4,976 research outputs found

    Positive regulation of meiotic DNA double-strand break formation by activation of the DNA damage checkpoint kinase Mec1(ATR)

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    During meiosis, formation and repair of programmed DNA double-strand breaks (DSBs) create genetic exchange between homologous chromosomes-a process that is critical for reductional meiotic chromosome segregation and the production of genetically diverse sexually reproducing populations. Meiotic DSB formation is a complex process, requiring numerous proteins, of which Spo11 is the evolutionarily conserved catalytic subunit. Precisely how Spo11 and its accessory proteins function or are regulated is unclear. Here, we use Saccharomyces cerevisiae to reveal that meiotic DSB formation is modulated by the Mec1(ATR) branch of the DNA damage signalling cascade, promoting DSB formation when Spo11-mediated catalysis is compromised. Activation of the positive feedback pathway correlates with the formation of single-stranded DNA (ssDNA) recombination intermediates and activation of the downstream kinase, Mek1. We show that the requirement for checkpoint activation can be rescued by prolonging meiotic prophase by deleting the NDT80 transcription factor, and that even transient prophase arrest caused by Ndt80 depletion is sufficient to restore meiotic spore viability in checkpoint mutants. Our observations are unexpected given recent reports that the complementary kinase pathway Tel1(ATM) acts to inhibit DSB formation. We propose that such antagonistic regulation of DSB formation by Mec1 and Tel1 creates a regulatory mechanism, where the absolute frequency of DSBs is maintained at a level optimal for genetic exchange and efficient chromosome segregation

    A uniform analysis of HD209458b Spitzer/IRAC lightcurves with Gaussian process models

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    We present an analysis of Spitzer/IRAC primary transit and secondary eclipse lightcurves measured for HD209458b, using Gaussian process models to marginalise over the intrapixel sensitivity variations in the 3.6 micron and 4.5 micron channels and the ramp effect in the 5.8 micron and 8.0 micron channels. The main advantage of this approach is that we can account for a broad range of degeneracies between the planet signal and systematics without actually having to specify a deterministic functional form for the latter. Our results do not confirm a previous claim of water absorption in transmission. Instead, our results are more consistent with a featureless transmission spectrum, possibly due to a cloud deck obscuring molecular absorption bands. For the emission data, our values are not consistent with the thermal inversion in the dayside atmosphere that was originally inferred from these data. Instead, we agree with another re-analysis of these same data, which concluded a non-inverted atmosphere provides a better fit. We find that a solar-abundance clear-atmosphere model without a thermal inversion underpredicts the measured emission in the 4.5 micron channel, which may suggest the atmosphere is depleted in carbon monoxide. An acceptable fit to the emission data can be achieved by assuming that the planet radiates as an isothermal blackbody with a temperature of 1484±181484\pm 18 K.Comment: 18 pages, 5 figures, 6 tables. Accepted by MNRA

    Utilising family-based designs for detecting rare variant disease associations.

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    Rare genetic variants are thought to be important components in the causality of many diseases but discovering these associations is challenging. We demonstrate how best to use family-based designs to improve the power to detect rare variant disease associations. We show that using genetic data from enriched families (those pedigrees with greater than one affected member) increases the power and sensitivity of existing case-control rare variant tests. However, we show that transmission- (or within-family-) based tests do not benefit from this enrichment. This means that, in studies where a limited amount of genotyping is available, choosing a single case from each of many pedigrees has greater power than selecting multiple cases from fewer pedigrees. Finally, we show how a pseudo-case-control design allows a greater range of statistical tests to be applied to family data

    Events, processes, and the time of a killing

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    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 Genetic and Environmental Sources of Resemblance Between Normative Personality and Personality Disorder Traits

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    Recent work has suggested a high level of congruence between normative personality, most typically represented by the big five factors, and abnormal personality traits. In 2,293 Norwegian adult twins ascertained from a population-based registry, the authors evaluated the degree of sharing of genetic and environmental influences on normative personality, assessed by the Big Five Inventory (BFI), and personality disorder traits (PDTs), assessed by the Personality Inventory for DSM-S-Norwegian Brief Form (PID-5NBF). For four of the five BFI dimensions, the strongest genetic correlation was observed with the expected PID-5-NBF dimension (e.g., neuroticism with negative affectivity [+], conscientiousness with disinhibition [-]). However, neuroticism, conscientiousness, and agreeableness had substantial genetic correlations with other PID-S-NBF dimensions (e.g., neuroticism with compulsivity [+], agreeableness with detachment [-]). Openness had no substantial genetic correlations with any PID-5-NBF dimension. The proportion of genetic risk factors shared in aggregate between the BFI traits and the PID-5-NBF dimensions was quite high for conscientiousness and neuroticism, relatively robust for extraversion and agreeableness, but quite low for openness. Of the six PID-S-NBF dimensions, three (negative affectivity, detachment, and disinhibition) shared, in aggregate, most of their genetic risk factors with normative personality traits. Genetic factors underlying psychoticism, antagonism, and compulsivity were shared to a lesser extent, suggesting that they are influenced by etiological factors not well indexed by the BFI

    Context Dependence, MOPs,WHIMs and procedures Recanati and Kaplan on Cognitive Aspects in Semantics

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    After presenting Kripke’s criticism to Frege’s ideas on context dependence of thoughts, I present two recent attempts of considering cognitive aspects of context dependent expressions inside a truth conditional pragmatics or semantics: Recanati’s non-descriptive modes of presentation (MOPs) and Kaplan’s ways of having in mind (WHIMs). After analysing the two attempts and verifying which answers they should give to the problem discussed by Kripke, I suggest a possible interpretation of these attempts: to insert a procedural or algorithmic level in semantic representations of indexicals. That a function may be computed by different procedures might suggest new possibilities of integrating contextual cognitive aspects in model theoretic semanti

    Minimising medicine use in organic dairy herds through animal health and welfare planning

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    Livestock is important in many organic farming systems, and it is an explicit goal to ensure high levels of animal health and welfare (AHW) through good management. This will lead to reduced medicine use and better quality of animal products. In two EU network projects NAHWOA & SAFO it was concluded that this is not guaranteed merely by following organic standards. Both networks recommended implementation of individual animal health plans to stimulate organic farmers to improve AHW. These plans should include a systematic evaluation of AHW and be implemented through dialogue with each farmer in order to identify goals and plan improvements. 15 research institutions in 8 European countries are involved in the proposed project with the main objective to minimise medicine use in organic dairy herds through active and well planned AHW promotion and disease prevention. The project consists of 5 work packages, 4 of which comprise research activities building on current research projects, new applications across borders, exchange of knowledge, results and conclusions between participating countries, and adopting them to widely different contexts. International and national workshops facilitate this exchange. Focus areas are animal health planning, AHW assessment using animal based parameters and development of advisory systems and farmer groups. Epidemiological analyses of the effect on AHW from reduced medicine use and herd improvements are planned in all participating countries

    PAH- and PCB-induced Alterations of Protein Tyrosine Kinase and Cytokine Gene Transcription in Harbor Seal (Phoca Vitulina) PBMC

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    Mechanisms underlying in vitro immunomodulatory effects of polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs) were investigated in harbor seal peripheral leukocytes, via real-time PCR. We examined the relative genetic expression of the protein tyrosine kinases (PTKs) Fyn and Itk, which play a critical role in T cell activation, and IL-2, a cytokine of central importance in initiating adaptive immune responses. IL-1, the macrophage-derived pro-inflammatory cytokine of innate immunity, was also included as a measure of macrophage function. Harbor seal PBMC were exposed to the prototypic immunotoxic PAH benzo[a]pyrene (BaP), 3,3',4,4',5,5'-hexachlorobiphenyl (CB-169), a model immunotoxic PCB, or DMSO (vehicle control). Exposure of Con A-stimulated harbor seal PBMC to both BaP and CB-169 produced significantly altered expression in all four targets relative to vehicle controls. The PTKs Fyn and Itk were both up-regulated following exposure to BaP and CB-169. In contrast, transcripts for IL-2 and IL-1 were decreased relative to controls by both treatments. Our findings are consistent with those of previous researchers working with human and rodent systems and support a hypothesis of contaminant-altered lymphocyte function mediated (at least in part) by disruption of T cell receptor (TCR) signaling and cytokine production

    Vulnerability to bullying in children with a history of specific speech and language difficulties

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    This is an electronic version of an article published in Lindsay, Geoff and Dockrell, Julie and Mackie, Clare (2008) Vulnerability to bullying in children with a history of specific speech and language difficulties. European Journal of Special Needs Education, 23 (1). pp. 1-16. European Journal of Special Needs Education is available online at: http://www.informaworld.com/10.1080/0885625070179120
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