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    Research of environmental sensitive magnetic nanoparticles preparation and drug release behavior I.Synthesis of hollow magnetic particles by emulsifier-free emulsion polymerization II.Synthesis of self-assembly nanoparticles by living radical polymerization

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    本研究利用兩種方法製備組成中含有氮-異丙基丙烯醯胺與丙烯酸類衍生物之乳膠顆粒,藉由聚-氮-異丙基丙烯醯胺對於溫度的感應性質與丙烯酸類對於酸鹼的感應性質,合成對於環境變化產生感應之藥物載體。 第一種方法以無乳化劑乳化聚合法合成具空心結構之雙層磁性高分子顆粒。作為核心的聚甲基丙烯酸甲酯與與聚甲基丙烯酸共聚合物,外層包覆具交聯之聚異丙基丙烯醯胺與聚甲基丙烯酸共聚合物;鹼處理後,未交聯核心被洗去形成中空顆粒結構,再於此中空顆粒上添加磁性顆粒並討論合成起始酸鹼值之影響;最後合成第二層殼層包覆固定磁流體並穩定顆粒表面性質,得到雙層磁性中空奈米顆粒。實驗結果發現較鹼環境進行第二層高分子合成時,羧基讓顆粒表面有較好的分散性,包覆較均勻;若進料中羧基單體過少,合成產物與磁性粒子間正負電性之吸引力較小,便容易產生大量自成核於顆粒外。藥物釋放方面,酸性環境時,未解離之羧基導致顆粒緊縮且疏水,載藥或藥物釋放效果較差;高溫時,聚異丙基丙烯醯胺的疏水現象發生,顆粒更加緊縮,此環境下藥物釋放初期發生突釋;鹼性環境下,顆粒親水性提升,高溫時聚異丙基丙烯醯胺的疏水性質被競爭漸弱,溫度感應性質較不明顯,突釋現象也因此減緩許多。 第二種方法以可逆性分裂加成鏈轉移活性聚合法合成聚(異丙基丙烯醯胺-丙烯酸)之嵌段共聚合物。高溫時,聚異丙基丙烯醯胺呈疏水態,聚丙烯酸則為親水;藉由親疏水性質的差異進行自組裝以製備具溫度與酸鹼感應性質之顆粒。實驗結果發現鏈段轉移劑使氧化還原之起始系統對分子量可以有更好的控制,聚合度分佈也控制在1.3以下;且合成之聚異丙基丙烯醯胺末端被改質為羧基,使高分子鏈段具酸鹼及溫度感應性質;鹼性環境中,最低臨界溶解溫度升高;隨分子量增加,酸鹼感應性質則不明顯。此法合成之聚異丙基丙烯醯胺與聚乙烯酸嵌段共聚合物在不同比例下的自組裝型態亦被探討與觀察。In this study, stimuli responsive latex nanoparticles composed of copolymers of N-isoprylacrylamide(NIPAAm) and acrylic acid(AA) derivatives were synthesized by two methods. Because of the thermo-sensitivity of polyNIPAAm and the pH-sensitivity of polyAA derivatives, these nanoparticles which is sensitive to both temperature and pH can be used in drug release system as a drug carrier. In the first method, emulsifier-free emulsion polymerization were used to synthesize magnetic hollow particles composed of random copolymer of NIPAAm and methacrylic acid(MAA) . Particle morphology. drug loading and release behavior were discussed. The magnetic hollow particles which can respond to temperature and pH were synthesized successful. The largest drug release percentage was found in the condition of room temperature and basic system. The drug bust phenomena occurred when particles were put into acidic solution. In the second method, well-defined living block copolymer of PNIPAAm and PAA was synthesized by Reversible Addition-Fragmentation Ttransfer (RAFT) to achieve self-assembly behavior at high temperature. When the poly(NIPAAm-b-AA) aqueous solution was heated, various morphologies in different ratios of PNIPAAm and PAA were observed due to the hydrophobic nature of PNIPAAm above its LCST. Sensitivities of temperature and pH were also confirmed in the lowest critical solution temperature experiment

    Investigation of Nonlinear Response of a Cantilevered Piezoelectric Oscillator Under Amplified Excitation

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    本研究主要探討懸臂樑式壓電振子所具有的不同非線性因素,在強激振的環境下,對於系統整體動態響應所造成的影響。本研究除了探討壓電材料中之非線性組成律外,亦考慮了懸臂樑在大幅度變形時,所出現的幾何非線性與慣性非線性。在尤拉-柏努利與不可伸縮樑的兩種假設下,結合瑞利-里茲近似法(Raleigh-Ritz approximation),最後透過漢米爾頓原理(Hamilton’s principle)推導出壓電懸臂樑的控制方程式。 為進一步了解控制方程式中,各係數對於系統整體所造成的影響,本研究使用了多尺度分析法求解出系統之近似解析解,並定義非線性的等效參數Neff,發現此參數對於懸臂樑振子的動態響應特性上,扮演極為重要之角色。並以實際振子參數,分別使用三種不同形狀函數進行模擬,根據比較結果發現,以懸臂樑於點外力作用下所產生的靜態變形曲線為形狀函數,可作為本研究系統中,控制方程式的係數來源之標準。 接著藉由實驗數據得到的頻率響應曲線,與近似解析解中的頻率響應關係式進行曲線擬合,即可推測出系統的機械阻尼係數以及材料非線性等效係數,並可連同其它等效係數一併進行數值模擬。最後,根據比較結果顯示,本研究所建立的壓電振子數學模型無論是在系統的共振頻率,或是輸出端的電壓峰值預測上,與實驗所得的頻率響應曲線皆具有優異的一致性。A study of nonlinear vibration of MEMs cantilevered piezoelectric oscillator subjected to intense excitations is presented. Several nonlinear sources within the oscillator will be considered and discussed for the effect to the dynamic response of the system. First, the material nonlinearity in the PZT layer of cantilever beam is considered, the geometrical nonlinearity and inertia nonlinearity which caused by the large deformation of cantilever beam are taken into account in this thesis as well. The derivation of governing equations is based on Hamilton variational principle, together with several assumptions including Euler-Bernoulli beam theory and inextensible beam condition. Reduced-order models by Rayleigh-Ritz approximation are also developed to focus on the first vibration mode of the system. For further understanding of the system, the approximation analytic solution of the system can be obtained by the method of multiple scale analysis. The effective nonlinear parameter Neff defined in the frequency-response equation is found to be a key parameter for the dynamic response of the system. By substituting the real system dimensions into the simulation, the shape function with point load exerted on the end tip of the beam is found to be a choice to become a standard for the effective coefficients of the governing equations. The damping and material nonlinearity coefficients in the governing equations are estimated by the curve fitting via experimental data. A good qualitative agreement is obtained between experimental and numerical results

    Application of Naltrexone and Nalmefene for alleviation of airway inflammation in OVA-induced murine model of asthma

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    氣喘是現在工業化社會常見的慢性呼吸道發炎性疾病,在許多開發中國家或已開發國家中非常普遍,主要造成氣喘的原因是遺傳因子、環境影響以及生活型態。氣喘的發生主要是T輔助型細胞的不正常偏向Th2細胞型免疫反應所導致,其症狀為間歇性與可逆性之呼吸道阻礙造成之週期性氣喘、胸腔緊繃與呼吸急促、支氣管過度敏感以及慢性的呼吸道發炎等。有許多研究指出類鴉片接受器位於免疫細胞上,參與調節免疫反應。納美芬與納美芬酮是一種類鴉片受體的對抗劑,可以透過阻斷類鴉片受體來達到抗發炎效果。所以本實驗主要目的是探討納美芬與納美芬酮在氣喘動物模式中抑制小鼠呼吸道發炎反應的效果。體外實驗中發現,經LPS刺激後的樹突細胞與巨噬細胞以納美芬與納美芬酮處理,可以使得IL-6、IL-12、IL-10與TNF-α的表現量明顯降低,顯示出納美芬與納美芬酮可以有效的抑制發炎相關的細胞激素表現。所以進一步,想利用卵清蛋白誘導小鼠的氣喘動物模式去研究納美芬與納美芬酮在動物實驗中之抗發炎效果,將實驗小鼠分為七組,每組約5–6隻,各組分別以不同方式處理。小鼠犧牲後,分析其呼吸道阻力、肺功能、引起發炎相關的細胞激素及趨化因子與卵清蛋白專一性抗體可以發現,在動物實驗中納美芬與納美芬酮可以有效抑制呼吸道阻力產生,且可以減少在肺沖洗液中與發炎相關的細胞激素與趨化因子eotaxin、IL-6與TNF-α之分泌,以及抑制嗜酸性白血球之聚集現象,但是卻不會影響血清中抗原專一性的抗體分泌與肺沖洗液中的IL-5分泌,而在脾臟細胞之IL-5、IL-10與IL-12之分泌與細胞增生反應的狀況亦不會受到影響。因此可推論納美芬與納美芬酮應可以透過阻斷類鴉片接受器方式抑制發炎反應,改善氣喘中呼吸道的發炎反應,但是卻不會影響免疫反應的走向。但是由於詳細的作用機制仍然不明確,所以未來仍有待進一步的研究去確認。Asthma is one of the most common airway inflammatory disease in the industrialized society and is the prevalence is very high in developed and developing countries. It might be caused by many factors including genetic factors, environmental factors and life style. The immune mechanism of asthma is that T helper cells are abnormally differentiated to Th2 immune response. The symptoms of asthma are intermittent and reversible airway obstruction leading to recurrent episodes of wheezing, breathlessness, chest tightness, and cough; bronchial hyperresponsiveness (BHR), which is defined as an increased sensitivity to bronchoconstrictors such as histamine or cholinergic agonists; and airway inflammation. Many researches have indicated that opioid receptors are found on immune cells, and participate in regulation of immune response. Naltrexone and nalmefene are antagonists of opioid receptors, and they can suppress inflammation with blocking the opioid receptors. For this reason, the aim of this study is to find out if naltrexone and nalmefene could suppress airway inflammation in OVA-induced murine model of asthma. The secretion of IL-6, IL-12, IL-10 and TNF-α of dentritic cells and macrophages stimulated with LPS were decreased by treatment with naltrexone and nalmefene. These results showed that naltrexone and nalmefene can reduce the secretion of cytokines related with inflammation. Further, in the OVA-induced murine model of asthma, analyzing the AHR, lung fuction, cytokines and chemokines which is related to inflammation suggesting that naltrexone and nalmefene can suppress the AHR and eosinophils assembling, and reduce the production of cytokines and chemokines connected with inflammation such as eotaxin, IL-6 and TNF-α in BALF. However, naltrexone and nalmefene can not affect the levels of antigen-specific antibodies in serum and the production of IL-5 in BALF, and have no effect in the levels of IL-5, IL-10 and IL-12 produced by splenocytes. Therefore, the results of study suggest that naltrexone and nalmefene can suppress the inflammation by blocking the opioid receptor, and reduce the airway inflammation in asthma, but have no effect to change the immune response. Finally, the mechanisms are not clear, so it needs futher investigation further in the future.口試委員審定書………………………………………………………………………1謝……………………………………………………………………………2文摘要………………………………………………………………………4文摘要……………………………………………………………………… 5寫對照表…………………………………………………………………………7錄…………………………………………………………………………… 8一章 研究背景…………………………………………………………… 11-1. 氣喘疾病之介紹……………………………………………………… 12-2. 衛生假說………………………………………………………13-3. 氣喘疾病的致病過程………………………………………………… 13-4. 氣喘疾病的產生機制……………………………………………… 14-5. 氣喘疾病的調控………………………………………………………… 15-6. 參與氣喘疾病的細胞與IgE抗體及其扮演之角色…………………… 18-7. 氣喘動物模式的建立………………………………………………… 20-8. 治療氣喘的方式…………………………………………………… 20-9. 類鴉片接受器的介紹………………………………………………… 22-10. Naltrexone與Nalmefene之介紹………………………………… 23二章 研究動機與目的…………………………………………………… 25三章 探討納美芬與納美芬酮在樹突細胞及巨噬細胞培養中的抗發炎效果………………………………………………………………… 27-1. 研究方法與材料………………………………………………… 28-1-1. 小鼠來源……………………………………………………… 28-1-2. 培養樹突細胞………………………………………………… 28-1-3. 培養巨噬細胞………………………………………………… 29-1-4. 螢光流式細胞儀…………………………………………………29-1-5. 測量細胞激素…………………………………………………30-1-6. 統計方法………………………………………………………… 31-2. 實驗結果……………………………………………………………… 31-2-1. 樹突細胞的培養狀況……………………………………………31-2-2. 巨噬細胞之培養狀況…………………………………………32-2-3. Naltrexone與Nalmefene對以LPS刺激的樹突細胞之細胞激素分泌量之影響…………………………………………………………… 32-2-4. Naltrexone與Nalmefene對以LPS刺激的巨噬細胞之細胞激素分泌量之影響…………………………………………………………… 33四章 探討納美芬與納美芬酮在氣喘之小鼠動物模式中的抗發炎效果………………………………………………………………………34-1. 研究方法與材料……………………………………………………… 35-1-1. 小鼠來源………………………………………………………… 35-1-2. 建立對OVA過敏之氣喘動物模式及治療……………………… 35-1-3. 測量對OVA有專一性之血清抗體……………………………… 36-1-4. 呼吸道阻力測試……………………………………………………37-1-5. 肺沖洗液之收集………………………………………………… 38-1-6. 肺沖洗液中血球分類計算……………………………………… 38-1-7. 肺沖洗液中細胞激素及發炎介質分泌量之測量…………………38-1-8. 脾臟細胞之收集取得………………………………………………40-1-9. OVA專一性之脾臟增生反應………………………………………40-1-10. OVA專一性抗原刺激脾臟細胞之細胞激素測量…………………41-1-11. 統計方法……………………………………………………………42-2. 實驗結果…………………………………………………………………42-2-1. 氣喘動物模式的OVA專一性抗體IgE、IgG1及IgG2a的表現狀況……………………………………………………………………42-2-2. Naltrexone與Nalmefene對於呼吸道阻力的治療效果………43-2-3. 以Naltrexone與Nalmefene治療過後小鼠肺部之細胞激素與發炎介質的分泌量變化…………………………………………………43-2-4. 以Naltrexone與Nalmefene治療過後對小鼠肺部之嗜酸性白血球聚集的影響……………………………………………………44-2-5. 以Naltrexone與Nalmefene治療小鼠過後對OVA專一性脾臟細胞增生反應之影響………………………………………………44-2-6. 以Naltrexone與Nalmefene治療小鼠過後對OVA專一性刺激之脾臟細胞的細胞激素分泌量影響………………………………44五章 討論………………………………………………………………………46…………………………………………………………………………………52考文獻……………………………………………………………………………7

    Going Beyond Counting First Authors in Author Co-citation Analysis

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    The 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

    Variations on the Author

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    “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

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    We 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

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    We 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

    Author Index

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