Effects of monthly intravenous ibandronate on bone mineral density and microstructure in patients with primary osteoporosis after teriparatide treatment: The MONUMENT study

Purpose: To investigate the effects of sequential therapy with monthly intravenous ibandronate on bone mineral density (BMD) and microstructure in patients with primary osteoporosis who received teriparatide treatment. Methods: Sixty-six patients with primary osteoporosis who had undergone teriparatide treatment for more than 12 months (mean 18.6 months) received sequential therapy with 1 mg/month intravenous ibandronate for 12 months. The patients were evaluated using dual-energy X-ray absorptiometry (DXA), quantitative ultrasound, bone turnover markers, and high-resolution peripheral quantitative computed tomography (HR-pQCT) at baseline and 6 and 12 months after beginning administration. Results: At 12 months after beginning sequential therapy,the bone resorption marker, tartrate-resistant acid phosphatase-5b, decreased by 39.5%, with 82.3% of the patients exhibiting levels within the normal limit. DXA revealed that the BMD of the lumbar spine increased by 3.2%, with 79.0% of the patients exhibiting a response, and 40.3% experiencing an increase in BMD over 5%. HR-pQCT revealed that the cortical thickness of the distal tibia was increased by 2.6%. The cortical area increased by 2.5%, and the buckling ratio (an index of cortical instability) decreased by 2.5%. Most parameters of the trabecular bone showed no significant changes. These changes in the cortical bone were observed in both the distal radius and tibia and appeared beginning 6 months after treatment initiation. Conclusions: Sequential therapy with monthly intravenous ibandronate increased the BMD and improved the cortical bone microstructure of osteoporotic patients who had undergone teriparatide treatment

人総研シンポジウム抄録 : 福島原発事故12年の経験から学ぶ -当時小学生だった若者達との対話から(第2回)-

departmental bulletin pape

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

ニホンザルノセイコウドウ

京都大学0048新制・論文博士理学博士乙第3918号論理博第656号新制||理||313(附属図書館)6468UT51-54-P329(主査)教授 日高 敏隆, 教授 池田 次郎, 教授 河合 雅雄学位規則第5条第2項該当Kyoto UniversityDA

ラット前立腺におけるエストロゲン結合物質の性状

前立腺腫瘍の治療としてエストロゲン投与がおこなわれるが， その作用機序を明らかにする手始めとして，去勢ラット腹側前立腺の胞体可溶分画および核におけるエストロゲン結合物質の性状について検討を加えた。その結果，次の諸点が明らかとなった. (1)各臓器の胞体可溶分商を得た後，それに対する放射性エストラジオールー17βの結合を炭末吸着法によって検討すると，前立腺において最もよく結合し，続いて肝臓，腎臓，精巣，精嚢の順となり，骨格筋にはわずかしか結合しなかった. (2)前立腺可溶分画を放射性エストラジオールー17βのみ， あるいはそれに非放射性の各種ステロイドを加えてインキュペーションした後，ポリアクリルアミドゲル電気泳動法によって分析を加えると， エストロゲンに特異的に結合するものと，ステロイド特異性のないものの2種の物質が認められた。ともに血清タンパクの混入によるものではない。また炭末吸着法を用いたスキャッチヤード・プロット分析によって，結合部位数および解離定数を求めると，それぞれ9.3x10[-16]モル/mgタンパクKd=2.2 X 10[-11]M と計算された. (3)前立腺組織細片を放射性エストラジオールー17βを含む培養液でインキュベーションした場合でも，核抽出液および胞体可溶分画中に2種の結合物質が認められた. (4)放射性エストラジオールー17βとインキュベーションした組織から得た核と担体可溶分画に対して，薄層クロマトグラフィーによってステロイド分析をおこなうと，胞体可溶分画においては， エストラジオールー17βの多くがエストロンに変換されているが，核においてはその多くがエストラジオールー17βのままで寄在することが明らかになった。これらの結果は，去勢ラットの腹側前立腺に，結合部位数が少なくエストロゲンに親和性の高い高分子物質の存在を強く示唆している。Polyacrylamide gel electrophoresis, dextran-coated charcoal adsorption, Sephadex gel filtration and thin-layer chromatography allowed us to attempt the characterization of estrogen-binding components in the castrated rat prostate. The results are as follows: 1) Among various tissue cytosols examined, the ventral prostate cytosol showed the highest binding of 3H-estradiol-17β, followed by the cytosols of the liver, kidney, testis, seminal vesicle and skeletal muscle. 2) After incubation of the ventral prostate cytosol with [3]H-estradiol-17βin the absence or the presence of various unlabeled steroids, a specific estrogen-binding material was found with low binding capacity and high affinity for this hormone. This binding was found not due to the contamination of blood serum proteins. 3) After incubation of the ventral prostate with [3]H-estradiol-17β, estrogen-binding material was also found both in the cytosol and in the nucleus of the tissue. 4) Using the thin-layer chromatographic technique it was found that estrone and estradiol-1 7βoccupied most of the radioactivity in various subcellular fractions obtained from the ventral prostate incubated with 3H-estradiol-17β, and the ratio of estradiol: estrone was highest in the nucleus, followed by the binding component of the cytosol and the cytosol. These results may suggest that there is a specific low capacity-high affinity estrogenbinding component in the adult rat prostate

Microbial Communities Associated with Holothurians: Presence of Unique Bacteria in the Coelomic Fluid

Marine invertebrates interact with various microorganisms ranging from pathogens to symbionts. One-to-one symbiosis between a single microbial species and a single host animal has served as a model for the study of host-microbe interactions. In addition, increasing attention has recently been focused on the complex symbiotic associations, e.g., associations between sponges and their symbionts, due to their biotechnological potential; however, relatively little is known about the microbial diversity associated with members of the phylum Echinodermata. Here, for the first time, we investigated microbial communities associated with a commercially important holothurian species, Apostichopus japonicus, using culture-dependent and-independent methods. Diverse and abundant heterotrophs, mostly Gammaproteobacteria members, were cultured semi-quantitatively. Using the cloning and sequencing technique, different microbial communities were found in different holothurian tissues. In the holothurian coelomic fluid, potentially metabolically active and phylogenetically unique members of Epsilonproteobacteria and Rickettsiales were discovered. This study suggests that coelomic fluids of marine invertebrates, at least those inhabiting intertidal areas where physical and chemical conditions fluctuate, provide microbes with unique and stable habitats. Key words: holothurians, microbial diversity, coelomic fluid, host-microbe association, fisheries implications Marine invertebrates harbor a wide array of ecto- and endo-symbiotic microbes. One-to-one symbiosis between