of multiple synthetic insecticides, suggesting the discovery of novel NPs could lead to the development of highly effective insecticides. </p> <p><br></p> <p>In this thesis, I report two studies with a main goal to identify novel mosquito-active insecticide leads that operate via modes of action distinct from existing insecticides. First, I tested the hypothesis that new mosquito-active insecticide leads with novel chemical structures, possibly operating via novel modes of action, can be identified by high-content larval phenotypic screening against a natural product collection and using novel phenotypic endpoints in addition to mortality endpoints. Here, I performed a high-content larval phenotypic screen using first instar (L1) larvae of <em>Aedes aegypti</em> (Linnaeus, 1762) against 3,680 compounds from the AnalytiCon MEGx Natural Product Libraries and a screening platform developed by Murgia et al., (2022). Compounds were screened in a 384-well plate format using the Perkin Elmer Opera Phenix and larvae were scored for lethal and novel phenotypic endpoints. Screening revealed five chemistries that caused larval mortality, including rotenone and a new NP chemistry, NP-4. The identification of rotenone confirmed the ability of the screen to detect mosquito-active NP chemistries. NP-4 caused high levels of larval mortality in the screen, and toxicity was confirmed in a subsequent concentration-response assay against third instar (L3) larvae of <em>Ae. aegypti</em>. 140 chemistries that caused atypical larval phenotypes, including cuticular pigmentation and morphometric changes relative to negative controls, were also identified by the screen. Some of these chemistries may operate by disruption of pathways regulating melanization, growth and development, and novel targets in the insect nervous systems, thus representing potential leads for further insecticide toxicity and mode of action studies. To facilitate quantitative analyses of atypical phenotypes, an attempt was made to assess the morphometrics of the thorax in larvae exposed to test chemistry, relative to control larvae. However, assessment was limited by the number of larvae images of suitable quality for measurements. </p> <p><br></p> <p>In the second study, I tested the hypothesis that metergoline (Murgia et al., 2022) and NP-4 (this study), two chemistries identified by the HTP phenotypic screen described in this project, operate via disruption of targets in the insect nervous systems that are distinct from the current insecticidal modes of products used in mosquito control programs. Specifically, I explored the hypothesis that metergoline operates via one or more insect orthologs of the mammalian G protein-coupled serotonin and dopamine receptors. An electrophysiology study was performed using the suction electrode technique and ganglia of the German cockroach, <em>Blattella germanica </em>(Linnaeus, 1767). To facilitate the investigation of metergoline agonism/antagonism and disruption of invertebrate GPCR signaling, 5-hydroxytryptamine (5-HT; serotonin) was included as a chemical probe. Electrophysiological recordings showed 5-HT (10µM and 1mM) and metergoline (10µM) caused no significant neurological activity at the tested concentrations in comparison to the saline control. However, a consistent neuro-inhibitory trend was observed, suggesting possible agonism of a 5-HT1-like receptor ortholog and antagonism of a putative 5-HT7-like receptor ortholog in the cockroach, respectively.  NP-4 caused significant neuro-inhibition at the tested concentration of 20µM, in comparison to the negative saline control. Given the demonstration of rapid contact toxicity to <em>Ae. aegypti</em> larvae and neurological inhibition in <em>B. germanica</em>, we propose NP-4 may act at one or more conserved targets in the insect nervous systems, which remain to be elucidated. </p> <p><br></p> <p>The significance of the present study is three-fold. First, this study reports the first high-content phenotypic screen of mosquito larvae against a NP collection and identification of 145 mosquito-active chemistries associated with lethal and phenotypic endpoints. These data confirm that the screening platform provided an innovative and effective system to rapidly identify mosquito-active small molecules with potential novel modes of action. Second, metergoline and NP-4 represent potential novel chemical leads for the development of new insecticides that can be incorporated into vector control programs targeting insecticide-resistant populations. Lastly, the study describes the first electrophysiology study of 5-HT, metergoline, and NP-4 via the suction electrode technique in an insect system and contributes new knowledge to the study of the insect serotonergic system, which represents an expanding area of vector biology research given its roles in feeding regulation.  </p> <p><br></p> <p>Future studies resulting from this thesis might include: (1) development of a set of morphometric criteria for quantitative analyses of atypical larval phenotypes, (2) incorporation of new phenotypic endpoints to expand the capacity of the screen to identify novel mode of action chemistries for insecticide discovery, and (3) identification of chemistry candidates suitable for further development from the 140 chemistries associated with atypical larval phenotypes in the primary screen using chemo-informatic and toxicological studies. In addition, studies using reverse transcription-polymerase chain reaction (RT-PCR), cell-based expression systems, mutant/insecticide resistant strains, and patch clamp electrophysiology could be pursued to further investigate the molecular mode of action of metergoline and NP-4, and potential for vector control.</p>

[pt] Testes de formação são normalmente realizados para determinar as propriedades rochosas do reservatório e os dados obtidos costumam ser interpretados com base no pressuposto que o reservatório é homogêneo na direção vertical e descrito por um modelo uni dimensional. No entanto, muitos reservatórios são compostos por diversas camadas que possuem características diferentes. Os poços de produção nesses reservatórios podem receber óleo de mais de uma camada. Em um sistema de reservatório estratificado, o comportamento da pressão e da temperatura não é necessariamente o mesmo de um sistema em camada única e raramente revela as mesmas propriedades médias de todo o sistema. Prever as características das camadas individuais é importante para descrever adequadamente o reservatório e melhorar o gerenciamento da produção. Este trabalho apresenta um modelo numérico, transiente-térmico para um sistema acoplado poço - reservatório 2D, levando-se em consideração efeitos Joule-Thompson responsáveis pelo aquecimento / resfriamento do fluido, expansão/compressão adiabática, além de efeitos de condução e convecção para o poço e o reservatório em um escoamento monofásico. A análise bidimensional do reservatório permite que se simule zonas de estratificação e barreiras. O modelo permite fluxo através de camadas adjascentes com propriedades de rocha diferentes. Pressão e temperatura a uma certa posição no poço produtor são avaliadas ao longo do tempo. Resultados mostram que a análise do transiente de pressão (PTA) e a análise do transiente de temperatura (TTA) podem ser utilizadas para caracterizar diferentes configurações de um reservatório estratificado. / [en] Well formation tests are usually performed to determine rock properties of a reservoir and the obtained data has often been interpreted based on an assumption that the reservoir is homogeneous in the vertical direction and described by a 1-D model. However, many reservoirs are found to be composed of different number of layers that have different characteristics. Production wells in such reservoirs may receive oil from more than one layer. In stratified reservoir system, the pressure and temperature behavior are not necessarily the same as in single layered system, and rarely reveals the same average properties of the entire system. The prediction of the characteristics of the individual layers is important to describe properly the reservoir and improve production management. This work presents a numerical transient-thermal model for a coupled wellbore/2D-reservoir considering Joule-Thompson heating/cooling, adiabatic fluid expansion/compression, conduction and convection effects for both wellbore and reservoir for a single-phase fluid flow. The two-dimensional reservoir model allows the analysis of stratified zones and barriers. The model allows cross flow between the adjacent layers with different rock properties.Wellbore temperature and pressure at a certain gauge depth are evaluated along the time. Results show how pressure transient analysis (PTA) and temperature transient analysis (TTA) can be used to characterize different configuration of stratified reservoirs.

[pt] A caracterização de reservatórios é uma ferramenta importante para a gestão da produção do mesmo. Testes de poços são comumente usados para caracterizar reservatórios, pois são as únicas fontes de dados dinâmicos durante a etapa de exploração. Esses testes medem as respostas de pressão e temperatura nos poços, dadas condições controladas de produção, injeção ou estática. Geralmente, apenas os dados de pressão são pós-processados para caracterizar o reservatório. Entretanto considerar apenas os dados de pressão podem levar a interpretações errôneas devido ao negligenciamento dos efeitos térmicos, causando erros na estimativa de propriedades do reservatório e, consequentemente, um gerenciamento ineficiente do mesmo. Além disso, os dados de pressão possuem diversas fontes de ruído que podem comprometer a precisão dos resultados dos testes. Trabalhos recentes mostram que o uso de dados de temperatura podem melhorar a estimativa de parâmetros do reservatório. Neste trabalho, o método ensemble smoother with multiple data assimilation (ES-MDA) foi aplicado em casos sintéticos criados por um simulador não-isotérmico de fluxo no reservatório-poço que considera o aquecimento de Joule-Thomson e efeitos de resfriamento, expansão / compressão de fluido adiabático, condução e convecção na equação de balanço de energia. Os dados sintéticos medidos foram obtidos adicionandose ruídos gaussianos e harmônicos aos sinais calculados para simular ruídos nas medições e efeitos de maré, respectivamente. Foi realizada uma análise de sensibilidade da matriz CD do método ES-MDA utilizada na atualização dos parâmetros a serem estimados. Os resultados mostram que o acoplamento dos dados de temperatura aos dados de pressão no ajuste de histórico promoveu uma melhora nas estimativas dos parâmetros do reservatório, principalmente para a região de dano e a porosidade do reservatório. Para as análises, nas quais os dados de pressão tiveram a inclusão de ruído harmônico, a adição de dados de temperatura também se mostrou de grande importância para a caracterização precisa do reservatório. / [en] Reservoir characterization is an important tool for production/reservoir management. Well tests are commonly used in reservoir characterization and are the only source of dynamic data during the exploration period. These tests typically measure the pressure, rate and temperature responses at a well during controlled production, injection, or static conditions. Generally, only pressure data is post-processed in reservoir characterization. However, considering only pressure data can lead to misinterpretation associated with the neglected thermal effects, causing errors in reservoir properties estimation and consequently inefficient reservoir management. Besides that, pressure data have several noise sources that may compromise the accuracy of test results. Recent results have shown that temperature data can be used to improve reservoir parameter estimation. In this work, the ensemble smoother with multiple data assimilation method (ES-MDA) was applied in synthetic cases created by an in-house non-isothermal reservoir-well flow simulator that considers the Joule-Thomson heating and cooling, adiabatic fluid expansion/compression, conduction, and convection effects in the thermal energy balance equation. The synthetic measured data was obtained by adding gaussian and harmonics noises to the numerical predictions to simulate equipment and tidal effects, respectively. A sensitivity analysis of the effect of the CD matrix used for updating parameters of the ES-MDA method on the parameters estimations was carried out. The results show that adding temperature data to the observed data in the history matching improves the estimates of the reservoir parameters, especially for the skin region and reservoir porosity. For the analyses in which the pressure data had the addition of harmonic noise, the inclusion of temperature data also proved to be of great importance for an accurate characterization of the reservoir.

As permanent tattoos are becoming more popular and common, an increased number of allergic reactions to tattoos is reported. The purpose of this project was to analyze tattoo inks for hazardous substances, and whether they comply to current Swedish and European legislative requirements. The tattoo inks were qualitatively analyzed for pigments, and quantitatively analyzed for metals. A total of 73 tattoo inks were collected from various sources such as a tattoo ink supplier, online retailers, and provided directly from tattoo artists. The labels of each tattoo ink bottle were inspected to investigate their compliance with the Council of Europe and the Swedish Medical Products Agency. Matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-ToF-MS) was used to qualitatively analyze 20 selected tattoo inks for different pigments. Inductively coupled plasma mass spectrometry (ICP-MS) was used to quantitatively analyze trace metals in 70 of the samples. A large majority (90%) of the tested samples violated the requirements and criteria in the European resolution ResAP 2008(1), such as information on name and address of the manufacturer, minimum date of durability, sterility, batch number, and storage. Patch and allergy testing were incorrectly recommended for many samples in a way that is not accepted by dermatologists. In a worst-case scenario, this testing could be a sensitizing step. Also, it can not prevent future allergic reactions from occurring or provide any juridical insurance. Only one brand, World Famous, fulfilled the requirements for labeling for six of the seven samples (one sample failed due to a faulty declared pigment). The brands Tang Dragon and Dynamic did not fulfill any of the requirements listed in ResAP 2008(1). The list of ingredients was incorrect for all samples from Tang Dragon (bought prior to 2019 online). Also, six of the other 50 samples from different brands (World Famous, Intenze, Fusion Tattoo Ink, Eternal Ink, Solid Ink) declared at least one pigment incorrectly in their ingredients list. 25% of the declared and theoretically detectable pigments were detected by means of MALDI-ToF-MS, whereas the other pigments were either absent or below the limit of detection. Future analyses should include an MS/MS analysis. Polyethylene glycol (PEG) was identified qualatively in 15 of the 20 samples analyzed with MALDI-ToF-MS but was not listed in any of the ingredients lists. ICP-QQQ-MS is a very sensitive technique and could both detect and verify the presence of all metal-containing pigments, as well as the level of impurities. Copper was clearly more present in green and blue colors, regardless of the brand. The metal content was evidently dependent on the brand for arsenic, aluminum, bismuth, chromium, nickel, zinc, and strontium. Elevated levels of barium and strontium (partially very high levels: up to 727 mg/kg barium and up to 8.06 g/kg strontium) were found in several samples. High amounts of aluminum (4 to 11,0 g/kg) and titanium (as judged from white precipitates and ingredients lists) were present in most samples. Nickel (0.1 to 41 mg/kg) and chromium (0.1 to 139 mg/kg) were also present in the samples. Some other impurities were also present (arsenic – 3.8 mg/kg, mercury – 1.6 mg/kg, and lead – 5.4 mg/kg for one sample, respectively). Known sensitizing pigments were declared and partially confirmed by MALDI-ToF-MS in 17 of 53 samples of the brands Radiant Colour, Eternal Ink, Fusion Tattoo Ink, and Kuro Sumi. Four samples (from Intenze, Eternal Ink, and Kuro Sumi) also declared pigments listed as non-suitable substance according to the European Commission regulation on cosmetic products from 2009.

A key consideration in seismic design of buildings is to ensure that the lateral load resisting system has an appropriate combination of strength, stiffness and energy dissipation capacity. Hybrid coupled wall systems, in which steel beams are used to couple two or more reinforced concrete shear walls in series, can be designed to have these attributes and therefore have the potential to deliver good performance under severe seismic loading. This research presents an investigation of the seismic behavior of this type of structural system. System response of 12- and 18-story high prototypes is studied using transient finite element analyses that accounts for the most important aspects of material nonlinear behavior including concrete cracking, tension stiffening, and compressive behavior for both confined and unconfined concrete as well as steel yielding. The developed finite element models are calibrated using more detailed models developed in previous research and are validated through numerous comparisons with test results of reinforced concrete walls and wall-beam subassemblages. Suites of transient inelastic analyses are conducted to investigate pertinent parameters including hazard level, earthquake record scaling, dynamic base shear magnification, interstory drift, shear distortion, coupling beam plastic rotation, and wall rotation. Different performance measures are proposed to judge and compare the behavior of the various systems. The analyses show that, in general, hybrid coupled walls are particularly well suited for use in regions of high seismic risk. The results of the dynamic analyses are used to judge the validity of and to refine a previously proposed design method based on the capacity design concept and the assumption of behavior dominated by the first vibration mode. The adequacy of design based on the pushover analysis procedure as promoted in FEMA-356 (2000) is also investigated using the dynamic analysis results. Substantial discrepancies between both methods are observed, especially in the case of the 18-story system. A critical assessment of dynamic base shear magnification is also conducted, and a new method for estimating its effects is suggested. The method is based on a modal combination procedure that accounts for presence of a plastic hinge at the wall base. Finally, the validity of limitations in FEMA-368 (2000) on building height, particularly for hybrid coupled wall systems, is discussed.

Non-Small Cell Lung Cancer (NSCLC), which accounts for 80% of all lung cancer cases, is associated with resistance to chemotherapy and poor prognosis. Exploitation of NSCLC-upregulated pathways that can either be targeted by novel therapeutics or used to improve the tumour-delivery of current chemotherapeutics are required. Among the matrix metalloproteinases (MMPs) that are essential for tumour development, MMP10 is a potential candidate as a therapeutic target based on its expression and contribution to NSCLC development. This research aims to explore the expression and functions of MMP10 in the tumour microenvironment of NSCLC and evaluate the potential of MMP10 as a target for therapeutic intervention. Herein, MMP10 expression at gene and protein levels were analysed in a panel of NSCLC cell lines using RT-PCR and Western blotting analysis. To determine MMP10 functional relevance, an in vitro angiogenesis assay using cell conditioned media was carried out. To identify specific peptide sequences for the design of prodrugs rationalised to be MMP10 activated, in vitro substrate cleavage studies were performed using a mass spectrometry approach to differentiate between MMP10 and the structurally similar MMP3. This study demonstrates that MMP10 is highly expressed in NSCLC and that high levels of MMP10 are associated with induction of angiogenesis, a crucial process supporting tumour growth. In addition to the achievement of having been able to differentiate between closely similar MMP3 and MMP10 through carefully monitoring the hydrolysis rate of compound 444259 (a known MMP substrate), data generated herein provides the basis for further studies to exploit MMP10 as a prodrug-activator. / Full text was made available at the end of the embargo period, 12th Dec 2019