5,304 research outputs found

    Evidence that MEK1 positively promotes interhomologue double-strand break repair

    Get PDF
    During meiosis there is an imperative to create sufficient crossovers for homologue segregation. This can be achieved during repair of programmed DNA double-strand breaks (DSBs), which are biased towards using a homologue rather than sister chromatid as a repair template. Various proteins contribute to this bias, one of which is a meiosis specific kinase Mek1. It has been proposed that Mek1 establishes the bias by creating a barrier to sister chromatid repair, as distinct from enforcing strand invasion with the homologue. We looked for evidence that Mek1 positively stimulates strand invasion of the homologue. This was done by analysing repair of DSBs induced by the VMA1- derived endonuclease (VDE) and flanked by directly repeated sequences that can be used for intrachromatid single-strand annealing (SSA). SSA competes with interhomologue strand inva- sion significantly more successfully when Mek1 function is lost. We suggest the increase in intrachromosomal SSA reflects an opportunistic default repair pathway due to loss of a MEK1 stimulated bias for strand invasion of the homologous chromosome. Making use of an inhibitor sensitive mek1-as1 allele, we found that Mek1 function influences the repair pathway throughout the first 4-5 h of meiosis. Perhaps reflecting a particular need to create bias for successful interhomologue events before chromosome pairing is complete. © The Author(s) 2010. Published by Oxford University Pres

    PyMT-Maclow: A novel, inducible, murine model for determining the role of CD68 positive cells in breast tumor development

    Get PDF
    CD68+ tumor-associated macrophages (TAMs) are pro-tumorigenic, pro-angiogenic and are associated with decreased survival rates in patients with cancer, including breast cancer. Non-specific models of macrophage ablation reduce the number of TAMs and limit the development of mammary tumors. However, the lack of specificity and side effects associated with these models compromise their reliability. We hypothesized that specific and controlled macrophage depletion would provide precise data on the effects of reducing TAM numbers on tumor development. In this study, the MacLow mouse model of doxycycline-inducible and selective CD68+ macrophage depletion was crossed with the murine mammary tumor virus (MMTV)-Polyoma virus middle T antigen (PyMT) mouse model of spontaneous ductal breast adenocarcinoma to generate the PyMT-MacLow line. In doxycycline-treated PyMT-MacLow mice, macrophage numbers were decreased in areas surrounding tumors by 43%. Reducing the number of macrophages by this level delayed tumor progression, generated less proliferative tumors, decreased the vascularization of carcinomas and down-regulated the expression of many pro-angiogenic genes. These results demonstrate that depleting CD68+ macrophages in an inducible and selective manner delays the development of mammary tumors and that the PyMT-MacLow model is a useful and unique tool for studying the role of TAMs in breast cancer

    Events, processes, and the time of a killing

    Get PDF
    The paper proposes a novel solution to the problem of the time of a killing (ToK), which persistently besets theories of act-individuation. The solution proposed claims to expose a crucial wrong-headed assumption in the debate, according to which ToK is essentially a problem of locating some event that corresponds to the killing. The alternative proposal put forward here turns on recognizing a separate category of dynamic occurents, viz. processes. The paper does not aim to mount a comprehensive defense of process ontology, relying instead on extant defenses. The primary aim is rather to put process ontology to work in diagnosing the current state of play over ToK, and indeed in solving it

    The utility of twins in developmental cognitive neuroscience research: How twins strengthen the ABCD research design

    Get PDF
    The ABCD twin study will elucidate the genetic and environmental contributions to a wide range of mental and physical health outcomes in children, including substance use, brain and behavioral development, and their interrelationship. Comparisons within and between monozygotic and dizygotic twin pairs, further powered by multiple assessments, provide information about genetic and environmental contributions to developmental associations, and enable stronger tests of causal hypotheses, than do comparisons involving unrelated children. Thus a sub-study of 800 pairs of same-sex twins was embedded within the overall Adolescent Brain and Cognitive Development (ABCD) design. The ABCD Twin Hub comprises four leading centers for twin research in Minnesota, Colorado, Virginia, and Missouri. Each site is enrolling 200 twin pairs, as well as singletons. The twins are recruited from registries of all twin births in each State during 2006–2008. Singletons at each site are recruited following the same school-based procedures as the rest of the ABCD study. This paper describes the background and rationale for the ABCD twin study, the ascertainment of twin pairs and implementation strategy at each site, and the details of the proposed analytic strategies to quantify genetic and environmental influences and test hypotheses critical to the aims of the ABCD study. Keywords: Twins, Heritability, Environment, Substance use, Brain structure, Brain functio

    Twenty-three unsolved problems in hydrology (UPH) – a community perspective

    Get PDF
    This paper is the outcome of a community initiative to identify major unsolved scientific problems in hydrology motivated by a need for stronger harmonisation of research efforts. The procedure involved a public consultation through online media, followed by two workshops through which a large number of potential science questions were collated, prioritised, and synthesised. In spite of the diversity of the participants (230 scientists in total), the process revealed much about community priorities and the state of our science: a preference for continuity in research questions rather than radical departures or redirections from past and current work. Questions remain focused on the process-based understanding of hydrological variability and causality at all space and time scales. Increased attention to environmental change drives a new emphasis on understanding how change propagates across interfaces within the hydrological system and across disciplinary boundaries. In particular, the expansion of the human footprint raises a new set of questions related to human interactions with nature and water cycle feedbacks in the context of complex water management problems. We hope that this reflection and synthesis of the 23 unsolved problems in hydrology will help guide research efforts for some years to come

    Associations between diurnal preference, sleep quality and externalizing behaviours: a behavioural genetic analysis

    Get PDF
    Background - Certain aspects of sleep co-occur with externalizing behaviours in youth, yet little is known about these associations in adults. The present study: (1) examines the associations between diurnal preference (morningness versus eveningness), sleep quality and externalizing behaviours; (2) explores the extent to which genetic and environmental influences are shared between or are unique to these phenotypes; (3) examines the extent to which genetic and environmental influences account for these associations. Method - Questionnaires assessing diurnal preference, sleep quality and externalizing behaviours were completed by 1556 young adult twins and siblings. Results - A preference for eveningness and poor sleep quality were associated with greater externalizing symptoms [r=0.28 (95% CI 0.23–0.33) and 0.34 (95% CI 0.28–0.39), respectively]. A total of 18% of the genetic influences on externalizing behaviours were shared with diurnal preference and sleep quality and an additional 14% were shared with sleep quality alone. Non-shared environmental influences common to the phenotypes were small (2%). The association between diurnal preference and externalizing behaviours was mostly explained by genetic influences [additive genetic influence (A)=80% (95% CI 0.56–1.01)], as was the association between sleep quality and externalizing behaviours [A=81% (95% CI 0.62–0.99)]. Non-shared environmental (E) influences accounted for the remaining variance for both associations [E=20% (95% CI −0.01 to 0.44) and 19% (95% CI 0.01–0.38), respectively]. Conclusions - A preference for eveningness and poor sleep quality are moderately associated with externalizing behaviours in young adults. There is a moderate amount of shared genetic influences between the phenotypes and genetic influences account for a large proportion of the association between sleep and externalizing behaviours. Further research could focus on identifying specific genetic polymorphisms common to both sleep and externalizing behaviours

    Influence of Behavioral State, Sex, and Season on Resource Selection by Jaguars (Panthera onca): Always on the Prowl?

    Get PDF
    How a predator uses its landscape to move through its territory and acquire prey is a fundamental question for scientific research. The influence of abiotic and biotic factors on space use of large carnivores has profound implications for their future management and conservation. In the Pantanal, Brazil, jaguars (Panthera onca) are the apex predator, but conflicts with cattle depredations pose a risk to their future conservation. We examined whether behavioral state, sex, and season influenced how jaguars used the landscape in the Pantanal. To accomplish this, we radio‐collared four females and six males; radio‐collared jaguars were monitored for 76 radio‐months with 11,787 GPS locations acquired. We developed resource selection functions (RSFs) examining how female and male jaguars used their landscape during three behavioral states (moving, killing native prey, killing cattle) during two seasons (dry, wet). From the RSF models, we found similar variables and relationships of landscape characteristics that jaguars selected for when moving and when depredating native prey and cattle. While moving, jaguars selected for locations that were either in dense cover or very near dense cover, with higher plant diversity and closer to water than available across the landscape. While null models suggested jaguars opportunistically depredated native prey in the dry season and cattle in the wet season, there was some indication they selected for specific landscape characteristics, mainly dense cover when killing cattle in the dry season and native prey in the wet season. Both sexes killed native prey and cattle within dense cover or close to dense cover as expected of an ambush predator. Particular habitat types were not important as long as there was dense cover for concealment. Additionally, jaguars killed prey closer to water than was available on the landscape. The similar variables across the models showed the importance of dense cover and distance to dense cover during all three behavioral states indicating jaguars in the Pantanal were “always on the prowl.” Understanding the spatial requirements for jaguars during the acquisition of native prey and cattle may lead to improved management strategies to allow for continued coexistence of jaguars in an area of traditional cattle production

    Influence of behavioral state, sex, and season on resource selection by jaguars (\u3ci\u3ePanthera onca\u3c/i\u3e): Always on the prowl?

    Get PDF
    How a predator uses its landscape to move through its territory and acquire prey is a fundamental question for scientific research. The influence of abiotic and biotic factors on space use of large carnivores has profound implications for their future management and conservation. In the Pantanal, Brazil, jaguars (Panthera onca) are the apex predator, but conflicts with cattle depredations pose a risk to their future conservation. We examined whether behavioral state, sex, and season influenced how jaguars used the landscape in the Pantanal. To accomplish this, we radio-collared four females and six males; radiocollared jaguars were monitored for 76 radio-months with 11,787 GPS locations acquired. We developed resource selection functions (RSFs) examining how female and male jaguars used their landscape during three behavioral states (moving, killing native prey, killing cattle) during two seasons (dry, wet). From the RSF models, we found similar variables and relationships of landscape characteristics that jaguars selected for when moving and when depredating native prey and cattle. While moving, jaguars selected for locations that were either in dense cover or very near dense cover, with higher plant diversity and closer to water than available across the landscape. While null models suggested jaguars opportunistically depredated native prey in the dry season and cattle in the wet season, there was some indication they selected for specific landscape characteristics, mainly dense cover when killing cattle in the dry season and native prey in the wet season. Both sexes killed native prey and cattle within dense cover or close to dense cover as expected of an ambush predator. Particular habitat types were not important as long as there was dense cover for concealment. Additionally, jaguars killed prey closer to water than was available on the landscape.The similar variables across the models showed the importance of dense cover and distance to dense cover during all three behavioral states indicating jaguars in the Pantanal were “always on the prowl.” Understanding the spatial requirements for jaguars during the acquisition of native prey and cattle may lead to improved management strategies to allow for continued coexistence of jaguars in an area of traditional cattle production

    Source regions of infragravity waves recorded at the bottom of the equatorial Atlantic Ocean, using OBS of the PI‐LAB experiment

    Get PDF
    Infragravity waves are generated along coasts, and some small fraction of their energy escapes to the open oceans and propagates with little attenuation. Due to the scarcity of deep‐ocean observations of these waves, the mechanism and the extent of the infragravity waves energy leakage from the coasts remains poorly understood. Understanding the generation and pathways of infragravity wave energy is important among others for understanding the breakup of ice‐shelves and the contamination of high‐resolution satellite radar altimetry measurements of sea level. We examine data from 37 differential pressure gauges of Ocean Bottom Seismometers (OBS) near the equatorial mid‐Atlantic ridge, deployed during the Passive Imaging of the Lithosphere‐Asthenosphere Boundary (PI‐LAB) experiment. We use the beamforming technique to investigate the incoming directions of infragravity waves. Next, we develop a graph‐theory‐based global back‐projection method of noise cross‐correlation function envelopes, which minimizes the effects of array geometry using an adaptive weighting scheme. This approach allows us to locate the sources of the infragravity energy. We assess our observations by comparing to a global model of infragravity wave heights. Our results reveal strong coherent energy from sources and/or reflected phases at the west coast of Africa and some sources from South America. These energy sources are in good agreement with the global infragravity wave model. In addition, we also observe infragravity waves arriving from North America during specific events that mostly occur during October–February 2016. Finally, we find indications of waves that propagate with little attenuation, long distances through sea ice, reflecting off Antarctica
    corecore