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1.
Nat Biotechnol ; 41(2): 222-231, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36138169

RESUMO

Methods to spatially profile the transcriptome are dominated by a trade-off between resolution and throughput. Here we develop a method named Enhanced ELectric Fluorescence in situ Hybridization (EEL FISH) that can rapidly process large tissue samples without compromising spatial resolution. By electrophoretically transferring RNA from a tissue section onto a capture surface, EEL speeds up data acquisition by reducing the amount of imaging needed, while ensuring that RNA molecules move straight down toward the surface, preserving single-cell resolution. We apply EEL on eight entire sagittal sections of the mouse brain and measure the expression patterns of up to 440 genes to reveal complex tissue organization. Moreover, EEL can be used to study challenging human samples by removing autofluorescent lipofuscin, enabling the spatial transcriptome of the human visual cortex to be visualized. We provide full hardware specifications, all protocols and complete software for instrument control, image processing, data analysis and visualization.


Assuntos
RNA , Transcriptoma , Humanos , Animais , Camundongos , RNA Mensageiro/genética , Hibridização in Situ Fluorescente/métodos , RNA/análise , Transcriptoma/genética , Enguias/genética , Perfilação da Expressão Gênica/métodos
4.
Nat Commun ; 12(1): 3545, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112806

RESUMO

Multiplexed fluorescence in situ hybridization techniques have enabled cell-type identification, linking transcriptional heterogeneity with spatial heterogeneity of cells. However, inaccurate cell segmentation reduces the efficacy of cell-type identification and tissue characterization. Here, we present a method called Spot-based Spatial cell-type Analysis by Multidimensional mRNA density estimation (SSAM), a robust cell segmentation-free computational framework for identifying cell-types and tissue domains in 2D and 3D. SSAM is applicable to a variety of in situ transcriptomics techniques and capable of integrating prior knowledge of cell types. We apply SSAM to three mouse brain tissue images: the somatosensory cortex imaged by osmFISH, the hypothalamic preoptic region by MERFISH, and the visual cortex by multiplexed smFISH. Here, we show that SSAM detects regions occupied by known cell types that were previously missed and discovers new cell types.


Assuntos
Encéfalo/citologia , Biologia Computacional/métodos , Perfilação da Expressão Gênica/métodos , Processamento de Imagem Assistida por Computador/métodos , Imageamento Tridimensional/métodos , Hibridização in Situ Fluorescente/métodos , Análise de Célula Única/métodos , Algoritmos , Animais , Encéfalo/diagnóstico por imagem , Simulação por Computador , Camundongos , Neurônios/citologia , Neurônios/metabolismo , Área Pré-Óptica/citologia , Área Pré-Óptica/diagnóstico por imagem , Córtex Somatossensorial/citologia , Córtex Somatossensorial/diagnóstico por imagem , Transcriptoma/genética , Córtex Visual/citologia , Córtex Visual/diagnóstico por imagem
5.
Mol Psychiatry ; 26(11): 6820-6832, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976392

RESUMO

The G protein-coupled receptor kinase (GRK) family member protein GRK3 has been linked to the pathophysiology of schizophrenia and bipolar disorder. Expression, as well as protein levels, of GRK3 are reduced in post-mortem prefrontal cortex of schizophrenia subjects. Here, we investigate functional behavior and neurotransmission related to immune activation and psychosis using mice lacking functional Grk3 and utilizing a variety of methods, including behavioral, biochemical, electrophysiological, molecular, and imaging methods. Compared to wildtype controls, the Grk3-/- mice show a number of aberrations linked to psychosis, including elevated brain levels of IL-1ß, increased turnover of kynurenic acid (KYNA), hyper-responsiveness to D-amphetamine, elevated spontaneous firing of midbrain dopamine neurons, and disruption in prepulse inhibition. Analyzing human genetic data, we observe a link between psychotic features in bipolar disorder, decreased GRK expression, and increased concentration of CSF KYNA. Taken together, our data suggest that Grk3-/- mice show face and construct validity relating to the psychosis phenotype with glial activation and would be suitable for translational studies of novel immunomodulatory agents in psychotic disorders.


Assuntos
Transtorno Bipolar , Transtornos Psicóticos , Esquizofrenia , Animais , Transtorno Bipolar/genética , Transtorno Bipolar/metabolismo , Encéfalo/metabolismo , Ácido Cinurênico/metabolismo , Camundongos , Transtornos Psicóticos/genética , Transtornos Psicóticos/metabolismo , Esquizofrenia/metabolismo
6.
Nat Biotechnol ; 39(8): 968-977, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33875865

RESUMO

Several techniques are currently being developed for spatially resolved omics profiling, but each new method requires the setup of specific detection strategies or specialized instrumentation. Here we describe an imaging-free framework to localize high-throughput readouts within a tissue by cutting the sample into thin strips in a way that allows subsequent image reconstruction. We implemented this framework to transform a low-input RNA sequencing protocol into an imaging-free spatial transcriptomics technique (called STRP-seq) and validated it by profiling the spatial transcriptome of the mouse brain. We applied the technique to the brain of the Australian bearded dragon, Pogona vitticeps. Our results reveal the molecular anatomy of the telencephalon of this lizard, providing evidence for a marked regionalization of the reptilian pallium and subpallium. We expect that STRP-seq can be used to derive spatially resolved data from a range of other omics techniques.


Assuntos
Perfilação da Expressão Gênica/métodos , Imagem Molecular/métodos , Tomografia/métodos , Algoritmos , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Química Encefálica , Lagartos , Camundongos , Transcriptoma/genética
8.
Stem Cell Res Ther ; 11(1): 320, 2020 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-32727554

RESUMO

BACKGROUND: There are multiple promising treatment strategies for central nervous system trauma and disease. However, to develop clinically potent and safe treatments, models of human-specific conditions are needed to complement in vitro and in vivo animal model-based studies. METHODS: We established human brain stem and spinal cord (cross- and longitudinal sections) organotypic cultures (hOCs) from first trimester tissues after informed consent by donor and ethical approval by the Regional Human Ethics Committee, Stockholm (lately referred to as Swedish Ethical Review Authority), and The National Board of Health and Welfare, Sweden. We evaluated the stability of hOCs with a semi-quantitative hOC score, immunohistochemistry, flow cytometry, Ca2+ signaling, and electrophysiological analysis. We also applied experimental allogeneic human neural cell therapy after injury in the ex vivo spinal cord slices. RESULTS: The spinal cord hOCs presented relatively stable features during 7-21 days in vitro (DIV) (except a slightly increased cell proliferation and activated glial response). After contusion injury performed at 7 DIV, a significant reduction of the hOC score, increase of the activated caspase-3+ cell population, and activated microglial populations at 14 days postinjury compared to sham controls were observed. Such elevation in the activated caspase-3+ population and activated microglial population was not observed after allogeneic human neural cell therapy. CONCLUSIONS: We conclude that human spinal cord slice cultures have potential for future structural and functional studies of human spinal cord development, injury, and treatment strategies.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Traumatismos da Medula Espinal , Animais , Terapia Baseada em Transplante de Células e Tecidos , Humanos , Neurônios , Medula Espinal , Traumatismos da Medula Espinal/terapia
9.
Nat Commun ; 10(1): 4137, 2019 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-31515492

RESUMO

Developmental cell death plays an important role in the construction of functional neural circuits. In vertebrates, the canonical view proposes a selection of the surviving neurons through stochastic competition for target-derived neurotrophic signals, implying an equal potential for neurons to compete. Here we show an alternative cell fitness selection of neurons that is defined by a specific neuronal heterogeneity code. Proprioceptive sensory neurons that will undergo cell death and those that will survive exhibit different molecular signatures that are regulated by retinoic acid and transcription factors, and are independent of the target and neurotrophins. These molecular features are genetically encoded, representing two distinct subgroups of neurons with contrasted functional maturation states and survival outcome. Thus, in this model, a heterogeneous code of intrinsic cell fitness in neighboring neurons provides differential competitive advantage resulting in the selection of cells with higher capacity to survive and functionally integrate into neural networks.


Assuntos
Modelos Biológicos , Células Receptoras Sensoriais/citologia , Animais , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Embrião de Galinha , Subunidade alfa 3 de Fator de Ligação ao Core/metabolismo , Camundongos Endogâmicos C57BL , Propriocepção/efeitos dos fármacos , Receptor trkC/metabolismo , Células Receptoras Sensoriais/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Tretinoína/farmacologia
10.
J Exp Med ; 216(8): 1904-1924, 2019 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-31196979

RESUMO

Rheumatoid arthritis-associated joint pain is frequently observed independent of disease activity, suggesting unidentified pain mechanisms. We demonstrate that antibodies binding to cartilage, specific for collagen type II (CII) or cartilage oligomeric matrix protein (COMP), elicit mechanical hypersensitivity in mice, uncoupled from visual, histological and molecular indications of inflammation. Cartilage antibody-induced pain-like behavior does not depend on complement activation or joint inflammation, but instead on tissue antigen recognition and local immune complex (IC) formation. smFISH and IHC suggest that neuronal Fcgr1 and Fcgr2b mRNA are transported to peripheral ends of primary afferents. CII-ICs directly activate cultured WT but not FcRγ chain-deficient DRG neurons. In line with this observation, CII-IC does not induce mechanical hypersensitivity in FcRγ chain-deficient mice. Furthermore, injection of CII antibodies does not generate pain-like behavior in FcRγ chain-deficient mice or mice lacking activating FcγRs in neurons. In summary, this study defines functional coupling between autoantibodies and pain transmission that may facilitate the development of new disease-relevant pain therapeutics.


Assuntos
Anticorpos Monoclonais/imunologia , Complexo Antígeno-Anticorpo/metabolismo , Artralgia/imunologia , Artrite Reumatoide/imunologia , Autoanticorpos/imunologia , Cartilagem/imunologia , Neurônios/metabolismo , Animais , Anticorpos Monoclonais/uso terapêutico , Artralgia/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Autoanticorpos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Proteína de Matriz Oligomérica de Cartilagem/imunologia , Colágeno Tipo II/imunologia , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Transgênicos , Receptores de IgG/deficiência , Receptores de IgG/genética
11.
Mol Oncol ; 13(2): 202-211, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30358081

RESUMO

Bacillus Calmette-Guérin (BCG) is widely used in the clinic to effectively treat superficial urinary bladder cancer. However, a significant proportion of patients who fail to respond to BCG risk cystectomy or death. Though more than 3 million cancer treatments with BCG occur annually, surprisingly little is known about the initial signaling cascades activated by BCG. Here, we report that BCG induces a rapid intracellular Ca2+ (calcium ion) signal in bladder cancer cells that is essential for activating the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and for synthesizing and secreting proinflammatory cytokines, including interleukin 8 (IL-8). A similar Ca2+ response was observed when cells were exposed to the supernatant of BCG. Studying cellular molecular mechanisms involved in the BCG signaling event, we found pivotal roles for phospholipase C and the Toll-like receptor 4. Further assessment revealed that this signaling pathway induces synthesis of IL-8, whereas exocytosis appeared to be controlled by global Ca2+ signaling. These results shed new light on the molecular mechanisms underlying BCG treatment of bladder cancer, which can help in improving therapeutic efficacy and reducing adverse side effects.


Assuntos
Sinalização do Cálcio , Citocinas/metabolismo , Mycobacterium bovis/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Cálcio/metabolismo , Linhagem Celular Tumoral , Citosol/metabolismo , Humanos , Interleucina-8/metabolismo , NF-kappa B/metabolismo , Receptor 4 Toll-Like/metabolismo
12.
Nat Methods ; 15(11): 932-935, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30377364

RESUMO

Global efforts to create a molecular census of the brain using single-cell transcriptomics are producing a large catalog of molecularly defined cell types. However, spatial information is lacking and new methods are needed to map a large number of cell type-specific markers simultaneously on large tissue areas. Here, we describe a cyclic single-molecule fluorescence in situ hybridization methodology and define the cellular organization of the somatosensory cortex.


Assuntos
Mapeamento Encefálico/métodos , Processamento de Imagem Assistida por Computador/métodos , Hibridização in Situ Fluorescente/métodos , RNA/análise , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Córtex Somatossensorial/fisiologia , Animais , Feminino , Corantes Fluorescentes/química , Masculino , Córtex Somatossensorial/citologia
13.
Cell ; 174(4): 999-1014.e22, 2018 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-30096314

RESUMO

The mammalian nervous system executes complex behaviors controlled by specialized, precisely positioned, and interacting cell types. Here, we used RNA sequencing of half a million single cells to create a detailed census of cell types in the mouse nervous system. We mapped cell types spatially and derived a hierarchical, data-driven taxonomy. Neurons were the most diverse and were grouped by developmental anatomical units and by the expression of neurotransmitters and neuropeptides. Neuronal diversity was driven by genes encoding cell identity, synaptic connectivity, neurotransmission, and membrane conductance. We discovered seven distinct, regionally restricted astrocyte types that obeyed developmental boundaries and correlated with the spatial distribution of key glutamate and glycine neurotransmitters. In contrast, oligodendrocytes showed a loss of regional identity followed by a secondary diversification. The resource presented here lays a solid foundation for understanding the molecular architecture of the mammalian nervous system and enables genetic manipulation of specific cell types.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Redes Reguladoras de Genes , Sistema Nervoso/metabolismo , Análise de Célula Única/métodos , Transcriptoma , Animais , Feminino , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sistema Nervoso/crescimento & desenvolvimento
14.
J Neurosci ; 38(2): 452-464, 2018 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-29175959

RESUMO

Immune-related events in the periphery can remotely affect brain function, contributing to neurodegenerative processes and cognitive decline. In mice, peripheral surgery induces a systemic inflammatory response associated with changes in hippocampal synaptic plasticity and transient cognitive decline, however, the underlying mechanisms remain unknown. Here we investigated the effect of peripheral surgery on neuronal-glial function within hippocampal neuronal circuits of relevance to cognitive processing in male mice at 6, 24, and 72 h postsurgery. At 6 h we detect the proinflammatory cytokine IL-6 in the hippocampus, followed up by alterations in the mRNA and protein expression of astrocytic and neuronal proteins necessary for optimal energy supply to the brain and for the reuptake and recycling of glutamate in the synapse. Similarly, at 24 h postsurgery the mRNA expression of structural proteins (GFAP and AQP4) was compromised. At this time point, functional analysis in astrocytes revealed a decrease in resting calcium signaling. Examination of neuronal activity by whole-cell patch-clamp shows elevated levels of glutamatergic transmission and changes in AMPA receptor subunit composition at 72 h postsurgery. Finally, lactate, an essential energy substrate produced by astrocytes and critical for memory formation, decreases at 6 and 72 h after surgery. Based on temporal parallels with our previous studies, we propose that the previously reported cognitive decline observed at 72 h postsurgery in mice might be the consequence of temporal hippocampal metabolic, structural, and functional changes in astrocytes that lead to a disruption of the neuroglial metabolic coupling and consequently to a neuronal dysfunction.SIGNIFICANCE STATEMENT A growing body of evidence suggests that surgical trauma launches a systemic inflammatory response that reaches the brain and associates with immune activation and cognitive decline. Understanding the mechanisms by which immune-related events in the periphery can influence brain processes is essential for the development of therapies to prevent or treat postoperative cognitive dysfunction and other forms of cognitive decline related to immune-to-brain communication, such as Alzheimer's and Parkinson's diseases. Here we describe the temporal orchestration of a series of metabolic, structural, and functional changes after aseptic trauma in mice related to astrocytes and later in neurons that emphasize the role of astrocytes as key intermediaries between peripheral immune events, neuronal processing, and potentially cognition.


Assuntos
Hipocampo/metabolismo , Neuroglia/metabolismo , Neuroimunomodulação/fisiologia , Neurônios/metabolismo , Osteotomia/efeitos adversos , Animais , Citocinas/biossíntese , Hipocampo/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
15.
Sci Rep ; 7(1): 6031, 2017 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-28729663

RESUMO

Significant heterogeneities in gene expression among individual cells are typically interrogated using single whole cell approaches. However, tissues that have highly interconnected processes, such as in the brain, present unique challenges. Single-nucleus RNA sequencing (SNS) has emerged as an alternative method of assessing a cell's transcriptome through the use of isolated nuclei. However, studies directly comparing expression data between nuclei and whole cells are lacking. Here, we have characterized nuclear and whole cell transcriptomes in mouse single neurons and provided a normalization strategy to reduce method-specific differences related to the length of genic regions. We confirmed a high concordance between nuclear and whole cell transcriptomes in the expression of cell type and metabolic modeling markers, but less so for a subset of genes associated with mitochondrial respiration. Therefore, our results indicate that single-nucleus transcriptome sequencing provides an effective means to profile cell type expression dynamics in previously inaccessible tissues.


Assuntos
Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Análise de Célula Única , Transcriptoma , Animais , Núcleo Celular/genética , Córtex Cerebral/metabolismo , Feminino , Perfilação da Expressão Gênica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Masculino , Camundongos , Neurônios/metabolismo , Especificidade de Órgãos , Análise de Célula Única/métodos
16.
Exp Cell Res ; 357(2): 236-242, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28587745

RESUMO

Traumatic spinal cord injury is characterized by an initial cell loss that is followed by a concerted cellular response in an attempt to restore the damaged tissue. Nevertheless, little is known about the signaling mechanisms governing the cellular response to injury. Here, we have established an adult ex vivo system that exhibits multiple hallmarks of spinal cord injury and allows the study of complex processes that are difficult to address using animal models. We have characterized the ependymal cell response to injury in this model system and found that ependymal cells can become activated, proliferate, migrate out of the central canal lining and differentiate in a manner resembling the in vivo situation. Moreover, we show that these cells respond to external adenosine triphosphate and exhibit spontaneous Ca2+ activity, processes that may play a significant role in the regulation of their response to spinal cord injury. This model provides an attractive tool to deepen our understanding of the ependymal cell response after spinal cord injury, which may contribute to the development of new treatment options for spinal cord injury.


Assuntos
Proliferação de Células/fisiologia , Epêndima/patologia , Neuroglia/patologia , Traumatismos da Medula Espinal/patologia , Envelhecimento , Animais , Modelos Animais de Doenças , Camundongos
17.
Cell ; 167(2): 566-580.e19, 2016 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-27716510

RESUMO

Understanding human embryonic ventral midbrain is of major interest for Parkinson's disease. However, the cell types, their gene expression dynamics, and their relationship to commonly used rodent models remain to be defined. We performed single-cell RNA sequencing to examine ventral midbrain development in human and mouse. We found 25 molecularly defined human cell types, including five subtypes of radial glia-like cells and four progenitors. In the mouse, two mature fetal dopaminergic neuron subtypes diversified into five adult classes during postnatal development. Cell types and gene expression were generally conserved across species, but with clear differences in cell proliferation, developmental timing, and dopaminergic neuron development. Additionally, we developed a method to quantitatively assess the fidelity of dopaminergic neurons derived from human pluripotent stem cells, at a single-cell level. Thus, our study provides insight into the molecular programs controlling human midbrain development and provides a foundation for the development of cell replacement therapies.


Assuntos
Neurônios Dopaminérgicos/citologia , Mesencéfalo/citologia , Mesencéfalo/embriologia , Células-Tronco Neurais/citologia , Neurogênese , Células-Tronco Pluripotentes/citologia , Animais , Linhagem Celular , Técnicas de Reprogramação Celular , Humanos , Aprendizado de Máquina , Mesencéfalo/metabolismo , Camundongos , Neuroglia/citologia , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos
19.
Science ; 353(6294): 78-82, 2016 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-27365449

RESUMO

Analysis of the pattern of proteins or messengerRNAs (mRNAs) in histological tissue sections is a cornerstone in biomedical research and diagnostics. This typically involves the visualization of a few proteins or expressed genes at a time. We have devised a strategy, which we call "spatial transcriptomics," that allows visualization and quantitative analysis of the transcriptome with spatial resolution in individual tissue sections. By positioning histological sections on arrayed reverse transcription primers with unique positional barcodes, we demonstrate high-quality RNA-sequencing data with maintained two-dimensional positional information from the mouse brain and human breast cancer. Spatial transcriptomics provides quantitative gene expression data and visualization of the distribution of mRNAs within tissue sections and enables novel types of bioinformatics analyses, valuable in research and diagnostics.


Assuntos
Perfilação da Expressão Gênica/métodos , Análise de Sequência de RNA/métodos , Transcriptoma , Animais , Encéfalo/metabolismo , Neoplasias da Mama/metabolismo , DNA Complementar/biossíntese , Feminino , Humanos , Camundongos , Especificidade de Órgãos , RNA Mensageiro/metabolismo
20.
Science ; 352(6291): 1326-1329, 2016 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-27284195

RESUMO

Oligodendrocytes have been considered as a functionally homogeneous population in the central nervous system (CNS). We performed single-cell RNA sequencing on 5072 cells of the oligodendrocyte lineage from 10 regions of the mouse juvenile and adult CNS. Thirteen distinct populations were identified, 12 of which represent a continuum from Pdgfra(+) oligodendrocyte precursor cells (OPCs) to distinct mature oligodendrocytes. Initial stages of differentiation were similar across the juvenile CNS, whereas subsets of mature oligodendrocytes were enriched in specific regions in the adult brain. Newly formed oligodendrocytes were detected in the adult CNS and were responsive to complex motor learning. A second Pdgfra(+) population, distinct from OPCs, was found along vessels. Our study reveals the dynamics of oligodendrocyte differentiation and maturation, uncoupling them at a transcriptional level and highlighting oligodendrocyte heterogeneity in the CNS.


Assuntos
Encéfalo/crescimento & desenvolvimento , Neurogênese , Oligodendroglia/citologia , Animais , Antígenos/genética , Antígenos/metabolismo , Biomarcadores/metabolismo , Encéfalo/citologia , Linhagem da Célula , Células Cultivadas , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Aprendizagem/fisiologia , Camundongos , Atividade Motora/fisiologia , Bainha de Mielina/genética , Bainha de Mielina/metabolismo , Oligodendroglia/metabolismo , Proteoglicanas/genética , Proteoglicanas/metabolismo , RNA Mensageiro/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Análise de Sequência de RNA , Análise de Célula Única
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