78 results on '"Kumasaka N"'
Search Results
2. Magnetic properties of multilayered Fe-Si films.
- Author
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Kumasaka, N., Saito, N., Shiroishi, Y., Shiiki, K., Fujiwara, H., and Kudo, M.
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- 1984
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3. Wp index: A new substorm index derived from high-resolution geomagnetic field data at low latitude.
- Author
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Nosé, M., Iyemori, T., Wang, L., Hitchman, A., Matzka, J., Feller, M., Egdorf, S., Gilder, S., Kumasaka, N., Koga, K., Matsumoto, H., Koshiishi, H., Cifuentes-Nava, G., Curto, J. J., Segarra, A., and Çelik, C.
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- 2012
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4. A rapidly growing pigmented nail streak resulting in diffuse melanosis of the nail. A possible sign of subungual melanoma in situ.
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Kato, Taizo, Usuba, Yasuko, Takematsu, Hideaki, Kumasaka, Naka, Tanita, Yasuo, Hashimoto, Kumiko, Tomita, Yasushi, Tagami, Hachiro, Kato, T, Usuba, Y, Takematsu, H, Kumasaka, N, Tanita, Y, Hashimoto, K, Tomita, Y, and Tagami, H
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- 1989
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5. Clinicopathological study of acral melanoma in situ in 44 Japanese patients.
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Kato, T., Kumasaka, N., Suetake, T., Tabata, N., and Tagami, H.
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- 1996
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6. Probe type thin film head for perpendicular magnetic recording.
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Shiiki, K., Shiroishi, Y., Shinagawa, K., Kumasaka, N., and Kudo, M.
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- 1984
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7. Malignant melanoma complicated by schwannoma.
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Matsumura, N., Kato, T., Kumasaka, N., Watanabe, M., Kumasaka, K., and Tagami, H.
- Subjects
MELANOMA ,SKIN cancer - Abstract
We report two cases of malignant melanoma associated with a schwannoma. Case 1 is a 32-year-old Japanese man who had a nodular melanoma in his epigastrium, associated with one subcutaneous nodule on the neck and another on the right thigh, both of which were histologically-proven schwannomas. Case 2 is a 48-year-old Japanese woman with an acral lentiginous melanoma on her right sole who later developed a schwannoma of the cerebello-pontine angle. Of all 146 malignant melanoma cases found in our clinic during the past 20 years, 1.4% were associated with a neurogenic tumour, a significant association. [ABSTRACT FROM AUTHOR]
- Published
- 1992
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8. Magnetic properties of multilayered Fe-C film formed by dual ion beam sputtering.
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Kobayashi, T., Nakatani, R., Otomo, S., and Kumasaka, N.
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- 1987
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9. Magnetic properties and corrosion resistance of Fe-based sputtered films.
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Otomo, S., Nakatani, R., Kobayashi, T., and Kumasaka, N.
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- 1987
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10. 5.25 inch floppy disk drive using perpendicular magnetic recording.
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Okuwaki, T., Kugiya, F., Kumasaka, N., Yoshida, K., Tsumita, N., and Tamura, T.
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- 1985
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11. Topical chemotherapy (PUVA) for the relief of uremic pruritus in patients undergoing hemodialysis.
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Uesugi, Y, Kumasaka, N, Okada, Y, Ito, S, Matsumura, N, and Tagami, H
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- 1996
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12. Perpendicular Recording Characteristics of Eight-Turn Probe Type Thin Film Head.
- Author
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Shiroishi, Y., Shiiki, K., Yuitoo, I., Nakamura, H., Hamakawa, Y., and Kumasaka, N.
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- 1985
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13. Disturb properties of exchange-coupled composite plated wires.
- Author
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Sugita, Y., Kumasaka, N., Nishida, H., and Fujiwara, H.
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- 1971
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14. Magnetic Properties of Fe-Si-Ru Sputtered Films.
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Shiiki, K., Shiroishi, Y., Kumasaka, N., and Aoki, S.
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- 1985
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15. Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease
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Christopher L. Bowlus, Sören Mucha, Piotr Milkiewicz, Jennifer G. Sambrook, Michael P. Manns, Peter R. Durie, Daniel J. Gaffney, Catalina Coltescu, Konstantinos N. Lazaridis, David Ellinghaus, Daniel Gotthardt, George F. Mells, Espen Melum, Joseph A. Odin, Mattias Laudes, Cisca Wijmenga, Kris V. Kowdley, Annarosa Floreani, Tejas S. Shah, Richard Sandford, Erik M. Schlicht, Kirsten Muri Boberg, Javier Gutierrez-Achury, Felix Braun, Martina Sterneck, Carl A. Anderson, Tom H. Karlsen, Andre Franke, Velimir A. Luketic, Brijesh Srivastava, Aliya Gulamhusein, Elizabeth C. Goode, Kelly Spiess, Gunnar Jacobs, Olivier Chazouillères, Wolfgang Lieb, Tobias Müller, Andreas Teufel, Trine Folseraas, Roger W. Chapman, Hanns-Ulrich Marschall, David J. Roberts, Christoph Schramm, Sun-Gou Ji, Albert Parés, Mariza de Andrade, Stefan Schreiber, Elizabeth J. Atkinson, Kimmo Kontula, Pietro Invernizzi, Simon M. Rushbrook, Luke Jostins, Carmel Moore, Naga Chalasani, Jimmy Z. Liu, Brian D. Juran, Willem H. Ouwehand, Graeme J.M. Alexander, John E. Eaton, Gideon M. Hirschfield, Natsuhiko Kumasaka, Martti Färkkilä, Annika Bergquist, Kapil B. Chopra, John Danesh, Bertus Eksteen, Tobias J. Weismüller, Rinse K. Weersma, Ulrich Beuers, Severine Vermeire, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Gastroenterology and Hepatology, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Ji, S, Juran, B, Mucha, S, Folseraas, T, Jostins, L, Melum, E, Kumasaka, N, Atkinson, E, Schlicht, E, Liu, J, Shah, T, Gutierrez Achury, J, Boberg, K, Bergquist, A, Vermeire, S, Eksteen, B, Durie, P, Farkkila, M, Müller, T, Schramm, C, Sterneck, M, Weismüller, T, Gotthardt, D, Ellinghaus, D, Braun, F, Teufel, A, Laudes, M, Lieb, W, Jacobs, G, Beuers, U, Weersma, R, Wijmenga, C, Marschall, H, Milkiewicz, P, Pares, A, Kontula, K, Chazouillères, O, Invernizzi, P, Goode, E, Spiess, K, Moore, C, Sambrook, J, Ouwehand, W, Roberts, D, Danesh, J, Floreani, A, Gulamhusein, A, Eaton, J, Schreiber, S, Coltescu, C, Bowlus, C, Luketic, V, Odin, J, Chopra, K, Kowdley, K, Chalasani, N, Manns, M, Srivastava, B, Mells, G, Sandford, R, Alexander, G, Gaffney, D, Chapman, R, Hirschfield, G, de Andrade, M, Rushbrook, S, Franke, A, Karlsen, T, Lazaridis, K, Anderson, C, and Universitat de Barcelona
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0301 basic medicine ,Genome-wide association study ,VARIANTS ,Bioinformatics ,Gastroenterology ,Inflammatory bowel disease ,0302 clinical medicine ,Risk Factors ,Gastroenterologia ,education.field_of_study ,digestive, oral, and skin physiology ,REGIONS ,Ulcerative colitis ,Inflamació ,3. Good health ,Malalties inflamatòries intestinals ,ULCERATIVE-COLITIS ,030211 gastroenterology & hepatology ,medicine.medical_specialty ,SUSCEPTIBILITY LOCI ,Population ,Cholangitis, Sclerosing ,Locus (genetics) ,Biology ,Inflammatory bowel diseases ,digestive system ,Polymorphism, Single Nucleotide ,Article ,Primary sclerosing cholangitis ,03 medical and health sciences ,Internal medicine ,REVEALS ,Genetics ,medicine ,SNP ,Humans ,RNA, Messenger ,Allele ,TRANSCRIPTOME ,education ,METAANALYSIS ,Alleles ,Adaptor Proteins, Signal Transducing ,Inflammation ,medicine.disease ,Inflammatory Bowel Diseases ,digestive system diseases ,030104 developmental biology ,PSORIATIC-ARTHRITIS ,Colitis, Ulcerative ,Genome-Wide Association Study - Abstract
Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; similar to 75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (r(G)) between PSC and ulcerative colitis (UC) (r(G) = 0.29) was significantly greater than that between PSC and Crohn's disease (CD) (r(G) = 0.04) (P = 2.55 x 10(-15)). UC and CD were genetically more similar to each other (r(G) = 0.56) than either was to PSC (P
- Published
- 2016
16. Genetic association mapping leveraging Gaussian processes.
- Author
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Kumasaka N
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- Humans, Normal Distribution, Genetic Predisposition to Disease, Genome-Wide Association Study methods, Chromosome Mapping methods, Genetic Association Studies methods, Genetic Variation, Models, Genetic
- Abstract
Gaussian processes (GPs) are a powerful and useful approach for modelling nonlinear phenomena in various scientific fields, including genomics and genetics. This review focuses on the application of GPs in genetic association mapping. The aim is to identify genetic variants that alter gene regulation along continuous cellular states at the molecular level, as well as disease susceptibility over time and space at the population level. The challenges and opportunities in this field are also addressed., (© 2024. The Author(s).)
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- 2024
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17. Parental stress and food allergy phenotypes in young children: A National Birth Cohort (JECS).
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Yamamoto-Hanada K, Pak K, Iwamoto S, Konishi M, Saito-Abe M, Sato M, Miyaji Y, Mezawa H, Nishizato M, Yang L, Kumasaka N, and Ohya Y
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- Humans, Female, Male, Child, Preschool, Birth Cohort, Japan epidemiology, Infant, Surveys and Questionnaires, Adult, Cohort Studies, Food Hypersensitivity epidemiology, Food Hypersensitivity psychology, Food Hypersensitivity diagnosis, Parents psychology, Stress, Psychological epidemiology, Phenotype
- Abstract
Background: Food allergy children and their families tend to have emotional distress and anxiety. There have been few reports of differences in parenting stress and a child's food allergy phenotypes., Methods: We examined the associations between food allergy phenotypes in children and parenting stress assessed by the Parenting Stress Index-Short Form (PSI-SF) from a national birth cohort (Japan Environment and Children's Study)., Results: We included 65,805 children for statistical analysis. Of them, 7.2% of children had a food allergy diagnosis at 2 years old. The means of the total PSI-SF (39.9 ± 10.3, 39.1 ± 9.9), CD-SF (19.5 ± 5.4, 19.1 ± 5.2), and PD-SF (20.5 ± 6.3, 20.0 ± 6.1) scores are similar for caregivers in the with and without food allergy groups. Food allergy diagnosis resulted in significantly higher total PSI scores (coefficient .47, 95% CI 0.19-0.75, p = .001), CD-SF (coefficient .22, 95% CI 0.07-0.38, p = .004), and PD-SF (coefficient .24, 95% CI 0.08-0.41, p = .004). A similar trend was observed for allergy reactions to hen's egg. However, there was no clear relationship between allergic reactions to milk, wheat, nuts, and PSI-SF., Conclusions: Parental stress was significantly related to a child's food allergy. Furthermore, hen's egg allergy increased parental stress. Multiple food avoidance might also increase parental stress. Healthcare providers need to be aware of parental stress in our daily clinic., (© 2024 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)
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- 2024
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18. Human skeletal muscle aging atlas.
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Kedlian VR, Wang Y, Liu T, Chen X, Bolt L, Tudor C, Shen Z, Fasouli ES, Prigmore E, Kleshchevnikov V, Pett JP, Li T, Lawrence JEG, Perera S, Prete M, Huang N, Guo Q, Zeng X, Yang L, Polański K, Chipampe NJ, Dabrowska M, Li X, Bayraktar OA, Patel M, Kumasaka N, Mahbubani KT, Xiang AP, Meyer KB, Saeb-Parsy K, Teichmann SA, and Zhang H
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- Humans, Animals, Mice, Adult, Aged, Sarcopenia pathology, Sarcopenia metabolism, Male, Neuromuscular Junction metabolism, Middle Aged, Female, Aging physiology, Muscle, Skeletal metabolism, Muscle, Skeletal physiology
- Abstract
Skeletal muscle aging is a key contributor to age-related frailty and sarcopenia with substantial implications for global health. Here we profiled 90,902 single cells and 92,259 single nuclei from 17 donors to map the aging process in the adult human intercostal muscle, identifying cellular changes in each muscle compartment. We found that distinct subsets of muscle stem cells exhibit decreased ribosome biogenesis genes and increased CCL2 expression, causing different aging phenotypes. Our atlas also highlights an expansion of nuclei associated with the neuromuscular junction, which may reflect re-innervation, and outlines how the loss of fast-twitch myofibers is mitigated through regeneration and upregulation of fast-type markers in slow-twitch myofibers with age. Furthermore, we document the function of aging muscle microenvironment in immune cell attraction. Overall, we present a comprehensive human skeletal muscle aging resource ( https://www.muscleageingcellatlas.org/ ) together with an in-house mouse muscle atlas to study common features of muscle aging across species., (© 2024. The Author(s).)
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- 2024
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19. Teenage and young adult pregnancy and depression: findings from the Japan environment and children's study.
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Ishitsuka K, Yamamoto-Hanada K, Mezawa H, Yang L, Saito-Abe M, Nishizato M, Sato M, Miyaji Y, Kumasaka N, Ohya Y, Kamijima M, Yamazaki S, Kishi R, Yaegashi N, Hashimoto K, Mori C, Ito S, Yamagata Z, Inadera H, Nakayama T, Iso H, Shima M, Nakamura H, Suganuma N, Kusuhara K, and Katoh T
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- Child, Adolescent, Pregnancy, Female, Young Adult, Humans, Adult, Japan epidemiology, Prospective Studies, Pregnant Women psychology, Depression epidemiology, Pregnancy in Adolescence
- Abstract
Teenage pregnancy increases the threat of depression because of its many factors. Pregnancy during young adulthood may also have several risk factors for depression compared to older pregnancies. However, data on depression in young adult pregnancies are lacking. This study investigated the association between teenage and young adult pregnancy and depression. Data from the Japan Environment and Children's study was used as a nationwide multicenter prospective cohort study. A multivariate logistic regression was performed to investigate the association between age groups (14-19, 20-24, 25-29, 30-34, ≥ 35 years) and depression, adjusted for behavioral and sociodemographic characteristics. Depression was assessed using the Kessler Psychological Distress Scale. In total, 96,808 pregnant women responded to the questionnaire. Teenage (14-19 years) and young adult (20-24 years) pregnancy were associated with an increased risk of depression compared to older pregnancy (≥ 35 years) (teenage: OR 4.28, 95% confidence interval, CI [3.24-5.64]; young adult: OR 3.00, 95% CI [2.64-3.41]). After adjusting for covariates, the magnitude of the risk of depression was attenuated. However, teenage and young adult pregnancy remained at a significantly increased risk of depression compared to older pregnancy (teenage: OR 2.38, 95% CI [1.77-3.21]; young adult: OR 2.14, 95% CI [1.87-2.46]). Our findings indicate that teenage and young adults' pregnancy are at an increased risk of depression compared to older pregnancy. These findings suggest prioritizing teenage and young pregnant women for prevention and interventions related to depression., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)
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- 2024
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20. Effect of PCDH19 missense mutations on cell-to-cell proximity and neuronal development under heterotypic conditions.
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Motosugi N, Sugiyama A, Otomo A, Sakata Y, Araki T, Hadano S, Kumasaka N, and Fukuda A
- Abstract
The mutation of the X-linked protocadherin (PCDH) 19 gene in heterozygous females causes epilepsy. However, because of the erosion of X-chromosome inactivation (XCI) in female human pluripotent stem cells, precise disease modeling often leads to failure. In this study, using a mathematical approach and induced pluripotent stem cells retaining XCI derived from patients with PCDH19 missense mutations, we found that heterotypic conditions, which are composed of wild-type and missense PCDH19, led to significant cell-to-cell proximity and impaired neuronal differentiation, accompanied by the aberrant accumulation of doublecortin, a microtubule-associated protein. Our findings suggest that ease of adhesion between cells expressing either wild-type or missense PCDH19 might lead to aberrant cell aggregation in early embryonic phases, causing poor neuronal development., (© The Author(s) 2024. Published by Oxford University Press on behalf of National Academy of Sciences.)
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- 2024
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21. Spatially resolved multiomics of human cardiac niches.
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Kanemaru K, Cranley J, Muraro D, Miranda AMA, Ho SY, Wilbrey-Clark A, Patrick Pett J, Polanski K, Richardson L, Litvinukova M, Kumasaka N, Qin Y, Jablonska Z, Semprich CI, Mach L, Dabrowska M, Richoz N, Bolt L, Mamanova L, Kapuge R, Barnett SN, Perera S, Talavera-López C, Mulas I, Mahbubani KT, Tuck L, Wang L, Huang MM, Prete M, Pritchard S, Dark J, Saeb-Parsy K, Patel M, Clatworthy MR, Hübner N, Chowdhury RA, Noseda M, and Teichmann SA
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- Humans, Cell Communication, Fibroblasts cytology, Glutamic Acid metabolism, Ion Channels metabolism, Myocytes, Cardiac cytology, Neuroglia cytology, Pericardium cytology, Pericardium immunology, Plasma Cells immunology, Receptors, G-Protein-Coupled metabolism, Sinoatrial Node anatomy & histology, Sinoatrial Node cytology, Sinoatrial Node physiology, Heart Conduction System anatomy & histology, Heart Conduction System cytology, Heart Conduction System metabolism, Cellular Microenvironment, Heart anatomy & histology, Heart innervation, Multiomics, Myocardium cytology, Myocardium immunology, Myocardium metabolism
- Abstract
The function of a cell is defined by its intrinsic characteristics and its niche: the tissue microenvironment in which it dwells. Here we combine single-cell and spatial transcriptomics data to discover cellular niches within eight regions of the human heart. We map cells to microanatomical locations and integrate knowledge-based and unsupervised structural annotations. We also profile the cells of the human cardiac conduction system
1 . The results revealed their distinctive repertoire of ion channels, G-protein-coupled receptors (GPCRs) and regulatory networks, and implicated FOXP2 in the pacemaker phenotype. We show that the sinoatrial node is compartmentalized, with a core of pacemaker cells, fibroblasts and glial cells supporting glutamatergic signalling. Using a custom CellPhoneDB.org module, we identify trans-synaptic pacemaker cell interactions with glia. We introduce a druggable target prediction tool, drug2cell, which leverages single-cell profiles and drug-target interactions to provide mechanistic insights into the chronotropic effects of drugs, including GLP-1 analogues. In the epicardium, we show enrichment of both IgG+ and IgA+ plasma cells forming immune niches that may contribute to infection defence. Overall, we provide new clarity to cardiac electro-anatomy and immunology, and our suite of computational approaches can be applied to other tissues and organs., (© 2023. The Author(s).)- Published
- 2023
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22. Genome-wide association study of preterm birth and gestational age in a Japanese population.
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Hasegawa K, Kumasaka N, Nakabayashi K, Kamura H, Maehara K, Kasuga Y, Hata K, and Tanaka M
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Preterm birth (PTB), defined as the birth of a baby at <37 weeks of gestation, is known to be the main cause of neonatal morbidity and mortality. Here, we report genetic associations between preterm birth and gestational age in a Japanese population. We conducted a genome-wide association study (GWAS) of 384 cases who delivered prematurely and 644 controls and considered gestational age as a quantitative trait in 1028 Japanese women. Unfortunately, we were unable to identify any significant variants associated with PTB or gestational age using the current sample. We also examined genetic associations previously reported in European populations and identified no associations, even with the genome-wide subthreshold (p value < 10
-6 ). This data report aims to provide summary statistics of current GWASs on PTB in a Japanese population for future meta-analyses of genetics and PTB with larger sample sizes., (© 2023. The Author(s).)- Published
- 2023
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23. Mapping interindividual dynamics of innate immune response at single-cell resolution.
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Kumasaka N, Rostom R, Huang N, Polanski K, Meyer KB, Patel S, Boyd R, Gomez C, Barnett SN, Panousis NI, Schwartzentruber J, Ghoussaini M, Lyons PA, Calero-Nieto FJ, Göttgens B, Barnes JL, Worlock KB, Yoshida M, Nikolić MZ, Stephenson E, Reynolds G, Haniffa M, Marioni JC, Stegle O, Hagai T, and Teichmann SA
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- Humans, Genome-Wide Association Study, Immunity, Innate, COVID-19, Autoimmune Diseases, Pentaerythritol Tetranitrate
- Abstract
Common genetic variants across individuals modulate the cellular response to pathogens and are implicated in diverse immune pathologies, yet how they dynamically alter the response upon infection is not well understood. Here, we triggered antiviral responses in human fibroblasts from 68 healthy donors, and profiled tens of thousands of cells using single-cell RNA-sequencing. We developed GASPACHO (GAuSsian Processes for Association mapping leveraging Cell HeterOgeneity), a statistical approach designed to identify nonlinear dynamic genetic effects across transcriptional trajectories of cells. This approach identified 1,275 expression quantitative trait loci (local false discovery rate 10%) that manifested during the responses, many of which were colocalized with susceptibility loci identified by genome-wide association studies of infectious and autoimmune diseases, including the OAS1 splicing quantitative trait locus in a COVID-19 susceptibility locus. In summary, our analytical approach provides a unique framework for delineation of the genetic variants that shape a wide spectrum of transcriptional responses at single-cell resolution., (© 2023. The Author(s).)
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- 2023
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24. Maternal Dietary Zinc Intake during Pregnancy and Childhood Allergic Diseases up to Four Years: The Japan Environment and Children's Study.
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Yang L, Sato M, Saito-Abe M, Miyaji Y, Shimada M, Sato C, Nishizato M, Kumasaka N, Mezawa H, Yamamoto-Hanada K, Ohya Y, and The Japan Environment And Children's Study Jecs Group
- Subjects
- Pregnancy, Female, Humans, Child, Child, Preschool, Japan epidemiology, Zinc, Diet adverse effects, Asthma, Food Hypersensitivity epidemiology, Prenatal Exposure Delayed Effects
- Abstract
Maternal dietary zinc intake and childhood allergy have inconsistent relationships. Thus, this study aimed to evaluate the influence of low maternal dietary zinc intake during pregnancy on developing pediatric allergic diseases. This study was designed using the Japan Environment and Children's Study dataset. The model building used data from 74,948 mother-child pairs. Maternal dietary zinc intake was estimated based on the food frequency questionnaire, collecting the intake information of 171 food and beverage items. Fitted logistic regression models and generalized estimating equation models (GEEs) estimated the association between energy-adjusted zinc intake and childhood allergic conditions. The energy-adjusted zinc intake did not affect the risk of developing allergic disorders (wheeze, asthma, atopic dermatitis, rhinitis, and food allergy) in offspring. The GEE model revealed similar insignificant odds ratios. No significant association was found between zinc intake during pregnancy and allergic diseases in offspring in early childhood. Further study remains necessary to examine the association between zinc and allergy with reliable zinc status biomarkers in the body.
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- 2023
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25. Endotoxin concentration and persistent eczema in early childhood.
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Irahara M, Yamamoto-Hanada K, Sato M, Saito-Abe M, Miyaji Y, Yang L, Nishizato M, Kumasaka N, Mezawa H, and Ohya Y
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- Child, Humans, Child, Preschool, Infant, Endotoxins adverse effects, Dust, Dermatitis, Atopic epidemiology, Dermatitis, Atopic etiology, Prurigo complications, Eczema etiology, Eczema complications
- Abstract
Although endotoxin concentration in the environment is negatively associated with atopic dermatitis (AD) onset in early childhood, the association between endotoxin concentration in the environment and eczema resolution in children with preexisting eczema is unclear. The aim of this study was to evaluate the association between endotoxin concentration in house dust and eczema persistence in young children. The authors used data from children participating in JECS (Japan Environment and Children's Study). In children who had AD or AD-like lesions at the age of 1 year, the authors investigated the association between the prevalence of eczema at the age of 3 years and endotoxin concentration (categorized by quartiles) in the dust on children's mattresses at the ages of 1.5 and 3 years. This study included 605 children. Eczema was significantly less prevalent among children whose mattresses were in the second and third quartiles of endotoxin concentration when they were 18 months old than among children whose mattresses were in the first quartile (adjusted odds ratio, 0.57 [95% confidence interval, 0.35-0.93] and adjusted odds ratio, 0.49 [95% confidence interval, 0.29-0.83], respectively). Moreover, of the children with eczema at age 3 years, those whose mattresses had endotoxin concentrations in the first quartile had significantly worse sleep disturbance caused by itchy rash (>1 time per week) than did those whose mattresses were in the third and fourth quartiles (20.0% vs 3.3% and 3.7%, both p values < 0.01). The findings indicate that low endotoxin exposure is associated with a higher prevalence of persistent eczema during early childhood., (© 2022 Japanese Dermatological Association.)
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- 2023
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26. Prenatal antibiotic use, caesarean delivery and offspring's food protein-induced enterocolitis syndrome: A National Birth Cohort (JECS).
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Yamamoto-Hanada K, Pak K, Saito-Abe M, Sato M, Miyaji Y, Mezawa H, Nishizato M, Yang L, Kumasaka N, Nomura I, and Ohya Y
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- Female, Pregnancy, Humans, Body Mass Index, Cesarean Section adverse effects, Birth Cohort, Overweight
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- 2023
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27. Relationship between Food Allergy and Endotoxin Concentration and the Toleration Status at 2 Years: The Japan Environment and Children's Study.
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Irahara M, Yamamoto-Hanada K, Sato M, Saito-Abe M, Miyaji Y, Yang L, Nishizato M, Kumasaka N, Mezawa H, Ohya Y, and On Behalf Of The Japan Environment And Children's Study Jecs Group
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- Cattle, Animals, Female, Chickens, Japan, Allergens, Food Hypersensitivity, Egg Hypersensitivity, Milk Hypersensitivity, Eczema
- Abstract
Changes in household endotoxin concentration may affect the prognosis of food allergy (FA), but data on the association between household endotoxin concentration and an already-developed FA are scarce. Thus, we investigated the association between environmental endotoxin exposure and tolerance to hen's egg (HE) and cow's milk (CM) using data from children participating in the Japan Environment and Children's Study who had HE allergies ( n = 204) and CM allergy ( n = 72) in their first year of life. We grouped the endotoxin results into quartiles 1-4 (Q1-Q4). In children with HE allergy and with CM allergy, there was no significant difference in the prevalence of tolerance to HE and CM at 2 years old when comparing endotoxin levels of the children in Q1 with those in Q2, Q3, and Q4, respectively. However, subgroup analyses by the presence of eczema and causal foods revealed that children in Q1 had a lower prevalence of tolerance to foods in some subgroup analyses and lower causal allergen-specific immunoglobulin G4 levels. Although an individually based approach against endotoxin according to background characteristics, such as eczema and causal foods, is necessary, preventing excessive endotoxin removal might contribute to FA resolution in some children.
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- 2023
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28. A spatially resolved atlas of the human lung characterizes a gland-associated immune niche.
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Madissoon E, Oliver AJ, Kleshchevnikov V, Wilbrey-Clark A, Polanski K, Richoz N, Ribeiro Orsi A, Mamanova L, Bolt L, Elmentaite R, Pett JP, Huang N, Xu C, He P, Dabrowska M, Pritchard S, Tuck L, Prigmore E, Perera S, Knights A, Oszlanczi A, Hunter A, Vieira SF, Patel M, Lindeboom RGH, Campos LS, Matsuo K, Nakayama T, Yoshida M, Worlock KB, Nikolić MZ, Georgakopoulos N, Mahbubani KT, Saeb-Parsy K, Bayraktar OA, Clatworthy MR, Stegle O, Kumasaka N, Teichmann SA, and Meyer KB
- Subjects
- Humans, Epithelial Cells metabolism, B-Lymphocytes, Immunoglobulin A metabolism, Respiratory Mucosa metabolism, Lung
- Abstract
Single-cell transcriptomics has allowed unprecedented resolution of cell types/states in the human lung, but their spatial context is less well defined. To (re)define tissue architecture of lung and airways, we profiled five proximal-to-distal locations of healthy human lungs in depth using multi-omic single cell/nuclei and spatial transcriptomics (queryable at lungcellatlas.org ). Using computational data integration and analysis, we extend beyond the suspension cell paradigm and discover macro and micro-anatomical tissue compartments including previously unannotated cell types in the epithelial, vascular, stromal and nerve bundle micro-environments. We identify and implicate peribronchial fibroblasts in lung disease. Importantly, we discover and validate a survival niche for IgA plasma cells in the airway submucosal glands (SMG). We show that gland epithelial cells recruit B cells and IgA plasma cells, and promote longevity and antibody secretion locally through expression of CCL28, APRIL and IL-6. This new 'gland-associated immune niche' has implications for respiratory health., (© 2022. The Author(s).)
- Published
- 2023
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29. Congenital hypothyroidism and thyroid function in a Japanese birth cohort: data from The Japan Environment and Children's Study.
- Author
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Yang L, Sato M, Saito-Abe M, Miyaji Y, Sato C, Nishizato M, Kumasaka N, Mezawa H, Yamamoto-Hanada K, and Ohya Y
- Abstract
The most common hormonal and metabolic disease in early childhood is congenital hypothyroidism (CH). This study aimed to describe CH in large-scale birth cohort data and summarize the results of serum thyroid-stimulating hormone (TSH) and free thyroxine (fT4) levels in 2-yr-old children. Data were obtained from the Japan Environment and Children's Study (JECS), and we identified 171 children with CH detected in newborn screenings or medical records (170.5 per 100,000 population). Infants with CH are at higher risk of developing congenital diseases than those without CH. Of 171 children with CH, 20 (11.7%) were diagnosed with congenital heart defects, 33 (19.3%) had chromosomal or other congenital abnormalities, and 23 (13.5%) had Down syndrome. At the age of 2 yr old, the median and 95% reference range values for TSH and fT4 were 2.13 (0.78-5.52) μIU/mL and 1.2 (1.0-1.5) ng/dL, respectively. Moreover, boys had slightly higher TSH and fT4 levels than did girls. Data on the distribution of TSH and fT4 in 2-yr-old children should be useful for decreasing the misclassification of thyroid disorders in the pediatric population. Trial-off treatment and re-evaluation of thyroid function are needed to classify permanent congenital hypothyroidism and transient congenital hypothyroidism after 3 yr of age., Competing Interests: The authors declare no conflict of interest., (2023©The Japanese Society for Pediatric Endocrinology.)
- Published
- 2023
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30. Allergic Disorders and Risk of Anemia in Japanese Children: Findings from the Japan Environment and Children's Study.
- Author
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Yang L, Sato M, Saito-Abe M, Miyaji Y, Shimada M, Sato C, Nishizato M, Kumasaka N, Mezawa H, Yamamoto-Hanada K, Ohya Y, and On Behalf Of The Japan Environment And Children's Study Jecs Group
- Subjects
- Child, Humans, Child, Preschool, Japan epidemiology, Cross-Sectional Studies, Dermatitis, Atopic, Rhinitis, Allergic complications, Rhinitis, Allergic epidemiology, Anemia epidemiology, Anemia etiology
- Abstract
Previous epidemiological studies have reported an increased risk of anemia in people with allergic disorders. However, previous studies have followed a cross-sectional design. The aim of this study was to investigate the association between the two conditions with a cohort dataset. We used data of 80,943 children in the Japan Environment and Children's Study, the largest birth cohort in Japan. The association between anemia and allergic disorders was evaluated with a logistic regression model and propensity score analysis. After adjusting for potential confounders, children with asthma (odds ratio [OR], 1.85; 95% confidence interval [CI], 1.32-2.60), atopic dermatitis (OR, 2.18; 95% CI, 1.66-2.85), allergic rhinitis (OR, 1.35; 95% CI, 1.05-1.74), allergic rhinoconjunctivitis (OR, 2.95; 95% CI, 1.91-4.54), and food allergies (OR, 1.92; 95% CI, 1.44-2.56) at 2 years of age predicted high odds of developing anemia in the next year. Any allergy at 2 years of age was associated with an increased risk of anemia at the age of 3 years (OR, 1.80; 95% CI, 1.41-2.29). The findings remained stable in the propensity score analysis. Results suggest that allergic diseases were related to caregiver-reported anemia in children.
- Published
- 2022
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31. How a Family History of Allergic Diseases Influences Food Allergy in Children: The Japan Environment and Children's Study.
- Author
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Saito-Abe M, Yamamoto-Hanada K, Pak K, Iwamoto S, Sato M, Miyaji Y, Mezawa H, Nishizato M, Yang L, Kumasaka N, Kobayashi T, Ohya Y, and On Behalf Of The Japan Environment And Children's Study Jecs Group
- Subjects
- Child, Female, Humans, Cohort Studies, Japan epidemiology, Dermatitis, Atopic etiology, Dermatitis, Atopic genetics, Food Hypersensitivity epidemiology, Food Hypersensitivity complications, Asthma epidemiology, Asthma etiology
- Abstract
The influence of family allergic history on food allergy in offspring in Japan is unknown. We analyzed data from a nationwide birth cohort study using logistic regression models to examine the associations of maternal, paternal, and both parental histories of allergic diseases (food allergy, atopic dermatitis, asthma, and rhinitis) with their child’s food allergy at 1.5 and 3 years of age. This analysis included 69,379 singleton full-term mothers and 37,179 fathers and their children. All parental histories of allergic diseases showed significant positive associations with their child’s food allergy. When both parents had a history of allergic diseases, the adjusted odds ratio (aOR) tended to be higher than when either parent had allergic diseases (p for trend < 0.0001). The highest aOR was detected when both parents had food allergy (2.60; 95% confidential interval, 1.58−4.27), and the aOR was 1.71 when either parent had food allergy (95% confidential interval, 1.54−1.91). The aORs were attenuated but still had significant positive associations after adjusting for the child’s atopic dermatitis, a risk factor for allergy development. In conclusion, all parental allergic diseases were significantly positively associated with their child’s food allergy. The effect of family history showed a stepwise increase in risk from either parent to both parents, and the highest risk of allergic disease was a parental history of food allergy.
- Published
- 2022
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32. Smoking Exposure Is Associated with Serum Vitamin D Deficiency in Children: Evidence from the Japan Environment and Children's Study.
- Author
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Yang L, Sato M, Saito-Abe M, Miyaji Y, Sato C, Nishizato M, Kumasaka N, Mezawa H, Yamamoto-Hanada K, and Ohya Y
- Subjects
- Child, Child, Preschool, Cohort Studies, Humans, Japan epidemiology, Smoking, Vitamin D, Tobacco Smoke Pollution adverse effects, Vitamin D Deficiency epidemiology
- Abstract
Tobacco smoke exposure is known to lower serum 25-hydroxyvitamin D (25(OH)D) concentrations. This study evaluated the association between passive smoking and vitamin D deficiency (VDD) in young children using data from the Japan Environment and Children's Study (JECS), the largest birth cohort study in Japan. Information on parental smoking status was extracted from a survey of JECS for children aged 1.5 years and data for serum 25(OH)D concentrations were obtained from blood tests in the Sub-Cohort Study of JECS performed at age 2 years. Logistic regression and linear models were fitted to evaluate the association between these variables. Data were analyzed for 4593 children. After adjusting for covariates, smoke exposure was significantly associated with increased incidence of VDD (OR 1.35; 95% CI, 1.14-1.59) according to the logistic model. The linear model indicated that passive smoking negatively predicted de-seasonalized serum 25(OH)D concentrations (β -0.5; 95% CI -0.95 to -0.08) in children aged 2 years. The results suggest that smoke exposure is a risk factor for VDD in children. Given that VD plays a crucial role in bone metabolism and the immune system, our findings are significant for clinical and public health.
- Published
- 2022
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33. Local and systemic responses to SARS-CoV-2 infection in children and adults.
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Yoshida M, Worlock KB, Huang N, Lindeboom RGH, Butler CR, Kumasaka N, Dominguez Conde C, Mamanova L, Bolt L, Richardson L, Polanski K, Madissoon E, Barnes JL, Allen-Hyttinen J, Kilich E, Jones BC, de Wilton A, Wilbrey-Clark A, Sungnak W, Pett JP, Weller J, Prigmore E, Yung H, Mehta P, Saleh A, Saigal A, Chu V, Cohen JM, Cane C, Iordanidou A, Shibuya S, Reuschl AK, Herczeg IT, Argento AC, Wunderink RG, Smith SB, Poor TA, Gao CA, Dematte JE, Reynolds G, Haniffa M, Bowyer GS, Coates M, Clatworthy MR, Calero-Nieto FJ, Göttgens B, O'Callaghan C, Sebire NJ, Jolly C, De Coppi P, Smith CM, Misharin AV, Janes SM, Teichmann SA, Nikolić MZ, and Meyer KB
- Subjects
- Adult, Bronchi immunology, Bronchi virology, COVID-19 pathology, Chicago, Cohort Studies, Disease Progression, Epithelial Cells cytology, Epithelial Cells immunology, Epithelial Cells virology, Female, Humans, Immunity, Innate, London, Male, Nasal Mucosa immunology, Nasal Mucosa virology, SARS-CoV-2 growth & development, Single-Cell Analysis, Trachea virology, Young Adult, COVID-19 blood, COVID-19 immunology, Dendritic Cells immunology, Interferons immunology, Killer Cells, Natural immunology, SARS-CoV-2 immunology, T-Lymphocytes, Cytotoxic immunology
- Abstract
It is not fully understood why COVID-19 is typically milder in children
1-3 . Here, to examine the differences between children and adults in their response to SARS-CoV-2 infection, we analysed paediatric and adult patients with COVID-19 as well as healthy control individuals (total n = 93) using single-cell multi-omic profiling of matched nasal, tracheal, bronchial and blood samples. In the airways of healthy paediatric individuals, we observed cells that were already in an interferon-activated state, which after SARS-CoV-2 infection was further induced especially in airway immune cells. We postulate that higher paediatric innate interferon responses restrict viral replication and disease progression. The systemic response in children was characterized by increases in naive lymphocytes and a depletion of natural killer cells, whereas, in adults, cytotoxic T cells and interferon-stimulated subpopulations were significantly increased. We provide evidence that dendritic cells initiate interferon signalling in early infection, and identify epithelial cell states associated with COVID-19 and age. Our matching nasal and blood data show a strong interferon response in the airways with the induction of systemic interferon-stimulated populations, which were substantially reduced in paediatric patients. Together, we provide several mechanisms that explain the milder clinical syndrome observed in children., (© 2021. The Author(s).)- Published
- 2022
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34. Cells of the human intestinal tract mapped across space and time.
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Elmentaite R, Kumasaka N, Roberts K, Fleming A, Dann E, King HW, Kleshchevnikov V, Dabrowska M, Pritchard S, Bolt L, Vieira SF, Mamanova L, Huang N, Perrone F, Goh Kai'En I, Lisgo SN, Katan M, Leonard S, Oliver TRW, Hook CE, Nayak K, Campos LS, Domínguez Conde C, Stephenson E, Engelbert J, Botting RA, Polanski K, van Dongen S, Patel M, Morgan MD, Marioni JC, Bayraktar OA, Meyer KB, He X, Barker RA, Uhlig HH, Mahbubani KT, Saeb-Parsy K, Zilbauer M, Clatworthy MR, Haniffa M, James KR, and Teichmann SA
- Subjects
- Adult, Animals, Child, Crohn Disease pathology, Datasets as Topic, Enteric Nervous System anatomy & histology, Enteric Nervous System embryology, Enteric Nervous System growth & development, Epithelial Cells cytology, Female, Fetus anatomy & histology, Fetus embryology, Humans, Intestines embryology, Intestines innervation, Lymph Nodes embryology, Lymph Nodes pathology, Mice, Mice, Inbred C57BL, Organogenesis, Receptors, IgG metabolism, Signal Transduction, Spatio-Temporal Analysis, Time Factors, Aging, Enteric Nervous System cytology, Fetus cytology, Health, Intestines cytology, Intestines growth & development, Lymph Nodes cytology, Lymph Nodes growth & development
- Abstract
The cellular landscape of the human intestinal tract is dynamic throughout life, developing in utero and changing in response to functional requirements and environmental exposures. Here, to comprehensively map cell lineages, we use single-cell RNA sequencing and antigen receptor analysis of almost half a million cells from up to 5 anatomical regions in the developing and up to 11 distinct anatomical regions in the healthy paediatric and adult human gut. This reveals the existence of transcriptionally distinct BEST4 epithelial cells throughout the human intestinal tract. Furthermore, we implicate IgG sensing as a function of intestinal tuft cells. We describe neural cell populations in the developing enteric nervous system, and predict cell-type-specific expression of genes associated with Hirschsprung's disease. Finally, using a systems approach, we identify key cell players that drive the formation of secondary lymphoid tissue in early human development. We show that these programs are adopted in inflammatory bowel disease to recruit and retain immune cells at the site of inflammation. This catalogue of intestinal cells will provide new insights into cellular programs in development, homeostasis and disease., (© 2021. The Author(s).)
- Published
- 2021
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35. A map of transcriptional heterogeneity and regulatory variation in human microglia.
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Young AMH, Kumasaka N, Calvert F, Hammond TR, Knights A, Panousis N, Park JS, Schwartzentruber J, Liu J, Kundu K, Segel M, Murphy NA, McMurran CE, Bulstrode H, Correia J, Budohoski KP, Joannides A, Guilfoyle MR, Trivedi R, Kirollos R, Morris R, Garnett MR, Timofeev I, Jalloh I, Holland K, Mannion R, Mair R, Watts C, Price SJ, Kirkpatrick PJ, Santarius T, Mountjoy E, Ghoussaini M, Soranzo N, Bayraktar OA, Stevens B, Hutchinson PJ, Franklin RJM, and Gaffney DJ
- Subjects
- Alzheimer Disease genetics, Humans, Models, Genetic, Quantitative Trait Loci genetics, Sequence Analysis, RNA, Single-Cell Analysis, Gene Expression Regulation, Microglia metabolism, Transcription, Genetic
- Abstract
Microglia, the tissue-resident macrophages of the central nervous system (CNS), play critical roles in immune defense, development and homeostasis. However, isolating microglia from humans in large numbers is challenging. Here, we profiled gene expression variation in primary human microglia isolated from 141 patients undergoing neurosurgery. Using single-cell and bulk RNA sequencing, we identify how age, sex and clinical pathology influence microglia gene expression and which genetic variants have microglia-specific functions using expression quantitative trait loci (eQTL) mapping. We follow up one of our findings using a human induced pluripotent stem cell-based macrophage model to fine-map a candidate causal variant for Alzheimer's disease at the BIN1 locus. Our study provides a population-scale transcriptional map of a critically important cell for human CNS development and disease.
- Published
- 2021
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36. Single-cell multi-omics analysis of the immune response in COVID-19.
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Stephenson E, Reynolds G, Botting RA, Calero-Nieto FJ, Morgan MD, Tuong ZK, Bach K, Sungnak W, Worlock KB, Yoshida M, Kumasaka N, Kania K, Engelbert J, Olabi B, Spegarova JS, Wilson NK, Mende N, Jardine L, Gardner LCS, Goh I, Horsfall D, McGrath J, Webb S, Mather MW, Lindeboom RGH, Dann E, Huang N, Polanski K, Prigmore E, Gothe F, Scott J, Payne RP, Baker KF, Hanrath AT, Schim van der Loeff ICD, Barr AS, Sanchez-Gonzalez A, Bergamaschi L, Mescia F, Barnes JL, Kilich E, de Wilton A, Saigal A, Saleh A, Janes SM, Smith CM, Gopee N, Wilson C, Coupland P, Coxhead JM, Kiselev VY, van Dongen S, Bacardit J, King HW, Rostron AJ, Simpson AJ, Hambleton S, Laurenti E, Lyons PA, Meyer KB, Nikolić MZ, Duncan CJA, Smith KGC, Teichmann SA, Clatworthy MR, Marioni JC, Göttgens B, and Haniffa M
- Subjects
- Cross-Sectional Studies, Humans, Monocytes immunology, Receptors, Antigen, B-Cell immunology, Receptors, Antigen, T-Cell immunology, T-Lymphocytes immunology, COVID-19 immunology, Proteome, SARS-CoV-2 immunology, Single-Cell Analysis methods, Transcriptome
- Abstract
Analysis of human blood immune cells provides insights into the coordinated response to viral infections such as severe acute respiratory syndrome coronavirus 2, which causes coronavirus disease 2019 (COVID-19). We performed single-cell transcriptome, surface proteome and T and B lymphocyte antigen receptor analyses of over 780,000 peripheral blood mononuclear cells from a cross-sectional cohort of 130 patients with varying severities of COVID-19. We identified expansion of nonclassical monocytes expressing complement transcripts (CD16
+ C1QA/B/C+ ) that sequester platelets and were predicted to replenish the alveolar macrophage pool in COVID-19. Early, uncommitted CD34+ hematopoietic stem/progenitor cells were primed toward megakaryopoiesis, accompanied by expanded megakaryocyte-committed progenitors and increased platelet activation. Clonally expanded CD8+ T cells and an increased ratio of CD8+ effector T cells to effector memory T cells characterized severe disease, while circulating follicular helper T cells accompanied mild disease. We observed a relative loss of IgA2 in symptomatic disease despite an overall expansion of plasmablasts and plasma cells. Our study highlights the coordinated immune response that contributes to COVID-19 pathogenesis and reveals discrete cellular components that can be targeted for therapy.- Published
- 2021
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37. Author Correction: Genome-wide meta-analysis, fine-mapping and integrative prioritization implicate new Alzheimer's disease risk genes.
- Author
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Schwartzentruber J, Cooper S, Liu JZ, Barrio-Hernandez I, Bello E, Kumasaka N, Young AMH, Franklin RJM, Johnson T, Estrada K, Gaffney DJ, Beltrao P, and Bassett A
- Published
- 2021
- Full Text
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38. Genome-wide meta-analysis, fine-mapping and integrative prioritization implicate new Alzheimer's disease risk genes.
- Author
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Schwartzentruber J, Cooper S, Liu JZ, Barrio-Hernandez I, Bello E, Kumasaka N, Young AMH, Franklin RJM, Johnson T, Estrada K, Gaffney DJ, Beltrao P, and Bassett A
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Chromosome Mapping, Cytoskeletal Proteins genetics, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Microglia physiology, Oncogene Proteins genetics, Polymorphism, Single Nucleotide, Protein Interaction Maps genetics, Quantitative Trait Loci, Risk Factors, Tetraspanins genetics, Alzheimer Disease genetics
- Abstract
Genome-wide association studies have discovered numerous genomic loci associated with Alzheimer's disease (AD); yet the causal genes and variants are incompletely identified. We performed an updated genome-wide AD meta-analysis, which identified 37 risk loci, including new associations near CCDC6, TSPAN14, NCK2 and SPRED2. Using three SNP-level fine-mapping methods, we identified 21 SNPs with >50% probability each of being causally involved in AD risk and others strongly suggested by functional annotation. We followed this with colocalization analyses across 109 gene expression quantitative trait loci datasets and prioritization of genes by using protein interaction networks and tissue-specific expression. Combining this information into a quantitative score, we found that evidence converged on likely causal genes, including the above four genes, and those at previously discovered AD loci, including BIN1, APH1B, PTK2B, PILRA and CASS4.
- Published
- 2021
- Full Text
- View/download PDF
39. Population-scale single-cell RNA-seq profiling across dopaminergic neuron differentiation.
- Author
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Jerber J, Seaton DD, Cuomo ASE, Kumasaka N, Haldane J, Steer J, Patel M, Pearce D, Andersson M, Bonder MJ, Mountjoy E, Ghoussaini M, Lancaster MA, Marioni JC, Merkle FT, Gaffney DJ, and Stegle O
- Subjects
- Cell Differentiation genetics, Genetic Predisposition to Disease, Humans, Induced Pluripotent Stem Cells physiology, Neurogenesis genetics, Oxidative Stress drug effects, Receptor, Fibroblast Growth Factor, Type 1 genetics, Rotenone toxicity, Sequence Analysis, RNA, Single-Cell Analysis, Dopaminergic Neurons cytology, Dopaminergic Neurons physiology, Induced Pluripotent Stem Cells cytology, Quantitative Trait Loci, Transcriptome
- Abstract
Studying the function of common genetic variants in primary human tissues and during development is challenging. To address this, we use an efficient multiplexing strategy to differentiate 215 human induced pluripotent stem cell (iPSC) lines toward a midbrain neural fate, including dopaminergic neurons, and use single-cell RNA sequencing (scRNA-seq) to profile over 1 million cells across three differentiation time points. The proportion of neurons produced by each cell line is highly reproducible and is predictable by robust molecular markers expressed in pluripotent cells. Expression quantitative trait loci (eQTL) were characterized at different stages of neuronal development and in response to rotenone-induced oxidative stress. Of these, 1,284 eQTL colocalize with known neurological trait risk loci, and 46% are not found in the Genotype-Tissue Expression (GTEx) catalog. Our study illustrates how coupling scRNA-seq with long-term iPSC differentiation enables mechanistic studies of human trait-associated genetic variants in otherwise inaccessible cell states.
- Published
- 2021
- Full Text
- View/download PDF
40. High-resolution genetic mapping of putative causal interactions between regions of open chromatin.
- Author
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Kumasaka N, Knights AJ, and Gaffney DJ
- Subjects
- Autoimmune Diseases genetics, Bayes Theorem, Chromosome Mapping methods, Chromosomes genetics, Clustered Regularly Interspaced Short Palindromic Repeats genetics, Gene Editing methods, Genome-Wide Association Study methods, High-Throughput Nucleotide Sequencing methods, Humans, Polymorphism, Single Nucleotide genetics, Transposases genetics, Chromatin genetics, Genome, Human genetics, Regulatory Sequences, Nucleic Acid genetics
- Abstract
Physical interaction of regulatory elements in three-dimensional space poses a challenge for studies of disease because non-coding risk variants may be great distances from the genes they regulate. Experimental methods to capture these interactions, such as chromosome conformation capture, usually cannot assign causal direction of effect between regulatory elements, an important component of fine-mapping studies. We developed a Bayesian hierarchical approach that uses two-stage least squares and applied it to an ATAC-seq (assay for transposase-accessible chromatin using sequencing) data set from 100 individuals, to identify over 15,000 high-confidence causal interactions. Most (60%) interactions occurred over <20 kb, where chromosome conformation capture-based methods perform poorly. For a fraction of loci, we identified a single variant that alters accessibility across multiple regions, and experimentally validated the BLK locus, which is associated with multiple autoimmune diseases, using CRISPR genome editing. Our study highlights how association genetics of chromatin state is a powerful approach for identifying interactions between regulatory elements.
- Published
- 2019
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41. Influence of adaptive mutations, from thermal adaptation experiments, on the infection cycle of RNA bacteriophage Qβ.
- Author
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Kashiwagi A, Kadoya T, Kumasaka N, Kumagai T, Tsushima FS, and Yomo T
- Subjects
- Adaptation, Physiological, Escherichia coli virology, Genome, Viral, Hot Temperature, Phenotype, RNA Phages chemistry, RNA Phages physiology, Mutation, RNA Phages genetics
- Abstract
A population's growth rate is determined by multiple 'life history traits'. To quantitatively determine which life history traits should be improved to allow a living organism to adapt to an inhibitory environment is an important issue. Previously, we conducted thermal adaptation experiments on the RNA bacteriophage Qβ using three independent replicates and reported that all three end-point populations could grow at a temperature (43.6°C) that inhibited the growth of the ancestral strain. Even though the fitness values of the endpoint populations were almost the same, their genome sequence was not, indicating that the three thermally adapted populations may have different life history traits. In this study, we introduced each mutation observed in these three end-point populations into the cDNA of the Qβ genome and prepared three different mutants. Quantitative analysis showed that they tended to increase their fitness by increasing the adsorption rate to their host, shortening their latent period (i.e., the duration between phage infection and progeny release), and increasing the burst size (i.e., the number of progeny phages per infected cell), but all three mutants decreased their thermal stability. However, the degree to which these traits changed differed. The mutant with the least mutations showed a smaller decrease in thermal stability, the largest adsorption rate to the host, and the shortest latent period. These results indicated that several different adaptive routes exist by which Qβ can adapt to higher temperatures, even though Qβ is a simple RNA bacteriophage with a small genome size, encoding only four genes.
- Published
- 2018
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42. Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease.
- Author
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Ji SG, Juran BD, Mucha S, Folseraas T, Jostins L, Melum E, Kumasaka N, Atkinson EJ, Schlicht EM, Liu JZ, Shah T, Gutierrez-Achury J, Boberg KM, Bergquist A, Vermeire S, Eksteen B, Durie PR, Farkkila M, Müller T, Schramm C, Sterneck M, Weismüller TJ, Gotthardt DN, Ellinghaus D, Braun F, Teufel A, Laudes M, Lieb W, Jacobs G, Beuers U, Weersma RK, Wijmenga C, Marschall HU, Milkiewicz P, Pares A, Kontula K, Chazouillères O, Invernizzi P, Goode E, Spiess K, Moore C, Sambrook J, Ouwehand WH, Roberts DJ, Danesh J, Floreani A, Gulamhusein AF, Eaton JE, Schreiber S, Coltescu C, Bowlus CL, Luketic VA, Odin JA, Chopra KB, Kowdley KV, Chalasani N, Manns MP, Srivastava B, Mells G, Sandford RN, Alexander G, Gaffney DJ, Chapman RW, Hirschfield GM, de Andrade M, Rushbrook SM, Franke A, Karlsen TH, Lazaridis KN, and Anderson CA
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Alleles, Colitis, Ulcerative genetics, Genome-Wide Association Study methods, Humans, Polymorphism, Single Nucleotide genetics, RNA, Messenger genetics, Risk Factors, Cholangitis, Sclerosing genetics, Inflammatory Bowel Diseases genetics
- Abstract
Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; ∼75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (r
G ) between PSC and ulcerative colitis (UC) (rG = 0.29) was significantly greater than that between PSC and Crohn's disease (CD) (rG = 0.04) (P = 2.55 × 10-15 ). UC and CD were genetically more similar to each other (rG = 0.56) than either was to PSC (P < 1.0 × 10-15 ). Our study represents a substantial advance in understanding of the genetics of PSC.- Published
- 2017
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43. Mutational History of a Human Cell Lineage from Somatic to Induced Pluripotent Stem Cells.
- Author
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Rouhani FJ, Nik-Zainal S, Wuster A, Li Y, Conte N, Koike-Yusa H, Kumasaka N, Vallier L, Yusa K, and Bradley A
- Subjects
- Adult, Cells, Cultured, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Young Adult, Cell Lineage, Induced Pluripotent Stem Cells cytology, Mutation
- Abstract
The accuracy of replicating the genetic code is fundamental. DNA repair mechanisms protect the fidelity of the genome ensuring a low error rate between generations. This sustains the similarity of individuals whilst providing a repertoire of variants for evolution. The mutation rate in the human genome has recently been measured to be 50-70 de novo single nucleotide variants (SNVs) between generations. During development mutations accumulate in somatic cells so that an organism is a mosaic. However, variation within a tissue and between tissues has not been analysed. By reprogramming somatic cells into induced pluripotent stem cells (iPSCs), their genomes and the associated mutational history are captured. By sequencing the genomes of polyclonal and monoclonal somatic cells and derived iPSCs we have determined the mutation rates and show how the patterns change from a somatic lineage in vivo through to iPSCs. Somatic cells have a mutation rate of 14 SNVs per cell per generation while iPSCs exhibited a ten-fold lower rate. Analyses of mutational signatures suggested that deamination of methylated cytosine may be the major mutagenic source in vivo, whilst oxidative DNA damage becomes dominant in vitro. Our results provide insights for better understanding of mutational processes and lineage relationships between human somatic cells. Furthermore it provides a foundation for interpretation of elevated mutation rates and patterns in cancer.
- Published
- 2016
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44. Corrigendum: Fine-mapping cellular QTLs with RASQUAL and ATAC-seq.
- Author
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Kumasaka N, Knights AJ, and Gaffney DJ
- Published
- 2016
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45. Fine-mapping cellular QTLs with RASQUAL and ATAC-seq.
- Author
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Kumasaka N, Knights AJ, and Gaffney DJ
- Subjects
- Genetics, Population, Genomic Imprinting, Genotype, Humans, Polymorphism, Single Nucleotide, White People genetics, High-Throughput Nucleotide Sequencing, Quantitative Trait Loci
- Abstract
When cellular traits are measured using high-throughput DNA sequencing, quantitative trait loci (QTLs) manifest as fragment count differences between individuals and allelic differences within individuals. We present RASQUAL (Robust Allele-Specific Quantitation and Quality Control), a new statistical approach for association mapping that models genetic effects and accounts for biases in sequencing data using a single, probabilistic framework. RASQUAL substantially improves fine-mapping accuracy and sensitivity relative to existing methods in RNA-seq, DNase-seq and ChIP-seq data. We illustrate how RASQUAL can be used to maximize association detection by generating the first map of chromatin accessibility QTLs (caQTLs) in a European population using ATAC-seq. Despite a modest sample size, we identified 2,707 independent caQTLs (at a false discovery rate of 10%) and demonstrated how RASQUAL and ATAC-seq can provide powerful information for fine-mapping gene-regulatory variants and for linking distal regulatory elements with gene promoters. Our results highlight how combining between-individual and allele-specific genetic signals improves the functional interpretation of noncoding variation., Competing Interests: Conflicts of Interest: None declared
- Published
- 2016
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- View/download PDF
46. Epithelial IL-22RA1-mediated fucosylation promotes intestinal colonization resistance to an opportunistic pathogen.
- Author
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Pham TA, Clare S, Goulding D, Arasteh JM, Stares MD, Browne HP, Keane JA, Page AJ, Kumasaka N, Kane L, Mottram L, Harcourt K, Hale C, Arends MJ, Gaffney DJ, Dougan G, and Lawley TD
- Subjects
- Animals, Bacterial Translocation, Citrobacter rodentium physiology, Colitis chemically induced, Disease Susceptibility, Dysbiosis, Enterococcus faecalis physiology, Fucosyltransferases metabolism, Mice, Mice, Knockout, Receptors, Interleukin genetics, Signal Transduction, Galactoside 2-alpha-L-fucosyltransferase, Citrobacter rodentium immunology, Colitis prevention & control, Enterococcus faecalis immunology, Intestinal Mucosa immunology, Intestinal Mucosa metabolism, Microbial Interactions, Receptors, Interleukin metabolism
- Abstract
Our intestinal microbiota harbors a diverse microbial community, often containing opportunistic bacteria with virulence potential. However, mutualistic host-microbial interactions prevent disease by opportunistic pathogens through poorly understood mechanisms. We show that the epithelial interleukin-22 receptor IL-22RA1 protects against lethal Citrobacter rodentium infection and chemical-induced colitis by promoting colonization resistance against an intestinal opportunistic bacterium, Enterococcus faecalis. Susceptibility of Il22ra1(-/-) mice to C. rodentium was associated with preferential expansion and epithelial translocation of pathogenic E. faecalis during severe microbial dysbiosis and was ameloriated with antibiotics active against E. faecalis. RNA sequencing analyses of primary colonic organoids showed that IL-22RA1 signaling promotes intestinal fucosylation via induction of the fucosyltransferase Fut2. Additionally, administration of fucosylated oligosaccharides to C. rodentium-challenged Il22ra1(-/-) mice attenuated infection and promoted E. faecalis colonization resistance by restoring the diversity of anaerobic commensal symbionts. These results support a model whereby IL-22RA1 enhances host-microbiota mutualism to limit detrimental overcolonization by opportunistic pathogens., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
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47. Genetic background drives transcriptional variation in human induced pluripotent stem cells.
- Author
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Rouhani F, Kumasaka N, de Brito MC, Bradley A, Vallier L, and Gaffney D
- Subjects
- Adult, Base Sequence, Cells, Cultured, Endothelial Cells cytology, Epigenomics, Female, Fibroblasts cytology, Humans, Keratinocytes cytology, Male, Sequence Alignment, Sequence Analysis, RNA, Cell Differentiation genetics, Embryonic Stem Cells cytology, Induced Pluripotent Stem Cells cytology, Transcription, Genetic genetics
- Abstract
Human iPS cells have been generated using a diverse range of tissues from a variety of donors using different reprogramming vectors. However, these cell lines are heterogeneous, which presents a limitation for their use in disease modeling and personalized medicine. To explore the basis of this heterogeneity we generated 25 iPS cell lines under normalised conditions from the same set of somatic tissues across a number of donors. RNA-seq data sets from each cell line were compared to identify the majority contributors to transcriptional heterogeneity. We found that genetic differences between individual donors were the major cause of transcriptional variation between lines. In contrast, residual signatures from the somatic cell of origin, so called epigenetic memory, contributed relatively little to transcriptional variation. Thus, underlying genetic background variation is responsible for most heterogeneity between human iPS cell lines. We conclude that epigenetic effects in hIPSCs are minimal, and that hIPSCs are a stable, robust and powerful platform for large-scale studies of the function of genetic differences between individuals. Our data also suggest that future studies using hIPSCs as a model system should focus most effort on collection of large numbers of donors, rather than generating large numbers of lines from the same donor.
- Published
- 2014
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48. A genome-wide association study identifies 2 susceptibility Loci for Crohn's disease in a Japanese population.
- Author
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Yamazaki K, Umeno J, Takahashi A, Hirano A, Johnson TA, Kumasaka N, Morizono T, Hosono N, Kawaguchi T, Takazoe M, Yamada T, Suzuki Y, Tanaka H, Motoya S, Hosokawa M, Arimura Y, Shinomura Y, Matsui T, Matsumoto T, Iida M, Tsunoda T, Nakamura Y, Kamatani N, and Kubo M
- Subjects
- Adult, Age Distribution, Aged, Asian People genetics, Case-Control Studies, Crohn Disease epidemiology, Female, Gene Expression Regulation, Genotype, Humans, Incidence, Japan epidemiology, Male, Middle Aged, Odds Ratio, Polymorphism, Single Nucleotide, Reference Values, Sex Distribution, Crohn Disease genetics, Genetic Loci genetics, Genetic Predisposition to Disease epidemiology, Genome-Wide Association Study methods
- Abstract
Background & Aims: Crohn's disease is an inflammatory bowel disease induced by multiple genetic and environmental factors. Genome-wide association studies have identified genetic factors that affect the risk for Crohn's disease in European populations, but information from other ethnic groups is scarce. We therefore investigated genetic factors associated with Crohn's disease in the Japanese population., Methods: We performed a genome-wide association study with 372 individuals with Crohn's disease (cases) and 3389 controls, all from the Japanese population. To confirm identified associations, we performed a replication study with an independent panel of 1151 Crohn's disease cases and 15,800 controls. We also performed an association analysis using genome-wide genotype imputation in the discovery cohort., Results: We confirmed associations of Crohn's disease with variants in MHC (rs7765379, P = 2.11 × 10(-59)), TNFSF15 (rs6478106, P = 3.87 × 10(-45)), and STAT3 (rs9891119, P = 2.24 × 10(-14)). We identified 2 new susceptibility loci: on chromosome 4p14 (rs1487630, P = 2.40 × 10(-11); odds ratio, 1.33), and in the SLC25A15-ELF1-WBP4 region on 13q14 (rs7329174 in ELF1, P = 5.12 × 10(-9); odds ratio, 1.27)., Conclusions: In a genome-wide association study, we identified 2 new susceptibility loci for Crohn's disease in a Japanese population. These findings could increase our understanding of the pathogenesis of Crohn's disease., (Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Published
- 2013
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49. Reduction of laser-induced choroidal neovascularization by intravitreal vasohibin-1 in monkey eyes.
- Author
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Onami H, Nagai N, Machida S, Kumasaka N, Wakusawa R, Ishikawa Y, Sonoda H, Sato Y, and Abe T
- Subjects
- Angiogenesis Inhibitors metabolism, Animals, Cell Cycle Proteins metabolism, Choroidal Neovascularization metabolism, Choroidal Neovascularization pathology, Choroidal Neovascularization physiopathology, Disease Models, Animal, Electroretinography drug effects, Enzyme-Linked Immunosorbent Assay, Fluorescein Angiography, Immunohistochemistry, Intravitreal Injections, Macaca, Ophthalmoscopy, Tomography, Optical Coherence, Vascular Endothelial Growth Factor A metabolism, Angiogenesis Inhibitors administration & dosage, Cell Cycle Proteins administration & dosage, Choroidal Neovascularization drug therapy
- Abstract
Purpose: To determine whether intravitreal vasohibin-1 will reduce the grade of the choroidal neovascularization in monkey eyes., Methods: Choroidal neovascularizations were induced in 12 monkey eyes by laser photocoagulation. Three monkeys were evaluated for the safety of the vasohibin-1 injections, 6 monkeys for the effects of a single injection, and 3 monkeys for repeated injections of vasohibin-1. Ophthalmoscopy, fluorescein angiography, focal electroretinograms, and optical coherence tomography were used for the evaluations. The level of vascular endothelial growth factor in the aqueous was determined by enzyme-linked immunosorbent assay. Immunohistochemistry was performed., Results: An intravitreal injection of 10 μg of vasohibin-1 induced mild intraocular inflammation. Eyes with an intravitreal injection of 0.1 μg and 1.0 μg of vasohibin-1 had significant less fluorescein leakage from the choroidal neovascularizations and larger amplitude focal electroretinograms than that of vehicle-injected eyes. Similar results were obtained by repeated injections of 0.1 μg of vasohibin-1. Immunohistochemistry showed that vasohibin-1 was expressed mainly in the endothelial cells within the choroidal neovascularizations. The vascular endothelial growth factor level was not significantly altered by intravitreal vasohibin-1., Conclusion: The reduction of the laser-induced choroidal neovascularizations and preservation of macular function in monkey by intravitreal vasohibin-1 suggest that it should be considered for suppressing choroidal neovascularizations in humans.
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- 2012
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50. Genetic differences in the two main groups of the Japanese population based on autosomal SNPs and haplotypes.
- Author
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Yamaguchi-Kabata Y, Tsunoda T, Kumasaka N, Takahashi A, Hosono N, Kubo M, Nakamura Y, and Kamatani N
- Subjects
- Gene Frequency, Genome-Wide Association Study, Genotype, Homozygote, Humans, Asian People genetics, Chromosome Mapping, Genetic Variation, Haplotypes genetics, Polymorphism, Single Nucleotide genetics, Population Groups genetics
- Abstract
Although the Japanese population has a rather low genetic diversity, we recently confirmed the presence of two main clusters (the Hondo and Ryukyu clusters) through principal component analysis of genome-wide single-nucleotide polymorphism (SNP) genotypes. Understanding the genetic differences between the two main clusters requires further genome-wide analyses based on a dense SNP set and comparison of haplotype frequencies. In the present study, we determined haplotypes for the Hondo cluster of the Japanese population by detecting SNP homozygotes with 388,591 autosomal SNPs from 18,379 individuals and estimated the haplotype frequencies. Haplotypes for the Ryukyu cluster were inferred by a statistical approach using the genotype data from 504 individuals. We then compared the haplotype frequencies between the Hondo and Ryukyu clusters. In most genomic regions, the haplotype frequencies in the Hondo and Ryukyu clusters were very similar. However, in addition to the human leukocyte antigen region on chromosome 6, other genomic regions (chromosomes 3, 4, 5, 7, 10 and 12) showed dissimilarities in haplotype frequency. These regions were enriched for genes involved in the immune system, cell-cell adhesion and the intracellular signaling cascade. These differentiated genomic regions between the Hondo and Ryukyu clusters are of interest because they (1) should be examined carefully in association studies and (2) likely contain genes responsible for morphological or physiological differences between the two groups.
- Published
- 2012
- Full Text
- View/download PDF
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