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  • Hyperbilirubinemia
    Porphyrins Porphyrins (Porphins) are cyclic tetrapyrol compounds formed by the linkage )). of four pyrrole rings through methenyl bridges (( HC In the reduced porphyrins (Porphyrinogens) the linkage of four pyrrole rings (tetrapyrol) through methylene bridges (( CH2 )) The characteristic property of porphyrins is the formation of complexes with the metal ion bound to nitrogen atoms of the pyrrole rings. e.g. Heme (iron porphyrin). Proteins which contain heme ((hemoproteins)) are widely distributed e.g. Hemoglobin, Myoglobin, Cytochromes, Catalase & Tryptophan pyrrolase. Natural porphyrins have substituent side chains on the eight hydrogen atoms numbered on the pyrrole rings. These side chains are: CH 1-Methyl-group (M)… (( 3 )) 2-Acetate-group (A)… (( CH2COOH )) 3-Propionate-group (P)… (( CH2CH2COOH )) 4-Vinyl-group (V)… (( CH CH2 )) Porphyrins with asymmetric arrangement of the side chains are classified as type III porphyrins while those with symmetric arrangement of the side chains are classified as type I porphyrins. Only types I & III are present in nature & type III series is more important because it includes heme. 1 Heme Biosynthesis Heme biosynthesis occurs through the following steps: 1-The starting reaction is the condensation between succinyl-CoA ((derived from citric acid cycle in the mitochondria)) & glycine, this reaction is a rate limiting reaction in the hepatic heme synthesis, it occurs in the mitochondria & is catalyzed by ALA synthase (Aminolevulinate synthase) enzyme in the presence of pyridoxal phosphate as a cofactor. The product of this reaction is α-amino-β-ketoadipate which is rapidly decarboxylated to form δ-aminolevulinate (ALA). 2-In the cytoplasm condensation reaction between two molecules of ALA is catalyzed by ALA dehydratase enzyme to form two molecules of water & one 2 molecule of porphobilinogen (PBG) which is a precursor of pyrrole.
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  • 35 Disorders of Purine and Pyrimidine Metabolism
    35 Disorders of Purine and Pyrimidine Metabolism Georges van den Berghe, M.- Françoise Vincent, Sandrine Marie 35.1 Inborn Errors of Purine Metabolism – 435 35.1.1 Phosphoribosyl Pyrophosphate Synthetase Superactivity – 435 35.1.2 Adenylosuccinase Deficiency – 436 35.1.3 AICA-Ribosiduria – 437 35.1.4 Muscle AMP Deaminase Deficiency – 437 35.1.5 Adenosine Deaminase Deficiency – 438 35.1.6 Adenosine Deaminase Superactivity – 439 35.1.7 Purine Nucleoside Phosphorylase Deficiency – 440 35.1.8 Xanthine Oxidase Deficiency – 440 35.1.9 Hypoxanthine-Guanine Phosphoribosyltransferase Deficiency – 441 35.1.10 Adenine Phosphoribosyltransferase Deficiency – 442 35.1.11 Deoxyguanosine Kinase Deficiency – 442 35.2 Inborn Errors of Pyrimidine Metabolism – 445 35.2.1 UMP Synthase Deficiency (Hereditary Orotic Aciduria) – 445 35.2.2 Dihydropyrimidine Dehydrogenase Deficiency – 445 35.2.3 Dihydropyrimidinase Deficiency – 446 35.2.4 Ureidopropionase Deficiency – 446 35.2.5 Pyrimidine 5’-Nucleotidase Deficiency – 446 35.2.6 Cytosolic 5’-Nucleotidase Superactivity – 447 35.2.7 Thymidine Phosphorylase Deficiency – 447 35.2.8 Thymidine Kinase Deficiency – 447 References – 447 434 Chapter 35 · Disorders of Purine and Pyrimidine Metabolism Purine Metabolism Purine nucleotides are essential cellular constituents 4 The catabolic pathway starts from GMP, IMP and which intervene in energy transfer, metabolic regula- AMP, and produces uric acid, a poorly soluble tion, and synthesis of DNA and RNA. Purine metabo- compound, which tends to crystallize once its lism can be divided into three pathways: plasma concentration surpasses 6.5–7 mg/dl (0.38– 4 The biosynthetic pathway, often termed de novo, 0.47 mmol/l). starts with the formation of phosphoribosyl pyro- 4 The salvage pathway utilizes the purine bases, gua- phosphate (PRPP) and leads to the synthesis of nine, hypoxanthine and adenine, which are pro- inosine monophosphate (IMP).
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  • Page Numbers in Bold Indicate Main Discus- Sion of Topic. Page Numbers
    168397_P489-520.qxd7.0:34 Index 6-2-04 26p 2010.4.5 10:03 AM Page 489 source of, 109, 109f pairing with thymine, 396f, 397, 398f in tricarboxylic acid cycle, 109–111, 109f Adenine arabinoside (vidarabine, araA), 409 Acetyl CoA-ACP acetyltransferase, 184 Adenine phosphoribosyltransferase (APRT), Index Acetyl CoA carboxylase, 183, 185f, 190 296, 296f in absorptive/fed state, 324 Adenosine deaminase (ADA), 299 allosteric activation of, 183–184, 184f deficiency of, 298, 300f, 301–302 allosteric inactivation of, 183, 184f gene therapy for, 485, 486f dephosphorylation of, 184 Adenosine diphosphate (ADP) in fasting, 330 in ATP synthesis, 73, 77–78, 78f Page numbers in bold indicate main discus- hormonal regulation of, 184, 184f isocitrate dehydrogenase activation by, sion of topic. Page numbers followed by f long-term regulation of, 184 112 denote figures. “See” cross-references direct phosphorylation of, 183–184 transport of, to inner mitochondrial short-term regulation of, 183–184, 184f membrane, 79 the reader to the synonymous term. “See Acetyl CoA carboxylase-2 (ACC2), 191 in tricarboxylic acid cycle regulation, 114, also” cross-references direct the reader to N4-Acetylcytosine, 292f 114f related topics. [Note: Positional and configura- N-Acetyl-D-glucosamine, 142 in urea cycle, 255–256 N-Acetylgalactosamine (GalNAc), 160, 168 ribosylation, 95 tional designations in chemical names (for N-Acetylglucosamindase deficiency, 164f Adenosine monophosphate (AMP; also called example, “3-“, “α”, “N-“, “D-“) are ignored in N-Acetylglucosamine (GlcNAc),
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  • Review Article
    REVIEW ARTICLE COLLAGEN METABOLISM COLLAGEN METABOLISM Types of Collagen 228 Structure of Collagen Molecules 230 Synthesis and Processing of Procollagen Polypeptides 232 Transcription and Translation 233 Posttranslational Modifications 233 Extracellular Processing of Procollagen and Collagen Fibrillogenesis 240 Functions of Collagen in Connective rissue 243 Collagen Degradation 245 Regulation of the Metabolism of Collagen 246 Heritable Diseases of Collagen 247 Recessive Dermatosparaxis 248 Recessive Forms of EDS 251 EDS VI 251 EDS VII 252 EDS V 252 Lysyl Oxidase Deficiency in the Mouse 253 X-Linked Cutis Laxa 253 Menke's Kinky Hair Syndrome 253 Homocystinuria 254 EDS IV 254 Dominant Forms of EDS 254 Dominant Collagen Packing Defect I 255 Dominant and Recessive Forms of Osteogenesis Imperfecta 258 Dominant and Recessive Forms of Cutis Laxa 258 The Marfan Syndrome 259 Acquired Diseases and Repair Processes Affecting Collagen 259 Acquired Changes in the Types of Collagen Synthesis 260 Acquired Changes in Amounts of Collagen Synthesized 263 Acquired Changes in Hydroxylation of Proline and Lysine 264 Acquired Changes in Collagen Cross-Links 265 Acquired Defects in Collagen Degradation 267 Conclusion 267 Bibliography 267 Collagen Metabolism A Comparison of Diseases of Collagen and Diseases Affecting Collagen Ronald R. Minor, VMD, PhD COLLAGEN CONSTITUTES approximately one third of the body's total protein, and changes in synthesis and/or degradation of colla- gen occur in nearly every disease process. There are also a number of newly described specific diseases of collagen in both man and domestic animals. Thus, an understanding of the synthesis, deposition, and turnover of collagen is important for the pathologist, the clinician, and the basic scientist alike.
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  • Porphyrins & Bile Pigments
    Bio. 2. ASPU. Lectu.6. Prof. Dr. F. ALQuobaili Porphyrins & Bile Pigments • Biomedical Importance These topics are closely related, because heme is synthesized from porphyrins and iron, and the products of degradation of heme are the bile pigments and iron. Knowledge of the biochemistry of the porphyrins and of heme is basic to understanding the varied functions of hemoproteins in the body. The porphyrias are a group of diseases caused by abnormalities in the pathway of biosynthesis of the various porphyrins. A much more prevalent clinical condition is jaundice, due to elevation of bilirubin in the plasma, due to overproduction of bilirubin or to failure of its excretion and is seen in numerous diseases ranging from hemolytic anemias to viral hepatitis and to cancer of the pancreas. • Metalloporphyrins & Hemoproteins Are Important in Nature Porphyrins are cyclic compounds formed by the linkage of four pyrrole rings through methyne (==HC—) bridges. A characteristic property of the porphyrins is the formation of complexes with metal ions bound to the nitrogen atom of the pyrrole rings. Examples are the iron porphyrins such as heme of hemoglobin and the magnesium‐containing porphyrin chlorophyll, the photosynthetic pigment of plants. • Natural Porphyrins Have Substituent Side Chains on the Porphin Nucleus The porphyrins found in nature are compounds in which various side chains are substituted for the eight hydrogen atoms numbered in the porphyrin nucleus. As a simple means of showing these substitutions, Fischer proposed a shorthand formula in which the methyne bridges are omitted and a porphyrin with this type of asymmetric substitution is classified as a type III porphyrin.
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  • UROPORPHYRINOGEN HII COSYNTHETASE in HUMAN Hemolysates from Five Patientswith Congenital Erythropoietic Porphyriawas Much Lower
    UROPORPHYRINOGEN HII COSYNTHETASE IN HUMAN CONGENITAL ERYTHROPOIETIC PORPHYRIA * BY GIOVANNI ROMEO AND EPHRAIM Y. LEVIN DEPARTMENT OF PEDIATRICS, THE JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE Communicated by William L. Straus, Jr., April 24, 1969 Abstract.-Activity of the enzyme uroporphyrinogen III cosynthetase in hemolysates from five patients with congenital erythropoietic porphyria was much lower than the activity in control samples. The low cosynthetase activity in patients was not due to the presence of a free inhibitor or some competing en- zymatic activity, because hemolysates from porphyric subjects did not interfere either with the cosynthetase activity of hemolysates from normal subjects or with cosynthetase prepared from hematopoietic mouse spleen. This partial deficiency of cosynthetase in congenital erythropoietic porphyria corresponds to that shown previously in the clinically similar erythropoietic porphyria of cattle and explains the overproduction of uroporphyrin I in the human disease. Erythropoietic porphyria is a rare congenital disorder of man and cattle, characterized by photosensitivity, erythrodontia, hemolytic anemia, and por- phyrinuria.1 Many of the clinical manifestations of the disease can be explained by the production in marrow, deposition in tissues, and excretion in the urine and feces, of large amounts of uroporphyrin I and coproporphyrin I, which are products of the spontaneous oxidation of uroporphyrinogen I and its decarboxyl- ated derivative, coproporphyrinogen I. In cattle, the condition is inherited
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  • Forms of Hypoxanthine Or, Through Interconversions, Guanine Or Adenine
    826 GENETICS: GOTS AND GOLLUB PROC. N. A. S. Summary.-The ribonucleic acids of isolated thymus nuclei can be separated into two distinct fractions, one of which probably represents ribonucleic acid of the nu- cleolus. Studies of the incorporation of orotic acid-6-C"4 and adenosine-8-C'4 into these RNA fractions in vitro show great differences in their metabolic activity and different susceptibilities to an inhibitor of RNA synthesis, the "nucleolar" RNA being by far the more active. It is a pleasure to acknowledge our indebtedness to Mr. Rudolf Meudt for his careful and expert technical assistance. * This research was supported in part by a grant (RG-4919 M&G) from the United States Public Health Service. I V. G. Allfrey, A. E. Mirsky, and S. Osawa, Nature, 176, 1042, 1955. 2 V. G. Allfrey, A. E. Mirsky, and S. Osawa, J. Gen. Physiol., 40, 451, 1957. 3 R. Logan and J. N. Davidson, Biochim. et Biophys. Acta, 24, 196, 1957. 4 S. Osawa, K. Takata, and Y. Hotta (in press). 6 J. M. Webb, J. Biol. Chem., 221, 635, 1956. 6 M. Bessis, in Traite de cytologie sanguine (Paris: Masson & Cie, 1954), p. 83. J. N. Davidson and R. M. S. Smellie. Biochem. J.. 52, 594, 1952. SEQUENTIAL BLOCKADE IN ADENINE BIOSYNTHESIS BY GENETIC LOSS OF AN APPARENT BIFUNCTIONAL DEACYLASE* By JOSEPH S. GOTS AND EDITH G. GOLLUB DEPARTMENT OF MICROBIOLOGY, SCHOOL OF MEDICINE, UNIVERSITY OF PENNSYLVANIA, PHILADELPHIA, PENNSYLVANIA Communicated by D. Wright Wilson, July 3, 1957 Along the biosynthetic pathway to the purines of nucleic acids, inosinic acid occurs as a pivotal point in a bifurcation which leads to adenylic acid along one branch and to guanylic acid along the other: (B) r- Adenylic acid (AMP) (A) Inosinic acid (IMP) (C) L|_ * Guanylic acid (GMP) Bacterial mutations may result in genetic impairments at three locations with respect to the pivotal inosinic acid, thus yielding auxotrophs with three broad classes of nutritional response.
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  • Biochemistry I Enzymes
    BIOCHEMISTRY I 3rd. Stage Lec. ENZYMES Biomedical Importance: Enzymes, which catalyze the biochemical reactions, are essential for life. They participate in the breakdown of nutrients to supply energy and chemical building blocks; the assembly of those building blocks into proteins, DNA, membranes, cells, and tissues; and the harnessing of energy to power cell motility, neural function, and muscle contraction. The vast majority of enzymes are proteins. Notable exceptions include ribosomal RNAs and a handful of RNA molecules imbued with endonuclease or nucleotide ligase activity known collectively as ribozymes. The ability to detect and to quantify the activity of specific enzymes in blood, other tissue fluids, or cell extracts provides information that complements the physician’s ability to diagnose and predict the prognosis of many diseases. Further medical applications include changes in the quantity or in the catalytic activity of key enzymes that can result from genetic defects, nutritional deficits, tissue damage, toxins, or infection by viral or bacterial pathogens (eg, Vibrio cholerae). Medical scientists address imbalances in enzyme activity by using pharmacologic agents to inhibit specific enzymes and are investigating gene therapy as a means to remedy deficits in enzyme level or function. In addition to serving as the catalysts for all metabolic processes, their impressive catalytic activity, substrate specificity, and stereospecificity enable enzymes to fulfill key roles in additional processes related to human health and well-being. Proteases and amylases augment the capacity of detergents to remove dirt and stains, and enzymes play important roles in producing or enhancing the nutrient value of food products for both humans and animals.
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  • 1 AMINO ACIDS Commonly, 21 L-Amino Acids Encoded by DNA Represent the Building Blocks of Animal, Plant, and Microbial Proteins
    1 AMINO ACIDS Commonly, 21 L-amino acids encoded by DNA represent the building blocks of animal, plant, and microbial proteins. The basic amino acids encountered in proteins are called proteinogenic amino acids 1.1). Biosynthesis of some of these amino acids proceeds by ribosomal processes only in microorganisms and plants and the ability to synthesize them is lacking in animals, including human beings. These amino acids have to be obtained in the diet (or produced by hydrolysis of body proteins) since they are required for normal good health and are referred to as essential amino acids. The essential amino acids are arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine. The rest of encoded amino acids are referred to as non-essential amino acids (alanine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, proline, serine, and tyrosine). Arginine and histidine are classified as essential, sometimes as semi-essential amino acids, as their amount synthesized in the body is not sufficient for normal growth of children. Although it is itself non-essential, cysteine (classified as conditionally essential amino acid) can partly replace methionine, which is an essential amino acid. Similarly, tyrosine can partly replace phenylalanine. 1.1 The glutamic acid group 1.1.1 Glutamic acid and glutamine Free ammonium ions are toxic to living cells and are rapidly incorporated into organic compounds. One of such transformations is the reaction of ammonia with 2-oxoglutaric acid from the citric acid cycle to produce L-glutamic acid. This reaction is known as reductive amination. Glutamic acid is accordingly the amino acid generated first as both constituent of proteins and a biosynthetic precursor.
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  • Sample Thesis Title with a Concise And
    DESIGN, SYNTHESIS AND STUDIES OF GUANIDINIUM-BASED INHIBITORS FOR ISOPRENOID BIOSYNTHETIC PATHWAY ENZYMES by Walid Abdelmagid MChem., The University of Liverpool, 2011 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF Doctor of Philosophy in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Chemistry) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) October 2019 © Walid Abdelmagid, 2019 i The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: DESIGN, SYNTHESIS AND STUDIES OF GUANIDINIUM-BASED INHIBITORS FOR ISOPRENOID BIOSYNTHETIC PATHWAY ENZYMES submitted by Walid Abdelmagid in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry Examining Committee: Martin Tanner Supervisor Stephen Withers Supervisory Committee Member Glenn Sammis Supervisory Committee Member Kathryn Ryan University Examiner David Chen University Examiner Additional Supervisory Committee Members: Supervisory Committee Member Supervisory Committee Member ii Abstract In this thesis an inhibition strategy was developed to target enzymes that utilize allylic diphosphates. Positively-charged inhibitors that mimic the transition states/intermediates formed with these enzymes were synthesized. In chapter two, inhibitor 2 containing a guanidinium moiety appended to a phosphonylphosphinate was designed to mimic the transition state for the dissociation of dimethylallyl diphosphate into an allylic carbocation-pyrophosphate ion-pair. To test for the effectiveness of incorporating a guanidinium functionality into inhibitors of human farnesyl diphosphate synthase, inhibitors 3 and 4 were also prepared. Inhibitor 3 has a positive charge localized onto one atom, and inhibitor 4 is isosteric to inhibitor 2, but lacks positive charge. The inhibitors displayed IC50 values that were significantly higher than the substrate Km value, indicating that the positive charge did not result in tight binding to the enzyme.
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  • Michael Koch Strukturanalyse Der Mitochondrialen
    Michael Koch Strukturanalyse der mitochondrialen Protoporphyrinogen IX Oxidase aus Nicotiana tabacum und von zwei weiteren Proteinen: Blaues Cupredoxin Umecyanin aus Meerrettich (Armoracia rusticana) Lumazinsynthase-W27Y-Mutante aus Spalthefe (Schizosaccharomyces pombe) Technische Universität München Max-Planck-Institut für Biochemie Abteilung Strukturforschung Strukturanalyse der mitochondrialen Protoporphyrinogen IX Oxidase aus Nicotiana tabacum und von zwei weiteren Proteinen: Umecyanin und Lumazinsynthase-W27Y-Mutante Michael Koch Vollständiger Abdruck der von der Fakultät für Chemie der Technischen Universität München zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften (Dr. rer. nat.) genehmigten Dissertation. Vorsitzender: Univ.-Prof. Dr. W. Hiller Prüfer der Dissertation 1. apl. Prof. Dr. Dr. h. c. R. Huber 2. Univ.-Prof. Dr. Dr. A. Bacher Die Dissertation wurde am 24.02.2004 bei der Technischen Universität München eingereicht und durch die Fakultät für Chemie am 23.03.2004 angenommen. Dissertation Michael Koch Seite 3 Teile der Arbeit sind zur Veröffentlichung eingereicht bzw. wurden bereits veröffentlicht in: Koch, M., Breithaupt, C., Kiefersauer, R., Freigang, J., Huber, R., Messerschmidt, A. Crystal Structure of Protoporphyrinogen IX Oxidase: A key enzyme in heme and chlorophyll biosynthesis (EMBO J., online veröffentlicht 1. April 2004) Koch, M., Breithaupt, C., Kiefersauer, R., Freigang, J., Huber, R. and Messerschmidt, A. (2004). Crystal Structure of Protoporphyrinogen IX Oxidase. Jahrestagung der Deutschen Gesellschaft für Kristallographie 2004, Jena (Vortrag) Koch, M., Kiefersauer, R., Huber, R. (2002) Improvement of freezing protein crystals by accurately controlled humidity changes. Poster presentation at the XIX Congress and general assembly of the International Union of Crystallography, Geneva, Switzerland (Posterpräsentation) Koch, M., Velarde, M., Echt, S., Harrison, M., Dennison, C., Messerschmidt, A.
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  • WO 2008/073367 Al
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date PCT (10) International Publication Number 19 June 2008 (19.06.2008) WO 2008/073367 Al (51) International Patent Classification: Quinn, Qun [US/US], 544 Revere Road, West Chester, C12N 1/16 (2006 01) C07C 403/24 (2006 01) Pennsylvania 19381 (US) C12N 1/15 (2006 01) (74) Agent: FELTHAM, S., NeU, E I du Pont de Nemours and (21) International Application Number: Company, Legal Patent Records Center, 4417 Lancaster PCT/US2007/025222 Pike, Wilmington, Delaware 19805 (US) (22) International Filing Date: (81) Designated States (unless otherwise indicated for every 10 December 2007 (10 12 2007) kind of national protection available): AE, AG, AL, AM, (25) Filing Language: English AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY,BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, (26) Publication Language: English ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, (30) Priority Data: IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, 60/869,576 12 December 2006 (12 12 2006) US LR, LS, LT, LU, LY,MA, MD, ME, MG, MK, MN, MW, 60/869,574 12 December 2006 (12 12 2006) US MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, 60/869,591 12 December 2006 (12 12 2006) US PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, 60/869,582 12 December 2006 (12 12 2006) US TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, 60/869,580 12 December 2006 (12 12 2006) US ZM, ZW (71) Applicant (for all designated States except US): E.
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