Experimental gout from alloxan in pigeons. Findings in the joints and serous membranes

Zusammenfassung Bei Tauben erzeugt intravenös gegebenes Alloxan bekanntlich Läsionen, die denen der Eingeweidegicht ähneln. Chemische und mikroskopische Untersuchungen zeigten eine große Menge von Uraten auf Perikardium, Peritoneum und Pleura. Die große Zunahme der Harnsäure im Blute, die von anderen Autoren kolorimetrisch festgestellt wurde, wird durch die Urikasemethode bestätigt. In der vorliegenden Mitteilung wird weiterhin über ein der Gelenkgicht ähnliches Bild bei alloxanbehandelten Tauben berichtet. Verschiedene Tierarten mit einem «ureotelic-proteic metabolism» zeigen nach Alloxan weder eine nennenswerte Harnsäurezunahme im Blut noch eine Gicht der Eingeweide oder der Gelenke.     

The serini reaction

Zusammenfassung Der Mechanismus der Serini-Reaktion wird kurz erörtert und ein 17, 20-Oxyd als Zwischenprodukt vorgeschlagen. Das stereochemische Ergebnis der Reaktion soll von zwei Faktoren abhängig sein, und zwar: 1. von der Geometrie des « transition state » und 2. von der Konfiguration des Oxydrings. Ausgehend von diesen Überlegungen, kann vorausgesagt werden, daßReichsteins Substanz 0-Diacetat durch die Serini-Reaktion in ein 17-Iso-20-keton und nicht in ein 17-Normal-20-keton umgewandelt werden soll. Tatsächlich ist das 17-Isoallopregnanol-(3)-on-20 als einziges Produkt experimentell aufgefunden worden.     

Regulation of insulin receptor function

Resistance to the biological actions of insulin contributes to the development of type 2 diabetes and risk of cardiovascular disease. A reduced biological response to insulin by tissues results from an impairment in the cascade of phosphorylation events within cells that regulate the activity of enzymes comprising the insulin signaling pathway. In most models of insulin resistance, there is evidence that this decrement in insulin signaling begins with either the activation or substrate kinase activity of the insulin receptor (IR), which is the only component of the pathway that is unique to insulin action. Activation of the IR can be impaired by post-translational modifications of the protein involving serine phosphorylation, or by binding to inhibiting proteins such as PC-1 or members of the SOCS or Grb protein families. The impact of these processes on the conformational changes and phosphorylation events required for full signaling activity, as well as the role of these mechanisms in human disease, is reviewed in this article. Received 3 August 2006; received after revision 1 December 2006; accepted 8 January 2007     

Systematic pathway analysis using high-resolution fitness profiling of combinatorial gene deletions

Systematic genetic interaction studies have illuminated many cellular processes. Here we quantitatively examine genetic interactions among 26 Saccharomyces cerevisiae genes conferring resistance to the DNA-damaging agent methyl methanesulfonate (MMS), as determined by chemogenomic fitness profiling of pooled deletion strains. We constructed 650 double-deletion strains, corresponding to all pairings of these 26 deletions. The fitness of single- and double-deletion strains were measured in the presence and absence of MMS. Genetic interactions were defined by combining principles from both statistical and classical genetics. The resulting network predicts that the Mph1 helicase has a role in resolving homologous recombination-derived DNA intermediates that is similar to (but distinct from) that of the Sgs1 helicase. Our results emphasize the utility of small molecules and multifactorial deletion mutants in uncovering functional relationships and pathway order.     

The human genome and understanding of common disease: present and future technologies

The study of candidate genes over the past three decades has yielded notable successes in common-disease genetics. During this time, however, interpretation of genetic association studies has been hampered by the use of clinical cohorts of inadequate power and insufficient information on genetic variation in candidate genes. The unavailability of highthroughput and low-cost genotyping technologies has also limited the scope of complex-disease genetic studies. More recently, however, the sequencing and characterization of variation within the human genome has revolutionized genetic studies and enabled full genome-wide scans for genes associated with disease. The identification of disease-associated (causative) genes has illuminated disease mechanisms. The translation of this knowledge into direct clinical benefit in diagnosis, prognosis and therapy for an individual’s disease still remains a challenge. Received 11 September 2006; received after revision 17 December 2006; accepted 18 January 2007     

Pierre Duhem’s virtue epistemology

Duhem’s concept of ‘good sense’ is central to his philosophy of science, given that it is what allows scientists to decide between competing theories. Scientists must use good sense and have intellectual and moral virtues in order to be neutral arbiters of scientific theories, especially when choosing between empirically adequate theories. I discuss the parallels in Duhem’s views to those of virtue epistemologists, who understand justified belief as that arrived at by a cognitive agent with intellectual and moral virtues, showing how consideration of Duhem as a virtue epistemologist offers insights into his views, as well as providing possible answers to some puzzles about virtue epistemology. The extent to which Duhem holds that the intellectual and moral virtues of the scientist determine scientific knowledge has not been generally noticed.     

Genetic studies of diseases

Genomic alterations lead to cancer complexity and form a major hurdle for comprehensive understanding of the molecular mechanisms underlying oncogenesis. In this review, we describe recent advances in studying cancer-associated genes from a systems biology point of view. The integration of known cancer genes onto protein and signaling networks reveals the characteristics of cancer genes within networks. This approach shows that cancer genes often function as network hub proteins which are involved in many cellular processes and form focal nodes in information exchange between many signaling pathways. Literature mining allows constructing gene-gene networks, in which new cancer genes can be identified. The gene expression profiles of cancer cells are used for reconstructing gene regulatory networks. By doing so, genes which are involved in the regulation of cancer progression can be picked up from these networks, after which their functions can be further confirmed in the laboratory.     

Cellular internalization of proinsulin C-peptide

Proinsulin C-peptide is known to bind specifically to cell membranes and to exert intracellular effects, but whether it is internalized in target cells is unknown. In this study, using confocal microscopy and immunostained or rhodamine-labeled peptide, we show that C-peptide is internalized and localized to the cytosol of Swiss 3T3 and HEK-293 cells. In addition, transport into nuclei was found using the labeled peptide. The internalization was followed at 37°C for up to 1 h, and was reduced at 4°C and after preincubation with pertussis toxin. Hence, it is concluded to occur via an energy-dependent, pertussis toxin-sensitive mechanism and without detectable degradation within the experimental time course. Surface plasmon resonance measurements demonstrated binding of HEK-293 cell extract components to C-peptide, and subsequent elution of bound material revealed the components to be intracellular proteins. The identification of C-peptide cellular internalization, intracellular binding proteins, absence of rapid subsequent C-peptide degradation and apparent nuclear internalization support a maintained activity similar to that of an intracrine peptide hormone. Hence, the data suggest the possibility of one further C-peptide site of action. Received 31 October 2006; received after revision 27 December 2006; accepted 30 December 2006     

New Membranes Based on Polybenzimidazole for Polymer Fuel Cells

1 Results Acid-doped polybenzimidazoles[1] are particularly appealing because of high proton conductivity with no or low humidification and promising fuel cells performances. PBI, in fact, contains basic functional groups which can easily interact with strong oxo-acids, such as H3PO4 and H2SO4. The acid partially protonates the polymer and partially is freely dispersed in the polymer backbone, so allowing proton migration via Grotthuss mechanism along the anionic chains[2]. Anyway, a technological limit...