226 research outputs found

    Genetically variant human pluripotent stem cells selectively eliminate wild-type counterparts through YAP-mediated cell competition

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    The appearance of genetic changes in human pluripotent stem cells (hPSCs) presents a concern for their use in research and regenerative medicine. Variant hPSCs that harbor recurrent culture-acquired aneuploidies display growth advantages over wild-type diploid cells, but the mechanisms that yield a drift from predominantly wild-type to variant cell populations remain poorly understood. Here, we show that the dominance of variant clones in mosaic cultures is enhanced through competitive interactions that result in the elimination of wild-type cells. This elimination occurs through corralling and mechanical compression by faster-growing variants, causing a redistribution of F-actin and sequestration of yes-associated protein (YAP) in the cytoplasm that induces apoptosis in wild-type cells. YAP overexpression or promotion of YAP nuclear localization in wild-type cells alleviates their “loser” phenotype. Our results demonstrate that hPSC fate is coupled to mechanical cues imposed by neighboring cells and reveal that hijacking this mechanism allows variants to achieve clonal dominance in cultures

    Effect of halo modelling on WIMP exclusion limits

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    WIMP direct detection experiments are just reaching the sensitivity required to detect galactic dark matter in the form of neutralinos. Data from these experiments are usually analysed under the simplifying assumption that the Milky Way halo is an isothermal sphere with maxwellian velocity distribution. Observations and numerical simulations indicate that galaxy halos are in fact triaxial and anisotropic. Furthermore, in the cold dark matter paradigm galactic halos form via the merger of smaller subhalos, and at least some residual substructure survives. We examine the effect of halo modelling on WIMP exclusion limits, taking into account the detector response. Triaxial and anisotropic halo models, with parameters motivated by observations and numerical simulations, lead to significant changes which are different for different experiments, while if the local WIMP distribution is dominated by small scale clumps then the exclusion limits are changed dramatically.Comment: 9 pages, 9 figures, version to appear in Phys. Rev. D, minor change

    Sorting Nexin 24 is required for α-granule biogenesis and cargo delivery in megakaryocytes

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    Germline defects affecting the DNA-binding domain of the transcription factor FLI1 are associated with a bleeding disorder that is characterised by the presence of large, fused α-granules in platelets. We investigated whether the genes showing abnormal expression in FLI1-deficient platelets could be involved in platelet α-granule biogenesis by undertaking transcriptome analysis of control platelets and platelets harbouring a DNA-binding variant of FLI1. Our analysis identified 2276 transcripts that were differentially expressed in FLI1- deficient platelets. Functional annotation clustering of the coding transcripts revealed significant enrichment for gene annotations relating to protein transport, and identified Sorting nexin 24 (SNX24) as a candidate for further investigation. Using an iPSC-derived megakaryocyte model, SNX24 expression was found to be increased during the early stages of megakaryocyte differentiation and downregulated during proplatelet formation, indicating tight regulatory control during megakaryopoiesis. CRISPR-Cas9 mediated knockout (KO) of SNX24 led to decreased expression of immature megakaryocyte markers, CD41 and CD61, and increased expression of the mature megakaryocyte marker CD42b (p=0.0001), without affecting megakaryocyte polyploidisation, or proplatelet formation. Electron microscopic analysis revealed an increase in empty membrane-bound organelles in SNX24 KO megakaryocytes, a reduction in α-granules and an absence of immature and mature multivesicular bodies, consistent with a defect in the intermediate stage of α-granule maturation. Co-localisation studies showed that SNX24 associates with each compartment of α-granule maturation. Reduced expression of CD62P and VWF was observed in SNX24 KO megakaryocytes. We conclude that SNX24 is required for α-granule biogenesis and intracellular trafficking of α-granule cargo within megakaryocytes

    Luminosity functions for galaxies and quasars in the Spitzer Wide-area Infrared Extragalactic Legacy Survey

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    We construct rest-frame luminosity functions (LFs) at 3.6, 4.5, 5.8, 8 and 24 ÎŒm over the redshift range 0 < z < 2 for galaxies and 0 < z < 4 for optical quasi-stellar objects (QSOs), using optical and infrared (IR) data from the Spitzer Wide-area Infrared Extragalactic (SWIRE) Survey. The 3.6- and 4.5-ÎŒm galaxy LFs show evidence for moderate positive luminosity evolution up to z∌ 1.5, consistent with the passive ageing of evolved stellar populations. Their comoving luminosity density was found to evolve passively, gradually increasing out to z∌ 0.5–1 but flattening, or even declining, at higher redshift. Conversely, the 24-ÎŒm galaxy LF, which is more sensitive to obscured star formation and/or active galactic nuclei (AGN) activity, undergoes strong positive evolution, with the derived IR energy density and star formation rate (SFR) density ∝ (1 +z)Îł with Îł= 4.5+0.7−0.6 and the majority of this evolution occurring since z∌ 1. Optical QSOs, however, show positive luminosity evolution in all bands, out to the highest redshifts (3 < z < 4). Modelling as L*∝ (1 +z)Îł gave Îł= 1.3+0.1−0.1 at 3.6 ÎŒm, Îł= 1.0+0.1−0.1 at 4.5 ÎŒm and stronger evolution at the longer wavelengths (5.8, 8 and 24 ÎŒm), of ÎłâˆŒ 3. Comparison of the galaxy LFs to predictions from a semi-analytic model based on cold dark matter (CDM) indicates that an initial mass function (IMF) skewed towards higher mass star formation in bursts compared to locally be preferred. As a result, the currently inferred massive SFRs in distant submm sources may require substantial downwards revision

    Fitting the integrated Spectral Energy Distributions of Galaxies

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    Fitting the spectral energy distributions (SEDs) of galaxies is an almost universally used technique that has matured significantly in the last decade. Model predictions and fitting procedures have improved significantly over this time, attempting to keep up with the vastly increased volume and quality of available data. We review here the field of SED fitting, describing the modelling of ultraviolet to infrared galaxy SEDs, the creation of multiwavelength data sets, and the methods used to fit model SEDs to observed galaxy data sets. We touch upon the achievements and challenges in the major ingredients of SED fitting, with a special emphasis on describing the interplay between the quality of the available data, the quality of the available models, and the best fitting technique to use in order to obtain a realistic measurement as well as realistic uncertainties. We conclude that SED fitting can be used effectively to derive a range of physical properties of galaxies, such as redshift, stellar masses, star formation rates, dust masses, and metallicities, with care taken not to over-interpret the available data. Yet there still exist many issues such as estimating the age of the oldest stars in a galaxy, finer details ofdust properties and dust-star geometry, and the influences of poorly understood, luminous stellar types and phases. The challenge for the coming years will be to improve both the models and the observational data sets to resolve these uncertainties. The present review will be made available on an interactive, moderated web page (sedfitting.org), where the community can access and change the text. The intention is to expand the text and keep it up to date over the coming years.Comment: 54 pages, 26 figures, Accepted for publication in Astrophysics & Space Scienc

    Effekte von Morphin, Fentanyl und Ketamin auf leukozytÀre Funktion, Transkriptionsfaktoren und Interleukin-8-Synthese

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    In der hier vorliegenden Arbeit wird der Einfluß der in der AnĂ€sthesie gebrĂ€uchlichen Analgetika Morphin, Fentanyl und Ketamin auf die Funktion neutrophiler Granulozyten dargelegt. Dazu wurden immunologische, durchflußzytometrische und molekularbiologische Untersuchungsverfahren eingesetzt. Die untersuchten Substanzen modulieren die Funktion, transkriptionelle Regulation und Proteinexpression von Granulozyten in unterschiedlicher Weise. Morphin hemmt die Funktion neutrophiler Granulozyten konzentrations- und zeitabhĂ€ngig. Erstmals wird dargestellt, daß der inhibitorische Effekt von Morphin auf die Phagozytose und den Oxidativen Burst durch die Freisetzung von NO als second messenger hervorgerufen wird. Die verminderte Expression von Komplement-, Fcg- und CD14-Rezeptoren korreliert mit diesen FunktionseinschrĂ€nkungen. Zudem reguliert Morphin die intrazellulĂ€re Signaltransduktion und fĂŒhrt dadurch zu einer Minderung der LPS-induzierten DNA-BindungsaktivitĂ€t der Transkriptionsfaktoren NF-kB und AP-1. Die hemmende Wirkung von Morphin auf transkriptionsregulierende Proteine wird in dieser Arbeit erstmals an humanen Leukozyten nachgewiesen. Dabei stellt die Morphin-abhĂ€ngige Freisetzung von NO das SchlĂŒsselereignis fĂŒr die hemmenden Effekte von Morphin dar: Durch NOS-Antagonisten kann die Morphin-induzierte Hemmung von Rezeptorenexpression, Granulozytenfunktion und Transkriptionsfaktoren verhindert werden, wĂ€hrend NO-Donoren die Morphin-Wirkung imitieren. Die Blockade von Opiatrezeptoren mit Naloxon hebt die inhibierende Wirkung von Morphin ebenfalls auf, so daß eine Bindung an NO-freisetzende ”-Rezeptoren auf Granulozyten als kausaler Mechanismus angesehen werden kann. Die Inhibierung der Transkriptionsfaktoren NF-kB und AP-1 korreliert im Vollblut nicht mit einer verminderten Produktion von IL-8 als NF-kB- bzw. AP-1-abhĂ€ngigem Mediator. Die exakten intrazellulĂ€ren Mechanismen und die funktionelle Bedeutung dieser Granulozyten-inhibierenden Effekte von Morphin auf das EntzĂŒndungsgeschehen mĂŒssen in zukĂŒnftigen Untersuchungen geklĂ€rt werden. Fentanyl zeigt weder aktivierende noch inhibierende Wirkungen auf Granulozytenfunktion und Expression von OberflĂ€chenrezeptoren. Grundlage hierfĂŒr kann die mangelnde AffinitĂ€t von Fentanyl fĂŒr die auf Leukozyten exprimierten Opiatrezeptoren sein. Basierend auf der Annahme, daß diese Substanz immunologisch inert ist, wurden Effekte auf transkriptionelle Regulation und Proteinsynthese nicht untersucht. Ketamin hemmt die Granulozytenfunktion und die Expression von Komplement-, Fcg- und CD14-Rezeptoren konzentrationsabhĂ€ngig, wobei die Dauer der Ketamin-Inkubation nicht von Bedeutung ist. Erstmals wird in dieser Arbeit ein inhibitorischer Effekt von Ketamin auf die LPS-induzierte DNA-BindungsaktivitĂ€t der Transkriptionsfaktoren NF-kB und AP-1 beschrieben, wobei konsekutiv die leukozytĂ€re Produktion von IL-8 auf transkriptioneller Ebene gehemmt wird. Das Ausmaß der Hemmung durch Ketamin hĂ€ngt dabei von der zur Stimulation eingesetzten LPS-Dosierung ab. Im Gegensatz zu Morphin-induzierten VerĂ€nderungen sind diese Effekte unabhĂ€ngig von NO als second messenger und werden nicht durch Opiat- oder NMDA-Rezeptoren vermittelt. Damit unterscheiden sich die Signaltransduktionswege Ketamin-vermittelter Effekte auf Immunzellen grundlegend von denjenigen, die fĂŒr die anĂ€sthetische und psychomimetische Wirkung dieser Substanz im ZNS verantwortlich sind. Enantiomer-spezifische Effekte spielen fĂŒr die immunsupprimierende Wirkung von Ketamin nur eine untergeordnete Rolle. Folgestudien sind erforderlich, um die an der Ketamin-abhĂ€ngigen Inhibierung beteiligten intrazellulĂ€ren Mediatoren und Stoffwechselwege in Leukozyten zu definieren. Der in dieser Studie erstmals zur Untersuchung von Analgetika-induzierten VerĂ€nderungen von Transkriptionsfaktoren angewandte durchflußzytometrische Vollblut-Assay weist eine hohe Reproduzierbarkeit auf, ermöglicht eine verlĂ€ĂŸliche und schnelle Quantifizierung des nukleĂ€ren NF-kB- bzw. AP-1-Gehalts und liefert mit klassischen Verfahren vergleichbare Ergebnisse. Bei dieser Technik kann auf eine Zellseparation verzichtet werden, so daß die physiologischen ZustĂ€nde im Vollblut berĂŒcksichtigt werden. Eine eventuelle Anwendung dieses Verfahrens zum Screening von Risikopatienten in AnĂ€sthesie und Intensivmedizin sollte in zukĂŒnftigen Untersuchungen evaluiert werden. Der differente Einfluß dieser Analgetika auf das Immunsystem sollte bei den verschiedenen Indikationen in AnĂ€sthesie, Intensivmedizin und Schmerztherapie Beachtung finden und in klinischen Studien weiter abgeklĂ€rt werden, um nicht nur eine effiziente Analgesie zu erzielen, sondern auch um etwaige Vor- bzw. Nachteile einer Immunmodulation durch diese Substanzen berĂŒcksichtigen zu können

    Anemia prevalence in women of reproductive age in low- and middle-income countries between 2000 and 2018

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    Anemia is a globally widespread condition in women and is associated with reduced economic productivity and increased mortality worldwide. Here we map annual 2000–2018 geospatial estimates of anemia prevalence in women of reproductive age (15–49 years) across 82 low- and middle-income countries (LMICs), stratify anemia by severity and aggregate results to policy-relevant administrative and national levels. Additionally, we provide subnational disparity analyses to provide a comprehensive overview of anemia prevalence inequalities within these countries and predict progress toward the World Health Organization’s Global Nutrition Target (WHO GNT) to reduce anemia by half by 2030. Our results demonstrate widespread moderate improvements in overall anemia prevalence but identify only three LMICs with a high probability of achieving the WHO GNT by 2030 at a national scale, and no LMIC is expected to achieve the target in all their subnational administrative units. Our maps show where large within-country disparities occur, as well as areas likely to fall short of the WHO GNT, offering precision public health tools so that adequate resource allocation and subsequent interventions can be targeted to the most vulnerable populations.Peer reviewe

    Search for the Chiral Magnetic Effect in Au+Au collisions at sNN=27\sqrt{s_{_{\rm{NN}}}}=27 GeV with the STAR forward Event Plane Detectors

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    A decisive experimental test of the Chiral Magnetic Effect (CME) is considered one of the major scientific goals at the Relativistic Heavy-Ion Collider (RHIC) towards understanding the nontrivial topological fluctuations of the Quantum Chromodynamics vacuum. In heavy-ion collisions, the CME is expected to result in a charge separation phenomenon across the reaction plane, whose strength could be strongly energy dependent. The previous CME searches have been focused on top RHIC energy collisions. In this Letter, we present a low energy search for the CME in Au+Au collisions at sNN=27\sqrt{s_{_{\rm{NN}}}}=27 GeV. We measure elliptic flow scaled charge-dependent correlators relative to the event planes that are defined at both mid-rapidity ∣η∣<1.0|\eta|<1.0 and at forward rapidity 2.1<∣η∣<5.12.1 < |\eta|<5.1. We compare the results based on the directed flow plane (Κ1\Psi_1) at forward rapidity and the elliptic flow plane (Κ2\Psi_2) at both central and forward rapidity. The CME scenario is expected to result in a larger correlation relative to Κ1\Psi_1 than to Κ2\Psi_2, while a flow driven background scenario would lead to a consistent result for both event planes[1,2]. In 10-50\% centrality, results using three different event planes are found to be consistent within experimental uncertainties, suggesting a flow driven background scenario dominating the measurement. We obtain an upper limit on the deviation from a flow driven background scenario at the 95\% confidence level. This work opens up a possible road map towards future CME search with the high statistics data from the RHIC Beam Energy Scan Phase-II.Comment: main: 8 pages, 5 figures; supplementary material: 2 pages, 1 figur

    Measurement of the cross section for isolated-photon plus jet production in pp collisions at √s=13 TeV using the ATLAS detector

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    The dynamics of isolated-photon production in association with a jet in proton–proton collisions at a centre-of-mass energy of 13 TeV are studied with the ATLAS detector at the LHC using a dataset with an integrated luminosity of 3.2 fb−1. Photons are required to have transverse energies above 125 GeV. Jets are identified using the anti- algorithm with radius parameter and required to have transverse momenta above 100 GeV. Measurements of isolated-photon plus jet cross sections are presented as functions of the leading-photon transverse energy, the leading-jet transverse momentum, the azimuthal angular separation between the photon and the jet, the photon–jet invariant mass and the scattering angle in the photon–jet centre-of-mass system. Tree-level plus parton-shower predictions from Sherpa and Pythia as well as next-to-leading-order QCD predictions from Jetphox and Sherpa are compared to the measurements
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