289 research outputs found

    Linkage studies in a Li-Fraumeni family with increased expression of p53 protein but no germline mutation in p53.

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    We report a family with the Li-Fraumeni syndrome (LFS) in whom we have been unable to detect a mutation in the coding sequence of the p53 gene. Analysis of linkage to three polymorphic markers within p53 enabled direct involvement of p53 to be excluded. This is the first example of a LFS family in whom exclusion of p53 has been possible. Four affected members of the family with sarcoma or premenopausal breast cancer showed increased expression of p53 protein in their normal tissues as detected by immunohistochemistry. It therefore appears that the LFS phenotype has been conferred by an aberrant gene, showing a dominant pattern of inheritance, which may be acting to compromise normal p53 function rather than by a mutation in p53 itself. In order to try to determine the chromosomal location of this putative gene, we have carried out studies of linkage to candidate loci. By these means we have excluded involvement of Rb1 and BRCA1 on chromosomes 13q and 17q respectively. The MDM2 oncogene on chromosome 12q was considered to be the prime candidate as MDM2 is amplified in sarcomas and the MDM2 product binds to p53. Furthermore, p53 mutation and amplification of MDM2 have been shown to be mutually exclusive events in tumour development. Linkage analysis to two polymorphic markers within MDM2 yielded a three-point LOD score of -5.4 at a recombination fraction theta equal to zero. Therefore MDM2 could be excluded. It is possible that the gene which is responsible for cancer susceptibility in this family, possibly via interaction with p53, will be important in the histogenesis of breast cancer in general. We are now carrying out further studies to locate and identify this gene

    Planktonic foraminiferal assemblages reflect warming during two recent mid-latitude marine heatwaves

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    Under future climate scenarios, ocean temperatures that are presently extreme and qualify as marine heatwaves (MHW) are forecasted to increase in frequency and intensity, but little is known about the impact of these events on one of the most common paleoproxies, planktonic foraminifera. Planktonic foraminifera are globally ubiquitous, shelled marine protists. Their abundances and geochemistry vary with ocean conditions and fossil specimens are commonly used to reconstruct ancient ocean conditions. Planktonic foraminiferal assemblages are known to vary globally with sea surface temperature, primary productivity, and other hydrographic conditions, but have not been studied in the context of mid-latitude MHWs. For this study, the community composition and abundance of planktonic foraminifera were quantified for 2010-2019 along the Newport Hydrographic Line, a long-term monitoring transect at 44.6°N in the Northern California Current (NCC). Samples were obtained from archived plankton tows spanning 46 to 370 km offshore during annual autumn (August – October) cruises. Two MHWs impacted the region during this timeframe: the first during 2014-2016 and a second, shorter duration MHW in 2019. During the 2014-2016 MHW, warm water subtropical and tropical foraminifera species were more prevalent than the typical polar, subpolar, and transitional species common to this region. Cold water species were abundant again after the first MHW dissipated in late 2016. During the second, shorter-duration MHW in 2019, the assemblage consisted of a warm water assemblage but did not include tropical species. The foraminiferal assemblage variability correlated with changes in temperature and salinity in the upper 100 meters and was not correlated with distance offshore or upwelling. These results suggest that fossil foraminiferal assemblages from deep sea sediment cores may provide insight into the magnitude and frequency of past MHWs

    DNA methylation dynamics of the human preimplantation embryo

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    In mammals, cytosine methylation is predominantly restricted to CpG dinucleotides and stably distributed across the genome, with local, cell type-specific regulation directed by DNA binding factors1-3. This comparatively static landscape dramatically contrasts the events of fertilization, where the paternal genome is globally reprogrammed. Paternal genome demethylation includes the majority of CpGs, though methylation is maintained at several notable features4-7. While these dynamics have been extensively characterized in the mouse, only limited observations are available in other mammals, and direct measurements are required to understand the extent to which early embryonic landscapes are conserved8-10. We present genome-scale DNA methylation maps of human preimplantation development and embryonic stem cell (ESC) derivation, confirming a transient state of global hypomethylation that includes most CpGs, while sites of persistent maintenance are primarily restricted to gene bodies. While most features share similar dynamics to mouse, maternally contributed methylation is divergently targeted to species-specific sets of CpG island (CGI) promoters that extend beyond known Imprint Control Regions (ICRs). Retrotransposon regulation is also highly diverse and transitions from maternally to embryonically expressed, species-specific elements. Together, our data confirm that paternal genome demethylation is a general attribute of early mammalian development that is characterized by distinct modes of epigenetic regulation

    The North American tree-ring fire-scar network

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    Fire regimes in North American forests are diverse and modern fire records are often too short to capture important patterns, trends, feedbacks, and drivers of variability. Tree-ring fire scars provide valuable perspectives on fire regimes, including centuries-long records of fire year, season, frequency, severity, and size. Here, we introduce the newly compiled North American tree-ring fire-scar network (NAFSN), which contains 2562 sites, >37,000 fire-scarred trees, and covers large parts of North America. We investigate the NAFSN in terms of geography, sample depth, vegetation, topography, climate, and human land use. Fire scars are found in most ecoregions, from boreal forests in northern Alaska and Canada to subtropical forests in southern Florida and Mexico. The network includes 91 tree species, but is dominated by gymnosperms in the genus Pinus. Fire scars are found from sea level to >4000-m elevation and across a range of topographic settings that vary by ecoregion. Multiple regions are densely sampled (e.g., >1000 fire-scarred trees), enabling new spatial analyses such as reconstructions of area burned. To demonstrate the potential of the network, we compared the climate space of the NAFSN to those of modern fires and forests; the NAFSN spans a climate space largely representative of the forested areas in North America, with notable gaps in warmer tropical climates. Modern fires are burning in similar climate spaces as historical fires, but disproportionately in warmer regions compared to the historical record, possibly related to under-sampling of warm subtropical forests or supporting observations of changing fire regimes. The historical influence of Indigenous and non-Indigenous human land use on fire regimes varies in space and time. A 20th century fire deficit associated with human activities is evident in many regions, yet fire regimes characterized by frequent surface fires are still active in some areas (e.g., Mexico and the southeastern United States). These analyses provide a foundation and framework for future studies using the hundreds of thousands of annually- to sub-annually-resolved tree-ring records of fire spanning centuries, which will further advance our understanding of the interactions among fire, climate, topography, vegetation, and humans across North America

    Study of the psi(2)(3823) and chi(c1)(3872) states in B+->(J/psi pi(+)pi(-))K(+)decays

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    The decays B+J/ψπ+πK+B^+\rightarrow J/\psi \pi^+ \pi^- K^+ are studied using a data set corresponding to an integrated luminosity of 9fb1^{-1} collected with the LHCb detector in proton-proton collisions between 2011 and 2018. Precise measurements of the ratios of branching fractions with the intermediate ψ2(3823)\psi_2(3823), χc1(3872)\chi_{c1}(3872) and ψ(2S)\psi(2S) states are reported. The decay of B+ψ2(3872)K+B^+\rightarrow \psi_2(3872)K^+ with ψ2(3823)Jψπ+π\psi_2(3823)\rightarrow J\psi\pi^+\pi^- is observed for the first time with a significance of 5.1 standard deviations. The mass differences between the ψ2(3823)\psi_2(3823), χc1(3872)\chi_{c1}(3872) and ψ(2S)\psi(2S) states are measured to be mχc1(3872)mψ2(3823)=47.50±0.53±0.13MeV/c2,mψ2(3823)mψ(2S)=137.98±0.53±0.14MeV/c2,mχc1(3872)mψ(2S)=185.49±0.06±0.03MeV/c2, \begin{array}{rcl} m_{\chi_{c1(3872)}} - m_{\psi_2(3823)} &= & 47.50 \pm 0.53 \pm 0.13\,\mathrm{MeV/}c^2\,, \\ m_{\psi_2(3823)} - m_{\psi(2S)} &= & 137.98 \pm 0.53 \pm 0.14\,\mathrm{MeV/}c^2\,, \\ m_{\chi_{c1}(3872)} - m_{\psi(2S)} &= & 185.49 \pm 0.06 \pm 0.03\,\mathrm{MeV/}c^2\,, \end{array} resulting in the most precise determination of the χc1(3782)\chi_{c1}(3782) mass. The width of the ψ2(3823)\psi_2(3823) state is found to be below 5.2MeV at 90\% confidence level. The Breit-Wigner width of the χc1(3872)\chi_{c1}(3872) state is measured to be Γχc1(3872)BW=0.960.18+0.19±0.21MeV, \Gamma^{\mathrm{BW}}_{\chi_{c1}(3872)} = 0.96^{+0.19}_{-0.18}\pm0.21 \mathrm{MeV}, which is inconsistent with zero by 5.5 standard deviations.Comment: 26 pages, 3 figures. All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2020-009.html (LHCb public pages

    Search for CP Violation in D-s(+) -> K-S(0)pi(+), D+ -> (KSK+)-K-0, and D+ -> phi pi(+) Decays

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    A search for charge-parity (CPCP) violation in Cabibbo-suppressed Ds+KS0π+D_s^+\to K_S^0 \pi^+, D+KS0K+D^+\to K_S^0 K^+ and D+ϕπ+D^+\to \phi \pi^+ decays is reported using proton-proton collision data, corresponding to an integrated luminosity of 3.8 fb1^{-1}, collected at a center-of-mass energy of 13 TeV with the LHCb detector. High-yield samples of kinematically and topologically similar Cabibbo-favored D(s)+D_{(s)}^+ decays are analyzed to subtract nuisance asymmetries due to production and detection effects, including those induced by CPCP violation in the neutral kaon system. The results are \begin{align*} \mathcal{A}_{CP}(D_s^+\to K_S^0 \pi^+) &=\left(\phantom{-}1.3\phantom{0}\pm1.9\phantom{0}\pm0.5\phantom{0}\right)\times10^{-3},\\ \mathcal{A}_{CP}(D^+\to K_S^0 K^+) &=\left(-0.09\pm0.65\pm0.48\right)\times10^{-3},\\ \mathcal{A}_{CP}(D^+\to \phi \pi^+) &=\left(\phantom{-}0.05\pm0.42\pm0.29\right)\times10^{-3}, \end{align*} where the first uncertainties are statistical and the second systematic. They are the most precise measurements of these quantities to date, and are consistent with CPCP symmetry.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2019-002.htm
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