Ras proteins in the control of the cell cycle and cell differentiation

The Ras family of small GTPases includes three closely related proteins: H-, K-, and N-Ras. Ras proteins are involved in the transduction of signals elicited by activated surface receptors, acting as key components by relaying signals downstream through diverse pathways. Mutant, constitutively activated forms of Ras proteins are frequently found in cancer. While constitutive Ras activation induces oncogenic-like transformation in immortalized fibroblasts, it causes growth arrest in primary vertebrate cells. Induction of p53 and cyclin-dependent kinase inhibitors such as p15^INK4b, p16^INK4a, p19^ARF, and p21^WAF1 accounts for this response. Interestingly, while ras has usually been regarded as a transforming oncogene, the analysis of Ras function in most of the cellular systems studied so far indicates that the promotion of differentiation is the most prominent effect of Ras. While in some cell types, particularly muscle, Ras inhibits differentiation, in others such as neuronal, adipocytic, or myeloid cells, Ras induces differentiation, in some cases accompanied by growth arrest. Several possible mechanisms for the pleiotropic effects of Ras in animal cells are discussed. Received 8 March 2000; received after revision 24 May 2000; accepted 24 May 2000     

Enzymes catalyzing the reduction of aldopentoses and the oxidation of pentitols in Mycobacteria]

M. phlei, grown on synthetic Sauton medium (with 6% glycerol as carbon source), had NADPH- and NADH-aldopentose reductase, as well as NAD-pentitol dehydrogenase activities; some of their properties are studied. These activities are not present in BCG grown on the same medium. All experiments of aldopentose-reductase induction in BCG on a D(+)xylose medium were negative.     

Glutamate transporters in the biology of malignant gliomas

Malignant gliomas are relentless tumors that offer a dismal clinical prognosis. They develop many biological advantages that allow them to grow and survive in the unique environment of the brain. The glutamate transporters system x _c ^? and excitatory amino acid transporters (EAAT) are emerging as key players in the biology and malignancy of these tumors. Gliomas manipulate glutamate transporter expression and function to alter glutamate homeostasis in the brain, which supports their own growth, invasion, and survival. As a consequence, malignant cells are able to quickly destroy and invade surrounding normal brain. Recent findings are painting a larger picture of these transporters in glioma biology, and as such are providing opportunities for clinical intervention for patients. This review will detail the current understanding of glutamate transporters in the biology of malignant gliomas and highlight some of the unique aspects of these tumors that make them so devastating and difficult to treat.     

Welcome the Family of FANCJ-like Helicases to the Block of Genome Stability Maintenance Proteins

The FANCJ family of DNA helicases is emerging as an important group of proteins for the prevention of human disease, cancer, and chromosomal instability. FANCJ was identified by its association with breast cancer, and is implicated in Fanconi Anemia. Proteins with sequence similarity to FANCJ are important for maintenance of genomic stability. Mutations in genes encoding proteins related to FANCJ, designated ChlR1 in human and Chl1p in yeast, result in sister chromatid cohesion defects. Nematodes mutated in dog-1 show germline as well as somatic deletions in genes containing guanine-rich DNA. Rtel knockout mice are embryonic lethal, and embryonic stem cells show telomere loss and chromosomal instability. FANCJ also shares sequence similarity with human XPD and yeast RAD3 helicases required for nucleotide excision repair. The recently solved structure of XPD has provided new insight to the helicase core and accessory domains of sequence related Superfamily 2 helicases. The functions and roles of members of the FANCJ-like helicase family will be discussed. Received 17 September 2008; received after revision 24 October 2008; accepted 28 October 2008     

Lecticans: organizers of the brain extracellular matrix

Lecticans are a family of chondroitin sulfate proteoglycans, encompassing aggrecan, versican, neurocan and brevican. These proteoglycans are characterized by the presence of ahyaluronan-binding domain and a C-type lectin domain in their core proteins. Through these domains, lecticans interact with carbohydrate and protein ligands in the extracellular matrix and act as linkers of these extracellular matrix molecules. In adult brain, lecticans are thought to interact with hyaluronan and tenascin-R to form a ternary complex. We propose that the hyaluronan-lectican-tenascin-R complex constitutes the core assembly of the adult brain extracellular matrix, which is found mainly in pericellular spaces of neurons as ‘perineuronal nets’. Received 27 September 1999; accepted 26 October 1999     

Naturally occurring hemagglutinins in the hemolymph of the scorpionParuroctonus mesaensis Stahnke

Summary Lectins which bind sialic acid-containing receptors are present in the hemolymph of the scorpionParuroctonus mesaensis Stahnke. Glycoproteins like bovine submaxillary mucin, fetuin and human orosomucoid behave as strong inhibitors forParuroctonus lectins; desialylation of glycoproteins results in a drastic reduction of their inhibitory capabilities confirming that sialic acids are the terminal monosaccharides ofParuroctonus lectin receptors.We wish to thank Dr H. L. Stahnke, Arizona State University, Tempe, Arizona, for taxonomic assistance. This work received fellowship support from the Consejo Nacional de Investigaciones Cientificas y Técnicas de la República Argentina.     

UV guided dendritic growth patterns and the networking of melanocytes

Whole skin organ cultures of vitiliginous, skin show that the marginal melanocytes are highly sensitive to a pulse of UV exposure (210–380 nm) during the G₂ phase of the cell cycle, as seen by prominent dendricity. Melanocytes are highly dendritic in the epidermis overlying rapidly growing tumors, as well as within proliferative lesions such as basal cell carcinomas and aggressive seborrheic keratosis. In the organ cultures the dendrites extend towards the source of UV, i.e. the surface, while the main body lies along the basement membrane. The epidermal melanocytes overlying tumors lie, almost vertically, dendrites aligned towards the underlying tumor on one side and the surface on the other. Within tumors dendritic elongation is guided by mitotic and PCNA positive (S-phase) tumor cells, which are a source of ultraweak UV emissions in the range of 210–330 nm. These observations indicate that ultraweak biophoton emissions from neighbouring cells can simulate environmental cues and contribute to the plasticity of networks such as the melanocytes or the visual pathways.     

Towards a science of the individual: the Aristotelian search for scientific knowledge of individual entities

This article seeks to take a step towards recognizing that science can deal with the concrete and individual as well as the universal. I shall concentrate on some of Aristotle’s texts, as there is a long tradition going back to Aristotle, according to which science deals only with the universal, although his work also contains texts of a very different tenor. He tries to improve the process of definition as an attempt to bring science closer to the concrete, but ends up realizing that there are some unreachable limits. There is, however, a second Aristotelian approach to the problem in Metaphysica M 10, a passage which takes scientific rapprochement to the individual further by introducing a distinction between science in potential and science in act. The former is universal, but the latter deals with individual substances and processes. Aristotle himself acknowledges here that in one sense science is universal and in another it is not, a position that raises important ontological and epistemological problems. Some suggestions are also offered concerning the kind of truth applicable to science in act, that is, practical truth.     

Formation of coronary arteries sprouting from the primitive aortic sinus wall of the chick embryo

Summary The formation of coronary arteries in chick embryos was observed by scanning electron microscopy on injected casts as well as by transmission election microscopy. Usually, 2–4 primitive coronary arteries appear from the right aortic sinus below the level of the cusp margin, and 1–3 from the left one. As development proceeds, the arteries are generally reduced in number to form a single definitive coronary artery on each side. Canalization of the arteries seems to take place by partially degenerative changes of the primordia.Thanks are given to Prof. M. Mato, Department of Anatomy, Jichi Medical School, Tochigi for valuable suggestions, and Dr R.J. Adams for stylistic suggestions. The skillful technical assistance of MrS. Ide is acknowledged.     

Drugs of the future: the hormone relaxin

The peptide hormone relaxin is emerging as a multi-functional factor in a broad range of target tissues including several non-reproductive organs, in addition to its historical role as a hormone of pregnancy. This review discusses the evidence that collectively demonstrates the many diverse and vital roles of relaxin: the homeostatic role of endogenous relaxin in mammalian pregnancy and ageing; its gender-related effects; the therapeutic effects of relaxin in the treatment of fibrosis, inflammation, cardioprotection, vasodilation and wound healing (angiogenesis) amongst other pathophysiological conditions, and its potential mechanism of action. Furthermore, translational issues using experimental models (to humans) and its use in various clinical trials, are described, each with important lessons for the design of future trials involving relaxin. The diverse physiological and pathological roles for relaxin have led to the search for its significance in humans and highlight its potential as a drug of the future. Received 12 December 2006; received after revision 12 February 2007; accepted 15 March 2007     

Effects of water acidification on the distribution pattern and the reproductive success of amphibians

Summary Nine amphibian species were encountered in poorly buffered waters of The Netherlands (alkalinity 1 meq·l^–1). These soft water systems are highly sensitive to acidifying precipitation. The number of species as well as the percentage of waters which harbour amphibian populations are strongly reduced in the extremely acid pH-class . The reproductive success of amphibians is negatively affected by low pH. The eggs become heavily infested with fungi (Saprolegniaceae). In acidifying systems many physico-chemical parameters are significantly correlated with the pH of the water. Strongly acidified waters are characterized by low alkalinity, conductivity and ionic content but high acidity and high concentrations of (heavy) metals and ammonium and a high relative sulphate concentration. Culture experiments with eggs and larvae ofRana arvalis. Rana esculenta, Rana temporaria andBufo bufo show that apart from the pH, elevated aluminium, cadmium and ammonium contents may also affect the reproductive success of amphibians.     

Studies on the survival time of the eupyrene and oligopyrene spermatozoa of the prosobranch,Vivipara bengalensis (Lamarck)

Summary Vivipara bengalensis, like many other gastropods, produces two types of spermatozoa viz., eupyrene (normal) and oligopyrene (abnormal). The eupyrene ones are comparatively small and uniflagellated, whereas the oligopyrene ones are much larger, worm-like and each with a tuft of tail flagella. Eupyrene and oligopyrene spermatozoa reveal in vitro differential survival characteristics; the eupyrene spermatozoa exhibit considerably shorter survival as compared with their oligopyrene counterparts.     

William Stukeley and the early history of the Orrery

Relations between J. A. C. Chaptal, pioneer of heavy chemical industry in France, and A. L. Lavoisier, reformer of chemical theory, are examined in the light of unpublished correspondence they exchanged in the period 1784–1790. The letters, together with Chaptal's early publications, allow a reconstruction of his conversion to Lavoisier's antiphlogistic chemistry. They also reveal a series of petitions that Chaptal made to Lavoisier, in the latter's official capacity as a director of the Régie des poudres et salpêtres, for relief from the controlled price of saltpetre for his acid works in Languedoc. Finally, the relationship is explored as a window on the interplay between chemical theory and industrial practice during the period of the Industrial Revolution.     

Newtonianism and the enthusiasm of Enlightenment

The career of John Jackson (1686-1763), Arian theologian and controversialist, provides a key to unlocking the early reception and quick collapse of a Newtonian natural apologetic originally developed by Samuel Clarke. The importance of friendship and discipleship in eighteenth-century intellectual enquiry is emphasised, and the links between Newton and his followers are traced alongside those of a group of Cambridge Lockeans, led by Jackson’s direct contemporary Daniel Waterland, who proved instrumental in the initial dismantling of Clarke’s brand of Newtonian apologetic. The controversial context of this engagement is shown to have been largely provided by the religiously compromising rise of freethinking, and Tindal’s Christianity as old as the creation (1731) signalled the dangers to proponents of natural religion as an adjunct of Christian apologetic in such a heated atmosphere. Religious division of the sort that resulted paradoxically played into the hands of the freethinkers in the anticlerical atmosphere of the 1730s, and accusations were exchanged between Newtonians and Lockeans accordingly. The dynamic of England’s Enlightenment experience is, then, a complicated one, and, as the career and writings of Jackson and William Whiston demonstrate, it was one which absorbed as well as repudiated ‘enthusiasm’.     

On the solvent-extraction of acetylcholine receptor

Summary Chloroform/methanol rechromatography on Sephadex LH-20 of fractions isolated from organic solvent extracts ofE. electricus electric organs exhibited alterations in elution point compared to the original chromatography. Additionally,³H decamethonium bromide did not coelute with any of the observed fractions. It is concluded that as presently described the organic solvent isolation procedure for the cholinergic receptor exhibits undesirable characteristics.Acknowledgments. The authors thank Dan Burrough and Rick O'Brien for their competent technical assistance. Naval Medical Research Development and Command, Research Work Unit No. MRO41.06.01.0021. The opinions and assertions contained herein are the private ones of the writers and are not to be construed as official or reflecting the views of the Navy Department or the naval service at large.     

Duhem’s theory of mixture in the light of the Stoic challenge to the Aristotelian conception

The bulk of Duhem’s writing which bears on the understanding of mixtures suggests he adopted an Aristotelian position which he opposed only to the atomic view. A third view from antiquity—that of the Stoics—seems not to be taken into account. But his lines of thought are not always as explicit as could be wished. The Stoic view is considered here from a perspective which Duhem might well have adopted. This provides a background against which his somewhat unorthodox Aristotelianism might be understood.