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

Neuronal and astrocytic apoptosis after subarachnoid hemorrhage: A possible cause for poor prognosis

Clinical evidence suggests that factors other than cerebral vasospasm, such as delayed neuronal and astrocytic cell death, may play a role in the poor prognosis of patients with subarachnoid hemorrhage (SAH). Here we examined this using immunohistochemistry and confocal microscopy in 3 different brain areas in a dog model of SAH. Using antibodies against neuronal marker neuronal nuclear protein (NeuN) and astrocyte marker glial fibrillary acidic protein (GFAP) in conjunction with apoptosis marker (cleaved caspase-3), we quantified neurons and astrocytes to monitor the degree of apoptosis in both groups. Experimental SAH group showed 44 ± 1% caspase-3 positive neurons in comparison to the 2.0 ± 0.1% in the control group (P \u3c 0.001, 6 animals each group). For astrocytes, a total 25 ± 1% were caspase-3 positive in day 7 SAH group, as compared to 0.40 ± 0.01% for controls (P \u3c 0.001). Regional analysis revealed that neuronal caspase-3 immunoreactivity in all 3 regions were significantly higher (P \u3c 0.001) in SAH animals than that in the control animals. However, the analysis of total area, size and signal co-localization of GFAP with caspase-3 indicated that astrocytic reactivity and proliferation are seen primarily in the hippocampal area, with the least changes detectable in the brainstem. We conclude that in the dog model, there was a significant increase of neuronal and astrocytic cleaved caspase-3, possibly reflecting apoptosis, following SAH induction. These changes coupled with neurological deterioration seen in patients may present a possible reason for the poor outcome in SAH patients. © 2008 Elsevier B.V. All rights reserved

Neuronal and astrocytic apoptosis after subarachnoid hemorrhage: A possible cause for poor prognosis

Clinical evidence suggests that factors other than cerebral vasospasm, such as delayed neuronal and astrocytic cell death, may play a role in the poor prognosis of patients with subarachnoid hemorrhage (SAH). Here we examined this using immunohistochemistry and confocal microscopy in 3 different brain areas in a dog model of SAH. Using antibodies against neuronal marker neuronal nuclear protein (NeuN) and astrocyte marker glial fibrillary acidic protein (GFAP) in conjunction with apoptosis marker (cleaved caspase-3), we quantified neurons and astrocytes to monitor the degree of apoptosis in both groups. Experimental SAH group showed 44 ± 1% caspase-3 positive neurons in comparison to the 2.0 ± 0.1% in the control group (P \u3c 0.001, 6 animals each group). For astrocytes, a total 25 ± 1% were caspase-3 positive in day 7 SAH group, as compared to 0.40 ± 0.01% for controls (P \u3c 0.001). Regional analysis revealed that neuronal caspase-3 immunoreactivity in all 3 regions were significantly higher (P \u3c 0.001) in SAH animals than that in the control animals. However, the analysis of total area, size and signal co-localization of GFAP with caspase-3 indicated that astrocytic reactivity and proliferation are seen primarily in the hippocampal area, with the least changes detectable in the brainstem. We conclude that in the dog model, there was a significant increase of neuronal and astrocytic cleaved caspase-3, possibly reflecting apoptosis, following SAH induction. These changes coupled with neurological deterioration seen in patients may present a possible reason for the poor outcome in SAH patients. © 2008 Elsevier B.V. All rights reserved

Bilateral cochlear ossification in a patient with Takayasu arteritis

Takayasu arteritis (TAK) is a rare type of noninfectious, systemic vasculitis of unknown etiology. A 45-year-old female diagnosed with TAK complained of acute onset bilateral deafness. Auditory tests revealed complete deafness in both ears. Magnetic resonance imaging with fluid-attenuation inversion recovery of her temporal bone demonstrated high signal intensity in the whole cochlea and vestibule in both ears. Computed tomography carried out 10 months after the onset of bilateral deafness revealed prominent ossification localized in the area around the modiolus in both cochleae. The patient underwent cochlear implantation in both ears. The cochlear lumens were narrowed and filled with scar tissue, which hindered the insertion of an electrode in both ears. In TAK, cases associated with bilateral severe to profound SNHL where corticosteroid therapy is ineffective in improving hearing, cochlear implantation should be considered within a reasonable period to avoid the difficulty of electrode insertion associated with cochlear ossification

Usefulness of Denoising Process to Depict Myopic Choroidal Neovascularisation Using a Single Optical Coherence Tomography Angiography Image

Quality of single optical coherence tomography angiography (OCTA) images of myopic choroidal neovascularisation (mCNV) is poorer than in averaged images, although obtaining averaged images takes much time. This study evaluated the clinical usefulness of novel denoising process for depicting mCNV. This study included 20 eyes of 20 patients with mCNV. Ten en face images taken in a 3 × 3 mm macular cube were obtained from outer-retina-to-choriocapillaris layer. Three image types were prepared for analysis; single images before and after the denoising process accomplished deep learning (single and denoising groups, respectively) and up to 10 images were averaged (averaging group). Pairwise comparisons showed vessel density, vessel length density, and fractal dimension (FD) were higher; whereas, vessel density index (VDI) was lower in single group than in denoising and averaging groups. Detectable CNV indices, contrast-to-nose ratio, and CNV diagnostic scores were higher in denoising and averaging groups than in single group. No significant differences were detected in VDI, FD, or CNV diagnostic scores between denoising and averaging groups. The denoising process can utilise single OCTA images to provide results comparable to averaged OCTA images, which is clinically useful for shortening examination times with quality similar to averaging

Usefulness and Validity of a Jaw-Closing Force Meter in Older Adults

We prototyped a new device with a soft and flexible pressure sensor to measure the force to close the mandible with or without occlusal support (jaw-closing force, JCF). This study aimed to clarify the practicality of this instrument. Healthy young and older adults with occlusal support were recruited. Intra- and inter-rater reliability of the JCF meter was examined using data from younger participants. Data regarding age, sex, body mass index, remaining teeth, and dentures of the older adults were obtained. Furthermore, the right and left JCFs were measured using a JCF meter; occlusal force was measured using an existing occlusal force-measuring device. Intra- and inter-rater correlation coefficients were significantly reproducible (0.691–0.811, p < 0.05). JCF was correlated with occlusal force (p < 0.05). Multiple regression analysis revealed that factors significantly associated with JCF included denture status (p < 0.001), age (p = 0.038), and occlusal force (p = 0.043). The prototyped JCF meter can measure JCF with high reproducibility, reliability, and validity. Further, association with occlusal force, which is an existing index, was observed. This device could be used to measure the JCF with or without occlusal support as a new method of evaluating oral function in older adults

Case Report Near-Infrared Spectroscopy during the Verbal Fluency Task before and after Treatment with Image Exposure and SSRI Therapy in Patients with Obsessive-Compulsive Disorder

Drug therapy with selective serotonin reuptake inhibitors (SSRIs) has been used as a treatment for obsessive-compulsive disorder (OCD). In the present case report, exposure therapy was used in addition to escitalopram (20 mg) to treat a 28-year-old female patient with OCD for 6 months. Her obsessive-compulsive symptoms comprised thoughts of words such as rape, crematorium, neck hanging, unhappy, death, die, and kill and images such as a shelf of gods, a shrine, a Buddhist altar, the sun, the sky, and the faces of her parents, siblings, and relatives. As exposure therapy, she was asked to view the images associated with these symptoms three times a day along with drug therapy. With the combination of drug and exposure therapies, her obsessive-compulsive symptoms improved within 6 months, with no interference in her daily life. Multichannel near-infrared spectroscopy (NIRS) showed improvement of brain function in the temporal and frontal lobes after treatment. These results suggest that NIRS can be used as an indicator of brain function improvement in patients with OCD

Human genetic research, race, ethnicity and the labeling of populations: recommendations based on an interdisciplinary workshop in Japan.

[Background]A challenge in human genome research is how to describe the populations being studied. The use of improper and/or imprecise terms has the potential to both generate and reinforce prejudices and to diminish the clinical value of the research. The issue of population descriptors has not attracted enough academic attention outside North America and Europe. In January 2012, we held a two-day workshop, the first of its kind in Japan, to engage in interdisciplinary dialogue between scholars in the humanities, social sciences, medical sciences, and genetics to begin an ongoing discussion of the social and ethical issues associated with population descriptors. [Discussion]Through the interdisciplinary dialogue, we confirmed that the issue of race, ethnicity and genetic research has not been extensively discussed in certain Asian communities and other regions. We have found, for example, the continued use of the problematic term, “Mongoloid” or continental terms such as “European,” “African,” and “Asian,” as population descriptors in genetic studies. We, therefore, introduce guidelines for reporting human genetic studies aimed at scientists and researchers in these regions. [Conclusion]We need to anticipate the various potential social and ethical problems entailed in population descriptors. Scientists have a social responsibility to convey their research findings outside of their communities as accurately as possible, and to consider how the public may perceive and respond to the descriptors that appear in research papers and media articles

Conformations of Disulfide-Intact and -Reduced Lysozyme Ions Probed by Proton-Transfer Reactions at Various Temperatures

Proton-transfer reactions of disulfide-intact and -reduced lysozyme ions (7+ through 14+) to 2,6-dimethylpyridine were examined in the gas phase using tandem mass spectrometry with electrospray ionization. By changing temperature of a collision cell from 280 to 460 K, temperature dependence of reaction rate constants and branching fractions was measured. Absolute reaction rate constants for the protein ions of specific charge states were determined from intensities of parent and product ions in the mass spectra. Remarkable change was observed for the rate constants and distribution of product ions. The rate constants for disulfide-intact ions changed more drastically with change of charge states and temperature than those for disulfide-reduced ions. Observed branching fractions for parent and product ions were represented by calculated reaction rate constants with a scheme of sequential process. The reaction rate constants are closely related to conformation changes with change of temperature, which are profoundly influenced by amputation of disulfide bonds