Fanning the flames: How the European Union is fuelling a new arms race - Executive Summary

At the time of writing in March 2022, a war has broken out in eastern Europe following the illegal invasion of Ukraine by Russian troops. Towards the end of 2021 unrest in the Balkans came close to boiling point. Tensions in the South China Sea continue to simmer and threaten regional and global stability. Wars and violence continue in Afghanistan, in Central Africa, Iraq, several countries across the Sahel, Syria, and Yemen among other countries and regions experiencing constant violence and consequent displacement. Some of the world's most powerful nations are sabre-rattling, drafting and deploying troops, stockpiling military materiel, and actively preparing for war – including the European Union (EU) and some of its member states. Contrary to the EU's founding principle of promoting peace, it too has been charting a course to establish itself as a global military power. History has shown, however, that far from contributing to stability and peace, militarism fuels tension, instability, destruction and devastation.In a 'watershed moment', in response to the war in Ukraine, the EU announced that it would, for the first time, fund and supply lethal weapons to a country under attack through the European Peace Facility (EPF). While this move is unprecedented, it is not unexpected. The EU has been pursuing a military path since the entry in to force of the Lisbon Treaty in 2009, which provides the legal underpinning to create a common security and defence policy. Less than a decade later, in a new point of departure, the EU created specific budget lines to allocate funding to military-related projects. This decision firmly set the EU on a new and deeply worrying trajectory, where international political and social problems were to be addressed not only through dialogue and diplomacy, but also through the threat of military solutions

SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes.

We investigated SARS-CoV-2 potential tropism by surveying expression of viral entry-associated genes in single-cell RNA-sequencing data from multiple tissues from healthy human donors. We co-detected these transcripts in specific respiratory, corneal and intestinal epithelial cells, potentially explaining the high efficiency of SARS-CoV-2 transmission. These genes are co-expressed in nasal epithelial cells with genes involved in innate immunity, highlighting the cells' potential role in initial viral infection, spread and clearance. The study offers a useful resource for further lines of inquiry with valuable clinical samples from COVID-19 patients and we provide our data in a comprehensive, open and user-friendly fashion at www.covid19cellatlas.org.This work was supported by the Wellcome Sanger Institute core funding (WT206194) and the Wellcome Strategic Scientific Support award “Pilot projects for the Human Cell Atlas” (WT211276/Z/18/Z), a Seed Network grant from the Chan Zuckerberg Initiative to P.B., T.D., T.E.D., O.E., P.H., N.H., N.K., M.K., K.B.M., A.M., M.C.N., M.N., D.P., J.R., P.R.T., S.Q., A.R., O.R., M.S., J.S., J.G.S., C.E.S., H.B.S., D.S., A.T., J.W. and K.Z. and by the European Union’s H2020 research and innovation program under grant agreement No 874656 (discovAIR) to P.B., A.B., M.K., S.L., J.L., K.B.M., M.C.N., K.S.P., C.S., H.B.S., J.S., F.J.T. and M.vd.B. W.S. acknowledges funding from the Newton Fund, Medical Research Council (MRC), The Thailand Research Fund (TRF), and Thailand’s National Science and Technology Development Agency (NSTDA). M.C.N acknowledges funding from GSK Ltd, Netherlands Lung Foundation project no. 5.1.14.020 and 4.1.18.226. T.D. acknowledges funding from HubMap consortium and Stanford Child Health Research Institute- Woods Family Faculty Scholarship. T.E.D. acknowledges funding from HubMap. P.H. acknowledges funding from LENDULET-BIOMAG Grant (2018-342) and the European Regional Development Funds (GINOP-2.3.2-15-2016-00006, GINOP-2.3.2-15-2016-00026, GINOP-2.3.2-15-2016-00037). J.L.B. acknowledges funding from Medical Research Council (MRC), and the UK Regenerative Medicine Platform (MR/ 5005579/1). P.B. acknowledges funding from Fondation pour la Recherche Médicale (DEQ20180339158), Agence Nationale de la Recherche (UCAJEDI, ANR-15-IDEX-01; SAHARRA, ANR-19-CE14-0027; France Génomique, ANR-10-INBS-09-03), and Conseil Départemental des Alpes Maritimes (2016-294DGADSH-CV; 2019-390DGADSH-CV). N.E.B. and J.K. acknowledge funding from NIH grant R01HL145372 and DOD grant W81XWH1910416. I.G. acknowledges funding from NIH (5R24HD000836) and the Eunice Kennedy Shriver National Institute of Child Health and Human. N.H., J.G.S. and C.E.S. acknowledge funding by the Leducq foundation. N.H. is recipient of an ERC Advanced Grant. J.K. acknowledges funding from NIH grant K08HL130595 and the Doris Duke Charitable Foundation. N.K. acknowledges funding from NIH grants R01HL127349, U01HL145567 and an unrestricted grant from Three Lakes Foundation. M.K. acknowledges HHMI and Wall Center for Pulmonary Vascular Disease. H.L. acknowledges funding from National Research Foundation of Korea. K.M. acknowledges funding from Wellcome Trust. A.M. acknowledges funding from NIH grants HL135124, AG049665 and AI135964. M.Z.N. acknowledges funding from Rutherford Fund Fellowship allocated by the Medical Research Council and the UK Regenerative Medicine Platform (MR/ 5005579/1 to M.Z.N.). M.Z.N. and M.Y. have been funded by the Rosetrees Grant (Grant number M899). M.N. acknowledges funding from a BHF/DZHK grant and British Heart Foundation (PG/16/47/32156). J.O.-M. acknowledges funding from Richard and Susan Smith Family Foundation. D.P. acknowledges funding from Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center. J.P. acknowledges funding from National Health and Medical Research Council. P.R.T. acknowledges funding from R01HL146557 from NHLBI/NIH. E.L.R. acknowledges funding from MRC MR/P009581/1 and MR/SO35907/1. A.R. and O. R. acknowledge HHMI, the Klarman Cell Observatory, and the Manton Foundation. K.S.-P. acknowledges NIHR Cambridge Biomedical Research Centre. C.S. acknowledges Swedish research Council, Swedish Cancer Society, and CPI. H.B.S. acknowledges German Center for Lung Research and Helmholtz Association. J.S. acknowledges Boehringer Ingelheim, by the German Research Foundation (DFG; EXC2151/1, ImmunoSensation2 - the immune sensory system, project number 390873048), project numbers 329123747, 347286815) and by the HGF grant sparse2big. A.K.S. acknowledges the Beckman Young Investigator Program, a Sloan Fellowship in Chemistry, the NIH (5U24AI118672), and the Bill and Melinda Gates Foundation. F.J.T. acknowledges the German Center for Lung Research. M.vd.B. acknowledges from Ministry of Economic Affairs and Climate Policy by means of the PPP. K.B.W. is funded by the University College London-Birkbeck MRC Doctoral Training Programme. J.W. and Y.Y. acknowledge NIH, U01 HL148856 LungMap Phase II. R.X. acknowledges the NIH (DK043351). H.Z. is supported by the National Key R&D Program (no. 2019YFA0801703) and National Natural Science Foundation of China (no. 31871370

PPM1D modulates hematopoietic cell fitness and response to DNA damage and is a therapeutic target in myeloid malignancy

PPM1D encodes a phosphatase that is recurrently activated across cancer, most notably in therapy-related myeloid neoplasms. However, the function of PPM1D in hematopoiesis and its contribution to tumor cell growth remain incompletely understood. Using conditional mouse models, we uncover a central role for Ppm1d in hematopoiesis and validate its potential as a therapeutic target. We find that Ppm1d regulates the competitive fitness and self-renewal of hematopoietic stem cells (HSCs) with and without exogenous genotoxic stresses. We also show that while Ppm1d activation confers cellular resistance to cytotoxic therapy, it does so to a lesser degree than p53 loss, informing the clonal competition phenotypes often observed in human studies. Notably, loss of Ppm1d sensitizes leukemias to cytotoxic therapies in vitro and in vivo, even in the absence of a Ppm1d mutation. Vulnerability to PPM1D inhibition is observed across many cancer types and dependent on p53 activity. Importantly, organism-wide loss of Ppm1d in adult mice is well tolerated, supporting the tolerability of pharmacologically targeting PPM1D. Our data link PPM1D gain-of-function mutations to the clonal expansion of HSCs, inform human genetic observations, and support the therapeutic targeting of PPM1D in cancer

Mapping interindividual dynamics of innate immune response at single-cell resolution

Common genetic variants across individuals modulate the cellular response to pathogens and are implicated in diverse immune pathologies, yet how they dynamically alter the response upon infection is not well understood. Here, we triggered antiviral responses in human fibroblasts from 68 healthy donors, and profiled tens of thousands of cells using single-cell RNA-sequencing. We developed GASPACHO (GAuSsian Processes for Association mapping leveraging Cell HeterOgeneity), a statistical approach designed to identify nonlinear dynamic genetic effects across transcriptional trajectories of cells. This approach identified 1,275 expression quantitative trait loci (local false discovery rate 10%) that manifested during the responses, many of which were colocalized with susceptibility loci identified by genome-wide association studies of infectious and autoimmune diseases, including the OAS1 splicing quantitative trait locus in a COVID-19 susceptibility locus. In summary, our analytical approach provides a unique framework for delineation of the genetic variants that shape a wide spectrum of transcriptional responses at single-cell resolution

Maternal education and cognitive development in 15 European very-preterm birth cohorts from the RECAP Preterm platform

Background: Studies are sparse and inconclusive about the association between maternal education and cognitive development among children born very preterm (VPT). Although this association is well established in the general population, questions remain about its magnitude among children born VPT whose risks of medical and developmental complications are high. We investigated the association of maternal education with cognitive outcomes in European VPT birth cohorts. Methods: We used harmonized aggregated data from 15 population-based cohorts of children born at = 37 weeks of GA) were available in eight cohorts. Maternal education was classified as: low (primary/lower secondary); medium (upper secondary/short tertiary); high (bachelor's/higher). Pooled standardized mean differences (SMDs) in cognitive scores were estimated (reference: high educational level) for children assessed at ages 2-3, 4-7 and 8-15 years. Results: The study included 10 145 VPT children from 12 cohorts at 2-3 years, 8829 from 12 cohorts at 4-7 years and 1865 children from 6 cohorts at 8-15 years. Children whose mothers had low, compared with high, educational attainment scored lower on cognitive measures [pooled unadjusted SMDs: 2-3 years = -0.32 (95% confidence intervals: -0.43 to -0.21); 4-7 years = -0.57 (-0.67; -0.47); 8-15 years = -0.54 (-0.72; -0.37)]. Analyses by GA subgroups (= 27 weeks) in children without severe neonatal morbidity and term controls yielded similar results. Conclusions: Across diverse settings and regardless of the degree of prematurity, low maternal education was associated with lower cognition.Peer reviewe

Development of a UK core dataset for geriatric medicine research: : a position statement and results from a Delphi consensus process

Funding AS and MW are funded by the Newcastle National Institute for Health (NIHR) Biomedical Research Centre, which also funded the initial meeting of academic clinicians in geriatric medicine during the Delphi process. The views expressed in this article are those of the authors and not necessarily those of the NIHR, the NHS, or the Department of Health. Acknowledgements The authors acknowledge the contributions of members of the UK Geriatric Medicine Core Dataset Extended Working Group.Peer reviewedPublisher PD

Bitter Taste Receptors Influence Glucose Homeostasis

TAS1R- and TAS2R-type taste receptors are expressed in the gustatory system, where they detect sweet- and bitter-tasting stimuli, respectively. These receptors are also expressed in subsets of cells within the mammalian gastrointestinal tract, where they mediate nutrient assimilation and endocrine responses. For example, sweeteners stimulate taste receptors on the surface of gut enteroendocrine L cells to elicit an increase in intracellular Ca2+ and secretion of the incretin hormone glucagon-like peptide-1 (GLP-1), an important modulator of insulin biosynthesis and secretion. Because of the importance of taste receptors in the regulation of food intake and the alimentary responses to chemostimuli, we hypothesized that differences in taste receptor efficacy may impact glucose homeostasis. To address this issue, we initiated a candidate gene study within the Amish Family Diabetes Study and assessed the association of taste receptor variants with indicators of glucose dysregulation, including a diagnosis of type 2 diabetes mellitus and high levels of blood glucose and insulin during an oral glucose tolerance test. We report that a TAS2R haplotype is associated with altered glucose and insulin homeostasis. We also found that one SNP within this haplotype disrupts normal responses of a single receptor, TAS2R9, to its cognate ligands ofloxacin, procainamide and pirenzapine. Together, these findings suggest that a functionally compromised TAS2R receptor negatively impacts glucose homeostasis, providing an important link between alimentary chemosensation and metabolic disease

Single-cell multi-omics analysis of the immune response in COVID-19

Peer reviewedPublisher PD

Revised age and stratigraphy of the classic Homo erectus-bearing succession at Trinil (Java, Indonesia)

Obtaining accurate age control for fossils found on Java (Indonesia) has been and remains challenging due to geochronologic and stratigraphic uncertainties. In the 1890s, Dubois excavated numerous faunal fossils—including the first remains of Homo erectus—in sediments exposed along the Solo River at Trinil. Since then, various, and often contradictory age estimates have been proposed for the Trinil site and its fossils. However, the age of the fossil-bearing layers and the fossil assemblage remains inconclusive. This study constructs a chronostratigraphic framework for the Trinil site by documenting new stratigraphic sections and test pits, and by applying 40Ar/39Ar, paleomagnetic, and luminescence (pIRIR290) dating methods. Our study identifies two distinct, highly fossiliferous channel fills at the Trinil site. The stratigraphically lower Bone-Bearing Channel 1 (BBC-1) dates to 830–773 ka, while Bone-Bearing Channel 2 (BBC-2) is substantially younger with a maximum age of 450 ± 110 ka and an inferred minimum age of 430 ± 50 ka. Furthermore, significantly younger T2 terrace deposits are present at similar low elevations as BBC-1 and BBC-2. Our results demonstrate the presence of Early and Middle Pleistocene, and potentially even late Middle to Late Pleistocene fossiliferous sediments within the historical excavation area, suggesting that Dubois excavated fossils from at least three highly fossiliferous units with different ages. Moreover, evidence for reworking suggests that material found in the fossil-rich strata may originate from older deposits, introducing an additional source of temporal heterogeneity in the Trinil fossil assemblage. This challenges the current assumption that the Trinil H.K. fauna –which includes Homo erectus-is a homogeneous biostratigraphic unit. Furthermore, this scenario might explain why the Trinil skullcap collected by Dubois is tentatively grouped with Homo erectus fossils from Early Pleistocene sediments at Sangiran, while Trinil Femur I shares affinities with hominin fossils of Late Pleistocene age