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1.
Melatonin is a well-known, nighttime-produced indole found in bacteria, eukaryotic unicellulars, animals or vascular plants. In vertebrates, melatonin is the major product of the pineal gland, which accounts for its increase in serum during the dark phase, but it is also produced by many other organs and cell types. Such a wide distribution is consistent with its multiple and well-described functions which include from the circadian regulation and adaptation to seasonal variations to immunomodulatory and oncostatic actions in different types of tumors. The discovery of its antioxidant properties in the early 1990s opened a new field of potential protective functions in multiple tissues. A special mention should be made regarding the nervous system, where the indole is considered a major neuroprotector. Furthermore, mitochondria appear as one of the most important targets for the indole’s protective actions. Melatonin’s mechanisms of action vary from the direct molecular interaction with free radicals (free radical scavenger) to the binding to membrane (MLT1A and MLT1B) or nuclear receptors (RZR/RORα). Receptor binding has been associated with some, but not all of the indole functions reported to date. Recently, two new mechanisms of cellular uptake involving the facilitative glucose transporters GLUT/SLC2A and the proton-driven oligopeptide transporter PEPT1/2 have been reported. Here we discuss the potential importance that these newly discovered transport systems could have in determining the actions of melatonin, particularly in the mitochondria. We also argue the relative importance of passive diffusion vs active transport in different parts of the cell.  相似文献   
2.
A common intuition about evidence is that if data x have been used to construct a hypothesis H, then x should not be used again in support of H. It is no surprise that x fits H, if H was deliberately constructed to accord with x. The question of when and why we should avoid such “double-counting” continues to be debated in philosophy and statistics. It arises as a prohibition against data mining, hunting for significance, tuning on the signal, and ad hoc hypotheses, and as a preference for predesignated hypotheses and “surprising” predictions. I have argued that it is the severity or probativeness of the test—or lack of it—that should determine whether a double-use of data is admissible. I examine a number of surprising ambiguities and unexpected facts that continue to bedevil this debate.  相似文献   
3.
Sigal A  Kim JT  Balazs AB  Dekel E  Mayo A  Milo R  Baltimore D 《Nature》2011,477(7362):95-98
Latency and ongoing replication have both been proposed to explain the drug-insensitive human immunodeficiency virus (HIV) reservoir maintained during antiretroviral therapy. Here we explore a novel mechanism for ongoing HIV replication in the face of antiretroviral drugs. We propose a model whereby multiple infections per cell lead to reduced sensitivity to drugs without requiring drug-resistant mutations, and experimentally validate the model using multiple infections per cell by cell-free HIV in the presence of the drug tenofovir. We then examine the drug sensitivity of cell-to-cell spread of HIV, a mode of HIV transmission that can lead to multiple infection events per target cell. Infections originating from cell-free virus decrease strongly in the presence of antiretrovirals tenofovir and efavirenz whereas infections involving cell-to-cell spread are markedly less sensitive to the drugs. The reduction in sensitivity is sufficient to keep multiple rounds of infection from terminating in the presence of drugs. We examine replication from cell-to-cell spread in the presence of clinical drug concentrations using a stochastic infection model and find that replication is intermittent, without substantial accumulation of mutations. If cell-to-cell spread has the same properties in vivo, it may have adverse consequences for the immune system, lead to therapy failure in individuals with risk factors, and potentially contribute to viral persistence and hence be a barrier to curing HIV infection.  相似文献   
4.
The neurohumoral regulation of growth hormone secretion is mediated in part by two hypothalamic peptides that reach the anterior pituitary via the hypothalamo-hypophysial portal blood system. Somatostatin inhibits the release of growth hormone, whereas growth hormone-releasing factor (GRF) positively regulates both growth hormone synthesis and secretion. Two forms of human GRF, 40 and 44 amino acids long, have been characterized from extra-hypothalamic tumours as well as from the hypothalamus. Analysis of human GRF complementary DNA and genomic clones indicates that the GRF peptides are first synthesized as a 107- or 108-amino-acid precursor protein. To examine the physiological consequences of GRF expression, we have established strains of transgenic mice containing a fusion gene including the promoter/regulatory region of the mouse metallothionein-I (MT-I) gene and the coding region of the human GRF gene. We report that expression of the human GRF precursor protein in these animals results in measurable levels of human GRF and increased levels of mouse growth hormone in plasma and accelerated growth rates relative to control littermates. These results demonstrate a direct role for GRF in the positive regulation of somatic growth. Unexpectedly, female transgenic mice carrying the MT-GRF fusion gene are fertile, in contrast to female transgenic mice expressing human or rat growth hormone, which are generally infertile. These transgenic mouse strains should provide useful animal models for the study of several types of human growth disorders.  相似文献   
5.
Lipid peroxide content in hepatocytes isolated from ketotic diabetic rats was higher than normal, and the release of peroxide into the media was also elevated for the initial 18 h. Insulin suppressed both peroxide release and synthesis by cultured hepatocytes isolated from normal and from diabetic rats.  相似文献   
6.
Iron deficiency is usually attributed to chronic blood loss or inadequate dietary intake. Here, we show that iron deficiency anemia refractory to oral iron therapy can be caused by germline mutations in TMPRSS6, which encodes a type II transmembrane serine protease produced by the liver that regulates the expression of the systemic iron regulatory hormone hepcidin. These findings demonstrate that TMPRSS6 is essential for normal systemic iron homeostasis in humans.  相似文献   
7.
Summary Most studies of the evolution of clutch size have concentrated on changes in the mean and have neglected the variance of clutch size. We suggest that the variance is very important and discuss how it might be fruitfully analyzed.Acknowledgment. I thank the Royal Australasian Ornithologists Union and the North American Nest Record Card Program for access to records of shorebird reproductive performance and Dr P. A. Baghurst for considerable assistance.  相似文献   
8.
Zusammenfassung Theodoridis undStark 1 haben vorgeschlagen, dass der Informationsinhalt der Biosphäre ein objektives Kriterium des Evolutionsfortschritts schafft. In dieser Aufzeichnung prüfe ich diesen Informationsbegriff nach und schliesse daraus: 1. dass ein zuständiges Mass noch nicht vorhanden ist; 2. dass die Informationsbeweise in der genetischen Evolution irreführend sein mögen; und 3. dass wir vorerst die folgenden Parameter zu bestimmen und zu messen versuchen sollten: die Gesamtinformationen der Biosphär; die mindeste Obergrenze der Eingangsinformationen, die für jede besondere Lage der Biosphäre unentbehrlich ist; und die überholte Informationenmenge in dem Genom der einzelnen verschiedenen Spezies.  相似文献   
9.
Summary Lipid peroxide content in hepatocytes isolated from ketotic diabetic rats was higher than normal, and the release of peroxide into the media was also elevated for the initial 18 h. Insulin suppressed both peroxide release and synthesis by cultured hepatocytes isolated from normal and from diabetic rats.  相似文献   
10.
K E Mayo  G M Cerelli  M G Rosenfeld  R M Evans 《Nature》1985,314(6010):464-467
Growth hormone-releasing factor (GHRF) is a hypothalamic peptide which positively regulates the synthesis and secretion of growth hormone in the anterior pituitary. The amino-acid sequence of a 43-residue GHRF peptide isolated from rat hypothalamus was recently determined. Immunocytochemical techniques have been used to localize GHRF-containing cell bodies and nerve fibres largely to the medial-basal region of the rat hypothalamus. The rat has also been used extensively as an animal model to study the effects of GHRF on growth hormone synthesis and secretion and on somatic growth. To pursue questions concerning the biosynthesis of GHRF, the expression of the ghrf gene, and its regulation in the hypothalamus by neural and hormonal influences, we have now isolated and characterized both complementary DNA and genomic clones encoding rat hypothalamic GHRF. The rat ghrf gene spans nearly 10 kilobases (kb) of rat genomic DNA, contains 5 exons and encodes a 104-amino-acid precursor to the rat GHRF peptide. Comparison with previously characterized human ghrf cDNA and genomic clones has allowed patterns of conservation of amino-acid and nucleotide sequences between the human and rat GHRFs to be determined.  相似文献   
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