| 1. |
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| 2. |
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| 3. |
- Glasbey, JC, et al.
(author)
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- 2021
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swepub:Mat__t
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| 4. |
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| 5. |
- Namkoong, H, et al.
(author)
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DOCK2 is involved in the host genetics and biology of severe COVID-19
- 2022
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 609:7928, s. 754-
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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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| 6. |
- 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
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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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| 7. |
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| 8. |
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| 9. |
- De Oliveira Santos, F., et al.
(author)
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Study of 19Na at SPIRAL
- 2005
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In: European Physical Journal A. - : Springer Science and Business Media LLC. - 1434-601X .- 1434-6001. ; 24:2, s. 237-247
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Journal article (peer-reviewed)abstract
- The excitation function for the elastic-scattering reaction p( 18 Ne, p) 18 Ne was measured with the first radioactive beam from the SPIRAL facility at the GANIL laboratory and with a solid cryogenic hydrogen target. Several broad resonances have been observed, corresponding to new excited states in the unbound nucleus 19 Na. In addition, two-proton emission events have been identified and are discussed.
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| 10. |
- Aharonian, Felix, et al.
(author)
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Atmospheric gas dynamics in the Perseus cluster observed with Hitomi
- 2018
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In: Publications of the Astronomical Society of Japan. - : Oxford University Press (OUP). - 0004-6264 .- 2053-051X. ; 70:2
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Journal article (peer-reviewed)abstract
- Extending the earlier measurements reported in Hitomi collaboration (2016, Nature, 535, 117), we examine the atmospheric gas motions within the central 100 kpc of the Perseus cluster using observations obtained with the Hitomi satellite. After correcting for the point spread function of the telescope and using optically thin emission lines, we find that the line-of-sight velocity dispersion of the hot gas is remarkably low and mostly uniform. The velocity dispersion reaches a maxima of approximately 200 km s(-1) toward the central active galactic nucleus (AGN) and toward the AGN inflated northwestern ghost bubble. Elsewhere within the observed region, the velocity dispersion appears constant around 100 km s(-1). We also detect a velocity gradient with a 100 km s(-1) amplitude across the cluster core, consistent with large-scale sloshing of the core gas. If the observed gas motions are isotropic, the kinetic pressure support is less than 10% of the thermal pressure support in the cluster core. The well-resolved, optically thin emission lines have Gaussian shapes, indicating that the turbulent driving scale is likely below 100 kpc, which is consistent with the size of the AGN jet inflated bubbles. We also report the first measurement of the ion temperature in the intracluster medium, which we find to be consistent with the electron temperature. In addition, we present a new measurement of the redshift of the brightest cluster galaxy NGC 1275.
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| 11. |
- Aharonian, Felix, et al.
(author)
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Atomic data and spectral modeling constraints from high-resolution X-ray observations of the Perseus cluster with Hitomi
- 2018
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In: Publications of the Astronomical Society of Japan. - : Oxford University Press (OUP). - 0004-6264 .- 2053-051X. ; 70:2
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Journal article (peer-reviewed)abstract
- The Hitomi Soft X-ray Spectrometer spectrum of the Perseus cluster, with similar to 5 eV resolution in the 2-9 keV band, offers an unprecedented benchmark of the atomic modeling and database for hot collisional plasmas. It reveals both successes and challenges of the current atomic data and models. The latest versions of AtomDB/APEC (3.0.8), SPEX (3.03.00), and CHIANTI (8.0) all provide reasonable fits to the broad-band spectrum, and are in close agreement on best-fit temperature, emission measure, and abundances of a few elements such as Ni. For the Fe abundance, the APEC and SPEX measurements differ by 16%, which is 17 times higher than the statistical uncertainty. This is mostly attributed to the differences in adopted collisional excitation and dielectronic recombination rates of the strongest emission lines. We further investigate and compare the sensitivity of the derived physical parameters to the astrophysical source modeling and instrumental effects. The Hitomi results show that accurate atomic data and models are as important as the astrophysical modeling and instrumental calibration aspects. Substantial updates of atomic databases and targeted laboratory measurements are needed to get the current data and models ready for the data from the next Hitomi-level mission.
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| 12. |
- Aharonian, Felix, et al.
(author)
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Detection of polarized gamma-ray emission from the Crab nebula with the Hitomi Soft Gamma-ray Detector
- 2018
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In: Publications of the Astronomical Society of Japan. - : Oxford University Press (OUP). - 0004-6264 .- 2053-051X. ; 70:6
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Journal article (peer-reviewed)abstract
- We present the results from the Hitomi Soft Gamma-ray Detector (SGD) observation of the Crab nebula. The main part of SGD is a Compton camera, which in addition to being a spectrometer, is capable of measuring polarization of gamma-ray photons. The Crab nebula is one of the brightest X-ray / gamma-ray sources on the sky, and, the only source from which polarized X-ray photons have been detected. SGD observed the Crab nebula during the initial test observation phase of Hitomi. We performed the data analysis of the SGD observation, the SGD background estimation and the SGD Monte Carlo simulations, and, successfully detected polarized gamma-ray emission from the Crab nebula with only about 5 ks exposure time. The obtained polarization fraction of the phase-integrated Crab emission (sum of pulsar and nebula emissions) is (22.1% +/- 10.6%), and, the polarization angle is 110.degrees 7 + 13.degrees 2 /-13.degrees 0 in the energy range of 60-160 keV (The errors correspond to the 1 sigma deviation). The confidence level of the polarization detection was 99.3%. The polarization angle measured by SGD is about one sigma deviation with the projected spin axis of the pulsar, 124.degrees 0 +/- 0.degrees 1.
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| 13. |
- Aharonian, Felix, et al.
(author)
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Glimpse of the highly obscured HMXB IGR J16318-4848 with Hitomi
- 2018
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In: Publications of the Astronomical Society of Japan. - : Oxford University Press (OUP). - 0004-6264 .- 2053-051X. ; 70:2
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Journal article (peer-reviewed)abstract
- We report on a Hitomi observation of IGR J16318-4848, a high-mass X-ray binary system with an extremely strong absorption of N-H similar to 10(24) cm(-2). Previous X-ray studies revealed that its spectrum is dominated by strong fluorescence lines of Fe as well as continuum emission lines. For physical and geometrical insight into the nature of the reprocessing material, we utilized the high spectroscopic resolving power of the X-ray microcalorimeter (the soft X-ray spectrometer: SXS) and the wide-band sensitivity by the soft and hard X-ray imagers (SXI and HXI) aboard Hitomi. Even though the photon counts are limited due to unintended off-axis pointing, the SXS spectrum resolves Fe K alpha(1) and K alpha(2) lines and puts strong constraints on the line centroid and line width. The line width corresponds to a velocity of 160(-70)(+300) km s(-1). This represents the most accurate, and smallest, width measurement of this line made so far from the any X-ray binary, much less than the Doppler broadening and Doppler shift expected from speeds that are characteristic of similar systems. Combined with the K-shell edge energy measured by the SXI and HXI spectra, the ionization state of Fe is estimated to be in the range of Fe I-IV. Considering the estimated ionization parameter and the distance between the X-ray source and the absorber, the density and thickness of the materials are estimated. The extraordinarily strong absorption and the absence of a Compton shoulder component have been confirmed. These characteristics suggest reprocessing materials that are distributed in a narrow solid angle or scattering, primarily by warm free electrons or neutral hydrogen. This measurement was achieved using the SXS detection of 19 photons. It provides strong motivation for follow-up observations of this and other X-ray binaries using the X-ray Astrophysics Recovery Mission and other comparable future instruments.
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| 14. |
- Aharonian, Felix, et al.
(author)
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Hitomi observation of radio galaxy NGC 1275 : The first X-ray microcalorimeter spectroscopy of Fe-K alpha line emission from an active galactic nucleus
- 2018
-
In: Publications of the Astronomical Society of Japan. - : Oxford University Press (OUP). - 0004-6264 .- 2053-051X. ; 70:2
-
Journal article (peer-reviewed)abstract
- The origin of the narrow Fe-K alpha fluorescence line at 6.4 keV from active galactic nuclei has long been under debate; some of the possible sites are the outer accretion disk, the broad line region, a molecular torus, or interstellar/intracluster media. In 2016 February-March, we performed the first X-ray microcalorimeter spectroscopy with the Soft X-ray Spectrometer (SXS) on board the Hitomi satellite of the Fanaroff-Riley type I radio galaxy NGC 1275 at the center of the Perseus cluster of galaxies. With the high-energy resolution of similar to 5 eV at 6 keV achieved by Hitomi/SXS, we detected the Fe-K alpha line with similar to 5.4 sigma significance. The velocity width is constrained to be 500-1600 km s(-1) (FWHM for Gaussian models) at 90% confidence. The SXS also constrains the continuum level from the NGC 1275 nucleus up to similar to 20 keV, giving an equivalent width of similar to 20 eV for the 6.4 keV line. Because the velocity width is narrower than that of the broad H alpha line of similar to 2750 km s(-1), we can exclude a large contribution to the line flux from the accretion disk and the broad line region. Furthermore, we performed pixel map analyses on the Hitomi/SXS data and image analyses on the Chandra archival data, and revealed that the Fe-K alpha line comes from a region within similar to 1.6 kpc of the NGC 1275 core, where an active galactic nucleus emission dominates, rather than that from intracluster media. Therefore, we suggest that the source of the Fe-K alpha line from NGC 1275 is likely a low-covering-fraction molecular torus or a rotating molecular disk which probably extends from a parsec to hundreds of parsecs scale in the active galactic nucleus system.
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| 15. |
- Aharonian, Felix, et al.
(author)
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Hitomi observations of the LMC SNR N 132 D : Highly redshifted X-ray emission from iron ejecta
- 2018
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In: Publications of the Astronomical Society of Japan. - : Oxford University Press (OUP). - 0004-6264 .- 2053-051X. ; 70:2
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Journal article (peer-reviewed)abstract
- We present Hitomi observations of N 132 D, a young, X-ray bright, O-rich core-collapse supernova remnant in the Large Magellanic Cloud (LMC). Despite a very short observation of only 3.7 ks, the Soft X-ray Spectrometer (SXS) easily detects the line complexes of highly ionized S K and Fe K with 16-17 counts in each. The Fe feature is measured for the first time at high spectral resolution. Based on the plausible assumption that the Fe K emission is dominated by He-like ions, we find that the material responsible for this Fe emission is highly redshifted at similar to 800 km s(-1) compared to the local LMC interstellar medium (ISM), with a 90% credible interval of 50-1500 km s(-1) if a weakly informative prior is placed on possible line broadening. This indicates (1) that the Fe emission arises from the supernova ejecta, and (2) that these ejecta are highly asymmetric, since no blueshifted component is found. The S K velocity is consistent with the local LMC ISM, and is likely from swept-up ISM material. These results are consistent with spatial mapping that shows the He-like Fe concentrated in the interior of the remnant and the S tracing the outer shell. The results also show that even with a very small number of counts, direct velocity measurements from Doppler-shifted lines detected in extended objects like supernova remnants are now possible. Thanks to the very low SXS background of similar to 1 event per spectral resolution element per 100 ks, such results are obtainable during short pointed or slew observations with similar instruments. This highlights the power of high-spectral-resolution imaging observations, and demonstrates the new window that has been opened with Hitomi and will be greatly widened with future missions such as the X-ray Astronomy Recovery Mission (XARM) and Athena.
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| 16. |
- Aharonian, Felix, et al.
(author)
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Hitomi X-ray observation of the pulsar wind nebula G21.5-0.9
- 2018
-
In: Publications of the Astronomical Society of Japan. - : Oxford University Press (OUP). - 0004-6264 .- 2053-051X. ; 70:3
-
Journal article (peer-reviewed)abstract
- We present results from the Hitomi X-ray observation of a young composite-type supernova remnant (SNR) G21.5-0.9, whose emission is dominated by the pulsar wind nebula (PWN) contribution. The X-ray spectra in the 0.8-80 keV range obtained with the Soft X-ray Spectrometer (SXS), Soft X-ray Imager, and Hard X-ray Imager (HXI) show a significant break in the continuum as previously found with the NuSTAR observation. After taking into account all known emissions from the SNR other than the PWN itself, we find that the Hitomi spectra can be fitted with a broken power law with photon indices of Gamma(1) = 1.74 +/- 0.02 and Gamma(2) = 2.14 +/- 0.01 below and above the break at 7.1 +/- 0.3 keV, which is significantly lower than the NuSTAR result (similar to 9.0 keV). The spectral break cannot be reproduced by time-dependent particle injection one-zone spectral energy distribution models, which strongly indicates that a more complex emission model is needed, as suggested by recent theoretical models. We also search for narrow emission or absorption lines with the SXS, and perform a timing analysis of PSR J1833-1034 with the HXI and the Soft Gamma-ray Detector. No significant pulsation is found from the pulsar. However, unexpectedly, narrow absorption line features are detected in the SXS data at 4.2345 keV and 9.296 keV with a significance of 3.65 sigma. While the origin of these features is not understood, their mere detection opens up a new field of research and was only possible with the high resolution, sensitivity, and ability to measure extended sources provided by an X-ray microcalorimeter.
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| 17. |
- Aharonian, Felix, et al.
(author)
-
Hitomi X-ray studies of giant radio pulses from the Crab pulsar
- 2018
-
In: Publications of the Astronomical Society of Japan. - : Oxford University Press (OUP). - 0004-6264 .- 2053-051X. ; 70:2
-
Journal article (peer-reviewed)abstract
- To search for giant X-ray pulses correlated with the giant radio pulses (GRPs) from the Crab pulsar, we performed a simultaneous observation of the Crab pulsar with the X-ray satellite Hitomi in the 2-300 keV band and the Kashima NICT radio telescope in the 1.4-1.7 GHz band with a net exposure of about 2 ks on 2016 March 25, just before the loss of the Hitomi mission. The timing performance of the Hitomi instruments was confirmed to meet the timing requirement and about 1000 and 100 GRPs were simultaneously observed at the main pulse and inter-pulse phases, respectively, and we found no apparent correlation between the giant radio pulses and the X-ray emission in either the main pulse or inter-pulse phase. All variations are within the 2 sigma fluctuations of the X-ray fluxes at the pulse peaks, and the 3 sigma upper limits of variations of main pulse or inter-pulse GRPs are 22% or 80% of the peak flux in a 0.20 phase width, respectively, in the 2-300 keV band. The values for main pulse or inter-pulse GRPs become 25% or 110%, respectively, when the phase width is restricted to the 0.03 phase. Among the upper limits from the Hitomi satellite, those in the 4.5-10 keV and 70-300 keV bands are obtained for the first time, and those in other bands are consistent with previous reports. Numerically, the upper limits of the main pulse and inter-pulse GRPs in the 0.20 phase width are about (2.4 and 9.3) x 10(-11) erg cm(-2), respectively. No significant variability in pulse profiles implies that the GRPs originated from a local place within the magneto-sphere. Although the number of photon-emitting particles should temporarily increase to account for the brightening of the radio emission, the results do not statistically rule out variations correlated with the GRPs, because the possible X-ray enhancement may appear due to a > 0.02% brightening of the pulse-peak flux under such conditions.
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| 18. |
- Aharonian, Felix, et al.
(author)
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Measurements of resonant scattering in the Perseus Cluster core with Hitomi SXS
- 2018
-
In: Publications of the Astronomical Society of Japan. - : Oxford University Press (OUP). - 0004-6264 .- 2053-051X. ; 70:2
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Journal article (peer-reviewed)abstract
- Thanks to its high spectral resolution (similar to 5 eV at 6 keV), the Soft X-ray Spectrometer (SXS) on board Hitomi enables us to measure the detailed structure of spatially resolved emission lines from highly ionized ions in galaxy clusters for the first time. In this series of papers, using the SXS we have measured the velocities of gas motions, metallicities and the multi-temperature structure of the gas in the core of the Perseus Cluster. Here, we show that when inferring physical properties from line emissivities in systems like Perseus, the resonant scattering effect should be taken into account. In the Hitomi waveband, resonant scattering mostly affects the Fe XXV He alpha line (w)-the strongest line in the spectrum. The flux measured by Hitomi in this line is suppressed by a factor of similar to 1.3 in the inner similar to 30 kpc, compared to predictions for an optically thin plasma; the suppression decreases with the distance from the center. The w line also appears slightly broader than other lines from the same ion. The observed distortions of the w line flux, shape, and distance dependence are all consistent with the expected effect of the resonant scattering in the Perseus core. By measuring the ratio of fluxes in optically thick (w) and thin (Fe XXV forbidden, He beta, Ly alpha) lines, and comparing these ratios with predictions from Monte Carlo radiative transfer simulations, the velocities of gas motions have been obtained. The results are consistent with the direct measurements of gas velocities from line broadening described elsewhere in this series, although the systematic and statistical uncertainties remain significant. Further improvements in the predictions of line emissivities in plasma models, and deeper observations with future X-ray missions offering similar or better capabilities to the Hitomi SXS, will enable resonant scattering measurements to provide powerful constraints on the amplitude and anisotropy of cluster gas motions.
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| 19. |
- Aharonian, Felix, et al.
(author)
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Search for thermal X-ray features from the Crab nebula with the Hitomi soft X-ray spectrometer
- 2018
-
In: Publications of the Astronomical Society of Japan. - : Oxford University Press (OUP). - 0004-6264 .- 2053-051X. ; 70:2
-
Journal article (peer-reviewed)abstract
- The Crab nebula originated from a core-collapse supernova (SN) explosion observed in 1054 AD. When viewed as a supernova remnant (SNR), it has an anomalously low observed ejecta mass and kinetic energy for an Fe-core-collapse SN. Intensive searches have been made for a massive shell that solves this discrepancy, but none has been detected. An alternative idea is that SN 1054 is an electron-capture (EC) explosion with a lower explosion energy by an order of magnitude than Fe-core-collapse SNe. X-ray imaging searches were performed for the plasma emission from the shell in the Crab outskirts to set a stringent upper limit on the X-ray emitting mass. However, the extreme brightness of the source hampers access to its vicinity. We thus employed spectroscopic technique using the X-ray micro-calorimeter on board the Hitomi satellite. By exploiting its superb energy resolution, we set an upper limit for emission or absorption features from as yet undetected thermal plasma in the 2-12 keV range. We also re-evaluated the existing Chandra and XMM-Newton data. By assembling these results, a new upper limit was obtained for the X-ray plasma mass of less than or similar to 1 M-circle dot for a wide range of assumed shell radius, size, and plasma temperature values both in and out of collisional equilibrium. To compare with the observation, we further performed hydrodynamic simulations of the Crab SNR for two SN models (Fe-core versus EC) under two SN environments (uniform interstellar medium versus progenitor wind). We found that the observed mass limit can be compatible with both SN models if the SN environment has a low density of less than or similar to 0.03 cm(-3) (Fe core) or less than or similar to 0.1 cm(-3) (EC) for the uniform density, or a progenitor wind density somewhat less than that provided by amass loss rate of 10(-5) M-circle dot yr(-1) at 20 km s(-1) for the wind environment.
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| 20. |
- Aharonian, Felix, et al.
(author)
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Solar abundance ratios of the iron-peak elements in the Perseus cluster
- 2017
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 551:7681, s. 478-
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Journal article (peer-reviewed)abstract
- The metal abundance of the hot plasma that permeates galaxy clusters represents the accumulation of heavy elements produced by billions of supernovae(1). Therefore, X-ray spectroscopy of the intracluster medium provides an opportunity to investigate the nature of supernova explosions integrated over cosmic time. In particular, the abundance of the iron-peak elements (chromium, manganese, iron and nickel) is key to understanding how the progenitors of typical type Ia supernovae evolve and explode(2-6). Recent X-ray studies of the intracluster medium found that the abundance ratios of these elements differ substantially from those seen in the Sun(7-11), suggesting differences between the nature of type Ia supernovae in the clusters and in the Milky Way. However, because the K-shell transition lines of chromium and manganese are weak and those of iron and nickel are very close in photon energy, highresolution spectroscopy is required for an accurate determination of the abundances of these elements. Here we report observations of the Perseus cluster, with statistically significant detections of the resonance emission from chromium, manganese and nickel. Our measurements, combined with the latest atomic models, reveal that these elements have near-solar abundance ratios with respect to iron, in contrast to previous claims. Comparison between our results and modern nucleosynthesis calculations(12-14) disfavours the hypothesis that type Ia supernova progenitors are exclusively white dwarfs with masses well below the Chandrasekhar limit (about 1.4 times the mass of the Sun). The observed abundance pattern of the iron-peak elements can be explained by taking into account a combination of near-and sub-Chandrasekhar-mass type Ia supernova systems, adding to the mounting evidence that both progenitor types make a substantial contribution to cosmic chemical enrichment(5,15,16).
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| 21. |
- Aharonian, Felix, et al.
(author)
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Temperature structure in the Perseus cluster core observed with Hitomi
- 2018
-
In: Publications of the Astronomical Society of Japan. - : Oxford University Press (OUP). - 0004-6264 .- 2053-051X. ; 70:2
-
Journal article (peer-reviewed)abstract
- The present paper explains the temperature structure of X-ray emitting plasma in the core of the Perseus cluster based on 1.8-20.0 keV data obtained with the Soft X-ray Spectrometer (SXS) on board the Hitomi Observatory. A series of four observations was carried out, with a total effective exposure time of 338 ks that covered a central region of similar to 7' in diameter. SXS was operated with an energy resolution of similar to 5 eV (full width at half maximum) at 5.9 keV. Not only fine structures of K-shell lines in He-like ions, but also transitions from higher principal quantum numbers were clearly resolved from Si through Fe. That enabled us to perform temperature diagnostics using the line ratios of Si, S, Ar, Ca, and Fe, and to provide the first direct measurement of the excitation temperature and ionization temperature in the Perseus cluster. The observed spectrum is roughly reproduced by a single-temperature thermal plasma model in collisional ionization equilibrium, but detailed line-ratio diagnostics reveal slight deviations from this approximation. In particular, the data exhibit an apparent trend of increasing ionization temperature with the atomic mass, as well as small differences between the ionization and excitation temperatures for Fe, the only element for which both temperatures could be measured. The best-fit two-temperature models suggest a combination of 3 and 5 keV gas, which is consistent with the idea that the observed small deviations from a single-temperature approximation are due to the effects of projecting the known radial temperature gradient in the cluster core along the line of sight. A comparison with the Chandra/ACIS and the XMM-Newton/RGS results, on the other hand, suggests that additional lower-temperature components are present in the intracluster medium (ICM), but not detectable with Hitomi/SXS giving its 1.8-20 keV energy band.
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| 22. |
- Dyrskjot, L., et al.
(author)
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Analysis of molecular intra-patient variation and delineation of a prognostic 12-gene signature in non-muscle invasive bladder cancer; technology transfer from microarrays to PCR
- 2012
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In: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 107:8, s. 1392-1398
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Journal article (peer-reviewed)abstract
- BACKGROUND: Multiple clinical risk factors and genetic profiles have been demonstrated to predict progression of non-muscle invasive bladder cancer; however, no easily clinical applicable gene signature has been developed to predict disease progression independent of disease stage and grade. METHODS: We measured the intra-patient variation of an 88-gene progression signature using 39 metachronous tumours from 17 patients. For delineation of the optimal quantitative reverse transcriptase PCR panel of markers, we used 115 tumour samples from patients in Denmark, Sweden, UK and Spain. RESULTS: Analysis of intra-patient variation of the molecular markers showed 71% similar classification results. A final panel of 12 genes was selected, showing significant correlation with outcome. In multivariate Cox regression analysis, we found that the 12-gene signature was an independent prognostic factor (hazard ratio = 7.4 (95% confidence interval: 3.4-15.9), P < 0.001) when adjusting for stage, grade and treatment. Independent validation of the 12-gene panel and the determined cut-off values is needed and ongoing. CONCLUSION: Intra-patient marker variation in metachronous tumours is present. Therefore, to increase test sensitivity, it may be necessary to test several metachronous tumours from a patient's disease course. A PCR-based 12-gene signature significantly predicts disease progression in patients with non-muscle invasive bladder cancer.
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| 23. |
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| 24. |
- Rockström, Johan, et al.
(author)
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The unfolding water drama in the Anthropocene : towards a resilience-based perspective on water for global sustainability
- 2014
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In: Ecohydrology. - : Wiley. - 1936-0584 .- 1936-0592. ; 7:5, s. 1249-1261
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Journal article (peer-reviewed)abstract
- The human influence on the global hydrological cycle is now the dominant force behind changes in water resources across the world and in regulating the resilience of the Earth system. The rise in human pressures on global freshwater resources is in par with other anthropogenic changes in the Earth system (from climate to ecosystem change), which has prompted science to suggest that humanity has entered a new geological epoch, the Anthropocene. This paper focuses on the critical role of water for resilience of social-ecological systems across scales, by avoiding major regime shifts away from stable environmental conditions, and in safeguarding life-support systems for human wellbeing. It highlights the dramatic increase of water crowding: near-future challenges for global water security and expansion of food production in competition with carbon sequestration and biofuel production. It addresses the human alterations of rainfall stability, due to both land-use changes and climate change, the ongoing overuse of blue water, reflected in river depletion, expanding river basin closure, groundwater overexploitation and water pollution risks. The rising water turbulence in the Anthropocene changes the water research and policy agenda, from a water-resource efficiency to a water resilience focus. This includes integrated land and water stewardship to sustain wetness-dependent ecological functions at the landscape scale and a stronger emphasis on green water management for ecosystem services. A new paradigm of water governance emerges, encouraging land-use practices that explicitly take account of the multifunctional roles of water, with adequate attention to planetary freshwater boundaries and cross-scale interactions.
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| 25. |
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| 26. |
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| 27. |
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| 28. |
- Hedegaard, Jakob, et al.
(author)
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Comprehensive Transcriptional Analysis of Early-Stage Urothelial Carcinoma
- 2016
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In: Cancer Cell. - : Elsevier BV. - 1535-6108 .- 1878-3686. ; 30:1, s. 27-42
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Journal article (peer-reviewed)abstract
- Non-muscle-invasive bladder cancer (NMIBC) is a heterogeneous disease with widely different outcomes. We performed a comprehensive transcriptional analysis of 460 early-stage urothelial carcinomas and showed that NMIBC can be subgrouped into three major classes with basal-and luminal-like characteristics and different clinical outcomes. Large differences in biological processes such as the cell cycle, epithelial-mesenchymal transition, and differentiation were observed. Analysis of transcript variants revealed frequent mutations in genes encoding proteins involved in chromatin organization and cytoskeletal functions. Furthermore, mutations in well-known cancer driver genes (e.g., TP53 and ERBB2) were primarily found in high-risk tumors, together with APOBEC-related mutational signatures. The identification of subclasses in NMIBC may offer better prognostication and treatment selection based on subclass assignment.
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| 29. |
- Kamat, Ashish M, et al.
(author)
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Bladder cancer
- 2016
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In: The Lancet. - 0140-6736 .- 1474-547X. ; 388:10061, s. 2796-2810
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Research review (peer-reviewed)abstract
- Bladder cancer is a complex disease associated with high morbidity and mortality rates if not treated optimally. Awareness of haematuria as the major presenting symptom is paramount, and early diagnosis with individualised treatment and follow-up is the key to a successful outcome. For non-muscle-invasive bladder cancer, the mainstay of treatment is complete resection of the tumour followed by induction and maintenance immunotherapy with intravesical BCG vaccine or intravesical chemotherapy. For muscle-invasive bladder cancer, multimodal treatment involving radical cystectomy with neoadjuvant chemotherapy offers the best chance for cure. Selected patients with muscle-invasive tumours can be offered bladder-sparing trimodality treatment consisting of transurethral resection with chemoradiation. Advanced disease is best treated with systemic cisplatin-based chemotherapy; immunotherapy is emerging as a viable salvage treatment for patients in whom first-line chemotherapy cannot control the disease. Developments in the past 2 years have shed light on genetic subtypes of bladder cancer that might differ from one another in response to various treatments.
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| 30. |
- Martinez-Assucena, A., et al.
(author)
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Rehabilitation for multiple sclerosis, in adults (II); management and impact on impairment, functioning, and quality of life : An overview
- 2010
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In: Critical Reviews in Physical and Rehabilitation Medicine. - 0896-2960. ; 22:1-4, s. 179-240
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Journal article (peer-reviewed)abstract
- Multiple sclerosis (MS) often leads to different levels of severity and progression of impairment and disability and to dissimilar levels of limitation in activities and participation in different social domains, with varying impacts on quality of life (QoL) among people with MS (PwMS). Results have shown that, for PwMS, prioritizing goal setting may enhance adherence to treatment. Interdisciplinary rehabilitation may prolong the functional status level of PwMS, may result in transient improvement in the aspects of impairment features, may increase their participation in activities, and may improve their QoL, even when disease progression is not modified. Single rehabilitation packages of comprehensive care have proven beneficial, such as physiotherapy, which enhances aerobic capacity, strength, pain, mood, mobility, and QoL. Occupational therapy can help reduce the impact of impairment on QoL, especially fatigue. Neuropsychological interventions, such as learning and memory remediation, psychological intervention for depressive disorders, and acquistion of coping skills and self-management techniques help PwMS to adjust to disease and disability. Speech therapy can improve intelligibility of communication. Learning swallowing techniques can help prevent material from entering the airway. Clean intermittent self-catheterization can help prevent urinary tract infections. Power wheelchairs enhance occupational performance and energy conservation. Further vocational rehabilitation settings and research are required for more appropriate interventions due to high unemployment rates among PwMS. Comprehensive care for PwMS should include planning for future independent living and long-term care needs.
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| 31. |
- Möhlmann, Tim, et al.
(author)
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Latitudinal diversity of biting midge species within the Obsoletus group across three habitats in Europe
- 2019
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In: Medical and Veterinary Entomology. - : WILEY. - 0269-283X .- 1365-2915. ; 33:3, s. 420-426
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Journal article (peer-reviewed)abstract
- Culicoides species from the Obsoletus group are important vectors of bluetongue and Schmallenberg virus. This group consists of several species that cannot easily be identified using morphological characteristics. Therefore, limited information is available about their distribution and habitat preferences. In this study, we aimed to elucidate the species composition of the Obsoletus group in three habitat types at climatically different latitudes across Europe. Traps were placed in three habitat types in three countries at different latitudes. After DNA extraction, biting midges were identified using PCR and gel electrophoresis. Extraction of DNA using Chelex proved to be a cost and time efficient method for species identification. A latitudinal effect on the relative abundance of species from the Obsoletus group was found. Species composition was unique for most country-habitat combinations. The majority of biting midges were either C. obsoletus s.s. or C. scoticus, and both species were found at all latitudes and habitats. Their wide distribution and their high abundance at livestock farms make these species likely candidates for rapid farm-to-farm transmission of pathogens throughout Europe. Our results emphasize the need to differentiate Obsoletus group species to better understand their ecology and contribution to pathogen transmission.
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| 32. |
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| 33. |
- Alam, M.T., et al.
(author)
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The importance of being knotted : Effects of the C-terminal knot structure on enzymatic and mechanical properties of bovine carbonic anhydrase II1
- 2002
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In: FEBS Letters. - 0014-5793 .- 1873-3468. ; 519:1-3, s. 35-40
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Journal article (peer-reviewed)abstract
- In order to better understand the contribution of the knotted folding pattern to the enzymatic and mechanical properties of carbonic anhydrases, we replaced Gln-253 of bovine carbonic anhydrase II with Cys, which allowed us to measure the mechanical strength of the protein against tensile deformation by avoiding knot tightening. The expressed protein, to our surprise, turned out to contain two conformational isomers, one capable of binding an enzymatic inhibitor and the other not, which led to their separation through affinity chromatography. In near- and far-UV circular dichroism and fluorescence spectra, the separated conformers were very similar to each other and to the wild-type enzyme, indicating that they both had native-like conformations. We describe new evidence which supports the notion that the difference between the two conformers is likely to be related to the completeness of the C-terminal knot formation. © 2002 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.
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| 34. |
- Chan, Owen T. M., et al.
(author)
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Association of MMP-2, RB and PAI-1 with decreased recurrence-free survival and overall survival in bladder cancer patients
- 2017
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In: Oncotarget. - : IMPACT JOURNALS LLC. - 1949-2553. ; 8:59, s. 99707-99721
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Journal article (peer-reviewed)abstract
- Background: We previously reported an accurate urine-based bladder cancer (BCa)-associated diagnostic signature that can be used to non-invasively detect BCa. In this study, we investigated whether a component of this signature could risk stratify patients with BCa. Methods: Utilizing immunohistochemistry, we investigated angiogenin, MMP-2, p53, RB and PAI-1 expression from 939 patients with BCa. The expression levels were scored by assigning a proportion score and an intensity score to yield a total staining score for each protein. The expressions of each protein individually and as an aggregate were then correlated with progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS). Results: Differential expressions of these markers were noted in BCa. With multivariate analysis in non-muscle invasive bladder cancer (NMIBC) age, tumor grade portended a worse PFS, while age, tumor grade, nodal status, MMP2, RB and PAI-1 expression portended a worse OS. As for multivariate analysis in muscle invasive bladder cancer (MIBC), age MMP-2 and RB were associated with a worse PFS, while age, nodal status, MMP-2, RB and PAI-1 were associated with a worse OS. Using Kaplan-Meier survival analysis, we noted a significant reduction in OS as more of the five biomarkers were expressed in a tumor. Thus, overall, high expressions of MMP-2, RB and/or PAI-1 in bladder tumors were markers of poor prognosis. Conclusion: Individually, MMP-2, RB and PAI-1, as well as in aggregate correlated with poor survival in patients with BCa. Thus, patients whose bladder tumors express these biomarkers may benefit from early radical treatment and/or neoadjuvant or adjuvant therapies.
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| 35. |
- Dyrskjøt, Lars, et al.
(author)
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Gene expression signatures predict outcome in non-muscle-invasive bladder carcinoma : a multicenter validation study
- 2007
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In: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 13:12, s. 3545-3551
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Journal article (peer-reviewed)abstract
- Purpose: Clinically useful molecular markers predicting the clinical course of patients diagnosed with non–muscle-invasive bladder cancer are needed to improve treatment outcome. Here, we validated four previously reported gene expression signatures for molecular diagnosis of disease stage and carcinoma in situ (CIS) and for predicting disease recurrence and progression. Experimental Design: We analyzed tumors from 404 patients diagnosed with bladder cancer in hospitals in Denmark, Sweden, England, Spain, and France using custom microarrays. Molecular classifications were compared with pathologic diagnosis and clinical outcome. Results: Classification of disease stage using a 52-gene classifier was found to be highly significantly correlated with pathologic stage (P < 0.001). Furthermore, the classifier added information regarding disease progression of Ta or T1 tumors (P < 0.001). The molecular 88-gene progression classifier was highly significantly correlated with progression-free survival (P < 0.001) and cancer-specific survival (P = 0.001). Multivariate Cox regression analysis showed the progression classifier to be an independently significant variable associated with disease progression after adjustment for age, sex, stage, grade, and treatment (hazard ratio, 2.3; P = 0.007). The diagnosis of CIS using a 68-gene classifier showed a highly significant correlation with histopathologic CIS diagnosis (odds ratio, 5.8; P < 0.001) in multivariate logistic regression analysis. Conclusion: This multicenter validation study confirms in an independent series the clinical utility of molecular classifiers to predict the outcome of patients initially diagnosed with non–muscle-invasive bladder cancer. This information may be useful to better guide patient treatment.
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| 36. |
- Edstam, Monika M., et al.
(author)
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Coexpression patterns indicate that GPI-anchored non-specific lipid transfer proteins are involved in accumulation of cuticular wax, suberin and sporopollenin
- 2013
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In: Plant Molecular Biology. - : Springer Netherlands. - 0167-4412 .- 1573-5028. ; 83:6, s. 625-649
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Journal article (peer-reviewed)abstract
- The non-specific lipid transfer proteins (nsLTP) are unique to land plants. The nsLTPs are characterized by a compact structure with a central hydrophobic cavity and can be classified to different types based on sequence similarity, intron position or spacing between the cysteine residues. The type G nsLTPs (LTPGs) have a GPI-anchor in the C-terminal region which attaches the protein to the exterior side of the plasma membrane. The function of these proteins, which are encoded by large gene families, has not been systematically investigated so far. In this study we have explored microarray data to investigate the expression pattern of the LTPGs in Arabidopsis and rice. We identified that the LTPG genes in each plant can be arranged in three expression modules with significant coexpression within the modules. According to expression patterns and module sizes, the Arabidopsis module AtI is functionally equivalent to the rice module OsI, AtII corresponds to OsII and AtIII is functionally comparable to OsIII. Starting from modules AtI, AtII and AtIII we generated extended networks with Arabidopsis genes coexpressed with the modules. Gene ontology analyses of the obtained networks suggest roles for LTPGs in the synthesis or deposition of cuticular waxes, suberin and sporopollenin. The AtI-module is primarily involved with cuticular wax, the AtII-module with suberin and the AtIII-module with sporopollenin. Further transcript analysis revealed that several transcript forms exist for several of the LTPG genes in both Arabidopsis and rice. The data suggests that the GPI-anchor attachment and localization of LTPGs may be controlled to some extent by alternative splicing.
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| 37. |
- Furuya, Hideki, et al.
(author)
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PAI-1 is a potential transcriptional silencer that supports bladder cancer cell activity
- 2022
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In: Scientific Reports. - : Springer Nature. - 2045-2322. ; 12:1
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Journal article (peer-reviewed)abstract
- The extracellular activity of Plasminogen activator inhibitor-1 (PAI-1) is well described, acting as an inhibitor of tissue plasminogen activator and urokinase-type plasminogen activator, impacting fibrinolysis. Recent studies have revealed a pro-tumorigenic role of PAI-1 in human cancers, via the regulation of angiogenesis and tumor cell survival. In this study, immunohistochemical staining of 939 human bladder cancer specimens showed that PAI-1 expression levels correlated with tumor grade, tumor stage and overall survival. The typical subcellular localization of PAI-1 is cytoplasmic, but in approximately a quarter of the cases, PAI-1 was observed to be localized to both the tumor cell cytoplasm and the nucleus. To investigate the potential function of nuclear PAI-1 in tumor biology we applied chromatin immunoprecipitation (ChIP)-sequencing, gene expression profiling, and rapid immunoprecipitation mass spectrometry to a pair of bladder cancer cell lines. ChIP-sequencing revealed that PAI-1 can bind DNA at distal intergenic regions, suggesting a role as a transcriptional coregulator. The downregulation of PAI-1 in bladder cancer cell lines caused the upregulation of numerous genes, and the integration of ChIP-sequence and RNA-sequence data identified 57 candidate genes subject to PAI-1 regulation. Taken together, the data suggest that nuclear PAI-1 can influence gene expression programs and support malignancy.
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| 38. |
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| 39. |
- Hammarström, Per, et al.
(author)
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High-resolution probing of local conformational changes in proteins by the use of multiple labeling : Unfolding and self-assembly of human carbonic anhydrase II monitored by spin, fluorescent, and chemical reactivity probes
- 2001
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In: Biophysical Journal. - 0006-3495 .- 1542-0086. ; 80:6, s. 2867-2885
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Journal article (peer-reviewed)abstract
- Two different spin labels, N-(1-oxyl-2,2,5,5-tetramethyl-3-pyrrolidinyl)iodoacetamide (IPSL) and (1-oxyl-2.2,5,5-tetramethylpyrroline-3-methyl) methanethiosulfonate (MTSSL), and two different fluorescent labels 5-((((2-iodoacetyl)amino)ethyl)amino)naphtalene-1 -sulfonic acid (IAEDANS) and 6-bromoacetyl-2-dimetylaminonaphtalene (BADAN), were attached to the introduced C79 in human carbonic anhydrase (HCA II) to probe local structural changes upon unfolding and aggregation, HCA II unfolds in a multi-step manner with an intermediate state populated between the native and unfolded states. The spin label IPSL and the fluorescent label IAEDANS reported on a substantial change in mobility and polarity at both unfolding transitions at a distance of 7.4-11.2 Angstrom from the backbone of position 79. The shorter and less flexible labels BADAN and MTSSL revealed less pronounced spectroscopic changes in the native-to-intermediate transition, 6.6-9.0 Angstrom from the backbone. At intermediate guanidine (Gu)-HCl concentrations the occurrence of soluble but irreversibly aggregated oligomeric protein was identified from refolding experiments. At similar to1 M Gu-HCl the aggregation was found to be essentially complete. The size and structure of the aggregates could be varied by changing the protein concentration. EPR measurements and line-shape simulations together with fluorescence lifetime and anisotropy measurements provided a picture of the self-assembled protein as a disordered protein structure with a representation of both compact as well as dynamic and polar environments at the site of the molecular labels. This suggests that a partially folded intermediate of HCA II self-assembles by both local unfolding and intermolecular docking of the intermediates vicinal to position 79. The aggregates were determined to be 40-90 Angstrom in diameter depending on the experimental conditions and spectroscopic technique used.
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| 40. |
- Hammarström, Per, 1972-, et al.
(author)
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Protein substrate binding induces conformational changes in the chaperonin GroEL : A suggested mechanism for unfoldase activity
- 2000
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In: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 275:30, s. 22832-22838
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Journal article (peer-reviewed)abstract
- Chaperonins are molecules that assist proteins during folding and protect them from irreversible aggregation. We studied the chaperonin GroEL and its interaction with the enzyme human carbonic anhydrase II (HCA II), which induces unfolding of the enzyme. We focused on conformational changes that occur in GroEL during formation of the GroEL-HCA II complex. We measured the rate of GroEL cysteine reactivity toward iodo[2-(14)C]acetic acid and found that the cysteines become more accessible during binding of a cysteine free mutant of HCA II. Spin labeling of GroEL with N-(1-oxy1-2,2,5,5-tetramethyl-3-pyrrolidinyl)iodoacetamide revealed that this additional binding occurred because buried cysteine residues become accessible during HCA II binding. In addition, a GroEL variant labeled with 6-iodoacetamidofluorescein exhibited decreased fluorescence anisotropy upon HCA II binding, which resembles the effect of GroES/ATP binding. Furthermore, by producing cysteine-modified GroEL with the spin label N-(1-oxyl-2,2,5,5-tetramethyl-3-pyrrolidinyl)iodoacetamide and the fluorescent label 5-((((2-iodoacetyl)amino)ethyl)amino)naphthalene-1-sulfonic acid, we detected increases in spin-label mobility and fluorescence intensity in GroEL upon HCA II binding. Together, these results show that conformational changes occur in the chaperonin as a consequence of protein substrate binding. Together with previous results on the unfoldase activity of GroEL, we suggest that the chaperonin opens up as the substrate protein binds. This opening mechanism may induce stretching of the protein, which would account for reported unfoldase activity of GroEL and might explain how GroEL can actively chaperone proteins larger than HCA II.
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| 41. |
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| 42. |
- Håkansson, Nina, et al.
(author)
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A strategic analysis of slaughterhouses and animal transportation in Sweden
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Other publication (other academic/artistic)abstract
- The number of slaughterhouses in Sweden has decreased over time. Fewer slaughterhouses are expected to affect the transport time for animals and as a consequence animal welfare. We have analyzed the transportto- slaughter system, for pigs and cattle, using transport-data from 2008, geographical information for slaughterhouses and farms, and actual route distances between facilities. We made a strategic analysis of the existing slaughterhouses and tested the impact of numbers decreasing further. With strategic planning the potential reduction of transport distance is 25% for pigs and 40% for cattle. About 50% of the slaughterhouses in Sweden could be closed down with small effect on the total transport work. This implies that for the national total animal welfare which animals are sent where, is much more important than the number of slaughterhouses. However for the welfare (transport time and distance) of the animals in long transports number of slaughterhouses (regular or mobile) is important. Animal welfare weights of distances in the objective function decreases the amount of transports with long route times. We have investigated where in Sweden it would be beneficial to use mobile slaughterhouses. Animals are usually not sent to closest slaughterhouse; we show how slaughterhouse capacity must change if that transport strategy was applied.
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| 43. |
- Håkansson, Nina, et al.
(author)
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Improvement of animal welfare by strategic analysis and logistic optimisation of animal slaughter transportation
- 2016
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In: Animal Welfare. - : Universities Federation for Animal Welfare. - 0962-7286 .- 2054-1538. ; 25:2, s. 255-263
-
Journal article (peer-reviewed)abstract
- The transportation of animals to slaughterhouses is a major welfare concern. The number of slaughterhouses has decreased over time in Europe due to centralisation. This is expected to increase transport time for animals and as a consequence negatively affect animal welfare. We propose an optimisation model based on a facility location model to perform strategic analysis to improve transportation logistics. The model is tested on the Swedish slaughter transport system. We show that, by strategic planning and redirection of transports while keeping the slaughterhouse capacities as of the originaldata, the potential exists to reduce transport distance by 25% for pigs and 40% for cattle. Furthermore, we demonstrated that approximately 50% of Swedish slaughterhouses can be shut down with a minimal effect on total transport distances. This implies that in terms of the overall welfare picture, the decision of which animals to send where plays a for more significant role than the number of slaughterhouses. In addition, by changing relative weights on distances in the optimisation function the amount of individualtransports with longjourney times can be decreased. We also show results from altered slaughterhouse capacity and geographical location of slaughterhouses. This is the first time an entire country has been analysed in great detail with respect to the location, capacity and number of slaughterhouses. The focus is mainly on the analysis of unique and detailed information of actual animal transports in Sweden and a demonstration of the potential impact redirection of the transports and/ or altering of slaughterhouses can have on animal welfare.
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| 44. |
- Håkansson, Nina, et al.
(author)
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Route planning reduces the costs of animal transportation : Animal welfare versus economics
- 2007
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In: XIII International Congress in Animal Hygiene, June 17–21, 2007, Tartu, Estonia. - 9789949426300 ; , s. 1044-1048
-
Conference paper (peer-reviewed)abstract
- Animals are more stressed on long transport routes with stops at many farms. The positions of farms and abattoirs are the basic properties that set the limits for route planning. Mobile abattoirs can reduce the cost of transportation and increase the welfare for the animals. The trade-offs between welfare and profit can be reduced by effective route planning. We have, by computer simulations, investigated how trade-offs differs between areas in Sweden and in general landscapes. The general results are applicable to any area and hence for animal transportation in general.
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| 45. |
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| 46. |
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| 47. |
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| 48. |
- Kerzeli, Iliana Kyriaki, et al.
(author)
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Proximity Extension Assay reveals MMP12 in plasma as a predictor of outcome in urothelial bladder cancer
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Other publication (other academic/artistic)abstract
- Background Urothelial bladder cancer (UBC) is most-frequently diagnosed at the non-muscle-invasive stage (NMIBC). However, recurrences and interventions for intermediate and high-risk NMIBC patients impact quality of life. Biomarkers for patient stratification can help to avoid unnecessary interventions whilst indicating aggressive measures when required.Methods Proximity Extension Assay (PEA) was utilised to analyse plasma (n=90) and urine (n=40) samples from 90 newly-diagnosed and treatment-naïve UBC patients with an immuno-oncology protein panel. Public single-cell and bulk RNA sequencing data from patient tumour tissues and a murine OH-BBN induced UBC model were also explored. Results Plasma samples from muscle-invasive UBC patients displayed higher levels of MMP7 and CCL23 compared to NMIBC patients, whereas urine samples displayed higher levels of CD27 and CD40 in the NMIBC group. Increased MMP12 plasma levels were identified as an independent marker of poor survival outcome and this finding was further validated in an independent cohort. Moreover, scRNA-seq data analysis indicated tumour infiltrating macrophages as a putative source of MMP12. Conclusion The local production, but systemic diffusion of MMP12, suggests that MMP12 could be an important biomarker to complement histopathology-based risk stratification. Additionally, it may represent a pharmacological target in bladder cancer.
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| 49. |
- Kerzeli, Iliana Kyriaki, et al.
(author)
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The immunological landscape in bladder cancer: a single cell RNA seq analysis of tumor bearing mouse bladders with a focus on sex differences
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Other publication (other academic/artistic)abstract
- In urothelial bladder cancer differences in clinical outcomes and responses to immunotherapy associate with tumor stage and sex. However, the tumor microenvironment landscape in urothelial cancer and its contexture in different stages and sexes is not fully deciphered. We utilized an autochthonous urothelial cancer model sampled at the non-muscle and muscle invasive stage from both sexes. Single cell RNA sequencing was applied to analyze intercellular interactions and sex differences in the two stages with focus on immune cell subsets. We discerned the Cd6-Alcam interaction to occur between lymphoid, tumor and myeloid cells and that female tumor bearing bladders were enriched in cells of lymphoid lineage compared to males, although male lymphoid cells were metabolically more active. Furthermore, we identified two subsets of Macrophages, Ccl8+ and Spp1+ that were characteristic for NMIBC and MIBC respectively, however both were found to be more active in immune cell recruitment, activation and cytokine signaling in females than males. Analysis of intercellular interactions of immune cells subsets revealed the role of Lyc6c2+ and Ace+ Monocytes as antigen presenting cells equipped with co-stimulatory receptors, and the Anxa1-Fpr2 immune suppressive axis to be active among tumor cells and subsets of granulocytes, macrophages and monocytes. Collectively our results demonstrate the complexity and sex specific differences of the tumor microenvironment in urothelial cancer using a clinically relevant murine model of progressive disease, and distinguish the Cd6-Alcam and Anxa1-Fpr2 interaction pathways of lymphoid, myeloid and tumor cells as potential targets of immune modulation for cancer therapy.
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| 50. |
- Kågedal, Katarina, et al.
(author)
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Lysosomal membrane permeabilization during apoptosis : Involvement of Bax?
- 2005
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In: International journal of experimental pathology (Print). - : John Wiley & Sons. - 0959-9673 .- 1365-2613. ; 86:5, s. 309-321
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Journal article (peer-reviewed)abstract
- Bcl-2 family members have long been known to control permeabilization of the mitochondrial membrane during apoptosis, but involvement of these proteins in lysosomal membrane permeabilization (LMP) was not considered until recently. The aim of this study was to investigate the mechanism underlying the release of lysosomal proteases to the cytosol seen during apoptosis, with special emphasis on the role of Bax. In human fibroblasts, exposed to the apoptosis-inducing drug staurosporine (STS), the release of the lysosomal protease cathepsin D to the cytosol was observed by immunocytochemistry. In response to STS treatment, there was a shift in Bax immunostaining from a diffuse to a punctate pattern. Confocal microscopy showed co-localization of Bax with both lysosomes and mitochondria in dying cells. Presence of Bax at the lysosomal membrane was confirmed by immuno-electron microscopy. Furthermore, when recombinant Bax was incubated with pure lysosomal fractions, Bax inserted into the lysosomal membrane and induced the release of lysosomal enzymes. Thus, we suggest that Bax is a mediator of LMP, possibly promoting the release of lysosomal enzymes to the cytosol during apoptosis.
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