Absence of naturally occurring coronary atherosclerosis in squirrel monkeys (Saimiri sciurea) treated with chondroitin sulfate A

Zusammenfassung Die überraschende Atheromatosehemmende Wirkung von Chondroitin-Sulfat konnte nun auch beiSaimiri scurea, einem Primaten mit hoher Inzidenz von Atheromatose, nachgewiesen werden.

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Supported in part by grants from the Heart Institute of the National Institutes of Health, U. S. Public Health Service, John A. Hartford Foundation, Inc., and other donors.     

Sodium channel mutation leading to saxitoxin resistance in clams increases risk of PSP

Bivalve molluscs, the primary vectors of paralytic shellfish poisoning (PSP) in humans, show marked inter-species variation in their capacity to accumulate PSP toxins (PSTs) which has a neural basis. PSTs cause human fatalities by blocking sodium conductance in nerve fibres. Here we identify a molecular basis for inter-population variation in PSP resistance within a species, consistent with genetic adaptation to PSTs. Softshell clams (Mya arenaria) from areas exposed to 'red tides' are more resistant to PSTs, as demonstrated by whole-nerve assays, and accumulate toxins at greater rates than sensitive clams from unexposed areas. PSTs lead to selective mortality of sensitive clams. Resistance is caused by natural mutation of a single amino acid residue, which causes a 1,000-fold decrease in affinity at the saxitoxin-binding site in the sodium channel pore of resistant, but not sensitive, clams. Thus PSTs might act as potent natural selection agents, leading to greater toxin resistance in clam populations and increased risk of PSP in humans. Furthermore, global expansion of PSP to previously unaffected coastal areas might result in long-term changes to communities and ecosystems.     

Thermal and electrical conductivity of iron at Earth's core conditions

The Earth acts as a gigantic heat engine driven by the decay of radiogenic isotopes and slow cooling, which gives rise to plate tectonics, volcanoes and mountain building. Another key product is the geomagnetic field, generated in the liquid iron core by a dynamo running on heat released by cooling and freezing (as the solid inner core grows), and on chemical convection (due to light elements expelled from the liquid on freezing). The power supplied to the geodynamo, measured by the heat flux across the core-mantle boundary (CMB), places constraints on Earth's evolution. Estimates of CMB heat flux depend on properties of iron mixtures under the extreme pressure and temperature conditions in the core, most critically on the thermal and electrical conductivities. These quantities remain poorly known because of inherent experimental and theoretical difficulties. Here we use density functional theory to compute these conductivities in liquid iron mixtures at core conditions from first principles--unlike previous estimates, which relied on extrapolations. The mixtures of iron, oxygen, sulphur and silicon are taken from earlier work and fit the seismologically determined core density and inner-core boundary density jump. We find both conductivities to be two to three times higher than estimates in current use. The changes are so large that core thermal histories and power requirements need to be reassessed. New estimates indicate that the adiabatic heat flux is 15 to 16 terawatts at the CMB, higher than present estimates of CMB heat flux based on mantle convection; the top of the core must be thermally stratified and any convection in the upper core must be driven by chemical convection against the adverse thermal buoyancy or lateral variations in CMB heat flow. Power for the geodynamo is greatly restricted, and future models of mantle evolution will need to incorporate a high CMB heat flux and explain the recent formation of the inner core.     

MEGF10 and MEGF11 mediate homotypic interactions required for mosaic spacing of retinal neurons

In many parts of the nervous system, neuronal somata display orderly spatial arrangements. In the retina, neurons of numerous individual subtypes form regular arrays called mosaics: they are less likely to be near neighbours of the same subtype than would occur by chance, resulting in 'exclusion zones' that separate them. Mosaic arrangements provide a mechanism to distribute each cell type evenly across the retina, ensuring that all parts of the visual field have access to a full set of processing elements. Remarkably, mosaics are independent of each other: although a neuron of one subtype is unlikely to be adjacent to another of the same subtype, there is no restriction on its spatial relationship to neighbouring neurons of other subtypes. This independence has led to the hypothesis that molecular cues expressed by specific subtypes pattern mosaics by mediating homotypic (within-subtype) short-range repulsive interactions. So far, however, no molecules have been identified that show such activity, so this hypothesis remains untested. Here we demonstrate in mouse that two related transmembrane proteins, MEGF10 and MEGF11, have critical roles in the formation of mosaics by two retinal interneuron subtypes, starburst amacrine cells and horizontal cells. MEGF10 and 11 and their invertebrate relatives Caenorhabditis elegans CED-1 and Drosophila Draper have hitherto been studied primarily as receptors necessary for engulfment of debris following apoptosis or axonal injury. Our results demonstrate that members of this gene family can also serve as subtype-specific ligands that pattern neuronal arrays.     

Analysis of the DNA sequence and duplication history of human chromosome 15

Here we present a finished sequence of human chromosome 15, together with a high-quality gene catalogue. As chromosome 15 is one of seven human chromosomes with a high rate of segmental duplication, we have carried out a detailed analysis of the duplication structure of the chromosome. Segmental duplications in chromosome 15 are largely clustered in two regions, on proximal and distal 15q; the proximal region is notable because recombination among the segmental duplications can result in deletions causing Prader-Willi and Angelman syndromes. Sequence analysis shows that the proximal and distal regions of 15q share extensive ancient similarity. Using a simple approach, we have been able to reconstruct many of the events by which the current duplication structure arose. We find that most of the intrachromosomal duplications seem to share a common ancestry. Finally, we demonstrate that some remaining gaps in the genome sequence are probably due to structural polymorphisms between haplotypes; this may explain a significant fraction of the gaps remaining in the human genome.     

Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer's disease

Senile plaques accumulate over the course of decades in the brains of patients with Alzheimer's disease. A fundamental tenet of the amyloid hypothesis of Alzheimer's disease is that the deposition of amyloid-beta precedes and induces the neuronal abnormalities that underlie dementia. This idea has been challenged, however, by the suggestion that alterations in axonal trafficking and morphological abnormalities precede and lead to senile plaques. The role of microglia in accelerating or retarding these processes has been uncertain. To investigate the temporal relation between plaque formation and the changes in local neuritic architecture, we used longitudinal in vivo multiphoton microscopy to sequentially image young APPswe/PS1d9xYFP (B6C3-YFP) transgenic mice. Here we show that plaques form extraordinarily quickly, over 24 h. Within 1-2 days of a new plaque's appearance, microglia are activated and recruited to the site. Progressive neuritic changes ensue, leading to increasingly dysmorphic neurites over the next days to weeks. These data establish plaques as a critical mediator of neuritic pathology.     

In situ analyses of genome instability in breast cancer

Transition through telomere crisis is thought to be a crucial event in the development of most breast carcinomas. Our goal in this study was to determine where this occurs in the context of histologically defined breast cancer progression. To this end, we assessed genome instability (using fluorescence in situ hybridization) and other features associated with telomere crisis in normal ductal epithelium, usual ductal hyperplasia, ductal carcinoma in situ and invasive cancer. We modeled this process in vitro by measuring these same features in human mammary epithelial cell cultures during ZNF217-mediated transition through telomere crisis and immortalization. Taken together, the data suggest that transition through telomere crisis and immortalization in breast cancer occurs during progression from usual ductal hyperplasia to ductal carcinoma in situ.     

C. elegans ORFeome version 1.1: experimental verification of the genome annotation and resource for proteome-scale protein expression

To verify the genome annotation and to create a resource to functionally characterize the proteome, we attempted to Gateway-clone all predicted protein-encoding open reading frames (ORFs), or the 'ORFeome,' of Caenorhabditis elegans. We successfully cloned approximately 12,000 ORFs (ORFeome 1.1), of which roughly 4,000 correspond to genes that are untouched by any cDNA or expressed-sequence tag (EST). More than 50% of predicted genes needed corrections in their intron-exon structures. Notably, approximately 11,000 C. elegans proteins can now be expressed under many conditions and characterized using various high-throughput strategies, including large-scale interactome mapping. We suggest that similar ORFeome projects will be valuable for other organisms, including humans.