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

Relationship between bovine endometrial thickness and plasma progesterone and estradiol concentrations in natural and induced estrus

The objective of this study was to investigate cyclical changes in endometrial thickness in relation to progesterone (P-4) and estradiol-17 beta (E-2) concentrations during natural and induced estrus in 15 cows. In the prostaglandin (PG) F-2 alpha induced estrus group, ultrasonography (USG) at 6-h intervals was used to determine endometrial thickness 48-24 h before the PGF(2 alpha), treatment until 24 h after ovulation (ovulation = Day 0). In the natural estrus group, USG was performed every 48 h from Day 3 to Days 15-18 after the first ovulation, and then every 6 h until 24 h after ovulation. Endometrial thickness was standardized using Day 13 as a reference day. Blood was collected during every USG examination and plasma P-4 and E-2 concentrations were determined. Endometrial thickness of the induced estrus group (n = 11) was greater than that of the natural estrus group (n = 9) between 60 and 12 h before ovulation (P < 0.05). In the natural estrus group, prior to an increase in endometrial thickness, a decrease in P-4 and an increase in E-2 were detected. In the induced estrus group, based on the time of ovulation, an increase in endometrial thickness was detected at the same time of a decrease in P-4 before an increase in E-2. These results suggest that decreases in P-4 concentrations may be a cue to changes in endometrial thickness, while increases in E-2 concentrations appear to sustain and/or enhance these changes

Relationship between bovine endometrial thickness and plasma progesterone and estradiol concentrations in natural and induced estrus

The objective of this study was to investigate cyclical changes in endometrial thickness in relation to progesterone (P_4) and estradiol-17β (E_2) concentrations during natural and induced estrus in 15 cows. In the prostaglandin (PG) |-induced estrus group, ultrasonography (USG) at 6-h intervals was used to determine endometrial thickness 48–24 h before the PGF_ treatment until 24 h after ovulation (ovulation = Day 0). In the natural estrus group, USG was performed every 48 h from Day 3 to Days 15–18 after the first ovulation, and then every 6 h until 24 h after ovulation. Endometrial thickness was standardized using Day 13 as a reference day. Blood was collected during every USG examination and plasma P_4 and E_2 concentrations were determined. Endometrial thickness of the induced estrus group (n = 11) was greater than that of the natural estrus group (n = 9) between 60 and 12 h before ovulation (P < 0.05). In the natural estrus group, prior to an increase in endometrial thickness, a decrease in P_4 and an increase in E_2 were detected. In the induced estrus group, based on the time of ovulation, an increase in endometrial thickness was detected at the same time of a decrease in P_4 before an increase in E_2. These results suggest that decreases in P_4 concentrations may be a cue to changes in endometrial thickness, while increases in E_2 concentrations appear to sustain and/or enhance these changes

Supramolecular sulfur-containing polymers with hydrogen bonding

Although sulfur-containing polymers have been realized by various methods such as copolymerization and reverse vulcanization, there are few reports on the synthesis of supramolecular sulfur-containing polymers in which a supramolecular polymer is fused with a sulfur-containing polymer. Herein, we prepare a supramolecular sulfur-containig polymer by introducing a 2-ureido-4[1H]pyrimidinone (UPy) unit at both ends of linear sulfur and connecting between the UPys via hydrogen bonding.This is an Accepted Manuscript of an article published by Taylor & Francis in Journal of Sulfur Chemistry on 03 Mar 2023, available at 10.1080/17415993.2023.2183773

Reconstruction and Regulation of the Central Catabolic Pathway in the Thermophilic Propionate-Oxidizing Syntroph Pelotomaculum thermopropionicum

Obligate anaerobic bacteria fermenting volatile fatty acids in syntrophic association with methanogenic archaea share the intermediate bottleneck step in organic-matter decomposition. These organisms (called syntrophs) are biologically significant in terms of their growth at the thermodynamic limit and are considered to be the ideal model to address bioenergetic concepts. We conducted genomic and proteomic analyses of the thermophilic propionate-oxidizing syntroph Pelotomaculum thermopropionicum to obtain the genetic basis for its central catabolic pathway. Draft sequencing and subsequent targeted gap closing identified all genes necessary for reconstructing its propionate-oxidizing pathway (i.e., methylmalonyl coenzyme A pathway). Characteristics of this pathway include the following. (i) The initial two steps are linked to later steps via transferases. (ii) Each of the last three steps can be catalyzed by two different types of enzymes. It was also revealed that many genes for the propionate-oxidizing pathway, except for those for propionate coenzyme A transferase and succinate dehydrogenase, were present in an operon-like cluster and accompanied by multiple promoter sequences and a putative gene for a transcriptional regulator. Proteomic analysis showed that enzymes in this pathway were up-regulated when grown on propionate; of these enzymes, regulation of fumarase was the most stringent. We discuss this tendency of expression regulation based on the genetic organization of the open reading frame cluster. Results suggest that fumarase is the central metabolic switch controlling the metabolic flow and energy conservation in this syntroph

Differences and relationships between weightbearing and non-weightbearing dorsiflexion range of motion in foot and ankle injuries

Abstract Background This study aimed to: (1) identify assessment methods that can detect greater ankle dorsiflexion range of motion (DROM) limitation in the injured limb; (2) determine whether differences in weightbearing measurements exist even in the absence of DROM limitations in the injured limb according to non-weightbearing measurements; and (3) examine associations between DROM in the weightbearing and non-weightbearing positions and compare those between a patient group with foot and ankle injuries and a healthy group. Methods Eighty-two patients with foot and ankle injuries (e.g., fractures, ligament and tendon injuries) and 49 healthy individuals participated in this study. Non-weightbearing DROM was measured under two different conditions: prone position with knee extended and prone position with knee flexed. Weightbearing DROM was measured as the tibia inclination angle (weightbearing angle) and distance between the big toe and wall (weightbearing distance) at maximum dorsiflexion. The effects of side (injured, uninjured) and measurement method on DROM in the patient groups were assessed using two-way repeated-measures ANOVA and t-tests. Pearson correlations between measurements were assessed. In addition, we analyzed whether patients without non-weightbearing DROM limitation (≤ 3 degrees) showed limitations in weightbearing DROM using t-tests with Bonferroni correction. Results DROM in patient groups differed significantly between legs with all measurement methods (all: P < 0.001), with the largest effect size for weightbearing angle (d = 0.95). Patients without non-weightbearing DROM limitation (n = 37) displayed significantly smaller weightbearing angle and weightbearing distance on the injured side than on the uninjured side (P < 0.001 each), with large effect sizes (d = 0.97–1.06). Correlation coefficients between DROM in non-weightbearing and weightbearing positions were very weak (R = 0.17, P = 0.123) to moderate (R = 0.26–0.49, P < 0.05) for the patient group, and moderate to strong for the healthy group (R = 0.51–0.69, P < 0.05). Conclusions DROM limitations due to foot and ankle injuries may be overlooked if measurements are only taken in the non-weightbearing position and should also be measured in the weightbearing position. Furthermore, DROM measurements in non-weightbearing and weightbearing positions may assess different characteristics, particularly in patient group. Level of evidence Level IV, cross-sectional study

Multicenter, Randomized, Investigator-Masked Study Comparing Brimonidine Tartrate 0.1% and Timolol Maleate 0.5% as Adjunctive Therapies to Prostaglandin Analogues in Normal-Tension Glaucoma

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