489 research outputs found

    The MRN complex is transcriptionally regulated by MYCN during neural cell proliferation to control replication stress

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    The MRE11/RAD50/NBS1 (MRN) complex is a major sensor of DNA double strand breaks, whose role in controlling faithful DNA replication and preventing replication stress is also emerging. Inactivation of the MRN complex invariably leads to developmental and/or degenerative neuronal defects, the pathogenesis of which still remains poorly understood. In particular, NBS1 gene mutations are associated with microcephaly and strongly impaired cerebellar development, both in humans and in the mouse model. These phenotypes strikingly overlap those induced by inactivation of MYCN, an essential promoter of the expansion of neuronal stem and progenitor cells, suggesting that MYCN and the MRN complex might be connected on a unique pathway essential for the safe expansion of neuronal cells. Here, we show that MYCN transcriptionally controls the expression of each component of the MRN complex. By genetic and pharmacological inhibition of the MRN complex in a MYCN overexpression model and in the more physiological context of the Hedgehog-dependent expansion of primary cerebellar granule progenitor cells, we also show that the MRN complex is required for MYCN-dependent proliferation. Indeed, its inhibition resulted in DNA damage, activation of a DNA damage response, and cell death in a MYCN- and replication-dependent manner. Our data indicate the MRN complex is essential to restrain MYCN-induced replication stress during neural cell proliferation and support the hypothesis that replication-born DNA damage is responsible for the neuronal defects associated with MRN dysfunctions.Cell Death and Differentiation advance online publication, 12 June 2015; doi:10.1038/cdd.2015.81

    Exploring rationales for branding a university: Should we be seeking to measure branding in UK universities?

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    Although branding is now widespread among UK universities, the application of branding principles in the higher education sector is comparatively recent and may be controversial for internal audiences who question its suitability and efficiency. This paper seeks to investigate how and whether the effectiveness of branding activity in the higher education sector should be evaluated and measured, through exploratory interviews with those who often drive it; UK University marketing professionals. Conclusions suggest that university branding is inherently complex and therefore application of commercial approaches may be over simplistic. Whilst marketing professionals discuss challenges they do not necessarily have a consistent view of the objectives of branding activity although all were able to clearly articulate branding objectives for their university, including both qualitative and, to some extent, quantitative metrics. Some measures of the real value of branding activity are therefore suggested but a key debate is perhaps whether the objectives and role of branding in higher education needs to be clarified, and a more consistent view of appropriate metrics reached? Various challenges in implementing branding approaches are also highlighted

    Imaging the square of the correlated two-electron wave function of a hydrogen molecule

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    The toolbox for imaging molecules is well-equipped today. Some techniques visualize the geometrical structure, others the electron density or electron orbitals. Molecules are many-body systems for which the correlation between the constituents is decisive and the spatial and the momentum distribution of one electron depends on those of the other electrons and the nuclei. Such correlations have escaped direct observation by imaging techniques so far. Here, we implement an imaging scheme which visualizes correlations between electrons by coincident detection of the reaction fragments after high energy photofragmentation. With this technique, we examine the H2two-electron wave function in which electron-electron correlation beyond the mean-field level is prominent. We visualize the dependence of the wave function on the internuclear distance. High energy photoelectrons are shown to be a powerful tool for molecular imaging. Our study paves the way for future time resolved correlation imaging at FELs and laser based X-ray sourcesThis work was funded by the Deutsche Forschungsgemeinschaft, the BMBF, the European Research Council under the European Union Seventh Framework Programme (FP7/2007-2013)/ERC grant agreement 290853 XCHEM, the MINECO projects FIS2013-42002-R and FIS2016-77889-R, and the European COST Action XLIC CM1204. All calculations were performed at the CCC-UAM and Mare Nostrum Supercomputer Centers. We are grateful to the staff of PETRA III for excellent support during the beam time. K.M. and M.M. would like to thank the DFG for support via SFB925/A3. A.K. and V.S. thank the Wilhelm und Else Heraeus-Foundation for support. J.L. would like to thank the DFG for support. S.K. acknowledges support from the European Cluster of Advanced Laser Light Sources (EUCALL) project which has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 654220. T.W. was supported by the U.S. Department of Energy Basic Energy Sciences under Contract No. DE-AC02-05CH11231. A.P. acknowledges a Ramón y Cajal contract from the Ministerio de Economa y Competitivida

    Butterflies as bioindicators of metal contamination

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    Anthropogenic trace metal contamination has significantly increased and has caused many hazardous consequences for the ecosystems and human health. The Terni basin valley (Central Italy) shows a heavy load of pollutants from industrial activities, while the characteristic orography structure of the valley favours air stagnation, thus limiting air pollution dispersal. The present study conducted in 2014 aimed to determine the concentration of ten metals in five species of butterflies at nine sites in the Terni valley along a 21-km-long transect, including both relatively pristine and industrial areas. At sites where soil contamination was high for a given metal, such as for chromium as in the case of site 4 (the closest to the steel plant) and for lead as in the case of site 2 (contaminated by a firing range), higher levels of contamination were observed in the tissues of butterflies. We found a correlation between soil contamination and the concentration of Cr, Al and Sr in the tissues of some species of butterflies. The sensitivity to contamination differed among the five species; in particular, Coenonympha pamphilus was generally the species that revealed the highest concentrations of all the ten trace metals at the sites closer to the industrial area. It is known that C. pamphilus is a sedentary species and that its host plants are the Poaceae, capable of accumulating high quantities of metals in their rhizosphere region, thus providing the link with soil contamination. Therefore, monitoring the metal concentration levels in butterflies might be a good indicator and a control tool of environmental quality, specifically in areas affected by high anthropogenic pollution loads linked to a specific source

    Influence of final state interactions in attosecond photoelectron interferometry

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    Fano resonances are ubiquitous phenomena appearing in many fields of physics, e.g., atomic or molecular photoionization, or electron transport in quantum dots. Recently, attosecond interferometric techniques have been used to measure the amplitude and phase of photoelectron wave packets close to Fano resonances in argon and helium, allowing for the retrieval of the temporal dynamics of the photoionization process. In this work, we study the photoionization of argon atoms close to the 3s13p64p autoionizing state using an interferometric technique with high spectral resolution. The phase shows a monotonic 2π variation across the resonance or a nonmonotonic less than π variation depending on experimental conditions, e.g., the probe laser bandwidth. Using three different, state-of-the-art calculations, we show that the measured phase is influenced by the interaction between final states reached by two-photon transitionsThe authors acknowledge support from the Swedish Research Council (2013-8185, 2016-04907, 2018-03731, 2020-0520, 2020-03315, 2020-06384, 2023-04603), the European Research Council (advanced grant QPAP, 884900) and the Knut and Alice Wallenberg Foundation. This work was developed in the framework of the COST action CA18222 Attosecond Chemistry (AttoChem) supported by European Cooperation in Science and Technology. A.L. and M.A. are partly supported by the Wallenberg Center for Quantum Technology (WACQT) funded by the Knut and Alice Wallenberg Foundation. L.A. and C.M. acknowledge the NSF Grant No. PHY-1912507. R.Y.B. and F.M. acknowledge the Ministerio de Ciencia e Innovacien MICINN (Spain) through projects PID2022-138288NB-C31 and PID2022-138288NB-C32, the Severo Ochoa Programme for Centres of Excellence in R & D (CEX2020-001039-S) and the Maria de Maeztu Programme for Units of Excellence in R & D (CEX2018-000805-M). xchem calculations were performed at the Marenostrum Barcelona Supercomputer Center of the R
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