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Functional Regulation of Histone Methyltransferases and the Downstream Genes by HCV Core Protein
No full textC 型肝炎病毒感染在台灣已經成為慢性肝炎以及肝癌的主要致病原因，然而其致病機制並不清楚。核心蛋白為C 型肝炎病毒的結構蛋白，已被發現能調節許多細胞訊息傳遞路徑以及轉錄因子功能，並能於基因轉殖鼠內造成肝癌。因此，核心蛋白與細胞中分子的相互作用在致病機制中很可能扮演著重要的角色。在此篇論文中，我們探討了C型肝炎病毒核心蛋白對組蛋白甲基化酵素活性的調控。甲基化酵素為染色質修飾蛋白之一，而染色質修飾蛋白是由轉錄因子將其帶到基因的啟動子(promoter)對組蛋白進行修飾，使基因活化或抑制其表現。
利用組蛋白甲基化實驗(histone methyltransferase assay) ，我們發現C型肝炎病毒核心蛋白在試管內能抑制組蛋白甲基化酵素CARM1、PRMT1及SET9對組蛋白H3/H4的活性。核心蛋白本身亦能被CARM1及PRMT1進行甲基化，而SET9對於組蛋白H1的活性反而受核心蛋白影響而增加。利用核心蛋白的缺失突變，我們發現胺基酸51到101的片段對於核心蛋白抑制甲基化酵素是不可缺少的。目前已有許多報導指出C型肝炎病毒核心蛋白能調控細胞內許多轉錄因子如p53和NF-κB。我們的實驗發現核心蛋白會被帶到具有NF-κB結合位置的DNA上。利用luciferase assay，在HuH-7細胞中一些NF-κB下游基因Cox-2、IL-8、MCP-1 及 RANTES其啟動子的活性皆會被核心蛋白所抑制。而目前已知這三個甲基化酵素皆為p53的輔激活蛋白而CARM1在最近也被發現為NF-κB的輔激活蛋白。GST pull-down實驗的結果告訴我們全長的核心蛋白與細胞內的NF-κB組成分子p65、CARM1、PRMT1以及SET9有交互作用。此外，在HuH-7細胞中，核心蛋白的另一個目標基因—p53下游基因p21其啟動子活性也會受到核心蛋白所抑制。由chromatin immunoprecipitation實驗的結果，我們發現在HuH-7細胞中，在p21啟動子上，核心蛋白會減少CARM1以及PRMT1對其標的組蛋白精胺酸位置的甲基化。
總而言之，C型肝炎病毒核心蛋白抑制NF-κB及p53下游基因可能是經由抑制NF-κB及p53輔激活蛋白CARM1、PRMT1及SET9對組蛋白H3/H4的活性。我們的研究提供了一個C型肝炎病毒核心蛋白調控NF-κB和p53活性的新機制。其他受甲基化酵素調控的路徑亦可能會受到核心蛋白的影響。Hepatitis C virus (HCV) infection is a major cause of chronic hepatitis and hepatocellular carcinoma, especially in Taiwan. However, the detailed pathogenic mechanism remains unclear. It has been reported that core protein, a structure protein of HCV, regulates several cellular signaling pathways and transcriptional factors and induces hepatocellular carcinoma in transgenic mice. Thus, the interaction between core protein and its cellular targets may play important roles in the pathogenesis. Here, we characterize HCV core protein-mediated functional regulation of histone mehtyltransferases (HMTs). HMTs belong to members of chromatin modifiers that have to be recruited by specific transcription factors to the promoter region of genes to achieve transcriptional activation or repression.
By performing in vitro HMT assays, we found that core protein represses the HMT activity of arginine-specific HMTs (R-HMTs) CARM1 and PRMT1 as well as lysine-specific HMT (K-HMT) SET9 on their target sites of histone H3 or H4. In contrast, core protein increases SET9 activity on histone H1. Interestingly, core protein itself can be methylated by CARM1 and PRMT1 in the presence of histones. By using deletion mutants in HMT assays, amino acids 51 to 101 of core protein seem to be the inhibitory domain on HMT. Core protein has been reported to regulate functions of cellular transcription factors, such as p53 and NF-κB. DNA affinity protein assays show that core protein is recruited to the NF-κB binding site, and the promoter activities of certain NF-κB target genes, Cox-2, IL-8, MCP-1 and RANTES, are reduced in the presence of core protein in HuH-7 cells. CARM1 has been reported as a novel coactivator of NF-κB. Our GST pull-down assay shows that full length core interacts with endogenous NF-κB p65 subunit, CARM1 and SET9. Moreover, CARM1, PRMT1 and SET9 have been reported to be coactivators of p53. The promoter activity of another core protein target, p53 downstream gene p21, is also repressed in the presence of core protein in HuH-7 cells, and the result of chromatin immunoprecipitation shows that core protein reduces CARM1-mediated histone H3 dimethylation at R2 and R17 and PRMT1-mediated histone H4 R3 dimethylation on p21 promoter in HuH-7 cells.
Taken together, HCV core protein-mediated downregulation of NF-κB and p53 target genes may likely occur through repression of activities of p53 and NF-κB coactivators, CARM1, PRMT1 and SET9 on histone H3/H4 methylation. Our study provides a novel pathway of core protein to modulate the activities of NF-κB and p53. And likely more HMT-regulated effects could be modulated by core protein.Abstract………………………………………………………………1
中文摘要………………………………………………………………3
Introduction…………………………………………………………5
Hepatitis C virus is an important human pathogen…………5
Core protein may contribute to HCV pathogenesis……………6
1. Core protein has three isoforms……………………………6
2. Core protein interacts with several cellular proteins…………7
3. Core protein regulates the activity of transcription factors……………8
Histones can be post-translationally modified………………9
1. Histone acetylation and methylation are keys to gene regulation……………10
2. Hsitone methyltransferases, CARM1, PRMT1 and SET9 are coactivators……………………………………………10
3. Histone modifiers are regulated by viral proteins……12
Study Purposes……………………………………………………14
Materials and Methods………………………………………………15
Cell culture and transfections…………………………………15
Plasmids and antibodies……………………………………………15
Purification of GST-fusion HCV core protein…………………17
Purification of His-tagged HPV E6 and E7 protein…………18
GST pull-down assay…………………………………………………19
In vitro histone methyltransferase assay……………………19
Preparation of cytoplasmic and nuclear fractions…………20
DNA affinity protein assay………………………………………21
Luciferase Assay……………………………………………………22
Chromatin immunoprecipitation……………………………………22
Results…………………………………………………………………24
GST-fusion HCV core protein and its deletion mutants are successfully purified………24
HCV core protein regulates CARM1 activity……………………24
HCV core protein regulates PRMT1 activity……………………26
HCV core protein regulates SET9 activity……………………26
Core protein regulates NF-κB activity possibly via HMT inhibition……………………28
Core protein reduces histone arginine dimethylation on p21 promoter in HuH-7 cells……………………………………………30
Discussion……………………………………………………………32
HCV core protein regulates HMT activity with specificity…………32
Histone H1 might be a novel target of SET9…………………33
Amino acids 51 to 101 of core inhibit CARM1-, PRMT1- and SET9-mediated H3/H4 methylation…………………………………34
The trnafected core protein locates in the nucleus………34
Core protein may downregulate NF-κB activity through HMT inhibition……………35
A novel pathway of p53 downregulation by core protein……37
References……………………………………………………………39
Figure 1. HCV Core protein and its deletion mutants are successfully purified……..49
Figure 2. HCV core protein inhibits the HMT activity of CARM1 on histone H3 and core itself is methylated by CARM1…………………………………………………50
Figure 3. HCV core protein inhibits the HMT activity of PRMT1 on histone H4 and is methylated by PRMT1……………………………………………………………….51
Figure 4. HCV core protein inhibits the HMT activity of SET9 on histone H3 and increases the HMT activity on Histone H1……………………………………………52
Figure 5. HPV type 11, 16 and 18 E6 protein regulate the activities of HMTs…………53
Figure 6. HPV type 16 and 18 E7 protein regulate the activities of HMTs………54
Figure 7. Regulation of NF-κB activity by HCV core protein…………………55
Figure 8. Regulation of p53 activity by HCV core protein………………………56
Table 1. Summary of the in vitro HMT assay…………………5
Two Dimensional Photonic Crystals Band Gap and Device of Application
No full text光子晶體經適當的設計後將具有光子晶體能隙。其中二維光子晶體在製造上比三維光子晶體容易許多，所以應用的範圍較廣。本論文中先利用平面波展開法，探討光子晶體在TE mode及TM mode的能帶關係，並嘗試藉由調整光子晶體的介電質材料截面形狀與其排列的方式，讓TE mode與TM mode的能帶能夠在相同頻率的部分重疊，在應用時可以說是更加的方便。
另外若在光子晶體結構體中製造出一線缺陷，則可以得到光子晶體光波導，在能帶頻隙內的光波會被侷限在線缺陷通道，即使是彎曲通道高達90度的光波導結構，傳遞的能量也不會有很大的損耗，表示光波仍舊能順利地沿著通道行進。如果要將光波訊號一分為二，對於光子晶體波導結構也是非常容易的，只要在通道結構上設計成對稱的兩個通道，就能得到兩個幾乎完全一樣的光訊號。光子晶體也能應用在多頻道的分波多工系統。利用線缺陷製成的波導結構及具有頻率選擇效果的共振腔，我們可以得到一個具有濾波效用的分波多工系統，使兩種不同的頻率的光波經由分別兩個通道傳遞出來，更可以經由改變點缺陷的參數來控制我們想要的頻率，當然也可以將雙通道設計成一分為四的通道，藉以得到更多希望能到不同頻率的光波。第一章 緒論…………………………………………1
1.1 研究動機………………………………………1
1.2 光子晶體簡介…………………………………1
1.3 光子晶體之應用文……………………………2
1.4 文獻回顧………………………………………4
1.5 章節介紹………………………………………5
第二章 平面波展開法………………………………6
2.1 數值方法介紹…………………………………6
2.2 特徵值方程式…………………………………6
2.3 Bloch理論與倒晶格向量………………………8
2.4 平面波展開法…………………………………9
2.5 二維平面波展開………………………………10
2.5.1 TM mode………………………………………10
2.5.2 TE mode………………………………………11
2.6 介電質函數……………………………………12
第三章 時域有限差分法……………………………15
3.2 簡介……………………………………………15
3.2 時域有限差分法………………………………15
3.3 吸收邊界………………………………………20
3.4 穩定因數………………………………………27
第四章 光子晶體能帶分析…………………………28
4.1 平面波展開法計算光子晶體能帶……………28
4.1.1 TM mode………………………………………28
4.1.2 TE mode………………………………………31
4.2 Absolute Band Gap……………………………34
4.3 三維F.C.C與Diamond結構能帶………………48
第五章 光子晶體波導與應用………………………53
5.1 光子晶體波導管………………………………53
5.2 光子晶體分光器………………………………59
5.3 光子晶體多波分工器…………………………61
第六章 結論…………………………………………66
參考文獻………………………………………………6
Two-dimensional modeling of two-phase transport in the cathode of a PEMFC with the influences of clamping pressure
No full text本論文利用有限元素工程模擬軟體COMSOL建立二維兩相流質子交換膜燃料電池數值模型。本論文研究燃料電池陰極側輸入為空氣時，組裝壓力的不同對於氣體擴散層氧氣和液態水的分布情形。使用的模組包含應力應變模組，計算氣體擴散層經過壓縮之後的孔隙度，氧氣和液態水的擴散對流模組、質量守衡模組和動量模組。此外並分析雙極板材料為不鏽鋼時，質子交換膜燃料電池性能和氧氣和液態水飽和度的分布情形。究結果得知，當組裝壓力增加時，肋條下之氣體擴散層受到壓縮而變形，使得孔隙度降低，以致於影響到氣體擴散層的滲透性和擴散性，造成氧氣不易傳輸，質傳阻抗增加，導致燃料供應不足發生質傳損失，使電池性能受到影響。雖然組裝壓力的增加會減少接觸阻抗，但必須另外考慮燃料的質傳阻抗和電池性能的影響，才能找出較佳化的組裝壓力性能曲線。當雙極板材料為不鏽鋼時，由於組裝壓力較小時，接觸阻抗明顯較大，以至於歐姆阻抗相對增加，導致歐姆損失較為嚴重。因此當組裝壓力增加時，不鏽鋼的歐姆損失相對較低，使性能曲線較佳。This study uses the finite element simulation software COMSOL project to establish two-dimensional two-phase proton exchange membrane fuel cell by numerical model. When air is input into the fuel cell cathode-side gas diffusion layer, this paper studies the distribution of generated oxygen and liquid water. Including the use of the theory of compressed gas diffusion layer of stress and strain module, oxygen and liquid water diffusive convection module, mass conservation module and momentum module, in addition to analyze the performance and the concentration distribution of the bipolar plate, which is stainless steel.esearch results show that high clamping pressure will make the gas diffuser layer deformed and decrease the porosity of gas diffuser layer. The transport resistance increases with decreasing diffusion and permeability coefficients depending on the gas diffusion layer porosity. It leads to a small effective reaction area, when the saturation of liquid water is larger to study the elastic deformation of the gas diffusion layer and the mass transport of the reactants and products. It is found that there exists a better clamping force to obtain the higher power density for the proton exchange membrane fuel cell with the interdigitated gas distributors.致謝...................................................I文摘要..............................................II文摘要............................................ III錄..................................................IV目錄................................................VI目錄.............................................. VII號說明...............................................X一章 序論............................................1.1燃料電池簡介........................................1.1.1燃料電池歷史發展..................................1.1.2燃料電池種類......................................2.1.3燃料電池基本原理..................................6.2文獻回顧............................................7.3研究動機...........................................15二章 理論分析.......................................18.1基本假設...........................................18.2統御方程式.........................................18.3邊界條件...........................................24.4性能曲線...........................................25.5計算模擬流程.......................................27三章 結果與討論.....................................31.1指叉型流道.........................................31.1.1不同組裝壓力.....................................31.1.2雙極板為不鏽鋼...................................33.2平板型流道.........................................35.2.1不同組裝壓力.....................................35.2.2雙極板為不鏽鋼...................................38四章 結論與未來展望.................................57.1結論...............................................57.2未來研究方向和建議.................................61五章 文獻參考.......................................6
Antidepressants and valvular heart disease: A nested case-control study in Taiwan
No full text研究背景
已知藥品引發的心臟瓣膜疾病之致病機轉可能與血清素(serotonin)濃度、受體(receptor)、運輸體(transporter)相關，如serotonin、fenfluramine及pergolide等，而抗憂鬱藥品其藥理機轉也與serotonin有關，然而之前文獻並沒有發現抗憂鬱藥品與心臟瓣膜疾病(valvular heart disease; VHD)之間的相關性。除研究方法及族群不同外，目前缺乏心臟瓣膜閉鎖不全(cardiac-valve regurgitation；CVR)之International Classification of Diseases-9th edition-Clinical Modification codes (ICD-9-CM code)編碼確效研究，因此，利用臺灣健康保險資料庫(National Health Insurance Research Database；NHIRD)來進行VHD之研究。
研究目的 本研究首先進行住院與門診病人之ICD-9-CM code編碼與CVR之確效研究，以確認VHD病例設定條件。其次，利用臺灣健康保險資料庫探討華人族群抗憂鬱藥品之使用與VHD的相關性。
研究方法
本研究分兩大部分，第一部分，利用2007至2011年臺大醫院住院及門診病人之病歷資料，篩選符合病例條件之住院或門診病人。進一步確認心臟超音波報告中CVR之嚴重程度，將至少有一瓣膜CVR大於等於中度之病人視為確認病例，並計算陽性預測值(positive predictive value；PPV)。第二部分，利用1999至2011年健保資料庫2000、2005、2010之百萬承保歸人檔(約300萬人)建立嵌入型病例對照研究。先排除在1999至2001曾使用抗憂鬱藥品之病人後，收錄2002至2010年大於等於20歲至少使用三次抗憂鬱藥品之病人，並且將第一次使用抗憂鬱藥品日期設定為cohort entry date。排除在cohort entry date前一年曾有VHD、相關病因與可疑藥品之病人後，剩下的人進入研究世代。在研究世代中，篩選出在2002至2011年符合VHD條件之住院病人定義為病例，並且將第一次符合VHD的住院日期定義為index date。排除開始用藥後90天內發生VHD之病例病人，剩下之病例病人以1:4的比例與未發生心臟瓣膜疾病之抗憂鬱藥品使用者，進行年齡、性別、cohort entry date之配對，得到病例組與對照組。分析事件前三年內兩組抗憂鬱藥品的使用狀況，主要分析為將所有抗憂鬱藥品視為一個類別，暴露變項包含使用時序、累積時間、累積劑量以及最後一劑每日劑量；次要分析則依照藥理特性、對serotonin transporter親和力，以及單獨抗憂鬱藥品進行分類。利用
conditional logistic regression進行odds ratio的預測並校正干擾因子，以評估抗憂鬱藥品與VHD之相關性。
研究結果
住院與門診病人之ICD-9-CM code編碼確效研究結果不同，住院病人之PPV高達84.5%，相較之下，門診病人只有33.7%，因此只納入住院病人為病例組。收錄研究族群154,416人，排除14,824人，最後有139,592人進入到研究世代。研究世代中有1,792人符合病例條件，進一步排除從第一次使用抗憂鬱藥品到發生心臟瓣膜疾病小於90天之133名病人，剩下病人經過配對得病例組1,618人與對照組6,742人。結果顯示，主要分析中整體抗憂鬱藥品之使用者，相較於三年內未使用者，與心臟瓣膜疾病之發生不存在顯著相關性(adjusted odds ratio[aOR] 1.05; 95% confidence interval[CI] 0.89-1.23)。另外，累積時間、累積劑量與最後一劑每日劑量亦皆無發現兩者之間的關係性。但是，次要分析則發現在trazodone(aOR 1.26 [1.00-1.59])、imipramine(aOR 1.29 [1.03-1.62])、citalopram(aOR 1.70 [1.06-2.72])、duloxetine(aOR 2.41 [1.11-5.25])之current user與bupropion(aOR 2.87 [1.09-7.56])之recent user有看到顯著增加心臟瓣膜疾病之發生風險。
結論
整體而言，本研究並未發現整體抗憂鬱藥品與心臟瓣膜疾病之相關性，但是值得注意的是，半年內曾經暴露過citalopram、imipramine、duloxetine的患者，以及在半年到一年內曾經暴露過bupropion的患者，相較於三年內未使用抗憂鬱藥品者，可能會增加1.26至2.87倍心臟瓣膜疾病之發生機率。Background Concentration, receptor, transporter of serotonin may involve in mechanisms of drug induced valvular heart disease such as serotonin, fenfluramine, pergolide and so on. Additionally, pharmacologic mechanism of antidepressants are related to serotonin. Nevertheless, no clinical study shows a potential link between use of antidepressants and risk of valvular heart disease (VHD). In addition to different study method and population, the validation of International Classification of Diseases-9th edition-Clinical Modification codes (ICD-9-CM codes) for cardiac-valve regurgitation (CVR) has never been done to study VHD by Taiwan’s National Health Insurance Research Database (NHIRD).
Objective First, to determine the definition of VHD, we conducted two validations of ICD-9-CM codes for inpatients and outpatients with CVR, respectively. Second, we used NHIRD to evaluate the association between use of antidepressants and VHD among Chinese population.
Methods Our study was divided into two parts. In the first part, we requested inpatients’ and outpatients’ medical information from National Taiwan University Hospital and identified patients who met case definition during 2007-2011. The echocardiographic reports were reviewed to confirm the severity of CVR. Potential cases with at least one cardiac valve of moderate regurgitation were defined as confirmed cases and positive predictive value (PPV) were calculated. In the second part, a nested case-control study using 2000, 2005, 2010 Longitudinal health insurance database during 1999-2011 as study resource (covering about a population of 3 millions) was conducted. After excluding patients who used antidepressants in 1999 to 2001, we identified patients aged over 20 years with at least 3 prescriptions of antidepressants during 2002-2010. The cohort entry date was the date of the first prescription of antidepressants. Nevertheless, patients who were diagnosed with VHD or related etiologies, or who used drugs that potential causing DIVHD within 1 year before the cohort entry date were excluded. Among study population, we identified inpatients who first hospitalized with incident VHD during 2002-2011 as cases and the date was defined as index date. We further excluded cases with VHD 90 days after the first use of antidepressants. The cases were matched with 4 controls by age, sex and cohort entry date. All prescriptions of antidepressants 3 year before index date were included. In primary analysis, different type of antidepressants were considered as one group and exposure assessment included timing of use, cumulative duration, cumulative dose and last daily dose. In secondary analyses, we further classified antidepressants by type of antidepressants, affinity for serotonin transporter and individual antidepressants. Conditional logistic regression models were used to estimate odds ratio of VHD associated with use of antidepressants.
Results The validity of ICD-9-CM code for inpatients with CVR was distinct from outpatients with CVR. The PPV of inpatients was as high as 84.5%. In contrast, the PPV of outpatients was only 33.7%. Therefore, definition of cases was decided to include inpatients solely. In the study period, 154,416 patients met the inclusion criteria. After excluding 14,824 patients, 139,592 patients served as the study population. Among study population, we identified 1,792 inpatients who met case definition and further excluded 133 cases with days between cohort entry date and index date less than 90 days. After matching, 1,618 and 6,742 were the cases and controls, respectively. In primary analysis, users of all antidepressants were not associated with risk of VHD (adjusted odds ratio [aOR] 1.05; 95% confidence interval [CI] 0.89-1.23) when compared with ever users who did not use antidepressants 3 year before index date. In addition, no dose-response was observed by cumulative duration, cumulative dose and last daily dose. In secondary analysis, only current users of trazodone (aOR 1.26 [1.00-1.59]), imipramine (aOR 1.29 [1.03-1.62]), citalopram (aOR 1.70 [1.06-2.72]), duloxetine (aOR 2.41 [1.11-5.25]) and recent users of bupropion (aOR 2.87 [1.09-7.56]) significantly increased the risk of incident VHD.
Conclusions Overall, we found antidepressants was not associated with risk of VHD. Nonetheless, it is rather remarkable that patients used trazodone, imipramine, citalopram, duloxetine or bupropion may increase 1.26 to 2.87-fold risk of incident VHD.致謝 i
中文摘要 iii
Abstract v
目錄 vii
表目錄 x
圖目錄 xi
縮寫表 xii
第１章 前言 1
第２章 文獻回顧 2
2.1 藥品引起心臟瓣膜疾病之文獻回顧 2
2.1.1藥品引起的心臟瓣膜疾病之定義、診斷與治療 2
2.1.2可疑藥品與致病機轉 3
2.1.3 藥品引起的心臟瓣膜疾病之發生率與風險因子 5
2.2 抗憂鬱藥品在臺灣之使用情況與適應症 6
2.3 抗憂鬱藥品與藥品引起的心臟瓣膜疾病之研究文獻 7
2.4 藥品引起的心臟瓣膜疾病之評估與資料庫編碼確效 8
第３章 研究目的 9
第４章 研究方法 10
4.1 資料庫編碼之確效-住院病人 10
4.1.1 資料來源與研究對象 10
4.1.2 心臟瓣膜疾病確效之定義 10
4.1.3 心臟超音波報告之選擇步驟 10
4.2 資料庫編碼之確效-門診病人 11
4.2.1 資料來源與研究對象 11
4.2.2 心臟瓣膜疾病確效之定義 11
4.2.3 心臟超音波報告之選擇步驟 12
4.3 嵌入型病例對照研究之研究設計 12
4.4 資料來源 12
4.4.1 臺灣全民健康保險研究資料庫 12
4.4.2 百萬人承保抽樣歸人檔 12
4.5 研究對象 13
4.5.1 病人族群與研究世代(cohort)之建立 13
4.5.2 病例組定義 13
4.5.3 對照組定義 14
4.6 抗憂鬱藥品之暴露變項 14
4.6.1 抗憂鬱藥品使用資料 14
4.6.2 抗憂鬱藥品使用時序之定義 14
4.6.3 抗憂鬱藥品累積用藥時間與劑量之定義 15
4.6.4 不同抗憂鬱藥品之分類 15
4.7 統計分析 16
4.7.1 描述性統計分析 16
4.7.2 條件式邏輯迴歸分析 16
4.7.3 統計軟體 16
第５章 研究結果 17
5.1心臟瓣膜疾病的資料庫編碼之確效-住院病人 17
5.2心臟瓣膜疾病的資料庫編碼之確效-門診病人 17
5.3病例組與對照組之建立 18
5.4 病人基本特性比較 18
5.5抗憂鬱藥品與心臟瓣膜疾病之風險相關性 19
5.5.1抗憂鬱藥品之使用時序 19
5.5.2抗憂鬱藥品之累積用藥時間 19
5.5.3抗憂鬱藥品之累積劑量及最後一劑每日劑量 19
5.5.4不同抗憂鬱藥品與心臟瓣膜疾病之相關性 20
5.6 建立心臟瓣膜疾病與其風險因子之統計模型 21
第６章 討論 22
6.1 心臟瓣膜疾病的資料庫編碼之確效-住院病人 22
6.2 心臟瓣膜疾病的資料庫編碼之確效-門診病人 23
6.3 研究族群之特性與藥品之使用 24
6.4 抗憂鬱藥品與心臟瓣膜疾病之相關性 24
6.4.1 抗憂鬱藥品之使用時序 24
6.4.2抗憂鬱藥品之累積時間、累積劑量及最後一劑每日劑量 25
6.4.3不同種類抗憂鬱藥品之使用時序 26
6.5 心臟瓣膜疾病之風險因子 28
6.6 研究特點與限制 29
6.6.1 研究之特色與優點 29
6.6.2 研究限制 30
第７章 結論 31
表 32
圖 48
參考文獻 5
Characterization of HBV-producing HepAD38 cell line
No full textB 型肝炎病毒為急性肝炎(acute hepatitis)或慢性肝炎(chronic hepatitis)的主原 因之一，全世界約有 20 億人口感染過 B 型肝炎病毒，其中有多於 3 億 5 千萬人 為 B 肝表面抗原(HBsAg)陽性的慢性帶原者，而慢性肝炎有極高的比例演變成肝 硬化(cirrhosis)或是肝癌 hepatocellular carcinoma (HCC)，其死亡率高達 25%。重 要的是，B 型肝炎慢性患者均無法靠目前的藥物痊癒。B 型肝炎感染肝細胞有許 多機制目前都還不是很清楚，我們必需要建立一個穩定的 B 型肝炎感染系統，用 以研究這些未知的機制並找到慢性 B 肝可能的解藥。過去以來，B 型肝炎在細胞 模式上的感染一直都困難重重，要提升感染率就必須要額外添加 PEG 及 DMSO。 直到發現 HBV 受體 NTCP，這對細胞模式上的感染來說是相當大的進展。而最 近也發現除了 NTCP 以外應該還有其他宿主蛋白會幫助 HBV 進入細胞之後的進 程，使 HBV 可以成功感染肝細胞。因此我們希望可以朝著找到其他影響 HBV 感 染的宿主因子，首先第一步就是要建立一個穩定的細胞模式感染系統。而我們所 使用的是廣為人知的 HepAD38 細胞株，這是一個會自己產生 HBV 的細胞株。 我們以西方墨點法來分析 HepAD38 細胞內的蛋白，發現看不到任何表面蛋白的 訊號，為了找到原因，我們以西方、北方墨點法及細胞培養上的改變去分析 HepAD38 的表面蛋白。最後發現，在 HepAD38 誘導後繼代培養對於 HepAD38 表面抗原之表現有極大的影響，並且發現表面抗原的抗體 13H10 無法辨識到 D 基因型的 HBV。我們也試了幾支不同的抗體，找到了 E11E4 和 Bioss 是可以辨 識 D 基因型 HBV 的表面抗原。簡單來說，沒有繼代對於 HepAD38 表面蛋白的 產生來說是有幫助的，加上使用可以辨認 D 基因型表面蛋白的抗體，使之在西 方墨點法上可以測得 D 基因型表面蛋白的表現。Among the 2 billion global populations once infected with Hepatitis B virus (HBV), 350 million people remain HBV positive carriers. These chronic Hepatitis B (CHB) patients have high risks of developing more severe forms of liver diseases, such as liver cirrhosis and hepatocellular carcinoma (HCC), with a mortality rate of 25%. More importantly, these HBV long-term carriers stay uncured, with relapses andreoccurrences, even under current anti-viral treatments. In order to find possible cure to HBV, establishing a stable HBV infection cell model system is required to investigate the many unknown HBV pathways. However, over the past few years, HBV infection has faced many limitations in cell culture. Although HBV infection can be achieved by adding the two essential components PEG and DMSO, the infection rate was greatly improved after the discovery of the HBV receptor, NTCP. Such discovery took a huge leap forward not only for HBV infection in cell culture, but also for other HBV-related studies. Recently, some research pointed out that other host factors, in addition to NCTP, may contribute to sequential viral pathways, specifically related to viral-host interactions, in both hepatocytes and culture cell lines after HBV entry. Therefore, we aim to examine other possible factors that can affect HBV infection. First of all, to establish a stable infection system in cell culture, HepAD38, a widely known cell line that can produce HBV after induction in tet-off system, was used to serve as the viral source for this study. To confirm that HepAD38 can synthesize functional infectious particles as indicated in previous literature, the protein extract from the cell line was examined using Western Blot, but the results showed no surface protein. A series of experiments were carried out to investigate why there was no surface protein in western blot. I hypothesize that the antibody affinity to recognize HBsAg epitopes, and the cell culture methods are possible factors to impact surface antigen protein detection. To investigate such matter, western blot, northern blot, and alternative ways to culture cells were used in this study. The results showed that the surface antigen antibody 13H10 was unable to recognize the epitope on HBV genotype D whereas other surface antigen antibodies, E11E4 and Bioss, yielded promising outcomes. Moreover, in cell culture, whether HepAD38 was passaged after induction has a huge influence on the expression of surface antigen. Passaging HepAD38 after induction could reduce surface protein quantity by almost ten folds in comparison to the ones without. This implies that the first Western Blot results showing no surface protein could be due to its inadequate protein amount collected. Overall, the results in this study suggest that only two surface antigen antibodies, E11E4 and Bioss, and cell culture methods determine whether the surface protein of genotype D would be recognized
Numerical Study of Pile Foundation on Sloping Ground under Seismic Loading
No full text台灣位於環太平洋地震帶(又稱環太平洋火山帶)上，每年大大小小地震不斷，根據中央氣象局的研究，台灣地區平均每年約發生18500次地震，其中有感的地震約有1000次。地震來臨時，短時間內的巨大能量會使建築物產生嚴重的損害，進而波及到生命財產安全。再者台灣的地形中，山地與丘陵等地形占大多數，此類區域的建築物在受到地震影響時可能會因為如地形效應等因素更為嚴重，因此根據內政部營建署的建築物耐震設計規範，在設計一建築物時，有許多需要考量的地方，從地形、斷層遠近到土壤性質，都是針對建築物耐震設計必要的考量。 因此，本研究欲利用有限差分數值模擬軟體FLAC模擬樁基礎位在傾斜地盤受震的反應。首先利用從規範得到的該區設計譜加速度並繪出該地的設計反應譜，再根據此反應譜從Pacific Earthquake Engineering Research (PEER)的強地動資料庫得到的相似於目標反應譜的不同的地震加速度歷時，接著將這些地震歷時加載至FLAC模型，並藉由改變樁基礎長度、樁長與至基盤長度之比值等因素進行探討，將最後模擬所得之結果，從許多不同地震參數的角度進行探討，希望能找出其中的關聯性。Pile foundation is a very common way to support the structures built on slopes. When earthquakes strike, they may drive the slopes to move and slide, which would exert additional loading to the piles. In addition, the cyclic loading may weaken the soil surrounding the pile if the induced strain is large. All of these may cause damages to the pile foundation which, in turn, affect the structure supported by the foundation. In the discipline of geotechnical earthquake engineering, the seismic behavior of pile can be analyzed by dynamic p-y method, or dynamic finite element / finite difference analysis. In this research, finite difference analysis (using commercial software FLAC) is utilized to model the behavior of pile installed in sloping areas. Different pile lengths, ratios of bedrock depth to pile lengths and locations of piles would be considered. Moreover, effect of input ground motion variability on pile response is studied. This is achieved by using 30 input ground motions (each with different ground motion characteristics). These ground motions are selected based on the target design spectrum for Taipei Basin, which has 10-percent probability of exceedance in 50 years (corresponding to the return period of 475 years). Pile performance considered in this study includes maximum moment, maximum shear force and maximum lateral displacement. Trends of the pile response with ground motion parameters, model geometry, pile configuration and analysis types are evaluated
Atrial Fibrillation with Rapid Ventricular Response in Pregnancy
No full textObjective: To report a case of atrial fibrillation with rapid ventricular response occurring during pregnancy. Case Report: A 35-year-old woman, gravida 3, para 1, abortus 1, with a history of persistent supraventricular arrhythmia, presented at 22 weeks' gestation. After adenosine administration, electrocardiography revealed atrial fibrillation with rapid ventricular response. The episode was complicated by hemodynamic instability and was refractory to verapamil. Sinus rhythm was restored after synchronized electrical cardloversion under sedation. Sotalol (80 mg) was given for arrhythmia and to control heart rate. The patient experienced a second episode of supraventricular arrhythmia at 26 weeks' gestation, which was also reversed after cardioversion. She delivered a healthy male baby at 38 weeks' gestation via scheduled cesarean section. Conclusion: Arrhythmias with underlying heart disease can result in serious hemodynamic deterioration. Electrical cardloversion is well-tolerated and effective in pregnant women and should not be withheld if clinically indicated
The Study of Relationship Between Spiritual Care and Life Adaptation in Retirement Home Residents
No full text研究背景與目的 「靈性照顧」是長期照顧特殊的服務方式，已在國外老人照顧專業領域中受到關注及倡議，目前在國內老人機構的服務模式對此議題探討甚少，且機構式照顧大部分仍著重在生物醫療層面，忽略老年人的心理及靈性需求的滿足。而靈性照顧場域不僅在安寧病房的服務，而是需提早在長輩們身體健康時就開始著手，以因應未來高齡化社會老化人口的需求，因此靈性照顧實有探究之必要。故本研究之探討目的有三：（一）了解住民對靈性照顧在生活適應的感受與看法；（二）照顧服務者如何在生活上運用靈性照顧協助住民生活之適應；（三）從靈性照顧身、心、社會及靈性觀點，探討住民成功老化的關聯性。 研究方法 本研究為質性研究，研究對象針對佛教安養機構安老所的長者15人，工作人員5人共20人，從研究者事先建立的訪談摘要進行半結構式訪談，以Maslow需求層次理論為理論架構，並以樣板式分析法，建立分析架構進行本文分析。 研究結果 研究結果包括： （一）老人居住的安養機構有佛教靈性的支持環境，能減少老人從原居住地移居至安養機構時的焦慮情緒，有助於靈性照顧的心理適應，其宗教資源的可近性及可及性，使老人增加參與宗教活動頻率，滿足靈性需求，進而提高社交網絡的機會，維持社會關係。佛教環境具有靈性及健康發展的雙重意義，有助於老人生活的適應。 （二）宗教繞佛活動提供老人健康促進方式，老人從靈性需求層面尋找到能增加運動以及身體保健的方法，也滿足其靈性需求。 （三）宗教師透過宗教義理為工具，傳播信仰的觀念，以教育者角度教育老人正向的思考與負面行為的規範，協助老人察覺靈性需求的成長，具有傳播宗教信仰的弘法者及教育者雙重角色。 （四）靈性照顧提供住民心靈沉殿及適應機構生活的照顧方式，而宗教為工作人員帶來便利性且正當性的工具與方法。 研究討論與建議 Maslow需求層次理論對安老所的老年人而言，靈性需求滿足不是最高層次的追求，老年人的需求是先透過高層次靈性需求的滿足而達成低層次需求滿足。透過靈性照顧老年人可以滿足其生理、安全、愛與隸屬、自尊、自我實現等層面的需求，朝向達成正向的成功老化目標一致。 依據研究結果，提出下列建議：（一）家屬能多陪伴老年人共同參與靈性休閒活動，協助老人獲得屬於親情的靈性關懷；（二）提供工作人員相關靈性照顧訓練，培養靈性服務的專業能力，給予個別化的靈性照顧；（三）舉辦增加靈性休閒活動，提高個人身體及心理健康，啟發心靈省思、解決靈性困擾。Background and purpose： Spiritual care has been an important concern in long-term care, but has received less attention in institutional care in Taiwan. Most of the Seniors’ long-term care institutions for older adults in Taiwan only focus on the basic needs of physiological care, and neglect their mental and spiritual needs. The purpose of this study was：(a) to understand the spiritual needs of older adults living in a retirement home ; (b) to discuss the current situation with the staff on how to provide spiritual resources allowing them to turn to for help in times of crisis or concern ; (c) to discuss the relationship between the spiritual care and successful aging in retirement home. Research method: This qualitative study was based on the theory of Maslow''s hierarchy of needs. Semi-structured interviews were conducted by a researcher following a written interview guide. In this study 15 elderly residents and 5 staff members who work in the Buddhist private retirement home were interviewed. Findings: Highlights from the study''s findings included: (a) The Buddhism building and environment of the institution served as a great support for spiritual care and reduced older adults'' anxiety resulted from moving to the retirement home from their homes . A good accessibility to religious resources may increase the participation of religious activities and increase their social networks and social relationships with others among older adults. Through these activities older adults are more likely to meet their spiritual needs. The Buddhism environment also adds significant meaning to spirituality and the health of older adults living in the retirement home. . (b) Through the ritual of walking around the Buddha, older adults were able to increase their physical activity and to maintain physical health as well as meeting their spiritual needs. (c) Through Buddhism, the Buddhist nun served as a mentor of the older adults and was able to help older adults to think positively and to fulfill older adults'' needs for spiritual care. (d) Spiritual care can provide elder residents a source of calm and healthy life. Religion can be a good tool for providing spiritual care. Discussion and Recommendations: Spiritual needs are not considered priority in the theory of Maslow’s Hierachy Needs. In long-term care setting, older adults'' spiritual needs should be considered while meeting older adults'' basic needs and more advanced needs. Through spiritual care, older adults living in a retirement home can meet the needs of physiological, safety, love, ''esteem, and self-actualization, and move forward toward successful aging. According to our study findings, we recommended: (a) Families'' acknowledgment of spiritual care can have a great influence on elder residents. (b) Staffs'' training in providing spiritual care should be strengthened. (c) Spiritual care related activities are strongly recommended for institutionalized elders, which may improve their health both physically and psychologically
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
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