Accumulation of oxidized lipid-protein complexes alters phagosome maturation in retinal pigment epithelium

Lipid peroxidation has been implicated in many age-associated disorders including macular degeneration of the retina. We sought to elucidate the mechanism by which accumulation of oxidized LDL (oxLDL) reduces the ability of retinal pigment epithelium (RPE) to process photoreceptor outer segments (OS) as a model of peroxidation-induced disruption of phagocytosis. OxLDL did not reduce the lysosomal hydrolytic capacity of the RPE, but efficiently inhibited processing of various internalized proteins. OxLDL caused a delay in the acquisition of late lysosomal markers by newly formed phagosomes. At the same time, an excessive accumulation of markers of early phagosomal compartments was also observed. The activity of phosphatidylinositol 3-kinase (PI3K) was reduced in phagosomes of the RPE treated with oxLDL. These results suggest that accumulation of oxidized lipid-protein complexes in the RPE impedes phagosome maturation by blocking PI3K recruitment to the phagosomal membrane, leading to delayed processing of internalized OS.Received 24 February 2004; received after revision 12 April 2004; accepted 4 May 2004     

Recombination rate and reproductive success in humans

Intergenerational mixing of DNA through meiotic recombinations of homologous chromosomes during gametogenesis is a major event that generates diversity in the eukaryotic genome. We examined genome-wide microsatellite data for 23,066 individuals, providing information on recombination events of 14,140 maternal and paternal meioses each, and found a positive correlation between maternal recombination counts of an offspring and maternal age. We postulated that the recombination rate of eggs does not increase with maternal age, but that the apparent increase is the consequence of selection. Specifically, a high recombination count increased the chance of a gamete becoming a live birth, and this effect became more pronounced with advancing maternal age. Further support for this hypothesis came from our observation that mothers with high oocyte recombination rate tend to have more children. Hence, not only do recombinations have a role in evolution by yielding diverse combinations of gene variants for natural selection, but they are also under selection themselves.     

Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease

Genes and mechanisms involved in common complex diseases, such as the autoimmune disorders that affect approximately 5% of the population, remain obscure. Here we identify polymorphisms of the cytotoxic T lymphocyte antigen 4 gene (CTLA4)--which encodes a vital negative regulatory molecule of the immune system--as candidates for primary determinants of risk of the common autoimmune disorders Graves' disease, autoimmune hypothyroidism and type 1 diabetes. In humans, disease susceptibility was mapped to a non-coding 6.1 kb 3' region of CTLA4, the common allelic variation of which was correlated with lower messenger RNA levels of the soluble alternative splice form of CTLA4. In the mouse model of type 1 diabetes, susceptibility was also associated with variation in CTLA-4 gene splicing with reduced production of a splice form encoding a molecule lacking the CD80/CD86 ligand-binding domain. Genetic mapping of variants conferring a small disease risk can identify pathways in complex disorders, as exemplified by our discovery of inherited, quantitative alterations of CTLA4 contributing to autoimmune tissue destruction.     

Earliest known crown-group salamanders

Salamanders are a model system for studying the rates and patterns of the evolution of new anatomical structures. Recent discoveries of abundant Late Jurassic and Early Cretaceous salamanders are helping to address these issues. Here we report the discovery of well-preserved Middle Jurassic salamanders from China, which constitutes the earliest known record of crown-group urodeles (living salamanders and their closest relatives). The new specimens are from the volcanic deposits of the Jiulongshan Formation (Bathonian), Inner Mongolia, China, and represent basal members of the Cryptobranchidae, a family that includes the endangered Asian giant salamander (Andrias) and the North American hellbender (Cryptobranchus). These fossils document a Mesozoic record of the Cryptobranchidae, predating the previous record of the group by some 100 million years. This discovery provides evidence to support the hypothesis that the divergence of the Cryptobranchidae from the Hynobiidae had taken place in Asia before the Middle Jurassic period.     

Controlling molecular deposition and layer structure with supramolecular surface assemblies

Selective non-covalent interactions have been widely exploited in solution-based chemistry to direct the assembly of molecules into nanometre-sized functional structures such as capsules, switches and prototype machines. More recently, the concepts of supramolecular organization have also been applied to two-dimensional assemblies on surfaces stabilized by hydrogen bonding, dipolar coupling or metal co-ordination. Structures realized to date include isolated rows, clusters and extended networks, as well as more complex multi-component arrangements. Another approach to controlling surface structures uses adsorbed molecular monolayers to create preferential binding sites that accommodate individual target molecules. Here we combine these approaches, by using hydrogen bonding to guide the assembly of two types of molecules into a two-dimensional open honeycomb network that then controls and templates new surface phases formed by subsequently deposited fullerene molecules. We find that the open network acts as a two-dimensional array of large pores of sufficient capacity to accommodate several large guest molecules, with the network itself also serving as a template for the formation of a fullerene layer.     

Investigation of the electrical potential of the isolated midgut of the freshwater teleost,Ameiurus nebulosus

Zusammenfassung Durch Veränderung des innern oder äussern Milieus beim isolierten Mitteldarm eines Teleostiers wird das Potential quer zur Wand verändert. Dies ermöglicht Schlüsse auf die Ionenwanderung und damit Ionenregulation dieses Süsswasserfisches.