| 1. |
- Kanai, M, et al.
(author)
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- 2023
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swepub:Mat__t
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| 2. |
- Niemi, MEK, et al.
(author)
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- 2021
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swepub:Mat__t
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| 3. |
- Namkoong, H, et al.
(author)
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DOCK2 is involved in the host genetics and biology of severe COVID-19
- 2022
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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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| 4. |
- Wang, QBS, et al.
(author)
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The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force
- 2022
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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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| 20. |
- Kessing, C. F., et al.
(author)
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High Number of Activated CD8(+) T Cells Targeting HIV Antigens Are Present in Cerebrospinal Fluid in Acute HIV Infection
- 2017
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In: Jaids-Journal of Acquired Immune Deficiency Syndromes. - 1525-4135. ; 75:1, s. 108-117
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Journal article (peer-reviewed)abstract
- Background: Central nervous system (CNS) infiltration by CD8(+) T cells is associated with neuroinflammation in many neurodegenerative diseases, including HIV-associated dementia. However, the role of CD8(+) T cells in the CNS during acute HIV infection (AHI) is unknown. Methods: We analyzed the phenotype, gene expression, T cell receptor (TCR) repertoire, and HIV specificity of CD8(+) T cells in cerebrospinal fluid (CSF) of a unique cohort captured during the earliest stages of AHI (n = 26), chronic (n = 23), and uninfected (n = 8). Results: CSF CD8(+) T cells were elevated in AHI compared with uninfected controls. The frequency of activated CSF CD8(+) T cells positively correlated to CSF HIV RNA and to markers of CNS inflammation. In contrast, activated CSF CD8(+) T cells during chronic HIV infection were associated with markers of neurological injury and microglial activation. CSF CD8(+) T cells in AHI exhibited increased functional gene expression profiles associated with CD8(+) T cells effector function, proliferation, and TCR signaling, a unique restricted TCR Vbeta repertoire and contained HIV-specific CD8(+) T cells directed to unique HIV epitopes compared with the periphery. Conclusions: These results suggest that CSF CD8(+) T cells in AHI expanding in the CNS are functional and directed against HIV antigens. These cells could thus play a beneficial role protective of injury seen in chronic HIV infection if combination antiretroviral therapy is initiated early.
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| 23. |
- Pälike, Heiko, et al.
(author)
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A Cenozoic record of the equatorial Pacific carbonate compensation depth
- 2012
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 488:7413, s. 609-614
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Journal article (peer-reviewed)abstract
- Atmospheric carbon dioxide concentrations and climate are regulated on geological timescales by the balance between carbon input from volcanic and metamorphic outgassing and its removal by weathering feedbacks; these feedbacks involve the erosion of silicate rocks and organic-carbon-bearing rocks. The integrated effect of these processes is reflected in the calcium carbonate compensation depth, which is the oceanic depth at which calcium carbonate is dissolved. Here we present a carbonate accumulation record that covers the past 53 million years from a depth transect in the equatorial Pacific Ocean. The carbonate compensation depth tracks long-term ocean cooling, deepening from 3.0-3.5 kilometres during the early Cenozoic (approximately 55 million years ago) to 4.6 kilometres at present, consistent with an overall Cenozoic increase in weathering. We find large superimposed fluctuations in carbonate compensation depth during the middle and late Eocene. Using Earth system models, we identify changes in weathering and the mode of organic-carbon delivery as two key processes to explain these large-scale Eocene fluctuations of the carbonate compensation depth.
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| 25. |
- Yamada, K., et al.
(author)
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Targeted Therapy for Low Back Pain in Elderly Degenerative Lumbar Scoliosis
- 2016
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In: Spine. - : Ovid Technologies (Wolters Kluwer Health). - 0362-2436. ; 41:10, s. 872-879
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Journal article (peer-reviewed)abstract
- Study Design. Prospective cohort study. Objective. To compare the novel treatment procedure with nonoperative treatment for low back pain (LBP) in elderly patients with degenerative lumbar scoliosis (DLS). Summary of Background Data. Treatment of LBP associated with elderly DLS is controversial. We developed a novel treatment procedure, termed percutaneous intervertebral-vacuum polymethylmethacrylate injection (PIPI). Methods. We included patients with de novo DLS aged >= 65 years who had LBP with a visual analogue scale (VAS) score of >50 for >= 6 months with intervertebral vacuum and vertebral bone marrow edema (BME) defined on fat-saturated T2-weighted or gadolinium-enhanced T1-weighted magnetic resonance imaging. The primary outcomes were evaluated using the VAS score and modified Oswestry Disability Index (ODI). As an objective measurement, we scored BME on magnetic resonance imaging. Results. Between August 2004 and July 2011, 109 patients underwent PIPI and 53 received nonoperative treatment. At 1 month, mean improvements in VAS scores were -55.3 (95% CI, -60.5 to -50.1) and -1.9 (CI, -7.7 to 3.8) and mean improvements in ODI were -22.7 (CI, -27.3 to -18.2) and -0.6 (CI, -6.6 to 5.4) for the PIPI and nonoperative groups, respectively. At 2 years, mean improvements in VAS scores were -52.2 (CI, -59.9 to -44.4) and -4.0 (CI, -10.9 to 3.0) and mean improvements in ODI were -20.7 (CI, -27.3 to -14.5) and -1.0 (CI, -7.7 to 5.7) for the PIPI and nonoperative groups, respectively. BME substantially decreased in the PIPI group compared with the nonoperative group (P < 0.001) and correlated with VAS score and ODI improvements (VAS score: r = 0.502, P < 0.001; ODI: r = 0.372, P< 0.001). Conclusion. PIPI improved treatment for LBP, with a sustained clinical benefit for at least 2 years.
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| 26. |
- Yu, Hoi-Fung, et al.
(author)
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Bayesian Inference on the Radio-quietness of Gamma-ray Pulsars
- 2018
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In: Astrophysical Journal. - : IOP PUBLISHING LTD. - 0004-637X .- 1538-4357. ; 857:2
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Journal article (peer-reviewed)abstract
- For the first time we demonstrate using a robust Bayesian approach to analyze the populations of radio-quiet (RQ) and radio-loud (RL) gamma-ray pulsars. We quantify their differences and obtain their distributions of the radiocone opening half-angle d and the magnetic inclination angle a by Bayesian inference. In contrast to the conventional frequentist point estimations that might be non-representative when the distribution is highly skewed or multi-modal, which is often the case when data points are scarce, Bayesian statistics displays the complete posterior distribution that the uncertainties can be readily obtained regardless of the skewness and modality. We found that the spin period, the magnetic field strength at the light cylinder, the spin-down power, the gamma-rayto-X-ray flux ratio, and the spectral curvature significance of the two groups of pulsars exhibit significant differences at the 99% level. Using Bayesian inference, we are able to infer the values and uncertainties of d and a from the distribution of RQ and RL pulsars. We found that d is between 10 degrees and 35 degrees and the distribution of a is skewed toward large values.
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| 27. |
- Zhao, H. L., et al.
(author)
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Heme Oxygenase-1 Mediates Neuroprotection Conferred by Argon in Combination with Hypothermia in Neonatal Hypoxia-Ischemia Brain Injury
- 2016
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In: Anesthesiology. - : Ovid Technologies (Wolters Kluwer Health). - 0003-3022. ; 125:1, s. 180-192
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Journal article (peer-reviewed)abstract
- Background: Hypoxic-ischemic encephalopathy is a major cause of mortality and disability in the newborn. The authors investigated the protective effects of argon combined with hypothermia on neonatal rat hypoxic-ischemic brain injury. Methods: In in vitro studies, rat cortical neuronal cell cultures were challenged by oxygen and glucose deprivation for 90 min and exposed to 70% Ar or N-2 with 5% CO2 balanced with O-2, at 33 degrees C for 2 h. Neuronal phospho-Akt, heme oxygenase-1 and phospho-glycogen synthase kinase-3a expression, and cell death were assessed. In in vivo studies, neonatal rats were subjected to unilateral common carotid artery ligation followed by hypoxia (8% O-2 balanced with N-2 and CO2) for 90 min. They were exposed to 70% Ar or N-2 balanced with oxygen at 33 degrees, 35 degrees, and 37 degrees C for 2 h. Brain injury was assessed at 24 h or 4 weeks after treatment. Results: In in vitro studies, argon-hypothermia treatment increased phospho-Akt and heme oxygenase-1 expression and significantly reduced the phospho-glycogen synthase kinase-3 beta Tyr-216 expression, cytochrome C release, and cell death in oxygen-glucose deprivation-exposed cortical neurons. In in vivo studies, argon-hypothermia treatment decreased hypoxia/ischemia-induced brain infarct size (n = 10) and both caspase-3 and nuclear factor-kappa B activation in the cortex and -hippocampus. It also reduced hippocampal astrocyte activation and proliferation. Inhibition of phosphoinositide-3-kinase (PI 3K)/Akt pathway through LY294002 attenuated cerebral protection conferred by argon-hypothermia treatment (n = 8). Conclusion: Argon combined with hypothermia provides neuroprotection against cerebral hypoxia-ischemia damage in neonatal rats, which could serve as a new therapeutic strategy against hypoxic-ischemic encephalopathy.
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