筋強直性ジストロフィー1型における脳卒中に関する危険因子の臨床的特徴

Objective: Myotonic dystrophy type 1 (DM1) is a rare autosomal dominant disorder with highly variable phenotypic expression. Some patients have diabetes mellitus, dyslipidemia, and/or arrhythmias, which are risk factors for stroke. However, the mechanism of stroke is poorly understood in patients with DM1. We studied the characteristics of risk-factor profiles for stroke associated with DM1. Patients and methods: We studied 77 patients with DM1 (45 men and 32 women) on the basis of the patients’ clinical histories and laboratory and genetic examination results. Results: The analysis showed that 26 patients (34%) had dyslipidemia, and 16 (21%) had diabetes. Arrhythmias were diagnosed in 46 patients (61%), including 11 (14%) with atrial fibrillation and 9 (12%) with conduction defects. Echocardiographic abnormalities were found in 28 patients (37%). Eight patients (11%) met the criteria for metabolic syndrome. We identified 2 patients (2.6%) with ischemic stroke caused by cardiogenic embolism among 77 patients with DM1. One had paroxysmal atrial fibrillation and sick sinus syndrome, and the other had cardiac dysfunction with an ejection-fraction of 35% and dyslipidemia. Both patients had highly expanded numbers of CTG repeats (1000 and 1500). Conclusion: To our knowledge, this is the first study to report a comprehensive analysis of risk-factor profiles for stroke in patients with DM1. Stroke is a relatively rare, but severe complication of DM1. Our results indicate that it is important to manage risk factors for stroke, especially cardiac involvement and arrhythmias.博士（医学）・乙第1392号・平成29年3月15日Copyright: © 2016 Sugie M, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

等質テスト構成における整数計画法を用いた最大クリーク探索の並列化

本論文では，等質テスト構成のための整数計画法を用いた最大クリークの並列化探索手法を提案する．等質テストとは各テストで出題される項目が異なるが，受験者得点の予測誤差が等質なテスト群である．等質テストでは同一能力の受験者が異なるテストを受験しても同一の得点となる保証があり，アイテムバンクから可能な限り多く生成することが望ましい．石井ら（2017）は等質テスト構成を最大クリーク問題と整数計画法により，従来手法より多くのテストを構成できる手法を提案した．本論文では，石井ら（2017）の手法で最も時間を要する整数計画法による逐次的頂点追加処理を並列化することを考える．具体的には，探索中のクリークの全頂点と隣接する頂点集合を候補頂点集合として，逐次的に整数計画法の解を追加し，要素数が一定となるまで並列化して繰り返し，この要素の最大クリークを追加することで探索を高速化できる．この提案手法の有効性は最大で従来手法で生成されるテスト数が194575個であったのに対し，438950個にテスト生成数を更新した．Educational assessments occasionally require uniform test forms for which each test form consists of a different set of items, but the forms meet uniform test specifications. For uniform test assembly, one of the most important issues is to incarease the number of assembled tests. Ishii et al. (2017) proposed using maximum clique problem and interger programming. The method assembled more uniform tests than traditional methods do. The proposal can be parallel searching vertices connected to all vertices in current clique. Ishii et al. (2017) method spend almost time for this process and impossible parallel algorithm, thus, the proposal can assemble a greater number of tests then the previous methods. As a result, the proposal assembled 438950 uniform tests as compared with 194575 uniform tests using the previous methods

Comparison of the effects of forefoot joint-preserving arthroplasty and resection-replacement arthroplasty on walking plantar pressure distribution and patient-based outcomes in patients with rheumatoid arthritis

Purpose: The purpose of this retrospective study is to clarify the difference in plantar pressure distribution during walking and related patient-based outcomes between forefoot joint-preserving arthroplasty and resection-replacement arthroplasty in patients with rheumatoid arthritis (RA). Methods: Four groups of patients were recruited. Group1 included 22 feet of 11 healthy controls (age 48.6 years), Group2 included 36 feet of 28 RA patients with deformed non-operated feet (age 64.8 years, Disease activity score assessing 28 joints with CRP [DAS28-CRP] 2.3), Group3 included 27 feet of 20 RA patients with metatarsal head resection-replacement arthroplasty (age 60.7 years, post-operative duration 5.6 years, DAS28-CRP 2.4), and Group4 included 34 feet of 29 RA patients with metatarsophalangeal (MTP) joint-preserving arthroplasty (age 64.6 years, post-operative duration 3.2 years, DAS28-CRP 2.3). Patients were cross-sectionally examined by F-SCAN II to evaluate walking plantar pressure, and the self-administered foot evaluation questionnaire (SAFE-Q). Twenty joint-preserving arthroplasty feet were longitudinally examined at both pre- and post-operation. Results: In the 1st MTP joint, Group4 showed higher pressure distribution (13.7%) than Group2 (8.0%) and Group3 (6.7%) (P<0.001). In the 2nd-3rd MTP joint, Group4 showed lower pressure distribution (9.0%) than Group2 (14.5%) (P<0.001) and Group3 (11.5%) (P<0.05). On longitudinal analysis, Group4 showed increased 1st MTP joint pressure (8.5% vs. 14.7%; P<0.001) and decreased 2nd-3rd MTP joint pressure (15.2% vs. 10.7%; P<0.01) distribution. In the SAFE-Q subscale scores, Group4 showed higher scores than Group3 in pain and pain-related scores (84.1 vs. 71.7; P<0.01) and in shoe-related scores (62.5 vs. 43.1; P<0.01). Conclusions: Joint-preserving arthroplasty resulted in higher 1st MTP joint and lower 2nd-3rd MTP joint pressures than resection-replacement arthroplasty, which were associated with better patient-based outcomes.Ebina K., Hirao M., Takagi K., et al. (2017) Comparison of the effects of forefoot joint-preserving arthroplasty and resection-replacement arthroplasty on walking plantar pressure distribution and patient-based outcomes in patients with rheumatoid arthritis. PLoS ONE 12(8): e0183805. doi: 10.1371/journal.pone.0183805

間欺的低酸素はヒト神経細胞においてGATA転写因子を介してPOMCとCARTのmRNAを増加させる

Sleep apnea syndrome (SAS) is characterized by intermittent hypoxia (IH) during sleep. SAS and obesity are strongly related to each other. Here, we investigated the effect of IH on the expression of major appetite regulatory genes in human neuronal cells. We exposed NB-1, SH-SY5Y, and SK-N-SH human neuronal cells to IH (64 cycles of 5 min hypoxia and 10 min normoxia), normoxia, or sustained hypoxia for 24 h and measured the mRNA levels of proopiomelanocortin (POMC), cocaine- and amphetamine-regulated transcript (CART), galanin, galanin-like peptide, ghrelin, pyroglutamylated RFamide peptide, agouti-related peptide, neuropeptide Y, and melanocortin 4 receptor by real-time RT-PCR. IH significantly increased the mRNA levels of POMC and CART in all the neuronal cells. Deletion analysis revealed that the -705 to -686 promoter region of POMC and the -950 to -929 region of CART were essential for the IH-induced promoter activity. As possible GATA factor binding sequences were found in the two regions, we performed real-time RT-PCR to determine which GATA family members were expressed and found that GATA2 and GATA3 mRNAs were predominantly expressed. Therefore, we introduced siRNAs against GATA2 and GATA3 into NB-1 cells and found that GATA2 and GATA3 siRNAs abolished the IH-induced up-regulation of both POMC and CART mRNAs. These results indicate that IH stress up-regulates the mRNA levels of anorexigenic peptides, POMC and CART, in human neuronal cells via GATA2 and GATA3. IH can have an anorexigenic effect on SAS patients through the transcriptional activation of POMC and CART in the central nervous system.博士（医学）・甲第685号・平成30年6月27日© 2017 Elsevier Ltd. All rights reserved

Fundamental Parameters of the Milky Way Galaxy Based on VLBI astrometry

We present analyses to determine the fundamental parameters of the Galaxy based on VLBI astrometry of 52 Galactic maser sources obtained with VERA, VLBA and EVN. We model the Galaxy's structure with a set of parameters including the Galaxy center distance R_0, the angular rotation velocity at the LSR Omega_0, mean peculiar motion of the sources with respect to Galactic rotation (U_src, V_src, W_src), rotation-curve shape index, and the V component of the Solar peculiar motions V_sun. Based on a Markov chain Monte Carlo method, we find that the Galaxy center distance is constrained at a 5% level to be R_0 = 8.05 +/- 0.45 kpc, where the error bar includes both statistical and systematic errors. We also find that the two components of the source peculiar motion U_src and W_src are fairly small compared to the Galactic rotation velocity, being U_src = 1.0 +/- 1.5 km/s and W_src = -1.4 +/- 1.2 km/s. Also, the rotation curve shape is found to be basically flat between Galacto-centric radii of 4 and 13 kpc. On the other hand, we find a linear relation between V_src and V_sun as V_src = V_sun -19 (+/- 2) km/s, suggesting that the value of V_src is fully dependent on the adopted value of V_sun. Regarding the rotation speed in the vicinity of the Sun, we also find a strong correlation between Omega_0 and V_sun. We find that the angular velocity of the Sun, Omega_sun, which is defined as Omega_sun = Omega_0 + V_sun/R_0, can be well constrained with the best estimate of Omega_sun = 31.09 +/- 0.78 km/s/kpc. This corresponds to Theta_0 = 238 +/- 14 km/s if one adopts the above value of R_0 and recent determination of V_sun ~ 12 km/s.Comment: 14 pages, 6 figures, PASJ in pres

VLBI Astrometry of AGB Variables with VERA -- A Semiregular Variable S Crateris --

We present a distance measurement for the semiregular variable S Crateris (S Crt) based on its annual parallax. With the unique dual beam system of the VLBI Exploration for Radio Astrometry (VERA) telescopes, we measured the absolute proper motion of a water maser spot associated with S Crt, referred to the quasar J1147-0724 located at an angular separation of 1.23$^{\circ}$. In observations spanning nearly two years, we have detected the maser spot at the LSR velocity of 34.7 km s$^{-1}$, for which we measured the annual parallax of 2.33$\pm$0.13 mas corresponding to a distance of 430$^{+25}_{-23}$ pc. This measurement has an accuracy one order of magnitude better than the parallax measurements of HIPPARCOS. The angular distribution and three-dimensional velocity field of maser spots indicate a bipolar outflow with the flow axis along northeast-southwest direction. Using the distance and photospheric temperature, we estimate the stellar radius of S Crt and compare it with those of Mira variables.Comment: 9 pages, 4 figures, accepted for publication in PASJ (Vol.60, No.5, October 25, VERA special issue

The SARS-CoV-2 Lambda variant exhibits enhanced infectivity and immune resistance

SARS-CoV-2ラムダ株のウイルス学的・免疫学的性状の解明. 京都大学プレスリリース. 2021-12-23.SARS-CoV-2 Lambda, a variant of interest, has spread in some South American countries; however, its virological features and evolutionary traits remain unknown. In this study, we use pseudoviruses and reveal that the spike protein of the Lambda variant is more infectious than that of other variants due to the T76I and L452Q mutations. The RSYLTPGD246-253N mutation, a unique 7-amino-acid deletion in the N-terminal domain of the Lambda spike protein, is responsible for evasion from neutralizing antibodies and further augments antibody-mediated enhancement of infection. Although this mutation generates a nascent N-linked glycosylation site, the additional N-linked glycan is dispensable for the virological property conferred by this mutation. Since the Lambda variant has dominantly spread according to the increasing frequency of the isolates harboring the RSYLTPGD246-253N mutation, our data suggest that the RSYLTPGD246-253N mutation is closely associated with the substantial spread of the Lambda variant in South America

Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity

The SARS-CoV-2 Omicron BA.1 variant emerged in 20211 and has multiple mutations in its spike protein2. Here we show that the spike protein of Omicron has a higher affinity for ACE2 compared with Delta, and a marked change in its antigenicity increases Omicron’s evasion of therapeutic monoclonal and vaccine-elicited polyclonal neutralizing antibodies after two doses. mRNA vaccination as a third vaccine dose rescues and broadens neutralization. Importantly, the antiviral drugs remdesivir and molnupiravir retain efficacy against Omicron BA.1. Replication was similar for Omicron and Delta virus isolates in human nasal epithelial cultures. However,&nbsp;in lung cells and gut cells, Omicron demonstrated lower replication. Omicron spike protein was less efficiently cleaved compared with Delta. The differences in replication were mapped to the entry efficiency of the virus on the basis&nbsp;of spike-pseudotyped&nbsp;virus assays. The defect in entry of Omicron pseudotyped virus to specific cell types effectively correlated with higher cellular RNA expression of TMPRSS2, and deletion of TMPRSS2 affected Delta entry to a greater extent than Omicron. Furthermore, drug inhibitors targeting specific entry pathways3 demonstrated that the Omicron spike inefficiently uses the cellular protease TMPRSS2, which promotes cell entry through plasma membrane fusion, with greater dependency on cell entry through the endocytic pathway. Consistent with suboptimal S1/S2 cleavage and inability to use TMPRSS2, syncytium formation by the Omicron spike was substantially impaired compared with the Delta spike. The less efficient spike cleavage of Omicron at S1/S2 is associated with a shift in cellular tropism away from TMPRSS2-expressing cells, with implications for altered pathogenesis

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