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Biomarkers are not just ANY indicator

Biomarkers: distinct indicators that help define the physiology or state of a living system. Marcelle uses his fingers as an indicator of how close we came to shit-creek. But that’s not a biomarker.

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Biomarkers are not just ANY indicator

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  1. Biomarkers: distinct indicators that help define the physiology or state of a living system

  2. Marcelle uses his fingers as an indicator of how close we came to shit-creek. But that’s not a biomarker Chris uses a YSI probe to measure dissolved oxygen. But that’s not a biomarker. Biomarkers are not just ANY indicator

  3. When hypoxia sets in, a yawn indicates the homeostatic mechanism to increase oxygen uptake AKA the Boopathy Biomarker Biomarkers represent the complexity of life

  4. Biomarkers include Any indicator of a biological phenomenon: Microbiological biomarkers to indicate cloning ampicillin resistance Expression markers for biosynthesis/ trafficking gfp protein tagging Genetic biomarkers of disease in humans Induced biomarkers as evidence of abnormality

  5. Genetic Biomarkers 2002 Nobel Laureate: Sydney Brenner

  6. Caenorhabditis elegans, Apoptosis model

  7. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. AUTHORS: The Huntington's Disease Collaborative Research Group aka MCDONALD,M., AMBROSE,C.M., DUYAO,M.P., MYERS,R.H., LIN,C.S., SRINIDHI,J., BARNES,G., TAYLOR,S.A., JAMES,M., GROOT,N., MCFARLANE,H., JENKINS,B., ANDERSON,M.A., WEXLER,N.S., GUSELLA,J.F., BATES,G.P., BAXENDALE,S., HUMMERICH,H., KIRBY,S., NORTH,M., YOUNGMAN,S., MOTT,R., ZEHETNER,G., SEDLACEK,Z., POUSTKA,A., FRISCHAUF,A.-M., LEHRACH,H., BUCKLER,A.J., CHURCH,D., DOUCETTE-STAMM,L., O'DONOVAN,M.C., RIBA-RAMIREZ,L., SHAH,M., STANTON,V.P., STROBEL,S.A., DRATHS,K.M., WALES,J.L., DERVAN,P., HOUSMAN,D.E., ALTHERR,M., SHIANG,R., THOMPSON,L., FIELDER,T., WASMUTH,J.J., TAGLE,D., VALDES,J., ELMER,L., ALLARD,M., CASTILLA,L., SWAROOP,M., BLANCHARD,K., COLLINS,F.S., SNELL,R., HOLLOWAY,T., GILLESPIE,K., DATSON,N., SHAW,S. and HARPER,P.S. … I count 58 authors in all

  8. Poly-glutamine stretch of huntingtin coded for by CAG repeats • matleklmka feslksfqqq qqqqqqqqqq qqqqqqqqqq pppppppppp pqlpqpppqa • qpllpqpqpp ppppppppgp avaeeplhrp kkelsatkkd rvnhcltice nivaqsvrns • pefqkllgia melfllcsdd aesdvrmvad eclnkvikal mdsnlprlql elykeikkng • aprslraalw rfaelahlvr pqkcrpylvn llpcltrtsk rpeesvqetl aaavpkimas • fgnfandnei kvllkafian lksssptirr taagsavsic qhsrrtqyfy swllnvllgl POLYGLUTAMINE EXPANSION LEADS TO ELEVATED SUSCEPTIBILITY TO APOPAIN CLEAVAGE AND LIKELY RESULTS IN ACCELERATED NEURONAL APOPTOSIS

  9. Huntington’s Disease Repeats Human ortholog of ced 3 is caspase 3 Huntingtin is cleaved by caspase 3, and this change is associated with neuronal death

  10. Genetic Biomarkers Allow the elimination of imperfect embryos Plus… Potential for both Germline or Somatic Gene Therapy

  11. Woody Guthrie 1930’s

  12. Woody and Arlo, 1950’s

  13. Arlo still performing in 2002

  14. Woody, Krisna, Abe Guthrie

  15. Rachel Carson published Silent Spring 1962 raising concerns on DDT Heptachlor Dieldrin Advocating integrated pest management, she referred to work by Henry Long who reported that heptachlor used to treat fire ants had INCREASED cane borer damage.

  16. Only a small modification b/w estrogen and testosterone

  17. Conventional Intracellular receptor MOA

  18. Several environmental pollutants have been defined as estrogenic: Endocrine disruptors

  19. Estrogen imparts a 3 layered effect Transcription of Primary genes Transcription of Secondary genes A stabilization of cytoplasmic mRNA Final Result: A gradual and long lasting cell response such as synthesis of vitellogenin by liver

  20. The Endocrine Disruptor Hypothesis Compounds from a variety of sources, once thought to be safe, are having a non-lethal but devastating impact on normal biological signaling • Human Medicine • 2. Vertebrate Metamorphosis • 3. Invertebrate Sex determination • 4. Vetebrate Sex determination

  21. 1950 – 1970s DES prescribed to prevent miscarriages DES mothers with 30% higher breast cancer 1980’s DES daughters with 9x ectopic preg, 2x miscarriage, 5x premature delivery, 2x pre-cancerous dysplasia, 3-5x cervical cancer , vaginal cancer ages 14-22.

  22. John McLachlan DES studies, NIEHS, Tulane biomarkers: transferrin, uterine cancer

  23. Methoprene inhibits mosqui pupation but bd products disrupt vertebrate ret acid signalling

  24. Tyrone Hayes: Atrazine effects biormarker: frog gonadal abnormalities

  25. Lou Guillette and Lake Apopka: 1992 feminization of gators

  26. 2002 Lou says DDE is still in water; gator sexes still confused Biomarker: steroid levels

  27. Chain of Causation: • Chemical spill in 1992 contained DDT, DDE and more • Juvenile alligator population has decreased • females have elevated levels of estradiol • males have depressed levels of testo • Females have altered aromatase activity • Males have poorly organized testes • Males have reduced penis size • Testes have elevated estradiol production • Females have poyovular follicles • Many contaminants bind to alligator est receptors

  28. biomarkers in certain species have become useful as indicators of environmental health

  29. Biomarkers for estrogen induction can be applied to test for normal reproductive health As well as Environmental Stress such as Endocrine Disruption By far the most famous endocrine disruption biomarker is the yolk protein precursor, vitellogenin made by the liver under estrogen induction, transported by the blood and stored in the oocyte

  30. VITELLOGENINS AND CHORIOGENINS

  31. Biomarkers 2005 Expect to teach me what YOU learn A semester-long biomarker study design of biomarker experimental induction assay and publication A survey of biomarker techniques from our department and the literature

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