Significant Research Achievements of ACADEMIA SINICA

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1 2015 Significant Research Achievements of ACADEMIA SINICA

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3 Message From the President Pursuing Excellence As the most eminent research institution in Taiwan, Academia Sinica has the mission to conduct cutting edge research in humanities and sciences, nurture academic talents, and facilitates the societal advancement of Taiwan. It encompasses 24 research institutes and 7 research centers, which are organized into three research divisions: Mathematics and Physical Sciences, Life Sciences, and the Humanities and Social Sciences. In the past year, a continuous and fruitful growth was observed for Academia Sinica from many aspects. These include production of high quality academic papers, conference proceedings and books, growth of international exchanges, and increase of collaboration with industry and/or other research institutes. These are not only presentations of our efforts but also a symbol of passion and enthusiasm for the pursuit of academic excellence. Consistent and measurable progress has made Academia Sinica the leading research institution nationwide and a competitive opponent to its neighboring countries. In 2015, its number of papers listed in SCI, SSCI, and A&HCI has reached 2,285, equivalent to an average of 2.72 per researcher. Furthermore, according to ISI Essential Sciences Indicators (ESI), the amount of paper being cited in the top 1% division has reached 100. In the past 10 years, Academia Sinica has consistently been ranked among the top 1% of research institutions in 18 fields. The number of highly cited papers also increased remarkably and the influence of publication published by Academia Sinica has also been noteworthy in the international academic community. The efforts made by Academia Sinica are well recognized internationally. Academia Sinica was ranked 22 on the Thomson Reuter s Top 25 Global Innovators Government. This list identifies and ranks publicly funded institutes (government research institute) doing the most to advance science and technology. Thomson Reuters also emphasized that Academia Sinica is pushing new programs designed to encourage technology transfer. The publication of Significant Research Achievements is to share our research results with the public. 77 papers and books are selected this year, covering a wide range of research fields and including a selection of research competencies. In the humanities and social sciences, topics 2

4 ranging from new advances in Formosan Linguistics, analysis of the mapping and description of reclaimed and prohibited paddy and dry land in Taiwan to the research about global exposure in East Asia are included. In mathematics and physical sciences, this issue features a synthesis of timeresolved luminescence nanothermometry with the nitrogen-vacancy centers in nanodiamonds, observations of the models of landslide seismic magnitude, development of high-potential compound for use in next generation electronic devices, and the application of multimedia. In life sciences, important topics in the studies of the causes of human diseases, the mechanism of evolution, and new drug design are presented. Innovation is the key to the continuous growth in Taiwan s knowledge-based economy. With emerging basic research as a solid foundation, further economic development can be established through research commercialisation. By assuring the protection of intellectual property rights and holding joint conferences on research achievements with other domestic research institutions, Academia Sinica hopes to strengthen the cooperation between research and industry and assist the government in developing emerging industries. At present, crucial areas awaiting further research include translational medicine, biomass and solar energy, issues concerning environmental changes and global warming, gene transformation and stem cell research, knowledge economy and cultural industry studies. Academia Sinica will continue to explore these areas and endeavor to promote Taiwan s economy and the well-being of the people. ACADEMIA SINICA Acting President of Academia Sinica 3

5 CONTENTS 02 Message From the President 06 Introduction of Academia Sinica Academic Achievements 08 Research Achievements 10 Competencies Talent Development 11 Doctorate Program 12 Nurturing Young Talent-Postdoctoral Training 13 International Academic Exchange and Cooperation Social Contribution 14 Awards and Honors 15 Intellectual Property Management and Technology Transfer Areas of Strength 18 Cancer Vaccine and Therapeutic Antibody Development 20 Structural Biology 22 Earthquake Research at the Institute of Earth Sciences 24 Chemical Dynamics : From Fundamental Understanding to Practical Problem-Solving 26 Ecology, Evolution and Biodiversity 28 Taiwan Biobank 30 New Perspectives on Chinese History 32 Panel Study of Family Dynamics 2015 Significant Research Achievements of Academia Sinica Division of Mathematics and Physical Sciences 36 R331W Missense Mutation of Oncogene YAP1 Is a Germline Risk Allele for Lung Adenocarcinoma With Medical Actionability Hsuan-Yu Chen, Yi-Chiung Hsu, Chi-Sheng Chang, Yu-Cheng Li, Shi-Yi Yang, Hao Ho, Ya-Hsuan Chang, Hwai-I Yang, Shinsheng Yuan, Chia-Hsin Liu, Guan-I Wu, Chien-Jen Chen, and Ker-Chau Li 4

6 ACADEMIA SINICA 38 Direct Kinetic Measurement of the Reaction of the Simplest Criegee Intermediate With Water Vapor Wen Chao, Jun-Ting Hsieh, Chun-Hung Chang, and Jim Jr-Min Lin 40 Time-Resolved Luminescence Nanothermometry With Nitrogen-Vacancy Centers in Nanodiamonds Yan-Kai Tzeng, Pei-Chang Tsai, Hsiou-Yuan Liu, Oliver Y. Chen, Hsiang Hsu, Fu-Goul Yee, Ming-Shien Chang, and Huan-Cheng Chang Division of Life Sciences 42 At14a-Like1 Participates in Membrane Associated Mechanisms Promoting Growth During Drought in Arabidopsis thaliana M. Nagaraj Kumar, Yi-Fang Hsieh, and Paul E. Verslues 44 Circulating Cells Contribute to Cardiomyocyte Regeneration After Injury Jasmine M.F. Wu,Ying-Chang Hsueh, Hui-Ju Ch'ang, Chwan-Yau Luo, Li-Wha Wu, Hiromitsu Nakauchi, and Patrick C.H. Hsieh ACADEMIA SINICA 46 A Common Glycan Structure on Immunoglobulin G for Enhancement of Effector Functions Chin-Wei Lin, Shiou-Ting Li, Tsung-I Tsai, Meng-Yu Lai, Chia-Yu Wu, Yung-Chieh Tseng, Chia-Lin Chen, Che Ma, Chung-Yi Wu, and Chi-Huey Wong Division of Humanities and Social Sciences 48 Gendered Words: Sentiments and Expression in Changing Rural China Fei-Wen Liu 50 Guxin Shengjing Cangao Sher-Shiueh Li 52 The Purple Aboriginal Boundary: Analyzing the Map and Description of Reclaimed and Prohibited Paddy and Dry Land in Taiwan Yu-Ju Lin, Su-Chuan Chan, and Chih-Hao Chen 54 Abstracts of Other Significant Publications in

7 Introduction of Academia Sinica Academia Sinica, founded in 1928, is the most preeminent academic institution in Taiwan with a mission to pursue research excellence, nurture academic talents, and issue policy advisories. Former President Dr. Chi-Huey Wong, assisted by Vice Presidents, Yu Wang, Andrew H.-J. Wang and Fan-Sen Wang, has taken the leadership to make further progress in improving research conditions and results. Academia Sinica currently has 24 institutes and 7 research centers under three divisions: the Division of Mathematics and Physical Sciences, the Division of Life Sciences, and the Division of Humanities and Social Sciences. At present, there are more than 2,000 researchers with Ph.D. degree. Among 263 academicians, there are 7 Nobel laureates. Central Office of Administration and Central Academic Advisory Committee were later established to facilitate the general administration and the promotion of academic development. The purpose of academic research is to improve human life. Academia Sinica will continue its tradition of pursuing solid research while exploring new knowledge and will remain focused on the needs of society in the hope of enriching human civilization. Organization Council of Academia Sinica President Convocation of Academicians Vice President Central Academic Advisory Committee General Assembly Academic Advisory Committees for the Institutes and Research Centers Institutes and Research Centers Central Office of Administration 6

8 ACADEMIA SINICA Institutes and Research Centers Division of Mathematics and Physical Sciences Division of Life Sciences Division of Humanities and Social Sciences Institute of Mathematics Institute of Physics Institute of Chemistry Institute of Earth Sciences Institute of Information Science Institute of Statistical Science Institute of Atomic and Molecular Sciences Institute of Astronomy and Astrophysics Research Center for Applied Sciences Research Center for Environmental Changes Institute of Plant and Microbial Biology Institute of Cellular and Organismic Biology Institute of Biological Chemistry Institute of Molecular Biology Institute of Biomedical Sciences Agricultural Biotechnology Research Center Genomics Research Center Biodiversity Research Center Institute of History and Philology Institute of Ethnology Institute of Modern History Institute of Economics Institute of European and American Studies Institute of Chinese Literature and Philosophy Institute of Taiwan History Institute of Sociology Institute of Linguistics Institute of Political Science Institutum Iurisprudentiae ACADEMIA SINICA Research Center for Information Technology Innovation Research Center for Humanities and Social Sciences 7

9 Academic Achievements Analysis of Published Paper Academia Sinica endeavors to achieve excellence in research. The quantity and quality of paper published have increased progressively during the past ten years. In 2015, there were 2,285 papers listed in Web of Science Core Collection (WoSCC). The average number of paper published by researchers showed a steady increase since Average number of paper listed in SCI, SSCI, and A&HCI (excluding conference abstracts, or other similar type of article) per researcher also experienced a steady increase taking the total to 2.72 in When observing the top 1%, 10%, and 20% of numbers of citation in various research disciplines from the Essential Science Indicators (ESI) database, the number of paper in 1% and 10% experienced a noticeable growth reaching 100 in Number of Papers & Average Papers Published per Researcher Number of Highly Cited Papers Source: WoSCC, period cover: , accessed Mar Source: ESI & WoSCC, period cover: , accessed Mar From the analysis shown by Scival, a web-based strategic analysis tool, it is evident that Academia Sinica exhibited a strong academic performance in 2015 compare to Taiwan s overall performance. For example, Academia Sinica achieved 21.4% in the Top 10% of the world index compare to 12.4%, and the Publications in top 10 journal percentile was 62.3% compare to 36.6%. When examining field-weighted citation impact (FWCI) value, Academia Sinica achieved 1.44, indicating Academia Sinica s publication was cited 44% more than the world s average. A holistic view of Academia Sinica s FWCI in the period , Academia Sinica was shown to remain well above the world s average and was above the North American s average since In addition, Academia Sinica is dedicated to promoting global visibility, and the positive result is shown by the high international collaboration rate of 48.2%. FWCI for Academia Sinica and Selected Areas, Academia Sinica North America Europe Four Asian Tigers World Taiwan Asia Pacific Source: Elsevier SciVal Analytics, Scopus data, accessed Mar

10 According to the analysis of ESI during the past ten years, Academia Sinica was ranked among the top 1% of research institutions in 18 fields, which are Physics, Chemistry, Space Science, Clinical Medicine, Biology & Biochemistry, Molecular Biology & Genetics, Plant & Animal Science, Material Science, Geosciences, Neuroscience & Behavior, Microbiology, Pharmacology & Toxicology, Environment & Ecol ogy, Immunology, Engineering, Computer Science, Agricultural Sciences, and Social Sciences, General, of which Space Science field is the most recent addition. Academia Sinica Ranked among Top 1% of Research Institutions in 18 Fields, Field No. of Papers Citations Citations per Paper Physics 4,184 64, Chemistry 2,642 40, Space Science (New) 1,274 30, Clinical Medicine 1,450 29, Biology & Biochemistry 1,613 23, Molecular Biology & Genetics 1,279 27, Plant & Animal Science 1,298 15, Material Science , Geosciences 1,204 15, Neuroscience & Behavior 386 5, Microbiology 302 5, Pharmacology & Toxicology 360 5, Environment & Ecology 364 4, Immunology 255 4, Engineering 559 3, Computer Science 667 3, Agricultural Sciences 212 2, Social Sciences, General 399 1, ACADEMIA SINICA Source : ESI, period cover: , accessed Mar The quantitative analysis provided by WoSCC, ESI and Scival does not completely reflect the significance and contribution of many publications in the Humanities Science division, particularly in the form of Chinese books, or in disciplines focusing conference publication (e.g. information technology). For example, Academia Sinica performed extraordinarily in the Information Technology discipline with almost 300 conference papers published in Furthermore, institutes in the Division of Humanities and Social Sciences published more than 60 books, including Periphery and Center : Archaeological Research of Anyang and the Surrounding Regions, An Investigation of the Aborigines in Taiwan: Vol.8 Paiwan, SaySiat / Vol.3 Cou, Hla alua, Kanakanav, Economic Policy in Taiwan: Essays in Honor of Academician Tzong-Shian Yu, Shaping the New Man: CCP Propaganda and Soviet Experiences, The Other and Asian American Literature, Translation and Transcultural Movement: Knowledge Construction and the Transmission of Texts and Literary Style, Reading Antique Cartography, On Language Change, Japanese Government's Policy towards the Taiwan Strait, Policy Responses to Precarious Work in Asia, Local Realities and Changes in the History of East Asia, and many more not listed in this section. 9

11 Academic Achievements Competencies SciVal s competencies analysis is a bibliometric analysis on institutional strengths based on five year publication data from Scopus. This offers an interdisciplinary perspective of research performance showing an institution s leading position in terms of number of publications, number of highly cited publications or innovation (the recentness of cited publications). According to the analysis of SciVal, the number of Academia Sinica s identified competencies has grown significantly from 112 to 166 since Number of Competencies, No. of Cometencies No. of DCs No. of ECs Source: Elsevier SciVal Analytics, Scopus data, accessed Mar An analysis of all Academia Sinica s papers published over the five years ending 2014 revealed 166 competencies, including 13 Distinctive Competencies (DCs) and 153 Emerging Competency (ECs). As indicated by Academia Sinca s 2014 competencies map, Biochemistry, Genetics and Molecular Biology (revealed 67 competencies), Physics and Astronomy (revealed 35 competencies), Medicine (revealed 31 competencies) and Chemistry (revealed 21 competencies) are the key fields of Academia Sinica, which have the greatest potential to achieve leading positions. Moreover, many of Academia Sinca s 2014 competencies are located within the interior of the Wheel of Science, and this spatial distribution indicates that Academia Sinica excels in multidisciplinary research. SciVal competencies map for 2014, showing 166 competencies in Academia Sinica Source : Scopus data up to 9 Mar Retrieved 21 Mar from SciVal Source : Elsevier SciVal Analytics, Scopus data, accessed Mar

12 Talent Development Doctorate Program Taiwan International Graduate Program (TIGP) To keep up with the pace of today s fast evolving scientific and technological world and to promote the internationalization of higher education in Taiwan, Academia Sinica established the TIGP in collaboration with key domestic research universities. In addition to the all-english teaching and research environment, state-of-the-art facilities and globally renowned faculty, the TIGP also provides its Ph.D. students with the following benefits:1) a non-taxable monthly stipend of NT$34,000 (~US$1,133) for up to 36 months; 2) free Chinese language courses at primary level; 3) a cozy and convenient on-campus student dormitory at affordable rates. TIGP has taken a step forward to fulfill its main mission promoting the internationalization of higher education in Taiwan. The followings are also features that may help TIGP students extend their learning : Exceptional scientists have been invited to address and share with the TIGP students their unique stories on achieving success in their academic career. TIGP Student Travel Grant has been provided to encourage students to participate in important international conferences. The travel grant is intended to offer students the opportunities to meet and learn from experts in their related fields. Academia Sinica has substantial connections with distinguished overseas research universities and institutions providing TIGP students with great opportunities to visit and conduct research work in renowned laboratories/institutes. In order to attract more young and talented scholars to apply for the TIGP Ph.D. program, the TIGP International Internship Program (TIGP-IIP) was launched in It is an intensive pre-doctoral research training program that prepares its participating interns with the necessary knowledge and skills for future research or career development through rigorous hands-on training. Degree Program (DP) More recently, in 2008, Academia Sinica established the Degree Program (DP) to provide a more advanced higher education environment for domestic students. Similar in design to the TIGP, the DP is also coestablished with domestic universities. Currently the DP offers 7 interdisciplinary Ph.D. programs. Left : 2015 TIGP 10 th Certificate Conferral Ceremony. Right : TIGP students participated in the Dragon Boat Festival. Programs Cancer Biology and Drug Discovery Marine Biotechnology Translational Medicine Degree Program TIGP and Partner Universities Program Partner Universities Departments/Institutes Chemical Biology and Molecular Biophysics Molecular Science and Technology Molecular and Biological Agricultural Sciences Molecular and Cell Biology Bioinformatics Nano Science and Technology NANO/ Molecular Medicine Earth System Science Biodiversity Interdisciplinary Neuroscience Sustainable Chemical Science and Technology Social Networks and Human- Centered Computing National Taiwan University National Tsing Hua University National Tsing Hua University National Central University National Chung Hsing University National Defense Medical Center National Yang-Ming University National Tsing Hua University National Chiao Tung University National Taiwan University National Tsing Hua University National Yang-Ming Universityhttp:// National Central University National Taiwan Normal University National Yang-Ming University National Cheng Kung University National Chiao Tung University National Tsing Hua University National Chengchi University DP and Partner Universities Partner Universities China Medical University Taipei Medical University National Sun Yat-Sen University National Taiwan Ocean University National Taiwan University Kaohsiung Medical University China Medical University Taipei Medical University National Yang-Ming University Tzu Chi University National Defense Medical Center 1. Institute of Biochemical Sciences 2. Department of Chemistry 1. College of Life Sciences 2. Department of Chemistry Department of Chemistry Department of Physics 1. Biotechnology Center 2. Graduate Institute of Biotechnology Graduate Institute of Life Sciences Institute of Biomedical Informatics Institute of Bioinformatics and Structural Biology Institute of Bioinformatics and Systems Biology 1. Department of Chemistry 2. Department of Physics Department of Engineering and System Science Program in Molecular Medicine College of Earth Sciences Department of Life Science School of Life Sciences Institute of Clinical Medicine Taiwan International Graduate Program of Sustainable Chemical Science and Technology Institute of Information Systems and Applications Department of Computer Science National Sun Yat-Sen University National Taiwan Ocean University Genome and Systems Biology National Taiwan University Microbial Genetics and Genomics National Chung Hsing University Information and Network Systems National Chiao Tung University Multimedia Systems and Intelligent Computing National Cheng Kung University ACADEMIA SINICA 11

13 Talent Development Nurturing Young Talent-Postdoctoral Traning Academia Sinica (AS) has the mission to nurture academic talents. Providing postdoctoral positions to young PhD graduates is one of strategies we adopt for this mission. We offer a favorable research opportunity for both domestic and international candidates. They can easily find their fields of interests in areas of mathematics and physical sciences, life sciences, humanities and social sciences at AS. In AS, postdoctoral fellows can be supported by various financial resources as follows: 1. The grant for Postdoctoral Fellow Program funded by AS approximately with 200 million NTD per year in support of 200 young researchers conferred PhD degree within 4 or 6 years. 2. Internal funding from intramural budget of AS not including that allocated for Postdoctoral Fellow Program. 3. External funding granted by other agencies such as Ministry of Science and Technology, National Health and Research Institutes, Council of Agriculture or the Ministry of Education. From 2005 through 2015, the postdoctoral population in AS increased significantly from 517 to 1,225, a 2.4-fold growth. In addition, its distribution of budget invested differed greatly. The number of postdoctoral fellows supported by the intramural budget rose markedly with a fivefold increase during the past decade and has become the largest group. A 2-fold rise in the number of postdoctoral fellows funded by external agencies was also observed. The group supported by the Postdoctoral Fellow Program was relatively consistent in size, though decreasing from 40% to 20% over the period. Career Development After Postdoctoral Training Academia Sinica continues to keep track of the career development of young scientists after finishing postdoctoral training. According to the information we collected, most postdoctoral fellows aim for academic careers, 35% as researchers in research institutions and 33% as faculty members in universities. Meanwhile, 13% of them seek opportunities in enterprise outside the academics. 12

14 International Academic Exchange and Cooperation In order to construct close connection with the international scientific community, Academia Sinica has signed cooperation agreements with more than 380 academic research institutions and universities in over 40 countries spanning five continents. The notable partners include The European Molecular Biology Organization (EMBO) and The European Molecular Biology Conference (EMBC), the National Aeronautics and Space Administration (NASA) and National Institutes of Health (NIH) of the US, The Swedish Research Council, Indian National Science Academy (INSA), The Mongolian Academy of Sciences, and East Asian Core Observatories Association. Other than that, Academia Sinica has dedicated to the talent cultivation and training by signing cooperation agreements with academic and educational institutions in the US, including Stanford University; College of Chemistry, University of California, Berkeley; University of California, San Diego; University of California, Davis, and The Scripps Research Institute. As of the end of 2015, ten postdoctoral fellows of Academia Sinica were sent to the partner institutions in the US for research. Academia Sinica also reached a Memorandum of Understanding with the National Cancer Institute (NCI) of the US National Institute of Health (NIH) to provide a framework by which cooperative programs may be implemented to improve human health as a whole. Academia Sinica also plays an active role in many international organizations such as The World Academy of Sciences (TWAS). The main mission of the academy is to promote scientific excellence and capacity in the South for science-based sustainable development. In 2015, Academician Jing Yu of Academia Sinica was elected to be a new member of TWAS. In addition, Taiwan scholar Professor Pi-Tai Chou received a TWAS Prize, and a research fellow of Academia Sinica was elected a TWAS Young Affiliate. In the last two years, Academia Sinica has been the host of several important international conferences such as the 2014 IUBMB Conference and the 17th International Conference on Emerging Infectious Diseases. Academia Sinica is also the official conference host of the 23rd Pacific Science Congress (PSC-23) of Pacific Science Association to be held in June In addition, Academia Sinica will host the next triennial ICSU General Assembly in ICSU is a non-governmental organization with a global membership of national scientific bodies (122 members) and International Scientific Unions (31 members). All national members and unions will discuss the directions and priorities in science in the GA, and the conclusions will serve as guidelines on policy for the government of the national members. Every year many distinguished international scholars are invited to give lectures at Academia Sinica. Invited speakers in 2015 include Dr. Bruce Beutler, Dr. Randy Schekman, Dr. Tetsuya Ishikawa, Dr. Ehud Keinan, Dr. Jeffrey Ravetch, Dr. Cass R. Sunstein and Dr. Peter Schultz. The Canadian philosopher and the Kluge Prize winner Dr. Charles Taylor will visit the academy as Academia Sinica Lecturer for Dr. Ivet Bahar of the University of Pittsburgh will also visit Academia Sinica this year as Distinguished Speaker of the Taiwan International Graduate Program (TIGP). ACADEMIA SINICA Nobel Prize laureate Dr. Bruce Beutler visited as the 9 th Academia Sinica Lecturer. Collaborative agreement with Swedish Research Council made in December

15 Social Contribution Awards and Honors The academic competitiveness of Academia Sinica is best demonstrated by the number of prestigious awards and honors bestowed upon its researchers. In 2015, many researchers have been winning global recognition for their outstanding accomplishments, for instance, Chi-Huey Wong was bestowed Robert Robinson Award in Chemistry. Many researchers have also been recognized for their accomplishment through awards and honors in Taiwan, for example, Wen-Harn Pan was awarded Outstanding Contributions in Science & Technology Award of Executive Yuan. Kou-I Lin and Patrick C. H. Hsieh won TBF chair awarded by Taiwan Bio-Development Foundation. In the past 5 years, many Academia Sinica researchers won National Science Council awards: 52 researchers received the Outstanding Research Award, 4 researchers received the Merit Research Fellow Award, and 17 researchers received the Ta-You Wu Memorial Award. List of Domestic Awards and Honors in 2015 List of International Awards and Honors in 2015 Awards & Honors Outstanding Contributions in Science & Technology Award of Executive Yuan, Taiwan Annual Top Ten Distinguished Young Woman, Taiwan MOST Outstanding Research Award Academic Award, Ministry of Education, Taiwan Special Outstanding Researcher, Ministry of Science and Technology Ta-You Wu Memorial Award Scholarly Monograph Award in the Humanities and Social Sciences Academia Sinica Research Award for Junior Research Investigators Academia Sinica Researchers Wen-Harn Pan Ya-Jen Chang, Ching-Ju Lin Chung-Li Wu, Shu-Hsing Wu, Han-Chung Wu, Jim Jr-Min Lin, Yi-Ling Lin, Yeu-Kuang Hwu, Ming-Chorng Hwang,Hsiang-Lin Lei, Elizabeth Zeitoun, Ming-Chang Tsai, Patrick C.H. Hsieh Man-Houng Lin, Bor-Shouh Huang, Shu-Hsing Wu, Ruey-Hwa Chen Sue Lin-Chao, Ruey-Hwa Chen Chi-Ren Jiang, Thung-Hong Lin, Yuan-Hao Chang, Yun-Ru Chen, Wei-Yuan Yang Pei-Feng Chen, Wen-Chin Chang, Hsian-Lin Lei De-Nian Yang, Haino Sadakazu, John Wang, Yuki Nakamura, Yun-Ru Chen, Yu-Chin Hsu, Yun-Chien Chang Robert Robinson Award Awards & Honors International Union for Biochemistry and Molecular Biology (IUBMB) President Elect Khwarizmi International Award TWAS Young Affiliate Top 10% Paper Award, 2015 IEEE International Workshop on Multimedia Signal Processing (MMSP) Outstanding Reviewer Award, 2015 ACM International Conference on Internet Multimedia Computing and Service (ICIMCS) Best Paper Award, IEEE International Conference on Multimedia Expo (ICME) PAKDD Best Paper Runner-Up Award The Best Presentation Award at the 5th International Conference on Analytical Proteomics (Lisbon, Portugal 2015) Prix de la Fondation scientifique franco-taïwanais Academia Sinica Researchers Chi-Huey Wong Andrew H.-J. Wang Fu-Tong Liu Yun-Ru Chen Wen-Huang Cheng Wen-Huang Cheng Yi-Hsuan Yang De-Nian Yang Tzu-Ching Meng Yia-Chuang Chang Dr. Hu Shih Memorial Chair Fang-Yi Chiou National Innovation Award Shih-Chang Lee, Ping-Kun Teng, Ming-Lee Chu, Chih-Hsun Lin, Yeu-Kuang Hwu TBF Chair Kou-I Lin, Patrick C. H. Hsieh Professor CY Lin Memorial Award for Innovative Research Program Shang-Fa Yang Young Scientist Award Young Scholars Creativity Award, Foundations for the Advancement of Outstanding Scholarship Wang Ming-Ning Award Yet-Ran Chen Yet Ran Chen Yi-Hsuan Yang, Ya-Jen Chang Shih-Hsiung Wu Wen-Harn Pan was awarded Outstanding Contributions in Science & Technology Award of Executive Yuan. Ya-Jen Chang, Ching-Ju Lin received Annual Top Ten Distinguished Young Woman Award. Y. Z. Hsu Science Award - Science Paper Award Pi-Cheng Hsiu, Yun-Ru Chen TECO Award Sun Yat Sen Academic Works Award Award for Special Talent Researchers, Ministry of Science and Technology Outstanding Electrical Engineer Award-The Chinese Institute of Electrical Engineering Taiwan Information Storage Information- Outstanding Information Storage Award Tei-Wei Kuo Kwang-Che Pan Yet-Ran Cheng Wen-Huang Cheng Din-Ping Tsai This Award encourages junior researchers in Taiwan to publish papers of major contribution in their research fields. 14

16 Intellectual Property Management and Technology Transfer Academia Sinica attempts to benefit society through its outstanding research achievements. Department of Intellectual Property and Technology Transfer is responsible for protecting and managing Academia Sinica s intellectual property rights, encouraging the disclosure of new discoveries, developing partnerships and collaborations with private sectors, and promoting technology transfer. In 2015, Academia Sinica filed 165 patent applications, was granted 108 patents, and signed 98 licenses as well as 46 cooperative research and development agreements (CRADA). By technology transfer, Academia Sinica has assisted the establishment of startup companies and provided them with crucial support for the commercialization and development of research outcomes of Academia Sinica with the goal improving the development of Taiwan s industry and its international competitiveness. Academia Sinica was ranked 22 on the Thomson Reuters Top 25 Global Innovators Government this year. This list identifies and ranks publicly funded institutes (government research institute) doing the most to advance science and technology. Thomson Reuters also emphasized that Academia Sinica is pushing new programs to encourage technology transfer. License Agreements Executed in D6 antibody drug development A knockout-transgenic mouse model of spinal muscular atrophy Large Scale Enzymatic Synthesis of Oligosaccharides Anti-PEG Antibodies Academia Corpus 4.0 Anti-VEGFR2 antibody drug development Fabricating scaffolds and other cell-growth structures using Microfluidics to culture biological samples Dual functional adenosine analogues and use thereof in treating neurodegenerative diseases Cooling system for an electronic rack Intellectual Property Rights and Technology Transfer in 2015 Patent Applications Filed 165 Patent Issued 108 (*33) License Executed 98 Licensing Deal (NT$ in Millions) 168 Licensing Revenue (NT$ in Millions) 56 Royalties (NT$ in Millions) 9 CRADA Executed 46 CRADA Grant (NT$ in Millions) 93 (*) Cases of US patents ACADEMIA SINICA Academia Sinica Patents and Revenue-based Licenses No. of License Accumulated No. of License No. of Applications filed No.of Patents Issued NT in Millions NT in Millions License Income Accumulated License Income Accumulated Royalty Income Royalty Income

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18 Areas of Strength

19 Areas of Strength Cancer Vaccine and Therapeutic Antibody Development Through collaborations with leading experts in areas such as antibodies, glycan, protein structure, cancer research, and infectious diseases, and by leveraging cutting edge resources and state-of-the-art facilities, Academia Sinica aims to develop a pioneering antibody technology platform and facilitate the development of biotechnology industry in Taiwan. The institute draws on molecular and genetic epidemiological studies, as well as exome sequencing technology, to investigate the causes of cancer and develop treatment strategies. Through research on carbohydratebased anti-cancer vaccines, researchers at Academia Sinica were able to attach the hexasaccharide Globo-H in cancer cells to a diphtheria toxin mutant protein or novel adjuvant, thus inducing the discriminating antibody IgG. This development has great potential for use in the development of therapeutic and prophylactic vaccines effective against a wide range of cancers. Recently, tour research team has discovered a common glycan structure on immunoglobulin G for enhancement of effector functions (Figure 1). Fc glycosylation is crucial for the interactions of antibodies with various effector cells that may result in several effects, including cancer killing, defense Figure 1. against pathogens, and anti-inflammation. The team has found that antibodies with 2, 6-sialylated Fc glycosylation display superior binding affinity towards FcγRIIIa, and demonstrate remarkable antibody-dependent cell-mediated cytotoxicity (ADCC) against both breast cancer cells and B cell lymphoma. Significantly enhanced efficacy was also observed when the same strategy was used to target anti-h1n1 influenza with homogenous glycan antibodies, thus implying that a single Fc glycan form of 2, 6-sialylation has multifaceted functions. In order to increase therapeutic efficacy while reducing the side effects of small molecule drugs, our research team has successfully developed a novel targeted drug delivery system by conjugating antibodies or targeted peptides to the surface of drug delivery systems, thus enabling the delivery of high doses of small molecule drugs to cancer cells with high precision. The research team has demonstrated that the new targeted drug delivery system can increase the therapeutic efficacies of drugs while reducing their side effects (Figure 2). Antibody therapeutic developments are a mainstay of the biotechnology industry. A research team at Academia Sinica has developed cutting-edge antibody technology platforms, including phage-displayed human antibody libraries and single B cells. Using these antibody platforms, research teams can quickly develop therapeutic antibodies for treatment of human diseases. Human antibody libraries serve as an enabling core technology for high throughput antibody therapeutic discoveries: Academia Sinica has developed phage-displayed human antibody libraries, which have been used as robust frameworks capable of encoding highly functional antibodies against diverse antigens (Figure 3). Antibody engineering platforms based on human antibody libraries have provided a key impetus for the development of novel antibody diagnostic s and therapeutics for the treatment of human diseases. Antibodies against cancer cells or infectious diseases, as well as specific antigens with high specificity obtained through a combination of phage display and high throughput screening, can be useful in the development of techniques for disease diagnosis and therapy. Single B cell platform: Single B cell platforms are used to produce antigen-specific human monoclonal antibodies (hmabs) from the peripheral blood B cells of patients with cancer or infectious disease. Such a platform has been 18

20 Major Participants: Chi-Huey Wong 1, Chung-Yi Wu 1, Che Ma 1, An-Suei Yang 1, Kuo-I Lin 1, Fu-Tong Liu 2, Han-Chung Wu 3 1 Genomics Research Center, Academia Sinica 2 Institute of Biomedical Sciences, Academia Sinica 3 Institute of Cellular and Organismic Biology, Academia Sinica established at Academia Sinica (Figure 4). The IgH and IgL gene transcripts of isolated antigen-specific single B cells can be identified by RT-PCR. The resultant hmabs are of use for further functional validations and clinical applications. This approach can be used to rapidly generate numerous antigen-specific hmabs in a short time, and these hmabs can be potentially further developed as emergen t treatments for new pandemic infections or cancer therapy. Through interdisciplinar y collaborations with researchers from different fields, Academia Sinica intends to develop innovative protein drugs and vaccines for the treatment of human diseases. The results have made significant contributions to the advancement of both basic research as well as applied science, thereby building a strong foundation for the future development of protein drugs at National Bio-Medical Park in Taiwan. Figure 2. Figure 3. ACADEMIA SINICA Figure 4. 19

21 Areas of Strength Structural Biology Structural biology aims to understand the biological processes at molecular and atomic levels. In the past two years, researchers in Academia Sinica have successfully tackled several important and challenging systems in areas such as signal transduction, gene regulation, disease formation, and mechanism of drug action. The researchers have used a combination of frontier techniques including X-ray crystallography, nuclear magnetic resonance (NMR), mass spectrometry, computation, small angle X-ray scattering (SAXS), and CryoEM. Selected successful examples are briefly described here: The teams led by Dr. Andrew HJ Wang and Dr. Tzu-Ching Meng of IBC determined the structure of p38γ-ptp complex (Figure 1A), which provided structural basis for drug design in colon cancer and rectum cancer therapy. Dr. Hanna Yuan of IMB uncovered the mechanism of a DNA repair process by determining the RNase T:DNA binary complex structure (Figure 1B). The team led by Dr. Ju-Yu Chen of IoC conducted large-scale determination of absolute phosphorylation stoichiometries in human cells by motif-targeting quantitative proteomics, and identified the protein networks of EGFR and CK2 (Figure 1C). The teams led by Dr. Hsuenh-Chi Sherry Yen of IMB and Dr. Kay-Hooi Khoo of IBC discovered that CRL2 aided elimination of truncated selenoproteins produced by failed UGA/Sec decoding (Figure 1D). The teams led by Dr. Chinpan Chen of IBMS and Dr. Chwan-Deng Hsiao of IMB determined the PmrA-promotor DNA complex, and provided the molecular basis of polymyxin-resistance-associated response for the pathogen Klebsiella pneumoniae (Figure 1E). The teams of Chung-I Chang and Guang-Chao Chen of IBC determined the structure of yeast Ape1 and revealed its role in autophagic vesicle formation (Figure 1F). Dr. Ming-Daw Tsai and Dr. Wen- Jin Wu of IBC determined the crystal structures of human DNA polymerase λ in its apo and dntp-bound forms, and provided the structural basis for the fidelity modulation of Pol λ (Figure 1G). The teams led by Dr. Shih-Hsiung Wu and Shang-Te Danny Hsu of IBC determined the crystal structure of a novel lectin from Crenomytilus grayanus, known as CGL and showed that it contains a beta-trefoil fold with three distinct carbohydrate binding sites through which breast cancer cell surface marker globotriose Gb3 is recognized; in addition, NMR analysis also confirmed the multivalency of carbohydrate binding that is implicated in its hemagglutinin activity (Figure 1H). Figure 1. 20

22 Major Participants: Ming-Daw Tsai, Kai-Fa Huang, Wen-Jin Wu Institute of Biological Chemistry, Academia Sinica B a s e d o n t h e s e f ro n t i e r re s e a rc h topics a n d technologies, Academia Sinica will continue the efforts in researcher training, instrument upgrade and technology implementation, particularly in the new area of SAXS and CryoEM in order to determine structures of important macromolecular complexes, and to stay at the frontier in structural biology. A major effor t in AS structural biology is the establishment of the Taiwan Protein Project (TPP, Figure 2) led by Academicians Ming-Daw Tsai and Andrew Wang. The goal of TPP is to help Taiwan establish worldclass protein research, and build up the next generation biotech industry. TPP has three focuses: supporting cutting edge research in academia, creating a bridge between academia and the industry, and supporting the building of protein research facilities. TPP has established three flagship projects as exemplars of academic collaboration with other fields in protein research: individualizing cancer proteomics for identification of potential drug targets in Taiwan s major cancers; structural analysis of cancer related protein-phosphoprotein complexes; and epitope mapping for antibody drugs and disease-relevant antibodies. From these structural approaches, drug development and design will be more precise and have more solid scientific basis. TPP actively reaches out to the uprising biotech companies to help boost their research and development in protein-based drug development. TPP also reaches out to the academic labs to facilitate moving their existing projects to downstream application. In addition, TPP is invested in supporting protein research in Southern Taiwan for long-term sustainability. Finally, TPP helps to support national level high-end facilities, to ensure that the protein technology is maintained at a global level. ACADEMIA SINICA Figure 2. Taiwan Protein Project 21

23 Areas of Strength Earthquake Research At the Institute of Earth Sciences The Island of Taiwan is created by the collision between the Philippine Sea and the Eurasian plates. Frequent earthquakes on the island and in the subduction zones surrounding it make Taiwan one of the world s best natural laboratory for earthquake research. Ever since its establishment in 1981, the Institute of Earth Sciences (IES) has made seismology the main focus of its research efforts. Over the years, IES scientists have established and maintained the seismic network BATS (Broadband Array in Taiwan for Seismology) to monitor earthquakes and the IES data management center (IES-DMC) to archive the data for the use of seismologists worldwide. In addition, seismology research at IES has also covered a wide range of topics, including earthquake physics, inversion of earthquake sources, earthquake strong motion observation and interpretation, seismic hazard assessment and mitigation, seismic tomography, earthquake precursor study, and oceanbottom seismology. In the past few years, IES scientists have made concerted efforts in applying results in their research to earthquake-related hazard monitoring, assessment and mitigation, with the following achievements: 1. Taiwan Earthquake Science Information System Currently, earthquake prediction is still an impossible task in Earth science. Therefore, when an earthquake occurs, it is very important for seismologists to quickly provide information on the earthquake source with all possible details for three main purposes: (1) the identification of the fault involved and the assessment of further seismic activity in the immediate future; (2) the estimation of earthquake-induced ground motion and possible damage; and (3) providing the public and the media scientifically reliable facts on the earthquake. Under the support of two Academia Sinica Thematic Projects, several IES scientists, led by Drs. Cheng-Horng Lin, Bor-Shouh Huang, Jian-Cheng Lee, and Wen-Tzong Liang have been developing the computational and seismological infrastructure for the rapid collection of earthquake data, near real-time inversions of earthquake source parameters and estimations of ground shaking, and the preparation of accurate and targeted information for the purpose of providing both the scientific community and the public with the knowledge on earthquakes as soon as they occur. At present, a Taiwan Earthquake Science Figure 1. Seismic analysis of Hsiaolin Village landslide. Left panels show (top) the morphology around Hsiaolin Village and (bottom) locations of seismic stations. Right panels display the (top) raw seismic records and (bottom) after being bandpass filtered to Hz. 22

24 Major Participants: Cheng-Horng Lin, Bor-Shouh Huang, Jian-Cheng Lee, Li Zhao, Ya-Ju Hsu, Shiann-Jong Lee, Wen-Tzong Liang Institute of Earth Sciences, Academia Sinica Information System (TESIS) is online at IES ( sinica.edu.tw/). Within a few minutes after the occurrence of an earthquake in Taiwan, the system can provide the observed ground shaking intensity map, the moment tensor solution of the earthquake, and the predicted shake movie and shake map obtained in 3D structural model with realistic topography. A comprehensive earthquake report is also quickly and automatically generated by combining the quantitative seismology results with the geologic and seismotectonic information of the earthquake source region from a pre-established knowledge database. Some of the techniques developed by IES scientists have also been transferred to the Central Weather Bureau to enhance the capability in its earthquake early warning system. 2. Landslide monitoring Taiwan is a heavily populated island with many people living in mountainous areas. Landslides caused by earthquakes, typhoons and heavy rainfalls have also been one of the most frequently occurring types of natural hazards. The devastating Typhoon Morakot on August 8, 2009, caused numerous landslides in Taiwan. Among the deadliest was the one located near Hsiaolin Village in Kaohsiung County in southern Taiwan. In recent years, new technologies have been developed to use seismic instruments to monitor and study landslides. Seismic records during a typhoon passage are usually dominated by high-frequency noises. However, Dr. Cheng-Horng Lin of IES discovered that after band-pass filtering to Hz, the records during the passage of Typhoon Morakot display clear waveforms of seismic signals generated by the landslide (Figure 1). Using these filtered waveforms, Dr. Lin was able to determine the time, location and magnitude of the Hsiaolin Village landslide. These types of information can be critical for the real-time detection of disastrous landslides and for rapid emergency responses. Similar approach can also be used to identify hazardous dam-forming landslides that may temporarily block rivers and eventually lead to floods. This novel usage of seismic records to monitor surface movements, especially the damaging ones such as landslides, is a new trend in seismology research in the world today. 3. Tsunami earthquake monitoring around the South China Sea Recent research developments suggest that the Manila Trench on the northeast margin of the South China Sea has the potential of producing magnitude 8 and larger earthquakes, which are capable of generating tsunamis that threaten the populations surrounding the South China Sea. Under the leadership of Dr. Bor-Shouh Huang, IES has established close and effective collaborations with seismic monitoring authorities around the South China Sea, including the Philippines, Malaysia, Laos, Vietnam, and Fujian Province in mainland China. These collaborations have led to the establishment of a network of seismic stations surrounding the South China Sea (Figure 2). Seismic data from most stations can be transferred via satellite to the data center at IES in Taiwan, which enables real-time monitoring of earthquakes in the region for tsunami warning purpose. ACADEMIA SINICA Figure 2. Virtual seismic network composed of stations from different countries to monitor large earthquakes in the Manila Trench for tsunami warning purpose. 23

25 Areas of Strength Chemical Dynamics : From Fundamental Understanding to Practical Problem-Solving The research activity of the Chemical Dynamics Group at IAMS spans from fundamental understanding of chemical reactivity to diverse applications to solving important problems in atmospheric chemistry and life science. Highlighted below are three notable examples over the past two years. Stereo-Specific Bimolecular Reaction The concept of geometrical constraints and steric hindrance in chemical reactions is deeply implanted in a chemist s intuition. Yet, a true three-dimensional view of these steric effects has not, until recently, been experimentally realized in full for any chemical reaction. By exploiting the polarization of an infrared laser to align a chemical bond and followed by measuring the dependence of the product state-resolved angular distributions on the direction of the reactive bond thus aligned in a crossed molecular beam experiment, we revealed the complete, three-dimensional characterization of the sterics of a benchmark polyatomic reaction, Cl + CHD 3 (v 1 =1) CD 3 (v=0) + HCl(v). Figure 1 (Top) depicts how the chemical transformation takes place for three representative reactive events delineated directly from the experimental data. A complementary approach to elucidate the geometric structure of the reaction transition state has also been explored by examining the reactivity dependency on the initial rotational quantum state of the reactants CHD 3 (v 1 =1, J,K ). We found that the rotation (J) of CHD 3 (v 1 =1) promotes the reaction rate. More intriguingly, the rate enhancement also depends on how the reactant rotates, the tumbling (K=0) versus the spinning (K=J) motions, as illustrated in Figure 1 (Bottom). X CI θ=90 H y C θ=180 H y CI X C z (K) H CI H y H CI θ=45 CI X H C z (K) CI z (K) Figure 1. (Top) A cartoon-type representation of the experimental results at three product scattering angles to illustrate the angular correlation between the HCl (v=0) product recoil direction and the initial C-H bond axis direction. (Bottom) A visualization of how different rotational motions, tumbling (K=0) and spinning (K=J), affect the chemical reactivity. 24

26 Major Participants: Yuan-Tseh Lee, Jim Jr-Min Lin, Chi-Kung Ni, Kopin Liu Institute of Atomic and Molecular Sciences, Academia Sinica Reaction of the Simple Criegee Intermediates with Water Vapor Large amounts of unsaturated hydrocarbons are emitting into atmosphere from biogenic and anthropogenic sources. Ozonolysis of unsaturated hydrocarbons produces Criegee intermediates (CIs), which are strong oxidizing agents and may oxidize atmospheric SO 2 and NO 2, Figure 2 (Top). The oxidation of SO 2 is of particular importance, because the SO 3 products would be converted into sulfuric acid, an important source of aerosols and acid rain. Previous detection of CI by mass spectrometry was limited in low pressure conditions (< 0.01 atm). With UV absorption, we have overcome the pressure limitation and detected CI under near atmospheric conditions. We found the reaction of water dimer with the simplest CI, CH 2 OO, is extremely fast (Figure 2, Bottom); it would be the main decay pathway of CH 2 OO in the troposphere. However, an alkyl substitution group can change the reactivity drastically, such that some Criegee intermediates can survive high humidity and may oxidize atmospheric SO 2. Figure 2. (Top) Possible reaction pathways of a Criegee intermediate in the atmosphere. (Bottom) Effective pseudo-first-order rate coefficient of CH 2 OO reaction with water vapor as a function of relative humidity. The inset shows the structure of the reaction intermediate between the Criegee radical and water dimer. ACADEMIA SINICA How does MALDI occur? Matrix-assisted laser desorption ionization (MALDI) is a soft ionization method widely used in mass spectrometry for biomolecules (Figure 3). Although it has been invented near three decades, the ionization mechanism was not clear for long time. We measured the desorbed ion-to-neutral ratio using ion imaging mass spectrometer and cross molecular beam apparatus, demonstrating that ion-to-neutral ratio of analyte was mistakenly used as that of matrix in the past 20 years and led to the wrong conclusion. According to our measurement and new experimental results, we proposed a thermal model to explain the ionization mechanism of MALDI. Figure 3. Thermally induced proton transfer in MALDI. 25

27 Areas of Strength Ecology, Evolution and Biodiversity Environmental change, caused by overconsumption of natural resources, has modified the biogeochemical balance and has forced the Earth ecosystem to enter the Era of Anthropogene. As a result, in the ocean, the coral reef ecosystem has been depleted dramatically. For example, loss of large coral living areas due to overgrowth by the coralkilling sponge Terpios hoshinota has raised serious concern in Taiwan. Field studies and stable isotope labeling experiments suggested that Terpios might have to accumulate resources to fight with corals for substrate, and such resources might be derived from photosynthates released by cyanobacteria or supplied by inorganic nitrogen during the process of overgrowing on encountered corals. However, the question of whether eutrophication caused by human activity is promoting Terpios to kill corals remains to be explored. Coral reefs worldwide are now depleting, causing low-density populations and low success of fertilization. Our data from in situ crossing experiments showed that the fertilization rate peaked (>75 %) at a sperm concentration of ~1,000,000 sperm/ ml but rapidly declined to <50 % at a concentration of 10,000 sperm/ml, providing a baseline information for conservation and management of degraded and low-density populations of reef-building corals. The fish database from northern Taiwan accumulated over past 30 years revealed a dramatic drop in diversity and biomass. The causes include overfishing, habitat destruction, pollution, invasive species and probably also climate change. A highly significant decline in diversity and number of fishes was observed in 2008, which is probably related to the catastrophic impacts due to the closure of the Yangtze River dam in 2006, the La-Niña between 2007 and 2008, or China s snow storm in Precautions should be taken into consideration to set up conservation priorities before scientific study concludes the causes of the fish depletion in northern Taiwan. Avian skin appendages (feathers, scales, claws and beaks) are mainly made of α and β keratins. Recently, we studied how the evolution of keratin genes has contributed to evolutionary novelty and adaptation in birds. Using chicken as a model, we applied RNA-seq and in situ hybridization to map α and β keratin genes in various skin appendages at Fertilized egg of coral Temporal variation of number of species of impinged fish collected at the 1st and 2nd Nuclear Power Plants in Taiwan during the periods and

28 Major Participants: Wen-Hsiung Li, Kwang-Tsao Shao, Chih-Yu Chiu, Ming-Shiou Jeng, Chaolum Allen Chen,Sen-Lin Tang, Kwok-Kan Chan, Yoko Nozawa, Ryuji Machida, John Wang, Sheng-Feng Shen, Yin-Ru Chiang, Isheng-Jason Tsai Biodiversity Research Center, Academia Sinica embryonic developmental stages. We found that temporal and spatial α and β keratin expression is involved in establishing the diversity of skin appendage phenotypes. In feather filament morphogenesis, β keratins showed intricate complexity in feather branches. To explore functional interactions, we utilized a retrovirus transgenic system to ectopically express mutant α or antisense β keratin forms. α and β keratins showed mutual dependence and mutations in either keratin type resulted in disrupted keratin networks and failure to form proper feather branches. Our data suggest that combinations of α and β keratin genes contribute to the morphological and structural diversity of avian skin appendages, with feather β keratins conferring more composites in building intra-feather architecture complexity. Our study set up a platform for studying the evolution of functional forms in feathers. ACADEMIA SINICA Structures of avian skin appendages and RNA-seq analysis Functional study shown by overexpressing α-keratins KRT5 mutant and feather β-keratin antisense form in embryonic feather development. Summary of topographic expression patterns of α- and β-keratin genes in different skin appendages. 27

29 Areas of Strength Taiwan Biobank Advances in medicine have resulted in an aging population and longer life expectancy worldwide, leading to more attention being paid to health promotion and chronic disease prevention. In Taiwan, chronic diseases such as cancer, cardiovascular diseases, diabetes, and chronic kidney diseases are among the leading causes of mortality in recent decades. Hence, the prevention of chronic disease and the development of tools for precise prediction of disease progression and useful treatment approaches have become the primary goal. Due to the relatively small population size of Taiwanese, the sample size of most studies in Taiwan in the past has been relatively small. This has prevented solid conclusions from being drawn from the study results, especially for chronic diseases of multifactorial aetiology, and increases the importance of conducting large-scale cohort studies on common chronic diseases. To fulfil the new vision of biomedical research, there is an urgent need to provide the medical research community with sufficient and stable research resources that combine genetic and other medical information. The Taiwan Biobank was developed to meet this need. Similarly, this rationale has supported many countries to establish national biobanks as biomedical and public health infrastructure. The UK biobank, having collected blood and urine specimens together with questionnaires from 500,000 participants in 2010, and the Biobank Japan, having collected blood and tissue specimen from 300,000 patients of chronic diseases in 2009 are two notable examples. In Taiwan, the Taiwan Biobank was formally approved by the Department of Health on October 24, 2012 and has been in operation since this time. The Taiwan Biobank is a scientific infrastructure accessible to biomedical researchers aimed at furthering understanding of the relationships between environmental exposure, diet, genetics, and the aetiology and progression of chronic disease. Through the recruitment and follow-up of a cohort of 200,000 individuals from the general population with no history of cancer and a cohort of 100,000 patients with chronic diseases of public health importance from medical centres, the Taiwan Biobank aims to improve the health of future generations and facilitate genomic/ epigenomic research in the post-genomic era. (A) (B) Figure 1. Future for personalized medical care (A) and personalized health promotion (B). 28

30 Major Participants: Fu-Tong Liu, Chen-Yang Shen Institute of Biomedical Sciences, Academia Sinica Currently, more than 60,000 participants from different regions of Taiwan have been recruited (Figure 2), and more than 1,000,000 biospecimens, including blood, urine, and DNA, have been collected (Figure 3). Electronic, structured questionnaires have been administrated to collect comprehensive information on risk factors, dietary patterns, lifestyle, and family history of diseases. Physical examinations and biochemical measurements have been performed. Whole-genome genotyping of more than 10,000 individuals using a chip designed by the Taiwan Biobank, which contains 653,291 single-nucleotide polymorphisms, has been performed, and whole-genome sequencing of 1,000 individuals has been completed in October To keep pace with global scientific community, the whole genome methylation, proteomics, and metabolomics studies were also implemented in the Taiwan Biobank. ACADEMIA SINICA Figure 2. The number of the Taiwan Biobank participants in different regions of Taiwan. Figure 3. The number of tubes and the kinds of biospecimens collected in the Taiwan Biobank. All the collected information and biospecimens in the Taiwan Biobank had been released to the research societies since September As of December 2015, about 40 requests for data and biomaterials from the communitybased cohort had been approved. The requests were submitted by researchers from a variety of institutes for a wide variety of research purposes, including genomewide association analyses, validation of biomarkers, and development of diagnostic tools. During the past few years, Taiwan Biobank has organized twelve biosignatures consortia, including hepatocellular carcinoma, lung cancer, breast cancer, colorectal cancer, head and neck cancer, urothelial carcinoma, stroke, cardiovascular disease, endometriosis, asthma, Alzheimer s disease, and diabetes, aiming to improving the prediction of disease progression. The analysis of patient outcomes would be undertaken to identify points in the clinical decision pathway of early detection or predicting response to treatment. The goal is to develop personalized and precision medicine in which progressive elucidation of molecular pathogenesis of disease will improve disease prevention and facilitate therapy development for individuals and generations to come. 29

31 Areas of Strength New Perspectives on Chinese History The Institute of History and Philology of Academia Sinica is known internationally for its publication of numerous high quality research papers and books. Since its founding over 80 years ago, this institute has published over a thousand publications, many of which have played a ground-breaking role in shaping the field of Chinese history. In line with its publication tradition, the Institute of History and Philology celebrated its 80th anniversary in 2008 with the publication of the New Perspectives on Chinese History series. The publication of this series also serves another key purpose. Over the past two decades, the field of history has seen the rise of significant new trends and developments. In light of these changes, colleagues at the Institute of History and Philology have strove to reflect these new trends in their endeavors by exploring new fields of study, and investigating new research perspectives. Besides taking into account these new developments, it is also crucial to bring together key fellow researchers, in Fu Sinian s words bringing together the masses, in order to make these research insights available to an even larger audience, offering inspiration for future scholars. New Perspectives on Chinese History includes a total of ten volumes: Gudai wenming de xingcheng (The Emergence of Ancient Civilization) edited by Ming-Chorng Hwang, Jiceng shehui (Primary Level Society) edited by Kuan-Chung Huang, Shenghuo yu wenhua (Life and Culture) edited by Chung-Lin Chiu, Sixiang shi (Intellectual History) edited by Jo-Shui Chen, Meishu kaogu (Archaeology of Art) edited by Chuan-Ying Yen, Falü shi (History of Law) edited by Nap-Yin Lau, Yiliao shi (History of Medicine) edited by Research Center of History of Health and Healing, Zongjiao shi (History of Religion) edited by Fu- Shih Lin, Xingbie shi (History of Gender) edited by Jen-Der Lee, and Keji yu zhongguo shehui (Technology and Chinese Society) edited by Ping-Yi Chu. Encompassing nearly a hundred scholarly papers that cover a variety of diverse topics and themes, these ten volumes have brought together renowned researchers from around the world to accomplish the goal of outlining recent breakthroughs and transformations within various fields. The impetus for New Perspectives on Chinese History dates back to the 1990s when diverse new research trends emerged in the field of history. With an emphasis on new perspectives, this series seeks to concretely reflect these new theories through its selection of topics as well as its use of sources and tools. This series showcases a number of new research priorities as well as the emergence of new areas of study such as image artifacts, religious rites, history of medicine, history of daily life, cultural history, legal history, and technology and society. In contrast with the focus of history over the past half-century, these areas are considered rather new and seldom researched, with some being peripheral subjects that have gradually moved into the mainstream. Thus, the questions addressed are also the ones that have never been raised in the past. For instance, local community and daily life are common themes that appear in every single volume. Furthermore, the emergence of new sources and the use of databases have also allowed this series to present new and more in-depth perspectives. Even traditional fields can evolve info new state. For example, Sixiang shi uses the early 1970s as a starting point and takes into account the influences of Western historiography to offer a new take on the concept of inner logic, emphasizing that intellectual history should focus on the evolution and changes of ideology. Researchers should delve into the structure of past thoughts and thought traditions. In this volume, while thought itself is still a key focus, what is added is external ideological concerns. These include using the history of thought formation to understand how and why these thoughts are the way they are while also noticing the 30

32 Fan-Sen Wang Institute of History and Philology, Academia Sinica spread of these thoughts within lower rungs of society and the addition of elements of cultural history. Another example of this new state of development can be seen through the study of political history, a core traditional field of study in history. Political history does not have its own volume within the New Perspectives on Chinese History, which indicates the challenges that this traditional field faces in light of new trends. This however does not mean that political history is no longer an area of concern in history; instead, it reveals that elements of this study have been dispersed and integrated into other areas of study. For instance, the themes of political power and bureaucracy can be found in various articles throughout this series. All these changes reflect the trends and developments within the past two decades. On the surface, many chapters in this series may not seem special because the subjects covered are now mainstream themes of discussion. However, looking through a comparative lens and understanding the evolution of these themes within the past two to three decades, the gradual changes that can help us answer the key question of this field What becomes history? becomes evident. Another brand new outlook this series offers is it strives to offer new perspectives as well as answers to the question What becomes history? In summary, this series shows two shifts in attitude in the study of history. The first is the shift from the focus on rationalism and scientism of the May Fourth Movement to the focus on understanding and communication cultural aspects such as customs and traditions. The second shift is the incorporation of world history in order to take a broader look at Chinese history. Change is slow to take hold in the study of history; it is a long continuous journey. Instead of saying that the publication of New Perspectives on Chinese History strives to offer a summary on a particular stage of development in history, it is more fitting to say that this series offers observations of a particular stage of history, providing food for thought to inspire future generations to come. ACADEMIA SINICA 31

33 Areas of Strength Panel Study of Family Dynamics The Panel Study of Family Dynamics (PSFD) project originates from the belief that the types, structures, and patterns of interaction of families in Chinese societies are more complicated than those in Western societies. Correspondently, the theoretical models embodied in the values and practices of Chinese families should be more complicated than those built up from Western ones. The PSFD project aims to develop a research agenda which is both consistent with the local observations and endorsed by the mainstream of social scientists. The project was initiated in 1998 by the coordinator, Prof. Cyrus Chu, and a group of researchers in economics, sociology, and psychology. The data collection started from Taiwan. The main targeted respondents of the PSFD are the adult population in Taiwanese families, covering different birth cohorts. Children of the main respondents were added into the sample afterwards. The follow-up surveys of the main respondents and their children have been conducted on an annual or biennial basis. With the collaboration of the Chinese Academy of Social Science, the respondents were then extended to three Chinese locations, Fujian and Zhejiang provinces, as well as Shanghai, in order to carry out comparative studies. The goal is to examine whether existing theories of the family can be applied to Chinese society. Furthermore, based on the findings from PSFD, new theoretical frameworks different from Western ones are expected to be discovered and explored. The construction of this dataset is expected to profoundly contribute to research on economic, sociological, and psychological aspects of Chinese families. On the part of Taiwan, it has been seventeen years (sixteen waves) since the first wave of face-to-face survey was conducted in 1999, making this study the longest panel in Chinese society. The questionnaire of the main respondents includes questions on education, work, marriage, expenditures, children, etc. It also contains demographic characteristics of parents, parents-in-law, and siblings, as well as interactions with PSFD Survey Structure Note: Surveys on main respondents are in blue. Surveys on 25-year-old children of main respondents are in green. Surveys on 16 to 24-year-old children of main respondents are in yellow. 32

34 Chin-Yi Cyrus Chu 1, Ruoh-Rong Yu 2 1 Institute of Economics, 2 Research Center for Humanities and Social Sciences, Academia Sinica these relatives. This helps to build up and analyze husbandwife, parent-child, sibling, or even multi-generational data. Furthermore, because main respondents children are also interviewees of PSFD, intergenerational studies can be easily implemented. In addition to questions contained in the main respondent s questionnaire, the children s questionnaire mainly focuses on educational experience. Up to now, the survey data of Taiwan have been released. The figure on page 32 presents the structure of surveys conducted in Taiwan. As to the China counterpart, the face-to-face survey project in collaboration with the Institute of Population and Labor Economics, Chinese Academy of Social Sciences (IPLE-CASS) was launched in The targeted population is adults born between 1935 and 1976 residing in Fujian, Zhejiang, and Shanghai. The questionnaire is basically the same as that of the 2003 Taiwan survey, with only slight changes to accommodate cross-strait differences in vocabulary and script, and some questions added based on the research interest of IPLE-CASS. Due to similar sample structure and questionnaire contents, the Taiwan and China PSFD data are unique in conducting comparative studies between these two Chinese societies. The three follow-up surveys of China were conducted in 2006, 2011, and 2013, respectively. The 2004, 2006, 2011, and 2013 survey data are now accessible. In the past four years ( ), the numbers of downloads of the PSFD data are 1315, 2112, 1757, and 1510, respectively. Up to the end of 2015, the number of publications based on PSFD data has accumulated to 304, including 57 journal articles, 5 book chapters, 83 conference papers, 144 dissertations, and 15 other papers. In addition, a monograph has been published by the Oxford University Press. ACADEMIA SINICA 33

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36 Significant Research Achievements in 2015 In 2015, Academia Sinica had more than 4,100 scientific publications including journal articles, books and proceedings papers. 2,285 papers have been listed in SCI, SSCI and A&HCI with an average of 2.72 papers per researcher. This current issue of research achievements highlights a selection of nine key papers published in the last twelve months, covering a wide range of topics presented by each of the following divisions: Mathematics and Physical Sciences, Life Sciences, and the Humanities and Social Sciences. The Division of Mathematics and Physical Sciences currently comprises of eight institutes and three research centers. Each researcher in the division has published an average of 4.8 papers listed in SCI, SSCI and A&HCI in The total number of journal articles, books, and proceedings papers amounts to around 1,800 with an average of 6.1 publications per researcher. Over the years, the researchers in the Division of Mathematics and Physical Sciences have been carrying out high-quality basic researches to discover new phenomena, understand their properties, and create new knowledge. Important results include: identifying R331W missense mutation of oncogene YAP1 to be the germline risk allele for lung adenocarcinoma with medical actonability; overcoming the pressure limitation to investigate the reaction kinetics of the simplest Criegee intermediate with water vapor; developing time-resolved luminescence nanothermometry with nitrogen-vacancy centers in nanodiamonds to measure temperature with nanoscale spatial resolution, etc. The Division of Life Sciences comprises five institutes and three research centers. In 2015, researchers in this division published an average of 4.3 papers listed in SCI, SSCI and A&HCI. The total number of journal articles, books and proceedings papers has amounted to nearly 1,000 with an average of 4.5 publications per researcher. The researches of the institutes/centers cover a broad range of life sciences from basic to translational studies. Major research highlights include: At14a-Like1 in the model plant Arabidopsis thaliana promotes growth and productivity during drought stress without negative effects on unstress plants; using mouse model demonstrates that bone marrow-derived circulating cells have the ability to engraft into the injured myocardium and to repair heart by fusing with resident cardiac myocytes and transdifferentiation; 2,6-sialylated antibody improves the cytotoxic efficacy of antibodies against drug-resistant cancer cells and mediates interactions with various effectors cells to activate immune system, including cancer killing, pathogen defending and anti-inflammation, etc. The Division of the Humanities and Social Sciences is comprised of eleven institutes and one research center. In 2015, researchers in this division altogether produced over 1,300 publications including journal articles, books and proceedings papers with an average of 4.3 publications per researcher. The studies of the members of the institutes and center cover a wide range of important issues in humanities and social sciences, including the first full-length ethnography on nüshu Gender Words: Sentiments and Expression in Changing Rural China not only enriches our understanding of scripts developed by women in Jiangyong County, but also helps to develop the theoretical construct of expressive depths ; Guxin Shengjing Cango is the Louis de Poirot s Chinese Vulgate Bible which represents the time point when colloquial idiom became popular in China; The Purple Aboriginal Boundary discusses the old Purple Aboriginal Boundary Map in great details with GIS and field surveys in order to stimulate more research on the imperial policy of frontier governance, and on the development of border areas and ethnic relations in 18 th century Taiwan.

37 Division of Mathematics and Physical Sciences R331W Missense Mutation of Oncogene YAP1 Is a Germline Risk Allele for Lung Adenocarcinoma With Medical Actionability Abstract The lack of noticeable symptoms at the early disease stage makes screening and early detection of lung cancer extremely difficult to perform. To search for germline risk alleles, we conducted whole genome sequencing for members of an unusually-high density lung adenocarcinoma family. Extensive data analysis and confirmation identified a missense mutation R331W located on the oncogene YAP1. Validation was conducted in an external cohort of over 1,000 normal subjects and over 1,000 patients, obtaining an adjusted odds ratio of 5.9 for this risk allele. Family follow-ups were performed. Out of the 13 YAP1- mutantcarrying relatives, 4 had lung cancer and 6 had ground glass opacity lung lesions. These results implicated that YAP1 R331W is a predisposed allele of lung adenocarcinoma with high familial penetrance. Low dose CT may be recommended to this high risk subpopulation for early detection and disease prevention. Lung cancer is the leading cause of death from cancer worldwide. Only about 30% of the lung cancers are diagnosed at stage one, and yet up to 40% of these early-stage patients will relapse within 5 years. Screening of lung cancer by lowdose helical computed tomography (CT ) has shown the mortality reduction in certain high risk populations. But confined by the cost-effect and other considerations, it is impractical and unsuitable to screen the general population. A more promising strategy of utilizing CT scan for early detection of lung cancer is to narrow down the target population for screening and the discovery of high-risk biomarkers of lung cancer is a critical first step. The hereditary factors of lung cancer remain largely unknown. Genetic polymorphism studies had suggested some potential susceptibility loci of lung cancer, but their causative factors were unknown. Many large-scale case-control studies on lung adenocarcinoma used single nucleotide polymorphism (SNP) microarray. The resulting SNPs were often located in the intron, had small odds ratio, and had little biological meaning. Some common genetic variants identified from genome-wide association study (GWAS) showed susceptible to lung adenocarcinoma. However, the findings were common alleles with low penetrance. Furthermore, the high frequency of the risk allele makes it difficult to take clinical action on any such large implicated population. The ability of using next generation sequencers (NGS) on patient genomes to generate voluminous sequence Figure 1. Pedigree of the original family 36

38 Hsuan-Yu Chen 1, Yi-Chiung Hsu 1, Chi-Sheng Chang 1, Yu-Cheng Li 1, Shi-Yi Yang 2, Hao Ho 1, Ya-Hsuan Chang 1, Hwai-I Yang 2, Shinsheng Yuan 1, Chia-Hsin Liu 1, Guan-I Wu 1, Chien-Jen Chen 2, and Ker-Chau Li 1 1 Institute of Statistical Science, Academia Sinica 2 Genomics Research Center, Academia Sinica Publication: Journal of Clinical Oncology 33 (2015): data has led to the revelation of many genomic variations in several diseases. However, the lacks of sufficient validation and follow-up have hindered the progress of applying them for clinical usage. In this study, we first performed the whole genome sequencing for an unusually-high density lung adenocarcinoma family with available buffy coat DNA from the affected mother, 4 affected daughters, and 1 nonaffected son. Extensive data analysis and validation led to the discovery of a rare germline mutation R331W located on the gene YAP1 (Figure 1) which has very low frequency in the general population based on the 1000 genome project database. The adjusted odds ratio of YAP1 R331W was 5.9 from the comparison of 1,312 patients and 1,135 normal control subjects (Table 1). We then conducted family followup and found that YAP1-mutant carriers in the relatives have overwhelmingly higher frequencies of developing lung adenocarcinoma or ground glass opacity (GGO) lung lesions. Out of a total of 13 relatives who were mutant carriers, 4 had lung cancer and 6 had GGO (Figure 1 and 2). Finally, functional characterization of YAP1 mutation showed YAP1 R331W had higher colony formation ability and the invasion potential. Taken together, results of this study implicated that YAP1 R331W is a predisposed allele of lung adenocarcinoma with high familial penetrance. Persons with YAP1 R331W mutation may have high lung cancer risk. Low-dose computed tomography (LDCT) screening may be recommended to this high risk population for personalized prevention and health management in precision medicine. ACADEMIA SINICA Lung adenocarcinoma Newly diagnosed Lungadenocarcinoma GGO No cancer with LDCT confirmation Other cancer No cancer No information Figure 2. Pedigrees of the probands Variable Odds ratio* 95% CI P value YAP1 R331W Age < Gender < Smoking < *:adjusted odds ratio CI:confidence interval Table 1. Risk analysis of YAP1 R331W 37

39 Division of Mathematics and Physical Sciences Direct Kinetic Measurement of the Reaction of the Simplest Criegee Intermediate With Water Vapor Abstract Large amounts of unsaturated hydrocarbons are emitting into atmosphere from biogenic and anthropogenic sources. Ozonolysis of unsaturated hydrocarbons produces Criegee intermediates (CIs), which are strong oxidizing agents and may oxidize atmospheric SO 2 and NO 2. The oxidation of SO 2 is of particular importance, because the SO 3 product would be converted into sulfuric acid, an important source of aerosols and acid rain. Previous detection of CI by mass spectrometry was limited in low pressure conditions (< 0.01 atm). With UV absorption, we have overcome the pressure limitation and detected CI under near atmospheric conditions. We found the reaction of water dimer with the simplest CI, CH 2 OO, is extremely fast; it would be the main decay pathway of CH 2 OO in the troposphere. Being extremely reactive, Criegee intermediates (CIs) are short lived and hard to study and scientists know little about them. Typical reaction pathways of a CI in the atmosphere are shown in Figure. 1. As water vapor has a concentration much higher than those of other trace species like SO 2 in the troposphere, the reaction of CH 2 OO with water has been an important issue. However, there were controversial results in the literature, such that scientists had a hard time to assess the concentration of CH 2 OO in the troposphere and whether CH 2 OO can oxidize atmospheric SO 2. The basic idea of our experiment is the following. A mixture of N 2, O 2, H 2 O, and CH 2 I 2 is photolyzed by an excimer laser beam at 248 nm (Figure 2) to induce the reactions below. CH 2 I 2 + hν CH 2 I + I CH 2 I + O 2 CH 2 OO + I CH 2 OO + H 2 O products The absorption of CH 2 OO at 340 nm (Figure 3) was recorded as a function of the reaction time to study the reaction kinetics. The probe light was filtered by a bandpass filter ( nm) and detected by a balanced photodiode detec tor ; the signal was then recorded by a digital oscilloscope. Figure 4 shows the absorbance change at 340 nm in the photolysis system of CH 2 I 2 /O 2. In our selected wavelength range ( nm), the contribution of CH 2 OO to the absorption is much larger than those of other species, such that we may use the absorbance to represent the concentration of CH 2 OO. It is clear that the decay of CH 2 OO is faster at higher humidity levels, indicating reaction of CH 2 OO with water vapor. Such data were fitted with a single exponential decay function to obtain the pseudo-first-order rate coefficients, which are plotted in Figure. 5. It is interesting to note that the data in Figure 5 show clear second-order dependence on the water concentration, indicating water dimer is the relevant reactant in this reaction. This result also explained why previous investigation by Taatjes group in Sandia Laboratories [Science 335, 204 (2012)] did not observed the reaction of CH 2 OO with water vapor; it is because their water pressure was quite low (~ 1 Torr), such that the water dimer concentration was not high enough to affect the lifetime of CH 2 OO. We clarified and measured precisely the reaction kinetics of CH 2 OO with water vapor; the high concentration of water dimer in the troposphere would lead to fast decay of CH 2 OO. Scientists believe CIs play an impor tant role in atmospheric chemistry. However, there is no method to measure the concentration of a CI in the atmosphere. The concentration can only be estimated by its production rates and decay rates. Previous investigations indicate the reaction rates of CH 2 OO with SO 2 and with NO 2 are much faster than previously thought; but they were not able to have conclusive results in the kinetics of CH 2 OO reaction with water vapor. We have overcome the limitation of the experimental pressure and studied the kinetics of CH 2 OO reaction with water vapor at near atmospheric conditions. Due to the extremely high concentration of water in the troposphere, our data is crucial for understanding the chemistry of atmospheric CIs. 38

40 Wen Chao 1,2, Jun-Ting Hsieh 1,3, Chun-Hung Chang 1, and Jim Jr-Min Lin 1,2,4 1 Institute of Atomic and Molecular Sciences, Academia Sinica, Taiwan 2 Department of Chemistry, National Taiwan University, Taiwan 3 Stanford University, USA 4 Department of Applied Chemistry, National Chiao Tung University, Taiwan Publication: Science 347 (2015): 克里奇中間體例如 : other species peroxides Figure 1. Possible reaction pathways of a Criegee intermediate in the atmosphere. Figure 4. Absorbance change of CH 2 OO as a function of the reaction time at various humidity levels. Here the absorption at 340 nm is mainly due to CH 2 OO. The negative baseline at long time is due to the depletion of the CH 2 I 2 precursor. ACADEMIA SINICA Figure 2. (Upper) schematic of the photochemical reaction cell; (Lower) schematic of the multiple-pass design of the probe beam. Figure 5. Effective pseudo-first-order rate coefficient of CH 2 OO reaction with water vapor as a function of relative humidity. Figure 3. Time-resolved UV difference absorption spectra of the CH 2 I 2 /O 2 system. The time zero is defined as the laser pulse, which induced the reactions. The absorption due to CH 2 OO decays with time; the absorption due to IO increases with time; the depletion of the CH 2 I 2 precursor can also be observed. 39

41 Division of Mathematics and Physical Sciences Time-Resolved Luminescence Nanothermometry With Nitrogen-Vacancy Centers in Nanodiamonds Abstract Measuring temperature in nanoscale spatial resolution either at or far from equilibrium is important in many scientific and technological applications. Although negatively charged nitrogen-vacancy centers in diamond have recently emerged as a promising nanometric temperature sensor, the technique has been applied only under steady state conditions. Here, we present a novel method that allows real-time monitoring of the temperature changes over ±100 K and the study of nanoscale heat transfer with a temporal resolution of better than 10 μs. The utility of the time-resolved luminescence nanothermometry was demonstrated with 100 nm nanodiamonds spin-coated on a glass substrate and submerged in gold nanorod solution heated by a near-infrared laser. The validity of the measurements was verified with finite-element numerical simulations. The measurement of temperature with nanoscale spatial resolution is an emerging new technology in recent years, and the development of this so-called nanothermometry is expected to have important impacts in various fields of science and technology. An ideal nanothermometer should be not only accurate but also applicable over a wide temperature range and under diverse environmental conditions, and the measurement time should be short enough to allow following the time evolution of the system under interrogation. Here, we use fluorescent nanodiamonds (FNDs) to realize the concept. FND is a carbon-based nanomaterial containing negatively charged nitrogen-vacancy (NV ) color centers as structural defects (Figure 1a). The ground state of the center is a spin triplet formed by two unpaired electrons with a crystal field splitting of 2.87 GHz separating m s = 0 and m s = ±1 sublevels (Figure 1b). Interestingly, the spin states of NV can be optically polarized and coherently manipulated by microwave radiation, a technique known as optically detected magnetic resonance (ODMR). As the spin properties of NV are sensitive to environmental temperature changes, the FND can serve as a nanoscale quantum thermometer. A c o m m o n m e t h o d t o r e a l i z e t h e N V - b a s e d nanothermometry is to measure the thermal shifts of the ODMR peaks. However, it is time consuming to acquire the whole ODMR spectrum and post-data processing is required to determine the peak position. To circumvent this problem, we have developed a three-point sampling method which not only allows the determination of the temperature change over ±100 K, but also provides a temporal resolution down to 10 μs. The method is based on the observations that the peak positions of the ODMR peaks are shifted by more than 20 MHz over K, while their corresponding widths (typically 10 MHz) stay nearly the same (varying by less than 10%). Assuming a constant width, one can determine the temperature shift by measuring the changes of the fluorescence dip at three preselected frequencies only without scanning the whole ODMR spectrum (Figure 2a). This enables real-time measurement of the temperature changes over a wide range and, more importantly, the study of nanoscale heat transfer dynamics in a pump-probe configuration with a pulsed heating source (Figure 2b). I n applying NV for time -resolved luminescence nanothermometry, we chose to use FNDs of ~100 nm in diameter as the temperature sensor and gold nanorods (GNRs) with a diameter of 10 nm and a length of 41 nm as the photon energy absorber. The FND prepared for this work has a NV density close to 10 ppm, or ~900 NV centers per 100 nm particle. The GNR, on the other hand, has an intense longitudinal surface plasmon resonance (SPR) band peaking at ~800 nm, which is well separate from both the excitation wavelength ( nm) and emission wavelength ( nm) of the NV centers. We first employed near-infrared light to achieve highly localized heating of the GNRs in aqueous solution and then applied the three-point method to monitor the local temperature changes with single FNDs spincoated on a glass substrate (Figure. 3 and inset in Figure. 4). Pump-probe-type experiments were subsequently carried out to determine the heat transfer rates using microsecond laser pulses. Results of the measurements were finally compared with finite-element numerical simulations. Figure 4 shows a typical result of the nanothermometric measurement with a single FND submerged in the GNR solution. A precision of better than ±1 K over a temperature variation range of 100 K within a measurement time of 30 s could be achieved. Such technological developments have enabled us to study highly inhomogeneous heating of water 40

42 Yan-Kai Tzeng 1,2, Pei-Chang Tsai 1, Hsiou-Yuan Liu 1,3, Oliver Y. Chen 1, Hsiang Hsu 1, Fu-Goul Yee 3, Ming-Shien Chang 1, and Huan-Cheng Chang *1,4 1 Institute of Atomic and Molecular Sciences, Academia Sinica, Taiwan 2 Department of Chemistry, National Taiwan University, Taiwan 3 Department of Physics, National Taiwan University, Taiwan 4 Department of Chemical Engineering, National Taiwan University of Science and Technology, Taiwan Publication: Nano Letters 15 (2015): in the focal volume of a tightly focused laser beam by direct temperature measurements and to observe superheating of aqueous solution near the water-glass interface. In combination with numerical simulations, this experimental approach is expected to find practical use as a new tool to investigate nanoscale heat transfer, a process of not only fundamental interest but also technological importance. The present study represents the first demonstration of thermometric investigation at the nanometric length scale with microsecond time resolution. Figure 1. (a) Structure and (b) energy level diagram of the NV center in diamond. The red sphere, blue dashed circle, and black spheres in (a) denote nitrogen, vacancy, and carbon atoms, respectively. The green, red, blue sinusoidal, and black dashed arrows in (b) denote optical excitation, fluorescence emission, microwave excitation, and intersystem crossing relaxation, respectively. Figure 3. Schematic diagram of the experimental setup for time-resolved nanothermometric measurement. APD: avalanche photodiode, BS: beam splitter, CCD: charge-coupled device, DM: dichroic mirror, L: lens, M: mirror, and Obj: objective. Red dots on the glass coverslip denote FNDs. ACADEMIA SINICA Figure 2. (a) Pictorial presentation of the three-point method based on an ODMR spectrum consisting of only one peak. The peaks before (blue) and after (red) temperature change are both Lorentzian and have the same width. Overlaid on the spectra are three frequencies (f 1,f 2,f 3 ) chosen for the intensity measurement. (b) Timing sequences of the laser irradiation, microwave excitation, and fluorescence detection for n cycles in the three-point method. Figure 4. Time evolution of the heat dissipation in a GNR solution at z ~ 0 μm and r = 1.0 and 1.5 μm. Insets: Pictorial presentation of the experiment using a near-infrared nm laser for heating of the GNRs in water and a single FND particle for temperature sensing. The separation between FND and the laser beam focus is denoted as r and the distance from the waterglass interface to the point of interest is z. Simulated results are also shown for comparison. 41

43 Division of Life Sciences At14a-Like1 Participates in Membrane Associated Mechanisms Promoting Growth During Drought in Arabidopsis thaliana Abstract Drought is a major cause of lost agricultural productivity worldwide; however, the mechanisms of stress sensing and cellular regulation that determine plant growth and productivity during drought are little understood. In this study we identified a new type of plant stress signaling protein, At14a-Like1 (AFL1) involved in previously uncharacterized membrane-associated drought sensing or signaling mechanisms. Increased expression of AFL1 led to increased growth during drought stress without negative effects on unstressed plants. Transcriptome analysis indicated that AFL1 may promote growth in part by suppression of negative regulatory genes. AFL1 protein interactions, plasma membrane association and co-localization with clathrin light chain, as well as AFL1 structure all indicated a role in vesicle formation or trafficking. Drought and soil drying restrict the amount of water available to plants and lead to many changes in gene expression, metabolism and growth. In crop plants limited water availability during drought leads to severe losses in productivity. Drought stress is one of the most serious limitations on agriculture production globally. Limited k nowledge of how plants regulate their growth and metabolism in response to drought and reduced soil water potential has impeded efforts to improve plant stress tolerance. Sensing and early signaling of drought stress may involve membrane-associated proteins; however, these proteins and signaling mechanisms are yet to be identified. We investigated the stress function of At14a-Like1 (AFL1) because of its stress-induced expression and possible role as a membrane signaling protein. Overexpression of AFL1 in the model plant Arabidopsis thaliana led to increased growth and increased accumulation of the stress-protective metabolite proline during drought stress without negative effect on unstressed plants (Figure 1). Conversely, suppression of AFL1 made the plants more sensitive to growth inhibition by water limitation and also impaired proline accumulation. Gene expression analysis showed that increased AFL1 expression led to decreased expression of many other genes during drought. Thus, the effect of AFL1 on drought response may occur in part through suppression of genes which downregulate growth. Figure 1. AFL1 promotes growth under stress without detrimental effect on unstressed plants. Representative Arabidopsis thaliana seedlings of Columbia-0 (Col) wild type and AFL1 overexpression (AFL1 O.E.) ten days after transfer to either unstressed control or moderate severity low water potential (drought) stress (-0.7 MPa). Overexpression of AFL1 increased growth in both conditions but much more dramatically in the stress treatment. Scale bars = 1 cm. 42

44 M. Nagaraj Kumar, Yi-Fang Hsieh, Paul E. Verslues Institute of Plant and Microbial Biology, Academia Sinica Publication: Proceedings of the National Academy of Sciences USA 112 (2015): AFL1 is an uncharacterized protein and at the outset of our study nothing was known of its cellular function. We identified AFL1 interacting proteins as one way to better understand AFL1 molecular function. AFL1 interaction with Adaptor protein 2-2A (AP2-2A), a protein involved in vesicle formation, indicated a role for AFL1 in endocytosis of plasma membrane vesicles. Consistent with this function, we observed co-localization of AFL1 with clathrin light chain (CLC) in small foci along the plasma membrane indicative of vesicle formation (Figure 2). In addition to its localization and function at the plasma membrane, AFL1 also interacted with endoplasmic reticulum signaling proteins PDI5 and NAI2 and analysis of pdi5 and nai2 mutants indicated that they act as negative regulators of growth during drought. Thus AFL1 effect on plant growth and stress resistance may involve both plasma membrane and ER functions of AFL1 (Figure 3). Understanding these AFL1 functions is a topic of continuing research in our laboratory. This mechanistic analysis of AFL1 demonstrated that it affects drought resistance via mechanisms distinct from known plant stress signaling pathways. It is also consistent with the hypothesis that plants down-regulate their growth more than needed during mild stress as a conservative strategy to prepare for survival of more severe soil drying. Disabling such negative regulator y mechanisms is a promising way to improve plant growth during drought and is potentially more publically acceptable than biotechnology strategies that involve expression of foreign genes in plants. AFLl overexpression does not inhibit growth in the absence of stress and thus circumvents a common problem seen plant stress research. Further experiments to test whether AFL1 can increase growth when expressed in other plant species are ongoing. This is a first step to assess the potential translational use of AFL1 to improve drought resistance of economically important plant species. ACADEMIA SINICA Figure 2. AFL1 colocalization with clathrin light chain (CLC) indicates a role in endocytosis of plasma membrane vesicles. Confocal microscope images where green indicates fluorescently labeled AFL1, orange indicates CLC and blue indicates regions where both proteins are found (colocalization). AFL1-CLC colocalization is seen at the margins of vesicle like particles or at sites indicative of the early stages of vesicle formation (marked by arrows) along the plasma membrane. Scale bars = 5 μm. Figure 3. Summary of AFL1 interactions and localization. AFL1 was found to be a peripheral membrane protein associated with both plasma membrane and endomembrane. At the plasma membrane, AFL1 interaction with AP2-2a and colocalization with CLC indicate a role in vesicle formation. In endomembranes, AFL1 interacted with PDI5 and NAI2 which are negative effectors of drought response. Together, these roles of AFL1 have dramatic impact on plant growth during drought stress. 43

45 Division of Life Sciences Circulating Cells Contribute to Cardiomyocyte Regeneration After Injury Abstract The contribution of bone marrow-borne hematopoietic cells to the ischemic myocardium has been documented. However, a pivotal study reported no evidence of myocardial regeneration from hematopoietic derived cells. The study did not take into account the possible effect of early injury-induced signaling as the test mice were parabiotically paired to partners immediately after surgery-induced myocardial injury when cross-circulation has not yet developed. By combining pulse-chase labeling and parabiosis model, we show that circulating cells derived from the parabiont expressed cardiac-specific markers in the injured myocardium. Genetic fate mapping also revealed that circulating hematopoietic cells acquired cardiac cell fate by means of cell fusion and transdifferentiation. These results suggest that circulating cells participate in cardiomyocyte regeneration in a mouse model of parabiosis when the circulatory system is fully developed before surgery-induced heart injury. During the past decade, numerous studies have provided evidence that mammalian heart contains different populations of resident cardiac progenitors or stem cells which possess the ability to differentiate into cardiac myocytes and also give rise to other cardiac cell types. Several lines of evidence suggest that bone marrow serves as a reservoir for stem or progenitor cells. However, the ability of bone marrow borne or circulation-borne cells to adopt cardiac cell fate remains controversial. Unlike bone marrow transplantation, parabiosis requires additional time for the cross-circulatory system to be developed in the animals. Because injury-induced signals are important modulators of stem cell activities and are only transiently elevated at the early stage of injury, we hypothesized that contribution of bone marrow borne circulating cells to cardiac repair may only be observed when cross-circulation has already been established at the time of injury. To examine when blood circulation was developed after parabiosis, the whole body of a GFP transgenic mouse was surgically joined to a wild-type (WT) mouse. Peripheral blood chimerism in the WT parabiont was then analyzed at different time points after surgery. Flow cytometric analysis and microbubble contrast intensity evaluation indicate that the cross-circulatory system requires at least 7 to 10 days to be stabilized in parabionts (Figure 1). To trace the fate of the circulating cells, a WT mouse was surgically stitched to a GFP transgenic mouse and MI was induced by surgery after stabilization of crosscirculation at 1 month after parabiotic surgery (Figure 2A). The immunostaining result showed that the GFP + cells were positive for isolectin and smooth muscle 22α which are endothelial and smooth muscle cell markers, respectively (Figure 2B), suggesting that the circulating cells participate in microvasculature reconstitution. However, the majority of circulation-derived GFP + cells had adopted hematopoietic cell fates, of which 21.25±0.05% of cells were T cells, whereas 39.25±2.35% and 29.9±1.90% of circulating cells had committed to B cell and macrophage lineages, respectively (Figure 2C and 2D). To test whether the circulating cells also contribute to cardiomyocyte regeneration, the MCM transgenic mice expressing α-mhc promoter driven MCM fusion protein was surgically paired to GFP transgenic mice. Quantification of cells in the ischemic region of injured hearts revealed that 9.39% of GFP + /Cre +, suggesting that the circulating GFP + cells had fused with the resident cardiac myocytes (Figure 3C). We also detected 0.17% GFP + /Cre cardiac myocytes, which are representative of transdifferentiated cells (Figure 3C). From dissociated ventricular cardiac myocytes, we identified 0.17±0.034% GFP + cardiac myocytes coexpressing Cre, suggesting that they arose from cell fusion (Figure 3D). Our findings suggested that contribution of circulating cells to cardiomyocyte regeneration could be observed after stabilization of the cross-circulatory system. To strengthen our findings that a stabilized circulatory system at the time of injury was the key for cardiac fate acquisition by bone marrow borne circulating cells in the injured myocardium, MCM mice were subjected to MI surgery when the cross-circulation had been partially developed or not yet developed. Compared to mice with fully developed cross-circulation, the frequency of cell fusion decreased when cross-circulation had only been established for 5 days at the time of MI surgery (Figure 4B and 4D). The frequency dropped more in the MCM mice that had only been joined to Z/EG 44

46 1 Jasmine M.F. Wu, 1 Ying-Chang Hsueh, 2 Hui-Ju Ch'ang, 3 Chwan-Yau Luo, 4 Li-Wha Wu, 5 Hiromitsu Nakauchi, and 6 Patrick C.H. Hsieh 1 Institute of Basic Medical Sciences, National Cheng Kung University,Taiwan 2 National Institute of Cancer Research, National Health Research Institutes,Taiwan 3 Department of Surgery, National Cheng Kung University Hospital, Taiwan 4 Institute of Molecular Medicine, National Cheng Kung University Hospital, Taiwan 5 Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Japan 6 Institute of Biomedical Sciences, Academia Sinica Publication: Circulation Research 116 (2015): for 3 days before MI was induced (Figure 4B and 4D). We only observed 1.33±0.24% of fused cardiac myocytes in the mouse that had been subjected to MI surgery before parabiosis (Figure 4C and 4D). Collectively, these observations indicate that a limited cross-circulation has a profound impact on the acquisition of cardiac cell fate by circulating cells via fusion. In conclusion, our findings provide evidence that bone marrow derived circulating cells have the ability to engraft into the injured myocardium and to repair heart by fusing with resident cardiac myocytes and transdifferentiation. Figure 3. Circulating cells adopt cardiac cell fate after heart injury. A, Schematic illustration of the experimental procedure to examine the fate of circulating cells in the injured myocardium. B, Representative images of circulation-derived GFP + cells costained with ctnt (left) and α-sma (right). Scale bars, 20 μm. C, Representative immunohistochemical images showing the GFP + cells with (left) or without (right) Cre expression. Scale bars, 20 μm. D, Representative images and quantification of isolated cardiac myocytes arisen from cell fusion (left) and transdifferentiation (right). Scale bars, 100 μm. ACADEMIA SINICA Figure 1. Development of stabilized cross-circulation requires 7 to 10 days. A, Left, Lineage of GFP + cells observed in the WT parabiont was analyzed by costaining with CD45. Right, Blood chimerism in the peripheral blood of a WT parabiont (n=2). B, Schematic diagram explaining the in vivo imaging analysis of blood flow using contrast-enhanced agent microbubbles. C, Left, Background noise and microbubble contrast signal intensity in the ventricles of both donor and recipient mice. Right, Fold change in microbubble contrast signal intensity. Figure 2. Circulating cells engraft into the injured myocardium and acquire mature hematopoietic cell fate. A, Diagram illustrating the experimental procedure designed to analyze the vascular and hematopoietic cell fates of GFP + circulating cells. B, Immunostaining results of ischemic myocardium of a WT mouse. Scale bar, 5 μm. C, Flow cytometric analyses of the hematopoietic phenotypes adopted by GFP + circulating cells. D, Percentages of different mature hematopoietic cell lineages. Figure 4. Limited cross-circulation affects the number of circulating cells adopting cardiac cell fate in the injured myocardium. A, Schematic diagram explaining the experiment designed to examine whether limited crosscirculation could affect the circulating cells to acquire cardiac cell fate. B and C, Representative immunohistochemical images of GFP + cardiac myocytes derived from fusion of circulating cells mobilized from the Z/ EG parabiont. 5 days (left), 3 days (right) or 0 day (C) before myocardial infarction (MI) was induced. Scale bars, 20 μm. D, Quantification of fused GFP + cells identified in the injured hearts. 45

47 Division of Life Sciences A Common Glycan Structure on Immunoglobulin G for Enhancement of Effector Functions Abstract Fc glycosylation is crucial for antibodies to mediate interactions with various effector cells to gain functions in immune system, including cancer killing, pathogen defending, and anti-inflammation, etc. To identify the optimal glycan structure on antibodies for desired functions, various well-defined homogeneous glycosylated antibodies were prepared for activity assessment. Significantly, it was found that antibodies with the 2, 6-sialylated Fc glycosylation, a known potent composition of intravenous immunoglobulin for exhibiting anti-inflammatory activity, display superior binding affinity towards FcγRIIIa, remarkable antibodydependent cell-mediated cytotoxicity against both breast cancer cells and resistant/non-resistant strain of abnormal B cells, and good anti-h1n1 influenza activity, implying multifaceted functions derived from single Fc glycan form of 2, 6-sialylation. Antibodies are crucial glycoproteins that consist of two antigen binding fragments (Fab) and one crystalizable fragment (Fc). At the Fc region, there are asparagine-linked glycosylations which function to mediate and modulate its recruitments or interactions with various effector cells or receptors. Through such modulations, one antibody can display different strength in functions, including cancer killing, pathogen defending, and anti-inflammation, etc. Pharmaceutically, many FDA-approved immunoglobulin G monoclonal antibodies have been successfully administrated to patients with leukemia, solid tumors, or autoimmune diseases. However, these antibodies are all heterogeneous in glycosylation and may contain few or none of the optimal glycan form for best efficacy of treatment. Therefore, high dosage of antibody is often indispensable and it follows high cost and high frequency of injection. In addition, the inaccessibility of pure antibody with homogeneous glycosylation further troubles researchers in defining and comparing the impact of each specific Fc glycan on activity, half-life and side effects. To overcome the aforementioned problems, we use endoglycosidase incorporating with fucosidase to treat IgG1 antibody to prepare the basic homogeneous antibody with the glycan form of mono-glcnac on the Fc region. Then, a set of various synthesized oxazoline glycan donors were enzymatically transferred to the modified IgG to obtain various well-defined Fc-glycoengineered IgG1 antibodies (Figure 1). Two therapeutic anti-cancer antibodies were chosen as paradigms. One is Rituximab, an anti-cd20 antibody which is used to treat non-hodgkin s lymphoma and arthritis. The other is Herceptin, an anti-her2 antibody which is for treatment of breast cancer. In the systematic SPR binding study towards FcγRIIIa, both antibodies surprisingly display superior binding affinity under the 2, 6-sialylated Fc glycosylation, a known major composition of intravenous immunoglobulin for exhibiting anti-inflammatory activity. To further assess the cytotoxicity of these glycoengineered antibodies, we performed cell-based assay, including V158- FcγRIIIa engineered signaling reporter assay of Herceptins (Figure 2A and 2B) and peripheral blood mononuclear cell (PBMC) mediated B-cell depletion of Rituximabs (Figure 2C). Corresponding to the SPR data, both the 2, 6-sialylated Rituximab and Herceptin show good antibody dependent cell-mediated cytotoxicity (ADCC), implying not only antiinflammatory activity but also good cytotoxicity efficacy of 2, 6-sialylated Fc engineered antibody. Interestingly, Fc glycosylation of 2, 6-sialylation is different from that of 2, 3-sialylation which makes Herceptin show higher EC50, indicating the reduced killing activity of 2, 3-NSCT-Herceptin compared to the 2, 6-linked analogue (Figure 2A). In addition, the 2, 6-sialylation may further improve the cytotoxicity efficacy of antibodies against drug-resistant strains. Compared to the non-modified Rituximab, the 2, 6-sialylated Rituximab was found to display better cytotoxicity against both not-resistant and resistant B lymphoma cells, Ramos and Ramos-R respectively (Figure 3A). Similar results were also found for the other B lymphoma cells, Raji and Raji-R (Figure 3B). Finally, to explore the multifaceted killing effect of the 2, 6-sialylated antibody, we also applied the same glycan to engineer H1N1 influenza neutralizing antibody, FI6, and examined its ability to remove virus-infected cells. No matter in the V158-FcγRIIIa engineered signaling reporter assay (Figure 4A) or the PBMC-mediated killing of influenza-infected HEK293T cell mimicry (Figure 4B), the 2, 6-sialylated FI6 indeed shows better ADCC compared to the non-treated FI6 antibody. 46

48 Chin-Wei Lin 1,2, Shiou-Ting Li 1, Tsung-I Tsai 1, Meng-Yu Lai 1, Chia-Yu Wu 1, Yung-Chieh Tseng 1, Chia-Lin Chen 1,2, Che Ma 1, Chung-Yi Wu 1,2, and Chi-Huey Wong 1,2 1 Genomics Research Center, Academia Sinica 2 Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, Academia Sinica Publication: Proceedings of the National Academy of Sciences USA 112 (2015): Importantly, these in vitro results can successfully translate to protection against mice which were challenged with A/ California/07/2009H1N1 virus (Figure 4C). In summary, Fc glycosylation is crucial for mediating mutilple functions of antibodies. Herein, we have shown that various glycosylations on Fc establish different killing profiles and binding affinity for both therapeutic antibodies, Herceptin and Rituximab.In addition, the linkage of sialylation dramatically affects these functions, and the afucosylated bi-antennary N-linked Fc glycan structure with two terminal alpha-2,6-linked sialic acids has been suggested to display activity for antibodies in anti-inflammation, anti-cancer and anti-viral infection. Figure 1. A general strategy for the preparation of homogeneous antibodies with a well-defined glycan structure through in vitro enzymatic remodeling of a mixture of antibody glycoforms. The mixture was first treated with a combination of endos and the fucosidase from Bacteroides fragilis to generate mono-glcnac antibody, followed by ligation with a synthetic glycan oxazoline catalyzed by an endos mutant. Figure 3. EC50 of glycoengineered Herceptin glycoforms in V158 FcγRIIIa mediated ADCC reporter bioassay (A, B). Experiments were performed under the E/T ratio of 6 to 1 with SKBR3 target cells and the V158 FcγRIIIa engineered effector Jurkat cells. All data shown in the same graph were experiments done in the same microplate and the same batch of effector cells; bars of 95% confidence interval were plotted. (C) Antibody-dependent B-cell depletion activity of various Rituximab glycoforms. The depletion of human B cells was conducted using freshly prepared human PBMC cells and analyzed with FACS, based on the CD19 + CD3 - B cells. Compared to a series of different glycoengineered Riruximab glycoforms, the 2,6-NSCT Rituximab showed higher depletion ability. ACADEMIA SINICA Figure 2. The 2,6-NSCT Rituximab showed remarkable ADCC efficacy towards both normal and resistant cells for Ramos (A) and Raji (B), whereas the non-treated antibody dramatically lost its activity towards resistant strains. Figure 4. Anti-influenza antibody FI6 with 2,6-NSCT glycan attached to its Fc Asn297 (FI6m) significantly enhances its ADCC activity towards hemagglutinin (HA)-expressing HEK293T cells and prophylactically protects mice from a lethal dose of H1N1 virus (A/California/07/09) challenge. (A) ADCC activity is shown as fold increases of bioluminescence from a luciferase reporter assay. (B) PBMCs mediated cytotoxicity is represented as the percentage of lysed HA-expressing HEK293T cells. (C) Survival of mice was monitored upon lethal dose (10 MLD 50 ) infection of influenza virus A/California/07/09 (H1N1). The FI6 and FI6m groups had significant survival difference (P<0.01). 47

49 Division of Humanities and Social Sciences Gendered Words: Sentiments and Expression in Changing Rural China Abstract This book is the first full-length ethnography on nüshu the world's only gender-defined script that men could not read, script developed by women in Jiangyong County, Hunan Province, China. Also heuristically, though written, nüshu must be performed in singing or chanting. Since at least the late imperial China, Jiangyong women have used the sung nüshu to express their selfreflective comments on society and articulate their sentiments of kelian (one s misery). Nonetheless, this centuries-old nüshu was unknown to the outside world until 1982, just as its use had nearly faded away. Based on twenty years of fieldwork, and through four women s life narratives, this book proposes an innovative approach combining writing, singing, and orality, along with practice-oriented and performance-sensitive perspectives to capture women s dialogically-inspired subjectivities, and to develop the theoretical construct of expressive depths. As an anthropological monograph, this book is also an attempt to document the true face of nüshu and restore it to history before it is too late. This book is the first full-length ethnography on nüshu the world's only gender-defined script that men could not read, a script developed by women in Jiangyong County, Hunan Province, China. Also heuristically, although in written form, nüshu must be performed in singing or chanting. Since at least the nineteenth century, nüshu has been used by women in rural Jiangyong to construct cross-village sisterhood networks, compose biographic narratives, articulate women's virtue and vulnerability, and supplicate divine blessing. Nevertheless, if you ask "What nüshu was written about?" The answer is only one: su kelian or "lamenting one's misery." The kelian-tuned nüshu has silently safeguarded women ever since, psychologically and socially. "Silently" means that though centuries-old, nüshu was largely unknown to the outside world until 1982, just as its use had nearly faded away. The "discovery" of nüshu provides us with a window into women's lifeworlds, especially those of the peasant class. Based on twenty years of fieldwork, and through four women's life narratives, this book proposes an innovative approach combining writing, singing, and orality, along with practice-oriented and performance-sensitive perspectives to capture women's dialogically-inspired subjectivities, to illuminate nüshu's humanistic and social implications in areas of gender, class, voice, expression, and emotion, and to develop the theoretical construct of "expressive depths." As an anthropological monograph, this book is also an attempt to document, if not salvage, the true face of nüshu and restore it to history before it is too late. Succinctly speaking, this book demonstrates how nüshu sheds light on contemporary scholarships, conceptually or ethnographically, in at least the following four areas: Gender-Class Embedded Subjectivities: Writing history in China had long been the exclusive preserve of men, in particular, elite men; and women were usually objects to be documented, rather than subjects who wrote. Nüshu now provides us with a view of peasant women's writing of their own lived experiences, their perceptions, emotions, moral pursuits, and hopes and aspirations. What then does peasant women's account of their life histories bring to the fore epistemologically and historiographically? Expressive Depths: Writing is consummated by reading. But for nüshu, reading also means singing or chanting, and this makes it mostly interchangeable, but not identical, with local women's singing tradition, called nüge. How nüshu and nüge intertextually inspire one another urges us to inquire into how writing and singing maintain their distinct "expressive niches." This is to say, form of expression (e.g., writing, singing, oral, genre, tune) defines, and by the same token, confines the voice expressed and this is the gist of my theoretical construct of "expressive depths." With this scope in mind, to more comprehensively capture women's sense and 48

50 Fei-Wen Liu Institute of Ethnology, Academia Sinica Publication: New York: Oxford University Press (2015), 252 pages. sensibilities, this book include also women's life narratives, as an intertextual reference to nüshu and nüge, to unfold peasant women's lifeworlds in changing rural China. Emotion as a Dynamic Inspiration Field: In traditional China writing often carries a tinge of moral justification; in West, influenced by the Enlightenment, rationality enjoys quite a privileged position. Nüshu as a genre for "lamenting one's misery," however, opens up a new horizon as to how emotion functions as a source of inspiration in practice and through performance. Specifically, the emotion of "misery" not only speaks to one's phenomenological existence, whether psychological or material, but also entails the power to evoke sympathy and other corresponding or oppositional sentiments, and even meta-sentiments, and through which, one's miserable state of being is counterbalanced and transformed. Here, emotion constructs a humanistic-social field wherein the vulnerable can stand strong, hold tight to an optimistic mindset in the face of life's challenges, and share stories to inspire one another. Whither Nüshu: Nüshu was already on the verge of extinction when it was identified in With a sense of urgency about salvaging this endangered heritage, scholars made great efforts to collect nüshu since then. Starting 2000s, the local government paid attention to its nüshu heritage, with the institutionalization of the officially-endowed "nüshu transmitter"; and the various cultural practitioners introduce calligraphic art to "advance" nüshu from a local vernacular tradition to a form of high culture. These multiple efforts, though coming from different arenas, tend to perceive nüshu from the same looking lens: Han chauvinism. With Han chauvinism, the new poetics of nüshu has taken shape, poetics that privileges writing over singing/orality, official propaganda request over women's spontaneous expression, male-written classical poetry over women's folkloristic verse, and calligraphic aesthetics over nüshu's stiff brushstrokes. When nüshu is no longer a tool of women's self-expression, can it still be counted as a "women's script?" Historically nüshu was developed to give voice to peasant women's experiences, but it also became a form of lamentation at women's failure to be heard. If this form was part of a struggle to gain recognition over the course of history, its current challenge is to survive the threat posed by the new nüshu propelled by Han chauvinism. Nüshu as women's expressive culture will certainly move along with society, and in this sense, even the new nüshu has distinct cultural significance. But it should not thus overwrite the history of how nüshu has stood for women and transformed their vulnerable existence into a hopeful becoming. Nüshu was silent for so long, and history may just repeat itself if we let the "women's script" become blurred beyond recognition and slip into oblivion. Figure 1. Book cover of Gendered Words Figure 2. Author and nüshu writers Tang Baozhen (center) and He Yanxin (right) ACADEMIA SINICA 49

51 Division of Humanities and Social Sciences Guxin Shengjing Cangao Abstract The linguistic tools that European Jesuits employed to proselytize in the transitional period between the Ming and the Qing can be divided into two tracks: the one is the traditional wenyen (classical Chinese), while the other is the vernacular, one form that has long been neglected in the Jesuit history in China. This newly edited Bible argues that the vernacular line of the Jesuit writings was inaugurated even during Matteo Ricci s lifetime and the movement continued to flourish thereafter, culminating in Louis de Poirot s translation of the Vulgate Bible into colloquial idiom spoken by people of lower class in Beijing. Since it was a translation yet to be completed, it is thus entitled Guxin Shengjing Cangao (literally, the incomplete translation of the Vulgate Bible). The editors are primarily Sher-Shiueh Li and Zheng Haijuan. As indicated in the brief introduction to Louis de Poirot s Chinese Vulgate Bible which was translated in the period between the Qianglong and the Jiaqing reigns, the linguistic tools that European Jesuits employed to proselytize in the transitional period between the Ming and the Qing can be divided into two tracks: the one is the traditional wenyen (classical Chinese), while the other is the vernacular, one form that has long been neglected in the Jesuit history in China. This newly edited Bible argues that the vernacular line of the Jesuit writings was inaugurated even during Matteo Ricci s lifetime and the movement continued to flourish thereafter, culminating in Louis de Poirot s translation of the Vulgate Bible into colloquial idiom spoken by lower-class people in Beijing. Before 1803 when the Vatican officially declined to have Poirot s Vulgate or Guxin Shengjing published, he had already translated about fifty-seven of the seventy-three books of the Vulgate Bible. Nevertheless, Poirot s merit lies in his use of a Chinese style that was not only colloquial but also Latinate. This new type of vernacular Chinese, Europeanized as it is called today, disappeared until the last decade of the Nineteenth century. It is because of this particular style that Poirot s Chinese Vulgate, in addition to its influence upon syntax and terminology of later Bibles put into Chinese, paved the way for the newly developed Mandarin Chinese, which prevails in China today. Since the Roman Catholic Church s interpretation of the Bible defied opposition, Louis de Poirot s Guxin Shengjing bears a large number of annotations that generally follow the Church s teachings. For example, it cites St. Augustine, St. Chrysostom, and St. Jerome, among others. Yet Poirot s interpretations, more often than not, drew from sources beyond the Catholic tradition, too. His text attempted to accommodate the ideas of the Hellenistic Jewish exegete Philo of Alexandria and the Byzantine bishop Theodoret of Cyrus. Poirot s annotations to the first two chapters of Genesis, for instance, places special attention to God s role in the creation of heaven, earth, and human beings. Following his Jesuit precursors in Ming and Qing China, Poirot emphasized such topics as the Trinity and the nature of God. To help his Chinese readers access more to Genesis, Poirot also followed Catholic biblical exegesis with references to Ptolemy s and even to Tycho s theories of the sphere, both of which had made their appearances as early as the late Ming. Poirot s allusions to geocentrism are thus conservative because at his time Protestants had already embraced Copernics cosmology instead. When it comes to human beings, Poirot, following other Jesuits earlier than him, talks a lot in his annotations to the second chapter of his Bible about how Adam and Eve were made and how important anima was in their lives and movement. Poirot s annotations to the first two chapters of the Genesis closes by outlining his stress on monogamy, taking Adam and Eve as an example, on which Diego de Pontoja, a Spanish Jesuit in Ming China, had laid some two hundred years before him. By annotating Genesis, Poirot has also criticized traditional Chinese polygamy and conjugal relations abused. 50

52 Sher-Shiueh Li Institute of Chinese Literature and Philosophy, Academia Sinica Publication: Beijing: Zhonghua Book Company ( ), 9 volumes, 3512 pages. ACADEMIA SINICA 51

53 Division of Humanities and Social Sciences The Purple Aboriginal Boundary: Analyzing the Map and Description of Reclaimed and Prohibited Paddy and Dry Land in Taiwan Abstract The research fellows of the Institute of Taiwan History, Academia Sinica, worked closely with scholars from different universities between 2012 and 2014 to study the Purple Aboriginal-boundary Map in great detail by organizing several workshops. GIS (Geographic Information System) and field surveys were employed to locate the places on the map. The publication of this book not only makes available this important but previously unknown historical map to both academia and the general public, but also constitutes a significant achievement of the Institute in collecting overseas documentary materials and fostering international cooperation. We look forward to stimulating more research on the imperial policy of frontier governance, and on the development of border areas and ethnic relations in eighteenth-century Taiwan. The Map and Description of Reclaimed and Prohibited Paddy and Dry Land in Taiwan, ink and color on paper, 657 x 62cm, is kept in the Palace Museum in Beijing, China. It is a traditional landscape-style map painted in 1784 (or the forty-ninth year of the Qianlong Emperor s reign) as part of a government project to redefine the aboriginal boundary directed by Yang Tinghua, the assistant commissioner of the Taiwan Intendancy. The map may be compared with the Red and Blue Aboriginal-boundary Map, which is currently kept in the Institute of History and Philology, Academia Sinica, Taiwan, and thus is the second thematic map on the aboriginal boundary to be recently discovered. The map depicts the landscape of the western part of contemporary Taiwan and includes over 1,700 place names. The areas around the aboriginal boundary are described in more detail since they are the major focus of the map. The cartographer employed six different kinds of ink markers for more than 300 places in order to illustrate the official response of the Qing Empire toward the aboriginal-boundary areas. There are 116 entries with more than 14,000 characters of description on the top section of the map. The content is divided into five sections based on the contemporary administrative units, namely the Danshui Subprefecture, Changhua County, Chulo County, Taiwan County, and Fengshan County of Taiwan under the Qing Empire. For each section, more detailed information is given: the local place names, the representatives of the reclaimers, the numbers indicating land measurements, and the planned official solutions. Since the map is distinguished from the aforementioned Red and Blue Aboriginal-boundary Map by the purple color for the new aboriginal boundary, it is also called the Purple Aboriginal-boundary Map. The Purple Aboriginal-boundary Map explains in detail plans for the management of hillside territory that overstepped the boundary in western Taiwan before the uprising led by Lin Shuang-Wen, such as places where reclamation was allowed or forbidden, confiscated property, previously registered property, new ai (frontier forts), and forbidden areas. In The GIS visual representation of the research results based on the documentary, toponymic and cartographic source materials. 52

54 Yu-Ju Lin 1, Su-Chuan Chan 1, and Chih-Hao Chen 2 (Editor-in-chief) 1 Institute of Taiwan History, Academia Sinica 2 Department of History, Soochow University Publication: Taipei: Institute of Taiwan History, Academia Sinica (2015), 248 pages. addition, it illustrates the development outside the boundaries, and the status of the territory of raw savages. This map is also the combined achievement of previous aboriginal maps, as well as of contemporary understandings of the geography and topography of Taiwan, and of cartography. It is far more elaborate and detailed than the one kept in Academia Sinica, and it will surely take us a step further in understanding the context of eighteenth-century cartography and the geospatial constitution of Taiwan under the Qing Empire. It could also help us to understand more deeply land development, frontier society, and ethnic relations outside the boundaries of Qing territory during the Qianlong Emperor s reign. The areas around Chip-chip-po on the original purple-line manuscript. The east is on the top. Both the old red and blue lines are discernible. Owing to the significance of the map, the research fellows of the Institute of Taiwan History, Academia Sinica, worked closely with scholars from different universities between 2012 and 2014 to study it in great detail by organizing several workshops. GIS (Geographic Information System) and field surveys were employed in order to locate the places on the map. The current book is the cumulative result of these scholarly efforts. It is also the fruit of a research workshop led by Lin Yu-ju and Chan Su-chuan since 2012, which verified the drawings and descriptions on the map and interpreted the space of the map, among other things. The content of the book was written by Lee Wen-liang and six other team members, who took charge of the explanatory wording and annotations of each county. Lin Yu-ju, Chan Su-chuan, and Chen Chi-hau are responsible for the introduction of the book, and Su Feng-nan for the cartography and GIS mapping. The publication of this book not only makes available a previously unknown historical map to both the academic world and the general public, but also bears witness to a significant achievement by the Institute in collecting overseas documentary materials and in fostering international cooperation. We look forward to stimulating more research and discussion on the imperial policy of frontier governance, and on the development of border areas and ethnic relations in eighteenth-century Taiwan. ACADEMIA SINICA A reproduction of the areas around Chip-chip-po from the original manuscript for the convenience of the readers. The GIS visual representation of the research results based on the documentary, toponymic and cartographic source materials. 53

55 Division of Mathematics and Physical Sciences Evolutionary Prisoner s Dilemma Games with Local Interaction and Best- Response Dynamics Yun-Shyong Chow Institute of Mathematics, Academia Sinica Frontiers of Mathematics in China 10 (2015): Two prisoners are put in custody. They have to choose independently whether to confess or not. Since a > b > c > d, (D, D) is the unique Nash equilibrium. Nevertheless, (C, C) yields higher payoff than (D, D). Another scenario is that two competing company have to decide independently the price of a certain commodity to be low or high. Apparently (high, high) is more profitable. Yet (low, low) is the Nash equilibrium. It is an interesting issue whether full cooperation can be sustained in repeatedly played PD games. Assume n players sit sequentially around a circle. Each player has exactly two neighbors. At time period t, each player has to decide his boundedly rational strategy. In the beginning of each period, players' actions and payoffs occurred in the last period are observable to their neighbors. The best response dynamics fails as strategy D maximizes each player's payoff if he plays with each of his neighbors once. The proverb charity begins at home means that one should first take care of one's family and neighbors. So we modify the best-response updating by requiring each player to choose the strategy that maximizes the sum of his payoff and those of his two neighbors. Mutation mechanism is also introduced. Under some mild condition on the payoff parameters, full cooperation among players is possible in the long run. The payoff matrix. D means defect, i.e., to confess, and C means cooperation, i.e., not to confess. Umbilicity and Characterization of Pansu Spheres in the Heisenberg Group Jih-Hsin Cheng, Hung-Lin Chiu, Jenn-Fang Hwang, and Paul Yang Institute of Mathematics, Academia Sinica Journal für die reine und angewandte Mathematik (2015): In Euclidean space, the famous Alexandrov Theorem says that any closed hypersurface of positive constant mean curvature must be a sphere. We can ask the similar question for Heisenberg group: whether a closed hypersurface of positive constant (p-)mean curvature must be a Pansu sphere. Observe that the original proof of Alexandrov s theorem uses the method of moving planes, which produces touching points, and then the strong maximum principle is applied. But this approach does not work for the Heisenberg case. On the other hand, Heisenberg group is a subriemannian manifold. We lack the strong maximum principle of comparison functions for p-mean curvature equation. We consider umbilic hypersurfaces of positive constant p-mean curvature in Heisenberg group. We show that the properties of such a hypersurface are determined by a pair of functions ( α,β) satisfying an ODE system. Except some special points, the integral curves exist and is unique. We prove that there are three cases for integral curves: stationary points, closed curves, and the straight line β 0. But the previous two cases correspond to non-closed hypersurfaces. Only β 0 corresponds to a closed hypersurface, a Pansu sphere. We therefore complete the proof of our theorem. Notice that a closed hypersurface of positive constant p-mean curvature must have points of α=. But in Figure 1, the integral curves of ( α, β ) are all closed or stationary points having no points of α=. Only in the case β 0, the points of α= are included at and this corresponds to a Pansu sphere. 54

56 The Change of Spectral Indices in Very High Energy Cosmic-Ray Proton and Helium Flux Shih-Chang Lee, Haino Sadakazu, Chih-Hsun Lin, and AMS collaboration Institute of Physics, Academia Sinica Physical Review Letters 114 (2015): Physical Review Letters 115 (2015): We published the proton flux and helium flux in two Physical Review Letters. Both were selected as Editor s Suggestions. We discovered that the spectral indices change into new values near rigidity 300GV. The spectral index of the ratio of proton over helium remains unchanged. This discovery is inconsistent with our understanding of cosmic ray energy spectrum. We have a new understanding of the sources of cosmic rays. Self-Repairing Symmetry in Jellyfish Through Mechanically Driven Reorganization ACADEMIA SINICA M. J. Abrams, T. Basinger, W. Yuan, Chin-Lin Guo, and L. Goentoro Institute of Physics, Academia Sinica Proceedings of National Academy of Sciences of the United States of America 112 (2015): E3365-E3373. What happens when an animal is injured? This is an important issue in regenerative medicine. Here, we report a previously unidentified strategy of self-repair, where moon jellyfish respond to injuries by reorganizing existing parts, and rebuilding essential body symmetry, without regenerating. This work is broadcasted on Washington post and New York Times. 55

57 Division of Mathematics and Physical Sciences Construction of a Near-Infrared-Activatable Enzyme Platform to Remotely Trigger Intracellular Signal Transduction Using an Upconversion Nanoparticle Hua-De Gao, Pounraj Thanasekaran, Chao-Wei Chiang, Jia-Lin Hong, Yen-Chun Liu, Yu-Hsu Chang, and Hsien-Ming Lee Institute of Chemistry, Academia Sinica ACS NANO 9 (2015): Photoactivatable (caged) bio-effectors provide a way to remotely trigger or disable biochemical pathways in living organisms at a desired time and location with a pulse of light (uncaging), but the phototoxicity of ultraviolet (UV) often limits its application. In this study, we have demonstrated the near-infrared (NIR) photoactivatable enzyme platform using protein kinase A (PKA), an important enzyme in cell biology. We successfully photoactivated PKA using NIR to phosphorylate its substrate, and this induced a downstream cellular response in living cells with high spatiotemporal resolution. In addition, this system allows NIR to selectively activate the caged enzyme immobilized on the nanoparticle surface without activating other caged proteins in the cytosol. This NIR-responsive enzyme-nanoparticle system provides an innovative approach to remote-control proteins and enzymes, which can be used by researchers who need to avoid direct UV irradiation or use UV as a secondary channel to turn on a bio-effector. Figure 1. Crosslinked caged kinase / nanoparticle, upon the NIR irradiation, can upconvert the NIR to UV, and activate the caged kinase on its surface to restore its kinase activity. Figure 2. The spatial resolution of this technique can reach to mm level (yellow region shows stress fiber unbundled by NIR light. Large-Scale Determination of Absolute Phosphorylation Stoichiometries in Human Cells by Motif-Targeting Quantitative Proteomics Chia-Feng Tsai, Yi-Ting Wang, Hsin-Yung Yen, Chih-Chiang Tsou, Wei-Chi Ku, Pei-Yi Lin, Hsuan-Yu Chen, Alexey I. Nesvizhskii, Yasushi Ishihama and Yu-Ju Chen Institute of Chemistry, Academia Sinica; Genomics Research Center, Academia Sinica; Institute of Statistical Science, Academia Sinica Nature Communcation 6 (2015). doi : /ncomms7622. Protein phosphorylation is one of the most critical posttranslational modifications to regulate cellular function. Measuring the phosphorylation event at the proteome scale provides a system view for activated signaling pathway. We have developed a motif-targeting quantitative proteomic approach by integrating enzymatic kinase reaction and isotope-ba sed quantitative proteomic strategy. To our knowledge, this approach reveals the first large-scale measurement on the basal level of phosphorylation stoichiometry in a single state human phosphoproteome. On the comparison of TKI (tyrosine kinase inhibitor) sensitive (PC9) and resistance lung cancer cell (PC9/gef.), the quantitative information not only illuminated that the post-translational phosphorylation changes are significantly more dramatic than those at protein as well as mrna levels, but also suggested potential drug-targeting proteins in the kinase-substrate network associated with acquired drug-resistance. We expected that this newly developed approach will have wide applications to provide system-wide maps of protein phosphorylation stoichiometry under physiological or pathological regulation. Comparison of phosphorylation stoichiometries between drug sensitive and resistant lung cancer cells. (a) The number of identified phosphorylation sites for three kinases. (b) Analysis of phosphorylation stoichiometry distribution in motifs matched to EGFR, CK2 and MAPK in drug sensitive (PC9) and resistant (PC9/gef.) lung cancer cells. 56

58 Expanding Ligand Framework Diversity of Carbodicarbenes and Direct Observation of Boron Activation in Methylation of Amines with CO 2 Wen-Ching Chen, Jiun-Shian Shen, Titel Jurca, Chun-Jung Peng, Yen-Hsu Lin, Yi-Ping Wang, Wei-Chih Shih, Glenn P. A. Yap, and Tiow-Gan Ong Institute of Chemistry, Academia Sinica Angewandte Chemie 54 (2015): A simple and convergent synthetic strategy was developed to increase the diversity of the carbodicarbene framework by incorporation of unsymmetrical units. Reactivity studies revealed that carbodicarbenes are competent organocatalysts for amine methylation using CO 2 as a synthon. Large-Scale Thermo-Chemical Structure of the Deep Mantle: Observations and Models ACADEMIA SINICA Frederic Deschamps, Yang Li, and P. J. Tackley Institute of Earth Sciences, Academia Sinica Amir Khan and Frédéric Deschamps eds., The Earth's heterogeneous Mantle, Springer (2015): Seismic tomography indicates that the Earth s lowermost mantle ( km) is strongly heterogeneous. The most striking features are two large low-shear wave velocity provinces (LLSVPs), where shear-wave velocity drops by a few percent. Both thermal and compositional changes are required to explain these anomalies. In the meantime, models of thermo-chemical convection showed that reservoirs of dense, chemically differentiated material can be maintained in the lowermost mantle over long periods of time, with thermal plumes being generated at their tops. These models further explain details revealed by seismic travel-time data, in particular LLSVPs sharp edges. A remaining question is the nature of chemical heterogeneities. Seismic anomalies modelled from mineral physics data suggest that LLSVPs are better explained by warm material enriched in iron resulting from mantle early partial differentiation, than by hot subducted oceanic crust. Finally, the post-pervoskite phase may play a role in explaining the D" discontinuity. These features are summarized in the figure below. 57

59 Division of Mathematics and Physical Sciences Landslide Seismic Magnitude Cheng-Horng Lin, Jyh-Cherng Jan, Hsin-Chieh Pu, Yoho Tu, Chien-Chih Chen, and Yih-Min Wu Institute of Earth Sciences, Academia Sinica Earth Planetary Science Letters 429 (2015): Landslides have become one of the most deadly natural disasters on earth, not only due to a significant increase in extreme climate change caused by global warming, but also rapid economic development in topographic relief areas. How to detect landslides using a real-time system has become an important question for reducing possible landslide impacts on human society. However, traditional detection of landslides is highly time consuming. Here we analyze very long period seismic signals (20 50 s) (Figure. 1) generated by large landslides during Typhoon Morakot, which passed though Taiwan in August In addition to successfully locating 109 large landslides, we define landslide seismic magnitude based on an empirical formula (Figure 2): ml = log (A) log ( ) We conclude that both the location and seismic magnitude of large landslides can be rapidly estimated from broadband seismic networks for both academic and applied purposes, similar to earthquake monitoring. Figure 1. Very-long-period (20-50 s) seismic signals generated by a landslide. Figure 2. Seismic amplitudes generated by different landslide seismic magnitudes decay with distances. Reliable Multicast Routing for Software-Defined Networks Shan-Hsiang Shen, Liang-Hao Huang, De-Nian Yang, and Wen-Tsuen Chen Institute of Information Science, Academia Sinica IEEE International Conference on Computer Communications, IEEE INFOCOM (2015). Current traffic engineering in SDN mostly focuses on unicast. By contrast, compared with individual unicast, multicast can effectively reduce network resources consumption to serve multiple clients jointly. Since many important applications require reliable transmissions, it is envisaged that reliable multicast plays a crucial role when an SDN operator plans to provide multicast services. H owever, the shortest-path tree (SPT) adopted in current Internet is not bandwidth-efficient, while the Steiner tree (ST) in Graph Theory is not designed to support reliable transmissions since the selection of recovery nodes is not examined. In this paper, therefore, we propose a new reliable multicast tree for SDN, named Recover-aware Steiner Tree (RST). The goal of RST is to minimize both tree and recovery costs, while finding an RST is very challenging. We prove that the RST problem is NP-Hard and inapproximable within k, which is the number of destination nodes. Thus, we design an approximate algorithm, called Recover Aware Edge Reduction Algorithm (RAERA), to solve the problem. The simulation results on real networks and large synthetic networks, together with the experiment on our SDN testbed with real YouTube traffic, all manifest that RST outperforms both SPT and ST. Also, the implementation of RAERA in SDN controllers shows that an RST can be returned within a few seconds and thereby is practical for SDN networks. (a) Original Network (b) Shortest-path tree Tree cost = 40 Recovery = 58 (c) Steiner tree Tree cost = 22 Recovery = 66 (d) Recover-aware Steiner tree Tree cost = 25 Recovery = 32 58

60 Non-black-box Techniques for Zero-Knowledge Protocols Kai-Min Chung Institute of Information Science, Academia Sinica Paper presented at the 35th International Cryptology Conference (2015). This report summarizes our works on zero-knowledge (ZK) proofs in past years. ZK proofs is a fundamental primitive in cryptography that allows a party (called the Prover) to convince another party (called the Verifier) that a given claim is true without revealing any additional introduction. For example, an agent can prove that he has the right to enter a building without revealing his identity or password. Paradoxical as it may sound, it is extremely useful and has pervasive applications in cryptography. Most ZK constructions are black-box, but black-box constructions cannot achieve several stronger notions of ZK proofs (see Figures). Achieving such notions are often long-standing open problems. Our works develop non-black-box techniques to bypass such limit, and achieve the following two notions of ZK proofs: (i) constant round concurrent ZK proofs from indistinguishability obfuscation (the paper cited below), and (ii) simultaneously resettable ZK proofs from the minimal assumption of one-way functions (published in FOCS 2013). Optimal Experimental Designs for fmri via Circulant Biased Weighing Designs ACADEMIA SINICA Ching-Shui Cheng and Ming-Hung Kao Institute of Statistical Science, Academia Sinica Annals of Statistics 43 (2015): Functional magnetic resonance imaging (fmri) technology is widely used for studying how the brain reacts to mental stimuli. Identifying optimal fmri experimental designs (i.e. sequences of stimuli) is crucial for collecting informative data to render precise statistical inference. However, research on this topic is very lacking. Here, we investigate optimal fmri designs for the estimation of the individual hemodynamic response function (HRF) that describes the effect over time of a stimulus, and for the comparison between HRFs. We provide a useful connection between the fmri design issues and circulant biased weighing design problems to derive analytical results to guide the selection of fmri designs. Our results allow to establish the statistical optimality of some well-known fmri designs, and to identify several new classes of designs. Construction methods of these designs are provided. 59

61 Division of Mathematics and Physical Sciences Charge Density Wave Transition in Single-Layer Titanium Diselenide Peng Chen, Yang-Hao Chan, Xin-Yue Fang, Yi Zhang, Mei-Yin Chou, Sung-Kwan Mo, Zahid Hussain, Alexei-V. Fedorov, and Tai-Chang Chiang Institute of Atomic and Molecular Sciences, Academia Sinica Nature Communications 6 (2015): DOI : /ncomms9943. A single molecular layer of titanium diselenide (TiSe2) is a promising material for advanced electronics beyond graphene a strong focus of current research. Such molecular layers are at the quantum limit of device miniaturization and can show enhanced electronic effects not realizable in thick films. In this study, we find that single-layer TiSe2 exhibits a charge density wave (CDW) transition at critical temperature TC = 232±5 K, which is higher than the bulk TC = 200±5 K. A combined investigation of angleresolved photoemission spectroscopy (ARPES) measurements and first-principles calculations confirm a 2x2 CDW ordering in the monolayer. A small absolute band gap is observed at room temperature, which grows wider with decreasing temperature T below TC. The observed Bardeen-Cooper-Schrieffer (BCS) behavior of the gap implies a mean-field CDW order in the single layer and an anisotropic CDW order in the bulk. ARPES maps taken from a single layer of TiSe2 along the Γ-M direction for the (1x1) normal phase at room temperature and the (2x2) CDW phase at 10 K. Also shown are calculated DFT band structure of the (1x1) and (2x2) phases with the HSE hybrid functional. Estimating Black Hole Mass in the Lensing Galaxy of the Gravitational Lens SDP.81 Using ALMA Kenneth C. Wong, Sherry H. Suyu, and Satoki Matsushita Institute of Astronomy and Astrophysics, Academia Sinica Astrophysical Journal 811 (2015): 115. If there is a massive galaxy coincidentally located in front of a background galaxy, the background galaxy image will be deformed into a ring-shape, known as an Einstein Ring, due to the gravitational lensing effect. This effect also produces a central image, and the lensing theory predicts that the central image is very sensitive to the mass of the nuclear black hole in the foreground lens galaxy: the more massive the black hole, the fainter the central image. Using this theory, it is possible to estimate the black hole mass in the foreground galaxy. A gravitational lensing system, SDP.81, consists of a foreground lens galaxy, which is 4 billion light years away, and a background galaxy, whose light has taken 12 billion years to reach us. This system has been observed by the Atacama Large Millimeter/submillimeter Array (ALMA) with the highest-ever resolution. The obtained image exhibits an Einstein Ring as shown in Figure 1. The central regions of SDP.81 has been carefully analyzed and the predicted central image of the background galaxy has been found to be extremely faint. From this, it is calculated that the black hole, located very close to the center of the SDP.81, may contain over 300 million times the mass of the sun. ALMA now allows us to determine the mass of distant black holes, which was very difficult in the past. ALMA image of the Einstein Ring, SDP.81. The faint central image allows us to place a lower limit on the nuclear black hole mass of 300 million solar masses. 60

62 Three-Dimensional Multi-Probe Analysis of the Galaxy Cluster A1689 Keiichi Umetsu, Mauro Sereno, Elinor Medezinski, Mario Nonino, Tony Mroczkowski, Jose Maria Diego, Stefano Ettori, Nobuhiro Okabe, Tom Broadhurst, and Doron Lemze Institute of Astronomy and Astrophysics, Academia Sinica Astrophysical Journal 807 (2015): 207. The galaxy cluster A1689 (z=0.183) is one of the most powerful known lenses on the sky, characterized by a large Einstein radius of 47 arc-seconds (for a reference source at z=2). This indicates an exceptionally high degree of mass concentration in projection of the cluster. As such, A1689 is known as a superlens cluster. In a parametric triaxial framework, we have studied the intrinsic 3D structure and geometry of the dark-matter (DM) and hot-gas distributions in A1689, by performing a joint analysis of weak+strong lensing, X-ray, and Sunyaev-Zel'dovich effect (SZE) data with minimal geometric assumptions. This multi-probe analysis uses Subaru telescope (weak-lensing shear and magnification), Hubble Space Telescope (strong lensing), XMM- Newton (X-ray), and BIMA+OVRO+SZA (SZE) observations. We have shown that the data favor an ellipsoidal, triaxial geometry of the DM halo, where its long axis is closely, but not perfectly (22 ±10 ), aligned with the line of sight to the observer. This orientation alignment boosts the projected surface mass density and thus explains the exceptional lensing strength of the cluster. We show that the cluster has a relatively dense DM core but is not over-concentrated, implying a formation time consistent with expectations from standard Λ cold DM models. The shape of the hot gas is found to be rounder than the DM but quite elongated. The gas-to-total mass fraction within 0.9Mpc is f gas = 10% (+2%, -3%), a typical value observed for high-mass clusters. Mass distribution (white contours) of the superlens cluster A1689 overlaid on the Subaru BVRiz composite color image. The cluster mass distribution on large scales (> 1 arcminute) is reconstructed from a joint weak-lensing shear and magnification analysis of wide-field Subaru observations. Compounding Effects of Warm SST and Reduced Sea Ice on the Extreme Circulation Over the Extratropical North Pacific and North America During 2013/2014 Boreal Winter ACADEMIA SINICA Ming-Ying Lee, Chi-Chong Hong, and Huang-Hsiung Hsu Research Center for Environmental Changes, Academia Sinica Geophysical Research Letters 42 (2015): Unprecedented atmospheric circulations with extreme weather were observed in the extratropical Northern Hemisphere during the winter of The anomalous circulations were the manifestation of known pattern but with extremely large amplitude. Simulation results suggest that the anomalously strong atmospheric circulations were constructively induced by anomalous sea surface temperature in the tropical Pacific and extratropical North Pacific, as well as the low sea ice concentration in the Arctic. Natural variability played a major role in inducing the anomaly pattern, whereas the anomalously warm sea surface temperature and low Arctic sea ice concentration in the Bering Sea contributed to the extreme intensity. If the anthropogenic warming has a significant impact on causing the synchronization of the aforementioned anomalies in sea surface temperature and sea ice concentration and this trend continues, severe winters similar to that in may occur more frequently in the future. 2013/14 winter sea surface temperature and sea ice anomalies: anomalously low sea ice content in the Arctic, extremely high temperature in the extratropical North Pacific and the tropical western Pacific, cooler in the tropical eastern Pacific. (a) Observed 2013/14 winter 500-hPa height anomaly. (b) Observed anomalies were realistically simulated by forcing model with observed sea ice and sea surface temperature. 61

63 Division of Mathematics and Physical Sciences Seasonal Variations of Ultra-Fine and Submicron Aerosols in Taipei, Taiwan: Implications for Particle Formation Processes in a Subtropical Urban Area Hing Cho Cheung, Chung-Kuang Chou, Mei-June Chen, Wei-Ru Huang, Shu-Hui Huang, Chao-Yang Tsai, and Siu-Lan Lee Research Center for Environmental Changes, Academia Sinica Atmospheric Chemistry and Physics Discussion 15 (2015): The aim of this study is to investigate the seasonal variations in the physicochemical properties of atmospheric ultrafine (UFPs) and sub-micron (PM 1 ) particles in Taipei from 2012 to The measurements included the mass concentration and chemical composition of UFPs and PM 1, as well as the particle number concentration (PNC) and number size distribution (PSD) with size range of nm. The results indicated that the mass concentration of PM 1 was elevated during cold seasons with a peak level in spring, whereas the highest UFPs concentration was measured in summertime. Chemical analysis revealed that the UFPs and PM 1 were characterized by distinct composition; UFPs were composed mostly of organics, whereas ammonium and sulfate were the major constituents in PM 1. For number concentrations, nucleation mode (<25nm) peaked in winter, whereas Aitken (25-100nm) and accumulation ( nm) modes exhibited summer maxima. The results implied that the enhanced photochemical reaction was the major aerosol source in Taipei, while the photochemical production of condensable organic matter contributing to the stabilization of newly formed particles in the atmosphere. In addition, the influences of continental pollution outbreaks on PM 1 was observed, but not significant for UFPs. Monolayer MoS2-WSe2 Lateral Heterostructure Ming-Yang Li, Yumeng Shi, Chia-Chin Cheng, Li-Syuan Lu, Yung-Chang Lin, Hao-Lin Tang, Meng-Lin Tsai, Chih-Wei Chu, Kung-Hwa Wei, Jr-Hau He, Wen-Hao Chang, Kazu Suenaga, Lain-Jong Li Research Center for Applied Sciences, Academia Sinica Science 349 (2015): The p-n junction is one of important part in electronic circuits. Our work successfully developed a two-step growth method to synthesize monolayer MoS 2 -WSe 2 lateral p-n junction. By carefully controlling the ratio of precursor, the MoS 2 can grow from the WSe 2 edge to form lateral junction with atomically sharp interface and without alloy formation. Our lateral junction exhibits rectifying behavior and photovoltaic effect confirming it is a monolayer p-n junction. The two-step growth method can also be applied to per-patterned edge to form large area heterostructures, which imply the potential for developing ultra-thin integrated electronics. Furthermore, the atomically sharp interface provide a new platform for condense physics, which shows great potential for research and application. 62

64 Extended Resolution Structured Illumination Imaging of Endocytic and Cytoskeletal Dynamics Dong Li, Lin Shao, Bi-Chang Chen, Xi Zhang, Mingshu Zhang, Brian Moses, Daniel E. Milkie, Jordan R. Beach, John A. Hammer III, Mithun Pasham, Tomas Kirchhausen, Michelle A. Baird, Michael W. Davidson, Pingyong Xu, and Eric Betzig Research Center for Applied Sciences, Academica Sinica Science 349 (2015): aab3500. Super-resolution (SR) fluorescence microscopy is unique among nanoscale imaging tools in its ability to image protein dynamics in living cells. Among SR methods, structured illumination microscopy (SIM) stands out in this regard due to its high speed and low illumination intensities, but it typically offers only a twofold gain in resolution. We extended the resolution of live cell SIM by two different approaches: ultra-high numerical aperture SIM at 84 nm lateral resolution for 100 or more multicolor frames, and nonlinear SIM with patterned activation at nm resolution for ~20-30 time points. We applied these methods to image the dynamics near the plasma membrane of spatially resolved assemblies of clathrin and caveolin, Rab5a in early endosomes, and α-actinin, often in relationship to the cortical actin cytoskeleton. With One Look? Robust Face Recognition with Only One Training Image ACADEMIA SINICA Chia-Po Wei and Yu-Chiang Frank Wang Research Center for Information Technology Innovation, Academia Sinica IEEE Transactions on Image Processing 24 (2015): Traditional pattern recognition methods require one to collect a sufficient amount of training data, which will be utilized to observe the underlying data distributions, and thus the unseen test data can be classified accordingly. However, in realworld scenarios like in security or forensics, the above requirement might not be applicable. In other words, one typically needs to recognize the test input based one few or even a single training image. In our work, we focus on single-sample face recognition, and propose a dictionary learning based algorithm which allows one to exploit information from face images not of interest, and exhibits promising ability in describing and discriminating between the images to be recognized. 63

65 Division of Life Sciences The Axial Element Protein DESYNAPTIC2 Mediates Meiotic Double-Strand Break Formation and Synaptonemal Complex Assembly in Maize Ding Hua Lee, Yu-Hsin Kao, Jai-Chi Ku, Chien-Yu Lin, Robert Meeley, Ya-Shiun Jan, and Chung-Ju Rachel Wang Institute of Plant and Microbial Biology, Academia Sinica The Plant Cell 27 (2015): A research team led by Dr. Chung-Ju Rachel Wang, Assistant Research Fellow at the IPMB, recently reported the discovery of a protein DSY2 in the major crop maize and revealed its important functions during sexual reproduction. In this study, the team identified a maize protein, DSY2, and revealed that it acts as an important component of meiotic chromosome axes and showed that DSY2 is required for DNA double-strand break formation and synapsis. They further demonstrated that DSY2 serves as a key factor for synaptonemal complex (sc) assembly by interacting with two other components, ZYP1 and ASY1. This study provides novel insight into the role of chromosome axis-associated proteins and reveals the molecular mechanism of SC assembly at the molecular level in plants. This finding enhances the understanding of meiotic recombination during sexual reproduction, and was nominated as noteworthy maize primary literature by the US federally-funded informatics database on maize, the MaizeGDB. The super-resolution image of maize synaptonemal complex The Molecular Basis for Flexibility in the Flexible Filamentous Plant Viruses Frank DiMaio, Chun-Chieh Chen, Xiong Yu, Brandom Frenz, Yau-Heiu Hsu, Na-Sheng Lin, and Edward H. Egelman Institute of Plant and Microbial Biology, Academia Sinica Nature Structural and Molecular Biology 22 (2015): Flexible filamentous plant viruses cause more than half the viral crop damage in the world, but are also potentially useful for application in agriculture and biotechnology. In collaboration with Dr. Yau-Heiu Hsu and Dr. Edward H. Egelman, we used cryoelectron microscopy, captured the images by a direct electron detector, and followed by 3D reconstruction using Iterative Helical Real Space Reconstruction (IHRSR) software, we determined the first near atomic structural model of local filamentous flexible virus, Bamboo mosaic virus (BaMV), at 5.6Å resolution. The structural model of BaMV shows that the capsid protein subunits are lefthanded and loosely packed. Its N terminus is well exposed and the C terminus is pointing toward the center of the virion. This new finding not only provides insight into filamentous virus assembly and structural stability but also can be further applied to both biotechnology (for the design of vaccines and protein carriers) and nanotechnology. 64

66 Logics and Properties of a Genetic Regulatory Program that Drives Embryonic Muscle Development in an Echinoderm C. Andrikou, C. Y. Pai, Yi-Hsien Su, and M. I. Arnone Institute of Cellular and Organismic Biology, Academia Sinica elife 4 (2015): e Evolutionary origin of muscle is a central question when discussing mesoderm evolution. Developmental mechanisms underlying somatic muscle development have mostly been studied in vertebrates and fly where multiple signals and hierarchic genetic regulatory cascades selectively specify myoblasts from a pool of naive mesodermal progenitors. However, due to the increased organismic complexity and distant phylogenetic position of the two systems, a general mechanistic understanding of myogenesis is still lacking. In this study, we propose a gene regulatory network (GRN) model that promotes myogenesis in the sea urchin embryo, an early branching deuterostome. A fibroblast growth factor signaling and four Forkhead transcription factors consist the central part of our model and appear to orchestrate the myogenic process. The topological properties of the network reveal dense gene interwiring and a multilevel transcriptional regulation of conserved and novel myogenic genes. Finally, the comparison of the myogenic network architecture among different animal groups highlights the evolutionary plasticity of developmental GRNs. -Enolase-Binding Peptide Enhances Drug Delivery Efficiency and Therapeutic Efficacy Against Colorectal Cancer ACADEMIA SINICA Chien-Hsun Wu, Yi-Huei Kuo, Ruey-Long Hong, and Han-Chung Wu Institute of Cellular and Organismic Biology, Academia Sinica Science Translational Medicine 7 (2015): 290ra91. In this study, in vitro biopanning of a phage-displayed peptide library was used to identify specific peptides binding to human colorectal carcinoma (hcrc) cells. The targeting peptide phct74 showed the greatest potential for drug delivery in both in vitro and in vivo studies. The use of biotinylated peptides combined with an affinity trapping method and LC-MS/MS identified the target protein for the phct74 peptide as α-enolase. In animal model studies, combined phct74-conjugated liposomal doxorubicin (phct74-ld) and phct74-conjugated liposomal vinorelbine (phct74-slv) therapy exhibited an enhanced antitumor effect and markedly extended the survival of mice with human colorectal cancer in subcutaneous and orthotopic models. Our findings indicate that α-enolase-targeted lipid nanoparticles have great potential for application in targeted drug delivery systems for colorectal cancer therapy. phct74-ld phct74-slv 65

67 Division of Life Sciences Lhx2 Regulates the Timing of -catenin-dependent Cortical Neurogenesis Shen-Ju Chou Institute of Cellular and Organismic Biology, Academia Sinica Proceedings of the National Academy of Sciences of the United States of America 112 (2015): The timing of cortical neurogenesis has a major effect on the size and organization of the mature cortex. The deletion of the LIM-homeodomain transcription factor Lhx2 in cortical progenitors by Nestin-cre leads to a dramatically smaller cortex. Here we report that Lhx2 regulates the cortex size by maintaining the cortical progenitor proliferation and delaying the initiation of neurogenesis. The loss of Lhx2 in cortical progenitors results in precocious radial glia differentiation and a temporal shift of cortical neurogenesis. We further investigated the underlying mechanisms at play and demonstrated that in the absence of Lhx2, the Wnt/ β-catenin pathway failed to maintain progenitor proliferation. We developed and applied a mathematical model that reveals how precocious neurogenesis affected cortical surface and thickness. Thus, we concluded that Lhx2 is required for β-catenin function in maintaining cortical progenitor proliferation and controls the timing of cortical neurogenesis. Exploitation of the Ability of g-tocopherol to Facilitate Membrane Co-localization of Akt and PHLPP1 to Develop PHLPP1-Targeted Akt Inhibitors Ribai Yan, Hsiao-Ching Chuang, Naval Kapuriya, Chih-Chien Chou, Po-Ting Lai, Hsin-Wen Chang, Chia-Ning Yang, Samuel K. Kulp, and Ching-Shih Chen Institute of Biological Chemistry, Academia Sinica Journal of Medicinal Chemistry 58 (2015): Previously, we reported that Akt inactivation by γ-tocopherol in PTENnegative prostate cancer cells resulted from its unique ability to facilitate membrane co-localization of Akt and PHLPP1 (PH domain leucine-rich repeat protein phosphatase isoform 1), a Ser473-specific Akt phosphatase, through pleckstrin homology (PH) domain binding [Science Signaling (2013)]. This finding provided a basis for exploiting γ-tocopherol to develop a novel class of PHLPP1-targeted Akt inhibitors. Here, we used γ-ve5, a side chaintruncated γ-tocopherol derivative, as a scaffold for lead optimization. The proof-of-concept of this structural optimization was obtained by VE-R16, which exhibited higher antitumor efficacy than γ-ve5 in PTEN-negative cancer cells through PHLPP1-facilitated Akt inactivation. Like γ-ve5, VE-R16 preferentially recognized the PH domains of Akt and PHLPP1, as its binding affinities for other PH domains, including those of ILK and PDK1, were an order-of-magnitude lower. Moreover, VE-R16 was orally active in suppressing xenograft tumor growth in nude mice, which underlines the translational potential of this new class of Akt inhibitor in PTEN-deficient cancers. Copyright 2015 American Chemical Society 66

68 Structural Analysis Reveals the Molecular Basis for Substrate Specificity and Plasticity of Protein Tyrosine Phosphatases Kai-En Chen, Meng-Yen Li, Chia-Cheng Chou, Meng-Ru Ho, Guang-Chao Chen, Tzu-Ching Meng, and Andrew H.-J. Wang Institute of Biological Chemistry, Academia Sinica Structure 23 (2015): The molecular basis for substrate specificity of enzymes involved in signaling regulation, including all members in the superfamily of protein tyrosine phosphatases (PTPs), is a key question in the field. Nonetheless, the underlying mechanism of this process remains largely elusive. In this study, we applied X-ray crystallography, protein engineering and site-direct mutagenesis to investigate how substrate specificity among five PTPs containing a FERM domain (PTPN3, N4, N13, N14 and N21) is determined. Eps15, a regulator in the EGF receptor signaling pathway, serves as a substrate of these PTPs. Examining the complex structure by X-ray crystallography, we identified His812 of PTPN3 and Pro850 of Eps15 being critical residues for enzyme-substrate recognition. Tyr676 in PTPN3, which is replaced by Ile in PTPN14, also determines the specific interaction with Eps15. Moreover, the essential Asp in the WPD loop, which appears in PTPN3, N4, N13 and N14, is replaced by Glu in PTP21. As elucidated by our structural analysis, the short side-chain of Glu results in loss of PTP21 s catalytic activity for protein tyrosine dephosphorylation. These key findings were validated by cell-based in vivo experiments. Together, the new insights into substrate specificity and plasticity open an avenue towards inhibitor design targeting FERM-containing PTPs involved in human diseases. The recognition of Eps15 as a substrate by PTPN3 is biologically significant. Pro850 of Eps15 and His812 of PTPN3 plays a central role in substrate specificity. Other residues responsible for substrate specificity in the subfamily are also shown in the figure. E811 in WPE loop of PTPN21 is unfavorable to act as a general acid during dephosphorylation. Aberrant Astrocytes Impair Vascular Reactivity in Huntington s Disease ACADEMIA SINICA Han-Yun Hsiao, Yu-Chen Chen, Chien-Hsiang Huang, Chiao-Chi Chen, Yi-Hua Hsu, Hui-Mei Chen, Feng-Lan Chiu, Hung-Chih Kuo, Chen Chang, and Yijuang Chern Institute of Biomedical Sciences, Academia Sinica Annals of Neurology 78 (2015): Neurovascular abnormalities occur in many brain disorders and neurodegenerative diseases, including Huntington s disease (HD). We demonstrate that the brain vessel density is higher in mice and patients with HD than in controls. A fraction of these cortical blood vessels in the brains of HD mice is nonreactive to carbogen. Such impaired blood vessels in HD brains is caused by an increased ability of HD astrocytes to produce more VEGF and inflammatory mediators. The resultant impaired VR may hinder cerebral hemodynamics and increase brain atrophy during HD progression. Our study presents the first evidence of impairment of VR in HD. The MRI and mechanistic findings from our experiments have established a foundation for using VR as a prognostic HD marker. This study has been selected by HD Insights < hdinsights.org> as one of the most influential papers in HD of the past year. 67

69 Division of Life Sciences Precision Medicine Can Be a Clinical Reality: Use of HLA-B*58:01 Genotyping to Prevent Allopurinol Induced Severe Cutaneous Adverse Reactions in Taiwan Chen-Yang Shen, T. M. Ko, C. S. Chang, P. Chen, C. H. Chen, J. Y. Wu, and Y. T. Chen Institute of Biomedical Sciences, Academia Sinica The British Medical Journal 351 (2015): h4848. Severe cutaneous adverse reactions (SCARs) constitute a set of life threatening conditions that include drug rash with eosinophilia and systemic symptoms, Stevens- Johnson syndrome, and toxic epidermal necrolysis, with the lethality rate of toxic epidermal necrolysis at up to 35%. Allopurinol, a first line prescription drug treatment for gout and hyperuricaemia, is one of the most common causes of SCARs, but is still a common treatment owing to relative low cost, efficacy, and convenience. Allopurinol induced SCARs is known to correlate strongly with the allele human leukocyte antigen (HLA)-B*58:01 in Han Chinese populations. In this study, the research team of Drs. Chen-Yang Shen and Yuan-Tsong Chen therefore sought to determine whether screening via HLA-B*58:01 genotyping could reduce allopurinol induced SCARs, and demonstrated that prospective screening of the HLA-B*58:01, coupled with an alternative treatment for carriers, significantly decreased the incidence of allopurinol induced SCARs. This result clearly demonstrates that precision medicine begins to deliver on its promises. A Novel Mechanism for Prp5 Function in Prespliceosome Formation and Proofreading the Branch Site Sequence Wen-Wei Liang and Soo-Chen Cheng Institute of Molecular Biology, Academia Sinica Genes & Development 29 (2015): We have uncovered a novel mechanism for how Prp5 functions in prespliceosome formation and proofreading of branch site sequence. Prp5 binds to the spliceosome in association with U2 by interacting with BSL, and is released upon base pairing of U2 with the branch site to allow the recruitment of the tri-snrnp. Mutations impairing U2-branch site base pairing retard Prp5 release and impede tri-snrnp association. Prp5 mutations that destabilize Prp5-U2 interaction suppress branch site mutations by allowing progression of the pathway. 68

70 CRL2 Aids Elimination of Truncated Selenoproteins From Failed UGA/Sec Decoding Hsiu-Chuan Lin, Szu-Chi Ho, Yi-Yun Chen, Kay-Hooi Khoo, Pang-Hung Hsu, and Hsueh-Chi S. Yen Institute of Molecular Biology, Academia Sinica Science 349 (2015): We identified a novel protein quality control system mediated by a CRL2 ubiquitin ligase, which controls the fidelity of selenoproteins. Selenium is an essential trace element that executes its biological function in the form of selenoproteins. Selenoproteins contain an unusual amino acid, the selenocysteine. Proteins containing this amino acid frequently encounter premature termination of synthesis, resulting in a smaller protein that lacks functionality. We reported that CRL2 recognizes the exposed tails of these shortened selenoproteins and marks it for degradation. This is the most stringent protein quality control system ever documented, where a change in protein length by just a single amino acid is sufficient to signal degradation. Defective proteins have been implicated in aging, neurodegenerative diseases, and cancer, making understanding the quality control mechanisms of the cell crucial. Our work paves the way for clinical strategies based on the cell s own machinery to improve overall human health. Figure : CRL2 aids elimination of selenoproteins from failed translation and guard the fidelity of selenoproteome. Selenocysteine (Sec) is translated from the UGA codon (red) on selenoprotein mrnas. Correct translation of Sec generates fulllength selenoproteins as shown by the intact color bars. Failed Sec translation leads to truncations as shown by the red-capping bars, revealed termination at the UGA codon. CRL2 helps the elimination of truncated proteins and leaves an intact selenoproteome. Deltex1 Antagonizes HIF-1 T Cells in vivo and Sustains the Stability of Regulatory Huey-Wen Hsiao #, Tzu-Sheng Hsu #, Wen-Hsien Liu, Wan-Chen Hsieh, Ting-Fang Chou, Yu-Jung Wu, Si-Tse Jiang, and Ming-Zong Lai ( # Co-first author) Institute of Molecular Biology, Academia Sinica Nature Communications 6 (2015): ACADEMIA SINICA Regulatory T cell (Treg) is one of the major components in the maintenance of immune tolerance by suppressing inflammatory T cell activation. In this work, deletion of Deltex1 gene in Treg alone is found to lead to autoantibodies generation in mice. The inhibitory activities of Deltex1-deficient Tregs are normal when analyzed in vitro. However, the ability of Deltex1- knockout Tregs to suppress colitis and airway hypersensitivity induced by effector T cells is greatly impaired in vivo. Analysis of the in vivo transferred Deltex1-knockout Tregs reveal a diminished expression of Foxp3, the master transcription factor dictating the functional stability of Tregs. Antagonism between Deltex1 and HIF-1α, observing that Deltex1 binds HIF-1α and promotes HIF- 1α protein degradation, is further demonstrated. Consequently, Deltex1 effectively protects Foxp3 from HIF-1α-mediated downregulation in inflammatory tissues. This finding reveals that Deltex1 exerts a new level of control on Treg stability in vivo by sustaining the expression of Foxp3 protein in Treg, providing the basis for future development of therapy against autoimmune diseases and inflammatory immune diseases. Figure 1. Dtx1 -/- Tregs were unable to suppress effector T cell-induced colitis and HIF-1α knockout enables Dtx1 -/- Tregs to inhibit colitis. Colitis was scored and colon morphology was examined in Rag1 -/- mice transferred with effector T cells, and WT (Foxp3 Cre ), Dtx1 -/- (Foxp3 Cre Dtx1 f/f ), Hif1a -/- (Foxp3 Cre Hif1a f/f ), or Hif1a -/- Dtx1 -/- (Foxp3 Cre Dtx1 f/f Hif1a f/f ) ttreg cells. Figure 2. Depiction on how Deltex1 protects Foxp3 from HIF-1α mediated degradation and sustains Treg stability in vivo by down-regulation of HIF-1α. 69

71 Division of Life Sciences MIG-7 and Phosphorylated Prohibition Coordinately Regulate Lung Cancer Invasion/Metastasis Ming-Yi Ho, Chi-Ming Liang, and Shu-Mei Liang Agricultural Biotechnology Center, Academia Sinica Oncotarget 6 (2015): Growth factors and COX-2/PGE2 enhance lung cancer invasion/metastasis via PI3K/Akt and RAS/Raf. Here, we explored their mechanism of action further. We found first that higher levels of migration inducting gene-7 protein (MIG-7) and PHB phosphorylated at threonine 258 (phospho-phb T258 ) are positively correlated with advanced stages of human lung cancer in tissue microarray. PGE2 or growth factors such as EGF, HGF and IGF-1 increased complex formation of phospho-phb T258 with Ras, phospho-akt S473, phospho-raf-1 S338, MEKK1 and IKKα/β S176/180 in the raft domain transiently within 1 hour and MIG-7 in the cytosol hours later. Association of phospho-phbt258 with MEKK1 but not MEKK3 activates IKK/IκB/NF-κB and MEK/ ERK to increase cellular COX-2/PGE2 and an E-cadherin suppressor Snail leading to enhancement of epithelial-mesenchymal transition (EMT) and lung cancer migration/ invasion. MIG-7, on the other hand, was induced by growth factors and PGE2 via Akt/ GSK-3β in a phospho-phb T258 independent manner. MIG-7 increased two E-cadherin suppressors ZEB-1 and Twist to enhance EMT and cancer migration/invasion. Downregulating phospho-phb T258 and MIG-7 had an additive effect on attenuating lung cancer invasion/metastasis and prolonging the survival of xenograft mice. Phospho- PHB T258 and MIG-7 may thus play complementary roles in the initiation and sustainment of the effects of growth factors and COX-2/PGE2 on cancer invasion/metastasis. positive correlation between MIG-7 and phosphorylated PHB in human lung tumor tissues The roles of PHB and MIG-7 in regulating the effects of growth factors and PGE2 on lung cancer migration/ invasion. A Salt-Regulated Peptide Derived From the CAP Superfamily Protein Negatively Regulates Salt-Stress Tolerance in Arabidopsis Pei-Shan Chien, Hong Gil Nam, and Yet-Ran Chen Agricultural Biotechnology Research Center, Academia Sinica Journal of Experimental Botany 66 (2015): doi: /jxb/erv263. High salinity has negative impacts on plant growth through altered water uptake and ion-specific toxicities. However, current understanding of the plant peptides involved in this regulatory network remains limited. Based on the discovery of a wound-induced tomato peptide CAPE1 (CAP-derived peptide1) functioning as a key systemic immune signal, a homolog CAPE1 peptide in Arabidopsis (AtCAPE1) was found to regulate salt-tolerance of the plant. The induction of AtCAPE1 peptide by high salinity was confirmed and found that a key amino acid residue in precursor protein is critical for AtCAPE1 production. Moreover, although precursor gene was expressed mainly in the roots, AtCAPE1 was discovered to be upregulated systemically upon salt treatment. This study demonstrates that AtCAPE1, a homolog of tomato immune regulator CAPE1, plays an important role in the regulation of salt stress responses, and which also suggests that CAPEs may function in the tradeoff between pathogen defense and salt tolerance. NaCl (mm) (μm) AtCAPE WT [ proatcape ] Bar indicates 2 cm Phenotypic pattern (%) * 1I 2II 3III 4IV ** ** AtCAPE1 (μm) proatcape1 125 mm NaCl AtCAPE1 negatively regulates the salt-tolerance response in Arabidopsis. A. B. C. 30 R Co RL CL St F Si Root 25 ** Shoot PROAtCAPE1 20 ** S rrna 10 ** PROAtCAPE1 mrna (2 - Ct x1000) (h) Relative levels of AtCAPE1 (Endogenous/IS) /2 MS 125 mm NaCl ** ** Shoot Root Mediu AtCAPE1 precursor (PROAtCAPE1) mainly expresses in the roots (A). Upon salt stress, the transcriptional levels of AtCAPE1 precursor in shoots was not induced (B), but AtCAPE1 was induced both in the roots and shoots (C). 70

72 Glutathione Plays an Essential Role in Nitric Oxide-Mediated Iron Deficiency Signaling and Iron Deficiency Tolerance in Arabidopsis Varanavasiappan Shanmugam, Yi-Wen Wang, Munkhtsetseg Tsednee, Krithika Karunakaran, and Kuo-Chen Yeh Agricultural Biotechnology Research Center, Academia Sinica The Plant Journa l 84 (2015): In this study, we found that the zir1 mutant, defective in glutathione production, was more sensitive to Fe deficiency than the wild type, and grew poorly in alkaline soil. Furthermore, the key genes involved in Fe uptake were expressed at low levels in zir1. The expression of these genes was positively correlated to the accumulation of nitric oxide (NO) under Fe deficiency. NO was proposed to be a signaling molecule involved in the up-regulation of Fe-uptake-related genes during Fe deficiency. We found that zir1 failed to accumulate NO under Fe deficiency and demonstrated that the NO mediated induction of Fe uptake genes was dependent on glutathione supply in the zir1 mutant. The results provide direct evidence that glutathione plays an essential role in Fe deficiency tolerance and NO-mediated Fe deficiency signaling. Total Synthesis of Tetraacylated Phosphatidylinositol Hexamannoside and Evaluation of Its Immunomodulatory Activity ACADEMIA SINICA Pratap S. Patil, Ting-Jen Rachel Cheng, Medel Manuel L. Zulueta, Shih-Ting Yang, Larry S. Lico, and Shang-Cheng Hung Genomics Research Center, Academia Sinica Nature Communications 6 (2015): 7239/1-7239/9. Tuberculosis, aggravated by drug-resistant strains and HIV co-infection of the causative agent Mycobacterium tuberculosis, is a global problem that affects millions of people. With essential immunoregulatory roles, phosphatidylinositol mannosides are among the cell-envelope components critical to the pathogenesis and survival of M. tuberculosis inside its host. Here we report the first synthesis of the highly complex tetraacylated phosphatidylinositol hexamannoside (Ac 2 PIM 6 ), having stearic and tuberculostearic acids as lipid components. Our effort makes use of stereoelectronic and steric effects to control the regioselective and stereoselective outcomes and minimize the synthetic steps, particularly in the key desymmetrization and functionalization of myoinositol. Mice exposed to the synthesized Ac 2 PIM 6 exhibit increased production of interleukin-4 and interferon-γ, and the corresponding adjuvant effect is shown by the induction of ovalbumin- and tetanus toxoid-specific antibodies. 71

73 Division of Life Sciences Fine Particle Pollution, Alanine Aminotransferase, and Liver Cancer Wen-Chi Pan, Chih-Da Wu, Mu-Jean Chen, Yen-Tsung Huang, Chien-Jen Chen, Huey-Jen Su, and Hwai-I Yang Genomics Research Center, Academia Sinica Journal of the National Cancer Institute 108 (2015): djv341. Using a large-scale long-term follow-up cohort in Taiwan, the investigators found that long-term PM2.5 exposure may lead to liver cancer, and chronic inflammation of the liver may underlie the pathogenesis. A cohort of participants who were 30 years or more was recruited from the Main Island of Taiwan and Penghu Islets. During a median 16.9 years of follow-up, a total of 464 cases of liver cancer were newly diagnosed. The participant s home address was linked to the EPA PM2.5 monitoring data. This study shows that liver cancer risk increased by 22% per PM2.5 interquartile range increment exposure in Penghu Islets (0.73 ug/m3) and in Taiwan Main Island (13.1 ug/m3). A significant positive association between long-term PM2.5 exposure and serum alanine aminotransferase (ALT) level was found, which is a documented seromarker of liver inflammation and damage. In the mediation analysis, ALT showed a statistically significant mediation effect on PM2.5-associated HCC incidence. To our knowledge, this is the first study to demonstrate the hazard effect of long-term PM2.5 exposure on liver cancer. Topographical Mapping of α- and β-keratins on Developing Chicken Skin Integuments : Functional Interaction and Evolutionary Perspectives Ping Wu, Chen Siang Ng, Jie Yan, Yung-Chih Lai, Chih-Kuan Chen, Yu-Ting Lai, Siao-Man Wu, Jiun-Jie Chen, Weiqi Luo, Randall B. Widelitz, Wen-Hsiung Li, and Cheng-Ming Chuong Biodiversity Research Center, Academia Sinica Proceedings of the National Academy of Sciences of the United States of America 112 (2015): E6770-E6779. Avian skin appendages include feathers, scales, claws, and beaks. They are mainly composed of α-keratins, found in all vertebrates, and β-keratins, found only in birds and reptiles. Scientists have wondered how keratins are interwoven to form different skin appendages. By studying keratin gene expression patterns in different chicken skin appendages, we found α- and β-keratin interactions crucial for appendage morphogenesis. Mutations in either α- or β-keratins can disrupt keratin expression and cause structural defects. Thus, different combinations of α- and β-keratins contribute to the structural diversity of feathers. The expansion of β-keratin genes during bird evolution might have greatly increased skin appendage diversity because it increased the possible interactions between α- and β-keratins. Summary of topographic expression patterns of α- and β-keratin genes in different skin appendages. Structures of avian skin appendages and RNA-seq analysis. Functional study shown by overexpressingα-keratins KRT5 mutant and featherβ-keratin antisense form in embryonic feather development. 72

74 Prokaryotic Assemblages and Metagenomes in Pelagic Zones of the South China Sea Ching-Hung Tseng, Pei-Wen Chiang, Hung-Chun Lai, Fuh-Kwo Shiah, Ting-Chang Hsu, Yi-Lung Chen, Liang-Saw Wen, Chun-Mao Tseng, Wung-Yang Shieh, Isaam Saeed, Saman Halgamuge, and Sen-Lin Tang Biodiversity Research Center, Academia Sinica; The Center for Environmental Changes, Academia Sinica BMC Genomics 16 (2015): 219. Marine microbes play a key role in global element cycles; however, their high diversity impeded in-depth studies using traditional methods. Thanks to advances of next generation sequencing technique, it becomes feasible to detect composition and dynamics of microbial communities. Metagenomic approach is one of the nuclear techniques to obtain the information of structure and metabolic pathways of microbial communities. Current marine metagenomic studies are mostly focused on surface water or water at specific intriguing depths that could not provide a comprehensive view to microbial community in the ocean s interior. Only few metagenome studies describing stratified microbial assemblage in the water column. The South China Sea (SCS) is the largest marginal sea and comprises consistent and stable stratified water. SCS is, except for both poles, one of the most important heat engines for global climate. We investigated metagenomes from the epipelagic, mesopelagic and bathypelagic zones in SCS, and found that microbiota differed between the water zones and shared higher dissimilarity with samples more distant from each other (Figure 1). Interestingly, in archaeal distribution, SCS different from other oceans (e.g. the Pacific Ocean) was Euryarchaeota dominating water, not Thaumarchaeota (Figure 2). This is one of the most unique characteristics of the SCS s microbiota. Moreover, plenty of osmoregulatory genes were detected at 100m where the salinity was greatly affected by the Kuroshio Current invaded from the western Pacific Ocean. In addition, there are numerous cyanobacteria were discovered in bathypelagic zone where is completely lightless. This is a novel discovery in cyanobacterial ecology because cyanobacteria were commonly believed light-dependent and photosynthesis bacteria. Anthropogenic effect was also detected at our studying site that many ammonium or urea metabolism-related genes were identified in the surface water, suggesting that ammonium pollutants were likely from the Pearl River. Our study is the first metagenomes in Asia, also one of few reports in the world, about the stratified microbial assemblages in the ocean s interior. Our paper has been highlighted with a permanent flag Highly Access of BMC journals after being published with only two weeks. Figure 1. Distribution variation of microbial OTUs in different depths of the South China Sea. SEATs: the Station of South Eastern Time Series Figure 2. Distribution of Archaea in the South China Sea. Euryarchaeota (MG II, III and Methano.) and Thaumarcheota (MG I) Influence of Sperm Dilution and Gamete Contact Time on the Fertilization Rates of Scleractinian Corals ACADEMIA SINICA Yoko Nozawa, N Isomura, and H Fukami Biodiversity Research Center, Academia Sinica Coral Reefs 34 (2015): We investigated two key factors influencing fertilization success of scleractinian corals, i.e. sperm concentration and gamete contact time. Together with previous information, we reported for the first time a general relationship between fertilization rate and sperm concentration in 17 broadcast-spawning scleractinian coral species; the fertilization rate peaked (>75 %) at a sperm concentration of approximately 10 6 sperm ml -1 (optimal concentration) and rapidly declined to <50 % at a concentration of 10 4 sperm ml -1. Experiments on gamete contact time revealed a rapid fertilization capability of scleractinian corals: the decline in the fertilization rate occurred only in the 30 min treatments. These data promote our understanding of in situ fertilization success of broadcast-spawning scleractinian corals, particularly in degraded, low-density populations where the degree of fertilization success is of management concern. 73

75 Division of Humanities and Social Sciences Reflexive Historiography and Rethinking History: An Analysis of Texts and Representations Ming-Ke Wang Institute of History and Philology, Academia Sinica Taipei : Asian Culture (2015), 368 pages. Following the current epistemological skepticism in humanities and social sciences, this book depicts that human sociality and all the related knowledge as well as social memories construct a world of representation in which people live, and it is hence difficult for humans to see the reality beneath. Master History is among the knowledge that constructs this world of representation; people tend to naturalize and to fatalize the social world constructed by the history they have been taught, and accordingly, fail to have reflexive cognition and reactions to social realities. By pairing concepts such as representation and realit y, memor y and societ y, tex t and context, this book proposes a new methodology and research strategies to analyze texts and representations. Hopefully this new research method for the studies of history and social sciences in general would enable us to have reflexive knowledge to all kinds of social realities and their historical changes, and accordingly bring forth reflexive actions that may bring about a positive change in the society. The photograph taken in 1934 in Western Hunan shows natives playing swing; the reality hidden underneath was modern minority-building under China s nationalism. The photograph shows girls of the Qiang nationality wearing different dresses; the reality hidden behind was the socializing process (shown in their dresses) of a girl in the society. Shuowen Jiezi (Tang Manuscript) Zong-Kun Li (Editor) Institute of History and Philology, Academia Sinica Shanghai : Zhongxi Book Company (2015), 172 pages. This book is a collection of all the remaining fragments of the Tang manuscript Shuowen Jiezi, namely one volume from Mu Bu (the tree radical) and three volumes from Kou Bu (the mouth radical). The originals of the four of them are currently kept in Japan. Other related research findings are also included in this book. This book also reprints Mo Youzhi s 1864 publication Fang Tang Xieben Shuowen Jiezi Mubu Jianyi (Notes on the Tree Radical for Tang Manuscript Shuowen Jiezi) with modern punctuations. A substantive portion of Mo s manuscript and later collation, both stored at the National Central Library in Taipei, are also annotated in this new edition. This book furthermore provides notes in Mo s style for the fragmented volumes from Kou Bu, as well as explanatory notes for the foreword, postscript and seals on the fragmented volumes from Mu Bu. The book is concluded by an academic article by the editor, discussing the background, academic value, its relation to the Li Yangbing edition, and authenticity of the Tang manuscript Shuowen Jiezi. Left : Cover of the book Right : Excerpt from Mu Bu of Shuowen Jiezi (Tang Manuscript) 74

76 The Statue of Mazu, Appropriation, and the Discussion on Watson s Concept of Standardization Hsun Chang Institute of Ethnology, Academia Sinica Journal of Archaeology and Anthropology 82 (2015): After 1980 temples of folk religion in China were renovated, statues were re-sculptured and worshipped. A giant granite statue of Mazu erected on the island of Mei was a turning point for these newly sculptured statues. It symbolized a new style of modern city planning and spirit of universal fraternity. This statue was designed to indicate the transformation of Chinese folk religion from the superstitious, feudalistic, to the folkloric, tourist, and finally, to intangible cultural heritage. This Mei Mazu statue were largely imitated and appropriated along the northern and southern China coastal cities, and even in overseas Chinese communities and Taiwan. This phenomenon implied not only artistic appropriation, but also the complicity of the central and local government officers, local elites, designers, carvers, and folk believers. The author will discuss James Watson s concept of standardization and argue that when the state tries to standardize a religious cultural model it involves visual and artistic appropriation and complicity from the local society among other cultural strategies. Shaping the New Man: CCP Propaganda and Soviet Experiences ACADEMIA SINICA Miin-Ling Yu Institute of Modern History, Academia Sinica Taipei: Institute of Modern History, Academia Sinica (2015), 405 pages. From the perspectives of politics, foreign relations, culture and society, this book explores what the Chinese Communist Party learned from the Soviet experiences of utilizing novels, textbooks, songs, films, model workers, and female tractor drivers to popularize the concept of the new man, including class consciousness, collectivism, the glorification of labor, and gender equality. Soviet experiences were important references for CCP policy-making. When the Sino-Soviet relations shifted from the honeymoon to the split, the CCP changed the contents of the new man accordingly. The book elucidates the complicated nature of post-1949 Sino-Soviet relationship and of Mao s regime. Mao s radical policy since late 1950s is a crucial revision of Stalinist model. Also, the CCP emphasizes social education via various media to publicize the correct ideology explains the success of its propaganda. Studying the propaganda on the new man sheds light on the Red Guards education before the Cultural Revolution. 75

77 Division of Humanities and Social Sciences Merchants and Chinese Communist Revolution, Ta-Chia Li Institute of Modern History, Academia Sinica Taipei : Institute of Modern History, Academia Sinica (2015), 563 pages. This book is arguably the first academic monograph to have looked in depth into the relations between the Chinese Communist Party and merchants. In contrast to previous academic studies that had focused on how the CCP manage to organize and mobilize workers and peasants, while paying much less attention to its relations to merchants. The book has emphasized the point that though the CCP s goal was to overthrow the bourgeoisie, it did pay, in its development of worker s movements specifically considered here, considerable attention to establish a united front with the merchants. The CCP s united front had taken fully the advantages in various fuzzy areas such as those between nationalism and antiimperialism, and the CCP and the Kuomintang, as well as the national revolution and the proletarian revolution, all of which were aimed to create conditions for its eventual proletarian revolution. This book is expected to throw new light on the CCP s early history of revolution. On-the-Job Learning and News-Driven Business Cycles Kuan-Jen Chen and Ching-Chong Lai Institute of Economics, Academia Sinica Journal of Money, Credit, and Banking (2015): This paper proposes a new channel of on-the-job learning to explain the positive co-movement between consumption and employment following good news about future productivity. The new recruits can generate an additional stream of output production in all future periods, and the firm s labor demand is thus characterized by the forward-looking property. Therefore, the firm is motivated to hire more new recruits in advance in response to good news about future productivity. Once the increase in labor demand is greater than the decrease in labor supply caused by the income effect, the coincident rise in consumption and employment can be driven by the news shock. When such a channel is paired with investment adjustment costs and the endogenous capacity utilization rate, this paper provides a plausible explanation for simultaneous booms in current consumption, investment, output, and employment to match the empirical evidence under the news shock. 76

78 Weak Assumption and Iterative Admissibility Chih-Chun Yang Institute of Economics, Academia Sinica Journal of Economic Theory 158, Part A (2015): Brandenburger et al. (Econometrica, 2008) show that rationality and common assumption of rationality (RCAR) is impossible in a complete and continuous type structure. We reconsider the epistemic foundation for iterative admissibility: We show, by introducing an alternative notion of assumption, weak assumption, that rationality and common weak assumption of rationality (RCWAR) is possible in a complete and continuous type structure. This possibility result provides an epistemic characterization for iterative admissibility. The Stone Camp Allendorf. On the History of the POW Camp of the German Generals after the Second World War ACADEMIA SINICA Chern Chen Institute of European and American Studies, Academia Sinica Zeitschrift für hessische Geschichte und Landeskunde 120 (2015): The article "Das Steinlager Allendorf. Zur Geschichte der Kriegsgefangenenlager deutscher Generälen nach dem Zweiten Weltkrieg" (The stone camp Allendorf. On the history of the POW camp of the German generals after the Second World War) on the prisoner-of-war camp for German staff officers and generals after WWII is based on careful and original archival research, using collections in Germany (Military Historical archives), the US Army records (National Archives), the memoirs and the diaries of the German generals, and documents the interesting and little known work of the US Army Historical Division that recruited more than a hundred German generals in compiling a history of WWII military operations in western Europe. This article is in fact of greater interest to a wider circle of historians. 77

79 Division of Humanities and Social Sciences Claiming the Sacred: Indigenous Knowledge, Spiritual Ecology, and the Emergence of Eco-cosmopolitanism Shiuhhuah Serena Chou Institute of European and American Studies, Academia Sinica Cultura : International Journal of Philosophy of Culture and Axiology 12.1 (2015): This essay examines the persistent engagement with cosmopolitan inclusivity through the endorsement of indigenous sacredness in works of ethnographic fiction. I focus on Ursula K. Le Guin s Always Coming Home, James Cameron s Avatar, and Taiwanese writer Ming-yi Wu s science fiction The Man with the Compound Eyes, three iconic environmental representations of indigenous knowledge. These texts illustrate how indigenous thinking has very often been transformed from place-bound, locallyembedded cultural traditions to an embodiment of Euro-American eco-spirituality that overturns both national boundaries and the human-nature divide at the turn of the twenty-first century. In settler environmental narratives, the insistence on the ethnographic mode strengthens the desire for authenticity and intimacy. Governing Natural Disasters: State Capacity, Democracy, and Human Vulnerability Thung-Hong Lin Institute of Sociology, Academia Sinica Social Forces 93.3 (2015): From the perspective of historical institutionalism, I argue that state capacity, democracy, and their interaction shape the distribution of human vulnerability in natural disasters. The ruling elite, irrespective of whether it is democratic, has the incentive to develop state capacity to prevent damage caused by natural disasters, which is considered a threat to its rule and revenue. To win elections in a democracy, the elite may increase public spending for disaster mitigation in favor of voters demands. Democracy also empowers civil society and stimulates social spending, which benefit vulnerable citizens. Thus, a strong state capacity effectively reduces human vulnerability, especially in a democracy. I used panel data from 150 countries between 1995 and 2009 to demonstrate the relationship among state capacity, democracy, and the impact of disasters. ln human-loss rate Fitted valuess of ln affected rate / ln mortality rate CHN PHL BGD VNM IND LKA THA HND MDG MOZ NIC KHM NPL NER COL IDN PER ETH PAK ZMB BOL MWIKEN TCD MEX CRI PNG BDI NAM ECU BEN BRA HTI SLV IRN USA UGA MRT BFA GTMLAO GNB PRY TZA CHL MYSPAN AGO ARG AUS JPN ROM SEN TUR ZWE BLZ DOM TGO MLI ZAR GMB GHA RWA MNG RUS FJI SWZ ZAF ALBLBRAZE URY VEN KOR JAM COG DZA COM NGA GEO DMA GRC KGZ MKD TWN SLE MDA UKR BIH GIN CAN BWA CMR KAZ MAR SRB CPV NZL HUN FRA YEM CIV GAB ARM CYP VCT MDV BLRCZEBRB HRV HKG CHE MUS SVN GBR TTO NOR JOR LBNTUNLCAPOL PRT SGP BGR BTN BEL ISL LUX UZB MNE SVK TKM GRD AUTEST FIN DEU ITAMLTLVA EGY IRL ESP LTU NLD Government Expenditure of GDP 95% CI Fitted values ln human-loss rate Natural Disaster Affected Index: per 100,000 persons Government Expenditure of GDP 95% CI ln affected rate (democracy) 95% CI ln affected rate (non-democracy) 95% CI ln mortality rate (democracy) 95% CI ln mortality rate (non-democracy) ISR SWE DNK 78

80 Formation and Transformation of Three-tier Ethnic-Spatial Regime in Qing Taiwan: A Comparison of pre and post Purple-Line Borders Chih-Ming Ka Institute of Sociology, Academia Sinica Taiwan Historical Research 22.2 (2015): This study explores the boundary drawings and arrangements of ethnic land tenure along the frontier area to explicate the ethnic-spatial deployment by the state power in Qing Taiwan circa (Qianlong era). It was the state s intention since 1745 to initiate a three-tier ethnic-spatial regime, through creating a buffer zone at the foothill boundary separating head-hunting mountain aborigines and coastal-plain Chinese settlers with plain aborigines sandwiched in between. The aim was to quarantine Chinese reclamation of aboriginal land and preempt security harass beyond the borderline. To achieve this aim, a plain aborigine border guard (ai fan) system was implemented concomitantly, with the reallocation of plain aborigine land rights to the buffer zone for segmentation as well as providing rations to border sentry posts. However, the state s effort to counter cross-border reclamation and thus prevent Chinese encroachers from developing into unruly force proved in vain. Even worse, it backfired, as shown in the Lin Shuang-wen revolt ( ). With the aborted purple borderline of 1784 as the benchmark, a comparison of the pre- and post-1784 boundary redrawings, blue borderline of 1760 and green borderline of 1790 respectively, as well as concomitant reallocations and rearrangements of aborigine land rights indicates a transformation of the three-tier ethnic-spatial regime, as witnessed in the shift of governance rationality from quarantine to active alliance with plain aborigines through fostering its militia forces (tun fan). Kant's Metaphysics of Morals: Translation With Annotations ACADEMIA SINICA Immanuel Kant (author), Ming-Huei Lee (translator) Institute of Chinese Literature and Philosophy, Academia Sinica Taipei: Linking Publishing Company (2015), 564 pages. Kant s Metaphysics of Morals encompasses two parts, namely Metaphysical First Principles of the Doctrine of Right and Metaphysical First Principles of the Doctrine of Virtue. Both of them have special significance for Kant s philosophy: The former is Kant s only work that completely discusses the philosophy of law, whereas the latter is his third ethical work, after Groundwork of the Metaphysics of Morals (1785) and Critique of Practical Reason (1788). This work is an annotated Chinese edition of Kant s Metaphysics of Morals. In addition to the text, there is also translator s introduction which elucidates the Entstehungsgeschichte of this work, the developments of its editions, and its philosophical significance for Kant s philosophy. 79

81 Division of Humanities and Social Sciences Reading Antique Cartography : Historical Chinese Maps in the British Library Kuo-Hsing Hsieh and Tiien-Jen Lin (editors) Institute of Taiwan History, Academia Sinica Taipei : Institute of Taiwan History and ASDC, Academia Sinica (2015), 234 pages. Numerous Min-Qing Chinese maps were dispersed abroad, and many of them are now housed in the US Library of Congress, the British Library, the National Archives UK, and the Bibliothèque nationale de France. The National Archives UK holds about 72 sets of Chinese maps and atlas, 125 maps in total, comprising mainly Guangdong and Guangxi military maps, were already interpreted and published by scholars. On the other hands, the British Library holds about 200 sets of ancient Chinese maps and atlas, including administrative maps, city maps, economic and transportation maps, famous historical sites maps, flood control and embankment maps and military maps. Among them, a large part of the military maps, about 70 maps in total, covers the area of Jiangsu and Zhejiang. Maps of Fujian, Taiwan and Guangdong form another parts of the collection as well. Reading Antique Cartography: Historical Chinese Maps in the British Library includes 129 maps selected from the British Library s collection of Chinese maps with explanation notes. The selected maps are either rich in information, representative in style, or rarely seen among collecting institutions. The explanation notes were written by Dr. Lin Tien-jen of the National Palace Museum, Taipei. He provided basic knowledge of the maps by examining the creation dates and explaining the details shown on the maps, as well as including titles of similar maps for comparison. The book also contains an essay written by Peter Barber, retired Head of Map Collections at the British Library, on the development of the British Library s Chinese map collection. According to the essay, the maps were mainly collected through purchase and missionaries donation or resale. In addition, many of the military maps of Jiangsu were originally collected and later donated by Charles Gordon, who was known for helping Qing court put down the Taiping Rebellion. Maps included in the books are all beautifully printed, making the book easy to use and valuable for collection. This book marks a milestone in the field of Chinese ancient maps publishing. All of the explanation notes will be imported to the Academia Sinica hosted database Reading Digital Atlas ( for the public to use. Prosodic Contrast and Categorical Differentiation Chiu-yu Tseng Institute of Linguistics, Academia Sinica Chinese Journal of Phonetics 5 (2015): The paper employs a corpus analysis of speech data to address issues of phonology- and syntax-specified canonical prosodic differentiations, and provides an acoustic account of why sufficient degree of contrast is necessary to express categorical differentiations and why categorical differentiation is more about realizing systematic discrimination instead of maintaining canonical forms. Our data of Mandarin tones demonstrate how lexically defined tone categories are realized in prosodically discriminative patterns that may deviate from the canonical forms considerably. In the case of syntactically defined sentence, we cite Mandarin evidence of why modulations of intonation contour patterns are predictable instead of random variation. In the case of lexically defined 3-way stress categories in English, our data further demonstrate how the categories are often merged into predictable binary contrasts in realized speech and why. We therefore conclude that more accurate understanding of communicative speech can be achieved from better clarification of how canonical categories are derived in speech output rather than taken by face value. Comparison between L1/L2 English speakers and among lexical stress categories by F0 & Duration (P/S/T : Primary/Secondary/Tertiary Stress) L1/L2 ratio of PVI by acoustic parameter and word The dotted line represents equal L1/L2 PVI. Values above the dotted line indicate a higher level of stability as an indicator to distinguish L1 and L2. 80

82 New Advances in Formosan Linguistics Elizabeth Zeitoun, Stacy F. Teng, and Joy J. Wu (editors) Institute of Linguistics, Academia Sinica Canberra : Asia-Pacific Linguistics, College of Asia and the Pacific, The Australian National University (2015), 558 pages. The present monograph is a festschrift in honor of Prof. Lillian M. Huang that was offered to her at ICAL-13 (July 18-23, 2015). The present volume includes 22 papers. All the papers are concerned specifically with the Formosan languages (phonology, lexicon, historical linguistics, morphology, syntax, discourse, sociolinguistics, corpus linguistics). The volume is organized by subfields, with a forward that summarizes Lillian M. Huang s work and provides her relevant bibliographies regarding Formosan linguistics/languages. The volume covers data from nearly all the extant Formosan languages, Atayal, Amis (five dialects: Nataoran, Sakizaya, Kakacawan, Paheko, and Falangaw), Bunun, Kanakanavu, Kavalan, Rukai (three dialects: Budai, Tona and Mantauran), Paiwan, Puyuma (three dialects: Nanwang, Katripul and Tamalakaw), Saaroa, Saisiyat, Seediq (three dialects: Toda, Tgdaya and Truku), Thao, Tsou, and Yami. The volume is arranged as follows. After papers on diachronic and synchronic phonology (chapters 1 4), advances in Formosan morpho-syntax (chapters 5 14) are presented. A feature of Saisiyat discourse is examined in chapter 15, followed by three crossdialectal studies (chapters 16 18). The four final chapters focus on the lexicon, from different perspectives: semantic extension, language contact and corpus linguistics (chapters 19 22). Millennials and East Asia s Democratic Future Yun-Han Chu and Bridget Welsh Institute of Political Science, Academic Sinica Journal of Democracy 26.2 (2015): ACADEMIA SINICA In East Asia today, economic and political clout may still belong mainly to baby-boomers-the generation born between 1946 and 1964-but it is their offspring, the millennials, who will shape the region s democratic prospects tomorrow. We explore how this generation will shape the region s democratic future, highlighting the ways in which millennials differ from earlier generations (and among themselves) as well as their distinctive political predispositions. We base our analysis largely on data from the Asian Barometer Survey (ABS). If, for the most part, East Asian millennials have yet to exercise their collective power on behalf of political reform, the potential remains for them to become agents of democratic change. They exhibit three promising characteristics of democratic citizens. First, contrary to popular belief, East Asian youth are not politically apathetic. Although many eschew traditional forms of political participation such as voting, campaigning, and joining political parties, they are more likely than their older cohorts to politically engage with others about public policies and common concerns through informal political participation, social networks and online social media. Second, East Asian millennials tend to be well-educated, making them competent and confident in understanding politics and forming opinions, and they stay abreast of what is happening in government and politics. As a result, they also tend to have a higher sense of political empowerment compared to older generations. Third, millennials are just as committed as older cohorts to democracy. That support, however, is not unconditional. It is tied to their satisfaction with the output of the political system, and their expectations of quality governance and the provision of social equity are high-higher than those of older citizens. In short, East Asia s millennials have the makings of critical citizens. Asian Barometer Survey fieldwork in Cambodia. 81

83 Division of Humanities and Social Sciences When Do Dictators Decide to Liberalize Trade Regimes? Inequality and Trade Openness in Authoritarian Countries Wen-Chin Wu Institute of Political Science, Academic Sinica International Studies Quarterly 59.4 (2015): This paper investigates how authoritarian leaders employ trade openness as a response to rising inequality. The conventional wisdom posits that the existence of democratic institutions make democracies have higher trade openness than their authoritarian counterparts. However, this argument fails to explain why many authoritarian regimes have high levels of trade openness as well. In addition, it contradicts to the implication of modernization theory, which predicts that trade-induced economic growth would facilitate democratization. Therefore, it look like committing political suicide for dictatorships to embrace trade liberalization. Based on the Heckscher Ohlin model of international trade and models of democratic transition, I argue that unskilled laborers in authoritarian regimes can benefit from engaging in international trade, thus becoming more compliant to the authoritarian rules as their countries integrate into the world economy. Therefore, dictators in more labor-abundant countries are more likely to expand trade to neutralize democratization threats initiated by rising inequality. My argument uses supporting data from around eighty authoritarian regimes during the period from 1963 to I address endogeneity problems with dynamic panel data and instrumental variable regression models in this paper. My analyses suggest that economic globalization helps strengthen authoritarian regimes. The marginal effect plot suggests that when income inequality increases, the level of trade openness would also increase with the level of labor endowment in authoritarian regimes (The dash lines are 90% confidence intervals, and the grey areas are the histogram of the sample). The Normative Significance of the Empirical Dimensions: On the Role of Empirical Studies in the Doctrinal Study of Law Peng-Hsiang Wang and Yun-Chien Chang Institutum Iurisprudentiae, Academia Sinica Academia Sinica Law Journal 17 (2015): Conventionally, the doctrinal study of law is regarded as a normative discipline. As a result, empirical legal research is often considered an external approach, or even non-legal scholarship. In this article, we contest this position. After re-examining the nature of the doctrinal study of law and that of empirical legal research, this article argues that the empirical and the normative dimensions intertwine in at least two perspectives. First, empirical facts for instance, whether a regulation is able to achieve a given statutory goal or bring about certain consequences are often employed as normative reasons in legal reasoning, and a carefully designed quantitative empirical research can tease out normatively significant difference-making facts by means of causal inference. Second, the knowledge and description of valid or effective law fall within the domain of the doctrinal study of law, as such descriptions and observations of law are empirical in nature. By employing social scientific methods, empirical legal studies broaden the ways to understand and describe the law. This article classifies empirical legal research into three types: the first identifies difference-making facts ; the second explores the effectiveness of law and delineates institutional behaviors; and the third systematically describes how legal arguments are used in practice. 82

84 From Autocratic to Democracy: The Unfolding of Western Democratic Thought Ying-Wen Tsai Research Center for Humanities and Social Sciences, Academia Sinica Taipei : Linking Publishing Company Press (2015), 408 pages. The author of this book is concerned with the political problems facing Taiwan s democratic transition, and think about how far democracy is the appropriate criterion for political normality and political decency for Taiwan. With this regard, the author tries to explore the unfolding of western democratic thought, starting from the origin of democratic idea in Ancient Greece, through the long period of autocratic regimes (i.e. monarchy and Empire) to the democratic revolutions in eighteen and nineteen centuries. Apart from these historical explanations of democratic thought, the author also deals with the diagnostic practice of democracy in three prominent political thinkers, Carl Schmitt, Hannah Arendt and Claude Lefort. Throughout such an historical interpretation of western democratic thought, the main argumentation lies in that while accepting democracy as the best form of government, and only legitimate regime in contemporary world, we need to attend to its ambiguities and conflicts that underpin the history of western democracy. Global Exposure in East Asia ACADEMIA SINICA Ming-Chang Tsai Research Center for Humanities and Social Sciences, Academia Sinica London: Routledge/Ashgate (2015), 208 pages. This monograph shows the critical influence of an individual s economic resources and cultural capital in differential global exposure in East Asian societies. The evidence from the East Asian Social Survey reveals that border crossing and transnational relationships remain a class-stratified phenomenon. The effects of global exposure on trade policy preference, nationalism, cultural distance, and value orientation are further investigated. In China, a positive evaluation of globalization leads to a stance in favor of protectionism, while in Japan, South Korea and Taiwan, it encourages acceptance of market openness. These cross-national differences are much conditioned by the distinct historical and geopolitical factors of a country. This book sets an example of how globalization can be conceptualized as exerting an impact at the level of the individual, and how that impact can be assessed. 83