Chemical synthesis of a hexadecapeptide segment of ubiquitin that activates adenylate cyclase and induces lymphocytes to differentiate

Summary A hexadecapeptide corresponding to positions 59–74 of ubiquitin was synthesized and purified. The peptide was characterized by its mobility in TLC and electrophoresis, amino acid sequence and composition, and molar rotation. The peptide possessed approximately 40% activity compared with native ubiquitin in each of 3 biological assays in vitro: a) thymocyte induction, b) B cell induction and c) elevation of intracellular cyclic AMP levels in sarcoma 180 cells.Acknowledgments. We thank Dr Geoffrey Tregear for helpful suggestions for the synthesis strategy, Dr Jim Burton for guidance with the methods for establishing peptide purity, and Ronald King, Miriam Miller, Jeanette Dilley and Linda Townley for excellent technical assistance. This work was supported by U.S. Public Health Service Grants CA-08748, CA-16889, CA-08415, CA-17085 and AI-12487, and by NCI Contract CB-53868.     

Studies on the regional biosynthesis and metabolism of catecholamines in the central nervous system of the monkey

Zusammenfassung Nach intraventrikulärer Verabreichung von Tyrosin-C¹⁴ oder Dopamin-H³ wurden die Biosynthese und der Stoffwechsel des Katecholamins in verschiedenen Regionen des ZNS bei Affen (Cercopithecus sabaeus) untersucht. Die grössten Katecholaminmengen wurden aus Tyrosin-C¹⁴ im Nucleus caudatus gebildet. Ebenso ist dort, wie im Putamen, die Tyrosin-Hydroxylase-Aktivität am grössten. Die Bildung des Noradrenalins aus Dopamin konnte im Hypothalamus, Hirnstamm, sowie im Nucleus caudatus nachgewiesen werden. Die Verteilung des radioaktiven Dopamins entspricht nicht in allen Hirnregionen der Verteilung des endogenen Dopamins.

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Supported by P.H.S. Grants No. MH-02717, No. NB-5480 and No. NB-04257.     

Synthesis of the skeleton of the morphine molecule by mammalian liver

The possibility that morphine could be synthesized in animals has long been considered and a pathway in mammalian brain analogous to that in the opium poppy has been proposed. Substances have been detected in mammalian brain that are recognized by antisera raised against morphine. Recently we reported the presence of three such immunoreactive substances in bovine hypothalamus and adrenal, and in rat brain, and the definitive identification of two of them by gas chromatography-mass spectrometry as morphine and codeine. Incorporation of a labelled precursor has demonstrated the biosynthesis of morphine in the opium poppy from tyrosine-derived units (see Fig. 1). Intramolecular coupling of reticuline to form salutaridine is the critical step that generates the morphine skeleton (morphinan) and the stereochemistry of the morphinan series. We now report the conversion in vivo and in vitro of reticuline to salutaridine by rat liver, but this conversion is not detectable in rat brain and bovine adrenal. This is the first direct demonstration of the synthesis of a morphinan in an animal tissue and also supports the hypothesis that morphine and codeine in brain and adrenal are of endogenous origin.     

The relative metabolic rates of norepinephrine-7-H3 and epinephrine-1-C14

Zusammenfassung Ratten wurden gleichzeitig mit Noradrenalin-H³ und Adrenalin-C¹⁴ belastet und die Ausscheidung im Harn verfolgt. Die Analyse der Metabolite hat unter anderem ergeben, dass Noradrenalin-H³ zu Adrenalin-H³ verwandelt wird, und dass diese Reaktion irreversibel ist. Dasin vivo synthetisierte Adrenalin-H³ wird in geringerem Masse inaktiviert als das injizierte Adrenalin-C¹⁴. Ein neutrales Stoffwechselprodukt (wahrscheinlich ein Alkohhol) wurde aus dem Harn isoliert.     

Biological actions of estradiol-17β after prolonged ovarian hormonal deficits

Riassunto Si dimostra che l'utero di ratta, sottoposta ad ablazione della ovaie 15 mesi e mezzo prima, risponde nettamente a tre iniezioni sottocutanee quotidiane di 17-estradiolo: si ottennero aumenti di peso del 92, 207 e 231% al di sopra del peso degli uteri di controlli sottoposti ad ovariectomia e trattati con semplice olio di sesamo. Si conclude, percio, che l'utero di ratta esposta a deficienza ormonica ovarica di lunga durata è notevolmente sensibile a trattamento con estrogeni.     

Mutations in SUFU predispose to medulloblastoma

Enchondromas are common benign cartilage tumors of bone. They can occur as solitary lesions or as multiple lesions in enchondromatosis (Ollier and Maffucci diseases). Clinical problems caused by enchondromas include skeletal deformity and the potential for malignant change to chondrosarcoma. The extent of skeletal involvement is variable in enchondromatosis and may include dysplasia that is not directly attributable to enchondromas. Enchondromatosis is rare, obvious inheritance of the condition is unusual and no candidate loci have been identified. Enchondromas are usually in close proximity to, or in continuity with, growth-plate cartilage. Consequently, they may result from abnormal regulation of proliferation and terminal differentiation of chondrocytes in the adjoining growth plate. In normal growth plates, differentiation of proliferative chondrocytes to post-mitotic hypertrophic chondrocytes is regulated in part by a tightly coupled signaling relay involving parathyroid hormone related protein (PTHrP) and Indian hedgehog (IHH). PTHrP delays the hypertrophic differentiation of proliferating chondrocytes, whereas IHH promotes chondrocyte proliferation. We identified a mutant PTH/PTHrP type I receptor (PTHR1) in human enchondromatosis that signals abnormally in vitro and causes enchondroma-like lesions in transgenic mice. The mutant receptor constitutively activates Hedgehog signaling, and excessive Hedgehog signaling is sufficient to cause formation of enchondroma-like lesions.     

Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors

Autoreactive B cells are present in the lymphoid tissues of healthy individuals, but typically remain quiescent. When this homeostasis is perturbed, the formation of self-reactive antibodies can have serious pathological consequences. B cells expressing an antigen receptor specific for self-immunoglobulin-gamma (IgG) make a class of autoantibodies known as rheumatoid factor (RF). Here we show that effective activation of RF+ B cells is mediated by IgG2a-chromatin immune complexes and requires the synergistic engagement of the antigen receptor and a member of the MyD88-dependent Toll-like receptor (TLR) family. Inhibitor studies implicate TLR9. These data establish a critical link between the innate and adaptive immune systems in the development of systemic autoimmune disease and explain the preponderance of autoantibodies reactive with nucleic acid-protein particles. The unique features of this dual-engagement pathway should facilitate the development of therapies that specifically target autoreactive B cells.     

The effect of tilting ultrathin sections on the image of the Z-disc of skeletal muscle

Résumé A l'aide du microscope électronique muni d'un goniomètre, la structure tri-dimensionelle du disque Z de la fibre musculaire striée a été analysée. Les résultats obtenus sont comparés avec un modèle construit en perspex et avec les images conventionnelles du disque Z.

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Acknowledgment. We wish to thank Pye Unicam (Philips) an Jeol (U. K.) Ltd. for kindly allowing us to use their electron microscopes. Technical assistance from Messrs.H. Fisher, J. Manston andR. Birchenough is gratefully acknowledged.     

Patterns of neuroglial proliferation in spinal cord white matter following exposure to ionizing radiation

Summary X-irradiation temporarily decreases the proliferative activity of neuroglia in immature rat spinal cord. Later, the proliferative activity in these irradiated regions surpasses that noted in control rats. Areas adjacent to the irradiated region have a greater than normal percentage of labelled neuroglia and may also be a source for neuroglia which re-populate the irradiated zone.Acknowledgments. Sincere thanks to Ms Jane Leiting for her assistance in doing the cell counts and to Mr Napoleon Phillips for preparing the autoradiographs. Supported by USPHS grant NS 04761.