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Cryo-focused ion beam for in situ structural biology: State of the art, challenges, and perspectives 用于原位结构生物学的低温聚焦离子束:技术现状、挑战和前景
IF 6.8 2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-06-19 DOI: 10.1016/j.sbi.2024.102864
Alex J. Noble, Alex de Marco

Cryogenic-focused ion beam (cryo-FIB) instruments became essential for high-resolution imaging in cryo-preserved cells and tissues. Cryo-FIBs use accelerated ions to thin samples that would otherwise be too thick for cryo-electron microscopy (cryo-EM). This allows visualizing cellular ultrastructures in near-native frozen hydrated states. This review describes the current state-of-the-art capabilities of cryo-FIB technology and its applications in structural cell and tissue biology. We discuss recent advances in instrumentation, imaging modalities, automation, sample preparation protocols, and targeting techniques. We outline remaining challenges and future directions to make cryo-FIB more precise, enable higher throughput, and be widely accessible. Further improvements in targeting, efficiency, robust sample preparation, emerging ion sources, automation, and downstream electron tomography have the potential to reveal intricate molecular architectures across length scales inside cells and tissues. Cryo-FIB is poised to become an indispensable tool for preparing native biological systems in situ for high-resolution 3D structural analysis.

低温聚焦离子束(Cryo-FIB)仪器对于低温保存的细胞和组织的高分辨率成像至关重要。低温聚焦离子束利用加速离子来稀释样本,否则样本太厚就无法进行低温电子显微镜(cryo-EM)成像。这样就可以观察到近原生冷冻水合状态下的细胞超微结构。本综述介绍了冷冻-FIB 技术的当前最新能力及其在细胞和组织结构生物学中的应用。我们讨论了仪器、成像模式、自动化、样品制备方案和靶向技术方面的最新进展。我们概述了要使冷冻-FIB 技术更加精确、实现更高通量和广泛应用所面临的挑战和未来发展方向。在靶向、效率、稳健的样品制备、新兴离子源、自动化和下游电子断层扫描方面的进一步改进有可能揭示细胞和组织内部跨长度尺度的复杂分子结构。Cryo-FIB 将成为原位制备本地生物系统以进行高分辨率三维结构分析的不可或缺的工具。
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引用次数: 0
Advances in cryo-ET data processing: meeting the demands of visual proteomics 低温电子显微镜数据处理的进展:满足视觉蛋白质组学的需求。
IF 6.8 2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-06-17 DOI: 10.1016/j.sbi.2024.102861
Abigail J.I. Watson , Alberto Bartesaghi

Cryogenic electron tomography (cryo-ET), a method that enables the viewing of biomolecules in near-native environments at high resolution, is rising in accessibility and applicability. Over the past several years, once slow sample preparation and data collection procedures have seen innovations which enable rapid collection of the large datasets required for attaining high resolution structures. Increased data availability has provided a driving force for exciting improvements in cryo-ET data processing methodologies throughout the entire processing pipeline and the development of accessible graphical user interfaces (GUIs) that enable individuals inexperienced in computational fields to convert raw tilt series into 3D structures. These advances in data processing are enabling cryo-ET to attain higher resolution and extending its applicability to more complex samples.

低温电子断层扫描(cryo-ET)是一种能够在近原生环境中以高分辨率观察生物分子的方法,其可获得性和适用性正在不断提高。在过去的几年中,曾经缓慢的样品制备和数据收集程序有了创新,能够快速收集获得高分辨率结构所需的大量数据集。数据可用性的提高推动了整个处理流程中低温电子显微镜数据处理方法的重大改进,也推动了图形用户界面(GUI)的发展,使缺乏计算领域经验的人也能将原始倾斜序列转换成三维结构。数据处理方面的这些进步使低温电子显微镜能够达到更高的分辨率,并将其适用范围扩展到更复杂的样本。
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引用次数: 0
Nuclear periphery and its mechanical regulation in cell fate transitions 细胞命运转换中的核外围及其机械调控
IF 6.8 2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-06-17 DOI: 10.1016/j.sbi.2024.102867
Rebecca K. Stephens, Yekaterina A. Miroshnikova

Cell fate changes require rewiring of transcriptional programs to generate functionally specialized cell states. Reconfiguration of transcriptional networks requires overcoming epigenetic barriers imposed by silenced heterochromatin in order to activate lineage-specific genes. Further, cell fate decisions are made in a tissue-specific context, where cells are physically linked to each other as well as to the connective tissue environment. Here, cells are continuously exposed to a multitude of mechanical forces emanating from cellular dynamics in their local microenvironments, for example through cell movements, cell divisions, tissue contractions, or fluid flow. Through their ability to deform cellular structures and activate receptors, mechanical forces can be sensed at the plasma membrane, but also at the nuclear periphery through direct or cytoskeleton-mediated deformation of the nuclear envelope. This deformation and the associated signaling is capable of triggering changes in the mechanical state of the nuclear membranes, the organization and rigidity of the underlying nuclear lamina, compaction state of chromatin, and ultimately transcription. This review focuses on the role of nuclear architecture, particularly the nuclear lamina-chromatin interface, and its mechanical regulation in cell fate decisions as well as its physiological role in development and cellular reprogramming.

细胞命运的改变需要转录程序的重新布线,以产生功能特化的细胞状态。转录网络的重新配置需要克服沉默的异染色质所造成的表观遗传学障碍,以激活特定世系的基因。此外,细胞命运的决定是在组织特异性的背景下做出的,细胞之间以及细胞与结缔组织环境之间都存在物理联系。在这种情况下,细胞会不断受到来自其局部微环境中细胞动态的多种机械力的影响,例如通过细胞运动、细胞分裂、组织收缩或液体流动产生的机械力。机械力不仅能使细胞结构变形并激活受体,还能通过核膜的直接变形或细胞骨架介导的变形在细胞核外围感知到机械力。这种变形和相关信号能够引发核膜的机械状态、底层核薄层的组织和刚性、染色质的压实状态以及最终转录的变化。这篇综述将重点探讨核结构(尤其是核薄层-染色质界面)的作用及其在细胞命运决定中的机械调控,以及它在发育和细胞重编程中的生理作用。
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引用次数: 0
Single-molecule fluorescence imaging of DNA maintenance protein binding dynamics and activities on extended DNA 扩展 DNA 上 DNA 维护蛋白结合动态和活动的单分子荧光成像
IF 6.8 2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-06-15 DOI: 10.1016/j.sbi.2024.102863
Elizabeth Marie Irvin , Hong Wang

Defining the molecular mechanisms by which genome maintenance proteins dynamically associate with and process DNA is essential to understand the potential avenues by which these stabilizing mechanisms are disrupted. Single-molecule fluorescence imaging (SMFI) of protein dynamics on extended DNA has greatly expanded our ability to accomplish this, as it captures singular biomolecular interactions – in all their complexity and diversity – without relying on ensemble-averaging of bulk protein activity as most traditional biochemical techniques must do. In this review, we discuss how SMFI studies with extended DNA have substantially contributed to genome stability research over the past two years.

要了解这些稳定机制被破坏的潜在途径,就必须确定基因组维护蛋白与 DNA 动态关联和处理 DNA 的分子机制。对扩展 DNA 上蛋白质动态的单分子荧光成像(SMFI)极大地拓展了我们实现这一目标的能力,因为它能捕捉单个生物分子的相互作用--其复杂性和多样性--而不像大多数传统生化技术那样必须依赖于大量蛋白质活性的集合平均。在这篇综述中,我们将讨论在过去两年中,利用扩展 DNA 进行的 SMFI 研究是如何为基因组稳定性研究做出重大贡献的。
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引用次数: 0
DNA topology: A central dynamic coordinator in chromatin regulation DNA 拓扑学:染色质调控的核心动态协调器
IF 6.8 2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-06-14 DOI: 10.1016/j.sbi.2024.102868
Shuai Li, Charan Vemuri, Chongyi Chen

Double helical DNA winds around nucleosomes, forming a beads-on-a-string array that further contributes to the formation of high-order chromatin structures. The regulatory components of the chromatin, interacting intricately with DNA, often exploit the topological tension inherent in the DNA molecule. Recent findings shed light on, and simultaneously complicate, the multifaceted roles of DNA topology (also known as DNA supercoiling) in various aspects of chromatin regulation. Different studies may emphasize the dynamics of DNA topological tension across different scales, interacting with diverse chromatin factors such as nucleosomes, nucleic acid motors that propel DNA-tracking processes, and DNA topoisomerases. In this review, we consolidate recent studies and establish connections between distinct scientific discoveries, advancing our current understanding of chromatin regulation mediated by the supercoiling tension of the double helix. Additionally, we explore the implications of DNA topology and DNA topoisomerases in human diseases, along with their potential applications in therapeutic interventions.

双螺旋 DNA 缠绕在核小体上,形成串珠阵列,进一步促进了高阶染色质结构的形成。染色质中的调控成分与 DNA 相互作用,经常利用 DNA 分子固有的拓扑张力。最近的发现揭示了 DNA 拓扑学(也称为 DNA 超卷曲)在染色质调控各方面的多方面作用,同时也使其变得更加复杂。不同的研究可能会强调 DNA 拓扑张力在不同尺度上的动态变化,并与核小体、推动 DNA 跟踪过程的核酸马达和 DNA 拓扑异构酶等多种染色质因子相互作用。在这篇综述中,我们整合了最近的研究,并在不同的科学发现之间建立了联系,从而推进了我们目前对由双螺旋超卷曲张力介导的染色质调控的理解。此外,我们还探讨了DNA拓扑学和DNA拓扑异构酶对人类疾病的影响,以及它们在治疗干预中的潜在应用。
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引用次数: 0
Editorial overview–Artificial intelligence methodologies in structural biology: Bridging the gap to medical applications 编辑综述-结构生物学中的人工智能方法:缩小医学应用差距
IF 6.8 2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-06-12 DOI: 10.1016/j.sbi.2024.102862
Tero Aittokallio, Evandro Fei Fang
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引用次数: 0
Microscale measurements of protein complexes from single cells 单细胞蛋白质复合物的微尺度测量
IF 6.8 2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-06-07 DOI: 10.1016/j.sbi.2024.102860
Tanushree Dutta, Julea Vlassakis

Proteins execute numerous cell functions in concert with one another in protein–protein interactions (PPI). While essential in each cell, such interactions are not identical from cell to cell. Instead, PPI heterogeneity contributes to cellular phenotypic heterogeneity in health and diseases such as cancer. Understanding cellular phenotypic heterogeneity thus requires measurements of properties of PPIs such as abundance, stoichiometry, and kinetics at the single-cell level. Here, we review recent, exciting progress in single-cell PPI measurements. Novel technology in this area is enabled by microscale and microfluidic approaches that control analyte concentration in timescales needed to outpace PPI disassembly kinetics. We describe microscale innovations, needed technical capabilities, and methods poised to be adapted for single-cell analysis in the near future.

蛋白质在蛋白质-蛋白质相互作用(PPI)中相互配合,执行着众多细胞功能。虽然这种相互作用在每个细胞中都必不可少,但细胞与细胞之间并不完全相同。相反,PPI 的异质性导致了健康和癌症等疾病中细胞表型的异质性。因此,要了解细胞表型的异质性,就必须在单细胞水平上测量 PPI 的特性,如丰度、化学计量学和动力学。在此,我们回顾了最近在单细胞 PPI 测量方面取得的令人振奋的进展。该领域的新技术得益于微尺度和微流体方法,这些方法能在所需的时间尺度内控制分析物浓度,以超越 PPI 分解动力学。我们介绍了微尺度创新、所需的技术能力以及在不久的将来可用于单细胞分析的方法。
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引用次数: 0
Structural overview of DNA and RNA G-quadruplexes in their interaction with proteins DNA 和 RNA G 型四联体与蛋白质相互作用的结构概述
IF 6.8 2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-06-07 DOI: 10.1016/j.sbi.2024.102846
Romualdo Troisi , Filomena Sica

Since the discovery of G-quadruplex (G4) participation in vital cellular processes, the regulation of the interaction of naturally occurring G4s with the relative target proteins has emerged as a promising approach for therapeutic development. Additionally, a synthetic strategy has produced several oligonucleotide aptamers, embodying a G4 module, which exhibit relevant biological activity by binding selectively to a target protein. In this context, the G4-protein structures available in the Protein Data Bank represent a valuable molecular view of the different G4 topologies involved in protein interaction. Interestingly, recent results have showed the co-existence of G4s with other structural domains such as duplexes. Overall, these findings allow a better understanding of the mechanisms that regulate intricate biological functions and suggest new design for innovative medical treatments.

自从发现 G-四叠体(G4)参与重要的细胞过程以来,调节天然存在的 G4 与相关靶蛋白的相互作用已成为一种很有前景的治疗开发方法。此外,一种合成策略已经产生了几种包含 G4 模块的寡核苷酸适配体,它们通过选择性地与靶蛋白结合而表现出相关的生物活性。在这种情况下,蛋白质数据库(Protein Data Bank)中的 G4 蛋白结构代表了参与蛋白质相互作用的不同 G4 拓扑的宝贵分子视图。有趣的是,最近的研究结果表明,G4 与其他结构域(如双链)共存。总之,这些发现使人们能够更好地了解调节复杂生物功能的机制,并为创新医学治疗提出了新的设计建议。
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引用次数: 0
Structure-based virtual screening of vast chemical space as a starting point for drug discovery 以结构为基础,对广阔的化学空间进行虚拟筛选,作为药物发现的起点
IF 6.8 2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-06-06 DOI: 10.1016/j.sbi.2024.102829
Jens Carlsson , Andreas Luttens

Structure-based virtual screening aims to find molecules forming favorable interactions with a biological macromolecule using computational models of complexes. The recent surge of commercially available chemical space provides the opportunity to search for ligands of therapeutic targets among billions of compounds. This review offers a compact overview of structure-based virtual screens of vast chemical spaces, highlighting successful applications in early drug discovery for therapeutically important targets such as G protein-coupled receptors and viral enzymes. Emphasis is placed on strategies to explore ultra-large chemical libraries and synergies with emerging machine learning techniques. The current opportunities and future challenges of virtual screening are discussed, indicating that this approach will play an important role in the next-generation drug discovery pipeline.

基于结构的虚拟筛选旨在利用复合物的计算模型找到与生物大分子形成有利相互作用的分子。最近商业化化学空间的激增为从数十亿化合物中寻找治疗靶标的配体提供了机会。这篇综述简要概述了基于结构的巨大化学空间虚拟筛选,重点介绍了在治疗重要靶点(如 G 蛋白偶联受体和病毒酶)的早期药物发现中的成功应用。重点是探索超大化学库的策略以及与新兴机器学习技术的协同作用。讨论了虚拟筛选当前的机遇和未来的挑战,表明这种方法将在下一代药物发现管道中发挥重要作用。
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引用次数: 0
Integrating AI in fighting advancing Alzheimer: diagnosis, prevention, treatment, monitoring, mechanisms, and clinical trials 将人工智能融入抗击阿尔茨海默氏症的工作中:诊断、预防、治疗、监测、机制和临床试验
IF 6.8 2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-06-04 DOI: 10.1016/j.sbi.2024.102857
Francesco Angelucci , Alice Ruixue Ai , Lydia Piendel , Jiri Cerman , Jakub Hort

The application of artificial intelligence (AI) in neurology is a growing field offering opportunities to improve accuracy of diagnosis and treatment of complicated neuronal disorders, plus fostering a deeper understanding of the aetiologies of these diseases through AI-based analyses of large omics data. The most common neurodegenerative disease, Alzheimer’s disease (AD), is characterized by brain accumulation of specific pathological proteins, accompanied by cognitive impairment. In this review, we summarize the latest progress on the use of AI in different AD-related fields, such as analysis of neuroimaging data enabling early and accurate AD diagnosis; prediction of AD progression, identification of patients at higher risk and evaluation of new treatments; improvement of the evaluation of drug response using AI algorithms to analyze patient clinical and neuroimaging data; the development of personalized AD therapies; and the use of AI-based techniques to improve the quality of daily life of AD patients and their caregivers.

人工智能(AI)在神经病学中的应用是一个不断发展的领域,它为提高复杂神经元疾病的诊断和治疗的准确性提供了机会,并通过基于 AI 的大型 omics 数据分析加深了对这些疾病病因的理解。最常见的神经退行性疾病阿尔茨海默病(AD)的特征是大脑中特定病理蛋白的积累,并伴有认知障碍。在这篇综述中,我们总结了人工智能在不同的阿尔茨海默病相关领域应用的最新进展,如通过分析神经影像学数据实现阿尔茨海默病的早期准确诊断;预测阿尔茨海默病的进展、识别高风险患者并评估新疗法;利用人工智能算法分析患者的临床和神经影像学数据改善药物反应评估;开发个性化的阿尔茨海默病疗法;以及利用基于人工智能的技术改善阿尔茨海默病患者及其护理人员的日常生活质量。
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引用次数: 0
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Current opinion in structural biology
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