DOCSLIB.ORG

WO 2012/177639 A2 27 December 2012 (27.12.2012) P O P C T

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
WO 2012/177639 A2 27 December 2012 (27.12.2012) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2012/177639 A2 27 December 2012 (27.12.2012) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C12N 15/87 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (21) International Application Number: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, PCT/US20 12/043 148 DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (22) International Filing Date: HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, 19 June 2012 (19.06.2012) KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (25) Filing Language: English OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, (26) Publication Language: English SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 61/499,757 22 June 201 1 (22.06.201 1) (84) Designated States (unless otherwise indicated, for every 61/639,333 27 April 2012 (27.04.2012) kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (71) Applicant (for all designated States except US): UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, ALNYLAM PHARMACEUTICALS, INC. [US/US]; TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, 300 Third Street, Cambridge, Massachusetts 02142 (US). EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, (72) Inventors; and TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, (75) Inventors/ Applicants (for US only): HINKLE, Gregory ML, MR, NE, SN, TD, TG). [US/US]; c/o Alnylam Pharmaceuticals, Inc., 300 Third Street, Cambridge, Massachusetts 02142 (US). BETTEN- Published: COURT, Brian [US/US]; c/o Alnylam Pharmaceuticals, — without international search report and to be republished Inc., 300 Third Street, Cambridge, Massachusetts 02142 upon receipt of that report (Rule 48.2(g)) (US). — with sequence listing part of description (Rule 5.2(a)) (74) Agent: WARD, Donna T.; Dt Ward, P.C., 292 Main Street, Suite 2, Groton, Massachusetts 01450 (US). < l © (54) Title: BIOPROCESSING AND BIOPRODUCTION USING AVIAN CELL LINES (57) Abstract: The invention relates to compositions and methods of modulating the status, activity or expression of avian tran- ¾ scripts in the process of bioproduction. In one aspect, the invention provides for a method for producing a biological product from S an avian host cell. BIOPROCESSING AND BIOPRODUCTION USING AVIAN CELL LINES CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 61/499,757, filed June 22, 201 1, entitled "BIOPROCESSING AND BIOPRODUCTION USING AVIAN CELL LINES" and U.S. Provisional Patent Application No. 61/639,333, filed April 27, 2012, entitled "BIOPROCESSING AND BIOPRODUCTION USING AVIAN CELL LINES" the contents, each of which is incorporated by reference in its entirety. REFERENCE TO SEQUENCE LISTING The instant application contains a "lengthy" Sequence Listing which has been submitted via CD-R in lieu of a printed paper copy, and is hereby incorporated by reference in its entirety. This sequence listing text file which is part of the originally filed subject matter has the following features: File name: 200212pc.TXT; File size: 622,641,152 Bytes; Date created: May 22, 2012. These CD-Rs are labeled "CRF," "Copy 1,", "Copy 2," and "Copy 3" respectively, and each contains only one identical file, as identified immediately above. REFERENCE TO LENGTHY TABLE The specification includes Lengthy Table 1. Lengthy Table 1 has been submitted via EFS-Web in electronic format as follows: File name: AvianTranscripts.PDF; Date created: June 19, 2012; File size: 1,928,702 Bytes, and is incorporated herein by reference in its entirety. Please refer to the end of the specification for access instructions. FIELD OF THE INVENTION The invention relates generally to avian transcriptomes, organized transcriptomes and systems and methods (including methods of doing business) using transcriptomes for the design of targeting constructs useful in the production of biomolecules in avian cells and avian cell cultures. The invention further relates to engineering avian cells and cell lines for more effective and efficient production of biological products and biomolecules. BACKGROUND OF THE INVENTION Cell culture and bioprocessing techniques are used to manufacture a wide range of biological products, including biopharmaceuticals, biofuels, metabolites, vitamins and nutraceuticals. A number of strategies have been developed to enhance productivity, yield, efficiency, and other aspects of cell culture bioprocesses in order to facilitate industrial scale production and meet applicable standards for product quality and consistency. Traditional strategies for optimizing cell culture bioprocesses involve adjusting physical and biochemical parameters, such as culture media (e.g., pH, nutrients) and conditions (e.g., temperature, duration), and selecting host cells having desirable phenotypes. More recently, genetic approaches have been developed for optimizing cell culture bioprocesses by introducing recombinant DNA into host cells, where the DNA encodes an exogenous protein that influences production of a biological product or regulates expression of an endogenous protein that influences production of the biological product. However, such methods require costly and time-consuming laboratory manipulations and can be incompatible with certain genes, proteins, host cells, and biological products. Avian cells have been used in the production of biomolecules, particularly complex proteins such as antibodies. However, little is known about the coordinate expression and modulation of genes in these cells, and thus, optimized and targeted modulation of bioprocesses of these cells is unavailable presently. Accordingly, there is a need in the art for new genetic approaches for optimizing cell culture bioprocesses involving a wide range of host cells, including avian cells, and biological products produced in these cells. SUMMARY OF THE INVENTION The invention is based at least in part on the surprising discovery that Targeting Constructs (TCs) can be applied to cells in culture to effect potent, durable modulation of gene expression, such that the quality and quantity of biological product that is produced by an avian host cell can be improved without the need for extensive cell line engineering. As such, in a first aspect, the invention provides compositions and methods for producing a biological product from a host cell. In one embodiment the host cell is an avian cell or cell derived from avian cells. In various embodiments, the biological product is a polypeptide (including enzymes), a metabolite, a nutraceutical, a chemical intermediate, abiofuel, a food additive, or an antibiotic (e.g., antiviral, antibacterial, antifungal, and the like, etc). The methods of the present invention also find utility in the fields of chemical manufacture, textiles and electronics. The details of various embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and the drawings, and from the claims. DETAILED DESCRIPTION OF THE INVENTION The invention provides methods for producing a biological product in an avian host cell, the methods including the steps of contacting the cell with at least one or more Targeting Construct (TC), maintaining the avian cell for a time sufficient to modulate expression of the target gene or alter a cellular process, wherein the modulation and/or alteration enhances production of the biological product, and recovering the biological product from the cell, cell culture or supernatant. The description provided herein discloses how to make and use targeting constructs (TCs) to produce a biological product in an avian host cell or cell culture according to methods provided herein. Also disclosed are cell culture reagents and compositions comprising the targeting constructs and kits for carrying out the disclosed methods. Also described herein are compositions and methods of modulation the status, activity, or expression of Avian Transcripts (ATs) in an avian cell (or cell culture), tissue or organism. Further provided are compositions and methods for treating pathological conditions and diseases in a mammal using a biological product or targeting construct of the present invention. Further disclosed are screening methods, kits and assays which are designed to utilize the cellular pathways and systems associated with avian transcripts and their manipulation in bioprocessing and bioproduction. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the targeting constructs (TC) and methods featured in the invention, suitable methods and materials are described below. The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which
Load more

Recommended publications
  • Nucleotide Metabolism
    NUCLEOTIDE METABOLISM General Overview • Structure of Nucleotides Pentoses Purines and Pyrimidines Nucleosides Nucleotides • De Novo Purine Nucleotide Synthesis PRPP synthesis 5-Phosphoribosylamine synthesis IMP synthesis Inhibitors of purine synthesis Synthesis of AMP and GMP from IMP Synthesis of NDP and NTP from NMP • Salvage pathways for purines • Degradation of purine nucleotides • Pyrimidine synthesis Carbamoyl phosphate synthesisOrotik asit sentezi • Pirimidin nükleotitlerinin yıkımı • Ribonükleotitlerin deoksiribonükleotitlere dönüşümü Basic functions of nucleotides • They are precursors of DNA and RNA. • They are the sources of activated intermediates in lipid and protein synthesis (UDP-glucose→glycogen, S-adenosylmathionine as methyl donor) • They are structural components of coenzymes (NAD(P)+, FAD, and CoA). • They act as second messengers (cAMP, cGMP). • They play important role in carrying energy (ATP, etc). • They play regulatory roles in various pathways by activating or inhibiting key enzymes. Structures of Nucleotides • Nucleotides are composed of 1) A pentose monosaccharide (ribose or deoxyribose) 2) A nitrogenous base (purine or pyrimidine) 3) One, two or three phosphate groups. Pentoses 1.Ribose 2.Deoxyribose •Deoxyribonucleotides contain deoxyribose, while ribonucleotides contain ribose. •Ribose is produced in the pentose phosphate pathway. Ribonucleotide reductase converts ribonucleoside diphosphate deoxyribonucleotide. Nucleotide structure-Base 1.Purine 2.Pyrimidine •Adenine and guanine, which take part in the structure
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 6,822,071 B1 Stephens Et Al
    USOO6822071B1 (12) United States Patent (10) Patent No.: US 6,822,071 B1 Stephens et al. (45) Date of Patent: Nov. 23, 2004 (54) POLYPEPTIDES FROM CHLAMYDIA (56) References Cited PNEUMONIAE AND THEIR USE IN THE DIAGNOSIS, PREVENTION AND FOREIGN PATENT DOCUMENTS TREATMENT OF DISEASE WO 99/27105 * 6/1999 (75) Inventors: Richard S. Stephens, Orinda, CA (US); OTHER PUBLICATIONS Wayne Mitchell, San Francsico, CA Gerhold et al-BioEssays 18(12):973-981, 1996.* (US); Sue S. Kalman, Saratoga, CA Wells et al Journal of Leukocyte Biology 61(5):545-550, (US); Ronald Davis, Palo Alto, CA 1997.* (US) Russell et al Journal of Molecular Biology 244:33-350, 1994.* (73) Assignee: The Regents of the University of Rudinger et al., in “Peptide Hormones' Parsons, TA ets, California, Oakland, CA (US) University Park Press pp. 1–6, 1976.* Burgess et al, The Journal of Cell Biology, 111:2129-2138, Notice: Subject to any disclaimer, the term of this 1990.* patent is extended or adjusted under 35 Lazar et al, Molecular and Cellular Biology U.S.C. 154(b) by 0 days. 8(3):1247–1252, 1988.* Jobling et al, Mol-Microbiol. 5(7): 1755–67, 1991.* (21) Appl. No.: 09/438,185 Pir-68 Database Accession No. E72002 Kalmar et al. Apr. (22) Filed: Nov. 11, 1999 23, 1999.* (Under 37 CFR 1.47) * cited by examiner Primary Examiner Patricia A. Duffy Related U.S. Application Data (74) Attorney, Agent, or Firm Townsend and Townsend (60) Provisional application No. 60/128,606, filed on Apr. 8, and Crew 1999, and provisional application No.
    [Show full text]
  • Prolonging Healthy Aging: Longevity Vitamins and Proteins PERSPECTIVE Bruce N
    PERSPECTIVE Prolonging healthy aging: Longevity vitamins and proteins PERSPECTIVE Bruce N. Amesa,1 Edited by Cynthia Kenyon, Calico Labs, San Francisco, CA, and approved September 13, 2018 (received for review May 30, 2018) It is proposed that proteins/enzymes be classified into two classes according to their essentiality for immediate survival/reproduction and their function in long-term health: that is, survival proteins versus longevity proteins. As proposed by the triage theory, a modest deficiency of one of the nutrients/cofactors triggers a built-in rationing mechanism that favors the proteins needed for immediate survival and reproduction (survival proteins) while sacrificing those needed to protect against future damage (longevity proteins). Impairment of the function of longevity proteins results in an insidious acceleration of the risk of diseases associated with aging. I also propose that nutrients required for the function of longevity proteins constitute a class of vitamins that are here named “longevity vitamins.” I suggest that many such nutrients play a dual role for both survival and longevity. The evidence for classifying taurine as a conditional vitamin, and the following 10 compounds as putative longevity vitamins, is reviewed: the fungal antioxidant ergo- thioneine; the bacterial metabolites pyrroloquinoline quinone (PQQ) and queuine; and the plant antioxidant carotenoids lutein, zeaxanthin, lycopene, α-andβ-carotene, β-cryptoxanthin, and the marine carotenoid astaxanthin. Because nutrient deficiencies are highly prevalent in the United States (and elsewhere), appro- priate supplementation and/or an improved diet could reduce much of the consequent risk of chronic disease and premature aging. vitamins | essential minerals | aging | nutrition I propose that an optimal level of many of the known adverse health effects.
    [Show full text]
  • Discovery of Novel Bacterial Queuine Salvage Enzymes and Pathways in Human Pathogens
    Discovery of novel bacterial queuine salvage enzymes and pathways in human pathogens a,1 b,1 c,1 b d a Yifeng Yuan , Rémi Zallot , Tyler L. Grove , Daniel J. Payan , Isabelle Martin-Verstraete , Sara Sepic´ , Seetharamsingh Balamkundue, Ramesh Neelakandane, Vinod K. Gadie, Chuan-Fa Liue, Manal A. Swairjof,g, Peter C. Dedone,h,i, Steven C. Almoc, John A. Gerltb,j,k, and Valérie de Crécy-Lagarda,l,2 aDepartment of Microbiology and Cell Science, University of Florida, Gainesville, FL 32611; bInstitute for Genomic Biology, University of Illinois at Urbana–Champaign, Urbana, IL 61801; cDepartment of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461; dLaboratoire de Pathogénèse des Bactéries Anaérobies, Institut Pasteur et Université de Paris, F-75015 Paris, France; eSingapore-MIT Alliance for Research and Technology, Infectious Disease Interdisciplinary Research Group, 138602 Singapore, Singapore; fDepartment of Chemistry and Biochemistry, San Diego State University, San Diego, CA 92182; gThe Viral Information Institute, San Diego State University, San Diego, CA 92182; hDepartment of Biological Engineering and Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139; iCenter for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139; jDepartment of Biochemistry, University of Illinois at Urbana–Champaign, Urbana, IL 61801; kDepartment of Chemistry, University of Illinois at Urbana–Champaign, Urbana, IL 61801; and lUniversity of Florida Genetics Institute, Gainesville, FL 32610 Edited by Tina M. Henkin, The Ohio State University, Columbus, OH, and approved August 1, 2019 (received for review June 16, 2019) Queuosine (Q) is a complex tRNA modification widespread in 1A. The TGT enzyme, which is responsible for the base ex- eukaryotes and bacteria that contributes to the efficiency and accuracy change, is the signature enzyme in the Q biosynthesis pathway.
    [Show full text]
  • Poultry, Pigeon & Eggs
    POULTRY, PIGEON & EGGS Competition Schedule 30 August - 8 September 2019 | theshow.com.au 2019 POULTRY, PIGEONS AND EGGS IMPORTANT INFORMATION ARRIVAL/DELIVERY, JUDGING AND DEPARTURE TIMES Poultry and Pigeons ARRIVAL - Exhibits must be penned between 10.00 am and 9.00 pm on Thursday 29 August. Exhibitors delivering exhibits may enter and exit via the Leader Street entrance. The Poultry & Pigeon Pavilion is situated on the first floor of the Stirling/Angas Hall, west of the Hamilton Boulevard and you will be required to bring your vehicle via the western ramp entry. The exhibits must be accompanied by computer printout entry details. No exhibits will be permitted inside the pavilion other than those which have been entered for competition. JUDGING - will commence at 8.00 am on Friday 30 August. The Society reserves the right to re-allocate breeds to judges after closing date depending on entry numbers. DEPARTURE - Between 6.00 pm and 10.00 pm Sunday 8 September (boxing from 5.00 pm) or Between 6.00 am and 10.30 am Monday 9 September When collecting exhibits, you must produce your Entry Details Return (computer pen number print out) and be accompanied by an official who will assist in checking out each exhibit. Sunday 8 September Departure Birds may be boxed from 5.00 pm. Departure on foot - Exhibitors will be permitted to leave on foot with their birds between 6pm and 8:30pm only. Vehicle collection – Exhibitors with many birds may bring a single vehicle onsite via the Leader Street gate to assist with collection between 8:30pm and 10pm only.
    [Show full text]
  • Effects of Allopurinol and Oxipurinol on Purine Synthesis in Cultured Human Cells
    Effects of allopurinol and oxipurinol on purine synthesis in cultured human cells William N. Kelley, James B. Wyngaarden J Clin Invest. 1970;49(3):602-609. https://doi.org/10.1172/JCI106271. Research Article In the present study we have examined the effects of allopurinol and oxipurinol on thed e novo synthesis of purines in cultured human fibroblasts. Allopurinol inhibits de novo purine synthesis in the absence of xanthine oxidase. Inhibition at lower concentrations of the drug requires the presence of hypoxanthine-guanine phosphoribosyltransferase as it does in vivo. Although this suggests that the inhibitory effect of allopurinol at least at the lower concentrations tested is a consequence of its conversion to the ribonucleotide form in human cells, the nucleotide derivative could not be demonstrated. Several possible indirect consequences of such a conversion were also sought. There was no evidence that allopurinol was further utilized in the synthesis of nucleic acids in these cultured human cells and no effect of either allopurinol or oxipurinol on the long-term survival of human cells in vitro could be demonstrated. At higher concentrations, both allopurinol and oxipurinol inhibit the early steps ofd e novo purine synthesis in the absence of either xanthine oxidase or hypoxanthine-guanine phosphoribosyltransferase. This indicates that at higher drug concentrations, inhibition is occurring by some mechanism other than those previously postulated. Find the latest version: https://jci.me/106271/pdf Effects of Allopurinol and Oxipurinol on Purine Synthesis in Cultured Human Cells WILLIAM N. KELLEY and JAMES B. WYNGAARDEN From the Division of Metabolic and Genetic Diseases, Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, North Carolina 27706 A B S TR A C T In the present study we have examined the de novo synthesis of purines in many patients.
    [Show full text]
  • Aberdeen & Northern Marts SPECIAL SALE of RARE & MINORITY
    Aberdeen & Northern Marts A member of ANM GROUP LTD. THAINSTONE CENTRE, INVERURIE TELEPHONE : 01467 623710 SPECIAL SALE OF RARE & MINORITY BREEDS OF POULTRY & EGGS INCLUDING ◼ TURKEYS ◼ GUINEA FOWL ◼ LARGE FOWL ◼ PIGEONS ◼ BANTAMS ◼ GEESE ◼ PHEASANTS ◼ DUCKS ◼ PEAFOWL ◼ EGGS ◼ QUAIL ◼ POULTRY EQUIPMENT within THAINSTONE CENTRE, INVERURIE on SATURDAY 7th MARCH 2020 from 10.00 am PROSPECTIVE PURCHASERS PLEASE REGISTER AT THE MAIN OFFICE AND OBTAIN A BUYERS NUMBER Please note that a Buyers Premium of 10% + VAT with a maximum of £50.00 per lot will be added to the sale price of Poultry, Eggs and Poultry Equipment. PRICE £2.00 2 ALL POULTRY ENTRIES MUST BE PENNED BY 9.30 am ANY PEN OF POULTRY FAILING TO ATTRACT AN OPENING BID OF £5 WILL BE PASSED OVER UNSOLD NO POULTRY TO BE REMOVED WITHOUT A PASS OR IN THE ABSENCE OF AN ATTENDANT PURCHASERS MUST INSPECT STOCK PRIOR TO BIDDING TO SATISFY THEMSELVES THAT THE LOT CONFORMS TO THE DESCRIPTION IN THE CATALOGUE. SALES ARRANGEMENTS 10.00am Exchange Turkeys and Large Fowl, Bantams, Pheasants, Peafowl, Quail, Guinea Fowl, Ducks and Geese. All entries must be in place by 9.30am 11.30am Concourse Hatching Eggs—Please note that all egg entries must be in place by 9.30am followed by Yard Poultry Equipment (Subject to Arrival) 3 PURCHASERS MUST INSPECT STOCK PRIOR TO BIDDING TO SATISFY THEMSELVES THAT THE LOT CONFORMS TO THE DESCRIPTION IN THE CATALOGUE. TURKEYS Charles Barron Blairindinnie Gartly Huntly 1 Broad Breast Bronze Hen - 2019 Hatch One 2 Broad Breast Bronze Hen - 2019 Hatch One Mrs M Leggate
    [Show full text]
  • Purine and Pyrimidine Biosynthesis
    Biosynthesis of Purine & Pyrimidi ne Introduction Biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined together to form macromolecules. This process often consists of metabolic pathways. The purines are built upon a pre-existing ribose 5- phosphate. Liver is the major site for purine nucleotide synthesis. Erythrocytes, polymorphonuclear leukocytes & brain cannot produce purines. Pathways • There are Two pathways for the synthesis of nucleotides: 1. De-novo synthesis: Biochemical pathway where nucleotides are synthesized from new simple precursor molecules 2. Salvage pathway: Used to recover bases and nucleotides formed during the degradation of RNA and DNA. Step involved in purine biosynthesis (Adenine & Guanine) • Ribose-5-phosphate, of carbohydrate metabolism is the starting material for purine nucleotide synthesis. • It reacts with ATP to form phosphoribosyl pyrophosphate (PRPP). • Glutamine transfers its amide nitrogen to PRPP to replace pyrophosphate & produce 5- phosphoribosylamine. Catalysed by PRPP glutamyl amidotransferase. • This reaction is the committed. • Phosphoribosylamine reacts with glycine in the presence of ATP to form glycinamide ribosyl 5- phosphate or glycinamide ribotide (GAR).Catalyzed by synthetase. • N10-Formyl tetrahydrofolate donates the formyl group & the product formed is formylglycinamide ribosyl 5-phosphate. Catalyzed by formyltransferase. • Glutamine transfers the second amido amino group to produce formylglycinamidine ribosyl 5- phosphate. Catalyzed by synthetase. • The imidazole ring of the purine is closed in an ATP dependent reaction to yield 5- aminoimidazole ribosyl 5-phosphate. Catalyzed by synthetase. • Incorporation of CO2 (carboxylation) occurs to yield aminoimidazole carboxylate ribosyl 5- phosphate.
    [Show full text]
  • Induced Alterations in the Urine Metabolome in Cardiac Surgery
    www.nature.com/scientificreports OPEN Bretschneider solution- induced alterations in the urine metabolome in cardiac surgery Received: 16 August 2018 Accepted: 1 November 2018 patients Published: xx xx xxxx Cheng-Chia Lee1,3, Ya-Ju Hsieh 2, Shao-Wei Chen3,4, Shu-Hsuan Fu2, Chia-Wei Hsu 2, Chih-Ching Wu 2,5,6, Wei Han7, Yunong Li7, Tao Huan7, Yu-Sun Chang2,6,8, Jau-Song Yu2,9,10, Liang Li7, Chih-Hsiang Chang1,3 & Yi-Ting Chen 1,2,11,12 The development of Bretschneider’s histidine-tryptophan-ketoglutarate (HTK) cardioplegia solution represented a major advancement in cardiac surgery, ofering signifcant myocardial protection. However, metabolic changes induced by this additive in the whole body have not been systematically investigated. Using an untargeted mass spectrometry-based method to deeply explore the urine metabolome, we sought to provide a holistic and systematic view of metabolic perturbations occurred in patients receiving HTK. Prospective urine samples were collected from 100 patients who had undergone cardiac surgery, and metabolomic changes were profled using a high-performance chemical isotope labeling liquid chromatography-mass spectrometry (LC-MS) method. A total of 14,642 peak pairs or metabolites were quantifed using diferential 13C-/12C-dansyl labeling LC-MS, which targets the amine/phenol submetabolome from urine specimens. We identifed 223 metabolites that showed signifcant concentration change (fold change > 5) and assembled several potential metabolic pathway maps derived from these dysregulated metabolites. Our data indicated upregulated histidine metabolism with subsequently increased glutamine/glutamate metabolism, altered purine and pyrimidine metabolism, and enhanced vitamin B6 metabolism in patients receiving HTK.
    [Show full text]
  • CATAIR Appendix
    CBP and Trade Automated Interface Requirements Appendix: PGA February 12, 2021 Pub # 0875-0419 Contents Table of Changes .................................................................................................................................................... 4 PG01 – Agency Program Codes ........................................................................................................................... 18 PG01 – Government Agency Processing Codes ................................................................................................... 22 PG01 – Electronic Image Submitted Codes.......................................................................................................... 26 PG01 – Globally Unique Product Identification Code Qualifiers ........................................................................ 26 PG01 – Correction Indicators* ............................................................................................................................. 26 PG02 – Product Code Qualifiers........................................................................................................................... 28 PG04 – Units of Measure ...................................................................................................................................... 30 PG05 – Scientific Species Code ........................................................................................................................... 31 PG05 – FWS Wildlife Description Codes ...........................................................................................................
    [Show full text]
  • NUCLEOTIDE METABOLISM Mark Rush
    NUCLEOTIDE METABOLISM Mark Rush Nucleotides serve various metabolic functions. For example, they are: • Substrates (building blocks) for nucleic acid biosynthesis and repair, • The main storage form of “high energy phosphate”, • Components of many “so-called” co-enzymes (NAD, NADP, FAD, CoA), • Components of many activated metabolic intermediates (such as UDPG, SAM), • Major allosteric effectors (such as AMP, ADP, ATP, GTP), • Major second messengers (such as 3',5' cAMP), and • Precursors for the biosynthesis of a variety of important compounds (such as biopterin and histidine). Nucleotide biochemistry can be treated both as an aspect of nitrogen metabolism, along with such compounds as amino acids and porphyrins, and as an aspect of nucleic acid metabolism. When the focus is on the biosynthesis and degradation of nucleotides, in other words on their turnover, the treatment is similar to that of other nitrogenous compounds. When the focus is on the role of nucleotides in overall nucleic acid metabolism, the treatment is included in molecular biology. Both aspects will be considered here with the major emphasis directed toward relating defects in nucleotide turnover to either metabolic diseases or chemotherapy. I. Nomenclature (pages 11 and 12). II. Overall metabolic pathways (page 4). 1) PRPP synthetase. 2) Nucleoside phosphorylases. 3) Phosphoribosyl transferases. nucleotides - 1 III. Biosynthesis of purines and pyrimidines (pages 5, 6, 8). A minimum amount of time will be spent discussing these pathways in lecture. Please examine them carefully in the text and note that: 1) Purine synthesis begins at the nucleotide level, while pyrimidine synthesis does not. 2) Both syntheses are regulated at their committed steps.
    [Show full text]
  • Synthesis of Tritium Labeled Queuine, Preq1 and Related Azide Probes Toward Examining the Prevalence of Queuine
    Synthesis of Tritium Labeled Queuine, PreQ1 and Related Azide Probes Toward Examining the Prevalence of Queuine by Allen F. Brooks A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Medicinal Chemistry) in the University of Michigan 2012 Doctoral Committee: Research Professor Hollis D. Showalter, Co-Chair Associate Professor George A. Garcia, Co-Chair Professor Hashim M. Al-Hashimi Assistant Professor Garry D. Dotson Assistant Professor Matthew B. Soellner © Allen F. Brooks 2012 In memory of Edward and Lillian Pederson ii Acknowledgements With my remaining time short, it is appropriate to look back and thank those that supported me in my dissertation work either professionally or as a friend. First and foremost, I have to acknowledge my best friend from the program, Adam Lee. If it was not for the trip to the ACS meeting in Chicago, Adam and I likely would have never got to know each other. Luckily, fate arranged such an occurrence. If not for Adam’s friendship and the support of some others, I likely would have left the program in my second year. I also have to thank Jason Witek, an undergraduate who worked in the Showalter lab. We actually met during the Organic Mechanisms course, as he was in an academic program of his own design. The time we worked together in the lab was a productive one, and interestingly an amusing time as well. I also have to thank several other associates for their help in progressing my research as well as making time here more pleasant, those individuals being: Dr.
    [Show full text]