781 research outputs found

    The human RecQ helicases BLM and RECQL4 cooperate to preserve genome stability

    Get PDF
    Bacteria and yeast possess one RecQ helicase homolog whereas humans contain five RecQ helicases, all of which are important in preserving genome stability. Three of these, BLM, WRN and RECQL4, are mutated in human diseases manifesting in premature aging and cancer. We are interested in determining to which extent these RecQ helicases function cooperatively. Here, we report a novel physical and functional interaction between BLM and RECQL4. Both BLM and RECQL4 interact in vivo and in vitro. We have mapped the BLM interacting site to the N-terminus of RECQL4, comprising amino acids 361-478, and the region of BLM encompassing amino acids 1-902 interacts with RECQL4. RECQL4 specifically stimulates BLM helicase activity on DNA fork substrates in vitro. The in vivo interaction between RECQL4 and BLM is enhanced during the S-phase of the cell cycle, and after treatment with ionizing radiation. The retention of RECQL4 at DNA double-strand breaks is shortened in BLM-deficient cells. Further, depletion of RECQL4 in BLM-deficient cells leads to reduced proliferative capacity and an increased frequency of sister chromatid exchanges. Together, our results suggest that BLM and RECQL4 have coordinated activities that promote genome stabilit

    Replication of LIN28B SNP association with age of menarche in young Filipino women: LIN28Bassociation with age of menarche

    Get PDF
    Age of menarche, or the timing of first menses in girls, is a physiological trait that shows substantial genetic heritability. Earlier age of menarche is associated with increased childhood adiposity and with adult risk of obesity and cardiovascular disease. In 827 young Filipino women from the Cebu Longitudinal Health and Nutrition Survey (CLHNS), we observed nominal association with age of menarche (ÎČ = −0.118 years, 95% confidence interval = (−0.216, −0.020), P = 0.019) for the single nucleotide polymorphism (SNP) rs7759938 from the menarche locus LIN28B with an effect direction consistent with the previous report. We also tested whether childhood adiposity, as measured by body mass index (BMI) at age 8, mediated the relationship between rs7759938 and age of menarche. We observed suggestive evidence that the effect of the SNP on age of menarche was independent of childhood adiposity. These data confirm the strongest gene reported in Europeans (LIN28B) as a contributor to age of menarche in an Asian population

    The politics of playing along: radio and regulation in democratic Europe

    Get PDF
    The loss of localism has been a common trend in most radio markets in Europe and the United States. Deregulation of ownership led to a concentration phenomenon that has affected local radios in several western democracies. New forms of regulation have been considered as possible ways to stop the erosion of localism by applying rules to markets in the defense of diversity, pluralism, and the local dimension. This article analyses the local radio market in Portugal, by assessing the changes in the legislation and by examining the regulatory action that can, according to its remit, act preventively to avoid market forces to harm these principles.info:eu-repo/semantics/publishedVersio

    Effect of strain rate on tensile mechanical properties of high-purity niobium single crystals for SRF applications

    Get PDF
    An investigation of the mechanical properties of high-purity niobium single crystals is presented. Specimens were cut with different crystallographic orientations from a large grain niobium disk and uniaxial tensile tests were conducted at strain rates between 10-4 and 103 s-1. The logarithmic strain rate sensitivity for crystals oriented close to the center of a tensile axis inverse pole figure (IPF) is ~0.14 for all strain rates. The strain at failure (ranging from 0.4 to 0.9) is very sensitive to crystal orientation and maximal at ~10-2 s-1 for crystals oriented close to the center of an IPF. The high anisotropy observed at quasi-static strain rates decreased with increasing strain rate. The activation of multiple slip systems in the dynamic tests could account for this reduction in anisotropy. A transition from strain hardening to softening in the plastic domain was observed at strain rates greater than approximately 6 × 10-2 s-1 for crystals oriented close to the center of a tensile axis IPF. Shear bands were observed in specimens with orientations having similarly high Schmid factors on both {110} and {112} slip families, and they are correlated with reduced ductility. Crystal rotations at fracture are compared for the different orientations using scanning electron microscopy images and EBSD orientation maps. A rotation toward the terminal stable [101] orientation was measured for the majority of specimens (with tensile axes more than ~17° from the [001] direction) at strain rates between 1.28 × 10-2 and 1000 s-1.The authors would like to acknowledge the work of CERN's Materials, Metrology and Non-Destructive Testing (EN-MME-MM) section for granting access to their equipment for specimen preparation and scanning electron microscope (SEM) analyses. The authors would also like to thank Mr. Larry Vladic of Elite Motion LLC for lending us the high-speed camera during the high strain rate tests performed ASU. This Marie Sklodowska-Curie Action (MSCA) Innovative Training Network (ITN) receives funding from the European Union's H2020 Framework Programme under grant agreement no. 764879. T.R. Bieler, D. Kang, E. Pai Kulyadi, P. Eisenlohr, C. Kale, and K.N. Solanki acknowledge support from DOE/OHEP grant DE-SC0009962

    Partial Liver Kinase B1 (LKB1) Deficiency Promotes Diastolic Dysfunction, De Novo Systolic Dysfunction, Apoptosis, and Mitochondrial Dysfunction with Dietary Metabolic Challenge

    Get PDF
    Background - Myocardial hypertrophy and dysfunction are key features of metabolic heart disease due to dietary excess. Metabolic heart disease manifests primarily as diastolic dysfunction but may progress to systolic dysfunction, although the mechanism is poorly understood. Liver kinase B1 (LKB1) is a key activator of AMP-activated protein kinase and possibly other signaling pathways that oppose myocardial hypertrophy and failure. We hypothesized that LKB1 is essential to the heart's ability to withstand the metabolic stress of dietary excess. Methods and Results - Mice heterozygous for cardiac LKB1 were fed a control diet or a high-fat, high-sucrose diet for 4 months. On the control diet, cardiac LKB1 hearts had normal structure and function. After 4 months of the high-fat, high-sucrose diet, there was left ventricular hypertrophy and diastolic dysfunction in wild-type mice. In cardiac LKB1 (versus wild-type) mice, high-fat, high-sucrose feeding caused more hypertrophy (619 versus 553 ÎŒm(2), P<0.05), the de novo appearance of systolic dysfunction (left ventricular ejection fraction; 41% versus 59%, P<0.01) with left ventricular dilation (3.6 versus 3.2 mm, P<0.05), and more severe diastolic dysfunction with progression to a restrictive filling pattern (E/A ratio; 5.5 versus 1.3, P=0.05). Myocardial dysfunction in hearts of cardiac LKB1 mice fed the high-fat, high-sucrose diet was associated with evidence of increased apoptosis and apoptotic signaling via caspase 3 and p53/PUMA (p53 upregulated modulator of apoptosis) and more severe mitochondrial dysfunction. Conclusions - Partial deficiency of cardiac LKB1 promotes the adverse effects of a high-fat, high-sucrose diet on the myocardium, leading to worsening of diastolic function and the de novo appearance of systolic dysfunction. LKB1 plays a key role in protecting the heart from the consequences of metabolic stress.Edward J. Miller, Timothy Calamaras, Aly Elezaby, Aaron Sverdlov, Fuzhong Qin, Ivan Luptak, Ke Wang, Xinxin Sun, Andrea Vijay, Dominique Croteau, Markus Bachschmid, Richard A. Cohen, Kenneth Walsh, Wilson S. Colucc

    Cytotoxicity of ZnO Nanoparticles Can Be Tailored by Modifying Their Surface Structure: A Green Chemistry Approach for Safer Nanomaterials

    Get PDF
    ZnO nanoparticles (NP) are extensively used in numerous nanotechnology applications; however, they also happen to be one of the most toxic nanomaterials. This raises significant environmental and health concerns and calls for the need to develop new synthetic approaches to produce safer ZnO NP, while preserving their attractive optical, electronic, and structural properties. In this work, we demonstrate that the cytotoxicity of ZnO NP can be tailored by modifying their surface-bound chemical groups, while maintaining the core ZnO structure and related properties. Two equally sized (9.26 ± 0.11 nm) ZnO NP samples were synthesized from the same zinc acetate precursor using a forced hydrolysis process, and their surface chemical structures were modified by using different reaction solvents. X-ray diffraction and optical studies showed that the lattice parameters, optical properties, and band gap (3.44 eV) of the two ZnO NP samples were similar. However, FTIR spectroscopy showed significant differences in the surface structures and surface-bound chemical groups. This led to major differences in the zeta potential, hydrodynamic size, photocatalytic rate constant, and more importantly, their cytotoxic effects on Hut-78 cancer cells. The ZnO NP sample with the higher zeta potential and catalytic activity displayed a 1.5-fold stronger cytotoxic effect on cancer cells. These results suggest that by modifying the synthesis parameters/conditions and the surface chemical structures of the nanocrystals, their surface charge density, catalytic activity, and cytotoxicity can be tailored. This provides a green chemistry approach to produce safer ZnO NP

    A haplotype variation affecting the mitochondrial transportation of hMYH protein could be a risk factor for colorectal cancer in Chinese

    Get PDF
    <p>Abstract</p> <p>Background</p> <p>The human MutY homolog (<it>hMYH</it>), a DNA glycolsylase involved in the excision repair of oxidative DNA damage, is currently studied in colorectal cancer (CRC). We previously demonstrated a haplotype variant c.53C>T/c.74G>A of <it>hMYH </it>(T/A) increasing the risk for gastric cancer in Chinese. However, most investigations on correlation between <it>hMYH </it>and CRC are conducted in Western countries and the underlying mechanism has been poorly understood.</p> <p>Methods</p> <p>To determine whether the haplotype T/A variant of <it>hMYH </it>was related to colorectal carcinogenesis, we performed a case-control study in 138 colorectal cancer (CRC) patients and 343 healthy controls in a Chinese population. Furthermore, the C/G for wild-type, C/A or T/G for single base variant and T/A for haplotype variant <it>hMYH </it>cDNAs with a flag epitope tag were cloned into pcDNA3.1+ vector and transfected into cos-7 cell line. Their subcellular localizations were determined by immunofluorescence assay.</p> <p>Results</p> <p>It was found that the frequency of haplotype variant allele was statistically higher in CRC patients than that in controls (<it>P </it>= 0.02, odds ratio = 5.06, 95% confidence interval = 1.26 – 20.4). Similarly, significant difference of heterozygote frequency was indicated between the two groups (<it>P </it>= 0.019), while no homozygote was found. In addition, immunofluorescence analysis showed that hMYH protein with haplotype T/A variation presented in both nucleus and mitochondria, in contrast to the wild-type protein only converging in mitochondria. However, neither of the single missense mutations alone changed the protein subcelluar localization.</p> <p>Conclusion</p> <p>Although preliminarily, these results suggest that: the haplotype variant allele of <it>hMYH </it>leads to a missense protein, which partly affects the protein mitochondrial transportation and results as nuclear localization. This observation might be responsible for the increased susceptibility to cancers, including CRC, in Chinese.</p

    Non-standard management of breast cancer increases with age in the UK: a population based cohort of women â©Ÿ65 years

    Get PDF
    Evidence suggests that compared to younger women, older women are less likely to receive standard management for breast cancer. Whether this disparity persists once differences in tumour characteristics have been adjusted for has not been investigated in the UK. A retrospective cohort study involving case note review was undertaken, based on the North Western Cancer Registry database of women aged â©Ÿ65 years, resident in Greater Manchester with invasive breast cancer registered over a 1-year period (n=480). Adjusting for tumour characteristics associated with age by logistic regression analyses, older women were less likely to receive standard management than younger women for all indicators investigated. Compared to women aged 65–69 years, women aged â©Ÿ80 years with operable (stage 1–3a) breast cancer have increased odds of not receiving triple assessment (OR=5.5, 95% confidence interval (CI): 2.1–14.5), not receiving primary surgery (OR=43.0, 95% CI: 9.7–191.3), not undergoing axillary node surgery (OR=27.6, 95% CI: 5.6–135.9) and not undergoing tests for steroid receptors (OR=3.0, 95% CI: 1.7–5.5). Women aged 75–79 years have increased odds of not receiving radiotherapy following breast-conserving surgery compared to women aged 65–69 years (OR=11.0, 95% CI: 2.0–61.6). These results demonstrate that older women in the UK are less likely to receive standard management for breast cancer, compared to younger women and this disparity cannot be explained by differences in tumour characteristics
    • 

    corecore