Childhood intelligence predicts premature mortality : Results from a 40-year population-based longitudinal study

Acknowledgements This study was supported by a grant from the Luxembourg Fonds National de la Recherche (VIVRE FNR/06/09/18) and a PhD scholarship awarded to the first author by the Fonds National de la Recherche.Peer reviewedPostprin

Charakterisierung des STAT3-Signalwegs in der NFATc1-abhängigen Genese und Progression des Pankreaskarzinoms

Das duktale Adenokarzinom des Pankreas zählt zu den aggressivsten soliden Tumoren und ist durch eine ausgeprägte Resistenz gegenüber Standardchemotherapeutika sowie eine infauste Prognose gekennzeichnet. Detaillierte Untersuchungen der zugrunde lie-genden Mechanismen beschreiben eine zentrale Rolle inflammatorischer Signalwege in der Karzinogenese und Progression des Pankreaskarzinoms. In Vorarbeiten konnte un-sere Arbeitsgruppe den inflammatorischen Transkriptionsfaktor NFATc1 als wichtiges Onkogen in der Entzündungs-assoziierten Pankreaskarzinogenese identifizieren. Mole-kulare Analysen in diversen in vitro und in vivo Modellen des Pankreaskarzinoms erga-ben darüber hinaus, dass NFATc1 in einem hohen Prozentsatz humaner Pankreaskar-zinome überexprimiert wird und funktionell mit dem inflammatorischen Transkriptions-faktor STAT3 interagiert, um onkogene Gensignaturen während der Progression des Pankreaskarzinoms zu kontrollieren. Ziel dieser Arbeit war es, den Mechanismus der NFATc1:STAT3-abhängigen Genregu-lation genauer zu untersuchen und die Komplexbildung beider Partner an der DNA zu charakterisieren. Weiterhin sollte die biologische Relevanz eines konditionalen STAT3-Verlusts im Kontext einer pankreasspezifischen KRASG12D- sowie NFATc1-Aktivierung in einem transgenen Mausmodell in vivo analysiert werden. Die im Rahmen der vorliegenden Arbeit gewonnen Daten zeigen, dass die NFATc1-ab-hängige transkriptionelle Regulation onkogener Gensignaturen die Bindung des Tran-skriptionsfaktors an Enhancerregionen ausgewählter Zielgene voraussetzt. Im Gegen-satz dazu identifizierten ChIP-Analysen das NFATc1-Partnerprotein STAT3 an den je-weiligen Promotoren NFATc1-kontrollierter Zielgene. Darüber hinaus werden sowohl die NFATc1-Bindung an dessen Zielgenen sowie deren transkriptionelle Aktivierung durch NFATc1 maßgeblich von der Aktivität des IL-6-STAT3-Signalwegs determiniert. Diese Ergebnisse suggerieren eine Enhancer-Promotor-Loop-Formation als Mechanismus der Transkriptionskontrolle onkogener Signaturen durch NFATc1:STAT3 Komplexe. Um die biologische Relevanz dieser Interaktion in vivo zu untersuchen, wurde ein trans-genes Mausmodell generiert, das zusätzlich zu den konstitutiven Aktivierungen von KRASG12D und NFATc1 einen Verlust der STAT3-Expression im Pankreas aufweist. Diese Mäuse zeigten entgegen der Erwartungen eine beschleunigte Pankreaskarzinom-progression und eine deutlich verringerte mittlere Überlebenszeit von nur 60 Tagen gegenüber ihren Wurfgeschwistern ohne pankreasspezifischen STAT3-Verlust. Morpholo-gisch waren die Pankreaskarzinome STAT3-defizienter Mäuse durch eine ausgeprägte Zunahme des stromalen Tumoranteils gekennzeichnet. Diese Arbeit unterstreicht die onkogenen Funktionen von NFATc1 in der Karzinogenese und Progression des Pankreaskarzinoms und identifiziert die Komplexbildung mit STAT3 als zentralen transkriptionellen Mechanismus für die Kontrolle onkogener Gensignaturen im inflammations-assoziierten Pankreaskarzinom. Trotz der Charakterisierung von NFATc1 als vielversprechende Zielstruktur in der Behandlung des Pankreaskarzinoms existieren bis dato keine therapeutischen Strategien, die eine spezifische pharmakologi-sche Inhibition von NFATc1 in der Tumorzelle ermöglichen. Vor dem Hintergrund erfolgsversprechender Daten einer aktuellen klinischen Studie zur Inhibition des Jak/STAT3-Signalwegs in der Therapie des Pankreaskarzinoms und der hier beschriebenen zentralen Funktion von STAT3 in der NFATc1-abhängigen Tran-skriptionskontrolle erscheint die pharmakologische Inhibition des NFATc1-Partnerpro-teins STAT3 ein vielversprechender indirekter therapeutischer Ansatz für die Blockade der NFATc1-vermittelten Tumorprogression zu sein. Die beschleunigte Tumorprogres-sion im STAT3-defizienten in vivo Modell auf der Basis einer konstitutiven NFATc1-Akti-vierung hingegen deutet darauf hin, dass eine Inhibition des Jak/STAT3-Signalwegs v.a. in NFATc1-negativen Pankreaskarzinomen wirksam sein könnte und unterstreicht somit die Notwendigkeit der molekularen Stratifizierung für die Therapie dieser heterogenen Tumorerkrankung

CAMELS-CH: hydro-meteorological time series and landscape attributes for 331 catchments in hydrologic Switzerland

We present CAMELS-CH (Catchment Attributes and MEteorology for Large-sample Studies – Switzerland), a large-sample hydro-meteorological data set for hydrologic Switzerland in central Europe. This domain covers 331 basins within Switzerland and neighboring countries. About one-third of the catchments are located in Austria, France, Germany and Italy. As an Alpine country, Switzerland covers a vast diversity of landscapes, including mountainous environments, karstic regions, and several strongly cultivated regions, along with a wide range of hydrological regimes, i.e., catchments that are glacier-, snow- or rain dominated. Similar to existing data sets, CAMELS-CH comprises dynamic hydro-meteorological variables and static catchment attributes. CAMELS-CH (Höge et al., 2023; available at https://doi.org/10.5281/zenodo.7784632) encompasses 40 years of data between 1 January 1981 and 31 December 2020, including daily time series of stream flow and water levels, and of meteorological data such as precipitation and air temperature. It also includes daily snow water equivalent data for each catchment starting from 2 September 1998. Additionally, we provide annual time series of land cover change and glacier evolution per catchment. The static catchment attributes cover location and topography, climate, hydrology, soil, hydrogeology, geology, land use, human impact and glaciers. This Swiss data set complements comparable publicly accessible data sets, providing data from the “water tower of Europe”

Cytosolic 5'-nucleotidase 1A is overexpressed in pancreatic cancer and mediates gemcitabine resistance by reducing intracellular gemcitabine metabolites.

BACKGROUND: Cytosolic 5'-nucleotidase 1A (NT5C1A) dephosphorylates non-cyclic nucleoside monophosphates to produce nucleosides and inorganic phosphates. Here, we investigate NT5C1A expression in pancreatic ductal adenocarcinoma (PDAC) and its impact on gemcitabine metabolism and therapeutic efficacy. METHODS: NT5C1A expression was determined by semiquantitative immunohistochemistry using tissue microarrays. Gemcitabine metabolites and response were assessed in several human and murine PDAC cell lines using crystal violet assays, Western blot, viability assays, and liquid chromatography tandem mass-spectrometry (LC-MS/MS). FINDINGS: NT5C1A was strongly expressed in tumor cells of a large subgroup of resected PDAC patients in two independent patient cohorts (44-56% score 2 and 8-26% score 3, n = 414). In contrast, NT5C1A was expressed at very low levels in the tumor stroma, and neither stromal nor tumoral expression was a prognostic marker for postoperative survival. In vitro, NT5C1A overexpression increased gemcitabine resistance by reducing apoptosis levels and significantly decreased intracellular amounts of cytotoxic dFdCTP in +NT5C1A tumor cells. Co-culture experiments with conditioned media from +NT5C1A PSCs improved gemcitabine efficacy in tumor cells. In vivo, therapeutic efficacy of gemcitabine was significantly decreased and serum levels of the inactive gemcitabine metabolite dFdU significantly increased in mice bearing NT5C1A overexpressing tumors. INTERPRETATION: NT5C1A is robustly expressed in tumor cells of resected PDAC patients. Moreover, NT5C1A mediates gemcitabine resistance by decreasing the amount of intracellular dFdCTP, leading to reduced tumor cell apoptosis and larger pancreatic tumors in mice. Further studies should clarify the role of NT5C1A as novel predictor for gemcitabine treatment response in patients with PDAC

Bratislava Statement: consensus recommendations for improving pancreatic cancer care

Pancreatic cancer is one of the most lethal tumours, and it is the fourth cause of cancer death in Europe. Despite its important public health impact, no effective treatments exist, nor are there high-visibility research efforts to improve care. This alarming situation is emblematic of a larger group of cancer diseases, known as neglected cancers. To address the impact of these diseases, the European Commission-supported Innovative Partnership for Action Against Cancer launched a multi-stakeholder initiative to determine key steps that healthcare systems can rapidly implement to improve their response. A working group comprising 20 representatives from European medical societies, patient associations, cancer plan organisations and other relevant European healthcare stakeholders was organised. A consensus process based on the results of different studies, discussion of research outcomes, and development and endorsement of draft statements resulted in 22 consensus recommendations (the Bratislava Statement). The statement argues that substantial improvements can be achieved in patient outcomes by centralising pancreatic cancer care around state-of-the-art reference centres, staffed by expert multidisciplinary teams capable of providing high-quality care. This organisational model requires a specific care framework encompassing primary, palliative and survivorship care, and a policy environment prioritising the use of quality criteria and performance assessments as well as research investments dedicated to prevention, risk prediction, early detection and diagnosis. In order to address the challenges posed by neglected cancers in general and pancreatic cancer in particular, a specific control strategy tailored to this reality is required

USP9X stabilizes XIAP to regulate mitotic cell death and chemoresistance in aggressive B-cell lymphoma

The mitotic spindle assembly checkpoint (SAC) maintains genome stability and marks an important target for antineoplastic therapies. However, it has remained unclear how cells execute cell fate decisions under conditions of SAC‐induced mitotic arrest. Here, we identify USP9X as the mitotic deubiquitinase of the X‐linked inhibitor of apoptosis protein (XIAP) and demonstrate that deubiquitylation and stabilization of XIAP by USP9X lead to increased resistance toward mitotic spindle poisons. We find that primary human aggressive B‐cell lymphoma samples exhibit high USP9X expression that correlate with XIAP overexpression. We show that high USP9X/XIAP expression is associated with shorter event‐free survival in patients treated with spindle poison‐containing chemotherapy. Accordingly, aggressive B‐cell lymphoma lines with USP9X and associated XIAP overexpression exhibit increased chemoresistance, reversed by specific inhibition of either USP9X or XIAP. Moreover, knockdown of USP9X or XIAP significantly delays lymphoma development and increases sensitivity to spindle poisons in a murine Eμ‐Myc lymphoma model. Together, we specify the USP9X–XIAP axis as a regulator of the mitotic cell fate decision and propose that USP9X and XIAP are potential prognostic biomarkers and therapeutic targets in aggressive B‐cell lymphoma

Mapping and assessment of forest ecosystems and their services - Applications and guidance for decision making in the framework of MAES

The aim of this report is to illustrate by means of a series of case studies the implementation of mapping and assessment of forest ecosystem services in different contexts and geographical levels. Methodological aspects, data issues, approaches, limitations, gaps and further steps for improvement are analysed for providing good practices and decision making guidance. The EU initiative on Mapping and Assessment of the state of Ecosystems and their Services (MAES), with the support of all Member States, contributes to improve the knowledge on ecosystem services. MAES is one of the building-block initiatives supporting the EU Biodiversity Strategy to 2020.JRC.H.3-Forest Resources and Climat

Joint Constraints on Galactic Diffuse Neutrino Emission from the ANTARES and IceCube Neutrino Telescopes

[EN] The existence of diffuse Galactic neutrino production is expected from cosmic-ray interactions with Galactic gas and radiation ¿elds. Thus, neutrinos are a unique messenger offering the opportunity to test the products of Galactic cosmic-ray interactions up to energies of hundreds of TeV. Here we present a search for this production using ten years of Astronomy with a Neutrino Telescope and Abyss environmental RESearch (ANTARES) track and shower data, as well as seven years of IceCube track data. The data are combined into a joint likelihood test for neutrino emission according to the KRAg model assuming a 5 PeV per nucleon Galactic cosmic-ray cutoff. No signi¿cant excess is found. As a consequence, the limits presented in this Letter start constraining the model parameter space for Galactic cosmic-ray production and transport.Albert, A.; Andre, M.; Anghinolfi, M.; Ardid Ramírez, M.; Aubert, J-.; Aublin, J.; Avgitas, T.... (2018). Joint Constraints on Galactic Diffuse Neutrino Emission from the ANTARES and IceCube Neutrino Telescopes. The Astrophysical Journal. 868(2):1-7. https://doi.org/10.3847/2041-8213/aaeecfS178682Aartsen, M. G., Ackermann, M., Adams, J., Aguilar, J. A., Ahlers, M., Ahrens, M., … Anderson, T. (2017). Search for Astrophysical Sources of Neutrinos Using Cascade Events in IceCube. The Astrophysical Journal, 846(2), 136. doi:10.3847/1538-4357/aa8508Aartsen, M. G., Abraham, K., Ackermann, M., Adams, J., Aguilar, J. A., Ahlers, M., … Archinger, M. (2015). A COMBINED MAXIMUM-LIKELIHOOD ANALYSIS OF THE HIGH-ENERGY ASTROPHYSICAL NEUTRINO FLUX MEASURED WITH ICECUBE. The Astrophysical Journal, 809(1), 98. doi:10.1088/0004-637x/809/1/98Aartsen, M. G., Abraham, K., Ackermann, M., Adams, J., Aguilar, J. A., Ahlers, M., … Anderson, T. (2017). All-sky Search for Time-integrated Neutrino Emission from Astrophysical Sources with 7 yr of IceCube Data. The Astrophysical Journal, 835(2), 151. doi:10.3847/1538-4357/835/2/151Aartsen, M. G., Ackermann, M., Adams, J., Aguilar, J. A., Ahlers, M., Ahrens, M., … Anderson, T. (2017). Constraints on Galactic Neutrino Emission with Seven Years of IceCube Data. The Astrophysical Journal, 849(1), 67. doi:10.3847/1538-4357/aa8dfbAartsen, M. G., Ackermann, M., Adams, J., Aguilar, J. A., Ahlers, M., Ahrens, M., … Ansseau, I. (2017). The IceCube Neutrino Observatory: instrumentation and online systems. Journal of Instrumentation, 12(03), P03012-P03012. doi:10.1088/1748-0221/12/03/p03012Ackermann, M., Ajello, M., Atwood, W. B., Baldini, L., Ballet, J., Barbiellini, G., … Berenji, B. (2012). FERMI-LAT OBSERVATIONS OF THE DIFFUSE γ-RAY EMISSION: IMPLICATIONS FOR COSMIC RAYS AND THE INTERSTELLAR MEDIUM. The Astrophysical Journal, 750(1), 3. doi:10.1088/0004-637x/750/1/3Adrián-Martínez, S., Ageron, M., Aguilar, J. A., Samarai, I. A., Albert, A., André, M., … Ardid, M. (2012). The positioning system of the ANTARES Neutrino Telescope. Journal of Instrumentation, 7(08), T08002-T08002. doi:10.1088/1748-0221/7/08/t08002Ageron, M., Aguilar, J. A., Al Samarai, I., Albert, A., Ameli, F., André, M., … Ardid, M. (2011). ANTARES: The first undersea neutrino telescope. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 656(1), 11-38. doi:10.1016/j.nima.2011.06.103Ahn, H. S., Allison, P., Bagliesi, M. G., Beatty, J. J., Bigongiari, G., Childers, J. T., … Zinn, S. Y. (2010). DISCREPANT HARDENING OBSERVED IN COSMIC-RAY ELEMENTAL SPECTRA. The Astrophysical Journal, 714(1), L89-L93. doi:10.1088/2041-8205/714/1/l89Albert, A., André, M., Anghinolfi, M., Anton, G., Ardid, M., Aubert, J.-J., … Basa, S. (2017). New constraints on all flavor Galactic diffuse neutrino emission with the ANTARES telescope. Physical Review D, 96(6). doi:10.1103/physrevd.96.062001Antoni, T., Apel, W. D., Badea, A. F., Bekk, K., Bercuci, A., Blümer, J., … Zabierowski, J. (2005). KASCADE measurements of energy spectra for elemental groups of cosmic rays: Results and open problems. Astroparticle Physics, 24(1-2), 1-25. doi:10.1016/j.astropartphys.2005.04.001Apel, W. D., Arteaga-Velázquez, J. C., Bekk, K., Bertaina, M., Blümer, J., Bozdog, H., … Cossavella, F. (2013). KASCADE-Grande measurements of energy spectra for elemental groups of cosmic rays. Astroparticle Physics, 47, 54-66. doi:10.1016/j.astropartphys.2013.06.004Gaggero, D., Grasso, D., Marinelli, A., Taoso, M., & Urbano, A. (2017). Diffuse Cosmic Rays Shining in the Galactic Center: A Novel Interpretation of H.E.S.S. and Fermi-LAT γ -Ray Data. Physical Review Letters, 119(3). doi:10.1103/physrevlett.119.031101Gaggero, D., Grasso, D., Marinelli, A., Urbano, A., & Valli, M. (2015). THE GAMMA-RAY AND NEUTRINO SKY: A CONSISTENT PICTURE OF FERMI -LAT, MILAGRO, AND ICECUBE RESULTS. The Astrophysical Journal, 815(2), L25. doi:10.1088/2041-8205/815/2/l25Gaggero, D., Urbano, A., Valli, M., & Ullio, P. (2015). Gamma-ray sky points to radial gradients in cosmic-ray transport. Physical Review D, 91(8). doi:10.1103/physrevd.91.083012Vladimirov, A. E., Digel, S. W., Jóhannesson, G., Michelson, P. F., Moskalenko, I. V., Nolan, P. L., … Strong, A. W. (2011). GALPROP WebRun: An internet-based service for calculating galactic cosmic ray propagation and associated photon emissions. Computer Physics Communications, 182(5), 1156-1161. doi:10.1016/j.cpc.2011.01.01

MUSiC : a model-unspecific search for new physics in proton-proton collisions at root s=13TeV

Results of the Model Unspecific Search in CMS (MUSiC), using proton-proton collision data recorded at the LHC at a centre-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 35.9 fb(-1), are presented. The MUSiC analysis searches for anomalies that could be signatures of physics beyond the standard model. The analysis is based on the comparison of observed data with the standard model prediction, as determined from simulation, in several hundred final states and multiple kinematic distributions. Events containing at least one electron or muon are classified based on their final state topology, and an automated search algorithm surveys the observed data for deviations from the prediction. The sensitivity of the search is validated using multiple methods. No significant deviations from the predictions have been observed. For a wide range of final state topologies, agreement is found between the data and the standard model simulation. This analysis complements dedicated search analyses by significantly expanding the range of final states covered using a model independent approach with the largest data set to date to probe phase space regions beyond the reach of previous general searches.Peer reviewe

Measurement of prompt open-charm production cross sections in proton-proton collisions at root s=13 TeV

The production cross sections for prompt open-charm mesons in proton-proton collisions at a center-of-mass energy of 13TeV are reported. The measurement is performed using a data sample collected by the CMS experiment corresponding to an integrated luminosity of 29 nb(-1). The differential production cross sections of the D*(+/-), D-+/-, and D-0 ((D) over bar (0)) mesons are presented in ranges of transverse momentum and pseudorapidity 4 < p(T) < 100 GeV and vertical bar eta vertical bar < 2.1, respectively. The results are compared to several theoretical calculations and to previous measurements.Peer reviewe