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Linking patient-specific basal MET phosphorylation levels to liver health. 将特定患者的基础 MET 磷酸化水平与肝脏健康联系起来。
IF 9.9 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-03-01 Epub Date: 2024-02-16 DOI: 10.1038/s44320-024-00023-y
Fabian Fröhlich
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引用次数: 0
The population context is a driver of the heterogeneous response of epithelial cells to interferons. 种群背景是上皮细胞对干扰素作出不同反应的驱动因素。
IF 9.9 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-03-01 Epub Date: 2024-01-25 DOI: 10.1038/s44320-024-00011-2
Camila Metz-Zumaran, Zina M Uckeley, Patricio Doldan, Francesco Muraca, Yagmur Keser, Pascal Lukas, Benno Kuropka, Leonie Küchenhoff, Soheil Rastgou Talemi, Thomas Höfer, Christian Freund, Elisabetta Ada Cavalcanti-Adam, Frederik Graw, Megan Stanifer, Steeve Boulant

Isogenic cells respond in a heterogeneous manner to interferon. Using a micropatterning approach combined with high-content imaging and spatial analyses, we characterized how the population context (position of a cell with respect to neighboring cells) of epithelial cells affects their response to interferons. We identified that cells at the edge of cellular colonies are more responsive than cells embedded within colonies. We determined that this spatial heterogeneity in interferon response resulted from the polarized basolateral interferon receptor distribution, making cells located in the center of cellular colonies less responsive to ectopic interferon stimulation. This was conserved across cell lines and primary cells originating from epithelial tissues. Importantly, cells embedded within cellular colonies were not protected from viral infection by apical interferon treatment, demonstrating that the population context-driven heterogeneous response to interferon influences the outcome of viral infection. Our data highlights that the behavior of isolated cells does not directly translate to their behavior in a population, placing the population context as one important factor influencing heterogeneity during interferon response in epithelial cells.

同源细胞对干扰素的反应是异质的。我们采用微图案方法,结合高内容成像和空间分析,描述了上皮细胞的群体背景(细胞相对于邻近细胞的位置)如何影响它们对干扰素的反应。我们发现,位于细胞集落边缘的细胞比嵌入集落内的细胞反应更强。我们确定,干扰素反应的这种空间异质性是由极化的基底侧干扰素受体分布造成的,这使得位于细胞集落中心的细胞对异位干扰素刺激的反应较弱。这一点在细胞系和源自上皮组织的原代细胞中是一致的。重要的是,顶端干扰素处理并不能保护嵌入细胞集落内的细胞免受病毒感染,这表明群体背景驱动的对干扰素的异质性反应会影响病毒感染的结果。我们的数据强调,孤立细胞的行为并不能直接转化为它们在群体中的行为,因此群体背景是影响上皮细胞干扰素反应异质性的一个重要因素。
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引用次数: 0
Deep learning for protein structure prediction and design-progress and applications. 用于蛋白质结构预测和设计的深度学习--进展与应用。
IF 8.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-03-01 Epub Date: 2024-01-30 DOI: 10.1038/s44320-024-00016-x
Jürgen Jänes, Pedro Beltrao

Proteins are the key molecular machines that orchestrate all biological processes of the cell. Most proteins fold into three-dimensional shapes that are critical for their function. Studying the 3D shape of proteins can inform us of the mechanisms that underlie biological processes in living cells and can have practical applications in the study of disease mutations or the discovery of novel drug treatments. Here, we review the progress made in sequence-based prediction of protein structures with a focus on applications that go beyond the prediction of single monomer structures. This includes the application of deep learning methods for the prediction of structures of protein complexes, different conformations, the evolution of protein structures and the application of these methods to protein design. These developments create new opportunities for research that will have impact across many areas of biomedical research.

蛋白质是协调细胞所有生物过程的关键分子机器。大多数蛋白质折叠成对其功能至关重要的三维形状。研究蛋白质的三维形状可以让我们了解活细胞中生物过程的基本机制,在研究疾病突变或发现新型药物治疗方法方面也有实际应用。在此,我们回顾了基于序列的蛋白质结构预测所取得的进展,重点关注单个单体结构预测以外的应用。这包括应用深度学习方法预测蛋白质复合物结构、不同构象、蛋白质结构进化以及将这些方法应用于蛋白质设计。这些发展为研究创造了新的机遇,将对生物医学研究的许多领域产生影响。
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引用次数: 0
Author Correction: Bacterial expression of a designed single-chain IL-10 prevents severe lung inflammation. 作者更正:细菌表达设计的单链 IL-10 可预防严重的肺部炎症。
IF 9.9 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-03-01 DOI: 10.1038/s44320-023-00008-3
Ariadna Montero-Blay, Javier Delgado Blanco, Irene Rodriguez-Arce, Claire Lastrucci, Carlos Piñero-Lambea, Maria Lluch-Senar, Luis Serrano
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引用次数: 0
Detection of PatIent-Level distances from single cell genomics and pathomics data with Optimal Transport (PILOT). 利用优化传输(PILOT)从单细胞基因组学和病理组学数据中检测专利级距离。
IF 9.9 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-02-01 Epub Date: 2023-12-19 DOI: 10.1038/s44320-023-00003-8
Mehdi Joodaki, Mina Shaigan, Victor Parra, Roman D Bülow, Christoph Kuppe, David L Hölscher, Mingbo Cheng, James S Nagai, Michaël Goedertier, Nassim Bouteldja, Vladimir Tesar, Jonathan Barratt, Ian Sd Roberts, Rosanna Coppo, Rafael Kramann, Peter Boor, Ivan G Costa

Although clinical applications represent the next challenge in single-cell genomics and digital pathology, we still lack computational methods to analyze single-cell or pathomics data to find sample-level trajectories or clusters associated with diseases. This remains challenging as single-cell/pathomics data are multi-scale, i.e., a sample is represented by clusters of cells/structures, and samples cannot be easily compared with each other. Here we propose PatIent Level analysis with Optimal Transport (PILOT). PILOT uses optimal transport to compute the Wasserstein distance between two individual single-cell samples. This allows us to perform unsupervised analysis at the sample level and uncover trajectories or cellular clusters associated with disease progression. We evaluate PILOT and competing approaches in single-cell genomics or pathomics studies involving various human diseases with up to 600 samples/patients and millions of cells or tissue structures. Our results demonstrate that PILOT detects disease-associated samples from large and complex single-cell or pathomics data. Moreover, PILOT provides a statistical approach to find changes in cell populations, gene expression, and tissue structures related to the trajectories or clusters supporting interpretation of predictions.

虽然临床应用是单细胞基因组学和数字病理学的下一个挑战,但我们仍然缺乏分析单细胞或病理组学数据的计算方法,以找到与疾病相关的样本级轨迹或集群。这仍然具有挑战性,因为单细胞/病理组学数据是多尺度的,即样本由细胞/结构集群表示,样本之间不易比较。在此,我们提出了采用最优传输技术的实体级分析(PILOT)。PILOT 使用最优传输计算两个单细胞样本之间的瓦瑟斯坦距离。这样,我们就能在样本水平上进行无监督分析,发现与疾病进展相关的轨迹或细胞集群。我们在涉及各种人类疾病的单细胞基因组学或病理组学研究中评估了 PILOT 和其他竞争方法,这些研究涉及多达 600 个样本/患者和数百万个细胞或组织结构。结果表明,PILOT 能从大量复杂的单细胞或病理组学数据中检测出疾病相关样本。此外,PILOT 还提供了一种统计方法,用于发现与轨迹或集群相关的细胞群、基因表达和组织结构的变化,从而支持对预测结果的解释。
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引用次数: 0
Derailed protein turnover in the aging mammalian brain. 哺乳动物大脑衰老过程中的蛋白质周转失调。
IF 9.9 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-02-01 Epub Date: 2024-01-05 DOI: 10.1038/s44320-023-00009-2
Nalini R Rao, Arun Upadhyay, Jeffrey N Savas

Efficient protein turnover is essential for cellular homeostasis and organ function. Loss of proteostasis is a hallmark of aging culminating in severe dysfunction of protein turnover. To investigate protein turnover dynamics as a function of age, we performed continuous in vivo metabolic stable isotope labeling in mice along the aging continuum. First, we discovered that the brain proteome uniquely undergoes dynamic turnover fluctuations during aging compared to heart and liver tissue. Second, trends in protein turnover in the brain proteome during aging showed sex-specific differences that were tightly tied to cellular compartments. Next, parallel analyses of the insoluble proteome revealed that several cellular compartments experience hampered turnover, in part due to misfolding. Finally, we found that age-associated fluctuations in proteasome activity were associated with the turnover of core proteolytic subunits, which was recapitulated by pharmacological suppression of proteasome activity. Taken together, our study provides a proteome-wide atlas of protein turnover across the aging continuum and reveals a link between the turnover of individual proteasome subunits and the age-associated decline in proteasome activity.

高效的蛋白质周转对细胞平衡和器官功能至关重要。蛋白质失去平衡是衰老的一个标志,最终导致蛋白质周转严重失调。为了研究蛋白质随年龄变化的动态变化,我们在小鼠体内进行了连续的代谢稳定同位素标记。首先,我们发现与心脏和肝脏组织相比,大脑蛋白质组在衰老过程中经历了独特的动态周转波动。其次,大脑蛋白质组在衰老过程中的蛋白质周转趋势显示出性别差异,这种差异与细胞区隔密切相关。接下来,对不溶性蛋白质组的平行分析表明,一些细胞区系的蛋白质周转受阻,部分原因是折叠错误。最后,我们发现与年龄相关的蛋白酶体活性波动与核心蛋白水解亚基的周转有关,这一点可以通过药物抑制蛋白酶体活性来重现。综上所述,我们的研究提供了一个蛋白质组范围内的跨衰老过程蛋白质周转图谱,并揭示了单个蛋白酶体亚基的周转与年龄相关的蛋白酶体活性下降之间的联系。
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引用次数: 0
Identifying Spatial Co-occurrence in Healthy and InflAmed tissues (ISCHIA). 在健康和炎症组织中识别空间共现(ISCHIA)。
IF 9.9 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-02-01 Epub Date: 2024-01-15 DOI: 10.1038/s44320-023-00006-5
Atefeh Lafzi, Costanza Borrelli, Simona Baghai Sain, Karsten Bach, Jonas A Kretz, Kristina Handler, Daniel Regan-Komito, Xenia Ficht, Andreas Frei, Andreas Moor

Sequencing-based spatial transcriptomics (ST) methods allow unbiased capturing of RNA molecules at barcoded spots, charting the distribution and localization of cell types and transcripts across a tissue. While the coarse resolution of these techniques is considered a disadvantage, we argue that the inherent proximity of transcriptomes captured on spots can be leveraged to reconstruct cellular networks. To this end, we developed ISCHIA (Identifying Spatial Co-occurrence in Healthy and InflAmed tissues), a computational framework to analyze the spatial co-occurrence of cell types and transcript species within spots. Co-occurrence analysis is complementary to differential gene expression, as it does not depend on the abundance of a given cell type or on the transcript expression levels, but rather on their spatial association in the tissue. We applied ISCHIA to analyze co-occurrence of cell types, ligands and receptors in a Visium dataset of human ulcerative colitis patients, and validated our findings at single-cell resolution on matched hybridization-based data. We uncover inflammation-induced cellular networks involving M cell and fibroblasts, as well as ligand-receptor interactions enriched in the inflamed human colon, and their associated gene signatures. Our results highlight the hypothesis-generating power and broad applicability of co-occurrence analysis on spatial transcriptomics data.

基于测序的空间转录组学(ST)方法可以在条形码点上无偏见地捕获 RNA 分子,描绘出细胞类型和转录本在组织中的分布和定位。虽然这些技术的分辨率较低被认为是一个缺点,但我们认为,可以利用捕获点上转录组固有的接近性来重建细胞网络。为此,我们开发了 ISCHIA(在健康和炎症组织中识别空间共现),这是一种分析斑点内细胞类型和转录本物种空间共现的计算框架。共现分析是对差异基因表达的补充,因为它并不取决于特定细胞类型的丰度或转录本的表达水平,而是取决于它们在组织中的空间关联。我们应用 ISCHIA 分析了人类溃疡性结肠炎患者 Visium 数据集中细胞类型、配体和受体的共现,并在基于匹配杂交数据的单细胞分辨率上验证了我们的发现。我们发现了炎症诱导的细胞网络,其中涉及 M 细胞和成纤维细胞,以及富集在炎症人类结肠中的配体-受体相互作用及其相关基因特征。我们的研究结果凸显了空间转录组学数据共现分析的假设生成能力和广泛适用性。
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引用次数: 0
Systematic discovery of protein interaction interfaces using AlphaFold and experimental validation. 利用 AlphaFold 系统发现蛋白质相互作用界面并进行实验验证。
IF 8.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-02-01 Epub Date: 2024-01-15 DOI: 10.1038/s44320-023-00005-6
Chop Yan Lee, Dalmira Hubrich, Julia K Varga, Christian Schäfer, Mareen Welzel, Eric Schumbera, Milena Djokic, Joelle M Strom, Jonas Schönfeld, Johanna L Geist, Feyza Polat, Toby J Gibson, Claudia Isabelle Keller Valsecchi, Manjeet Kumar, Ora Schueler-Furman, Katja Luck

Structural resolution of protein interactions enables mechanistic and functional studies as well as interpretation of disease variants. However, structural data is still missing for most protein interactions because we lack computational and experimental tools at scale. This is particularly true for interactions mediated by short linear motifs occurring in disordered regions of proteins. We find that AlphaFold-Multimer predicts with high sensitivity but limited specificity structures of domain-motif interactions when using small protein fragments as input. Sensitivity decreased substantially when using long protein fragments or full length proteins. We delineated a protein fragmentation strategy particularly suited for the prediction of domain-motif interfaces and applied it to interactions between human proteins associated with neurodevelopmental disorders. This enabled the prediction of highly confident and likely disease-related novel interfaces, which we further experimentally corroborated for FBXO23-STX1B, STX1B-VAMP2, ESRRG-PSMC5, PEX3-PEX19, PEX3-PEX16, and SNRPB-GIGYF1 providing novel molecular insights for diverse biological processes. Our work highlights exciting perspectives, but also reveals clear limitations and the need for future developments to maximize the power of Alphafold-Multimer for interface predictions.

蛋白质相互作用的结构解析有助于机理和功能研究以及疾病变异的解释。然而,由于我们缺乏大规模的计算和实验工具,大多数蛋白质相互作用的结构数据仍然缺失。这对于由发生在蛋白质无序区域的短线性基团介导的相互作用来说尤其如此。我们发现,当使用小的蛋白质片段作为输入时,AlphaFold-Multimer 可以高灵敏度地预测结构域-基元相互作用的结构,但特异性有限。当使用长蛋白质片段或全长蛋白质时,灵敏度大幅下降。我们定义了一种特别适合预测结构域-结构基元界面的蛋白质片段策略,并将其应用于与神经发育障碍有关的人类蛋白质之间的相互作用。我们还通过实验进一步证实了 FBXO23-STX1B、STX1B-VAMP2、ESRRG-PSMC5、PEX3-PEX19、PEX3-PEX16 和 SNRPB-GIGYF1 的相互作用,为不同的生物过程提供了新的分子见解。我们的工作凸显了令人兴奋的前景,但也揭示了明显的局限性和未来发展的需要,以最大限度地提高 Alphafold-Multimer 在界面预测方面的能力。
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引用次数: 0
Illuminating phenotypic drug responses of sarcoma cells to kinase inhibitors by phosphoproteomics. 通过磷酸蛋白组学阐明肉瘤细胞对激酶抑制剂的表型药物反应。
IF 9.9 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-01-01 Epub Date: 2023-12-18 DOI: 10.1038/s44320-023-00004-7
Chien-Yun Lee, Matthew The, Chen Meng, Florian P Bayer, Kerstin Putzker, Julian Müller, Johanna Streubel, Julia Woortman, Amirhossein Sakhteman, Moritz Resch, Annika Schneider, Stephanie Wilhelm, Bernhard Kuster

Kinase inhibitors (KIs) are important cancer drugs but often feature polypharmacology that is molecularly not understood. This disconnect is particularly apparent in cancer entities such as sarcomas for which the oncogenic drivers are often not clear. To investigate more systematically how the cellular proteotypes of sarcoma cells shape their response to molecularly targeted drugs, we profiled the proteomes and phosphoproteomes of 17 sarcoma cell lines and screened the same against 150 cancer drugs. The resulting 2550 phenotypic profiles revealed distinct drug responses and the cellular activity landscapes derived from deep (phospho)proteomes (9-10,000 proteins and 10-27,000 phosphorylation sites per cell line) enabled several lines of analysis. For instance, connecting the (phospho)proteomic data with drug responses revealed known and novel mechanisms of action (MoAs) of KIs and identified markers of drug sensitivity or resistance. All data is publicly accessible via an interactive web application that enables exploration of this rich molecular resource for a better understanding of active signalling pathways in sarcoma cells, identifying treatment response predictors and revealing novel MoA of clinical KIs.

激酶抑制剂(KIs)是重要的抗癌药物,但往往具有分子上不为人知的多药理作用。这种脱节在肉瘤等癌症实体中尤为明显,因为肉瘤的致癌驱动因素往往并不明确。为了更系统地研究肉瘤细胞的细胞蛋白型如何影响它们对分子靶向药物的反应,我们分析了 17 种肉瘤细胞系的蛋白质组和磷酸蛋白组,并针对 150 种抗癌药物进行了筛选。由此产生的 2550 个表型图谱揭示了不同的药物反应,而从深度(磷酸)蛋白质组(每个细胞系有 9-10,000 个蛋白质和 10-27,000 个磷酸化位点)中得出的细胞活性图谱促成了多种分析方法。例如,将(磷酸化)蛋白质组数据与药物反应联系起来,可以揭示 KIs 的已知和新型作用机制 (MoAs),并确定药物敏感性或耐药性的标记。所有数据都可通过一个交互式网络应用程序公开访问,通过该程序可以探索这一丰富的分子资源,从而更好地了解肉瘤细胞中的活性信号通路,确定治疗反应预测因子,并揭示临床 KIs 的新作用机制。
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引用次数: 0
Hotspot propensity across mutational processes. 不同突变过程中的热点倾向
IF 9.9 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-01-01 Epub Date: 2023-12-20 DOI: 10.1038/s44320-023-00001-w
Claudia Arnedo-Pac, Ferran Muiños, Abel Gonzalez-Perez, Nuria Lopez-Bigas

The sparsity of mutations observed across tumours hinders our ability to study mutation rate variability at nucleotide resolution. To circumvent this, here we investigated the propensity of mutational processes to form mutational hotspots as a readout of their mutation rate variability at single base resolution. Mutational signatures 1 and 17 have the highest hotspot propensity (5-78 times higher than other processes). After accounting for trinucleotide mutational probabilities, sequence composition and mutational heterogeneity at 10 Kbp, most (94-95%) signature 17 hotspots remain unexplained, suggesting a significant role of local genomic features. For signature 1, the inclusion of genome-wide distribution of methylated CpG sites into models can explain most (80-100%) of the hotspot propensity. There is an increased hotspot propensity of signature 1 in normal tissues and de novo germline mutations. We demonstrate that hotspot propensity is a useful readout to assess the accuracy of mutation rate models at nucleotide resolution. This new approach and the findings derived from it open up new avenues for a range of somatic and germline studies investigating and modelling mutagenesis.

在肿瘤中观察到的突变稀少,阻碍了我们以核苷酸分辨率研究突变率变化的能力。为了避免这种情况,我们在这里研究了突变过程形成突变热点的倾向,以此作为单碱基分辨率下突变率变异性的读数。突变特征 1 和 17 具有最高的热点倾向(比其他过程高 5-78 倍)。在考虑了三核苷酸突变概率、序列组成和 10 Kbp 的突变异质性后,大多数(94-95%)特征 17 热点仍无法解释,这表明局部基因组特征起着重要作用。对于特征 1,将甲基化 CpG 位点的全基因组分布纳入模型可以解释大部分(80-100%)的热点倾向。在正常组织和新生种系突变中,特征 1 的热点倾向增加。我们证明,热点倾向是评估核苷酸分辨率突变率模型准确性的有用读数。这种新方法和由此得出的发现为一系列体细胞和种系研究调查和模拟突变开辟了新途径。
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引用次数: 0
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