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  • 1
    Online Resource
    Online Resource
    Morphological diversity of single neurons in molecularly defined cell types
    Springer Science and Business Media LLC ; 2021
    In:  Nature Vol. 598, No. 7879 ( 2021-10-07), p. 174-181
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 598, No. 7879 ( 2021-10-07), p. 174-181
    Abstract: Dendritic and axonal morphology reflects the input and output of neurons and is a defining feature of neuronal types 1,2 , yet our knowledge of its diversity remains limited. Here, to systematically examine complete single-neuron morphologies on a brain-wide scale, we established a pipeline encompassing sparse labelling, whole-brain imaging, reconstruction, registration and analysis. We fully reconstructed 1,741 neurons from cortex, claustrum, thalamus, striatum and other brain regions in mice. We identified 11 major projection neuron types with distinct morphological features and corresponding transcriptomic identities. Extensive projectional diversity was found within each of these major types, on the basis of which some types were clustered into more refined subtypes. This diversity follows a set of generalizable principles that govern long-range axonal projections at different levels, including molecular correspondence, divergent or convergent projection, axon termination pattern, regional specificity, topography, and individual cell variability. Although clear concordance with transcriptomic profiles is evident at the level of major projection type, fine-grained morphological diversity often does not readily correlate with transcriptomic subtypes derived from unsupervised clustering, highlighting the need for single-cell cross-modality studies. Overall, our study demonstrates the crucial need for quantitative description of complete single-cell anatomy in cell-type classification, as single-cell morphological diversity reveals a plethora of ways in which different cell types and their individual members may contribute to the configuration and function of their respective circuits.
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/s41586-021-03941-1
    RVK:
    TA 1000
    RVK:
    UA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 120714-3
    detail.hit.zdb_id: 1413423-8
    SSG: 11
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  • 2
    Online Resource
    Online Resource
    A multimodal cell census and atlas of the mammalian primary motor cortex
    Springer Science and Business Media LLC ; 2021
    In:  Nature Vol. 598, No. 7879 ( 2021-10-07), p. 86-102
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 598, No. 7879 ( 2021-10-07), p. 86-102
    Abstract: Here we report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties and cellular resolution input–output mapping, integrated through cross-modal computational analysis. Our results advance the collective knowledge and understanding of brain cell-type organization 1–5 . First, our study reveals a unified molecular genetic landscape of cortical cell types that integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a consensus taxonomy of transcriptomic types and their hierarchical organization that is conserved from mouse to marmoset and human. Third, in situ single-cell transcriptomics provides a spatially resolved cell-type atlas of the motor cortex. Fourth, cross-modal analysis provides compelling evidence for the transcriptomic, epigenomic and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types. We further present an extensive genetic toolset for targeting glutamatergic neuron types towards linking their molecular and developmental identity to their circuit function. Together, our results establish a unifying and mechanistic framework of neuronal cell-type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties.
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/s41586-021-03950-0
    RVK:
    TA 1000
    RVK:
    UA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 120714-3
    detail.hit.zdb_id: 1413423-8
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  • 3
    Online Resource
    Online Resource
    H7N9 Influenza Viruses Are Transmissible in Ferrets by Respiratory Droplet
    American Association for the Advancement of Science (AAAS) ; 2013
    In:  Science Vol. 341, No. 6144 ( 2013-07-26), p. 410-414
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 341, No. 6144 ( 2013-07-26), p. 410-414
    Abstract: A newly emerged H7N9 virus has caused 132 human infections with 37 deaths in China since 18 February 2013. Control measures in H7N9 virus–positive live poultry markets have reduced the number of infections; however, the character of the virus, including its pandemic potential, remains largely unknown. We systematically analyzed H7N9 viruses isolated from birds and humans. The viruses were genetically closely related and bound to human airway receptors; some also maintained the ability to bind to avian airway receptors. The viruses isolated from birds were nonpathogenic in chickens, ducks, and mice; however, the viruses isolated from humans caused up to 30% body weight loss in mice. Most importantly, one virus isolated from humans was highly transmissible in ferrets by respiratory droplet. Our findings indicate nothing to reduce the concern that these viruses can transmit between humans.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.1240532
    RVK:
    TA 1000
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    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2013
    detail.hit.zdb_id: 128410-1
    detail.hit.zdb_id: 2066996-3
    detail.hit.zdb_id: 2060783-0
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  • 4
    Online Resource
    Online Resource
    miR-495 is a tumor-suppressor microRNA down-regulated in MLL -rearranged leukemia
    Proceedings of the National Academy of Sciences ; 2012
    In:  Proceedings of the National Academy of Sciences Vol. 109, No. 47 ( 2012-11-20), p. 19397-19402
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 109, No. 47 ( 2012-11-20), p. 19397-19402
    Abstract: Acute myeloid leukemia (AML) is a heterogeneous group of hematopoietic malignancies with variable response to treatment. AMLs bearing MLL (mixed lineage leukemia) rearrangements are associated with intermediate or poor survival. MicroRNAs (miRNAs), a class of small noncoding RNAs, have been postulated to be important gene expression regulators virtually in all biological processes, including leukemogenesis. Through a large-scale, genome-wide miRNA expression profiling assay of 85 human AML and 15 normal control samples, we show that among 48 miRNAs that are significantly differentially expressed between MLL - and non– MLL -rearranged AML samples, only one (miR-495) is expressed at a lower level in MLL -rearranged AML than in non– MLL -rearranged AML; meanwhile, miR-495 is also significantly down-regulated in MLL -rearranged AML samples compared with normal control samples. Through in vitro colony-forming/replating assays and in vivo bone marrow transplantation studies, we show that forced expression of miR-495 significantly inhibits MLL-fusion-mediated cell transformation in vitro and leukemogenesis in vivo. In human leukemic cells carrying MLL rearrangements, ectopic expression of miR-495 greatly inhibits cell viability and increases cell apoptosis. Furthermore, our studies demonstrate that PBX3 and MEIS1 are two direct target genes of miR-495, and forced expression of either of them can reverse the effects of miR-495 overexpression on inhibiting cell viability and promoting apoptosis of human MLL -rearranged leukemic cells. Thus, our data indicate that miR-495 likely functions as a tumor suppressor in AML with MLL rearrangements by targeting essential leukemia-related genes.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1217519109
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2012
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  • 5
    Online Resource
    Online Resource
    TET1 plays an essential oncogenic role in MLL -rearranged leukemia
    Proceedings of the National Academy of Sciences ; 2013
    In:  Proceedings of the National Academy of Sciences Vol. 110, No. 29 ( 2013-07-16), p. 11994-11999
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 110, No. 29 ( 2013-07-16), p. 11994-11999
    Abstract: The ten-eleven translocation 1 ( TET1 ) gene is the founding member of the TET family of enzymes (TET1/2/3) that convert 5-methylcytosine to 5-hydroxymethylcytosine. Although TET1 was first identified as a fusion partner of the mixed lineage leukemia ( MLL ) gene in acute myeloid leukemia carrying t(10,11), its definitive role in leukemia is unclear. In contrast to the frequent down-regulation (or loss-of-function mutations) and critical tumor-suppressor roles of the three TET genes observed in various types of cancers, here we show that TET1 is a direct target of MLL-fusion proteins and is significantly up-regulated in MLL -rearranged leukemia, leading to a global increase of 5-hydroxymethylcytosine level. Furthermore, our both in vitro and in vivo functional studies demonstrate that Tet1 plays an indispensable oncogenic role in the development of MLL -rearranged leukemia, through coordination with MLL-fusion proteins in regulating their critical cotargets, including homeobox A9 ( Hoxa9 )/myeloid ecotropic viral integration 1 ( Meis1 )/pre-B-cell leukemia homeobox 3 ( Pbx3 ) genes. Collectively, our data delineate an MLL-fusion/Tet1/Hoxa9/Meis1/Pbx3 signaling axis in MLL -rearranged leukemia and highlight TET1 as a potential therapeutic target in treating this presently therapy-resistant disease.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1310656110
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2013
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
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  • 6
    Online Resource
    Online Resource
    miR-9 is an essential oncogenic microRNA specifically overexpressed in mixed lineage leukemia –rearranged leukemia
    Proceedings of the National Academy of Sciences ; 2013
    In:  Proceedings of the National Academy of Sciences Vol. 110, No. 28 ( 2013-07-09), p. 11511-11516
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 110, No. 28 ( 2013-07-09), p. 11511-11516
    Abstract: MicroRNAs (miRNAs), small noncoding RNAs that regulate target gene mRNAs, are known to contribute to pathogenesis of cancers. Acute myeloid leukemia (AML) is a group of heterogeneous hematopoietic malignancies with various chromosomal and/or molecular abnormalities. AML with chromosomal translocations involving the mixed lineage leukemia ( MLL ) gene are usually associated with poor survival. In the present study, through a large-scale, genomewide miRNA expression assay, we show that microRNA-9 (miR-9) is the most specifically up-regulated miRNA in MLL- rearranged AML compared with both normal control and non– MLL -rearranged AML. We demonstrate that miR-9 is a direct target of MLL fusion proteins and can be significantly up-regulated in expression by the latter in human and mouse hematopoietic stem/progenitor cells. Depletion of endogenous miR-9 expression by an appropriate antagomiR can significantly inhibit cell growth/viability and promote apoptosis in human MLL -rearranged AML cells, and the opposite is true when expression of miR-9 is forced. Blocking endogenous miR-9 function by anti-miRNA sponge can significantly inhibit, whereas forced expression of miR-9 can significantly promote, MLL fusion–induced immortalization/transformation of normal mouse bone marrow progenitor cells in vitro. Furthermore, forced expression of miR-9 can significantly promote MLL fusion–mediated leukemogenesis in vivo. In addition, a group of putative target genes of miR-9 exhibited a significant inverse correlation of expression with miR-9 in a series of leukemia sample sets, suggesting that they are potential targets of miR-9 in MLL -rearranged AML. Collectively, our data demonstrate that miR-9 is a critical oncomiR in MLL -rearranged AML and can serve as a potential therapeutic target to treat this dismal disease.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1310144110
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2013
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 7
    Online Resource
    Online Resource
    The landscape of accessible chromatin in mammalian preimplantation embryos
    Springer Science and Business Media LLC ; 2016
    In:  Nature Vol. 534, No. 7609 ( 2016-06-30), p. 652-657
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 534, No. 7609 ( 2016-06-30), p. 652-657
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/nature18606
    RVK:
    TA 1000
    RVK:
    UA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2016
    detail.hit.zdb_id: 120714-3
    detail.hit.zdb_id: 1413423-8
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  • 8
    Online Resource
    Online Resource
    Allelic reprogramming of the histone modification H3K4me3 in early mammalian development
    Springer Science and Business Media LLC ; 2016
    In:  Nature Vol. 537, No. 7621 ( 2016-09-22), p. 553-557
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 537, No. 7621 ( 2016-09-22), p. 553-557
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/nature19361
    RVK:
    TA 1000
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    UA 1000
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2016
    detail.hit.zdb_id: 120714-3
    detail.hit.zdb_id: 1413423-8
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  • 9
    Online Resource
    Online Resource
    Photosynthetic metabolism of C 3 plants shows highly cooperative regulation under changing environments: A systems biological analysis
    Proceedings of the National Academy of Sciences ; 2009
    In:  Proceedings of the National Academy of Sciences Vol. 106, No. 3 ( 2009-01-20), p. 847-852
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 106, No. 3 ( 2009-01-20), p. 847-852
    Abstract: We studied the robustness of photosynthetic metabolism in the chloroplasts of C 3 plants under drought stress and at high CO 2 concentration conditions by using a method called Minimization of Metabolic Adjustment Dynamic Flux Balance Analysis (M_DFBA). Photosynthetic metabolism in the chloroplasts of C 3 plants applies highly cooperative regulation to minimize the fluctuation of metabolite concentration profiles in the face of transient perturbations. Our work suggests that highly cooperative regulation assures the robustness of the biological system and that there is closer cooperation under perturbation conditions than under normal conditions. This results in minimizing fluctuations in the profiles of metabolite concentrations, which is the key to maintaining a system's function. Our methods help in understanding such phenomena and the mechanisms of robustness for complex metabolic networks in dynamic processes.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0810731105
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2009
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
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  • 10
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    Associations of maternal glycemia and prepregnancy BMI with early childhood growth: a prospective cohort study
    Wiley ; 2020
    In:  Annals of the New York Academy of Sciences Vol. 1465, No. 1 ( 2020-04), p. 89-98
    Details
    In: Annals of the New York Academy of Sciences, Wiley, Vol. 1465, No. 1 ( 2020-04), p. 89-98
    Abstract: The prevalence of maternal and child overweight/obesity and gestational hyperglycemia has increased greatly in China in recent years. However, studies examining the relationship between maternal hyperglycemia, maternal prepregnancy body mass index (ppBMI), and offspring obesity in China are limited. Here, we conducted a prospective study of 6684 mother−child pairs in Wuhan, China in 2012–2015. Maternal glucose concentrations were measured at approximately 24–28 weeks of gestation; children's weight and length were measured at birth and at 6, 12, and 24 months of age; and BMI‐for‐age Z‐scores (BMIZ) were calculated for different time points. We found that maternal fasting plasma glucose (FPG) concentrations were positively associated with offspring ponderal index and the risk of macrosomia at birth, but not with BMIZ or the risk of overweight/obesity at 6, 12, and 24 months of age. By contrast, maternal ppBMI was positively associated with both an increased risk of macrosomia at birth and overweight/obesity at 6, 12, and 24 months of age. Here, we observed an interaction effect of the association of FPG and ppBMI on offspring macrosomia and a mediating effect of gestational diabetes mellitus on the pathway between ppBMI and macrosomia. Our findings suggest that maternal ppBMI is a more pronounced predictor than gestational FPG concentrations in both the relation to BMIZ and the risk of overweight/obesity in early childhood.
    Type of Medium: Online Resource
    ISSN: 0077-8923 , 1749-6632
    URL: Issue
    URL: Article
    DOI: 10.1111/nyas.v1465.1
    DOI: 10.1111/nyas.14258
    RVK:
    TD 7650
    Language: English
    Publisher: Wiley
    Publication Date: 2020
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    detail.hit.zdb_id: 211003-9
    detail.hit.zdb_id: 2071584-5
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