| 1. |
- 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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| 2. |
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| 3. |
- 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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| 4. |
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| 7. |
- Abe, O, et al.
(author)
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Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials
- 2005
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In: The Lancet. - 1474-547X. ; 365:9472, s. 1687-1717
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Journal article (peer-reviewed)abstract
- Background Quinquennial overviews (1985-2000) of the randomised trials in early breast cancer have assessed the 5-year and 10-year effects of various systemic adjuvant therapies on breast cancer recurrence and survival. Here, we report the 10-year and 15-year effects. Methods Collaborative meta-analyses were undertaken of 194 unconfounded randomised trials of adjuvant chemotherapy or hormonal therapy that began by 1995. Many trials involved CMF (cyclophosphamide, methotrexate, fluorouracil), anthracycline-based combinations such as FAC (fluorouracil, doxombicin, cyclophosphamide) or FEC (fluorouracil, epirubicin, cyclophosphamide), tamoxifen, or ovarian suppression: none involved taxanes, trastuzumab, raloxifene, or modem aromatase inhibitors. Findings Allocation to about 6 months of anthracycline-based polychemotherapy (eg, with FAC or FEC) reduces the annual breast cancer death rate by about 38% (SE 5) for women younger than 50 years of age when diagnosed and by about 20% (SE 4) for those of age 50-69 years when diagnosed, largely irrespective of the use of tamoxifen and of oestrogen receptor (ER) status, nodal status, or other tumour characteristics. Such regimens are significantly (2p=0 . 0001 for recurrence, 2p<0 . 00001 for breast cancer mortality) more effective than CMF chemotherapy. Few women of age 70 years or older entered these chemotherapy trials. For ER-positive disease only, allocation to about 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31% (SE 3), largely irrespective of the use of chemotherapy and of age (<50, 50-69, &GE; 70 years), progesterone receptor status, or other tumour characteristics. 5 years is significantly (2p<0 . 00001 for recurrence, 2p=0 . 01 for breast cancer mortality) more effective than just 1-2 years of tamoxifen. For ER-positive tumours, the annual breast cancer mortality rates are similar during years 0-4 and 5-14, as are the proportional reductions in them by 5 years of tamoxifen, so the cumulative reduction in mortality is more than twice as big at 15 years as at 5 years after diagnosis. These results combine six meta-analyses: anthracycline-based versus no chemotherapy (8000 women); CMF-based versus no chemotherapy (14 000); anthracycline-based versus CMF-based chemotherapy (14 000); about 5 years of tamoxifen versus none (15 000); about 1-2 years of tamoxifen versus none (33 000); and about 5 years versus 1-2 years of tamoxifen (18 000). Finally, allocation to ovarian ablation or suppression (8000 women) also significantly reduces breast cancer mortality, but appears to do so only in the absence of other systemic treatments. For middle-aged women with ER-positive disease (the commonest type of breast cancer), the breast cancer mortality rate throughout the next 15 years would be approximately halved by 6 months of anthracycline-based chemotherapy (with a combination such as FAC or FEC) followed by 5 years of adjuvant tamoxifen. For, if mortality reductions of 38% (age <50 years) and 20% (age 50-69 years) from such chemotherapy were followed by a further reduction of 31% from tamoxifen in the risks that remain, the final mortality reductions would be 57% and 45%, respectively (and, the trial results could well have been somewhat stronger if there had been full compliance with the allocated treatments). Overall survival would be comparably improved, since these treatments have relatively small effects on mortality from the aggregate of all other causes. Interpretation Some of the widely practicable adjuvant drug treatments that were being tested in the 1980s, which substantially reduced 5-year recurrence rates (but had somewhat less effect on 5-year mortality rates), also substantially reduce 15-year mortality rates. Further improvements in long-term survival could well be available from newer drugs, or better use of older drugs.
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| 11. |
- Endo, T, et al.
(author)
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Cortical changes following spinal cord injury with emphasis on the Nogo signaling system
- 2009
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In: The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry. - : SAGE Publications. - 1073-8584. ; 15:3, s. 291-299
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Journal article (peer-reviewed)abstract
- After spinal cord injury, structural as well as functional modifications occur in the adult CNS. Sites of plastic changes include the injured spinal cord itself as well as cortical and subcortical structures. Previously, cortical reorganization in response to sensory deprivation has mainly been studied using peripheral nerve injury models, and has led to a degree of understanding of mechanisms underlying reorganization and plastic changes. Deprivation or damage-induced CNS plasticity is not always beneficial for patients, and may underlie the development of conditions such as neuropathic pain and phantom sensations. Therefore, efforts not only to enhance, but also to control the capacity of plastic changes in the CNS, are of clinical relevance. Novel methods to stimulate plasticity as well as to monitor it, such as transcranial magnetic stimulation and functional magnetic resonance imaging, respectively, may be useful in diverse clinical situations such as spinal cord injury and stroke. Here, human and animal studies of spinal cord injury are reviewed, with special emphasis on the contribution of the Nogo signaling system to cortical plasticity.
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| 15. |
- Martrat, Griselda, et al.
(author)
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Exploring the link between MORF4L1 and risk of breast cancer
- 2011
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In: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 13:2
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Journal article (peer-reviewed)abstract
- Introduction: Proteins encoded by Fanconi anemia (FA) and/or breast cancer (BrCa) susceptibility genes cooperate in a common DNA damage repair signaling pathway. To gain deeper insight into this pathway and its influence on cancer risk, we searched for novel components through protein physical interaction screens. Methods: Protein physical interactions were screened using the yeast two-hybrid system. Co-affinity purifications and endogenous co-immunoprecipitation assays were performed to corroborate interactions. Biochemical and functional assays in human, mouse and Caenorhabditis elegans models were carried out to characterize pathway components. Thirteen FANCD2-monoubiquitinylation-positive FA cell lines excluded for genetic defects in the downstream pathway components and 300 familial BrCa patients negative for BRCA1/2 mutations were analyzed for genetic mutations. Common genetic variants were genotyped in 9,573 BRCA1/2 mutation carriers for associations with BrCa risk. Results: A previously identified co-purifying protein with PALB2 was identified, MRG15 (MORF4L1 gene). Results in human, mouse and C. elegans models delineate molecular and functional relationships with BRCA2, PALB2, RAD51 and RPA1 that suggest a role for MRG15 in the repair of DNA double-strand breaks. Mrg15-deficient murine embryonic fibroblasts showed moderate sensitivity to g-irradiation relative to controls and reduced formation of Rad51 nuclear foci. Examination of mutants of MRG15 and BRCA2 C. elegans orthologs revealed phenocopy by accumulation of RPA-1 (human RPA1) nuclear foci and aberrant chromosomal compactions in meiotic cells. However, no alterations or mutations were identified for MRG15/MORF4L1 in unclassified FA patients and BrCa familial cases. Finally, no significant associations between common MORF4L1 variants and BrCa risk for BRCA1 or BRCA2 mutation carriers were identified: rs7164529, P-trend = 0.45 and 0.05, P-2df = 0.51 and 0.14, respectively; and rs10519219, P-trend = 0.92 and 0.72, P-2df = 0.76 and 0.07, respectively. Conclusions: While the present study expands on the role of MRG15 in the control of genomic stability, weak associations cannot be ruled out for potential low-penetrance variants at MORF4L1 and BrCa risk among BRCA2 mutation carriers.
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| 16. |
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| 17. |
- Tominaga, N., et al.
(author)
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Brain metastatic cancer cells release microRNA-181c-containing extracellular vesicles capable of destructing blood-brain barrier
- 2015
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
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Journal article (peer-reviewed)abstract
- Brain metastasis is an important cause of mortality in breast cancer patients. A key event during brain metastasis is the migration of cancer cells through blood-brain barrier (BBB). However, the molecular mechanism behind the passage through this natural barrier remains unclear. Here we show that cancer-derived extracellular vesicles (EVs), mediators of cell-cell communication via delivery of proteins and microRNAs (miRNAs), trigger the breakdown of BBB. Importantly, miR-181c promotes the destruction of BBB through the abnormal localization of actin via the downregulation of its target gene, PDPK1. PDPK1 degradation by miR-181c leads to the downregulation of phosphorylated cofilin and the resultant activated cofilin-induced modulation of actin dynamics. Furthermore, we demonstrate that systemic injection of brain metastatic cancer cell-derived EVs promoted brain metastasis of breast cancer cell lines and are preferentially incorporated into the brain in vivo. Taken together, these results indicate a novel mechanism of brain metastasis mediated by EVs that triggers the destruction of BBB.
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| 18. |
- 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
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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 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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| 19. |
- Morokuma, Tomoki, et al.
(author)
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OISTER optical and near-infrared monitoring observations of peculiar radio-loud active galactic nucleus SDSSJ110006.07+442144.3
- 2017
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In: Nippon Tenmon Gakkai obun kenkyu hokoku. - : Oxford University Press (OUP). - 0004-6264. ; 69:5
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Journal article (peer-reviewed)abstract
- We present monitoring campaign observations at optical and near-infrared (NIR) wavelengths for a radio-loud active galactic nucleus (AGN) at z = 0.840, SDSSJ110006.07+442144.3 (hereafter, J1100+4421), which was identified during a flare phase in late 2014 February. The campaigns consist of three intensive observing runs from the discovery to 2015 March, mostly within the scheme of the OISTER collaboration. Optical-NIR light curves and simultaneous spectral energy distributions (SEDs) are obtained. Our measurements show the strongest brightening in 2015 March. We found that the optical-NIR SEDs of J1100+4421 show an almost steady shape despite the large and rapid intranight variability. This constant SED shape is confirmed to extend to similar to 5 mu m in the observed frame using the archival WISE data. Given the lack of absorption lines and the steep power-law spectrum of alpha(upsilon) similar to -1.4, where f(v) proportional to v(alpha upsilon), synchrotron radiation by a relativistic jet with no or small contributions from the host galaxy and the accretion disk seemsmost plausible as an optical-NIR emission mechanism. The steep optical-NIR spectral shape and the large amplitude of variability are consistent with this object being a low.peak jet-dominated AGN. In addition, sub-arcsecond resolution optical imaging data taken with Subaru Hyper Suprime-Cam does not show a clear extended component and the spatial scales are significantly smaller than the large extensions detected at radio wavelengths. The optical spectrum of a possible faint companion galaxy does not show any emission lines at the same redshift, and hence a merging hypothesis for this AGN-related activity is not supported by our observations.
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| 20. |
- Pilla, Rachel M., et al.
(author)
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Global data set of long-term summertime vertical temperature profiles in 153 lakes
- 2021
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In: Scientific Data. - : Springer Nature. - 2052-4463. ; 8:1
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Journal article (peer-reviewed)abstract
- Climate change and other anthropogenic stressors have led to long-term changes in the thermal structure, including surface temperatures, deepwater temperatures, and vertical thermal gradients, in many lakes around the world. Though many studies highlight warming of surface water temperatures in lakes worldwide, less is known about long-term trends in full vertical thermal structure and deepwater temperatures, which have been changing less consistently in both direction and magnitude. Here, we present a globally-expansive data set of summertime in-situ vertical temperature profiles from 153 lakes, with one time series beginning as early as 1894. We also compiled lake geographic, morphometric, and water quality variables that can influence vertical thermal structure through a variety of potential mechanisms in these lakes. These long-term time series of vertical temperature profiles and corresponding lake characteristics serve as valuable data to help understand changes and drivers of lake thermal structure in a time of rapid global and ecological change.
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| 21. |
- Tanaka, Masaomi, et al.
(author)
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DISCOVERY OF DRAMATIC OPTICAL VARIABILITY IN SDSS J1100+4421 : A PECULIAR RADIO-LOUD NARROW-LINE SEYFERT 1 GALAXY?
- 2014
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In: Astrophysical Journal Letters. - 2041-8205 .- 2041-8213. ; 793:2, s. L26-
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Journal article (peer-reviewed)abstract
- We present our discovery of dramatic variability in SDSS J1100+4421 by the high-cadence transient survey Kiso Supernova Survey. The source brightened in the optical by at least a factor of three within about half a day. Spectroscopic observations suggest that this object is likely a narrow-line Seyfert 1 galaxy (NLS1) at z = 0.840, however, with unusually strong narrow emission lines. The estimated black hole mass of similar to 10(7) M-circle dot implies bolometric nuclear luminosity close to the Eddington limit. SDSS J1100+4421 is also extremely radio-loud, with a radio loudness parameter of R similar or equal to 4 x 10(2)-3 x 10(3), which implies the presence of relativistic jets. Rapid and large-amplitude optical variability of the target, reminiscent of that found in a few radio- and gamma-ray-loud NLS1s, is therefore produced most likely in a blazar-like core. The 1.4 GHz radio image of the source shows an extended structure with a linear size of about 100 kpc. If SDSS J1100+4421 is a genuine NLS1, as suggested here, this radio structure would then be the largest ever discovered in this type of active galaxies.
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| 22. |
- Tominaga, Koji, et al.
(author)
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Predicting Acidification Recovery at the Hubbard Brook Experimental Forest, New Hampshire: Evaluation of Four Models
- 2010
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In: Environmental Science & Technology. - : American Chemical Society (ACS). - 1520-5851 .- 0013-936X. ; 44:23, s. 9003-9009
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Journal article (peer-reviewed)abstract
- The performance and prediction uncertainty (owing to parameter and structural uncertainties) of four dynamic watershed acidification models (MAGIC, PnET-BGC, SAFE, and VSD) were assessed by systematically applying them to data from the Hubbard Brook Experimental Forest (HBEF), New Hampshire, where long-term records of precipitation and stream chemistry were available. In order to facilitate systematic evaluation, Monte Carlo simulation was used to randomly generate common model input data sets (n ) 10 000) from parameter distributions; input data were subsequently translated among models to retain consistency. The model simulations were objectively calibrated against observed data (streamwater: 1963-2004, soil: 1983). The ensemble of calibrated models was used to assess future response of soil and stream chemistry to reduced sulfur deposition at the HBEF. Although both hindcast (1850-1962) and forecast (2005-2100) predictions were qualitatively similar across the four models, the temporal pattern of key indicators of acidification recovery (stream acid neutralizing capacity and soil base saturation) differed substantially. The range in predictions resulted from differences in model structure and their associated posterior parameter distributions. These differences can be accommodated by employing multiple models (ensemble analysis) but have implications for individual model applications.
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| 23. |
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