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CASCADE REACTIONS. “Steroid and thyroid hormones, along with vitamins A and D, were elucidated based on their endocrine origin and the physiologic processes that they regulate. Each of these small molecules is chemically distinct, and although there was initially no presumption that they might have a shared signaling mechanism, initial biochemical experiments revealed the presence of an intracellular receptor that, upon ligand addition, activated transcription of tissue-specific sets of target genes.” https://lnkd.in/dXjCCgQ View in LinkedIn

THEN CAME THE ORPHANS. “This discovery sparked identification of numerous genes encoding related proteins, termed orphan receptors. Characterization of these orphan receptors and, in particular, of the retinoid X receptor (RXR) positioned nuclear receptors at the epicenter of the “Big Bang” of molecular endocrinology.” https://lnkd.in/dXjCCgQ View in LinkedIn

FIRST ORPHAN ASSIGNED. “Applying the reverse endocrinology approach to the retinoid X receptor (RXR) led to the identification of the first endogenous ligand for an orphan nuclear receptor (9-cis retinoic acid, a metabolite of vitamin A), establishing RXR as the founding member of the “adopted” orphan class.” https://lnkd.in/dXjCCgQ View in LinkedIn

NEW FAST COTRANSFECTION ASSAY. “This “reverse endocrinology” concept allowed for high-throughput screens of natural, synthetic, and xenobiotic ligands that required less-than-micromolar concentrations to unearth which receptors might mediate their signaling.” https://lnkd.in/dXjCCgQ View in LinkedIn

OLD BRUTE FORCE METHODS. “In comparison, the classic endocrinology methods that led to the isolation of thyroid hormone in 1914 required 3.5 tons of bovine thyroid gland.” https://lnkd.in/dXjCCgQ View in LinkedIn

THE NEED TO ID PATHWAYS. Now that the nuclear receptor pathways and functions needed elucidating, new fast screening methods had to be developed, since old methods were very slow and laborious. View in LinkedIn

THE OUTLINES OF PATHWAYS. “That there were orphan receptors immediately suggested the existence of a host of previously unknown signaling pathways regulated by a myriad of undiscovered ligands.” https://lnkd.in/dXjCCgQ View in LinkedIn

CONSERVED AND LINEAGE-SPECIFIC. “Of further phylogenic significance, these orphan receptors were shown to be conserved throughout metazoan evolution, although it should be noted that nuclear receptors are absent in protozoans, fungi, and plants.” https://lnkd.in/dXjCCgQ View in LinkedIn

FUNCTIONS UNKNOWN. “Because the associated small-molecule ligands were unknown, they garnered the name “orphan” receptors.” https://lnkd.in/dXjCCgQ View in LinkedIn

OPPONENTS OF HUMAN AUGMENTATION are often quick to point out the dangers of military augmentation. While they have invested heavily in this technology and advanced the field, the downsides are obvious. Just as sex is supposed to have driven the internet, it could be said that the military applications drive augmentation. View in LinkedIn