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  • 1
    Online Resource
    Online Resource
    Propagation of trimethylated H3K27 regulated by polycomb protein EED is required for embryogenesis, hematopoietic maintenance, and tumor suppression
    Proceedings of the National Academy of Sciences ; 2016
    In:  Proceedings of the National Academy of Sciences Vol. 113, No. 37 ( 2016-09-13), p. 10370-10375
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 113, No. 37 ( 2016-09-13), p. 10370-10375
    Abstract: Polycomb repressive complex 2 (PRC2) catalyzes the monomethylation, dimethylation, and trimethylation of histone H3 Lys27 (H3K27) and acts as a central epigenetic regulator that marks the repressive chromatin domain. Embryonic ectoderm development (EED), an essential component of PRC2, interacts with trimethylated H3K27 (H3K27me3) through the aromatic cage structure composed of its three aromatic amino acids, Phe97, Trp364, and Tyr365. This interaction allosterically activates the histone methyltransferase activity of PRC2 and thereby propagates repressive histone marks. In this study, we report the analysis of knock-in mice harboring the myeloid disorder-associated EED Ile363Met (I363M) mutation, analogous to the EED aromatic cage mutants. The I363M homozygotes displayed a remarkable and preferential reduction of H3K27me3 and died at midgestation. The heterozygotes increased the clonogenic capacity and bone marrow repopulating activity of hematopoietic stem/progenitor cells (HSPCs) and were susceptible to leukemia. Lgals3, a PRC2 target gene encoding a multifunctional galactose-binding lectin, was derepressed in I363M heterozygotes, which enhanced the stemness of HSPCs. Thus, our work provides in vivo evidence that the structural integrity of EED to H3K27me3 propagation is critical, especially for embryonic development and hematopoietic homeostasis, and that its perturbation increases the predisposition to hematologic malignancies.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1600070113
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2016
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  • 2
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    Online Resource
    MBTD1 preserves adult hematopoietic stem cell pool size and function
    Proceedings of the National Academy of Sciences ; 2023
    In:  Proceedings of the National Academy of Sciences Vol. 120, No. 32 ( 2023-08-08)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 120, No. 32 ( 2023-08-08)
    Abstract: Mbtd1 (mbt domain containing 1 ) encodes a nuclear protein containing a zinc finger domain and four malignant brain tumor (MBT) repeats. We previously generated Mbtd1 -deficient mice and found that MBTD1 is highly expressed in fetal hematopoietic stem cells (HSCs) and sustains the number and function of fetal HSCs. However, since Mbtd1 -deficient mice die soon after birth possibly due to skeletal abnormalities, its role in adult hematopoiesis remains unclear. To address this issue, we generated Mbtd1 conditional knockout mice and analyzed adult hematopoietic tissues deficient in Mbtd1 . We observed that the numbers of HSCs and progenitors increased and Mbtd1 -deficient HSCs exhibited hyperactive cell cycle, resulting in a defective response to exogenous stresses. Mechanistically, we found that MBTD1 directly binds to the promoter region of FoxO3a , encoding a forkhead protein essential for HSC quiescence, and interacts with components of TIP60 chromatin remodeling complex and other proteins involved in HSC and other stem cell functions. Restoration of FOXO3a activity in Mbtd1- deficient HSCs in vivo rescued cell cycle and pool size abnormalities. These findings indicate that MBTD1 is a critical regulator for HSC pool size and function, mainly through the maintenance of cell cycle quiescence by FOXO3a.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2206860120
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2023
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
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  • 3
    Online Resource
    Online Resource
    Generation of articulatory movements by using a kinematic triphone model
    Acoustical Society of America (ASA) ; 2001
    In:  The Journal of the Acoustical Society of America Vol. 110, No. 1 ( 2001-07-01), p. 453-463
    Details
    In: The Journal of the Acoustical Society of America, Acoustical Society of America (ASA), Vol. 110, No. 1 ( 2001-07-01), p. 453-463
    Abstract: The method described here predicts the trajectories of articulatory movements for continuous speech by using a kinematic triphone model and the minimum-acceleration model. The kinematic triphone model, which is constructed from articulatory data obtained from experiments using an electro-magnetic articulographic system, is characterized by three kinematic features of a triphone and by the intervals between two successive phonemes in the triphone. After a kinematic feature of a phoneme in a given sentence is extracted, the minimum-acceleration trajectory that coincides with the extremum of the time integral of the squared magnitude of the articulator acceleration is formulated. The calculation of the minimum acceleration requires only linear computation. The method predicts both the qualitative features and the quantitative details of experimentally observed articulation.
    Type of Medium: Online Resource
    ISSN: 0001-4966 , 1520-8524
    URL: Article
    DOI: 10.1121/1.1377633
    RVK:
    EQ 1000
    Language: English
    Publisher: Acoustical Society of America (ASA)
    Publication Date: 2001
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  • 4
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    Online Resource
    Requirement of full TCR repertoire for regulatory T cells to maintain intestinal homeostasis
    Proceedings of the National Academy of Sciences ; 2015
    In:  Proceedings of the National Academy of Sciences Vol. 112, No. 41 ( 2015-10-13), p. 12770-12775
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 112, No. 41 ( 2015-10-13), p. 12770-12775
    Abstract: The regulation of intestinal homeostasis by the immune system involves the dynamic interplay between gut commensal microbiota and resident immune cells. It is well known that a large and diverse lymphocyte antigen receptor repertoire enables the immune system to recognize and respond to a wide range of invading pathogens. There is also an emerging appreciation for a critical role the T-cell receptor (TCR) repertoire serves in the maintenance of peripheral tolerance by regulatory T cells (Tregs). Nevertheless, how the diversity of the TCR repertoire in Tregs affects intestinal homeostasis remains unknown. To address this question, we studied mice whose T cells express a restricted TCR repertoire. We observed the development of spontaneous colitis, accompanied by the induction of T-helper type 17 cells in the colon that is driven by gut commensal microbiota. We provide further evidence that a restricted TCR repertoire causes a loss of tolerogenicity to microbiota, accompanied by a paucity of peripherally derived, Helios − Tregs and hyperactivation of migratory dendritic cells. These results thus reveal a new facet of the TCR repertoire in which Tregs require a diverse TCR repitoire for intestinal homeostasis, suggesting an additional driving force in the evolutional significance of the TCR repertoire.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1516617112
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2015
    detail.hit.zdb_id: 209104-5
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    SSG: 11
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  • 5
    Online Resource
    Online Resource
    A trajectory formation model of articulatory movements
    Acoustical Society of America (ASA) ; 1992
    In:  The Journal of the Acoustical Society of America Vol. 92, No. 4_Supplement ( 1992-10-01), p. 2389-2389
    Details
    In: The Journal of the Acoustical Society of America, Acoustical Society of America (ASA), Vol. 92, No. 4_Supplement ( 1992-10-01), p. 2389-2389
    Abstract: The generation of articulatory movements suffers from the degrees-of-freedom problem in determining the phoneme-related shape of the vocal tract. This model is intended to study the coordinative movement of articulatory organs. The redundancies of the articulation system are solved by minimizing an appropriate objective function to determine articulatory movement uniquely. In the model, articulatory movements are represented as the output of a multi-dimensional second-order linear system driven by input forces. These movements are partially constrained by phoneme-related features of the vocal tract shape at given instants. The input forces are determined by minimizing the cost function, represented as the energy sum of the time-differentiated system inputs and outputs. Then, articulatory movements are obtained as the system response to the optimum inputs. The trajectory formation model is computer-simulated to generate tongue, lip, and jaw movements for VCV segments. Comparison of simulated trajectories with data measured using a magnetic position-sensing device shows that the model is able to generate accurate jaw–lip or jaw–tongue coproductions and anticipatory coarticulation for the segments.
    Type of Medium: Online Resource
    ISSN: 0001-4966 , 1520-8524
    URL: Article
    DOI: 10.1121/1.404781
    RVK:
    EQ 1000
    Language: English
    Publisher: Acoustical Society of America (ASA)
    Publication Date: 1992
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  • 6
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    Online Resource
    Changes in the vocal tract shape of sopranos at high pitch
    Acoustical Society of America (ASA) ; 2012
    In:  The Journal of the Acoustical Society of America Vol. 131, No. 4_Supplement ( 2012-04-01), p. 3378-3378
    Details
    In: The Journal of the Acoustical Society of America, Acoustical Society of America (ASA), Vol. 131, No. 4_Supplement ( 2012-04-01), p. 3378-3378
    Abstract: As sopranos increase their fundamental frequency (F0) to sing at higher pitches, they also increase the first resonance frequency (R1) of their vocal tract. This is probably to avoid sudden F0 changes when F0 and R1 cross. It is unclear, however, how sopranos change vocal tract shape to increase R1. Therefore, the vocal tract shapes of two Japanese sopranos during production of the sung vowel /a/ in the modal register (A4 and D5) and in the falsetto register (G5) were measured by MRI. The measured vocal tract shapes were compared with each other and their area functions were extracted to calculate acoustic characteristics. Results showed that changes in the vocal tract shape were small between A4 and D5, while changes were large between D5 and G5. At G5, it was observed in both subjects that the lower jaw opened, the pharyngeal wall and tongue root advanced, and the larynx retracted. In addition, one subject shortened the laryngeal cavity length. All these changes achieved R1 increase, in agreement with the acoustic sensitivity function. Thus, in conclusion, sopranos selectively modified parts of the vocal tract with high sensitivity to R1. This research was partly supported by Kakenhi (Grant Nos. 21500184, 21300071, 22520156).
    Type of Medium: Online Resource
    ISSN: 0001-4966 , 1520-8524
    URL: Article
    DOI: 10.1121/1.4708739
    RVK:
    EQ 1000
    Language: English
    Publisher: Acoustical Society of America (ASA)
    Publication Date: 2012
    detail.hit.zdb_id: 1461063-2
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  • 7
    Online Resource
    Online Resource
    Induction of Colonic Regulatory T Cells by Indigenous Clostridium Species
    American Association for the Advancement of Science (AAAS) ; 2011
    In:  Science Vol. 331, No. 6015 ( 2011-01-21), p. 337-341
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 331, No. 6015 ( 2011-01-21), p. 337-341
    Abstract: CD4 + T regulatory cells (T regs ), which express the Foxp3 transcription factor, play a critical role in the maintenance of immune homeostasis. Here, we show that in mice, T regs were most abundant in the colonic mucosa. The spore-forming component of indigenous intestinal microbiota, particularly clusters IV and XIVa of the genus Clostridium , promoted T reg cell accumulation. Colonization of mice by a defined mix of Clostridium strains provided an environment rich in transforming growth factor–β and affected Foxp3 + T reg number and function in the colon. Oral inoculation of Clostridium during the early life of conventionally reared mice resulted in resistance to colitis and systemic immunoglobulin E responses in adult mice, suggesting a new therapeutic approach to autoimmunity and allergy.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.1198469
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2011
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  • 8
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    Online Resource
    Ectopic colonization of oral bacteria in the intestine drives T H 1 cell induction and inflammation
    American Association for the Advancement of Science (AAAS) ; 2017
    In:  Science Vol. 358, No. 6361 ( 2017-10-20), p. 359-365
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 358, No. 6361 ( 2017-10-20), p. 359-365
    Abstract: Intestinal colonization by bacteria of oral origin has been correlated with several negative health outcomes, including inflammatory bowel disease. However, a causal role of oral bacteria ectopically colonizing the intestine remains unclear. Using gnotobiotic techniques, we show that strains of Klebsiella spp. isolated from the salivary microbiota are strong inducers of T helper 1 (T H 1) cells when they colonize in the gut. These Klebsiella strains are resistant to multiple antibiotics, tend to colonize when the intestinal microbiota is dysbiotic, and elicit a severe gut inflammation in the context of a genetically susceptible host. Our findings suggest that the oral cavity may serve as a reservoir for potential intestinal pathobionts that can exacerbate intestinal disease.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.aan4526
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2017
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    detail.hit.zdb_id: 2066996-3
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  • 9
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    Secretory IgA-mediated protection against V. cholerae and heat-labile enterotoxin-producing enterotoxigenic Escherichia coli by rice-based vaccine
    Proceedings of the National Academy of Sciences ; 2010
    In:  Proceedings of the National Academy of Sciences Vol. 107, No. 19 ( 2010-05-11), p. 8794-8799
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 107, No. 19 ( 2010-05-11), p. 8794-8799
    Abstract: Cholera and enterotoxigenic Escherichia coli (ETEC) are among the most common causes of acute infantile gastroenteritis globally. We previously developed a rice-based vaccine that expressed cholera toxin B subunit (MucoRice-CTB) and had the advantages of being cold chain–free and providing protection against cholera toxin (CT)–induced diarrhea. To advance the development of MucoRice-CTB for human clinical application, we investigated whether the CTB-specific secretory IgA (SIgA) induced by MucoRice-CTB gives longstanding protection against diarrhea induced by Vibrio cholerae and heat-labile enterotoxin (LT)–producing ETEC (LT-ETEC) in mice. Oral immunization with MucoRice-CTB stored at room temperature for more than 3 y provided effective SIgA-mediated protection against CT- or LT-induced diarrhea, but the protection was impaired in polymeric Ig receptor–deficient mice lacking SIgA. The vaccine gave longstanding protection against CT- or LT-induced diarrhea (for ≥6 months after primary immunization), and a single booster immunization extended the duration of protective immunity by at least 4 months. Furthermore, MucoRice-CTB vaccination prevented diarrhea in the event of V. cholerae and LT-ETEC challenges. Thus, MucoRice-CTB is an effective long-term cold chain–free oral vaccine that induces CTB-specific SIgA-mediated longstanding protection against V. cholerae – or LT-ETEC–induced diarrhea.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0914121107
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2010
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  • 10
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    The COUP-TFII/Neuropilin-2 is a molecular switch steering diencephalon-derived GABAergic neurons in the developing mouse brain
    Proceedings of the National Academy of Sciences ; 2015
    In:  Proceedings of the National Academy of Sciences Vol. 112, No. 36 ( 2015-09-08)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 112, No. 36 ( 2015-09-08)
    Abstract: The preoptic area (POa) of the rostral diencephalon supplies the neocortex and the amygdala with GABAergic neurons in the developing mouse brain. However, the molecular mechanisms that determine the pathway and destinations of POa-derived neurons have not yet been identified. Here we show that Chicken ovalbumin upstream promoter transcription factor II (COUP-TFII)–induced expression of Neuropilin-2 (Nrp2) and its down-regulation control the destination of POa-derived GABAergic neurons. Initially, a majority of the POa-derived migrating neurons express COUP-TFII and form a caudal migratory stream toward the caudal subpallium. When a subpopulation of cells steers toward the neocortex, they exhibit decreased expression of COUP-TFII and Nrp2. The present findings show that suppression of COUP-TFII/Nrp2 changed the destination of the cells into the neocortex, whereas overexpression of COUP-TFII/Nrp2 caused cells to end up in the medial part of the amygdala. Taken together, these results reveal that COUP-TFII/Nrp2 is a molecular switch determining the pathway and destination of migrating GABAergic neurons born in the POa.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1420701112
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2015
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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