An Efficient Protocol for the Synthesis of N-Alkyl- and N-Arylimides Using the Lewis Acidic Ionic Li

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1NATURAL PRODUCTSCharles B.Spainhour1.1INTRODUCTION12 1.2HISTORY AND BACKGROUND OF THE USE OFNATURAL PRODUCTS AS THERAPEUTIC AGENTS12 1.3NATURAL PRODUCTS RESEARCH ANDDEVELOPMENT—AN UPDATE14 1.4DISCOVERY OF NATURAL PRODUCTS22Literature Sources22 Environmental Sources23 1.5ESSENTIAL PHARMACODYNAMICS33Protein Targets of Drug Action33 General Principles of Drug Action34 Molecular Aspects of Drug Action—Receptors37 Molecular Aspects of Drug Action—Ion Channels39 Molecular Aspects of Drug Action—G-Protein-Coupled Systems40 Molecular Aspects of Drug Action—Receptors as Enzymes40 Molecular Aspects of Drug Action—Transcription Factors41 Molecular Aspects of Drug Action—Other Targets41 Drug Tolerance42 1.6SCREENING FOR NATURAL PRODUCT ACTIVITY43 1.7ISOLATION AND PURIFICATION OF NATURAL PRODUCTS47 1.8STRUCTURE IDENTIFICATION OF NATURAL PRODUCTS51 1.9SYNTHESIS OF NATURAL PRODUCTS53 1.10DEVELOPMENT OF NATURAL PRODUCTS55Regulatory Guidelines and Nonclinical Development55 Learning from the Mistakes of the Past in the Development ofNatural Products58 1.11FUTURE OF NATURAL PRODUCTS60References63 Drug Discovery Handbook,by Shayne Cox GadCopyright © 2005 by John Wiley & Sons,Inc.1112NATURAL PRODUCTS 1.1INTRODUCTIONBy deﬁnition,the word natural is an adjective referring to something that is present in or produced by nature and not artiﬁcial or man-made.When the word natural is used in verbiage or written,many times it is assumed that the deﬁnition is something good or pure.However,many effective poisons are natural products [145].The term natural products today is quite commonly understood to refer to herbs,herbal concoctions,dietary supplements,tradi-tional Chinese medicine,or alternative medicine [72].That will not be the case in this chapter.The information presented here will be restricted to the dis-covery and development of modern drugs that have been isolated or derived from natural sources.While in some cases,such discovery and development may have been based on herbs,folklore,or traditional or alternative medicine, the research and discovery of,along with the development of,herbal remedies or dietary supplements typically present different challenges with different goals [93,152].So while the stories of herbs and drugs are very much inter-twined,it needs to be fully appreciated that the use of herbs as natural product therapy is different than the use of herbs as a platform for drug discovery and further development.1.2HISTORY AND BACKGROUND OF THE USE OF NATURAL PRODUCTS AS THERAPEUTIC AGENTSNatural products are generally either of prebiotic origin or originate from microbes,plants,or animal sources [115,116].As chemicals,natural products include such classes of compounds as terpenoids,polyketides,amino acids, peptides,proteins,carbohydrates,lipids,nucleic acid bases,ribonucleic acid (RNA),deoxyribonucleic acid (DNA),and so forth.Natural products are not just accidents or products of convenience of nature.More than likely they are a natural expression of the increase in complexity of organisms [76].Interest in natural sources to provide treatments for pain,palliatives,or curatives for a variety of maladies or recreational use reaches back to the earliest points of history.Nature has provided many things for humankind over the years,including the tools for the ﬁrst attempts at therapeutic intervention [115,116].Nean-derthal remains have been found to contain the remnants of medicinal herbs [72].The Nei Ching is one of the earliest health science anthologies ever pro-duced and dates back to the thirtieth century bc[115,116].Some of the ﬁrst records on the use of natural products in medicine were written in cuneiform in Mesopotamia on clay tablets and date to approximately 2600 bc[29,30,115, 116].Indeed,many of these agents continue to exist in one form or another to this day as treatments for inﬂammation,inﬂuenza,coughing,and parasitic infestation.Chinese herb guides document the use of herbaceous plants as far back in time as 2000 bc[72].In fact,The Chinese Materia Medica has beenHISTORY AND BACKGROUND OF THE USE OF NATURAL PRODUCTS13 repeatedly documented over centuries starting at about 1100 bc[29,30].Egyp-tians have been found to have documented uses of various herbs in 1500 bc [29,30,72].The best known of these documents is the Ebers Papyrus,which documents nearly 1000 different substances and formulations,most of which are plant-based medicines [115,116].Asclepius (in 1500 bc) was a physician in ancient Greece who achieved fame in part because of his use of plants in medicine [72].A collection of Ayurvedic hymns in India from 1000 bc and earlier describes the uses of over 1000 different herbs.This work served as the basis for Tibetan Medicine translated from Sanskrit during the eighth century [29,30].Theophrastus,a philosopher and natural scientist in approximately 300 bc,wrote a History of Plants in which he addressed the medicinal quali-ties of herbs and the ability to cultivate them.The Greek botanist Pedanious Dioscorides in approximately ad100 produced a work entitled De Materia Medica,which today is still a very well-known European document on the use of herbs in medicine.Galen (ad130–200),practiced and taught pharmacy and medicine in Rome and published over two dozen books on his areas of inter-est.Galen was well-known for his complex formulations containing numerous and multiple ingredients.Monks in monasteries in the Middle Ages (ﬁfth to the twelfth centuries) copied manuscripts about herbs and their uses [29,30, 72].However,it should not go unrecognized that it was the Arabs who were responsible for maintaining the documentation of much of the Greek and Roman knowledge of herbs and natural products and expanding that infor-mation with their own knowledge of Chinese and Indian herbal medicine [29, 30].The Persian philosopher and physician Avicenna produced a work enti-tled Canon Medicinae,which is considered to be the deﬁnitive summarization of Greek and Roman medicine.Li Shih-Chen produced a Chinese drug ency-clopedia during the Ming Dynasty entitled Pen-ts’as kang mu in ad1596,which records 1898 herbal drugs and 8160 prescriptions [115,116].John Wesley,the founder of Methodism,had a profoundly negative view on the status of physi-cians within society and in 1747 wrote a book entitled Primitive Physic,which was a popular reference book of the time detailing numerous natural cures [72].When the colonists originally came to America,they lacked trained physi-cians and so turned to the Native Americans for advice in healing practices. Such a lack of conventional medicine and physicians in early America spawned the production of various types of almanacs and other publications that con-tained various natural product-based recipes and assorted tidbits of medical information.Indeed,in an effort to curry favor with commoners,physicians themselves turned to the production of self-treatment guides for the general public.Various types of societies and botanical clubs held meetings and pub-lished different types of communiqués to educate the public with regard to the availability of natural products and how they could be helpful to an indi-vidual’s health.Samuel Thompson’s Thompson’s New Guide to Health was one very popular publication.For a variety of different reasons,the interest in natural products continues to this very day [6,8,17,39,72,81,88,90,104].The ﬁrst commercial pure natural product introduced for therapeutic use is gen-14NATURAL PRODUCTS erally considered to be the narcotic morphine,marketed by Merck in 1826 [118].The ﬁrst semisynthetic pure drug based on a natural product,aspirin, was introduced by Bayer in 1899.1.3NATURAL PRODUCT RESEARCH AND DEVELOPMENT—AN UPDATEThe World Health Organization estimates that approximately 80 percent of the world’s population relies primarily on traditional medicines as sources for their primary health care [44].Over 100 chemical substances that are consid-ered to be important drugs that are either currently in use or have been widely used in one or more countries in the world have been derived from a little under 100 different plants.Approximately 75 percent of these substances were discovered as a direct result of chemical studies focused on the isolation of active substances from plants used in traditional medicine [29,30].The number of medicinal herbs used in China in 1979 has been estimated to be numbered at 5267 [115,116].More current statistics based on prescription data from 1993 in the United States show that over 50 percent of the most prescribed drugs had a natural product either as the drug or as the starting point in the syn-thesis or design of the actual end chemical substance [118].Thirty-nine percent of the 520 new drugs approved during the period 1983 through 1994 were either natural products or derivatives of natural products [65].Indeed,if one looks at new drugs from an indication perspective over the same period of time,over 60 percent of antibacterials and antineoplastics were again either natural products themselves or based on structures of natural products.Of the 20 top-selling drugs on the market in the year 2000 that are not proteins,7 of these were either derived from natural products or developed from leads gen-erated from natural products.This select group of drugs generates over 20 billion U.S.dollars of revenue on an annual basis [60,65].Drug development over the years has relied only on a small number of mol-ecular prototypes to produce new medicines [65].Indeed,only approximately 250 discrete chemical structure prototypes have been used up to 1995,but most of these chemical platforms have been derived from natural sources.While recombinant proteins and peptides are gaining market share,low-molecular-weight compounds still remain the predominant pharmacologic choice for therapeutic intervention [60].Just a small sampling of the many available examples of the commercialization of modern drugs from natural products along with their year of introduction,indication,and company are: Orlistat,1999,obesity,Roche;Miglitol,1996,antidiabetic (Type II),Bayer; Topotecan,1996,antineoplastic,SmithKline Beecham;Docetaxel,1995,anti-neoplastic,Rhône-Poulenc Rorer;Tacrolimus,1993,immunosuppressant, Fujisawa;Paclitaxel,1993,antineoplastic,Bristol-Myers Squibb.The overwhelming concern today in the pharmaceutical industry is to improve the ability to ﬁnd new drugs and to accelerate the speed with whichNATURAL PRODUCT RESEARCH AND DEVELOPMENT—AN UPDATE15 new drugs are discovered and developed.This will only be successfully accom-plished if the procedures for drug target elucidation and lead compound iden-tiﬁcation and optimization are themselves optimized.Analysis of the human genome will provide access to a myriad number of potential targets that will need to be evaluated [60,65].The process of high-throughput screening enables the testing of increased numbers of targets and samples to the extent that approximately 100,000 assay points per day are able to be generated. However,the ability to accelerate the identiﬁcation of pertinent lead com-pounds will only be achieved with the implementation of new ideas to gener-ate varieties of structurally diverse test samples [60,65,66].Experience has persistently and repeatedly demonstrated that nature has evolved over thou-sands of years a diverse chemical library of compounds that are not accessi-ble by commonly recognized and frequently used synthetic approaches. Natural products have revealed the ways to new therapeutic approaches, contributed to the understanding of numerous biochemical pathways and have established their worth as valuable tools in biological chemistry and molecular and cellular biology.Just a few examples of some natural products that are currently being evaluated as potential drugs are (natural product, source,target,indication,status):manoalide,marine sponge,phospholipage-A2Ca2+-release,anti-inﬂammatory,clincial trials;dolastatin 10,sea hare, microtubules,antineoplastic,nonclinical;staurosporine,streptomyces,protein kinase C,antineoplastic,clinical trials;epothilone,myxobacterium,micro-tubules,antineoplastic,research;calanolide A,B,tree,DNA polymerase action on reverse transcriptase,acquired immunodeﬁciency syndrome (AIDS),clinical trials;huperzine A,moss,cholinesterase,alzheimer’s disease, clinical trials [60].The costs of drug discovery and drug development continue to increase at astronomical rates,yet despite these expenditures,there is a decrease in the number of new medicines introduced into the world market.Despite the suc-cesses that have been achieved over the years with natural products,the inter-est in natural products as a platform for drug discovery has waxed and waned in popularity with various pharmaceutical companies.Natural products today are most likely going to continue to exist and grow to become even more valu-able as sources of new drug leads.This is because the degree of chemical diver-sity found in natural products is broader than that from any other source,and the degree of novelty of molecular structure found in natural products is greater than that determined from any other source [31,65,142].Where are these opportunities?Well,research into the use of plant-derived natural products alone in just the ﬁeld of medicine covers a broad spectrum of activities [35,67,166,168,169].Examples of such biological activity proﬁles would include,but are not limited to,nootropics,psychoactive agents,depen-dence attenuators,anticonvulsants,sedatives,analgesics,anti-inﬂammatory agents,antipyretics,neurotransmission modulators,autonomic activity modulators,autacoid activity modulators,anticoagulants,hyoplipidemics, antihypertensive agents,cardioprotectants,positive ionotropes,antitussives,16NATURAL PRODUCTS antiasthmatics,pulmonary function enhancers,antiallergens,hypoglycemic agents,antifertility agents,fertility-enhancing agents,wound healing agents, dermal healing agents,bone healing agents,compounds useful in the preven-tion of urinary calculi as well as their dissolution,gastrointestinal motility modulators,gastric ulcer protectants,immunomodulators,hepato-protective agents,myelo-protective agents,pancreato-protective agents,oculo-protective agents,membrane stabilizers,hemato-protective agents,antioxidants,agents protective against oxidative stress,antineoplastics,antimicrobials,antifungal agents,antiprotozoal agents,antihelminthics,and nutraceuticals [35].Many frontiers remain within the ﬁeld of natural products that can provide oppor-tunities to improve our quality of life.Fungal disease has historically been a difﬁcult clinical entity with which to effectively deal.Fungal diseases can include more than just a mycosis and can also include allergic reactions to fungal proteins and toxic reactions to fungal toxins.Mycoses as a group include diseases that are signiﬁcantly more serious and life-threatening than nail infestations,athletes foot,or “jock-itch.”Indeed, increasing numbers of overtly healthy individuals are becoming victims of the complications of fungal infestation.The reasons for this are that increasing numbers of people are receiving immunomodulatory treatment for an organ transplant or some underlying chronic systemic pathology,antineoplastic chemotherapy for cancer,or have been the recipients of proper or improper use of powerful antibiotics.Additionally there are a number of individuals within society that are infected with the human immunodeﬁciency virus (HIV).The available drugs to treat mycoses have been limited [5].Further-more,in this armamentarium,there are problems with dose-limiting nephro-toxicity,the rapid development of resistance,drug–drug interactions of concern,and a fungistatic mechanism of action.Thus there is an urgent need for the development of more efﬁcacious antifungal agents with fewer limita-tions and less side effects.Ideally such compounds should possess good dis-tribution characteristics,a novel mechanism of action,and a broad-spectrum cidal antifungal activity.The discovery and isolation of an echinocandin-type lipopeptide (FR901379) and lipopeptidolactone (FR901469) from microbes has been a signiﬁcant achievement.These compounds are water soluble and inhibit the synthesis of 1,3-b-glycan,a key component of the fungal cell wall. Furthermore,since the cell wall is a feature particular to fungi and is not present in eukaryotic cells,such inhibitors certainly have the potential to demonstrate selective toxicity against the fungi and not against the animal or human host.The ultimate modiﬁcations of the lipopeptide and lipopepti-dolactone referenced above led to the discovery of micafungin (FK463),which is currently in phase III clinical trials.This work along with the relatively recent approval of caspofungin (Merck) as a therapeutic agent for the treatment of disseminated aspergillosis are signiﬁcant achievements in that they demon-strate that a melding of the proper research to identify and develop appro-priate targets with the chemical and biological diversity found in natural products can be very rewarding.NATURAL PRODUCT RESEARCH AND DEVELOPMENT—AN UPDATE17 Much ado has been made over recent years about endocrine disruptors and their effects on humans [33].It needs to be recognized that endocrine disrup-tors are not just synthetic chemicals but can also be natural products.The use of natural product endocrine disruptors may provide signiﬁcant insight into our understanding of the mechanisms by which the evolution of the genome can protect transactivation of the sex hormone receptors and aid in the devel-opment of drugs,which can protect the embryo during its development from hormone disruptive effects.Diabetes is a multisystemic afﬂiction,having impact on nearly every body organ.As a disease,it kills more individuals on a per annum basis than AIDS and breast cancer combined [148].The impact on the quality of life of an indi-vidual suffering with diabetes is profound.A number of natural products cur-rently exist that demonstrate hypoglycemic activity.Indeed,depending upon the source that one might use,there are approximately 800 to 1200 plants that exhibit hypoglycemic activity.While research and development efforts in this particular area thus far are largely restricted to traditional medicine uses, future research may well identify a potent antidiabetic agent.The incidences of neuropsychiatric disorders are steadily increasing as our population increases in size and age.Such disorders include,but are not limited to,seizure disorders,schizophrenia,dementia,mania,aggression, memory loss,psychoses,age-related cognitive decline,depression,anxiety states,mood disorders,substance abuse,and substance dependence.There is a large body of data available that suggests the use of many natural products as potential treatments for these conditions and other neuropsychiatric disor-ders [18,91,92].Indeed,a number of plant extracts have been associated with the treatment of various categories of mental symptoms and various types of receptor selectivity [18].A very controversial potential psychotherapeutic agent is Gingko biloba[52].A lack of understanding of mechanism of action, misidentiﬁcation of materials,contamination of materials,intrinsic toxicity,and absence of standardization all contribute to this controversy.Further frac-tionation,isolation,and characterization of active components of these and other plants will undoubtedly lead to the discovery of novel neuropsychiatric agents as well as the debunking of other alleged therapies.There are numerous blood-based diseases that afﬂict humans.These would include,but are not limited to,anemia,blood group incompatibility,blood protein disorders,bone marrow diseases,hemoglobinopathies,hemorrhagic diatheses,leukemia,disorders of leukocyte dysfunction,platelet disorders,and erythrocyte aggregation disorders.A number of natural products have been reported in the literature to be of value in the treatment of Epstein-Barr virus infection,leukemia,thrombosis and coagulopathy,malaria,anemia,and bone marrow diseases [113].Extracts from the fungus Trichothecium roseum,the sea cucumber Cucumaria japonica,the legume Amorpha fruitcosa,the tree Magnolia ofﬁcinalis,and others may be useful in the therapeutic management of Epstein-Barr virus infection.Extracts from the basidiomycetes Mycena pura and Nidula candida may be useful in the treatment of -18NATURAL PRODUCTS pounds isolated from Streptomyces platensis may be useful in the treatment of pounds obtained from the marine sponge Aplysina archeri have been reported to inhibit the growth of the feline leukemia virus. Scalarane-type bishomo-sesterterpenes isolated from the marine sponge Phyl-lospongia foliascens have been reported to exhibit cytotoxic,antithrombocytic, and vasodilation activities.It should be noted that a number of natural prod-ucts are based on the coumarin nucleus and as such may exhibit antithrom-botic and antiplatelet activities.A number of blood-sucking animals have small,low-molecular-weight proteins in their salivas that interfere with the clotting of blood and therefore might be of value as potential anticoagulants. Streptomyces hygroscopicus ascomyceticus manufactures a macrolide that has been reported to have immunosuppressant activity and may prove to be ben-eﬁcial in preventing transplant rejection in humans.It is entirely possible that these compounds and others offer sufﬁcient structural diversity,range of bio-logical activities,and differing mechanisms of action that new,safer,and more efﬁcacious drugs to treat blood-based disorders could well burgeon from this library.A wide variety of natural products are claimed to possess immunosup-pressant activity,but it is often difﬁcult to dissect this activity away from asso-ciated cytotoxicity [101].Since the ﬁrst heart transplant in the late 1960s, medicine has progressed to the point where most organ transplants have become relatively routine procedures.The survival of individuals with trans-plants is owed in large part to the discovery of the fungal metabolite cyclosporine A in 1970 and its widespread use starting in 1978.Indeed, cyclosporine A has achieved such success that it is currently being evaluated for value in the treatment of Crohn’s disease,systemic lupus erythematosus, and rheumatoid arthritis.Research efforts abound in the area of natural prod-ucts and immunosuppression.A methyl analog of oligomycin F isolated from Streptomyces ostreogriseus has been reported to quite effectively suppress B-cell activation and T-cell activation in the presence of mitogens at concentra-tions comparable to that of cyclosporine A.Concanamycin F ﬁrst isolated from Streptomyces diastatochromogenes in 1992 has been found to possess a wide array of biological activities including immunosuppressive and antiviral activ-ities.The experimental immunosuppressant (+)-discodermolide isolated from the marine sponge Discodermia dissoluta exhibits relatively nonspeciﬁc immunosuppression,causing the cell cycle to arrest during G2and M phases. This compound’s current primary interest is as a potential antineoplastic agent since it stabilizes microtubules and prevents depolymerization,effectively causing cell cyclic arrest during the metaphase to anaphase transition.This same mode of activity is shared with Taxol (Paclitaxel),the epothilones, eleutherobin,and the sarcodictyins.The didemnins,cyclic peptides,were ﬁrst isolated from the marine tunicate Trididemnum solidum and exhibit immuno-suppressive activity through a generalized cytotoxicity mediated by inhibition of progression through the G1phase of the cell cycle by an unknown mecha-nism.The trichopolyns I to V from the fungus Trichoderma polysporum areNATURAL PRODUCT RESEARCH AND DEVELOPMENT—AN UPDATE19 lipopeptides that suppress the proliferation of lymphocytes in the murine allo-geneic mixed lymphocyte response assay.Triptolide from the plant Triptery-gium winfordii demonstrates immunosuppressant activity through the inhibition of IL-2 receptor expression and signal transduction.The novel het-eroaromatic compound lymphostin,obtained from Streptomyces KY11783 has demonstrated immunosuppressant activity through its potent inhibition of the lymphocyte kinase p56lck.Over the last decade,research activities on immuno-suppressants of natural product origin have focused on the mechanisms of inhibition of T-cell activation and proliferation.This approach has been fruit-ful,leading to the generation of signiﬁcant information about signaling path-ways between T cells,greater detail about the roles of T cells in immune function,and the discovery of Tacrolimus (Prograf) from the soil fungus Strep-tomyces tsukubaensis.As immunological research progresses,increasingly more potential targets will be elucidated for immunomodulatory therapeutic intervention.Natural products will undoubtedly provide a sound platform for the delivery of natural-product-based therapeutic agent candidates.Natural-products-based anticancer drug discovery continues to be an active area of research throughout the world [34,102,112,147].While cancer inci-dences and the frequencies of types of cancer may vary from country to country,the most common sites for the development of neoplasia are gener-ally considered to be the breast,colon/rectum,prostate,cervix/uterus,esoph-agus/stomach,pancreas,liver,lung,urinary bladder,kidney,ovary,oral cavity, and blood (leukemia and non-Hodgkin lymphoma) [147].Currently,the chemotherapeutic management of these tumors involves a variety of different plant-based chemicals that are either currently in use or in clinical trials and include such drug classes as the vinca alkaloids,lignans,taxanes,stilbenes,ﬂavones,cephalotaxanes,camptothecins,and taxanes.Despite the wide range of organ structure,type,and function,great similarities exist between the organs with regard to the pathogenesis of cancer.As more and more details of the molecular biology of cancer are revealed,more targets will present themselves for possible therapeutic chemical intervention in the growth and development of neoplasms.A somewhat new approach is that of cancer chemoprevention,where chemoprevention is deﬁned as the prevention,delay, or reversal of carcinogenesis [112].A few of the more promising cancer chemopreventive agents are (compound,plant source,target):brusatol, Brucea javanica,differentiation;zapotin,Casimiroa edulis,differentiation and apoptosis;apigenin,Mezoneuron cacullatum,antimutagenesis;deguelin, Mundelea sericea,inhibitor of ornithine decarboxylase;brassinin,Brassica spp.,inducer of quinine reductase;and resveratrol,Cassia quinquangulata, cyclooxygenase inhibitor.A ﬁnal note with regard to this approach is that it is important to appreciate that the distinction between chemopreventive agent and chemotherapeutic agent can become quite blurred.A recurrent theme in neoplasia is the alteration of cell cycle control.One therapeutic approach to the treatment of neoplasia is the development of a treatment that would return to normal the altered cell cycle [143].Cyclin-20NATURAL PRODUCTS dependent kinases (CDKs) control the progression of a cell through its growth cycle.CDKs are regulated through a series of site-speciﬁc complex mecha-nisms,and the components of such mechanisms include activating cyclins and endogenous CDK inhibitors.Processes of such mechanisms involve regulatory phosphorylation.There are natural products such as butyrolactone and stau-rosporine that are currently known to be able to provide such activity.These compounds and others generated from their platform are adenosine 5¢-triphosphate (ATP) site-directed inhibitors and directly antagonize the activ-ity of CDKs.Further research should more fully elucidate the most efﬁcacious endpoint of CDK inhibition and lead to the control of neoplastic growth and possibly even bring about cytostasis or apoptosis.The introduction of active agents derived from natural sources into the anti-cancer weaponry has already signiﬁcantly changed the futures of many indi-viduals afﬂicted with cancer of many different types.Continued research into natural sources will continue to deliver newer and more promising chemicals and chemical classes of anticancer agents with novel mechanisms of action that will improve survival rates to even higher degrees.Human immunodeﬁciency virus infection is a devastating,globally wide-spread disease that consumes signiﬁcant health-care dollars in the due course of management of patients [79].Most of the currently useful anti-HIV agents are nucleosides and are limited in use due to severe toxicity and emerging drug resistance.Natural products,with their broad chemical structural diversity, provide an excellent opportunity to deliver signiﬁcant therapeutic advances in the treatment of HIV [167].Many natural products with novel structures have been identiﬁed as having anti-HIV activities [79,167].Betulinic acid,a triter-penoid isolated from Syzigium claviﬂorum,has been found to contain anti-HIV activity in lymphocytes.The quassinoside glycoside isolated from Allanthus altissima has been found to inhibit HIV replication.Artemisinin, isolated from Artemisia anuua,is a sesquiterpene lactone that is of special interest because of its novel structure,potent antimalarial activity,and activ-ity against Pneumocystis carinii. A novel phorbol ester isolated from Excoecaria agallocba has been reported to be a potent inhibitor of HIV-1 reverse transcriptase.Indeed,most of the natural product chemicals that are attracting interest in this area of research are secondary metabolites such as terpenes,phenolics,peptides,alkaloids,and carbohydrates and are also inhibitors of HIV reverse transcriptase.Other target opportunities in the life cycle of the human immunodeﬁciency virus available for exploitation are:(1) attachment of virus to cell surface,(2) penetration and fusion of the virus with the cell membrane,(3) reverse transcription via reverse transcriptase,(4) inte-gration into the host genome,(5) synthesis of viral proteins including zinc ﬁngers,and (6) processing of viral polypeptide with HIV protease and assem-bly of viral proteins and DNA into a viral particle,maturation,and extrusion of the mature virus [167].Infectious viral diseases remain a worldwide problem.Viruses have been resistant to therapy or treatment longer than most other forms of life because。

PeerReviewShouldWeModifyOurProcess

measure of the peer review process. We typi-cally use two and sometimes three reviewers when the decision rendered is significantly different. In our experience, if there is inter-reviewer agreement, specifically on the qual-ity of the manuscript, the end result is that articles receive more attention (press releas-es) and are more frequently cited by other researchers. Finally, reviewer bias has been suggested as a negative factor for the peer review process. In our experience, reviewer bias may include research bias (“I’m an ex-pert in the field so no one else can be”), au-thor bias (chemistry issues when a reviewer thinks he or she knows the authors), institu-tion bias, and vendor bias. In these situations, our reviewers are instructed to recuse them-selves and decline review of the manuscript.Suggestions for alternatives to the peer review process have increased in the past de-cades [2, 4]. Our ability to modify the peer review process has been presented with more options, partially driven by the electronic era and the multiple online tools available. Open peer review, community peer review, and re-viewer bidding are a few of the options cur-rently under discussion or implementation by other journals [2, 7]. The open peer review process identifies the reviewers. The litera-ture regarding this approach to peer review is limited [2, 7]. It has been argued that if the reviewers are known to the submitting authors, reviewers will be more consistent in providing quality reviews. If we were to make this change, I suspect we would have more trouble getting reviewers to accept our invitations to review. However, I would agree they may be more inclined to provide more in-depth reviews. An additional concern is the potential for conflict of interest issues in our small community of subspecialty authors and reviewers.Community or public review enables open evaluation by interested parties for a defined period once the manuscript is launched elec-tronically. This results in a period of po-tentially dynamic change in the content of the article, presumably resulting in the fin-ished product once the active online period is completed. There are concerns with this approach. First, if the manuscript is cited during the active review process, those cit-ate each manuscript with CrossCheck to avoid duplicating previously published work before consideration for peer review [4]. The staff also checks each submission to ensure the correct manuscript category has been selected and the authors have made substan-tive contributions. Once the initial check is complete, the manuscript is forwarded to the appropriate section editor for assignment to peer review. We typically select two review-ers by matching their expertise to that of the submitted manuscript. When the reviews are discrepant, additional reviewers are invited.Other radiology journals may use similar, or in some cases quite different, approaches to peer review. For example, some open ac-cess journals do not clearly define their peer review process. In addition, several open ac-cess journals allow the authors to maintain the copyright. This may potentially increase the already large number of duplicate publi-cations listed in PubMed. What are and have been the criticisms of the peer review process and should we modify our current approach?First, as noted, there are inconsistencies in how each journal approaches the peer review process. With the electronic era, the variety of approaches has become even more diverse [1, 2, 4]. Birukou et al. [2] provided a superb discussion of the controversies and potential approaches to manuscript evaluation. Scien-tific data on the value or lack thereof for peer review are most often focused on what can or cannot be accomplished—namely, detecting errors in content and determining the impact of the article on future medical practice [2, 5, 6]. Some data suggest that the peer review process is effective, at least in the former, whereas other data suggest the process is in-effective [2, 5, 6].Birukou et al. [2] reviewed potential met-rics of peer review, including impact of peer-reviewed manuscripts, interreviewer agree-ment, and bias. For example, if reviewers improve manuscripts and scientific content, do the articles accepted provide significant new material and are they cited more fre-quently? Once again, some data suggest that if reviewers’ recommendations are followed, the articles become more important. Other data suggest this may not be the case [2]. In-terreviewer agreement may be an additional Peer Review: Should We Modify Our Process?The peer review process for bio-medical publications began in the 1700s with the Royal Soci-ety of Edinburg’s Medical Es-says and Observations [1]. Since that time, most medical journals have used peer review to ensure scientific integrity. However, the methods of peer review vary extensively [2]. The approaches are definitely evolving and variable. For example, the processes insti-tuted by a given journal may include single- and double-blinded peer review, open peer review, and postpublishing peer review. Peer review has become even more controversial in the electronic era with the recent explo-sion in the number of open access journals. There are currently more than 100 radiology journals throughout the world.The American Journal of Roentgenology (AJR) follows the International Committee for Medical Journal Editors (ICMJE) guide-lines for scientific publications (). The ICM JE guidelines clearly define the role of editors and reviewers in the peer review process [3].Editors“The editor of the journal is the person responsible for its entire content. Editors must have full authority for determining the editorial content of the journal” ().ReviewersPeer review must provide an “unbiased, independent, critical assessment that is an intrinsic part of all scholarly work, includ-ing the scientific process. Peer review is the critical assessment of manuscripts submitted to journals by experts who are not part of the editorial staff. Peer review can therefore be viewed as an important extension of the sci-entific process” ().Historically, we have used a double-blinded process in which the authors and reviewers remain anonymous. The editors are responsible for the scientific content and quality of the AJR . Therefore, on occasion a submission may be rejected without review if there are concerns about content or the manuscript is not considered suitable for our readership. The normal process is to evalu-EditorialD o w n l o a d e d f r o m w w w .a j r o n l i n e .o r g b y 220.176.50.14 o n 07/22/16 f r o m I P a d d r e s s 220.176.50.14. C o p y r i g h t A R R S . F o r p e r s o n a l u s e o n l y ; a l l r i g h t s r e s e r v e dEditorialing the manuscript may have to retract as-pects of their study once the review period is completed. This issue may result in fewer citations. Second, how do you prevent pro-fessional antagonistic activity?Finally, bidding for peer review is another method presented so that researchers may assist the authors in improving their product because of the high level of interest in the work and expertise of the bidder to review a given topic [2]. There are electronic systems to assist with this approach. Although more data are required, this approach does allow the reviewer to select a topic that is of high interest. The end result is that the reviewer may be able to assist the authors more effec-tively. The downside is the potential increase in turn-around time for the article and the potential for reviewers with a negative bias on the topic to bid [2, 4].How should the AJR approach potential changes to improve our peer review process? The editorial staff members have clearly de-fined job descriptions regarding their roles in the peer review process. The content of these job descriptions is reviewed annually and revised as necessary. We have a well-defined process for reviewing and decision making, and for potential author appeals de-pending on the final decision. Our process is designed to be author friendly and provideoptimal turn-around time from submission to final decision. Our new online vendor, Atypon, provides the ability to publish ahead of print for key manuscripts. This gives us the opportunity to present key manuscripts to our readers far ahead of the normal publi-cation process time. However, publish ahead of print will not change the fact that full co-pyediting and layout will occur before on-line publication. We want to avoid ongoing changes in articles that can occur with the public review process.We’ve taken some important new steps in our approaches to reviewer assistance so that reviews are more complete and useful to the authors. We now require new reviewers to at-tend an orientation WebEx session. We also have new reviewer assistance material on our reviewer site, including templates for review-ing each of the manuscript types that authors may select. We also plan on holding “how to get published” sessions at the ARRS annual meetings and will offer our WebEx sessions to all reviewers beginning this year.At this time, we have no plans to modify our current peer review process. However, we will continue to monitor the changing electronic environment for potential ways to improve the peer review process for the AJR . Our goal is to define the best mechanisms to optimize constructive, consistent reviews forour authors and provide manuscripts with significant practice impact for our readers.Thomas H. BerquistEditor in Chief ******************DOI:10.2214/AJR.13.12415References1. Kronick DA. Peer review in 18th-century scien-tific journalism. JAMA 1990; 263:1321–13222. Birukou A, Wakeling JR, Bartolini C, et al. Alter-natives to peer review: novel approaches for re-search evaluation. Front Comput Neurosci 2011; 5:563. Berquist TH. Editors and reviewers: roles and re-sponsibilities. AJR 2012; 198:2454. Berquist TH. Peer review: is the process broken.AJR 2012; 199:2435. Godlee F, Gale CR, M artyn CN. Effect on thequality of peer of blinded reviewers and asking them to sign their reports in a randomized con-trolled trial. JAMA 1998; 280:237–2406. Goodman SN, Berlin J, Fletcher SW, et al. Manu-script quality before and after peer review and editing at Annals of Internal Medicine. Ann In-tern Med 1994; 121:11–217. Solomon DJ. The role of peer review for scholarlyjournals in the information age. Journal of Elec-tronic Publishing website. /j/jep /3336451.0010.107?rgn=main;view=fulltext. Pub-lished Winter 2007. Accessed December 19, 2013\D o w n l o a d e d f r o m w w w .a j r o n l i n e .o r g b y 220.176.50.14 o n 07/22/16 f r o m I P a d d r e s s 220.176.50.14. C o p y r i g h t A R R S . F o r p e r s o n a l u s e o n l y ; a l l r i g h t s r e s e r v e d。

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History of infrared detectorsA.ROGALSKI*Institute of Applied Physics, Military University of Technology, 2 Kaliskiego Str.,00–908 Warsaw, PolandThis paper overviews the history of infrared detector materials starting with Herschel’s experiment with thermometer on February11th,1800.Infrared detectors are in general used to detect,image,and measure patterns of the thermal heat radia−tion which all objects emit.At the beginning,their development was connected with thermal detectors,such as ther−mocouples and bolometers,which are still used today and which are generally sensitive to all infrared wavelengths and op−erate at room temperature.The second kind of detectors,called the photon detectors,was mainly developed during the20th Century to improve sensitivity and response time.These detectors have been extensively developed since the1940’s.Lead sulphide(PbS)was the first practical IR detector with sensitivity to infrared wavelengths up to~3μm.After World War II infrared detector technology development was and continues to be primarily driven by military applications.Discovery of variable band gap HgCdTe ternary alloy by Lawson and co−workers in1959opened a new area in IR detector technology and has provided an unprecedented degree of freedom in infrared detector design.Many of these advances were transferred to IR astronomy from Departments of Defence ter on civilian applications of infrared technology are frequently called“dual−use technology applications.”One should point out the growing utilisation of IR technologies in the civilian sphere based on the use of new materials and technologies,as well as the noticeable price decrease in these high cost tech−nologies.In the last four decades different types of detectors are combined with electronic readouts to make detector focal plane arrays(FPAs).Development in FPA technology has revolutionized infrared imaging.Progress in integrated circuit design and fabrication techniques has resulted in continued rapid growth in the size and performance of these solid state arrays.Keywords:thermal and photon detectors, lead salt detectors, HgCdTe detectors, microbolometers, focal plane arrays.Contents1.Introduction2.Historical perspective3.Classification of infrared detectors3.1.Photon detectors3.2.Thermal detectors4.Post−War activity5.HgCdTe era6.Alternative material systems6.1.InSb and InGaAs6.2.GaAs/AlGaAs quantum well superlattices6.3.InAs/GaInSb strained layer superlattices6.4.Hg−based alternatives to HgCdTe7.New revolution in thermal detectors8.Focal plane arrays – revolution in imaging systems8.1.Cooled FPAs8.2.Uncooled FPAs8.3.Readiness level of LWIR detector technologies9.SummaryReferences 1.IntroductionLooking back over the past1000years we notice that infra−red radiation(IR)itself was unknown until212years ago when Herschel’s experiment with thermometer and prism was first reported.Frederick William Herschel(1738–1822) was born in Hanover,Germany but emigrated to Britain at age19,where he became well known as both a musician and an astronomer.Herschel became most famous for the discovery of Uranus in1781(the first new planet found since antiquity)in addition to two of its major moons,Tita−nia and Oberon.He also discovered two moons of Saturn and infrared radiation.Herschel is also known for the twenty−four symphonies that he composed.W.Herschel made another milestone discovery–discov−ery of infrared light on February11th,1800.He studied the spectrum of sunlight with a prism[see Fig.1in Ref.1],mea−suring temperature of each colour.The detector consisted of liquid in a glass thermometer with a specially blackened bulb to absorb radiation.Herschel built a crude monochromator that used a thermometer as a detector,so that he could mea−sure the distribution of energy in sunlight and found that the highest temperature was just beyond the red,what we now call the infrared(‘below the red’,from the Latin‘infra’–be−OPTO−ELECTRONICS REVIEW20(3),279–308DOI: 10.2478/s11772−012−0037−7*e−mail: rogan@.pllow)–see Fig.1(b)[2].In April 1800he reported it to the Royal Society as dark heat (Ref.1,pp.288–290):Here the thermometer No.1rose 7degrees,in 10minu−tes,by an exposure to the full red coloured rays.I drew back the stand,till the centre of the ball of No.1was just at the vanishing of the red colour,so that half its ball was within,and half without,the visible rays of theAnd here the thermometerin 16minutes,degrees,when its centre was inch out of the raysof the sun.as had a rising of 9de−grees,and here the difference is almost too trifling to suppose,that latter situation of the thermometer was much beyond the maximum of the heating power;while,at the same time,the experiment sufficiently indi−cates,that the place inquired after need not be looked for at a greater distance.Making further experiments on what Herschel called the ‘calorific rays’that existed beyond the red part of the spec−trum,he found that they were reflected,refracted,absorbed and transmitted just like visible light [1,3,4].The early history of IR was reviewed about 50years ago in three well−known monographs [5–7].Many historical information can be also found in four papers published by Barr [3,4,8,9]and in more recently published monograph [10].Table 1summarises the historical development of infrared physics and technology [11,12].2.Historical perspectiveFor thirty years following Herschel’s discovery,very little progress was made beyond establishing that the infrared ra−diation obeyed the simplest laws of optics.Slow progress inthe study of infrared was caused by the lack of sensitive and accurate detectors –the experimenters were handicapped by the ordinary thermometer.However,towards the second de−cade of the 19th century,Thomas Johann Seebeck began to examine the junction behaviour of electrically conductive materials.In 1821he discovered that a small electric current will flow in a closed circuit of two dissimilar metallic con−ductors,when their junctions are kept at different tempera−tures [13].During that time,most physicists thought that ra−diant heat and light were different phenomena,and the dis−covery of Seebeck indirectly contributed to a revival of the debate on the nature of heat.Due to small output vol−tage of Seebeck’s junctions,some μV/K,the measurement of very small temperature differences were prevented.In 1829L.Nobili made the first thermocouple and improved electrical thermometer based on the thermoelectric effect discovered by Seebeck in 1826.Four years later,M.Melloni introduced the idea of connecting several bismuth−copper thermocouples in series,generating a higher and,therefore,measurable output voltage.It was at least 40times more sensitive than the best thermometer available and could de−tect the heat from a person at a distance of 30ft [8].The out−put voltage of such a thermopile structure linearly increases with the number of connected thermocouples.An example of thermopile’s prototype invented by Nobili is shown in Fig.2(a).It consists of twelve large bismuth and antimony elements.The elements were placed upright in a brass ring secured to an adjustable support,and were screened by a wooden disk with a 15−mm central aperture.Incomplete version of the Nobili−Melloni thermopile originally fitted with the brass cone−shaped tubes to collect ra−diant heat is shown in Fig.2(b).This instrument was much more sensi−tive than the thermometers previously used and became the most widely used detector of IR radiation for the next half century.The third member of the trio,Langley’s bolometer appea−red in 1880[7].Samuel Pierpont Langley (1834–1906)used two thin ribbons of platinum foil connected so as to form two arms of a Wheatstone bridge (see Fig.3)[15].This instrument enabled him to study solar irradiance far into its infrared region and to measure theintensityof solar radia−tion at various wavelengths [9,16,17].The bolometer’s sen−History of infrared detectorsFig.1.Herschel’s first experiment:A,B –the small stand,1,2,3–the thermometers upon it,C,D –the prism at the window,E –the spec−trum thrown upon the table,so as to bring the last quarter of an inch of the read colour upon the stand (after Ref.1).InsideSir FrederickWilliam Herschel (1738–1822)measures infrared light from the sun– artist’s impression (after Ref. 2).Fig.2.The Nobili−Meloni thermopiles:(a)thermopile’s prototype invented by Nobili (ca.1829),(b)incomplete version of the Nobili−−Melloni thermopile (ca.1831).Museo Galileo –Institute and Museum of the History of Science,Piazza dei Giudici 1,50122Florence, Italy (after Ref. 14).Table 1. Milestones in the development of infrared physics and technology (up−dated after Refs. 11 and 12)Year Event1800Discovery of the existence of thermal radiation in the invisible beyond the red by W. HERSCHEL1821Discovery of the thermoelectric effects using an antimony−copper pair by T.J. SEEBECK1830Thermal element for thermal radiation measurement by L. NOBILI1833Thermopile consisting of 10 in−line Sb−Bi thermal pairs by L. NOBILI and M. MELLONI1834Discovery of the PELTIER effect on a current−fed pair of two different conductors by J.C. PELTIER1835Formulation of the hypothesis that light and electromagnetic radiation are of the same nature by A.M. AMPERE1839Solar absorption spectrum of the atmosphere and the role of water vapour by M. MELLONI1840Discovery of the three atmospheric windows by J. HERSCHEL (son of W. HERSCHEL)1857Harmonization of the three thermoelectric effects (SEEBECK, PELTIER, THOMSON) by W. THOMSON (Lord KELVIN)1859Relationship between absorption and emission by G. KIRCHHOFF1864Theory of electromagnetic radiation by J.C. MAXWELL1873Discovery of photoconductive effect in selenium by W. SMITH1876Discovery of photovoltaic effect in selenium (photopiles) by W.G. ADAMS and A.E. DAY1879Empirical relationship between radiation intensity and temperature of a blackbody by J. STEFAN1880Study of absorption characteristics of the atmosphere through a Pt bolometer resistance by S.P. LANGLEY1883Study of transmission characteristics of IR−transparent materials by M. MELLONI1884Thermodynamic derivation of the STEFAN law by L. BOLTZMANN1887Observation of photoelectric effect in the ultraviolet by H. HERTZ1890J. ELSTER and H. GEITEL constructed a photoemissive detector consisted of an alkali−metal cathode1894, 1900Derivation of the wavelength relation of blackbody radiation by J.W. RAYEIGH and W. WIEN1900Discovery of quantum properties of light by M. PLANCK1903Temperature measurements of stars and planets using IR radiometry and spectrometry by W.W. COBLENTZ1905 A. EINSTEIN established the theory of photoelectricity1911R. ROSLING made the first television image tube on the principle of cathode ray tubes constructed by F. Braun in 18971914Application of bolometers for the remote exploration of people and aircrafts ( a man at 200 m and a plane at 1000 m)1917T.W. CASE developed the first infrared photoconductor from substance composed of thallium and sulphur1923W. SCHOTTKY established the theory of dry rectifiers1925V.K. ZWORYKIN made a television image tube (kinescope) then between 1925 and 1933, the first electronic camera with the aid of converter tube (iconoscope)1928Proposal of the idea of the electro−optical converter (including the multistage one) by G. HOLST, J.H. DE BOER, M.C. TEVES, and C.F. VEENEMANS1929L.R. KOHLER made a converter tube with a photocathode (Ag/O/Cs) sensitive in the near infrared1930IR direction finders based on PbS quantum detectors in the wavelength range 1.5–3.0 μm for military applications (GUDDEN, GÖRLICH and KUTSCHER), increased range in World War II to 30 km for ships and 7 km for tanks (3–5 μm)1934First IR image converter1939Development of the first IR display unit in the United States (Sniperscope, Snooperscope)1941R.S. OHL observed the photovoltaic effect shown by a p−n junction in a silicon1942G. EASTMAN (Kodak) offered the first film sensitive to the infrared1947Pneumatically acting, high−detectivity radiation detector by M.J.E. GOLAY1954First imaging cameras based on thermopiles (exposure time of 20 min per image) and on bolometers (4 min)1955Mass production start of IR seeker heads for IR guided rockets in the US (PbS and PbTe detectors, later InSb detectors for Sidewinder rockets)1957Discovery of HgCdTe ternary alloy as infrared detector material by W.D. LAWSON, S. NELSON, and A.S. YOUNG1961Discovery of extrinsic Ge:Hg and its application (linear array) in the first LWIR FLIR systems1965Mass production start of IR cameras for civil applications in Sweden (single−element sensors with optomechanical scanner: AGA Thermografiesystem 660)1970Discovery of charge−couple device (CCD) by W.S. BOYLE and G.E. SMITH1970Production start of IR sensor arrays (monolithic Si−arrays: R.A. SOREF 1968; IR−CCD: 1970; SCHOTTKY diode arrays: F.D.SHEPHERD and A.C. YANG 1973; IR−CMOS: 1980; SPRITE: T. ELIOTT 1981)1975Lunch of national programmes for making spatially high resolution observation systems in the infrared from multielement detectors integrated in a mini cooler (so−called first generation systems): common module (CM) in the United States, thermal imaging commonmodule (TICM) in Great Britain, syteme modulaire termique (SMT) in France1975First In bump hybrid infrared focal plane array1977Discovery of the broken−gap type−II InAs/GaSb superlattices by G.A. SAI−HALASZ, R. TSU, and L. ESAKI1980Development and production of second generation systems [cameras fitted with hybrid HgCdTe(InSb)/Si(readout) FPAs].First demonstration of two−colour back−to−back SWIR GaInAsP detector by J.C. CAMPBELL, A.G. DENTAI, T.P. LEE,and C.A. BURRUS1985Development and mass production of cameras fitted with Schottky diode FPAs (platinum silicide)1990Development and production of quantum well infrared photoconductor (QWIP) hybrid second generation systems1995Production start of IR cameras with uncooled FPAs (focal plane arrays; microbolometer−based and pyroelectric)2000Development and production of third generation infrared systemssitivity was much greater than that of contemporary thermo−piles which were little improved since their use by Melloni. Langley continued to develop his bolometer for the next20 years(400times more sensitive than his first efforts).His latest bolometer could detect the heat from a cow at a dis−tance of quarter of mile [9].From the above information results that at the beginning the development of the IR detectors was connected with ther−mal detectors.The first photon effect,photoconductive ef−fect,was discovered by Smith in1873when he experimented with selenium as an insulator for submarine cables[18].This discovery provided a fertile field of investigation for several decades,though most of the efforts were of doubtful quality. By1927,over1500articles and100patents were listed on photosensitive selenium[19].It should be mentioned that the literature of the early1900’s shows increasing interest in the application of infrared as solution to numerous problems[7].A special contribution of William Coblenz(1873–1962)to infrared radiometry and spectroscopy is marked by huge bib−liography containing hundreds of scientific publications, talks,and abstracts to his credit[20,21].In1915,W.Cob−lentz at the US National Bureau of Standards develops ther−mopile detectors,which he uses to measure the infrared radi−ation from110stars.However,the low sensitivity of early in−frared instruments prevented the detection of other near−IR sources.Work in infrared astronomy remained at a low level until breakthroughs in the development of new,sensitive infrared detectors were achieved in the late1950’s.The principle of photoemission was first demonstrated in1887when Hertz discovered that negatively charged par−ticles were emitted from a conductor if it was irradiated with ultraviolet[22].Further studies revealed that this effect could be produced with visible radiation using an alkali metal electrode [23].Rectifying properties of semiconductor−metal contact were discovered by Ferdinand Braun in1874[24],when he probed a naturally−occurring lead sulphide(galena)crystal with the point of a thin metal wire and noted that current flowed freely in one direction only.Next,Jagadis Chandra Bose demonstrated the use of galena−metal point contact to detect millimetre electromagnetic waves.In1901he filed a U.S patent for a point−contact semiconductor rectifier for detecting radio signals[25].This type of contact called cat’s whisker detector(sometimes also as crystal detector)played serious role in the initial phase of radio development.How−ever,this contact was not used in a radiation detector for the next several decades.Although crystal rectifiers allowed to fabricate simple radio sets,however,by the mid−1920s the predictable performance of vacuum−tubes replaced them in most radio applications.The period between World Wars I and II is marked by the development of photon detectors and image converters and by emergence of infrared spectroscopy as one of the key analytical techniques available to chemists.The image con−verter,developed on the eve of World War II,was of tre−mendous interest to the military because it enabled man to see in the dark.The first IR photoconductor was developed by Theodore W.Case in1917[26].He discovered that a substance com−posed of thallium and sulphur(Tl2S)exhibited photocon−ductivity.Supported by the US Army between1917and 1918,Case adapted these relatively unreliable detectors for use as sensors in an infrared signalling device[27].The pro−totype signalling system,consisting of a60−inch diameter searchlight as the source of radiation and a thallous sulphide detector at the focus of a24−inch diameter paraboloid mir−ror,sent messages18miles through what was described as ‘smoky atmosphere’in1917.However,instability of resis−tance in the presence of light or polarizing voltage,loss of responsivity due to over−exposure to light,high noise,slug−gish response and lack of reproducibility seemed to be inhe−rent weaknesses.Work was discontinued in1918;commu−nication by the detection of infrared radiation appeared dis−tinctly ter Case found that the addition of oxygen greatly enhanced the response [28].The idea of the electro−optical converter,including the multistage one,was proposed by Holst et al.in1928[29]. The first attempt to make the converter was not successful.A working tube consisted of a photocathode in close proxi−mity to a fluorescent screen was made by the authors in 1934 in Philips firm.In about1930,the appearance of the Cs−O−Ag photo−tube,with stable characteristics,to great extent discouraged further development of photoconductive cells until about 1940.The Cs−O−Ag photocathode(also called S−1)elabo−History of infrared detectorsFig.3.Longley’s bolometer(a)composed of two sets of thin plati−num strips(b),a Wheatstone bridge,a battery,and a galvanometer measuring electrical current (after Ref. 15 and 16).rated by Koller and Campbell[30]had a quantum efficiency two orders of magnitude above anything previously studied, and consequently a new era in photoemissive devices was inaugurated[31].In the same year,the Japanese scientists S. Asao and M.Suzuki reported a method for enhancing the sensitivity of silver in the S−1photocathode[32].Consisted of a layer of caesium on oxidized silver,S−1is sensitive with useful response in the near infrared,out to approxi−mately1.2μm,and the visible and ultraviolet region,down to0.3μm.Probably the most significant IR development in the United States during1930’s was the Radio Corporation of America(RCA)IR image tube.During World War II, near−IR(NIR)cathodes were coupled to visible phosphors to provide a NIR image converter.With the establishment of the National Defence Research Committee,the develop−ment of this tube was accelerated.In1942,the tube went into production as the RCA1P25image converter(see Fig.4).This was one of the tubes used during World War II as a part of the”Snooperscope”and”Sniperscope,”which were used for night observation with infrared sources of illumination.Since then various photocathodes have been developed including bialkali photocathodes for the visible region,multialkali photocathodes with high sensitivity ex−tending to the infrared region and alkali halide photocatho−des intended for ultraviolet detection.The early concepts of image intensification were not basically different from those today.However,the early devices suffered from two major deficiencies:poor photo−cathodes and poor ter development of both cathode and coupling technologies changed the image in−tensifier into much more useful device.The concept of image intensification by cascading stages was suggested independently by number of workers.In Great Britain,the work was directed toward proximity focused tubes,while in the United State and in Germany–to electrostatically focused tubes.A history of night vision imaging devices is given by Biberman and Sendall in monograph Electro−Opti−cal Imaging:System Performance and Modelling,SPIE Press,2000[10].The Biberman’s monograph describes the basic trends of infrared optoelectronics development in the USA,Great Britain,France,and Germany.Seven years later Ponomarenko and Filachev completed this monograph writ−ing the book Infrared Techniques and Electro−Optics in Russia:A History1946−2006,SPIE Press,about achieve−ments of IR techniques and electrooptics in the former USSR and Russia [33].In the early1930’s,interest in improved detectors began in Germany[27,34,35].In1933,Edgar W.Kutzscher at the University of Berlin,discovered that lead sulphide(from natural galena found in Sardinia)was photoconductive and had response to about3μm.B.Gudden at the University of Prague used evaporation techniques to develop sensitive PbS films.Work directed by Kutzscher,initially at the Uni−versity of Berlin and later at the Electroacustic Company in Kiel,dealt primarily with the chemical deposition approach to film formation.This work ultimately lead to the fabrica−tion of the most sensitive German detectors.These works were,of course,done under great secrecy and the results were not generally known until after1945.Lead sulphide photoconductors were brought to the manufacturing stage of development in Germany in about1943.Lead sulphide was the first practical infrared detector deployed in a variety of applications during the war.The most notable was the Kiel IV,an airborne IR system that had excellent range and which was produced at Carl Zeiss in Jena under the direction of Werner K. Weihe [6].In1941,Robert J.Cashman improved the technology of thallous sulphide detectors,which led to successful produc−tion[36,37].Cashman,after success with thallous sulphide detectors,concentrated his efforts on lead sulphide detec−tors,which were first produced in the United States at Northwestern University in1944.After World War II Cash−man found that other semiconductors of the lead salt family (PbSe and PbTe)showed promise as infrared detectors[38]. The early detector cells manufactured by Cashman are shown in Fig. 5.Fig.4.The original1P25image converter tube developed by the RCA(a).This device measures115×38mm overall and has7pins.It opera−tion is indicated by the schematic drawing (b).After1945,the wide−ranging German trajectory of research was essentially the direction continued in the USA, Great Britain and Soviet Union under military sponsorship after the war[27,39].Kutzscher’s facilities were captured by the Russians,thus providing the basis for early Soviet detector development.From1946,detector technology was rapidly disseminated to firms such as Mullard Ltd.in Southampton,UK,as part of war reparations,and some−times was accompanied by the valuable tacit knowledge of technical experts.E.W.Kutzscher,for example,was flown to Britain from Kiel after the war,and subsequently had an important influence on American developments when he joined Lockheed Aircraft Co.in Burbank,California as a research scientist.Although the fabrication methods developed for lead salt photoconductors was usually not completely under−stood,their properties are well established and reproducibi−lity could only be achieved after following well−tried reci−pes.Unlike most other semiconductor IR detectors,lead salt photoconductive materials are used in the form of polycrys−talline films approximately1μm thick and with individual crystallites ranging in size from approximately0.1–1.0μm. They are usually prepared by chemical deposition using empirical recipes,which generally yields better uniformity of response and more stable results than the evaporative methods.In order to obtain high−performance detectors, lead chalcogenide films need to be sensitized by oxidation. The oxidation may be carried out by using additives in the deposition bath,by post−deposition heat treatment in the presence of oxygen,or by chemical oxidation of the film. The effect of the oxidant is to introduce sensitizing centres and additional states into the bandgap and thereby increase the lifetime of the photoexcited holes in the p−type material.3.Classification of infrared detectorsObserving a history of the development of the IR detector technology after World War II,many materials have been investigated.A simple theorem,after Norton[40],can be stated:”All physical phenomena in the range of about0.1–1 eV will be proposed for IR detectors”.Among these effects are:thermoelectric power(thermocouples),change in elec−trical conductivity(bolometers),gas expansion(Golay cell), pyroelectricity(pyroelectric detectors),photon drag,Jose−phson effect(Josephson junctions,SQUIDs),internal emis−sion(PtSi Schottky barriers),fundamental absorption(in−trinsic photodetectors),impurity absorption(extrinsic pho−todetectors),low dimensional solids[superlattice(SL), quantum well(QW)and quantum dot(QD)detectors], different type of phase transitions, etc.Figure6gives approximate dates of significant develop−ment efforts for the materials mentioned.The years during World War II saw the origins of modern IR detector tech−nology.Recent success in applying infrared technology to remote sensing problems has been made possible by the successful development of high−performance infrared de−tectors over the last six decades.Photon IR technology com−bined with semiconductor material science,photolithogra−phy technology developed for integrated circuits,and the impetus of Cold War military preparedness have propelled extraordinary advances in IR capabilities within a short time period during the last century [41].The majority of optical detectors can be classified in two broad categories:photon detectors(also called quantum detectors) and thermal detectors.3.1.Photon detectorsIn photon detectors the radiation is absorbed within the material by interaction with electrons either bound to lattice atoms or to impurity atoms or with free electrons.The observed electrical output signal results from the changed electronic energy distribution.The photon detectors show a selective wavelength dependence of response per unit incident radiation power(see Fig.8).They exhibit both a good signal−to−noise performance and a very fast res−ponse.But to achieve this,the photon IR detectors require cryogenic cooling.This is necessary to prevent the thermalHistory of infrared detectorsFig.5.Cashman’s detector cells:(a)Tl2S cell(ca.1943):a grid of two intermeshing comb−line sets of conducting paths were first pro−vided and next the T2S was evaporated over the grid structure;(b) PbS cell(ca.1945)the PbS layer was evaporated on the wall of the tube on which electrical leads had been drawn with aquadag(afterRef. 38).。

开启片剂完整性的窗户(中英文对照)

开启片剂完整性的窗户日本东芝公司，剑桥大学摘要：由日本东芝公司和剑桥大学合作成立的公司向《医药技术》解释了FDA支持的技术如何在不损坏片剂的情况下测定其完整性。

太赫脉冲成像的一个应用是检查肠溶制剂的完整性，以确保它们在到达肠溶之前不会溶解。

关键词：片剂完整性，太赫脉冲成像。

能够检测片剂的结构完整性和化学成分而无需将它们打碎的一种技术，已经通过了概念验证阶段，正在进行法规申请。

由英国私募Teraview公司研发并且以太赫光（介于无线电波和光波之间）为基础。

该成像技术为配方研发和质量控制中的湿溶出试验提供了一个更好的选择。

该技术还可以缩短新产品的研发时间，并且根据厂商的情况，随时间推移甚至可能发展成为一个用于制药生产线的实时片剂检测系统。

TPI技术通过发射太赫射线绘制出片剂和涂层厚度的三维差异图谱，在有结构或化学变化时太赫射线被反射回。

反射脉冲的时间延迟累加成该片剂的三维图像。

该系统使用太赫发射极，采用一个机器臂捡起片剂并且使其通过太赫光束，用一个扫描仪收集反射光并且建成三维图像(见图)。

技术研发太赫技术发源于二十世纪九十年代中期13本东芝公司位于英国的东芝欧洲研究中心，该中心与剑桥大学的物理学系有着密切的联系。

日本东芝公司当时正在研究新一代的半导体，研究的副产品是发现了这些半导体实际上是太赫光非常好的发射源和检测器。

二十世纪九十年代后期，日本东芝公司授权研究小组寻求该技术可能的应用，包括成像和化学传感光谱学，并与葛兰素史克和辉瑞以及其它公司建立了关系，以探讨其在制药业的应用。

虽然早期的结果表明该技术有前景，但日本东芝公司却不愿深入研究下去，原因是此应用与日本东芝公司在消费电子行业的任何业务兴趣都没有交叉。

这一决定的结果是研究中心的首席执行官DonArnone和剑桥桥大学物理学系的教授Michael Pepper先生于2001年成立了Teraview公司一作为研究中心的子公司。

TPI imaga 2000是第一个商品化太赫成像系统，该系统经优化用于成品片剂及其核心完整性和性能的无破坏检测。

synthetic division method -回复

synthetic division method -回复Synthetic division is a method used in algebra to perform division of polynomials. It is particularly useful in dividing a polynomial by a linear factor, as it provides a straightforward and efficient approach. In this article, we will explore the concept of synthetic division, step by step, to understand the process and how it can be applied in various mathematical problems.Step 1: Understanding the BasicsTo begin with, let's have a brief overview of the key terms related to synthetic division. A polynomial is an algebraic expression comprising of variables, coefficients, and exponents. Division, in this context, refers to dividing one polynomial by another. Finally, synthetic division is a simplified method to perform polynomial division. It is often used when we need to find the quotient and remainder of dividing one polynomial by a linear factor.Step 2: Identify the DivisorIn synthetic division, the first step is to identify the divisor. The divisor is a linear factor of the polynomial we wish to divide. A linear factor is an expression of the form (ax+b), where 'a' and 'b' are constants. For example, consider the polynomial (3x^3 - 4x^2+ 2x + 1) and the linear factor (x - 2). Here, (x - 2) is the divisor.Step 3: Arrange the PolynomialNext, we arrange the polynomial in descending order, based on the exponent of the variable. In our example, the polynomial (3x^3 - 4x^2 + 2x + 1) is already arranged in descending order. However, if the polynomial is not in the desired order, we may need to rearrange it before proceeding.Step 4: Determine the Synthetic Division TableThe synthetic division table is a tabular representation that helps us perform the division efficiently. The table starts with a row representing the coefficients of the polynomial and an empty space to the right for the synthetic division steps. In our example, the synthetic division table would appear as follows:2 3 -4 2 1 -> (coefficients)Step 5: Perform the Synthetic DivisionNow we are ready to perform the synthetic division. Starting from the left, we take the first coefficient (3) and bring it down directlybelow the line in the synthetic division table. Then we multiply the divisor (2) by the number we just brought down and write the result in the next column. In this case, 2 multiplied by 3 is 6, so we write 6 below the next column.2 3 -4 2 16________Next, add the value in the second column (6) to the coefficient in the second column (-4). The sum is 2, which we write below the line in the same column.2 3 -4 2 16________2Repeat this process for each subsequent column. Multiply the result from the previous step (2) by the divisor (2) and write the product below the next column. Then add the value in the newcolumn to the coefficient in the corresponding column of the polynomial.2 3 -4 2 16 8________2 4Continue this process until you reach the last column of the polynomial.Step 6: Interpret the ResultsOnce we have completed the synthetic division, we can interpret the results. The numbers in the last row of the synthetic division table represent the coefficients of the quotient polynomial. In our example, the coefficients are 2 and 4. Therefore, the quotient polynomial is represented as (2x + 4).Step 7: Analyze the RemainderLastly, the number in the bottom-right cell of the synthetic division table represents the remainder of the division. In our example, the remainder is 1. Hence, the entire synthetic division can beexpressed as (3x^3 - 4x^2 + 2x + 1) = (2x + 4) + (1/(x - 2)).Synthetic division is an effective method for dividing polynomials, especially when dealing with linear factors. By following these step-by-step instructions, you can confidently apply synthetic division to solve various polynomial division problems.。

经合组织风险认识工具OECD Risk Awareness tool

OECD Risk Awareness Tool for Multinational Enterprises in Weak
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An efficient synthetic-route to prepare

An eﬃcient synthetic-route to prepare[2,3,6-tri-O -(2-bromo-2-methylpropionyl]-b -cyclodextrin)Jianshu Li and Huining Xiao *Department of Chemical Engineering,University of New Brunswick,Fredericton,NB,Canada E3B 5A3Received 29December 2004;revised 3February 2005;accepted 4February 2005Abstract—The eﬃcient approach for the synthesis of [2,3,6-tri-O -(2-bromo-2-methylpropionyl]-b -cyclodextrin)(21Br-b -CD)is described.The reaction between 2-bromoisobutyric bromide and b -cyclodextrin was performed directly in 1-methyl-2-pyrrolidione solvent,leading to much less complicated procedures and higher yield (up to 89.5%)compared with those reported previously (17%yield).The product is an extremely useful initiator in synthesizing star polymers with well-deﬁned structures using atom transfer radical polymerization for biomedical applications.Ó2005Elsevier Ltd.All rights reserved.1.IntroductionStar-like polymers have attracted enormous research interest in the past decade due to their unique solution and solid-state properties:Star polymers provide most of the properties of high molecular weight materials without the solution viscosity penalty of linear materials of similar molecular weight.1Living polymerization,atom transfer radical polymerization (ATRP)in partic-ular,has been extensively used for the synthesis of star polymers through either a core-ﬁrst method or an arm-ﬁrst approach.In the arm-ﬁrst method,monofunc-tional and living linear macromolecules are initially syn-thesized.The star is then formed either through the cross-linking by a difunctional comonomer during propa-gation 2or by the connecting of a precise number of arms with a multifunctional terminating agent.3In contrast,in the core-ﬁrst method,star polymers are made with a multifunctional initiator to induce the growth of the arms,which has been employed successfully to acquire well-deﬁned stars with a discrete number of arms.For instance,several styrenic and (meth)acrylic star poly-mers have been prepared by the living radical polymer-ization using the multifunctional core of initiators such as cyclotriphosphazenes,cyclosiloxanes,and organic polyols.4Star polymers have branches radiating from a central core that could be one atom,a small molecule,or a vol-ume of material.b -Cyclodextrin (b -CD)is a cyclic oligo-saccharide consisting of seven glucose units linked by a -1,4-glucosidic bonds.It has a speciﬁc steric structure of truncated conical shape with 1.53and 0.78nm of outer and inner periphery diameter,respectively.5The 21sub-stitutable hydroxyl groups on the outside surface of b -CD provide the possibility to make a core with 21initi-ation sites for forming star polymers with 21arms.In order to utilize ATRP to synthesize star polymers using b -CD as cores,it is essential to introduce halogens into the cyclodextrin.Ohno et al.6ﬁrst reported a b -CD initiator with 21ATRP initiation sites and synthesized several neutral star polymers in an organic solvent.With the b -CD-based initiator,upto 21arms could be created in star polymers.For the conventional star polymers,however,the number of arms is rarely greater than four.However,the synthetic route proposed by Ohno et al.was complicated and the yield was also low:the ﬁnal yield of [2,3,6-tri-O -(2-bromo-2-methylpropionyl]-b -cyclodextrin)(i.e.,21Br-b -CD)through the reaction between b -CD and 2-bromoisobutyric anhydride only reached 17%.In view of previous reports using 2-bromopropionyl bromide or 2-bromoisobutyl bromide to directly modify the compounds containing hydroxyl groups to produce multifunctional initiators,7,8it ap-pears to be feasible to synthesize the 21Br-b -CD directly with 2-bromoisobutyl bromide.0040-4039/$-see front matter Ó2005Elsevier Ltd.All rights reserved.doi:10.1016/j.tetlet.2005.02.027Keywords :21Br-b -cyclodextrin;ATRP initiator;Star polymer.*Corresponding author.Tel.:+15064533532;fax:+15064533591;e-mail:hxiao@unb.caTetrahedron Letters 46(2005)2227–2229Tetrahedron LettersIn this work,we developed a simpliﬁed route to synthe-size the21Br-b-CD initiator through reacting2-bromo-isobutyric bromide with b-cyclodextrin directly in 1-methyl-2-pyrrolidione solvent(see Scheme1).The challenge lies on the solvent used for the synthesis. Pyridine is a good solvent for cyclodextrin,but it is immiscible with2-bromoisobutyl bromide,inducing the precipitation observed in our trial experiments.As a result,the reaction yield was reduced signiﬁcantly. The similar precipitation was also reported elsewhere7 when2-bromopropionyl bromide was used,and the pre-cipitate was pyridine–HBr.In the work performed by Ohno et al.6the precipitation was avoided by replacing 2-bromoisobutyl bromide with2-bromoisobutyric anhy-dride,which eliminated the formation of HBr when the anhydride reacted with b-CD,thus resulting in no pyri-dine–HBr precipitate.Alternatively,the problem can be solved if an appropriate solvent for b-CD is identiﬁed. The solvent is expected to be compatible with both 2-bromoisobutyl bromide and small amounts of HBr. 1-methyl-2-pyrrolidione(NMP)is one of such solvents. In this work,we focused on using NMP as solvent or reaction medium for the reaction between2-bromo-isobutyl bromide and b-CD.The results indicated that 21Br-b-CD was obtained at high yield:upto89.5% based on dialysis puriﬁcation and66.8%according to the conventional washing puriﬁcation.The process and yield comparisons between our current work and the previous research6are shown in Scheme2.The21Br-b-CD obtained is white powder,which is moderately soluble in aqueous solution and highly soluble in most organic solvents,including ether,toluene and dichloro-methane.The aqueous solubility is extremely valuable in preparing water-soluble star polymers for various biomedical applications.From the viewpoints of simple operation and eﬀective yield,the present route provides a novel approach for the synthesis of21Br-b-CD.2.Synthesis of heptak is[2,3,6-tri-O-(2-bromo-2-methyl-propionyl]-b-cyclodextrin)(21Br-b-CD)b-CD(3.41g,3mmol,vacuum dried at80°C over phosphorus pentoxide overnight immediately before use)was dissolved in30mL anhydrous1-methyl-2-pyrrolidione(NMP)and was cooled to0°C.2-bromo-isobutyryl bromide(29.0mL,126mmol)dissolved in anhydrous NMP(15mL)at0°C was then added drop-wise to the b-CD solution with magnetic stirring.The reaction temperature was maintained at0°C for2h and then allowed to rise slowly to ambient temperature after which the reaction was allowed to continue for 18h.The brown solution obtained was concentrated in a vacuum oven for24h.There are two optional methods in purifying the concentrated syrup:(1)di-rectly purify the syrup by dialysis(Spectra/Por dialysis membrane,MWCO1000,Spectrum Laboratories Inc.) against distilled and de-ionized water,refreshing the water every2h for a period of24h.The pale yellow product obtained was concentrated in a vacuum oven and then crystallized in cold n-hexane to obtain a white precipitate(11.45g,yield89.5%);(2)dilute the syrup with50mL dichloromethane,and then wash sequen-tially with saturated NaHCO3aqueous solution (2·100mL)and water(2·100mL).The organic layer obtained was concentrated in a vacuum oven and then crystallized in cold n-hexane to produce a white precipit-ate(8.54g,yield66.8%).The structure of21Br-b-CD was conﬁrmed using:FTIR(zinc selenide):2931cmÀ12228J.Li,H.Xiao/Tetrahedron Letters46(2005)2227–2229(m C–H),1737cmÀ1(m C@O),1158cmÀ1(m C–O–C),1039and 1105cmÀ1(coupled m C–C and m C–O);1H NMR(CDCl3, 300MHz):d1.2–2.2(126H,CH3),3.5–5.5(49H,resi-dues of b-CD);13C NMR(CDCl3,100MHz):d30.8–31.3(a-CH3),56.4(C–Br),64.0,69.9–73.6,74.4,80.5, 98.6(residues of b-CD),171.3(C@O).The characteris-tic peaks of the21Br-b-CD synthesized in the current work appear to be identical with those reported by Ohno et al.6AcknowledgementsFinancial support for this work from the NSERC Canada is gratefully acknowledged.References and notes1.Simms,J.A.;Spinelli,H.J.In Macromolecular Design ofPolymeric Materials;Hatada,K.,Kitayama,T.,Vogl,O., Eds.;Marcel Dekker Inc.:New York,1997;pp379–391.2.Morton,M.;Helminiak,T.E.;Gadkary,S.D.;Bueche,F.J.Polym.Sci.1962,57,471–482.3.Takeichi,T.;Stille,J.K.Macromolecules1986,19,2093–2102.4.Matyjaszewski,K.;Miller,P.J.;Pyun,J.,et al.Macro-molecules1999,32,6526–6535.5.Szejtli,J.Chem.Rev.1998,98,1743–1753.6.Ohno,K.;Wong,B.;Haddleton,D.M.J.Polym.Sci.Polym.Chem.2001,39,2206–2214.7.Matyjaszewski,K.;Gaynor,S.G.;Kulfan,A.;Podwika,M.Macromolecules1997,30,5192–5194.8.Yu,W.H.;Kang,E.T.;Neoh,K.G.;Zhu,S.J.Phys.Chem.B2003,107,10198–10205.J.Li,H.Xiao/Tetrahedron Letters46(2005)2227–22292229。

2015版英国药典灭菌法的翻译

Appendix XVIII Methods of Sterilisation(Ph. Eur. general texts 5.1.1)Sterility is the absence of viable micro-organisms. The sterility of a product cannot be guaranteed by testing; it has to be assured by the application of a suitably validated production process. It is essential that the effect of the chosen sterilisation procedure on the product (including its final container or package) is investigated to ensure effectiveness and the integrity of the product and that the procedure is validated before being applied in practice. It is recommended that the choice of the container is such as to allow the optimum sterilisation to be applied. Failure to follow meticulously a validated process involves the risk of a non-sterile product or of a deteriorated product. Revalidation is carried out whenever major changes in the sterilisation procedure, including changes in the load, take place. It is expected that the principles of good manufacturing practice (as described in, for example, the European Community Guide to GMP) will have been observed in the design of the process including, in particular, the use of:无菌性是没有存活的微生物。

Improving Photosynthetic Efficiency for Greater Yield

RE V I E WSI NAD V ANC EImproving Photosynthetic Efﬁciency for Greater YieldXin-Guang Zhu,1,2,3Stephen P .Long,3,4and Donald R.Ort 3,4,51CAS-MPG Partner Institute for Computational Biology,SIBS,Shanghai,China 2000312Institute of Plant Physiology and Ecology,SIBS,Shanghai,China 2000323Institute of Genomic Biology,University of Illinois at Urbana Champaign,Illinois 618014Departments of Plant Biology and Crop Sciences,University of Illinois at Urbana Champaign,Illinois 618015Photosynthesis Research Unit,USDA/ARS,Urbana,Illinois,61801;emails:zhuxinguang@,slong@,d-ort@Annu.Rev.Plant Biol.2010.61:29.1–29.27The Annual Review of Plant Biology is online at This article’s doi:10.1146/annurev-arplant-042809-112206Copyright c2010by Annual Reviews.All rights reserved1543-5008/10/0602-0001$20.00Key Wordscrop yield,global climate change,photoprotection,photorespiration,Rubisco,systems biologyAbstractIncreasing the yield potential of the major food grain crops has con-tributed very signiﬁcantly to a rising food supply over the past 50years,which has until recently more than kept pace with rising global de-mand.Whereas improved photosynthetic efﬁciency has played only a minor role in the remarkable increases in productivity achieved in the last half century,further increases in yield potential will rely in large part on improved photosynthesis.Here we examine inefﬁcien-cies in photosynthetic energy transduction in crops from interception to carbohydrate synthesis,and how classical breeding,systems biology,and synthetic biology is providing new opportunities to develop more productive germplasm.Near-term opportunities include improving the display of leaves in crop canopies to avoid light saturation of individual leaves and further investigation of a photorespiratory bypass that has already improved the productivity of model species.Longer-term op-portunities include engineering into plants carboxylases that are better adapted to current and forthcoming CO 2concentration,and the use of modeling to guide molecular optimization of resource investment among the components of the photosynthetic apparatus,to maximize carbon gain without increasing crop inputs.Collectively,these changes have the potential to more than double the yield potential of our major crops.29.1A n n u . R e v . P l a n tB i o l . 2010.61. D o w n l o a d e d f r o m a r j o u r n a l s .a n n u a l r e v i e w s .o r g b y S h a n g h a i I n f o r m a t i o nC e n t e r f o r L i f e S c i e n c e s o n 04/19/10. F o r p e r s o n a l u s e o n l y .ContentsINTRODUCTION..................29.2Estimation of the TheoreticalMaximal εc for both C3and C4Plants..........................29.6THE PHOTOSYNTHETIC ENERGY CONVERSIONEFFICIENCY IN THE FIELD ...29.8Measurements of εc in the Field ....29.8Variations of εc in the Field.........29.9Why the Maximum Observed εc Is Lower Than the MaximaumTheoretical εc ..................29.9Light Saturation...................29.9Rising CO 2Concentration .........29.11Carbon Metabolism Engineering ...29.14Decreasing PhotorespiratoryLosses..........................29.15Plant Architecture Modiﬁcation ....29.15Fine-T uning Antenna Size..........29.16Fine-T uning Photoprotection ......29.17Perspectives .......................29.19INTRODUCTIONIn the last ten years,increases in yield for some major crops such as rice have shown littleYearG r a i n y i e l d (t h a –1)Grain yield (GJ ha –1)Figure 1Average annual yield of rice per unit land area in China.Each data point is the average of all harvested areas in China (34).The line is a third-order polynomial best ﬁt to the trend of yield against time.improvement (98).This slowing pace of yield increase is occurring in a context of increas-ing world population,climate change,the di-version of an increasing proportion of the grain harvest to meat production,and the emergence of bioenergy production.This is coupled with losses of agricultural land to urbanization and soil degradation.In 2008,the world saw the lowest wheat stockpiles of the past 30years (136)and fears of a rice shortage incited ri-ots in some countries.Adding to this,the rapid growth in the Chinese and Indian economies has resulted in never before seen demands on grain supplies.Increasing grain crop productiv-ity is the foremost challenge facing agricultural research.Although photosynthesis is the ulti-mate basis of yield,improving photosynthetic efﬁciency has played only a minor role in im-proving yields to date.However,the yield traits that drove the remarkable yield increases dur-ing the green revolution appear to have little remaining potential for further increases.Glob-ally,rice is the world’s most important crop in terms of the number of people who depend upon it as their major source of calories and nutrition.After rapid increases in yield over the latter half of the twentieth century,further yield increases appear harder to obtain.As an exam-ple,between 1987and 1997China increased its average rice yields from 5.4t ha −1to 6.4t ha −1,yet between 1997and 2007no further clear in-crease has been achieved (Figure 1).Jacques Diouf,head of the United Nation’s Food and Agriculture Organization,projected that it will be essential to double grain yields to meet in-creasing global demand across the next 50years.As we show below,this may now be possible only by improving photosynthetic efﬁciency.Why might increasing photosynthesis be criti-cal to gaining further grain crop yields?While realized yields have improved in part through better fertilization and improved dis-ease protection,they have also improved very substantially as a result of increased genetic yield potential (Y)(see the sidebar,Glossary of T erms and Abbreviations,below,for a sum-mary of the abbreviations used in this review).This is deﬁned as the yield that a crop can attain29.2Zhu·Long·OrtA n n u . R e v . P l a n tB i o l . 2010.61. D o w n l o a d e d f r o m a r j o u r n a l s .a n n u a l r e v i e w s .o r g b y S h a n g h a i I n f o r m a t i o nC e n t e r f o r L i f e S c i e n c e s o n 04/19/10. F o r p e r s o n a l u s e o n l y .GLOSSARY OF TERMS AND ABBREVIATIONSA Rate of leaf photosynthetic CO 2uptake per unit leaf area.A c Integrated daily canopy carbon uptake.A sat Light-saturated rate of photosynthetic CO 2uptake.C3Plants in which the primary carboxylase is Rubisco and the primary carboxylation product of RuBP is a three-carbon sugar.Rubisco in C3plants also catalyzes the oxygenation of RuBP ,the initial step of pho-torespiration.C4Plants in which the primary carboxylase is PEPcase and the primary carboxylation product in the light is afour-carbon compound.Rubisco is a secondary carboxylase in C4plants that functions in a high-CO 2environment suppressing oxygenation and photorespiration.C a CO 2concentration in the ambient atmosphere surrounding the leaf.C c CO 2concentration at the site of carboxylation in the chloroplast.C i CO 2concentration in inner cellular airspaces within the leaf.D1A protein of the photosystem II reaction center involved in charge separation,and vulnerable to oxidativedamage,with the result of a high repair turnover.FACE Free Air Concentration Enrichment is employed under ﬁeld conditions to raise the concentration of CO 2to mimic future atmospheric conditions without disturbing other interactions.g m Mesophyll conductance;numerical measure of the rate of diffusion of CO 2from the intercellular airspacethrough the liquid phase to the site of carboxylation in the chloroplast.g s Stomatal conductance;numerical measure of the rate of diffusion of water vapor,carbon dioxide or othergases through the stomatal pore.I Photon ﬂux density.I Cumulative intercepted radiation.J max Maximum capacity for regeneration of RuBP .k c c Maximum catalytic rate of Rubisco carboxylation per active I Leaf Area Index is deﬁned as the one sided green leaf area per unit ground area in broadleaf canopies,oras the projected needle leaf area per unit ground area in needle canopies.LHCII The light-harvesting complex.An array of protein-chlorophyll molecules within the thylakoid membranecontaining both chlorophylls a and b that transfer light energy to the photosystem II reaction center.LSU Large subunit of Rubisco;eukaryotic Rubisco has eight large chloroplast-encoded and eight small nuclear-encoded protein subunits.NPQ Nonphotochemical quenching of chlorophyll ﬂuorescence due to the thermal dissipation of chlorophyllexcited states,which competes with photosystem II ﬂuorescence emission as well as with photochemistry.PEP Phosphoenol pyruvate is the three carbon carboxylation substrate for PEPcase in C4plants.PEPcase Phosphoenol pyruvate (PEP)carboxylase;the primary carboxylase of C4photosynthesis,which catalyzesthe ﬁxation of CO 2to phosphoenol pyruvate.PPDK Pyruvate Pi dikinase regenerates PEP in the mesophyll cells during C4photosynthesis.psbS A protein of photosystem II that is involved in NPQ and heat dissipation of excess absorbed energy.Q cycle Describes a series of redox reactions by the cytochrome b 6f complex located in the thylakoid membrane,which results in the net oxidation of one plastoquinol molecule,the net reduction of two plastocyanin molecules,and the translocation of four protons into the thylakoid lumen storing energy in the form of a transmembrane electrochemical potential of protons.Rubisco Ribulose-1,5-bisphosphate carboxylase oxygenase;the primary carboxylase in C3plants and the secondarycarboxylase in C4plants that carboxylates RuBP to form a three carbon •Improving Photosynthesis for Yield 29.3A n n u . R e v . P l a n tB i o l . 2010.61. D o w n l o a d e d f r o m a r j o u r n a l s .a n n u a l r e v i e w s .o r g b y S h a n g h a i I n f o r m a t i o nC e n t e r f o r L i f e S c i e n c e s o n 04/19/10. F o r p e r s o n a l u s e o n l y .RuBP Ribulose-1,5-bisphosphate is the ﬁve-carbon carboxylation substrate for Rubisco.S tT otal solar full-spectrum radiation across the growing season incident at the earth’s surface.V c ,max Maximum capacity for Rubisco catalyzed carboxylation of RuBP .W T otal above ground crop biomass.W Cumulative above ground crop biomass.Y Genetic yield potential:the yield that a crop can attain under optimal management practices and in the absence of biotic and abiotic stressesαc Fraction of incident light intercepted by a plant canopy.εc Conversion efﬁciency is the ratio of biomass energy produced over a given period to the radiative energy intercepted by the canopy over the same period.εi Light interception efﬁciency of photosynthetically active radiation (400–700nm).εp Partitioning efﬁciency,also termed harvest index,is the amount of the total biomass energy partitioned into the harvested portion of the crop.θConvexity of the nonrectangular hyperbola that describes the dependence of photosynthesis on light intensity (I ).λRubisco speciﬁcity factor represents the discrimination between CO 2and O 2,the two competing sub-strates of Rubisco that will lead to either the carboxylation or the oxygenation of RuBP .τc Fraction of incident light transmitted by a plant canopy.CO 2Maximum quantum efﬁciency of CO 2ﬁxation,or the maximal fractional number of CO 2molecules that can be ﬁxed with the absorption of one photon.Y:genetic yieldpotential;the yield that a crop can attain under optimal management practices and in the absence of biotic and abiotic stresses S t :total solar full-spectrum radiation across the growing season incident at the earth’s surfaceunder optimal management practices and in the absence of biotic and abiotic stresses.Adapting the equation of Monteith (83):Y =0.487·S t ·εi ·εc ·εp1.where S t (GJ m −2)is the total incident solar radiation across the growing season.Leaves of healthy crops typically absorb approxi-mately 90%of the photosynthetically active radiation (400–700nm)but transmit most of the near infrared radiation (>700nm),approximately half of the energy of sunlight.T o limit the analysis to photosynthetically active radiation,S t is multiplied by 0.487.Light interception efﬁciency (εi )of photo-synthetically active radiation is determined by the speed of canopy development and closure,leaf absorbance,canopy longevity,size,and architecture.Conversion efﬁciency (εc )is the combined gross photosynthesis of all leaves within the canopy,less all plant respiratory losses.Partitioning efﬁciency (εp ),also termed harvest index,is the amount of thetotal biomass energy partitioned into the har-vested portion of the crop.The equation gives the harvestable yield in MJ m −2;converting this to mass depends on the energy content of the harvested material.For nonoil grains this will be 18MJ g −1but can rise to 35–40MJ g −1for oil-rich seeds.In the context of Equation 1,in-crease in potential yield over the past 50years has resulted largely from increase in εp and εi .Increased εp has resulted in large part through dwarﬁng of the stem and increase in the po-tential number of seeds set.Increased εi has resulted through the development of larger-leafed cultivars and more rapid coverage of the ground after germination.Dwarﬁng has also in-directly improved realized εi by improving the standing power of the crop to adverse weather conditions,such as rain,wind,and/or hail (i.e.,decreased lodging)(12,31,47).Healthy crops of modern cultivars at opti-mized spacing intercept most of the available radiation within their growing season,limiting prospects for any further improvement of εi .One caveat is that most crops do not currently29.4Zhu·Long·OrtA n n u . R e v . P l a n tB i o l . 2010.61. D o w n l o a d e d f r o m a r j o u r n a l s .a n n u a l r e v i e w s .o r g b y S h a n g h a i I n f o r m a t i o nC e n t e r f o r L i f e S c i e n c e s o n 04/19/10. F o r p e r s o n a l u s e o n l y .Table 1Analysis of determinants of soybean yield when grown under ambient and elevated [CO 2]YW b ,cS t εi εc εp c Measure (units)a MJ m −2(t ha −1)MJ m −2(t ha −1)MJ m −2(Dimensionless:0–1)380ppm 10.6(4.60)17.7(8.76)6200.890.0320.60550ppm 12.2(5.29)20.9(10.40)6200.890.0380.58%difference15.018.218.8−2.7Component analysis of the yield of soybean (Glycine max L.,cv.93B15)grown in 2002at SoyFACE (soybean Free Air Concentration Enrichment facility,Urbana,Illinois),based on Equation 1.Yields are based on four control and four elevated CO 2plots.The analysis is based on the data of Morgan et al.(84)and Dermody et al.(24).aAbbreviations are as given for Equation 1.bW is the total dry matter content in both energy and mass.cW and εp were modiﬁed from Dermody et al.(24)to include root biomass,which was 18.5%of the total biomass,with the proportion unaffected by the CO 2treatment.The energy content of the seeds was assumed to be 23MJ/kg and the remainder of the biomass,17MJ/kg (24).use the full potential growing season,i.e.,the period when temperatures and water are ade-quate for plant growth.The effects on biomass production of extending the growing season can be seen by comparing biomass production of the unusually cold-tolerant perennial C4grass Miscanthus x giganteus with its relative maize.Although its εc was almost identical to maize,it produced 60%more biomass in the Midwest,where recorded yields of maize are among the highest in the world.The higher productivity of M.x giganteus was due simply to its having pro-duced a closed canopy,with an εi >0.9,four weeks before maize and having maintained it for a further four weeks after the maize had senesced (25).Extending the growing season increased the cumulative intercepted radiation by approximately 60%(8,14).Soybean is the most important dicotyle-donous crop,in terms of total global grain pro-duction,and the fourth most important grain crop,after maize,rice,and wheat.Table 1shows that a modern soybean cultivar devel-oped for Midwest conditions,grown under normal production conditions and at current atmospheric [CO 2],intercepted almost 90%(εi =0.89)of the photosynthetically active radiation across the growing season.Further,60%of the biomass energy was partitioned into the harvested seed (εp =0.60).This shows that breeding has succeeded in maxi-mizing both εi and εp in soybean.Given that the crop will inevitably fail to intercept some radiation between sowing and canopy closure εi :light interception efﬁciency ofphotosynthetically active radiation (400–700nm)εc :conversionefﬁciency;the ratio of biomass energyproduced over a given period to the radiative energy intercepted by the canopy over the same periodεp :partitioningefﬁciency,also termed harvest index;the amount of the total biomass energy partitioned into the harvested portion of the cropW:total above ground crop biomass C3:plants in which the primarycarboxylase is Rubisco and the primarycarboxylation product of RuBP is a three-carbon sugar.Rubisco in C3plants also catalyzes theoxygenation of RuBP ,the initial step of photorespirationand that cell wall material cannot be recy-cled to the seed from leaves,roots,and stems,there is little or no prospect of further im-proving εi or εp .Analyses of the other major grain crops (maize,wheat,and rice)provide similar ﬁndings (31,47,115)(Figure 1).With reference to Equation 1,therefore,only two prospects may remain.Extending the grow-ing season to increase S t ,as noted above,or increasing εc .There has been a reluctance to invest in increased photosynthesis,and there-fore increased εc .As reviewed previously (72),such reluctance arises from the argument that,ﬁrst,there is no correlation between the yield of a broad range of crops and photosynthe-sis and,second,yield is limited by sinks for photosynthate and not by photosynthetic ca-pacity.Table 1illustrates one of several data sets that now disprove these expectations.El-evated [CO 2]increased leaf photosynthesis in this soybean crop by 22.6%over the growing season (17),corresponding in turn to an 18.8%increase in εc and an 18.2%increase of total above ground biomass (W)shown in Table 1.This experiment,in which photosynthesis was increased by artiﬁcial elevation of [CO 2],pro-vides direct evidence that increasing photosyn-thesis in a crop under standard ﬁeld produc-tion conditions does result in an increase in yield.The increase in yield of 15%as com-pared to a 23%increase in photosynthesis re-ﬂects an increase in respiration associated with the greater biomass and yield (63)and may also indicate a lack of adequate sink capacity to fully •Improving Photosynthesis for Yield29.5A n n u . R e v . P l a n tB i o l . 2010.61. D o w n l o a d e d f r o m a r j o u r n a l s .a n n u a l r e v i e w s .o r g b y S h a n g h a i I n f o r m a t i o nC e n t e r f o r L i f e S c i e n c e s o n 04/19/10. F o r p e r s o n a l u s e o n l y .utilize the increased supply of photosynthate,but it nevertheless results in a large increase in yield.This review examines the prospects for genetically achieving a similar result,i.e.,without increasing [CO 2].Table 1shows an εc of 0.032calculated on the basis of photosyn-thetically active radiation,which would amount to an efﬁciency of conversion of full-spectrum solar radiation into biomass of approximately 1.5%.6.6Photochemical inefﬁciency 51.3Outside photosynthetically active spectrum 4.9Reﬂected and transmitted Carbohydrate biosynthesis Energy loss17.5Photorespiration 0Respiration2.57.2Thermodynamic limitSolar energyC46.08.58.5C36.54.612.613.41.96.137.243.8100%48.726.0Biomass 4.6%Biomass 6.0%Figure 2Minimum energy losses showingthe percentage remaining (inside arrows )andpercentage losses (at right )from an original 100%calculated for stage of photosynthetic energy transduction from sunlight incident on a leaf to plant biomass.Both C3and C4(NADP–malic enzyme type)photosynthesis arepresented.Calculations assume a leaf temperature of 30◦C and an atmospheric [CO 2]of 387ppm.The theoretical maximal photosynthetic energy conversion efﬁciency (εc )is 4.6%for C3and 6%for C4plants.These values are for total full-spectrum solar radiation.If the analysis is limited to photosynthetically active radiation (400–700nm),then these values become 9.4%for C3and 12.3%for C4.This analysis is redrawn,with modiﬁcations explained in the text,from (141).Estimation of the TheoreticalMaximal εc for both C3and C4PlantsThe foregoing has established that realized ef-ﬁciencies of two of the three efﬁciency com-ponents determining grain crop yield potential are close to their theoretical maxima for ma-jor crops.T o determine whether there is po-tential to improve εc ,it is ﬁrst necessary to es-tablish the theoretical maximum that could be attained under ideal conditions as it has evolved in C3and C4plants.A detailed stepwise bio-physical and biochemical analysis of efﬁciency of energy transduction from interception of ra-diation to carbohydrate formation has been pre-sented previously (142),and a slightly modiﬁed analysis is explained in Figure 2.For oxygen-evolving photosynthesis,only a limited portion of the solar spectrum can be used.Although photons in the waveband 350–740nm may be used,below 400nm and above 700nm,photons can only be used at low efﬁciency,if at all.For the purposes of this review,photosynthetically active radiation is therefore deﬁned for practical purposes as 400–700nm,representing 48.7%of the to-tal incident solar energy;i.e.,51.3%is lost at this point (Figure 2).Because of the weaker absorbance of chlorophyll in the green band,vegetation is not a perfect absorber of photo-synthetically active radiation,which limits max-imum interception of 400-nm to 700-nm light in healthy leaves to approximately 90%.Al-though a blue photon (400nm)has 75%more energy than a red photon (700nm),higher ex-cited states of chlorophyll very rapidly relax,and all photochemistry is driven in the pho-tosynthetic reaction centers with the energy of a red photon regardless of the wavelength that was originally absorbed,accounting for a 6.6%energy loss as heat,the “photochemical inefﬁ-ciency”of Figure 2.It is assumed here that in noncyclic electron transport,the partitioning of photons between photosystem I and photosys-tem II is equal.At the reaction centers,thermodynamics limit the amount of energy available to do pho-tosynthetic work in terms of charge separation.29.6Zhu·Long·OrtA n n u . R e v . P l a n tB i o l . 2010.61. D o w n l o a d e d f r o m a r j o u r n a l s .a n n u a l r e v i e w s .o r g b y S h a n g h a i I n f o r m a t i o nC e n t e r f o r L i f e S c i e n c e s o n 04/19/10. F o r p e r s o n a l u s e o n l y .In our previous analysis (142),the energy loss associated with the “thermodynamic limit”over the efﬁciency of charge separation was consid-ered together with energy losses associated with “carbohydrate biosynthesis.”Figure 2sepa-rates these.Thermodynamics limit the energy available for work to 63%of the total energy in a red photon (685nm),resulting in an en-ergy loss of 37%.A more detailed quantitative explanation of the “thermodynamic limit”de-picted in Figure 2is included in accompanying supplemental materials.There are energy expenditures associated with electron and proton transport and in the reduction of carbon dioxide to carbohydrate in the C3cycle,with additional losses in the C 4-dicarboxylate cycle of C4photosynthsis.In C3photosynthesis,a minimum of 3ATP and 2NADPH is required to assimilate one molecule of CO 2into carbohydrate and to regenerate 1RuBP to complete the C3cycle.In whole chain linear electron transport,the absorption of a minimum of 4photons is needed to re-duce one molecule of NADPH while translo-cating a maximum of 6protons into the thy-lakoid lumen:2from water oxidation and 4from plastoquinol oxidation by the cytochrome b 6/f complex via the Q cycle (59).Given that two NADPH are required for assimilation of one CO 2into carbohydrate,the absorption of 8photons results in a maximum of 12protons transported into the lumen.Since 4protons are needed for the synthesis of 1ATP (36,109,124),these 12protons transported are just sufﬁcient to support the synthesis of the 3ATP required to balance 2NADPH in the assimilation of one CO 2.The 8moles of red photons,the minimum required to convert 1mole of CO 2to carbo-hydrate,represents 874kJ energy available for work.One-sixth of a mole of glucose,i.e.,a 1-C carbohydrate unit,contains 477kJ of energy.Therefore,the minimum energy expenditure in “carbohydrate biosynthesis”is 1-(477/874)or 10.78%of the original incident solar radi-ation (Figure 2).In turn,the maximal energy conversion efﬁciency (εc )of C3photosynthe-sis,prior to photorespiration and respiration,is 12.6%(Figure 2)(142).C4:plants in which the primarycarboxylase is PEPcase and the primarycarboxylation product in the light is a four-carbon compound.Rubisco is a secondary carboxylase in C4plants that functions in a high-CO 2environment suppressingoxygenation and photorespiration RuBP:ribulose-1,5-bisphosphate is the ﬁve-carboncarboxylation substrate for RubiscoQ cycle:a series of redox reactions by the cytochrome b6fcomplex located in the thylakoid membrane,which results in the net oxidation of one plastoquinol molecule,the net reduction of two plastocyanin molecules,and the translocation of four protons into the thylakoid lumen storing energy in the form of atransmembrane electrochemical potential of protons Rubisco:ribulose-1,5-bisphosphatecarboxylase oxygenase;the primarycarboxylase in C3plants and thesecondary carboxylase in C4plants that carboxylates RuBP to form a three-carbon sugarAll the major C4crops—maize,sorghum,and sugar cane,as well as the emerging bioen-ergy crop Miscanthus —belong to the most efﬁ-cient C4subtype (29)(NADP–malic enzyme).This subtype requires an additional 2ATP rela-tive to C3photosynthesis for the phosphoryla-tion of pyruvate to phosphoenol pyruvate;i.e.,5ATP and 2NADPH are required to assimilate 1CO 2.Increased demand for ATP is underlined by the fact that the bundle sheath chloroplasts in this C4subtype are often deﬁcient in grana and photosystem II,implying increased cyclic electron transport.Here,electrons from pho-tosystem I are returned to the Cyt b 6/f com-plex,resulting in the translocation of 2protons per photon into the thylakoid lumen (22,114).Thus the translocation of the 8protons needed to produce the 2additional ATP ,require the ab-sorption of an additional 4photons by PSI,rais-ing the minimum total quantum requirement for CO 2assimilated in C4photosynthesis to 12.Following earlier calculations for C3pho-tosynthesis (142),the maximal energy conver-sion efﬁciency (εc )of C4photosynthesis,prior to respiration,is 8.5%(Figure 2).With the investment of 2extra ATP ,CO 2is concentrated at the site of carboxylation by Rubisco in bundle sheath cells to a sufﬁ-cient extent to competitively inhibit oxygena-tion (40)under most conditions.However,in C3species,oxygenation and the ensuing pho-torespiratory metabolism represents a signiﬁ-cant energy loss,essentially halving the maxi-mum energy conversion efﬁciency from 12.6%to 6.1%(Figure 2).Thus the “quantum re-quirement penalty”for each oxygenation event is ∼9photons (4).The actual extent of this penalty in raising the quantum requirement for CO 2ﬁxation in a C3leaf depends on the Rubisco speciﬁcity factor (λ),the temperature,and the [CO 2].At 25◦C under current atmo-spheric [CO 2]of 387ppm for a typical C3crop λ,photorespiration raises the minimum quan-tum requirement of a C3plant from 8to 13photons per CO 2assimilated.Mitochondrial respiration is another nec-essary expenditure of energy that must be subtracted in estimating the theoretical •Improving Photosynthesis for Yield29.7A n n u . R e v . P l a n tB i o l . 2010.61. D o w n l o a d e d f r o m a r j o u r n a l s .a n n u a l r e v i e w s .o r g b y S h a n g h a i I n f o r m a t i o nC e n t e r f o r L i f e S c i e n c e s o n 04/19/10. F o r p e r s o n a l u s e o n l y .。

The Economics of Organization,The Transaction Cost Approach

Article: The Economics of Organization: The Transaction Cost ApproachAuthors: Oliver E. WilliamsonCitation: The American Journal of Sociology, Vol. 87, No. 3 (Nov., 1981), pp. 548-577Type of Research: Theoretical ResearchTopics:To describe transaction costs and effort to economize thereon.1)The antecedent literature from which the transaction cost approach derives.2)The rudiments of the approach, including the dimensionalizing of transactions.3)Applications to the study of efficient boundaries.4)Employment relation issues.5)Comparisons with selected aspects of the organization theory literature and contrasts with“power” approaches to eh study of organizations.6)Concluding remarks.1.ANTECEDENTS●The transaction cost approach to the study of organizations relates to three relativelyindependent literatures.1)Economics literature2)Organization theory literature3)Contract law literature, in which contract is addressed as a governance issue● A deepening awareness of transaction cost issues marks the progression of each of theliteratures:1)The study of organizations was a comparative institutional undertaking in which alternativegovernance structures –both within and between firms and markets –required explicit attention.2)As the transactions of interest were not all of a kind, differences among them wouldevidently have to be recognized.3)Put differently, transaction cost economizing needs to be located within a lager economizingframework and the relevant trade-offs need to be recognized.2.SOME RUDIMENTS●Motivation:Can we identify the factors that permit transactions to be classified as one kind or another?Can we identify the alternative governance structures within which transactions can be organized?Can we match governance structures with transactions in a discriminating (transaction-cost-economizing) way?●Behavioral Assumptions –“human nature as we know it”1)The recognition that human agents are subject to bounded rationality.Given bounded rationality, it is impossible to deal with complexity in all contractually relevant respects. As a consequence, incomplete contracting is the best that can be achieved.2)The assumption that at least some agents are given to opportunism.When effective ex ante and ex post competition can both be presumed, autonomous contracting will be efficacious.Ex ante competition is a much easier condition to satisfy: it merely requires that there be large numbers of qualified bidders at the outset.Ex post competition: depend on the characteristics of the transactions in question, which brings us to the matter of dimensionalizing.●DimensionalizingThe critical dimensions of describing transactions are:1)Uncertainty2)The frequency with which transactions recur3)The degree to which durable, transaction-specific investments are required to realize last costsupplyFocus on uncertainty and asset specificity, especially the latter.Site specificityAsset specificity Physical asset specificityHuman asset specificityWhere asset specificity is great, buyer and seller will make special efforts to design an exchange that has good continuity properties.Site specificity: Assume that all site-specific stations constitute a technological core the common ownership of which will be taken as given.The efficient governance structure for these turns on physical asset and human asset specificity.3.EFFICIENT BOUNDARIES – physical asset specificityTo describe how the economizing decisions which define the outer boundaries of this division are made.● A Simple ModelTransaction cost reasoning is central to this analysis, but trade-offs between production cost economies and governance cost economies need to be recognized.✓Central points:1)Physical asset specificity is never valued by itself but only because demand is therebyincreased in design or performance respects;2)Such valued demand consequences are often realized only at greater production expense;3)The optimal choice of asset specificity requires that demand and production costconsequences be taken into account simultaneously;4)Governance costs also vary with asset specificity, and there also have to be introduced intothe calculus.✓The governance of recurrent transactions for which uncertainty is held constant will vary as follows:Classical market contracting will be efficacious whenever assets are nonspecific to the trading parties; bilateral or obligational market contracting will appear as assets become semi specific; internal organization will displace markets as assets take on a highly specific character.✓The incentive to shift bilateral transactions from markets to firms increases as uncertainty is greater.✓Figure 2- Representative net production and governance cost differences: Positive – market procurement enjoys the advantage;0 – indifference between governance structures obtains;Negative – internal procurement enjoys the advantage.●Two Examples:1)Automobile body manufactureFrom long-term contracting to common ownership because of highly specialized product and uncertainty.2)Forward integrationThe progression of forward integration contingent on differential degrees of asset specificity and the differential hazards of opportunism.4.MANAGING HUMAN ASSETS: THE EMPLOYMENT RELATION●Questions:How are human asset differences best described, what are the employment relation alternatives, and what is the appropriate correspondence between them?●At the staff level – Governance, Generalhuman asset the degree to which they are firm-specificthe ease with which productivity can be metered.1)Firm-specific:Skills acquired in a learning-by-doing fashion and imperfectly transferable across employers need to be embedded in a protective governance structure, lest productive values be sacrificed if the employment relation is unwittingly severed.2)Metering:The internal organizational counterpart for uncertainty is the ease with which the productivity of human assets can be evaluated.3)Figure 3 – The governance of internal organization●At the production level – Some remarks on Union OrganizationThe transaction cost approach to the study of unionization yields testable implications.1)The incentive to organize production workers within a collective governance structureincreases with the degree of human asset specificity;2)The degree to which an internal governance structure is elaborated will vary directly with thedegree of human asset specificity.5.RELATION TO THE ORGANIZATIONAL LITERATURE●&Population Ecology●&Thompson’s workSimilarities:bounded rationality, uncertainty, efficient boundaries, coordination costs, technique core Differences:Trade-offs between production economies and transaction cost economies;Dimensionalize transactions;The governance structure within which collective bargaining operates will be specifically attuned to the nature of the human assets.●&Inter-organizational linkages●Power6.CONCLUDING REMARKSLimits:Transaction cost reasoning probably has greater relevance for studying commercial than noncommercial enterprise.Methodology features:1)The transaction cost approach employs functional analysis.2)The approach straddles the methodological dispute that separates maximizers and satisficers.3)The transaction cost approach relies –in a somewhat informal, background, and long-runway – on the operation of natural selection forces.The transaction cost approach employs A semi-micro-analytic level of analysis.。

EFFICIENT IMPLEMENTATION OF ANALYSIS AND SYNTHESI

专利名称：EFFICIENT IMPLEMENTATION OF ANALYSIS AND SYNTHESIS FILTERBANKS FOR MPEGAAC AND MPEG AAC ELDENCODERS/DECODERS发明人：REZNIK, Yuriy,CHIVUKULA, Ravi Kiran申请号：US2008080211申请日：20081016公开号：WO09/052317P1公开日：20090423专利内容由知识产权出版社提供摘要：An encoder may include a core MDCT filterbank that can be used to implement an advanced audio coding (AAC) algorithm, an AAC-enhanced low delay (ELD) algorithm or both algorithms. For the AAC algorithm, a sequence of input samples is sent directly to the MDCT filterbank to obtain a sequence of output samples. For the AAC-ELD algorithm, the signs of input samples of the sequence of input samples are inverted, the MDCT analysis filterbank is applied to the sign-inverted sequence of input samples to obtain a sequence of output samples, the order of the sequence of output samples is reversed, and the signs of alternating output samples of the sequence of output samples are inverted. Similarly, a decoder may include a core IMDCT synthesis filterbank that can be used to implement AAC-ELD or both AAC and AAC-ELD algorithms. The steps for the decoder are merely the reverse of the encoder.申请人：REZNIK, Yuriy,CHIVUKULA, Ravi Kiran地址：US,US,US国籍：US,US,US代理机构：DIAZ HIDALGO, Espartaco 更多信息请下载全文后查看。

GenScript siRNA Cassette Protocol Technical Manual

GenScript siRNA Cassette ProtocolTechnical Manual No. 0168 Version 20040510I Introduction (1)II siRNA Cassette (1)III Product Description (2)IV Transfecting Mammalian Cells (3)V References (5)I. IntroductionRNAi (RNA interference) is a phenomenon that small double-stranded RNA (Referred as small interfering RNA or siRNA) can knock down the expression of its corresponding gene. RNAi has been observed in plants, C.elegans, and Drosophila long time ago. It was until recently that RNAi was discovered to work in mammalian system [1].Small interfering RNA (siRNA) is 19-22 nt double-stranded RNA. It works by cleaving and destroying its cognate RNA. siRNA first assembles into RNA-induced silencing complexes (RISCs), and it then activates the complex by unwinding its RNA strands. The unwound RNA strands subsequently guide the complex to the complementary RNA molecules, where the complex cleaves and destroys the cognate RNA, which results in RNAi phenomenon.RNAi has evolved into a powerful tool to study gene functions. Here are some of its applications: ∙ A stable cell line with a specific gene knocked-out can be established, and its phenotype can be studied [2-5].∙ A knock-out mouse line can be established using transgenic siRNA method [8].∙siRNA can be put into a vector with an inducible promoter to study its effect.∙siRNA can be delivered by using viral vector [6,7] and used for gene therapy purpose.∙siRNA can be mimicked by chemical molecule and used for drug development.II. siRNA cassettesiRNA cassette is a PCR product which consists of a promoter (e.g. U6 or H1 promoter) and terminator sequence flanking a DNA insert encoding a hairpin siRNA. After transfected into cells, the DNA insert encoding a hairpin siRNA is expressed from the PCR product, and induces gene specific silencing.siRNA cassette is the most cost-effective way for identifying siRNA target sequences. By screening multiple siRNA cassettes, you can find the most potent and most specific siRNA target. Here are the key features of GenScript siRNA cassette technology:1. The most cost-effective: Genscript siRNA cassette costs less than half of the corresponding syntheticsiRNA oligos.2. More stable: siRNA cassette is delivered as DNA fragment, which is much more stable than RNA.It is recommended that multiple siRNA cassettes (at least 8 target sequences) be screened for each gene to find the most potent and most specific siRNA target. Here are the reasons:1. Not all siRNA target sequences are equally potent:Because of secondary structure and otherfactors, some target sequences are more potent than others. It is better to find out the most potent target by using multiple siRNA cassette screening.2. Not all siRNA silencing effects are gene-specific: It has been reported that some siRNA silencingeffects are not gene-specific because of various reasons. It is better to identify specific siRNA targets by using multiple siRNA cassette screening.3. The experiment is still the gold test stone: Although we are proud of our siRNA design program, thebest design is still not as good as what the experiments can tell you.III. Product DescriptionsiRNA cassette is a PCR product which consists of a promoter (e.g. U6 or H1 promoter) and terminator sequence flanking a DNA insert encoding a hairpin siRNA.∙Promoter: Options include human U6 or human H1 promoter.∙Stuffed: additional sequences added to the upstream of promoter to facilitate quality control.∙Modified bases (P): To increase the stability of PCR product in transfected cells.∙Term: Poly(T) termination signal.∙Mlu I and Hin d III can be used to subclone the fragment into GenScript pRNA vectors.Quantity: 20 µg.Quality Control:The PCR fragment is analyzed by 2% agarose gel electrophoresis. The expected size of products:∙Human U6 promoter siRNA Cassette: 808 bp∙Human H1 promoter siRNA Cassette: 505 bpStorage: -20 °C after receiving.IV. Transfecting mammalian cells.General considerations before transfection: siRNA cassette is delivered as a lyophilized DNA fragment (20 μg). Before use, add 40 μl of sterilized water into each tube (0.5 μg/μl concentration), vortex it diligently. Incubate the tube at room temperature for at least 10 min so that the lyophilized DNA is completely dissolved. The behavior of siRNA cassette in transfection is different from that of plasmid. We recommend using Lipofectamin Plus TM reagent for transfection. The following are important issues to consider before performing the transfection:a. Cell density: The recommended cell density for transfection using Lipofectamine Plus TM is 50-90%. If thecell density is less than 50%, the Lipofectamine Plus TM may have some toxicity on the cells.b. siRNA cassette amount: For 12-well plates, it is recommended to use 0.2 μg as a starting point. siRNAcassette is very potent. As little as 50 ng of siRNA cassette has effect in 12-well plates. To screen most potent siRNA cassette, it is recommended to use less DNA. For other plate size, the DNA amount can be increased proportionally.c. Cell Proliferation: Maintaining healthy cell culture is essential for cell transfection. It is essential tominimize decreased cell growth associated with nonspecific transfection effects and to maintain cell culture under sub-confluent conditions to assure rapid cell division.d. Positive control and negative control: It is always a good idea to include a positive and a negative control inthe experiment. Since there are a lot of uncertainties in siRNA experiments, it is recommended to use a positive control to optimize your system. GenScript positive control is siFluc cassette (Cat. No. SC0001 and SC0002), which is targeted to firefly luciferase (pGL-3 control vector from Promega).e. Time: The optimal time after transfection for analyzing siRNA effects has to be determined empirically bytesting a range of incubation time. The time can vary from 24 to 96 hrs depending on the cells used and the experimental targets tested.f. Transfection efficiency: High transfection efficiency is essential for achieving siRNA effect using a transienttransfection approach. You can use a GFP plasmid as a transfection efficiency control.A protocol based on Lipofectamine Plus TM from Invitrogen for 293-H cells:1. Purchase Lipofectamine Plus™ reagent from Invitr ogen. Lipofectamine™ Reagent (Invitrogen Cat. 11514-015) and Plus™ Reagent (Invitrogen Cat. 18324-012)2. Plate 293-H cells (Invitrogen Cat. 11631017) the day before transfection so that they are 50-90% confluenton the day of transfection. At the time of plating and diluting transfection, avoid antibiotics - this helps cell growth and allows transfection without rinsing the cells. The cell density of 50-90% is very important. If the cell density is less than 50%, the transfection may have toxicity on the cells.3. Pre-complex the DNA with the Plus™Reagent: dilute siRNA cassette with Opti-MEM (Invitrogen Cat.31985062) from Invitrogen and mix. Mix Plus™ Reagent before use, add to DNA, mix again, and incubate at room temperature (RT) for 15 min. It is very important to dilute DNA into medium and mix before adding Plus™ Reagent, or DNA may precipitate. For 12-well plate, 0.2 μg of DNA should be diluted with 50 μl Opti-MEM and mix, and 5 μl Plus™ reagent is added later.4. Dilute Lipofectamine™ Reagent into Opti-MEM medium in a second tube and mix. For 12-well plate, 2 μl ofLipofectamine™is added to 50μl Opti-MEM medium.5. Combine pre-complexed DNA (from Step 3) and diluted lipofectamine™ Reagent (from step 4); mix andincubate for 15 min at RT. While complexes are forming, replace medium on the cells with transfection medium (Opti-MEM).6. Add the DNA-Plus™ Lipofectamine™ Reagent complexes to each well containing fresh medium on cells(from Step 5). Mix complexes into the medium gently; incubate at 37 o C at 5% CO2 for 3 h.7. After 3 h incubation, add the complete medium (containing serum) to increase the medium volume to thenormal volume.8. Perform assays on the cells 24-48 h after the start of transfection.Table I. Suggested starting amounts of reagents for transfection in different culture vessels:Table 2. Transfection optimization suggested ranges for different culture vessels:A brief protocol for siFLuc cassette (Cat. No. SC0001 or SC0002) transfection:1. To use siFLuc cassette, pGL-3 control vector (Promega, Cat. #E1741) and pRL-TK vector (Promega,Cat. #E2241) need to be purchased from Promega.2. To observe the silencing effect of siLuc, four sets of transfection are needed: a. pGL-3 control and pRL-TK vector alone; b. pGL-3 control, pRL-TK, and siFLuc plasmid (Cat. No. SD1501); c. pGL-3 control, pRL-TK, and an empty pRNA vector (Cat. No. SD1201); d. pGL-3 control, pRL-TK, and siFLuc cassette.3. For cell transfection, 12-well plates can be used. For 293-H cell from Invitrogen, 300,000 cells can beseeded the day before transfection.4. The amount of siLuc cassette used for transfection should be about 2 fold higher than that of pGL-3control plasmid. For 293-H, 0.16 μg of pGL-3 control and 0.16 μg pRL-TK vector are used, 0.05 μg to0.8 μg of siFluc cassette are used for each well.5. The plasmid can be transfected into mammalian cells using Lipofectamine Plus TM following the protocol.6. The Firefly and Renilla luciferase activities can be measured using Dual Luciferase assay kit fromPromega (Cat. #E1910) after 36 hrs of transfection.7. The activities of Firefly luciferase need to be normalized using Renilla luciferase activity.8. Typical inhibition of Firefly luciferase by siFLuc cassette is about 70% (Figure 1).Figure 1.∙CTL: 0.16 μg of pGL3-control and 0.16 μg of pRL-TK plasmid∙U6-siFLuc: pGL3-control (0.16 μg), pRL-TK (0.16 μg), and 1.6 μg of pRNA-U6.1/Neo/siLuc (Cat.No. SD1501).∙U6-empty: pGL3-control (0.16 μg), pRL-TK (0.16 μg), and 1.6 μg of pRNA-U6.1/Neo empty vector (Cat. No. SD1201).∙U6-siFLuc cassette: pGL3-control (0.16 μg), pRL-TK (0.16 μg), plus 0.8 μg, 0.2 μg, or 0.05 μg of U6-siFluc cassette (Cat. No. SC0001).V. References1. Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T. (2001) Duplexes of 21-nucleotideRNAs mediate RNA interference in cultured mammalian cells. Nature 411: 494-498.2. Yu JY, DeRuiter SL, Turner DL. (2002) RNA interference by expression of short-interfering RNAs andhairpin RNAs in mammalian cells. Proc Natl Acad Sci U S A. 99(9):6047-6052.3. Brummelkamp, T.R., Bernards, R., and Agami, R. (2002) A system for stable expression of shortinterfering RNAs in mammalian cells. Science 296: 550-553.4. Jacque, J.-M., Triques, K., and Stevenson, M. (2002) Modulation of HIV-1 replication by RNAinterference. Nature 418: 435-438.5. Sui, G., Soohoo, C., Affar, E.B., Gay, F., Shi, Y., Forrester, W.C., and Shi, Y. (2002) A DNA vector-based RNAi technology to suppress gene expression in mammalian cells. Proc. Natl. Acad. Sci. USA 99(8): 5515-5520.6. Shen C, Buck AK, Liu X, Winkler M, and Reske SN. (2003) Gene silencing by adenovirus-deliveredsiRNA. FEBS Lett 539(1-3):111-114.7. Barton GM, and Medzhitov R. (2002) Retroviral delivery of small interfering RNA into primary cells. ProcNatl Acad Sci U S A 99(23):14943-14945.8. Kunach T, Gish G, Lickert H, Jones N, Pawson T, and Rossant J. (2003) Transgenic RNA interferencein ES cell-derived embryos recapitulates a genetic null phenotype. Nature Biotechnology 21:559-561. Limited Use Label LicenseThis product is the subject of the following patents: U.S. Patent No. 6,573,099 and foreign counterparts co-owned by Benitec Australia Ltd. Not-for-profit and academic entities who purchase this product receive thenon-transferable right to use the product and its components in non-Commercial Purpose internal research.All commercial and for-profit purchasers using this product for a Commercial Purpose are required to execute a ******************************************************************************.Entitieswishingto use ddRNAi as a therapeutic agent or as a method to treat/prevent human disease also should contact Benitec ***********************.Commercial Purpose means any activity by a party for tangible consideration and may include, but is not limited to, (i) use of the product in manufacturing; (ii) use of the product to provide services, information or data for a compensatory fee; (iii) use of the product for therapeutic, diagnostic or prophylactic purposes; (iv) use of the product in drug discovery or target validation and/or (v) resale of the product or its components whether or not the product is resold for use in research.If purchaser is not willing to accept the limitations of this label license, seller is willing to accept the return of the product with a full refund. For terms and additional information relating to a commercial research license, or for licensing for any human therapeutic purpose, contact Benitec by email at ********************* .* Limited Use Label License: The use of CMV promoter is covered under U. S. Patent No. 5,168,062 and5,385,839 owned and licensed by the University of Iowa Research Foundation and is sold for research use only. Commercial users must obtain a license to these patents directly from the University of Iowa Research Foundation (UIRF), 214 Technology Innovation Center, Iowa City, Iowa 52242. For further information, please contact the Associate Director of UIRF, at 319-335-4546.GenScript Corporation120 Centennial Ave., Piscataway, NJ 08854Tel: 732-885-9188, 732-885-9688Fax: 732-210-0262, 732-885-5878Email: ******************Web: 。

Parker Zander ecosep S 系列油水分离器说明书

Proven securityThe new Oil-Water Separators of the extended ecosep S series provide the prerequisites for the economic and reliable processing of compres-sor condensate.The problem solved by the ecosep S Oil-Water Separators is well-known: in compressed air systems, con-densates form that contain not only water but also dirt, oil, and other impurities. The condensate is removed from the supply network by drains. It may not be piped into the sewage system because of the high oil content, and disposal by external companies is expensive.Processing technology provides a remedy for this: modern Oil-Water Separators enable the separation of the condensates into clean water and retained oil content. The water can be piped legally and without further ado into the sewage system. Parker Zander offer the Oil-Water Separators in three versions:ecosep S compact, ecosep S stan-dard, ecosep S plus and in eighteen output sizes. This corresponds to compressor capacities of around 72 to 6,000 m 3/h.The legal provisions and environ-mental objectives are unambiguous: condensate from a compressed air network contains mineral oils.Therefore it may only be piped into waste water if the remaining oil con-tent is below 20 mg/l.Some regions even demand values ≤ 10 mg/l. This is to protect both our environment and ultimately our own health.The Oil-Water Separators ecosep S offer more security than is required by German law.They have been constructed espe-cially for the processing of com-pressed air condensate, have been produced in their thousands and have proven themselves in usewhere safe separation of condensa-tes into their oil and water parts is required.The result: the ecosep S series, the ‘S-class“ of Oil-Water separation:ecosep S compactecosep S mini and standard ecosep S plus +General technical approval fromthe German Institute for Construc-tion Technology in Berlin.A two-phase test to ensure the safechecking of the cleaned condensate (test valve) is standard.Flow-optimized layout and enlargedtank volumes increase the degreeof separation.A range of sizes for every possible use and outputs up to 100 m 3/min.Generous dimensions ensure con- tingency reserves.Throughout development, emphasis has been placed on user-friendliness and economic efficiency.ecosep SOil-Water SeparatorEffective combination of pre-filter and activated carbon filter en- sures long service life and prevents overloading of the activatedcarbon.A special document compartmentkeeps the maintenance log andoperating instructions clean andto hand.for most models.3 or4 possible connections 1/2” for the condensate intake.The advantages of the ecosep S speak for themselvesecosep S Oil-Water Separatorecosep S compactOil-Water SeparatorThe ecosep S compact reliably re-moves the oil - through a combination of different filter materials - from the arising condensate. If sizes of the eco-sep S compact are correct, the water retains an oil content of < 2mg/l and can be piped directly into the sewage system.General technical approval fromthe German Institute for Construc tion Technology in Berlin.3-4 possible connections for the condensate intake.3-stage combi-filterA two-phase test to ensure the safe checking of the cleaned condensate (test valve) is standard.Secure wall and floor mounting A special document compartment keeps the maintenance log and operating instructions clean and to hand.Six sizes for outputs to 12 m 3/min.ecosep S compact: highly economiccondensate processing in a compact format:Oil-Water Separators cannot process any stable emulsions or water-soluble oils.and other compressor oils (see below).Technical Speciﬁcationsecosep S compactOil-Water SeparatorSepaKit contents: Air filter and 3-stage water filter, sturdy disposal sack, extra long glovesLoose accessoriesFrom ecosep S 6 compact a 115 V heater is available on request.ecosep S mini and standardOil-Water SeparatorThis standard production range has proven itself a thousand times over and features:General technical approval from the German Institute for Construc- tion Technology in Berlin.Four possible connections 1/2” for the condensate intake.Effective combination of pre-filter and activated carbon filter ensures long service life and prevents overloading of the activated carbon.Flow-optimized layout and en- larged tank volumes increase the degree of separation.Generous dimensions ensure contingency reserves.Identical filters for all models (from e cosep S 2) ensure simple stock control, no confusion, and cost-effective purchasing.A two-phase test to ensure the safe checking of the cleaned con densate (test valve) is standard.An oil leakage sump keeps the compressor station clean.A special document compartment keeps the maintenance log and operating instructions clean and to hand.Eight sizes for outputs to 70 m 3/ min.Advantages of the ecosep S mini + standard:ecosep S mini and standardOil-Water SeparatorOil-Water Separators cannot process any stable emulsions or water-soluble oils.* Output ratings for rotary screw air compressors in use for non-emulsifying oils. Output must be adjusted for other compressor types and other compressor oils (see below).Technical SpeciﬁcationsSepaKit contents:Air and water filters (activated carbon), sturdy disposal sack, extra long glovesLoose accessoriesecosep S plusOil-Water SeparatorThroughout further development, emphasis has been placed on grea-ter efficiency at higher output levels. This is achieved through the use of a special flow filter. Ecosep S plus is particularly suited for use with problematic condensates.General technical approval from the German Institute for Construction Technology in Berlin.Four possible connections 1/2” for the condensate intake.Effective combination of pre-filter and activated carbon filter ensures long service life and prevents overloading of the activated carbon.Generous dimensions ensure contingency reserves.Fluidic layout and enlarged tank volumes increase the degree of separation.A two-phase test to ensure the safe checking of the cleaned con densate (test valve) is standard.An oil leakage sump keeps the compressor station clean.A special document compartment keeps the maintenance log and operating instructions clean and to hand.Thermostatically controlled heater (optional).Four sizes for outputs to 100 m 3/ min.Advantages of the ecosep S plus.Improved design for large output:Oil-Water Separators cannot process any stable emulsions or water-soluble oils.* Output ratings for rotary screw air compressors in use for non-emulsifying oils. Output must be adjusted for other compressor types and other compressor oils (see below).Technical Speciﬁcationsecosep S plusOil-Water SeparatorSepaKit contents:Air filter, pre-filter, and water filter (activated carbon), sturdy disposal sack, long glovesLoose accessoriesA 115 V heater is available on request. 2 heaters are required for ecosep S 61 plus.Supplementary products Condensate drain ecodrain ED 3000Short descriptionElectronic condensate drains fromthe ecodrain ED3000 series aredistinguished by the following features:- Wear and tear resistant magnetic corelevel regulation for optimum and loss-free draining of condensate.- Integrated dirt filter between fill-levelindicator and drain valve to protect thediaphragm valve during continual alarmmonitoring.- Generous diaphragm valve withcondensate pre-activation for a longlifespan.- Dry alarm contact (exceptions ED3002,ED3004)Application: Compressed air to 16 bar – normal condensatesCondensate drain ecodrain ED 2000 Short descriptionElectronic condensate drains fromthe ecodrain ED2000 series aredistinguished by the following features:- Wear and tear resistant magnetic corelevel regulation for optimum and loss-free draining of condensate.- Sturdy and high-pressure resistantdesign in compacted and sealed metal,additionally protected both inside andout by a powder coating.- Generous diaphragm valve for a longlifespan.- Dry alarm contact.- Versions to 50 bar.A pplications: Compressed air and (certain) technical gases to 50 bar normal and problem condensatesBULS-01-ENYour local authorized Parker distributor© 2013 Parker Hannifi n Corporation. A ll rights reserved.EMEA Product Information CentreFree phone: 00 800 27 27 5374(from AT , BE, CH, CZ, DE, DK, EE, ES, FI, FR, IE, IL, IS, IT , LU, MT , NL, NO, PL, PT , RU, SE, SK, UK, ZA)US Product Information Centre Toll-free number: 1-800-27 27 537/hzfdWater separator WS2 - WS19Efﬁ cient ﬂ uids separator for compressed air networksShort descriptionParker Zander Separators from the WSseries are designed to be effi cient liquid separators and to remove large quanti-ties of fl uids from compressed air. Water separators from the WS series remove fl uids in the form of droplets and as wall fl ow, where it occurs for example on chillers and refrigeration dryers, over a wide nominal output range of 25 to 125 % with a high degree of effi ciency of 92 - 99 % and are also suitable for use with frequency controlled condensing.Innovative construction features of the casing as well as of the separator appli-cations provide optimum fl ow manage-ment with the lowest possible pressure drag in relation to the required through-put rate: This enables a cost reduction during operation with reliable separation performance. To do this, the water se-parators are equipped with electronically controlled condensate drains from the ED3000 series, which reliably separate even large condensate volumes without loss of compressed air.Preventive annual maintenance of the condensate drain is recommended; the water separator itself requires no main-tenance.Output overview by pressure drag。

处理问题英语短语

处理问题英语短语English Phrases" that is over 1,000 words long, written entirely in English without any additional titles or extraneous punctuation.Handling problems is an essential skill in both personal and professional life. When faced with challenges, it is important to have a toolbox of English phrases that can help navigate the situation effectively. These phrases can be used to express concerns, seek clarification, propose solutions, and collaborate with others to reach a resolution.One common phrase used to raise a problem is "There seems to be an issue with..." This allows the speaker to objectively identify the problem at hand without placing blame. For example, "There seems to be an issue with the deadline for the project report." This opens the door for further discussion and problem-solving.Similarly, "I've noticed that..." can be used to bring attention to a concern. This phrasing focuses on the observation rather than making accusations. An example would be, "I've noticed that the sales figures have been declining over the past quarter." This allows the issue to be addressed without creating a confrontationalatmosphere.When seeking more information about a problem, "Can you clarify..." is a courteous way to request additional details. For instance, "Can you clarify the steps that need to be taken to resolve this technical problem?" Asking for clarification demonstrates a willingness to understand the situation fully before proposing solutions.In some cases, it may be necessary to express a stronger concern. The phrase "I'm worried that..." can convey a sense of urgency while still maintaining a professional tone. An example would be, "I'm worried that if we don't find a solution soon, the project will fall behind schedule." This highlights the gravity of the situation without placing blame.When it comes to proposing solutions, "What if we..." is an inclusive way to generate ideas. For example, "What if we adjust the workflow to allow more time for quality assurance?" This phrasing encourages collaboration and avoids imposing a single solution.Another useful phrase is "Perhaps we could..." This allows the speaker to make a suggestion while still being open to other ideas. An example would be, "Perhaps we could reallocate resources from the marketing budget to address this issue." The use of "perhaps" conveys flexibility and a willingness to consider alternativeapproaches.In some cases, it may be necessary to take a more assertive stance. The phrase "I recommend that..." can be used to put forth a specific course of action. For instance, "I recommend that we schedule a meeting with the client to discuss these concerns." This phrasing conveys confidence in the proposed solution while still leaving room for discussion.When dealing with a sensitive or complex problem, it can be helpful to use the phrase "Let's explore..." This encourages a collaborative approach to problem-solving. For example, "Let's explore the root causes of the customer complaints and brainstorm potential solutions." This language fosters an environment of mutual understanding and joint problem-solving.In situations where a problem requires immediate attention, "We need to address..." can convey a sense of urgency. For instance, "We need to address the IT security breach as soon as possible to mitigate any potential damage." This phrasing underscores the importance of taking prompt action.It's also important to acknowledge when progress has been made. The phrase "I'm pleased to report that..." can be used to highlight positive developments. For example, "I'm pleased to report that wehave identified the source of the technical issue and are implementing a solution." This encourages a sense of momentum and collaboration.Finally, when a problem has been resolved, the phrase "I'm confident that..." can be used to express assurance in the outcome. For instance, "I'm confident that the new process we've put in place will prevent this issue from occurring again in the future." This language conveys a sense of closure and confidence in the solution.In conclusion, having a repertoire of English phrases for handling problems can be invaluable in both personal and professional settings. These phrases can help to express concerns, seek clarification, propose solutions, and collaborate with others to reach a resolution. By using these phrases effectively, individuals can navigate challenging situations with confidence and professionalism.。

交替类比法的英语作文

交替类比法的英语作文Title: The Interplay of Nature and Technology: An Alternating Analogy。

In the tapestry of existence, nature and technology dance a delicate duet, each influencing and shaping theother in profound ways. Just as the sun alternates with the moon in the sky, so too do these two forces ebb and flow, intertwining to create the rich fabric of human experience. Through the lens of alternating analogy, let us explore the intricate relationship between nature and technology, illuminating their parallels and contrasts.Firstly, consider the vast expanse of the natural world, where ecosystems thrive in harmonious balance. Much likethe intricate networks of interconnected devices in a technological system, ecosystems rely on a delicate equilibrium to function effectively. Just as a disruptionin one part of a computer network can cause a cascade of errors, so too can the introduction of a foreign speciesupset the delicate balance of an ecosystem, leading to unforeseen consequences.Furthermore, both nature and technology exhibit remarkable resilience in the face of adversity. Just as a tree bends but does not break in the face of a fierce storm, so too do technological systems adapt and evolve to overcome challenges. From the development of resilient infrastructure to the creation of adaptive software algorithms, humanity draws inspiration from the resilienceof the natural world to innovate and improve technological solutions.Yet, for all their similarities, nature and technology also diverge in fundamental ways. While nature operates according to the immutable laws of physics and biology, technology is bound only by the limits of human imagination and ingenuity. Where nature evolves slowly over millennia through the process of natural selection, technology advances at an exponential pace, driven by the relentless march of innovation.Moreover, the consequences of human intervention in nature and technology differ markedly. While technological advancements have the potential to revolutionize societyand improve human well-being, they also carry the risk of unintended consequences and unforeseen side effects. From the environmental impacts of industrialization to theethical dilemmas posed by artificial intelligence, humanity grapples with the ethical implications of its technological creations.In conclusion, the alternating analogy between nature and technology offers a powerful lens through which to understand the complex interplay between these two forces. From their shared resilience in the face of adversity to their divergent paths of evolution, nature and technology offer valuable insights into the nature of existence itself. As we navigate the ever-changing landscape of the 21st century, may we draw inspiration from the beauty and complexity of the natural world, while harnessing the transformative power of technology for the benefit of all.。

bechet- beaujard method -回复

bechet- beaujard method -回复Bechet Beaujard method is a highly effective productivity and time-management technique that helps individuals prioritize their tasks, stay focused, and achieve their goals efficiently. Developed by productivity expert Bechet Beaujard, this method combines elements of various productivity systems and incorporates innovative strategies for optimal results. In this article, we will explore the Bechet Beaujard method in detail, explaining itsstep-by-step process and discussing its benefits.Step 1: Set Clear GoalsThe first step in the Bechet Beaujard method is to set clear and specific goals. Identify what you want to achieve, whether it's completing a project, reaching a personal milestone, or developing a new skill. Setting clear goals helps provide direction and motivation, making it easier to prioritize tasks and allocate time effectively.Step 2: Break Down Goals into Manageable TasksOnce you have set your goals, it's essential to break them down into smaller, manageable tasks. This makes them less overwhelming and enables you to tackle them more efficiently.Prioritize these tasks based on their importance and deadline, ensuring that the most crucial tasks receive appropriate attention.Step 3: Use Time BlockingTime blocking is a core component of the Bechet Beaujard method. It involves scheduling dedicated time blocks for specific tasks or activities. By allocating specific time slots to work on particular tasks, you create structure and discipline in your routine. This helps you focus on the task at hand and eliminates distractions, increasing productivity.Step 4: Employ the Pomodoro TechniqueThe Pomodoro Technique, popularized by Francesco Cirillo, is an effective time-management strategy that fits well with the Bechet Beaujard method. It involves breaking work into intervals of focused work (typically 25 minutes) followed by short breaks. Use a timer to set the interval for focused work and ensure that you take regular breaks to recharge and maintain productivity throughout the day.Step 5: Utilize Prioritization TechniquesTo ensure maximum efficiency, the Bechet Beaujard methodencourages the use of prioritization techniques. The Eisenhower Matrix is an excellent tool for this purpose, dividing tasks into four categories: urgent and important, important but not urgent, urgent but not important, and not urgent, not important. This helps you identify tasks that need immediate attention and those that can be delegated or eliminated.Step 6: Minimize DistractionsDistractions can significantly hinder productivity. To combat this, the Bechet Beaujard method emphasizes the need to minimize distractions. Turn off notifications on your phone, close unnecessary browser tabs, and create a dedicated workspace free from distractions. This helps you maintain focus on your tasks and complete them efficiently.Step 7: Practice Self-Care and ReflectionThe Bechet Beaujard method emphasizes the importance ofself-care and reflection in maintaining productivity. Take regular breaks to relax, exercise, and rejuvenate. Additionally, take some time at the end of each day to reflect on your achievements, assess your progress, and make adjustments to your approach as needed. This reflection allows you to continually improve your productivityand maximize your results.Benefits of the Bechet Beaujard MethodThe Bechet Beaujard method offers several benefits for individuals looking to improve their productivity and time-management skills. By implementing this method, individuals can:1. Increase efficiency and productivity: By following a structured approach and utilizing various techniques, individuals can optimize their time and accomplish tasks more effectively.2. Improve focus and concentration: Through time blocking and minimizing distractions, individuals can enhance their focus and concentration, allowing for better quality work.3. Prioritize tasks effectively: The Bechet Beaujard method provides strategies for prioritizing tasks based on importance, urgency, and personal goals, ensuring that individuals spend their time on what matters most.4. Reduce stress and overwhelm: Breaking down goals and tasks into manageable pieces and practicing self-reflection helpsindividuals minimize stress and avoid feeling overwhelmed by their workload.5. Enhance work-life balance: By increasing productivity and optimizing time usage, individuals can free up more time for activities they enjoy, improving their overall work-life balance.The Bechet Beaujard method is a comprehensive approach to productivity and time management. By following the step-by-step process outlined above, individuals can significantly improve their efficiency, effectively manage their time, and achieve their goals with greater success.。

27040646_原位形成碳酸钙协同纳米纤维素对老化纸张脱酸增强的研究

China Pulp &PaperVol.41，No.5，2022·老化纸张脱酸增强·原位形成碳酸钙协同纳米纤维素对老化纸张脱酸增强的研究祁石任俊莉*曹显何贝樊慧明（华南理工大学制浆造纸工程国家重点实验室，广州市岭南文献保护研究中心，广东广州，510640）摘要：本课题提出在老化纸张中原位形成碳酸钙并协同纳米纤维素脱酸处理增强的保护措施，探讨了不同处理方式及纳米纤维素浓度对老化纸张性能的影响。

结果表明，先利用0.1mol/L 丙酸钙及0.1mol/L 碳酸钠水溶液压力雾化处理纸张，在纸张中原位形成碳酸钙进行脱酸，再利用1wt%纳米纤维素进行增强。

处理后老化纸样pH 值达8.40，碱存储量约245mmol/kg ，抗张指数和耐折度较处理前分别提升了19%、109%，且具有优异的抗老化和防霉性能。

关键词：老化纸张；碳酸钙原位形成；纳米纤维素；脱酸；增强中图分类号：TS761文献标识码：ADOI ：10.11980/j.issn.0254-508X.2022.05.008Study on Deacidification and Reinforcement of Aged Paper by Nanocellulose Collaboratedin -situ Synthesized Calcium CarbonateQI Shi REN Junli *CAO Xian HE Bei FAN Huiming（State Key Lab of Pulp and Paper Engineering ，Guangzhou Lingnan Literature Preservation Research Center ，South China University of Technology ，Guangzhou ，Guangdong Province ，510640）（*E -mail ：renjunli@ ）Abstract ：A protection method for deacidification and reinforcement of aged paper by synthesized calcium carbonate in -situ and collaborated nanocellulose was proposed.The effects of different treatment methods and nanocellulose concentration on properties of aged paper were dis⁃cussed.The results showed that the paper was treated by pressure atomization of 0.1mol/L calcium propionate and 0.1mol/L sodium car⁃bonate aqueous solution to synthesize calcium carbonate in the paper in -situ for deacidification.Then the paper was enhanced by 1wt%nanocellulose.After treatment ，the pH value of the aged paper sample reached 8.40，the alkaline reserve was about 245mmol/kg ，the ten⁃sile index and the folding endurance increased by 19%and 109%，respectively ，compared with the untreated sample.The treated paper also had excellent anti -aging and mold resistance.Key words ：aged paper ；in -situ synthesis of calcium carbonate ；nanocellulose ；deacidification ；reinforcement纸质文献是人类文明传承的重要载体，具有学术性、艺术性、历史性等多重价值属性[1-2]。

《植物质体PCR协议》

Extraction and PCR of plastid DNA from a plantCharles Hill, Wymondham College, Norwich, UKLevel of difficultyAlthough this is not an easy experiment to be performed at school, it can be organisedwith help from scientists or other experienced teachers. If you need support inidentifying a scientist or an experienced teacher to contact in your area, please ask us,sending an email to scisoc@.PrefaceThe D1 protein in the Photosystem II Reaction Centre in plant chloroplasts plays a keyrole in electron transport, and the structure and function of Photosystem II has beenreviewed (Hankamer, Barber and Boekma, 1997, and Raghavendra, 2000). It has beenknown for some time that the site of action of certain herbicides is this D1 protein (seeDe Prado, and Jorrín and García-Torres, 1997). Hirschberg and MacIntosh (1983)analysed the sequence of the plastid psbA gene in Amaranthus hybridus and found thatresistance was due to a point mutation in codon 264 causing the amino acid serine to bereplaced by glycine. This was due to the substitution of the base A by G at position 790.This mutation has also been found in Solanum nigrum (Goloubinoff, Edelman, andHallick, 1984) and Senecio vulgaris (Frey, 1999), and has been associated with resistanceto the triazine herbicides. DCMU (Diuron) is also known to inhibit electron transportby binding to the D1 protein. This point mutation (SNP) creates a restriction site for therestriction enzyme BstX 1.IntroductionThis protocol provides a means of identifying either the resistant or the herbicidesusceptible genotype of Rapid Cycling Brassicas by amplifying a 963 basepair (bp)fragment of the psbA gene (from the coding region) and subsequent incubation with therestriction enzyme BstX 1, which cleaves the gene for resistance into 764bp and 199bpfragments but has no effect on the non-resistance gene.The protocol is divided into 4 stages: extraction, PCR, restriction digest, and gelelectrophoresis. Certain aspects of this protocol have been designed to match aprotocol for the amplification of human mitochondrial DNA (Schollar and Harrison,2002), and readers may find reference to this protocol helpful.If a restriction digest has been carried out, it should be possible to see a differencebetween the uncut fragment (963bp) and the larger fragment resulting from thedigestion of the resistant gene product (764bp). It may not be possible to see thesmaller fragment due to the sensitivity of the staining procedure. If bromophenol blue isused as the loading dye then its position on the gel after electrophoresis and the smallamount of diffusion which occurs, may mask the smaller fragment.Apparatus needed (for reagents, see experimental protocol that follows)• micropipettes to measure volumes from 1 to 50 µl, and tips (e.g. Gilson orEppendorf pipettes)• plastic reaction tubes, 500 µl and 1,5 ml sizes• microcentrifuge suitable for these tubes• PCR thermal cycler (heating block with variable programme) or constant temperature water baths• agarose gel apparatus (tank)• high voltage power supply capable of delivering up to 300 volts D.C. (a lower voltage supply can be used with lon ger running times)Sources of Biological MaterialSeeds for Rapid Cycling Brassicas can be obtained from the Crucifer Genetics Cooperative at the University of Wisconsin in the USA[/research/phenotype.html]. Seeds can also be obtained in the UK from Blades Biological [] although they may not hold the atrazine resistant biotype in stock.A convenient source of leaf tissue for PCR only is salad rape (Brassica napus). Senecio vulgaris and lettuce (Lactuca) have also given positive results but the primers do not appear to work with barley (Hordeum spp).Analyses of the psbA gene sequences from other plants suggest that Nicotiana tabacum, Solanum nigrum, Arabidopsis thaliana, Chenopodium rubrum and Amaranthus hybridus should all give a PCR product using the same primer sequences.1st stage: High pH extraction method for Plastid DNAMaterial:• Forceps• Cocktail stick or toothpick at least 6cm long• 1.5 ml microcentrifuge tube• Plastic drinking straw cut into approx 5cm lengths• Micropestle* or glass rod to fit tube• Micropipette to measure 50µl with tips• 70% ethanol for sterilisation• Plastic gloves• Leaf material – the cotyledon leaves of rape (Brassica napus) or other related Brassicas work wellSolution A 50µl 0.9M KCl 0.1M KOH10mM EDTASolution B50µl 0.9M KCl0.1M HCl 10mM EDTA 0.2M Tris pH 8.8If in doubt about the cleanliness of forceps or micropestle, rinse with 70% ethanol and dry.The micropestles and cocktail sticks/toothpicks could be autoclaved.Procedure:1.Pick a healthy leaf with the forceps. Use the straw to punch a small disk about2mm2 (= 1.4 x 1.4 mm or 1.6 mm diameter). It is helpful to support the disk ona soft surface e.g. a plastic glove on a finger tip. Use the stick to push the leafdisk into the bottom of the 1.5ml tube.2.Add 50µl solution A and homogenise with the micropestle but proceed carefullyto ensure homogenisation is complete and that the micropestle does not pushliquid out of the tube if pushed down too quickly. A clear green solution should be the result3.Add 50µl solution B with the micropestle still in the tube, remove themicropestle, close the top and mix by flicking the base of the microcentrifugetube two or three times.4.Place the tube in the fridge until required – Dilute the extract 15x with sterilewater (e.g. 10 µl extract + 140 µl) water. Use 15 µl of diluted extract per 25 µlPCR reaction mix.. (The extract will keep for at least a week in a fridge)The method is a modification of methods used in the following references: P Matthews et al, (2001) Molecular Breeding 7 (3) 195 – 202D Thompson & R Henry (1995) BioTechniques 19 (3) 394 – 400*Autoclavable, reuseable micropestles obtained from Anachem K749520-00002nd stage: Polymerase Chain Reaction (PCR) – Amplification of the plastid gene using PCRMaterial:•DNA-containing extract from plants•Ready-To-Go PCR bead (Amersham Biosciences puReTaq™ Cat No. 27-9559-01, supplied as pack of 96 0.2 ml tubes, but I have also used BioTaq polymerase (at 0.05U per µl) from Bioline with KCl buffer(BIO-21040 + BIO-37027), plusdNTPs at a final concentration of 0.25mM each.•Primers: purchased from Invitrogen using 50 nmol synthesis:P1 = 5’-CGAAAGCGAAAGCCTATGGG-3’P2 = 5’-TCCATACCAAGGTTAGCACGG-3’Primers are dissolved in TE buffer to provide a stock solution of 1 µg/µl (approx. 150µM).Procedure:1.Before use, primers are diluted 30 times with DNA-free water (e.g. 5 µl primer+ 145 µl water). If volumes smaller than 10 µl cannot be easily pipetted, thenequal volumes of the two primers might be mixed and 10 µl of the mixtureadded. In this case primers should be mixed immediately before adding to thePCR tube and kept on ice once mixed.2.Set up the PCR reaction mix. The total volume in the tube is 25 µl. Thisincludes:15 µl diluted extract [or 14 µl of DNA free water + 1 µl of original DNA extract(add water first)]5 µl of Forward Primer P1 (Final concentration = 1 µM)5 µl of Reverse Primer P2 (Final concentration = 1 µM)3. PCR reaction. The following programme is used in the PCR machine:1. 94°C for 2 minutes (initial denaturation)2. Denature - 94°C for 30 s3. Anneal - 55°C for 30 s 30 cycles4. Extend - 72°C for 30 s5. 72°C for 5 minutes6. Hold at 4°CKeep the tubes on ice until the restriction enzyme digest.3rd stage: Restriction enzyme digest of the PCR productReagents:PCR productRestriction enzyme: BstX I, 1000 units, New England BioLabs (NEB) R0113S Buffer: NEB Buffer 3 (supplied with the enzyme)Procedure:Carry out for PCR product of both Atrazine Resistant and Sensitive plant extracts.1.Add the following to a microcentrifuge tube (approx. 50 ml total volume):25 ml PCR product20 ml DNA-free water5 ml Buffer X101-2 ml BstX I enzyme (10 - 20 units)2.incubate at 50°C for 1hPut samples on ice until the next stepUse at least 30 ml of digest per well for electrophoresis – check that the wells of the gel have the right size.4th stage: Gel Electrophoresis and StainingReagents:PCR-product after restriction digest (use at least 30 µl)Gel: 1% agarose in 0.5 X TBE Buffer with wells 5.5mm x 1.5mmLoading dye: Orange G (acid orange) at 6x final concentration: 25 mg dye + 3 ml glycerol +7 ml water (or instead of glycerol use 4g sucrose in final volume of 10 ml water) Buffer: TBE = 90 mM Tris base, 90mM Boric acid, 2mM EDTA, pH 8.3Staining solution: 0.1% methylene blueProcedure:1.Remove the tube from ice.2.Set the micropipette to 5µl and, using a clean tip for each PCR tube, load 5µl ofloading dye (LD) (Orange G in a glycerol solution). This colours the samples and makes them denser than the electrophoresis buffer.3.Add the loading dye to each tube (and, if several tubes are to be done, eject thetip into the tube – the tip can be used again to load the sample onto the gel –see below). Make sure that the loading dye is deposited near the contents at the bottom of the tube.4.The gel is in a tank with electrophoresis buffer covering it. Each participantshould be able to load at least one well. Make sure that you label the gel map.5.Reset the micropipette to 20µl. For each tube mix the contents by pipetting upand down, and then load the sample into a well on the gel.6.When loading the gel ensure that the pipette tip is below the surface of thebuffer but just above the well. The loading buffer will allow the sample to sinkinto the well but depress the plunger slowly while adding the sample to the well.7.The gels can be run for about 20 minutes at 100V (the optimum is 5V per cmbetween electrodes).8.When the electrophoresis is finished, the buffer must be poured off carefully,using a gloved hand to keep the gel in position.9.The gel is then removed in its carrier and added to a plastic tray containing 0.1%methylene blue. It should be left in the tray for 3 minutes with gentle movement now and again to aid the staining of the gel.10. After 3 minutes pour off the methylene blue stain and add water to cover thegel well.11. Leave for 10 – 15 minutes; if possible change the water once during this period.Destaining may be speeded up slightly by using a steady but gentle stream ofwater direct from the tap.Safety WarningIf using voltages above 25V, then designated equipment must be used so that live terminals are properly shielded.Alternative staining:As an alternative to the staining of the gel with methylene blue, Nile Blue sulphate can be dissolved in the TBE buffer (1µg/ml) used to make the agarose gel and in the running buffer. This stain attaches to the DNA as it migrates through the gel and results in a much lower level of background staining, and the DNA bands stain during the actual electrophoresis. With this method gels are best observed immediately as the stain may fade with time.ReferencesWeed and Crop Resistance to Herbicides (1997) Ed. De Prado, R, Jorrín, J and García-Torrres L (Kluwer Academic Publishers ISBN 0 7923 4581 9)Frey J (1999) Genetic Flexibility of Plant Chloroplasts Nature 398 115-116 Goloubinoff, P, Edelman, and Hallick, R (1984) Chloroplast coded resistance in Solanum nigrum: psbA loci from susceptible and resistant biotypes are isogenic except for a single codon change. Nucleic Acids Research 12 (24) 9489-9496Hankamer, B, Barber, J and Boekema, E, (1997) Structure and Membrane Organisation of Photosystem II in Green Plants. Annual Review of Plant Physiology and Plant Molecular Biology 48 641-671Hirschberg, J and McIntosh, L (1983) Molecular basis of herbicide resistance in Amaranthus hybridus. Science 222 1346-1348Photosytnhesis: A Comprehensive Treatise (2000) Ed. Raghavendra A.S., Cambridge University Press ISBN 0 521 78444 1 (esp Chs 2 and 3)Schollar, J and Harrison, A (2002) Amplification of Human Mitochondrial DNA Bioscience explained 1 (2) 1-10AcknowledgementsCharles Hill gratefully acknowledges the support given through Science and Plants for Schools (SAPS)/Robinson College, Cambridge School Teacher Fellowship and the subsequent support of SAPS and the John Innes Centre, Norwich, UK for the final stages of the development of this protocol.Diagram 1: Extraction and PCRTake care!!Diagram 2: Electrophoresis5 µl 25 µl 20 µl。

SignallingandScreening-LSE

Signaling and Screening: Theory and EvidenceEc 423. Labour EconomicsLent Term 2009Papers:StiglizSpenceLang and KroppSpence, QJE 1973“Job Market Signaling”The big point:If there is a heterogeneity of types and there exists a signal which has a cost that is negatively correlated with productivity then there exist an infinite number of equlibirium which produce perfect information.Spence hopes to generate a model that “a considerable variety of market and quasi-market phenomena like admissions procedures, promotion in organizations, loans and consumer credit can be usefully viewed through.”This may generally be useful in cases where the incentive for truthfully revelation is low and thus observable characteristics become the basis of decisions.The key assumptions: Signal cost must be negatively correlated with ability. This is a prerequisite for the an observable, alterable characteristic to be a persistently informative signal in the market.The model works: There is an information feedback loop. As new market information comes into an employer (through either observation, hiring, etc.) they form beliefs on productive capabilities which are related to observable signals and adjust their beliefs accordinglyAn equilibrium is when “a set of employer beliefs...generate offered wage schedules, applicant signaling decisions, hiring and ultimately new market data over time that are consistent with the initial beliefs.”To find an equilibrium: we guess a set of self-confirming beliefs and then check that they are indeed confirmed by the feedback loop.The striking features of this are that1. there are an infinite number of equilibrium for a given level of education that generates a maximum productivity that perfectly inform the employer.2. The equilibria are not equivalent in terms of welfare3. There are also equilibria that do not perfectly inform the employer.4. The assumption of negative correlation between signal cost and productivity is necessary but not sufficient for signaling. We need a significant number of signals Stigliz, AER 1975“A Theory of Screening, Education, and the Distribution of Income”The Big Points:Education when used as a screening mechanism can actually lead to worse social conditions because if education provides information as well as skills, then it is working within a market that fails. Why does this happen?1. Social returns to education differ from private returns. Thus, while screening has productivity returns, it will decrease equality. Thus for some regions there is a tradeoff between efficiency and distributional concerns.2. There is also a region in which education expenditure may both increase inequality and decrease net national income. Overspending happens because the median voter does not pay the median share of education and thus has an incentive to overconsume—especially in publicly funded schools3. Attempts to curtail education as screening may just shift screening and actually lead to worse conditionsStigliz explicitly notes that these results are based on his highly stylized model and may not hold without these assumptions:1. The more able are better in every relevant sense, so there is an unambiguous ranking of abilities2. Labor is inelastically supplied3. Individuals have perfect information4. There is not method of on-the-job screening5. The screening is accurate6. The information acquired is “general”, i.e. not firm specificThe Model:We have a population with individuals with ability level θ , where the probability of being of typeθ is h(θ). Productivity p is defined as Lp=m θwhere m is set to unity WLOGThen make the following assumptions:1. ability is private information2. absent information, all firms (which are risk neutral) treat individuals the same.3. Productivity of a single employee cannot bet determinedThen consider the simplifications with two types 1 (high ability) and 2 (low ability) Where there is an accurate screening mechanism which costs c/individual and labor supply is inelastic. Parameterize c as follows:1. θ1 −θ2 > c > θ1 − θavg2. θavg = E(θavg)Then we get 2 equilibrium:1. Pooling:getsθavgContact—EveryoneHigh ability types have no incentive to screen because by 1 they make more than if they screened because they would only getθ -c < θavg2. Separating:Contract—If you screen you getθ1 -cIf you do not screen you getθ2Important aspects of these results:1. there may be multiple equilibria2. The equilibria can be pareto ranked3. In both equilibria the presence of the lower type decreases the wage of the higher type while the presence of the high type gives the low type at least their marginal product and maybe more4. Social returns to screening mechanisms (e.g. education) differ from private returns. Which causes a divergence between pareto optimality and equality.The separating equilibrium may not exist in the following cases:1. If there are self-employment opportunities that can realize the same returns that would have been realized by accurate screening without the screening2. If individuals are perfectly certain of their abilities and can demonstrate them on the job3. If individuals are very risk averse and not perfectly certain of their abilitiesThe Social benefits from Screening:1. If screening costs are low and labor supply is elastic then everyone can be made better off from screening by using an appropriate redistributive tax to compensate the worse off.2. If there are returns to group homogeneity, then matching with screening may produce better allocation of laborEmpirical Evidence on Signaling/ScreeningDoes the signaling model share any implications with the Human Capital model?1. People who attend additional years of schooling are more productive. YES.2. People who attend additional years of schooling receive higher wages. YES.3. The rate of return to schooling should be roughly equal to the rate of interest. NO PREDICTION.4. People will attend school while they are young, i.e., before they enter the workforce. YES.How do you empirically distinguish the human capital and signaling models?1. Measure whether more educated people are more productive? (Would be true for either model.)2. Measure people’s productivity before and after they receive education — see if it improves. (Conceptually okay, very difficult to do.)3. Test whether higher ability people go to school? (Could be true in either case—certainly true in the signaling case.)4. Find people of identical ability and randomly assign some of them to go to college. Check if the college educated ones earn more? (Both models say they would.)5. Find people of identical ability and randomly assign them a diploma. See if the ones with the diploma earn more. (A pure test of signaling.)Because their empirical implications appear so similar, many economists had begun to conclude that these models could not be empirically distinguished. The empirical papers on the syllabus by Lang and Kropp (1986) and Bedard (2001) offer some evidence. Weiss(1995) provides a survey.All of the empirical papers implement closely related indirect tests of the signaling model along the following lines. If we are initially at a separating equilibrium, how does an exogenous decline in the cost of schooling for one group affect the education choices of other worker groups who are not directly affected by the price change?Lang and Kropp look at college going as a function of school leaving laws (which primarily directly affect secondary school attendance). The General Idea: Compulsory schooling should have different effects on educational attendance depending on whether education is a tool for human capital accumulation or if it is a form of signaling. The two potential effects:In a signaling model if the lowest ability increase their educational attainment so will some higher abilities since they must do this to differentiate themselves from the lowest type. If CAL imposes a certain signal for the lowest type, then the signaling hypothesis suggests some individuals not bound by the law will still increase their educational attainment.In the human capital model, a change in the CAL will not change the return to education (by using the factor price equalization assumption). Therefore, workers for whom the return to schooling sufficiently low as to choose dropping out will be bound to stay in school if they are affected by the law. However, individuals who are not bound by the law should be unaffected.The Results:To test this, they use a SUR with time and state fixed effects for two age groups, 16 year olds (affected by the law) and 17-18 year olds (unaffected by the law). The educational attainment of non-affected groups (i.e. the 17-18 year olds for whom the law was non-binding) increased and thus Lang and Kropp conclude that this is consistent with the signaling hypothesis.Some Problems:Factor price equalization: It is not clear that that this is operable1. wages are the same across states for the same education-ability pair2. the return to education is the same in each state3. If there is correlation between ability and mobility the theorem will fall apart There may be some of both going on: There may be some value to the signal but there are also productivity gains. More broadly, this test is pretty weak because they are testing second order predictions of the signaling model without testing if there is an actual value for a “signal” which is the first order prediction of the model. The issue is we need a signal which has no impact on humancapital production and is as if randomly assigned to otherwise identical expected productivity. A clever paper by Tyler, Murnane, and Willet (TWM) does just that.TMW are interested in knowing whether the General Educational Development (GED certificate(GED) raises the subsequent earnings of recipients. This is not just interesting for the signaling model but also for public policy—there is pretty big differences in high school completion rates between states, income and race/ethnicity groups (see table 1 of the paper)Of course we cannot simply compare GED holders to High School grads because of the obvious self-selection problems: GED holders probably would have earned less than HS Diploma holders regardless. But they are also not really comparable to other high school drop outs. We can see this in the summary statistics provided by TMW where relative to other dropouts, GED holders have more years of schooling and socioeconomic/demographic characteristics associated with higher incomes.TMW use the variation in GED passing standards by U.S. states to generate random variation. Some test takers who would receive a GED in Texas with a passing score of 40 − 44 would not receive a GED in New York, Florida, Oregon or Connecticut with the identical scores. If GED score is a good measure of a person’s ability/productivity, then people with same ‘ability’ (40 − 44) are assigned a GED in Texas but not in New York. The use 3 of the 7 possible different standards in the US.(1) a minimum score of at least 40 or a mean score of at least 45(2) a minimum score of at least 35 and a mean score of at least 45(3) a minimum score of at least 40 and a mean score of at least 45Using these groups they can define 3 distinct, treatment control group? (as you read this think: who is the marginal candidate in each of these groups? This is where the identification is coming from ).In the language of the paper“Experiment 4” variation in GED status by state is in group•the treatment states are those states that award a GED in score groups 4 and higher•the comparison states are those that award a GED in score groups 5 and higher “Experiment 3” variation in GED status by state is in group 3•the treatment states are those states that award a GED in score groups 3 and higher•the comparison states are those that award a GED in score groups 5 and higher“Experiment 3*” variation in GED status by state is in group 3•the treatment states are those states that award a GED in score groups 3 and higher•the comparison states are those that award a GED in score groups 4 and higher. The identifying assumption in this quasi-experiment is that the state of taking the test is effectively randomly and thus randomly assigns the GED ‘signal’ to people with the same GED scores across different U.S. states. We’ll return to this assumption shortly. We also must assume that firms cannot observe worker ability independent of the GED. Given the quasi-experimental setup, the signaling model predicts that workers with GED scores of 40 − 44 will earn more if they receive the GED certificate than if they do not. The Human Capital model implies that since ability is comparable among these groups, wages will also be comparable.Using a difference in difference-estimate they find some signal value (though the magnitude is somewhat sensitive to the definition of the control and treatment group). Part of what makes this such an excellent paper is that TMW now take the next step of considering what might make their identifying assumption invalid. The answer is that different passing standards influence individual behavior in systematic ways. They separate this into different responses:(1) the decision to attempt the test. They can’t test this and it would likely upward bias the estimates(2) the decision to migrate to another state: They can test the effect on migration. They should observe individuals who would have been in high standard states migrating but there is not much empirical evidence of this(3) the decision about how much effort to exert on the test: There may be clumping in the values around the standard—thus we don’t observe a true distribution of abilities since workers know that the employers can’t observe their true ability. In this case, our GED level is not a good control for underlying human capital. They model this and find their results are robust.Separately they also note that the results for minorities differed dramatically from those of whites. There’s a couple of reasons for this: First, many minority men take GED while incarcerated. The stigma of incarceration may depress the post-prison earnings of dropouts, and eliminate any positive signaling value of the GED credential. Additionally, if ,any dropouts who obtained a GED while incarcerated may have zero earnings five years later because they are still in prison. Second, there is likely heterogeneity in why individuals decide to get a GED. Consider two groupsGroup 1: value on the credential or they perceive that employers place a value on the credential.Group 2: ‘‘quasi-compulsory’’ in a social program from which they are seeking benefits. In this situation, the GED may be a signal of productive attributes for group 1 and a signal of ‘‘government program participation’’ for group 2. Employers discount the value of the ‘‘incidental’’ GED (group 2) . If the distributions of groups 1 and 2 differ by raceand employers statistically discriminate blacks will tend to experience lower returns than whites. #General ConclusionsTo the disappointment of some, signaling models have not dramatically changed the way mosteconomists view education. In fact, economic interest in the efficiency of educational productionhas burgeoned in the last decade — which would not be true if economists generally believedthat schooling is about testing how long students can tolerate sitting in a chair. Nevertheless, it’s reasonably clear that signals do carry value in some markets, and that this could possibly give rise to distortions like those envisioned by Spence. It’s unclear whetherthose distortions are economically significant.The link between human capital, signaling, and wages opens up three important questions(1) Can employers “learn” about workers continuously (that is why is education thesignal?)(2) If the signal is different for different groups, what happens (is this“discrimination”)?(3) If there is sorting across different types of occupations/sectors, what is the“signal” for each sector (example: illegal markets)。

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An Efficient Protocol for the Synthesis of N -Alkyl-and N -Arylimides Usingthe Lewis Acidic Ionic Liquid Choline Chloride·2ZnCl 2You-Teng Xie a (),Rei-Sheu Hou b *(),Huey-Min Wang b (),Iou-Jiun Kang c ()and Ling-Ching Chen a *()aGraduate Institute of Pharmaceutical Sciences,College of Pharmacy,Kaohsiung Medical University,Kaohsiung 807,Taiwan,R.O.C.bChung Hwa University of Medical Technology,Tainan 717,Taiwan,R.O.C.cDivision of Biotechn ology and Pharmaceutical Research,National Health Research Institutes,Miaoli County 350,Taiwan,R.O.C.Lewis acidic ionicliquid choline chloride·2ZnCl 2is shown to be for the first time an excellent medium and efficient catalyst for the synthesis of N -alkyl-and N -arylimides in good yields under mild condi-tions.Keywords:Choline chloride·2ZnCl 2;Succinic anhydride;Phthalic anhydride;Ionic liquid.INTRODUCTIONImide derivatives are an important class of substrates for biological and chemical applications.1Accordingly,ex-tensive progress toward the synthesis of these derivatives has been made in recent years.Well known methods in-clude (1)dehydrative condensation of anhydride and amine catalyzed by conc.H 2SO 4in acetic anhydride under reflux conditions,2(2)Direct N -alkylation of phthaloyl dichloride with azide in the presence of PPh 3in CH 2Cl 2,3(3)N -alkyla-tion of imides using of alcohol promoted by PPh 3and DIAP in THF,4etc.These methods have not been entirely satis-factory owing to the drawbacks such as using of organic solvents.It is necessary to develop an alterative solvent for the synthesis of imides under mild and environmentally benign conditions.Ionic liquids have been the subject of consideeable interest in the context of green synthesis because of their wide acceptability as alternative green reaction media.5Re-cently,the alkylimidazolium-aluminium chloride mixtureshave been studied extensively for use in acid-catalysed re-actions,particularly in Friedel-Crafts reactions.6However,for practical utilization,these imidazolium-based ionic liq-uids still suffer from the relatively expensive cost.In the case of chloroaluminate ionic liquid,its poor stability to-ward moisture can lead to undesired side reactions.More recently,a series of inexpensive and moisture-stable Lewis acidic ionic liquids have been prepared from choline chlo-ride and ZnCl 2,7and been used in Diels–Alder reactions 8and Fischer indole synthesis.9We have reported an effi-cient protocol for the Friedländer quinoline synthesis using Lewis acidic ionic liquid choline chloride·2ZnCl 2.10In this paper,we report the use of choline chloride·2ZnCl 2as a sol-vent and catalyst for the synthesis of N -alkyl-and N -aryl-imides (Scheme I).First,we found that the reaction of succinic anhydride with aniline in ionic liquid choline chloride·2ZnCl 2at 60°C for 1h to gave N -phenylsuccinimide (3a )in 90%yield.In a similar fashion,the reaction of phthalic anhydride withJournal of the Chinese Chemical Society ,2009,56,839-842839Scheme Ia variety of amines also underwent smooth dehydrative condensation to afford the respective imides in good yields.As can be seen from Table 1,the reaction is general and ap-plicable to aliphatic and aromatic amines bearing different functionalities such as methyl,methoxy,chloro,nitro and cyano groups.When the reaction was conducted in ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate ([bmim][PF 6]),however,the preparation of N -phenylphthal-imide (3f )required 8h at 80°C to go to completion.11The ionic liquid choline chloride·2ZnCl 2can typi-cally be recovered by extracting it from the reaction mix-tures and next by vacuum drying.The recovered solvent can be reused with no appreciable decrease in yields.The representative results are summarized in Table 2.The pres-ent method has many advantages including high efficiency,operational simplicity,environmentally benign character and ability to be recycled.In conclusion,we describe a mild and efficient route for the synthesis of N -alkyl-and N -arylimides utilizing choline chloride·2ZnCl 2as a solvent and catalyst in good yields under mild pared to imidazolium-based ionic liquids,choline chloride·2ZnCl 2is easier to the prepared,less moisture-sensitive and cheaper.EXPERIMENTAL SECTIONAll melting points are uncorrected.The IR spectra were recorded on a Shimadzu IR-27G spectrophotometer.1H NMR and 13C NMR spectra were recorded on a Varian Unity Plus 400MHz.Chemical shifts (d )were measured in ppm with respect to TMS.MS were obtained on a JEOL JMS D-300instrument.Elemental analyses were per-formed on an EA-1110instrument.N -Phenylsuccinimide (3a);Typical procedureA mixture of succinic anhydride (100mg,1.0mmol)and aniline (93mg,1.0mmol)in ionic liquid choline chlo-ride·2ZnCl 2(0.5mL)was stirred for 1h at 60°C.The reac-tion mixture was extracted with ethyl acetate.The remain-ing ionic liquid was reused after drying in vacuum.The ex-tract was dried (MgSO 4)and concentrated under reduced pressure and the residue was purified by chromatography on a silica gel column eluting with n -hexane-ethyl acetate (1:1)to give 3a ,mp 152-154°C (lit.12mp 156-167°C),yield 90%.IR (KBr)n :3054,2935,1708,1500,1390,1187,764,699cm -1;1H NMR (CDCl 3)d :2.90(s,4H),7.28(d,J =7.2Hz,2H),7.39-7.40(m,1H),7.49-7.50(m,2H);13C NMR (CDCl 3,100MHz)d :28.4,126.4,128.6,129.2,131.8,176.2;EI-MS m/z (relative intensity)175(M +),147,840J.Chin.Chem.Soc.,Vol.56,No.4,2009Xie et al.Table 1.The synthesis of N -alkyl-and N -arylimides using ionicliquid choline chloride·2ZnCl 2EntryAnhydrideAmine Product Yield (%)1O OO1aNH 22a3a 9021a CH 2NH 22b 3b 8631an-C 4H 9NH 22c3c844O O O1b 2a 3d 8851b2b3e 926O O O1c2a 3f 8771cNH 2Me2d3g 8981cNH 2MeO2e3h 8291cNH 2Cl2f3i 84101cNH 2Br2g3j 87111cNH 2O 2N2h3k 90121c NH 2CN 2i 3l 85131c2b3m8314O O O1d2b 3n 87120,119,118,93.N-Benzylsuccinimide(3b)mp99-100°C(lit.12mp98-99°C).IR(KBr)n:3307, 3036,1695,1431,1307,713,698cm-1;1H NMR(CDCl3) d:2.67(s,4H),4.64(s,2H),7.26-7.32(m,3H),7.38(d,J= 6.0Hz,2H);13C NMR(CDCl3,100MHz)d:28.1,42.3, 127.9,128.5,128.8,135.7,176.8;EI-MS m/z(relative in-tensity)189(M+),161,160,132,119,104.N-Butylsuccinimide(3c)Oily compound(lit.13oily compound).IR(neat)n: 2957,1767,1697,1403,875,731cm-1;1H NMR(CDCl3) d:0.85(t,J=7.6Hz,3H),1.47(m,2H),1.25(m,2H),2.64 (s,4H),3.43(t,J=7.6Hz,2H);13C NMR(CDCl3,100 MHz)d:13.4,19.9,28.0,29.6,38.4,177.2;EI-MS m/z (relative intensity)156(M+),113,100,84.N-Phenylmaleimide(3d)mp86-87°C(lit.12mp89-90°C).IR(KBr)n:3158, 3092,1709,1594,1503,1391,1144,831,694cm-1;1H NMR(CDCl3)d:6.86(s,2H),7.33-7.39(m,3H),7.47(t,J =8.0Hz,2H);13C NMR(CDCl3,100MHz)d:126.1, 128.0,129.2,131.1,134.2,169.5;EI-MS m/z(relative in-tensity)173(M+),129.N-Benzylmaleimide(3e)mp83-84°C(lit.12mp69-70°C).IR(KBr)n:3092, 3062,3033,1700,1576,1497,1342,1308,1136,841,781, 724,693cm-1;1H NMR(CDCl3)d:4.67(s,2H),6.70(s, 2H),7.25-7.35(m,5H);13C NMR(CDCl3,100MHz)d: 41.3,127.8,128.3,128.6,134.1,136.1,170.4;EI-MS m/z (relative intensity)187(M+),169,130,106.N-Phenylphthalimide(3f)mp206-208°C(lit.12mp208-209°C).IR(KBr)n: 3047,1771,1699,1495,1380,1109,755,703cm-1;1H NMR(CDCl3)d:7.39-7.53(m,5H),7.80(dd,J=5.4,2.8 Hz,2H),7.96(dd,J=5.6,3.2Hz,2H);13C NMR(CDCl3, 100MHz)d:123.7,126.5,128.1,129.1,131.7,134.4, 167.3;EI-MS m/z(relative intensity)223(M+),179,178, 76.N-(4-Methylphenyl)phthalimide(3g)mp200-202°C(lit.11mp203-204°C).IR(KBr)n:3033,1771,1713,1513,1382,1116,792,720cm-1;1H NMR(CDCl3)d:2.41(s,3H),7.31(s,4H),7.80(dd,J= 5.2,3.2Hz,2H),7.95(dd,J=5.4,2.8Hz,2H);13C NMR (CDCl3,100MHz)d:21.1,123.7,126.4,128.9,129.7, 131.7,134.3,138.2,167.4;EI-MS m/z(relative intensity) 237(M+),194,193,192,165,76.N-(4-Methoxyphenyl)phthalimide(3h)mp164-166°C.IR(KBr)n:3064,1715,1516,1387, 1102,784,713cm-1;1H NMR(CDCl3)d:3.83(s,3H),7.01 (dt,J=9.6,2.4Hz,2H),7.33(dt,J=9.6,2.4Hz,2H),7.76 (dd,J=5.4,2.8Hz,2H),7.92(dd,J=5.6,2.8Hz,2H);13C NMR(CDCl3,100MHz)d:55.4,114.4,123.5,124.1, 127.8,131.6,134.2,159.1,167.5;EI-MS m/z(relative in-tensity)253(M+),238,210,130.Anal.Calcd for C15H11NO3:C,71.14;H,4.38;N,5.53.Found:C,71.32;H, 4.15;N,5.78.N-(4-Chlorophenyl)phthalimide(3i)mp202-204°C(lit.11mp192-194°C).IR(KBr)n: 3060,1789,1711,1494,1389,1118,789,715cm-1;1H NMR(CDCl3)d:7.39-7.49(m,4H),7.80(dd,J=5.4,2.8 Hz,2H),7.95(dd,J=5.4,2.8Hz,2H);13C NMR(CDCl3, 100MHz)d:123.8,127.6,129.3,130.1,131.5,133.8, 134.5,167.0;EI-MS m/z(relative intensity)259(M++2) 257(M+),178,76.N-(4-Bromophenyl)phthalimide(3j)mp205-206°C(lit.11mp202-204°C).IR(KBr)n: 3060,1787,1710,1491,1386,1118,789,715cm-1;1H NMR(CDCl3)d:7.36(dt,J=9.2,2.2Hz,2H),7.61-7.64 (m,2H),7.80(dd,J=5.6,3.2Hz,2H),7.95(dd,J=5.6,2.8 Hz,2H);13C NMR(CDCl3,100MHz)d:121.8,123.8, 127.9,130.7,131.6,132.3,134.5,166.9;EI-MS m/z(rela-tive intensity)303(M++2),301(M+),259,257,178.N-(4-Nitrophenyl)phthalimide(3k)mp266-267°C(lit.11mp264-266°C).IR(KBr)n: 3061,1782,1732,1520,1343,1077,747,709cm-1;1H NMR(CDCl3)d:7.75-7.79(m,2H),7.84-7.86(m,2H), 8.01(dd,J=5.6,3.2Hz,2H),8.38(dt,J=9.6,2.0Hz,2H); 13C NMR(CDCl3,100MHz)d:24.1,124.4,126.3,131.3, 135.0,137.5,146.4,166.4;EI-MS m/z(relative intensity) 268(M+),238,178,166,76.N-(4-Cyanophenyl)phthalimide(3l)mp184-186°C.IR(KBr)n:3063,1781,1720,1508, 1377,1079,785,710cm-1;1H NMR(CDCl3)d:7.67-7.70 (m,2H),7.78-7.81(m,2H),7.82-7.84(m,2H),7.98(dd,J =5.6,2.8Hz,2H);13C NMR(CDCl3,100MHz)d:111.3, 118.2,124.1,126.4,131.3,132.9,134.9,135.9,166.4; EI-MS m/z(relative intensity)248(M+),205,204,177.Synthesis of N-Alkyl-and N-Arylimides J.Chin.Chem.Soc.,Vol.56,No.4,2009841 Table2.Results obtained using recycled ionic liquid cholinechloride·2ZnCl2Entry Product Cycle Yield(%)13a19023a29133a389Anal.Calcd for C15H8N2O2:C,72.58;H,3.25;N,11.28. Found:C,72.63;H,3.46;N,11.37.N-Benzylphthalimide(3m)mp118-119°C(lit.12mp118-119°C).IR(KBr)n: 3055,1767,1701,1392,1106,951,787,722cm-1;1H NMR(CDCl3)d:4.83(s,2H),7.24-7.31(m,3H),7.41(d,J =6.8Hz,2H),7.65-7.67(m,2H),7.80-7.82(m,2H);13C NMR(CDCl3,100MHz)d:41.5,123.2,127.7,128.5, 128.6,132.0,134.0,136.2,167.9;EI-MS m/z(relative in-tensity)237(M+),219,208,130,105,104,78,77.N-Benzylglutarimide(3n)Oily compound(lit.1(e)oily compound).IR(neat)n: 3025,2924,1723,1457,1355,755,702cm-1;1H NMR (CDCl3)d:1.94(q,J=6.8Hz,3H),2.68(q,J=6.8Hz, 4H),4.95(s,2H),7.23-7.37(m,5H);13C NMR(CDCl3, 100MHz)d:17.0,32.8,42.6,127.4,128.3,128.8,137.2, 172.4;EI-MS m/z(relative intensity)203(M+),175,146, 118,104,92,84.ACKNOWLEDGEMENTWe gratefully acknowledge the National Science Council of the Republic of China for financial support of this work.Received September3,2008.REFERENCES1.(a)Da Settimo,A.;Primofiore,G.;Da Settimo,F.;Simorini,F.;La Motta,C.;Martinelli,A.;Boldrine,E.Eur.J.Med.Chem.1996,31,69.(b)Langmuir,M.E.;Yang,J.R.;Moussa,A.M.;Laura,R.;Lecompte,K.A.Tetrahedron Lett.1995,36,3989.(c)Mayer,A.;Neuenhofer,S.Angew.Chem.Int.Ed.Engl.1994,33,1044.(d)Rusiecki,V.K.;Warne,S.A.Biorg.Med.Chem.Lett.1993,3,707.(e) Reddy,P.Y.;Kondo,S.;Toru,T.;Ueno,.Chem.1997,62,2652.2.Prapas,.Chem.1959,24,388.3.Aubert,M.T.;Farnier,M.;Guilard,R.Tetrahedron1991,47,53.4.Walker,.Chem.1995,60,5352.5.Welton,T.Chem.Rev.1999,99,2071.6.Earle,M.J.;Seddon,K.R.Pure Appl.Chem.2000,39,3772.7.(a)Abbott,A.P.;Capper,G.;Davies,D.L.;Munro,H.L.;Rasheed,R.K.;Tambyrajah,mun.2001, 2010.(b)Zhiying,D.;Yanlong,G.;Youquan,D.Catal.Commun.2006,7,651.8.Abbott,A.P.;Capper,G.;Davies,D.L.;Munro,H.L.;Rasheed,R.K.;Tambyrajah,V.Green Chem.2002,4,24.9.Morales,R.C.;Tambyrajah,V.;Jenkins,P.R.;Davies,D.L.;Abbott,mun.2004,158.10.Wang,H.-M.;Hou,R.-S.;Cheng,H.-T.;Chen,L.-C.Heterocycles2009,487.11.Zhou,M.-Y.;Li,Y.-Q.;Xu,mun.2003,33,3777.12.Le,Z.-G.;Chen,Z.-C.;Hu,Y.;Zheng,Q.-G.Synthesis2004,7,995.13.Puertas,S.;Reboiledo,F.;Gotor,V.Tetrahedron1995,51,1495.842J.Chin.Chem.Soc.,Vol.56,No.4,2009Xie et al.。