354 results on '"Suzuki, Ken"'
Search Results
2. Multi-omics characterization of type 2 diabetes associated genetic variation.
- Author
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Mandla R, Lorenz K, Yin X, Bocher O, Huerta-Chagoya A, Arruda AL, Piron A, Horn S, Suzuki K, Hatzikotoulas K, Southam L, Taylor H, Yang K, Hrovatin K, Tong Y, Lytrivi M, Rayner NW, Meigs JB, McCarthy MI, Mahajan A, Udler MS, Spracklen CN, Boehnke M, Vujkovic M, Rotter JI, Eizirik DL, Cnop M, Lickert H, Morris AP, Zeggini E, Voight BF, and Mercader JM
- Abstract
Discerning the mechanisms driving type 2 diabetes (T2D) pathophysiology from genome-wide association studies (GWAS) remains a challenge. To this end, we integrated omics information from 16 multi-tissue and multi-ancestry expression, protein, and metabolite quantitative trait loci (QTL) studies and 46 multi-ancestry GWAS for T2D-related traits with the largest, most ancestrally diverse T2D GWAS to date. Of the 1,289 T2D GWAS index variants, 716 (56%) demonstrated strong evidence of colocalization with a molecular or T2D-related trait, implicating 657 cis -effector genes, 1,691 distal-effector genes, 731 metabolites, and 43 T2D-related traits. We identified 773 of these cis - and distal-effector genes using either expression QTL data from understudied ancestry groups or inclusion of T2D index variants enriched in underrepresented populations, emphasizing the value of increasing population diversity in functional mapping. Linking these variants, genes, metabolites, and traits into a network, we elucidated mechanisms through which T2D-associated variation may impact disease risk. Finally, we showed that drugs targeting effector proteins were enriched in those approved to treat T2D, highlighting the potential of these results to prioritize drug targets for T2D. These results represent a leap in the molecular characterization of T2D-associated genetic variation and will aid in translating genetic findings into novel therapeutic strategies., Competing Interests: Disclosures J.B.M is an academic associate for Quest Diagnostics Inc. Endocrine R&D. MIMcC is now an employee of Genentech and a holder of Roche stock.
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- 2024
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3. Body mass index stratification optimizes polygenic prediction of type 2 diabetes in cross-biobank analyses.
- Author
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Ojima T, Namba S, Suzuki K, Yamamoto K, Sonehara K, Narita A, Kamatani Y, Tamiya G, Yamamoto M, Yamauchi T, Kadowaki T, and Okada Y
- Subjects
- Humans, Female, Male, Biological Specimen Banks, Middle Aged, Japan, Risk Factors, Aged, Polymorphism, Single Nucleotide, United Kingdom, Diabetes Mellitus, Type 2 genetics, Multifactorial Inheritance genetics, Body Mass Index, Genetic Predisposition to Disease, Genome-Wide Association Study
- Abstract
Type 2 diabetes (T2D) shows heterogeneous body mass index (BMI) sensitivity. Here, we performed stratification based on BMI to optimize predictions for BMI-related diseases. We obtained BMI-stratified datasets using data from more than 195,000 individuals (n
T2D = 55,284) from BioBank Japan (BBJ) and UK Biobank. T2D heritability in the low-BMI group was greater than that in the high-BMI group. Polygenic predictions of T2D toward low-BMI targets had pseudo-R2 values that were more than 22% higher than BMI-unstratified targets. Polygenic risk scores (PRSs) from low-BMI discovery outperformed PRSs from high BMI, while PRSs from BMI-unstratified discovery performed best. Pathway-specific PRSs demonstrated the biological contributions of pathogenic pathways. Low-BMI T2D cases showed higher rates of neuropathy and retinopathy. Combining BMI stratification and a method integrating cross-population effects, T2D predictions showed greater than 37% improvements over unstratified-matched-population prediction. We replicated findings in the Tohoku Medical Megabank (n = 26,000) and the second BBJ cohort (n = 33,096). Our findings suggest that target stratification based on existing traits can improve the polygenic prediction of heterogeneous diseases., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)- Published
- 2024
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4. Corticosteroid-triggered acute skeletal muscle loss in lipodystrophy: A case report.
- Author
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Sasako T, Suzuki K, Odawara S, Suwanai H, Akuta N, Kubota N, Ueki K, Kadowaki T, and Yamauchi T
- Subjects
- Humans, Female, Adult, Adrenal Cortex Hormones adverse effects, Adrenal Cortex Hormones therapeutic use, Lipodystrophy chemically induced, Lipodystrophy complications, Muscle, Skeletal drug effects, Muscle, Skeletal pathology, Muscle, Skeletal metabolism
- Abstract
The potential liability to hypercatabolism in lipodystrophy remains to be fully elucidated. Here we report a 28-year-old Japanese woman with acquired generalized lipodystrophy, who presented with recurrence of panniculitis and anemia. After corticosteroid treatment was started, she showed rapid reductions in body weight and lean mass by 15% at maximum, accompanied by an elevated urea nitrogen/creatinine ratio, which recovered almost fully as the corticosteroid treatment was tapered and discontinued. She had multiple risk factors for hypercatabolism: lack of metabolic reserves, insulin resistance, and hyperglycemia due to lipodystrophy, lowered daily activity due to anemia, persistent inflammation, and wasting associated with panniculitis, and relatively insufficient energy and protein intake during hospitalization. More attention should be paid to the potential liability to hypercatabolism in patients with lipodystrophy, and to skeletal muscle loss as an adverse effect of corticosteroid treatment in patients at high risk, such as those with diabetes or decreased metabolic reserves., (© 2024 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)
- Published
- 2024
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5. hoxc12/c13 as key regulators for rebooting the developmental program in Xenopus limb regeneration.
- Author
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Kawasumi-Kita A, Lee SW, Ohtsuka D, Niimi K, Asakura Y, Kitajima K, Sakane Y, Tamura K, Ochi H, Suzuki KT, and Morishita Y
- Subjects
- Animals, Cell Proliferation genetics, Gene Editing, Gene Expression Profiling, Larva growth & development, Larva genetics, Male, Female, Extremities physiology, Gene Expression Regulation, Developmental, Homeodomain Proteins metabolism, Homeodomain Proteins genetics, Regeneration genetics, Regeneration physiology, Xenopus laevis, Xenopus Proteins metabolism, Xenopus Proteins genetics
- Abstract
During organ regeneration, after the initial responses to injury, gene expression patterns similar to those in normal development are reestablished during subsequent morphogenesis phases. This supports the idea that regeneration recapitulates development and predicts the existence of genes that reboot the developmental program after the initial responses. However, such rebooting mechanisms are largely unknown. Here, we explore core rebooting factors that operate during Xenopus limb regeneration. Transcriptomic analysis of larval limb blastema reveals that hoxc12/c13 show the highest regeneration specificity in expression. Knocking out each of them through genome editing inhibits cell proliferation and expression of a group of genes that are essential for development, resulting in autopod regeneration failure, while limb development and initial blastema formation are not affected. Furthermore, the induction of hoxc12/c13 expression partially restores froglet regenerative capacity which is normally very limited compared to larval regeneration. Thus, we demonstrate the existence of genes that have a profound impact alone on rebooting of the developmental program in a regeneration-specific manner., (© 2024. The Author(s).)
- Published
- 2024
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6. Corrigendum to "Self-assembling peptide hydrogel enables instant epicardial coating of the heart with mesenchymal stromal cells for the treatment of heart failure" [Biomaterials 154 (2018) 12-23].
- Author
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Ichihara Y, Kaneko M, Yamahara K, Koulouroudias M, Sato N, Uppal R, Yamazaki K, Saito S, and Suzuki K
- Published
- 2024
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7. Author Correction: Toll-like receptor 9 protects non-immune cells from stress by modulating mitochondrial ATP synthesis through the inhibition of SERCA2.
- Author
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Shintani Y, Drexler HC, Kioka H, Terracciano CM, Coppen SR, Imamura H, Akao M, Nakai J, Wheeler AP, Higo S, Nakayama H, Takashima S, Yashiro K, and Suzuki K
- Published
- 2024
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8. Corrigendum to "On-site fabrication of bi-layered adhesive mesenchymal stromal cell dressings for the treatment of heart failure" [Biomaterials 209 (2019) 41-53].
- Author
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Kobayashi K, Ichihara Y, Sato N, Umeda N, Fields L, Fukumitsu M, Tago Y, Ito T, Kainuma S, Podaru M, Lewis-McDougall F, Yamahara K, Uppal R, and Suzuki K
- Published
- 2024
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9. Fgf10 mutant newts regenerate normal hindlimbs despite severe developmental defects.
- Author
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Suzuki M, Okumura A, Chihara A, Shibata Y, Endo T, Teramoto M, Agata K, Bronner ME, and Suzuki KT
- Subjects
- Animals, Hindlimb growth & development, Regeneration, Pleurodeles genetics, Pleurodeles growth & development, Pleurodeles metabolism, Fibroblast Growth Factor 10 genetics, Fibroblast Growth Factor 10 metabolism
- Abstract
In amniote limbs, Fibroblast Growth Factor 10 (FGF10) is essential for limb development, but whether this function is broadly conserved in tetrapods and/or involved in adult limb regeneration remains unknown. To tackle this question, we established Fgf10 mutant lines in the newt Pleurodeles waltl which has amazing regenerative ability. While Fgf10 mutant forelimbs develop normally, the hindlimbs fail to develop and downregulate FGF target genes. Despite these developmental defects, Fgf10 mutants were able to regenerate normal hindlimbs rather than recapitulating the embryonic phenotype. Together, our results demonstrate an important role for FGF10 in hindlimb formation, but little or no function in regeneration, suggesting that different mechanisms operate during limb regeneration versus development., Competing Interests: Competing interests statement:The authors declare no competing interest.
- Published
- 2024
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10. Genetic drivers of heterogeneity in type 2 diabetes pathophysiology.
- Author
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Suzuki K, Hatzikotoulas K, Southam L, Taylor HJ, Yin X, Lorenz KM, Mandla R, Huerta-Chagoya A, Melloni GEM, Kanoni S, Rayner NW, Bocher O, Arruda AL, Sonehara K, Namba S, Lee SSK, Preuss MH, Petty LE, Schroeder P, Vanderwerff B, Kals M, Bragg F, Lin K, Guo X, Zhang W, Yao J, Kim YJ, Graff M, Takeuchi F, Nano J, Lamri A, Nakatochi M, Moon S, Scott RA, Cook JP, Lee JJ, Pan I, Taliun D, Parra EJ, Chai JF, Bielak LF, Tabara Y, Hai Y, Thorleifsson G, Grarup N, Sofer T, Wuttke M, Sarnowski C, Gieger C, Nousome D, Trompet S, Kwak SH, Long J, Sun M, Tong L, Chen WM, Nongmaithem SS, Noordam R, Lim VJY, Tam CHT, Joo YY, Chen CH, Raffield LM, Prins BP, Nicolas A, Yanek LR, Chen G, Brody JA, Kabagambe E, An P, Xiang AH, Choi HS, Cade BE, Tan J, Broadaway KA, Williamson A, Kamali Z, Cui J, Thangam M, Adair LS, Adeyemo A, Aguilar-Salinas CA, Ahluwalia TS, Anand SS, Bertoni A, Bork-Jensen J, Brandslund I, Buchanan TA, Burant CF, Butterworth AS, Canouil M, Chan JCN, Chang LC, Chee ML, Chen J, Chen SH, Chen YT, Chen Z, Chuang LM, Cushman M, Danesh J, Das SK, de Silva HJ, Dedoussis G, Dimitrov L, Doumatey AP, Du S, Duan Q, Eckardt KU, Emery LS, Evans DS, Evans MK, Fischer K, Floyd JS, Ford I, Franco OH, Frayling TM, Freedman BI, Genter P, Gerstein HC, Giedraitis V, González-Villalpando C, González-Villalpando ME, Gordon-Larsen P, Gross M, Guare LA, Hackinger S, Hakaste L, Han S, Hattersley AT, Herder C, Horikoshi M, Howard AG, Hsueh W, Huang M, Huang W, Hung YJ, Hwang MY, Hwu CM, Ichihara S, Ikram MA, Ingelsson M, Islam MT, Isono M, Jang HM, Jasmine F, Jiang G, Jonas JB, Jørgensen T, Kamanu FK, Kandeel FR, Kasturiratne A, Katsuya T, Kaur V, Kawaguchi T, Keaton JM, Kho AN, Khor CC, Kibriya MG, Kim DH, Kronenberg F, Kuusisto J, Läll K, Lange LA, Lee KM, Lee MS, Lee NR, Leong A, Li L, Li Y, Li-Gao R, Ligthart S, Lindgren CM, Linneberg A, Liu CT, Liu J, Locke AE, Louie T, Luan J, Luk AO, Luo X, Lv J, Lynch JA, Lyssenko V, Maeda S, Mamakou V, Mansuri SR, Matsuda K, Meitinger T, Melander O, Metspalu A, Mo H, Morris AD, Moura FA, Nadler JL, Nalls MA, Nayak U, Ntalla I, Okada Y, Orozco L, Patel SR, Patil S, Pei P, Pereira MA, Peters A, Pirie FJ, Polikowsky HG, Porneala B, Prasad G, Rasmussen-Torvik LJ, Reiner AP, Roden M, Rohde R, Roll K, Sabanayagam C, Sandow K, Sankareswaran A, Sattar N, Schönherr S, Shahriar M, Shen B, Shi J, Shin DM, Shojima N, Smith JA, So WY, Stančáková A, Steinthorsdottir V, Stilp AM, Strauch K, Taylor KD, Thorand B, Thorsteinsdottir U, Tomlinson B, Tran TC, Tsai FJ, Tuomilehto J, Tusie-Luna T, Udler MS, Valladares-Salgado A, van Dam RM, van Klinken JB, Varma R, Wacher-Rodarte N, Wheeler E, Wickremasinghe AR, van Dijk KW, Witte DR, Yajnik CS, Yamamoto K, Yamamoto K, Yoon K, Yu C, Yuan JM, Yusuf S, Zawistowski M, Zhang L, Zheng W, Raffel LJ, Igase M, Ipp E, Redline S, Cho YS, Lind L, Province MA, Fornage M, Hanis CL, Ingelsson E, Zonderman AB, Psaty BM, Wang YX, Rotimi CN, Becker DM, Matsuda F, Liu Y, Yokota M, Kardia SLR, Peyser PA, Pankow JS, Engert JC, Bonnefond A, Froguel P, Wilson JG, Sheu WHH, Wu JY, Hayes MG, Ma RCW, Wong TY, Mook-Kanamori DO, Tuomi T, Chandak GR, Collins FS, Bharadwaj D, Paré G, Sale MM, Ahsan H, Motala AA, Shu XO, Park KS, Jukema JW, Cruz M, Chen YI, Rich SS, McKean-Cowdin R, Grallert H, Cheng CY, Ghanbari M, Tai ES, Dupuis J, Kato N, Laakso M, Köttgen A, Koh WP, Bowden DW, Palmer CNA, Kooner JS, Kooperberg C, Liu S, North KE, Saleheen D, Hansen T, Pedersen O, Wareham NJ, Lee J, Kim BJ, Millwood IY, Walters RG, Stefansson K, Ahlqvist E, Goodarzi MO, Mohlke KL, Langenberg C, Haiman CA, Loos RJF, Florez JC, Rader DJ, Ritchie MD, Zöllner S, Mägi R, Marston NA, Ruff CT, van Heel DA, Finer S, Denny JC, Yamauchi T, Kadowaki T, Chambers JC, Ng MCY, Sim X, Below JE, Tsao PS, Chang KM, McCarthy MI, Meigs JB, Mahajan A, Spracklen CN, Mercader JM, Boehnke M, Rotter JI, Vujkovic M, Voight BF, Morris AP, and Zeggini E
- Subjects
- Humans, Adipocytes metabolism, Chromatin genetics, Chromatin metabolism, Coronary Artery Disease complications, Coronary Artery Disease genetics, Diabetic Nephropathies complications, Diabetic Nephropathies genetics, Endothelial Cells metabolism, Enteroendocrine Cells, Epigenomics, Islets of Langerhans metabolism, Multifactorial Inheritance genetics, Peripheral Arterial Disease complications, Peripheral Arterial Disease genetics, Single-Cell Analysis, Diabetes Mellitus, Type 2 classification, Diabetes Mellitus, Type 2 complications, Diabetes Mellitus, Type 2 genetics, Diabetes Mellitus, Type 2 pathology, Diabetes Mellitus, Type 2 physiopathology, Disease Progression, Genetic Predisposition to Disease genetics, Genome-Wide Association Study
- Abstract
Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes
1,2 and molecular mechanisms that are often specific to cell type3,4 . Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10-8 ) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care., (© 2024. The Author(s).)- Published
- 2024
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11. Epicardial placement of human MSC-loaded fibrin sealant films for heart failure: Preclinical efficacy and mechanistic data.
- Author
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Fields L, Ito T, Kobayashi K, Ichihara Y, Podaru MN, Hussain M, Yamashita K, Machado V, Lewis-McDougall F, and Suzuki K
- Published
- 2024
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12. A CRISPR-Cas9-mediated versatile method for targeted integration of a fluorescent protein gene to visualize endogenous gene expression in Xenopus laevis.
- Author
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Mochii M, Akizuki K, Ossaka H, Kagawa N, Umesono Y, and Suzuki KT
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- Animals, Xenopus laevis genetics, Gene Expression, DNA, CRISPR-Cas Systems genetics, RNA, Guide, CRISPR-Cas Systems
- Abstract
Xenopus laevis is a widely used model organism in developmental and regeneration studies. Despite several reports regarding targeted integration techniques in Xenopus, there is still room for improvement of them, especially in creating reporter lines that rely on endogenous regulatory enhancers/promoters. We developed a CRISPR-Cas9-based simple method to efficiently introduce a fluorescent protein gene into 5' untranslated regions (5'UTRs) of target genes in Xenopus laevis. A donor plasmid DNA encoding an enhanced green fluorescent protein (eGFP) flanked by a genomic fragment ranging from 66 bp to 878 bp including target 5'UTR was co-injected into fertilized eggs with a single guide RNA and Cas9 protein. Injections for krt12.2.L, myod1.S, sox2.L or brevican.S resulted in embryos expressing eGFP fluorescence in a tissue-specific manner, recapitulating endogenous expression of target genes. Integrations of the donor DNA into the target regions were examined by genotyping PCR for the eGFP-expressing embryos. The rate of embryos expressing the specific eGFP varied from 2.1% to 13.2% depending on the target locus and length of the genomic fragment in the donor plasmids. Germline transmission of an integrated DNA was observed. This simple method provides a powerful tool for exploring gene expression and function in developmental and regeneration research in X. laevis., Competing Interests: Declaration of competing interest The authors declare no competing or financial interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2024
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13. Corrigendum to "Donor cell-type specific paracrine effects of cell transplantation for post-infarction heart failure" [J Mol Cell Cardiol 47 (2009) 288-295].
- Author
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Shintani Y, Fukushima S, Varela-Carver A, Lee J, Coppen SR, Takahashi K, Brouilette SW, Yashiro K, Terracciano CMN, Yacoub MH, and Suzuki K
- Published
- 2024
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14. [Safety and efficacy of 7-day administration of azacitidine and venetoclax combination therapy (7+7 therapy)].
- Author
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Osada Y, Kanai-Sudo H, Mizuki T, Tanosaki S, and Suzuki K
- Subjects
- Humans, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols adverse effects, Bridged Bicyclo Compounds, Heterocyclic adverse effects, Sulfonamides adverse effects, Azacitidine adverse effects, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute etiology
- Abstract
Acute myelogenous leukemia (AML) has a poor prognosis in patients who are ineligible for intensive chemotherapy. The combination of azacitidine and venetoclax has been shown to have high overall efficiency and remission rates, even in patients ineligible for aggressive chemotherapy. However, myelosuppression is often prolonged after treatment, and infection can also occur. Severe myelosuppression is often addressed by dose titration, but specific dose titration methods have not been clarified. We used the standard induction therapy with azacitidine plus venetoclax, and if blasts decreased to 20% or less, switched to 7+7 therapy to shorten venetoclax to 7 days starting from the next cycle. In the 19 patients we treated (median age 80 years), response rate above MLFS was 100%, CR 57.9%, CRc (CR+CRi) 78.8%, median OS 693 days, median PFS 458 days, and median OS was not reached in previously untreated patients. This indicates that 7+7 is a highly effective and well-tolerated treatment.
- Published
- 2024
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15. The uniaxial zero thermal expansion and zero linear compressibility in distorted Prussian blue analogue RbCuCo(CN) 6 .
- Author
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Wang L, Sun YN, Wei XD, Yin M, Chen Y, Miura H, Suzuki K, and Wang C
- Abstract
The uniaxial zero thermal expansion (ZTE) in distorted Prussian blue analogue (PBA) RbCuCo(CN)
6 is reproduced by employing first-principles calculations, which agrees well with the experimental data. Also, the zero linear compressibility (ZLC) behavior in RbCuCo(CN)6 can be found. The special Jahn-Teller distortion introduced by Cu2+ in RbCuCo(CN)6 is noticed by investigating the change of the local structure with temperature and hydrostatic pressure. The lattice thermal conductivity (LTC) and phonon group velocity of RbCuCo(CN)6 are studied, where the LTC and phonon group velocity are significantly anisotropic. Especially, RbCuCo(CN)6 exhibits a quite low LTC, and its c -axis shows a characteristic of glasslike LTC at low temperatures. Our work facilitates a deep understanding of the coexistence mechanisms of uniaxial ZTE and ZLC properties in RbCuCo(CN)6 .- Published
- 2023
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16. Medical advice lines offering on-demand access to providers reduced emergency department visits.
- Author
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Tran LD, Rose L, Suzuki K, Urech T, and Vashi A
- Abstract
Instant access to clinicians through virtual care is designed to allow patients to receive care they need while avoiding high-cost visits in acute-care settings. This study investigates the effect of offering patients the option to instantly connect with emergency care providers instead of being referred to the emergency department (ED) following calls to a medical advice line. We used a staggered rollout design to assess the effects of implementing this program on key outcomes among Veterans Affairs enrollees. Analyzing over 1 million calls from 2019 to 2022, we found that access to a provider reduced the proportion of patients who subsequently visited the ED compared with those with access to the standard medical advice line (38% vs 36%). There was no significant difference observed in subsequent inpatient admissions or 30-day mortality. We found that a majority of callers (65%) achieved issue resolution or were directed to lower acuity settings for further evaluation. Although substantial direct cost savings were not evident, our findings demonstrate that on-demand access to a virtual provider can effectively decrease ED visits., Competing Interests: Conflicts of interest Please see ICMJE form(s) for author conflicts of interest. These have been provided as supplementary materials., (Published by Oxford University Press on behalf of Project HOPE - The People-To-People Health Foundation, Inc. 2023.)
- Published
- 2023
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17. [A Case of Single Hole Ileal Resection for Ascendiry Colon Cancer with Ureterocutaneous Fistula in the Right Lower Abdomen].
- Author
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Hayashi N, Nishizawa Y, Kagawa Y, Inoue A, Kawabe Y, Sindo M, Suzuki K, Nakanishi M, Komatsu H, Hirota M, Miyazaki Y, Tomokuni A, Motoori M, Iwase K, and Fujitani K
- Subjects
- Female, Humans, Abdomen pathology, Biopsy, Colon, Ascending surgery, Aged, Colonic Neoplasms surgery, Fistula surgery, Laparoscopy
- Abstract
The patient is a 70s woman. She underwent cystectomy for bladder cancer 6 years ago and had a ureterocutaneous fistula in the right lower abdomen. After colonoscopy for positive fecal occult blood, a type 1 elevated lesion was found in the ascending colon, which was diagnosed as a well-differentiated adenocarcinoma on biopsy. Surgery was performed with a single hole. The approach from the right lower abdomen, where the ureterocutaneous fistula and ureter are located, was avoided, and the approach from the hepatic flexure of the transverse colon was used first. After the right colon was mobilized, the large mesh adhesions around the ureter were carefully dissected, and the right ureter was identified and preserved, extending from the lateral ascending colon to the abdominal wall. The ileal artery was dissected at the root and after dissection of the D3 lymph node, the intestine was dissected and anastomosed extracorporeally. The operative time was 246 minutes with small amount of blood loss. The patient was discharged on the 6th postoperative day without any postoperative complications. The pathology result was pT3N0M0, pStage Ⅱa, and radical resection had been performed. The patient is currently undergoing recurrence-free follow-up.
- Published
- 2023
18. [A Case of Conversion Surgery after Chemotherapy for Locally Advanced Unresectable Rectal Cancer].
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Kawabe Y, Inoue A, Kagawa Y, Nishizawa Y, Ozato Y, Hayashi N, Shindo M, Suzuki K, Komatsu H, Hirota M, Miyazaki Y, Tomokuni A, Motoori M, Iwase K, and Fujitani K
- Subjects
- Female, Humans, Aged, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Neoplasm Recurrence, Local surgery, Chemotherapy, Adjuvant, Rectal Neoplasms drug therapy, Rectal Neoplasms surgery, Rectal Neoplasms pathology, Laparoscopy
- Abstract
We report a case of locally advanced rectal cancer that could not be curatively resected, in which the patient underwent conversion surgery after chemotherapy. The patient is a 70-year-old woman. She came to our hospital with a chief complaint of lower abdominal pain, and a close examination revealed rectal cancer with invasion of the external iliac artery and pelvic wall. She was treated with mFOLFOX6 plus cetuximab for locally advanced rectal cancer that was not amenable to surgical resection. After 11 courses of chemotherapy, significant shrinkage of the tumor was observed, and robot assisted laparoscopic high-anterior resection was performed. The patient didn't relapse at 12 months after surgery without adjuvant chemotherapy.
- Published
- 2023
19. GFRA2 Identifies Cardiac Progenitors and Mediates Cardiomyocyte Differentiation in a RET-Independent Signaling Pathway.
- Author
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Ishida H, Saba R, Kokkinopoulos I, Hashimoto M, Yamaguchi O, Nowotschin S, Shiraishi M, Ruchaya P, Miller D, Harmer S, Poliandri A, Kogaki S, Sakata Y, Dunkel L, Tinker A, Hadjantonakis AK, Sawa Y, Sasaki H, Ozono K, Suzuki K, and Yashiro K
- Published
- 2023
- Full Text
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20. Protocols for transgenesis at a safe harbor site in the Xenopus laevis genome using CRISPR-Cas9.
- Author
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Shibata Y, Okumura A, Mochii M, and Suzuki KT
- Subjects
- Animals, Xenopus laevis genetics, Gene Transfer Techniques, Transgenes, CRISPR-Cas Systems genetics, RNA, Guide, CRISPR-Cas Systems
- Abstract
We have established a new transgenesis protocol based on CRISPR-Cas9, "New and Easy XenopusTransgenesis (NEXTrans)," and identified a novel safe harbor site in African clawed frogs, Xenopus laevis. We describe steps in detail for the construction of NEXTrans plasmid and guide RNA, CRISPR-Cas9-mediated NEXTrans plasmid integration into the locus, and its validation by genomic PCR. This improved strategy allows us to simply generate transgenic animals that stably express the transgene. For complete details on the use and execution of this protocol, please refer to Shibata et al. (2022).
1 ., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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21. Genome-Wide Association Study of Intracranial Artery Stenosis Followed by Phenome-Wide Association Study.
- Author
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Dofuku S, Sonehara K, Miyawaki S, Sakaue S, Imai H, Shimizu M, Hongo H, Shinya Y, Ohara K, Teranishi Y, Okano A, Ono H, Nakatomi H, Teraoka A, Yamamoto K, Maeda Y, Nii T, Kishikawa T, Suzuki K, Hirata J, Takahashi M, Matsuda K, Kumanogoh A, Matsuda F, Okada Y, and Saito N
- Subjects
- Humans, Genetic Predisposition to Disease genetics, Constriction, Pathologic genetics, Polymorphism, Single Nucleotide genetics, Arteries, Adenosine Triphosphatases genetics, Ubiquitin-Protein Ligases genetics, Genome-Wide Association Study, Vascular Diseases
- Abstract
The genetic background of intracranial artery stenosis (ICAS), a major cause of ischemic stroke, remains elusive. We performed the world's first genome-wide association study (GWAS) of ICAS using DNA samples from Japanese subjects, to identify the genetic factors associated with ICAS and their correlation with clinical features. We also conducted a phenome-wide association study (PheWAS) of the top variant identified via GWAS to determine its association with systemic disease. The GWAS involved 408 patients with ICAS and 349 healthy controls and utilized an Asian Screening Array of venous blood samples. The PheWAS was performed using genotypic and phenotypic data of the Biobank Japan Project, which contained information on 46 diseases and 60 quantitative trait data from > 150,000 Japanese individuals. The GWAS revealed that the East Asian-specific functional variant of RNF213, rs112735431 (c.14429G > A, p.Arg4810Lys), was associated with ICAS (odds ratio, 12.3; 95% CI 5.5 to 27.5; P = 7.8 × 10
-10 ). Stratified analysis within ICAS cases demonstrated that clinical features of those with and without the risk allele were different. PheWAS indicated that high blood pressure and angina were significantly associated with RNF213 rs112735431. The first GWAS of ICAS, which stratifies subpopulations within the ICAS cases with distinct clinical features, revealed that RNF213 rs112735431 was the most significant variant associated with ICAS. Thus, RNF213 rs112735431 shows potential as an important clinical biomarker that characterizes pleiotropic risk in various vascular diseases, such as blood pressure and angina, thereby facilitating personalized medicine for systemic vascular diseases in East Asian populations., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)- Published
- 2023
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22. Effect of mechanical tension on fibroblast transcriptome profile and regulatory mechanisms of myocardial collagen turnover.
- Author
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Shiraishi M, Suzuki K, and Yamaguchi A
- Subjects
- Humans, Silicone Gels, Myocardium, Collagen, Fibroblasts, Transcriptome, Heart Failure
- Abstract
Excess deposition of extracellular matrix in the myocardium is a predictor of reduced left ventricular function. Although reducing the hemodynamic load is known to improve myocardial fibrosis, the mechanisms underlying the reversal of the fibrosis have not been elucidated. We focused on the elasticity of myocardial tissue, which is assumed to influence the fibroblast phenotype. Normal and fibrotic myocardium were cultured in 16 kPa and 64 kPa silicone gel-coated dishes supplemented with recombinant TGFβ protein, respectively. Matrix-degrading myocardium was cultured in 64 kPa silicone gel-coated dishes with recombinant TGFβ protein and then in 16 kPa silicone gel-coated dishes. Cardiac fibroblasts were cultured in this three-part in vitro pathological models and compared. Fibroblasts differentiated into activated or matrix-degrading types in response to the pericellular environment. Comprehensive gene expression analysis of fibroblasts in each in vitro condition showed Selenbp1 to be one of the genes responsible for regulating differentiation of fibroblasts. In vitro knockdown of Selenbp1 enhanced fibroblast activation and inhibited conversion to the matrix-degrading form. In vivo knockdown of Selenbp1 resulted in structural changes in the left ventricle associated with progressive tissue fibrosis and left ventricular diastolic failure. Selenbp1 is involved in regulating fibroblast differentiation and appears to be one of the major molecules regulating collagen turnover in cardiac fibrosis., (© 2023 Federation of American Societies for Experimental Biology.)
- Published
- 2023
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23. Multi-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications.
- Author
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Suzuki K, Hatzikotoulas K, Southam L, Taylor HJ, Yin X, Lorenz KM, Mandla R, Huerta-Chagoya A, Rayner NW, Bocher O, Arruda ALSV, Sonehara K, Namba S, Lee SSK, Preuss MH, Petty LE, Schroeder P, Vanderwerff B, Kals M, Bragg F, Lin K, Guo X, Zhang W, Yao J, Kim YJ, Graff M, Takeuchi F, Nano J, Lamri A, Nakatochi M, Moon S, Scott RA, Cook JP, Lee JJ, Pan I, Taliun D, Parra EJ, Chai JF, Bielak LF, Tabara Y, Hai Y, Thorleifsson G, Grarup N, Sofer T, Wuttke M, Sarnowski C, Gieger C, Nousome D, Trompet S, Kwak SH, Long J, Sun M, Tong L, Chen WM, Nongmaithem SS, Noordam R, Lim VJY, Tam CHT, Joo YY, Chen CH, Raffield LM, Prins BP, Nicolas A, Yanek LR, Chen G, Brody JA, Kabagambe E, An P, Xiang AH, Choi HS, Cade BE, Tan J, Broadaway KA, Williamson A, Kamali Z, Cui J, Adair LS, Adeyemo A, Aguilar-Salinas CA, Ahluwalia TS, Anand SS, Bertoni A, Bork-Jensen J, Brandslund I, Buchanan TA, Burant CF, Butterworth AS, Canouil M, Chan JCN, Chang LC, Chee ML, Chen J, Chen SH, Chen YT, Chen Z, Chuang LM, Cushman M, Danesh J, Das SK, de Silva HJ, Dedoussis G, Dimitrov L, Doumatey AP, Du S, Duan Q, Eckardt KU, Emery LS, Evans DS, Evans MK, Fischer K, Floyd JS, Ford I, Franco OH, Frayling TM, Freedman BI, Genter P, Gerstein HC, Giedraitis V, González-Villalpando C, González-Villalpando ME, Gordon-Larsen P, Gross M, Guare LA, Hackinger S, Han S, Hattersley AT, Herder C, Horikoshi M, Howard AG, Hsueh W, Huang M, Huang W, Hung YJ, Hwang MY, Hwu CM, Ichihara S, Ikram MA, Ingelsson M, Islam MT, Isono M, Jang HM, Jasmine F, Jiang G, Jonas JB, Jørgensen T, Kandeel FR, Kasturiratne A, Katsuya T, Kaur V, Kawaguchi T, Keaton JM, Kho AN, Khor CC, Kibriya MG, Kim DH, Kronenberg F, Kuusisto J, Läll K, Lange LA, Lee KM, Lee MS, Lee NR, Leong A, Li L, Li Y, Li-Gao R, Lithgart S, Lindgren CM, Linneberg A, Liu CT, Liu J, Locke AE, Louie T, Luan J, Luk AO, Luo X, Lv J, Lynch JA, Lyssenko V, Maeda S, Mamakou V, Mansuri SR, Matsuda K, Meitinger T, Metspalu A, Mo H, Morris AD, Nadler JL, Nalls MA, Nayak U, Ntalla I, Okada Y, Orozco L, Patel SR, Patil S, Pei P, Pereira MA, Peters A, Pirie FJ, Polikowsky HG, Porneala B, Prasad G, Rasmussen-Torvik LJ, Reiner AP, Roden M, Rohde R, Roll K, Sabanayagam C, Sandow K, Sankareswaran A, Sattar N, Schönherr S, Shahriar M, Shen B, Shi J, Shin DM, Shojima N, Smith JA, So WY, Stančáková A, Steinthorsdottir V, Stilp AM, Strauch K, Taylor KD, Thorand B, Thorsteinsdottir U, Tomlinson B, Tran TC, Tsai FJ, Tuomilehto J, Tusie-Luna T, Udler MS, Valladares-Salgado A, van Dam RM, van Klinken JB, Varma R, Wacher-Rodarte N, Wheeler E, Wickremasinghe AR, van Dijk KW, Witte DR, Yajnik CS, Yamamoto K, Yamamoto K, Yoon K, Yu C, Yuan JM, Yusuf S, Zawistowski M, Zhang L, Zheng W, Raffel LJ, Igase M, Ipp E, Redline S, Cho YS, Lind L, Province MA, Fornage M, Hanis CL, Ingelsson E, Zonderman AB, Psaty BM, Wang YX, Rotimi CN, Becker DM, Matsuda F, Liu Y, Yokota M, Kardia SLR, Peyser PA, Pankow JS, Engert JC, Bonnefond A, Froguel P, Wilson JG, Sheu WHH, Wu JY, Hayes MG, Ma RCW, Wong TY, Mook-Kanamori DO, Tuomi T, Chandak GR, Collins FS, Bharadwaj D, Paré G, Sale MM, Ahsan H, Motala AA, Shu XO, Park KS, Jukema JW, Cruz M, Chen YI, Rich SS, McKean-Cowdin R, Grallert H, Cheng CY, Ghanbari M, Tai ES, Dupuis J, Kato N, Laakso M, Köttgen A, Koh WP, Bowden DW, Palmer CNA, Kooner JS, Kooperberg C, Liu S, North KE, Saleheen D, Hansen T, Pedersen O, Wareham NJ, Lee J, Kim BJ, Millwood IY, Walters RG, Stefansson K, Goodarzi MO, Mohlke KL, Langenberg C, Haiman CA, Loos RJF, Florez JC, Rader DJ, Ritchie MD, Zöllner S, Mägi R, Denny JC, Yamauchi T, Kadowaki T, Chambers JC, Ng MCY, Sim X, Below JE, Tsao PS, Chang KM, McCarthy MI, Meigs JB, Mahajan A, Spracklen CN, Mercader JM, Boehnke M, Rotter JI, Vujkovic M, Voight BF, Morris AP, and Zeggini E
- Abstract
Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7% non-European ancestry), including 428,452 T2D cases. We identify 1,289 independent association signals at genome-wide significance ( P <5×10
-8 ) that map to 611 loci, of which 145 loci are previously unreported. We define eight non-overlapping clusters of T2D signals characterised by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial, and enteroendocrine cells. We build cluster-specific partitioned genetic risk scores (GRS) in an additional 137,559 individuals of diverse ancestry, including 10,159 T2D cases, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned GRS are more strongly associated with coronary artery disease and end-stage diabetic nephropathy than an overall T2D GRS across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings demonstrate the value of integrating multi-ancestry GWAS with single-cell epigenomics to disentangle the aetiological heterogeneity driving the development and progression of T2D, which may offer a route to optimise global access to genetically-informed diabetes care., Competing Interests: R.A.S. is now an employee of GlaxoSmithKline. G.T. is an employee of deCODE genetics/Amgen Inc. A.S.B. reports institutional grants from AstraZeneca, Bayer, Biogen, BioMarin, Bioverativ, Novartis, Regeneron and Sanofi. J.Danesh serves on scientific advisory boards for AstraZeneca, Novartis, and UK Biobank, and has received multiple grants from academic, charitable and industry sources outside of the submitted work. L.S.E. is now an employee of Bristol Myers Squibb. J.S.F. has consulted for Shionogi Inc. T.M.F. has consulted for Sanofi, Boehringer Ingelheim, and received funding from GlaxoSmithKline. H.C.G. holds the McMaster-Sanofi Population Health Institute Chair in Diabetes Research and Care; reports research grants from Eli Lilly, AstraZeneca, Merck, Novo Nordisk and Sanofi; honoraria for speaking from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, DKSH, Zuellig, Roche, and Sanofi; and consulting fees from Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck, Novo Nordisk, Pfizer, Sanofi, Kowa and Hanmi.lth Institute Chair in Diabetes Research and Care; reports research grants from Eli Lilly, AstraZeneca, Merck, Novo Nordisk and Sanofi; honoraria for speaking from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Sanofi; and consulting fees from Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck, Novo Nordisk, Janssen, Sanofi, and Kowa. M.Ingelsson is a paid consultant to BioArctic AB. R.L.-G. is a part-time consultant of Metabolon Inc. A.E.L. is now an employee of Regeneron Genetics Center LLC and holds shares in Regeneron Pharmaceuticals. M.A.N. currently serves on the scientific advisory board for Clover Therapeutics and is an advisor to Neuron23 Inc. S.R.P. has received grant funding from Bayer Pharmaceuticals, Philips Respironics and Respicardia. N.Sattar has consulted for or been on speakers bureau for Abbott, Amgen, Astrazeneca, Boehringer Ingelheim, Eli Lilly, Hanmi, Novartis, Novo Nordisk, Sanofi and Pfizer and has received grant funding from Astrazeneca, Boehringer Ingelheim, Novartis and Roche Diagnostics. V.S. is now an employee of deCODE genetics/Amgen Inc. A.M.S. receives funding from Seven Bridges Genomics to develop tools for the NHLBI BioData Catalyst consortium. U.T. is an employee of deCODE genetics/Amgen Inc. E.Ingelsson is now an employee of GlaxoSmithKline. B.M.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. R.C.W.M. reports research funding from AstraZeneca, Bayer, Novo Nordisk, Pfizer, Tricida Inc. and Sanofi, and has consulted for or received speakers fees from AstraZeneca, Bayer, Boehringer Ingelheim, all of which have been donated to the Chinese University of Hong Kong to support diabetes research. D.O.M.-K. is a part-time clinical research consultant for Metabolon Inc. S.Liu reports consulting payments and honoraria or promises of the same for scientific presentations or reviews at numerous venues, including but not limited to Barilla, by-Health Inc, Ausa Pharmed Co.LTD, Fred Hutchinson Cancer Center, Harvard University, University of Buffalo, Guangdong General Hospital and Academy of Medical Sciences, Consulting member for Novo Nordisk, Inc; member of the Data Safety and Monitoring Board for a trial of pulmonary hypertension in diabetes patients at Massachusetts General Hospital; receives royalties from UpToDate; receives an honorarium from the American Society for Nutrition for his duties as Associate Editor. K.Stefansson is an employee of deCODE genetics/Amgen Inc. M.I.M. has served on advisory panels for Pfizer, NovoNordisk and Zoe Global, has received honoraria from Merck, Pfizer, Novo Nordisk and Eli Lilly, and research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Roche, Sanofi Aventis, Servier, and Takeda; and is now an employee of Genentech and a holder of Roche stock. J.B.M. is an Academic Associate for Quest Diagnostics R&D. A.Mahajan is an employee of Genentech, and a holder of Roche stock.- Published
- 2023
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24. Improvement in Processability for Injection Molding of Bisphenol-A Polycarbonate by Addition of Low-Density Polyethylene.
- Author
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Kuroda Y, Suzuki KI, Kikuchi G, Moonprasith N, Kida T, and Yamaguchi M
- Abstract
The rheological properties and processability at injection molding were studied for bisphenol-A polycarbonate (PC) that was modified by low-density polyethylene (LDPE) having a low shear viscosity. The LDPE addition significantly decreased the steady-state shear viscosity, especially in the high shear rate region. The decrease did not originate from slippage on the die wall but due to interfacial slippage between the PC and dispersed LDPE droplets that deformed to the flow direction to a great extent. As a result of the viscosity decrease, injection pressure largely decreased from 150 to 110 MPa with the addition only 5 wt.% of LDPE. The enhanced flowability also reduced the warpage of the molded product significantly, demonstrating that the processability at injection molding was improved by the addition of LDPE.
- Published
- 2023
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25. Identification of serum metabolome signatures associated with retinal and renal complications of type 2 diabetes.
- Author
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Tomofuji Y, Suzuki K, Kishikawa T, Shojima N, Hosoe J, Inagaki K, Matsubayashi S, Ishihara H, Watada H, Ishigaki Y, Inohara H, Murakami Y, Matsuda K, Okada Y, Yamauchi T, and Kadowaki T
- Abstract
Background: Type 2 diabetes is a common disease around the world and its major complications are diabetic retinopathy (DR) and diabetic kidney disease (DKD). Persons with type 2 diabetes with complications, especially who have both DR and DKD, have poorer prognoses than those without complications. Therefore, prevention and early identification of the complications of type 2 diabetes are necessary to improve the prognosis of persons with type 2 diabetes. The aim of this study is to identify factors associated with the development of multiple complications of type 2 diabetes., Methods: We profiled serum metabolites of persons with type 2 diabetes with both DR and DKD (N = 141) and without complications (N = 159) using a comprehensive non-targeted metabolomics approach with mass spectrometry. Based on the serum metabolite profiles, case-control comparisons and metabolite set enrichment analysis (MSEA) were performed., Results: Here we show that five metabolites (cyclohexylamine, P = 4.5 × 10
-6 ; 1,2-distearoyl-glycero-3-phosphocholine, P = 7.3 × 10-6 ; piperidine, P = 4.8 × 10-4 ; N-acetylneuraminic acid, P = 5.1 × 10-4 ; stearoyl ethanolamide, P = 6.8 × 10-4 ) are significantly increased in those with the complications. MSEA identifies fatty acid biosynthesis as the type 2 diabetes complications-associated biological pathway (P = 0.0020)., Conclusions: Our metabolome analysis identifies the serum metabolite features of the persons with type 2 diabetes with multiple complications, which could potentially be used as biomarkers., (© 2023. The Author(s).)- Published
- 2023
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26. Usefulness of HbA1c Measurements by HPLC- and Immuno-Assay for Screening Unstable Hemoglobinopathy.
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Wakuta N, Matsubayashi T, Oba K, Nakashima H, Suzuki K, Okumiya T, Ishibashi M, and Koga M
- Subjects
- Humans, Glycated Hemoglobin, Chromatography, High Pressure Liquid methods, Immunoassay, Hemoglobinopathies diagnosis, Anemia, Hemolytic, Congenital
- Abstract
Objective: Unstable hemoglobinopathy (UH), red blood cell membrane disease (MD), and red blood cell enzymopathy are known as major congenital hemolytic anemias. Specialized examinations are needed for their differential diagnosis. We hypothesized that simultaneous measurements of HbA1c levels using high-performance liquid chromatography (HPLC) by fast mode (FM) and immunoassay [HPLC (FM)-HbA1c and IA-HbA1c, respectively] are useful for the differential diagnosis of UH from other congenital hemolytic anemias and verified this hypothesis in this study., Methods: HPLC (FM)-HbA1c and IA-HbA1c levels were simultaneously measured in 5 variant hemoglobinopathy (VH) patients with β-chain heterozygous mutation, 8 MD patients, 6 UH patients, and 10 healthy controls. None of the patients had diabetes mellitus., Results: In VH patients, HPLC-HbA1c levels were low, whereas IA-HbA1c levels were within the reference range. In MD patients, HPLC-HbA1c and IA-HbA1c levels were similarly low. In UH patients, both HPLC-HbA1c and IA-HbA1c levels were low, but HPLC-HbA1c levels were significantly lower than IA-HbA1c levels. The HPLC-HbA1c/IA-HbA1c ratio was 90% or more in all MD patients and control subjects. This ratio was, however, less than 90% in all VH patients and UH patients., Conclusion: The HPLC (FM)-HbA1c/IA-HbA1c ratio calculated using simultaneous measurements of HPLC (FM)-HbA1c and IA-HbA1c levels is useful for the differential diagnosis of VH, MD, and UH., (© 2023 by the Association of Clinical Scientists, Inc.)
- Published
- 2023
27. CRISPR-Cas9-Based Functional Analysis in Amphibians: Xenopus laevis, Xenopus tropicalis, and Pleurodeles waltl.
- Author
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Suzuki M, Iida M, Hayashi T, and Suzuki KT
- Subjects
- Animals, Humans, Xenopus laevis genetics, Xenopus genetics, Gene Editing methods, CRISPR-Cas Systems genetics, Pleurodeles genetics
- Abstract
Amphibians have made many fundamental contributions to our knowledge, from basic biology to biomedical research on human diseases. Current genome editing tools based on the CRISPR-Cas system enable us to perform gene functional analysis in vivo, even in non-model organisms. We introduce here a highly efficient and easy protocol for gene knockout, which can be used in three different amphibians seamlessly: Xenopus laevis, Xenopus tropicalis, and Pleurodeles waltl. As it utilizes Cas9 ribonucleoprotein complex (RNP) for injection, this cloning-free method enables researchers to obtain founder embryos with a nearly complete knockout phenotype within a week. To evaluate somatic mutation rate and its correlation to the phenotype of a Cas9 RNP-injected embryo (crispant), we also present accurate and cost-effective genotyping methods using pooled amplicon-sequencing and a user-friendly web-based tool., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2023
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28. North-to-South diversity of lipomycetaceous yeasts in soils evaluated with a cultivation-based approach from 11 locations in Japan.
- Author
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Yamazaki A, Lorliam W, Uchino M, Suzuki KI, and Kawasaki H
- Abstract
To understand the species distribution, diversity, and density of lipomycetaceous yeasts in soil based on their north-to-south location in Japan, 1146 strains were isolated from soil samples at 11 locations from Hokkaido to Okinawa Prefecture and taxonomically characterized. Lipomycetaceous yeast strains were isolated efficiently from soil by selecting watery mucoid-like colonies on agar plates with nitrogen-depleted medium. Twenty-four (80%) of the 30 known species of the genus Lipomyces were isolated from the soil samples collected in Japan, including species recently proposed. Among the species isolated, L. starkeyi was the most predominant in Japan, except on Iriomote Island, Okinawa, and accounted for 60-98% of the isolated strains. Lipomyces yarrowii was the dominant species on Iriomote Island (64%). The second most dominant species were L. chichibuensis in Saitama Prefecture and L. doorenjongii from Yamaguchi to Okinawa Prefecture. The species diversity of lipomycetaceous yeasts was in Japan and the significant correlation with the latitude of the sampling sites was revealed., (2023, by The Mycological Society of Japan.)
- Published
- 2022
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29. Penta-graphene and phagraphene: thermal expansion, linear compressibility, and Poisson's ratio.
- Author
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Wang L, Chen Y, Miura H, Suzuki K, and Wang C
- Abstract
Nonplanar penta-graphene and planar phagraphene, which are connected by carbon pentagons and penta-hexa-hepta carbon rings, respectively, are two allotropes of graphene. Graphene as a star material in two-dimensional materials has been widely studied. However, the studies around penta-graphene and phagraphene are still insufficient. We are interested in both materials' response to temperature, hydrostatic pressure, and stress. In this work, the thermal expansion, linear compressibility, and Poisson's ratio of penta-graphene and phagraphene have been investigated systematically. It is found that both materials can exhibit abnormal negative thermal expansion behavior, while their linear compressibility behavior is normal. The negative Poisson's ratio behavior only occurs in penta-graphene, which is consistent with other work. Through an analysis of the lattice vibrations and associated mode Grüneisen parameters, it is found that there are anomalies in the phonon spectra of both penta-graphene and phagraphene. It is noted that acoustic phonons contribute most to their respective anomalies, especially the transverse acoustic mode. The librational motion of the lowest-frequency optical phonon of both materials is identified and also associated with their novel properties. In general, the unique topological arrangement of carbon atoms can play a decisive role in determining the performances of penta-graphene and phagraphene., (© 2022 IOP Publishing Ltd.)
- Published
- 2022
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30. CRISPR/Cas9-based simple transgenesis in Xenopus laevis.
- Author
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Shibata Y, Suzuki M, Hirose N, Takayama A, Sanbo C, Inoue T, Umesono Y, Agata K, Ueno N, Suzuki KT, and Mochii M
- Subjects
- Animals, Animals, Genetically Modified, Ribonucleoproteins genetics, Transgenes, Xenopus laevis genetics, CRISPR-Cas Systems genetics, Gene Transfer Techniques
- Abstract
Transgenic techniques have greatly increased our understanding of the transcriptional regulation of target genes through live reporter imaging, as well as the spatiotemporal function of a gene using loss- and gain-of-function constructs. In Xenopus species, two well-established transgenic methods, restriction enzyme-mediated integration and I-SceI meganuclease-mediated transgenesis, have been used to generate transgenic animals. However, donor plasmids are randomly integrated into the Xenopus genome in both methods. Here, we established a new and simple targeted transgenesis technique based on CRISPR/Cas9 in Xenopus laevis. In this method, Cas9 ribonucleoprotein (RNP) targeting a putative harbor site (the transforming growth factor beta receptor 2-like (tgfbr2l) locus) and a preset donor plasmid DNA were co-injected into the one-cell stage embryos of X. laevis. Approximately 10% of faithful reporter expression was detected in F0 crispants in a promoter/enhancer-specific manner. Importantly, efficient germline transmission and stable transgene expression were observed in the F1 offspring. The simplicity of this method only required preparation of a donor vector containing the tgfbr2l genome fragment and Cas9 RNP targeting this site, which are common experimental procedures used in Xenopus laboratories. Our improved technique allows the simple generation of transgenic X. laevis, so is expected to become a powerful tool for reporter assay and gene function analysis., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)
- Published
- 2022
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31. DOCK2 is involved in the host genetics and biology of severe COVID-19.
- Author
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Namkoong H, Edahiro R, Takano T, Nishihara H, Shirai Y, Sonehara K, Tanaka H, Azekawa S, Mikami Y, Lee H, Hasegawa T, Okudela K, Okuzaki D, Motooka D, Kanai M, Naito T, Yamamoto K, Wang QS, Saiki R, Ishihara R, Matsubara Y, Hamamoto J, Hayashi H, Yoshimura Y, Tachikawa N, Yanagita E, Hyugaji T, Shimizu E, Katayama K, Kato Y, Morita T, Takahashi K, Harada N, Naito T, Hiki M, Matsushita Y, Takagi H, Aoki R, Nakamura A, Harada S, Sasano H, Kabata H, Masaki K, Kamata H, Ikemura S, Chubachi S, Okamori S, Terai H, Morita A, Asakura T, Sasaki J, Morisaki H, Uwamino Y, Nanki K, Uchida S, Uno S, Nishimura T, Ishiguro T, Isono T, Shibata S, Matsui Y, Hosoda C, Takano K, Nishida T, Kobayashi Y, Takaku Y, Takayanagi N, Ueda S, Tada A, Miyawaki M, Yamamoto M, Yoshida E, Hayashi R, Nagasaka T, Arai S, Kaneko Y, Sasaki K, Tagaya E, Kawana M, Arimura K, Takahashi K, Anzai T, Ito S, Endo A, Uchimura Y, Miyazaki Y, Honda T, Tateishi T, Tohda S, Ichimura N, Sonobe K, Sassa CT, Nakajima J, Nakano Y, Nakajima Y, Anan R, Arai R, Kurihara Y, Harada Y, Nishio K, Ueda T, Azuma M, Saito R, Sado T, Miyazaki Y, Sato R, Haruta Y, Nagasaki T, Yasui Y, Hasegawa Y, Mutoh Y, Kimura T, Sato T, Takei R, Hagimoto S, Noguchi Y, Yamano Y, Sasano H, Ota S, Nakamori Y, Yoshiya K, Saito F, Yoshihara T, Wada D, Iwamura H, Kanayama S, Maruyama S, Yoshiyama T, Ohta K, Kokuto H, Ogata H, Tanaka Y, Arakawa K, Shimoda M, Osawa T, Tateno H, Hase I, Yoshida S, Suzuki S, Kawada M, Horinouchi H, Saito F, Mitamura K, Hagihara M, Ochi J, Uchida T, Baba R, Arai D, Ogura T, Takahashi H, Hagiwara S, Nagao G, Konishi S, Nakachi I, Murakami K, Yamada M, Sugiura H, Sano H, Matsumoto S, Kimura N, Ono Y, Baba H, Suzuki Y, Nakayama S, Masuzawa K, Namba S, Suzuki K, Naito Y, Liu YC, Takuwa A, Sugihara F, Wing JB, Sakakibara S, Hizawa N, Shiroyama T, Miyawaki S, Kawamura Y, Nakayama A, Matsuo H, Maeda Y, Nii T, Noda Y, Niitsu T, Adachi Y, Enomoto T, Amiya S, Hara R, Yamaguchi Y, Murakami T, Kuge T, Matsumoto K, Yamamoto Y, Yamamoto M, Yoneda M, Kishikawa T, Yamada S, Kawabata S, Kijima N, Takagaki M, Sasa N, Ueno Y, Suzuki M, Takemoto N, Eguchi H, Fukusumi T, Imai T, Fukushima M, Kishima H, Inohara H, Tomono K, Kato K, Takahashi M, Matsuda F, Hirata H, Takeda Y, Koh H, Manabe T, Funatsu Y, Ito F, Fukui T, Shinozuka K, Kohashi S, Miyazaki M, Shoko T, Kojima M, Adachi T, Ishikawa M, Takahashi K, Inoue T, Hirano T, Kobayashi K, Takaoka H, Watanabe K, Miyazawa N, Kimura Y, Sado R, Sugimoto H, Kamiya A, Kuwahara N, Fujiwara A, Matsunaga T, Sato Y, Okada T, Hirai Y, Kawashima H, Narita A, Niwa K, Sekikawa Y, Nishi K, Nishitsuji M, Tani M, Suzuki J, Nakatsumi H, Ogura T, Kitamura H, Hagiwara E, Murohashi K, Okabayashi H, Mochimaru T, Nukaga S, Satomi R, Oyamada Y, Mori N, Baba T, Fukui Y, Odate M, Mashimo S, Makino Y, Yagi K, Hashiguchi M, Kagyo J, Shiomi T, Fuke S, Saito H, Tsuchida T, Fujitani S, Takita M, Morikawa D, Yoshida T, Izumo T, Inomata M, Kuse N, Awano N, Tone M, Ito A, Nakamura Y, Hoshino K, Maruyama J, Ishikura H, Takata T, Odani T, Amishima M, Hattori T, Shichinohe Y, Kagaya T, Kita T, Ohta K, Sakagami S, Koshida K, Hayashi K, Shimizu T, Kozu Y, Hiranuma H, Gon Y, Izumi N, Nagata K, Ueda K, Taki R, Hanada S, Kawamura K, Ichikado K, Nishiyama K, Muranaka H, Nakamura K, Hashimoto N, Wakahara K, Sakamoto K, Omote N, Ando A, Kodama N, Kaneyama Y, Maeda S, Kuraki T, Matsumoto T, Yokote K, Nakada TA, Abe R, Oshima T, Shimada T, Harada M, Takahashi T, Ono H, Sakurai T, Shibusawa T, Kimizuka Y, Kawana A, Sano T, Watanabe C, Suematsu R, Sageshima H, Yoshifuji A, Ito K, Takahashi S, Ishioka K, Nakamura M, Masuda M, Wakabayashi A, Watanabe H, Ueda S, Nishikawa M, Chihara Y, Takeuchi M, Onoi K, Shinozuka J, Sueyoshi A, Nagasaki Y, Okamoto M, Ishihara S, Shimo M, Tokunaga Y, Kusaka Y, Ohba T, Isogai S, Ogawa A, Inoue T, Fukuyama S, Eriguchi Y, Yonekawa A, Kan-O K, Matsumoto K, Kanaoka K, Ihara S, Komuta K, Inoue Y, Chiba S, Yamagata K, Hiramatsu Y, Kai H, Asano K, Oguma T, Ito Y, Hashimoto S, Yamasaki M, Kasamatsu Y, Komase Y, Hida N, Tsuburai T, Oyama B, Takada M, Kanda H, Kitagawa Y, Fukuta T, Miyake T, Yoshida S, Ogura S, Abe S, Kono Y, Togashi Y, Takoi H, Kikuchi R, Ogawa S, Ogata T, Ishihara S, Kanehiro A, Ozaki S, Fuchimoto Y, Wada S, Fujimoto N, Nishiyama K, Terashima M, Beppu S, Yoshida K, Narumoto O, Nagai H, Ooshima N, Motegi M, Umeda A, Miyagawa K, Shimada H, Endo M, Ohira Y, Watanabe M, Inoue S, Igarashi A, Sato M, Sagara H, Tanaka A, Ohta S, Kimura T, Shibata Y, Tanino Y, Nikaido T, Minemura H, Sato Y, Yamada Y, Hashino T, Shinoki M, Iwagoe H, Takahashi H, Fujii K, Kishi H, Kanai M, Imamura T, Yamashita T, Yatomi M, Maeno T, Hayashi S, Takahashi M, Kuramochi M, Kamimaki I, Tominaga Y, Ishii T, Utsugi M, Ono A, Tanaka T, Kashiwada T, Fujita K, Saito Y, Seike M, Watanabe H, Matsuse H, Kodaka N, Nakano C, Oshio T, Hirouchi T, Makino S, Egi M, Omae Y, Nannya Y, Ueno T, Katayama K, Ai M, Fukui Y, Kumanogoh A, Sato T, Hasegawa N, Tokunaga K, Ishii M, Koike R, Kitagawa Y, Kimura A, Imoto S, Miyano S, Ogawa S, Kanai T, Fukunaga K, and Okada Y
- Subjects
- Alleles, Animals, Disease Models, Animal, Genetic Predisposition to Disease, Humans, Interferon Type I genetics, Interferon Type I immunology, Japan, Lung pathology, Macrophages, Mesocricetus, Middle Aged, Pneumonia complications, Pyrazoles pharmacology, RNA-Seq, Viral Load, Weight Loss, COVID-19 complications, COVID-19 genetics, COVID-19 immunology, COVID-19 physiopathology, GTPase-Activating Proteins antagonists & inhibitors, GTPase-Activating Proteins genetics, GTPase-Activating Proteins metabolism, Genome-Wide Association Study, Guanine Nucleotide Exchange Factors antagonists & inhibitors, Guanine Nucleotide Exchange Factors genetics, Guanine Nucleotide Exchange Factors metabolism, Host Microbial Interactions genetics, Host Microbial Interactions immunology, SARS-CoV-2 pathogenicity
- Abstract
Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge
1-5 . 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., (© 2022. The Author(s).)- Published
- 2022
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32. Tunable uniaxial, area, and volume negative thermal expansion in quartz-like and diamond-like metal-organic frameworks.
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Wang L, Chen Y, Miura H, Suzuki K, and Wang C
- Abstract
This paper proposes that it will be an effective way to discover and explore organic negative thermal expansion (NTE) materials based on the specific topologies in inorganic NTE materials. Various NTE behaviors from the uniaxial, area, and volume-NTE can be achieved by adjusting the topology, for instance, quartz-like and diamond-like. Zn(ISN)
2 and InH(BDC) metal-organic frameworks (MOFs) with quartz-like topology have been studied by first principles calculations. The calculated area-NTE of Zn(ISN)2 and uniaxial-NTE of InH(BDC) within quasi-harmonic approximation (QHA) agree well with the experimental data. Through the calculation of Grüneisen parameters, it is shown that low-frequency optical phonons appear dominant resulting in their NTE, but the coupling to high-frequency phonons is of greater ultimate importance. The lattice vibrational modes of great contribution to area-NTE of Zn(ISN)2 and uniaxial-NTE of InH(BDC) are analyzed in detail. Also, four MOFs with diamond-like topology are predicted to exhibit volume-NTE behavior. Moreover, it is found that there is a bulk modulus anomaly in some studied MOFs with the quartz-like and diamond-like framework, where the temperature dependence of bulk modulus does not follow the inverse dependence on that of volume. These specific topologies provide key geometric frameworks for various NTE behaviors of MOFs, and meanwhile, the local structure and bond environment in MOFs can lead to abnormal interatomic force, i.e. , bulk modulus anomaly. This abnormal elastic property also deserves more attention., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)- Published
- 2022
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33. A common deletion at BAK1 reduces enhancer activity and confers risk of intracranial germ cell tumors.
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Sonehara K, Kimura Y, Nakano Y, Ozawa T, Takahashi M, Suzuki K, Fujii T, Matsushita Y, Tomiyama A, Kishikawa T, Yamamoto K, Naito T, Suzuki T, Yamaguchi S, Miwa T, Sasaki H, Kitagawa M, Ohe N, Fukai J, Ogiwara H, Kawamura A, Miyawaki S, Matsuda F, Kiyokawa N, Ichimura K, Nishikawa R, Okada Y, and Terashima K
- Subjects
- Adolescent, Alleles, Child, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide, bcl-2 Homologous Antagonist-Killer Protein genetics, Brain Neoplasms genetics, Neoplasms, Germ Cell and Embryonal genetics, Testicular Neoplasms genetics
- Abstract
Intracranial germ cell tumors (IGCTs) are rare brain neoplasms that mainly occur in children and adolescents with a particularly high incidence in East Asian populations. Here, we conduct a genome-wide association study (GWAS) of 133 patients with IGCTs and 762 controls of Japanese ancestry. A common 4-bp deletion polymorphism in an enhancer adjacent to BAK1 is significantly associated with the disease risk (rs3831846; P = 2.4 × 10
-9 , odds ratio = 2.46 [95% CI: 1.83-3.31], minor allele frequency = 0.43). Rs3831846 is in strong linkage disequilibrium with a testicular GCTs susceptibility variant rs210138. In-vitro reporter assays reveal rs3831846 to be a functional variant attenuating the enhancer activity, suggesting its contribution to IGCTs predisposition through altering BAK1 expression. Risk alleles of testicular GCTs derived from the European GWAS show significant positive correlations in the effect sizes with the Japanese IGCTs GWAS (P = 1.3 × 10-4 , Spearman's ρ = 0.48). These results suggest the shared genetic susceptibility of GCTs beyond ethnicity and primary sites., (© 2022. The Author(s).)- Published
- 2022
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34. Immunocompetent cells in durable ventricular assist device-implanted non-ischaemic dilated cardiomyopathy.
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Koga-Ikuta A, Fukushima S, Ishibashi-Ueda H, Tadokoro N, Kakuta T, Watanabe T, Fukushima N, Suzuki K, Fukui T, and Fujita T
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- Humans, Stroke Volume, Ventricular Function, Left, Cardiomyopathy, Dilated therapy, Heart Failure etiology, Heart-Assist Devices adverse effects
- Abstract
Objective: Because the presence of immunocompetent cells in the myocardium is associated with the pathological stage and/or myocardial viability, we explored relationships between functional recovery after left ventricular assist device implantation and the distribution of immunocompetent cells in non-ischaemic dilated cardiomyopathy patients., Methods: We reviewed 50 consecutive dilated cardiomyopathy patients implanted with HeartMate II at our institute between April 2013 and December 2018 who were treated with optimal medical therapy during left ventricular assist device support. Patients were stratified by improvement of the left ventricular ejection fraction at 6 months after implantation: ≥ 10% increase (Gr ≥ 10%), 5-10% (Gr 5-10%), and ≤ 5% (Gr ≤ 5%). T cells and macrophages were evaluated in the apical myocardium after left ventricular assist device implantation., Results: During left ventricular assist device support, 12 patients underwent heart transplantation and 2 patients died. Four patients with Gr ≤ 5% were readmitted because of congestive heart failure, but none with Gr ≥ 10%. Macrophages and T cells in the left ventricular myocardium with Gr ≥ 10% were significantly more present compared to those in other groups., Conclusions: The distribution of immunocompetent cells in the left ventricular myocardium might predict myocardial viability of this pathology after implantation., (© 2022. The Author(s).)
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- 2022
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35. Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation.
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Mahajan A, Spracklen CN, Zhang W, Ng MCY, Petty LE, Kitajima H, Yu GZ, Rüeger S, Speidel L, Kim YJ, Horikoshi M, Mercader JM, Taliun D, Moon S, Kwak SH, Robertson NR, Rayner NW, Loh M, Kim BJ, Chiou J, Miguel-Escalada I, Della Briotta Parolo P, Lin K, Bragg F, Preuss MH, Takeuchi F, Nano J, Guo X, Lamri A, Nakatochi M, Scott RA, Lee JJ, Huerta-Chagoya A, Graff M, Chai JF, Parra EJ, Yao J, Bielak LF, Tabara Y, Hai Y, Steinthorsdottir V, Cook JP, Kals M, Grarup N, Schmidt EM, Pan I, Sofer T, Wuttke M, Sarnowski C, Gieger C, Nousome D, Trompet S, Long J, Sun M, Tong L, Chen WM, Ahmad M, Noordam R, Lim VJY, Tam CHT, Joo YY, Chen CH, Raffield LM, Lecoeur C, Prins BP, Nicolas A, Yanek LR, Chen G, Jensen RA, Tajuddin S, Kabagambe EK, An P, Xiang AH, Choi HS, Cade BE, Tan J, Flanagan J, Abaitua F, Adair LS, Adeyemo A, Aguilar-Salinas CA, Akiyama M, Anand SS, Bertoni A, Bian Z, Bork-Jensen J, Brandslund I, Brody JA, Brummett CM, Buchanan TA, Canouil M, Chan JCN, Chang LC, Chee ML, Chen J, Chen SH, Chen YT, Chen Z, Chuang LM, Cushman M, Das SK, de Silva HJ, Dedoussis G, Dimitrov L, Doumatey AP, Du S, Duan Q, Eckardt KU, Emery LS, Evans DS, Evans MK, Fischer K, Floyd JS, Ford I, Fornage M, Franco OH, Frayling TM, Freedman BI, Fuchsberger C, Genter P, Gerstein HC, Giedraitis V, González-Villalpando C, González-Villalpando ME, Goodarzi MO, Gordon-Larsen P, Gorkin D, Gross M, Guo Y, Hackinger S, Han S, Hattersley AT, Herder C, Howard AG, Hsueh W, Huang M, Huang W, Hung YJ, Hwang MY, Hwu CM, Ichihara S, Ikram MA, Ingelsson M, Islam MT, Isono M, Jang HM, Jasmine F, Jiang G, Jonas JB, Jørgensen ME, Jørgensen T, Kamatani Y, Kandeel FR, Kasturiratne A, Katsuya T, Kaur V, Kawaguchi T, Keaton JM, Kho AN, Khor CC, Kibriya MG, Kim DH, Kohara K, Kriebel J, Kronenberg F, Kuusisto J, Läll K, Lange LA, Lee MS, Lee NR, Leong A, Li L, Li Y, Li-Gao R, Ligthart S, Lindgren CM, Linneberg A, Liu CT, Liu J, Locke AE, Louie T, Luan J, Luk AO, Luo X, Lv J, Lyssenko V, Mamakou V, Mani KR, Meitinger T, Metspalu A, Morris AD, Nadkarni GN, Nadler JL, Nalls MA, Nayak U, Nongmaithem SS, Ntalla I, Okada Y, Orozco L, Patel SR, Pereira MA, Peters A, Pirie FJ, Porneala B, Prasad G, Preissl S, Rasmussen-Torvik LJ, Reiner AP, Roden M, Rohde R, Roll K, Sabanayagam C, Sander M, Sandow K, Sattar N, Schönherr S, Schurmann C, Shahriar M, Shi J, Shin DM, Shriner D, Smith JA, So WY, Stančáková A, Stilp AM, Strauch K, Suzuki K, Takahashi A, Taylor KD, Thorand B, Thorleifsson G, Thorsteinsdottir U, Tomlinson B, Torres JM, Tsai FJ, Tuomilehto J, Tusie-Luna T, Udler MS, Valladares-Salgado A, van Dam RM, van Klinken JB, Varma R, Vujkovic M, Wacher-Rodarte N, Wheeler E, Whitsel EA, Wickremasinghe AR, van Dijk KW, Witte DR, Yajnik CS, Yamamoto K, Yamauchi T, Yengo L, Yoon K, Yu C, Yuan JM, Yusuf S, Zhang L, Zheng W, Raffel LJ, Igase M, Ipp E, Redline S, Cho YS, Lind L, Province MA, Hanis CL, Peyser PA, Ingelsson E, Zonderman AB, Psaty BM, Wang YX, Rotimi CN, Becker DM, Matsuda F, Liu Y, Zeggini E, Yokota M, Rich SS, Kooperberg C, Pankow JS, Engert JC, Chen YI, Froguel P, Wilson JG, Sheu WHH, Kardia SLR, Wu JY, Hayes MG, Ma RCW, Wong TY, Groop L, Mook-Kanamori DO, Chandak GR, Collins FS, Bharadwaj D, Paré G, Sale MM, Ahsan H, Motala AA, Shu XO, Park KS, Jukema JW, Cruz M, McKean-Cowdin R, Grallert H, Cheng CY, Bottinger EP, Dehghan A, Tai ES, Dupuis J, Kato N, Laakso M, Köttgen A, Koh WP, Palmer CNA, Liu S, Abecasis G, Kooner JS, Loos RJF, North KE, Haiman CA, Florez JC, Saleheen D, Hansen T, Pedersen O, Mägi R, Langenberg C, Wareham NJ, Maeda S, Kadowaki T, Lee J, Millwood IY, Walters RG, Stefansson K, Myers SR, Ferrer J, Gaulton KJ, Meigs JB, Mohlke KL, Gloyn AL, Bowden DW, Below JE, Chambers JC, Sim X, Boehnke M, Rotter JI, McCarthy MI, and Morris AP
- Subjects
- Ethnicity, Genetic Predisposition to Disease, Humans, Polymorphism, Single Nucleotide genetics, Risk Factors, Diabetes Mellitus, Type 2 epidemiology, Genome-Wide Association Study
- Abstract
We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 × 10
-9 ), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)- Published
- 2022
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36. Newt Hoxa13 has an essential and predominant role in digit formation during development and regeneration.
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Takeuchi T, Matsubara H, Minamitani F, Satoh Y, Tozawa S, Moriyama T, Maruyama K, Suzuki KT, Shigenobu S, Inoue T, Tamura K, Agata K, and Hayashi T
- Subjects
- Animals, Extremities, Limb Buds metabolism, Mice, Salamandridae genetics, Salamandridae metabolism, Transcription Factors genetics, Transcription Factors metabolism, Gene Expression Regulation, Developmental, Homeodomain Proteins genetics, Homeodomain Proteins metabolism
- Abstract
The 5'Hox genes play crucial roles in limb development and specify regions in the proximal-distal axis of limbs. However, there is no direct genetic evidence that Hox genes are essential for limb development in non-mammalian tetrapods or for limb regeneration. Here, we produced single to quadruple Hox13 paralog mutants using the CRISPR/Cas9 system in newts (Pleurodeles waltl), which have strong regenerative capacities, and also produced germline mutants. We show that Hox13 genes are essential for digit formation in development, as in mice. In addition, Hoxa13 has a predominant role in digit formation, unlike in mice. The predominance is probably due to the restricted expression pattern of Hoxd13 in limb buds and the strong dependence of Hoxd13 expression on Hoxa13. Finally, we demonstrate that Hox13 genes are also necessary for digit formation in limb regeneration. Our findings reveal that the general function of Hox13 genes is conserved between limb development and regeneration, and across taxa. The predominance of Hoxa13 function both in newt limbs and fish fins, but not in mouse limbs, suggests a potential contribution of Hoxa13 function in fin-to-limb transition., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)
- Published
- 2022
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37. Generation and characterization of motor neuron progenitors and motor neurons using metachromatic leukodystrophy-induced pluripotent stem cells.
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Hossain MA, Hasegawa-Ogawa M, Manome Y, Igarashi M, Wu C, Suzuki K, Igarashi J, Iwamoto T, Okano HJ, and Eto Y
- Abstract
The pathological consequences leading to primary storage, autophagy impairment, impaired mitochondrial dynamics, and endoplasmic reticulum (ER) stress on neural cell dysfunction and apoptosis in metachromatic leukodystrophy (MLD) have been poorly elucidated. In the present study, we generated 2 cell lines of patient-specific-induced pluripotent stem cells (iPSCs) and modeled the progression of pathological events during the differentiation of iPSCs to motor neuron progenitors (MNPs) and mature motor neurons (MNs). The iPS cells were generated from two late-infantile MLD patient-derived skin fibroblasts using electroporation or the Sendai virus. Olig2
+ MNPs were generated from both iPSC lines using a combination of small molecules in a chemically defined neural medium. Furthermore, the MNPs could be differentiated into mature MNs, which was confirmed by RT-PCR and MN markers, including SMI32 and ChAT. The population of MNs was approximately 50% under the culture conditions. Pathological observation of MLD patient-derived iPSCs revealed lysosomal accumulation and impaired autophagy. In addition, both MNPs and MNs derived from MLD-iPSCs showed increased lysosomal accumulation, dysfunctional autophagy, impaired mitophagy, endoplasmic reticulum (ER) stress or unfolded protein response (UPR) activation, and premature cellular death., Competing Interests: MAH is currently an employee of JCR Pharmaceuticals Co. Ltd. However, the work does not have any relation with the company, and the research was conducted before joining the industry. YE received research grants from Sanofi Co. and Actelion Pharmaceuticals. The other authors have no conflicts of interest to declare., (© 2022 The Authors.)- Published
- 2022
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38. Nrg1/ErbB signaling-mediated regulation of fibrosis after myocardial infarction.
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Shiraishi M, Yamaguchi A, and Suzuki K
- Subjects
- Animals, Disease Models, Animal, Fibroblasts metabolism, Macrophages metabolism, Mice, Mice, Inbred C57BL, Myocytes, Cardiac metabolism, Signal Transduction physiology, ErbB Receptors metabolism, Fibrosis metabolism, Myocardial Infarction metabolism, Myocardium metabolism, Neuregulin-1 metabolism
- Abstract
Appropriate fibrotic tissue formation after myocardial infarction (MI) is crucial to the maintenance of the heart's structure. M2-like macrophages play a vital role in post-MI fibrosis by activating cardiac fibroblasts. Because the mechanism by which post-MI cardiac fibrosis is regulated is not fully understood, we investigated, in vitro and in vivo, the cellular and molecular mechanisms of post-MI fibrotic tissue formation, especially those related to the regulation of cellular senescence and apoptosis. CD206
+ F4/80+ CD11b+ M2-like macrophages collected from mouse hearts on post-MI day 7 showed increased expression of neuregulin 1 (Nrg1). Nrg1 receptor epidermal growth factor receptors ErbB2 and ErbB4 were expressed on cardiac fibroblasts in the infarct area. M2-like macrophage-derived Nrg1 suppressed both hydrogen peroxide-induced senescence and apoptosis of fibroblasts, whereas blockade of ErbB function significantly accelerated both processes. M2-like macrophage-derived Nrg1/ErbB/PI3K/Akt signaling, shown to be related to anti-senescence, was activated in damaged cardiac fibroblasts. Interestingly, systemic blockade of ErbB function in MI model mice enhanced senescence and apoptosis of cardiac fibroblasts and exacerbated inflammation. Further, increased accumulation of M2-like macrophages resulted in excessive post-MI progression of fibrosis in mice hearts. The molecular mechanism underlying the regulation of fibrotic tissue formation in the infarcted myocardium was shown in part to be attenuation of apoptosis and senescence of cardiac fibroblasts by the activation of Nrg1/ErbB/PI3K/Akt signaling. M2-like macrophage-mediated regulation of Nrg1/ErbB signaling has a substantial effect on fibrotic tissue formation in the infarcted adult mouse heart and is critical for suppressing the progression of senescence and apoptosis of cardiac fibroblasts., (© 2022 Federation of American Societies for Experimental Biology.)- Published
- 2022
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39. Stability and structural properties of vacancy-ordered and -disordered ZrC x .
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Davey T, Suzuki K, Miura H, and Chen Y
- Abstract
Vacancy-ordered superstructural phases of zirconium carbide have been intermittently observed at low temperatures for over 50 years. However, little is known about these ordered phases as they have proven to be challenging to fabricate experimentally, although theoretical predictions suggest that they should be significantly more stable than the more-observed vacancy-disordered solid solution ZrC
x ( x ≤ 1) phase at low temperatures. The stability and structural properties of the vacancy-ordered and vacancy-disordered phases are investigated using first-principles calculations. The stability of the ordered superstructural phases is related to the driving force from the relative instability of certain vacancy configurations, which are preferred or avoided in ordered structures. The trend of the vacancy ordering and the underlying mechanisms of the relative instability are explained in terms of the geometry of the crystal structures and the electronic charge distribution and atomic bonding features., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)- Published
- 2021
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40. A cross-population atlas of genetic associations for 220 human phenotypes.
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Sakaue S, Kanai M, Tanigawa Y, Karjalainen J, Kurki M, Koshiba S, Narita A, Konuma T, Yamamoto K, Akiyama M, Ishigaki K, Suzuki A, Suzuki K, Obara W, Yamaji K, Takahashi K, Asai S, Takahashi Y, Suzuki T, Shinozaki N, Yamaguchi H, Minami S, Murayama S, Yoshimori K, Nagayama S, Obata D, Higashiyama M, Masumoto A, Koretsune Y, Ito K, Terao C, Yamauchi T, Komuro I, Kadowaki T, Tamiya G, Yamamoto M, Nakamura Y, Kubo M, Murakami Y, Yamamoto K, Kamatani Y, Palotie A, Rivas MA, Daly MJ, Matsuda K, and Okada Y
- Subjects
- ABO Blood-Group System genetics, Biological Specimen Banks, Genetic Loci, Genetic Pleiotropy, Genome-Wide Association Study, Humans, Major Histocompatibility Complex genetics, Meta-Analysis as Topic, Mutation genetics, Phenotype, Genetic Association Studies, Genetic Predisposition to Disease
- Abstract
Current genome-wide association studies do not yet capture sufficient diversity in populations and scope of phenotypes. To expand an atlas of genetic associations in non-European populations, we conducted 220 deep-phenotype genome-wide association studies (diseases, biomarkers and medication usage) in BioBank Japan (n = 179,000), by incorporating past medical history and text-mining of electronic medical records. Meta-analyses with the UK Biobank and FinnGen (n
total = 628,000) identified ~5,000 new loci, which improved the resolution of the genomic map of human traits. This atlas elucidated the landscape of pleiotropy as represented by the major histocompatibility complex locus, where we conducted HLA fine-mapping. Finally, we performed statistical decomposition of matrices of phenome-wide summary statistics, and identified latent genetic components, which pinpointed responsible variants and biological mechanisms underlying current disease classifications across populations. The decomposed components enabled genetically informed subtyping of similar diseases (for example, allergic diseases). Our study suggests a potential avenue for hypothesis-free re-investigation of human diseases through genetics., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)- Published
- 2021
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41. Epicardial placement of human MSC-loaded fibrin sealant films for heart failure: Preclinical efficacy and mechanistic data.
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Fields L, Ito T, Kobayashi K, Ichihara Y, Podaru MN, Hussain M, Yamashita K, Machado V, Lewis-McDougall F, and Suzuki K
- Subjects
- Animals, Cell Polarity, Cell Proliferation, Cells, Cultured, Disease Models, Animal, Echocardiography, Female, Gene Expression Regulation, Heart Failure diagnostic imaging, Heart Failure genetics, Humans, Macrophages chemistry, Mesenchymal Stem Cell Transplantation, Mice, Rats, Fibrin chemistry, Heart Failure therapy, Macrophages cytology, Mesenchymal Stem Cells cytology
- Abstract
Mesenchymal stromal cell (MSC) transplantation has been investigated as an advanced treatment of heart failure; however, further improvement of the therapeutic efficacy and mechanistic understanding are needed. Our previous study has reported that epicardial placement of fibrin sealant films incorporating rat amniotic membrane-derived (AM)-MSCs (MSC-dressings) could address limitations of traditional transplantation methods. To progress this finding toward clinical translation, this current study aimed to examine the efficacy of MSC-dressings using human AM-MSCs (hAM-MSCs) and the underpinning mechanism for myocardial repair. Echocardiography demonstrated that cardiac function and structure were improved in a rat ischemic cardiomyopathy model after hAM-MSC-dressing therapy. hAM-MSCs survived well in the rat heart, enhanced myocardial expression of reparative genes, and attenuated adverse remodeling. Copy number analysis by qPCR revealed that upregulated reparative genes originated from endogenous rat cells rather than hAM-MSCs. These results suggest hAM-MSC-dressing therapy stimulates a secondary release of paracrine factors from endogenous cells improving myocardial repair ("secondary paracrine effect"), and cardiac M2-like macrophages were identified as a potential cell source of repair. We demonstrated hAM-MSCs increased M2-like macrophages through not only enhancing M2 polarization but also augmenting their proliferation and migration capabilities via PGE
2 , CCL2, and TGF-β1, resulting in enhanced cardiac function after injury., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2021
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42. Genotype-Structure-Phenotype Correlations of Disease-Associated IGF1R Variants and Similarities to Those of INSR Variants.
- Author
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Hosoe J, Kawashima-Sonoyama Y, Miya F, Kadowaki H, Suzuki K, Kato T, Matsuzawa F, Aikawa SI, Okada Y, Tsunoda T, Hanaki K, Kanzaki S, Shojima N, Yamauchi T, and Kadowaki T
- Subjects
- Animals, Antigens, CD metabolism, CHO Cells, Cricetinae, Cricetulus, Genetic Association Studies, Humans, Insulin Resistance genetics, Mutation, Missense, Phenotype, Receptor, IGF Type 1 metabolism, Receptor, Insulin metabolism, Retrospective Studies, Antigens, CD genetics, Body Height genetics, Growth Disorders genetics, Receptor, IGF Type 1 genetics, Receptor, Insulin genetics
- Abstract
We previously reported genotype-phenotype correlations in 12 missense variants causing severe insulin resistance, located in the second and third fibronectin type III (FnIII) domains of the insulin receptor (INSR), containing the α-β cleavage and part of insulin-binding sites. This study aimed to identify genotype-phenotype correlations in FnIII domain variants of IGF1R, a structurally related homolog of INSR, which may be associated with growth retardation, using the recently reported crystal structures of IGF1R. A structural bioinformatics analysis of five previously reported disease-associated heterozygous missense variants and a likely benign variant in the FnIII domains of IGF1R predicted that the disease-associated variants would severely impair the hydrophobic core formation and stability of the FnIII domains or affect the α-β cleavage site, while the likely benign variant would not affect the folding of the domains. A functional analysis of these variants in CHO cells showed impaired receptor processing and autophosphorylation in cells expressing the disease-associated variants but not in those expressing the wild-type form or the likely benign variant. These results demonstrated genotype-phenotype correlations in the FnIII domain variants of IGF1R , which are presumably consistent with those of INSR and would help in the early diagnosis of patients with disease-associated IGF1R variants., (© 2021 by the American Diabetes Association.)
- Published
- 2021
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43. Trans-Ethnic Fine-Mapping of the Major Histocompatibility Complex Region Linked to Parkinson's Disease.
- Author
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Naito T, Satake W, Ogawa K, Suzuki K, Hirata J, Foo JN, Tan EK, Toda T, and Okada Y
- Subjects
- Alleles, Genetic Predisposition to Disease genetics, Genome-Wide Association Study, Haplotypes, Histocompatibility Antigens, Histone-Lysine N-Methyltransferase, Humans, Major Histocompatibility Complex, Polymorphism, Single Nucleotide, Parkinson Disease genetics
- Abstract
Background: Despite evidence for the role of human leukocyte antigen (HLA) in the genetic predisposition to Parkinson's disease (PD), the complex haplotype structure and highly polymorphic feature of the major histocompatibility complex (MHC) region has hampered a unified insight on the genetic risk of PD. In addition, a majority of the reports focused on Europeans, lacking evidence on other populations., Objectives: The aim of this study is to elucidate the genetic features of the MHC region associated with PD risk in trans-ethnic cohorts., Methods: We conducted trans-ethnic fine-mapping of the MHC region for European populations (14,650 cases and 1,288,625 controls) and East Asian populations (7712 cases and 27,372 controls). We adopted a hybrid fine-mapping approach including both HLA genotype imputation of genome-wide association study (GWAS) data and direct imputation of HLA variant risk from the GWAS summary statistics., Results: Through trans-ethnic MHC fine-mapping, we identified the strongest associations at amino acid position 13 of HLA-DRβ1 (P = 6.0 × 10
-15 ), which explains the majority of the risk in HLA-DRB1. In silico prediction revealed that HLA-DRB1 alleles with histidine at amino acid position 13 (His13) had significantly weaker binding affinity to an α-synuclein epitope than other alleles (P = 9.6 × 10-4 ). Stepwise conditional analysis suggested additional independent associations at Ala69 in HLA-B (P = 1.0 × 10-7 ). A subanalysis in Europeans suggested additional independent associations at non-HLA genes in the class III MHC region (EHMT2; P = 2.5 × 10-7 )., Conclusions: Our study highlights the shared and distinct genetic features of the MHC region in patients with PD across ethnicities. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)- Published
- 2021
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44. A neuropathological cell model derived from Niemann-Pick disease type C patient-specific iPSCs shows disruption of the p62/SQSTM1-KEAP1-NRF2 Axis and impaired formation of neuronal networks.
- Author
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Saito R, Miyajima T, Iwamoto T, Wu C, Suzuki K, Hossain MA, Munakata M, Era T, and Eto Y
- Abstract
Niemann-Pick disease type C (NPC) is a rare neurodegenerative disorder caused by a recessive mutation in the NPC1 or NPC2 gene, in which patients exhibit lysosomal accumulation of unesterified cholesterol and glycolipids. Most of the research on NPC has been done in patient-derived skin fibroblasts or mouse models. Therefore, we developed NPC patient neurons derived from induced pluripotent stem cells (iPSCs) to investigate the neuropathological cause of the disease. Although an accumulation of cholesterol and glycolipids, which is characteristic of NPC, was observed in both undifferentiated iPSCs and derived neural stem cells (NSCs), we could not observed the abnormalities in differentiation potential and autophagic activity in such immature cells. However, definite neuropathological features were detected in mature neuronal cells generated from NPC patient-derived iPSCs. Abnormal accumulation of cholesterol and other lipids identified by lipid droplets and number of enlarged lysosomes was more prominent in mature neuronal cells rather than in iPSCs and/or NSCs. Thin-sectioning electron microscopic analysis also demonstrated numerous typical membranous cytoplasmic bodies in mature neuronal cells. Furthermore, TUJ1-positive neurite density was significantly reduced in NPC patient-derived neuronal cells. In addition, disruption of the p62/SQSTM1-KEAP1-NRF2 axis occurred in neurons differentiated from NPC patient-derived iPSCs. These data indicate the impairment of neuronal network formation associated with neurodegeneration in mature neuronal cells derived from patients with NPC., Competing Interests: Yoshikatsu Eto has received Y. E. Research grants from Sanofi Co. and Actelion Pharmaceuticals. Other authors has no conflict of interest., (© 2021 The Authors.)
- Published
- 2021
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45. Structural basis of ethnic-specific variants of PAX4 associated with type 2 diabetes.
- Author
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Hosoe J, Suzuki K, Miya F, Kato T, Tsunoda T, Okada Y, Horikoshi M, Shojima N, Yamauchi T, and Kadowaki T
- Abstract
Recently, we conducted genome-wide association studies of type 2 diabetes (T2D) in a Japanese population, which identified 20 novel T2D loci that were not associated with T2D in Europeans. Moreover, nine novel missense risk variants, such as those of PAX4, were not rare in the Japanese population, but rare in Europeans. We report in silico structural analysis of ethnic-specific variants of PAX4, which suggests the pathogenic effect of these variants.
- Published
- 2021
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46. Copper deficiency-induced pancytopenia after taking an excessive amount of zinc formulation during maintenance hemodialysis.
- Author
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Marumo A, Yamamura T, Mizuki T, Tanosaki S, and Suzuki K
- Abstract
Erythropoiesis-stimulating agent (ESA) has been recognized as an effective way in the treatment of anemia due to chronic kidney disease, but we sometimes see intractable hemodialysis (HD) patients. The causes of ESA-resistant anemia in HD patients include deficiency of trace elements. We report the case of an 89-year-old male who developed pancytopenia after taking an excessive amount of zinc formulation for ESA-resistant anemia during maintenance dialysis. He was prescribed zinc acetate hydrate formulation about 6 months before his presentation. He was found to have pancytopenia 1 month before his presentation, at which point he was introduced to our hospital. We suspected a copper deficiency at the first visit and stopped zinc and added copper, and his condition subsequently improved without being handicapped. Zinc antagonizes copper, so we must take care to diagnose patients ingesting zinc supplements., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Journal of Research in Medical Sciences.)
- Published
- 2021
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47. Development of Highly Sensitive Strain Sensor Using Area-Arrayed Graphene Nanoribbons.
- Author
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Suzuki K, Nakagawa R, Zhang Q, and Miura H
- Abstract
In this study, a basic design of area-arrayed graphene nanoribbon (GNR) strain sensors was proposed to realize the next generation of strain sensors. To fabricate the area-arrayed GNRs, a top-down approach was employed, in which GNRs were cut out from a large graphene sheet using an electron beam lithography technique. GNRs with widths of 400 nm, 300 nm, 200 nm, and 50 nm were fabricated, and their current-voltage characteristics were evaluated. The current values of GNRs with widths of 200 nm and above increased linearly with increasing applied voltage, indicating that these GNRs were metallic conductors and a good ohmic junction was formed between graphene and the electrode. There were two types of GNRs with a width of 50 nm, one with a linear current-voltage relationship and the other with a nonlinear one. We evaluated the strain sensitivity of the 50 nm GNR exhibiting metallic conduction by applying a four-point bending test, and found that the gauge factor of this GNR was about 50. Thus, GNRs with a width of about 50 nm can be used to realize a highly sensitive strain sensor., Competing Interests: The authors declare no conflict of interest.
- Published
- 2021
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48. Ethanol treatment for sterilization, concentration, and stabilization of a biodegradable plastic-degrading enzyme from Pseudozyma antarctica culture supernatant.
- Author
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Tanaka T, Suzuki K, Ueda H, Sameshima-Yamashita Y, and Kitamoto H
- Subjects
- Biodegradation, Environmental, Ustilaginales enzymology, Enzyme Stability, Fungal Proteins metabolism, Fungal Proteins chemistry, Basidiomycota enzymology, Ethanol metabolism, Sterilization, Plastics chemistry
- Abstract
Biodegradable plastics must be sufficiently stable to maintain functionality during use but need to be able to degrade rapidly after use. We previously reported that treatment with an enzyme named PaE, secreted by the basidiomycete yeast Pseudozyma antarctica can speed up this degradation. To facilitate the production of large quantities of PaE, here, we aimed to elucidate the optimal conditions of ethanol treatment for sterilization of the culture supernatant and for concentration and stabilization of PaE. The results showed that Pseudozyma antarctica completely lost its proliferating ability when incubated in ≥20% (v/v) ethanol. When the ethanol concentration was raised to 90% (v/v), PaE formed a precipitate; however, its activity was restored completely when the precipitate was dissolved in water. To reduce ethanol use, PaE was successfully concentrated and recovered by sequential ammonium sulfate precipitation and ethanol precipitation steps. Over 90% of the activity in the original culture supernatant was recovered and the specific activity was increased 3.4-fold. By preparing the enzyme solution at a final concentration of 20% (v/v) ethanol, about 60% of the initial activity was maintained at ambient temperature for over 6 months without growth of microbes. We conclude that ethanol treatment is effective for sterilization, concentration, and stabilization of PaE, and that concentrating PaE by sequential ammonium sulfate precipitation and ethanol precipitation substantially increases the PaE purity and decreases ethanol use., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2021
- Full Text
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49. Large-scale plasma-metabolome analysis identifies potential biomarkers of psoriasis and its clinical subtypes.
- Author
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Kishikawa T, Arase N, Tsuji S, Maeda Y, Nii T, Hirata J, Suzuki K, Yamamoto K, Masuda T, Ogawa K, Ohshima S, Inohara H, Kumanogoh A, Fujimoto M, and Okada Y
- Subjects
- Adult, Aged, Aged, 80 and over, Arthritis, Psoriatic blood, Arthritis, Psoriatic metabolism, Aspartic Acid blood, Aspartic Acid metabolism, Biomarkers blood, Biomarkers metabolism, Case-Control Studies, Diagnosis, Differential, Fatty Acids blood, Fatty Acids metabolism, Female, Healthy Volunteers, Humans, Male, Metabolomics, Middle Aged, Psoriasis blood, Psoriasis metabolism, Severity of Illness Index, Sugar Acids blood, Sugar Acids metabolism, Tyramine blood, Tyramine metabolism, Young Adult, Arthritis, Psoriatic diagnosis, Psoriasis diagnosis
- Abstract
Background: Psoriasis is an immune-mediated skin disease for which the crosstalk between genetic and environmental factors is responsible. To date, no definitive diagnostic criteria for psoriasis yet, and specific biomarkers are required., Objective: We performed metabolome analysis to identify metabolite biomarkers of psoriasis and its subtypes such as psoriatic arthritis (PsA) and cutaneous psoriasis (PsC)., Methods: We constructed metabolomics profiling of 130 plasma samples (42 PsA patients, 50 PsC patients, and 38 healthy controls) using a nontargeted metabolomics approach., Results: Psoriasis-control association tests showed that one metabolite (ethanolamine phosphate) was significantly increased in psoriasis samples than in the controls, whereas three metabolites decreased (false discovery rate [FDR] < 0.05; XA0019, nicotinic acid, and 20α-hydroxyprogesterone). In the association test between PsA and PsC, tyramine significantly increased in PsA than in PsC, whereas mucic acid decreased (FDR < 0.05). Molecular pathway analysis of the PsA-PsC association test identified enrichment of vitamin digestion and absorption pathway in PsC (P = 1.3 × 10
-4 ). Correlation network analyses elucidated that a subnetwork centered on aspartate was constructed among the psoriasis-associated metabolites; meanwhile, the major subnetwork among metabolites with differences between PsA and PsC was primarily formed from saturated fatty acids., Conclusion: Our large-scale metabolome analysis highlights novel characteristics of plasma metabolites in psoriasis and the differences between PsA and PsC, which could be used as potential biomarkers of psoriasis and its clinical subtypes. These findings contribute to our understanding of psoriasis pathophysiology., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2021
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50. Cell barrier function of resident peritoneal macrophages in post-operative adhesions.
- Author
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Ito T, Shintani Y, Fields L, Shiraishi M, Podaru MN, Kainuma S, Yamashita K, Kobayashi K, Perretti M, Lewis-McDougall F, and Suzuki K
- Subjects
- Animals, CD11b Antigen genetics, CD11b Antigen immunology, Epithelium immunology, Epithelium pathology, Humans, Interleukin-4, Male, Mice, Mice, Inbred C57BL, Peritoneum pathology, Postoperative Complications genetics, Postoperative Complications pathology, Tissue Adhesions genetics, Tissue Adhesions pathology, Macrophages, Peritoneal immunology, Peritoneum immunology, Postoperative Complications immunology, Tissue Adhesions immunology
- Abstract
Post-operative adhesions are a leading cause of abdominal surgery-associated morbidity. Exposed fibrin clots on the damaged peritoneum, in which the mesothelial barrier is disrupted, readily adhere to surrounding tissues, resulting in adhesion formation. Here we show that resident F4/80
High CD206- peritoneal macrophages promptly accumulate on the lesion and form a 'macrophage barrier' to shield fibrin clots in place of the lost mesothelium in mice. Depletion of this macrophage subset or blockage of CD11b impairs the macrophage barrier and exacerbates adhesions. The macrophage barrier is usually insufficient to fully preclude the adhesion formation; however, it could be augmented by IL-4-based treatment or adoptive transfer of this macrophage subset, resulting in robust prevention of adhesions. By contrast, monocyte-derived recruited peritoneal macrophages are not involved in the macrophage barrier. These results highlight a previously unidentified cell barrier function of a specific macrophage subset, also proposing an innovative approach to prevent post-operative adhesions.- Published
- 2021
- Full Text
- View/download PDF
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