Pex7p translocates in and out of peroxisomes in Saccharomyces cerevisiae

Pex7p is the soluble receptor responsible for importing into peroxisomes newly synthesized proteins bearing a type 2 peroxisomal targeting sequence. We observe that appending GFP to Pex7p's COOH terminus shifts Pex7p's intracellular distribution from predominantly cytosolic to predominantly peroxisomal in Saccharomyces cerevisiae. Cleavage of the link between Pex7p and GFP within peroxisomes liberates GFP, which remains inside the organelle, and Pex7p, which exits to the cytosol. The reexported Pex7p is functional, resulting in import of thiolase into peroxisomes and improved growth of the yeast on oleic acid. These results support the “extended shuttle” model of peroxisome import receptor function and open the way to future studies of receptor export

High levels of fluctuating asymmetry in populations of Apodemus flavicollis from the most contaminated areas in Chornobyl

Random deviations from the perfect symmetry of normally bilaterally symmetrical characters for an individual with a given genotype occur during individual development due to the influence of multiple environmental factors. Fluctuating asymmetry (FA) is often used as a measure of developmental instability, and can be estimated as the variance of the distribution of differences between the left and right sides. We addressed the question of whether levels of FA were elevated in radioactively contaminated populations living around Chornobyl compared to those in reference populations of the yellow-necked mouse (Apodemus flavicollis). In addition, we studied amounts of directional asymmetry (DA) when one side is larger than the other on average. There was a significant difference among populations, including reference populations, in the amount of both FA and DA. A higher level of FA was documented for the contaminated populations in close proximity to the failed Chornobyl reactor for both the asymmetry of size and shape. The FAs of size and shape were highest in populations from the most contaminated locations in the Chornobyl exclusion zone. Although the directional asymmetry of shape was also highest in the contaminated populations, it was not significantly different from those in most of the reference populations. Populations from less contaminated areas inside the Chornobyl exclusion zone did not express FA values different from those of the reference populations outside the affected area

Problems with developmental stability in two rodent species from Chornobyl

Changes in developmental patterns are some of the most important effects that may be observed at radioactively contaminated sites like those at Chornobyl. Developmental instability may arise from the interactions between an organism\u27s genotype and its environment and be manifested as deviant morphology. Fluctuating asymmetry (FA) is a measure of deviations from the expected bilateral symmetry of the body. Our objective was to test for differences in FA in two rodent species (Apodemus flavicollis and Clethrionomys glareolus) that live in habitats suirounding the failed Chornobyl reactor. Rodents were collected from four different locations (two contaminated and two reference sites), and a series of adult skulls were photographed and 24 landmarks on each skull were located on digital images from photographed skulls. FA was calculated from the differences in these landmarks on the right and left side of the skull. Significantly more asymmetry (~2X) was observed in mice and voles living around Chornobyl compared to those living at the uncontaminated reference sites. These are relatively large effects in comparison to those previously found for plants and swallows. FA can be a cheap, easily determined and sensitive indicator of radiation-induced stress in small mammals. FA can be used to prioritize environments for remediation efforts and to efficiently evaluate the effectiveness of the remediation efforts

Problems with developmental stability in two rodent species from Chornobyl

Changes in developmental patterns are some of the most important effects that may be observed at radioactively contaminated sites like those at Chornobyl. Developmental instability may arise from the interactions between an organism\u27s genotype and its environment and be manifested as deviant morphology. Fluctuating asymmetry (FA) is a measure of deviations from the expected bilateral symmetry of the body. Our objective was to test for differences in FA in two rodent species (Apodemus flavicollis and Clethrionomys glareolus) that live in habitats suirounding the failed Chornobyl reactor. Rodents were collected from four different locations (two contaminated and two reference sites), and a series of adult skulls were photographed and 24 landmarks on each skull were located on digital images from photographed skulls. FA was calculated from the differences in these landmarks on the right and left side of the skull. Significantly more asymmetry (~2X) was observed in mice and voles living around Chornobyl compared to those living at the uncontaminated reference sites. These are relatively large effects in comparison to those previously found for plants and swallows. FA can be a cheap, easily determined and sensitive indicator of radiation-induced stress in small mammals. FA can be used to prioritize environments for remediation efforts and to efficiently evaluate the effectiveness of the remediation efforts

Circulating resistin levels and risk of multiple myeloma in three prospective cohorts

BACKGROUND: Resistin is a polypeptide hormone secreted by adipose tissue. A prior hospital-based case-control study reported serum resistin levels to be inversely associated with risk of multiple myeloma (MM). To date, this association has not been investigated prospectively. METHODS: We measured resistin concentrations for pre-diagnosis peripheral blood samples from 178 MM cases and 358 individually matched controls from three cohorts participating in the MM cohort consortium. RESULTS: In overall analyses, higher resistin levels were weakly associated with reduced MM risk. For men, we observed a statistically significant inverse association between resistin levels and MM (odds ratio, 0.44; 95% confidence interval (CI) 0.24-0.83 and 0.54; 95% CI 0.29-0.99, for the third and fourth quartiles, respectively, vs the lowest quartile; Ptrend=0.03). No association was observed for women. CONCLUSIONS: This study provides the first prospective evidence that low circulating resistin levels may be associated with an increased risk of MM, particularly for men

Quantum noise in laser-interferometer gravitational-wave detectors with a heterodyne readout scheme

We analyze and discuss the quantum noise in signal-recycled laser interferometer gravitational-wave detectors, such as Advanced LIGO, using a heterodyne readout scheme and taking into account the optomechanical dynamics. Contrary to homodyne detection, a heterodyne readout scheme can simultaneously measure more than one quadrature of the output field, providing an additional way of optimizing the interferometer sensitivity, but at the price of additional noise. Our analysis provides the framework needed to evaluate whether a homodyne or heterodyne readout scheme is more optimal for second generation interferometers from an astrophysical point of view. As a more theoretical outcome of our analysis, we show that as a consequence of the Heisenberg uncertainty principle the heterodyne scheme cannot convert conventional interferometers into (broadband) quantum non-demolition interferometers.Comment: 16 pages, 8 figure

Sagnac Interferometer as a Speed-Meter-Type, Quantum-Nondemolition Gravitational-Wave Detector

According to quantum measurement theory, "speed meters" -- devices that measure the momentum, or speed, of free test masses -- are immune to the standard quantum limit (SQL). It is shown that a Sagnac-interferometer gravitational-wave detector is a speed meter and therefore in principle it can beat the SQL by large amounts over a wide band of frequencies. It is shown, further, that, when one ignores optical losses, a signal-recycled Sagnac interferometer with Fabry-Perot arm cavities has precisely the same performance, for the same circulating light power, as the Michelson speed-meter interferometer recently invented and studied by P. Purdue and the author. The influence of optical losses is not studied, but it is plausible that they be fairly unimportant for the Sagnac, as for other speed meters. With squeezed vacuum (squeeze factor $e^{-2R} = 0.1$) injected into its dark port, the recycled Sagnac can beat the SQL by a factor $\sqrt{10} \simeq 3$ over the frequency band 10 {\rm Hz} \alt f \alt 150 {\rm Hz} using the same circulating power $I_c\sim 820$ kW as is used by the (quantum limited) second-generation Advanced LIGO interferometers -- if other noise sources are made sufficiently small. It is concluded that the Sagnac optical configuration, with signal recycling and squeezed-vacuum injection, is an attractive candidate for third-generation interferometric gravitational-wave detectors (LIGO-III and EURO).Comment: 12 pages, 6 figure

Improved Imputation of Common and Uncommon Single Nucleotide Polymorphisms (SNPs) with a New Reference Set

Statistical imputation of genotype data is an important technique for analysis of genome-wide association studies (GWAS). We have built a reference dataset to improve imputation accuracy for studies of individuals of primarily European descent using genotype data from the Hap1, Omni1, and Omni2.5 human SNP arrays (Illumina). Our dataset contains 2.5-3.1 million variants for 930 European, 157 Asian, and 162 African/African-American individuals. Imputation accuracy of European data from Hap660 or OmniExpress array content, measured by the proportion of variants imputed with R^2^>0.8, improved by 34%, 23% and 12% for variants with MAF of 3%, 5% and 10%, respectively, compared to imputation using publicly available data from 1,000 Genomes and International HapMap projects. The improved accuracy with the use of the new dataset could increase the power for GWAS by as much as 8% relative to genotyping all variants. This reference dataset is available to the scientific community through the NCBI dbGaP portal. Future versions will include additional genotype data as well as non-European populations

Development of a macromolecular prodrug for the treatment of inflammatory arthritis: mechanisms involved in arthrotropism and sustained therapeutic efficacy.

INTRODUCTION: The purpose of the present manuscript is to test the hypothesis that arthrotropic localization and synovial cell internalization account for the unique capacity of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-dexamethasone conjugate (P-Dex, a macromolecular prodrug of dexamethasone) to induce sustained amelioration of joint inflammation and inhibition of tissue damage in an animal model of inflammatory arthritis. METHODS: Rats with adjuvant-induced arthritis (AA) were treated with P-Dex, free dexamethasone, saline or HPMA homopolymer. To define the biodistribution of P-Dex, conjugates with different imaging labels were given to AA rats and analyzed. Isolated joint tissues were evaluated by fluorescence-activated cell sorting (FACS) and immunohistochemical staining. Cellular uptake of P-Dex and its effects on apoptosis and production of proinflammatory cytokines were examined using human monocyte-macrophages and fibroblasts. RESULTS: A single systemic administration of P-Dex completely suppressed AA for \u3e20 days. Magnetic resonance imaging demonstrated higher HPMA copolymer influx into the inflamed joints than the normal joints. Immunohistochemistry and FACS analyses of arthritic joints revealed extensive uptake of the polymer conjugate by synovial fibroblasts and myeloid lineage cells. The capacity of P-Dex to suppress inflammation was confirmed in monocyte-macrophage cultures in which P-Dex treatment resulted in suppression of lipopolysaccharide-induced IL-6 and TNFα release. Similarly, TNFα-induced expression of matrix metalloproteinases (MMP1 and MMP3) in synovial fibroblasts from a rheumatoid arthritis patient was suppressed by P-Dex. P-Dex showed no detectable effect on monocyte apoptosis. CONCLUSIONS: P-Dex provides superior and sustained amelioration of AA compared with an equivalent dose of free dexamethasone. The arthrotropism and local retention of P-Dex is attributed to the enhanced vascular permeability in arthritic joints and the internalization of P-Dex by synovial cells. The uptake and processing of P-Dex by macrophages and fibroblasts, and downregulation of proinflammatory mediators, provides an explanation for the sustained anti-inflammatory efficacy of P-Dex in this model of inflammatory arthritis