ROS,autophagy, mitochondria and cancer: Ras,the hidden master?

Recent advances have highlighted the complex web of biological mechanisms and pathways involved in oncogenic transformation and maintenance of the cancer phenotype. To that end, a number of key factors have been identified and thoroughly investigated over the past couple of decades, such as redox regulation of cell fate decisions, cellular metabolism and bioenergetics, autophagy induction as a survival signal, and how these pathways interplay with oncogene-induced transformation. This has been particularly well documented for oncoprotein Ras-induced carcinogenesis, and recent reports provide ample evidence to indicate a well-coordinated crosstalk between these diverse cellular pathways in the process of cancer initiation and progression. Here we provide a brief summary of the recent advances in the field to illustrate the dual role of autophagy as a tumor suppressor and as a survival mechanism required for cancer maintenance as well as its implication in the complex relationship between Ras-mediated carcinogenesis, mitochondrial metabolism, cellular redox status and bioenergetics.     

The “polarizing inducer” in hydra: A reexamination of its properties and its origin

Summary In order to prove the gradient hypothesis an attempt was made to isolate and accumulate the polarizing inducer present in homogenates of hydra and assumed to be a neurosecretory product. By means of gel chromatography two fractions were obtained which brought about the development of supernumary apical structures (tentacles and hypostomes) thus exhibiting the symptoms attributed to this polarizing agent: a low molecular fraction with only modest effectiveness and a main fraction with strong animalizing ability. Increasing the concentration affected only the quantity but not the qualitative properties of the structures produced, a result inconsistent with the postulate of the gradient hypothesis. By analysing the chemical and biological nature of the main agent and by applying pure isolated toxins compelling evidence is given that the inducer in question is nothing but a component of the nematocyst toxins. This component, being heat-stable and trypsin-sensitive, elicites its animalizing effect in unspecific means by disturbing the normal pattern of morphallactic events. A side effect with interest in respect of graded tissue properties could be recorded: by the influence of the relevant toxin, growing together of regenerating animals occurs whereby predominantly apical primordia fuse with apical primordia, thus forming stable parabioses. This observation may indicate the significance of surface bound, contact establishing components in polar differentiation.

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Zusammenfassung Zur Prüfung der entwicklungsphysiologischen Gradiententheorie wird der Versuch unternommen, den polarisierenden Induktor zu isolieren und anzureichern, der in Homogenaten von Hydra zugegen ist und als neurosekretorisches Produkt angesehen wird. Die Gelchromatographie wäßriger Extrakte liefert 2 Fraktionen, welche die Entwicklung überzähliger apikaler Strukturen (Tentakel und Mundkegel) hervorrufen: eine niedermolekulare Fraktion mit nur mäßiger Wirksamkeit und eine Hauptfraktion im mittelmolekularen Bereich mit starker animalisierender Kapazität. Entgegen dem Postulat der Gradiententheorie besteht keine Korrelation zwischen der applizierten Konzentration und der Qualität ausgelöster Formbildungen. Nur die Anzahl überzähliger Strukturen ist dosisabhängig. Die Analyse der biologischen und chemischen Eigenschaften der Hauptfraktion bringt den Hinweis, daß das polarisierende Agens eine Hitze-stabile, Trypsin-sensitive Komponenteder Nesselgifte ist, die ihre animalisierende Wirkung in unspezifischer Weise zeitigt. Die Applikation isolierter, reiner Nesselgifte erhärtet diese Vermutung zum klaren Beweis. Ein Nebeneffekt des relevanten Gifts legt graduierte Gewebseigenschaften offen: Unter seinem Einfluß verwachsen die Testpolypen, sowie sie in Kontakt zueinander kommen. Hierbei verbinden sich vorzugsweise apikale Primordien mit apikalen Primordien, um stabile Parabiosen zu bilden. Diese Beobachtung mag die Bedeutung Kontakt-vermittelnder Oberflächenstrukturen für das polare Differenzierungsgeschehen anzeigen.

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Supported by Deutsche Forschungsgemeinschaft.     

The connections of Wnt pathway components with cell cycle and centrosome: side effects or a hidden logic?

Wnt signaling cascade has developed together with multicellularity to orchestrate the development and homeostasis of complex structures. Wnt pathway components – such as β-catenin, Dishevelled (DVL), Lrp6, and Axin-- are often dedicated proteins that emerged in evolution together with the Wnt signaling cascade and are believed to function primarily in the Wnt cascade. It is interesting to see that in recent literature many of these proteins are connected with cellular functions that are more ancient and not limited to multicellular organisms – such as cell cycle regulation, centrosome biology, or cell division. In this review, we summarize the recent literature describing this crosstalk. Specifically, we attempt to find the answers to the following questions: Is the response to Wnt ligands regulated by the cell cycle? Is the centrosome and/or cilium required to activate the Wnt pathway? How do Wnt pathway components regulate the centrosomal cycle and cilia formation and function? We critically review the evidence that describes how these connections are regulated and how they help to integrate cell-to-cell communication with the cell and the centrosomal cycle in order to achieve a fine-tuned, physiological response.     

Adélie penguin parental activities and reproduction: effects of device size and timing of its attachment during chick rearing period

Summary Effects of device attachment on parental activities and body mass change in instrumented birds and their mates, and on chick growth and survival, were studied in Adélie Penguins Pygoscelis adeliae in Lützow-Holm Bay, Antarclica. Penguins on which small devices were fitted with rubber band harnesses exhibited increased foraging trip duration, and decreased body mass, food delivery rate, chick growth and chick survival. Their mates did not increase food delivery rate. Those on which small or large devices were fitted with epoxy glue did not change foraging trip duration, body mass, or chick survival. However, large devices decreased chick growth. These effects were more obvious; among penguins fitted with devices later in the chick rearing period, and suggest that: 1) parents fitted with devices give a priority to maintenance of their own energy reserve over guarding and food delivery for chicks; and, 2) parents' decreasing energy reserves later in the breeding season might intensify the effects of devices.     

“Stable” effects of insulin and isoproterenol on adipocyte pyruvate dehydrogenase

Insulin, at a concentration of 1 mU/ml, stimulated glycogen synthase and pyruvate dehydrogenase about threefold in isolated rat adipocytes. Upon the removal of insulin, glycogen synthase activity remained in the activated state for 10 min and thereafter rapidly returned to basal level. On the other hand, insulin-stimulated pyruvate dehydrogenase activity remained elevated for at least 30 min. Isoproterenol (10⁻⁸m) stimulated phosphorylase and inhibited pyruvate dehydrogenase through the activation of β-adrenergic receptors. Addition of the β-antagonist, propranolol (10⁻⁵m), after isoproterenol reversed the action of isoproterenol on phosphorylase but not its action on pyruvate dehydrogenase. Dibutyryl cyclic AMP, when added to intact adipocytes, produced an effect on pyruvate dehydrogenase similar to that induced by isoproterenol. Our results indicate that both insulin and the β-agonist have a unique action on pyruvate dehydrogenase which is different from their effects on other enzymes such as glycogen synthase and phosphorylase.     

The effects of “Cell age” upon the lethal effects of physical and chemical mutagens in the yeast, Saccharomyces cerevisiae

Summary SummaryYeast cultures progressing from the exponential to the stationary phase of growth showed changes in cell sensitivity to physical agents such as UV light, heat shock at 52° C and the chemical mutagens ethyl methane sulphonate, nitrous acid and mitomycin C.Exponential phase cells showed maximum resistance to UV light and minimum resistance to heat shock and the three chemicals. The increased resistance of exponential phase cells to UV light was shown to be dependent upon the functional integrity of the RAD ₅₀ gene.Treatment of growing yeast cultures with radioactively labelled ethyl methane sulphonate indicated the preferential uptake of radioactivity during the sensitive exponential stage of growth. The results indicated that the differential uptake of the chemical mutagens was responsible for at least a fraction of the variations in cell sensitivity observed in yeast cultures at different phases of growth.     

In-depth exploration of Hevea brasiliensis latex proteome and “hidden allergens” via combinatorial peptide ligand libraries

The proteome of Hevea brasiliensis latex has been explored in depth via combinatorial peptide ligand libraries. A total of 300 unique gene products have been identified in this latex, whose proteome has been largely unknown up to the present. In search for unknown allergens, control latex and eluates from the ligand libraries have been fractionated by two-dimensional mapping, blotted and confronted with sera of 18 patients. In addition to the already known and named Hevea major allergens, we have unambiguously detected several others like, for instance: heat shock protein (81 kDa), proteasome subunit (30 kDa), protease inhibitor (8 kDa), hevamine A (43 kDa) and glyceraldehyde-3-phosphate dehydrogenase (37 kDa). Gene Ontology analysis of analyzed fractions has shown that major functions are substantially unchanged after sample treatment, while novel biological functions appeared that were undetectable in the crude sample.     

Who supports redistribution? Replicating and refining effects of compassion,malicious envy,and self-interest

Debate over wealth redistribution plays a prominent role in society, but the causes of differences in support for redistribution remain contested. A recent three-person two-situation model suggests these differences are shaped by evolved motivational systems of self-interest, compassion, and dispositional envy. We conducted a close replication testing this prediction, all subjects were British, recruited from an online subject pool. Study 1 (N = 206) confirmed the roles of self-interest (β = 0.20) and compassion for others (β = 0.37), as well as a predicted null effect of procedural fairness. Dispositional envy was non-significant (β = 0.06). In study 2 (N = 304), we tested whether it was better to conceptualize envy as being two separate emotions, benign envy and malicious envy. A significant effect of malicious envy was found (β = 0.13) and no significant effect of benign envy (β = ?0.06). Study 3 (N = 501) closely replicated this improved model, confirming significant effects of compassion (β = 0.40), self-interest (β = 0.21), and malicious envy (β = 0.15), accounting for one third of variance in support for redistribution. These results support the role of evolved motivational systems to explain and improve important aspects of contemporary economic redistribution.     

Information, evolution and “error-friendliness”

Information can be conceived as being composed of two complementary components: novelty and confirmation. Whenever either of the two is zero, information is zero. Genetic information too requires both novelty and confirmation. Evolution can be seen as the history of diversification. Selection alone reduces diversity. Recessivity appears to serve as a mechanism to protect diversity against selection. So does the geographical and behavioural “separation” of species. Both recessivity and separation can be seen as “error-friendly”, a broader concept that is supportive of diversity, learning and further evolution. The principle should also be obeyed in technological systems. Received: 4 October 1997 / Accepted in revised form: 26 August 1998     

Working on Sundays–effects on safety, health, and work-life balance

Several attributes of the work schedule can increase the risk of occupational injuries and accidents, health impairments, and reduced social participation. Although previous studies mainly focused on the effects of shiftwork and long working hours on employee health and safety, there is little evidence of a potential negative impact of working Sundays on the incidence of occupational accidents, health impairments, and work-life balance. A representative sample of employed workers in 31 member and associated states of the European Union (n?=?23,934) served as the database for a cross-sectional analysis. The sample was collected via face-to-face interviews in the year 2005. The association of the risks of occupational accidents, health impairments, and decreases in work-life balance with working Sundays was calculated using logistic regression models, controlling for potential confounders, such as shiftwork, workload, and demographic characteristics. The results indicated that working one or more Sundays/month was associated with increase both in the risk of reporting one or more health impairments (odds ratio [OR]: 1.17, 95% confidence interval [CI]: 1.06-1.29) and poorer work-life balance (OR: 1.15, 95% CI: 1.02-1.28). These effects remained after controlling for potentially confounding factors, such as other work schedule attributes, intensity of physical and mental workload, and individual characteristics. Furthermore, working Sundays was also related to increased risk of occupational accidents within the last year (OR: 1.34, 95% CI: 1.03-1.73). Controlling again for individual, workload, and working-time characteristics, a significant association with accident risk, however, remained only in work sectors with low a priori risk of occupational accidents (OR: 1.40, 95% CI: 1.02-1.91), although the increased risk could be observed for both medium and high a priori risk sectors working Sundays (without controlling for additional confounders). The results thus indicate that the detrimental effects of working Sundays on safety, health, and social well-being should be taken into account when designing work schedules. The potential hazards to employees' safety, health, and work-life balance, in particular, should be considered in discussions concerning extending work on Sundays in certain sectors, e.g., retail.