As human populations rise exponentially, agricultural production systems must be adapted to sustain ecosystem function. Government administered agricultural conservation programs may actualize greater gains in ecosystem services, including wildlife population gains, if conservation practices designed to target specific environmental outcomes are implemented strategically in agricultural landscapes. I evaluated multi-scale, multi-species, and multi-season avian population responses to a targeted native herbaceous buffer practice (CP33: Habitat Buffers for Upland Birds) under the continuous sign-up Conservation Reserve Program administered by the U.S. Department of Agriculture. CP33 is the first conservation practice targeted directly to support habitat and population recovery objectives of a national wildlife conservation initiative (Northern Bobwhite Conservation Initiative). I coordinated breeding season, fall, and winter point transect surveys for northern bobwhite (Colinus virginianus), priority early-succession, and overwintering birds on ≈1,150 buffered and non-buffered fields in 14 states (10 ecoregions) from 2006-2009. I also assessed northern bobwhite-landscape associations within each ecoregion to determine effects of landscape structure on observed northern bobwhite abundances. Breeding season and autumn northern bobwhite densities were 60-74% and 52% greater, respectively, over all survey points in the near term (1-4 years post-establishment). However, breeding season and autumn response and associations between northern bobwhite abundance and landscape structure exhibited substantial regional variation, suggesting northern bobwhite conservation and management should be implemented on a regional basis. Breeding season densities of dickcissel (Spiza americana) and field sparrow (Spizella pusilla) were up to 190% greater on buffered fields, whereas overwintering densities of several Emberizid sparrow species were up to 2,707% greater on buffered fields. Species sensitive to patch area or those requiring vegetation structure different from that provided by buffers exhibited limited, but regionally and annually variable responses to buffered habitats. Increased bird densities of several species in several seasons suggest wildliferiendly farming practices delivered strategically and requiring minimal change in primary land use can benefit species across broad landscapes when conservation practices are targeted toward specific recovery objectives. Targeted conservation systems combining multiple conservation practices to provide an array of ecosystem services may be a mechanism for meeting multifarious conservation objectives and enhancing biodiversity in agricultural landscapes.

Background and Objectives: Economic evaluation and decision analysis provide a framework to evaluate incremental costs and effects associated with alternative health interventions. These methods can also be used as a tool to evaluate alternative clinical behaviours or practice patterns. The objective of this thesis was to investigate the impact of current Canadian practices in human epidermal growth factor receptor-2 (HER2) testing to target trastuzumab in early-stage breast cancer (BC). Methods: Project 1: A systematic review of previous trastuzumab and HER2 testing economic analyses was conducted to identify methodological gaps and key lessons. Project 2: A population-level, retrospective cohort was studied to determine HER2 testing and trastuzumab treatment patterns in Ontario early-stage BC patients. Project 3: A cost-utility analysis of alternative test-treat strategies was conducted using a Markov model of BC calibrated to the Canadian setting, and incorporating Project 2 findings. Results: Project 1: Previous economic evaluations demonstrated that HER2 test accuracy and sequencing were key considerations when modelling the cost-effectiveness of trastuzumab treatment. Consideration of local testing and treatment practices was lacking. Project 2: HER2 testing and treatment practice differed from guidelines, where documentation was available. Only 88% of equivocal results were confirmed, while 57% of HER2 positive patients received trastuzumab. Project 3: Calibration of the BC model minimised gaps between trial-based survival and expected Canadian survival patterns. Deviations from guidelines in practice suggest that primary testing with fluorescence in situ hybridization (FISH) would produce greater health gains at a reduced cost vs. primary immunohistochemistry with FISH confirmation. This finding was more apparent as the prevalence of HER2 positive disease increased. Introduction of newer in situ hybridisation tests may be cost-effective as well. Conclusions: Practice deviations from guidelines are an important consideration when modelling the cost-effectiveness of trastuzumab therapy. Underlying local disease progression and prevalence can also significantly impact outcomes. / Dissertation / Doctor of Philosophy (PhD)

The method targeted memory reactivation (TMR) uses specific stimulation when subjects are completing tasks and during sleep. The TMR process is known to influence the consolidation of declarative memories. The aim of this thesis is to conduct a systematic review on the effects of TMR on declarative memory consolidation during slow-wave sleep (SWS). The research question is to answer what effect TMR during SWS has on the consolidation of declarative memory in healthy humans when presented with associated cues of the targeted learning experiences. Eighteen studies were included in this review. Four studies found a significant effect of TMR on declarative memory consolidation, and 10 found a non-significant effect. In four studies the effect of TMR depended on different inclusions, analyses, and factors, for example between slow oscillation up-and down-states and between participants that vary in pre-sleep performance in the examined task. In contrast to previous findings, this review does not provide evidence for the effect of TMR on declarative memories during SWS. More research analysing different factors, such as different cues, age of participants, duration of SWS, and specific experimental tasks, needs to be done in the fields of TMR and auditory cues.

京都大学 / 0048 / 新制・課程博士 / 博士(薬科学) / 甲第21715号 / 薬科博第106号 / 新制||薬科||11(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 山下 富義, 教授 髙倉 喜信, 講師 樋口 ゆり子 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

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Many attempts have been made to make cancer therapy more selective and less detrimental to the health of the patients. Nanoparticles have emerged as a way to solve some of the problems of traditional chemotherapy. Nanoparticles can provide protection for the therapeutic from degradation or clearance, as well as protection to healthy tissue from the damaging effects of chemotherapy drugs. Researchers are pursuing different strategies but all have the same goals of improving the outcomes of cancer patients. The field of controlled release of drugs has increased significantly in hopes of better treating diseases like cancer. Improved control of drug release has great potential for improving patient outcomes. Still there exist certain barriers such as circulation time, cell specificity, and endosomal escape.In this study a novel drug delivery vehicle was studied in vitro. The novel construct consisted of a liposome containing perfluorocarbon emulsions—an eLiposome—that was activated by ultrasound to break open on demand. Two targeting moieties were attached to the eLiposome to increase cell specificity and induce endocytosis. These studies determined the localization of eLiposomes in vitro using flow cytometry and confocal microscopy. Results indicated that eLiposomes modified with a targeting moiety attached to HeLa cells to a greater extent than non-targeting eLiposomes. Confocal images indicated localization of eLiposomes around the membrane of cells. Flow cytometer results indicated that ultrasound does in fact disrupt the eLiposomes but evidence of significant delivery to the cytoplasm was not obtained. However cells that were incubated with eLiposomes for 24 hours showed over 60% of the cells had green color association indicating eLiposome uptake.

From acid seeps and deep-sea thermal vents to glacial ice and hypersaline lakes, extreme environments contain relatively simplified communities consisting of extremophiles that have evolved to survive and thrive under adverse abiotic conditions. In more neutral environments, microorganisms use dormancy as a common life history strategy to weather temporal fluctuations of resources or stresses until more 'optimal' conditions are present. It is unclear if dormancy is an essential survival mechanism for microorganisms in extreme environments; however, recent studies suggest that extreme environments may create stable conditions for extremophiles to the extent that dormancy is of less ecological importance. Using lake salinity levels as measurements of "extreme," we evaluated the dormancy of bacterial and archaeal phyla and lake chemistry in five hypersaline and five freshwater lakes across the western United States. Dormancy was calculated using targeted metagenomics to analyze 16S rDNA and rRNA tag sequences. It was hypothesized that bacteria and archaea in hypersaline lake communities would exhibit lower levels dormancy than bacterial and archaeal communities in geologically similar freshwater lake controls. It was also hypothesized that microbial dormancy would decrease as the dominant extreme environmental variable increased in the lakes. As hypothesized, overall dormancy decreased at least 2-fold in hypersaline compared to freshwater lakes for both bacteria and archaea. Of the predominant phyla and subclasses, Firmicutes, Bacteroidetes, and Gammaproteobacteria each demonstrated at least a seven-fold decrease in dormancy in hypersaline lakes compared to freshwater lakes. Specifically, species within the genus Clostridium were responsible for 85% of the dormancy observed in the phylum Firmicutes. Also as hypothesized, microbial dormancy decreased as salinity increased in the lakes. Lower dormancy in hypersaline lakes correlated with increasing salinity while lower dormancy in freshwater lakes correlated with increasing total phosphorus levels. These results suggest that dormancy is a less common life history strategy for microorganisms in extreme environments; it is proposed that this is due to the relatively stable environment in hypersaline lakes and the reduced number of available microbial niches. These results also suggest that the dominant extreme stress (i.e., salinity) may override other driving factors in an environment to ultimately determine microbial community composition, diversity and richness.

BACKGROUND: Aberrant MET receptor tyrosine kinase (RTK) activation leads to invasive tumor growth in different types of cancer. Overexpression of MET and its ligand hepatocyte growth factor (HGF) occurs more frequently in glioblastoma (GBM) than in low-grade gliomas. Although we have shown previously that HGF-autocrine activation predicts sensitivity to MET tyrosine kinase inhibitors (TKIs) in GBM, whether it initiates tumorigenesis remains elusive. METHODS: Using a well-established Sleeping Beauty (SB) transposon strategy, we injected human and cDNA together with a short hairpin siRNA against (SB-hHgf.Met.ShP53) into the lateral ventricle of neonatal mice to induce spontaneous glioma initiation and characterized the tumors with H&E and immunohistochemistry analysis. Glioma sphere cells also were isolated for measuring the sensitivity to specific MET TKIs. RESULTS: Mixed injection of SB-hHgf.Met.ShP53 plasmids induced de novo glioma formation with invasive tumor growth accompanied by HGF and MET overexpression. While glioma stem cells (GSCs) are considered as the tumor-initiating cells in GBM, both SB-hHgf.Met.ShP53 tumor sections and glioma spheres harvested from these tumors expressed GSC markers nestin, GFAP, and Sox 2. Moreover, specific MET TKIs significantly inhibited tumor spheres' proliferation and MET/MAPK/AKT signaling. CONCLUSIONS: Overexpression of the HGF/MET axis along with p53 attenuation may transform neural stem cells into GSCs, resulting in GBM formation in mice. These tumors are primarily driven by the MET RTK pathway activation and are sensitive to MET TKIs. The SB-hHgf.Met.ShP53 spontaneous mouse glioma model provides a useful tool for studying GBM tumor biology and MET-targeting therapeutics.

Glioblastoma (GBM) is the most malignant primary brain tumor without effective therapies. Since bevacizumab was FDA approved for targeting vascular endothelial growth factor receptor 2 (VEGFR2) in adult patients with recurrent GBM, targeted therapy against receptor tyrosine kinases (RTKs) has become a new avenue for GBM therapeutics. In addition to VEGFR, the epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), hepatocyte growth factor receptor (HGFR/MET), and fibroblast growth factor receptor (FGFR) are major RTK targets. However, results from clinical Phase II/III trials indicate that most RTK-targeting therapeutics including tyrosine kinase inhibitors (TKIs) and neutralizing antibodies lack clinical efficacy, either alone or in combination. The major challenge is to uncover the genetic RTK alterations driving GBM initiation and progression, as well as to elucidate the mechanisms toward therapeutic resistance. In this review, we will discuss the genetic alterations in these 5 commonly targeted RTKs, the clinical trial outcomes of the associated RTK-targeting therapeutics, and the potential mechanisms toward the resistance. We anticipate that future design of new clinical trials with combination strategies, based on the genetic alterations within an individual patient's tumor and mechanisms contributing to therapeutic resistance after treatment, will achieve durable remissions and improve outcomes in GBM patients.