Investigation of the biomechanical effect of variable stiffness shoe on external knee adduction moment in various dynamic exercises

10.1186/1757-1146-6-39Journal of Foot and Ankle Research61

Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers

Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele frequencies in the surrounding genomic regions reflect adaptive or balancing selection. Such proposals predict long-range linkage disequilibrium (LD) resulting from a selective sweep, although genetic drift in a founder population may also act to create long-distance LD. To date, few studies have used the tools of statistical genomics to examine the likelihood of long-range LD at a deleterious locus in a population that faced a genetic bottleneck. We studied the genotypes of hundreds of women from a large international consortium of BRCA1 and BRCA2 mutation carriers and found that AJ women exhibited long-range haplotypes compared to CNJ women. More than 50% of the AJ chromosomes with the BRCA1 185delAG mutation share an identical 2.1 Mb haplotype and nearly 16% of AJ chromosomes carrying the BRCA2 6174delT mutation share a 1.4 Mb haplotype. Simulations based on the best inference of Ashkenazi population demography indicate that long-range haplotypes are expected in the context of a genome-wide survey. Our results are consistent with the hypothesis that a local bottleneck effect from population size constriction events could by chance have resulted in the large haplotype blocks observed at high frequency in the BRCA1 and BRCA2 regions of Ashkenazi Jews

The thiosemicarbazone Me2NNMe2 induces paraptosis by disrupting the ER thiol redox homeostasis based on protein disulfide isomerase inhibition

Due to their high biological activity, thiosemicarbazones have been developed for treatment of diverse diseases, including cancer, resulting in multiple clinical trials especially of the lead compound Triapine. During the last years, a novel subclass of anticancer thiosemicarbazones has attracted substantial interest based on their enhanced cytotoxic activity. Increasing evidence suggests that the double-dimethylated Triapine derivative Me2NNMe2 differs from Triapine not only in its efficacy but also in its mode of action. Here we show that Me2NNMe2- (but not Triapine)-treated cancer cells exhibit all hallmarks of paraptotic cell death including, besides the appearance of endoplasmic reticulum (ER)-derived vesicles, also mitochondrial swelling and caspase-independent cell death via the MAPK signaling pathway. Subsequently, we uncover that the copper complex of Me2NNMe2 (a supposed intracellular metabolite) inhibits the ER-resident protein disulfide isomerase, resulting in a specific form of ER stress based on disruption of the Ca2+ and ER thiol redox homeostasis. Our findings indicate that compounds like Me2NNMe2 are of interest especially for the treatment of apoptosis-resistant cancer and provide new insights into mechanisms underlying drug-induced paraptosis. © 2018, The Author(s)

Steps toward Determination of the Size and Structure of the Broad-Line Region in Active Galactic Nuclei. XI. Intensive Monitoring of the Ultraviolet Spectrum of NGC 7469

From 1996 June 10 to July 29, the International Ultraviolet Explorer monitored the Seyfert 1 galaxy NGC 7469 continuously in an attempt to measure time delays between the continuum and emission-line fluxes. From the time delays, one can estimate the size of the region dominating the production of the UV emission lines in this source. We find the strong UV emission lines to respond to continuum variations with time delays of about 2.(d)3-3.(d)1 for Ly alpha, 2.(d)7 for C IV lambda 1549, 1.(d)9-2.(d)4 for N V lambda 1240, 1.(d)7-1.(d)8 for Si IV lambda 1400, and 0.(d)7-1.(d)0 for He II lambda 1640. The most remarkable result, however, is the detection of apparent time delays between the different UV continuum bands. With respect to the UV continuum flux at 1315 Angstrom, the flux at 1485 Angstrom, 1740 Angstrom, and 1825 Angstrom lags with time delays of 0.(d)21, 0.(d)35, and 0.(d)28, respectively. Determination of the significance of this detection is somewhat problematic since it depends on accurate estimation of the uncertainties in the lag measurements, which are difficult to assess. We attempt to estimate the uncertainties in the time delays through Monte Carlo simulations, and these yield estimates of similar to 0.(d)07 for the 1 sigma uncertainties in the interband continuum time delays. Possible explanations for the delays include the existence of a continuum-flux reprocessing region close to the central source and/or a contamination of the continuum flux with a very broad time-delayed emission feature such as the Balmer continuum or merged Fe II multiplets.</p