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Engineering functional materials through bacteria-assisted living grafting. 通过细菌辅助活体接枝技术制造功能材料。
Pub Date : 2024-03-20 Epub Date: 2024-03-08 DOI: 10.1016/j.cels.2024.02.003
Runtao Zhu, Jiao Zhang, Lin Wang, Yunfeng Zhang, Yang Zhao, Ying Han, Jing Sun, Xi Zhang, Ying Dou, Huaxiong Yao, Wei Yan, Xiaozhou Luo, Junbiao Dai, Zhuojun Dai

Functionalizing materials with biomacromolecules such as enzymes has broad applications in biotechnology and biomedicine. Here, we introduce a grafting method mediated by living cells to functionalize materials. We use polymeric scaffolds to trap engineered bacteria and micron-sized particles with chemical groups serving as active sites for grafting. The bacteria synthesize the desired protein for grafting and autonomously lyse to release it. The released functional moieties are locally grafted onto the active sites, generating the materials engineered by living grafting (MELGs). MELGs are resilient to perturbations because of both the bonding and the regeneration of functional domains synthesized by living cells. The programmability of the bacteria enables us to fabricate MELGs that can respond to external input, decompose a pollutant, reconstitute synthetic pathways for natural product synthesis, and purify mismatched DNA. Our work establishes a bacteria-assisted grafting strategy to functionalize materials with a broad range of biological activities in an integrated, flexible, and modular manner. A record of this paper's transparent peer review process is included in the supplemental information.

用生物大分子(如酶)对材料进行功能化处理在生物技术和生物医学领域有着广泛的应用。在这里,我们介绍一种由活细胞介导的接枝方法,以实现材料的功能化。我们使用聚合物支架来捕获工程细菌和微米大小的颗粒,这些颗粒上的化学基团是接枝的活性位点。细菌合成所需的接枝蛋白质,并自主裂解释放。释放出的功能分子局部接枝到活性位点上,生成活体接枝工程材料(MELGs)。由于活细胞合成的功能域具有粘合和再生功能,因此活接枝工程材料具有抗干扰能力。细菌的可编程性使我们能够制造出能够响应外部输入、分解污染物、重组天然产物合成途径以及纯化不匹配 DNA 的 MELGs。我们的工作建立了一种细菌辅助接枝策略,以集成、灵活和模块化的方式使材料具有广泛的生物活性。本文的同行评审过程透明,其记录见补充信息。
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引用次数: 0
Sustainable protein regeneration in encapsulated materials. 封装材料中的可持续蛋白质再生。
Pub Date : 2024-03-20 DOI: 10.1016/j.cels.2024.02.004
Sourik Dey, Shrikrishnan Sankaran

Zhu et al. introduce MELG (materials engineered by living grafting), combining engineered microbes with non-living scaffolds for functional protein regeneration within. These MELGs can be used for long-term controlled release, enzyme-mediated biocatalysis, and DNA purification. This approach offers enhanced functionality and durability in bioactive materials compared to traditional non-living counterparts.

Zhu 等人介绍了 MELG(活体嫁接工程材料),将工程微生物与非活体支架结合起来,用于内部功能性蛋白质再生。这些 MELG 可用于长期控制释放、酶介导的生物催化和 DNA 纯化。与传统的非生物材料相比,这种方法增强了生物活性材料的功能性和耐久性。
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引用次数: 0
What can recent methodological advances help us understand about protein and genome evolution? 最新的方法论进展能帮助我们了解蛋白质和基因组进化的哪些方面?
Pub Date : 2024-03-20 DOI: 10.1016/j.cels.2024.02.006
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引用次数: 0
Widespread alteration of protein autoinhibition in human cancers. 人类癌症中蛋白质自身抑制的广泛改变。
Pub Date : 2024-03-20 Epub Date: 2024-02-15 DOI: 10.1016/j.cels.2024.01.009
Jorge A Holguin-Cruz, Jennifer M Bui, Ashwani Jha, Dokyun Na, Jörg Gsponer

Autoinhibition is a prevalent allosteric regulatory mechanism in signaling proteins. Reduced autoinhibition underlies the tumorigenic effect of some known cancer drivers, but whether autoinhibition is altered generally in cancer remains elusive. Here, we demonstrate that cancer-associated missense mutations, in-frame insertions/deletions, and fusion breakpoints are enriched within inhibitory allosteric switches (IASs) across all cancer types. Selection for IASs that are recurrently mutated in cancers identifies established and unknown cancer drivers. Recurrent missense mutations in IASs of these drivers are associated with distinct, cancer-specific changes in molecular signaling. For the specific case of PPP3CA, the catalytic subunit of calcineurin, we provide insights into the molecular mechanisms of altered autoinhibition by cancer mutations using biomolecular simulations, and demonstrate that such mutations are associated with transcriptome changes consistent with increased calcineurin signaling. Our integrative study shows that autoinhibition-modulating genetic alterations are positively selected for by cancer cells.

自身抑制是信号蛋白中一种普遍的异位调节机制。自抑制作用的降低是一些已知癌症驱动因子致癌作用的基础,但自抑制作用在癌症中是否普遍发生改变仍是未知数。在这里,我们证明了癌症相关的错义突变、框架内插入/缺失和融合断点在所有癌症类型的抑制性异位开关(IASs)中都有富集。对癌症中反复发生突变的 IASs 进行筛选,可以发现已确定的和未知的癌症驱动因素。这些驱动因素的 IASs 中的复发性错义突变与分子信号转导中不同的、癌症特异性变化有关。对于钙调神经蛋白催化亚基 PPP3CA 的具体情况,我们利用生物分子模拟深入了解了癌症突变改变自身抑制的分子机制,并证明这种突变与转录组变化相关,与钙调神经蛋白信号的增加一致。我们的综合研究表明,癌细胞会积极选择调节自身抑制的基因改变。
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引用次数: 0
Clonal differences underlie variable responses to sequential and prolonged treatment. 克隆差异是对连续和长期治疗产生不同反应的原因。
Pub Date : 2024-03-20 Epub Date: 2024-02-23 DOI: 10.1016/j.cels.2024.01.011
Dylan L Schaff, Aria J Fasse, Phoebe E White, Robert J Vander Velde, Sydney M Shaffer

Cancer cells exhibit dramatic differences in gene expression at the single-cell level, which can predict whether they become resistant to treatment. Treatment perpetuates this heterogeneity, resulting in a diversity of cell states among resistant clones. However, it remains unclear whether these differences lead to distinct responses when another treatment is applied or the same treatment is continued. In this study, we combined single-cell RNA sequencing with barcoding to track resistant clones through prolonged and sequential treatments. We found that cells within the same clone have similar gene expression states after multiple rounds of treatment. Moreover, we demonstrated that individual clones have distinct and differing fates, including growth, survival, or death, when subjected to a second treatment or when the first treatment is continued. By identifying gene expression states that predict clone survival, this work provides a foundation for selecting optimal therapies that target the most aggressive resistant clones within a tumor. A record of this paper's transparent peer review process is included in the supplemental information.

癌细胞在单细胞水平上的基因表达存在巨大差异,这可以预测它们是否会对治疗产生耐药性。治疗会延续这种异质性,导致耐药克隆中细胞状态的多样性。然而,目前仍不清楚这些差异是否会导致在采用另一种治疗方法或继续采用同一种治疗方法时产生不同的反应。在这项研究中,我们将单细胞 RNA 测序与条形码结合起来,通过长期和连续的治疗来追踪耐药克隆。我们发现,经过多轮治疗后,同一克隆内的细胞具有相似的基因表达状态。此外,我们还证明,当接受第二次治疗或继续第一次治疗时,单个克隆会有不同的命运,包括生长、存活或死亡。通过确定预测克隆存活的基因表达状态,这项工作为选择针对肿瘤内最具侵袭性的耐药克隆的最佳疗法奠定了基础。本文的同行评审过程透明,其记录见补充信息。
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引用次数: 0
Convolutions are competitive with transformers for protein sequence pretraining. 在蛋白质序列预训练方面,卷积与变换器具有竞争性。
Pub Date : 2024-03-20 Epub Date: 2024-02-29 DOI: 10.1016/j.cels.2024.01.008
Kevin K Yang, Nicolo Fusi, Alex X Lu

Pretrained protein sequence language models have been shown to improve the performance of many prediction tasks and are now routinely integrated into bioinformatics tools. However, these models largely rely on the transformer architecture, which scales quadratically with sequence length in both run-time and memory. Therefore, state-of-the-art models have limitations on sequence length. To address this limitation, we investigated whether convolutional neural network (CNN) architectures, which scale linearly with sequence length, could be as effective as transformers in protein language models. With masked language model pretraining, CNNs are competitive with, and occasionally superior to, transformers across downstream applications while maintaining strong performance on sequences longer than those allowed in the current state-of-the-art transformer models. Our work suggests that computational efficiency can be improved without sacrificing performance, simply by using a CNN architecture instead of a transformer, and emphasizes the importance of disentangling pretraining task and model architecture. A record of this paper's transparent peer review process is included in the supplemental information.

预训练的蛋白质序列语言模型已被证明能提高许多预测任务的性能,现在已被例行集成到生物信息学工具中。然而,这些模型在很大程度上依赖于转换器架构,而转换器架构在运行时间和内存方面都与序列长度成二次方关系。因此,最先进的模型对序列长度有限制。为了解决这一局限性,我们研究了卷积神经网络(CNN)架构是否能在蛋白质语言模型中与转换器一样有效,因为后者与序列长度成线性关系。通过掩码语言模型预训练,CNN 在下游应用中可与转换器竞争,有时甚至优于转换器,同时在比当前最先进的转换器模型所允许的序列长度更长的序列上保持强劲的性能。我们的工作表明,只需使用 CNN 架构而不是转换器,就能在不牺牲性能的情况下提高计算效率,并强调了将预训练任务和模型架构分开的重要性。本文的同行评审过程透明,其记录包含在补充信息中。
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引用次数: 0
Retrospective identification of cell-intrinsic factors that mark pluripotency potential in rare somatic cells. 在罕见体细胞中回溯鉴定标志多能潜能的细胞内在因子。
Pub Date : 2024-02-21 Epub Date: 2024-02-08 DOI: 10.1016/j.cels.2024.01.001
Naveen Jain, Yogesh Goyal, Margaret C Dunagin, Christopher J Cote, Ian A Mellis, Benjamin Emert, Connie L Jiang, Ian P Dardani, Sam Reffsin, Miles Arnett, Wenli Yang, Arjun Raj

Pluripotency can be induced in somatic cells by the expression of OCT4, KLF4, SOX2, and MYC. Usually only a rare subset of cells reprogram, and the molecular characteristics of this subset remain unknown. We apply retrospective clone tracing to identify and characterize the rare human fibroblasts primed for reprogramming. These fibroblasts showed markers of increased cell cycle speed and decreased fibroblast activation. Knockdown of a fibroblast activation factor identified by our analysis increased the reprogramming efficiency. We provide evidence for a unified model in which cells can move into and out of the primed state over time, explaining how reprogramming appears deterministic at short timescales and stochastic at long timescales. Furthermore, inhibiting the activity of LSD1 enlarged the pool of cells that were primed for reprogramming. Thus, even homogeneous cell populations can exhibit heritable molecular variability that can dictate whether individual rare cells will reprogram or not.

体细胞可通过表达 OCT4、KLF4、SOX2 和 MYC 诱导多能性。通常只有极少数的细胞亚群会进行重编程,而这一亚群的分子特征仍然未知。我们利用回顾性克隆追踪技术,鉴定并描述了可进行重编程的罕见人类成纤维细胞。这些成纤维细胞显示出细胞周期速度加快和成纤维细胞活化降低的标记。我们的分析发现,敲除一种成纤维细胞活化因子可提高重编程效率。我们为一个统一的模型提供了证据,在这个模型中,细胞可以随着时间的推移进入或退出初始状态,从而解释了为什么重编程在短时间内是确定性的,而在长时间内则是随机性的。此外,抑制 LSD1 的活性还能扩大启动重编程的细胞池。因此,即使是同质的细胞群也会表现出可遗传的分子变异性,从而决定单个稀有细胞是否会进行重编程。
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引用次数: 0
Mapping combinatorial expression perturbations to growth in Escherichia coli. 绘制组合表达扰动与大肠杆菌生长的关系图。
Pub Date : 2024-02-21 DOI: 10.1016/j.cels.2024.01.006
J Scott P McCain

The connection between growth and gene expression has often been considered in a single gene. Repurposing a drug-drug interaction model, the multidimensional effects of several simultaneous gene expression perturbations on growth have been examined in the model bacteria Escherichia coli.

生长与基因表达之间的联系通常只在单个基因中加以考虑。我们重新利用药物-药物相互作用模型,在模式细菌大肠杆菌中研究了同时发生的几种基因表达扰动对生长的多维影响。
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引用次数: 0
A top variant identification pipeline for protein engineering. 用于蛋白质工程的顶级变异识别管道。
Pub Date : 2024-02-21 DOI: 10.1016/j.cels.2024.01.010
Hui Chen, Zhike Lu, Lijia Ma

Understanding the fitness of protein variants with combinatorial mutations is critical for effective protein engineering. In this issue of Cell Systems, Chu et al. present TopVIP, a top variant identification pipeline that enables accurate picking of the greatest number of best-performing protein variants with high-fitness leveraging zero-shot predictor and low-N iterative sampling.

了解具有组合突变的蛋白质变体的适配性对于有效的蛋白质工程至关重要。在本期的《细胞系统》(Cell Systems)杂志上,Chu 等人介绍了 TopVIP,这是一种顶级变体识别管道,利用零次预测器和低 N 次迭代采样,能准确挑选出数量最多、表现最佳的高适配性蛋白质变体。
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引用次数: 0
Simple visualization of submicroscopic protein clusters with a phase-separation-based fluorescent reporter. 利用基于相分离的荧光报告器实现亚显微蛋白质团簇的简单可视化。
Pub Date : 2024-02-21 Epub Date: 2024-02-08 DOI: 10.1016/j.cels.2024.01.005
Thomas R Mumford, Diarmid Rae, Emily Brackhahn, Abbas Idris, David Gonzalez-Martinez, Ayush Aditya Pal, Michael C Chung, Juan Guan, Elizabeth Rhoades, Lukasz J Bugaj

Protein clustering plays numerous roles in cell physiology and disease. However, protein oligomers can be difficult to detect because they are often too small to appear as puncta in conventional fluorescence microscopy. Here, we describe a fluorescent reporter strategy that detects protein clusters with high sensitivity called CluMPS (clusters magnified by phase separation). A CluMPS reporter detects and visually amplifies even small clusters of a binding partner, generating large, quantifiable fluorescence condensates. We use computational modeling and optogenetic clustering to demonstrate that CluMPS can detect small oligomers and behaves rationally according to key system parameters. CluMPS detected small aggregates of pathological proteins where the corresponding GFP fusions appeared diffuse. CluMPS also detected and tracked clusters of unmodified and tagged endogenous proteins, and orthogonal CluMPS probes could be multiplexed in cells. CluMPS provides a powerful yet straightforward approach to observe higher-order protein assembly in its native cellular context. A record of this paper's transparent peer review process is included in the supplemental information.

蛋白质聚类在细胞生理和疾病中发挥着多种作用。然而,蛋白质寡聚体很难检测,因为它们通常太小,在传统荧光显微镜下无法显示为点状。在这里,我们描述了一种高灵敏度检测蛋白质团簇的荧光报告策略,称为 CluMPS(通过相分离放大的团簇)。CluMPS 报告器能检测并可视化地放大结合伙伴的小集群,产生可量化的大型荧光凝聚物。我们利用计算建模和光遗传聚类来证明,CluMPS 可以检测到小的寡聚体,并根据关键的系统参数做出合理的行为。CluMPS 能检测到病理蛋白的小聚集体,而相应的 GFP 融合体则呈现弥散状。CluMPS 还能检测和跟踪未修饰和标记的内源蛋白质群,而且正交的 CluMPS 探针可以在细胞中进行多重检测。CluMPS 提供了一种强大而直接的方法,用于观察高阶蛋白质在原生细胞环境中的组装情况。本文的同行评审过程透明,相关记录见补充信息。
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引用次数: 0
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Cell systems
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