An agrin minigene rescues dystrophic symptoms in a mouse model for congenital muscular dystrophy

Congenital muscular dystrophy is a heterogeneous and severe, progressive muscle-wasting disease that frequently leads to death in early childhood. Most cases of congenital muscular dystrophy are caused by mutations in LAMA2, the gene encoding the alpha2 chain of the main laminin isoforms expressed by muscle fibres. Muscle fibre deterioration in this disease is thought to be caused by the failure to form the primary laminin scaffold, which is necessary for basement membrane structure, and the missing interaction between muscle basement membrane and the dystrophin-glycoprotein complex (DGC) or the integrins. With the aim to restore muscle function in a mouse model for this disease, we have designed a minigene of agrin, a protein known for its role in the formation of the neuromuscular junction. Here we show that this mini-agrin-which binds to basement membrane and to alpha-dystroglycan, a member of the DGC-amends muscle pathology by a mechanism that includes agrin-mediated stabilization of alpha-dystroglycan and the laminin alpha5 chain. Our data provides in vivo evidence that a non-homologous protein in combination with rational protein design can be used to devise therapeutic tools that may restore muscle function in human muscular dystrophies.     

Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity

Natural killer (NK) cells attack many tumour cell lines, and are thought to have a critical role in anti-tumour immunity; however, the interaction between NK cells and tumour targets is poorly understood. The stimulatory lectin-like NKG2D receptor is expressed by NK cells, activated CD8+ T cells and by activated macrophages in mice. Several distinct cell-surface ligands that are related to class I major histocompatibility complex molecules have been identified, some of which are expressed at high levels by tumour cells but not by normal cells in adults. However, no direct evidence links the expression of these 'induced self' ligands with tumour cell rejection. Here we demonstrate that ectopic expression of the murine NKG2D ligands Rae1beta or H60 in several tumour cell lines results in potent rejection of the tumour cells by syngeneic mice. Rejection is mediated by NK cells and/or CD8+ T cells. The ligand-expressing tumour cells induce potent priming of cytotoxic T cells and sensitization of NK cells in vivo. Mice that are exposed to live or irradiated tumour cells expressing Rae1 or H60 are specifically immune to subsequent challenge with tumour cells that lack NKG2D ligands, suggesting application of the ligands in the design of tumour vaccines.     

Photochemical cycling of iron in the surface ocean mediated by microbial iron(III)-binding ligands

Iron is a limiting nutrient for primary production in large areas of the oceans. Dissolved iron(III) in the upper oceans occurs almost entirely in the form of complexes with strong organic ligands presumed to be of biological origin. Although the importance of organic ligands to aquatic iron cycling is becoming clear, the mechanism by which they are involved in this process remains uncertain. Here we report observations of photochemical reactions involving Fe(III) bound to siderophores--high-affinity iron(III) ligands produced by bacteria to facilitate iron acquisition. We show that photolysis of Fe(III)-siderophore complexes leads to the formation of lower-affinity Fe(III) ligands and the reduction of Fe(III), increasing the availability of siderophore-bound iron for uptake by planktonic assemblages. These photochemical reactions are mediated by the alpha-hydroxy acid moiety, a group which has generally been found to be present in the marine siderophores that have been characterized. We suggest that Fe(III)-binding ligands can enhance the photolytic production of reactive iron species in the euphotic zone and so influence iron availability in aquatic systems.     

The timing of the last deglaciation in North Atlantic climate records

To determine the mechanisms governing the last deglaciation and the sequence of events that lead to deglaciation, it is important to obtain a temporal framework that applies to both continental and marine climate records. Radiocarbon dating has been widely used to derive calendar dates for marine sediments, but it rests on the assumption that the 'apparent age' of surface water (the age of surface water relative to the atmosphere) has remained constant over time. Here we present new evidence for variation in the apparent age of surface water (or reservoir age) in the North Atlantic ocean north of 40 degrees N over the past 20,000 years. In two cores we found apparent surface-water ages to be larger than those of today by 1,230 +/- 600 and 1,940 +/- 750 years at the end of the Heinrich 1 surge event (15,000 years BP) and by 820 +/- 430 to 1,010 +/- 340 years at the end of the Younger Dryas cold episode. During the warm B?lling-Aller?d period, between these two periods of large reservoir ages, apparent surface-water ages were comparable to present values. Our results allow us to reconcile the chronologies from ice cores and the North Atlantic marine records over the entire deglaciation period. Moreover, the data imply that marine carbon dates from the North Atlantic north of 40 degrees N will need to be corrected for these highly variable effects.     

The physical maps for sequencing human chromosomes 1, 6, 9, 10, 13, 20 and X

We constructed maps for eight chromosomes (1, 6, 9, 10, 13, 20, X and (previously) 22), representing one-third of the genome, by building landmark maps, isolating bacterial clones and assembling contigs. By this approach, we could establish the long-range organization of the maps early in the project, and all contig extension, gap closure and problem-solving was simplified by containment within local regions. The maps currently represent more than 94% of the euchromatic (gene-containing) regions of these chromosomes in 176 contigs, and contain 96% of the chromosome-specific markers in the human gene map. By measuring the remaining gaps, we can assess chromosome length and coverage in sequenced clones.