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

Surface velocities and ice-front positions of eight major glaciers in the Southern Patagonian Ice Field, South America, from 2002 to 2011

The Patagonian Ice Fields are known to have undergone rapid retreat of frontal positions and significant thinning of its glaciers over the past decades. However, surface velocities have been measured at only a few of these glaciers. Thus, it remains uncertain if and to what extent the glacier dynamics has changed over time and contributed to ice loss in these ice fields. In this study, we examine the temporal evolution of flow velocities and ice-front positions at eight major glaciers in the Southern Patagonian Ice Field (SPI; Hielo Patagonico Sur) by using Advanced Synthetic Aperture Radar (ASAR) images from the Environmental Satellite (Envisat) launched in 2002 by the European Space Agency and Advanced Land Observation Satellite/Phased Array-type L-band Synthetic Aperture Radar (ALOS/PALSAR) data recorded from 2002 to 2011. The examined eight glaciers include Glaciar Jorge Montt, Occidental, Pio XI (or Briiggen), O'Higgins, Viedma, Upsala, Perito Moreno, and Grey. Not all the glaciers revealed significant changes in frontal positions and flow velocities in the study period. We detected significant temporal velocity changes at Glaciar Upsala, Jorge Montt, Occidental, and Pio XI. Among these four glaciers, Glaciars Upsala, Jorge Montt, and Occidental revealed significant acceleration and terminus retreat and were undergoing dynamic-thinning. The markedly different absolute velocities but equally large longitudinal near-terminus stretching at the three glaciers support a calving model based on crevasse-depth criteria, which predict a calving position where crevasse-depths are equal to ice thickness; crevasse-depths are controlled by the longitudinal stretching rate. Meanwhile, Glaciar Pio XI revealed complex spatial and temporal evolution in surface velocities without significant retreat, and its dynamics remains enigmatic. (C) 2013 Elsevier Inc. All rights reserved

Myeloid molecular characteristics of human γδ T cells support their acquisition of tumor antigen-presenting capacity

Human T cells expressing γδ T cell receptor have a potential to show antigen-presenting cell-like phenotype and function upon their activation. However, the mechanisms that underlie the alterations in human γδ T cells remain largely unclear. In this study, we have investigated the molecular characteristics of human γδ T cells related to their acquisition of antigen-presenting capacity in comparison with activated αβ T cells. We found that activated γδ but not αβ T cells upregulated cell surface expression of a scavenger receptor, CD36, which seemed to be mediated by signaling through mitogen-activated protein kinase and/or NF-κB pathways. Confocal microscopical analysis revealed that activated γδ T cells can phagocytose protein antigens. Activated γδ T cells could induce tumor antigen-specific CD8+ T cells using both apoptotic and live tumor cells as antigen resources. Furthermore, we detected that C/EBPα, a critical transcription factor for the development of myeloid-lineage cells, is expressed much higher in γδ T cells than in αβ T cells. These results unveiled the molecular mechanisms for the elicitation of antigen-presenting functions in γδ T cells and would also help designing new approaches for γδ T cell-mediated human cancer immunotherapy

A Biomechanical Comparison of Successful and Unsuccessful Snatch Attempts among Elite Male Weightlifters

The success factor of the snatch has not been identified. Determining the success factors of the snatch among elite weightlifters might help to attain a successful snatch. This study aimed at clarifying the factors that lead to a successful snatch based on barbell trajectory among elite male weightlifters. Data were collected at the 2017 World and Junior World Weightlifting Championships. We digitized the barbell trajectory of the successful and unsuccessful snatch attempts of 61 lifters—an unsuccessful lift would be as a result of a frontward barbell drop—and calculated the kinematic and kinetic parameters of the barbell. No significant difference was found in the barbell maximum height (Dy1) between the successful and unsuccessful lifts. The amount of backward displacement of the barbell in the second pull phase to the catch position (DxL) of the successful lift was significantly larger than that of the unsuccessful lift (successful: 0.11 ± 0.05 m; unsuccessful: 0.10 ± 0.06 m; p < 0.01; d = 0.278). The barbell drop distance in the catch phase (Dy3) of the successful lift was significantly smaller than that in the unsuccessful lift (successful: 0.17 ± 0.04 m; unsuccessful: 0.18 ± 0.04 m; p < 0.001, d = 0.361). These results suggest that DxL and Dy3 are factors leading to a successful snatch lift, but not Dy1. The relative position in the sagittal axis of the barbell and the lifter in the catch position, and catching the barbell when its momentum was low, are important in order to achieve a successful snatch

Licochalcone E, a β-Amyloid Aggregation Inhibitor, Regulates Microglial M1/M2 Polarization via Inhibition of CTL1-Mediated Choline Uptake

Alzheimer’s disease (AD) is thought to be a series of neuroinflammatory diseases caused by abnormal deposits of amyloid-β (Aβ) and tau protein in the brain as part of its etiology. We focused on Aβ aggregation and M1 and M2 microglial polarity in microglia to search for novel therapeutic agents. It has been reported that the inhibition of choline uptake via choline transporter-like protein 1 (CTL1) in microglia preferentially induces M2 microglial polarity. However, the role of the choline transport system on the regulation of microglial M1/M2 polarity in AD is not fully understood. Licochalcones (Licos) A–E, flavonoids extracted from licorice, have been reported to have immunological anti-inflammatory effects, and Lico A inhibits Aβ aggregation. In this study, we compared the efficacy of five Licos, from Lico A to E, at inhibiting Aβ1-42 aggregation. Among the five Licos, Lico E was selected to investigate the relationship between the inhibition of choline uptake and microglial M1/M2 polarization using the immortalized mouse microglial cell line SIM-A9. We newly found that Lico E inhibited choline uptake and Aβ1-42 aggregation in SIM-A9 cells in a concentration-dependent manner, suggesting that the inhibitory effect of Lico E on choline uptake is mediated by CTL1. The mRNA expression of tumor necrosis factor (TNF-α), a marker of M1 microglia, was increased by Aβ1-42, and its effect was inhibited by choline deprivation and Lico E in a concentration-dependent manner. In contrast, the mRNA expression of arginase-1 (Arg-1), a marker of M2 microglia, was increased by IL-4, and its effect was enhanced by choline deprivation and Lico E. We found that Lico E has an inhibitory effect on Aβ aggregation and promotes polarity from M1 to M2 microglia via inhibition of the CTL1 function in microglia. Thus, Lico E may become a leading compound for a novel treatment of AD

Licochalcone E, a β-Amyloid Aggregation Inhibitor, Regulates Microglial M1/M2 Polarization via Inhibition of CTL1-Mediated Choline Uptake

Alzheimer’s disease (AD) is thought to be a series of neuroinflammatory diseases caused by abnormal deposits of amyloid-β (Aβ) and tau protein in the brain as part of its etiology. We focused on Aβ aggregation and M1 and M2 microglial polarity in microglia to search for novel therapeutic agents. It has been reported that the inhibition of choline uptake via choline transporter-like protein 1 (CTL1) in microglia preferentially induces M2 microglial polarity. However, the role of the choline transport system on the regulation of microglial M1/M2 polarity in AD is not fully understood. Licochalcones (Licos) A–E, flavonoids extracted from licorice, have been reported to have immunological anti-inflammatory effects, and Lico A inhibits Aβ aggregation. In this study, we compared the efficacy of five Licos, from Lico A to E, at inhibiting Aβ1-42 aggregation. Among the five Licos, Lico E was selected to investigate the relationship between the inhibition of choline uptake and microglial M1/M2 polarization using the immortalized mouse microglial cell line SIM-A9. We newly found that Lico E inhibited choline uptake and Aβ1-42 aggregation in SIM-A9 cells in a concentration-dependent manner, suggesting that the inhibitory effect of Lico E on choline uptake is mediated by CTL1. The mRNA expression of tumor necrosis factor (TNF-α), a marker of M1 microglia, was increased by Aβ1-42, and its effect was inhibited by choline deprivation and Lico E in a concentration-dependent manner. In contrast, the mRNA expression of arginase-1 (Arg-1), a marker of M2 microglia, was increased by IL-4, and its effect was enhanced by choline deprivation and Lico E. We found that Lico E has an inhibitory effect on Aβ aggregation and promotes polarity from M1 to M2 microglia via inhibition of the CTL1 function in microglia. Thus, Lico E may become a leading compound for a novel treatment of AD