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1.
Drugs R D ; 24(3): 465-476, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39231890

RESUMO

BACKGROUND AND OBJECTIVE: Tinengotinib, a novel multi-target small molecule kinase inhibitor, is currently undergoing phase II clinical trial in the USA and China. The purpose of this open-label study was to investigate the absorption, metabolism, and excretion of [14C]tinengotinib following a single oral dose in healthy subjects. METHODS: Six healthy male subjects received a single oral dose of [14C]tinengotinib capsules at 10 mg/100 µCi, and blood, urine, and feces samples were collected. Phenotyping experiments were further conducted to confirm the enzymes involved in its metabolism. RESULTS: Tinengotinib was rapidly absorbed in plasma with a time to peak drug concentration (Tmax) of 1.0-4.0 h post-dose and a long terminal half-life (t½) of 23.7 h. Blood-to-plasma radioactivity concentration ratios across timepoints ranged from 0.780 to 0.827, which indicated minimal association of radioactivity with blood cells. The mean cumulative excreted radioactivity was 99.57% of the dose, including 92.46% (68.65% as unchanged) in feces and 7.11% (0.28% as unchanged) in urine. In addition to unchanged tinengotinib, a total of 11 radioactive metabolites were identified in plasma, urine, and feces. The most abundant circulating radioactivity was the parent drug in plasma, which comprised 88.23% of the total radioactivity area under the concentration-time curve (AUC). Metabolite M410-3 was a major circulating metabolite, accounting for 5.38% of the parent drug exposure and 4.75% of the total drug-related exposure, respectively. All excreted metabolites accounted for less than 5.10% and 1.82% of the dose in feces and urine, respectively. In addition, no unique metabolites were observed in humans. Tinengotinib was metabolized mainly via CYP3A4. CONCLUSIONS: Overall, tinengotinib demonstrated a complete mass balance with limited renal excretion, no disproportionate blood metabolism, and slow elimination, primarily through the fecal route. The results of this study provide evidence to support the rational use of tinengotinib as a pharmacotherapeutic agent. REGISTRATION: ChinadrugTrials.org.cn identifier: CTR20212852.


Assuntos
Biotransformação , Voluntários Saudáveis , Inibidores de Proteínas Quinases , Humanos , Masculino , Adulto , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/urina , Inibidores de Proteínas Quinases/administração & dosagem , Adulto Jovem , Fezes/química , Administração Oral , Meia-Vida , Radioisótopos de Carbono , Piridinas , Triazóis
2.
bioRxiv ; 2024 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-39314450

RESUMO

Spatially resolved omics (SRO) technologies enable the identification of cell types while preserving their organization within tissues. Application of such technologies offers the opportunity to delineate cell-type spatial relationships, particularly across different length scales, and enhance our understanding of tissue organization and function. To quantify such multi-scale cell-type spatial relationships, we developed CRAWDAD, Cell-type Relationship Analysis Workflow Done Across Distances, as an open-source R package with source code and additional documentation at https://jef.works/CRAWDAD/. To demonstrate the utility of such multi-scale characterization, recapitulate expected cell-type spatial relationships, and evaluate against other cell-type spatial analyses, we applied CRAWDAD to various simulated and real SRO datasets of diverse tissues assayed by diverse SRO technologies. We further demonstrate how such multi-scale characterization enabled by CRAWDAD can be used to compare cell-type spatial relationships across multiple samples. Finally, we applied CRAWDAD to SRO datasets of the human spleen to identify consistent as well as patient and sample-specific cell-type spatial relationships. In general, we anticipate such multi-scale analysis of SRO data enabled by CRAWDAD will provide useful quantitative metrics to facilitate the identification, characterization, and comparison of cell-type spatial relationships across axes of interest.

3.
Bioinformatics ; 40(7)2024 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-38902953

RESUMO

MOTIVATION: Spatial omics data demand computational analysis but many analysis tools have computational resource requirements that increase with the number of cells analyzed. This presents scalability challenges as researchers use spatial omics technologies to profile millions of cells. RESULTS: To enhance the scalability of spatial omics data analysis, we developed a rasterization preprocessing framework called SEraster that aggregates cellular information into spatial pixels. We apply SEraster to both real and simulated spatial omics data prior to spatial variable gene expression analysis to demonstrate that such preprocessing can reduce computational resource requirements while maintaining high performance, including as compared to other down-sampling approaches. We further integrate SEraster with existing analysis tools to characterize cell-type spatial co-enrichment across length scales. Finally, we apply SEraster to enable analysis of a mouse pup spatial omics dataset with over a million cells to identify tissue-level and cell-type-specific spatially variable genes as well as spatially co-enriched cell types that recapitulate expected organ structures. AVAILABILITY AND IMPLEMENTATION: SEraster is implemented as an R package on GitHub (https://github.com/JEFworks-Lab/SEraster) with additional tutorials at https://JEF.works/SEraster.


Assuntos
Software , Camundongos , Animais , Biologia Computacional/métodos , Perfilação da Expressão Gênica/métodos , Algoritmos
4.
Genome Biol ; 25(1): 153, 2024 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-38867267

RESUMO

BACKGROUND: Recent advances in imaging-based spatially resolved transcriptomics (im-SRT) technologies now enable high-throughput profiling of targeted genes and their locations in fixed tissues. Normalization of gene expression data is often needed to account for technical factors that may confound underlying biological signals. RESULTS: Here, we investigate the potential impact of different gene count normalization methods with different targeted gene panels in the analysis and interpretation of im-SRT data. Using different simulated gene panels that overrepresent genes expressed in specific tissue regions or cell types, we demonstrate how normalization methods based on detected gene counts per cell differentially impact normalized gene expression magnitudes in a region- or cell type-specific manner. We show that these normalization-induced effects may reduce the reliability of downstream analyses including differential gene expression, gene fold change, and spatially variable gene analysis, introducing false positive and false negative results when compared to results obtained from gene panels that are more representative of the gene expression of the tissue's component cell types. These effects are not observed with normalization approaches that do not use detected gene counts for gene expression magnitude adjustment, such as with cell volume or cell area normalization. CONCLUSIONS: We recommend using non-gene count-based normalization approaches when feasible and evaluating gene panel representativeness before using gene count-based normalization methods if necessary. Overall, we caution that the choice of normalization method and gene panel may impact the biological interpretation of the im-SRT data.


Assuntos
Perfilação da Expressão Gênica , Análise de Célula Única , Análise de Célula Única/métodos , Perfilação da Expressão Gênica/métodos , Transcriptoma , Humanos , Animais
5.
bioRxiv ; 2024 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-38826261

RESUMO

The Human BioMolecular Atlas Program (HuBMAP) aims to construct a reference 3D structural, cellular, and molecular atlas of the healthy adult human body. The HuBMAP Data Portal (https://portal.hubmapconsortium.org) serves experimental datasets and supports data processing, search, filtering, and visualization. The Human Reference Atlas (HRA) Portal (https://humanatlas.io) provides open access to atlas data, code, procedures, and instructional materials. Experts from more than 20 consortia are collaborating to construct the HRA's Common Coordinate Framework (CCF), knowledge graphs, and tools that describe the multiscale structure of the human body (from organs and tissues down to cells, genes, and biomarkers) and to use the HRA to understand changes that occur at each of these levels with aging, disease, and other perturbations. The 6th release of the HRA v2.0 covers 36 organs with 4,499 unique anatomical structures, 1,195 cell types, and 2,089 biomarkers (e.g., genes, proteins, lipids) linked to ontologies and 2D/3D reference objects. New experimental data can be mapped into the HRA using (1) three cell type annotation tools (e.g., Azimuth) or (2) validated antibody panels (OMAPs), or (3) by registering tissue data spatially. This paper describes the HRA user stories, terminology, data formats, ontology validation, unified analysis workflows, user interfaces, instructional materials, application programming interface (APIs), flexible hybrid cloud infrastructure, and previews atlas usage applications.

6.
bioRxiv ; 2024 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-38798365

RESUMO

Cellular senescence is an established driver of aging, exhibiting context-dependent phenotypes across multiple biological length-scales. Despite its mechanistic importance, profiling senescence within cell populations is challenging. This is in part due to the limitations of current biomarkers to robustly identify senescent cells across biological settings, and the heterogeneous, non-binary phenotypes exhibited by senescent cells. Using a panel of primary dermal fibroblasts, we combined live single-cell imaging, machine learning, multiple senescence induction conditions, and multiple protein-based senescence biomarkers to show the emergence of functional subtypes of senescence. Leveraging single-cell morphologies, we defined eleven distinct morphology clusters, with the abundance of cells in each cluster being dependent on the mode of senescence induction, the time post-induction, and the age of the donor. Of these eleven clusters, we identified three bona-fide senescence subtypes (C7, C10, C11), with C10 showing the strongest age-dependence across a cohort of fifty aging individuals. To determine the functional significance of these senescence subtypes, we profiled their responses to senotherapies, specifically focusing on Dasatinib + Quercetin (D+Q). Results indicated subtype-dependent responses, with senescent cells in C7 being most responsive to D+Q. Altogether, we provide a robust single-cell framework to identify and classify functional senescence subtypes with applications for next-generation senotherapy screens, and the potential to explain heterogeneous senescence phenotypes across biological settings based on the presence and abundance of distinct senescence subtypes.

7.
Nat Commun ; 15(1): 3530, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38664422

RESUMO

This paper explicates a solution to building correspondences between molecular-scale transcriptomics and tissue-scale atlases. This problem arises in atlas construction and cross-specimen/technology alignment where specimens per emerging technology remain sparse and conventional image representations cannot efficiently model the high dimensions from subcellular detection of thousands of genes. We address these challenges by representing spatial transcriptomics data as generalized functions encoding position and high-dimensional feature (gene, cell type) identity. We map onto low-dimensional atlas ontologies by modeling regions as homogeneous random fields with unknown transcriptomic feature distribution. We solve simultaneously for the minimizing geodesic diffeomorphism of coordinates through LDDMM and for these latent feature densities. We map tissue-scale mouse brain atlases to gene-based and cell-based transcriptomics data from MERFISH and BARseq technologies and to histopathology and cross-species atlases to illustrate integration of diverse molecular and cellular datasets into a single coordinate system as a means of comparison and further atlas construction.


Assuntos
Atlas como Assunto , Encéfalo , Transcriptoma , Animais , Encéfalo/metabolismo , Camundongos , Transcriptoma/genética , Processamento de Imagem Assistida por Computador/métodos , Perfilação da Expressão Gênica/métodos , Humanos
8.
Oncologist ; 29(4): e514-e525, 2024 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-38297981

RESUMO

PURPOSE: This first-in-human phase I dose-escalation study evaluated the safety, pharmacokinetics, and efficacy of tinengotinib (TT-00420), a multi-kinase inhibitor targeting fibroblast growth factor receptors 1-3 (FGFRs 1-3), Janus kinase 1/2, vascular endothelial growth factor receptors, and Aurora A/B, in patients with advanced solid tumors. PATIENTS AND METHODS: Patients received tinengotinib orally daily in 28-day cycles. Dose escalation was guided by Bayesian modeling using escalation with overdose control. The primary objective was to assess dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and dose recommended for dose expansion (DRDE). Secondary objectives included pharmacokinetics and efficacy. RESULTS: Forty-eight patients were enrolled (dose escalation, n = 40; dose expansion, n = 8). MTD was not reached; DRDE was 12 mg daily. DLTs were palmar-plantar erythrodysesthesia syndrome (8 mg, n = 1) and hypertension (15 mg, n = 2). The most common treatment-related adverse event was hypertension (50.0%). In 43 response-evaluable patients, 13 (30.2%) achieved partial response (PR; n = 7) or stable disease (SD) ≥ 24 weeks (n = 6), including 4/11 (36.4%) with FGFR2 mutations/fusions and cholangiocarcinoma (PR n = 3; SD ≥ 24 weeks n = 1), 3/3 (100.0%) with hormone receptor (HR)-positive/HER2-negative breast cancer (PR n = 2; SD ≥ 24 weeks n = 1), 2/5 (40.0%) with triple-negative breast cancer (TNBC; PR n = 1; SD ≥ 24 weeks n = 1), and 1/1 (100.0%) with castrate-resistant prostate cancer (CRPC; PR). Four of 12 patients (33.3%; HR-positive/HER2-negative breast cancer, TNBC, prostate cancer, and cholangiocarcinoma) treated at DRDE had PRs. Tinengotinib's half-life was 28-34 hours. CONCLUSIONS: Tinengotinib was well tolerated with favorable pharmacokinetic characteristics. Preliminary findings indicated potential clinical benefit in FGFR inhibitor-refractory cholangiocarcinoma, HER2-negative breast cancer (including TNBC), and CRPC. Continued evaluation of tinengotinib is warranted in phase II trials.


Assuntos
Antineoplásicos , Colangiocarcinoma , Hipertensão , Neoplasias , Neoplasias de Próstata Resistentes à Castração , Neoplasias de Mama Triplo Negativas , Masculino , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Teorema de Bayes , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular , Neoplasias/tratamento farmacológico , Neoplasias/genética , Antineoplásicos/efeitos adversos , Colangiocarcinoma/tratamento farmacológico , Hipertensão/induzido quimicamente , Dose Máxima Tolerável
9.
bioRxiv ; 2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-37693542

RESUMO

Recent advances in imaging-based spatially resolved transcriptomics (im-SRT) technologies now enable high-throughput profiling of targeted genes and their locations in fixed tissues. Normalization of gene expression data is often needed to account for technical factors that may confound underlying biological signals. Here, we investigate the potential impact of different gene count normalization methods with different targeted gene panels in the analysis and interpretation of im-SRT data. Using different simulated gene panels that overrepresent genes expressed in specific tissue regions or cell types, we demonstrate how normalization methods based on detected gene counts per cell differentially impact normalized gene expression magnitudes in a region- or cell type-specific manner. We show that these normalization-induced effects may reduce the reliability of downstream analyses including differential gene expression, gene fold change, and spatially variable gene analysis, introducing false positive and false negative results when compared to results obtained from gene panels that are more representative of the gene expression of the tissue's component cell types. These effects are not observed with normalization approaches that do not use detected gene counts for gene expression magnitude adjustment, such as with cell volume or cell area normalization. We recommend using non-gene count-based normalization approaches when feasible and evaluating gene panel representativeness before using gene count-based normalization methods if necessary. Overall, we caution that the choice of normalization method and gene panel may impact the biological interpretation of the im-SRT data.

10.
Brain Behav Immun ; 116: 160-174, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38070624

RESUMO

Acute cerebral ischemia triggers a profound inflammatory response. While macrophages polarized to an M2-like phenotype clear debris and facilitate tissue repair, aberrant or prolonged macrophage activation is counterproductive to recovery. The inhibitory immune checkpoint Programmed Cell Death Protein 1 (PD-1) is upregulated on macrophage precursors (monocytes) in the blood after acute cerebrovascular injury. To investigate the therapeutic potential of PD-1 activation, we immunophenotyped circulating monocytes from patients and found that PD-1 expression was upregulated in the acute period after stroke. Murine studies using a temporary middle cerebral artery (MCA) occlusion (MCAO) model showed that intraperitoneal administration of soluble Programmed Death Ligand-1 (sPD-L1) significantly decreased brain edema and improved overall survival. Mice receiving sPD-L1 also had higher performance scores short-term, and more closely resembled sham animals on assessments of long-term functional recovery. These clinical and radiographic benefits were abrogated in global and myeloid-specific PD-1 knockout animals, confirming PD-1+ monocytes as the therapeutic target of sPD-L1. Single-cell RNA sequencing revealed that treatment skewed monocyte maturation to a non-classical Ly6Clo, CD43hi, PD-L1+ phenotype. These data support peripheral activation of PD-1 on inflammatory monocytes as a therapeutic strategy to treat neuroinflammation after acute ischemic stroke.


Assuntos
Edema Encefálico , AVC Isquêmico , Humanos , Camundongos , Animais , Monócitos/metabolismo , Edema Encefálico/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Antígeno B7-H1/metabolismo , Infarto da Artéria Cerebral Média/metabolismo
11.
Nat Commun ; 14(1): 8123, 2023 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-38065970

RESUMO

Spatial transcriptomics (ST) technologies enable high throughput gene expression characterization within thin tissue sections. However, comparing spatial observations across sections, samples, and technologies remains challenging. To address this challenge, we develop STalign to align ST datasets in a manner that accounts for partially matched tissue sections and other local non-linear distortions using diffeomorphic metric mapping. We apply STalign to align ST datasets within and across technologies as well as to align ST datasets to a 3D common coordinate framework. We show that STalign achieves high gene expression and cell-type correspondence across matched spatial locations that is significantly improved over landmark-based affine alignments. Applying STalign to align ST datasets of the mouse brain to the 3D common coordinate framework from the Allen Brain Atlas, we highlight how STalign can be used to lift over brain region annotations and enable the interrogation of compositional heterogeneity across anatomical structures. STalign is available as an open-source Python toolkit at https://github.com/JEFworks-Lab/STalign and as Supplementary Software with additional documentation and tutorials available at https://jef.works/STalign .


Assuntos
Perfilação da Expressão Gênica , Software , Animais , Camundongos , Encéfalo , Tecnologia
12.
Sci Rep ; 13(1): 20888, 2023 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-38017015

RESUMO

T cells are important in the pathogenesis of acute kidney injury (AKI), and TCR+CD4-CD8- (double negative-DN) are T cells that have regulatory properties. However, there is limited information on DN T cells compared to traditional CD4+ and CD8+ cells. To elucidate the molecular signature and spatial dynamics of DN T cells during AKI, we performed single-cell RNA sequencing (scRNA-seq) on sorted murine DN, CD4+, and CD8+ cells combined with spatial transcriptomic profiling of normal and post AKI mouse kidneys. scRNA-seq revealed distinct transcriptional profiles for DN, CD4+, and CD8+ T cells of mouse kidneys with enrichment of Kcnq5, Klrb1c, Fcer1g, and Klre1 expression in DN T cells compared to CD4+ and CD8+ T cells in normal kidney tissue. We validated the expression of these four genes in mouse kidney DN, CD4+ and CD8+ T cells using RT-PCR and Kcnq5, Klrb1, and Fcer1g genes with the NIH human kidney precision medicine project (KPMP). Spatial transcriptomics in normal and ischemic mouse kidney tissue showed a localized cluster of T cells in the outer medulla expressing DN T cell genes including Fcer1g. These results provide a template for future studies in DN T as well as CD4+ and CD8+ cells in normal and diseased kidneys.


Assuntos
Injúria Renal Aguda , Linfócitos T CD8-Positivos , Humanos , Animais , Camundongos , Linfócitos T CD8-Positivos/metabolismo , Transcriptoma , Antígenos CD8/metabolismo , Antígenos CD4/metabolismo , Rim/metabolismo , Injúria Renal Aguda/patologia , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo
13.
Nature ; 2023 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-37106102
14.
bioRxiv ; 2023 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-37034802

RESUMO

This paper explicates a solution to the problem of building correspondences between molecular-scale transcriptomics and tissue-scale atlases. The central model represents spatial transcriptomics as generalized functions encoding molecular position and high-dimensional transcriptomic-based (gene, cell type) identity. We map onto low-dimensional atlas ontologies by modeling each atlas compartment as a homogeneous random field with unknown transcriptomic feature distribution. The algorithm presented solves simultaneously for the minimizing geodesic diffeomorphism of coordinates and latent atlas transcriptomic feature fractions by alternating LDDMM optimization for coordinate transformations and quadratic programming for the latent transcriptomic variables. We demonstrate the universality of the algorithm in mapping tissue atlases to gene-based and cell-based MERFISH datasets as well as to other tissue scale atlases. The joint estimation of diffeomorphisms and latent feature distributions allows integration of diverse molecular and cellular datasets into a single coordinate system and creates an avenue of comparison amongst atlas ontologies for continued future development.

15.
bioRxiv ; 2023 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-37090640

RESUMO

Spatial transcriptomics (ST) technologies enable high throughput gene expression characterization within thin tissue sections. However, comparing spatial observations across sections, samples, and technologies remains challenging. To address this challenge, we developed STalign to align ST datasets in a manner that accounts for partially matched tissue sections and other local non-linear distortions using diffeomorphic metric mapping. We apply STalign to align ST datasets within and across technologies as well as to align ST datasets to a 3D common coordinate framework. We show that STalign achieves high gene expression and cell-type correspondence across matched spatial locations that is significantly improved over landmark-based affine alignments. Applying STalign to align ST datasets of the mouse brain to the 3D common coordinate framework from the Allen Brain Atlas, we highlight how STalign can be used to lift over brain region annotations and enable the interrogation of compositional heterogeneity across anatomical structures. STalign is available as an open-source Python toolkit at https://github.com/JEFworks-Lab/STalign and as supplementary software with additional documentation and tutorials available at https://jef.works/STalign.

16.
Nat Commun ; 13(1): 2339, 2022 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-35487922

RESUMO

Recent technological advancements have enabled spatially resolved transcriptomic profiling but at multi-cellular pixel resolution, thereby hindering the identification of cell-type-specific spatial patterns and gene expression variation. To address this challenge, we develop STdeconvolve as a reference-free approach to deconvolve underlying cell types comprising such multi-cellular pixel resolution spatial transcriptomics (ST) datasets. Using simulated as well as real ST datasets from diverse spatial transcriptomics technologies comprising a variety of spatial resolutions such as Spatial Transcriptomics, 10X Visium, DBiT-seq, and Slide-seq, we show that STdeconvolve can effectively recover cell-type transcriptional profiles and their proportional representation within pixels without reliance on external single-cell transcriptomics references. STdeconvolve provides comparable performance to existing reference-based methods when suitable single-cell references are available, as well as potentially superior performance when suitable single-cell references are not available. STdeconvolve is available as an open-source R software package with the source code available at https://github.com/JEFworks-Lab/STdeconvolve .


Assuntos
Perfilação da Expressão Gênica , Transcriptoma , Software , Transcriptoma/genética
18.
Bioinformatics ; 38(2): 391-396, 2022 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-34500455

RESUMO

MOTIVATION: Single-cell transcriptomics profiling technologies enable genome-wide gene expression measurements in individual cells but can currently only provide a static snapshot of cellular transcriptional states. RNA velocity analysis can help infer cell state changes using such single-cell transcriptomics data. To interpret these cell state changes inferred from RNA velocity analysis as part of underlying cellular trajectories, current approaches rely on visualization with principal components, t-distributed stochastic neighbor embedding and other 2D embeddings derived from the observed single-cell transcriptional states. However, these 2D embeddings can yield different representations of the underlying cellular trajectories, hindering the interpretation of cell state changes. RESULTS: We developed VeloViz to create RNA velocity-informed 2D and 3D embeddings from single-cell transcriptomics data. Using both real and simulated data, we demonstrate that VeloViz embeddings are able to capture underlying cellular trajectories across diverse trajectory topologies, even when intermediate cell states may be missing. By considering the predicted future transcriptional states from RNA velocity analysis, VeloViz can help visualize a more reliable representation of underlying cellular trajectories. AVAILABILITY AND IMPLEMENTATION: Source code is available on GitHub (https://github.com/JEFworks-Lab/veloviz) and Bioconductor (https://bioconductor.org/packages/veloviz) with additional tutorials at https://JEF.works/veloviz/. Datasets used can be found on Zenodo (https://doi.org/10.5281/zenodo.4632471). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
RNA , Software , Perfilação da Expressão Gênica , Genoma , Análise de Sequência de RNA
19.
Ann N Y Acad Sci ; 1506(1): 74-97, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34605044

RESUMO

Single cell biology has the potential to elucidate many critical biological processes and diseases, from development and regeneration to cancer. Single cell analyses are uncovering the molecular diversity of cells, revealing a clearer picture of the variation among and between different cell types. New techniques are beginning to unravel how differences in cell state-transcriptional, epigenetic, and other characteristics-can lead to different cell fates among genetically identical cells, which underlies complex processes such as embryonic development, drug resistance, response to injury, and cellular reprogramming. Single cell technologies also pose significant challenges relating to processing and analyzing vast amounts of data collected. To realize the potential of single cell technologies, new computational approaches are needed. On March 17-19, 2021, experts in single cell biology met virtually for the Keystone eSymposium "Single Cell Biology" to discuss advances both in single cell applications and technologies.


Assuntos
Diferenciação Celular/fisiologia , Reprogramação Celular/fisiologia , Congressos como Assunto/tendências , Desenvolvimento Embrionário/fisiologia , Relatório de Pesquisa , Análise de Célula Única/tendências , Animais , Linhagem da Célula/fisiologia , Humanos , Macrófagos/fisiologia , Análise de Célula Única/métodos
20.
Neuron ; 109(20): 3239-3251.e7, 2021 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-34478631

RESUMO

Human accelerated regions (HARs) are the fastest-evolving regions of the human genome, and many are hypothesized to function as regulatory elements that drive human-specific gene regulatory programs. We interrogate the in vitro enhancer activity and in vivo epigenetic landscape of more than 3,100 HARs during human neurodevelopment, demonstrating that many HARs appear to act as neurodevelopmental enhancers and that sequence divergence at HARs has largely augmented their neuronal enhancer activity. Furthermore, we demonstrate PPP1R17 to be a putative HAR-regulated gene that has undergone remarkable rewiring of its cell type and developmental expression patterns between non-primates and primates and between non-human primates and humans. Finally, we show that PPP1R17 slows neural progenitor cell cycle progression, paralleling the cell cycle length increase seen predominantly in primate and especially human neurodevelopment. Our findings establish HARs as key components in rewiring human-specific neurodevelopmental gene regulatory programs and provide an integrated resource to study enhancer activity of specific HARs.


Assuntos
Encéfalo/embriologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Redes Reguladoras de Genes/genética , Animais , Evolução Biológica , Epigenômica , Evolução Molecular , Furões , Humanos , Macaca , Camundongos , Pan troglodytes
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