Biochemistry of liver development in the perinatal period

Just before birth, changes occur in the metabolic capacities of rat liver so that the animal can adapt to changes in the substrate supply. In utero, glucose is the main energy-generating fuel and the liver metabolism is directed towards glucose degradation. The activities of the rate-limiting enzymes of glycolysis, hexokinase and phosphofructokinase, are high. In preparation for post-natal life, when the continuous glucose supply from the mother is interrupted, very large amounts of glycogen are stored in the late fetal liver. With the intake of the fat-rich and carbohydrate-poor milk diet, the animal develops the ability to synthesize glucose de novo from non-carbohydrate precursors. During suckling, metabolic energy is derived mainly from the beta-oxidation of fatty acids, which in turn is an essential prerequisite for the high rate of gluconeogenesis, by yielding acetyl-CoA for the activation of pyruvate carboxylase and by generating a high NADH/NAD ratio for the shift of the glyceraldehyde 3-phosphate dehydrogenase reaction in the direction of glucose formation.--The developmental adaptation of metabolism and the process of enzymatic differentiation are closely connected with the maturation of the endocrine system and the changes in the concentration of circulating hormones. The neonatal regulation of phosphoenolpyruvate carboxykinase and of tyrosine aminotransferase by variations in the hormonal milieu around birth, and also the interaction of hormonal and nutritional factors in the induction of serine dehydratase and glucokinase at the end of the suckling period, will be discussed in detail.     

Agreement in endpoints from circadian rhythmometry on healthy human beings living on different continents

Zusammenfassung Circadiane Akrophasen — Gipfel der ungefähren 24-h-Periodik — von Blut- und Harnkortikosteroiden, Kalium im Harn, Körpertemperatur, Pulsrate und 2-min-Schätzung wurden mittels elektronischer Anpassung einer Kosinusfunktion vermöge der Methode der kleinsten Quadrate bestimmt. Solche Charakteristika circadianer Rhythmen empfehlen sich als Referenzstandarde dem Mediziner und Biologen durch ihre zufriedenstellende übereinstimmung in Daten von Untersuchungen auf verschiedenen Kontinenten mit zum Teil unterschiedlichen Methoden.     

The modular nature of apoptotic signaling proteins

Apoptosis, initiated by a variety of stimuli, is a physiological process that engages a well-ordered signaling cascade, eventually leading to the controlled death of the cell. The most extensively studied apoptotic stimulus is the binding of death receptors related to CD95 (Fas/Apo1) by their respective ligands. During the last years, a considerable number of proteins have been identified which act together in the receptor-proximal part of the signaling pathway. Based on localized regions of sequence similarity, it has been predicted that these proteins consist of several independently folding domains. In several cases these predictions have been confirmed by structural studies; in other cases they are at least supported by experimental data. This review focuses on the three most widespread domain families found in the apoptotic signaling proteins: the death domain, the death effector domain and the caspase recruitment domain. The recently discovered analogies between these domains, both in structure and in function, have shed some light on the overall architecture of the pathway leading from death receptor ligation to the activation of caspases and eventually to the apoptotic phenotype. Received 8 October 1998; received after revision 8 January 1999; accepted 8 January 1999     

Frequent pathway mutations of splicing machinery in myelodysplasia

Myelodysplastic syndromes and related disorders (myelodysplasia) are a heterogeneous group of myeloid neoplasms showing deregulated blood cell production with evidence of myeloid dysplasia and a predisposition to acute myeloid leukaemia, whose pathogenesis is only incompletely understood. Here we report whole-exome sequencing of 29 myelodysplasia specimens, which unexpectedly revealed novel pathway mutations involving multiple components of the RNA splicing machinery, including U2AF35, ZRSR2, SRSF2 and SF3B1. In a large series analysis, these splicing pathway mutations were frequent (～45 to ～85%) in, and highly specific to, myeloid neoplasms showing features of myelodysplasia. Conspicuously, most of the mutations, which occurred in a mutually exclusive manner, affected genes involved in the 3'-splice site recognition during pre-mRNA processing, inducing abnormal RNA splicing and compromised haematopoiesis. Our results provide the first evidence indicating that genetic alterations of the major splicing components could be involved in human pathogenesis, also implicating a novel therapeutic possibility for myelodysplasia.     

Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity

The endoplasmic reticulum (ER) is the main site of protein and lipid synthesis, membrane biogenesis, xenobiotic detoxification and cellular calcium storage, and perturbation of ER homeostasis leads to stress and the activation of the unfolded protein response. Chronic activation of ER stress has been shown to have an important role in the development of insulin resistance and diabetes in obesity. However, the mechanisms that lead to chronic ER stress in a metabolic context in general, and in obesity in particular, are not understood. Here we comparatively examined the proteomic and lipidomic landscape of hepatic ER purified from lean and obese mice to explore the mechanisms of chronic ER stress in obesity. We found suppression of protein but stimulation of lipid synthesis in the obese ER without significant alterations in chaperone content. Alterations in ER fatty acid and lipid composition result in the inhibition of sarco/endoplasmic reticulum calcium ATPase (SERCA) activity and ER stress. Correcting the obesity-induced alteration of ER phospholipid composition or hepatic Serca overexpression in vivo both reduced chronic ER stress and improved glucose homeostasis. Hence, we established that abnormal lipid and calcium metabolism are important contributors to hepatic ER stress in obesity.     

Konstitutionsaufklärung und Synthese von Psilocybin

Summary The structure of Psilocybin, the psychotropic active principle of the Mexican mushroomPsilocybe mexicana Heim, has been elucidated. Psilocybin is the phosphoric acid ester of 4-hydroxy-dimethyltryptamine. This structure was confirmed by total synthesis.     

Psilocybin,ein psychotroper Wirkstoff aus dem mexikanischen RauschpilzPsilocybe mexicana Heim

Summary The active principle ofPsilocybe mexicana Heim, a mexican mushroom with hallucinogenic properties, has been isolated in crystalline form. The compound has been given the namePsilocybin; it possesses indole characteristics and contains phosphorus. A second substance, closely related toPsilocybin but found only in traces, has been calledPsilocin.     

Coupled major and trace elements as indicators of the extent of melting in mid-ocean-ridge peridotites

Rocks in the Earth's uppermost sub-oceanic mantle, known as abyssal peridotites, have lost variable but generally large amounts of basaltic melt, which subsequently forms the oceanic crust. This process preferentially removes from the peridotite some major constituents such as aluminium, as well as trace elements that are incompatible in mantle minerals (that is, prefer to enter the basaltic melt), such as the rare-earth elements. A quantitative understanding of this important differentiation process has been hampered by the lack of correlation generally observed between major- and trace-element depletions in such peridotites. Here we show that the heavy rare-earth elements in abyssal clinopyroxenes that are moderately incompatible are highly correlated with the Cr/(Cr + Al) ratios of coexisting spinels. This correlation deteriorates only for the most highly incompatible elements-probably owing to late metasomatic processes. Using electron- and ion-microprobe data from residual abyssal peridotites collected on the central Indian ridge, along with previously published data, we develop a quantitative melting indicator for mantle residues. This procedure should prove useful for relating partial melting in peridotites to geodynamic variables such as spreading rate and mantle temperature.     

Melanopsin and rod-cone photoreceptive systems account for all major accessory visual functions in mice

In the mammalian retina, besides the conventional rod-cone system, a melanopsin-associated photoreceptive system exists that conveys photic information for accessory visual functions such as pupillary light reflex and circadian photo-entrainment. On ablation of the melanopsin gene, retinal ganglion cells that normally express melanopsin are no longer intrinsically photosensitive. Furthermore, pupil reflex, light-induced phase delays of the circadian clock and period lengthening of the circadian rhythm in constant light are all partially impaired. Here, we investigated whether additional photoreceptive systems participate in these responses. Using mice lacking rods and cones, we measured the action spectrum for phase-shifting the circadian rhythm of locomotor behaviour. This spectrum matches that for the pupillary light reflex in mice of the same genotype, and that for the intrinsic photosensitivity of the melanopsin-expressing retinal ganglion cells. We have also generated mice lacking melanopsin coupled with disabled rod and cone phototransduction mechanisms. These animals have an intact retina but fail to show any significant pupil reflex, to entrain to light/dark cycles, and to show any masking response to light. Thus, the rod-cone and melanopsin systems together seem to provide all of the photic input for these accessory visual functions.