DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. 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

High Contribution of Recalcitrant Organic Matter to DOC in a Japanese Oligotrophic Lake Revealed by 14

From the 20th International Radiocarbon Conference held in Kona, Hawaii, USA, May 31-June 3, 2009.Carbon isotopes (14C and 13C) of dissolved organic carbon (DOC) in a Japanese oligotrophic lake (Lake Towada) were measured to study the origin and cycling of dissolved organic matter (DOM) in Lake Towada. Lake water samples were collected at 3 depths (0, 30, and 80 or 85 m) during 4 months (April, June, August, and October) in 2006. 14C measurements of DOC were performed by accelerator mass spectrometry (AMS) at the National Institute for Environmental Studies (NIES-TERRA) in Japan. ∆14C and delta-13C values of DOC in Lake Towada showed light carbon isotopic values ranging from -750 to -514v and -29.0 to -27.8‰, respectively. These values are similar to those of humic substances reported. The very low carbon isotopic values of DOC in Lake Towada suggest a very small contribution of DOC derived from fresh phytoplankton to the lake DOC. There is an extremely high linear relationship between the ∆14C and delta-13C of DOC in Lake Towada when all data points are plotted (r2 = 0.818, p < 0.01), suggesting that the DOC in Lake Towada has 2 specific sources contributing heavy and light carbon isotopes. Although the freshly produced DOC of phytoplankton origin can be decomposed easily, the variation in the autochthonous DOC should influence the carbon isotopic values of DOC in Lake Towada.The Radiocarbon archives are made available by Radiocarbon and the University of Arizona Libraries. Contact [email protected] for further information.Migrated from OJS platform February 202

High Contribution of Recalcitrant Organic Matter to DOC in a Japanese Oligotrophic Lake Revealed by 14C Measurements

From the 20th International Radiocarbon Conference held in Kona, Hawaii, USA, May 31-June 3, 2009.Carbon isotopes (14C and 13C) of dissolved organic carbon (DOC) in a Japanese oligotrophic lake (Lake Towada) were measured to study the origin and cycling of dissolved organic matter (DOM) in Lake Towada. Lake water samples were collected at 3 depths (0, 30, and 80 or 85 m) during 4 months (April, June, August, and October) in 2006. 14C measurements of DOC were performed by accelerator mass spectrometry (AMS) at the National Institute for Environmental Studies (NIES-TERRA) in Japan. ∆14C and delta-13C values of DOC in Lake Towada showed light carbon isotopic values ranging from -750 to -514v and -29.0 to -27.8‰, respectively. These values are similar to those of humic substances reported. The very low carbon isotopic values of DOC in Lake Towada suggest a very small contribution of DOC derived from fresh phytoplankton to the lake DOC. There is an extremely high linear relationship between the ∆14C and delta-13C of DOC in Lake Towada when all data points are plotted (r2 = 0.818, p < 0.01), suggesting that the DOC in Lake Towada has 2 specific sources contributing heavy and light carbon isotopes. Although the freshly produced DOC of phytoplankton origin can be decomposed easily, the variation in the autochthonous DOC should influence the carbon isotopic values of DOC in Lake Towada.The Radiocarbon archives are made available by Radiocarbon and the University of Arizona Libraries. Contact [email protected] for further information.Migrated from OJS platform February 202

Correction: Normal Lung Quantification in Usual Interstitial Pneumonia Pattern: The Impact of Threshold-based Volumetric CT Analysis for the Staging of Idiopathic Pulmonary Fibrosis.

[This corrects the article DOI: 10.1371/journal.pone.0152505.]

Normal Lung Quantification in Usual Interstitial Pneumonia Pattern: The Impact of Threshold-based Volumetric CT Analysis for the Staging of Idiopathic Pulmonary Fibrosis.

Although several computer-aided computed tomography (CT) analysis methods have been reported to objectively assess the disease severity and progression of idiopathic pulmonary fibrosis (IPF), it is unclear which method is most practical. A universal severity classification system has not yet been adopted for IPF.The purpose of this study was to test the correlation between quantitative-CT indices and lung physiology variables and to determine the ability of such indices to predict disease severity in IPF.A total of 27 IPF patients showing radiological UIP pattern on high-resolution (HR) CT were retrospectively enrolled. Staging of IPF was performed according to two classification systems: the Japanese and GAP (gender, age, and physiology) staging systems. CT images were assessed using a commercially available CT imaging analysis workstation, and the whole-lung mean CT value (MCT), the normally attenuated lung volume as defined from -950 HU to -701 Hounsfield unit (NL), the volume of the whole lung (WL), and the percentage of NL to WL (NL%), were calculated.CT indices (MCT, WL, and NL) closely correlated with lung physiology variables. Among them, NL strongly correlated with forced vital capacity (FVC) (r = 0.92, P <0.0001). NL% showed a large area under the receiver operating characteristic curve for detecting patients in the moderate or advanced stages of IPF. Multivariable logistic regression analyses showed that NL% is significantly more useful than the percentages of predicted FVC and predicted diffusing capacity of the lungs for carbon monoxide (Japanese stage II/III/IV [odds ratio, 0.73; 95% confidence intervals (CI), 0.48 to 0.92; P < 0.01]; III/IV [odds ratio. 0.80; 95% CI 0.59 to 0.96; P < 0.01]; GAP stage II/III [odds ratio, 0.79; 95% CI, 0.56 to 0.97; P < 0.05]).The measurement of NL% by threshold-based volumetric CT analysis may help improve IPF staging