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A modular chemigenetic calcium indicator for multiplexed in vivo functional imaging 用于多路复用体内功能成像的模块化化学钙指示剂。
IF 36.1 1区 生物学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-09-20 DOI: 10.1038/s41592-024-02411-6
Helen Farrants, Yichun Shuai, William C. Lemon, Christian Monroy Hernandez, Deng Zhang, Shang Yang, Ronak Patel, Guanda Qiao, Michelle S. Frei, Sarah E. Plutkis, Jonathan B. Grimm, Timothy L. Hanson, Filip Tomaska, Glenn C. Turner, Carsen Stringer, Philipp J. Keller, Abraham G. Beyene, Yao Chen, Yajie Liang, Luke D. Lavis, Eric R. Schreiter
Genetically encoded fluorescent calcium indicators allow cellular-resolution recording of physiology. However, bright, genetically targetable indicators that can be multiplexed with existing tools in vivo are needed for simultaneous imaging of multiple signals. Here we describe WHaloCaMP, a modular chemigenetic calcium indicator built from bright dye-ligands and protein sensor domains. Fluorescence change in WHaloCaMP results from reversible quenching of the bound dye via a strategically placed tryptophan. WHaloCaMP is compatible with rhodamine dye-ligands that fluoresce from green to near-infrared, including several that efficiently label the brain in animals. When bound to a near-infrared dye-ligand, WHaloCaMP shows a 7× increase in fluorescence intensity and a 2.1-ns increase in fluorescence lifetime upon calcium binding. We use WHaloCaMP1a to image Ca2+ responses in vivo in flies and mice, to perform three-color multiplexed functional imaging of hundreds of neurons and astrocytes in zebrafish larvae and to quantify Ca2+ concentration using fluorescence lifetime imaging microscopy (FLIM). WHaloCaMP is a chemigenetic calcium indicator that can be combined with different rhodamine dyes for multiplexed or FLIM imaging in vivo, as demonstrated for calcium imaging in neuronal cultures, brain slices, Drosophila, zebrafish larvae and the mouse brain.
通过基因编码的荧光钙指示剂可以记录细胞分辨率的生理变化。然而,要同时对多种信号进行成像,还需要能与体内现有工具复用的明亮、基因靶向性指示剂。在这里,我们描述了 WHaloCaMP,一种由明亮染料配体和蛋白质传感器结构域组成的模块化化学基因钙指示剂。WHaloCaMP 中的荧光变化来自于通过策略性放置的色氨酸对结合染料的可逆淬灭。WHaloCaMP 与罗丹明染料配体兼容,这些染料配体可发出从绿色到近红外的荧光,其中包括几种可有效标记动物大脑的染料配体。当与近红外染料配体结合时,WHaloCaMP的荧光强度增加7倍,钙结合后的荧光寿命增加2.1-ns。我们利用 WHaloCaMP1a 对苍蝇和小鼠体内的 Ca2+ 反应进行成像,对斑马鱼幼体中的数百个神经元和星形胶质细胞进行三色多重功能成像,并利用荧光寿命成像显微镜(FLIM)对 Ca2+ 浓度进行量化。
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引用次数: 0
Gene-level alignment of single-cell trajectories 单细胞轨迹的基因水平配准
IF 48 1区 生物学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-09-19 DOI: 10.1038/s41592-024-02378-4
Dinithi Sumanaweera, Chenqu Suo, Ana-Maria Cujba, Daniele Muraro, Emma Dann, Krzysztof Polanski, Alexander S. Steemers, Woochan Lee, Amanda J. Oliver, Jong-Eun Park, Kerstin B. Meyer, Bianca Dumitrascu, Sarah A. Teichmann

Single-cell data analysis can infer dynamic changes in cell populations, for example across time, space or in response to perturbation, thus deriving pseudotime trajectories. Current approaches comparing trajectories often use dynamic programming but are limited by assumptions such as the existence of a definitive match. Here we describe Genes2Genes, a Bayesian information-theoretic dynamic programming framework for aligning single-cell trajectories. It is able to capture sequential matches and mismatches of individual genes between a reference and query trajectory, highlighting distinct clusters of alignment patterns. Across both real world and simulated datasets, it accurately inferred alignments and demonstrated its utility in disease cell-state trajectory analysis. In a proof-of-concept application, Genes2Genes revealed that T cells differentiated in vitro match an immature in vivo state while lacking expression of genes associated with TNF signaling. This demonstrates that precise trajectory alignment can pinpoint divergence from the in vivo system, thus guiding the optimization of in vitro culture conditions.

单细胞数据分析可以推断细胞群的动态变化,例如跨时间、跨空间或对扰动的反应,从而得出伪时间轨迹。目前比较轨迹的方法通常使用动态编程,但受到存在确定匹配等假设的限制。在此,我们介绍一种用于排列单细胞轨迹的贝叶斯信息论动态编程框架--Genes2Genes。它能捕捉参考轨迹和查询轨迹之间单个基因的连续匹配和不匹配,突出不同的配准模式群。在真实世界和模拟数据集上,它都能准确地推断出配准,并证明了它在疾病细胞状态轨迹分析中的实用性。在概念验证应用中,Genes2Genes 发现体外分化的 T 细胞与体内未成熟状态相匹配,但缺乏与 TNF 信号转导相关的基因表达。这表明,精确的轨迹比对可以精确定位与体内系统的差异,从而指导体外培养条件的优化。
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引用次数: 0
Arkitekt: streaming analysis and real-time workflows for microscopy Arkitekt:用于显微镜的流式分析和实时工作流程
IF 36.1 1区 生物学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-09-18 DOI: 10.1038/s41592-024-02404-5
Johannes Roos, Stéphane Bancelin, Tom Delaire, Alexander Wilhelmi, Florian Levet, Maren Engelhardt, Virgile Viasnoff, Rémi Galland, U. Valentin Nägerl, Jean-Baptiste Sibarita
Quantitative microscopy workflows have evolved dramatically over the past years, progressively becoming more complex with the emergence of deep learning. Long-standing challenges such as three-dimensional segmentation of complex microscopy data can finally be addressed, and new imaging modalities are breaking records in both resolution and acquisition speed, generating gigabytes if not terabytes of data per day. With this shift in bioimage workflows comes an increasing need for efficient orchestration and data management, necessitating multitool interoperability and the ability to span dedicated computing resources. However, existing solutions are still limited in their flexibility and scalability and are usually restricted to offline analysis. Here we introduce Arkitekt, an open-source middleman between users and bioimage apps that enables complex quantitative microscopy workflows in real time. It allows the orchestration of popular bioimage software locally or remotely in a reliable and efficient manner. It includes visualization and analysis modules, but also mechanisms to execute source code and pilot acquisition software, making ‘smart microscopy’ a reality. Arkitekt is an open-source platform that facilitates the implementation of complex quantitative bioimaging workflows in real time, from acquisition to visualization and analysis.
定量显微镜工作流程在过去几年中发生了巨大变化,随着深度学习的出现而逐渐变得更加复杂。复杂显微镜数据的三维分割等长期存在的难题终于得到了解决,新的成像模式在分辨率和采集速度上都打破了记录,每天产生的数据量达到千兆字节甚至万兆字节。随着生物成像工作流程的转变,对高效协调和数据管理的需求也与日俱增,这就需要多工具互操作性和跨越专用计算资源的能力。然而,现有的解决方案在灵活性和可扩展性方面仍然有限,而且通常仅限于离线分析。我们在此介绍 Arkitekt,它是用户与生物图像应用程序之间的开源中间人,可实时实现复杂的定量显微镜工作流程。它允许以可靠、高效的方式在本地或远程协调流行的生物图像软件。它不仅包括可视化和分析模块,还包括执行源代码和试点采集软件的机制,使 "智能显微镜 "成为现实。
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引用次数: 0
A polarized FGF8 source specifies frontotemporal signatures in spatially oriented cell populations of cortical assembloids 极化的 FGF8 信号源可确定大脑皮层集合体空间定向细胞群的额颞叶特征
IF 36.1 1区 生物学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-09-18 DOI: 10.1038/s41592-024-02412-5
Camilla Bosone, Davide Castaldi, Thomas Rainer Burkard, Segundo Jose Guzman, Tom Wyatt, Cristina Cheroni, Nicolò Caporale, Sunanjay Bajaj, Joshua Adam Bagley, Chong Li, Benoit Sorre, Carlo Emanuele Villa, Giuseppe Testa, Veronica Krenn, Jürgen Arthur Knoblich
Organoids generating major cortical cell types in distinct compartments are used to study cortical development, evolution and disorders. However, the lack of morphogen gradients imparting cortical positional information and topography in current systems hinders the investigation of complex phenotypes. Here, we engineer human cortical assembloids by fusing an organizer-like structure expressing fibroblast growth factor 8 (FGF8) with an elongated organoid to enable the controlled modulation of FGF8 signaling along the longitudinal organoid axis. These polarized cortical assembloids mount a position-dependent transcriptional program that in part matches the in vivo rostrocaudal gene expression patterns and that is lost upon mutation in the FGFR3 gene associated with temporal lobe malformations and intellectual disability. By producing spatially oriented cell populations with signatures related to frontal and temporal area identity within individual assembloids, this model recapitulates in part the early transcriptional divergence embedded in the protomap and enables the study of cortical area-relevant alterations underlying human disorders. Cortical development is influenced by morphogen gradients. To mimic patterning events during brain development, polarized cortical assembloids are generated with the help of a localized FGF8 source.
在不同区域生成主要皮质细胞类型的有机体被用于研究皮质的发育、进化和失调。然而,目前的系统缺乏传递大脑皮层位置信息和形貌的形态发生梯度,这阻碍了对复杂表型的研究。在这里,我们通过将表达成纤维细胞生长因子8(FGF8)的组织器样结构与拉长的类器官融合在一起来设计人类大脑皮层组装体,从而实现沿类器官纵轴对FGF8信号的可控调节。这些极化的皮质集合体安装了一个位置依赖性转录程序,该程序部分与体内喙向基因表达模式相匹配,而当与颞叶畸形和智力障碍相关的FGFR3基因发生突变时,该程序就会丢失。通过在单个拼装体中产生具有额叶和颞叶特征的空间定向细胞群,该模型部分重现了原图中的早期转录分化,并能研究人类疾病背后的皮质区域相关改变。
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引用次数: 0
Genomics 2 Proteins portal: a resource and discovery tool for linking genetic screening outputs to protein sequences and structures 基因组学 2 蛋白质门户网站:将基因筛选结果与蛋白质序列和结构联系起来的资源和发现工具
IF 36.1 1区 生物学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-09-18 DOI: 10.1038/s41592-024-02409-0
Seulki Kwon, Jordan Safer, Duyen T. Nguyen, David Hoksza, Patrick May, Jeremy A. Arbesfeld, Alan F. Rubin, Arthur J. Campbell, Alex Burgin, Sumaiya Iqbal
Recent advances in AI-based methods have revolutionized the field of structural biology. Concomitantly, high-throughput sequencing and functional genomics have generated genetic variants at an unprecedented scale. However, efficient tools and resources are needed to link disparate data types—to ‘map’ variants onto protein structures, to better understand how the variation causes disease, and thereby design therapeutics. Here we present the Genomics 2 Proteins portal ( https://g2p.broadinstitute.org/ ): a human proteome-wide resource that maps 20,076,998 genetic variants onto 42,413 protein sequences and 77,923 structures, with a comprehensive set of structural and functional features. Additionally, the Genomics 2 Proteins portal allows users to interactively upload protein residue-wise annotations (for example, variants and scores) as well as the protein structure beyond databases to establish the connection between genomics to proteins. The portal serves as an easy-to-use discovery tool for researchers and scientists to hypothesize the structure–function relationship between natural or synthetic variations and their molecular phenotypes. The Genomics 2 Proteins portal is an open-source tool for proteome-wide linking of human genetic variants to protein sequences and structures. The portal serves as a discovery tool to hypothesize the structure–function relationship between natural or synthetic variations and their molecular phenotypes.
基于人工智能方法的最新进展彻底改变了结构生物学领域。与此同时,高通量测序和功能基因组学以前所未有的规模产生了基因变异。然而,我们需要高效的工具和资源来连接不同的数据类型--将变异 "映射 "到蛋白质结构上,从而更好地了解变异如何导致疾病,进而设计治疗方法。在此,我们介绍基因组学 2 蛋白质门户网站 (https://g2p.broadinstitute.org/):这是一个全人类蛋白质组资源,可将 20,076,998 个基因变异映射到 42,413 个蛋白质序列和 77,923 个结构上,并提供一套全面的结构和功能特征。此外,"基因组学 2 蛋白质 "门户网站还允许用户交互上传蛋白质残基注释(如变异和得分)以及数据库之外的蛋白质结构,以建立基因组学与蛋白质之间的联系。该门户网站为研究人员和科学家提供了一个易于使用的发现工具,用于假设天然或合成变异与其分子表型之间的结构-功能关系。
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引用次数: 0
Search and match across spatial omics samples at single-cell resolution 在单细胞分辨率的空间全息样本中进行搜索和匹配
IF 36.1 1区 生物学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-09-18 DOI: 10.1038/s41592-024-02410-7
Zefang Tang, Shuchen Luo, Hu Zeng, Jiahao Huang, Xin Sui, Morgan Wu, Xiao Wang
Spatial omics technologies characterize tissue molecular properties with spatial information, but integrating and comparing spatial data across different technologies and modalities is challenging. A comparative analysis tool that can search, match and visualize both similarities and differences of molecular features in space across multiple samples is lacking. To address this, we introduce CAST (cross-sample alignment of spatial omics), a deep graph neural network-based method enabling spatial-to-spatial searching and matching at the single-cell level. CAST aligns tissues based on intrinsic similarities of spatial molecular features and reconstructs spatially resolved single-cell multi-omic profiles. CAST further allows spatially resolved differential analysis (∆Analysis) to pinpoint and visualize disease-associated molecular pathways and cell–cell interactions and single-cell relative translational efficiency profiling to reveal variations in translational control across cell types and regions. CAST serves as an integrative framework for seamless single-cell spatial data searching and matching across technologies, modalities and sample conditions. CAST is a deep learning-based method that enables across-sample searching and matching based on spatial molecular features and reconstructing spatially resolved single-cell multi-omic profiles, as well as supports downstream differential analysis.
空间 omics 技术利用空间信息表征组织分子特性,但整合和比较不同技术和模式的空间数据具有挑战性。目前还缺乏一种比较分析工具,能够搜索、匹配和直观显示多个样本空间分子特征的相似性和差异性。为了解决这个问题,我们引入了 CAST(空间 omics 跨样本配准),这是一种基于深度图神经网络的方法,能在单细胞水平上进行空间对空间的搜索和匹配。CAST 基于空间分子特征的内在相似性对组织进行配准,并重建空间分辨的单细胞多原子图谱。CAST 还允许进行空间分辨差异分析(Δ分析),以精确定位和可视化与疾病相关的分子通路和细胞间相互作用,以及单细胞相对翻译效率分析,以揭示不同细胞类型和区域之间翻译控制的差异。CAST 是一个综合框架,可用于跨技术、跨模式和跨样本条件的无缝单细胞空间数据搜索和匹配。
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引用次数: 0
Why they take risks 他们为何冒险
IF 36.1 1区 生物学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-09-18 DOI: 10.1038/s41592-024-02432-1
Vivien Marx
Developing new methods takes passion and a penchant for risk-taking.
开发新方法需要激情和冒险精神。
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引用次数: 0
Author Correction: scGHOST: identifying single-cell 3D genome subcompartments. 作者更正:scGHOST:识别单细胞三维基因组亚区。
IF 36.1 1区 生物学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-09-17 DOI: 10.1038/s41592-024-02462-9
Kyle Xiong, Ruochi Zhang, Jian Ma
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引用次数: 0
Propensity score matching 倾向得分匹配
IF 36.1 1区 生物学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-09-16 DOI: 10.1038/s41592-024-02405-4
Christoph F. Kurz, Martin Krzywinski, Naomi Altman
I don’t have good luck in the match points. —Rafael Nadal, Spanish tennis player.
我在赛点上运气不好。拉斐尔-纳达尔,西班牙网球运动员。
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引用次数: 0
Serialized on-grid lift-in sectioning for tomography (SOLIST) enables a biopsy at the nanoscale 用于断层扫描的序列化栅上抬入切片技术(SOLIST)实现了纳米级活检
IF 36.1 1区 生物学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2024-09-13 DOI: 10.1038/s41592-024-02384-6
Ho Thuy Dung Nguyen, Gaia Perone, Nikolai Klena, Roberta Vazzana, Flaminia Kaluthantrige Don, Malan Silva, Simona Sorrentino, Paolo Swuec, Frederic Leroux, Nereo Kalebic, Francesca Coscia, Philipp S. Erdmann
Cryo-focused ion beam milling has substantially advanced our understanding of molecular processes by opening windows into cells. However, applying this technique to complex samples, such as tissues, has presented considerable technical challenges. Here we introduce an innovative adaptation of the cryo-lift-out technique, serialized on-grid lift-in sectioning for tomography (SOLIST), addressing these limitations. SOLIST enhances throughput, minimizes ice contamination and improves sample stability for cryo-electron tomography. It thereby facilitates the high-resolution imaging of a wide range of specimens. We illustrate these advantages on reconstituted liquid–liquid phase-separated droplets, brain organoids and native tissues from the mouse brain, liver and heart. With SOLIST, cellular processes can now be investigated at molecular resolution directly in native tissue. Furthermore, our method has a throughput high enough to render cryo-lift-out a competitive tool for structural biology. This opens new avenues for unprecedented insights into cellular function and structure in health and disease, a ‘biopsy at the nanoscale’. Serialized on-grid lift-in sectioning for tomography (SOLIST) improves the throughput of the serial lift-out technique for creating lamellas, addressing a major bottleneck in the use of cryo-electron tomography for in situ structural biology.
低温聚焦离子束铣削技术为我们打开了进入细胞的窗口,极大地推动了我们对分子过程的了解。然而,将这种技术应用于组织等复杂样本却面临着相当大的技术挑战。在这里,我们介绍了一种创新的冷冻抬出技术,即用于断层扫描的序列化栅上抬入切片技术(SOLIST),以解决这些局限性。SOLIST 提高了吞吐量,最大限度地减少了冰污染,并提高了低温电子断层扫描的样品稳定性。因此,它有助于对各种标本进行高分辨率成像。我们在重组液-液相分离液滴、脑器官组织以及小鼠大脑、肝脏和心脏的原生组织上展示了这些优势。有了 SOLIST,现在可以直接在原生组织中以分子分辨率研究细胞过程。此外,我们的方法具有足够高的通量,使低温跃迁成为结构生物学的竞争工具。这为前所未有地深入了解健康和疾病中的细胞功能和结构开辟了新途径,是一种 "纳米级活检"。用于断层扫描的串行栅格抬入切片技术(SOLIST)提高了用于创建薄片的串行抬出技术的吞吐量,解决了低温电子断层扫描用于原位结构生物学的一个主要瓶颈。
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引用次数: 0
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