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Part 1. A Mechanistic Study of Pyreno[2,1-b]pyrrole and Bis(pyreno[2,1-b]pyrrole) as Selective Chemosensors of Fluoride Ion Part 2. Synthesis of Adenosine Analogues for Therapy of Huntington’s Disease
No full text第一部份：芘駢吡咯及雙芘駢吡咯做為氟離子偵測器之機制研究
本篇論文當中，我們運用本實驗室過去合成的芘駢吡咯及其衍生物－雙芘駢吡咯做為氟離子的偵測器，且選用多種常見的陰離子進行初步篩選，發現此二化合物對於氟離子具有良好選擇性及靈敏度。而在添加氟離子先後，此二化合物均在可見光波長區域產生明顯的吸收或螢光光譜變化，此一光物理性質將可應用於氟離子的即時偵測上。
我們利用螢光及核磁共振光譜對於氟離子的偵測機制進行詳盡的分析。實驗過程中發現，在初始模式中，芘駢吡咯及雙芘駢吡咯與氟離子形成氫鍵附合物；之後加入的氟離子，因其帶有極強的鹼性，將促使吡咯官能基中氮上氫進行去質子化，而造成吸收及螢光光譜的紅位移現象。另外在1H NMR光譜滴定實驗中，我們紀錄並解釋偵測器分子上其他氫訊號的特殊趨勢，並觀測到 [FHF]–陰離子的訊號，更進一步地證實偵測器分子與氟離子間進行去質子化的作用機制。
第二部分：抗神經退化性藥物之研究：腺苷酸類似物之合成
我們從傳統中藥材－天麻中萃取出兩種具有神經保護性的化合物：T1-C和T1-11，且利用有機合成的方法大量製備此二化合物。在老鼠腎上腺髓質嗜鉻細胞瘤細胞（PC12 cells）測試中發現，此二分子透過刺激A2A腺苷酸受體（A2A-R）使細胞免於凋亡。由於A2A-R屬於G蛋白質受體家族，在其單晶結構難以取得的條件下，我們利用電腦軟體建構的pharmacophore模型輔助整個藥物分子的設計。
因為T1-11具有更好的生物活性，所以本篇論文著重在T1-11的衍生。我們替換T1-11分子結構中N6-位置的取代基，並建立具有代表性的分子庫。進行測試後發現，這些腺苷酸類似物的神經保護性與T1-11相差無幾，也就是說A2A-R 刺激物對於N6-位置官能基變化具有一定程度的容忍性。此外，我們也嘗試修飾T1-11結構中的核糖部分，希望能進一步提高對於A2A-R的親和性。在其他生物活性測試中發現，T1-11分子扮演兩種角色：A2A-R 刺激物及腺苷酸轉運體抑制劑。我們認為這類型可針對多種目標物的藥物分子，對於亨丁頓氏舞蹈症或其他神經退化性疾病的臨床治療，具有一定的潛力。Part 1. A Mechanistic Study of Pyreno[2,1-b]pyrrole and Bis(pyreno[2,1-b]pyrrole) as Selective Chemosensors of Fluoride Ion
Pyreno[2,1-b]pyrrole and its dimeric derivative display excellent selectivity and sensitivity for detection of fluoride ion, in comparison with other anions. The bonding with fluoride ion, both in formation and in subsequent dissociation, provides remarkable colorimetric and fluorescent changes in the visible region that are advantageous for real-time and on-site application.
The mechanisms of detection were also investigated by detailed NMR and dynamic fluorescence spectroscopic analyses. The initial interaction modes of pyreno[2,1-b]pyrrole and its dimeric derivative with F− in MeCN can be understood as hydrogen-bonded complexes. Excess F− ions promotes deprotonation of N-protons and results in the bathochromic changes in both absorption and fluorescence spectra. The observation of [FHF]– by 1H NMR in DMSO-d6 also strongly supported the deprotonation mechanism.
Part 2. Synthesis of Adenosine Analogues for Therapy of Huntington’s Disease
We demonstrated the synthesis and biological function of T1-C and T1-11, which are isolated from a Chinese herb, Gastrodia elata (天麻), These compounds have been characterized to exert neuroprotective effect. Previous works has revealed the potency of T1-11 for the therapy of Huntington’s disease. The neuroprotection was mediated by A2A receptor in the apoptotic model of serum-deprived PC12 cells. Because A2A receptor is a GPCR, pharmacophore modeling was used to provide a putative image of the interactions between the target protein, A2A receptor, and its agonists.
There were two approaches to modify T1-11: the alternation of N6-substituted functional groups and the modification of ribose. A representative library of adenosine analogues was developed on the basis of pharmacophore model and screened for the biological activities assays. We also proposed a dual–function mechanism of T1-11, which acted as both A2A receptor agonist and nucleoside transporter inhibitor. Further development of these compounds may promise a novel therapeutic intervention for HD and other neurodegeneration diseases.Acknowledgements …..………………..……………………………….... I
Abstract in Chinese ……………………………………………………. III
Abstract in English ……………………………………………………... V
Table of Contents ……………………………………………………. VII
Index of Schemes …………………………………………………….. XI
Index of Figures ………………………………………………………. XII
Index of Tables ……………………………………………………....... XV
Abbreviations ……………………….………..…………………….. XVII
Part 1. A Mechanistic Study of Pyreno[2,1-b]pyrrole and Bis(pyreno[2,1-b]pyrrole) as Selective Chemosensors of Fluoride Ion
Chapter 1. Introduction ……………………………………………………………… 1
1.1 Anion Sensors ……………………………………………………………… 1
1.2 Synthetic Sensors for Fluoride Ion Detection …………………………… 2
1.3 NH-Based Fluoride Sensors ………………………………………………. 5
Chapter 2. Results and Discussions …………………………………………………. 7
2.1 Previous Researches ……………………………………………………… 7
2.2 Interaction Mode of Sensor 4 with Fluoride Ion ………………………… 10
2.3 Interaction Mode of Sensor 5 with Fluoride Ion ……………………….. 18
2.4 Conclusion …………………………………………………………………. 26
Part 2. Synthesis of Adenosine Analogues for Therapy of Huntington’s Disease
Chapter 3. Introduction ……………..……………………………………………… 27
3.1 Hutington’s Disease ……………………………………...……………… 27
3.2 Therapeutic Interventions ……………….......... ……………….......…….. 28
3.3 Adenosine Receptors …………………………………………………….. 30
3.4 Adenosine Transporter ………………………………………………….. 33
Chapter 4. Results and Discussions ……………………….…………. ……………. 39
4.1 Synthesis and Characterization of T1-C and T1-11 …...……………… 39
4.2 Pharmacophore Construction ………….................. …………………….. 44
4.3 Adenosine Analogues: N6-Substituted Derivatives ……………………. 47
4.4 Adenosine Analogues: Modification of Ribose ………………………… 54
4.5 Conclusion …………………………………………………………………. 56
Chapter 5. Experimental Sections Conclusion ……………………………………. 57
5.1 General Part …...………………………………………………………… 57
5.2 General Procedure for Absorption and Fluorescence Titrations
…...………………………………………………...………………………..… 58
5.3 General Procedure for Job’s Plot ………………………………………. 58
5.4 General Procedure for 1H and 19F NMR Titrations …………………….. 59
5.5 Molecular Calculation ……………………………………………………. 59
5.6 Syntheses of Sensors 4 and 5 ……………………………………………… 60
5.7 Synthesis of Sensors 6 …………………....................... ………………….. 61
5.8 Synthesis of T1-C …………………………...................………………….. 64
5.9 Syntheses of T1-11 and Other Adenosine Analogues ……………….…… 66
References ………………………..... ……..... ........... …...................… 87
Appendices ......……………………............ …............ …...................… 9
A Study on the Systematic Risk and its Impact on the Life Insurance Market
No full text臺灣壽險業近幾年總資產不斷增加，於2014年底達到18.6兆新台幣，在資產增加趨勢之下，保險公司必須審慎資產配置的策略以避免資產與負債不相匹配的情況發生。從歷史資料可發現，保險業淨值與股票市場有相當高的連動性，系統性風險無法透過資產組合而分散且具有事件觸發之特性，因此在研究中加入Hanson and Westman (2003)所提出的跳躍擴散過程以模擬股價動態過程，在負債面採利變型養老保險為例，透過模型的建構以做負債適足性測試來評估系統性風險對壽險公司所造成的破產機率與其破產價值。 研究結果顯示: (1)與B-S模型相比之下，跳躍擴散過程使資產得變動增加，因此跳躍過程之下的破產機率以及違約價值的絕對值越高。(2)壽險公司槓桿比例越高、股價平均參數上升或是負債風險溢酬上升時，會使得破產機率以及違約價值絕對值上升。In Taiwan, the total assets of the life insurance markets have reached NT18.6 billion at the end of 2014. Following this trend, an insurer should maintain prudent asset allocation strategies to prevent the mismatch from asset and liability. From the historical data, the net value of the life insurance company has high correlation with stock market, called systematic risk. Systematic risk cannot be removed by asset portfolio and has “event-trigger” property. In this research, we add the jump diffusion process to model the stock price dynamic process. We use a sample retirement insurance to fit in the liability side. With asset and liability models, we can do the liability adequacy test to find out the probability and default value when life insurance companies face systematic risk. The research shows that: (a) Compared to the B-S model, the jump diffusion process shows higher default probability and absolute value of default value. (b) Higher leverage, the mean of the stock, higher risk premium of the liability, and higher elasticity of the interest rate on the liability will cause higher default probability and absolute value of default value
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Development of a Patent Document Classification and Search Platform using a Back-propagation Network
No full textVariations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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