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

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.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

Effects on the radiation characteristics of using a corrugated reflector with a helical antenna and an electromagnetic band-gap reflector with a spiral antenna

An axial-mode helical antenna backed by a perfect electric conductor (PEC reflector) is optimized to radiate a circularly polarized (CP) wave, using the finite-difference time-domain method (FDTDM). After the optimization, the PEC reflector is replaced with a corrugated reflector. The effects of the corrugated reflector on the current distribution along the helical arm and the radiation pattern are investigated. A reduction in the backward radiation is attributed to the reduction in the current flowing over the rear surface of the corrugated reflector. A spiral antenna backed by a PEC reflector of finite extent is also analyzed using the FDTDM. As the antenna height decreases, the reverse current toward the feed point increases, resulting in deterioration of the axial ratio. To overcome this deterioration, the PEC reflector is replaced with an electromagnetic band-gap (EBG) reflector composed of mushroom-like elements. Analysis reveals that the spiral radiates a CP wave even when the spiral is located close to the reflector (0.06 wavelength above the EBG surface). The input impedance for the EBG reflector is more stable over a wide frequency band than that for the PEC reflector

Knee Laxity in the Menstrual Cycle after Anterior Cruciate Ligament Reconstruction: A Case Series

The aim of this study was to compare anterior knee laxity (AKL), genu recurvatum (GR), and muscle stiffness between reconstructed and contralateral sides in females who underwent anterior cruciate ligament (ACL) reconstruction during early follicular and ovulatory phases. AKL was measured as an anterior displacement of the tibia using a KS measure. GR was measured as the range of motion of knee hyperextension using a hyperextension apparatus. Muscle stiffness was measured for semitendinosus (ST) and biceps femoris long head (BF) using a MyotonPRO. The study investigated eighteen knees in nine females (Age, 20.4 ± 1.5 years; BMI, 21.5 ± 1.5) with normal menstrual cycles at least 1 year after reconstruction using hamstring autograft. E2 (Estradiol) concentration did not differ between the two phases, but AKL on the reconstructed side was lower during the ovulatory phase (8.3 [5.9–9.3] mm) than during the early follicular phase (9.4 [7.3–9.7] mm) (p = 0.044, r = 0.756), whereas there was no significant difference between the two phases on the contralateral side. AKL side-to-side difference, GR, and muscle stiffness (ST and BF) on both sides did not differ in either phase. These results indicate that AKL may behave differently on the reconstructed and contralateral sides during the menstrual cycle

Targeting VEGFR2 with Ramucirumab strongly impacts effector/ activated regulatory T cells and CD8+ T cells in the tumor microenvironment

Abstract Background Several studies have established a correlation between the VEGF–VEGFR2 axis and an immunosuppressive microenvironment; this immunosuppression can be overcome by anti-angiogenic reagents, such as ramucirumab (RAM). However, little is known about the immunological impact of anti-angiogenic reagents within the tumor microenvironment in human clinical samples. This study aimed at investigating the effects of RAM on the tumor microenvironmental immune status in human cancers. Methods We prospectively enrolled 20 patients with advanced gastric cancer (GC) who received RAM-containing chemotherapy. We obtained paired samples from peripheral blood mononuclear cells (PBMCs) and tumor-infiltrating lymphocytes (TILs) in primary tumors both pre- and post-RAM therapy to assess immune profiles by immunohistochemistry and flow cytometry. Results Within the tumor microenvironment, both PD-L1 expression and CD8+ T-cell infiltration increased after RAM-containing therapies. In addition, CD45RA−FOXP3highCD4+ cells (effector regulatory T cells [eTreg cells]) and PD-1 expression by CD8+ T cells were significantly reduced in TILs compared with PBMCs after RAM-containing therapies. Patients with partial response and longer progression-free survival had significantly higher pre-treatment eTreg frequencies in TILs than those with progressive disease. In in vitro analysis, VEGFR2 was highly expressed by eTreg cells. Further, VEGFA promoted VEGFR2+ eTreg cell proliferation, and this effect could be inhibited by RAM. Conclusions This study suggests that the frequency of eTreg cells in TILs could be a biomarker for stratifying clinical responses to RAM-containing therapies. Further, we propose that RAM may be employed as an immuno-modulator in combination with immune checkpoint blockade

Menstrual Cycle Changes Joint Laxity in Females—Differences between Eumenorrhea and Oligomenorrhea

The purpose of this study was to investigate the changes in anterior knee laxity (AKL), stiffness, general joint laxity (GJL), and genu recurvatum (GR) during the menstrual cycle in female non-athletes and female athletes with normal and irregular menstrual cycles. Participants were 19 female non-athletes (eumenorrhea, n = 11; oligomenorrhea, n = 8) and 15 female athletes (eumenorrhea, n = 8; oligomenorrhea, n = 7). AKL was measured as the amount of anterior tibial displacement at 67 N–133 N. Stiffness was calculated as change in (Δ)force/Δ anterior displacement. The Beighton method was used to evaluate the GJL. The GR was measured as the maximum angle of passive knee joint extension. AKL, stiffness, GJL, and GR were measured twice in four phases during the menstrual cycle. Stiffness was significantly higher in oligomenorrhea groups than in eumenorrhea groups, although no significant differences between menstrual cycle phases were evident in female non-athletes. GR was significantly higher in the late follicular, ovulation, and luteal phases than in the early follicular phase, although no significant differences between groups were seen in female athletes. Estradiol may affect the stiffness of the periarticular muscles in the knee, suggesting that GR in female athletes may change during the menstrual cycle