Action and interaction of two alpha 1-adrenoceptor agonists, methoxamine and St 587, on the rabbit's blood pressure and EEG

In rabbits methoxamine reversed the vasopressor effect of St 587 and abolished the EEG synchronizing action of St 587. The interaction on the blood pressure could be ascribed either to the different chemical structures of St 587 and methoxamine or to partial agonistic properties of St 587. The interaction on the EEG appears to be more complex.     

Vitamin D receptors in heart: Effects on atrial natiuretic factor

We report that receptors for vitamin D exist in distinct regions of the heart in female and male mice, predominantly in the right atrium where most of the cardial atrial natriuretic peptide (ANF) is produced. Tritiated 1,25-dihydroxyvitamin D₃ (1,25-D₃, vitamin D, soltriol) and ANF are colocalized in nuclei and cytoplasm respectively in identical cardiomyocytes. Changes of ANF tissue and blood levels under dietary deficiency and treatment with 1,25-D₃ suggest direct genomic actions of vitamin D on myoendocrine cells of the atrium for the regulation of ANF manufacture and secretion. These results were obtained by combining thaw-mount autoradiography with immunocytochemistry using tritiated 1,25-D₃ and an antibody against rat ANF. This antibody was also used in a radioimmunoassay to determine atrial natriuretic factor in plasma, atria and ventricles of normal or vitamin D-deficient mice.     

Cellular localization of androgen in the brain and pituitary after the injection of tritiated testosterone

Zusammenfassung Nach Injektion von³H-Testosteron wurde mit Hilfe der Trocken-Autoradiographie eine selektive Aufnahme und Speicherung von Radioaktivität in Kernen spezifischer Neurone im Hypothalamus, in der präoptisch-parolfaktorischen Region, im Septum, im Hippokampus und in der Amygdala beobachtet. Im Hypophysenvorderlappen war Radioaktivität in den Zellkernen von Basophilen nachweisbar. Die autoradiographischen Ergebnisse unterstützen das Konzept eines doppelten Androgen-Feedbacks auf der Ebene des Zentralnervensystems und der Hypophyse.

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We thank Mrs.Gerda Michalsky and Mrs.Anu Turnbull for their technical assistance. This study was supported by PHS grant No. AM1 929 to W.E.S. and a grant from the Rockefeller Foundation to the Laboratories for Reproductive Biology, Chapel Hill, North Carolina.     

The translational landscape of mTOR signalling steers cancer initiation and metastasis

The mammalian target of rapamycin (mTOR) kinase is a master regulator of protein synthesis that couples nutrient sensing to cell growth and cancer. However, the downstream translationally regulated nodes of gene expression that may direct cancer development are poorly characterized. Using ribosome profiling, we uncover specialized translation of the prostate cancer genome by oncogenic mTOR signalling, revealing a remarkably specific repertoire of genes involved in cell proliferation, metabolism and invasion. We extend these findings by functionally characterizing a class of translationally controlled pro-invasion messenger RNAs that we show direct prostate cancer invasion and metastasis downstream of oncogenic mTOR signalling. Furthermore, we develop a clinically relevant ATP site inhibitor of mTOR, INK128, which reprograms this gene expression signature with therapeutic benefit for prostate cancer metastasis, for which there is presently no cure. Together, these findings extend our understanding of how the 'cancerous' translation machinery steers specific cancer cell behaviours, including metastasis, and may be therapeutically targeted.     

Mitochondrial DNA replication and disease: insights from DNA polymerase γ mutations

DNA polymerase γ (pol γ), encoded by POLG, is responsible for replicating human mitochondrial DNA. About 150 mutations in the human POLG have been identified in patients with mitochondrial diseases such as Alpers syndrome, progressive external ophthalmoplegia, and ataxia-neuropathy syndromes. Because many of the mutations are described in single citations with no genotypic family history, it is important to ascertain which mutations cause or contribute to mitochondrial disease. The vast majority of data about POLG mutations has been generated from biochemical characterizations of recombinant pol γ. However, recently, the study of mitochondrial dysfunction in Saccharomyces cerevisiae and mouse models provides important in vivo evidence for the role of POLG mutations in disease. Also, the published 3D-structure of the human pol γ assists in explaining some of the biochemical and genetic properties of the mutants. This review summarizes the current evidence that identifies and explains disease-causing POLG mutations.     

Ecdysteroid receptors in the neuroendocrine-endocrine axis of a moth

With a combination of thaw-mount autoradiography using a tritiated 20-hydroxyecdysone agonist, ponasterone A, and immunocytochemistry with a monoclonal antibody to 29 K-prothoracicotropic hormone, high affinity binding sites for ecdysteroids were identified in the tissues of the neuroendocrine-endocrine axis inManduca sexta larvae. At specific times during larval-pupal development in fifth stadium larvae, nuclear ecdysteroid binding sites were present in the cerebral prothoracicotropes, the corpora allata and prothoracic glands, the main axis for the regulation and production of ecdysteroids. A stage-specific appearance of ecdysteroid receptors also occurred in cells of fat body, midgut and Malpighian tubules, tissues which convert ecdysone into 20-hydroxyecdysone. Our data identify new target tissues for ecdysteroids and suggest that ecdysteroids could affect their own production at the genomic level via long and short feedback loops.     

Vitamin D receptors in heart: effects on atrial natriuretic factor.

We report that receptors for vitamin D exist in distinct regions of the heart in female and male mice, predominantly in the right atrium where most of the cardial atrial natriuretic peptide (ANF) is produced. Tritiated 1,25-dihydroxyvitamin D3 (1,25-D3, vitamin D, soltriol) and ANF are colocalized in nuclei and cytoplasm respectively in identical cardiomyocytes. Changes of ANF tissue and blood levels under dietary deficiency and treatment with 1,25-D3 suggest direct genomic actions of vitamin D on myoendocrine cells of the atrium for the regulation of ANF manufacture and secretion. These results were obtained by combining thaw-mount autoradiography with immunocytochemistry using tritiated 1,25-D3 and an antibody against rat ANF. This antibody was also used in a radioimmunoassay to determine atrial natriuretic factor in plasma, atria and ventricles of normal or vitamin D-deficient mice.