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Determination of Sex 43, Elm Park Gardens, THOSE Who Are Interested in the Heredity of Sex Chelsea, S.W.Lo
APRIL 14, 1934 NATURE 579 sa was correctly computed in five minutes, 510 in genes outweigh the female and the result is the twenty seconds and 610 in seventy seconds. normal haplo-X male." Division was a slower process and 9 digits divided Thus, as my italics show, the experimental by 3 took times varying from two and a half to geneticist seems to agree with what Prof. MacBride seven and three quarters minutes. has expressed in more generally intelligible language ; Square roots of 6 digit numbers were extracted in not only in admitting the essential sameness of sex less than a minute while cube roots took longer. in all organisms but also in understanding the Curiously enough, the memorising of a number of function of proportion in its determination in some 27 digits was not done successfully, although he of them. Unanimity among the different branches of could repeat questions which had been put to him biology has therefore been reached after a long period and their answers after some days had elapsed, and of divergence, from entirely different data and, what would break off calculations in the middle to ask for is more, apparently unawares. Such an event, surely, milk or cigarettes, taking up the calculations again should not be allowed to pass without notice and where he had broken off. His methods of working without applause. The usual view that the chromo were not discovered, but he had obviously memorised some theory of sex determination criticised by the squares of two digit numbers, and less completely MacBride was a special hypothesis put forward by the products of two digit numbers. -
LSD), Which Produces Illicit Market in the USA
DEPENDENCE LIABILITY OF "NON-NARCOTIC 9 DRUGS 81 INDOLES The prototype drug in this subgroup (Table XVI) potentials. Ibogaine (S 212) has appeared in the is compound S 219, lysergide (LSD), which produces illicit market in the USA. dependence of the hallucinogen (LSD) type (see above). A tremendous literature on LSD exists which documents fully the dangers of abuse, which REFERENCES is now widespread in the USA, Canada, the United 304. Sandoz Pharmaceuticals Bibliography on Psychoto- Kingdom, Australia and many western European mimetics (1943-1966). Reprinted by the US countries (for references see Table XVI). LSD must Department of Health, Education, & Welfare, be judged as a very dangerous substance which has National Institute of Mental Health, Washington, no established therapeutic use. D.C. 305. Cerletti, A. (1958) In: Heim, R. & Wasson, G. R., Substances S 200-S 203, S 206, S 208, S 213-S 218 ed., Les champignons hallucinogenes du Mexique, and S 220-S 222 are isomers or congeners of LSD. pp. 268-271, Museum national d'Histoire natu- A number of these are much less potent than LSD in relle, Paris (Etude pharmacologique de la hallucinogenic effect or are not hallucinogenic at all psilocybine) (compounds S 203, S 213, S 216, S 217, S 220 and 306. Cohen, S. (1965) The beyond within. The LSD S 222) and accordingly carry a lesser degree of risk story. Atheneum, New York than LSD. None of these weak hallucinogens has 307. Cohen, S. & Ditman, K. S. (1963) Arch. gen. been abused. Other compounds are all sufficiently Psychiat., 8, 475 (Prolonged adverse reactions to potent to make it likely that they would be abused if lysergic acid diethylamide) 308. -
Risk Assessment of Argyreia Nervosa
Risk assessment of Argyreia nervosa RIVM letter report 2019-0210 W. Chen | L. de Wit-Bos Risk assessment of Argyreia nervosa RIVM letter report 2019-0210 W. Chen | L. de Wit-Bos RIVM letter report 2019-0210 Colophon © RIVM 2020 Parts of this publication may be reproduced, provided acknowledgement is given to the: National Institute for Public Health and the Environment, and the title and year of publication are cited. DOI 10.21945/RIVM-2019-0210 W. Chen (author), RIVM L. de Wit-Bos (author), RIVM Contact: Lianne de Wit Department of Food Safety (VVH) [email protected] This investigation was performed by order of NVWA, within the framework of 9.4.46 Published by: National Institute for Public Health and the Environment, RIVM P.O. Box1 | 3720 BA Bilthoven The Netherlands www.rivm.nl/en Page 2 of 42 RIVM letter report 2019-0210 Synopsis Risk assessment of Argyreia nervosa In the Netherlands, seeds from the plant Hawaiian Baby Woodrose (Argyreia nervosa) are being sold as a so-called ‘legal high’ in smart shops and by internet retailers. The use of these seeds is unsafe. They can cause hallucinogenic effects, nausea, vomiting, elevated heart rate, elevated blood pressure, (severe) fatigue and lethargy. These health effects can occur even when the seeds are consumed at the recommended dose. This is the conclusion of a risk assessment performed by RIVM. Hawaiian Baby Woodrose seeds are sold as raw seeds or in capsules. The raw seeds can be eaten as such, or after being crushed and dissolved in liquid (generally hot water). -
Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans
molecules Review Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans Paul Cumming 1,2,* , Milan Scheidegger 3 , Dario Dornbierer 3, Mikael Palner 4,5,6 , Boris B. Quednow 3,7 and Chantal Martin-Soelch 8 1 Department of Nuclear Medicine, Bern University Hospital, CH-3010 Bern, Switzerland 2 School of Psychology and Counselling, Queensland University of Technology, Brisbane 4059, Australia 3 Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital of the University of Zurich, CH-8032 Zurich, Switzerland; [email protected] (M.S.); [email protected] (D.D.); [email protected] (B.B.Q.) 4 Odense Department of Clinical Research, University of Southern Denmark, DK-5000 Odense, Denmark; [email protected] 5 Department of Nuclear Medicine, Odense University Hospital, DK-5000 Odense, Denmark 6 Neurobiology Research Unit, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark 7 Neuroscience Center Zurich, University of Zurich and Swiss Federal Institute of Technology Zurich, CH-8058 Zurich, Switzerland 8 Department of Psychology, University of Fribourg, CH-1700 Fribourg, Switzerland; [email protected] * Correspondence: [email protected] or [email protected] Abstract: Hallucinogens are a loosely defined group of compounds including LSD, N,N- dimethyltryptamines, mescaline, psilocybin/psilocin, and 2,5-dimethoxy-4-methamphetamine (DOM), Citation: Cumming, P.; Scheidegger, which can evoke intense visual and emotional experiences. We are witnessing a renaissance of re- M.; Dornbierer, D.; Palner, M.; search interest in hallucinogens, driven by increasing awareness of their psychotherapeutic potential. Quednow, B.B.; Martin-Soelch, C. As such, we now present a narrative review of the literature on hallucinogen binding in vitro and Molecular and Functional Imaging ex vivo, and the various molecular imaging studies with positron emission tomography (PET) or Studies of Psychedelic Drug Action in single photon emission computer tomography (SPECT). -
Diversification of Ergot Alkaloids in Natural and Modified Fungi
Toxins 2015, 7, 201-218; doi:10.3390/toxins7010201 OPEN ACCESS toxins ISSN 2072-6651 www.mdpi.com/journal/toxins Review Diversification of Ergot Alkaloids in Natural and Modified Fungi Sarah L. Robinson and Daniel G. Panaccione * Division of Plant and Soil Sciences, West Virginia University, Morgantown, WV 26506, USA; E-Mail: [email protected] * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +1-304-293-8819; Fax: +1-304-293-2960. Academic Editor: Christopher L. Schardl Received: 21 November 2014 / Accepted: 14 January 2015 / Published: 20 January 2015 Abstract: Several fungi in two different families––the Clavicipitaceae and the Trichocomaceae––produce different profiles of ergot alkaloids, many of which are important in agriculture and medicine. All ergot alkaloid producers share early steps before their pathways diverge to produce different end products. EasA, an oxidoreductase of the old yellow enzyme class, has alternate activities in different fungi resulting in branching of the pathway. Enzymes beyond the branch point differ among lineages. In the Clavicipitaceae, diversity is generated by the presence or absence and activities of lysergyl peptide synthetases, which interact to make lysergic acid amides and ergopeptines. The range of ergopeptines in a fungus may be controlled by the presence of multiple peptide synthetases as well as by the specificity of individual peptide synthetase domains. In the Trichocomaceae, diversity is generated by the presence or absence of the prenyl transferase encoded by easL (also called fgaPT1). Moreover, relaxed specificity of EasL appears to contribute to ergot alkaloid diversification. The profile of ergot alkaloids observed within a fungus also is affected by a delayed flux of intermediates through the pathway, which results in an accumulation of intermediates or early pathway byproducts to concentrations comparable to that of the pathway end product. -
The Structure of Dimethylallyl Tryptophan Synthase Reveals a Common Architecture of Aromatic Prenyltransferases in Fungi and Bacteria
The structure of dimethylallyl tryptophan synthase reveals a common architecture of aromatic prenyltransferases in fungi and bacteria Ute Metzgera,1, Christoph Schallb,1, Georg Zocherb, Inge Unso¨ lda, Edyta Stecc, Shu-Ming Lic, Lutz Heidea,2, and Thilo Stehleb,d aPharmazeutisches Institut, Universita¨t Tu¨ bingen, 72076 Tu¨bingen, Germany; bInterfakulta¨res Institut fu¨r Biochemie, Universita¨t Tu¨ bingen, 72076 Tu¨bingen, Germany; cInstitut fu¨r Pharmazeutische Biologie, Universita¨t Marburg, 35037 Marburg, Germany; and dDepartment of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN 37232 Edited by Arnold L. Demain, Drew University, Madison, NJ, and approved July 9, 2009 (received for review May 5, 2009) Ergot alkaloids are toxins and important pharmaceuticals that are farnesyl diphosphate synthase (11, 12), DMATS does not require produced biotechnologically on an industrial scale. The first com- magnesium or other divalent cations for its enzymatic activity, mitted step of ergot alkaloid biosynthesis is catalyzed by dimethy- although addition of 4 mM CaCl2 moderately increases its reaction lallyl tryptophan synthase (DMATS; EC 2.5.1.34). Orthologs of velocity (10). The structural gene coding for DMATS in Claviceps, DMATS are found in many fungal genomes. We report here the termed dmaW, was identified by Tsai et al. (13). A similar gene, x-ray structure of DMATS, determined at a resolution of 1.76 Å. A fgaPT2, exists in the biosynthetic gene cluster of fumigaclavine, in complex of DMATS from Aspergillus fumigatus with its aromatic the genome sequence of A. fumigatus. Expression of the DMATS substrate L-tryptophan and with an analogue of its isoprenoid sequence from A. -
Ergometrine Maleate
The European Agency for the Evaluation of Medicinal Products Veterinary Medicines Evaluation Unit EMEA/MRL/237/97-FINAL June 1999 COMMITTEE FOR VETERINARY MEDICINAL PRODUCTS ERGOMETRINE MALEATE SUMMARY REPORT 1. Ergometrine is a naturally occurring alkaloid found in ergot (Claviceps purpurea). It is classified as a water-soluble lysergic acid derivative, and is an orally-active stimulant of uterine contractions. The maleate salt (ergometrine maleate) exhibits greater stability than the free base and is the usual form in which the alkaloid is used in medicinal products. It is used in veterinary medicine in the control of postpartum uterine haemorrhage, removal of fluid from atonic uteri, to prevent pro-lapsed uteri, and judiciously in terms of timing to aid in suturing the uterus after caesarean section or in replacing an everted uterus. Dose regimens are: cows and mares: 2 to 5 mg/animal (intravenously or intramuscularly); ewes, goats and sows: 0.5 to 1 mg/animal (intramuscularly). In human medicine, it is used orally and parenterally in the prevention and treatment of postpartum haemorrhage caused by uterine atony and for the stimulation of uterine involution. Usual oral doses are 500 µg 3 times daily up to 1.8 mg daily (approximately 0.03 mg/kg bw). Ergot alkaloids have been reported to be present in flour from rye, wheat and barley in amounts ranging from 0.01 to 2.36 mg/kg flour. EU legislation restricts the maximum percentage of ergot tolerated in flour to 0.1%. Total daily human intake of ergot alkaloids from contaminated foodstuffs of plant origin has been estimated as up to 7.8 µg/person. -
Ergoline Alkaloids
Ergoline Alkaloids Prof. Dr. Ali H. Meriçli GENERALITIES All of the alkaloids in this group are derived from a tetracyclic, octahydroindoloquinoline nucleus, namely ergoline. Although these are commonly classified as clavines, simple lysergic acid derivatives, and ergopeptines, it is also possible, and less ambigous, to classify the various known alkaloids as a function of their basic nucleus. Ergoline nucleus Thus the following are distinguished : 1. Ergoline Alkaloids : Ergoline alkaloids can be substituted at C-8, most often by a methyl group (festuclavine), or a hydroxymethyl group (dihydrolysergol), or at C-8 and C-9 in rare cases. 2. 8-Ergolene Alkaloids . 8-Ergolene Alkaloids can be substituted at C-8 by a methyl group (agroclavine), a hydroxymethyl group (elymoclavine, or a carboxyl group (paspalic acid) 3. 9-Ergolene Alkaloids. 9-Ergolene alkaloids include the chief alkaloids of the ergot of rye, whether they have an amino acid structure (ergometrine), a peptide structure with a cyclol moiety (ergopeptines), or a peptide structure without a cyclol moiety (ergopeptams) 4. Secoergoline Alkaloids. Secoergoline alkaloids have an open D ring (chanoclavine I). 5. Related Structures. Related structures sometimes referred to as proergolines, include the precursor of all these compounds, in other words dimethylallyltryptophan, and products such as clavitipic acids. These alkaloids were initially characterized in the ergot of rye, Claviceps purpurea. Biosynthetic origin Labelling experiments show that the precursor of the ergoline nucleus are tryptophan, mevalonic acid and methionine. Several mechanisms have been proposed to rationalize the first step in the elaboration of ergoline, in other words the formation of dimethylallyltryptophan (= DMAT) : it involves the alkylation of tryptophan by dimethylallyl pyrophosphate, directly at C-4, catalyzed by a specific enzyme, DMAT synthetase. -
Biotechnology and Genetics of Ergot Alkaloids
Appl Microbiol Biotechnol (2001) 57:593–605 DOI 10.1007/s002530100801 MINI-REVIEW P. Tudzynski · T. Correia · U. Keller Biotechnology and genetics of ergot alkaloids Received: 28 May 2001 / Received revision: 8 August 2001 / Accepted: 17 August 2001 / Published online: 20 October 2001 © Springer-Verlag 2001 Abstract Ergot alkaloids, i.e. ergoline-derived toxic me- tions in the therapy of human CNS disorders. Chemical- tabolites, are produced by a wide range of fungi, pre- ly the ergot alkaloids are 3,4-substituted indol deriva- dominantly by members of the grass-parasitizing family tives having a tetracyclic ergoline ring structure (Fig. 1). of the Clavicipitaceae. Naturally occurring alkaloids like Based on their complexity, they can be divided into two the D-lysergic acid amides, produced by the “ergot fun- families of compounds. In the D-lysergic acid deriva- gus” Claviceps purpurea, have been used as medicinal tives, a simple amino alcohol or a short peptide chain agents for a long time. The pharmacological effects of (e.g. ergotamine) is attached to the ergoline nucleus in the various ergot alkaloids and their derivatives are due amide linkage via a carboxy group in the 8-position. In to the structural similarity of the tetracyclic ring system the simpler clavine alkaloids (e.g. agroclavine) that car- to neurotransmitters such as noradrenaline, dopamine or boxy group is replaced by a methyl or hydroxymethyl to serotonin. In addition to “classical” indications, e.g. mi- which attachment of side groups such as in the amide- graine or blood pressure regulation, there is a wide spec- type alkaloids is not possible. -
Clavine Alkaloids Gene Clusters of Penicillium and Related Fungi: Evolutionary Combination of Prenyltransferases, Monooxygenases and Dioxygenases
G C A T T A C G G C A T genes Review Clavine Alkaloids Gene Clusters of Penicillium and Related Fungi: Evolutionary Combination of Prenyltransferases, Monooxygenases and Dioxygenases Juan F. Martín *, Rubén Álvarez-Álvarez ID and Paloma Liras Department of Molecular Biology, Section of Microbiology, University of León, 24071 León, Spain; [email protected] (R.Á.-Á.); [email protected] (P.L.) * Correspondence: [email protected] Received: 19 October 2017; Accepted: 16 November 2017; Published: 24 November 2017 Abstract: The clavine alkaloids produced by the fungi of the Aspergillaceae and Arthrodermatacea families differ from the ergot alkaloids produced by Claviceps and Neotyphodium. The clavine alkaloids lack the extensive peptide chain modifications that occur in lysergic acid derived ergot alkaloids. Both clavine and ergot alkaloids arise from the condensation of tryptophan and dimethylallylpyrophosphate by the action of the dimethylallyltryptophan synthase. The first five steps of the biosynthetic pathway that convert tryptophan and dimethylallyl-pyrophosphate (DMA-PP) in chanoclavine-1-aldehyde are common to both clavine and ergot alkaloids. The biosynthesis of ergot alkaloids has been extensively studied and is not considered in this article. We focus this review on recent advances in the gene clusters for clavine alkaloids in the species of Penicillium, Aspergillus (Neosartorya), Arthroderma and Trychophyton and the enzymes encoded by them. The final products of the clavine alkaloids pathways derive from the tetracyclic ergoline ring, which is modified by late enzymes, including a reverse type prenyltransferase, P450 monooxygenases and acetyltransferases. In Aspergillus japonicus, a α-ketoglutarate and Fe2+-dependent dioxygenase is involved in the cyclization of a festuclavine-like unknown type intermediate into cycloclavine. -
Genetic Manipulation of the Ergot Alkaloid Pathway in Epichloë Festucae Var
toxins Article Genetic Manipulation of the Ergot Alkaloid Pathway in Epichloë festucae var. lolii and Its Effect on Black Beetle Feeding Deterrence Debbie Hudson 1, Wade Mace 1 , Alison Popay 2 , Joanne Jensen 2, Catherine McKenzie 1 , Catherine Cameron 2 and Richard Johnson 1,* 1 AgResearch Limited, Grasslands Research Centre, Private Bag 11008, Palmerston North, New Zealand; [email protected] (D.H.); [email protected] (W.M.); [email protected] (C.M.) 2 AgResearch Limited, Ruakura Research Centre, Private Bag 3123, Hamilton, New Zealand; [email protected] (A.P.); [email protected] (J.J.); [email protected] (C.C.) * Correspondence: [email protected] Abstract: Epichloë endophytes are filamentous fungi (family Clavicipitaceae) that live in symbiotic associations with grasses in the sub family Poöideae. In New Zealand, E. festucae var. lolii confers significant resistance to perennial ryegrass (Lolium perenne) against insect and animal herbivory and is an essential component of pastoral agriculture, where ryegrass is a major forage species. The fungus produces in planta a range of bioactive secondary metabolites, including ergovaline, which has demonstrated bioactivity against the important pasture pest black beetle, but can also cause mammalian toxicosis. We genetically modified E. festucae var. lolii strain AR5 to eliminate key enzymatic steps in the ergovaline pathway to determine if intermediate ergot alkaloid compounds Citation: Hudson, D.; Mace, W.; can still provide insecticidal benefits in the absence of the toxic end product ergovaline. Four genes Popay, A.; Jensen, J.; McKenzie, C.; (dmaW, easG, cloA, and lpsB) spanning the pathway were deleted and each deletion mutant was Cameron, C.; Johnson, R. -
LSD Chemistry
10. LSD Chemistry The following has been excerpted from KOSMOS - A Theory of Psychedelic Experience The following sections describe what I have found to be the best method for preparing the simple amides of lysergic acid such as LSD, using ergotamine tartrate as the starting material. Over the years I have met a few other “underground chemists” and read books and articles by and about them, and all seem to claim they had found or invented the “best” method for making LSD, while never specifying exactly what it might be! There are also a few “recipe books” available from various sources, and they also do not accurately present the procedures described below nor any alternative ones that work as well. And none even mention the “best” procedure for combining lysergic acid with simple amines (the second part of the preparation). So here I have decided to reveal all, with the conviction that if someone should decide to try to manufacture LSD or similar amides, he might as well have the best information available. The following is not to be taken as an encouragement to do so, and in fact should discourage “amateurs” from even trying. Although I have described the specifics of the procedure in great detail, only those with previous laboratory experience, excellent technique, and university training will be capable of understanding and performing the following with any measure of success, especially with regard to the quality of the product. Nevertheless, to rebut any objections to my description of these methods, there are really no secrets in the following—all the tricks and specifics of my method can be found in the scientific literature, available in any good university library.