Novel, Objective, Multivariate Biomarkers Composed of Plasma Amino Acid Profiles for the Diagnosis and Assessment of Inflammatory Bowel Disease

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic intestinal disorder that is associated with a limited number of clinical biomarkers. In order to facilitate the diagnosis of IBD and assess its disease activity, we investigated the potential of novel multivariate indexes using statistical modeling of plasma amino acid concentrations (aminogram). METHODOLOGY AND PRINCIPAL FINDINGS: We measured fasting plasma aminograms in 387 IBD patients (Crohn's disease (CD), n = 165; ulcerative colitis (UC), n = 222) and 210 healthy controls. Based on Fisher linear classifiers, multivariate indexes were developed from the aminogram in discovery samples (CD, n = 102; UC, n = 102; age and sex-matched healthy controls, n = 102) and internally validated. The indexes were used to discriminate between CD or UC patients and healthy controls, as well as between patients with active disease and those in remission. We assessed index performances using the area under the curve of the receiver operating characteristic (ROC AUC). We observed significant alterations to the plasma aminogram, including histidine and tryptophan. The multivariate indexes established from plasma aminograms were able to distinguish CD or UC patients from healthy controls with ROC AUCs of 0.940 (95% confidence interval (CI): 0.898-0.983) and 0.894 (95%CI: 0.853-0.935), respectively in validation samples (CD, n = 63; UC, n = 120; healthy controls, n = 108). In addition, other indexes appeared to be a measure of disease activity. These indexes distinguished active CD or UC patients from each remission patients with ROC AUCs of 0.894 (95%CI: 0.853-0.935) and 0.849 (95%CI: 0.770-0.928), and correlated with clinical disease activity indexes for CD (r(s) = 0.592, 95%CI: 0.385-0.742, p<0.001) or UC (r(s) = 0.598, 95%CI: 0.452-0.713, p<0.001), respectively. CONCLUSIONS AND SIGNIFICANCE: In this study, we demonstrated that established multivariate indexes composed of plasma amino acid profiles can serve as novel, non-invasive, objective biomarkers for the diagnosis and monitoring of IBD, providing us with new insights into the pathophysiology of the disease

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

Bilateral Pleural Effusions as an Initial Presentation in Primary Sjögren’s Syndrome

Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by sicca symptoms. Interstitial pulmonary fibrosis and tracheobronchial sicca are the most common symptoms of pulmonary involvement in primary SjS, and they are rarely accompanied by serositis such as pleuritis or pericarditis. We report a case of SS presenting initially with bilateral pleural effusions. A 63-year old man was admitted to our hospital with a one-month history of cough, dyspnea, and right chest pain. Chest-computed tomography revealed bilateral pleural effusions. Serum anti-SS-A antibody titer was 1 : 256. Ophthalmological examination revealed a positive Schirmer test. Lip biopsy showed atrophy and plasmacytic infiltration of the salivary gland. Corticosteroid treatment was initiated. Pleural effusions were almost completely resolved by day 30. The patient has not experienced any recurrence

Successful Treatment with Pemetrexed, Carboplatin, and Bevacizumab for Platinum-Resistant Adenocarcinoma of the Lung

We present two cases of relapsed adenocarcinoma of the lung: a 50-year-old male and a 67-year-old male. Both patients had previously been treated with platinum-containing systemic chemotherapy. In both cases, significant clinical efficacy was demonstrated with combination chemotherapy consisting of pemetrexed, carboplatin, and bevacizumab as salvage treatment. Adverse events were mild. This regimen might be a viable therapeutic option even after heavy treatment such as platinum-containing chemotherapy, especially for patients with preserved organ function and good performance status

Developing attainment targets in teaching practice for English teachers (III)

本研究は, 学部レベルで英語教員を養成する際に, 教育実習における到達目標を具体的に設定することを目的としたものである。研究の最終年度に当たる今年度は, 教育実習生の授業を設定した到達目標の規準に従って評価するための評価シートの作成と, その実効性の検証を行った。実効性とは, 記入がし易く, 評価の信頼性が高く, また, 教育実習生の指導にも活用できることである。評価シートの様式は, 指導教員が教育実習生の授業を観察しながら記入できるものであること, 改訂に当たっては評価の信頼性の高いものになることに留意した。さらに, 教育実習生が理解しやすいものになることにも留意した。 教育実習期間中に評価シートでの評価を試行したが, 指導への活用に関しては, 授業直後の短い時間でも簡潔でわかりやすい指導が行えた。評価の信頼性に関しては, 初段階の評価シートでは評価者(指導教員)間で評価のばらつきが顕著であった。改訂を重ねることでそのばらつきは改善され, 評価の信頼性を高めることができた

Making of A Can-Do lists based on the Course of Study for Upper Secondary Schools

全国の高等学校で,具体的な到達目標をCan-Doリストの形で作成することになっているが,作成されたリストの中には学習指導要領に準拠していないものも見られる。また,既成のリストを見ただけではどのようにして作成したのかがわかりにくい。本小論は,高等学校学習指導要領でどのような能力の育成を目指しているのかを明示し,学習指導要領に準拠したCan-Doリストの作成方法を具体的,かつ,わかりやすく示す。なお,本小論では,4技能のうち,「書くこと」についてのCan-Doリスト作成手順を対象にした。その手順は次の通りである。学習集指導要領で示された,目指す能力の一覧化→ カテゴリー分類→ 仮Can-Doの設定→ 検証テスト→Can-Doリストの編集・確定。この研究で実施した検証テストにより,このCan-Doリストは妥当であるという結果が得られた。Many Can-Do lists are not based on the Course of Study. It is difficult to learn how to make Can-Do lists by evaluating those made by high schools. This study clearly demonstrates the process of making Can-Do lists as follows. The abilities students should have are identified in the Course of Study. These abilities are categorized. A list of tentative can-dos is made. A test determines the reliability of the tentative can-dos. The tentative can-dos are improved according to the test result. The final list of can-dos is determined. The Can-Do lists presented in this thesis were proven to be appropriate by the test

Effective Methods for Teaching “English Expression”

平成25年度より施行されている高等学校学習指導要領において新設された英語表現Ⅰの中で言及されている，「論理構成及び表現の方法を工夫しながら伝える力」を育成するための具体的な実践報告である。実践においては，「論理構成及び表現の方法を工夫しながら伝える力」を，「英語で表現するにあたって，場面や状況，背景，相手の反応などを踏まえた上で，妥当な文章構成を用いる力」と定義した上で，英語の作文を書くための基本的な文章構成や，読み手の注意を引き付ける工夫，説得力のある意見文を書くための工夫を，英作文の比較や，ピアー・レビューなどの手法を織り交ぜながら指導を行った。結果としては，生徒が与えられたトピックについて，場面や目的を考えて，学んだ文章構成の工夫を活用している様子が見られた。The aim of this study is to demonstrate appropriate teaching methods for cultivating students’ ability to write passages in a style suitable for a particular audience and purpose. In the class, students learned the basics of English composition as well as how to attract the interest of readers and how to write in a persuasive style. The results indicated that the lesson taught the students how to write passages implementing their learning