Simulations of Surface X-ray Diffraction from a Monolayer 4He Film Adsorbed on Graphite

We carried out simulations of crystal truncation rod (CTR) scatterings, i.e., one of the surface X-ray diffraction techniques with atomic resolution, from a monolayer He film adsorbed on graphite. Our simulations reveal that the 00L rod scatterings from the He monolayer exhibit notable intensity modifications for those from a graphite surface in the ranges of approximately L = 0.6 - 1.7 and L = 2.2 - 3.5. The height of the He monolayer from the graphite surface largely affects the CTR scattering profiles, indicating that CTR scatterings have enough sensitivities to determine the surface structure of the various phases in the He layer. In particular, in the incommensurate solid phase, our preliminary experimental data show the intensity modulations that are expected from the present simulations.Comment: 6 pages, 4 figures, to be published in JPS Conf. Pro

Periostin Activation of Integrin Receptors on Sensory Neurons Induces Allergic Itch

Chronic allergic itch is a common symptom affecting millions of people and animals, but its pathogenesis is not fully explained. Herein, we show that periostin, abundantly expressed in the skin of patients with atopic dermatitis (AD), induces itch in mice, dogs, and monkeys. We identify the integrin αVβ3 expressed on a subset of sensory neurons as the periostin receptor. Using pharmacological and genetic approaches, we inhibited the function of neuronal integrin αVβ3, which significantly reduces periostin-induced itch in mice. Furthermore, we show that the cytokine TSLP, the application of AD-causing MC903 (calcipotriol), and house dust mites all induce periostin secretion. Finally, we establish that the JAK/STAT pathway is a key regulator of periostin secretion in keratinocytes. Altogether, our results identify a TSLP-periostin reciprocal activation loop that links the skin to the spinal cord via peripheral sensory neurons, and we characterize the non-canonical functional role of an integrin in itch

Experimental model for the irradiation-mediated abscopal effect and factors influencing this effect

Radiotherapy (RT) is the primary treatment for cancer. Ionizing radiation from RT induces tumor damage at the irradiated site, and, although clinically infrequent, may cause regression of tumors distant from the irradiated site-a phenomenon known as the abscopal effect. Recently, the abscopal effect has been related to prolongation of overall survival time in cancer patients, though the factors that influence the abscopal effect are not well understood. The aim of this study is to clarify the factors influencing on abscopal effect. Here, we established a mouse model in which we induced the abscopal effect. We injected MC38 (mouse colon adenocarcinoma) cells subcutaneously into C57BL/6 mice at two sites. Only one tumor was irradiated and the sizes of both tumors were measured over time. The non-irradiated-site tumor showed regression, demonstrating the abscopal effect. This effect was enhanced by an increase in the irradiated-tumor volume and by administration of anti-PD1 antibody. When the abscopal effect was induced by a combination of RT and anti-PD1 antibody, it was also influenced by radiation dose and irradiated-tumor volume. These phenomena were also verified in other cell line, B16F10 cells (mouse melanoma cells). These findings provide further evidence of the mechanism for, and factors that influence, the abscopal effect in RT

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

Comparison of topical tofacitinib and 0.1% hypochlorous acid in a murine atopic dermatitis model

Abstract Background Topical administration of PR022, 0.05% hypochlorous acid (HOCl) in gel has been demonstrated to be beneficial in a chronic murine atopic dermatitis model. In a follow up study we tested a higher concentration (0.1%) of PR022 HOCl gel in comparison to the Janus kinase inhibitor tofacitinib, both of which are currently in clinical phase studies for treatment of human atopic dermatitis. Methods The effect of topically administered HOCl (0.1%) in gel was compared to a topical formulation of tofacitinib (0.5%) in a therapeutic setting on atopic dermatitis-like lesions in NC/Nga mice as well as itch behaviour. NC/Nga mice were sensitized with house dust mite allergen. After reaching visible lesions, mice were treated either topically with HOCl or tofacitinib or gel vehicle for 17 days. After termination of the study, dorsal root ganglia were isolated for ex vivo stimulation and skin samples were taken for cytokine determination in inflamed skin. Results When administered onto lesional skin of NC/Nga mice, both HOCl and tofacitinib reduced lesions and scratching behaviour. The reduced inflammatory response by HOCl and tofacitinib treatment was demonstrated by diminished inflammatory cytokines in affected skin tissue from NC/Nga mice. Dorsal root ganglia neurons re-stimulated with a range of mediators of itch showed a reduced response compared to the vehicle control mice, when isolated from tofacitinib or HOCl treated mice. Conclusions These data indicate a similar beneficial potential of topical high dose PR022 HOCl (0.1%) in gel and tofacitinib, in a translational murine model of atopic dermatitis

Neuromedin B Induces Acute Itch in Mice via the Activation of Peripheral Sensory Neurons

Neuromedin B is expressed in nociceptive and itchsensitive dorsal root ganglia neurons, but its peripheral pruritogenic potential is not well described. The potential of neuromedin B as a pruritogen and pro-inflammatory peptide in the skin was tested in vivo in an acute model in mice and monkeys as well as an allergic dermatitis model in mice. To identify the underlying mechanisms in vitro real time PCR analysis for neuromedin B and its receptor expression in murine mast cells and dorsal root ganglia as well as functional calcium imaging in the ganglia was applied. Neuromedin B induces itch when injected intradermally, and the peripheral signal is likely transmitted through the activation of dorsal root ganglia. Thus, neuromedin B could be an interesting new therapeutic target for peripheral processing of itch at the level of sensory neurons

An antioxidant screen identifies ascorbic acid for prevention of light-induced mitotic prolongation in live cell imaging

Abstract Phototoxicity is an important issue in fluorescence live imaging of light-sensitive cellular processes such as mitosis. Among several approaches to reduce phototoxicity, the addition of antioxidants to the media has been used as a simple method. Here, we analyzed the impact of phototoxicity on the mitotic progression in fluorescence live imaging of human cells and performed a screen to identify the most efficient antioxidative agents that reduce it. Quantitative analysis shows that high amounts of light illumination cause various mitotic defects such as prolonged mitosis and delays of chromosome alignment and centrosome separation. Among several antioxidants, our screen reveals that ascorbic acid significantly alleviates these phototoxic effects in mitosis. Furthermore, we demonstrate that adding ascorbic acid to the media enables fluorescence imaging of mitotic events at very high temporal resolution without obvious photodamage. Thus, this study provides an optimal method to effectively reduce the phototoxic effects in fluorescence live cell imaging