Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature

We studied ten individuals from eight families showing features consistent with the immuno-osseous dysplasia spondyloenchondrodysplasia. Of particular note was the diverse spectrum of autoimmune phenotypes observed in these individuals (cases), including systemic lupus erythematosus, Sj?gren's syndrome, hemolytic anemia, thrombocytopenia, hypothyroidism, inflammatory myositis, Raynaud's disease and vitiligo. Haplotype data indicated the disease gene to be on chromosome 19p13, and linkage analysis yielded a combined multipoint log(10) odds (LOD) score of 3.6. Sequencing of ACP5, encoding tartrate-resistant acid phosphatase, identified biallelic mutations in each of the cases studied, and in vivo testing confirmed a loss of expressed protein. All eight cases assayed showed elevated serum interferon alpha activity, and gene expression profiling in whole blood defined a type I interferon signature. Our findings reveal a previously unrecognized link between tartrate-resistant acid phosphatase activity and interferon metabolism and highlight the importance of type I interferon in the genesis of autoimmunity.     

A Cenozoic record of the equatorial Pacific carbonate compensation depth

Atmospheric carbon dioxide concentrations and climate are regulated on geological timescales by the balance between carbon input from volcanic and metamorphic outgassing and its removal by weathering feedbacks; these feedbacks involve the erosion of silicate rocks and organic-carbon-bearing rocks. The integrated effect of these processes is reflected in the calcium carbonate compensation depth, which is the oceanic depth at which calcium carbonate is dissolved. Here we present a carbonate accumulation record that covers the past 53 million years from a depth transect in the equatorial Pacific Ocean. The carbonate compensation depth tracks long-term ocean cooling, deepening from 3.0-3.5?kilometres during the early Cenozoic (approximately 55?million years ago) to 4.6 kilometres at present, consistent with an overall Cenozoic increase in weathering. We find large superimposed fluctuations in carbonate compensation depth during the middle and late Eocene. Using Earth system models, we identify changes in weathering and the mode of organic-carbon delivery as two key processes to explain these large-scale Eocene fluctuations of the carbonate compensation depth.     

Weighing of biomolecules, single cells and single nanoparticles in fluid

Nanomechanical resonators enable the measurement of mass with extraordinary sensitivity. Previously, samples as light as 7 zeptograms (1 zg = 10(-21) g) have been weighed in vacuum, and proton-level resolution seems to be within reach. Resolving small mass changes requires the resonator to be light and to ring at a very pure tone-that is, with a high quality factor. In solution, viscosity severely degrades both of these characteristics, thus preventing many applications in nanotechnology and the life sciences where fluid is required. Although the resonant structure can be designed to minimize viscous loss, resolution is still substantially degraded when compared to measurements made in air or vacuum. An entirely different approach eliminates viscous damping by placing the solution inside a hollow resonator that is surrounded by vacuum. Here we demonstrate that suspended microchannel resonators can weigh single nanoparticles, single bacterial cells and sub-monolayers of adsorbed proteins in water with sub-femtogram resolution (1 Hz bandwidth). Central to these results is our observation that viscous loss due to the fluid is negligible compared to the intrinsic damping of our silicon crystal resonator. The combination of the low resonator mass (100 ng) and high quality factor (15,000) enables an improvement in mass resolution of six orders of magnitude over a high-end commercial quartz crystal microbalance. This gives access to intriguing applications, such as mass-based flow cytometry, the direct detection of pathogens, or the non-optical sizing and mass density measurement of colloidal particles.     

Annotated inventory of invertebrate populations of an alpine lake and stream chain in Colorado

Benthic macroinvertebrates were collected during the ice-free season (1 July-20 October) over a five-year period from a chain of alpine lakes and intervening streams in the Green Lakes Valley (3,347-3,615 m) in Boulder County, Colorado. A list of taxa was developed for 1981 and 1982, with taxonomic additions for 1983- 1985 and comments on community structure, seasonal and elevational changes in species abundance, and noteworthy occurrences. A total of 111 taxa was collected, of which 84% occurred in streams, 58% being exclusively lotic. Dipterans composed 73-81% of total abundance in streams. The littoral benthic zone of lakes was predominantly trichopterans and dipterans, 44-60% and 24-39%, respectively. Numerically important organisms in various lakes and streams were chironomids, simuliids (particularly Metacnephia ), oligochaetes, and the bivalve Pisidium casertanum . An isolated lake and its outlet stream, with unique characteristics, were the sole locations of Gammarus lacustris (Amphipoda) and Glossiphonia complanata (Hirudinea). Manipulated lowering of a lake along the main drainage exposed abundant and luxuriant colonies of the bryozoan Fredericella sultana . This organism was found on 43% of all rocks sampled, a preponderance heretofore unknown for this, or any, ectoproct in alpine or arctic lakes.     

Lung cancer: intragenic ERBB2 kinase mutations in tumours

The protein-kinase family is the most frequently mutated gene family found in human cancer and faulty kinase enzymes are being investigated as promising targets for the design of antitumour therapies. We have sequenced the gene encoding the transmembrane protein tyrosine kinase ERBB2 (also known as HER2 or Neu) from 120 primary lung tumours and identified 4% that have mutations within the kinase domain; in the adenocarcinoma subtype of lung cancer, 10% of cases had mutations. ERBB2 inhibitors, which have so far proved to be ineffective in treating lung cancer, should now be clinically re-evaluated in the specific subset of patients with lung cancer whose tumours carry ERBB2 mutations.     

Cell fusion is the principal source of bone-marrow-derived hepatocytes

Evidence suggests that haematopoietic stem cells might have unexpected developmental plasticity, highlighting therapeutic potential. For example, bone-marrow-derived hepatocytes can repopulate the liver of mice with fumarylacetoacetate hydrolase deficiency and correct their liver disease. To determine the underlying mechanism in this murine model, we performed serial transplantation of bone-marrow-derived hepatocytes. Here we show by Southern blot analysis that the repopulating hepatocytes in the liver were heterozygous for alleles unique to the donor marrow, in contrast to the original homozygous donor cells. Furthermore, cytogenetic analysis of hepatocytes transplanted from female donor mice into male recipients demonstrated 80,XXXY (diploid to diploid fusion) and 120,XXXXYY (diploid to tetraploid fusion) karyotypes, indicative of fusion between donor and host cells. We conclude that hepatocytes derived form bone marrow arise from cell fusion and not by differentiation of haematopoietic stem cells.     

A rhodopsin is the functional photoreceptor for phototaxis in the unicellular eukaryote Chlamydomonas

Rhodopsin is a visual pigment ubiquitous in multicellular animals. If visual pigments have a common ancient origin, as is believed, then some unicellular organisms might also use a rhodopsin photoreceptor. We show here that the unicellular alga Chlamydomonas does indeed use a rhodopsin photoreceptor. We incorporated analogues of its retinal chromophore into a blind mutant; normal photobehaviour was restored and the colour of maximum sensitivity was shifted in a manner consistent with the nature of the retinal analogue added. The data suggest that 11-cis-retinal is the natural chromophore and that the protein environment of this retinal is similar to that found in bovine rhodopsin, suggesting homology with the rhodopsins of higher organisms. This is the first demonstration of a rhodopsin photoreceptor in an alga or eukaryotic protist and also the first report of behavioural spectral shifts caused by exogenous synthetic retinals in a eukaryote. A survey of the morphology and action spectra of other protists suggests that rhodopsins may be common photoreceptors of chlorophycean, prasinophycean and dinophycean algae. Thus, Chlamydomonas represents a useful new model for studying photoreceptor cells.