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

Computer-Aided Diagnosis Scheme for Determining Histological Classification of Breast Lesions on Ultrasonographic Images Using Convolutional Neural Network

It can be difficult for clinicians to accurately discriminate among histological classifications of breast lesions on ultrasonographic images. The purpose of this study was to develop a computer-aided diagnosis (CADx) scheme for determining histological classifications of breast lesions using a convolutional neural network (CNN). Our database consisted of 578 breast ultrasonographic images. It included 287 malignant (217 invasive carcinomas and 70 noninvasive carcinomas) and 291 benign lesions (111 cysts and 180 fibroadenomas). In this study, the CNN constructed from four convolutional layers, three batch-normalization layers, four pooling layers, and two fully connected layers was employed for distinguishing between the four different types of histological classifications for lesions. The classification accuracies for histological classifications with our CNN model were 83.9–87.6%, which were substantially higher than those with our previous method (55.7–79.3%) using hand-crafted features and a classifier. The area under the curve with our CNN model was 0.976, whereas that with our previous method was 0.939 (p = 0.0001). Our CNN model would be useful in differential diagnoses of breast lesions as a diagnostic aid

Pressure Effects with Incorporated Particle Size Dependency in Graphene Oxide Layers through Observing Spin Crossover Temperature

This research highlights the pressure effects with the particle size dependency incorporated in two-dimensional graphene oxide (GO)/reduced graphene oxide (rGO). GO and rGO composites employing nanorods (NRs) of type [Fe(Htrz)2(trz)](BF4) have been prepared, and their pressure effects in the interlayer spaces through observing the changes of the spin crossover (SCO) temperature (T1/2) have been discussed. The composites show the decrease of interlayer spaces from 8.7 Å to 3.5 Å that is associated with GO to rGO transformation. The shorter interlayer spaces were induced by pressure effects, resulting in the increment of T1/2 from 357 K to 364 K. The pressure effects in the interlayers spaces estimated from the T1/2 value correspond to 24 MPa in pristine [Fe(Htrz)2(trz)](BF4) NRs under hydrostatic pressure. The pressure observed in the composites incorporating NRs (30 × 200 nm) is smaller than that observed in the composite incorporating nanoparticles (NPs) (30 nm). These results clearly demonstrated that the incorporated particle size and shape influenced the pressure effects between the GO/rGO layer

Synthesis of N-beta-brominated alkenyl isothiocyanates via dehydrogenation of alkyl isothiocyanates

This study presents a new dehydrogenative synthesis of alkenyl isothiocyanates, providing compounds with bromo and isothiocyanate groups. These reactive functionalities offer versatility for further transformations. Application in an amine sensor utilizing a coumarin-attached product demonstrates practical utility. This streamlined approach facilitates access to alkenyl isothiocyanates, valuable tools for biological studies

Complex surgical treatment of congenital tracheal stenosis with associated unilateral lung agenesis

Background: The combination of congenital tracheal stenosis (CTS) and unilateral pulmonary agenesis is rare and fatal. Especially, right lung agenesis is associated with dextrocardia and often causes tracheal alignment disorder. The mortality is estimated with 12.5–65%. Slide Tracheoplasty (ST) has been improved the prognosis, however, the postoperative course of CTS with single lung remains unclear. Here, we describe the postoperative challenging situation with bronchial intervention and other devices. Case presentation: A 9-month-old girl with CTS, right lung agenesis, dextrocardia, and bilateral superior vena cava underwent ST anterior to the aortic arch. On postoperative day 50, tracheostomy was performed for long-term airway pressure support. Six months after the ST, she showed severe bronchomalacia at the bifurcation of the lobar bronchi, which was sandwiched between the descending aorta and left pulmonary artery. Direct bronchopexy and mobilization of left pulmonary artery resolved the severe bronchomalacia. Additionally, the kinked trachea caused a tracheal ulcer and frequent accidental decannulations. The ulcer was made above the aortic arch by contact with the tracheal cannula. The customized Montgomery T-tube solved both problems and enabled the stable management for airway. Her condition eventually improved, and she was discharged home after 14 months of hospitalization. Conclusion: This case presented a very rare and critical condition. This is the first report to address the severe condition after ST anterior to the aortic arch. Surgical interventions or other devices for treatment are thought to be modified according to each condition. Keywords: Conjenital tracheal stenosis, Unilateral pulmonary agenesis, Dextorcardia, Bronchomalacia, Direct bronchopexy, Customized Montgomery T-tub

Microglial Contact Prevents Excess Depolarization and Rescues Neurons from Excitotoxicity123

Abstract Microglia survey and directly contact neurons in both healthy and damaged brain, but the mechanisms and functional consequences of these contacts are not yet fully elucidated. Combining two-photon imaging and patch clamping, we have developed an acute experimental model for studying the role of microglia in CNS excitotoxicity induced by neuronal hyperactivity. Our model allows us to simultaneously examine the effects of repetitive supramaximal stimulation on axonal morphology, neuronal membrane potential, and microglial migration, using cortical brain slices from Iba-1 eGFP mice. We demonstrate that microglia exert an acute and highly localized neuroprotective action under conditions of neuronal hyperactivity. Evoking repetitive action potentials in individual layer 2/3 pyramidal neurons elicited swelling of axons, but not dendrites, which was accompanied by a large, sustained depolarization of soma membrane potential. Microglial processes migrated to these swollen axons in a mechanism involving both ATP and glutamate release via volume-activated anion channels. This migration was followed by intensive microglial wrapping of affected axons and, in some cases, the removal of axonal debris that induced a rapid soma membrane repolarization back to resting potentials. When the microglial migration was pharmacologically blocked, the activity-induced depolarization continued until cell death ensued, demonstrating that the microglia–axon contact served to prevent pathological depolarization of the soma and maintain neuronal viability. This is a novel aspect of microglia surveillance: detecting, wrapping, and rescuing neuronal soma from damage due to excessive activity