DOCK2 is a Rac activator that regulates motility and polarity during neutrophil chemotaxis

Neutrophils are highly motile leukocytes, and they play important roles in the innate immune response to invading pathogens. Neutrophil chemotaxis requires Rac activation, yet the Rac activators functioning downstream of chemoattractant receptors remain to be determined. We show that DOCK2, which is a mammalian homologue of Caenorhabditis elegans CED-5 and Drosophila melanogaster Myoblast City, regulates motility and polarity during neutrophil chemotaxis. Although DOCK2-deficient neutrophils moved toward the chemoattractant source, they exhibited abnormal migratory behavior with a marked reduction in translocation speed. In DOCK2-deficient neutrophils, chemoattractant-induced activation of both Rac1 and Rac2 were severely impaired, resulting in the loss of polarized accumulation of F-actin and phosphatidylinositol 3,4,5-triphosphate (PIP3) at the leading edge. On the other hand, we found that DOCK2 associates with PIP3 and translocates to the leading edge of chemotaxing neutrophils in a phosphatidylinositol 3-kinase (PI3K)–dependent manner. These results indicate that during neutrophil chemotaxis DOCK2 regulates leading edge formation through PIP3-dependent membrane translocation and Rac activation

Application of Bio-Based Wrinkled Surfaces as Cell Culture Scaffolds

Microscopic surface architectures that can be easily manufactured have been in demand as mechano-structural cues for tissue engineering. Microscopic surface reliefs synthesized by wrinkling were expected as cell culture scaffolds for cell proliferation, control of cellular alignment and differentiation, and spheroid generation. We previously developed bio-based wrinkled films prepared via lignification-mimetic reactions and drying. Although these films are expected as a candidate for cell culture scaffolds, stability and morphology of the wrinkled surfaces in aqueous buffer solutions were not explored. Here, we investigate the surface morphologies of the wrinkled films in phosphate-buffered saline, and their application to 3T3 cell culture. The wrinkled film prepared with the immersion treatment at 40 °C maintained its wrinkled structure in phosphate-buffered saline even after five days, although the wrinkles were broadened by hydration of the skin layer. Interestingly, higher cell numbers were observed in the 3T3 cell culture using the wrinkled film than using flat film with the same surface composition. In addition, the high biocompatibility of the wrinkled film was confirmed by in vivo experiments. These results strongly encourage application of the wrinkled film as a mechano-structural cue. Studies of the advanced applications for the wrinkled films are now in progress

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

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

Influence of External Natural Environment Including Sunshine Exposure on Public Mental Health: A Systematic Review

The COVID-19 pandemic has been raging around the world and public health measures such as lockdowns have forced people to go out less often, reducing sunlight exposure time, green space use, and physical activity. It is well known that exercise has a positive impact on mental health, but the impact of external environmental factors such as sunlight exposure and green space use on mental health has not been systematically reviewed. In this review, we categorized the major factors that may affect people’s mental health into (1) external environmental factors such as exposure to sunlight and green spaces, (2) internal life factors such as physical activity and lifestyle, and (3) mixed external and internal factors, and systematically examined the relationship between each factor and people’s mental health. The results showed that exposure to sunlight, spending leisure time in green spaces, and physical activity each had a positive impact on people’s mental health, including depression, anxiety, and stress states. Specifically, moderate physical activity in an external environment with sunlight exposure or green space was found to be an important factor. The study found that exposure to the natural environment through sunbathing and exercise is important for people’s mental health

Application of Bio-Based Wrinkled Surfaces as Cell Culture Scaffolds

Microscopic surface architectures that can be easily manufactured have been in demand as mechano-structural cues for tissue engineering. Microscopic surface reliefs synthesized by wrinkling were expected as cell culture scaffolds for cell proliferation, control of cellular alignment and differentiation, and spheroid generation. We previously developed bio-based wrinkled films prepared via lignification-mimetic reactions and drying. Although these films are expected as a candidate for cell culture scaffolds, stability and morphology of the wrinkled surfaces in aqueous buffer solutions were not explored. Here, we investigate the surface morphologies of the wrinkled films in phosphate-buffered saline, and their application to 3T3 cell culture. The wrinkled film prepared with the immersion treatment at 40 °C maintained its wrinkled structure in phosphate-buffered saline even after five days, although the wrinkles were broadened by hydration of the skin layer. Interestingly, higher cell numbers were observed in the 3T3 cell culture using the wrinkled film than using flat film with the same surface composition. In addition, the high biocompatibility of the wrinkled film was confirmed by in vivo experiments. These results strongly encourage application of the wrinkled film as a mechano-structural cue. Studies of the advanced applications for the wrinkled films are now in progress