Mesoangioblast stem cells ameliorate muscle function in dystrophic dogs

Duchenne muscular dystrophy remains an untreatable genetic disease that severely limits motility and life expectancy in affected children. The only animal model specifically reproducing the alterations in the dystrophin gene and the full spectrum of human pathology is the golden retriever dog model. Affected animals present a single mutation in intron 6, resulting in complete absence of the dystrophin protein, and early and severe muscle degeneration with nearly complete loss of motility and walking ability. Death usually occurs at about 1 year of age as a result of failure of respiratory muscles. Here we report that intra-arterial delivery of wild-type canine mesoangioblasts (vessel-associated stem cells) results in an extensive recovery of dystrophin expression, normal muscle morphology and function (confirmed by measurement of contraction force on single fibres). The outcome is a remarkable clinical amelioration and preservation of active motility. These data qualify mesoangioblasts as candidates for future stem cell therapy for Duchenne patients.     

RPA regulates telomerase action by providing Est1p access to chromosome ends

Replication protein A (RPA) is a highly conserved single-stranded DNA-binding protein involved in DNA replication, recombination and repair. We show here that RPA is present at the telomeres of the budding yeast Saccharomyces cerevisiae, with a maximal association in S phase. A truncation of the N-terminal region of Rfa2p (associated with the rfa2Delta40 mutated allele) results in severe telomere shortening caused by a defect in the in vivo regulation of telomerase activity. Cells carrying rfa2Delta40 show impaired binding of the protein Est1p, which is required for telomerase action. In addition, normal telomere length can be restored by expressing a Cdc13-Est1p hybrid protein. These findings indicate that RPA activates telomerase by loading Est1p onto telomeres during S phase. We propose a model of in vivo telomerase action that involves synergistic action of RPA and Cdc13p at the G-rich 3' overhang of telomeric DNA.     

Essential role of limiting telomeres in the pathogenesis of Werner syndrome

Mutational inactivation of the gene WRN causes Werner syndrome, an autosomal recessive disease characterized by premature aging, elevated genomic instability and increased cancer incidence. The capacity of enforced telomerase expression to rescue premature senescence of cultured cells from individuals with Werner syndrome and the lack of a disease phenotype in Wrn-deficient mice with long telomeres implicate telomere attrition in the pathogenesis of Werner syndrome. Here, we show that the varied and complex cellular phenotypes of Werner syndrome are precipitated by exhaustion of telomere reserves in mice. In late-generation mice null with respect to both Wrn and Terc (encoding the telomerase RNA component), telomere dysfunction elicits a classical Werner-like premature aging syndrome typified by premature death, hair graying, alopecia, osteoporosis, type II diabetes and cataracts. This mouse model also showed accelerated replicative senescence and accumulation of DNA-damage foci in cultured cells, as well as increased chromosomal instability and cancer, particularly nonepithelial malignancies typical of Werner syndrome. These genetic data indicate that the delayed manifestation of the complex pleiotropic of Wrn deficiency relates to telomere shortening.     

Microdeletions in the human H19 DMR result in loss of IGF2 imprinting and Beckwith-Wiedemann syndrome

The overgrowth- and tumor-associated Beckwith-Wiedemann syndrome results from dysregulation of imprinted genes on chromosome 11p15.5. Here we show that inherited microdeletions in the H19 differentially methylated region (DMR) that abolish two CTCF target sites cause this disease. Maternal transmission of the deletions results in hypermethylation of the H19 DMR, biallelic IGF2 expression, H19 silencing and Beckwith-Wiedemann syndrome, indicative of loss of function of the IGF2-H19 imprinting control element.     

Dynamic control of positional information in the early Drosophila embryo

Morphogen gradients contribute to pattern formation by determining positional information in morphogenetic fields. Interpretation of positional information is thought to rely on direct, concentration-threshold-dependent mechanisms for establishing multiple differential domains of target gene expression. In Drosophila, maternal gradients establish the initial position of boundaries for zygotic gap gene expression, which in turn convey positional information to pair-rule and segment-polarity genes, the latter forming a segmental pre-pattern by the onset of gastrulation. Here we report, on the basis of quantitative gene expression data, substantial anterior shifts in the position of gap domains after their initial establishment. Using a data-driven mathematical modelling approach, we show that these shifts are based on a regulatory mechanism that relies on asymmetric gap-gap cross-repression and does not require the diffusion of gap proteins. Our analysis implies that the threshold-dependent interpretation of maternal morphogen concentration is not sufficient to determine shifting gap domain boundary positions, and suggests that establishing and interpreting positional information are not independent processes in the Drosophila blastoderm.     

Supramolecular self-assembled molecules as organic directing agent for synthesis of zeolites

Solid materials with uniform micropores, such as zeolites, can act as selective catalysts and adsorbents for molecular mixtures by separating those molecules small enough to enter their pores while leaving the larger molecules behind. Zeolite A is a microporous material with a high void volume. Despite its widespread industrial use in, for example, molecular separations and in detergency, its capability as a petroleum-refining material is limited owing to its poor acid-catalytic activity and hydrothermal stability, and its low hydrophobicity. These characteristics are ultimately a consequence of the low framework Si/Al ratio (normally around one) and the resulting high cationic fraction within the pores and cavities. Researchers have modified the properties of type-A zeolites by increasing the Si/Al compositions up to a ratio of three. Here we describe the synthesis of zeolite A structures exhibiting high Si/Al ratios up to infinity (pure silica). We synthesize these materials, named ITQ-29, using a supramolecular organic structure-directing agent obtained by the self-assembly, through pi-pi type interactions, of two identical organic cationic moieties. The highly hydrophobic pure-silica zeolite A can be used for hydrocarbon separations that avoid oligomerization reactions, whereas materials with high Si/Al ratios give excellent shape-selective cracking additives for increasing propylene yield in fluid catalytic cracking operations. We have also extended the use of our supramolecular structure-directing agents to the synthesis of a range of other zeolites.     

Low electrical resistivity associated with plunging of the Nazca flat slab beneath Argentina

Beneath much of the Andes, oceanic lithosphere descends eastward into the mantle at an angle of about 30 degrees (ref. 1). A partially molten region is thought to form in a wedge between this descending slab and the overlying continental lithosphere as volatiles given off by the slab lower the melting temperature of mantle material. This wedge is the ultimate source for magma erupted at the active volcanoes that characterize the Andean margin. But between 28 degrees and 33 degrees S the subducted Nazca plate appears to be anomalously buoyant, as it levels out at about 100 km depth and extends nearly horizontally under the continent. Above this 'flat slab', volcanic activity in the main Andean Cordillera terminated about 9 million years ago as the flattening slab presumably squeezed out the mantle wedge. But it is unknown where slab volatiles go once this happens, and why the flat slab finally rolls over to descend steeply into the mantle 600 km further eastward. Here we present results from a magnetotelluric profile in central Argentina, from which we infer enhanced electrical conductivity along the eastern side of the plunging slab, indicative of the presence of partial melt. This conductivity structure may imply that partial melting occurs to at least 250 km and perhaps to more than 400 km depth, or that melt is supplied from the 410 km discontinuity, consistent with the transition-zone 'water-filter' model of Bercovici and Karato.