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  1. AU="Levin, Joshua Z"
  2. AU="V.N. de Jonge"
  3. AU=Zhang Hongliang
  4. AU="Kumagai, A"
  5. AU="Jiménez, Karen Marcela"
  6. AU="Costello, Kelly L"
  7. AU="Sochacki, Mateusz"
  8. AU="Marja Koskuvi"
  9. AU="Hu, Xinfeng"
  10. AU=Sugarman Jeremy AU=Sugarman Jeremy
  11. AU="Tandale, Babasaheb"
  12. AU="Xie, Xinming"

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  1. Artikel ; Online: Pyramidal neuron subtype diversity governs microglia states in the neocortex.

    Stogsdill, Jeffrey A / Kim, Kwanho / Binan, Loïc / Farhi, Samouil L / Levin, Joshua Z / Arlotta, Paola

    Nature

    2022  Band 608, Heft 7924, Seite(n) 750–756

    Abstract: Microglia are specialized macrophages in the brain parenchyma that exist in multiple transcriptional states and reside within a wide range of neuronal ... ...

    Abstract Microglia are specialized macrophages in the brain parenchyma that exist in multiple transcriptional states and reside within a wide range of neuronal environments
    Mesh-Begriff(e) Animals ; Cell Count ; Mice ; Microglia/classification ; Microglia/physiology ; Neocortex/cytology ; Neocortex/physiology ; Pyramidal Cells/classification ; Pyramidal Cells/physiology ; Single-Cell Analysis ; Somatosensory Cortex/cytology ; Somatosensory Cortex/physiology ; Transcriptome
    Sprache Englisch
    Erscheinungsdatum 2022-08-10
    Erscheinungsland England
    Dokumenttyp Journal Article
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/s41586-022-05056-7
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: Lupus autoantibodies initiate neuroinflammation sustained by continuous HMGB1:RAGE signaling and reversed by increased LAIR-1 expression.

    Carroll, Kaitlin R / Mizrachi, Mark / Simmons, Sean / Toz, Bahtiyar / Kowal, Czeslawa / Wingard, Jeffrey / Tehrani, Nazila / Zarfeshani, Aida / Kello, Nina / El Khoury, Lara / Weissman-Tsukamoto, Rachel / Levin, Joshua Z / Volpe, Bruce T / Diamond, Betty

    Nature immunology

    2024  Band 25, Heft 4, Seite(n) 671–681

    Abstract: Cognitive impairment is a frequent manifestation of neuropsychiatric systemic lupus erythematosus, present in up to 80% of patients and leading to a diminished quality of life. In the present study, we used a model of lupus-like cognitive impairment that ...

    Abstract Cognitive impairment is a frequent manifestation of neuropsychiatric systemic lupus erythematosus, present in up to 80% of patients and leading to a diminished quality of life. In the present study, we used a model of lupus-like cognitive impairment that is initiated when antibodies that crossreact with excitatory neuronal receptors penetrate the hippocampus, causing immediate, self-limited, excitotoxic death of hippocampal neurons, which is then followed by a significant loss of dendritic complexity in surviving neurons. This injury creates a maladaptive equilibrium that is sustained in mice for at least 1 year. We identified a feedforward loop of microglial activation and microglia-dependent synapse elimination dependent on neuronal secretion of high mobility group box 1 protein (HMGB1) which binds the receptor for advanced glycation end products (RAGE) and leads to microglial secretion of C1q, upregulation of interleukin-10 with consequent downregulation of leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1), an inhibitory receptor for C1q. Treatment with a centrally acting angiotensin-converting enzyme inhibitor or with an angiotensin-receptor blocker restored a healthy equilibrium, microglial quiescence and intact spatial memory.
    Mesh-Begriff(e) Animals ; Mice ; Autoantibodies ; Complement C1q ; HMGB1 Protein/metabolism ; Neuroinflammatory Diseases ; Quality of Life ; Receptor for Advanced Glycation End Products/metabolism
    Chemische Substanzen Autoantibodies ; Complement C1q (80295-33-6) ; HMGB1 Protein ; Receptor for Advanced Glycation End Products ; HMGB1 protein, mouse ; leukocyte-associated immunoglobulin-like receptor 1 ; Ager protein, mouse
    Sprache Englisch
    Erscheinungsdatum 2024-03-06
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ZDB-ID 2016987-5
    ISSN 1529-2916 ; 1529-2908
    ISSN (online) 1529-2916
    ISSN 1529-2908
    DOI 10.1038/s41590-024-01772-6
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel: Massively parallel

    Zheng, Xinhe / Wu, Boli / Liu, Yuejia / Simmons, Sean K / Kim, Kwanho / Clarke, Grace S / Ashiq, Abdullah / Park, Joshua / Wang, Zhilin / Tong, Liqi / Wang, Qizhao / Xu, Xiangmin / Levin, Joshua Z / Jin, Xin

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Systematic analysis of gene function across diverse cell ... ...

    Abstract Systematic analysis of gene function across diverse cell types
    Sprache Englisch
    Erscheinungsdatum 2023-09-18
    Erscheinungsland United States
    Dokumenttyp Preprint
    DOI 10.1101/2023.09.18.558077
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  4. Artikel ; Online: The effect of background noise and its removal on the analysis of single-cell expression data.

    Janssen, Philipp / Kliesmete, Zane / Vieth, Beate / Adiconis, Xian / Simmons, Sean / Marshall, Jamie / McCabe, Cristin / Heyn, Holger / Levin, Joshua Z / Enard, Wolfgang / Hellmann, Ines

    Genome biology

    2023  Band 24, Heft 1, Seite(n) 140

    Abstract: Background: In droplet-based single-cell and single-nucleus RNA-seq experiments, not all reads associated with one cell barcode originate from the encapsulated cell. Such background noise is attributed to spillage from cell-free ambient RNA or barcode ... ...

    Abstract Background: In droplet-based single-cell and single-nucleus RNA-seq experiments, not all reads associated with one cell barcode originate from the encapsulated cell. Such background noise is attributed to spillage from cell-free ambient RNA or barcode swapping events.
    Results: Here, we characterize this background noise exemplified by three scRNA-seq and two snRNA-seq replicates of mouse kidneys. For each experiment, cells from two mouse subspecies are pooled, allowing to identify cross-genotype contaminating molecules and thus profile background noise. Background noise is highly variable across replicates and cells, making up on average 3-35% of the total counts (UMIs) per cell and we find that noise levels are directly proportional to the specificity and detectability of marker genes. In search of the source of background noise, we find multiple lines of evidence that the majority of background molecules originates from ambient RNA. Finally, we use our genotype-based estimates to evaluate the performance of three methods (CellBender, DecontX, SoupX) that are designed to quantify and remove background noise. We find that CellBender provides the most precise estimates of background noise levels and also yields the highest improvement for marker gene detection. By contrast, clustering and classification of cells are fairly robust towards background noise and only small improvements can be achieved by background removal that may come at the cost of distortions in fine structure.
    Conclusions: Our findings help to better understand the extent, sources and impact of background noise in single-cell experiments and provide guidance on how to deal with it.
    Mesh-Begriff(e) Animals ; Mice ; Sequence Analysis, RNA/methods ; RNA-Seq/methods ; RNA/genetics ; Genotype ; Single-Cell Analysis/methods ; Gene Expression Profiling/methods ; Cluster Analysis
    Chemische Substanzen RNA (63231-63-0)
    Sprache Englisch
    Erscheinungsdatum 2023-06-19
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2040529-7
    ISSN 1474-760X ; 1474-760X
    ISSN (online) 1474-760X
    ISSN 1474-760X
    DOI 10.1186/s13059-023-02978-x
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  5. Artikel: Lupus autoantibodies initiate a maladaptive equilibrium sustained by HMGB1:RAGE signaling and reversed by LAIR-1:C1q signaling.

    Carroll, Kaitlin R / Mizrachi, Mark / Simmons, Sean / Toz, Bahtiyar / Wingard, Jeffrey / Tehrani, Nazila / Zarfeshani, Aida / Kello, Nina / Kowal, Czeslawa / Levin, Joshua Z / Volpe, Bruce T / Diamond, Betty

    Research square

    2023  

    Abstract: Cognitive impairment is a frequent manifestation of neuropsychiatric systemic lupus erythematosus (NPSLE), present in up to 80% of patients and leading to a diminished quality of life. We have developed a model of lupus-like cognitive impairment which is ...

    Abstract Cognitive impairment is a frequent manifestation of neuropsychiatric systemic lupus erythematosus (NPSLE), present in up to 80% of patients and leading to a diminished quality of life. We have developed a model of lupus-like cognitive impairment which is initiated when anti-DNA, anti-N-methyl D-aspartate receptor (NMDAR) cross- reactive antibodies, which are present in 30% of SLE patients, penetrate the hippocampus
    Sprache Englisch
    Erscheinungsdatum 2023-05-22
    Erscheinungsland United States
    Dokumenttyp Preprint
    DOI 10.21203/rs.3.rs-2870168/v1
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  6. Artikel ; Online: Temporally divergent regulatory mechanisms govern neuronal diversification and maturation in the mouse and marmoset neocortex.

    Yuan, Wen / Ma, Sai / Brown, Juliana R / Kim, Kwanho / Murek, Vanessa / Trastulla, Lucia / Meissner, Alexander / Lodato, Simona / Shetty, Ashwin S / Levin, Joshua Z / Buenrostro, Jason D / Ziller, Michael J / Arlotta, Paola

    Nature neuroscience

    2022  Band 25, Heft 8, Seite(n) 1049–1058

    Abstract: Mammalian neocortical neurons span one of the most diverse cell type spectra of any tissue. Cortical neurons are born during embryonic development, and their maturation extends into postnatal life. The regulatory strategies underlying progressive ... ...

    Abstract Mammalian neocortical neurons span one of the most diverse cell type spectra of any tissue. Cortical neurons are born during embryonic development, and their maturation extends into postnatal life. The regulatory strategies underlying progressive neuronal development and maturation remain unclear. Here we present an integrated single-cell epigenomic and transcriptional analysis of individual mouse and marmoset cortical neuron classes, spanning both early postmitotic stages of identity acquisition and later stages of neuronal plasticity and circuit integration. We found that, in both species, the regulatory strategies controlling early and late stages of pan-neuronal development diverge. Early postmitotic neurons use more widely shared and evolutionarily conserved molecular regulatory programs. In contrast, programs active during later neuronal maturation are more brain- and neuron-specific and more evolutionarily divergent. Our work uncovers a temporal shift in regulatory choices during neuronal diversification and maturation in both mice and marmosets, which likely reflects unique evolutionary constraints on distinct events of neuronal development in the neocortex.
    Mesh-Begriff(e) Animals ; Callithrix ; Mammals ; Mice ; Neocortex ; Neurogenesis/physiology ; Neuronal Plasticity ; Neurons/physiology
    Sprache Englisch
    Erscheinungsdatum 2022-08-01
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 1420596-8
    ISSN 1546-1726 ; 1097-6256
    ISSN (online) 1546-1726
    ISSN 1097-6256
    DOI 10.1038/s41593-022-01123-4
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  7. Artikel ; Online: The evolution, evolvability and engineering of gene regulatory DNA.

    Vaishnav, Eeshit Dhaval / de Boer, Carl G / Molinet, Jennifer / Yassour, Moran / Fan, Lin / Adiconis, Xian / Thompson, Dawn A / Levin, Joshua Z / Cubillos, Francisco A / Regev, Aviv

    Nature

    2022  Band 603, Heft 7901, Seite(n) 455–463

    Abstract: Mutations in non-coding regulatory DNA sequences can alter gene expression, organismal phenotype and ... ...

    Abstract Mutations in non-coding regulatory DNA sequences can alter gene expression, organismal phenotype and fitness
    Mesh-Begriff(e) Biological Evolution ; DNA ; Evolution, Molecular ; Gene Expression Regulation ; Genetic Drift ; Models, Genetic ; Mutation/genetics ; Phenotype ; Saccharomyces cerevisiae/genetics
    Chemische Substanzen DNA (9007-49-2)
    Sprache Englisch
    Erscheinungsdatum 2022-03-09
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/s41586-022-04506-6
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  8. Artikel ; Online: Heterochronic parabiosis reprograms the mouse brain transcriptome by shifting aging signatures in multiple cell types.

    Ximerakis, Methodios / Holton, Kristina M / Giadone, Richard M / Ozek, Ceren / Saxena, Monika / Santiago, Samara / Adiconis, Xian / Dionne, Danielle / Nguyen, Lan / Shah, Kavya M / Goldstein, Jill M / Gasperini, Caterina / Gampierakis, Ioannis A / Lipnick, Scott L / Simmons, Sean K / Buchanan, Sean M / Wagers, Amy J / Regev, Aviv / Levin, Joshua Z /
    Rubin, Lee L

    Nature aging

    2023  Band 3, Heft 3, Seite(n) 327–345

    Abstract: Aging is a complex process involving transcriptomic changes associated with deterioration across multiple tissues and organs, including the brain. Recent studies using heterochronic parabiosis have shown that various aspects of aging-associated decline ... ...

    Abstract Aging is a complex process involving transcriptomic changes associated with deterioration across multiple tissues and organs, including the brain. Recent studies using heterochronic parabiosis have shown that various aspects of aging-associated decline are modifiable or even reversible. To better understand how this occurs, we performed single-cell transcriptomic profiling of young and old mouse brains after parabiosis. For each cell type, we cataloged alterations in gene expression, molecular pathways, transcriptional networks, ligand-receptor interactions and senescence status. Our analyses identified gene signatures, demonstrating that heterochronic parabiosis regulates several hallmarks of aging in a cell-type-specific manner. Brain endothelial cells were found to be especially malleable to this intervention, exhibiting dynamic transcriptional changes that affect vascular structure and function. These findings suggest new strategies for slowing deterioration and driving regeneration in the aging brain through approaches that do not rely on disease-specific mechanisms or actions of individual circulating factors.
    Mesh-Begriff(e) Animals ; Mice ; Transcriptome/genetics ; Endothelial Cells ; Aging/genetics ; Parabiosis ; Brain
    Sprache Englisch
    Erscheinungsdatum 2023-03-09
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 2662-8465
    ISSN (online) 2662-8465
    DOI 10.1038/s43587-023-00373-6
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  9. Artikel ; Online: Cell-type specific defects in PTEN-mutant cortical organoids converge on abnormal circuit activity.

    Pigoni, Martina / Uzquiano, Ana / Paulsen, Bruna / Kedaigle, Amanda J / Yang, Sung Min / Symvoulidis, Panagiotis / Adiconis, Xian / Velasco, Silvia / Sartore, Rafaela / Kim, Kwanho / Tucewicz, Ashley / Tropp, Sarah Yoshimi / Tsafou, Kalliopi / Jin, Xin / Barrett, Lindy / Chen, Fei / Boyden, Edward S / Regev, Aviv / Levin, Joshua Z /
    Arlotta, Paola

    Human molecular genetics

    2023  Band 32, Heft 18, Seite(n) 2773–2786

    Abstract: De novo heterozygous loss-of-function mutations in phosphatase and tensin homolog (PTEN) are strongly associated with autism spectrum disorders; however, it is unclear how heterozygous mutations in this gene affect different cell types during human brain ...

    Abstract De novo heterozygous loss-of-function mutations in phosphatase and tensin homolog (PTEN) are strongly associated with autism spectrum disorders; however, it is unclear how heterozygous mutations in this gene affect different cell types during human brain development and how these effects vary across individuals. Here, we used human cortical organoids from different donors to identify cell-type specific developmental events that are affected by heterozygous mutations in PTEN. We profiled individual organoids by single-cell RNA-seq, proteomics and spatial transcriptomics and revealed abnormalities in developmental timing in human outer radial glia progenitors and deep-layer cortical projection neurons, which varied with the donor genetic background. Calcium imaging in intact organoids showed that both accelerated and delayed neuronal development phenotypes resulted in similar abnormal activity of local circuits, irrespective of genetic background. The work reveals donor-dependent, cell-type specific developmental phenotypes of PTEN heterozygosity that later converge on disrupted neuronal activity.
    Mesh-Begriff(e) Humans ; Neurons/metabolism ; Cell Differentiation ; Organoids/metabolism ; Autism Spectrum Disorder/genetics ; Mutation ; PTEN Phosphohydrolase/genetics
    Chemische Substanzen PTEN protein, human (EC 3.1.3.67) ; PTEN Phosphohydrolase (EC 3.1.3.67)
    Sprache Englisch
    Erscheinungsdatum 2023-06-27
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 1108742-0
    ISSN 1460-2083 ; 0964-6906
    ISSN (online) 1460-2083
    ISSN 0964-6906
    DOI 10.1093/hmg/ddad107
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  10. Artikel ; Online: Brain-region-specific changes in neurons and glia and dysregulation of dopamine signaling in Grin2a mutant mice.

    Farsi, Zohreh / Nicolella, Ally / Simmons, Sean K / Aryal, Sameer / Shepard, Nate / Brenner, Kira / Lin, Sherry / Herzog, Linnea / Moran, Sean P / Stalnaker, Katherine J / Shin, Wangyong / Gazestani, Vahid / Song, Bryan J / Bonanno, Kevin / Keshishian, Hasmik / Carr, Steven A / Pan, Jen Q / Macosko, Evan Z / Datta, Sandeep Robert /
    Dejanovic, Borislav / Kim, Eunjoon / Levin, Joshua Z / Sheng, Morgan

    Neuron

    2023  Band 111, Heft 21, Seite(n) 3378–3396.e9

    Abstract: A genetically valid animal model could transform our understanding of schizophrenia (SCZ) disease mechanisms. Rare heterozygous loss-of-function (LoF) mutations in GRIN2A, encoding a subunit of the NMDA receptor, greatly increase the risk of SCZ. By ... ...

    Abstract A genetically valid animal model could transform our understanding of schizophrenia (SCZ) disease mechanisms. Rare heterozygous loss-of-function (LoF) mutations in GRIN2A, encoding a subunit of the NMDA receptor, greatly increase the risk of SCZ. By transcriptomic, proteomic, and behavioral analyses, we report that heterozygous Grin2a mutant mice show (1) large-scale gene expression changes across multiple brain regions and in neuronal (excitatory and inhibitory) and non-neuronal cells (astrocytes and oligodendrocytes), (2) evidence of hypoactivity in the prefrontal cortex (PFC) and hyperactivity in the hippocampus and striatum, (3) an elevated dopamine signaling in the striatum and hypersensitivity to amphetamine-induced hyperlocomotion (AIH), (4) altered cholesterol biosynthesis in astrocytes, (5) a reduction in glutamatergic receptor signaling proteins in the synapse, and (6) an aberrant locomotor pattern opposite of that induced by antipsychotic drugs. These findings reveal potential pathophysiologic mechanisms, provide support for both the "hypo-glutamate" and "hyper-dopamine" hypotheses of SCZ, and underscore the utility of Grin2a-deficient mice as a genetic model of SCZ.
    Mesh-Begriff(e) Animals ; Mice ; Brain/metabolism ; Dopamine/metabolism ; Neuroglia/metabolism ; Neurons/metabolism ; Prefrontal Cortex/metabolism ; Proteomics ; Disease Models, Animal ; Receptors, N-Methyl-D-Aspartate/genetics
    Chemische Substanzen Dopamine (VTD58H1Z2X) ; N-methyl D-aspartate receptor subtype 2A (VH92ICR8HX) ; Receptors, N-Methyl-D-Aspartate
    Sprache Englisch
    Erscheinungsdatum 2023-08-31
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 808167-0
    ISSN 1097-4199 ; 0896-6273
    ISSN (online) 1097-4199
    ISSN 0896-6273
    DOI 10.1016/j.neuron.2023.08.004
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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