Flavonoid glycosides are required for a number of crucial roles in planta and have the potential for development in a variety of agricultural, medicinal, and biotechnological applications. A number of recent advancements have been made in characterizing glycosyltransferases, the enzymes that are responsible for the synthesis of these important molecules. In this review, glycosyltransferases are considered with regard to biochemical properties, expression patterns, levels of enzyme activity during development, and structure/function relationships. This is presented with historical context to highlight critical findings, particularly with regard to the innovative work that has come from research on citrus species. The plant glycosyltransferase crystal structures that have been solved over the past decade, either alone or in complex with sugar donor and/or acceptor molecules, are discussed. The application of results from these structures to inform current structure/function work as well as implications and goals for future crystallography and tertiary modeling studies are considered. A thorough understanding of the properties of glycosyltransferases will be a critical step in any future biotechnological application of these enzymes in areas such as crop improvement and custom design of enzymes to produce desired compounds for nutritional and/or medicinal usage.

Background: Several European countries have demonstrated successful use of telephone screening tests for auditory function. The screening test consists of spoken three-digit sequences presented in a noise background. The speech-to-noise ratios of the stimuli are determined by an adaptive tracking method that converges on the level required to achieve 50% correct recognition.Purpose: A version of the three-digit telephone screening protocol for the United States was developed: the US National Hearing Test (NHT). The objective of the current study was to determine the sensitivity and specificity as well as the feasibility of the NHT for use within the Department of Veterans Affairs (VA).Research Design and Study Sample: Using a multisite study design with convenience sampling, we used the NHT to collect data from 693 participants (1379 ears) from three geographical areas of the United States (Florida, Tennessee, and California).Data Collection and Analysis: The NHT procedures were as follows: the participants (1) called a tollfree telephone number, (2) entered their assigned ear-specific identification code, (3) listened to 40-sets of digit triplets presented in speech-spectrum background noise, and (4) entered in the numbers that they heard on the telephone key pad. The NHT was performed on each ear, either at home or in a VA clinic. In addition to collecting data from the experimental task, we gathered demographic data and the data from other standard-of-care tests (i.e., audiometric thresholds and speech recognition tests in quiet and in noise).Results: A total of 505 participants completed the NHT at a VA clinic, whereas 188 completed the test at home. Although the ear-specific NHT and mean pure-tone threshold all correlated significantly (p < 0.001), there were more modest correlations in the low- and high-frequency ranges with the highest correlation seen with the 2000 Hz mean pure-tone threshold. When the NHT 50% point or threshold was compared with the three-frequency PTA at 500, 1000, and 2000 Hz, the sensitivity was 0.87 and specificity was 0.54. When comparing the NHT with the four-frequency PTA at 500, 1000, 2000, and 4000 Hz, the sensitivity was 0.81 and specificity increased to 0.65. The NHT also correlated strongly with other speech-in-noise measures.Conclusions: The NHT was found to correlate with other audiometric measures, including pure-tone thresholds and speech recognition tests in noise, at sufficiently high correlation values to support its use as a screening test of auditory function.

In the nervous system galanin primarily displays a modulatory role. The galaninergic system consists of a number of bioactive peptides with a highly plastic expression pattern and three different receptors. The lack of receptor subtype selective ligands and antibodies have severely hampered the charac-terization of this system. Therefore, most of the knowledge has been drawn from experiments with transgenic animals, which has given some major conclusions, despite the compensatory effects seen in several animal studies. Therefore, the production of subtype selective ligands is of great importance to delineate the galanin system and slowly experimental data from receptor subtype selective ligand trials is emerging. This thesis aims at studying galanin receptor-ligand interactions and to increase and improve the utilized tools in the galanin research field, espe-cially the development of novel galanin receptor subtype selective ligands. Paper I demonstrates the potential to N-terminally extend galanin ana-logues and the successful development of a galanin receptor 2 (GalR2) selec-tive ligand. In addition, a cell line stably expressing galanin receptor 3 (GalR3) was developed, to improve and simplify future evaluations of sub-type selective galanin ligands. Paper II measures the affinities of M617 and M871 to GalR3 and demon-strates that M871 preferentially binds GalR2. Furthermore, the relatively high affinity of M617 was evaluated by assessing the contribution in recep-tor interaction of individual amino acid residues in the C-terminal part of the M617. In conclusion, this thesis has provided a novel design strategy for galanin receptor ligands and increased the understanding of ligand interactions with the GalR3. Furthermore, M1145 has together with new analogues proven to be highly GalR2 specific, holding promises to future delineation of the galaninergic system as a therapeutic target.

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Dans l’histoire évolutive, deux gènes paralogues sont issus d’un évènement de duplication de leur ancêtre commun. Les gènes paralogues sont caractérisés par des duplications globales de génome (WGD) ou à petite échelle (SSD) et par leur datation. Les WGDs ont lieu à deux reprises à la base de la lignée des vertébrés. Les évènements de SSD ont lieu à plusieurs moments pouvant être plus récents, plus anciens ou contemporain de la période des évènements de WGD. La rétention des paralogues dans le génome, associée à une divergence de l’expression spatiale est une contribution importante pour l’augmentation de la complexité de l’organisme au cours de l’évolution. Certaines études ont montré que les duplications anciennes seraient plus associées aux maladies. L’objectif de la première partie de la thèse est de créer une ressource sur les paralogues en collectant et en analysant différentes annotations. Nous avons construit une ressource robuste de paralogues humains à partir de listes publiées mais aussi à partir d’annotations externes. L’exploration de différentes annotations nous a permis d’identifier une identité de séquence élevée entre gènes paralogues pouvant biaiser la mesure d’expression des gènes et diminuer leur expression. L’objectif de la seconde partie, est d’explorer l’expression spatiale et la co- expression des paralogues au sein du cerveau humain, à partir des données RNA-seq du consortium GTEx. Les données d’expression GTEx de 13 tissus cérébraux, nous ont permis de montrer que la datation récente mais aussi que le type SSD contribuaient à une expression plus tissu-spécifique. Nous avons utilisé l’analyse de la co-expression (WGCNA) afin de regrouper les paralogues possédant une expression similaire au travers des tissus et nous avons pu suggérer une co-expression des SSD récents. Nos études sur les maladies ont montré que les SSD récents accumulaient des mutations associées à des maladies cérébrales. Finalement, nous avons trouvé que la co-expression des paralogues et leur tissu-spécificité au travers des régions cérébrales pouvaient enrichir nos connaissances sur les gènes associés à des maladies cérébrales. / In evolution history, two paralogous genes originate from the duplication event of a common ancestor gene. Paralogous genes are characterized by whole genome (WGD) or small-scale (SSD) duplications and their duplication date. The WGDs happened twice in the early vertebrate lineage. SSD events take place at any moment in evolutionary history and can be younger, older or dating to the same period than WGD events. Retention of paralogs in the genome associated with divergence of spatial expression is an important contributor to the increase of organism complexity through evolution. Different studies found that old duplications are more associated with diseases. The objective of the first part of the thesis is to create a resource on paralogs by collecting and analyzing annotations. We built a robust resource of human paralogs from published lists of paralogous genes and also from external annotations. Annotation exploration allowed us to identify a high sequence identity between paralogous genes impacting the gene expression measurement from RNA-seq data and decreasing the gene expression. The objective of the second part is to explore spatial expression and co-expression of paralogs in the human brain, from the GTEx consortium RNA-seq data. The GTEx expression data of 13 brain tissues allowed us to show that duplication youth and SSD type contributed to a more tissue-specific expression. We used co-expression analyses (WGCNA) to group paralogs with similar expression across tissues and we suggested the co-expression of younger SSDs. Our disease studies showed the younger SSD accumulation of mutations associated with brain diseases. We finally found that paralog co-expression and their tissue-specificity across brain regions could enrich information of known brain disease-associated genes.

The Unified Neutral Theory of Biodiversity has been advanced as a universal theory for species coexistence in forests worldwide, but few studies have examined its relevance to high-elevation, stressful environments. I established the Utah Forest Dynamics Plot (UFDP) in a heterogeneous subalpine forest at 3,091 m elevation on the Colorado Plateau to examine three underlying assumptions of neutral theory (functional equivalence, ecological equivalence, and habitat generality) and one prediction (the species abundance distribution). The UFDP comprises 27,845 stems ≥1 cm diameter at breast height of 17 species, 10 genera, and 6 families over 13.6 ha. The neutral model was a poor fit to the observed species abundance distribution, but I did not find the alternative lognormal model to provide a better fit. Using spatial pattern analyses of tree data, topography, and soil type, I found some limited support for the neutral theory assumptions of functional and ecological equivalency, with notable exceptions. Populus tremuloides, Pinus flexilis, and Pinus longaeva were characterized by non-neutral recruitment processes, and Abies bifolia and Populus tremuloides exhibited asymmetric competitive and facilitative interactions. The assumption of habitat generality was strongly contradicted, with all ten abundant species in the UFDP having habitat preference. In this subalpine temperate forest, species diversity and community structure are influenced more by habitat heterogeneity, species differences, and niche selection, with neutral processes playing a lesser role.

This thesis presents two deduplication techniques that overcome the following critical and long-standing weaknesses of rule-based deduplication: (1) traditional rule-based deduplication requires significant manual tuning of the individual rules, including the selection of appropriate thresholds; (2) the accuracy of rule-based deduplication degrades when there are missing data values, significantly reducing the efficacy of the expert-defined deduplication rules. The first technique is a novel rule-level match-score fusion algorithm that employs kernel-machine-based learning to discover the decision threshold for the overall system automatically. The second is a novel clue-level match-score fusion algorithm that addresses both Problem 1 and 2. This unique solution provides robustness against missing/incomplete record data via the selection of a best-fit support vector machine. Empirical evidence shows that the combination of these two novel solutions eliminates two critical long-standing problems in deduplication, providing accurate and robust results in a critical area of rule-based deduplication.

京都大学 / 0048 / 新制・課程博士 / 博士(社会健康医学) / 甲第18907号 / 社医博第65号 / 新制||社医||9(附属図書館) / 31858 / 京都大学大学院医学研究科社会健康医学系専攻 / (主査)教授 川上 浩司, 教授 富樫 かおり, 教授 武藤 学 / 学位規則第4条第1項該当 / Doctor of Public Health / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(社会健康医学) / 甲第19969号 / 社医博第74号 / 新制||社医||9(附属図書館) / 33065 / 京都大学大学院医学研究科社会健康医学系専攻 / (主査)教授 小池 薫, 教授 福田 和彦, 教授 木村 剛 / 学位規則第4条第1項該当 / Doctor of Public Health / Kyoto University / DFAM

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