| 1. |
- Aharonian, Felix, et al.
(författare)
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Hitomi X-ray observation of the pulsar wind nebula G21.5-0.9
- 2018
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Ingår i: Publications of the Astronomical Society of Japan. - : Oxford University Press (OUP). - 0004-6264 .- 2053-051X. ; 70:3
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Tidskriftsartikel (refereegranskat)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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| 2. |
- Aharonian, Felix, et al.
(författare)
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Hitomi X-ray studies of giant radio pulses from the Crab pulsar
- 2018
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Ingår i: Publications of the Astronomical Society of Japan. - : Oxford University Press (OUP). - 0004-6264 .- 2053-051X. ; 70:2
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Tidskriftsartikel (refereegranskat)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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| 3. |
- Brozović, Danilo, et al.
(författare)
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The Impacts of Covid-19 on the Tourism Sector : Changes, Adaptations and Challenges
- 2022
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Ingår i: Tourism. - : Portal of Croatian scientific and professional journals - HRČAK. - 1332-7461 .- 1849-1545. ; 70:3, s. 465-479
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Tidskriftsartikel (refereegranskat)abstract
- This exploratory study charts the transformation of the tourism sector caused by the COVID-19 crisis. The article dissects five key domains of industry transformation: accelerated digitalisation, business model flexibility, human resources, travel restrictions, and risk perception and crisis management. It delineates the industry's changes, adaptations, and associated challenges in each domain. A review and content analysis of 240 publicly available online documents was conducted. The results provide managerial implications and avenues for future research in tourism, including the hybridisation of tourism products, transformation of the service encounter style, adaptation to a shifting travel mode, and increased risk awareness and preparedness.
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| 4. |
- Hakariya, Hayase, et al.
(författare)
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Continued cancer drug approvals in Japan and Europe after market withdrawal in the United States : A comparative study of accelerated approvals
- 2024
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Ingår i: Clinical and Translational Science. - 1752-8062. ; 17:7, s. 13879-13879
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Tidskriftsartikel (refereegranskat)abstract
- Regulatory authorities must balance ensuring evidence of efficacy and safety of new drugs. Various regulatory pathways, such as the accelerated approval program in the United States (US), allow authorities to quickly approve drugs for severely ill patients by granting market authorization based on surrogate end points and pending confirmatory trials. In this cross-sectional study, we considered 23 indications of cancer drugs that received accelerated approval by the US Food and Drug Administration (FDA) but were subsequently withdrawn as of April 2023. Our investigation extended to assessing the regulatory status of these accelerated approvals in the European Union (EU) and Japan, examining relevant regulatory documents and identifying factors contributing to the withdrawal in the United States. Comparing regions, we found that for 52% (12/23) and 30% (7/23) of withdrawn accelerated approvals in the United States, sponsors had also sought marketing authorization from the European Medicines Agency (EMA) and Japan's Pharmaceuticals and Medical Devices Agency (PMDA), respectively. As of the April 30, 2023 study cutoff date, 83% (10/12) of drug-indication pairs remained approved by the EMA, while the PMDA retained 100% (7/7). For these indications, the time from FDA withdrawal until the study cutoff date ranged from 0.23 years to 11.45 years for EMA approvals (median: 1.28 years) and 1.10 years to 11.45 years for PMDA approvals (median: 3.22 years). These findings highlight substantial regulatory discrepancies concerning cancer drugs with unconfirmed benefits. Addressing these discrepancies may involve requiring pharmaceutical companies to confirm clinical benefits using more robust end points and fostering international harmonization in regulators' assessment.
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| 5. |
- Kanayama, Kengo, et al.
(författare)
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Genome-wide mapping of bivalent histone modifications in hepatic stem/progenitor cells
- 2019
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Ingår i: Stem Cells International. - : Hindawi Limited. - 1687-966X .- 1687-9678. ; 2019
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Tidskriftsartikel (refereegranskat)abstract
- The “bivalent domain,” a distinctive histone modification signature, is characterized by repressive trimethylation of histone H3 at lysine 27 (H3K27me3) and active trimethylation of histone H3 at lysine 4 (H3K4me3) marks. Maintenance and dynamic resolution of these histone marks play important roles in regulating differentiation processes in various stem cell systems. However, little is known regarding their roles in hepatic stem/progenitor cells. In the present study, we conducted the chromatin immunoprecipitation (ChIP) assay followed by high-throughput DNA sequencing (ChIP-seq) analyses in purified delta-like 1 protein (Dlk + ) hepatic stem/progenitor cells and successfully identified 562 genes exhibiting bivalent domains within 2 kb of the transcription start site. Gene ontology analysis revealed that these genes were enriched in developmental functions and differentiation processes. Microarray analyses indicated that many of these genes exhibited derepression after differentiation toward hepatocyte and cholangiocyte lineages. Among these, 72 genes, including Cdkn2a and Sox4, were significantly upregulated after differentiation toward hepatocyte or cholangiocyte lineages. Knockdown of Sox4 in Dlk + cells suppressed colony propagation and resulted in increased numbers of albumin + /cytokeratin 7 + progenitor cells in colonies. These findings implicate that derepression of Sox4 expression is required to induce normal differentiation processes. In conclusion, combined ChIP-seq and microarray analyses successfully identified bivalent genes. Functional analyses of these genes will help elucidate the epigenetic machinery underlying the terminal differentiation of hepatic stem/progenitor cells.
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| 6. |
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| 7. |
- Miyashita, Naoya, et al.
(författare)
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ASCL1 promotes tumor progression through cell-autonomous signaling and immune modulation in a subset of lung adenocarcinoma
- 2020
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Ingår i: Cancer Letters. - : Elsevier BV. - 0304-3835 .- 1872-7980. ; 489, s. 121-132
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Tidskriftsartikel (refereegranskat)abstract
- The master regulator of neuroendocrine differentiation, achaete-scute complex homolog 1 (ASCL1) defines a subgroup of lung adenocarcinoma. However, the mechanistic role of ASCL1 in lung tumorigenesis and its relation to the immune microenvironment is principally unknown. Here, the immune landscape of ASCL1-positive lung adenocarcinomas was characterized by immunohistochemistry. Furthermore, ASCL1 was transduced in mouse lung adenocarcinoma cell lines and comparative RNA-sequencing and secretome analyses were performed. The effects of ASCL1 on tumorigenesis were explored in an orthotopic syngeneic transplantation model.ASCL1-positive lung adenocarcinomas revealed lower infiltration of CD8+, CD4+, CD20+, and FOXP3+ lymphocytes and CD163+ macrophages indicating an immune desert phenotype. Ectopic ASCL1 upregulated cyclin transcript levels, stimulated cell proliferation, and enhanced tumor growth in mice. ASCL1 suppressed secretion of chemokines, including CCL20, CXCL2, CXCL10, and CXCL16, indicating effects on immune cell trafficking. In accordance with lower lymphocytes infiltration, ASCL1-positive lung adenocarcinomas demonstrated lower abundance of CXCR3-and CCR6-expressing cells.In conclusion, ASCL1 mediates its tumor-promoting effect not only through cell-autonomous signaling but also by modulating chemokine production and immune responses. These findings suggest that ASCL1-positive tumors represent a clinically relevant lung cancer entity.
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| 8. |
- Movérare-Skrtic, Sofia, et al.
(författare)
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Osteoblast-derived WNT16 represses osteoclastogenesis and prevents cortical bone fragility fractures.
- 2014
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 20:11, s. 1279-88
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Tidskriftsartikel (refereegranskat)abstract
- The WNT16 locus is a major determinant of cortical bone thickness and nonvertebral fracture risk in humans. The disability, mortality and costs caused by osteoporosis-induced nonvertebral fractures are enormous. We demonstrate here that Wnt16-deficient mice develop spontaneous fractures as a result of low cortical thickness and high cortical porosity. In contrast, trabecular bone volume is not altered in these mice. Mechanistic studies revealed that WNT16 is osteoblast derived and inhibits human and mouse osteoclastogenesis both directly by acting on osteoclast progenitors and indirectly by increasing expression of osteoprotegerin (Opg) in osteoblasts. The signaling pathway activated by WNT16 in osteoclast progenitors is noncanonical, whereas the pathway activated in osteoblasts is both canonical and noncanonical. Conditional Wnt16 inactivation revealed that osteoblast-lineage cells are the principal source of WNT16, and its targeted deletion in osteoblasts increases fracture susceptibility. Thus, osteoblast-derived WNT16 is a previously unreported key regulator of osteoclastogenesis and fracture susceptibility. These findings open new avenues for the specific prevention or treatment of nonvertebral fractures, a substantial unmet medical need.
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| 9. |
- Ozieranski, Piotr, et al.
(författare)
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International comparison of pharmaceutical industry payment disclosures in the UK and Japan: implications for self-regulation, public regulation, and transparency
- 2023
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Ingår i: Globalization and Health. - : Springer Science and Business Media LLC. - 1744-8603. ; 19:14, s. 1-42
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundSelf-regulation of payment disclosure by pharmaceutical industry trade groups is a major global approach to increasing transparency of financial relationships between drug companies and healthcare professionals and organisations. Nevertheless, little is known about the relative strengths and weaknesses of self-regulation across countries, especially beyond Europe. To address this gap in research and stimulate international policy learning, we compare the UK and Japan, the likely strongest cases of self-regulation of payment disclosure in Europe and Asia, across three dimensions of transparency: disclosure rules, practices, and data.ResultsThe UK and Japanese self-regulation of payment disclosure had shared as well unique strengths and weaknesses. The UK and Japanese pharmaceutical industry trade groups declared transparency as the primary goal of payment disclosure, without, however, explaining the link between the two. The rules of payment disclosure in each country provided more insight into some payments but not others. Both trade groups did not reveal the recipients of certain payments by default, and the UK trade group also made the disclosure of some payments conditional on recipient consent. Drug company disclosure practices were more transparent in the UK, allowing for greater availability and accessibility of payment data and insight into underreporting or misreporting of payments by companies. Nevertheless, the share of payments made to named recipients was three times higher in Japan than in the UK, indicating higher transparency of disclosure data.ConclusionsThe UK and Japan performed differently across the three dimensions of transparency, suggesting that any comprehensive analysis of self-regulation of payment disclosure must triangulate analysis of disclosure rules, practices, and data. We found limited evidence to support key claims regarding the strengths of self-regulation, while often finding it inferior to public regulation of payment disclosure. We suggest how the self-regulation of payment disclosure in each country can be enhanced and, in the long run, replaced by public regulation to strengthen the industry’s accountability to the public.
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