Cover story: The leading story of this issue of Drug Discovery Today , by Antony J. Williams, Sean Ekins and Valery Tkachenko offers an overview of some of the experiences of the authors using online chemical compound databases, critiques the approaches taken to assemble data and the authors suggest approaches to deliver definitive reference data sources. Welcome to the latest issue of Drug Discovery Today , packed full of industry focused research articles, new developments in drug discovery, with expert comment and opinion. View the July Issue of July 2012 now July Issue review highlights include: Quality in public domain chemistry databases Expanding chemical space with compound libraries Natural polymers for oral insulin delivery Ribosome-inactivating proteins Remember - reading and downloading Drug Discovery Today is easy and free - you can access the July 2012 issue here . Enjoy your digital edition!
An Algorithm for Discovery David Paydarfar and William J. Schwartz Science 6 April 2001: 13.Published online 8 March 2001 1. Slow down to explore. Discovery is facilitated by an unhurried attitude. We favor a relaxed yet attentive and prepared state of mind that is free of the checklists, deadlines, and other exigencies of the workday schedule. Resist the temptation to settle for quick closure and instead actively search for deviations, inconsistencies, and peculiarities that don’t quite fit. Often hidden among these anomalies are the clues that might challenge prevailing thinking and conventional explanations. 2. Read, but not too much. It is important to master what others have already written. Published works are the forum for scientific discourse and embody the accumulated experience of the research community. But the influence of experts can be powerful and might quash a nascent idea before it can take root. Fledgling ideas need nurturing until their viability can be tested without bias. So think again before abandoning an investigation merely because someone else says it can’ be done or is unimportant. 3. Pursue quality for its own sake. Time spent refining methods and design is almost always rewarded. Rigorous attention to such details helps to avert the premature rejection or acceptance of hypotheses. Sometimes, in the process of perfecting one’s approach, unexpected discoveries can be made. An example of this is the background radiation attributed to the Big Bang, which was identified by Penzias and Wilson while they were pursuing the source of a noisy signal from a radio telescope. Meticulous testing is a key to generating the kind of reliable information that can lead to new breakthroughs. 4. Look at the raw data. There is no substitute for viewing the data at first hand. Take a seat at the bedside and interview the patient yourself; watch the oscilloscope trace; inspect the gel while still wet. Of course, there is no question that further processing of data is essential for their management, analysis, and presentation. The problem is that most of us don’t really understand how automated packaging tools work. Looking at the raw data provides a check against the automated averaging of unusual, subtle, or contradictory phenomena. 5. Cultivate smart friends. Sharing with a buddy can sharpen critical thinking and spark new insights. Finding the right colleague is in itself a process of discovery and requires some luck. Sheer intelligence is not enough; seek a pal whose attributes are also complementary to your own, and you may be rewarded with a new perspective on your work. Being this kind of friend to another is the secret to winning this kind of friendship in return. Although most of us already know these five precepts in one form or another, we have noticed some difficulty in putting them into practice. Many obligations appear to erode time for discovery. We hope that this essay can serve as an inspiration for reclaiming the process of discovery and making it a part of the daily routine. In 1936, in Physics and Reality, Einstein wrote, “The whole of science is nothing more than a refinement of everyday thinking.” Practicing this art does not require elaborate instrumentation, generous funding, or prolonged sabbaticals. What it does require is a commitment to exercising one’s creative spirit—for curiosity’s sake. Comment: common sense Omer Kucuk Wayne State University I agree with the authors. Perhaps the principles could be further reduced to: Use common sense and have fun. Published 4 May 2001 Comment: On Reading Timothy G. Buchman Washington University School of Medicine The authors suggest that one read, but not too much lest one get discouraged by claims of others. Certainly reading as a critical scientist requires both selectvity and skepticism. However there is a different kind of scientific reading that must be encouraged: reading outside one's own field. The understandable tendency to keep the mind uncluttered increasingly blinds professional scientists to reports from outside their particular field of study. The most successful scientists recall happening upon a paper, a lecture or a colleague by chance, a meeting that changes the course of their research. As Pasteur is oft quoted, "Chance favors the prepared mind." Gambling a little time by reading outside one's field can yield handsome rewards. It is a chance worth taking, frequently. Published 16 April 2001 Comment: Other Components of the Algorithm V. D. Ramanathan Tuberculosis Research Centre, Indian Council of Medical Research, India. Paydarfar and Schwartz have succinctly come out with these five cardinal principles to maximize the chances of discovery in science. One assumes that the basic ingredient of an almost insatiable curiosity for knowing more about the nature of the physical world is taken as an essential prerequisite by the authors. One wonders whether such a quality can be nurtured from scratch or at least be improved on once such a tendency is recognized. The principle of slowing down is very important. Perhaps we ought to cultivate a guide book approach rather than a cook book approach as advocated by Nick Herbert (in his book on "Reality of the Quantum World"). Too many projects are driven by "kit-oriented" or "common man -oriented" research. The principle of pursuing quality for its own sake has another component--the joy of doing science and devising aesthetically appealing experiments. It is well known that Paul Dirac firmly believed that if there is beauty in an equation, it is bound to be right! Published 9 April 2001 The Feynman Algorithm for Discovery -- the "simplest" as well as the "hardest" among all such algorithms!
Are the waste compounds of the pharmaceutical synthesis in drug discovery industry hazardous to the environment? Caiming Tang Chinese Academy of Sciences, Guangzhou, China In China, the contract research organization (CRO) corporations have witnessed a sharp increasing in both the magnitude and productivity. Many of these CRO companies are engaging in the pharmaceutical industry, focusing on the preclinical and clinical researches in drug discovery. The first procedure of the preclinical research is chemical synthesis, while the mainly business of the Chinese CROs is chemical synthesis. In drug discovery industry, tremendous compounds are synthesized. While after screening, only a few can be approved as successful drugs. Many compounds are excluded in the preliminarily screening processes. Some of them are bioactive and some not. Actually, these compounds are unknown chemicals. We have no idea whether they are hazardous or not to the environment. We always have the consciousness that “the unknown danger is the most dangerous”. Accordingly, these compounds should be carefully evaluated in terms of their potential eco-toxicity before being released into the environment, especially for those possessing bioactivities. The waste produced by those CROs should be strictly scrutinized before recycling or discharging. Recently, an increasingly environmental concern has been raised on the contamination caused by pharmaceuticals. 1 Since the pharmaceuticals and their metabolites can result in environmental contaminations and lead to potential healthy risks, 2 the byproducts and the unreacted compounds which possess the similar functional groups as the pharmaceuticals and their metabolites could contribute the similar adverse effect to the environment. Some byproducts and excluded compounds are probably much more hazardous compared with the approved pharmaceuticals, because those compounds would be excluded at the preliminary screening procedures due to their toxic properties. Although the amounts of these compounds are relatively limited, the increasing business of the Chinese CROs could increasingly produce these compounds, thus leading to environmental problem. Furthermore, we do not know how dangerous they are. Just as the example that some new species invade into a new environment can cause severe ecological problems for the local environment, some new compounds could bring the similar affect to the environment. Therefore, the waste form the chemical synthesis workshops should be cautiously deactivated and eliminated, thus reducing the environmental risks. (1) Escher B. I.; Fenner K. Recent Advances in Environmental Risk Assessment of Transformation Products. Environ. Sci. Technol. , 2011 , 45 (9), 3835–3847 . (2) Howard P. H.; Muir D. C. G. Identifying New Persistent and Bioaccumulative Organics Among Chemicals in Commerce II: Pharmaceuticals. Environ. Sci. Technol. , 2011 , 45 (16), 6938–6946.
The Discovery of New Antimalarial –Qinghaosu(Artemisinin) in China The Insiders* (revised on 2012.03.06) Since the fact that malarial parasites were resistant to frequently used antimalarials, in Vietnam War which started in 1964, the number of soldiers died of drug-resistant falciparum malaria was much higher than that of casualties from both combating sides. The then Leadership of Vietnam asked for help from China. The authorized “523 Leading Group” (523 领导小组 ) was inaugurated on May 23 rd in 1967 which was sponsored by a consortium among the General Logistics Department of the Chinese People’s Liberation Army ( 中国人民解放军总后勤部 ), the State Science and Technology Commission of China ( 国家科学技术委员会 ), Ministry of Public Health of PRC ( 中华人民共和国卫生部 ), Ministry of Chemical Industry of PRC ( 中华人民共和国化工部 ), Commission of Science and Technology for National Defence ( 国防科委 ), Chinese Academy of Sciences ( 中国科学院 ) and General Pharmaceutical Industry Corporation ( 医药工业总公司 ). The project was named “523 Project” (523 项目 ) ,which was supervised by the “523 Leading Group” (523 领导小组 ) and was kindly concerned by the late Premier Zhou En Lai. Even though it was at the time of “Cultural Revolution”, and normal working routines were severely interfered, the authorized “523 Leading Group” could still mobilize around five hundred scientific workers of different specialities from sixty-some institutions of the whole country, to form a closely related, united, well organized and versatile scientific troupe, which was supported by groups of various disciplines with most advanced equipments at hand. The main task of “523 Project” was to seek new antimalarials for the prevention and treatment of drug-resistant falciparum malaria in tropical area. The “General Leading Office of 523 Project” ( 全国五二三办公室 ) suggested the screening of new drugs to start from two aspects, one was synthesis of new drugs, and the other was investigation of anti-malarial drugs frequently used in traditional Chinese medicine and folklore medicine. Thus, two cooperative groups of the two aspects were established respectively. The Traditional Chinese Medicine and Folklore Medicine Group (TCMFM Group) ( 中医中药专业组 ) was one of the two groups, the main task of this group was attempting to search for the required new antimalarials from the traditional Chinese medicine or folklore medicine. This was the historical background and organization of the scientific troupe leading to the discovery of Qinghaosu (Artemisinin). ( Zhang Jianfang, A Detailed Chronological Record of Project 523 and the Discovery and Development of Qinghaosu (Artemisinin),Yangcheng Evening News Publisher, 2006. (Hereafter it is abbreviated as “Zhang Jianfang, “Chronological Record of Project 523”) p.5-11. ) Unlike the discovery of ordinary natural products, the discovery of Qinghaosu is meaningful because it is a new type of antimalarial, its novel chemical structure brings about its advantage of unique antimalarial efficacy without drug-resistance. In early 70s of last century, it happened that both Chinese and then Yugoslavian scientists had been engaged in the studies of natural products in Artemisia annua L., and discovered the compound with the same molecular formula C 15 H 22 O 5 and molecular weight, but the then Yugoslavian scientists gave an incorrect chemical structure to the compound ( Jeremic, D., Jokic, A. and Stefanovic, M., New Type of Sesquiterpenen Lactone isolated from Artemisia annua L.– Ozonide of Dihydroarteannuin, presented at the 8 th Int. Symp on Chemistry of Natural Products , New Delhi (1972) 222 (Posted by Gong Wai Lihm 江威廉 on http://panyutiger.blogspot.com/ at the time of May 3, 2008) ). Actually, Artemisia annua L. ( 黄花蒿， Huanghuahao) is the plant which the Chinese antimalarial herbal drug named Qinghao ( 青蒿 ) originates from. Owing at the time of “Cultural Revolution”, Chinese scientists could not get any scientific information published outside China, they knew nothing about what was going on in then Yugoslavia. In 1986, one of the then Yugoslavian scientists visited China, he said, “Even if we gave a correct chemical structure to the compound, we could never develop the compound as an antimalarial”, because they do not have the knowledge of using Artemisia annua L. in the treatment of malaria in Yugoslavia. So it is Chinese scientists who not only discovered a new natural product and gave it a correct chemical structure, more important is, based on the experience of traditional Chinese medicine in treatment of malaria, they discovered a new type of antimalarial as well. So we emphasize that the discovery of Qinghaosu (Artemisinin) should not be credited only to the person who first isolated the compound as people ordinarily do for the discovery of natural products. People who are engaged in the investigation and evaluation of the history of discovery of Qinghaosu should not only concern about who is the first person who isolated this natural compound, but also those persons who had made contribution to the elucidation of the chemical structure of the compound and the demonstration of the unique antimalarial efficacy of this antimalarial through clinical trials should also be concerned about. (I) Discovery of the new antimalarial Qinghaosu in China In 1969, Institute of Chinese Materia Medica (ICMM), Academy of Traditional Chinese Medicine (ATCM) under Ministry of Public Health ( 卫生部中医研究院中药研究所 ) in Beijing was invited by the “General Leading Office of 523 Project” to join in TCMFM Group. Tu Youyou( 屠呦呦 ) was designated by ICMM under ATCM as the team leader of “523 research team” in Department of Chemistry, and Yu Yagang( 余亚纲 ) was the team member. Tu Youyou began her work at the research of pepper extract, and study on it’s anti-malarial action was carried out in Academy of Military Medical Science of Chinese PLA (AMMS) ( 中国人民解放军军事医学科学院 ), but due to its ineffectiveness the work stopped ( Zhang Jianfang, “Chronological Record of Project 523” ， p.16 ). In 1970, Tu Youyou was asked to join in certain personnel investigation and left Yu Yagang alone. In the same year, “General Leading Office of 523 Project” dispatched Gu Guoming ( 顾国明 ) of AMMS to ICMM and worked cooperatively with Yu Yagang. They started to collect the prescriptions and single drugs of traditional and folklore medicines used in treatment of malaria. The investigation showed that the most frequently used traditional herbal drugs for treatment of malaria was Qinghao ( 青蒿 ). Yu Yagang and Gu Guoming prepared the ethyl alcohol extract from Qinghao, which was available in Beijing drug market and known as the arial part of the plant of “Huanghuahao” ( 植物黄花蒿 , Artemisia annua L.), the animal experiment was carried out by scientists in AMMS, the results showed that the inhibition rate for parasites in mice was 60-80% ( Zhang Jianfang, “Chronological Record of Project 523” ， p.16 ), and according to an insider it had been as high as 90%. Since Tu Youyou did not work with them, Yu Yagang reported the results to the team leader Tu Youyou and the director of ICMM. Later (New Year of 1971), Yu Yagang was asked to leave Beijing to join in another project, so Gu Guoming was back to AMMS. This arrangement caused the suspension of Yu Yagang and Gu Guoming’s work, which had not been thoroughly studied. In 1971, Tu Youyou returned to the team, and worked with new team members, Zhong Yurong ( 钟裕蓉 ). Lang Lingfu ( 郎林福 ) joined the team, and was responsible for testing inhibition rate for parasites in animals. They gave up the pepper research and started to reproduce Yu Yagang and Gu Guoming’s work, but the inhibition rates for parasites in mice of extracts from Qinghao were fluctuating. In comparison with different extraction methods, Tu Youyou got the clue from using of fresh juice of Qinghao, which was described by Ge Hong ( 葛洪， 281-341A.D.) in his “A Handbook of Prescriptions for Emergencies” ( 《肘后备急方》 ), so she modified the extraction procedure at low temperature, when they found the inhibition rate for parasites in mice of ethyl alcohol extract, which was prepared by infusion and concentrated at low temperature, was as high as 95% ( Tu Youyou, “qinghao ji qinghaosulei yaowu”, Printing House of Chemical Industry, 2009.01 (Hereafter it is abbreviated as Tu Youyou ,“qinghao ji qinghaosulei yaowu”), p.35 ). Later they found that the neutral portion of the ether extract was even more effective, the inhibition rates for parasites in mice and in monkey were as good as 100%, and the results were reproducible, it was in October ,1971 ( Tu Youyou, “qinghao ji qinghaosulei yaowu”, “discovery of qinghaosu” and p.34-36 ). In March 1972, Tu Youyou as a representative of ICMM under ATCM, reported the above results at the TCMFM Group meeting held by the “General Leading Office of 523 Project” in Nanjing. The report drew the attention of people who attended the meeting. On knowing the experience from ICMM under ATCM, people in Institute of Drug Research in Yunnan Province (Yunnan IDR) ( 云南省药物研究所 ) and Institute of Traditional Chinese Medicine in Shandong Province (Shandong ITCM) ( 山东省中医药研究所 ), who also joined in the “523 Project”, tried to get the active ingredient by using their local plant resources respectively. Between August and October of 1972, after finishing study on preclinical toxicity and oral administration of the ether extract-neutral portion in some healthy volunteer subjects, ICMM carried out the clinical trial of ether extract-neutral portion in 9 falciparum and 12 vivax malaria patients in Changjiang, Hainan ( 海南昌江 ), Tu Youyou joined this clinical trial ( Tu Youyou, “qinghao ji qinghaosulei yaowu”, p.39-41 ). Under the coordination of “General Leading Office of 523 Project”, 302 Hospital of PLA in Beijing also carried out the clinical trial of the ether extract-neutral portion in 9 vivax patients. All together 30 cases (20 cases of vivax and 10 cases of falciparum malaria patients) were observed. In her book, Tu Youyou described all these 30 cases were cured or effective ( Tu Youyou “qinghao ji qinghaosulei yaowu” .p.38-39 ), but according to the original clinical report, among the 9 falciparum malaria patients, 7 of them were effective and 2 of them failed ( 523 clinical trial group of ICMM under ATCM, Clinical Summary Report of 91 ＃ ( cf Zhang Jianfang,“Chronological Record of Project 523” ， p.17 and Note 13) ). These good antimalarial results in animal experiments and clinical trials of the ether extract –neutral portion of Qinghao which were achieved by Tu Youyou’s research team, were really an important step leading to the discovery of Qinghaosu. Ni Muyun ( 倪慕云 ) joined in Tu Youyou’s team, she designed the pre-column treatment of the ether extract-neutral portion of Qinghao, i.e., mixed the ether extract-neutral portion with polyamide, then percolated with 47% ethyl alcohol. After concentration of this ethyl alcohol solution, it was again extracted by ether, the antimalarial effectiveness of this ether extract was further improved. It was attempted to make further separation by aluminium oxide column chromatography, but failed to get any solid substance. After knowing from some reference maerials, that silica gel column chromatography could get better result for separation of neutral substance, Zhong Yurong and her assistant Cui Shulian ( 崔淑莲 ) used silica gel column chromatography instead of aluminium oxide chromatography and used petroleum and ethyl acetate-petroleum solvent as eluent for gradient elution. The primarily eluated crystal in square-shape was high in content, and was named “crystal I “, the secondly eluated crystal in needle–shape was low in content, and was named “crystal II”, which was followed by another needle-shaped crystal named “crystal III”. After testing their inhibition rates for parasites in mice, “crystal II” was the only substance confirmed as the antimalarial entity of Qinghao. According to their report written later to the “General Leading Office of 523 Project”, they named this “crystal II” ( 结晶 II) as “Qinghaosu II” ( 青蒿素 II). The date of discovery of “crystal II” (or “Qinghaosu II”) by Zhong Yurong was November 8, 1972, Tu Youyou was not there at all. The experience of traditional Chinese medicine in treatment of malaria leads to the key step taken by Yu Yagang and Gu Guomung. As the second step, based on Yu and Gu’s experiment, Tu Youyou and Zhong Yurong found the neutral portion of the ether extract of Qinghao, and demonstrated its antimalarial effect in treatment of both vivax and falciparum malaria. As the most important third step, based on the purification of the neutral portion of ether extract of Qinghao done by Ni Muyun, Zhong Yurong finally isolated the antimalarial “Qinghaosu II” by using silica gel chromatography. They are all who have made contribution to the discovery of the new antimalarial “Qinghaosu”. In the 70’s of last century, most people in ICMM knew this story very well. Being a team leader, Tu Youyou never mentioned about the story of discovery of “Qinghaosu II” to outsiders. Outsiders only knew that Tu Youyou was the person who discovered Qinghaosu, because she was the team leader, the main person who discovered the active extract portion from ether extract, the representative of ICMM under ATCM to take part in the nation-wide meetings. Along with the years, as Qinghaosu was more and more well known by people outside China, in interview with reporters inside and outside China, and in her book , Tu Youyou simply claims that “she is the first person who discovered Qinghaosu” ( Tu Youyou “qinghao ji qinghaosulei yaowu” , “preface three” ), it is she, “who finally and successfully explored the antimalarial entity from traditional Chinese medicine Qinghao” ( Tu Youyou “qinghao ji qinghaosulei yaowu” , “brief introduction of author” ), and it is she, “who isolated the antimalarial entity on November 8 th of 1972 ， and named it as Qinghaosu” ( Tu Youyou “qinghao ji qinghaosulei yaowu” , “Foreword” ). As a matter of fact, in December near the end of the year 1972, Zhong Yurong and Cui Shulian (ICMM, ATCM) isolated “Qinghaosu II” from Artemisia annua L. growing in Beijing; In April 1973, Luo Zeyuan( 罗泽渊 ) (Yunnan IDR) isolated “Huanghaosu” ( 黄蒿素 ) from A. annua L. f. macrocephala Pamp. growing in Kunming, Yunnan ( 云南昆明 ), and also from A. annua L. growing in Chongqing, Sichuan ( 四川重庆 ); and in November 1973, Weizhenxing ( 魏振兴 , deceased) (Shandong ITCM) isolated “Huanghuahaosu” ( 黄花蒿素 ) from A. annua L. growing in Taixing, Shandong ( 山东泰兴 ) ( Zhang Jianfang,“Chronological Record of Project 523” ， p.53 ). Although the isolation of the active ingredient, inhibition of parasites in mice and primary clinical trials were carried out by the three institutions respectively, crystals with different names were all isolated from Artemisia annua L., and was the only antimalarial substance in the plant, after the elucidation of their chemical structure, they were accepted to be the same chemical substance, and was designated “Qinghaosu” ( 青蒿素 ) as the official name in Chinese Pharmacopoeia (edited in 2000) after the name of the herbal drug. Tu Youyou is not the person who first discovered the antimalarial action of Qinghao extract, and not the first person who isolated the antimalarial Qinghaosu either, and these parts of work were not done under her instruction, so it was not only unfair and unreasonable, more over, it was not tally with the historical truth if Tu Youyou is the only person to be credited for. (II) Demonstration of antimalarial effectiveness for Qinghaosu in clinical trials Between September and October of 1973, Tu Youyou’s team applied “Qinghaosu II” for the treatment of 8 cases malaria patients in Changjiang, Hainan ( 海南昌江 ), but they did not get the expected results. According to their original report, among 5 cases of falciparum malaria treated with “Qinghaosu II” tablets (in total dosage of 4.5g), 1/5 case was effective, 2/5 cases discontinued the treatment because of appearance of premature heart beat, 2/5 cases failed. Among 3 cases of vivax malaria patients treated with “Qinghaosu II “capsules (in total dosage of 3-3.5g), 2/3 cases were cured, and 1/3 case was effective( Institute of Chinese Materia Medica under ATCM, “zhongyao qinghao de kangnue yanjiu(1971-1978)”, p.27 ). Tu Youyou did not take seriously to this unexpected clinical result, and explained the reason of clinical trial failures in the 5 falciparum patients as was caused by the disintegration problem of the tablets, but did not provide any data for her explanation ( Tu Youyou “qinghao ji qinghaosulei yaowu” ,p.43 ). As a matter of fact, the content of “Qinghaosu II” was rather low in Artemisia annua L. growing in Beijing, and the “Qinghaosu II” sample used for clinical trails which they separated by using column chromatography was not pure enough, and was mixed with certain amount of “Qinghaosu I”, the team members all knew that. She even did not investigate the relation between the purity of “Qinghaosu II”, the poor cure rate (only 50%), and its side-effect as well. In her book, she avoided to mention about the purity of “Qinghaosu II” and the clinical results of falciparum patients, but simply asserted, “the clinical results of the Qinghaosu capsules in treatment of 3 cases of vivax malaria can fully demonstrate the effectiveness of Qinghaosu — the active ingredient in Qinghao” ( Tu Youyou “qinghao ji qinghaosulei yaowu” , p.41 ). In May of 1974, scientific workers of Shandong ITCM and Institute of Parasiteses in Shandong Province (Shandong IP, 山东省寄生虫病研究所 ) carried out the treatment of 19 vivax malarial patients by using “Huanghuahaosu” . It was concluded that the efficacy of “Huanghuahaosu” in treatment of vivax malaria was promising, no significant toxicity or adverse effect were observed ( Zhang Jianfang,“Chronological Record of Project 523” ， p.53 ). In September of 1974, the Yunnan cooperative group of clinical trials ( 云南临床协作组 ) intended to carriy out the clinical trial of “Huanghaosu” in Fengqing and Yunxian ,Yunnan ( 云南凤庆和云县 ). Since it was difficult in searching of falciparum malaria patients in these areas, under coordination of the “General Leading Office of 523 Project” and the local Leading Office, Ludongwei ( 陆东伟 ) from Yunnan IDR was to be responsible for supplying “Huanghaosu”, and entrusted Li Guoqiao’s ( 李国桥 ) research group of Guangzhou University of Traditional Chinese Medicine (Guangzhou UTCM, 广州中医大学 ) to carry out the clinical trials in Gengma and Cangyuan, Yunnan ( 云南耿马和沧源 ), these were the high edemic areas of falciparum malaria. Li Guoqiao was well experienced in emergent treatment of cerebral malaria. Between October and December of 1974, he worked with the Yunnan cooperative group in treatment of the first 3 falciparum malaria patients, which showed unexpected good result. Li Guoqiao’s group continued the further clinical trial, and all together 18 malarial patients, which included 14 cases of falciparum malaria (3 cases of severe malaria, one of them was pregnant) and 4 cases of vivax malaria, were cured. The efficacy of “Huanghaosu” was even better than Choloroquine, and was characterized by quick onset of action with high efficiency in short term, low toxicity and adverse effect, and without drug-resistance, but the recrudescence rates were high. The efficacy and side-effect of “Huanghaosu” in treatment of drug-resistant falciparum malaria in tropical area was basically confirmed by the said evaluation ( Zhang Jianfang,“Chronological Record of Project 523” ， p.27-32 ), this is a new generation of antimalarial which exactly is what all the malaria patients in the world are expecting for. ICMM under ATCM had been a pioneer in isolation of the antimalarial entity, but in the clinical trials, they only got positive results in 3 cases of vivax malaria and 1 case of falciparum malaria. The characteristic effectiveness of Qinghaosu was eventually confirmed by 19 cases of vivax malaria patients treated with “Huanghuahaosu” prepared by Shandong ITCM and Shandong IP, and 14 cases of falciparum and 4 cases of vivax malaria patients treated with “Huanghaosu” prepared by Yunnan IDR and treatment carried out by Li Guoqiao’s group of Guangzhou UTCM. This was a good example of cooperative research in China that expedited the progress of antimalarial research with high speed. (III) Elucidation of chemical structure of Qinghaosu Under the instruction of Professor Lin Qishou ( 林启寿 , deceased) of Beijing Medical College ( 北京医学院 ) and Professor Liang Xiaotian ( 梁晓天 , deceased) of ICMM under China Academy of Medical Science (ICMM, CAMS) ( 中国医学科学院药物研究所 ) , Tu Youyou’s team carried out some experiments such as ultimate analysis, IR, 1 H NMR, MS spectrum, and some chemical reactions of Qinghaosu isolated, and found that there was no nitrogen atom in its molecule, so it is assumed to be a new type of sesquiterpenoid antimalarial. Owing to having no sufficient experience and technical equipments for elucidation of chemical structure, ICMM under ATCM negotiated with specialists of Shanghai Institute of Organic Chemistry (SIOC), Academia Sinica (AS) ( 中国科学院上海有机化学研究所 ), and under the coordination of “Shanghai Leading Office of 523 Project”, Professor Zhou Weishan( 周维善 ) of SIOC supervised the research team, Wu Zhaohua( 吴照华 ) and Wu Yulin( 吴毓林 ) were responsible for the research. They consented that ICMM under ATCM could dispatch one person to take part in the work. From February, 1974, ICMM in succession dispatched Ni Muyun , Liu Jingming ( 刘静明 ) and Fan Jufen ( 樊菊芬 ) to work with the team in SIOC for a short duration. Tu Youyou herself had not taken part in any research work in SIOC. Even for the experiment carried out in SIOC, Professor Liang Xiaotian still contributed much to the work, and gave good advice to SIOC through communication between Tu Youyou and her team member there. From 1974 to 1975, a series of chemical reactions of Qinghaosu were studied in SIOC, among those, four groups of reactions were valuable, one was demonstration of its peroxyl group by means of reacting with sodium iodide to form the colour of iodine, and reducing by triphenyl phosphine; the second one was demonstration of the lactonyl group by means of reacting with hydroxyl amine hydrochloride or titration with sodium hydroxide; the third one was the formation of a semiacetal by the reduction of the lactonyl group by sodium borohydride (NaBH 4 ) with the peroxyl group still kept intact, this product was initially named as “reduced Qinghaosu”, after the chemical structure of Qinghaosu was demonstrated, it was then named dihydroqinghaosu (or dihydroartemisinin) ; and the fourth one was hydrogenation of Qinghaosu by using palladium-calcium carbonate as catalyst to produce the deoxyqinghaosu (or deoxyartemisinin) . All these reactions laid the foundation of studies on the relationship between the chemical structure and its effectiveness, and the preparation of its derivatives as well ( Liu Jingming, Ni Muyun, Fan Jufen, Tu Youyou ( Institute of Chinese Materia Medica, Academy of Traditional Chinese Medicine Peking), Wu Zhaohua , Wu Yulin , Zhou Weishan (Institute of Organic Chemistry, Academia Sinica, Shanghai), Structure and Reaction of Arteannuin, Acta Chimica Sinica, 1979,37(2):129-143 ） Based on the IR spectrum, 1 H NMR and 13 C NMR data, ORD spectrum and chemical reactions of Qinghaosu, scientists of SIOC had deduced certain structural fragments of the molecule. It was interesting, enlightened by the chemical structure of Yingzhaosu A ( 鹰爪甲素 ) ， another new antimalarial entity with a peroxyl group, reported by scientists from ICMM, CAMS ( 中国医学科学院药物研究所 ), Wu Zhaohua with Wu Yulin demonstrated the endoperoxyl group in Qinghaosu by means of chemical reactions. However, the peculiarity of the structure made it difficult to ascertain the linkage of 15 carbon atoms and 5 oxygen atoms in the molecule. ICMM under ATCM then asked the help from Institute of Biophysics (IB), Academia Sinica (AS) ( 中国科学院生物物理所 ) in Beijing, Tu Youyou supplied them with qualified crystals of Qinghaosu for analysis, Li Pengfei ( 李鹏飞， deceased), Liang Li ( 梁丽 ) and their colleagues of Institute of Biophysics finally determined the chemical structure and relative configuration of Qinghaosu by means of X-ray single-crystal diffraction, and its absolute configuration was determined by means of anomalous dispersion of Cu-radiation by oxygen atoms ( Qinghaosu Research Group of Institute of Biophysic, Crystal Structure and Absolute Configuration of Qinghaosu, Scientia Sinica, 1980,23(3) 380-396,in English ), the time was November 30 of 1975 ( Tu Youyou “qinghao ji qinghaosulei yaowu” , p.44 ) . The results obtained from the elucidation of the chemical structure of Qinghaosu showed, Qinghaosu is so valuable in the treatment of malaria, first of all, is due to its novel and peculiar structure — a sesquiterpene lactone with no Nitrogen atom, and the endoperoxyl group links with an ethereal-like carbon and oxygen linkage in an order of O – C – O – C – O – C – O – O – C, propably is its antimalarial action site in the molecule. ( Li Ying, Yu Pei-Lin, Chen Yi-Xin, Li Liang-Quan, Gai Yuan-Zhu, Wang De-Sheng, Zheng Ya-Ping. Studies on analogs of artemisinin I. The synthesis of ethers, carboxylic esters and carbonates of dihydroartemisinin. Acta Pharmaceutica Sinica, 1981, 16(6): 429-439 ) In her book, Tu Youyou claimed that she “reduced Qinghaosu by using NaBH 4 as a reducer to produce dihydroqinghaosu, and was the first person who created dihydroqinghaosu as early as in 1973, and the carbonyl group of Qinghaosu was demonstrated through dihydroqinghaosu” ( Tu Youyou “qinghao ji qinghaosulei yaowu” , p.187 ) . According to the description of a report with the title of “Studies on the antimalarial research of Chinese herbal drug Qinghao” written by one of her team member in November of 1975, they had reduced Qinghaosu by using Zn(BH 4 ) 2 , KBH 4 and AlLiH 4 as reducers, the products all were white crystals, in comparison with Qinghaosu, the carbonyl peak in IR spectrum disappeared and was replaced by an hydroxyl peak, and the hydroxyl group could be acetylated (Institute of Chinese Materia Medica under ATCM, “zhongyao qinghao de kangnue yanjiu”,1975,11 ). So actually they had never used NaBH 4 as reducer, and no further chemical elucidation had been done , and even no name had been given to any of those compounds at the time of the report was written. As a matter of fact, it was Wu Yulin of SIOC who used NaBH 4 as reducer and got the said “reduced Qinghaosu” in 1975, and studied on its chemical structure as well. The chemical structure of “reduced Qinghaosu” was established after the successful elucidation of the chemical structure of Qinghaosu in 1975, and then was named as “dihydroqinghaosu” (or dihydroartemisinin). So nothing could prove that Tu Youyou was the first person who created dihydroartemisinin in 1973. (IV) The early publication of papers concerning the studies on structure and configuration of Qinghaosu The early publication of papers concerning the studies on structure and configuration of Qinghaosu were as follows: The first paper was “A New Type of Sesquiterpene Lactone-Qinghaosu ”(in Chinese) Cooperative Group of Qinghaosu Structural Research, A New Type of Sesquiterpene Lactone—Qinghaosu, Chinese Science Bulletin, 1977, 22(3)142) ( 青蒿素结构研究协作组 , 一种新型的倍半萜内酯 — 青蒿素 , 科学通报 , 1977, 22(3)142) The paper was prepared by some person of ICMM by putting together all the research results of ab o ve mentioned Institutions. The publication of this paper was approved by the Ministry of Public Health of PRC, but for the sake of security, it was not allowed to reveal its anti - malarial action. The second paper was “ Structure and Reaction of Arteannuin” ( in Chinese, with English abstract) Liu Jingming, Ni Muyun, Fan Jufen, Tu Youyou (Institute of Chinese Materia Medica, Academy of Traditional Chinese Medicine Peking), Wu Zhaohua , Wu Yulin , Zhou Weishan (Institute of Organic Chemistry, Academia Sinica, Shanghai), Structure and Reaction of Arteannuin, Acta Chimica Sinica, 1979,37(2):129-143 ( 刘静明、倪慕云、樊菊芬、屠呦呦（北京中医研究院中药研究所），吴照华、吴毓林、周维善（中国科学院，上海有机化学研究所），青蒿素（ Arteannuin ）的结构和反应， 1979,37(2):129-143) This paper was written by Professor Zhou Weishan. (Note: In the reference of her book, Tu Youyou had deleted the names of Fan Jufen, Wu Zhaohua, Wu Yulin, Zhou Weishan, and left the names of Liu Jingming, Ni Muyun and Tu Youyou ( Tu Youyou, “qinghao ji qinghaosulei yaowu”, p.144) The third paper was “Crystal Structure and Absolute Configuration of Qinghaosu “( in Chinese and English versions) Qinghaosu Research Group of Institute of Biophysic, Crystal Structure and Absolute Configuration of Qinghaosu, Scientia Sinica, 1980, 23(3) 380-396 (in English) 中科院生物物理所抗疟药青蒿素协作组，青蒿素晶体结构及其绝对构型，中国科学， 1979, (11) ： 1114-1128 (in Chinese) The studies on relative and absolute configuration of Qinghaosu were carried out and finalized in the Institute of Biophysics, but some of the details had already been introduced in the first paper and cited in the second paper, when this paper was waiting to be published. The fourth paper was “Chemical Studies on Qinghaosu (Artemisinine) “ ( in English) China cooperative Research Group on Qinghaosu and Its Derivatives as Antimalrials * , Chemical Studies on Qinghaosu (Artemisinine), Journal of Traditional Chinese Medicine, 1982,2(1):3-8. *The main research units:1.Institute of Chinese Materia Medica, Academy of Traditional Chinese Medicine; 2.Shanghai Institute of Organic Chemistry and Institute of Biophysics, Chinese Academy of Sciences. (Note: In the reference of her book, Tu Youyou deleted the names of the main research units, and replaced with her own name as “Tu Youyou” or “ 屠呦呦 ” （ Tu Youyou “qinghao ji qinghaosulei yaowu” p.69 ， p.140 and p.190 ） In that period of time in China, Chinese scientists had to avoid putting their own names in their published paper, because it was considered as a desire for personal fame and gain, so at that time, authors who published their papers mostly used the names of the Institutions where they worked for. From 1978, people were again allowed to sign their names on the papers. But since too many people from different Institutions had taken part in the research work of Qinghaosu, so some important published papers relating to Qinghaosu were still in the name of cooperative group. Tu Youyou might have taken part in some of the work mentioned above, but certainly, she was not the only person who had done all the research work of any of the paper mentioned above. In reviewing the history of discovery of the new antimalarial ¾ Qinghaosu in China, people could clearly realize that not a single person or institution could fulfill the whole process of those research work mentioned above, why only one single person should be credited for? The fact was that Chinese scientists of various disciplines took part in the research work and made their own contributions at different stages like in a scientific research relay race, and finally led to the discovery of the new antimalarial Qinghaosu (Artemisinin) — an historical pioneer work in last century. *This paper was written by insiders, as an important part of their investigation of the oral history relating to the discovery of the new antimalarial ¾ Qinghaosu in China . Since most of the scientists who had joined in the research work of Qinghaosu have retired and are residing inside and outside China separately, or passed away ， the writers hope that they can gain access to some of the original experimental records or related document for reference, but obstacles still exist. After almost 40 years, some insiders failed to remember things in details, some of them do not want to be disturbed. So we anxiously hope that any person in the know will help us to make this paper more tally with the historical truth.
I have lived in Honolulu for more than 10 years, so I know a lot of fun places and good restaurants. BUT, I don't know everything. Here is a list of things that I discovered today, when I "toured" some new and old friends from 8 am to 9 pm. 1) KCC Farmers' Market is packed with tourists, thanks to free drop off by Trolley. I stopped going there a while ago, because of parking; but I recommend my friends to go when they are here for a visit. I used to see lines as long as 10+ people, and now the lines are 40+ people! I may go back there next week, if I like the papayas I bought today. (Hey, it costs only $1 a piece.) I also like the sweets, called Hava (but I can't find anything on the internet about it). It's made from sesame seeds. 2) There is indeed a line outside a Pho place on the River Street near Chinatown. I read about it more than 10 years ago on the plane when I moved here. I don't like waiting in line, so I never bothered to check it out. Then, one year my friend Y.L. went when she was in the neighborhood, and said the Pho was really good. She even bought me a jar of chili sauce used by the restaurant. Still, I was not in a hurry to try, until today. Our tour group wanted to have lunch in Chinatown, and I thought about the Pho place. So, I called Y.L., and got the location. It's true, there was a line outside the restaurant, but not very long, about six people. (I didn't know the line could double, because the other half was parking or shopping elsewhere.) In any case, the wait was not painful, since we chatted while waiting. Everyone liked her order, but I didn't think the broth was as good as I expected. So, I will go back another time to see if the broth would be thicker if I am there earlier. (We were there after 1 pm.) 3) If you are Chinese, you definitely want to try the plain yogurt at Yogurtland. There is a Yogurtland near U. Hawaii, but I never cared to go. Thanks to M.Y., I will be going there often from now on. 4) There is a restaurant that serves dim sum for dinner! Yes, it's in Chinatown, and my friend Penny said it's the place for dim sum if you cannot get into the Legend's Seafood Restaurant at the Chinese Cultural Plaza, which is considered #1 dim sum place. I tried a few dishes there tonight, and will for sure go there again, for the sake of some friend who does not eat lunch. (How many people do you know who do NOT eat lunch?) 5) If you want to go to the airport from Chinatown, you can stay on Vineyard and get on H-1, thanks to my friend M.Y. (or to her iPhone). M.Y., you should visit Hawaii more often, and we can discover more things together! Guang, you were very much missed!
康州 Discovery Museum and Planetarium 掠影（二）（ 2010 年 12 月 19 日） 黄安年文 黄安年的博客 /2011 年12 月4 日 ( 美东时间 ) 发布 康州 Discovery Museum and Planetarium 是普及科学和天文知识的课堂 , 深受孩子们的喜爱。 2010 年 12 月 19 日，两个外孙来到这里参观。照片（一） 25 张 , （二）17张 , 是当日拍摄的。 ******************8 About The Discovery Museum and Planetarium The Discovery Museum functions as both a tourist attraction featuring science and space science exhibits and as an informal science education center. Through its exhibits , it enhances public understanding of science and technology by providing fun, instructive experiences that encourage participant interaction. As an informal science education center, it provides an extensive range of educational programs in science and technology and in the area where the two disciplines interact. Nearly 55,000 children participate in the museum’s science programs and outreach activities each year. The Discovery Museum’s 20,000 square foot facility includes changing and permanent interactive exhibit galleries, a 124 seat planetarium , Connecticut’s only Challenger Learning Center , an 80 seat auditorium, and five multi-purpose classrooms where hands-on science classes are conducted for schools, groups and the general public. Permanent exhibits include Green Energy, Sound, Light and Space Galleries and a simulated Moon Base Discovery play area for very young visitors. The recently upgraded Henry B. duPont III Planetarium offers traditional star shows and fulldome digital planetarium shows daily for both very young children and for ages 8 and up. The Discovery Museum, Inc. is an independent 501(c) 3 organization operated by a Board of Trustees. It is not affiliated with any government entity. It is located at 4450 Park Avenue, Bridgeport, CT, one mile south of Merritt Parkway Exit 47. http://www.discoverymuseum.org/about/about.html History of The Discovery Museum and Planetarium The Museum was founded in 1958 and opened to the public in 1962 as The Museum of Art Science and Industry. “M.A.S.I.” was the only non-historical, multi-disciplinary museum in the Greater Bridgeport area. Early exhibits ranged from the natural and physical sciences to decorative and fine arts. In 1985, recognizing the regional movement from industry to technology that occurred in the 70’s and 80’s, the museum’s Board of Trustees redefined the mission of the Museum to focus on two distinct areas: Science and Art. A master plan was developed which included the renovation of the facility, installation of interactive science exhibits, and improved gallery space. Exhibits moved away from natural science, expanded in the physical sciences, and added technology. In direct response to the pleas of educators who expressed the need for assistance in teaching the physical sciences, the museum developed a science curriculum that met the standards of the CT State Department of Education. In 1990 MASI became The Discovery Museum, reflecting a commitment to “hands-on” experiences and participatory education. In 1991 with the help of area corporations and the State of Connecticut, the Challenger Learning Center was installed as the only center of its kind within New England and the 6th nationwide. In 2000 the museum’s strategic plan called for a focus on science technology. In 2001, the Board of Trustees further focused the institution’s efforts on science and technology by adopting the current mission: “to educate, excite, and engage visitors in the exploration of science, technology, and ideas through interactive experiences that promote new insights.” In December of 2001, the museum established the practice of hosting traveling, hands-on science exhibitions three times a year. In 2004 Governor John Rowland announced substantial funding for The Discovery Museum as part of the state’s continued focus on advancing math and science education. In September 2009 ground was broken adjacent to the museum for a regional science magnet school which will share the name “Discovery”. It is scheduled to open in January of 2011. The Discovery Magnet School will collaborate with museum educators and Sacred Heart University to teach students, utilizing the hands-on scientific method long embraced by the museum. The school is expected to become a national model. 2010 Visiting Exhibits in the main level galleries continue to incorporate engaging, hands-on, interactive science experiences. The museum’s educational programs remain focused on the physical sciences and space science and reach more than 40,000 students each year. The Museum’s lower level is now a Space Gallery and includes a permanent live feed exhibit from the Space Telescope Institute. The Henry B. duPont III Planetarium presents entertaining and educational, full-dome, digital planetarium shows in addition to traditional star shows. A Green Energy exhibit on the Museum’s upper level and plans for a scale model Solar System Trail to open in the spring in the woods behind the museum, extend science education to include good stewardship of our planet. The Discovery Museum and Planetarium – History and Timeline 1936: Our roots go back to Oct 31, 1936, when 40 women, headed by Mrs. Henry D. Bradley, began planning for a children’s museum of American history, travel, art, industry, science and nature for Bridgeport. 1937: The museum opened in Bridgeport’s Black Rock Library basement. 1950: Activities were moved to Bridgeport’s North End Library basement. 1952 : Wonder Workshop was created using “experimental” educational techniques: interdisciplinary teaching! 1958: The Junior League of Eastern Fairfield County founded the Museum of Arts , Science Industry (MASI) to create a permanent facility. Bridgeport area industrial leaders, headed by William Simpson, played significant roles in the development and construction of the museum, which was the only non-historical museum in the greater Bridgeport area. 10 acres of “90 Acres Park” on Park Avenue were leased from the city for 100 years. 1960: Captain John Brooks House , the oldest house in Bridgeport, was donated and moved to museum grounds. A museum design by John Johansen, a member of “The Harvard Five”, was approved. 1962: The main building opened on January 21 st , with exhibits in industry, physical and natural science, as well as art. The museum’s new planetarium was ranked as one of the 12 major planetarium facilities in the nation. 1960s: Schools began to use the museum extensively both for its exhibits and the Wonder Workshop. 1976: The planetarium was renamed the Henry B. duPont III Planetarium to honor him. 1985: Recognizing the regional movement from industry to technology, the museum’s Board of Trustees redefined its mission to include the development of a technologically competent workforce. Exhibits moved away from natural science, expanded in the physical sciences, and added technology. 1985: The first interactive exhibits were installed. Attendance nearly doubled. 1987: A State of Connecticut grant funded a state-of-the-art Spitz System 512 planetarium instrument. 1988: The “Wonder Workshop” building was added. 1990: MASI became the Discovery Museum , reflecting a commitment to “hands-on” experiences and participatory education. An interactive science floor opened with over 100 hands-on exhibits. 1991: The museum’s Challenger Learning Center opened. It was the first in the Northeast, and the sixth in the country. 1992: The museum opened an Interactive Art Gallery, the first in the U.S. 1993: The Entrance Lobby was completed. 1995: The Norma Pfriem Dining Court, kitchen and classroom wing were added. 1997: The street and landscape program were completed on Park Avenue. 1999: Soundview Community Media public access station was created as an affiliate of the Discovery Museum. 2000: The museum’s new strategic plan called for a focus on science technology. 2001: The board of trustees decided to further focus the museum’s efforts on science and technology and adopted its current mission: “to educate, excite and engage visitors in the exploration of science, technology, and ideas through interactive experiences that promote new insights.” Discovery Museum’s first major traveling science exhibit, Hubble Space Telescope, opened in December, beginning the tradition of hosting three traveling science exhibits each year. 2002: The museum opened the region’s first high-definition CineMuse Theater. 2003: With the new focus on science the Wonder Workshop closed. 2004: Governor John Rowland announced substantial funding for The Discovery Museum as part of the state’s continued focus on advancing math and science education. 2007: Museum closed for one month for major renovations to the roof and HVAC system. 2008: Discovery Museum classrooms were upgraded with Smart Boards. The Museum was reintroduced as Southwestern Connecticut’s main resource for technology education through five week long “Digital Discovery” events. Henry B. duPont III Planetarium was outfitted with full dome digital planetarium equipment through the Norma Pfriem Foundation. 2009: Ground was broken for The Discovery Magnet School, a regional science magnet school due to open in January of 2011. A powerful new sound system was installed in the Henry B. duPont III Planetarium through the Leslie Birkmaier Fund. http://www.discoverymuseum.org/about/about/history.html Education Programs The Discovery Museum – Where Minds Soar! The Education Department at The Discovery Museum consists of scientists, educators and subject-matter experts. The one thing they all have in common is a love of science and the desire to excite young minds and inspire children to explore the world around them. Discovery’s education department offers classes and demonstrations, both at the museum and on an outreach basis. http://www.discoverymuseum.org/ed/education.html
康州 Discovery Museum and Planetarium 掠影（一）（ 2010 年 12 月 19 日） 黄安年文 黄安年的博客 /2011 年12 月4 日 ( 美东时间 ) 发布 康州 Discovery Museum and Planetarium 是普及科学和天文知识的课堂 , 深受孩子们的喜爱。 2010 年 12 月 19 日，两个外孙来到这里参观。照片（一） 25 张 , （二） 23 张 , 是当日拍摄的。 ******************8 About The Discovery Museum and Planetarium The Discovery Museum functions as both a tourist attraction featuring science and space science exhibits and as an informal science education center. Through its exhibits , it enhances public understanding of science and technology by providing fun, instructive experiences that encourage participant interaction. As an informal science education center, it provides an extensive range of educational programs in science and technology and in the area where the two disciplines interact. Nearly 55,000 children participate in the museum’s science programs and outreach activities each year. The Discovery Museum’s 20,000 square foot facility includes changing and permanent interactive exhibit galleries, a 124 seat planetarium , Connecticut’s only Challenger Learning Center , an 80 seat auditorium, and five multi-purpose classrooms where hands-on science classes are conducted for schools, groups and the general public. Permanent exhibits include Green Energy, Sound, Light and Space Galleries and a simulated Moon Base Discovery play area for very young visitors. The recently upgraded Henry B. duPont III Planetarium offers traditional star shows and fulldome digital planetarium shows daily for both very young children and for ages 8 and up. The Discovery Museum, Inc. is an independent 501(c) 3 organization operated by a Board of Trustees. It is not affiliated with any government entity. It is located at 4450 Park Avenue, Bridgeport, CT, one mile south of Merritt Parkway Exit 47. http://www.discoverymuseum.org/about/about.html History of The Discovery Museum and Planetarium The Museum was founded in 1958 and opened to the public in 1962 as The Museum of Art Science and Industry. “M.A.S.I.” was the only non-historical, multi-disciplinary museum in the Greater Bridgeport area. Early exhibits ranged from the natural and physical sciences to decorative and fine arts. In 1985, recognizing the regional movement from industry to technology that occurred in the 70’s and 80’s, the museum’s Board of Trustees redefined the mission of the Museum to focus on two distinct areas: Science and Art. A master plan was developed which included the renovation of the facility, installation of interactive science exhibits, and improved gallery space. Exhibits moved away from natural science, expanded in the physical sciences, and added technology. In direct response to the pleas of educators who expressed the need for assistance in teaching the physical sciences, the museum developed a science curriculum that met the standards of the CT State Department of Education. In 1990 MASI became The Discovery Museum, reflecting a commitment to “hands-on” experiences and participatory education. In 1991 with the help of area corporations and the State of Connecticut, the Challenger Learning Center was installed as the only center of its kind within New England and the 6th nationwide. In 2000 the museum’s strategic plan called for a focus on science technology. In 2001, the Board of Trustees further focused the institution’s efforts on science and technology by adopting the current mission: “to educate, excite, and engage visitors in the exploration of science, technology, and ideas through interactive experiences that promote new insights.” In December of 2001, the museum established the practice of hosting traveling, hands-on science exhibitions three times a year. In 2004 Governor John Rowland announced substantial funding for The Discovery Museum as part of the state’s continued focus on advancing math and science education. In September 2009 ground was broken adjacent to the museum for a regional science magnet school which will share the name “Discovery”. It is scheduled to open in January of 2011. The Discovery Magnet School will collaborate with museum educators and Sacred Heart University to teach students, utilizing the hands-on scientific method long embraced by the museum. The school is expected to become a national model. 2010 Visiting Exhibits in the main level galleries continue to incorporate engaging, hands-on, interactive science experiences. The museum’s educational programs remain focused on the physical sciences and space science and reach more than 40,000 students each year. The Museum’s lower level is now a Space Gallery and includes a permanent live feed exhibit from the Space Telescope Institute. The Henry B. duPont III Planetarium presents entertaining and educational, full-dome, digital planetarium shows in addition to traditional star shows. A Green Energy exhibit on the Museum’s upper level and plans for a scale model Solar System Trail to open in the spring in the woods behind the museum, extend science education to include good stewardship of our planet. The Discovery Museum and Planetarium – History and Timeline 1936: Our roots go back to Oct 31, 1936, when 40 women, headed by Mrs. Henry D. Bradley, began planning for a children’s museum of American history, travel, art, industry, science and nature for Bridgeport. 1937: The museum opened in Bridgeport’s Black Rock Library basement. 1950: Activities were moved to Bridgeport’s North End Library basement. 1952 : Wonder Workshop was created using “experimental” educational techniques: interdisciplinary teaching! 1958: The Junior League of Eastern Fairfield County founded the Museum of Arts , Science Industry (MASI) to create a permanent facility. Bridgeport area industrial leaders, headed by William Simpson, played significant roles in the development and construction of the museum, which was the only non-historical museum in the greater Bridgeport area. 10 acres of “90 Acres Park” on Park Avenue were leased from the city for 100 years. 1960: Captain John Brooks House , the oldest house in Bridgeport, was donated and moved to museum grounds. A museum design by John Johansen, a member of “The Harvard Five”, was approved. 1962: The main building opened on January 21 st , with exhibits in industry, physical and natural science, as well as art. The museum’s new planetarium was ranked as one of the 12 major planetarium facilities in the nation. 1960s: Schools began to use the museum extensively both for its exhibits and the Wonder Workshop. 1976: The planetarium was renamed the Henry B. duPont III Planetarium to honor him. 1985: Recognizing the regional movement from industry to technology, the museum’s Board of Trustees redefined its mission to include the development of a technologically competent workforce. Exhibits moved away from natural science, expanded in the physical sciences, and added technology. 1985: The first interactive exhibits were installed. Attendance nearly doubled. 1987: A State of Connecticut grant funded a state-of-the-art Spitz System 512 planetarium instrument. 1988: The “Wonder Workshop” building was added. 1990: MASI became the Discovery Museum , reflecting a commitment to “hands-on” experiences and participatory education. An interactive science floor opened with over 100 hands-on exhibits. 1991: The museum’s Challenger Learning Center opened. It was the first in the Northeast, and the sixth in the country. 1992: The museum opened an Interactive Art Gallery, the first in the U.S. 1993: The Entrance Lobby was completed. 1995: The Norma Pfriem Dining Court, kitchen and classroom wing were added. 1997: The street and landscape program were completed on Park Avenue. 1999: Soundview Community Media public access station was created as an affiliate of the Discovery Museum. 2000: The museum’s new strategic plan called for a focus on science technology. 2001: The board of trustees decided to further focus the museum’s efforts on science and technology and adopted its current mission: “to educate, excite and engage visitors in the exploration of science, technology, and ideas through interactive experiences that promote new insights.” Discovery Museum’s first major traveling science exhibit, Hubble Space Telescope, opened in December, beginning the tradition of hosting three traveling science exhibits each year. 2002: The museum opened the region’s first high-definition CineMuse Theater. 2003: With the new focus on science the Wonder Workshop closed. 2004: Governor John Rowland announced substantial funding for The Discovery Museum as part of the state’s continued focus on advancing math and science education. 2007: Museum closed for one month for major renovations to the roof and HVAC system. 2008: Discovery Museum classrooms were upgraded with Smart Boards. The Museum was reintroduced as Southwestern Connecticut’s main resource for technology education through five week long “Digital Discovery” events. Henry B. duPont III Planetarium was outfitted with full dome digital planetarium equipment through the Norma Pfriem Foundation. 2009: Ground was broken for The Discovery Magnet School, a regional science magnet school due to open in January of 2011. A powerful new sound system was installed in the Henry B. duPont III Planetarium through the Leslie Birkmaier Fund. http://www.discoverymuseum.org/about/about/history.html Education Programs The Discovery Museum – Where Minds Soar! The Education Department at The Discovery Museum consists of scientists, educators and subject-matter experts. The one thing they all have in common is a love of science and the desire to excite young minds and inspire children to explore the world around them. Discovery’s education department offers classes and demonstrations, both at the museum and on an outreach basis. http://www.discoverymuseum.org/ed/education.html
以色列理工学院（Israel Institute of Technology in Haifa）的化学家Daniel Shechtman因为“准晶体”的发现获得2011年诺贝尔化学奖（for the discovery of quasicrystals） 准晶体 以色列化学家Daniel Shechtman 来个潇洒点的 “准晶体”曾经遭人嘲笑
NTCIR-9 Cross-lingual Link Discovery Task http://ntcir.nii.ac.jp/CrossLink ############################################################ Introduction: Cross-lingual link discovery (CLLD) is a way of automatically finding potential linking between isolated documents in different languages. It is not very dissimilar from traditional cross-lingual information retrieval (CLIR) because CLIR can be viewed as a process of creating a virtual link between the provided cross-lingual query and the retrieved documents; on the other hand, CLLD recommends a set of meaningful anchors actively in the source document and use them as queries with the contextual information from the text to establish actual linking with documents in other languages. Wikipedia is an online multilingual encyclopaedia that contains enormous articles covering most written languages in this planet and so includes extensive hypertext links between documents of same language for easy reading and referencing. However, the pages in different languages are rarely interrelated except for the cross-lingual link between pages about the same subject. This could pose serious difficulties for users who try to seek information or knowledge from different lingual sources. Therefore, cross-lingual link discovery tries to break the language barrier in knowledge sharing. With CLLD users are allowed to discover documents in languages which they either are familiar with (or not), or which have a richer set of documents than in their language of choice. For English there are several link discovery tools, which assist topic curators in discovering prospective anchors and targets for a given document. No such tools yet exist, that support the cross linking of documents from multiple languages. This task aims to incubate the technologies assisting CLLD and enhance the user experience in viewing or editing documents in cross-lingual manner. The language difference, ambiguities and other language issues such as Chinese segmentation could all make this task even more challenging. Researchers who interest in cross-lingual link discovery are all welcome to join us. Particularly, researchers from either CLIR or link discovery community are encouraged to participate in this exciting task. To participate, please visit the registration pages: http://research.nii.ac.jp/ntcir/ntcir-9/howto.html , also you will have to sign a user agreement form - details will be announced from NII later Task Definition: Generally, the link between documents can be classified as either outgoing or incoming, but in this task we mainly focus on the outgoing link starting from English source documents and being pointed to Chinese, Korean, and Japanese target documents. The whole CLLD task is comprised of following three subtasks: * English to Chinese CLLD * English to Japanese CLLD * English to Korean CLLD Participants can choose one or more of the above three subtasks to participate in. The English topics and the target corpus consist of actual Wikipedia pages in xml format with rich structured information. To submit a run, participants are required to choose the most suitable anchors from the topic document, and for each anchor identify the most suitable documents in the test corpus. For each topic we will allow up to 50 anchors, each with up to 5 targets may, so there is a total of 250 outgoing links per topic. Topic and Document Collections: Two sets of 25 articles chosen from the English Wikipedia will be used as topics for the uses of creating dry run and formal run separately. These topics will be orphaned by removing all links to then (from the collection) and from them (to the collection). The corresponding pages in Chinese, Japanese and Korean will also be removed from those collections. The training and test collections for the three subtasks are exactly the same. The collections are formed by search engine friendly xml files created from Wikipedia mysql database dumps taken on June 2010. The details of the collections are given as following (the language of the corpus, the number of articles, the size of the corpus, and date of dump): Chinese 318,736 2.7G 27/06/2010 Japanese 716,088 6.1G 24/06/2010 Korean 201,596 1.2G 28/06/2010 Assessment and Evaluation: There will be two types of assessments: automatic assessment using the Wikipedia ground truth (existing cross-lingual links); and manual assessment done by human assessors. For the latter, all submissions will be pooled and a GUI tool for efficient assessment will be used. In manual assessment, either the anchor candidate or the target link could be identified relevant (or non-relevant). Once the anchor candidate is assessed as non-relevant, all anchors and associated links inside this anchor will become non-relevant. After the assessment, the performance of cross-lingual link discovery system then will be evaluated using Precision, Recall and Mean Average Precision metrics. FOR MORE DETAILS: Please visit http://ntcir.nii.ac.jp/CrossLink Please also note that the registration deadline is December 20, 2010 (for all NTCIR-9 tasks). ORGANIZERS: Shlomo Geva, Queensland University of Technology, Australia Andrew Trotman, University of Otago, New Zealand Yue Xu, Queensland University of Technology, Australia Eric Tang, Queensland University of Technology, Australia Darren Huang, Queensland University of Technology, Australia If you have any questions, please contact Eric Tang ( l4.tang@qut.edu.au ) or send an email to the task mailing list: crosslink@lists.otago.ac.nz
NATURE REVIEWS DRUG DISCOVERY November 2010 Volume 9 Number 11 Visit Nature Reviews Drug Discovery online to browse the journal. Now available at http://links.ealert.nature.com/ctt?kn=19m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 Please note that you need to be a subscriber to enjoy full text access to Nature Reviews Drug Discovery online. To purchase a subscription, please visit: http://links.ealert.nature.com/ctt?kn=82m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 Alternatively, to recommend a subscription to your library, please visit http://links.ealert.nature.com/ctt?kn=44m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 ********************************************************************* Nature Reviews Drug Discovery Impact Factor: 29.059* (*Journal Citation Reports, Thomson, 2009) ********************************************************************* =========================== ADVERTISEMENT =========================== ACQUITY UPLC H-Class Bio System: Ready for your biomolecular analysis Engineered with a bio-inert flow path made of non-stainless-steel materials, the ACQUITY UPLC H-Class Bio System keeps large molecules intact and on the move, for better sample recovery and no carryover, whether the chromatographic mode you're using is reversed phase (RP), ion exchange (IEX), size exclusion (SEC), or hydrophilic interaction (HILIC). Learn more http://links.ealert.nature.com/ctt?kn=79m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 =========================== ADVERTISEMENT =========================== Find over 5,000 vacancies across scientific disciplines as well as the latest job market news, career advice and more, only at... naturejobs.com http://links.ealert.nature.com/ctt?kn=42m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 ATTENTION EMPLOYERS! Stay up to date with Naturejobs advertising deadlines and upcoming features: http://links.ealert.nature.com/ctt?kn=122m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 or telephone: US: + 1 800 989 7718 EUR: +44 (0) 20 7843 4961 =========================== ADVERTISEMENT =========================== BioPharma Dealmakers Science, strategy innovation Recent content exclusively made freely available to you from Nature Biotechnology, Nature Reviews Drug Discovery and Nature Medicine Produced with support from TVG Sign up to receive this new bi-weekly newsletter today: http://links.ealert.nature.com/ctt?kn=84m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 =========================== ADVERTISEMENT =========================== BIOPARTNERING Visit our Biopartnering site to view Company Profiles and Partnership Opportunities: http://links.ealert.nature.com/ctt?kn=120m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 =========================== ADVERTISEMENT =========================== Personalized Medicine: Principles to Practice March 1, 2011 Dallas, TX, USA This symposium brings together leaders in the field to address key aspects of the science of therapeutic individualization, the enabling technologies underpinning this biomedical revolution, and the evolution in policies that will advance personalized medicine principles into healthcare management tools for individuals and populations. http://links.ealert.nature.com/ctt?kn=60m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 ===================================================================== This month's FEATURED article: The importance of new companies for drug discovery: origins of a decade of new drugs Robert Kneller p867 | doi:10.1038/nrd3251 http://links.ealert.nature.com/ctt?kn=91m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 ===================================================================== In this issue p821 | doi:10.1038/nrd3314 http://links.ealert.nature.com/ctt?kn=10m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 Comment: Accelerating the pulse of cardiovascular RD Andrew Plump p823 | doi:10.1038/nrd3315 Abstract: http://links.ealert.nature.com/ctt?kn=46m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 Article: http://links.ealert.nature.com/ctt?kn=13m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 ---------------------- NEWS AND ANALYSIS ---------------------- Modifying protein misfolding Dan Jones p825 | doi:10.1038/nrd3316 Two recent deals highlight growing interest in therapeutically targeting protein misfolding to treat both rare and common diseases. http://links.ealert.nature.com/ctt?kn=22m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 NEWS IN BRIEF Regulators restrict Avandia in the US and suspend it in the EU | First oral drug approved for multiple sclerosis in the US | Antibody-drug conjugates hit the headlines | Lasker awards go to obesity and VEGF researchers | Johnson Johnson bids to acquire vaccine firm Crucell | Embryonic stem cell trial begins p828 | doi:10.1038/nrd3317 http://links.ealert.nature.com/ctt?kn=47m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 BIOBUSINESS BRIEFS Deal watch: Acceleron and Shire to target the activin receptor pathway for muscular disorders p830 | doi:10.1038/nrd3308 http://links.ealert.nature.com/ctt?kn=113m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 Trial watch: Somatostatin analogue shows promise in Cushing's disease p830 | doi:10.1038/nrd3309 http://links.ealert.nature.com/ctt?kn=116m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 Deal watch: Co-promotion deals: panacea or poison pill? Nigel Borshell and Tibor Papp p831 | doi:10.1038/nrd3310 http://links.ealert.nature.com/ctt?kn=118m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 PATENT WATCH Triggering generics market exclusivity | Lead compounds not based on structure alone | Sphingosine 1-phosphate Charlotte Harrison p832 | doi:10.1038/nrd3312 http://links.ealert.nature.com/ctt?kn=50m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 AN AUDIENCE WITH Patrick Vallance p834 | doi:10.1038/nrd3307 The Senior Vice President of Medicines Discovery and Development at GlaxoSmithKline discusses the rationale for the recent evolution of the company's research and development strategy. http://links.ealert.nature.com/ctt?kn=111m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 FROM THE ANALYST'S COUCH Location of pharmaceutical innovation: 2000-2009 Yali Friedman p835 | doi:10.1038/nrd3298 http://links.ealert.nature.com/ctt?kn=102m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 FRESH FROM THE PIPELINE Velaglucerase alfa Johannes M. F. G. Aerts, Uma Yasothan and Peter Kirkpatrick p837 | doi:10.1038/nrd3311 http://links.ealert.nature.com/ctt?kn=100m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 ---------------------- RESEARCH HIGHLIGHTS ---------------------- Analgesics: Pain control at the periphery p839 | doi:10.1038/nrd3300 http://links.ealert.nature.com/ctt?kn=93m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 Inflammatory disorders: Constraining the complement cascade p840 | doi:10.1038/nrd3302 http://links.ealert.nature.com/ctt?kn=97m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 Fibrotic disease: Targeting the microenvironment p840 | doi:10.1038/nrd3303 http://links.ealert.nature.com/ctt?kn=95m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 Cancer: Targeting mutant BRAF in metastatic melanoma p841 | doi:10.1038/nrd3304 http://links.ealert.nature.com/ctt?kn=39m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 Antimalarial drugs: Speeding to a new lead p842 | doi:10.1038/nrd3301 http://links.ealert.nature.com/ctt?kn=41m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 IN BRIEF Pulmonary disorders | Anticancer drugs | Biotechnology | Neuordegenerative disease p842 | doi:10.1038/nrd3305 http://links.ealert.nature.com/ctt?kn=51m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 ---------------------- PERSPECTIVES ---------------------- OPINION Utilizing targeted cancer therapeutic agents in combination: novel approaches and urgent requirements Shivanni Kummar, Helen X. Chen, John Wright, Susan Holbeck, Myrtle Davis Millin, Joseph Tomaszewski, James Zweibel, Jerry Collins and James H. Doroshow p843 | doi:10.1038/nrd3216 Developing optimal combination strategies for molecularly targeted anticancer drugs is substantially more complex than for traditional chemotherapies. Here, Doroshow and colleagues discuss the lessons learned from the evaluation of combinations of molecularly targeted anticancer agents by the US National Cancer Institute (NCI), and highlight several new approaches that the NCI has initiated to improve the effectiveness of such combinations. Abstract: http://links.ealert.nature.com/ctt?kn=52m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 Article: http://links.ealert.nature.com/ctt?kn=32m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 OPINION Developing drug prototypes: pharmacology replaces safety and tolerability? Adam F. Cohen p856 | doi:10.1038/nrd3227 Currently, drug development is based on a consecutive phase model and Phase I clinical trials often have tolerability as their primary objective. Here, Cohen advocates new concepts for drug development that are based on pharmacological knowledge about the effects of the drug and an adaptive, cyclical development process. Abstract: http://links.ealert.nature.com/ctt?kn=53m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 Article: http://links.ealert.nature.com/ctt?kn=23m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 ---------------------- ANALYSIS ---------------------- The importance of new companies for drug discovery: origins of a decade of new drugs Robert Kneller p867 | doi:10.1038/nrd3251 Understanding the factors that promote drug innovation is important both for improvements in health care and the future of organizations engaged in the field. To investigate these factors, Kneller identifies the inventors of 252 new drugs approved by the US Food and Drug Administration from 1998 to 2007 and their places of work, and classifies these drugs according to innovativeness. This article presents a comprehensive analysis of these data, which highlight the strong contribution of biotechnology companies, particularly in the United States, to innovative drug discovery, and discusses potential contributing factors to the trends observed. Abstract: http://links.ealert.nature.com/ctt?kn=91m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 Article: http://links.ealert.nature.com/ctt?kn=5m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 ---------------------- REVIEW ---------------------- Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis Volker Brinkmann, Andreas Billich, Thomas Baumruker, Peter Heining, Robert Schmouder, Gordon Francis, Shreeram Aradhye and Pascale Burtin p883 | doi:10.1038/nrd3248 In September 2010, fingolimod (FTY720/Gilenya; Novartis) became the first oral disease-modifying therapy to be approved by the US Food and Drug Administration for relapsing-emitting multiple sclerosis. Brinkmann and colleagues describe its discovery and development, and how elucidation of its effects on sphingosine 1-phosphate receptors has improved the understanding of the biology of these receptors. Abstract: http://links.ealert.nature.com/ctt?kn=54m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 Article: http://links.ealert.nature.com/ctt?kn=1m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 ---------------------- CORRESPONDENCE ---------------------- Correspondence: Understanding transport through pharmacological barriers - are we there yet? Balazs Sarkadi and Gergely Szakacs p897 | doi:10.1038/nrd3187-c1 http://links.ealert.nature.com/ctt?kn=63m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 Corrigendum: Microtubule-binding agents: a dynamic field of cancer therapeutics Charles Dumontet and Mary Ann Jordan p897 | doi:10.1038/nrd3313 http://links.ealert.nature.com/ctt?kn=57m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 =========================== ADVERTISEMENT =========================== The Natureevents Directory 2011 http://links.ealert.nature.com/ctt?kn=81m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 Inform a potential 1 million scientists about your scientific events. Contact us now to be included in the 12th edition of the Natureevents directory: mailto:c.paulsen@us.nature.com T: +1 202 626 2522 ===================================================================== You have been sent this Table of Contents Alert because you have opted in to receive it. You can change or discontinue your e-mail alerts at any time, by modifying your preferences on your nature.com account at: http://links.ealert.nature.com/ctt?kn=43m=35933506r=NDU1MzI2NDExMwS2b=2j=ODUzNDU0OTQS1mt=1rt=0 (You will need to log in to be recognised as a nature.com registrant). For further technical assistance, please contact our registration department: registration@nature.com For print subscription enquiries, please contact our subscription department: subscriptions@nature.com For other enquiries, please contact our customer feedback department: feedback@nature.com Nature Publishing Group | 75 Varick Street, 9th Floor | New York | NY 10013-1917 | USA Nature Publishing Group's worldwide offices: London - Paris - Munich - New Delhi - Tokyo - Melbourne - San Diego - San Francisco - Washington - New York - Boston Macmillan Publishers Limited is a company incorporated in England and Wales under company number 785998 and whose registered office is located at Brunel Road, Houndmills, Basingstoke, Hampshire RG21 6XS. (c) Copyright 2010 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.
The Insiders* download: The Discovery of Artemisinin in China Since the fact that malarial parasites were resistant to frequently used antimalarials, in Vietnam War which started in 1964, the number of soldiers died of drug-resistant falciparum malaria was much higher than that of casualties from both combating sides. The then Leadership of Vietnam asked for help from China. The authorized “523 Leading Group” (523领导小组) was inaugurated on May 23rd in 1967 which was sponsored by a consortium among the General Logistics Department of the Chinese People’s Liberation Army(中国人民解放军总后勤部), the State Science and Technology Commission of China(国家科学技术委员会), Ministry of Public Health of PRC(中华人民共和国卫生部), Ministry of Chemical Industry of PRC(中华人民共和国化工部), Commission of Science and Technology for National Defence(国防科委), Chinese Academy of Sciences(中国科学院) and General Pharmaceutical Industry Corporation (医药工业总公司). The project was named “523 Project”(523项目) ,which was supervised by the “523 Leading Group”（523领导小组）and was kindly concerned by the late premier Zhou En Lai. Even though it was at the time of “Cultural Revolution”, and normal working routines were severely interfered, the authorized “523 Leading Group” could still mobilize around five hundred scientific workers of different specialities from sixty-some institutions of the whole country, to form a closely related, united, well organized and versatile scientific troupe, which was supported by groups of various disciplines with most advanced equipments at hand. The main task of “523 Project” was: to seek new antimalarials for the prevention and treatment of drug-resistant falciparum malaria in tropical area. The “General Leading Office of 523 Project” (全国五二三办公室)suggested the screening of new drugs to start from two aspects, one was synthesis of new drugs, and the other was investigation of anti-malarial drugs frequently used in traditional Chinese medicine and folklore medicine. Thus, two cooperative groups of the two aspects were established respectively. The Traditional Chinese Medicine and Folklore Medicine Group(TCMFM Group)(中医中药专业组) was one of the two groups, the main task of this group was attempting to search for the required new antimalarials from the traditional Chinese medicine or folklore medicine. This was the historical background and organization of the scientific troupe leading to the discovery of Qinghaosu (Artemisinin)( Zhang Jianfang, A Detailed Chronological Record of Project 523 and the Discovery and Development of Qinghaosu (Artemisinin),Yangcheng Evening News Publisher, 2006. (Hereafter it is abbreviated as “Zhang Jianfang, “Chronological Record of Project 523”) p.5-11.) Unlike the discovery of ordinary natural products, the discovery of Qinghaosu is meaningful because it is a new type of antimalarial, its novel chemical structure brings about its advantage of unique antimalarial efficacy without drug-resistance. In early 70s of last century, it happened that both Chinese and then Yugoslavian scientists had been engaged in the studies of natural products in Artemisia annua L. , and discovered the compound with the same molecular formula C15H22O5 and molecular weight, but the then Yugoslavian scientists gave an incorrect chemical structure to the compound (Jeremic, D., Jokic, A. and Stefanovic, M., New Type of Sesquiterpenen Lactone isolated from Artemisia annua L.– Ozonide of Dihydroarteannuin, presented at the 8th Int. Symp on Chemistry of Natural Products, New Delhi (1972) 222 (Posted by Gong Wai Lihm 江威廉on http://panyutiger.blogspot.com/ at the time of May 3, 2008)). Actually, Artemisia annua L.（黄花蒿，huanghuahao）is the plant which the Chinese antimalarial herbal drug named Qinghao(青蒿) originates from. Owing at the time of “Cultural Revolution”, Chinese scientists could not get any scientific information published outside China, they knew nothing about what was going on in then Yugoslavia. In 1986, one of the then Yugoslavian scientists visited China, he said, “Even if we gave a correct chemical structure to the compound, we could never develop the compound as an antimalarial”, because they do not have the knowledge of using Artemisia annua L. in the treatment of malaria in Yugoslavia. So it is Chinese scientists who not only discovered a new natural product and gave it a correct chemical structure, more important is, based on the experience of traditional Chinese medicine in treatment of malaria, they discovered a new type of antimalarial as well. So we emphasize that the discovery of Qinghaosu (Artemisinin) should not be credited only to the person who first isolated the compound as people ordinarily do for the discovery of natural products. People who are engaged in the investigation and evaluation of the history of discovery of Qinghaosu should not only concern about who is the first person who isolated this natural compound, but also those persons who had made contribution to the elucidation of the chemical structure of the compound and the demonstration of the unique antimalarial efficacy of this antimalarial through clinical trials should also be concerned about. (I) Discovery of the new antimalarial Qinghaosu in China In 1969, Institute of Chinese Materia Medica (ICMM), Academy of Traditional Chinese Medicine (ATCM) under Ministry of Public Health(卫生部中医研究院中药研究所) in Beijing was invited by the “ General Leading Office of 523 Project” to join in TCMFM Group . Tu Youyou(屠呦呦) was designated by ICMM under ATCM as the team leader of “523 research team” in Department of Chemistry, and Yu Yagang(余亚纲) was the team member. Tu Youyou began her work at the research of pepper extract, and study on it’s anti-malarial action was carried out in Academy of Military Medical Science of Chinese PLA (AMMS)(中国人民解放军军事医学科学院) , but due to its ineffectiveness the work stopped (Zhang Jianfang, “Chronological Record of Project 523”，p.16). In 1970, Tu Youyou was asked to join in certain personnel investigation and left Yu Yagang alone. In the same year, “General Leading Office of 523 Project” dispatched Gu Guoming (顾国明) of AMMS to ICMM and worked cooperatively with Yu Yagang. They started to collect the prescriptions and single drugs of traditional and folklore medicines used in treatment of malaria. The investigation showed that the most frequently used traditional herbal drugs for treatment of malaria was Qinghao(青蒿). Yu Yagang and Gu Guoming prepared the ethyl alcohol extract from Qinghao, which was available in Beijing drug market and known as the arial part of the plant of “Huanghuahao” (植物黄花蒿, Artemisia annua L.), the animal experiment was carried out by scientists in AMMS, the results showed that the inhibition rate for parasites in mice was 60-80%（Zhang Jianfang, “Chronological Record of Project 523”，p.16）, and according to an insider it had been as high as 90%. Since Tu Youyou did not work with them, Yu Yagang reported the results to the team leader Tu Youyou and the director of ICMM. Later, Yu Yagang was asked to leave Beijing to join in another project , so Gu Guoming was back to AMMS. This arrangement caused the suspension of Yu Yagang and Gu Guoming’s work , which had not been thoroughly studied. In 1971, Tu Youyou returned to the team, and worked with team member Zhong Yurong (钟裕蓉). Lang Lingfu(郎林福) joined the team, and was responsible for testing inhibition rate for parasites in animals. They gave up the pepper research and started to reproduce Yu Yagang and Gu Guoming’s work, but the inhibition rates for parasites in mice of extracts from Qinghao were fluctuating. In comparison with different extraction methods, Tu Youyou got the clue from using of fresh juice of Qinghao, which was described by Ge Hong(葛洪，281-341A.D.) in his “A Handbook of Prescriptions for Emergencies”（《肘后备急方》）, so she modified the extraction procedure at low temperature, when they found the inhibition rate for parasites in mice of ethyl alcohol extract, which was prepared by infusion and concentrated at low temperature, was as high as 95%（Tu Youyou, “qinghao ji qinghaosulei yaowu”, Printing House of Chemical Industry, 2009.01 （Hereafter it is abbreviated as Tu Youyou ,“qinghao ji qinghaosulei yaowu”）, p.35）. Later they found that the neutral portion of the ether extract was even more effective, the inhibition rates for parasites in mice and in monkey were as good as 100%, and the results were reproducible, it was in October ,1971（Tu Youyou, “qinghao ji qinghaosulei yaowu”, “discovery of qinghaosu” and p.34-36）. In March 1972, Tu Youyou as a representative of ICMM under ATCM, reported the above results at the TCMFM Group meeting held by the “General Leading Office of 523 Project” in Nanjing . The report drew the attention of people who attended the meeting. On knowing the experience from ICMM under ATCM, people in Institute of Drug Research in Yunnan Province (Yunnan IDR)(云南省药物研究所) and Institute of Traditional Chinese Medicine in Shangdong Province (Shangdong ITCM)(山东省中医药研究所), who also joined in the “523 Project”, tried to get the active ingredient by using their local plant resources respectively. Between August and October of 1972, after finishing study on preclinical toxicity and oral administration of the ether extract-neutral portion in some healthy volunteer subjects, ICMM carried out the clinical trial of ether extract-neutral portion in 9 falciparum and 12 vivax malaria patients in Changjiang, Hainan (海南昌江), Tu Youyou joined this clinical trial (Tu Youyou, “qinghao ji qinghaosulei yaowu”, p.39-41) . Under the coordination of “General Leading Office of 523 Project”, 302 Hospital of PLA in Beijing also carried out the clinical trial of the ether extract-neutral portion in 9 vivax patients. All together 30 cases (20 cases of vivax and 10 cases of falciparum malaria patients) were observed. In her book, Tu Youyou described all these 30 cases were cured or effective (Tu Youyou “qinghao ji qinghaosulei yaowu” .p.38-39), but according to the original clinical report, among the 9 falciparum malaria patients, 7 of them were effective and 2 of them failed（523 clinical trial group of ICMM under ATCM, Clinical Summary Report of 91＃(cf Zhang Jianfang,“Chronological Record of Project 523”，p.17 and Note 13). These good antimalarial results in animal experiments and clinical trials of the ether extract –neutral portion of Qinghao which were achieved by Tu Youyou’s research team, were really an important step leading to the discovery of Qinghaosu. Ni Muyun(倪慕云) joined in Tu Youyou’s team, she designed the pre-column treatment of the ether extract-neutral portion of Qinghao, i.e., mixed the ether extract-neutral portion with polyamide, then percolated with 47% ethyl alcohol. After concentration of this ethyl alcohol solution, it was again extracted by ether, the antimalarial effectiveness of this ether extract was further improved. It was attempted to make further separation by aluminium oxide column chromatography, but failed to get any solid substance. In December, near the end of 1972(Zhang Jianfang,“Chronological Record of Project 523”，p.18; Institute of Chinese Materia Medica under ATCM, “zhongyao qinghao de kangnue yanjiu”, “preface” ), Zhong Yurong and her assistant Cui Shulian (崔淑莲) used the pre-column treatment developed by Ni Muyun, and considered they had better use silica gel column chromatography instead of aluminium oxide for isolation of neutral substances, and used petroleum and ethyl acetate-petroleum solvent as eluent for gradient elution. The primarily eluated crystal in square-shape was high in content, and was named “crystal I “, the secondly eluated crystal in needle–shape was low in content, and was named “crystal II”, which was followed by another needle-shaped crystal named “crystal III”. After testing their inhibition rates for parasites in mice, “crystal II” was the only substance confirmed as the antimalarial entity of Qinghao. According to their report written later to the “General Leading Office of 523 Project”, they named this “crystal II”（结晶II） as “Qinghaosu II”(青蒿素II). The time of discovery of “crystal II” (or “Qinghaosu II”) by Zhong Yurong was near the end of the year 1972, Tu Youyou was not in Beijing then, and Ni Muyun was the acting team leader. The experience of traditional Chinese medicine in treatment of malaria leads to the key step taken by Yu Yagang and Gu Guomung. As the second step, based on Yu and Gu’s experiment, Tu Youyou and Zhong Yurong found the neutral portion of the ether extract of Qinghao, and demonstrated its antimalarial effect in treatment of both vivax and falciparum malaria. As the most important third step, based on the purification of the neutral portion of ether extract of Qinghao done by Ni Muyun, Zhong Yurong finally isolated the antimalarial “Qinghaosu II” by using silica gel chromatography. They are all who have made contribution to the discovery of the new antimalarial “Qinghaosu”. In the 70’s of last century, most people in ICMM knew this story very well. Being a team leader, Tu Youyou never mentioned about the story of discovery of “Qinghaosu II” to outsiders. Outsiders only knew that Tu Youyou was the person who discovered Qinghaosu, because she was the team leader, the main person who discovered the active extract portion from ether extract, the representative of ICMM under ATCM to take part in the nation-wide meetings. Along with the years, as Qinghaosu was more and more well known by people outside China, in interview with reporters inside and outside China, and in her book , Tu Youyou simply claims that “she is the first person who discovered Qinghaosu” (Tu Youyou “qinghao ji qinghaosulei yaowu” , “preface three”), it is she, “who finally and successfully explored the antimalarial entity from traditional Chinese medicine Qinghao” (Tu Youyou “qinghao ji qinghaosulei yaowu” , “brief introduction of author”) ,and it is she, “who isolated the antimalarial entity on November 8th of 1972，and named it as Qinghaosu” (Tu Youyou “qinghao ji qinghaosulei yaowu” , “Foreword” ). As a matter of fact, in December near the end of the year 1972, Zhong Yurong and Cui Shulian ( ICMM,ATCM) isolated “Qinghaosu II” from Artemisia annua L. growing in Beijing; In April 1973, Luo Zeyuan(罗泽渊) (Yunnan IDR) isolated “Huanghaosu” (黄蒿素) from A. annua L. f. macrocephala Pamp. growing in Kunming, Yunnan（云南昆明）, and also from A. annua L. growing in Chongqing, Sichuan（四川重庆）; and in November 1973, Weizhenxing (魏振兴,deceased)（Shandong ITCM）isolated “Huanghuahaosu”(黄花蒿素) from A. annua L. growing in Taixing,Shandong（山东泰兴）(Zhang Jianfang,“Chronological Record of Project 523”，p.53). Although the isolation of the active ingredient, inhibition of parasites in mice and primary clinical trials were carried out by the three institutions respectively, crystals with different names were all isolated from Artemisia annua L., and was the only antimalarial substance in the plant, after the elucidation of their chemical structure, they were accepted to be the same chemical substance, and was designated “Qinghaosu” (青蒿素) as the official name in Chinese Pharmacopoeia (edited in 2000) after the name of the herbal drug. Tu Youyou is not the person who first discovered the antimalarial action of Qinhao extract, and not the first person who isolated the antimalarial Qinghaosu either, and these parts of work were not done under her instruction, so it was not only unfair and unreasonable, more over, it was not tally with the historical truth if Tu Youyou is the only person to be credited for. (II) Demonstration of antimalarial effectiveness for Qinghaosu in clinical trials Between September and October of 1973, Tu Youyou’s team applied “Qinghaosu II” for the treatment of 8 cases malaria patients in Changjiang, Hainan(海南昌江), but they did not get the expected results. According to their original report, among 5 cases of falciparum malaria treated with “Qinghaosu II” tablets (in total dosage of 4.5g), 1/5 case was effective, 2/5 cases discontinued the treatment because of appearance of premature heart beat, 2/5 cases failed. Among 3 cases of vivax malaria patients treated with “Qinghaosu II “ capsules (in total dosage of 3-3.5g), 2/3 cases were cured, and 1/3 case was effective(Institute of Chinese Materia Medica under ATCM, “zhongyao qinghao de kangnue yanjiu”, p.27). Tu Youyou did not take seriously to this unexpected clinical result, and explained the reason of clinical trial failures in the 5 falciparum patients as was caused by the disintegration problem of the tablets, but did not provide any data for her explanation(Tu Youyou “qinghao ji qinghaosulei yaowu” ,p.43). As a matter of fact, the content of “Qinghaosu II” was rather low in Artemisia annua L. growing in Beijing, and the “Qinghaosu II” sample used for clinical trails which they separated by using column chromatography was not pure enough, and was mixed with certain amount of “Qinghaosu I”, the team members all knew that. She even did not investigate the relation between the purity of “Qinghaosu II” , the poor cure rate (only 50%), and its side-effect as well. In her book, she avoided to mention about the purity of “Qinghaosu II” and the clinical results of falciparum patients, but simply asserted, “the clinical results of the Qinghaosu capsules in treatment of 3 cases of vivax malaria can fully demonstrate the effectiveness of Qinghaosu — the active ingredient in Qinghao” (Tu Youyou “qinghao ji qinghaosulei yaowu” , p.41). In May of 1974, scientific workers of Shandong ITCM and Institute of Parasitoses in Shandong Province (Shandong IP,山东省寄生虫病研究所) carried out the treatment of 19 vivax malarial patients by using “Huanghuahaosu” . It was concluded that the efficacy of “Huanghuahaosu” in treatment of vivax malaria was promising, no significant toxicity or adverse effect were observed （Zhang Jianfang,“Chronological Record of Project 523”，p.53）. In September of 1974, the Yunnan cooperative group of clinical trials (云南临床协作组) intended to carriy out the clinical trial of “Huanghaosu” in Fengqing and Yunxian ,Yunnan(.云南凤庆和云县). Since it was difficult in searching of falciparum malaria patients in these areas, under coordination of the “General Leading Office of 523 Project” and the local Leading Office, Ludongwei (陆东伟) from Yunnan IDR was to be responsible for supplying “Huanghaosu”, and entrusted Li Guoqiao’s (李国桥) research group of Guangzhou University of Traditional Chinese Medicine （Guangzhou UTCM, 广州中医大学）to carry out the clinical trials in Gengma and Cangyuan, Yunnan (云南耿马和沧源), these were the high edemic areas of falciparum malaria. Li Guoqiao was well experienced in emergent treatment of cerebral malaria. Between October and December of 1974, he worked with the Yunnan cooperative group in treatment of the first 3 falciparum malaria patients, which showed unexpected good result. Li Guoqiao’s group continued the further clinical trial, and all together 18 malarial patients, which included 14 cases of falciparum malaria （3 cases of severe malaria, one of them was pregnant）and 4 cases of vivax malaria, were cured. The efficacy of “Huanghaosu ” was even better than Choloroquine, and was characterized by quick onset of action with high efficiency in short term, low toxicity and adverse effect, and without drug-resistance, but the recrudescence rates were high. The efficacy and side-effect of “Huanhaosu” in treatment of drug-resistant falciparum malaria in tropical area was basically confirmed by the said evaluation (Zhang Jianfang,“Chronological Record of Project 523”，p.27-32) , this is a new generation of antimalarial which exactly is what all the malaria patients in the world are expecting for. ICMM under ATCM had been a pioneer in isolation of the antimalarial entity, but in the clinical trials, they only got positive results in 3 cases of vivax malaria and 1 case of falciparum malaria. The characteristic effectiveness of Qinghaosu was eventually confirmed by 19 cases of vivax malaria patients treated with “Huanghuahaosu” prepared by Shandong ITCM and Shandong IP, and 14 cases of falciparum and 4 cases of vivax malaria patients treated with “Huanghaosu” prepared by Yunnan IDR and treatment carried out by Li Guoqiao’s group of Guangzhou UTCM. This was a good example of cooperative research in China that expedited the progress of antimalarial research with high speed. (III) Elucidation of chemical structure of Qinghaosu Under the instruction of Professor Lin Qishou (林启寿, deceased) of Beijing Medical College（北京医学院）and Professor Liang Xiaotian(梁晓天, deceased) of ICMM under China Academy of Medical Science (ICMM, CAMS)(中国医学科学院药物研究所), Tu Youyou’s team carried out some experiments such as ultimate analysis , IR , 1 H NMR, MS spectrum, and some chemical reactions of Qinghaosu isolated, and found that there was no nitrogen atom in its molecule, so it is assumed to be a new type of sesquiterpenoid antimalarial. Owing to having no sufficient experience and technical equipments for elucidation of chemical structure, ICMM under ATCM negotiated with specialists of Shanghai Institute of Organic Chemistry (SIOC), Academia Sinica (AS) (中国科学院上海有机化学研究所), and under the coordination of “Shanghai Leading Office of 523 Project”, Professor Zhou Weishan(周维善) of SIOC supervised the research team , Wu Zhaohua(吴照华) and Wu Yulin(吴毓林)were responsible for the research. They consented that ICMM under ATCM could dispatch one person to take part in the work. From February, 1974, ICMM in succession dispatched Ni Muyun , Liu Jingming(刘静明) and Fan Jufen(樊菊芬) to work with the team in SIOC for a short duration. Tu Youyou herself had not taken part in any research work in SIOC. Even for the experiment carried out in SIOC, Professor Liang Xiaotian still contributed much to the work, and gave good advice to SIOC through communication between Tu Youyou and her team member there. From 1974 to 1975, a series of chemical reactions of Qinghaosu were studied in SIOC, among those, four groups of reactions were valuable, one was demonstration of its peroxyl group by means of reacting with sodium iodide to form the colour of iodine, and reducing by triphenyl phosphine; the second one was demonstration of the lactonyl group by means of reacting with hydroxyl amine hydrochloride or titration with sodium hydroxide; the third one was the formation of a semiacetal by the reduction of the lactonyl group by sodium borohydride (NaBH4) with the peroxyl group still kept intact, this product was initially named as “reduced Qinghaosu”, after the chemical structure of Qinghaosu was demonstrated, it was then named dihydroqinghaosu (or dihydroartemisinin); and the fourth one was hydrogenation of Qinghaosu by using palladium-calcium carbonate as catalyst to produce the deoxyqinghaosu (or deoxyartemisinin). All these reactions laid the foundation of studies on the relationship between the chemical structure and its effectiveness, and the preparation of its derivatives as well(Liu Jingming, Ni Muyun, Fan Jufen, Tu Youyou ( Institute of Chinese Materia Medica, Academy of Traditional Chinese Medicine Peking), Wu Zhaohua , Wu Yulin , Zhou Weishan (Institute of Organic Chemistry, Academia Sinica, Shanghai), Structure and Reaction of Arteannuin, Acta Chimica Sinica, 1979,37(2):129-143）. Based on the IR spectrum, 1 H NMR and 13C NMR data, ORD spectrum and chemical reactions of Qinghaosu, scientists of SIOC had deduced certain structural fragments of the molecule. It was interesting, enlightened by the chemical structure of Yingzhaosu A（鹰爪甲素），another new antimalarial entity with a peroxyl group, reported by scientists from ICMM, CAMS (中国医学科学院药物研究所) ,Wu Zhaohua with Wu Yulin demonstrated the endoperoxyl group in Qinghaosu by means of chemical reactions. However, the peculiarity of the structure made it difficult to ascertain the linkage of 15 carbon atoms and 5 oxygen atoms in the molecule. ICMM under ATCM then asked the help from Institute of Biophysics (IB), Academia Sinica(AS)(中国科学院生物物理所) in Beijing, Tu Youyou supplied them with qualified crystals of Qinghaosu for analysis, Li Pengfei( 李鹏飞，deceased) , Liang Li （梁丽） and their colleagues of Institute of Biophysics finally determined the chemical structure and relative configuration of Qinghaosu by means of X-ray single-crystal diffraction, and its absolute configuration was determined by means of anomalous dispersion of Cu-radiation by oxygen atoms (Qinghaosu Research Group of Institute of Biophysic, Crystal Structure and Absolute Configuration of Qinghaosu, Scientia Sinica, 1980,23(3) 380-396,in English), the time was November 30 of 1975(Tu Youyou “qinghao ji qinghaosulei yaowu” , p.44) . The results obtained from the elucidation of the chemical structure of Qinghaosu showed, Qinghaosu is so valuable in the treatment of malaria, first of all, is due to its novel and peculiar structure — a sesquiterpene lactone with no Nitrogen atom, and the endoperoxyl group links with an ethereal-like carbon and oxygen linkage in an order of O – C – O – C – O – C – O – O – C , propably is its antimalarial action site in the molecule. (Li Ying, Yu Pei-Lin, Chen Yi-Xin, Li Liang-Quan, Gai Yuan-Zhu, Wang De-Sheng, Zheng Ya-Ping. Studies on analogs of artemisinin I. The synthesis of ethers, carboxylic esters and carbonates of dihydroartemisinin. Acta Pharmaceutica Sinica, 1981, 16(6): 429-439). In her book, Tu Youyou claimed that she “reduced Qinghaosu by using NaBH4 as a reducer to produce dihydroqinghaosu, and was the first person who created dihydroqinghaosu as early as in 1973, and the carbonyl group of Qinghaosu was demonstrated through dihydroqinghaosu”(Tu Youyou “qinghao ji qinghaosulei yaowu” , p.187). According to the description of a report with the title of “Studies on the antimalarial research of Chinese herbal drug Qinghao” written by one of her team member in November of 1975, they had reduced Qinghaosu by using Zn(BH4)2, KBH4 and AlLiH4 as reducers, the products all were white crystals, in comparison with Qinghaosu, the carbonyl peak in IR spectrum disappeared and was replaced by an hydroxyl peak, and the hydroxyl group could be acetylated (Institute of Chinese Materia Medica under ATCM, “zhongyao qinghao de kangnue yanjiu” ,1975,11). So actually they had never used NaBH4 as reducer, and no further chemical elucidation had been done , and even no name had been given to any of those compounds at the time of the report was written. As a matter of fact, it was Wu Yulin of SIOC who used NaBH4 as reducer and got the said “reduced Qinghaosu” in 1975, and studied on its chemical structure as well. The chemical structure of “reduced Qinghaosu” was established after the successful elucidation of the chemical structure of Qinghaosu in 1975, and then was named as “dihydroqinghaosu” (or dihydroartemisinin). So nothing could prove that Tu Youyou was the first person who created dihydroartemisinin in 1973. (IV) The early publication of papers concerning the studies on structure and configuration of Qinghaosu The early publication of papers concerning the studies on structure and configuration of Qinghaosu were as follows: The first paper was “A New Type of Sesquiterpene Lactone-Qinghaosu”(in Chinese) Cooperative Group of Qinghaosu Structural Research, A New Type of Sesquiterpene Lactone—Qinghaosu, Chinese Science Bulletin, 1977, 22(3)142) (青蒿素结构研究协作组, 一种新型的倍半萜内酯—青蒿素,科学通报, 1977, 22(3)142) The paper was prepared by some person of ICMM by putting together all the research results of above mentioned Institutions. The publication of this paper was approved by the Ministry of Public Health of PRC, but for the sake of security, it was not allowed to reveal its anti-malarial action. The second paper was “Structure and Reaction of Arteannuin” ( in Chinese, with English abstract) Liu Jingming, Ni Muyun, Fan Jufen, Tu Youyou (Institute of Chinese Materia Medica, Academy of Traditional Chinese Medicine Peking), Wu Zhaohua , Wu Yulin , Zhou Weishan (Institute of Organic Chemistry, Academia Sinica, Shanghai), Structure and Reaction of Arteannuin, Acta Chimica Sinica, 1979,37(2):129-143 (刘静明、倪慕云、樊菊芬、屠呦呦（北京中医研究院中药研究所），吴照华、吴毓林、周维善（中国科学院，上海有机化学研究所），青蒿素（Arteannuin）的结构和反应，1979,37(2):129-143) This paper was written by Professor Zhou Weishan. (Note: In the reference of her book, Tu Youyou had deleted the names of Fan Jufen, Wu Zhaohua, Wu Yulin, Zhou Weishan, and left the names of Liu Jingming, Ni Muyun and Tu Youyou (Tu Youyou, “qinghao ji qinghaosulei yaowu”, p.144) The third paper was “Crystal Structure and Absolute Configuration of Qinghaosu“(in Chinese and English versions) Qinghaosu Research Group of Institute of Biophysic, Crystal Structure and Absolute Configuration of Qinghaosu, Scientia Sinica, 1980, 23(3) 380-396 (in English) 中科院生物物理所抗疟药青蒿素协作组，青蒿素晶体结构及其绝对构型，中国科学，1979, (11)：1114-1128 (in Chinese) The studies on relative and absolute configuration of Qinghaosu were carried out and finalized in the Institute of Biophysics, but some of the details had already been introduced in the first paper and cited in the second paper, when this paper was waiting to be published. The fourth paper was “Chemical Studies on Qinghaosu (Artemisinine) “ ( in English) China cooperative Research Group on Qinghaosu and Its Derivatives as Antimalrials*, Chemical Studies on Qinghaosu (Artemisinine), Journal of Traditional Chinese Medicine, 1982,2(1):3-8. * The main research units:1.Institute of Chinese Materia Medica, Academy of Traditional Chinese Medicine; 2.Shanghai Institute of Organic Chemistry and Institute of Biophysics, Chinese Academy of Sciences. (Note: In the reference of her book, Tu Youyou deleted the names of the main research units, and replaced with her own name as “Tu Youyou” or “屠呦呦”（Tu Youyou “qinghao ji qinghaosulei yaowu” p.69，p.140 and p.190） In that period of time in China, Chinese scientists had to avoid putting their own names in their published paper, because it was considered as a desire for personal fame and gain, so at that time, authors who published their papers mostly used the names of the Institutions where they worked for. From 1978, people were again allowed to sign their names on the papers. But since too many people from different Institutions had taken part in the research work of Qinghaosu, so some important published papers relating to Qinghaosu were still in the name of cooperative group. Tu Youyou might have taken part in some of the work mentioned above, but certainly, she was not the only person who had done all the research work of any of the paper mentioned above. In reviewing the history of discovery of the new antimalarial ¾Qinghaosu in China, people could clearly realize that not a single person or institution could fulfill the whole process of those research work mentioned above, why only one single person should be credited for? The fact was that Chinese scientists of various disciplines took part in the research work and made their own contributions at different stages like in a scientific research relay race, and finally led to the discovery of the new antimalarial Qinghaosu (Artemisinin) — an historical pioneer work in last century. * This paper was written by insiders, as an important part of their investigation of the oral history relating to the discovery of the new antimalarial ¾Qinghaosu in China . Since most of the scientists who had joined in the research work of Qinghaosu have retired and are residing inside and outside China separately, or passed away，the writers hope that they can gain access to some of the original experimental records or related document for reference, but obstacles still exist. After almost 40 years, some insiders failed to remember things in details, some of them do not want to be disturbed. So we anxiously hope that any person in the know will help us to make this paper more tally with the historical truth.
NATURE REVIEWS DRUG DISCOVERY June 2010 Volume 9 Number 6 Visit Nature Reviews Drug Discovery online to browse the journal. Now available at http://links.ealert.nature.com/ctt?kn=19m=34936816r=NDU1MzI2NDExMwS2b=2j=NzQ4NjI1MzkS1mt=1rt=0 Please note that you need to be a subscriber to enjoy full text access to Nature Reviews Drug Discovery online. To purchase a subscription, please visit: http://links.ealert.nature.com/ctt?kn=76m=34936816r=NDU1MzI2NDExMwS2b=2j=NzQ4NjI1MzkS1mt=1rt=0 Alternatively, to recommend a subscription to your library, please visit http://links.ealert.nature.com/ctt?kn=46m=34936816r=NDU1MzI2NDExMwS2b=2j=NzQ4NjI1MzkS1mt=1rt=0
哈勃的15年科学探索 Hubble: 15 Years of Discovery Douban.prettify_form(document.getElementById('ssform')); 导演 : Lars Lindberg Christensen 制片国家/地区: Germany 语言: 英语 上映日期: 2005-04-24 imdb链接: tt1201062 X 登录 Email: 密 码: 忘记密码了 在这台电脑上记住我 还没有注册... 剧情简介 哈勃望远镜(Hubble Space Telescope)是欧洲太空总署(ESA)与美国太空总署(NASA)的长期合作计划，其放置于大气层之外，就好像是放在太空中的一座天文台一样，以 利国际太空天文学家共同研究，哈勃望远镜构想于1940年代，设计于70至80年代，1990年4月25日发射升空(任务编号STS-31)，是一具口径 2.4公尺的反射式望远镜，目前置于地球低卫星轨道上(600公里高空)。为了纪念Edwin Hubble对天文的贡献，所以命名为哈勃望远镜。 本电影讲述了15年哈勃望远镜计划的历史，由最初的艰苦经营到后期的科学发现 本片包含以下章节： 1 The Hubble Story 哈勃的故事 10:28 2 Hubble Up Close 近瞻哈勃 5:04 3 Planetary Tales 行星的故事 8:34 4 The Lives ... (展开全部) 哈勃望远镜(Hubble Space Telescope)是欧洲太空总署(ESA)与美国太空总署(NASA)的长期合作计划，其放置于大气层之外，就好像是放在太空中的一座天文台一样，以 利国际太空天文学家共同研究，哈勃望远镜构想于1940年代，设计于70至80年代，1990年4月25日发射升空(任务编号STS-31)，是一具口径 2.4公尺的反射式望远镜，目前置于地球低卫星轨道上(600公里高空)。为了纪念Edwin Hubble对天文的贡献，所以命名为哈勃望远镜。 本电影讲述了15年哈勃望远镜计划的历史，由最初的艰苦经营到后期的科学发现 本片包含以下章节： 1 The Hubble Story 哈勃的故事 10:28 2 Hubble Up Close 近瞻哈勃 5:04 3 Planetary Tales 行星的故事 8:34 4 The Lives Of Stars 恒星的一生 12:11 5 Cosmic Collisions 宇宙的碰撞 7:58 6 Monster In Space 宇宙中的怪兽 9:50 7 Gravitational Illusions 引力幻象 6:07 8 Birth And Death Of The Universe 宇宙的诞生与死亡 6:06 9 Looking At The End Of Time 遥望时间的尽头 14:53
《Data Mining and Knowledge Discovery》(简称DMKD)2009年的第一期，题目为Incremental Sequence-Based Frequent Query Pattern Mining from XML Queries的论文（作者为：李国良、冯建华、王建勇、周立柱）完全由清华大学独立完成并已被DMKD期刊录用。 以上信息来源于清华大学计算机系网站。 以下信息来自清华计算机系网站:http://www.cs.tsinghua.edu.cn/bgtz/2009-2-20.htm 标题: 我系数据库研究小组多篇论文被国际重要期刊及会议录用 内容 ： 2009 年初，计算机系数据库研究小组已有多篇论文先后在重要国际期刊及会议上发表或被录用。其中题目为 CONTOUR: An Efficient Algorithm for Discovering Discriminating Subsequences 的论文（作者为：王建勇、张宇宙、周立柱、 George Karypis 和 Charu Arggarwal ）发表于数据挖掘领域的重要国际期刊《 Data Mining and Knowledge Discovery 》 ( 简称 DMKD)2009 年的第一期，另一篇题目为 Incremental Sequence-Based Frequent Query Pattern Mining from XML Queries 的论文（作者为：李国良、冯建华、王建勇、周立柱）完全由清华大学独立完成并已被 DMKD 期刊录用。到目前为止尚没有完全由中国大陆研究人员独立完成的论文发表于 DMKD 。 此外，数据库研究小组另有 3 篇论文先后被 ICDE 2009 、 EDBT 2009 和 WWW 2009 所录用。其中，题目为 Progressive Top-k Keyword Search in Relational Databases 的论文（作者为：李国良、周晓方、冯建华、王建勇）被数据库领域的重要国际会议 ICDE 2009 录用为短文，题目为 FOGGER: An Algorithm for Graph Generator Discovery 的论文（作者为：曾志平、王建勇、张军、周立柱）被数据库领域的重要国际会议 EDBT 2009 所录用，题目为 Efficient Interactive Fuzzy Keyword Search 的论文（作者为：季声乐、李国良、李晨、冯建华）被万维网领域的重要国际会议 WWW 2009 录用为长文。 Abstract Existing algorithms of mining frequent XML query patterns (XQPs) employ a candidate generate-and-test strategy. They involve expensive candidate enumeration and costly tree-containment checking. Further, most of existing methods compute the frequencies of candidate query patterns from scratch periodically by checking the entire transaction database, which consists of XQPs transferred from user query logs. However, it is not straightforward to maintain such discovered frequent patterns in real XML databases as there may be frequent updates that may not only invalidate some existing frequent query patterns but also generate some new frequent query patterns. Therefore, a drawback of existing methods is that they are rather inefficient for the evolution of transaction databases. To address above-mentioned problems, this paper proposes an efficient algorithm ESPRIT to mine frequent XQPs without costly tree-containment checking. ESPRIT transforms XML queries into sequences using a one-to-one mapping technique and mines the frequent sequences to generate frequent XQPs. We propose two efficient incremental algorithms, ESPRIT - i and ESPRIT - i + , to incrementally mine frequent XQPs. We devise several novel optimization techniques of query rewriting, cache lookup, and cache replacement to improve the answerability and the hit rate of caching. We have implemented our algorithms and conducted a set of experimental studies on various datasets. The experimental results demonstrate that our algorithms achieve high efficiency and scalability and outperform state-of-the-art methods significantly. Keywords XML query patterns-Frequent query patterns-XML frequent pattern mining-Incremental mining-Sequential pattern mining 另一篇论文 ,来自http://dbgroup.cs.tsinghua.edu.cn/ligl/ Incremental Mining of Frequent Query Patterns from XML Queries for Caching (I EEE ICDM 2006) IEEE ICDM 2006 DM448 Incremental Mining of Frequent Query Patterns from XML Queries for Caching Guoliang Li, Jianhua Feng, Jianyong Wang, Yong Zhang , and Lizhu Zhou 清华大学数据库研究组 期刊文章地址
标签: Discovery
![[转载]免费下载最新一期：Drug Discovery Today，July 2012](http://image.sciencenet.cn/album/201207/13/154409ltagqqbmpkc1hc1p.jpg.thumb.jpg)
![[转载]An Algorithm for Discovery](http://image.sciencenet.cn/album/201206/03/1349507z8hyysxc89n4ycy.jpg.thumb.jpg)
