P605
886-2-2789-6721
phhwu [at] gate.sinica.edu.tw
hwu [at] phys.sinica.edu.tw
P605
886-2-2789-6721
phhwu [at] gate.sinica.edu.tw
hwu [at] phys.sinica.edu.tw
Lee, Fu Fang / 886-2-2789-8985
(1) | 國內學術研究獎項 | 2016-03 | 科技部104年度傑出研究獎 | |
(2) | 國內學術研究獎項 | 2015-12 | 第十二屆 國家新創獎之學研新創獎 | |
(3) | 國內學術研究獎項 | 2010 | 科技部台法科技獎 | |
(4) | 國內學術研究獎項 | 2005 | 行政院傑出科技榮譽獎 | |
(5) | 國內學術研究獎項 | 2004 | 國科會傑出研究獎 |
(1) | 西元年:2018 研究人員(中):胡宇光、黃啟峰、梁耕三、徐翠玲、李宗澤、陳怡云、楊舜閔、陳翔欣、黃士炘 章為皓 李定國 陳培菱、彭奎恩、陳健群、Cheng-Zhi Shi、胡宇方、Giorgio Margaritondo、翁啟惠、胡宇光 研究人員(英):HWU, YEU-KUANG, Chi-Feng Huang, Keng S. Liang, Tsui-Ling Hsu, Tsung-Tse Lee, Yi-Yun Chen, Shun-Min Yang, Hsiang-Hsin Chen, Shih-Hsin Huang, Wei-Hau Chang, Ting-Kuo Lee, Peilin Chen, Kuei-En Peng, Chien-Chun Chen, Cheng-Zhi Shi, Yu-Fang Hu, Giorgio Margaritondo, Tetsuya Ishikawa, Chi-Huey Wong and Y. Hwu* 研究成果名稱(中):以自由電子雷射同調繞射影像術解析水溶液中攜帶藥物之微脂體影像 研究成果名稱(英):Free-Electron-Laser Coherent Diffraction Images Individual Drug-Carrying Liposome Particles in Solution 簡要記述(中):微脂體是由脂質所組成,臨床上,許多廣泛性的抗癌藥物便是利用微脂體進行輸送。改變微脂體的大小及性質,對於醫療應用及社會貢獻度將具有相當價值。然而目前的成像方法要在天然的液體環境中,評估脂質體的形狀及尺寸具有相當的難度。X光自由電子雷射術(X-FEL)的發展,對於具有較大尺寸的金屬奈米粒子和病毒的影像特別有幫助。我們將包覆有doxorubicin之微脂體進行X-FEL照射後,取得影像以 CDI進行演算及重組,重組影像與低溫電子顯微鏡(Cyro-EM)所得到的影像或經由X光小角度散射(SAXS)分析所得的散斑圖案結果一致。然而值得注意的是,低溫電子顯微鏡並無法觀測在一般液態環境中的微脂體。而常規的SAXS無法偵測在水溶液中偵測非均質性及大小不均勻的奈米棒狀樣品。特別的是這些搭載藥物的奈米顆粒其典型結構是具特異性的並且大小不均勻。這樣的特性也會影響其他成像技術:例如,動態光散射儀,其測得平均值遠超過許多顆粒大小,同時也無法檢測奈米顆粒內的藥物。我們顯示了X-FEL結合CDI可以克服這些限制,並得到微脂體包覆藥物在水溶液中的影像。該方法可望做為日後,藥廠對於同類型藥物於水溶液中型態分析之方法。 簡要記述(英):Using the excellent performances of the SACLA (RIKEN/HARIMA, Japan) X-ray free electron laser (X-FEL), coherent diffraction imaging (CDI) was used to detect individual liposome particles in water, with or without inserted doxorubicin nanorods. This was possible because of the electron density differences between the carrier, the liposome, and the drug. The result is important since liposome nanocarriers dominate at present the drug delivery systems. In spite of the low cross section of the original ingredients, the diffracted intensity of drug-free liposomes was sufficient for spatial reconstruction yielding quantitative structural information. For particles containing doxorubicin, the structural parameters of the nanorods could be extracted from CDI. Furthermore, the measurement of the electron density of the solution enclosed in each liposome provides direct evidence of the incorporation of ammonium sulphate into the nanorods. Overall, ours is an important test for extending the X-FEL analysis of individual nanoparticles to low cross-section-systems in solution, and also for its potential use to optimize the manufacturing of drug nanocarriers. The complete results have been published in the Nanoscale. |
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(2) | 西元年:2017 研究人員(中):胡宇光、裴熙理、陳祥欣、NanoX 團隊(台灣)、INSERM 團隊(法國) 研究人員(英):HWU, YEU-KUANG, CYRIL PETIBOIS, Hsiang-Hsin Chen, NanoX group, INSERM (France) 研究成果名稱(中):利用定量遠紅外線顯微鏡構築全腦三維化學影像 研究成果名稱(英):3D chemical imaging of the brain using quantitative IR spectro-microscopy 簡要記述(中):三維組織學技術的建立是現代解剖病理學發展的當務之急。辨識組織中不正常的因子對於了解疾病發生原因是必須的。然而目前並沒有可以在體內或組織裡用以偵測這些不正常因子,並將其以高解析度的三維影像呈現出來的技術。本所客座專家裴熙理博士與胡宇光研究員團隊應用一具有獨特性且具高通量的遠紅外線顯微術進行組織病理學之研究,該技術可結合自動圖像校正及三維-遠紅外線(3D-IR)圖像的光譜數據分析加以重建。該團隊成功的將370片小鼠全腦之連續切片,進行全光譜3D-IR影像掃描後得到腦腫瘤內部精確的化學成分組成並加以圖像化,同時亦經由X光斷層掃描技術進一步確認該腫瘤在腦部的位置。3D-IR圖譜的建立,可利用解剖學、化學及代謝產物之資訊,將腫瘤組織於正常大腦區塊中辨識出來。該團隊亦證實組織的代謝參數可以從IR的光譜圖中取得、定量,其代謝特徵可做為正常腦組織與腫瘤間的區別,同時也可以印證腫瘤組織中的瓦氏效應。該團隊所建立的光譜學方法,可以經由搜索整個光譜分佈,進一步以非監控的方式來區分腫瘤與健康組織。詳細的結果已發表於Chemical Science。 簡要記述(英):Characterizing abnormal parameters in a tissue is essential to understand the rationale of pathology development. However, there is no analytical technique, in vivo or histological, able to discover such abnormal features and provide their 3D distribution at microscopic resolution. Here, we introduce a unique high-throughput infrared (IR) microscopy method, which combines automated image corrections and subsequent spectral data analysis for 3D-IR image reconstruction. We performed the spectral analysis of a complete organ for a small animal model, a mouse brain with an implanted glioma tumor. The 3D-IR image is reconstructed from 370 consecutive tissue sections and corrected with the X-ray tomogram of the organ for an accurate quantitative analysis of chemical contents. A 3D matrix of 89.106 IR spectra is generated, allowing to separate the tumor mass from healthy brain tissues based on various anatomical, chemical, and metabolic parameters. We demonstrate that quantitative metabolic parameters can be extracted from IR spectra for characterization of brain vs. tumor metabolism (assessing the Warburg effect in tumor). Our method can be further exploited by searching for whole spectral profile discriminating tumor vs. healthy tissue in a non-supervised manner, which we call ‘spectromics’. The complete results have been published in the Chemical Science.
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(3) | 西元年:2014 研究人員(中):胡宇光、蔡岳霖、李家維、洪在明、 研究人員(英):HWU, YEU-KUANG, Yueh-Lin Tsai, Chia-Wei li, Tzay-Ming Hong, Jen-Zon Ho, En-Cheng Yang, Wen-Yen Wu, G. Margaritondo, Su-Ting Hsu, Edwin B. L. Ong and Y. Hwu 研究成果名稱(中):利用X光三維成像技術解析螢火蟲發光之物理機制 研究成果名稱(英):X-ray 3D imaging elucidates firefly luminescence physical mechanism 簡要記述(中):中央研究院物理研究所NanoX研究團隊成功利用同步輻射X光顯微鏡觀測螢火蟲發光器的氣管系統並解析出螢火蟲控制螢光閃爍的物理機制。 幾千年以來,螢火蟲產生自發的螢光的現象,不斷吸引人類的幻想。螢光蛋白及酵素也早已被分離、萃取、合成,並產生了大量的應用。但是不同於其他可以自發產生螢光之生物體螢火蟲可以控制螢光的發光,進而利用螢光的閃爍,達到群體聯繫的目的。螢火蟲控制螢光閃爍的生化機制也是於最近幾年才被提出,認為一氧化氮與粒線體的作用,作為細胞層級開關的角色。但是在系統層面及氧氣供應機制方面這些研究並沒有清楚的圖像。而當螢火蟲發光時,其發光器內複雜的氣管系統藉由與氣孔與外界直接連結,利用氣體的擴散經微小的氣管,將氧氣輸送到螢火蟲體內的發光細胞中,並利用發光細胞裡的螢光酵素將螢光素及氧氣結合,使得螢光素因為氧化而激發出螢光。並且在氧氣消耗殆盡之後再度回覆穩態。因為螢光發光時氧氣的供應是唯一可被調控而造成閃爍的反應要件,所以其在完整生物系統所扮演的角色,不應只嘗試在細胞生化層面回答。 傳統生物學觀察方式,因為無法對活體昆蟲進行超過光學解析度的即時影像分析,因此無法斷定數種有關氧氣供應方式的假說。中央研究院物理研究所NanoX研究團隊此次利用我國國家同步輻射研究中心之高亮度X光,藉由X光顯微成像之高穿透力及三維奈米解析度,成功地對螢火蟲發光器進行了完整的三維顯微成像,包括螢火蟲的體內極為複雜的微氣管結構,以及直徑小於200奈米之支氣管。經過數值化處理所有的氣管系統後,我們可以精確地計算出氧氣到達發光細胞的流量,並藉由精確地測量螢光發光的能量消耗評估氧氣提供螢光發光的整體效率。 基於以證實之螢光持續的時間與粒線體的關聯,我們可以證實在正常代謝狀況時,粒線體將消耗所有氣管系統所提供之氧氣,完全阻隔氧氣進入發光細胞中的發光系統。因此螢光閃爍頻率的控制需藉由粒線體的鈍化來達成。例如藉由一氧化氮合酶(NOS)受到神經系統刺激產生快速擴散的一氧化氮與粒線體的生化結合,鈍化粒線體來造成發光系統可以得到足夠的氧氣供給發出螢光。一氧化氮與粒線體的生化結合極為短暫,一氧化氮消逝而粒線體消耗氧氣速率高於氧氣從氣管系統到發光細胞的擴散速率時,螢光素將會因為缺乏氧氣而逐漸回復穩態,並停止發光。此種中間歇性的氧氣供給,也就是造成可控制的螢光的閃爍現象。 此突破性的研究成果是由清華大學李家維教授、中央研究院物理研究所胡宇光研究員,與瑞士EPFL、特有生物保育中心、台灣大學國立臺灣大學昆蟲學系合作所共同完成,並發表於國際知名物理期刊(Phys. Rev. Lett. 2014, DOI: 10.1103/physrevlett.113.258103) 簡要記述(英):The Institute of Physics NanoX team has resolved an important physical phenomenon in firefly luminescence mechanism using bright synchrotron x-rays of National Synchrotron Radiation Research Center and the phase contrast microtomography and transmission x-ray microscopy with spatial resolution <20nm. Firefly luminescence occurs through the action of the enzyme luciferase, which combines luciferin and oxygen to make oxyluciferin in an electronically excited state and releases light as it relaxes. While its biochemistry background was only recently established, the physical aspect remains unclear specifically where oxygen supply mechanism for light flashing is concerned. The team resolved this problem by obtaining a detailed three-dimensional mapping of the firefly lantern – a complex microscopic structure of the tracheal system including the smallest tracheole branches (~200 nm diameter) critical for the gas exchange. They established that the oxygen consumption corresponding to mitochondria functions exceeds the maximum rate of oxygen diffusion from the tracheal system to the photocytes and leave no room for other hypothesized control mechanisms to waste the oxygen supply. Measurement of the energy consumption of flashing confirms that the flashing mechanism indeed uses a large portion of this maximum rate. The flashing control therefore requires the mitochondria functions, which is also require large oxygen supply, to be passivated, e.g., by nitric oxide, subsequently allowing the oxygen supply to be switched to photoluminescence. This groundbreaking research was led by Chia-Wei Li of National Tsing Hua University and Yeu-Kuang Hwu of Academia Sinica, in collaboration with the Swiss Institution EPFL (Phys. Rev. Lett. 2014, DOI: 10.1103/physrevlett.113.258103).
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(4) | 西元年:2004 研究人員(中):胡宇光 研究人員(英):HWU, YEU-KUANG 研究成果名稱(英):Real time high resolution X-ray microscopy observa 簡要記述(中):高解析、高速度之x光顯像術具有即時觀察電鍍鍍膜之成長能力。藉由此項優勢,我們成功的觀察到過去從未在電鍍時發現到的之現象,那就是金屬鍍膜將在非導電的水汽泡表面上成長(如圖1所示)。這項發現不只說明了水汽泡在這個特殊情況下具有導電性,而且也提供了充分的證據說明當電鍍未達到最佳化時缺陷之生成機制,這項發現已在2002年的”自然”雜誌中發表。我們亦用相同的成像機制觀察高速之活體動物影像,在2004年中的”自然”雜誌中亦發表了此項特殊成果。圖2顯示胚胎群分裂之化石結構的3維重組影像,此非破壞性之技術且同時具備高解析度三維影像之能力可用來鑑定特殊細胞分裂模式,此種特殊的細胞分化型式在5億4仟萬年前就已存在。 簡要記述(英):High resolution, high speed radiology allows us to monitor the electrodeposition process in real time and realistic electrochemical environment. The discovery of a special growth phenomenon demonstrated the first time that metal deposition can occur on the seemingly nonconducting hydrogen bubbles.(Fig. 1) This observation does not only prove that the hydrogen bubble surface in this case is conducting, but also provide evidence of the nature of one notorious type of defects often compromises the film quality in electrodeposition. This work was published in Nature 2002. Our work using similar approach in high speed animal imaging was also reported by Nature in 2004. Fig. 2 show the tomography reconstructed 3D model of a fossil embryo cluster frozen in time exactly at a 2-4 fold cell cleavage stage. The nondestructive high resolution 3D imaging allows us to identify the special division mode in cell and prove that such type of cell differentiation already existed 540 million years ago. |