| 1. |
- Kanai, M, et al.
(author)
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- 2023
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swepub:Mat__t
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| 2. |
- Niemi, MEK, et al.
(author)
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- 2021
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swepub:Mat__t
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| 3. |
- Namkoong, H, et al.
(author)
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DOCK2 is involved in the host genetics and biology of severe COVID-19
- 2022
-
In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 609:7928, s. 754-
-
Journal article (peer-reviewed)abstract
- Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1–5. Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.
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| 4. |
- Wang, QBS, et al.
(author)
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The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force
- 2022
-
In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1, s. 4830-
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Journal article (peer-reviewed)abstract
- Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection.
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| 5. |
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| 6. |
- Abe, K., et al.
(author)
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Neutron tagging following atmospheric neutrino events in a water Cherenkov detector
- 2022
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In: Journal of Instrumentation. - : Institute of Physics (IOP). - 1748-0221. ; 17:10
-
Journal article (peer-reviewed)abstract
- We present the development of neutron-tagging techniques in Super-Kamiokande IV using a neural network analysis. The detection efficiency of neutron capture on hydrogen is estimated to be 26%, with a mis-tag rate of 0.016 per neutrino event. The uncertainty of the tagging efficiency is estimated to be 9.0%. Measurement of the tagging efficiency with data from an Americium-Beryllium calibration agrees with this value within 10%. The tagging procedure was performed on 3,244.4 days of SK-IV atmospheric neutrino data, identifying 18,091 neutrons in 26,473 neutrino events. The fitted neutron capture lifetime was measured as 218 +/- 9 mu s.
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| 7. |
- Lorenz, M. W., et al.
(author)
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Predictive value for cardiovascular events of common carotid intima media thickness and its rate of change in individuals at high cardiovascular risk - Results from the PROG-IMT collaboration
- 2018
-
In: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 13:4
-
Journal article (peer-reviewed)abstract
- Aims Carotid intima media thickness (CIMT) predicts cardiovascular (CVD) events, but the predictive value of CIMT change is debated. We assessed the relation between CIMT change and events in individuals at high cardiovascular risk. From 31 cohorts with two CIMT scans (total n = 89070) on average 3.6 years apart and clinical follow-up, subcohorts were drawn: (A) individuals with at least 3 cardiovascular risk factors without previous CVD events, (B) individuals with carotid plaques without previous CVD events, and (C) individuals with previous CVD events. Cox regression models were fit to estimate the hazard ratio (HR) of the combined endpoint (myocardial infarction, stroke or vascular death) per standard deviation (SD) of CIMT change, adjusted for CVD risk factors. These HRs were pooled across studies. In groups A, B and C we observed 3483, 2845 and 1165 endpoint events, respectively. Average common CIMT was 0.79mm (SD 0.16mm), and annual common CIMT change was 0.01mm (SD 0.07mm), both in group A. The pooled HR per SD of annual common CIMT change (0.02 to 0.43mm) was 0.99 (95% confidence interval: 0.95-1.02) in group A, 0.98 (0.93-1.04) in group B, and 0.95 (0.89-1.04) in group C. The HR per SD of common CIMT (average of the first and the second CIMT scan, 0.09 to 0.75mm) was 1.15 (1.07-1.23) in group A, 1.13 (1.05-1.22) in group B, and 1.12 (1.05-1.20) in group C. We confirm that common CIMT is associated with future CVD events in individuals at high risk. CIMT change does not relate to future event risk in high-risk individuals.
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| 8. |
- Milstead, David A., et al.
(author)
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The active muon shield in the SHiP experiment
- 2017
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In: Journal of Instrumentation. - 1748-0221. ; 12
-
Journal article (peer-reviewed)abstract
- The SHiP experiment is designed to search for very weakly interacting particles beyond the Standard Model which are produced in a 400 GeV/c proton beam dump at the CERN SPS. An essential task for the experiment is to keep the Standard Model background level to less than 0.1 event after 2 x 10(20) protons on target. In the beam dump, around 10(11) muons will be produced per second. The muon rate in the spectrometer has to be reduced by at least four orders of magnitude to avoid muon-induced combinatorial background. A novel active muon shield is used to magnetically deflect the muons out of the acceptance of the spectrometer. This paper describes the basic principle of such a shield, its optimization and its performance.
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| 9. |
- Ahdida, C., et al.
(author)
-
Fast simulation of muons produced at the SHiP experiment using Generative Adversarial Networks
- 2019
-
In: Journal of Instrumentation. - : IOP PUBLISHING LTD. - 1748-0221. ; 14
-
Journal article (peer-reviewed)abstract
- This paper presents a fast approach to simulating muons produced in interactions of the SPS proton beams with the target of the SHiP experiment. The SHIP experiment will be able to search for new long-lived particles produced in a 400 GeV/c SPS proton beam dump and which travel distances between fifty metres and tens of kilometers. The SHiP detector needs to operate under ultra-low background conditions and requires large simulated samples of muon induced background processes. Through the use of Generative Adversarial Networks it is possible to emulate the simulation of the interaction of 400 GeV/c proton beams with the SHiP target, an otherwise computationally intensive process. For the simulation requirements of the SHiP experiment, generative networks are capable of approximating the full simulation of the dense fixed target, offering a speed increase by a factor of O(10(6)). To evaluate the performance of such an approach, comparisons of the distributions of reconstructed muon momenta in SHiP's spectrometer between samples using the full simulation and samples produced through generative models are presented. The methods discussed in this paper can be generalised and applied to modelling any non-discrete multi-dimensional distribution.
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| 10. |
- Ahdida, C., et al.
(author)
-
Sensitivity of the SHiP experiment to Heavy Neutral Leptons
- 2019
-
In: Journal of High Energy Physics (JHEP). - 1126-6708 .- 1029-8479. ; :4
-
Journal article (peer-reviewed)abstract
- Heavy Neutral Leptons (HNLs) are hypothetical particles predicted by many extensions of the Standard Model. These particles can, among other things, explain the origin of neutrino masses, generate the observed matter-antimatter asymmetry in the Universe and provide a dark matter candidate. The SHiP experiment will be able to search for HNLs produced in decays of heavy mesons and travelling distances ranging between O(50 m) and tens of kilometers before decaying. We present the sensitivity of the SHiP experiment to a number of HNL's benchmark models and provide a way to calculate the SHiP's sensitivity to HNLs for arbitrary patterns of flavour mixings. The corresponding tools and data files are also made publicly available.
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| 11. |
- Ahdida, C., et al.
(author)
-
The experimental facility for the Search for Hidden Particles at the CERN SPS
- 2019
-
In: Journal of Instrumentation. - : Institute of Physics Publishing (IOPP). - 1748-0221. ; 14
-
Journal article (peer-reviewed)abstract
- The Search for Hidden Particles (SHiP) Collaboration has shown that the CERN SPS accelerator with its 400 GeV/c proton beam offers a unique opportunity to explore the Hidden Sector [1-3]. The proposed experiment is an intensity frontier experiment which is capable of searching for hidden particles through both visible decays and through scattering signatures from recoil of electrons or nuclei. The high-intensity experimental facility developed by the SHiP Collaboration is based on a number of key features and developments which provide the possibility of probing a large part of the parameter space for a wide range of models with light long-lived super-weakly interacting particles with masses up to O(10) GeV/c(2) in an environment of extremely clean background conditions. This paper describes the proposal for the experimental facility together with the most important feasibility studies. The paper focuses on the challenging new ideas behind the beam extraction and beam delivery, the proton beam dump, and the suppression of beam-induced background.
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| 12. |
- Ahdida, C., et al.
(author)
-
The magnet of the scattering and neutrino detector for the SHiP experiment at CERN
- 2020
-
In: Journal of Instrumentation. - 1748-0221. ; 15:01
-
Journal article (peer-reviewed)abstract
- The Search for Hidden Particles (SHiP) experiment proposal at CERN demands a dedicated dipole magnet for its scattering and neutrino detector. This requires a very large volume to be uniformly magnetized at B > 1.2 T, with constraints regarding the inner instrumented volume as well as the external region, where no massive structures are allowed and only an extremely low stray field is admitted. In this paper we report the main technical challenges and the relevant design options providing a comprehensive design for the magnet of the SHiP Scattering and Neutrino Detector.
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| 13. |
- Ahdida, C., et al.
(author)
-
The SHiP experiment at the proposed CERN SPS Beam Dump Facility
- 2022
-
In: European Physical Journal C. - : Springer Nature. - 1434-6044 .- 1434-6052. ; 82:5
-
Journal article (peer-reviewed)abstract
- The Search for Hidden Particles (SHiP) Collaboration has proposed a general-purpose experimental facility operating in beam-dump mode at the CERN SPS accelerator to search for light, feebly interacting particles. In the baseline configuration, the SHiP experiment incorporates two complementary detectors. The upstream detector is designed for recoil signatures of light dark matter (LDM) scattering and for neutrino physics, in particular with tau neutrinos. It consists of a spectrometer magnet housing a layered detector system with high-density LDM/neutrino target plates, emulsion-film technology and electronic high-precision tracking. The total detector target mass amounts to about eight tonnes. The downstream detector system aims at measuring visible decays of feebly interacting particles to both fully reconstructed final states and to partially reconstructed final states with neutrinos, in a nearly background-free environment. The detector consists of a 50m\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\mathrm { \,m}$$\end{document} long decay volume under vacuum followed by a spectrometer and particle identification system with a rectangular acceptance of 5 m in width and 10 m in height. Using the high-intensity beam of 400GeV\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\,\mathrm {GeV}$$\end{document} protons, the experiment aims at profiting from the 4x1019\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$4\times 10<^>{19}$$\end{document} protons per year that are currently unexploited at the SPS, over a period of 5-10 years. This allows probing dark photons, dark scalars and pseudo-scalars, and heavy neutral leptons with GeV-scale masses in the direct searches at sensitivities that largely exceed those of existing and projected experiments. The sensitivity to light dark matter through scattering reaches well below the dark matter relic density limits in the range from a few MeV/c2\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\mathrm {\,MeV\!/}c<^>2}$$\end{document} up to 100 MeV-scale masses, and it will be possible to study tau neutrino interactions with unprecedented statistics. This paper describes the SHiP experiment baseline setup and the detector systems, together with performance results from prototypes in test beams, as it was prepared for the 2020 Update of the European Strategy for Particle Physics. The expected detector performance from simulation is summarised at the end.
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| 14. |
- Ahdida, C., et al.
(author)
-
Track reconstruction and matching between emulsion and silicon pixel detectors for the SHiP-charm experiment
- 2022
-
In: Journal of Instrumentation. - : IOP Publishing. - 1748-0221. ; 17:3
-
Journal article (peer-reviewed)abstract
- In July 2018 an optimization run for the proposed charm cross section measurement for SHiP was performed at the CERN SPS. A heavy, moving target instrumented with nuclear emulsion films followed by a silicon pixel tracker was installed in front of the Goliath magnet at the H4 proton beam-line. Behind the magnet, scintillating-fibre, drift-tube and RPC detectors were placed. The purpose of this run was to validate the measurement's feasibility, to develop the required analysis tools and fine-tune the detector layout. In this paper, we present the track reconstruction in the pixel tracker and the track matching with the moving emulsion detector. The pixel detector performed as expected and it is shown that, after proper alignment, a vertex matching rate of 87% is achieved.
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| 15. |
- Bahls, M., et al.
(author)
-
Progression of conventional cardiovascular risk factors and vascular disease risk in individuals: insights from the PROG-IMT consortium
- 2020
-
In: European Journal of Preventive Cardiology. - : Oxford University Press (OUP). - 2047-4873 .- 2047-4881. ; 27:3
-
Journal article (peer-reviewed)abstract
- Aims: Averaged measurements, but not the progression based on multiple assessments of carotid intima-media thickness, (cIMT) are predictive of cardiovascular disease (CVD) events in individuals. Whether this is true for conventional risk factors is unclear. Methods and results: An individual participant meta-analysis was used to associate the annualised progression of systolic blood pressure, total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with future cardiovascular disease risk in 13 prospective cohort studies of the PROG-IMT collaboration (n = 34,072). Follow-up data included information on a combined cardiovascular disease endpoint of myocardial infarction, stroke, or vascular death. In secondary analyses, annualised progression was replaced with average. Log hazard ratios per standard deviation difference were pooled across studies by a random effects meta-analysis. In primary analysis, the annualised progression of total cholesterol was marginally related to a higher cardiovascular disease risk (hazard ratio (HR) 1.04, 95% confidence interval (CI) 1.00 to 1.07). The annualised progression of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol was not associated with future cardiovascular disease risk. In secondary analysis, average systolic blood pressure (HR 1.20 95% CI 1.11 to 1.29) and low-density lipoprotein cholesterol (HR 1.09, 95% CI 1.02 to 1.16) were related to a greater, while high-density lipoprotein cholesterol (HR 0.92, 95% CI 0.88 to 0.97) was related to a lower risk of future cardiovascular disease events. Conclusion: Averaged measurements of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol displayed significant linear relationships with the risk of future cardiovascular disease events. However, there was no clear association between the annualised progression of these conventional risk factors in individuals with the risk of future clinical endpoints. © The European Society of Cardiology 2019.
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| 16. |
- Ahdida, C., et al.
(author)
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Measurement of the muon flux from 400 GeV/c protons interacting in a thick molybdenum/tungsten target
- 2020
-
In: European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 80:3
-
Journal article (peer-reviewed)abstract
- The SHiP experiment is proposed to search for very weakly interacting particles beyond the Standard Model which are produced in a 400 GeV/c proton beam dump at the CERN SPS. About 1011muons per spill will be produced in the dump. To design the experiment such that the muon-induced background is minimized, a precise knowledge of the muon spectrum is required. To validate the muon flux generated by our Pythia and GEANT4 based Monte Carlo simulation (FairShip), we have measured the muon flux emanating from a SHiP-like target at the SPS. This target, consisting of 13 interaction lengths of slabs of molybdenum and tungsten, followed by a 2.4 m iron hadron absorber was placed in the H4 400 GeV/c proton beam line. To identify muons and to measure the momentum spectrum, a spectrometer instrumented with drift tubes and a muon tagger were used. During a 3-week period a dataset for analysis corresponding to (3.27 +/- 0.07)x1011protons on target was recorded. This amounts to approximatively 1% of a SHiP spill.
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| 17. |
- Ahdida, C., et al.
(author)
-
Sensitivity of the SHiP experiment to dark photons decaying to a pair of charged particles
- 2021
-
In: European Physical Journal C. - : Springer Nature. - 1434-6044 .- 1434-6052. ; 81:5
-
Journal article (peer-reviewed)abstract
- Dark photons are hypothetical massive vector particles that could mix with ordinary photons. The simplest theoretical model is fully characterised by only two parameters: the mass of the dark photon m(gamma)D and its mixing parameter with the photon, epsilon. The sensitivity of the SHiP detector is reviewed for dark photons in the mass range between 0.002 and 10 GeV. Different productionmechanisms are simulated, with the dark photons decaying to pairs of visible fermions, including both leptons and quarks. Exclusion contours are presented and compared with those of past experiments. The SHiP detector is expected to have a unique sensitivity for m. D ranging between 0.8 and 3.3(-0.5)(+0.2) GeV, and epsilon(2) ranging between 10(-11) and 10(-17).
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| 18. |
- Ahdida, C., et al.
(author)
-
Sensitivity of the SHiP experiment to light dark matter
- 2021
-
In: Journal of High Energy Physics (JHEP). - : Springer Nature. - 1126-6708 .- 1029-8479. ; :4
-
Journal article (peer-reviewed)abstract
- Dark matter is a well-established theoretical addition to the Standard Model supported by many observations in modern astrophysics and cosmology. In this context, the existence of weakly interacting massive particles represents an appealing solution to the observed thermal relic in the Universe. Indeed, a large experimental campaign is ongoing for the detection of such particles in the sub-GeV mass range. Adopting the benchmark scenario for light dark matter particles produced in the decay of a dark photon, with αD = 0.1 and mA′ = 3mχ, we study the potential of the SHiP experiment to detect such elusive particles through its Scattering and Neutrino detector (SND). In its 5-years run, corresponding to 2 · 1020 protons on target from the CERN SPS, we find that SHiP will improve the current limits in the mass range for the dark matter from about 1 MeV to 300 MeV. In particular, we show that SHiP will probe the thermal target for Majorana candidates in most of this mass window and even reach the Pseudo-Dirac thermal relic.
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| 19. |
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| 20. |
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| 21. |
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| 22. |
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| 23. |
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| 24. |
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| 25. |
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| 26. |
- den Ruijter, H. M., et al.
(author)
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Common carotid intima-media thickness does not add to Framingham risk score in individuals with diabetes mellitus: the USE-IMT initiative
- 2013
-
In: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 56:7, s. 1494-1502
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Journal article (peer-reviewed)abstract
- The aim of this work was to investigate whether measurement of the mean common carotid intima-media thickness (CIMT) improves cardiovascular risk prediction in individuals with diabetes. We performed a subanalysis among 4,220 individuals with diabetes in a large ongoing individual participant data meta-analysis involving 56,194 subjects from 17 population-based cohorts worldwide. We first refitted the risk factors of the Framingham heart risk score on the individuals without previous cardiovascular disease (baseline model) and then expanded this model with the mean common CIMT (CIMT model). The absolute 10 year risk for developing a myocardial infarction or stroke was estimated from both models. In individuals with diabetes we compared discrimination and calibration of the two models. Reclassification of individuals with diabetes was based on allocation to another cardiovascular risk category when mean common CIMT was added. During a median follow-up of 8.7 years, 684 first-time cardiovascular events occurred among the population with diabetes. The C statistic was 0.67 for the Framingham model and 0.68 for the CIMT model. The absolute 10 year risk for developing a myocardial infarction or stroke was 16% in both models. There was no net reclassification improvement with the addition of mean common CIMT (1.7%; 95% CI -1.8, 3.8). There were no differences in the results between men and women. There is no improvement in risk prediction in individuals with diabetes when measurement of the mean common CIMT is added to the Framingham risk score. Therefore, this measurement is not recommended for improving individual cardiovascular risk stratification in individuals with diabetes.
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| 27. |
- Fukuda, M., et al.
(author)
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Reaction cross section studies at NIRS and RIBF
- 2010
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In: American Institute of Physics Conference Series. - American Institute of Physics : AIP. ; , s. 270-273
-
Conference paper (peer-reviewed)abstract
- Reaction cross sections for stable nuclei at intermediate energies have been measured precisely and systematically. The data have been found to be reproduced nicely by the optical‐limit approximation of Glauber theory modified to include the nucleon multiple scattering effect and the Fermi‐motion effect. Applying this prescription, the nucleon density distribution of 17Ne has been studied. The surface structure of 8B and 11Be has been also studied using this prescription and hydrogen targets. Using the RIBF that has just started application to studies of exotic nuclei, neutron‐rich Ne isotopes around the Island of Inversion have been investigated through measurements of their interaction cross sections.
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| 28. |
- Librado, P., et al.
(author)
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The origins and spread of domestic horses from the Western Eurasian steppes
- 2021
-
In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 598, s. 634-640
-
Journal article (peer-reviewed)abstract
- Analysis of 273 ancient horse genomes reveals that modern domestic horses originated in the Western Eurasian steppes, especially the lower Volga-Don region. Domestication of horses fundamentally transformed long-range mobility and warfare(1). However, modern domesticated breeds do not descend from the earliest domestic horse lineage associated with archaeological evidence of bridling, milking and corralling(2-4) at Botai, Central Asia around 3500 bc(3). Other longstanding candidate regions for horse domestication, such as Iberia(5) and Anatolia(6), have also recently been challenged. Thus, the genetic, geographic and temporal origins of modern domestic horses have remained unknown. Here we pinpoint the Western Eurasian steppes, especially the lower Volga-Don region, as the homeland of modern domestic horses. Furthermore, we map the population changes accompanying domestication from 273 ancient horse genomes. This reveals that modern domestic horses ultimately replaced almost all other local populations as they expanded rapidly across Eurasia from about 2000 bc, synchronously with equestrian material culture, including Sintashta spoke-wheeled chariots. We find that equestrianism involved strong selection for critical locomotor and behavioural adaptations at the GSDMC and ZFPM1 genes. Our results reject the commonly held association(7) between horseback riding and the massive expansion of Yamnaya steppe pastoralists into Europe around 3000 bc(8,9) driving the spread of Indo-European languages(10). This contrasts with the scenario in Asia where Indo-Iranian languages, chariots and horses spread together, following the early second millennium bc Sintashta culture(11,12).
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| 29. |
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| 30. |
- Bots, Michiel L., et al.
(author)
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Common Carotid Intima-Media Thickness Measurements Do Not Improve Cardiovascular Risk Prediction in Individuals With Elevated Blood Pressure The USE-IMT Collaboration
- 2014
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In: Hypertension. - 1524-4563. ; 63:6, s. 1173-1181
-
Journal article (peer-reviewed)abstract
- Carotid intima-media thickness (CIMT) is a marker of cardiovascular risk. It is unclear whether measurement of mean common CIMT improves 10-year risk prediction of first-time myocardial infarction or stroke in individuals with elevated blood pressure. We performed an analysis among individuals with elevated blood pressure (ie, a systolic blood pressure 140 mm Hg and a diastolic blood pressure 90 mm Hg) in USE-IMT, a large ongoing individual participant data meta-analysis. We refitted the risk factors of the Framingham Risk Score on asymptomatic individuals (baseline model) and expanded this model with mean common CIMT (CIMT model) measurements. From both models, 10-year risks to develop a myocardial infarction or stroke were estimated. In individuals with elevated blood pressure, we compared discrimination and calibration of the 2 models and calculated the net reclassification improvement (NRI). We included 17 254 individuals with elevated blood pressure from 16 studies. During a median follow-up of 9.9 years, 2014 first-time myocardial infarctions or strokes occurred. The C-statistics of the baseline and CIMT models were similar (0.73). NRI with the addition of mean common CIMT was small and not significant (1.4%; 95% confidence intervals, -1.1 to 3.7). In those at intermediate risk (n=5008, 10-year absolute risk of 10% to 20%), the NRI was 5.6% (95% confidence intervals, 1.6-10.4). There is no added value of measurement of mean common CIMT in individuals with elevated blood pressure for improving cardiovascular risk prediction. For those at intermediate risk, the addition of mean common CIMT to an existing cardiovascular risk score is small but statistically significant.
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| 31. |
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| 32. |
- Teixeira, J., et al.
(author)
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Tropical and Subtropical Cloud Transitions in Weather and Climate Prediction Models : The GCSS/WGNE Pacific Cross-Section Intercomparison (GPCI)
- 2011
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In: Journal of Climate. - 0894-8755 .- 1520-0442. ; 24:20, s. 5223-5256
-
Journal article (peer-reviewed)abstract
- A model evaluation approach is proposed in which weather and climate prediction models are analyzed along a Pacific Ocean cross section, from the stratocumulus regions off the coast of California, across the shallow convection dominated trade winds, to the deep convection regions of the ITCZ-the Global Energy and Water Cycle Experiment Cloud System Study/Working Group on Numerical Experimentation (GCSS/WGNE) Pacific Cross-Section Intercomparison (GPCI). The main goal of GPCI is to evaluate and help understand and improve the representation of tropical and subtropical cloud processes in weather and climate prediction models. In this paper, a detailed analysis of cloud regime transitions along the cross section from the subtropics to the tropics for the season June-July-August of 1998 is presented. This GPCI study confirms many of the typical weather and climate prediction model problems in the representation of clouds: underestimation of clouds in the stratocumulus regime by most models with the corresponding consequences in terms of shortwave radiation biases; overestimation of clouds by the 40-yr ECMWF Re-Analysis (ERA-40) in the deep tropics (in particular) with the corresponding impact in the outgoing longwave radiation; large spread between the different models in terms of cloud cover, liquid water path and shortwave radiation; significant differences between the models in terms of vertical cross sections of cloud properties (in particular), vertical velocity, and relative humidity. An alternative analysis of cloud cover mean statistics is proposed where sharp gradients in cloud cover along the GPCI transect are taken into account. This analysis shows that the negative cloud bias of some models and ERA-40 in the stratocumulus regions [as compared to the first International Satellite Cloud Climatology Project (ISCCP)] is associated not only with lower values of cloud cover in these regimes, but also with a stratocumulus-to-cumulus transition that occurs too early along the trade wind Lagrangian trajectory. Histograms of cloud cover along the cross section differ significantly between models. Some models exhibit a quasi-bimodal structure with cloud cover being either very large (close to 100%) or very small, while other models show a more continuous transition. The ISCCP observations suggest that reality is in-between these two extreme examples. These different patterns reflect the diverse nature of the cloud, boundary layer, and convection parameterizations in the participating weather and climate prediction models.
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| 33. |
- Den Ruijter, Hester M., et al.
(author)
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Common Carotid Intima-Media Thickness Measurements in Cardiovascular Risk Prediction A Meta-analysis
- 2012
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In: JAMA: The Journal of the American Medical Association. - : American Medical Association (AMA). - 1538-3598. ; 308:8, s. 796-803
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Journal article (peer-reviewed)abstract
- Context The evidence that measurement of the common carotid intima-media thickness (CIMT) improves the risk scores in prediction of the absolute risk of cardiovascular events is inconsistent. Objective To determine whether common CIMT has added value in 10-year risk prediction of first-time myocardial infarctions or strokes, above that of the Framingham Risk Score. Data Sources Relevant studies were identified through literature searches of databases (PubMed from 1950 to June 2012 and EMBASE from 1980 to June 2012) and expert opinion. Study Selection Studies were included if participants were drawn from the general population, common CIMT was measured at baseline, and individuals were followed up for first-time myocardial infarction or stroke. Data Extraction Individual data were combined into 1 data set and an individual participant data meta-analysis was performed on individuals without existing cardiovascular disease. Results We included 14 population-based cohorts contributing data for 45 828 individuals. During a median follow-up of 11 years, 4007 first-time myocardial infarctions or strokes occurred. We first refitted the risk factors of the Framingham Risk Score and then extended the model with common CIMT measurements to estimate the absolute 10-year risks to develop a first-time myocardial infarction or stroke in both models. The C statistic of both models was similar (0.757; 95% CI, 0.749-0.764; and 0.759; 95% CI, 0.752-0.766). The net reclassification improvement with the addition of common CIMT was small (0.8%; 95% CI, 0.1%-1.6%). In those at intermediate risk, the net reclassification improvement was 3.6% in all individuals (95% CI, 2.7%-4.6%) and no differences between men and women. Conclusion The addition of common CIMT measurements to the Framingham Risk Score was associated with small improvement in 10-year risk prediction of first-time myocardial infarction or stroke, but this improvement is unlikely to be of clinical importance. JAMA. 2012;308(8):796-803 www.jama.com
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| 34. |
- Eikendal, Anouk L M, et al.
(author)
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Common Carotid Intima-Media Thickness Relates to Cardiovascular Events in Adults Aged
- 2015
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In: Hypertension. - 1524-4563. ; 65:4, s. 707-707
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Journal article (peer-reviewed)abstract
- Although atherosclerosis starts in early life, evidence on risk factors and atherosclerosis in individuals aged <45 years is scarce. Therefore, we studied the relationship between risk factors, common carotid intima-media thickness (CIMT), and first-time cardiovascular events in adults aged <45 years. Our study population consisted of 3067 adults aged <45 years free from symptomatic cardiovascular disease at baseline, derived from 6 cohorts that are part of the USE-IMT initiative, an individual participant data meta-analysis of general-population-based cohort studies evaluating CIMT measurements. Information on risk factors, CIMT measurements, and follow-up of the combined end point (first-time myocardial infarction or stroke) was obtained. We assessed the relationship between risk factors and CIMT and the relationship between CIMT and first-time myocardial infarction or stroke using a multivariable linear mixed-effects model and a Cox proportional-hazards model, respectively. During a follow-up of 16.3 years, 55 first-time myocardial infarctions or strokes occurred. Median CIMT was 0.63 mm. Of the risk factors under study, age, sex, diastolic blood pressure, body mass index, total cholesterol, and high-density lipoprotein cholesterol related to CIMT. Furthermore, CIMT related to first-time myocardial infarction or stroke with a hazard ratio of 1.40 per SD increase in CIMT, independent of risk factors (95% confidence interval, 1.11-1.76). CIMT may be a valuable marker for cardiovascular risk in adults aged <45 years who are not yet eligible for standard cardiovascular risk screening. This is especially relevant in those with an increased, unfavor-able risk factor burden.
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| 35. |
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| 36. |
- Gijsberts, Crystel M, et al.
(author)
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Race/Ethnic Differences in the Associations of the Framingham Risk Factors with Carotid IMT and Cardiovascular Events.
- 2015
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:7
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Journal article (peer-reviewed)abstract
- Clinical manifestations and outcomes of atherosclerotic disease differ between ethnic groups. In addition, the prevalence of risk factors is substantially different. Primary prevention programs are based on data derived from almost exclusively White people. We investigated how race/ethnic differences modify the associations of established risk factors with atherosclerosis and cardiovascular events.
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| 37. |
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| 38. |
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| 39. |
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| 40. |
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| 41. |
- Kitagawa, H, et al.
(author)
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N-acetylgalactosamine (GalNAc) transfer to the common carbohydrate-protein linkage region of sulfated glycosaminoglycans : identification of UDP-GaINAc:chondro oligosaccharide aNacetylgalactosaminyltransferase in fetal bovine serum
- 1995
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In: The Journal of Biological Chemsitry. - 0021-9258. ; 270:38, s. 22190-22195
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Journal article (peer-reviewed)abstract
- During the course of a study to elucidate the role ofmodification of the common polysaccharide-protein linkagestructure, GlcAb1–3Galb1–3Galb1–4Xylb1-O-Ser, inbiosynthetic sorting mechanisms of the different sulfatedglycosaminoglycan chains, a novel N-acetylgalactosamine(GalNAc) transferase was discovered in fetalbovine serum. The enzyme catalyzed the transfer of[3H]GalNAc from UDP-[3H]GalNAc to linkage tetrasaccharideand hexasaccharide serines synthesized chemicallyand to various regular oligosaccharides containingterminal D-glucuronic acid (GlcA), which were preparedfrom chondroitin and chondroitin sulfate using testicularhyaluronidase digestion. The labeled products obtainedwith the linkage tetra- and hexasaccharideserines and with the tetrasaccharide (GlcAb1–3GalNAc)2were resistant to digestion with chondroitinase AC-IIand b-N-acetylhexosaminidase but sensitive to a-Nacetylgalactosaminidasedigestion, indicating that theenzyme is an a-N-acetylgalactosaminyltransferase. Thisfinding is in contrast to that of Rohrmann et al. (Rohrmann,K., Niemann, R., and Buddecke, E. (1985) Eur. J.Biochem., 148, 463–469), who reported that a correspondingproduct was susceptible to digestion with b-Nacetylhexosaminidase.The presence of a sulfate groupat C4 of the penultimate GalNAc or Gal units markedlyinhibited the transfer of GalNAc to the terminal GlcA,while a sulfate group at C6 of the GalNAc had little effecton the transfer. Moreover, a slight but significant transferof [3H]GalNAc was observed to an oligosaccharidecontaining terminal 2-O-sulfated GlcA as acceptor,whereas no incorporation was detected into oligosaccharidescontaining terminal unsaturated or 3-O-sulfatedGlcA units. These results suggest that this novelserum enzyme is a UDP-GalNAc:chondro-oligosaccharidea1–3- or 1–4-N-acetylgalactosaminyltransferase.
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| 42. |
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| 43. |
- Kitagawa, M, et al.
(author)
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Dual blockade of the lipid kinase PIP4Ks and mitotic pathways leads to cancer-selective lethality
- 2017
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8:1, s. 2200-
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Journal article (peer-reviewed)abstract
- Achieving robust cancer-specific lethality is the ultimate clinical goal. Here, we identify a compound with dual-inhibitory properties, named a131, that selectively kills cancer cells, while protecting normal cells. Through an unbiased CETSA screen, we identify the PIP4K lipid kinases as the target of a131. Ablation of the PIP4Ks generates a phenocopy of the pharmacological effects of PIP4K inhibition by a131. Notably, PIP4Ks inhibition by a131 causes reversible growth arrest in normal cells by transcriptionally upregulating PIK3IP1, a suppressor of the PI3K/Akt/mTOR pathway. Strikingly, Ras activation overrides a131-induced PIK3IP1 upregulation and activates the PI3K/Akt/mTOR pathway. Consequently, Ras-transformed cells override a131-induced growth arrest and enter mitosis where a131’s ability to de-cluster supernumerary centrosomes in cancer cells eliminates Ras-activated cells through mitotic catastrophe. Our discovery of drugs with a dual-inhibitory mechanism provides a unique pharmacological strategy against cancer and evidence of cross-activation between the Ras/Raf/MEK/ERK and PI3K/AKT/mTOR pathways via a Ras˧PIK3IP1˧PI3K signaling network.
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| 44. |
- Lidholt, Kerstin, et al.
(author)
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Assessment of glycosaminoglycan-protein linkage tetrasaccharides as acceptors for GalNAc- and GlcNAc-transferases from mouse mastocytoma.
- 1997
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In: Glycoconjugate Journal. - 0282-0080 .- 1573-4986. ; 14:6, s. 737-742
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Journal article (peer-reviewed)abstract
- Two glycosaminoglycan-protein linkage tetrasaccharide-serine compounds, GlcA beta 1-3Gal beta 1-3Gal beta 1-4Xyl beta 1-O-Ser and GlcA beta 1-3Gal(4-O-sulfate)beta 1-3Gal beta 1-4Xyl beta 1-O-Ser, were tested as hexosamine accepters, using UDP-[H-3]GlcNAc and UDP-[H-3]GalNAc as sugar donors, and solubilized mouse mastocytoma microsomes as enzyme source. The nonsulfated Ser-tetrasaccharide was found to function as an acceptor for a GalNAc residue, whereas the Ser-tetrasaccharide containing a sulfated galactose unit was inactive. Characterization of the radio-labelled product by digestion with alpha-N-acetylgalactosaminidase and beta-N-acetylhexosaminidase revealed that the [H-3]GalNAc unit was alpha-linked, as in the product previously synthesized using serum enzymes, and not beta-linked as found in the chondroitin sulfate polymer. Heparan sulfate/heparin biosynthesis could not be primed by either of the two linkage Ser-tetrasaccharides, since no transfer of [H-3]GlcNAc from UDP-[H-3]GlcNAc could be detected. By contrast, transfer of a [H-3]GlcNAc unit to a [GlcA beta 1-4GlcNAca1-4](2)-GlcA beta 1-4-aMan hexasaccharide acceptor used to assay the GlcNAc transferase involved in chain elongation, was readily detected. These results are in agreement with the recent proposal that two different N-acetylglucosaminyl transferases catalyse the biosynthesis of heparan sulfate. Although the mastocytoma system contains both the heparan sulfate/heparin and chondroitin sulfate biosynthetic enzymes the Ser-tetrasaccharides do not seem to fulfil the requirements to serve as accepters for the first HexNAc transfer reactions involved in the formation of these polysaccharides.
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| 45. |
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| 46. |
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| 47. |
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| 48. |
- Senay, Clair, et al.
(author)
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The EXT1/EXT2 tumor suppressors : catalytic activities and role in heparan sulfate biosynthesis
- 2000
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In: EMBO Reports. - : EMBO. - 1469-221X .- 1469-3178. ; 1:3, s. 282-286
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Journal article (peer-reviewed)abstract
- The D-glucuronyltransferase and N-acetyl-D-glucosaminyltransferase reactions in heparan sulfate biosynthesis have been associated with two genes, EXT1 and EXT2, which are also implicated in the inherited bone disorder, multiple exostoses. Since the cell systems used to express recombinant EXT proteins synthesize endogenous heparan sulfate, and the EXT proteins tend to associate, it has not been possible to define the functional roles of the individual protein species. We therefore expressed EXT1 and EXT2 in yeast, which does not synthesize heparan sulfate. The recombinant EXT1 and EXT2 were both found to catalyze both glycosyltransferase reactions in vitro. Coexpression of the two proteins, but not mixing of separately expressed recombinant EXT1 and EXT2, yields hetero-oligomeric complexes in yeast and mammalian cells, with augmented glycosyltransferase activities. This stimulation does not depend on the membrane-bound state of the proteins.
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| 49. |
- Svensson, Gunilla, et al.
(author)
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Evaluation of the Diurnal Cycle in the Atmospheric Boundary Layer Over Land as Represented by a Variety of Single-Column Models : The Second GABLS Experiment
- 2011
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In: Boundary-layer Meteorology. - : Springer Science and Business Media LLC. - 0006-8314 .- 1573-1472. ; 140:2, s. 177-206
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Journal article (peer-reviewed)abstract
- We present the main results from the second model intercomparison within the GEWEX (Global Energy and Water cycle EXperiment) Atmospheric Boundary Layer Study (GABLS). The target is to examine the diurnal cycle over land in today's numerical weather prediction and climate models for operational and research purposes. The set-up of the case is based on observations taken during the Cooperative Atmosphere-Surface Exchange Study-1999 (CASES-99), which was held in Kansas, USA in the early autumn with a strong diurnal cycle with no clouds present. The models are forced with a constant geostrophic wind, prescribed surface temperature and large-scale divergence. Results from 30 different model simulations and one large-eddy simulation (LES) are analyzed and compared with observations. Even though the surface temperature is prescribed, the models give variable near-surface air temperatures. This, in turn, gives rise to differences in low-level stability affecting the turbulence and the turbulent heat fluxes. The increase in modelled upward sensible heat flux during the morning transition is typically too weak and the growth of the convective boundary layer before noon is too slow. This is related to weak modelled near-surface winds during the morning hours. The agreement between the models, the LES and observations is the best during the late afternoon. From this intercomparison study, we find that modelling the diurnal cycle is still a big challenge. For the convective part of the diurnal cycle, some of the first-order schemes perform somewhat better while the turbulent kinetic energy (TKE) schemes tend to be slightly better during nighttime conditions. Finer vertical resolution tends to improve results to some extent, but is certainly not the solution to all the deficiencies identified.
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| 50. |
- Tsuchida, Kazunori, et al.
(author)
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Purification and characterization of fetal bovine serum beta-N-acetyl-D-galactosaminyltransferase and beta-D-glucuronyltransferase involved in chondroitin sulfate biosynthesis
- 1999
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In: European Journal of Biochemistry. - : Wiley. - 0014-2956 .- 1432-1033. ; 264:2, s. 461-467
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Journal article (peer-reviewed)abstract
- beta-N-Acetylgalactosaminyltransferase II and beta-glucuronyltransferase II, involved in chondroitin sulfate biosynthesis, transfer an N-acetylgalactosamine (GalNAc) and glucuronic acid (GlcA) residue, respectively, through beta-linkages to an acceptor chondroitin oligosaccharide derived from the repeating disaccharide region of chondroitin sulfate. They were copurified from fetal bovine serum approximately 2500-fold and 850-fold, respectively, by sequential chromatographies on Red A-agarose, phenyl-Sepharose, S-Sepharose and wheat germ agglutinin-agarose. Identical and inseparable chromatographic profiles of both glycosyltransferase activities obtained through the above chromatographic steps and gel filtration suggest that the purified enzyme activities are tightly coupled, which could imply a single enzyme with dual transferase activities; beta-N-acetylgalactosaminyltransferase and beta-glucuronyltransferase, reminiscent of the heparan sulfate polymerase reaction. However, when a polymerization reaction was performed in vitro with the purified serum enzyme preparation under the polymerization conditions recently developed for the chondroitin-synthesizing system, derived from human melanoma cells, each monosaccharide transfer took place, but no polymerization occurred. These results may suggest that the purified serum enzyme preparation contains both beta-N-acetylgalactosaminyltransferase II and beta-glucuronyltransferase II activities on a single polypeptide or on the respective polypeptides forming an enzyme complex, but is different from that obtained from melanoma cells in that it transfers a single GalNAc or GlcA residue but does not polymerize chondroitin.
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