Mutations in or near the Transmembrane Domain Alter PMEL Amyloid Formation from Functional to Pathogenic

PMEL is a pigment cell-specific protein that forms physiological amyloid fibrils upon which melanins ultimately deposit in the lumen of the pigment organelle, the melanosome. Whereas hypomorphic PMEL mutations in several species result in a mild pigment dilution that is inherited in a recessive manner, PMEL alleles found in the Dominant white (DW) chicken and Silver horse (HoSi)—which bear mutations that alter the PMEL transmembrane domain (TMD) and that are thus outside the amyloid core—are associated with a striking loss of pigmentation that is inherited in a dominant fashion. Here we show that the DW and HoSi mutations alter PMEL TMD oligomerization and/or association with membranes, with consequent formation of aberrantly packed fibrils. The aberrant fibrils are associated with a loss of pigmentation in cultured melanocytes, suggesting that they inhibit melanin production and/or melanosome integrity. A secondary mutation in the Smoky chicken, which reverts the dominant DW phenotype, prevents the accumulation of PMEL in fibrillogenic compartments and thus averts DW–associated pigment loss; a secondary mutation found in the Dun chicken likely dampens a HoSi–like dominant mutation in a similar manner. We propose that the DW and HoSi mutations alter the normally benign amyloid to a pathogenic form that antagonizes melanosome function, and that the secondary mutations found in the Smoky and Dun chickens revert or dampen pathogenicity by functioning as null alleles, thus preventing the formation of aberrant fibrils. We speculate that PMEL mutations can model the conversion between physiological and pathological amyloid

The genome of the sea urchin Strongylocentrotus purpuratus

We report the sequence and analysis of the 814-megabase genome of the sea urchin Strongylocentrotus purpuratus, a model for developmental and systems biology. The sequencing strategy combined whole-genome shotgun and bacterial artificial chromosome (BAC) sequences. This use of BAC clones, aided by a pooling strategy, overcame difficulties associated with high heterozygosity of the genome. The genome encodes about 23,300 genes, including many previously thought to be vertebrate innovations or known only outside the deuterostomes. This echinoderm genome provides an evolutionary outgroup for the chordates and yields insights into the evolution of deuterostomes

Exercise therapy in Type 2 diabetes

Structured exercise is considered an important cornerstone to achieve good glycemic control and improve cardiovascular risk profile in Type 2 diabetes. Current clinical guidelines acknowledge the therapeutic strength of exercise intervention. This paper reviews the wide pathophysiological problems associated with Type 2 diabetes and discusses the benefits of exercise therapy on phenotype characteristics, glycemic control and cardiovascular risk profile in Type 2 diabetes patients. Based on the currently available literature, it is concluded that Type 2 diabetes patients should be stimulated to participate in specifically designed exercise intervention programs. More attention should be paid to cardiovascular and musculoskeletal deconditioning as well as motivational factors to improve long-term treatment adherence and clinical efficacy. More clinical research is warranted to establish the efficacy of exercise intervention in a more differentiated approach for Type 2 diabetes subpopulations within different stages of the disease and various levels of co-morbidity

Utilisation des métallothionéines comme biomarqueur de la contamination métallique : variabilité entre sites et organes chez l'huı̂tre Crassostrea gigas

Heavy metals (Cd, Cu, Hg and Zn) and metallothionein levels were determined in oysters Crassostrea gigas from two sites: the Gironde Estuary (contaminated site) and Bourgneuf Bay (uncontaminated site). Metallothionein levels led us to suspect the presence of cadmium in the environment when quantified in the gills. Soluble cadmium and metallothioneins were positively correlated in the digestive gland of oysters from Gironde (contaminated site), but metallothionein levels in this organ were not significantly different from levels observed in the digestive gland of oysters from Bourgneuf Bay (uncontaminated site). Conversely, no correlation was noticed between metals and metallothioneins in the gills of oysters from Gironde despite metallothionein levels significantly higher than levels observed in oyster gills from Bourgneuf Bay. This significant difference of metallothionein levels is attributed to a higher ratio of soluble metals (Cd, Cu, Zn) in the gills of oysters from Gironde. The generalization of the use of metallothioneins as biomarkers of metal contamination of aquatic environments is questioned.Chez Crassostrea gigas, les teneurs en zinc, cuivre et cadmium dans les huı̂tres de Gironde sont significativement supérieures à celles des huı̂tres de la baie de Bourgneuf. Cadmium soluble et métallothionéines sont corrélés positivement dans la glande digestive des huı̂tres prélevées en Gironde (site contaminé). Pour autant, les teneurs en métallothionéines dans cet organe ne sont pas significativement différentes de celles d'huı̂tres de la baie de Bourgneuf (site de référence). À l'opposé, il n'y a pas de corrélation entre métaux et métallothionéines dans les branchies des huı̂tres de Gironde, mais leurs teneurs en métallothionéines sont significativement supérieures à celles des huı̂tres de la baie de Bourgneuf. L'augmentation significative des teneurs en métallothionéines est liée à une proportion plus importante des métaux (Cd, Cu, Zn) sous forme soluble dans les branchies des huı̂tres de Gironde. Chez l'huı̂tre Crassostrea gigas, les niveaux de métallothionéines dans les branchies permettent de préjuger de la présence de cadmium dans le milie

Bioaccumulation des métaux chez le mytilidae hydrothermal Bathymodiolus sp. de la ride médio-atlantique

The hydrothermal environment is characterised, among other things, by a high metal concentration, related to the convective sea-water circulation inside the oceanic crust and its interaction with basaltic rocks. The biological communities associated with the hydrothermal system can survive in this toxic environment owing to their ability to regulate their intracellular metal levels by excretion or accumulation of metal ions in non-toxic forms. Various detoxification processes have been previously studied within an hydrothermal organism: immobilisation and precipitation of the metal in lysosomal systems, or binding to specific and soluble ligands such as metallothioneins. The later are heat stable and characterised by a high content of cysteine. The quantification of Fe, Zn, Cu, Mn, Cd, Ag, Pa and Sr in the tissues of the vent mussel Bathymodiolus sp. indicates a high accumulation of these metals in two target organs, the gill and the digestive gland. This accumulation is in relation with high concentrations of metallothioneins, but the subcellular distribution of metals indicates a higher contribution of the insoluble compartment for detoxification processes. These results are compared with the literature data about metal bioaccumlation in Bathymodiolus thermophilus collected at the Galapagos Rift.L'environnement hydrothermal est caractérisé, entre autres, par une concentration élevée en métaux, due à la circulation convective de l'eau de mer dans la croûte océanique et à son interaction avec les roches volcaniques. Les organismes vivant à proximité des sources chaudes s'adaptent à cette richesse en métaux sous forme d'ions ou de sels en suspension, soit en maintenant constante leur teneur interne par des processus d'excrétion, soit en les accumulant sous des formes non toxiques. Différents procédés de détoxication ont été mis en évidence chez certaines espèces hydrothermales : immobilisation et précipitation du métal sous forme insoluble, dans les systèmes lysosomiaux, ou fixation à des ligands spécifiques et solubles dont les plus importants sont les métallothionéines, riches en cystéine et stables à la chaleur. Les teneurs en Fe, Zn, Cu, Mn, Cd, Ag, Ba et Sr dans les tissus de Bathymodiolus sp., espèce dont la physiologie est encore mal connue, montrent une accumulation importante dans les deux organes cibles, la branchie et la glande digestive. Cette accumulation est associée à des teneurs élevées en métallothionéines, mais la répartition des métaux montre une contribution plus importante du compartiment insoluble, dans les mécanismes de détoxication. Ces résultats sont comparés avec les données de la littérature concernant la bioaccumulation des métaux chez Bathymodiolus thermophilus des Galapagos