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In this essay I examine whether the CIA operatives can be considered as legitimate practitioners of violence in a conflict situation, thus looking through a lens where terrorism is treated as an act of war. This paper does not purport to evaluate and review the legality of targeted killing as a mean of warfare or a tool for criminal enforcement but rather the CIA agent’s status from an international law perspective, specifically humanitarian law. I further examine the role of CIA operatives from a moral perspective. Using the framework set up by Just War Theory I examine whether a CIA operative is regarded as a combatant or a civilian from a moral standpoint.

<p>Mammoths (<em>Mammuthus</em>) have been studied extensively at the genetic level. However due to both taphonomic and technological limitations, only one of several late Pleistocene mammoth species, the woolly mammoth (<em>M. primigenius</em>), has been investigated. This limits our impression of mammoth population history to the the northern latitudes, just one of several environments in which mammoths lived and went extinct. It also obscures their evolutionary chronology, which prevents proper climatic and biogeographic contextualization of their history. Fortunately recent technological advances in high-throughput sequencing and targeted enrichment promise to expand Pleistocene faunal population phylogeography to non-permafrost, non-cave burial contexts. However the capacity and behavior of these combined technologies for characterizing ancient DNA is largely unexplored, preventing efficient and routine use for population-level studies. In this thesis I test and apply these technologies to remains of mammoth species from throughout North America. I first demonstrate their potential for poorly-preserved DNA, and then I evaluate their efficient application to large sample sets, as well as for capturing complete nuclear genomes. I then use these technologies to sequence dozens of mitochondrial genomes from Columbian (<em>M. columbi</em>)<em> </em>and other non-woolly mammoths, reconstructing their matrilineal phylogeography south of the ice. The revealed patterns not only imply a deep chronology for mammoth matrilineal diversity, but also that North American mammoth evolution was occurred via separate episodes of interbreeding between resident and invading populations, and between ecotypes. Overall the biological and methodological discoveries afforded by this body of work outline future research avenues on mammoth evolution, behavior, and extinction.</p> / Doctor of Philosophy (PhD)

Why are some memories easy to retrieve, while others are more difficult to access? Here, we tested whether we could bias memory replay, a process whereby newly learned information is reinforced by reinstating the neuronal patterns of activation that were present during learning, towards particular memory traces. The goal of this biasing is to strengthen some memory traces, making them more easily retrieved. To test this, participants were scanned during interleaved periods of encoding and rest. Throughout the encoding runs, participants learned triplets of images that were paired with semantically related sound cues. During two of the three rest periods, novel, irrelevant sounds were played. During one critical rest period, however, the sound cues learned in the preceding encoding period were played in an effort to preferentially increase reactivation of the associated visual images, a manipulation known as targeted memory reactivation. Representational similarity analyses were used to compare multi-voxel patterns of hippocampal activation across encoding and rest periods. Our index of reactivation was selectively enhanced for memory traces that were targeted for preferential reactivation during offline rest, both compared to information that was not targeted for preferential reactivation and compared to a baseline rest period. Importantly, this neural effect of targeted reactivation was related to the difference in delayed order memory for information that was cued versus uncued, suggesting that preferential replay may be a mechanism by which specific memory traces can be selectively strengthened for enhanced subsequent memory retrieval. We also found partial evidence of discrimination of unique temporal sequences within the hippocampus. Over time, multi-voxel patterns associated with a given triplet sequence became more dissimilar to the patterns associated with the other sequences. Furthermore, this neural marker of sequence preservation was correlated with the difference in delayed order memory for cued versus uncued triplets, signifying that the ability to reactivate particular temporal sequences within the hippocampus may be related to enhanced temporal order memory for the cued information. Taken together, these findings support the claim that awake replay can be biased towards preferential reactivation of particular memory traces and also suggest that this preferential reactivation, as well as representations of reactivated temporal sequences, can be detected within patterns of hippocampal activation. / Psychology

Myocardial infarction (MI) is a leading cause of death in the United States, claiming the lives of approximately 500,000 people each year. The infarcted heart undergoes a compensatory process called cardiac remodeling, which adversely changes left ventricular (LV) size and function and eventually may lead to heart failure. To date, the only clinical treatments for this condition include surgical restoration of blood flow to the ischemic region (e.g., angioplasty), or pharmacological treatments (e.g., angiotensin converting enzyme inhibitors) which indirectly manage the symptoms of cardiac remodeling. Reperfusion of ischemic heart tissue significantly limits myocardial damage after an MI; however, many MI patients are not candidates for traditional reperfusion surgery. Recently, there has been much interest in non-surgical myocardial reperfusion via pro-angiogenic compounds, specifically vascular endothelial growth factor (VEGF). Although animal studies using therapeutic VEGF have shown promising results, these results have failed to translate into successful clinical trials. This may be due to the short half-life of VEGF in circulation. Increasing the dose of VEGF may increase its availability to the target tissue, but harmful side-effects remain a concert. Encapsulating VEGF and selectively targeting it to the MI border zone may improve vascularization, cardiac function, reduce adverse remodeling associated with MI, and may avoid harmful side effects associated with systemic delivery. Anti-P-selectin conjugated immunoliposomes containing VEGF were developed to target the P-selectin ligand overexpressed in the infarct border zone in a rat MI model. Serial echocardiography and Doppler imaging were used to characterize evolutionary changes in LV geometry and function over a period of four weeks after MI. At four weeks, hearts were excised and stained to measure vascularization and collagen deposition. Targeted VEGF treatment resulted in significant improvements in fractional shortening at four weeks post-infarction (32.9 ± 2.2% for targeted VEGF treated vs. 16.9 ± 1.4% for untreated MI). Functional improvements in treated MI hearts were accompanied by a 74% increase in perfused vessels in the MI border zone, compared to untreated MI hearts. Left ventricular filling dynamics were significantly improved in the targeted VEGF treated group, which resulted in a decrease in LV end diastolic pressure in VEGF treated hearts (23.4 ± 2.9 mm Hg), compared to untreated MIs (81.8 ± 31.8 mm Hg). At four weeks after infarction, hearts treated with targeted VEGF therapy exhibited a 37% reduction in collagen deposition, compared to untreated MI hearts. Targeted VEGF therapy significantly improves vascularization, cardiac function, and moderates adverse cardiac remodeling after an infarction. / Mechanical Engineering

Traumatic brain injury, hereon referred to as TBI, can be simply defined as a disruption to normal brain function as a result of an outside force to the head. TBI contributes to one third of all injury related deaths in the United States, and treatment strategies for TBI are supportive. Although primary and secondary mechanisms of injury have been clearly identified, the heterogeneous and intertwined pathophysiology of TBI is not fully understood. Primary injury results from the impact itself and causes immediate damage. However, secondary mechanisms of injury in TBI, such as oxidative stress and inflammation, are points at which intervention may reduce neuropathology. Trials taking advantage of the antioxidant and anti-inflammatory properties of several agents have had little clinical success, while the use of targeted therapeutics in TBI is relatively unexplored. Evidence suggests that reactive oxygen species (ROS) propagate blood-brain barrier (BBB) hyperpermeability and exacerbate inflammation following TBI. In the studies presented herein, we tested the hypothesis that targeted detoxification of ROS may improve the pathological outcomes using the controlled cortical impact mouse model of TBI. Following TBI, endothelial activation results in a time dependent increase in vascular expression of ICAM-1, an endothelial activation and cell adhesion molecule, as was observed by immunohistochemistry and immunofluorescence staining of isolated cortical microvessels. We conjugated catalase, an antioxidant enzyme, to anti-ICAM-1 antibodies and administered the conjugate intravenously to 8-week-old C57BL/6J mice at 30 minutes after moderate controlled cortical impact TBI. Results indicate that catalase targeted to ICAM-1 reduces markers of oxidative stress including levels of hydrogen peroxide and 3-nitrotyrosine detected in the cortex ipsilateral to the area of injury. Anti-ICAM-1/catalase also preserved BBB permeability based on two assays of barrier permeability to the plasma protein fibrinogen and small fluorescent tracer sodium fluorescein. Following TBI, mice receiving the conjugate exhibited attenuated neuropathological indices for astrocyte and microglia activation as well as cortical neuronal loss compared to controls. For each of these endpoints, anti-ICAM-1/catalase was found to be more effective than anti-ICAM-1 antibodies or catalase administered alone. An extensive study of microglia by two-photon microscopy of ex vivo brain segments from CX3CR1-GFP mice revealed that anti-ICAM-1/catalase prevented the transition of microglia to an activated phenotype after TBI. Finally, anti-ICAM-1/catalase offered functional improvement in Rotarod and elevated zero maze performance compared to controls at acute and chronic time points, respectively. Collectively, these findings demonstrate the use of a targeted antioxidant enzyme to interfere with oxidative stress mechanisms acutely in TBI. The results demonstrate histological and functional benefit of anti-ICAM-1/catalase administration and provide a proof-of-concept approach to improve acute TBI management that may also be applicable to other neuroinflammatory conditions. / Biomedical Sciences

Carbonic anhydrases (CAs, EC 4.2.1.1) are a class of metalloenzymes that catalyze the hydration of CO2 under physiologic conditions and are involved in many physiological and pathological processes. Modulation of CA activity, particularly CA inhibition is exploited pharmacologically for the treatment of many diseases such as cancer, glaucoma, edemas, mountain sickness. CA activation has been less frequently investigated till recently. Genetic deficiencies of several CA isozymes are reported in the literature and reflect the important role of carbonic anhydrases in human physiology and homeostasis. Activation of CA isozymes in brain have been correlated recently with spatial learning and memory. Based on these premises, activators of CA isozymes have the potential to alleviate mild dementias and to act as potential nootropic agents. In chapter 3, continuing our long-term interests towards the development of potent and selective CAAs, we carried out X-ray crystallographic studies with a small series of pyridinium histamine derivatives, previously developed as CAAs by our group. This study revealed important insights into the binding of this class of activators into the active site of CA II isozyme. A potent pyridinium histamine CAA 25i was successfully crystallized with CA II isozyme and was found to bind into the hydrophobic region of the active site, with two binding conformations being observed. This is one of the very few X-ray crystal structures of a CAA available. Based on the findings of this X-ray crystallographic study and building on our previously developed ethylene bis-imidazole CAAs, we advanced a novel series of lipophilic bis-imidazoles. Enzymatic assays carried out on purified human CA isozymes revealed several low nanomolar potent activators against various brain-relevant CA isozymes. Bis-imidazole 30e was found to be a nanomolar potent activator for CA IV, CA VA and CA IX. Due to their conjugated structure, these CAAs were also fluorescent and therefore were fully characterized in terms of photophysical properties, with several representatives proving to display very good fluorophores. The very good activation profile against several different CA isozymes, along with excellent fluorescence properties recommend these compounds as great molecular tools for elucidation of role of CA isozymes in brain physiology, as well as towards improvement of memory and learning. Focusing on inhibition of CA isozymes, it must be stressed that over the last decade a clear connection had been established between the expression of CA IX and CA XII and cancer. Since cancer is the second most common cause of death in the world, we explored the possibility to kill cancer cells via inhibition of different CA isozymes present in cancer cells. The membrane bound carbonic anhydrase IX (CA IX) isozyme represents a particularly interesting anticancer target as it is significantly overexpressed in many solid tumors as compared to normal tissues. In malign tissues this CA isozyme was found to play important role in pH homeostasis and promotes tumor cell survival, progression and metastasis. Thus, CA IX represents a potential biomarker and an appealing therapeutic target for the detection and treatment of cancer. CA IX can be targeted either through the development of small or large molecular weight, potent, and selective inhibitors or through the development of CA IX targeted drug delivery systems for selective delivery of potent chemotherapeutic agents. Building on these premises, in this dissertation, we also revealed our continuing efforts towards the development of potent and selective CA IX inhibitors along with their translation into the development of CA IX targeted drug delivery systems. In chapter 4, we designed a series of small molecular weight (MW) ureido 1,3,4-thiadiazole sulfonamide derivatives employing the “tail approach”, through the decoration of established sulfonamide CA inhibitor warheads with different tail moieties via ureido linker. The generated CAIs were tested against tumor associated CA IX and CA XII isozymes and off-target cytosolic isozymes CA I and CA II, and were revealed to be moderate to highly selective and nanomolar, even sub-nanomolar, potent CA IX inhibitors. Several potent pan-inhibitors were also identified in this section. We assessed these CAIs for their in vitro cell killing ability using MDA-MB 231 breast cancer cell line expressing CA IX and CA XII. The most efficient CAI proved to be ureido-1,3,4-thiadiazole-2-sulfonamide 69, which showed subnanomolar potency against purified human CA IX and CA XII isozymes, with good selectivity against CA I and CA II, and consistent, statistically significant cancer cell killing. In Chapter 5, continuing our efforts towards the development of potent and selective CA IX inhibitors, we designed, synthesized, characterized and evaluated a new series of PEGylated 1,3,4-thiadiazole-2-sulfonamide CAIs, bearing different PEG backbone length. We increased the PEG size from 1K to 20K, in order to better understand the impact of the PEG linker length on the in vitro cell killing ability against CA IX expressing cancer cell lines and also against a CA IX negative cell line. In vitro cell viability assays revealed the optimum PEG linker length for this type of bifunctional bis-sulfonamide CAIs in killing the tumor cells. The most efficient PEGylated CAI was found to bis-sulfonamide DTP1K 91, which showed consistent and significant cancer cell killing at concentrations of 10−100 μM across different CA IX and CA XII expressing cancer cell lines. DTP1K 91 did not affect the cell viability of CA IX negative NCI-H23 tumor cells, thus revealing a CA IX mediated cell killing for these inhibitors. In chapter 6, we decided to further explore the possibility of using CA IX as a targeting epitome for the development of a gold nanoparticle-based drug delivery system. We translated the oligoEG- and PEGylated CAI conjugates into efficient targeting ligands for gold nanoparticle decoration along with chemotherapeutic agent doxorubicin (Dox), in a novel multi-ligand gold nanoplatform designed to selectively release the drug intracellularly, in order to enhance the selective tumor drug uptake and tumor killing. We were successful in developing compatible CAI- and Dox- ligands for efficient dual functionalization of gold nanoparticles. Our optimized, CA IX targeted gold nanoplatform was found to be very efficient towards killing HT-29 tumor cells especially under hypoxic conditions, reducing the hypoxia-induced chemoresistance, thus confirmed the potentiating role of CA IX as a targeting epitome. / Pharmaceutical Sciences

This bachelor thesis highlights how queer women of color perceive their racial, gender and sexual identity in targeted areas in Sweden. This is achieved from a constructivist lens using a case studies design in qualitative research. By using Intersectional theory, exploring the connection between race, gender, queerness and class and the unique experience this creates. Six different queer women of color from targeted areas were interviewed and the results showcased exclusion in both targeted areas as well as general Swedish society because of their collective, unique experiences of inhabiting marginalized intersectional identities. Furthermore, the results are discussed as a consequence of oversexualizing black women’s bodies, a systemic creation of an excluding divide in Swedish society and the lack of belongingness for queer people of color.

京都大学 / 新制・課程博士 / 博士(薬科学) / 甲第24549号 / 薬科博第166号 / 新制||薬科||18(附属図書館) / 京都大学大学院薬学研究科薬科学専攻 / (主査)教授 髙倉 喜信, 教授 山下 富義, 教授 小野 正博 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

Research and analysis regarding the employment outcomes of vocational education completers are growing in importance. States and their educational systems are increasingly confronted with the need to justify programs and funding and to provide evidence of the numbers and status of students graduated, obtaining employment, and continuing in postseconday education. The need to review, improve, and implement effective programs, and to serve the practical needs of all students, including those in targeted populations, will continue in the future. The purposes of this study were to investigate and describe Virginia's vocational program completers by employment status, earnings, and job satisfaction through a review of three years of follow-up data. Descriptive statistics, including frequencies, percentages, and overall distributions, were used to identify characteristics of 9,474 employed vocational completers, in order to provide relevant data for improving vocational education in Virginia and for use in establishing baseline data for future studies. In looking at employment outcomes for targeted populations, this study found that employment figures resembled those of non-targeted populations, with high percentages reporting employment related to the service area completed. Vocational completers identified as having limited English proficiency were reported in very small numbers. Earnings data indicated clearly that with each consecutive year of the three years for which data were included, vocational completers were earning higher wages. Earnings also increased with each consecutive year for completers from targeted populations, with vocational completers who were academically disadvantaged or disabled receiving higher wages than completers from economically disadvantaged backgrounds. Completers from economically disadvantaged backgrounds also reported lower levels of job satisfaction and more part-time employment. Additionally, vocational completers in all service areas reported high levels of job satisfaction. Further longitudinal research should be conducted in order to better analyze vocational completers' transition to the workforce. Such research could be useful when planning and implementing policy, requesting grant funding, and instituting educational innovations. / Ph. D.