Selective alpha(1A)-Adrenoceptor Stimulation Induces Mueller's Smooth Muscle Contraction in an Isolated Canine Upper Eyelid Preparation

Purpose: It has been demonstrated that in patients with aponeurotic blepharoptosis, alpha(1)-adrenoceptor stimulation causes the contraction of the upper eyelid tarsal smooth muscle (Mueller's muscle) and opening of the eye. However, alpha(1)-adrenoceptor subtypes mediating the contraction of Mueller's muscle are still unclear. This study was designed to identify the alpha(1)-adrenoceptor subtypes in Mueller's muscle. Materials and Methods: A newly developed canine upper eyelid preparation was retrogradely perfused with a drug-containing Krebs-Henseleit solution through the angular vein in a temperature-controlled organ chamber. The contraction of the preparation was measured with a force-displacement transducer. Results: Phenylephrine, an alpha(1)-adrenoceptor agonist, increased the upper eyelid contractile force in a dose-dependent manner (K(0.5) = 110 nmol). Interestingly, the contraction in response to phenylephrine was persistent and hardly recovered to a base line level for more than 100 min after washout of the drug. WB4101 (100 nM), an alpha(1A)- and alpha(1D)-adrenoceptor antagonist, but not BMY7378 (100 nM), a selective alpha(1D)-adrenoceptor antagonist, competitively inhibited the phenylephrine-induced contraction. ABT-866, a selective alpha(1A)-adrenoceptor agonist, increased the upper eyelid contractile force as effectively as phenylephrine in a dose-dependent manner (K(0.5) = 190 nmol), and the contraction continued again for more than 100 min. Conclusion: These results suggest that selective alpha(1A)-adrenoceptor agonists, such as ABT-866, induce the sustained Mueller's muscle contraction and may be useful in pharmacological treatment of blepharoptosis.ArticleCURRENT EYE RESEARCH. 35(5):363-369 (2010)journal articl

Rapidly and Slowly Growing Lineages in Chromosomal Instability-Type Gland-Forming Gastric Carcinomas as Revealed by Multisampling Analysis of DNA Copy-Number Profile.

BACKGROUND:To examine whether gastric carcinoma (GC) with chromosomal instability (CIN-type GC), the largest category in the Cancer Genome Atlas classification, consists of a single genetic lineage, we conducted a multisampling analysis of genomic DNA copy-number profile.METHODS:We performed array-based comparative genomic hybridization using formalin-fixed paraffin-embedded tissues from 54 gland-forming GCs containing a total of 106 DNA samples from mucosal, extramucosal invasive, and lymph node lesions. Microarray data were analyzed by unsupervised hierarchical clustering and penetrance plots. Epstein-Barr virus infection status and mismatch repair(MMR) enzyme-silencing/p53/mucin expression were examined by in situ hybridization and immunohistochemistry, respectively.RESULTS:The samples examined were divided into gain-rich cluster A and loss-rich cluster B, which were different in tumor locus and patient age. The T1/T2-4 ratio, the frequency of small cancers (diameter 2-4 cm), and intestinal mucin expression were higher in cluster B than in cluster A, but there were no significant differences in the frequencies of MMR silencing, mutant p53 pattern, and lymph node metastasis between the 2 clusters.CONCLUSIONS:We demonstrated that CIN-type GC could be categorized into 2 genetic lineages which are different in terms of rapidity of local extension but similar in terms of nodal metastasis risk

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

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