Artemisinin

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Artemisinin
Artemisinin.svg
Systematic (IUPAC) name
(3R,5aS,6R,8aS,9R,12S,12aR)-Octahydro-3,6,9-trimethyl-3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepin-10(3H)-one
Clinical data
Pronunciation /ɑːrtᵻˈmɪsᵻnᵻn/
Routes of
administration		 Oral
Identifiers
CAS Number 63968-64-9 N
ATC code P01BE01 (WHO)
PubChem CID: 68827
ChemSpider 62060 YesY
UNII 9RMU91N5K2 YesY
KEGG D02481 YesY
ChEBI CHEBI:223316 YesY
ChEMBL CHEMBL77 N
Synonyms Artemisinine, qinghaosu
Chemical data
Formula C15H22O5
Molecular mass 282.332 g/mol
  • O=C3O[C@@H]4O[C@@]1(OO[C@@]42[C@@H](CC1)[C@H](C)CC[C@H]2[C@H]3C)C
  • InChI=1S/C15H22O5/c1-8-4-5-11-9(2)12(16)17-13-15(11)10(8)6-7-14(3,18-13)19-20-15/h8-11,13H,4-7H2,1-3H3/t8-,9-,10+,11+,13-,14-,15-/m1/s1 YesY
  • Key:BLUAFEHZUWYNDE-NNWCWBAJSA-N YesY
Physical data
Density 1.24 ± 0.1 g/cm3
Melting point 152 to 157 °C (306 to 315 °F)
Boiling point decomposes
 NYesY (what is this?)  (verify)

Artemisinin, also known as qinghaosu (Chinese: 青蒿素), and its semi-synthetic derivatives are a group of drugs that possess the most rapid action of all current drugs against Plasmodium falciparum malaria.[1] It was discovered by Tu Youyou, a Chinese scientist, who was awarded half of the 2015 Nobel Prize in Medicine for her discovery.[2] Treatments containing an artemisinin derivative (artemisinin-combination therapies, ACTs) are now standard treatment worldwide for P. falciparum malaria. Artemisinin is isolated from the plant Artemisia annua, sweet wormwood, an herb employed in Chinese traditional medicine. A precursor compound can be produced using genetically engineered yeast.

Chemically, artemisinin is a sesquiterpene lactone containing an unusual peroxide bridge. This peroxide is believed to be responsible for the drug's mechanism of action. Few other natural compounds with such a peroxide bridge are known.[3]

Artemisinin and its endoperoxides derivatives have been used for the treatment of P. falciparum related infections but low bioavaibility, poor pharmacokinetic properties and high cost of the drugs are a major drawback of their use.[4] Use of the drug by itself as a monotherapy is explicitly discouraged by the World Health Organization,[5] as there have been signs that malarial parasites are developing resistance to the drug. Therapies that combine artemisinin or its derivatives with some other antimalarial drug are the preferred treatment for malaria and are both effective and well tolerated in patients. The drug is also increasingly being used in Plasmodium vivax malaria,[6] as well as being a topic of research in cancer treatment.

Medical use

Uncomplicated malaria

Artemisinins can be used alone, but this leads to a high rate of recrudescence (return of parasites) and other drugs are required to clear the body of all parasites and prevent recurrence. The World Health Organization (WHO) is pressuring manufacturers to stop making the uncompounded drug available to the medical community at large, aware of the catastrophe that would result if the malaria parasite developed resistance to artemisinins.[7]

The WHO has recommended artemisinin combination therapies (ACT) be the first-line therapy for P. falciparum malaria worldwide.[8] Combinations are effective because the artemisinin component kills the majority of parasites at the start of the treatment, while the more slowly eliminated partner drug clears the remaining parasites.[9]

Several fixed-dose ACTs are now available containing an artemisinin component and a partner drug which has a long half-life, such as mefloquine (ASMQ[10]), lumefantrine (Coartem), amodiaquine (ASAQ), piperaquine (Duo-Cotecxin), and pyronaridine (Pyramax). Increasingly, these combinations are being made to GMP standard. A separate issue concerns the quality of some artemisinin-containing products being sold in Africa and Southeast Asia.[11][12]

Artemisinins are not used for malaria prophylaxis (prevention) because of the extremely short activity (half-life) of the drug. To be effective, it would have to be administered multiple times each day.

Severe malaria

Artesunate administered by intravenous or intramuscular injection has proven superior to quinine in large, randomised controlled trials in both adults [13] and children.[14] Combining all trials comparing these two drugs, artesunate is associated with a mortality rate that is approximately 30% lower than that of quinine.[14] Reasons for this difference include reduced incidence of hypoglycaemia, easier administration and more rapid action against circulating and sequestered parasites. Artesunate is now recommended by the WHO for treatment of all cases of severe malaria. Effective treatment with ACT (Artemisinin Combination Therapy) has proven to lower the morbidity and mortality from malaria within two years by around 70%.[15]

Cancer treatment

Artemisinin is undergoing early research and testing for the treatment of cancer.[16] Artemisinin has anticancer effects in experimental models of hepatocellular carcinoma.[17] Artemisinin has a peroxide lactone group in its structure, and it is thought that when the peroxide comes into contact with high iron concentrations (common in cancerous cells), the molecule becomes unstable and releases reactive oxygen species. It has been shown to reduce angiogenesis and the expression of vascular endothelial growth factor in some tissue cultures. Recent pharmacological evidence demonstrates the artemisinin derivative dihydroartemisinin targets human metastatic melanoma cells in vitro with induction of phorbol-12-myristate-13-acetate-induced protein 1 dependent mitochondrial apoptosis that occurs downstream of iron-dependent generation of cytotoxic oxidative stress.[18] A pilot study on the use of the artemisinin derivative artesunate yielded promising results for the treatment of colorectal cancer [19]

Helminth parasites

A serendipitous discovery was made in China while searching for novel anthelmintics for schistosomiasis that artemisinin was effective against schistosomes, the human blood flukes, which are the second-most prevalent parasitic infections, after malaria. Artemisinin and its derivatives are all potent anthelmintics.[20] Artemisinins were later found to possess a broad spectrum of activity against a wide range of trematodes, including Schistosoma japonicum, S. mansoni, S. haematobium, Clonorchis sinensis, Fasciola hepatica, and Opisthorchis viverrini. Clinical trials were also successfully conducted in Africa among patients with schistosomiasis.[21] A randomized, double-blind, placebo-controlled trial also revealed the efficacy against schistosome infection in Côte d'Ivoire[22] and China.[23]

Adverse effects

Artemisinins are generally well tolerated at the doses used to treat malaria.[24] The side effects from the artemisinin class of medications are similar to the symptoms of malaria: nausea, vomiting, anorexia, and dizziness. Mild blood abnormalities have also been noted. A rare but serious adverse effect is allergic reaction.[24][25] One case of significant liver inflammation has been reported in association with prolonged use of a relatively high-dose of artemisinin for an unclear reason (the patient did not have malaria).[26] The drugs used in combination therapies can contribute to the adverse effects experienced by those undergoing treatment. Adverse effects in patients with acute P. falciparum malaria treated with artemisinin derivatives tend to be higher.[27]

Resistance

Clinical evidence for artemisinin resistance in southeast Asia was first reported in 2008,[28] and was subsequently confirmed by a detailed study from western Cambodia.[29][30] Resistance in neighbouring Thailand was reported in 2012,[31] and in Northern Cambodia, Vietnam and Eastern Myanmar in 2014.[32][33] Emerging resistance was reported in Southern Laos, central Myanmar and North-Eastern Cambodia in 2014.[32][33] The parasite's kelch gene on chromosome 13 appears to be a reliable molecular marker for clinical resistance in southeast Asia.[34]

In April 2011, the WHO stated that resistance to the most effective antimalarial drug, artemisinin, could unravel national (India) malaria control programs, which have achieved significant progress in the last decade. WHO advocates the rational use of antimalarial drugs and acknowledges the crucial role of community health workers in reducing malaria in the region.[35]

Mechanism of action

Most artemisinins used today are prodrugs of the biologically active metabolite dihydroartemisinin, which is active during the stage when the parasite is located inside red blood cells. Although there is no consensus regarding the mechanism of action through which artemisinin derivatives kill the parasites,[36][37] several lines of evidence indicate that artemisinins exert their antimalarial action by radical formation that depends on their endoperoxide bridge. When the parasite that causes malaria infects a red blood cell, it consumes hemoglobin within its digestive vacuole, a process that generates oxidative stress.[38] In the primary theory of the mechanism of action, the iron of the heme directly reduces the peroxide bond in artemisinin, generating high-valent iron-oxo species and resulting in a cascade of reactions that produce reactive oxygen radicals which damage the parasite and lead to its death.[39] However, this mechanism has been debated and other hypotheses have been described.[40] One alternative is that artemisinins disrupt cellular redox cycling.[41] Artesunate has been shown to potently inhibit the essential Plasmodium falciparum exported protein 1 (EXP1), a membrane glutathione S-transferase.[42] Recently Shandilya et al. suggested a free radical mechanism in which artemisinin gets activated by iron present in the food vacuole which in turn inhibits PfATP6 by closing the phosphorylation, nucleotide binding, and actuator domains leading to loss of function of PfATP6 of the parasite and its death.[43]

Numerous studies have investigated the type of damage oxygen radicals may induce. For example, Pandey et al. have observed inhibition of digestive vacuole cysteine protease activity of malarial parasites by artemisinin.[44] These observations were supported by ex vivo experiments showing accumulation of hemoglobin in the parasites treated with artemisinin and inhibition of hemozoin formation by malaria parasites, although this inhibition was not seen in an in vitro B-hematin inhibition assay.[45] Electron microscopic evidence linking artemisinin action to the parasite's digestive vacuole has been obtained showing that the digestive vacuole membrane suffers damage soon after parasites are exposed to artemisinin.[46] This would also be consistent with data showing that the digestive vacuole is already established by the mid-ring stage of the parasite's blood cycle,[47] a stage that is sensitive to artemisinins but not other antimalarials. However, fluorescently tagged artemisinin was seen in the Golgi, ER and mitochondria, rather than the digestive vacuole, suggesting that the vacuolar damage may be a downstream effect, and also that tiny ring stages (containing minimal digested material) are highly susceptible to artemisinins.[48][49][50]

Other suggested targets include the mitochondrial electron transport chain [51] and the parasite's SERCA pump (PfATP6/PfSERCA).[52] Evidence to support the PfATP6 hypothesis includes studies reporting specific interactions between SERCAs and artemisinins,[52][53] undertaken in a Xenopus oocyte system that generated valuable results despite the challenges of working with low amounts of heterologous expressed material.[54] These findings have subsequently been confirmed in an independent series of experiments that use yeast expressing this calcium ATPase. Artemisinins selectively and reproducibly inhibit the yeast growth by their actions on PfATP6.[55] This methodology also provided information on the effects of mutations in PfATP6 on drug sensitivity.[53] In French Guiana and Senegal reduced sensitivity to artemisinins have been associated with single nucleotide polymorphisms in PfATP6.[56] In Tanzania, a significant increase in a predicted but previously undiscovered polymorphism in PfATP6 has been found after a period of artemisinin combination therapy.[57] The mammalian calcium ATPase SERCA1a was also inhibited by artemisinins in coupled enzyme assays,[58] and mutations in either SERCA1a or PfATP6 modulate their sensitivity to artemisinin.[53] Anomalously, if either PfATP6 or SERCA1a are detergent solubilised, they do not show sensitivity to artemisinins.[59][60][61]

Dosing

Artemisinin derivatives have half-lives on the order of an hour. Therefore, they require at least daily dosing over several days. For example, the WHO-approved adult dose of co-artemether (artemether-lumefantrine) is four tablets at 0, 8, 24, 36, 48, and 60 hours (six doses).[62][63]

Artemisinin is not soluble in water, therefore Artemisia annua tea is postulated not to contain pharmacologically significant amounts of artemesinin.[64] Artemisia tea is therefore not recommended as a substitute for the ACTs; however, clinical studies have been suggested.[65]

Production and price

China and Vietnam provide 70% and East Africa 20% of the raw plant material. Seedlings are grown in nurseries and then transplanted into fields. It takes about 8 months for them to reach full size. The plants are harvested, the leaves are dried and sent to facilities where the artemisinin is extracted using solvent, typically hexane. Alternative extraction methods have been proposed.[66] The market price for artemisinin has fluctuated widely, between $120 and $1200 per kilogram from 2005 to 2008.[67]

The Chinese company Artepharm created a combination artimisinin and piperaquine drug marketed as Artequick.[68] In addition to clinical studies performed in China and southeast Asia, Artequick was used in large scale malaria eradication efforts in the Comoros Islands. Those efforts, conducted in 2007, 2012, and 2013–2014, produced a 95–97% reduction in the number of malaria cases in the Comoros Islands.[69]

After negotiation with the WHO, Novartis and Sanofi-Aventis provide ACT drugs at cost on a nonprofit basis; however, these drugs are still more expensive than other malaria treatments.[70] Artesunate injection for severe malaria treatment is made by the Guilin Factory in China where production has received WHO prequalification,[71] an indicator of drug quality.

High-yield varieties of Artemisia are being produced by the Centre for Novel Agricultural Products at the University of York using molecular breeding techniques.[67]

Using seed supplied by Action for Natural Medicine (ANAMED), the World Agroforestry Centre (ICRAF) has developed a hybrid, dubbed A3, which can grow to a height of 3 m and produce 20 times more artemisinin than wild varieties. In northwestern Mozambique, ICRAF is working together with a medical organisation, Médecins sans frontières, ANAMED and the Ministry of Agriculture and Rural Development to train farmers on how to grow the shrub from cuttings, and to harvest and dry the leaves to make artemisia tea.

In April 2013, Sanofi announced the launch[72] of a production facility in Garessio, Italy, to manufacture the anti-plasmodial drug on a large scale. The partnership to create a new pharmaceutical manufacturing process was led by PATH’s Drug Development program (through an affiliation with OneWorld Health), with funding from the Bill & Melinda Gates Foundation and based on a modified biosynthetic process for artemisinic acid, initially designed by Jay Keasling at the University of California, Berkeley and optimized by Amyris. The reaction is followed by a photochemical process creating singlet oxygen to obtain the end product. Sanofi expects to produce 25 tons of artemisinin in 2013, ramping up the production to 55–60 tons in 2014. The price per kg will be $350–400, roughly the same as the botanical source.[73] Despite concerns that this equivalent source would lead to the demise of companies, which produce this substance conventionally through extraction of A. annua biomass, an increased supply of this drug will likely produce lower prices and therefore increase the availability for ACTs treatment. In August 2014, Sanofi announced the release of the first batch of semisynthetic artemisinin. 1.7 million doses of Sanofi's ArteSunate AmodiaQuine Winthrop (ASAQ Winthrop), a fixed-dose artemisinin-based combination therapy will be shipped to half a dozen African countries over the next few months.[74]

Synthesis

Biosynthesis in A. annua

The biosynthesis of artemisinin is believed to involve the mevalonate pathway (MVA) and the cyclization of farnesyl diphosphate (FDP). It is not clear whether the non-mevalonate pathway can also contribute 5-carbon precursors (IPP or/and DMAPP), as occurs in other sesquiterpene biosynthetic systems. The routes from artemisinic alcohol to artemisinin remain controversial, and they differ mainly in when the reduction step takes place. Both routes suggested dihydroartemisinic acid as the final precursor to artemisinin. Dihydroartemisinic acid then undergoes photo-oxidation to produce dihydroartemisinic acid hydroperoxide. Ring expansion by the cleavage of hydroperoxide and a second oxygen-mediated hydroperoxidation finish the biosynthesis of artemisinin.

Biosynthesis of Artemisinin

Chemical synthesis

The total synthesis of artemisinin has been performed from available organic starting materials, using basic organic reagents, many times. The first two total syntheses were a "remarkable... stereoselective synthesis" by Schmid and Hofheinz at Hoffmann-La Roche in Basel starting from (−)-isopulegol (13 steps, ~5% overall yield) and a concurrent synthesis by Zhou and coworkers at the Shanghai Institute of Organic Chemistry from (R)-(+)-citronellal (20 steps, ~0.3% overall yield).[75] Key steps of the Schmid-Hofheinz approach included an initial Ohrloff stereoselective hydroboration/oxidation to establish the "off-ring" methyl stereocenter on the propene side chain; two sequential lithium-reagent mediated alkylations that introduced all needed carbon atoms and that were, together highly diastereoselective; and further reduction, oxidation, and desilylation steps performed on this mono-carbocyclic intermediate, including a final singlet oxygen-utilizing photooxygenation and ene reaction, which, after acidic workup closed the three remaining oxacyclic rings of the desired product, artemisinin, in a single step.[75][76] (In essence, the final oxidative ring closing operation in these syntheses accomplishes the closing three biosynthetic steps shown above.)

A wide variety of further routes continue to be explored, from early days until today, including total synthesis routes from (R)-(+)-pulegone, isomenthene,[75] and even 2-cyclohexen-1-one,[77] as well as routes better described as partial or semisyntheses from a more plentiful biosynthetic precursor, artemisinic acid—in the latter case, including some very short and very high yielding biomimetic synthesis examples (of Roth and Acton, and Haynes et al., e.g., 3 steps, 30% yield), which again feature the singlet oxygen ene chemistry.[75][78][79]

Synthesis in engineered organisms

The partnership to develop semisynthetic artemisinin was led by PATH’s Drug Development program (through an affiliation with OneWorld Health), with funding from the Bill & Melinda Gates Foundation. The project began in 2004, and initial project partners included the University of California, Berkeley (which provided the technology on which the project was based – a process that genetically altered yeast to produce artemisinic acid); and Amyris, Inc. (a biotechnology firm in California, which refined the process to enable large-scale production and developed scalable processes for transfer to an industrial partner).

In 2006, a team from UC Berkeley reported they had engineered Saccharomyces cerevisiae yeast to produce small amount of the precursor artemisinic acid. The synthesized artemisinic acid can then be transported out, purified and chemically converted into artemisinin that they claim will cost roughly $0.25 per dose. In this effort of synthetic biology, a modified mevalonate pathway was used, and the yeast cells were engineered to express the enzyme amorphadiene synthase and a cytochrome P450 monooxygenase (CYP71AV1), both from A. annua. A three-step oxidation of amorpha-4,11-diene gives the resulting artemisinic acid.[80]

The Berkeley method was augmented using technology from various other organizations. The final successful technology is based on inventions licensed from UC Berkeley and the National Research Council (NRC) Plant Biotechnology Institute of Canada.

Commercial production of semisynthetic artemisinin is now underway at Sanofi's site in Garessio, Italy. This second source of artemisinin is poised to enable a more stable flow of key antimalarial treatments to those who need them most.[72] The production goal is set at 35 tons for 2013. It is expected to increase to 50–60 tons per year in 2014, supplying approximately 1/3 of the global annual need for artemisinin.

On May 8, 2013, WHO’s Prequalification of Medicines Programme announced the acceptability of semisynthetic artemisinin for use in the manufacture of active pharmaceutical ingredients submitted to WHO for prequalification, or that have already been qualified by WHO.[81] Sanofi’s API produced from semisynthetic artemisinin (artesunate) was also prequalified by WHO on May 8, 2013, making it the first semisynthetic artemisinin derivative prequalified.

In 2010, a team from Wageningen University reported they had engineered a close relative of tobacco, Nicotiana benthamiana, that can also produce the precursor artemisinic acid.[82]

History

Etymology

Artemisinin is an antimalarial lactone derived from qinghao 青蒿 (Artemisia annua or sweet wormwood). The medicinal value of this plant has been known to the Chinese for at least 2,000 years. In 1596, Li Shizhen recommended tea made from qinghao specifically to treat malaria symptoms in his "Compendium of Materia Medica". The genus name is derived from the Greek goddess Artemis and, more specifically, may have been named after Queen Artemisia II of Caria, a botanist and medical researcher in the fourth century BCE.[83]

Discovery

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Main article: Project 523

Artemisia annua is a common herb found in many parts of the world, and has been used by Chinese herbalists for more than 2000 years in the treatment of malaria. The earliest record dates back to 200 BC, in the Fifty-two Prescriptions unearthed from the Mawangdui Han Dynasty tombs.[84] Its antimalarial application was first described in Zhouhou Beiji Fang (The Handbook of Prescriptions for Emergencies, Chinese: 肘后备急方), edited in the middle of the fourth century by Ge Hong; in that book, 43 malaria treatment methods were recorded.[85] Images of the original scientific papers that record the history of the discovery, have been available online since 2006.[86]

Artemisia annua

In 1967, a plant screening research program, under the name Project 523, was set up by the People's Liberation Army to find an adequate treatment for malaria; the program and early clinical work were ordered of Chairman Mao Zedong at the request of North Vietnamese leaders to provide assistance for their malaria-ridden army.[87] In the course of this research, Tu Youyou discovered artemisinin in the leaves of Artemisia annua (annual wormwood; 1972).[88] The drug is named qinghaosu in Chinese.[88] It was one of many candidates tested as possible treatments for malaria by Chinese scientists, from a list of nearly 5000 traditional Chinese medicines.[citation needed] Tu Youyou also discovered that a low-temperature extraction process could be used to isolate an effective antimalarial substance from the plant. Tu says she was influenced by a traditional Chinese herbal medicine source The Handbook of Prescriptions for Emergency Treatments written in 340 BC by Ge Hong saying that this herb should be steeped in cold water.[89] This book contained the useful reference to the herb: "A handful of qinghao immersed with two litres of water, wring out the juice and drink it all." Tu's team subsequently isolated a useful extract.[88] The extracted substance, once subject to purification, proved to be useful starting point to obtain purified artemisinin.[88] A 2012 review reported that artemisinin-based therapies were the most effective drugs for treatment of malaria at that time;[90] it was also reported to clear malaria parasites from patients' bodies faster than other drugs. In addition to artemisinin, Project 523 developed a number of products that can be used in combination with artemisinin, including lumefantrine, piperaquine, and pyronaridine.[88]

Results were published in the Chinese Medical Journal in 1979.[88][91] The research was met with skepticism at first, partly because the chemical structure of artemisinin, particularly the peroxide portion, appeared to be too unstable to be a viable drug.[3]

In the late 1990s, Novartis filed a new Chinese patent for a combination treatment with artemether and lumefantrine, providing the first artemisinin-based combination therapies (ACTs) (Coartem) at reduced prices to the World Health Organisation.[92] In 2006, after artemisinin had become the treatment of choice for malaria, the WHO called for an immediate halt to single-drug artemisinin preparations in favor of combinations of artemisinin with another malaria drug, to reduce the risk of parasites developing resistance.[93]

In 2011, Tu Youyou was awarded the prestigious Lasker-DeBakey Clinical Medical Research Award for her role in the discovery and development of artemisinin.[88][94] On 5 October 2015, she was awarded half of the 2015 Nobel Prize in Physiology or Medicine for discovering Artemisinin, "a drug that has significantly reduced the mortality rates for patients suffering from Malaria".[2] The other half of the prize was awarded jointly to William C. Campbell and Satoshi Ōmura for discovering avermectin, "the derivatives of which have radically lowered the incidence of River blindness and Lymphatic filariasis, as well as showing efficacy against an expanding number of other parasitic diseases".[2]

Artemisinin derivatives

Because the physical properties of artemisinin itself, such as poor bioavailability, limit its effectiveness, semisynthetic derivatives of artemisinin have been developed. These include:

There are also simplified analogs in preclinical research.[95]

A synthetic compound with a similar trioxolane structure (ring containing three oxygen atoms) named arterolane[96] showed promise in in vitro testing. Phase II testing in patients with malaria was not as successful as hoped, but the manufacturer decided to start Phase III testing anyway.[97] A combination with piperaquine is also in development.[citation needed]

References

This article contains public domain text from the CDC as cited

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  70. ↑ Artemisinin combination therapies, CNAP Artemisia Project
  71. ↑ http://www.mmv.org/partnering/guilin-pharmaceutical-─-achieving-prequalification-price-affordable-in-africa
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  73. ↑ Mark Peplow (April 2013). "Sanofi launches malaria drug production to maintain stability in Artemisinin availability". chemistryworld online (RSC). Retrieved April 19, 2013.
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  80. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  81. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  82. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  83. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  84. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  85. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  86. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  87. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  88. ↑ 88.0 88.1 88.2 88.3 88.4 88.5 88.6 Lua error in package.lua at line 80: module 'strict' not found.
  89. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  90. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  91. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  92. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  93. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  94. ↑ Elizabeth Weise, "'America's Nobel' awarded to Chinese scientist", USA Today, 12 September 2011, accessed September 12, 2011.
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  96. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  97. ↑ Lua error in package.lua at line 80: module 'strict' not found.


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