21 results on '"Nomaru H"'
Search Results
2. 24 - Tissue Engineering, Embryonic, Organ and Other Tissue Specific Stem Cells: LABEL-FREE MACHINE VISION-BASED CELL SORTING FOR TISSUE ENGINEERING
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Nomaru, H., Shimizu, R., Teranishi, K., Asawa, Y., Kawamura, Y., Hikita, A., and Hoshi, K.
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- 2022
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3. Genome-Wide Association Study to Find Modifiers for Tetralogy of Fallot in the 22q11.2 Deletion Syndrome Identifies Variants in the GPR98 Locus on 5q14.3
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Guo, T, Repetto, GM, McDonald McGinn, DM, Chung, JH, Nomaru, H, Campbell, CL, Blonska, A, Bassett, AS, Chow, EWC, Mlynarski, EE, Swillen, A, Vermeesch, J, Devriendt, K, Gothelf, D, Carmel, M, Michaelovsky, E, Schneider, M, Eliez, S, Antonarakis, SE, Coleman, K, Tomita-Mitchell, A, Mitchell, ME, Digilio, MC, Dallapiccola, B, Marino, B, Philip, N, Busa, T, Kushan-Wells, L, Bearden, CE, Piotrowicz, M, Hawuła, W, Roberts, AE, Tassone, F, Simon, TJ, Van Duin, EDA, Van Amelsvoort, TA, Kates, WR, Zackai, E, Johnston, HR, Cutler, DJ, Agopian, AJ, Goldmuntz, E, Mitchell, LE, Wang, T, Emanuel, BS, and Morrow, BE
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International 22q11.2 Consortium/Brain and Behavior Consortium - Abstract
© 2017 The Authors. Background - The 22q11.2 deletion syndrome (22q11.2DS; DiGeorge syndrome/velocardiofacial syndrome) occurs in 1 of 4000 live births, and 60% to 70% of affected individuals have congenital heart disease, ranging from mild to severe. In our cohort of 1472 subjects with 22q11.2DS, a total of 62% (n=906) have congenital heart disease and 36% (n=326) of these have tetralogy of Fallot (TOF), comprising the largest subset of severe congenital heart disease in the cohort. Methods and Results - To identify common genetic variants associated with TOF in individuals with 22q11.2DS, we performed a genome-wide association study using Affymetrix 6.0 array and imputed genotype data. In our cohort, TOF was significantly associated with a genotyped single-nucleotide polymorphism (rs12519770, P=2.98×10-8) in an intron of the adhesion GPR98 (G-protein-coupled receptor V1) gene on chromosome 5q14.3. There was also suggestive evidence of association between TOF and several additional single-nucleotide polymorphisms in this region. Some genome-wide significant loci in introns or noncoding regions could affect regulation of genes nearby or at a distance. On the basis of this possibility, we examined existing Hi-C chromatin conformation data to identify genes that might be under shared transcriptional regulation within the region on 5q14.3. There are 6 genes in a topologically associated domain of chromatin with GPR98, including MEF2C (Myocyte-specific enhancer factor 2C). MEF2C is the only gene that is known to affect heart development in mammals and might be of interest with respect to 22q11.2DS. Conclusions - In conclusion, common variants may contribute to TOF in 22q11.2DS and may function in cardiac outflow tract development.
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- 2017
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4. Copy number elevation of 22q11.2 genes arrests the developmental maturation of working memory capacity and adult hippocampal neurogenesis
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Boku, S, primary, Izumi, T, additional, Abe, S, additional, Takahashi, T, additional, Nishi, A, additional, Nomaru, H, additional, Naka, Y, additional, Kang, G, additional, Nagashima, M, additional, Hishimoto, A, additional, Enomoto, S, additional, Duran-Torres, G, additional, Tanigaki, K, additional, Zhang, J, additional, Ye, K, additional, Kato, S, additional, Männistö, P T, additional, Kobayashi, K, additional, and Hiroi, N, additional
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- 2017
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5. Copy number elevation of 22q11.2 genes arrests the developmental maturation of working memory capacity and adult hippocampal neurogenesis
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Boku, S, Izumi, T, Abe, S, Takahashi, T, Nishi, A, Nomaru, H, Naka, Y, Kang, G, Nagashima, M, Hishimoto, A, Enomoto, S, Duran-Torres, G, Tanigaki, K, Zhang, J, Ye, K, Kato, S, Männistö, P T, Kobayashi, K, and Hiroi, N
- Abstract
Working memory capacity, a critical component of executive function, expands developmentally from childhood through adulthood. Anomalies in this developmental process are seen in individuals with autism spectrum disorder (ASD), schizophrenia and intellectual disabilities (ID), implicating this atypical process in the trajectory of developmental neuropsychiatric disorders. However, the cellular and neuronal substrates underlying this process are not understood. Duplication and triplication of copy number variants of 22q11.2 are consistently and robustly associated with cognitive deficits of ASD and ID in humans, and overexpression of small 22q11.2 segments recapitulates dimensional aspects of developmental neuropsychiatric disorders in mice. We capitalized on these two lines of evidence to delve into the cellular substrates for this atypical development of working memory. Using a region- and cell-type-selective gene expression approach, we demonstrated that copy number elevations of catechol-O-methyl-transferase (COMT) or Tbx1, two genes encoded in the two small 22q11.2 segments, in adult neural stem/progenitor cells in the hippocampus prevents the developmental maturation of working memory capacity in mice. Moreover, copy number elevations of COMT or Tbx1 reduced the proliferation of adult neural stem/progenitor cells in a cell-autonomous manner in vitro and migration of their progenies in the hippocampus granular layer in vivo. Our data provide evidence for the novel hypothesis that copy number elevations of these 22q11.2 genes alter the developmental trajectory of working memory capacity via suboptimal adult neurogenesis in the hippocampus.
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- 2018
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6. Galectin-1 promotes basal and kainate-induced proliferation of neural progenitors in the dentate gyrus of adult mouse hippocampus
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Kajitani, K, primary, Nomaru, H, additional, Ifuku, M, additional, Yutsudo, N, additional, Dan, Y, additional, Miura, T, additional, Tsuchimoto, D, additional, Sakumi, K, additional, Kadoya, T, additional, Horie, H, additional, Poirier, F, additional, Noda, M, additional, and Nakabeppu, Y, additional
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- 2008
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7. Galectin-1 promotes basal and kainate-induced proliferation of neural progenitors in the dentate gyrus of adult mouse hippocampus.
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Kajitani, K., Nomaru, H., Ifuku, M., Yutsudo, N., Dan, Y., Miura, T., Tsuchimoto, D., Sakumi, K., Kadoya, T., Horie, H., Poirier, F., Noda, M., and Nakabeppu, Y.
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LECTINS , *NEURONS , *CELL proliferation , *DENTATE gyrus , *HIPPOCAMPUS (Brain) - Abstract
We examined the expression of galectin-1, an endogenous lectin with one carbohydrate-binding domain, in the adult mouse hippocampus after systemic kainate administration. We found that the expression of galectin-1 was remarkably increased in activated astrocytes of the CA3 subregion and dentate gyrus of the hippocampus, and in nestin-positive neural progenitors in the dentate gyrus. Quantitative reverse transcription PCR (RT-PCR) analysis revealed that the galectin-1 mRNA level in hippocampus began to increase 1 day after kainate administration and that a 13-fold increase was attained within 3 days. Western blotting analysis confirmed that the level of galectin-1 protein increased to more than three-fold a week after the exposure. We showed that isolated astrocytes express and secrete galectin-1. To clarify the significance of the increased expression of galectin-1 in hippocampus, we compared the levels of hippocampal cell proliferation in galectin-1 knockout and wild-type mice after saline or kainate administration. The number of 5-bromo-2′-deoxyuridine (BrdU)-positive cells detected in the subgranular zone (SGZ) of galectin-1 knockout mice decreased to 62% with saline, and to 52% with kainate, as compared with the number seen in the wild-type mice. Most of the BrdU-positive cells in SGZ expressed doublecortin and neuron-specific nuclear protein, indicating that they are immature neurons. We therefore concluded that galectin-1 promotes basal and kainate-induced proliferation of neural progenitors in the hippocampus.Cell Death and Differentiation (2009) 16, 417–427; doi:10.1038/cdd.2008.162; published online 14 November 2008 [ABSTRACT FROM AUTHOR]
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- 2009
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8. Single cell multi-omic analysis identifies a Tbx1-dependent multilineage primed population in murine cardiopharyngeal mesoderm
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Wei Wang, Antonio Baldini, Claudia Angelini, Bernice E. Morrow, Chenleng Cai, Anelisa G. Dantas, Hansoo Song, Hiroko Nomaru, Lionel Christiaen, Lu Zhang, Deyou Zheng, Silvia E. Racedo, Dario Righelli, Yang Liu, Andrea Cirino, Christopher De Bono, Robert G. Kelly, Albert Einstein College of Medicine [New York], Institute for Applied Computing, National Research Council, Naples, Italy, Università degli Studi di Padova = University of Padua (Unipd), University of Naples Federico II = Università degli studi di Napoli Federico II, Center for Developmental Genetics, Department of Biology, New York University, New York, NY, USA, Federal University of Sao Paulo, Sao Paulo, Brazil., Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA., Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), Nomaru, H., Liu, Y., De Bono, C., Righelli, D., Cirino, A., Wang, W., Song, H., Racedo, S. E., Dantas, A. G., Zhang, L., Cai, C. -L., Angelini, C., Christiaen, L., Kelly, R. G., Baldini, A., Zheng, D., and Morrow, B. E.
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[SDV]Life Sciences [q-bio] ,Basic Helix-Loop-Helix Transcription Factor ,General Physics and Astronomy ,Mesoderm ,Mice ,Basic Helix-Loop-Helix Transcription Factors ,Gene Regulatory Networks ,education.field_of_study ,Gene Regulatory Network ,Multidisciplinary ,Stem Cells ,Gene Expression Regulation, Developmental ,Cell Differentiation ,Heart ,RNA sequencing ,TBX1 ,ATAC-seq ,Cell biology ,Chromatin ,ChIP-seq ,Single-Cell Analysi ,medicine.anatomical_structure ,Mechanisms of disease ,embryonic structures ,Single-Cell Analysis ,Haploinsufficiency ,Science ,Population ,Mice, Transgenic ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,Stem Cell ,Pharyngeal apparatus ,scRNA-seq ,medicine ,Animals ,Progenitor cell ,education ,Muscle, Skeletal ,Transcription factor ,Cell lineage ,Animal ,Gene Expression Profiling ,Myocardium ,General Chemistry ,Branchial Region ,T-Box Domain Proteins - Abstract
The poles of the heart and branchiomeric muscles of the face and neck are formed from the cardiopharyngeal mesoderm within the pharyngeal apparatus. They are disrupted in patients with 22q11.2 deletion syndrome, due to haploinsufficiency of TBX1, encoding a T-box transcription factor. Here, using single cell RNA-sequencing, we now identify a multilineage primed population within the cardiopharyngeal mesoderm, marked by Tbx1, which has bipotent properties to form cardiac and branchiomeric muscle cells. The multilineage primed cells are localized within the nascent mesoderm of the caudal lateral pharyngeal apparatus and provide a continuous source of cardiopharyngeal mesoderm progenitors. Tbx1 regulates the maturation of multilineage primed progenitor cells to cardiopharyngeal mesoderm derivatives while restricting ectopic non-mesodermal gene expression. We further show that TBX1 confers this balance of gene expression by direct and indirect regulation of enriched genes in multilineage primed progenitors and downstream pathways, partly through altering chromatin accessibility, the perturbation of which can lead to congenital defects in individuals with 22q11.2 deletion syndrome., Perturbations of the cardiopharyngeal mesoderm can lead to congenital defects in individuals with 22q11.2 deletion syndrome. Here the authors use single cell RNA-sequencing to identify a multilineage primed population within the mesoderm, marked by Tbx1, which has bipotent properties to form cardiac and branchiomeric muscle cells.
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- 2021
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9. Label-free ghost cytometry for manufacturing of cell therapy products.
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Teranishi K, Wagatsuma K, Toda K, Nomaru H, Yanagihashi Y, Ochiai H, Akai S, Mochizuki E, Onda Y, Nakagawa K, Sugimoto K, Takahashi S, Yamaguchi H, and Ota S
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- Humans, Machine Learning, Cell Survival, T-Lymphocytes cytology, T-Lymphocytes metabolism, Flow Cytometry methods, Leukocytes, Mononuclear cytology, Cell- and Tissue-Based Therapy methods, Quality Control
- Abstract
Automation and quality control (QC) are critical in manufacturing safe and effective cell and gene therapy products. However, current QC methods, reliant on molecular staining, pose difficulty in in-line testing and can increase manufacturing costs. Here we demonstrate the potential of using label-free ghost cytometry (LF-GC), a machine learning-driven, multidimensional, high-content, and high-throughput flow cytometry approach, in various stages of the cell therapy manufacturing processes. LF-GC accurately quantified cell count and viability of human peripheral blood mononuclear cells (PBMCs) and identified non-apoptotic live cells and early apoptotic/dead cells in PBMCs (ROC-AUC: area under receiver operating characteristic curve = 0.975), T cells and non-T cells in white blood cells (ROC-AUC = 0.969), activated T cells and quiescent T cells in PBMCs (ROC-AUC = 0.990), and particulate impurities in PBMCs (ROC-AUC ≧ 0.998). The results support that LF-GC is a non-destructive label-free cell analytical method that can be used to monitor cell numbers, assess viability, identify specific cell subsets or phenotypic states, and remove impurities during cell therapy manufacturing. Thus, LF-GC holds the potential to enable full automation in the manufacturing of cell therapy products with reduced cost and increased efficiency., (© 2024. The Author(s).)
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- 2024
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10. Label-free enrichment of human pluripotent stem cell-derived early retinal progenitor cells for cell-based regenerative therapies.
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Iwama Y, Nomaru H, Masuda T, Kawamura Y, Matsumura M, Murata Y, Teranishi K, Nishida K, Ota S, Mandai M, and Takahashi M
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- Humans, Animals, Rats, Reactive Oxygen Species, Retina, Stem Cell Transplantation methods, Pluripotent Stem Cells transplantation, Retinal Degeneration therapy, Retinitis Pigmentosa therapy
- Abstract
Pluripotent stem cell-based therapy for retinal degenerative diseases is a promising approach to restoring visual function. A clinical study using retinal organoid (RO) sheets was recently conducted in patients with retinitis pigmentosa. However, the graft preparation currently requires advanced skills to identify and excise suitable segments from the transplantable area of the limited number of suitable ROs. This remains a challenge for consistent clinical implementations. Herein, we enabled the enrichment of wild-type (non-reporter) retinal progenitor cells (RPCs) from dissociated ROs using a label-free ghost cytometry (LF-GC)-based sorting system, where a machine-based classifier was trained in advance with another RPC reporter line. The sorted cells reproducibly formed retinal spheroids large enough for transplantation and developed mature photoreceptors in the retinal degeneration rats. This method of enriching early RPCs with no specific surface antigens and without any reporters or chemical labeling is promising for robust preparation of graft tissues during cell-based therapy., Competing Interests: Declaration of interests T.M. and M. Matsumura are employees of Vision Care Inc. M.T. is the founder and president of Vision Care Inc. S.O. is a founder and shareholder of ThinkCyte K.K. H.N., Y.K., K.T., and Y.M. are employees of ThinkCyte K.K. and have shares of stock options of ThinkCyte K.K. S.O. and Y.K. have filed patent applications related to this study. All other authors declare they have no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2024
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11. An optimized approach for multiplexing single-nuclear ATAC-seq using oligonucleotide-conjugated antibodies.
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Bera BS, Thompson TV, Sosa E, Nomaru H, Reynolds D, Dubin RA, Maqbool SB, Zheng D, Morrow BE, Greally JM, and Suzuki M
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- Male, Female, Humans, Animals, Mice, Sequence Analysis, DNA methods, Chromatin genetics, Chromatin metabolism, Oligonucleotides metabolism, Chromatin Immunoprecipitation Sequencing, Cell Nucleus genetics, Cell Nucleus metabolism
- Abstract
Background: Single-cell technologies to analyze transcription and chromatin structure have been widely used in many research areas to reveal the functions and molecular properties of cells at single-cell resolution. Sample multiplexing techniques are valuable when performing single-cell analysis, reducing technical variation and permitting cost efficiencies. Several commercially available methods have been used in many scRNA-seq studies. On the other hand, while several methods have been published, multiplexing techniques for single nuclear assay for transposase-accessible chromatin (snATAC)-seq assays remain under development. We developed a simple nucleus hashing method using oligonucleotide-conjugated antibodies recognizing nuclear pore complex proteins, NuHash, to perform snATAC-seq library preparations by multiplexing., Results: We performed multiplexing snATAC-seq analyses on a mixture of human and mouse cell samples (two samples, 2-plex, and four samples, 4-plex) using NuHash. The analyses on nuclei with at least 10,000 read counts showed that the demultiplexing accuracy of NuHash was high, and only ten out of 9144 nuclei (2-plex) and 150 of 12,208 nuclei (4-plex) had discordant classifications between NuHash demultiplexing and discrimination using reference genome alignments. The differential open chromatin region (OCR) analysis between female and male samples revealed that male-specific OCRs were enriched in chromosome Y (four out of nine). We also found that five female-specific OCRs (20 OCRs) were on chromosome X. A comparative analysis between snATAC-seq and deeply sequenced bulk ATAC-seq on the same samples revealed that the bulk ATAC-seq signal intensity was positively correlated with the number of cell clusters detected in snATAC-seq. Moreover, when we categorized snATAC-seq peaks based on the number of cell clusters in which the peak was present, we observed different distributions over different genomic features between the groups. This result suggests that the peak intensities of bulk ATAC-seq can be used to identify different types of functional loci., Conclusions: Our multiplexing method using oligo-conjugated anti-nuclear pore complex proteins, NuHash, permits high-accuracy demultiplexing of samples. The NuHash protocol is straightforward, works on frozen samples, and requires no modifications for snATAC-seq library preparation., (© 2023. The Author(s).)
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- 2023
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12. In silico-labeled ghost cytometry.
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Ugawa M, Kawamura Y, Toda K, Teranishi K, Morita H, Adachi H, Tamoto R, Nomaru H, Nakagawa K, Sugimoto K, Borisova E, An Y, Konishi Y, Tabata S, Morishita S, Imai M, Takaku T, Araki M, Komatsu N, Hayashi Y, Sato I, Horisaki R, Noji H, and Ota S
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- Coloring Agents analysis, Computer Simulation, Humans, Machine Learning, Flow Cytometry instrumentation, Induced Pluripotent Stem Cells cytology, Leukocytes cytology, Staining and Labeling instrumentation
- Abstract
Characterization and isolation of a large population of cells are indispensable procedures in biological sciences. Flow cytometry is one of the standards that offers a method to characterize and isolate cells at high throughput. When performing flow cytometry, cells are molecularly stained with fluorescent labels to adopt biomolecular specificity which is essential for characterizing cells. However, molecular staining is costly and its chemical toxicity can cause side effects to the cells which becomes a critical issue when the cells are used downstream as medical products or for further analysis. Here, we introduce a high-throughput stain-free flow cytometry called in silico-labeled ghost cytometry which characterizes and sorts cells using machine-predicted labels. Instead of detecting molecular stains, we use machine learning to derive the molecular labels from compressive data obtained with diffractive and scattering imaging methods. By directly using the compressive 'imaging' data, our system can accurately assign the designated label to each cell in real time and perform sorting based on this judgment. With this method, we were able to distinguish different cell states, cell types derived from human induced pluripotent stem (iPS) cells, and subtypes of peripheral white blood cells using only stain-free modalities. Our method will find applications in cell manufacturing for regenerative medicine as well as in cell-based medical diagnostic assays in which fluorescence labeling of the cells is undesirable., Competing Interests: MU Former employee and holds shares of stock options of ThinkCyte, Inc. Has filed patent applications related to in silico-labeled ghost cytometry method. Patent number PCT/US2019/36849, YK Employee and holds share of stock options of ThinkCyte, Inc. Has filed patent applications related to in silico-labeled ghost cytometry method. Patent numbers PCT/JP2016/082089, PCT/US2019/36849, KT Employee and holds share of stock options of ThinkCyte, Inc. Has filed patent applications related to in silico-labeled ghost cytometry method. Patent number PCT/JP2021/013478, KT, HA, KN Employee and holds share of stock options of ThinkCyte, Inc, HM Employee and holds shares of stock options of ThinkCyte, Inc, RT, HN Employee of ThinkCyte, KS Former employee and holds share of stock options of ThinkCyte, Inc, EB, SM, MI, TT, MA, NK No competing interests declared, YA Employee of ThinkCyte, Inc, YK, ST Employee of Sysmex Corp, YH, HN Holds shares of stock options of ThinkCyte, Inc, IS Founder and shareholder of ThinkCyte, Inc. Has filed patent applications related to the in silico-labeled ghost cytometry method. Patent numbers PCT/JP2016/082089, PCT/US2019/36849, RH Founder and shareholder of ThinkCyte, Inc. Has filed patent applications related to the in silico-labeled ghost cytometry method. Patent numbers PCT/JP2016/055412, PCT/JP2016/082089, PCT/JP2018/005237, PCT/US2019/36849, SO Founder and shareholder of ThinkCyte, Inc. Has filed patent applications related to the in silico-labeled ghost cytometry method. Patent numbers PCT/JP2016/055412, PCT/JP2016/082089, PCT/JP2018/005237, PCT/US2019/36849, PCT/JP2021/013564, PCT/JP2021/013478, (© 2021, Ugawa et al.)
- Published
- 2021
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13. Single cell multi-omic analysis identifies a Tbx1-dependent multilineage primed population in murine cardiopharyngeal mesoderm.
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Nomaru H, Liu Y, De Bono C, Righelli D, Cirino A, Wang W, Song H, Racedo SE, Dantas AG, Zhang L, Cai CL, Angelini C, Christiaen L, Kelly RG, Baldini A, Zheng D, and Morrow BE
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- Animals, Basic Helix-Loop-Helix Transcription Factors genetics, Basic Helix-Loop-Helix Transcription Factors metabolism, Branchial Region embryology, Branchial Region metabolism, Cell Differentiation, Cell Lineage, Gene Expression Profiling, Gene Expression Regulation, Developmental, Gene Regulatory Networks, Heart embryology, Mesoderm embryology, Mesoderm metabolism, Mice, Mice, Transgenic, Muscle, Skeletal cytology, Muscle, Skeletal metabolism, Myocardium metabolism, Single-Cell Analysis, Stem Cells cytology, Stem Cells metabolism, T-Box Domain Proteins genetics, Branchial Region cytology, Mesoderm cytology, Myocardium cytology, T-Box Domain Proteins metabolism
- Abstract
The poles of the heart and branchiomeric muscles of the face and neck are formed from the cardiopharyngeal mesoderm within the pharyngeal apparatus. They are disrupted in patients with 22q11.2 deletion syndrome, due to haploinsufficiency of TBX1, encoding a T-box transcription factor. Here, using single cell RNA-sequencing, we now identify a multilineage primed population within the cardiopharyngeal mesoderm, marked by Tbx1, which has bipotent properties to form cardiac and branchiomeric muscle cells. The multilineage primed cells are localized within the nascent mesoderm of the caudal lateral pharyngeal apparatus and provide a continuous source of cardiopharyngeal mesoderm progenitors. Tbx1 regulates the maturation of multilineage primed progenitor cells to cardiopharyngeal mesoderm derivatives while restricting ectopic non-mesodermal gene expression. We further show that TBX1 confers this balance of gene expression by direct and indirect regulation of enriched genes in multilineage primed progenitors and downstream pathways, partly through altering chromatin accessibility, the perturbation of which can lead to congenital defects in individuals with 22q11.2 deletion syndrome., (© 2021. The Author(s).)
- Published
- 2021
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14. Deletion size analysis of 1680 22q11.2DS subjects identifies a new recombination hotspot on chromosome 22q11.2.
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Guo T, Diacou A, Nomaru H, McDonald-McGinn DM, Hestand M, Demaerel W, Zhang L, Zhao Y, Ujueta F, Shan J, Montagna C, Zheng D, Crowley TB, Kushan-Wells L, Bearden CE, Kates WR, Gothelf D, Schneider M, Eliez S, Breckpot J, Swillen A, Vorstman J, Zackai E, Benavides Gonzalez F, Repetto GM, Emanuel BS, Bassett AS, Vermeesch JR, Marshall CR, and Morrow BE
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- Chromosome Deletion, Chromosomes, Human, Pair 22 genetics, Female, Humans, Male, Alleles, Chromosome Mapping, DiGeorge Syndrome genetics, Meiosis
- Abstract
Recurrent, de novo, meiotic non-allelic homologous recombination events between low copy repeats, termed LCR22s, leads to the 22q11.2 deletion syndrome (22q11.2DS; velo-cardio-facial syndrome/DiGeorge syndrome). Although most 22q11.2DS patients have a similar sized 3 million base pair (Mb), LCR22A-D deletion, some have nested LCR22A-B or LCR22A-C deletions. Our goal is to identify additional recurrent 22q11.2 deletions associated with 22q11.2DS, serving as recombination hotspots for meiotic chromosomal rearrangements. Here, using data from Affymetrix 6.0 microarrays on 1680 22q11.2DS subjects, we identified what appeared to be a nested proximal 22q11.2 deletion in 38 (2.3%) of them. Using molecular and haplotype analyses from 14 subjects and their parent(s) with available DNA, we found essentially three types of scenarios to explain this observation. In eight subjects, the proximal breakpoints occurred in a small sized 12 kb LCR distal to LCR22A, referred to LCR22A+, resulting in LCR22A+-B or LCR22A+-D deletions. Six of these eight subjects had a nested 22q11.2 deletion that occurred during meiosis in a parent carrying a benign 0.2 Mb duplication of the LCR22A-LCR22A+ region with a breakpoint in LCR22A+. Another six had a typical de novo LCR22A-D deletion on one allele and inherited the LCR22A-A+ duplication from the other parent thus appearing on microarrays to have a nested deletion. LCR22A+ maps to an evolutionary breakpoint between mice and humans and appears to serve as a local hotspot for chromosome rearrangements on 22q11.2.
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- 2018
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15. Genome-Wide Association Study to Find Modifiers for Tetralogy of Fallot in the 22q11.2 Deletion Syndrome Identifies Variants in the GPR98 Locus on 5q14.3.
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Guo T, Repetto GM, McDonald McGinn DM, Chung JH, Nomaru H, Campbell CL, Blonska A, Bassett AS, Chow EWC, Mlynarski EE, Swillen A, Vermeesch J, Devriendt K, Gothelf D, Carmel M, Michaelovsky E, Schneider M, Eliez S, Antonarakis SE, Coleman K, Tomita-Mitchell A, Mitchell ME, Digilio MC, Dallapiccola B, Marino B, Philip N, Busa T, Kushan-Wells L, Bearden CE, Piotrowicz M, Hawuła W, Roberts AE, Tassone F, Simon TJ, van Duin EDA, van Amelsvoort TA, Kates WR, Zackai E, Johnston HR, Cutler DJ, Agopian AJ, Goldmuntz E, Mitchell LE, Wang T, Emanuel BS, and Morrow BE
- Subjects
- Chromatin metabolism, Chromosomes, Human, Pair 5, DiGeorge Syndrome complications, Genetic Loci, Genotype, High-Throughput Nucleotide Sequencing, Humans, Linkage Disequilibrium, MEF2 Transcription Factors genetics, Oligonucleotide Array Sequence Analysis, Phenotype, Polymorphism, Single Nucleotide, Receptors, G-Protein-Coupled metabolism, Sequence Analysis, DNA, Tetralogy of Fallot complications, DiGeorge Syndrome genetics, Genome-Wide Association Study, Receptors, G-Protein-Coupled genetics, Tetralogy of Fallot genetics
- Abstract
Background: The 22q11.2 deletion syndrome (22q11.2DS; DiGeorge syndrome/velocardiofacial syndrome) occurs in 1 of 4000 live births, and 60% to 70% of affected individuals have congenital heart disease, ranging from mild to severe. In our cohort of 1472 subjects with 22q11.2DS, a total of 62% (n=906) have congenital heart disease and 36% (n=326) of these have tetralogy of Fallot (TOF), comprising the largest subset of severe congenital heart disease in the cohort., Methods and Results: To identify common genetic variants associated with TOF in individuals with 22q11.2DS, we performed a genome-wide association study using Affymetrix 6.0 array and imputed genotype data. In our cohort, TOF was significantly associated with a genotyped single-nucleotide polymorphism (rs12519770, P =2.98×10
- 8 ) in an intron of the adhesion GPR98 (G-protein-coupled receptor V1) gene on chromosome 5q14.3. There was also suggestive evidence of association between TOF and several additional single-nucleotide polymorphisms in this region. Some genome-wide significant loci in introns or noncoding regions could affect regulation of genes nearby or at a distance. On the basis of this possibility, we examined existing Hi-C chromatin conformation data to identify genes that might be under shared transcriptional regulation within the region on 5q14.3. There are 6 genes in a topologically associated domain of chromatin with GPR98 , including MEF2C (Myocyte-specific enhancer factor 2C). MEF2C is the only gene that is known to affect heart development in mammals and might be of interest with respect to 22q11.2DS., Conclusions: In conclusion, common variants may contribute to TOF in 22q11.2DS and may function in cardiac outflow tract development., (© 2017 The Authors.)- Published
- 2017
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16. Molecular Histochemistry Identifies Peptidomic Organization and Reorganization Along Striatal Projection Units.
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Hishimoto A, Nomaru H, Ye K, Nishi A, Lim J, Aguilan JT, Nieves E, Kang G, Angeletti RH, and Hiroi N
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- Animals, Male, Mice, Mice, Inbred C57BL, Enkephalins metabolism, Neostriatum metabolism, Neuropeptides metabolism, Protein Precursors metabolism, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
- Abstract
Matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS) (MALDI-IMS) provides a technical means for simultaneous analysis of precise anatomic localization and regulation of peptides. We explored the technical capability of matrix-assisted laser desorption ionization mass spectrometry for characterization of peptidomic regulation by an addictive substance along two distinct projection systems in the mouse striatum. The spatial expression patterns of substance P and proenkephalin, marker neuropeptides of two distinct striatal projection neurons, were negatively correlated at baseline. We detected 768 mass/charge (m/z) peaks whose expression levels were mostly negatively and positively correlated with expression levels of substance P and proenkephalin A (amino acids 218-228), respectively, within the dorsal striatum. After nicotine administration, there was a positive shift in correlation of mass/charge peak expression levels with substance P and proenkephalin A (218-228). Our exploratory analyses demonstrate the technical capacity of MALDI-IMS for comprehensive identification of peptidomic regulation patterns along histochemically distinguishable striatal projection pathways., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)
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- 2016
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17. Fosb gene products contribute to excitotoxic microglial activation by regulating the expression of complement C5a receptors in microglia.
- Author
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Nomaru H, Sakumi K, Katogi A, Ohnishi YN, Kajitani K, Tsuchimoto D, Nestler EJ, and Nakabeppu Y
- Subjects
- Alternative Splicing, Animals, Antigens, CD metabolism, Antigens, Differentiation, Myelomonocytic metabolism, Astrocytes physiology, Calcium-Binding Proteins metabolism, Cells, Cultured, Chemotaxis physiology, Excitatory Amino Acid Agonists toxicity, Hippocampus drug effects, Hippocampus pathology, Interleukin-6 metabolism, Kainic Acid toxicity, Male, Mice, Inbred C57BL, Mice, Knockout, Microfilament Proteins metabolism, Microglia drug effects, Microglia pathology, Neurons physiology, Proto-Oncogene Proteins c-fos genetics, RNA, Messenger metabolism, Seizures pathology, Seizures physiopathology, Tumor Necrosis Factor-alpha metabolism, Hippocampus physiopathology, Microglia physiology, Proto-Oncogene Proteins c-fos metabolism, Receptor, Anaphylatoxin C5a metabolism
- Abstract
The Fosb gene encodes subunits of the activator protein-1 transcription factor complex. Two mature mRNAs, Fosb and ΔFosb, encoding full-length FOSB and ΔFOSB proteins respectively, are formed by alternative splicing of Fosb mRNA. Fosb products are expressed in several brain regions. Moreover, Fosb-null mice exhibit depressive-like behaviors and adult-onset spontaneous epilepsy, demonstrating important roles in neurological and psychiatric disorders. Study of Fosb products has focused almost exclusively on neurons; their function in glial cells remains to be explored. In this study, we found that microglia express equivalent levels of Fosb and ΔFosb mRNAs to hippocampal neurons and, using microarray analysis, we identified six microglial genes whose expression is dependent on Fosb products. Of these genes, we focused on C5ar1 and C5ar2, which encode receptors for complement C5a. In isolated Fosb-null microglia, chemotactic responsiveness toward the truncated form of C5a was significantly lower than that in wild-type cells. Fosb-null mice were significantly resistant to kainate-induced seizures compared with wild-type mice. C5ar1 mRNA levels and C5aR1 immunoreactivity were increased in wild-type hippocampus 24 hours after kainate administration; however, such induction was significantly reduced in Fosb-null hippocampus. Furthermore, microglial activation after kainate administration was significantly diminished in Fosb-null hippocampus, as shown by significant reductions in CD68 immunoreactivity, morphological change and reduced levels of Il6 and Tnf mRNAs, although no change in the number of Iba-1-positive cells was observed. These findings demonstrate that, under excitotoxicity, Fosb products contribute to a neuroinflammatory response in the hippocampus through regulation of microglial C5ar1 and C5ar2 expression., (© 2014 Wiley Periodicals, Inc.)
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- 2014
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18. Characterization of galectin-1-positive cells in the mouse hippocampus.
- Author
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Kajitani K, Kobayakawa Y, Nomaru H, Kadoya T, Horie H, and Nakabeppu Y
- Subjects
- Animals, Calbindin 2 metabolism, DNA-Binding Proteins, Glutamate Decarboxylase metabolism, Immunohistochemistry, Male, Mice, Mice, Inbred C57BL, Microscopy, Confocal, Microscopy, Fluorescence, Nerve Tissue Proteins metabolism, Neuropeptide Y metabolism, Nuclear Proteins metabolism, Parvalbumins metabolism, Somatostatin metabolism, Tubulin metabolism, Galectin 1 metabolism, Hippocampus cytology, Hippocampus metabolism, Interneurons metabolism
- Abstract
Galectin-1 (gal-1) is one of several well-studied proteins from the galectin families. It is a 14.5 kDa glycoprotein with a single carbohydrate-binding domain. To examine the distribution and properties of gal-1 in the mouse hippocampus, we performed immunohistochemistry using an anti-gal-1 antibody. We found that most gal-1-positive cells showed both NeuN and β-tubulin III (Tuj-1) immunoreactivity (NeuN: 93%, β-tubulin III: 88%). Furthermore, we clarified that 77% of gal-1-positive cells expressed somatostatin, 79% of gal-1-positive cells expressed GAD67, 34% of gal-1-positive cells expressed parvalbumin, 5% of gal-1-positive cells expressed calretinin, 2% of gal-1-positive cells expressed calbindin, and 31% of gal-1-positive cells expressed neuropeptide Y in the mouse hippocampus. These results indicate that gal-1 is expressed in interneurons that also express β-tubulin III and gal-1 may be a novel marker for interneuron subpopulations in the hippocampus.
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- 2014
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19. fosB-null mice display impaired adult hippocampal neurogenesis and spontaneous epilepsy with depressive behavior.
- Author
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Yutsudo N, Kamada T, Kajitani K, Nomaru H, Katogi A, Ohnishi YH, Ohnishi YN, Takase K, Sakumi K, Shigeto H, and Nakabeppu Y
- Subjects
- Animals, Bromodeoxyuridine metabolism, Cell Proliferation drug effects, Depression complications, Disease Models, Animal, Doublecortin Domain Proteins, Electroencephalography, Epilepsy complications, Excitatory Amino Acid Agonists pharmacology, Gene Expression Regulation drug effects, Gene Expression Regulation genetics, Kainic Acid pharmacology, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microarray Analysis, Microtubule-Associated Proteins metabolism, Neuropeptides metabolism, Phosphopyruvate Hydratase metabolism, Proto-Oncogene Proteins c-fos genetics, Depression genetics, Epilepsy genetics, Hippocampus pathology, Mutation genetics, Neurogenesis genetics, Proto-Oncogene Proteins c-fos deficiency
- Abstract
Patients with epilepsy are at high risk for major depression relative to the general population, and both disorders are associated with changes in adult hippocampal neurogenesis, although the mechanisms underlying disease onset remain unknown. The expression of fosB, an immediate early gene encoding FosB and ΔFosB/Δ2ΔFosB by alternative splicing and translation initiation, is known to be induced in neural progenitor cells within the subventricular zone of the lateral ventricles and subgranular zone of the hippocampus, following transient forebrain ischemia in the rat brain. Moreover, adenovirus-mediated expression of fosB gene products can promote neural stem cell proliferation. We recently found that fosB-null mice show increased depressive behavior, suggesting impaired neurogenesis in fosB-null mice. In the current study, we analyzed neurogenesis in the hippocampal dentate gyrus of fosB-null and fosB(d/d) mice that express ΔFosB/Δ2ΔFosB but not FosB, in comparison with wild-type mice, alongside neuropathology, behaviors, and gene expression profiles. fosB-null but not fosB(d/d) mice displayed impaired neurogenesis in the adult hippocampus and spontaneous epilepsy. Microarray analysis revealed that genes related to neurogenesis, depression, and epilepsy were altered in the hippocampus of fosB-null mice. Thus, we conclude that the fosB-null mouse is the first animal model to provide a genetic and molecular basis for the comorbidity between depression and epilepsy with abnormal neurogenesis, all of which are caused by loss of a single gene, fosB.
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- 2013
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20. 8-Oxoguanine causes neurodegeneration during MUTYH-mediated DNA base excision repair.
- Author
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Sheng Z, Oka S, Tsuchimoto D, Abolhassani N, Nomaru H, Sakumi K, Yamada H, and Nakabeppu Y
- Subjects
- Animals, Apoptosis Inducing Factor metabolism, Benzamides pharmacology, Calpain antagonists & inhibitors, Calpain metabolism, Cell Nucleus metabolism, Corpus Striatum pathology, DNA Breaks, Single-Stranded, DNA Glycosylases genetics, DNA Glycosylases metabolism, DNA, Mitochondrial genetics, Dipeptides pharmacology, Guanine metabolism, Guanine physiology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Microglia metabolism, Mitochondria metabolism, Motor Activity, Neurodegenerative Diseases etiology, Neurodegenerative Diseases pathology, Nitro Compounds, Phosphoric Monoester Hydrolases genetics, Poly (ADP-Ribose) Polymerase-1, Poly(ADP-ribose) Polymerase Inhibitors, Poly(ADP-ribose) Polymerases metabolism, Propionates, DNA Glycosylases physiology, DNA Repair, Guanine analogs & derivatives, Neurodegenerative Diseases metabolism, Oxidative Stress
- Abstract
8-Oxoguanine (8-oxoG), a common DNA lesion caused by reactive oxygen species, is associated with carcinogenesis and neurodegeneration. Although the mechanism by which 8-oxoG causes carcinogenesis is well understood, the mechanism by which it causes neurodegeneration is unknown. Here, we report that neurodegeneration is triggered by MUTYH-mediated excision repair of 8-oxoG-paired adenine. Mutant mice lacking 8-oxo-2'-deoxyguanosine triphosphate-depleting (8-oxo-dGTP-depleting) MTH1 and/or 8-oxoG-excising OGG1 exhibited severe striatal neurodegeneration, whereas mutant mice lacking MUTYH or OGG1/MUTYH were resistant to neurodegeneration under conditions of oxidative stress. These results indicate that OGG1 and MTH1 are protective, while MUTYH promotes neurodegeneration. We observed that 8-oxoG accumulated in the mitochondrial DNA of neurons and caused calpain-dependent neuronal loss, while delayed nuclear accumulation of 8-oxoG in microglia resulted in PARP-dependent activation of apoptosis-inducing factor and exacerbated microgliosis. These results revealed that neurodegeneration is a complex process caused by 8-oxoG accumulation in the genomes of neurons and microglia. Different signaling pathways were triggered by the accumulation of single-strand breaks in each type of DNA generated during base excision repair initiated by MUTYH, suggesting that suppression of MUTYH may protect the brain under conditions of oxidative stress.
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- 2012
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21. FosB is essential for the enhancement of stress tolerance and antagonizes locomotor sensitization by ΔFosB.
- Author
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Ohnishi YN, Ohnishi YH, Hokama M, Nomaru H, Yamazaki K, Tominaga Y, Sakumi K, Nestler EJ, and Nakabeppu Y
- Subjects
- Animals, Cadherins biosynthesis, Corpus Striatum metabolism, Dopamine physiology, Male, Maze Learning physiology, Mice, Mice, Mutant Strains, Motor Activity genetics, Proto-Oncogene Proteins c-akt metabolism, Proto-Oncogene Proteins c-fos genetics, Stress, Psychological genetics, Stress, Psychological metabolism, Adaptation, Psychological physiology, Exploratory Behavior physiology, Motor Activity physiology, Proto-Oncogene Proteins c-fos physiology, Stress, Psychological physiopathology
- Abstract
Background: Molecular mechanisms underlying stress tolerance and vulnerability are incompletely understood. The fosB gene is an attractive candidate for regulating stress responses, because ΔFosB, an alternative splice product of the fosB gene, accumulates after repeated stress or antidepressant treatments. On the other hand, FosB, the other alternative splice product of the fosB gene, expresses more transiently than ΔFosB but exerts higher transcriptional activity. However, the functional differences of these two fosB products remain unclear., Methods: We established various mouse lines carrying three different types of fosB allele, wild-type (fosB(+)), fosB-null (fosB(G)), and fosB(d) allele, which encodes ΔFosB but not FosB, and analyzed them in stress-related behavioral tests., Results: Because fosB(+/d) mice show enhanced ΔFosB levels in the presence of FosB and fosB(d/d) mice show more enhanced ΔFosB levels in the absence of FosB, the function of FosB can be inferred from differences observed between these lines. The fosB(+/d) and fosB(d/d) mice showed increased locomotor activity and elevated Akt phosphorylation, whereas only fosB(+/d) mice showed antidepressive-like behaviors and increased E-cadherin expression in striatum compared with wild-type mice. In contrast, fosB-null mice showed increased depression-like behavior and lower E-cadherin expression., Conclusions: These findings indicate that FosB is essential for stress tolerance mediated by ΔFosB. These data suggest that fosB gene products have a potential to regulate mood disorder-related behaviors., (Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)
- Published
- 2011
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