Some remarks on the compatibility between determinism and unpredictability

Determinism and unpredictability are compatible since deterministic flows can produce, if sensitive to initial conditions, unpredictable behaviors. Within this perspective, the notion of scenario to chaos transition offers a new form of predictability for the behavior of sensitive to initial condition systems under the variation of a control parameter. In this paper I first shed light on the genesis of this notion, based on a dynamical systems approach and on considerations of structural stability. I then suggest a link to the figure of epigenetic landscape, partially inspired by a dynamical systems perspective, and offering a theoretical framework to apprehend developmental noise.     

The relationship between changes in the cell wall, lipid peroxidation, proliferation, senescence and cell death

Plants and mammals contain polyunsaturated fatty acids (PUFAs) in their membranes. PUFAs belong to the most oxygen sensitive molecules encountered in nature. It would seem that nature has selected this property of PUFAs for signalling purposes: PUFAs are stored in the surface of cells and organelles not in free form but conjugated to phospho‐ and galactolipids. Any change in membrane structure apparently activates membrane‐bound phospholipases, which cleave the conjugates. The obtained free PUFAs are substrates for lipoxygenases (LOX). These transform PUFAs to lipidhydroperoxides (LOOHs). LOOHs are converted to a great variety of secondary products. These lipid‐peroxidation (LPO) products and the resulting generated products thereof represent biological signals, which do not require a preceding activation of genes. They are produced as a non‐specific response to a large variety of external or internal impacts, which therefore do not need interaction with specific receptors. When, due to an external impact, e.g. attack of a microorganism, or to a change in temperature, the amount of liberated free PUFAs exceeds a certain threshold, LOX commit suicide. Thus iron ions, located in the active centre of LOX, are liberated. Iron ions react with LOOHs in the close surroundings by generating alkoxy radicals (LO.). These induce a non‐enzymatic LPO. A fraction of the LO. radicals generated from linoleic acid (LPO products derived from linoleic acid play a dominant role in signalling which was previously overlooked) is converted to 2,4‐dienals which induce the programmed cell death (PCD) and the hypersensitive reaction (HR). While peroxyl radicals (LOO.) generated as intermediates in the course of an enzymatic LPO are transformed within the enzyme complex to corresponding anions (LOO^–), and thus lose their reactivity, peroxyl radicals generated in non‐enzymatic reactions are not deactivated. They not only react by abstraction of hydrogen atoms from activated X‐H bonds of molecules in their close vicinity, but also by epoxidation of double bonds and oxidation of a variety of biological molecules, causing a dramatic change in molecular structure which finally leads to cell death. As long as reducing agents, like glutathione, or compounds with free phenolic groups are available, the amount of LOOHs is kept low. Cell death is induced in a defined way by apoptosis. But when the reducing agents have been consumed, PCD seems to switch to necrotic processes. Thus proliferation is induced by minor changes at the cell membrane, while slow changes at cell membranes are linked with apoptosis (e.g. response to attack of microorganisms or drought) and necrosis (severe wounding), depending only on the amount, but not on the type, of applied stimulus.     

AMBRA1 and BECLIN 1 interplay in the crosstalk between autophagy and cell proliferation

Autophagy-promoting proteins and stimuli are often associated with inhibition of cell proliferation; in this context, we recently described a key role for the pro-autophagic protein AMBRA1. Indeed, AMBRA1, through its direct interaction with the protein phosphatase PP2A, tightly regulates the stability of the oncoprotein and pro-mitotic factor c-Myc. Moreover, the AMBRA1-mediated regulation of c-Myc affects both cell proliferation rate and tumorigenesis. Interestingly, AMBRA1/PP2A activity is under the control of the master regulator of autophagy and cell growth, the protein kinase mTOR. Besides the mechanistic details of this regulation pathway which we dissected previously, any possible interplay(s) between AMBRA1 and its interactor BECLIN 1 was not investigated in this scenario. Here we show that both AMBRA1 and BECLIN 1 affect c-Myc regulation, but through two different pathways. Nevertheless, these two pro-autophagic proteins are, together with PP2A, in the same macromolecular complex, whose functional significance of which will be addressed in future studies.     

Some remarks on the movement of chromosomes during cell division

The possibility of drawing conclusions about the nature of the forces acting upon the chromosomes during division from observation of the rates of their movement in anaphase is pointed out. Some available data are discussed, and shown to agree quantitatively with the assumption that during anaphase the chromosomes are pulled apart by contracting elastic fibers.     

The relationship between purines, pyrimidines, nucleosides, and glutamine for fibroblast cell proliferation

Previous studies indicate that glutamine is a critical requirement for cell proliferation in vitro. We recently showed that depletion of glutamine from the culture medium supporting growing cells significantly reduced the proportion of cells undergoing DNA synthesis. Similarly glutamine depletion significantly reduced the stimulatory response of quiescent cells to 10% serum. This study shows that the inhibitory effects of depletion of glutamine--in either of these two situations--can be overcome by the addition of adenine or adenosine. Adenine was the only nitrogen base and adenosine was the only nucleoside for which this effect was observed. Such effects could, however, also be achieved by addition of the purine metabolites hypoxantine and inosine. Furthermore, it was found that glutamine (or adenine/adenosine) is only required during a limited interval coinciding with the late part of the G1-phase and the beginning of S-phase. These data suggest the possibility that glutamine exerts its main regulatory effects on cell proliferation by acting as a precursor for adenine and adenosine.     

Dietary restriction and aging, 2009

Dietary restriction (DR) is a robust nongenetic, nonpharmacological intervention that is known to increase active and healthy lifespan in a variety of species. Despite a variety of differences in the protocols and the way DR is carried out in different species, conserved relationships are emerging among multiple species. 2009 saw the field of DR mature with important mechanistic insights from multiple species. A report of lifespan extension in rapamycin‐treated mice suggested that the TOR pathway, a conserved mediator of DR in invertebrates, may also be critical to DR effects in mammals. 2009 also saw exciting discoveries related to DR in various organisms including yeast, worms, flies, mice, monkeys and humans. These studies complement each other and together aim to deliver the promise of postponing aging and age‐related diseases by revealing the underlying mechanisms of the protective effects of DR. Here, we summarize a few of the reports published in 2009 that we believe provide novel directions and an improved understanding of dietary restriction.     

The restriction point and control of cell proliferation

Research over the past two decades has defined a window of time in the early/mid G₁ phase of the cell cycle during which mammalian cells are responsive to extracellular signals. Recent evidence indicates that this period ends with the phosphorylation of the retinoblastoma protein, enabling the cells to pass through the restriction point at the end of mid G₁ phase and to commit to completing the remaining phases of the growth cycle.     

The many faces of calmodulin in cell proliferation,programmed cell death,autophagy, and cancer

Calmodulin (CaM) is a ubiquitous Ca^2 + receptor protein mediating a large number of signaling processes in all eukaryotic cells. CaM plays a central role in regulating a myriad of cellular functions via interaction with multiple target proteins. This review focuses on the action of CaM and CaM-dependent signaling systems in the control of vertebrate cell proliferation, programmed cell death and autophagy. The significance of CaM and interconnected CaM-regulated systems for the physiology of cancer cells including tumor stem cells, and processes required for tumor progression such as growth, tumor-associated angiogenesis and metastasis are highlighted. Furthermore, the potential targeting of CaM-dependent signaling processes for therapeutic use is discussed.     

Gastric mucosal tyrosine kinase activity during aging and its relationship to cell proliferation in rats

The relationship between tyrosine kinase activity and cellular proliferative activity was investigated in the gastric mucosa. For the purpose of comparison, the liver and the pancreas were also included. Groups of 2-, 14- and 22-month-old male Fischer-344 rats were used. Tyrosine kinase activity was determined in the membrane fraction (30,000 x g pellet) utilizing a synthetic polymer, Glu-Tyr (4:1), as substrate. Cellular proliferative activity was assessed by measuring ornithine decarboxylase in the 20,000 x g supernatant. In all age groups, gastric mucosal tyrosine kinase activity was found to be 10-20-fold higher than in the liver or pancreas. In addition, gastric mucosal tyrosine kinase activity in 22-month-old rats was 35-70% higher than in their 2- and 14-month-old counterparts. Gastric mucosal ornithine decarboxylase activity also followed essentially the same pattern as that of tyrosine kinase in that the highest activity was observed in 22-month-old rats. Increased gastric mucosal proliferative activity in 22-month-old rats was also associated with increased tyrosine-phosphorylation of a mucosal membrane protein with an apparent Mr of 53,000. An opposite phenomenon occurred in the pancreas whose proliferative activity was found to be the lowest. It is concluded that the age-associated changes in gastric mucosal proliferative activity are accompanied by parallel alterations in tyrosine kinase activity. Tyrosine-phosphorylation of a 53 kDa membrane protein may play a role in the regulation of cell proliferation.     

Some remarks on synecology

Plant Ecology - Nach einer kritischen Besprechung der begriffsmässigen Trennung zwischen Autökologie und Synökologie weist der Autor darauf hin, daß die meisten sogenannten...     

AMBRA1: When autophagy meets cell proliferation

A growing amount of evidence reported in the literature in recent years strongly supports the relevance of the interplay between autophagy and other pathways. In this context, the study of the link between autophagy and cell proliferation regulation has been among the most challenging. In our recent publications, we finely characterize a role for the pro-autophagic protein AMBRA1 in the regulation of cell proliferation. AMBRA1 modulates autophagy and interacts with PPP2/PP2A (protein phosphatase 2), thus also modulating MYC protein levels and the cell proliferation rate. Interestingly, this pathway of regulation is controlled by the master regulator of autophagy and cell growth, MTORC1. Notably, in our study we demonstrate the relevance of the AMBRA1-mediated regulation of MYC in tumorigenesis, also identifying AMBRA1 as a tumor suppressor gene.     

The relationship between red cell aging and enzyme activities in experimental animals.

1. The relationship between red cell aging and enzyme activities was studied in rabbit, guinea-pig, hamster, rats (F344/N and SD), and mice (BALB/c and DBA/2). 2. The activities of six enzymes: glucose-6-phosphate dehydrogenase (G-6-PD), 6-phosphogluconate dehydrogenase (6-PGD), hexokinase (Hx), glutamate oxaloacetate transminase (GOT), lactate dehydrogenase (LDH) and acetylcholinesterase (AChE), were measured in the red cells of different ages which were obtained either by centrifugation or experimental anaemia. 3. Hx, AChE and GOT activities were much higher in younger red cells than in older cells, hence the activities of these enzymes may be used as an indicator of age of the cells.     

Some remarks on organization and structure

Self-organizing systems are defined as able to change their structure, according to need, within specific equivalence classes. Once hierarchical levels and their value functions are assigned, requirements of invariance under transformations within an equivalence class can be used as a principle to determine the population of each level. This program is carried out in complete detail, as an example, for a particular class of systems (called modular), for which it is shown that a full Thermodynamics can be constructed. Modular systems are compared with linguistic, monetary, and military organizations; they are found to describe exactly the empirical data available on monetary circulation over the world, and to offer other perhaps suggestive indications. The emerging picture is that of a development, for any such system, which alternates phases of evolution (changes of level occupation numbers) with phases of revolution (changes of level structure within the given equivalence class).