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

Missing Reactivity of Trimethylsilyl Reagents: Dehalogenative Activation Enabling One-Pot Generation of Aryne from 2-Iodophenol

Herein we present a missing reactivity of trimethylsilyl reagents; dehalogenative activation, which involves abstracting a halogen atom and anionically activating the substrate similar to the halogen-metal exchange reaction in classical carbanion species. This missing reactivity allowed for the one-pot generation of aryne from 2-iodophenol

Diverse Metastable Diarylacetonitrile Radicals Generated by Polymer Mechanochemistry

Fluorescent radicals have attracted great attention as luminescent materials, mostly on account of their potential to achieve higher luminescence efficiency than closed-shell molecules. However, analyzing fluorescent radicals at ambient conditions remains a challenging task, because radicals are usually unstable in air. In addition, to the best of our knowledge, research aimed at controlling fluorescence wavelengths through substituent changes has not yet been accomplished. Here, we report diverse metastable diarylacetonitrile (DAAN) radicals, which contain different substituents, generated by polymeric mechanochemical reactions. The DAAN radicals, generated by ball-milling powdered polystyrene together with DAAN derivatives, were dispersed within the polystyrene matrix, where they retained their radical state, which allowed measuring solid-state fluorescence spectra. These measurements revealed that a wide range of fluorescence wavelengths from green to red (λem,max = 517–635 nm) can be achieved only by changing the substituents on the aromatic rings in these DAAN radicals. This phenomenon has not been observed for the well-studied triarylmethyl radicals. The fluorescence wavelength of these DAAN radicals can be precisely estimated by time-dependent density-functional theory (TD-DFT) calculations. The amount of DAAN radicals generated upon ball-milling is discussed in conjunction with DFT calculations and experimental results. Our results suggest that the orbital interactions with polymeric mechanoradicals, the bond-dissociation enthalpy, and the steric protection of the radical center are of paramount importance for the generation of DAAN radicals. The results of this study can be expected to provide useful guidelines for the development of advanced fluorescent radicals

Spatial distribution of summer temperature in tokyo wards : observation results of metros

The urban heat island phenomena in summer over Tokyo Wards was studied by using the data obtained from METROS (Metropolitan Environmental Temperature and Rainfall Observation System), which is the high density heat island phenomena observation network. The observational results clarified the detailed spatial distributions of temperature never known before. Concerning the spatial distribution of daily maximum temperature, the region with a relatively high temperature extends from the central Tokyo district toward the northern and northwestern area. On the other hand, relatively high values in the daily minimum temperature are distributed around the coastal area of Tokyo Bay including the central Tokyo district. Since the central Tokyo district has significantly high temperatures both in the daytime and in the nighttime, and also raises the temperature in the adjacent north and northeast area, it is necessary to take countermeasures preferentially to this district

Synthesis and Characterization of the Germathioacid Chloride Coordinated by an N-Heterocyclic Carbene §

Carboxylic acid chlorides are useful substrates in organic chemistry. Many germanium analogues of carboxylic acid chloride have been synthesized so far. Nevertheless, all of the reported germathioacid chlorides use bidentate nitrogen ligands and contain germanium-nitrogen bonds. Our group synthesized germathioacid chloride, Ge(S)Cl{C6H3-2,6-Tip2}(Im-i-Pr2Me2), using N-heterocyclic carbene (Im-i-Pr2Me2). As a result of density functional theory (DFT) calculation, it was found that electrons are localized on sulfur, and the germanium-sulfur bond is a single bond with a slight double bond property

Aryne Polymerization Enabling Straightforward Synthesis of Elusive Poly(<i>ortho</i>-arylene)s

Herein we present the first straightforward aryne polymerization that successively connects aromatic rings at their <i>ortho</i>-positions, <i>directly</i> giving poly­(<i>ortho</i>-phenylene)­s of up to ca. 100-mer size. The polymerization proceeds smoothly in a chain-growth fashion in the presence of a monovalent copper reagent. Direct synthesis of poly­(<i>ortho</i>-arylene)­s has been a “missing piece” of aromatic chemistry for a long time (although the discovery of arynes dates back to 1902), in contrast to the well-investigated <i>para</i>- and <i>meta</i>-linked polyarylenes. Our achievement reported here is expected to open up new areas of nanocarbon and materials science

Intramolecular Transfer of Pd Catalyst on Carbon–Carbon Triple Bond and Nitrogen–Nitrogen Double Bond in Suzuki–Miyaura Coupling Reaction

Intramolecular transfer of t-Bu3P-ligated Pd catalyst on a carbon–carbon triple bond (C≡C) and nitrogen–nitrogen double bond (N=N) was investigated and compared with the case of a carbon–carbon double bond (C=C), which is resistant to intramolecular transfer of the Pd catalyst. Suzuki–Miyaura coupling reaction of equimolar 4,4’-dibromotolan (1a) or 4,4’-dibromoazobenzene (1b) with 3-isobutoxyphenylboronic acid (2) was carried out in the presence of t-Bu3P-ligated Pd precatalyst 3 and KOH/18-crown-6 as a base at room temperature. In both cases, the diphenyl-substituted product was selectively obtained, indicating that the Pd catalyst walked from one benzene ring to the other through the C≡C or N=N bond after the first substitution with 2. Taking advantage of this finding, we conducted unstoichiometric Suzuki–Miyaura polycondensation of 1.3 equiv. of 1 and 1.0 equiv. of phenylenediboronic acid (ester) 6 in the presence of 3 and CsF/18-crown-6 as a base, obtaining high-molecular-weight conjugated polymer with a boronic acid (ester) moiety at both ends, contrary to the Flory principle

Patterns of Interstitial Lung Disease During Everolimus Treatment in Patients with Metastatic Renal Cell Carcinoma

Objective: To elucidate the patterns of interstitial lung disease during everolimus treatment in patients with metastatic renal cell carcinoma, we reviewed seven cases of everolimus-induced interstitial lung disease. Methods: Seven patients with metastatic renal cell carcinoma, which continued to progress despite treatment with sunitinib or sorafenib, developed interstitial lung disease after treat-ment with everolimus. Results: Chest X-ray demonstrated diffuse infiltrates in lung fields, and chest computed tom-ography showed bilateral reticular and ground-glass opacities. Serum levels of lactate de-hydrogenase (7/7), C-reactive protein (6/7), pulmonary surfactant associated protein D (1/7) and Krebs von den Lungen 6 (5/7) were elevated. The bronchoalveolar lavage fluid obtained from four patients with Grade 3 interstitial lung disease showed lymphocytosis. The transbron-chial lung biopsy specimens showed interstitial lymphocytic infiltration and septal thickening of alveolar walls. In two cases with mild interstitial lung disease, the everolimus therapy was successfully continued. In four cases with Grade 3 interstitial lung disease, the drug was dis-continued and steroid therapy was initiated. Pulmonary symptoms and radiological abnormal

Assessment of electroencephalography modification by antipsychotic drugs in patients with schizophrenia spectrum disorders using frontier orbital theory: A preliminary study

Abstract Aim Schizophrenia is characterized by an abnormality in electroencephalography (EEG), which can be affected by antipsychotic drugs. Recently, the mechanism underlying these EEG alterations in schizophrenia patients was reframed from the perspective of redox abnormalities. The highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) can be calculated using a computational method and may be useful for evaluating the antioxidant/prooxidant effect of antipsychotic drugs. Thus, we examined the association between the effects of antipsychotic monotherapy on quantitative EEG and HOMO/LUMO energy. Methods We used medical report data including EEG results of psychiatric patients admitted to Hokkaido University Hospital. We extracted the EEG records of patients diagnosed with a schizophrenia spectrum disorder undergoing antipsychotic monotherapy during the natural course of treatment (n = 37). We evaluated the HOMO/LUMO energy of all antipsychotic drugs using computational methods. Multiple regression analyses were used to examine the relationship between the HOMO/LUMO energy of all antipsychotic drugs and spectral band power in all patients. Statistical significance was set at p < 6.25 × 10−4 adjusted with Bonferroni correction. Results We showed that the HOMO energy of all antipsychotic drugs had weak positive correlations with delta‐ and gamma‐band power (e.g., standardized β = 0.617 for delta in the F3 channel, p = 6.6 × 10−5; standardized β = 0.563 for gamma in the O1 channel, p = 5.0 × 10−4). Conclusion Although there may be unexpected bias and confounding factors, our findings suggest that the effect of antipsychotic drugs on EEG may be related to their antioxidant actions