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交通大学-生物科技学院

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研究发展

生医工程研究室    林志生博士(Biomedical Engineering Lab – PI: Dr. Chih-Sheng Lin )

  • 探讨心血管疾病中心脏组织之纤维化病变的分子调控机制 
    细胞外基质(extracellular matrix, ECM)的代谢调节失序是许多心血管主要的病理机转与病变特征。基质金属蛋白?(matrix metalloproteinase, MMPs)是一群可降解组织中ECM蛋白质的分解酵素,而基质金属蛋白?组织抑制因子(tissue inhibitors of MMPs, TIMPs)则为MMPs内源性抑制因子,其精密调控着MMPs的活性。尽管影响ECM的代谢与疾病发生关系密切,但MMPs、TIMPs与心脏组织结构性重塑(remodeling)病程的发生机制至今仍未解。本实验室利用心脏衰竭(heart failure)与心房颤动(atrial fibrillation)的动物模式来探讨ECM、MMPs、TIMPs及其相关因子于心脏重塑病程的交互影响网络。据此将有助于了解此复杂心血管疾病的致病机转,进而能研发出新颖且有效性的MMPs抑制药物,以及应用于心血管疾病的预防与治疗。
  • 发展临床与食品病原体检测用之生物传感系统 
    近年来生物传感器技术急遽发展,其中包括利用生物传感器来侦测人体感染与食物污染之病原体,而本实验室已发展可用于登革热病毒与大肠杆菌O157:H7的生物传感系统。我们利用网版印刷碳电极(screen-printing carbon electrode, SPCE)结合金奈米粒子(gold nanoparticles, AuNPs)加以修饰,经由此技术可大幅提昇SPCE系统的检测敏感度与侦测极限。 
  • 利用微藻技术进行二氧化碳的减量与生产生质柴油 
    微藻(microalgae)是行光合作用高效能之生物,它们有效率地利用阳光,将水与CO2转换成生质能(biomass),而某些微藻可合成高量油脂,其可用来转脂化成为生质柴油(biodiesel)。此外,微藻于培养过程中可大量消耗工厂所排放废气中的CO2,以达减碳之效益。本实验室在本项研究中主要的目的是设计光生物反应器(photobioreactor),并利用微藻技术进行CO2减量与生质柴油生产之研究。

临床生化工程研究室    毛仁淡博士(Clinical-Biochemical Engineering Lab – PI: Dr. Jen-Tan Mao)

  • Functional role of Haptoglobin in Atherosclerosis 
      Haptoglobin (Hp) is an acute-phase protein, with its plasma levels increasing consistently in response to infection and inflammation. Due to the existence of two different alleles (Hp1 and Hp2) in chromosome 16q22, three main Hp phenotypes exist: Hp1-1, Hp2-1 and Hp2-2. Apparently, the structural difference among the Hp types may drastically affect its biological function and clinical outcomes. So far, we have developed Hemoglobin affinity and monoclonal antibody affinity columns for purifying Hp from human plasma as reported in Protein Expression and Purification and Journal of Chromatography B, respectively. In our previous results, Hp was found to possess an extremely potent antioxidant activity (5 times greater than that of probucol, a well-known potent antioxidant), this finding was a critical milestone in currently related areas and has been published in Proteomics in 2004. Of remarkable interest, the antioxidant activity of the Hp β subunit was extremely potent and markedly greater than probucol (15X). Using a recombinant Hp, we demonstrate that the Hp β chain is an extremely potent antioxidant directly preventing LDL from oxidation as published in Protein Expression and Purification, 2007. It is conceivable that expressed β subunit may provide as an initial utility for the future design of “mini-Hp” for a potent antioxidant. In the clinical study, we established an ELISA assay to determine the phenotypes of Hp in plasma and the pure Hp 1-1, 2-1, and 2-2 were used as standards (Clinical Biochemistry in 2007). By collaborating with the Cardiology Division of Veterans General Hospital at Taipei, 1,200 subjects have been investigated to study whether or not Hp phenotype is associated with the risk in incident coronary artery disease (CAD). Using stepwise logistic regression analyses with the plasma apoA-I levels adjusted to determine the major risk factors, our data suggested that Hp 1-1 was associated with the risk of CAD by 2 times greater than Hp 2-1 and 2-2. Moreover, we are excited by finding the existence of a point deletion in Hp allele 1 mRNA present in all phenotypes of human samples. The deletion mutation resulted in the formation of a stop codon. To our best of knowledge, the existence of this truncated mRNA has never been reported and the critical report is almost done and ready to submit. 
  • Physiological role of milk β-lactoglobulin 
     β-Lactoglobulin (LG) is one of the major milk whey proteins, containing about 10% of the total protein by weight. The molecular mass of LG is 18.5 kDa belonging to the lipocalin family. The secondary structure, it consists of nine β strands and one alpha-helix. The central hydrophobic pocket (calyx) possesses the property of binding to vitamin D, vitamin A, and fatty acids. LG is quite sensitive to thermal denaturation; the secondary structure is altered upon the heating with a transition temperature at 70-80°C. In the last five and half years, we have constructed a detailed thermal denaturation curve for LG with its time and temperature, the data providing the dairy industry with a valuable reference (Journal of Dairy Science, 2005). We have also mapped out a specific amino acid sequence region that is responsible for the thermal change above 80 °C. Such changes also result in losing its ligand binding abilities (retinol and palmitic acid) (Journal of Biological Chemistry, 2004). In addition, we have reported that a monoclonal antibody can only recognize the native form of LG, so that the un-denatured LG content in the processed milk can be determined (Journal of Dairy Science, 2004 and 2006). We showed that LG is a mild antioxidant whose potency is less than that of vitamin E and probucol (the latter being an antioxidant used for clinical therapy). The conversion of the LG monomer to dimer was responsible, in part, for the mode of action in protecting low-density lipoproteins against copper-induced oxidation (Journal of Dairy Science, 2007). More recently, we have shown that LG dramatically stimulates the proliferation of hybridoma B cells, but thermal denaturation abolishes this ability of LG. It is an important observation that the LG receptor was identified as a membrane Ig M using mass spectrum. We identified first the second vitamin D binding site of LG using synchrotron X-ray in National Synchrotron Radiation Research Center (NSRRC) (PROTEINS: Structure, Function, and Bioinformatics, 2008). 
  • Mechanism involved in instant browning reaction over post-harvested fruit 
     Plant polyphenol oxidase (PPO), also known as tyrosinase in animals (EC 1.14.18.1), is an enzyme containing copper that catalyzes two different reactions using molecular oxygen, hydroxylation of monophenols to o-diphenols and oxidation of the o-diphenols to o-quinones. This enzyme, responsible for melanization in animals and for browning in fruits and vegetables, is widely distributed in microorganisms, animals, and plants. We developed a rapid gel-electrophoretic blotting technique to identify the possible molecular form of PPO on a dried chromatographic paper that was immobilized with a colorimetric substrate catechol (Journal of Chromatography B, 2007). The method also allows us to identify potentially potent inhibitors from natural products. Furthermore, in view of recent studies indicating that tyrosinase is responsible for hyperpigmentation in humans, tyrosinase inhibitors have become increasingly important in medical and cosmetic products. We show the presence of a potent volatile inhibitor(s) for PPO in litchi pericarp. The surface of post-harvesting litchi pericarp revealed an opening ultra structure under the scanning electron macroscopic examination, therefore allowing an instant evaporation of PPO inhibitor. As such, the PPO oxidation was proceeded. The novel finding clarifies the mechanism involved in the rapid browning phenomenon of post-harvesting litchi pericarp.


     

计算生物研究室   黄镇刚博士 (Bio-computational Lab – PI: Dr. Jenn-Kang Hwang)

  •  CELLO-- protein subcellular localization predictor

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  •  pKNOT -- the first knotted protein server

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智慧型计算实验室    何信莹博士 (Intelligent Computing Lab – PI: Dr. Shinn-Ying Ho)

  • We aim to develop various evolutionary computation algorithms and optimization methodologies, and provide user-friendly tools for system optimization. A representative paper is as follows: S.-Y. Ho*, L.-S. Shu and J.-H. Chen, "Intelligent Evolutionary Algorithms for Large Parameter Optimization Problems," IEEE Trans. Evolutionary Computation, vol. 8, no. 6, pp. 522-541, Dec. 2004. (Highly cited article) 
  •  Based on the expertise of intelligent computation, we develop various bio-inspired optimization algorithms for computational proteomics, computational systems biology, computational biology, bioinformatics, etc. 
  • We establish national/international interdisciplinary collaboration with biologists to investigate systems biology and validate our proposed models. 
  • We are interested in establishing a user-friendly system of computer-aid vaccine design.
     

酵素与蛋白质研究    杨裕雄博士(Enzyme and Protein Engineering Lab – PI: Dr. Yuh-Shyong Yang)

  • 杨裕雄教授的研究兴趣着重于生物科技跨领域研究,包含酵素反应机制、蛋白质工程、基因工程与生物电子等相关领域。近几年在生物传感电子方面积极开发新的传感元件,希望从生物角度出发为生物电子领域带来新的发展。实验室核心技术为酵素与抗体之制备、固定化及特性分析,并应用定点突变与生物资讯进行蛋白质工程以创造特有的酵素性质,进而开发及设计新颖的生物检验相关技术,尤其是应用半导体传感器及积体电路作为生物讯号之传感及处理方式,以建构一独立或可携式之生物传感系统。

应用微生物与生化研究    曾庆平博士(Applied Microbiology & Biochemistry Lab – PI: Dr. Ching-Ping Tseng)

  • 曾庆平教授致力于以生物技术去除空气污染之相关研究,成果卓越多次获得国科会奖项,并入选国科会2008年4月份月历封面。

      以固定化菌体反应器处理养殖场废气

      交通大学生物科技系曾庆平教授及其团队,由活性污泥中筛选出有效除臭菌株,并设计一套密闭循环之生物反应系统,可取代传统堆肥场及养殖场用大量木屑或水洗塔来除臭,不但提高除臭效率也减少二次污染,除臭过程干净且环保。

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生物药学与无机化学分析研究室    张正博士(Bioinorganic & Bioanalytical Chemistry Lab – PI: Dr. Cheng Chang)

  • 108+篇国内外重要SCI学术期刊论文(h-Index = 26,累计SCI论文总点数>320点,总被引用次数>2040次)、138+篇科技会议论文及摘要、60篇工业研究报告、130个以上受邀学术演;6+件专利申请及文件(美、中、台)。曾研发三种磁振造影剂(ProHance®、Omniscan®、Teslascan®:2000世界市场值约一亿美元);4个IND及2个NDA新药申请(美、欧)。财团法人杰出人才发展基金会「杰出人才讲座」奖(1995-2000)、Asia Pacific Society of Bioscientists 2nd International Symposium & Workshop Excellence Award(Hong Kong,1996)。 

    最常被引用之论文 (> 80 次):
    1. C.A. Chang*, H.G. Brittain, J. Telser, and M.F. Tweedle. "pH Dependence of Relaxivities and Hydration Numbers of Gadolinium(III) Complexes of Linear Aminocarboxylates", Inorg. Chem., 1990, 29, 4468-4473. [SCI: 4.123; Rank: 4/43; No. of Citations: 84 ]
    2. M.F. Tweedle, J.J. Hagan, S. Mantha, K. Kumar, and C.A. Chang. "Reaction of Gadolinium Chelates with Endogenously Available Ions", Mag. Reson. Imaging, 1991, 9, 409-415. [SCI: 1.486; Rank: 47/87; No. of Citations: 85 ]
    3. K. Kumar, C.A. Chang, and M.F. Tweedle. "Equilibrium and Kinetic Studies of Lanthanide Complexes of Macrocyclic Polyaminocarboxylates", Inorg. Chem., 1993, 32, 587-593. [SCI: 4.123; Rank: 4/43; No. of Citations: 102 ]
    4. C.A. Chang*, L. Francesconi, M.F. Tweedle, et. al. "Metal Complexes for Magnetic Resonance Imaging: Synthesis and Characterizations of Fe(DO3A), Na[Fe(DOTA)], Gd(DO3A), and Na[Gd(DOTA)]", Inorg. Chem., 1993, 32, 3501-3508. [SCI: 4.123; Rank: 4/43; No. of Citations: 150 ]
    5. C.A. Chang*, L.Francesconi, D. Dischino, M. Malley, J. Gougoutas, and M.F. Tweedle. "Synthesis, Stability, and Structures of Gd(III) and Y(III) Macrocyclic Polyaminocarboxylates". Inorg. Chem., 1994, 33, 3567-3575. [SCI: 4.123; Rank: 4/43; No. of Citations: 130 ]
     

药物设计与系统生物实验室    杨进木博士BioXGEM – PI: Dr. Jinn-Moon Yang )

  • 我的研究以电脑辅助药物设计(Computer-aided drug design)及结构生物资讯(Structural bioinformatics)为主轴。在电脑辅助药物设计方面,目前我们是分子对接(Molecular docking)软件(GEMDOCK)提供者之一,我们也与国内外超过十个实验室合作,经由生物实验证实我们的方法确实可找到药物标的(如Envelop protein、Skimate kinase、 influenza virus neuraminidase)前导药物(Lead compound)、功能催化部位(如ß-lactoglobulin)、及蛋白质功能设计(如endo-chitosanase to exo-chitosanase)等,这些成果已发表多篇论文在这些领域最好的期刊上。这些论文从2004年起被引用次数已超过70次 (根据ISI);另外GEMDOCK被国内外数十个实验室使用,除研究的应用外,此软件也使用在教学上。这些成果让我们获得2007年国家新创奖(由国家生技医疗产业策进会主办),是唯一以电脑软件获奖的团体。

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  • 在结构生物资讯方面,我们在蛋白质结构预测(PS2)、高速蛋白质结构的搜寻与应用(3D-BLAST)、及结构为基的蛋白质网络(3D-partner)已有相当成果,这些研究已发表在相关领域最好的期刊上(如Nucleic Acids Research、Genome Biology) 。最值得一提的研究成果是3D-BLAST,3D-BLAST搜寻蛋白质结构的速度与BLAST搜寻胺基酸序列一样快,同时具备BLAST的优点与操作接口,也就是能提供可信的统计基础(e-value)及高效率的搜寻能力。因此3D-BLAST可能成为蛋白质结构搜寻的标准,对于结构搜寻有巨大影响,此研究成果已引起相关学者的重视与讨论。2007年起这些论文被引用次数已超过13次,目前已有44个国家,超过5,100 人次使用我们提供的服务。

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心脏电气学及心血管生物资讯学实验室     杨腾芳博士
(Electrocardiology and Cardiovascular Bioinformatics Lab – PI: Dr. Ten-Fang Yang)

 

  • 平均讯号心电图,时域领域及频率领域之信号分析研究。 
  •  心率变异性,时域领域及频率领域之信号分析研究。
  • 血液透析肾衰竭病患之平均讯号心电图之研究。 
  •  血液透析肾衰竭病患之心率变异性之研究。 
  •  平均讯号心电图,性别、年龄、种族差异之研究。 
  •  心率变异性,性别、年龄、种族差异之研究。 
  •  正常台湾人之平均讯号心电图研究。 
  •  正常台湾人之心率变异性研究。 
  •  心脏猝死之病因及心脏电气学侦测方式之研究。 
  •  标准12导程心电图在心脏学之研究。 
  •  向量心电图在心脏电气学之研究。 
  •  平均讯号心电图模式分析研究。

 研究室    王云铭博士 ( Lab – PI: Dr. Yun-Ming Wang)

  • 2007 Joint Annual Meeting ISMRM (International Society for Magnetic Resonance in Medicine)-ESMRMB (European Society for Magnetic Resonance in Medicine and Biology) 2007 Poster Award 3rd place

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  • Synthesis, Complexation and Water Exchange Properties of Gd(III)–TTDA–Mono and Bis(amide) Derivatives and Their Binding Affinity to Human Serum Albumin, Dalton Trans., 2749-2759, 2007. (Selected as Journal Cover)
    我们成功的合成出一个单醯胺TTDA衍生物,TTDA-N-MOBA及两个双醯胺TTDA衍生物,TTDA-BMA与TTDA-BBA。TTDA-N-MOBA、TTDA-BMA及TTDA-BBA之钆金属错合物在20 MHz、37 C下,求得其弛缓率(r¬1)分别为4.23、3.92及4.41 mM1 s1。钆金属错合物之内层水分子交换速率(kex298)及分子转动相关时间(R)则利用9.4 T之17O NMR求得。实验结果显示TTDA单醯胺衍生物,[Gd(TTDA-MOBA)],其kex298值为29.1  106 s1,大约是[Gd(TTDA)]2−之kex298值的1/5。另一方面,TTDA双醯胺衍生物,[Gd(TTDA-BMA)]与[Gd(TTDA-BBA)],其kex298值分别为15.2  106 s1及15.6  106 s1,大约是[Gd(TTDA)]2−之kex298值的1/10。另外,由17O NMR实验结果显示, [Gd(TTDA-MOBA)]、[Gd(TTDA-BMA)]及[Gd(TTDA-BBA)]之分子转动相关时间分别为157、119及187 ps,其值高于[Gd(DTPA)]2(103 ps)与[Gd(TTDA)]2−(104 ps)。在 [Gd(TTDA-BBA)]与HSA形成非共价性键结实验中,分别求得键结常数(KA)为1.0  104 M1,而键结弛缓率( )分别为52.0 mM1 s1。最后,由弛缓率研究与超过滤实验发现,[Gd(TTDA-BBA)]与HSA之键结弛缓率高于商业化之磁振造影对比剂MS-325。
  • Synthesis and Characterization of a New Bio-activated Paramagnetic Gadolinium(III) Complex [Gd(DOTA-FPG)(H2O)] for Tracing Gene Expression, Bioconjugate Chem. 18, 1716-1727, 2007. (Selected as Journal cover)
    我们设计、合成出具有半乳喃醣官能基之新颖钆金属错合物 [Gd(DOTA-FPG)],并针对其物、化性及生物活性上做一系列之探讨。利用 17O NMR 测定Dy(III)金属离子诱导水中17O 核种之化学位移变化来测得 [Gd(DOTA-FPG)]之内层水分子数,得其内层水分子数q = 0.92,并利用 Eu(III)金属错合物的化学发光性质以萤光光谱仪测得之数值求得其内层水 分子数q = 1.08,由这两个实验结果来确定其内层水分子数。另外我们再以 17O 核磁共振光谱仪实验来求得钆金属错合物之弛缓率(1/ T1、1/ T2)以及化学位移(ω),再进行数据逼近,可计算出钆金属错合物之内层水分子停留时间(τM)及分子转动相关时间(τR)。弛缓率( r1 )主要受到内层水交换速率( kex298 )及分子转动相关时间(τR)影响,在17O-NMR 研究结果显示[Gd(DOTA-FPG)]之水交换速率kex298 近似于[Gd(DOTA)]− 及[Gd(DTPA)]2− , 明显较[Gd(TRITA-bz-NO2)]− 及[Gd(TTDA)]2− 来的低, 实验结果亦发现将[Gd(DOTA)]−的一个羧酸基置换成双氟甲苯基半乳喃糖使得分子转动相关时间增加。

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  • 由弛缓率的增加和磁振照影影像对比提高之证据说明了当[Gd(DOTA-FPG)]在有半乳喃醣酵素和人类血清蛋白(HSA, human serum albumin)表现的环境时,半乳喃醣酵素(β-gal)或人类血清蛋白(HSA)与切除了半乳喃醣官能基部分的钆金属错合物产生了共价性键结,相对增加了分子转动相关时间(τR)而使得弛缓率提高。在体内动物影像研究方面,具有半乳糖酵素基因表现之CT26(老鼠结肠癌细胞)/ β-gal 肿瘤在磁振造影影像中较CT26 肿瘤具有较高的讯号增强效果。因此,[Gd(DOTA-FPG)(H2O)] 为具有生物活性之磁振造影对比剂且有足够的潜力追踪基因表现。 

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生物资讯算法实验室   卢锦隆博士 (Bioinformatics Algorithm Lab– PI: Dr. Chin Lung Lu)

  • \Multiple Sequence Alignment with Constraints  (MuSiC, MuSiC-ME, RE-MuSiC) 
    We are the first to propose the concept of constrained sequence alignment that allows biologists to incorporate their knowledge about structures/functionalities/consensuses of their datasets into sequence alignment. By specifying known functionally, structurally or evolutionarily related residues/nucleotides of the input sequences as constraints, the output of the constrained sequence alignment is an optimal sequence alignment in the condition that the user-specified residues/nucleotides should be aligned together in the alignment, so that the output alignment can more accurately reflect the true biological relationships among the input sequences. In this study, we have first designed an efficient algorithm for computing a constrained alignment of multiple sequences and have also developed a web server, called MuSiC (Multiple Sequence alignment with Constraints), for the online analysis. Using MuSiC, we have successfully located the subsequence fragment of the RNA sequence of SARS that is capable of folding itself into a stable RNA secondary structure with pseudoknot responsible for the replication of SARS viruses (Bioinformatics, 20:2309-2311, 2004). Then we have further developed its memory-efficient version, called MuSiC-ME (Memory-Efficient Multiple Sequence alignment with Constraints), that allows the users to align multiple sequences of length up to several thousand residues (Bioinformatics, 21:20-30, 2005). More recently, we have developed RE-MuSiC by further enhancing the constraint formulation of MuSiC as regular expressions, which is convenient in expressing many biologically significant patterns like those collected in the PROSITE database, or structural consensuses that often involve variable ranges between conserved parts. Experiments demonstrate that RE-MuSiC can be used to help predict important residues and locate evolutionarily conserved structural elements (Nucleic Acids Research, 35:W639-644, 2007).

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Figure 1: Three GST (Glutathione S-Transferase) proteins: The structural similarity between these three proteins is very high, but their pairwise sequence identities are extremely low.

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Figure 2: The constrained sequence alignment produced by RE-MuSiC, using the pattern of "[ST]-x(2)-[DE]" as the constraint, in which the residues shaded in yellow match the pattern. In addition, the residues in green boxes that correspond to the active sites shared by these three GST proteins are aligned together.

生化及物理化学研究室    林苕吟博士(Resaerch and Application of Biological Macromolecules Lab – PI: Dr. Tiao-Yin Lin)

  • 氨基酸突变对thioredoxin reductase催化之电子传递的影响

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分子调控研究室    彭慧玲博士(Molecular regulation Lab – PI: Dr. Hwei-Ling Peng)

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生物有机与分子演化研究室    吴东昆博士(Bioorganic and Molecular Evolution Lab – PI: Dr. Tung-Kung Wu)

  • The structure-function-mechanism and molecular evolution studies of oxidosqualene cyclase enzymes: Our goals in this project are to gain in-depth insights of how cyclase enzymes catalyze the complex cyclization/rearrangement reactions during sterol and triterpene biosynthesis that have captivated chemists and biochemists for more than half a century, and to develop novel inhibitors of these enzymes for potential use as antifungal, hypocholesterolemic, and phytotoxic agents. In parallel, promiscuous residues of cyclase enzymes is subjected to protein engineering to study product specificity/diversity during the molecular evolutionary course of the cyclases. We have identified several important amino acid residues involved in the enzyme catalysis and substrate binding. Numerous truncated intermediates have also been isolated to directly demonstrate the function of the amino acids to the mechanism of the oxidosqualene cyclization/rearrangement cascade.

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  • The Research on the biosolar energy device design and biomass-directed renewable energy production: Our goals here are to use materials from organic, organometallic, nano-particles, and bio-molecules and integrate them into a biosensitized solar cell device for the conversion of solar energy into electric or chemical energy. Specifically, protein will be subjected to protein engineering to obtain mutants with altered or improved electron transfer activity and tested for biosolar energy conversion efficiency. In parallel, results from the ultrafast relaxation dynamics showed profound effects of the protein matrix on the prosthetic group in different environments. We have successfully demonstrated the first example of biosensitized solar cell made with artificial proteins as potential photosensitizers and opened up a new avenue for the design and development of new biosensors, photo-electrocatalysts, or bio-mimetic solar cells.

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分子遗传研究    杨昀良博士(Molecular Genetics Lab – PI: Dr. JYun-Liang Yan)

  • 发现白色念珠菌形态/毒性因子与抗药因子有协同调控及交互作用。两个途径(Pathways)都受已知的毒性因子Efg1 与Cph1的调控。 
  • 发现第一个抗登革热病毒的药物。

生物芯片与细胞生物研究室    袁俊杰博士(The Cell Biology and BioChip Lab – PI: Dr. Chiun-Jye Yuan)

  • Mst3所引发细胞凋亡之分子机转之研究
    在近期研究中我们发现Mst3 不只存在于细胞质内,亦存在于粒线体膜间隙(intermembrane space) 内。我们更进一步发现在粒线体膜间隙Mst3会与其中之诱发细胞凋亡蛋白,如 AIF 及 endonuclease G (EndoG),结合形成复合体。而经由免疫金粒子电子显微影像及西方墨点法进一步确认Mst3 存在于粒线体膜间隙的事实。在粒线体中,Mst3可能参与了调控诱发细胞凋亡蛋白(如 AIF 及 EndoG)的活性。然而,Mst3亦有可能激活附着于复合体上的未知的核酸内切酵素(DNase),而促成细胞凋亡。

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图一、Mst3在粒线体内与 AIF 及 endonuclease G (EndoG)形成复合体。图中所示,细胞内Mst3 (丝线状绿色萤光) 与 Mitotracker (专一性粒线体标记、红色萤光)、AIF 及 EndoG (皆为红色萤光)有重叠现象,即在萤光显微影像呈黄菊色讯号。

  • Mst3 在孕妇生产过程及怀孕期病变上角色之探讨
    由病理切片(图二)及细胞作用机转相关研究显示, Mst3 在孕妇怀孕后期会受到氧化逆境(oxidative stress)的刺激 (而非生产过程相关荷尔蒙,如、前列腺素 E1、摧产素、血管收缩素等) 在胎盘中大量表现活化,并进而激发胎盘内滋养细胞(trophoblasts)的凋亡现象。此一现象可能是促发胎儿生产的起始信号,并对生产后期的协助胎盘剥离子宫内膜有实际助益。 

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图二、人类自然产胎盘(a-d)、 剖腹产胎盘 (e-h)及产程第一期胎儿组织 (fetal membrane of first trimester) (i-l)。 Mst3 表现 (a,e,i)、细胞凋亡s (b,f,j)、 nitrotyrosine讯号s (c,g,k)及aspase3活化 (d,h,l)。

  • 研发奈米生物材料并应用于癌症治疗
    我们已开发一新颖的包裹山葵过氧化酵素的奈米粒子(horseradish peroxidase -encapsulated silica nanoparticles; HRP-SNP)。此一奈米粒子的平均大小约为直径 100 nm (图 3)。 实验证实HRP-SNP 可有效将无毒前驱药indole-3-acetic acid (IAA)摧化成有毒之抗癌药,并可应用于癌细胞的毒杀。进一步实验证实HRP-SNP 生物相容性高,对细胞并不具毒性,且因外源性蛋白被玻璃凝胶基质所保护,而具减少免疫反应及延长酵素活性及稳定性的优势。 

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图三、TEM of the developed ESNP.


分子生物物理研究室    张家靖博士(Nano-Biotechnolgy Lab – PI: Dr. Chia-Ching Chang)

  • Self-assembled molecular magnets on patterned silicon substrates: Bridging bio-molecules with nanoelectronics 
    The paper reports the methods of preparing molecular magnets and patterning of the molecules on a semiconductor surface. A highly magnetically aligned metallothionein containing Mn and Cd (Mn,Cd-MT-2) is first synthesized, and the molecules are then placed into nanopores prepared on silicon (0 0 1) surfaces using electron beam lithography and reactive ion-etching techniques. We have observed the self-assemble growth of the MT molecules on the patterned Si surface such that the MT molecules have grown into rod or ring type three dimensional nanostructures, depending on the patterned nanostructures on the surface. We also provide scanning electron microscopy, atomic force microscopy, and magnetic force microscope studies of the molecular nanostructures. This engineered molecule shows molecular magnetization and is biocompatible with conventional semiconductors. These features make Mn,Cd-MT-2 a good candidate for biological applications and sensing sources of new nanodevices. Using molecular self-assembly and topographical patterning of the semiconductor substrate, we can close the gap between bio-molecules and nanoelectronics built into the semiconductor chip.

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  • Laser induced popcornlike conformational transition of nanodiamond as a nanoknife 
    Nanodiamond (ND) is surrounded by layers of graphite on its surface. This unique structure feature creates unusual fluorescence spectra, which can be used as an indicator to monitor its surface modification. Meanwhile, the impurity, nitroso (C-N=O) inside the ND can be photolyzed by two-photon absorption, releasing NO to facilitate the formation of a sp3 diamond structure in the core of ND and transforming it into a sp2 graphite structure. Such a conformational transition enlarges the size of ND from 8 nm into 90 nm, resulting in a popcorn-like structure. This transition reaction may be useful as nano-knives in biomedical application.

    1. SEM images of the A549 cell lines, irradiated with/without laser following ND treatment.
    2. SEM image of 6 nm nano-diamond before and after laser radiated. The average size of laser radiated nano-diamond is about 90 nm.

 

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整合系统生物学研究室   黄宪达博士 (Integrative Systems Biology Lab – PI: Dr. Hsien-Da Huang)

 

  • [MicroRNA Regulation: Databases and Tools]
    Recent works have demonstrated that microRNAs (miRNAs) are involved in critical biological processes by suppressing the translation of coding genes. In order to facilitate the investigation of microRNA regulation, we developed several biological databases and computational tools in this important field. Six articles in this filed were published in Nucleic Acids Research (2007 SCI Impact = 6.954). miRNAMap was selected as hot research in 2006 NAR Database Issue. miRNAMap was genomics maps for microRNA genes and their targets in metazoan genomes (Nucl Acids Res, 2006, Nucl Acids Res, 2008). ViTa is a database of host microRNA targets on viruses (Nucl Acids Res, 2007). We also survey the literatures to extract the RNA structural motifs and their functions to construct the RegRNA database (Nucl Acids Res, 2006). The RNAMST web server was developed for searching RNA structural homologs (Nucl Acids Res, 2006). RNALogo is designed as a new approach to display structural RNA alignment (Nucl Acids Res, 2008). These databases and tools were cited more than 53 times during last two years.

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  • [Protein Post-translational Modification: Database and Tools]
    Protein Post-Translational Modification (PTM) plays an essential role in cellular control mechanisms that adjust protein physical and chemical properties, folding, conformation, stability and activity, thus also altering protein function. Four articles in this filed were published in Nucleic Acids Research (2007 SCI Impact = 6.954). dbPTM is a comprehensive information repository of protein post-translational modification (PTM) (Nucl Acids Res, 2006). Furthermore, we developed KinasePhos [1.0, 2.0], which is a web tool for identifying protein kinase-specific phosphorylation site (Nucl Acids Res, 2005, 2007, J. Comp Chem 2005). Besides, ProKware was designed as an integrated software for presenting protein structural properties in protein tertiary structures (Nucl Acids Res, 2006). These database and tools were totally cited more than 50 times during last three years.

 

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分子抗癌研究室   赵瑞益博士 (Molecular Anticancer Lab – PI: Dr. Jui-I Chao) 

  • 近几年我们针对癌细胞中的标靶基因survivin及securin等,进行深入的研究。例如多种人类癌细胞(包括肺癌、乳癌、大肠癌及子宫颈癌等)会大量表达survivin蛋白,但在正常成人细胞不会表达survivin。Survivin蛋白具有抗细胞凋亡及促细胞分裂的功能,调控癌细胞中survivin蛋白的表达,与癌症的发生有密切的关系,而抑制survivin蛋白的表达,也可能应用于治疗癌症。我们建立了cyclin B1/cdc2与p38 MAP kinase可分别为正调控及负调控survivin基因及蛋白的表现(Chao et al., 2004, JBC)。此外,利用共轭焦显微镜及免疫萤光染色,建立survivin蛋白会大量表达于癌细胞之有丝分裂期,并会聚集于细胞质分裂期的midbody位置(Kuo et al., 2004, JBC)。同时我们发现将survivin基因阻断,会促进抗癌药物抑制癌细胞的生长及促细胞凋亡之作用(Chao and Liu, 2006, Mol. Pharmacol.)。以COX-2的抑制剂,celecoxib及etodolac,发现抑制COX-2的活性会降低survivin蛋白表达,并加强抗癌药物oxaliplatin的抗癌效果(Lin et al., 2005, Biochem. Pharmacol.)。Celecoxib会经由活化p38 MAP kinase路径,抑制大肠癌细胞中survivin蛋白的表达(Hsiao et al., 2007, TAAP)。而黄芩素(baicalein)会抑制膀胱癌细胞中survivin的表达,并诱发癌细胞凋亡(Chao et al., 2007, Mol. Cancer Ther.)。在抗癌奈米科技(Anticancer Nanotechnology)的研究,我们发现奈米钻石具有特殊萤光特性及作用,被选为生物物理期刊的封面(Chao et al., 2007, Biophys. J.)。此奈米材质不会造成正常细胞毒性及细胞凋亡,具有高度的生物相容性,并且奈米钻石在细胞内的萤光强度可被检测及量化 (Liu et al., 2007, Nanotechnology),我们进一步以蛇毒蛋白连结奈米钻石,可辨识细胞上的接受器(Liu et al., 2008, Nanotechnology),目前我们已经开发出奈米钻石携带抗癌药物的方法。此外,我们进一步开发奈米钻石作为癌细胞及干细胞的标定、侦测及追踪等应用。

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生化与遗传工程研究室    邱显泰博士(Biochemical and Genetic Engineering Lab – PI: Dr. Hsien-Tai Chiu)

  • 天然药物生物合成基因群组的遗传基因选殖、定序分析、酵素功能鑑定,进行药物研发。
  • 天然物的组合式生物合成,以各种生合成基因或酵素,组合制造出一群具生物活性药物的衍生物,达生技制药目的。
  • 为台湾灵芝联盟成员,从事药用真菌灵芝的全基因体解码,及灵芝多醣体与三?类生合成途径基因与图谱建构研究,贡献于药用真菌的功能性基体研究及中草药科学化。
  • 研究致病微生物生合成遗传基因群组,解析基因并鑑定其酵素功能,结合生物资讯研发致病微生物的抑制药物,完成致病菌生物资讯与演化分析。
  • 完成新颖酵素的化学与生化机理研究(含受质专一性、立体与几何选择性),并设计与成功合成酵素抑制剂、得动力学结果,应用酵素于在有机化学与药物合成。
  • 干细胞导向分化与增殖。
  • 应用生物资讯成功预测RNA二级结构与物种基因体演化。

肿瘤免疫治疗研究室    廖光文博士(Immunology and Oncology Lab – PI: Dr. Kuang-Wen Liao)

  • 免疫学:已检验出幽门螺旋杆菌对于细胞产生影响之主要分子—Hsp-60,正深入探讨其诱发免疫反应之主要机制,并研究Hsp60对于其他细胞所产生之影响
  • 微脂体 (Liposome):已完成此构型之建构,深入研究其快速且稳定吸附的作用力之机制及原理,同时利用此微脂体之特性包复药物,并结合导向分子
    以达到专一性输送药物之目的。
  • 抗体之制作及蛋白质工程:完成以VEGF及IgG Fc部份结合之抗体生产,纯化及应用。
    发现其可有效达到治疗肿瘤之目的。

计算化学研究室   尤祯祥博士 (Computational Chemistry Lab– PI: Dr. Jen-Shiang Yu)

  • 理论配位化学:以量子化学理论研究过渡金属配位化合物的多重键结性质与反应途径,及配位化学在金属蛋白研究上之应用。

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  •  蛋白质结构与反应之理论:利用各种计算化学方法,如全初始化理论(ab initio)、密度泛函理论(density function theory)、半经验理论(semi-empirical methods)以及分子力学(molecular mechanics)等理论或其混合方法,探讨蛋白质构形与相关生化反应的理论性质。

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 演化生物资讯实验室     林勇欣博士 (Evolutionary Bioinformatics Lab – PI: Dr. Yeong-Shin Lin)

  • Many Saccharomyces cerevisiae duplicate genes that were derived from an ancient whole-genome duplication (WGD) unexpectedly show a small synonymous divergence (K S), a higher sequence similarity to each other than to orthologues in Saccharomyces bayanus, or slow evolution compared with the orthologue in Kluyveromyces waltii, a non-WGD species. This decelerated evolution was attributed to gene conversion between duplicates. Using ≈300 WGD gene pairs in four species and their orthologues in non-WGD species, we show that codon-usage bias and protein-sequence conservation are two important causes for decelerated evolution of duplicate genes, whereas gene conversion is effective only in the presence of strong codon-usage bias or protein-sequence conservation. Furthermore, we find that change in mutation pattern or in tDNA copy number changed codon-usage bias and increased the K S distance between K. waltii and S. cerevisiae. Intriguingly, some proteins showed fast evolution before the radiation of WGD species but little or no sequence divergence between orthologues and paralogues thereafter, indicating that functional conservation after the radiation may also be responsible for decelerated evolution in duplicates.

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Y.-S. Lin, J.K. Byrnes, J.-K. Hwang, and W.-H. Li*. (2006). Codon usage bias versus gene conversion in the evolution of yeast duplicate genes. Proc. Natl. Acad. Sci. USA. 103: 14412-14416.
 

 
认知行为与神经功能研究室    曲在雯博士 (Cognitive Neuroscience Lab – PI: Dr. Tzai-Wen Chiu)
 
听神经元之与音编码机制:
 
  • 单一听神经细胞对声音之反应特性

以单细胞外记录法记录大鼠单一听神经元对各种不同声音的感受野,此研究成果可进一步用在预测单一听神经细胞对于复杂声之反应特征。
 

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  • 人类听觉皮层对声音编码之神经生理机制
     
    本实验室与脑中心、成大生理所及美国爱荷华大学医学院神经外科共同合作,以侵入式大脑皮层电位(ECoG)录法探讨人类听觉皮层对声音反应之特性,以期找出人脑对于语音编码之神经生理机制。
 

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细胞骨架及型态发生实验室     黄兆棋博士 (Cytoskeleton and Cellular Morphogenesis Lab – PI: Dr. Eric Hwang)

  • We used pluripotent P19 cells to study the function of microtubule-associated proteins during neuritogenesis. Multi-dimensional protein identification technology (one type of gel-free high throughput proteomics) was performed on microtubule-associated proteins prepared before versus shortly after neurite induction. More than 800 proteins were consistently identified in both proteomes. Surprisingly, when these two proteomes were quantitatively compared, the majority of the proteome remain unchanged. Substantial changes in the microtubule-associated proteome occurred at the level of individual proteins. Based on our proteomic results, we assayed primary neurons using RNA interference to identify a novel inhibitory role for protein TRIM2 in neurite elongation.

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