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The complex regulation of Slo1 potassium channels from a structural perspective 从结构角度看 Slo1 钾通道的复杂调控

IF 3.7 4区生物学 Q2 Biochemistry, Genetics and Molecular Biology

Biological Chemistry

Pub Date : 2024-05-02 DOI: 10.1515/hsz-2024-0037

Tobias Raisch

Fast and regulated potassium efflux by Slo1 channels is crucial in many tissues in animals including neurons, the kidney and smooth muscle. During the last decade, structures have revealed many details about the gating mechanism and regulation of these large and complex molecular machines. This review summarizes these findings and the current knowledge about the intricate regulation of these important channels. Slo1 integrates sensing of the membrane potential via a voltage-sensor domain that undergoes subtle but significant structural rearrangements with a calcium-induced expansion of parts of the intracellular gating ring. Together, these two signals synergistically lead to changes in the conformation and chemical nature of the pore domain, allowing potassium ions to be translocated. In many native tissues, Slo1 channels are assembled with at least three classes of auxiliary subunits that change the gating kinetics or allow the channel to open also in absence of one of the two signals. Finally, Slo1 is inhibited, activated or deregulated by natural toxins and synthetic compounds, underlining the importance of the channel for the organism and as a potential target for drugs and other molecules.

在包括神经元、肾脏和平滑肌在内的许多动物组织中，通过 Slo1 通道快速调节钾外流至关重要。在过去十年中，有关这些大型复杂分子机器的门控机制和调控的许多细节已被结构所揭示。本综述总结了这些发现以及目前关于这些重要通道复杂调控的知识。Slo1 通过电压传感器结构域感知膜电位，该结构域发生了微妙但重要的结构重排，钙离子诱导细胞内门环部分扩张。这两种信号协同作用，导致孔域的构象和化学性质发生变化，使钾离子得以转运。在许多原生组织中，Slo1 通道至少与三类辅助亚基组装在一起，这些辅助亚基可改变门控动力学，或使通道在没有这两种信号之一的情况下也能打开。最后，天然毒素和合成化合物会抑制、激活或解除对 Slo1 的调控，这凸显了该通道对生物体的重要性，以及作为药物和其他分子潜在靶点的重要性。

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引用次数: 0

Unpaired cysteine insertions favor transmembrane dimerization and induce ligand-independent constitutive cytokine receptor signaling 非配对半胱氨酸插入有利于跨膜二聚化并诱导配体依赖性组成型细胞因子受体信号转导

IF 3.7 4区生物学 Q2 Biochemistry, Genetics and Molecular Biology

Biological Chemistry

Pub Date : 2024-05-02 DOI: 10.1515/hsz-2023-0344

Lynn Affrica Felicitas Baumgärtner, Julia Ettich, Helene Balles, Dorothee Johanna Lapp, Sofie Mossner, Christin Bassenge, Meryem Ouzin, Helmut Hanenberg, Jürgen Scheller, Doreen Manuela Floss

Naturally occurring gain-of-function (GOF) mutants have been identified in patients for a variety of cytokine receptors. Although this constitutive activation of cytokine receptors is strongly associated with malignant disorders, ligand-independent receptor activation is also a useful tool in synthetic biology e.g. to improve adoptive cellular therapies with genetically modified T-cells. Balanced Interleukin (IL-)7 signaling via a heterodimer of IL-7 receptor (IL-7Rα) and the common γ-chain (γc) controls T- and B-cell development and expansion, whereas uncontrolled IL-7 signaling can drive acute lymphoid leukemia (ALL) development. The ALL-driver mutation PPCL in the transmembrane domain of IL-7Rα is a mutational insertion of the four amino acids proline-proline-cysteine-leucine and leads to ligand-independent receptor dimerization and constitutive activation. We showed here in the cytokine-dependent pre-B-cell line Ba/F3 that the PPCL-insertion in a synthetic version of the IL-7Rα induced γc-independent STAT5 and ERK phosphorylation and also proliferation of the cells and that booster-stimulation by arteficial ligands additionally generated non-canonical STAT3 phosphorylation via the synthetic IL-7Rα-PPCL-receptors. Transfer of the IL-7Rα transmembrane domain with the PPCL insertion into natural and synthetic cytokine receptor chains of the IL-6, IL-12 and Interferon families also resulted in constitutive receptor signaling. In conclusion, our data suggested that the insertion of the mutated PPCL IL-7Rα transmembrane domain is an universal approach to generate ligand-independent, constitutively active cytokine receptors.

在患者体内发现了多种细胞因子受体的天然功能增益（GOF）突变体。虽然细胞因子受体的这种组成性激活与恶性疾病密切相关，但不依赖配体的受体激活也是合成生物学中的一种有用工具，例如，可用于改进使用转基因 T 细胞的收养性细胞疗法。白细胞介素（IL-）7 信号通过 IL-7 受体（IL-7Rα）和常见的 γ 链（γc）的异二聚体平衡地控制着 T 细胞和 B 细胞的发育和扩增，而不受控制的 IL-7 信号则会导致急性淋巴白血病（ALL）的发生。IL-7Rα跨膜结构域的ALL驱动突变PPCL是脯氨酸-脯氨酸-半胱氨酸-亮氨酸四个氨基酸的突变插入，导致配体依赖性受体二聚化和组成性激活。我们在细胞因子依赖性前 B 细胞系 Ba/F3 中发现，在 IL-7Rα 的合成版本中插入 PPCL 可诱导 γc 依赖性 STAT5 和 ERK 磷酸化，并使细胞增殖，而且通过合成的 IL-7Rα-PPCL 受体，表面配体的增效刺激还可产生非规范 STAT3 磷酸化。将带有 PPCL 插入物的 IL-7Rα 跨膜结构域转移到 IL-6、IL-12 和干扰素家族的天然和合成细胞因子受体链中也会导致组成型受体信号转导。总之，我们的数据表明，插入突变的 PPCL IL-7Rα 跨膜结构域是产生配体依赖性、组成型活性细胞因子受体的通用方法。

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引用次数: 0

Advances in preclinical TCR characterization: leveraging cell avidity to identify functional TCRs 临床前 TCR 特征描述的进展：利用细胞亲和力识别功能性 TCR

IF 3.7 4区生物学 Q2 Biochemistry, Genetics and Molecular Biology

Biological Chemistry

Pub Date : 2024-04-26 DOI: 10.1515/hsz-2023-0341

Andreas Carr, Laura M. Mateyka, Sebastian J. C. Scheu, Ana Bici, Joris Paijmans, Rogier M. Reijmers, Nina Dieminger, Shirin Dildebekova, Noomen Hamed, Karolin Wagner, Dirk H. Busch, Elvira D’Ippolito

T-cell therapy has emerged as an effective approach for treating viral infections and cancers. However, a significant challenge is the selection of T-cell receptors (TCRs) that exhibit the desired functionality. Conventionally in vitro techniques, such as peptide sensitivity measurements and cytotoxicity assays, provide valuable insights into TCR potency but are labor-intensive. In contrast, measuring ligand binding properties (z-Movi technology) could provide an accelerated processing while showing robust correlations with T-cell functions. In this study, we assessed whether cell avidity can predict functionality also in the context of TCR-engineered T cells. To this end, we developed a flexible system for TCR re-expression by generating a Jurkat-derived T cell clone lacking TCR and CD3 expression through CRISPR-Cas9-mediated TRBC knockout. The knockin of a transgenic TCR into the TRAC locus restored TCR/CD3 expression, allowing for CD3-based purification of TCR-engineered T cells. Subsequently, we characterized these engineered cell lines by functional readouts, and assessment of binding properties through the z-Movi technology. Our findings revealed a strong correlation between the cell avidities and functional sensitivities of Jurkat TCR-T cells. Altogether, by integrating cell avidity measurements with our versatile T cell engineering platform, we established an accelerated system for enhancing the in vitro selection of clinically relevant TCRs.

T 细胞疗法已成为治疗病毒感染和癌症的有效方法。然而，如何选择具有所需功能的 T 细胞受体（TCR）是一项重大挑战。传统的体外技术（如肽敏感性测量和细胞毒性测定）可提供有关 TCR 效能的宝贵信息，但需要耗费大量人力物力。相比之下，测量配体结合特性（z-Movi 技术）可以加速处理过程，同时显示出与 T 细胞功能的密切联系。在本研究中，我们评估了细胞热敏性是否也能预测 TCR 工程 T 细胞的功能。为此，我们开发了一种灵活的 TCR 重表达系统，通过 CRISPR-Cas9 介导的 TRBC 基因敲除，产生了一种缺乏 TCR 和 CD3 表达的 Jurkat 衍生 T 细胞克隆。将转基因 TCR 敲入 TRAC 基因座可恢复 TCR/CD3 的表达，从而可以基于 CD3 纯化 TCR 工程 T 细胞。随后，我们通过功能读数对这些工程细胞系进行了鉴定，并通过 z-Movi 技术对结合特性进行了评估。我们的研究结果表明，Jurkat TCR-T 细胞的细胞活性和功能敏感性之间存在很强的相关性。总之，通过将细胞热敏性测量与我们的多功能 T 细胞工程平台相结合，我们建立了一个加速系统，用于提高体外筛选临床相关 TCR 的能力。

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引用次数: 0

Structural homology of mite profilins to plant profilins is not indicative of allergic cross-reactivity. 螨虫廓清蛋白与植物廓清蛋白的结构同源性并不表明存在过敏性交叉反应。

IF 3.7 4区生物学 Q2 Biochemistry, Genetics and Molecular Biology

Biological Chemistry

Pub Date : 2024-04-26 DOI: 10.1515/hsz-2023-0366

A. O'Malley, Sahana Sankaran, Avery Carriuolo, Kriti Khatri, Krzysztof Kowal, M. Chruszcz

Structural and allergenic characterization of mite profilins has not been previously pursued to a similar extent as plant profilins. Here, we describe structures of profilins originating from Tyrophagus putrescentiae (registered allergen Tyr p 36.0101) and Dermatophagoides pteronyssinus (here termed Der p profilin), which are the first structures of profilins from Arachnida. Additionally, the thermal stabilities of mite and plant profilins are compared, suggesting that the high number of cysteine residues in mite profilins may play a role in their increased stability. We also examine the cross-reactivity of plant and mite profilins as well as investigate the relevance of these profilins in mite inhalant allergy. Despite their high structural similarity to other profilins, mite profilins have low sequence identity with plant and human profilins. Subsequently, these mite profilins most likely do not display cross-reactivity with plant profilins. At the same time the profilins have highly conserved poly(l-proline) and actin binding sites.

螨虫廓清蛋白的结构和过敏原特性研究以前还没有达到与植物廓清蛋白类似的程度。在这里，我们描述了源自Tyrophagus putrescentiae（注册过敏原Tyr p 36.0101）和Dermatophagoides pteronyssinus（此处称为Der p廓清蛋白）的廓清蛋白的结构，这是蛛形纲廓清蛋白的首次结构描述。此外，我们还比较了螨虫廓清蛋白和植物廓清蛋白的热稳定性，结果表明螨虫廓清蛋白中大量的半胱氨酸残基可能是其稳定性提高的原因之一。我们还研究了植物和螨虫廓清蛋白的交叉反应，并探讨了这些廓清蛋白与螨虫吸入性过敏的相关性。尽管螨虫廓清蛋白与其他廓清蛋白的结构高度相似，但它们与植物和人类廓清蛋白的序列同一性却很低。因此，这些螨虫廓清蛋白很可能不会与植物廓清蛋白产生交叉反应。同时，这些螨虫廓清蛋白具有高度保守的聚（l-脯氨酸）和肌动蛋白结合位点。

引用次数: 0

Integrated machine learning and multimodal data fusion for patho-phenotypic feature recognition in iPSC models of dilated cardiomyopathy. 在扩张型心肌病的 iPSC 模型中集成机器学习和多模态数据融合，实现病理表型特征识别。

IF 3.7 4区生物学 Q2 Biochemistry, Genetics and Molecular Biology

Biological Chemistry

Pub Date : 2024-04-24 DOI: 10.1515/hsz-2024-0023

Ruheen Wali, Hang Xu, Cleophas Cheruiyot, Hafiza Nosheen Saleem, Andreas Janshoff, Michael Habeck, A. Ebert

Integration of multiple data sources presents a challenge for accurate prediction of molecular patho-phenotypic features in automated analysis of data from human model systems. Here, we applied a machine learning-based data integration to distinguish patho-phenotypic features at the subcellular level for dilated cardiomyopathy (DCM). We employed a human induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) model of a DCM mutation in the sarcomere protein troponin T (TnT), TnT-R141W, compared to isogenic healthy (WT) control iPSC-CMs. We established a multimodal data fusion (MDF)-based analysis to integrate source datasets for Ca2+ transients, force measurements, and contractility recordings. Data were acquired for three additional layer types, single cells, cell monolayers, and 3D spheroid iPSC-CM models. For data analysis, numerical conversion as well as fusion of data from Ca2+ transients, force measurements, and contractility recordings, a non-negative blind deconvolution (NNBD)-based method was applied. Using an XGBoost algorithm, we found a high prediction accuracy for fused single cell, monolayer, and 3D spheroid iPSC-CM models (≥92 ± 0.08 %), as well as for fused Ca2+ transient, beating force, and contractility models (>96 ± 0.04 %). Integrating MDF and XGBoost provides a highly effective analysis tool for prediction of patho-phenotypic features in complex human disease models such as DCM iPSC-CMs.

在对人类模型系统的数据进行自动分析时，要准确预测分子病理表型特征，整合多个数据源是一项挑战。在这里，我们应用基于机器学习的数据整合来区分扩张型心肌病（DCM）亚细胞水平的病理表型特征。我们采用了一种人类诱导多能干细胞衍生心肌细胞（iPSC-CM）模型，与同源健康（WT）对照iPSC-CMs相比，该模型中的肌节蛋白肌钙蛋白T（TnT）发生了突变，即TnT-R141W。我们建立了一种基于多模态数据融合（MDF）的分析方法，以整合 Ca2+ 瞬态、肌力测量和收缩力记录的源数据集。我们还采集了单细胞、细胞单层和三维球状 iPSC-CM 模型这三种额外层类型的数据。在数据分析、数值转换以及融合 Ca2+ 瞬态、力测量和收缩力记录数据时，采用了基于非负盲解卷积（NNBD）的方法。通过使用 XGBoost 算法，我们发现融合单细胞、单层和三维球状 iPSC-CM 模型（≥92 ± 0.08 %）以及融合 Ca2+ 瞬态、搏动力和收缩力模型（>96 ± 0.04 %）的预测准确率很高。MDF 和 XGBoost 的整合为预测复杂人类疾病模型（如 DCM iPSC-CM）的病理表型特征提供了高效的分析工具。

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引用次数: 0

18β-glycyrrhetinic acid alleviates radiation-induced skin injury by activating the Nrf2/HO-1 signaling pathway 18β-甘草次酸通过激活 Nrf2/HO-1 信号通路减轻辐射引起的皮肤损伤

IF 3.7 4区生物学 Q2 Biochemistry, Genetics and Molecular Biology

Biological Chemistry

Pub Date : 2024-04-10 DOI: 10.1515/hsz-2023-0200

Zeng Wang, Ruiqing Chen, Junying Chen, Li Su

Radiation-induced skin injury is a common side effect of radiotherapy, but there are few therapeutic drugs available for prevention or treatment. In this study, we demonstrate that 18β-Glycyrrhetinic acid (18β-GA), a bioactive component derived from Glycyrrhiza glabra, substantially reduces the accumulation of reactive oxygen species (ROS) and inhibits apoptosis in HaCaT cells after ionizing radiation (IR), thereby mitigating radiation-induced skin injury. Mechanistically, 18β-GA promotes the nuclear import of Nrf2, leading to activation of the Nrf2/HO-1 signaling pathway in response to IR. Importantly, Nrf2 silencing increases cell apoptosis and reverse the protective effect of 18β-GA on radiation-induced skin injury. Furthermore, 18β-GA preserves skin tissue structure after irradiation, inhibits inflammatory cell infiltration, and alleviates radiation dermatitis. In conclusion, our results suggest that 18β-GA reduces intracellular ROS production and apoptosis by activating the Nrf2/HO-1 signaling pathway, leading to amelioration of radiation dermatitis.

放疗引起的皮肤损伤是放疗的常见副作用，但目前几乎没有治疗药物可用于预防或治疗。在这项研究中，我们证明了从甘草中提取的生物活性成分 18β-Glycyrrhetinic acid（18β-GA）能显著减少电离辐射（IR）后活性氧（ROS）的积累并抑制 HaCaT 细胞的凋亡，从而减轻辐射诱导的皮肤损伤。从机理上讲，18β-GA 可促进 Nrf2 的核导入，从而激活 Nrf2/HO-1 信号通路以应对 IR。重要的是，沉默 Nrf2 会增加细胞凋亡，并逆转 18β-GA 对辐射诱导的皮肤损伤的保护作用。此外，18β-GA 还能保护辐照后的皮肤组织结构，抑制炎症细胞浸润，缓解放射性皮炎。总之，我们的研究结果表明，18β-GA 可通过激活 Nrf2/HO-1 信号通路减少细胞内 ROS 的产生和细胞凋亡，从而改善辐射性皮炎。

引用次数: 0

Bovine ultralong CDR-H3 derived knob paratopes elicit potent TNF-α neutralization and enable the generation of novel adalimumab-based antibody architectures with augmented features. 牛超长CDR-H3衍生的旋钮副基团可产生强效的TNF-α中和作用，并能生成具有增强功能的新型阿达木单抗抗体结构。

IF 2.9 4区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biological Chemistry

Pub Date : 2024-02-20 Print Date: 2024-07-26 DOI: 10.1515/hsz-2023-0370

Paul Arras, Jasmin Zimmermann, Britta Lipinski, Bernhard Valldorf, Andreas Evers, Desislava Elter, Simon Krah, Achim Doerner, Enrico Guarnera, Vanessa Siegmund, Harald Kolmar, Lukas Pekar, Stefan Zielonka

In this work we have generated cattle-derived chimeric ultralong CDR-H3 antibodies targeting tumor necrosis factor α (TNF-α) via immunization and yeast surface display. We identified one particular ultralong CDR-H3 paratope that potently neutralized TNF-α. Interestingly, grafting of the knob architecture onto a peripheral loop of the CH₃ domain of the Fc part of an IgG1 resulted in the generation of a TNF-α neutralizing Fc (Fc_knob) that did not show any potency loss compared with the parental chimeric IgG format. Eventually, grafting this knob onto the CH₃ region of adalimumab enabled the engineering of a novel TNF-α targeting antibody architecture displaying augmented TNF-α inhibition.

在这项工作中，我们通过免疫和酵母表面展示产生了针对肿瘤坏死因子α（TNF-α）的牛源超长CDR-H3嵌合抗体。我们发现了一种能有效中和 TNF-α 的超长 CDR-H3 副配位体。有趣的是，将该旋钮结构嫁接到 IgG1 Fc 部分 CH3 结构域的外周环上可产生 TNF-α 中和 Fc（Fcknob），与亲代嵌合 IgG 格式相比，其效力没有任何下降。最后，将该钮嫁接到阿达木单抗的 CH3 区域，就能设计出一种新型 TNF-α 靶向抗体结构，显示出更强的 TNF-α 抑制作用。

引用次数: 0

Celastrol inhibits angiogenesis and the biological processes of MDA-MB-231 cells via the DEGS1/S1P signaling pathway Celastrol 通过 DEGS1/S1P 信号通路抑制血管生成和 MDA-MB-231 细胞的生物过程

IF 3.7 4区生物学 Q2 Biochemistry, Genetics and Molecular Biology

Biological Chemistry

Pub Date : 2023-12-11 DOI: 10.1515/hsz-2023-0324

Lulu Jia, Shengnan Zhu, Mingfei Zhu, Rongrong Nie, Lingyue Huang, Siyuan Xu, Yuqin Luo, Huazhen Su, Shaoyuan Huang, Qinyou Tan

Celastrol (Cel) shows potent antitumor activity in various experimental models. This study examined the relationship between Cel’s antivascular and antitumor effects and sphingolipids. CCK-8 assay, transwell assay, Matrigel, PCR-array/RT-PCR/western blotting/immunohistochemistry assay, ELISA and HE staining were used to detect cell proliferation, migration and invasion, adhesion and angiogenesis, mRNA and protein expression, S1P production and tumor morphology. The results showed that Cel could inhibit proliferation, migration or invasion, adhesion and angiogenesis of human umbilical vein endothelial cells (HUVECs) and MDA-MB-231 cells by downregulating the expression of degenerative spermatocyte homolog 1 (DEGS1). Transfection experiments showed that downregulation of DEGS1 inhibited the above processes and sphingosine-1-phosphate (S1P) production of HUVECs and MDA-MB-231 cells, while upregulation of DEGS1 had the opposite effects. Coculture experiments showed that HUVECs could promote proliferation, migration and invasion of MDA-MB-231 cells through S1P/sphingosine-1-phosphate receptor (S1PR) signaling pathway, while Cel inhibited these processes in MDA-MB-231 cells induced by HUVECs. Animal experiments showed that Cel could inhibit tumor growth in nude mice. Western blotting, immunohistochemistry and ELISA assay showed that Cel downregulated the expression of DEGS1, CD146, S1PR1-3 and S1P production. These data confirm that DEGS1/S1P signaling pathway may be related to the antivascular and antitumor effects of cel.

Celastrol (Cel) 在各种实验模型中显示出强大的抗肿瘤活性。本研究探讨了 Cel 的抗血管和抗肿瘤作用与鞘磷脂之间的关系。研究采用CCK-8检测法、Transwell检测法、Matrigel检测法、PCR-array/RT-PCR/Western印迹/免疫组化检测法、ELISA和HE染色法检测细胞增殖、迁移和侵袭、粘附和血管生成、mRNA和蛋白表达、S1P生成和肿瘤形态。结果表明，Cel能通过下调变性精母细胞同源物1（DEGS1）的表达，抑制人脐静脉内皮细胞（HUVECs）和MDA-MB-231细胞的增殖、迁移或侵袭、粘附和血管生成。转染实验表明，下调 DEGS1 可抑制 HUVECs 和 MDA-MB-231 细胞的上述过程和 1-磷酸鞘磷脂（S1P）的产生，而上调 DEGS1 则效果相反。共培养实验表明，HUVECs 能通过 S1P/鞘氨醇-1-磷酸受体（S1PR）信号通路促进 MDA-MB-231 细胞的增殖、迁移和侵袭，而 Cel 能抑制 HUVECs 诱导的 MDA-MB-231 细胞的这些过程。动物实验表明，Cel 能抑制裸鼠的肿瘤生长。Western印迹、免疫组织化学和ELISA检测表明，Cel能下调DEGS1、CD146、S1PR1-3的表达和S1P的产生。这些数据证实，DEGS1/S1P 信号通路可能与 Cel 的抗血管和抗肿瘤作用有关。

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引用次数: 0

Highlight: Horizons in Neuroscience - Organoids, Optogenetics and Remote Control. 亮点:神经科学的视野-类器官，光遗传学和远程控制。

IF 3.7 4区生物学 Q2 Biochemistry, Genetics and Molecular Biology

Biological Chemistry

Pub Date : 2023-11-27 Print Date: 2024-01-29 DOI: 10.1515/hsz-2023-0343

Rolf Heumann

引用次数: 0

Visualization of the membrane surface and cytoskeleton of oligodendrocyte progenitor cell growth cones using a combination of scanning ion conductance and four times expansion microscopy. 利用扫描离子电导和四倍扩增显微镜观察少突胶质祖细胞生长锥的膜表面和细胞骨架。

IF 3.7 4区生物学 Q2 Biochemistry, Genetics and Molecular Biology

Biological Chemistry

Pub Date : 2023-11-13 Print Date: 2024-01-29 DOI: 10.1515/hsz-2023-0217

Annika Haak, Heiko M Lesslich, Irmgard D Dietzel

Growth cones of oligodendrocyte progenitor cells (OPCs) are challenging to investigate with conventional light microscopy due to their small size. Especially substructures such as filopodia, lamellipodia and their underlying cytoskeleton are difficult to resolve with diffraction limited microscopy. Light microscopy techniques, which surpass the diffraction limit such as stimulated emission depletion microscopy, often require expensive setups and specially trained personnel rendering them inaccessible to smaller research groups. Lately, the invention of expansion microscopy (ExM) has enabled super-resolution imaging with any light microscope without the need for additional equipment. Apart from the necessary resolution, investigating OPC growth cones comes with another challenge: Imaging the topography of membranes, especially label- and contact-free, is only possible with very few microscopy techniques one of them being scanning ion conductance microscopy (SICM). We here present a new imaging workflow combining SICM and ExM, which enables the visualization of OPC growth cone nanostructures. We correlated SICM recordings and ExM images of OPC growth cones captured with a conventional widefield microscope. This enabled the visualization of the growth cones' membrane topography as well as their underlying actin and tubulin cytoskeleton.

少突胶质细胞祖细胞(OPCs)的生长锥由于其体积小，很难用常规光学显微镜进行研究。特别是亚结构，如丝状足、板足及其下面的细胞骨架是难以分辨的衍射限制显微镜。超过衍射极限的光学显微镜技术，如受激发射耗尽显微镜，通常需要昂贵的设备和受过专门训练的人员，这使得小型研究小组无法使用。最近，扩展显微镜(ExM)的发明使得任何光学显微镜都可以进行超分辨率成像，而不需要额外的设备。除了必要的分辨率之外，研究OPC生长锥还面临另一个挑战:对膜的形貌进行成像，特别是无标签和无接触的，只有很少的显微镜技术才能实现，其中一种是扫描离子电导显微镜(SICM)。本文提出了一种结合SICM和ExM的新型成像工作流程，实现了OPC生长锥纳米结构的可视化。我们将SICM记录与常规宽视场显微镜捕获的OPC生长锥的ExM图像相关联。这使得生长锥的膜地形以及它们潜在的肌动蛋白和微管蛋白细胞骨架的可视化成为可能。

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