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Computationally guided AAV engineering for enhanced gene delivery 计算引导的 AAV 工程,用于增强基因递送。
IF 13.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-05-01 DOI: 10.1016/j.tibs.2024.03.002
Jingxuan Guo , Li F. Lin , Sydney V. Oraskovich , Julio A. Rivera de Jesús , Jennifer Listgarten , David V. Schaffer

Gene delivery vehicles based on adeno-associated viruses (AAVs) are enabling increasing success in human clinical trials, and they offer the promise of treating a broad spectrum of both genetic and non-genetic disorders. However, delivery efficiency and targeting must be improved to enable safe and effective therapies. In recent years, considerable effort has been invested in creating AAV variants with improved delivery, and computational approaches have been increasingly harnessed for AAV engineering. In this review, we discuss how computationally designed AAV libraries are enabling directed evolution. Specifically, we highlight approaches that harness sequences outputted by next-generation sequencing (NGS) coupled with machine learning (ML) to generate new functional AAV capsids and related regulatory elements, pushing the frontier of what vector engineering and gene therapy may achieve.

基于腺相关病毒(AAV)的基因递送载体在人体临床试验中取得了越来越多的成功,为治疗各种遗传性和非遗传性疾病带来了希望。然而,必须提高递送效率和靶向性,才能实现安全有效的治疗。近年来,人们投入了大量精力来创造可改善递送的 AAV 变体,计算方法也越来越多地被用于 AAV 工程。在这篇综述中,我们将讨论计算设计的 AAV 库如何实现定向进化。具体来说,我们重点介绍利用下一代测序(NGS)输出的序列结合机器学习(ML)生成新的功能性 AAV 外壳和相关调控元件的方法,从而推动载体工程和基因治疗的发展。
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引用次数: 0
Team science: building, nurturing, and expanding research collaborations 团队科学:建立、培育和扩大研究合作。
IF 13.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-05-01 DOI: 10.1016/j.tibs.2023.10.010
Arun K. Shukla

Science is a collaborative endeavor, and the importance of collaborations across disciplines and boundaries is becoming clearer with the advent of new technologies. This article focuses on key aspects of initiating and sustaining new collaborations, and expanding from bilateral to multilateral efforts to create major impact through team science.

科学是一项合作的努力,随着新技术的出现,跨学科和跨界合作的重要性变得越来越明显。本文主要关注发起和维持新合作的关键方面,并通过团队科学从双边努力扩展到多边努力,以产生重大影响。
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引用次数: 0
A left-handed RNA quadruplex directs gene silencing 左手 RNA 四重链引导基因沉默。
IF 13.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-05-01 DOI: 10.1016/j.tibs.2024.01.009
Samuel E. Butcher

Poly(UG) or ‘pUG’ dinucleotide repeats direct gene silencing in Caenorhabditis elegans by adopting an unusual quadruplex structure. Humans have thousands of pUG sequences and proteins that interact with them. The pUG fold reveals new aspects of gene regulation and RNA folding, highlighting how a simple sequence can encode a complex structure.

多聚(UG)或 "pUG "二核苷酸重复序列通过采用不寻常的四重结构,在秀丽隐杆线虫体内引导基因沉默。人类有数以千计的 pUG 序列和与它们相互作用的蛋白质。pUG 折叠揭示了基因调控和 RNA 折叠的新方面,突出了简单序列如何编码复杂结构。
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引用次数: 0
Protein–membrane interactions: sensing and generating curvature 蛋白质与膜的相互作用:感应和产生曲率。
IF 13.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-05-01 DOI: 10.1016/j.tibs.2024.02.005
David H. Johnson , Orianna H. Kou , Nicoletta Bouzos , Wade F. Zeno

Biological membranes are integral cellular structures that can be curved into various geometries. These curved structures are abundant in cells as they are essential for various physiological processes. However, curved membranes are inherently unstable, especially on nanometer length scales. To stabilize curved membranes, cells can utilize proteins that sense and generate membrane curvature. In this review, we summarize recent research that has advanced our understanding of interactions between proteins and curved membrane surfaces, as well as work that has expanded our ability to study curvature sensing and generation. Additionally, we look at specific examples of cellular processes that require membrane curvature, such as neurotransmission, clathrin-mediated endocytosis (CME), and organelle biogenesis.

生物膜是一种可弯曲成各种几何形状的完整细胞结构。这些弯曲结构在细胞中大量存在,因为它们对各种生理过程至关重要。然而,弯曲的膜本身并不稳定,尤其是在纳米长度范围内。为了稳定弯曲的膜,细胞可以利用能感知和产生膜曲率的蛋白质。在这篇综述中,我们总结了最近的研究,这些研究推进了我们对蛋白质与弯曲膜表面之间相互作用的理解,也拓展了我们研究曲率感应和产生的能力。此外,我们还探讨了需要膜曲率的细胞过程的具体实例,如神经传递、凝集素介导的内吞(CME)和细胞器的生物生成。
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引用次数: 0
Advisory Board and Contents 咨询委员会和内容
IF 13.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-05-01 DOI: 10.1016/S0968-0004(24)00089-6
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引用次数: 0
TrkB transmembrane domain: bridging structural understanding with therapeutic strategy TrkB 跨膜结构域:结构理解与治疗策略的桥梁。
IF 13.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-05-01 DOI: 10.1016/j.tibs.2024.02.001
Giray Enkavi , Mykhailo Girych , Rafael Moliner , Ilpo Vattulainen , Eero Castrén

TrkB (neuronal receptor tyrosine kinase-2, NTRK2) is the receptor for brain-derived neurotrophic factor (BDNF) and is a critical regulator of activity-dependent neuronal plasticity. The past few years have witnessed an increasing understanding of the structure and function of TrkB, including its transmembrane domain (TMD). TrkB interacts with membrane cholesterol, which bidirectionally regulates TrkB signaling. Additionally, TrkB has recently been recognized as a binding target of antidepressant drugs. A variety of different antidepressants, including typical and rapid-acting antidepressants, as well as psychedelic compounds, act as allosteric potentiators of BDNF signaling through TrkB. This suggests that TrkB is the common target of different antidepressant compounds. Although more research is needed, current knowledge suggests that TrkB is a promising target for further drug development.

TrkB(神经元受体酪氨酸激酶-2,NTRK2)是脑源性神经营养因子(BDNF)的受体,是活动依赖性神经元可塑性的关键调节因子。过去几年中,人们对 TrkB 的结构和功能(包括其跨膜结构域(TMD))的了解不断加深。TrkB 与膜胆固醇相互作用,双向调节 TrkB 信号传导。此外,TrkB 最近被认为是抗抑郁药物的结合靶点。各种不同的抗抑郁药物,包括典型抗抑郁药物和速效抗抑郁药物,以及迷幻化合物,都可通过 TrkB 作为 BDNF 信号的异构增效剂。这表明TrkB是不同抗抑郁化合物的共同靶点。尽管还需要更多的研究,但目前的知识表明,TrkB 是一个有希望进一步开发药物的靶点。
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引用次数: 0
Glucocorticoid receptor signaling: intricacies and therapeutic opportunities 糖皮质激素受体信号传导:错综复杂与治疗机会。
IF 13.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-05-01 DOI: 10.1016/j.tibs.2024.01.012
Dorien Clarisse , Laura Van Moortel , Chloé Van Leene , Kris Gevaert , Karolien De Bosscher

The glucocorticoid receptor (GR) is a major nuclear receptor (NR) drug target for the treatment of inflammatory disorders and several cancers. Despite the effectiveness of GR ligands, their systemic action triggers a plethora of side effects, limiting long-term use. Here, we discuss new concepts of and insights into GR mechanisms of action to assist in the identification of routes toward enhanced therapeutic benefits. We zoom in on the communication between different GR domains and how this is influenced by different ligands. We detail findings on the interaction between GR and chromatin, and highlight how condensate formation and coregulator confinement can perturb GR transcriptional responses. Last, we discuss the potential of novel ligands and the therapeutic exploitation of crosstalk with other NRs.

糖皮质激素受体(GR)是治疗炎症性疾病和多种癌症的主要核受体(NR)药物靶点。尽管 GR 配体很有效,但其全身作用会引发大量副作用,限制了长期使用。在此,我们将讨论有关 GR 作用机制的新概念和新见解,以帮助确定提高治疗效果的途径。我们将深入探讨不同 GR 结构域之间的交流,以及不同配体如何影响这种交流。我们详细介绍了 GR 与染色质之间相互作用的发现,并强调了凝集物的形成和核心调节剂的限制如何扰乱 GR 的转录反应。最后,我们讨论了新型配体的潜力以及利用与其他 NRs 的串扰进行治疗的可能性。
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引用次数: 0
The RNA tether model for human chromosomal translocation fragile zones 人类染色体易位脆区的 RNA 系链模型。
IF 13.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-05-01 DOI: 10.1016/j.tibs.2024.02.003
Di Liu , Chih-Lin Hsieh , Michael R. Lieber

One of the two chromosomal breakage events in recurring translocations in B cell neoplasms is often due to the recombination-activating gene complex (RAG complex) releasing DNA ends before end joining. The other break occurs in a fragile zone of 20–600 bp in a non-antigen receptor gene locus, with a more complex and intriguing set of mechanistic factors underlying such narrow fragile zones. These factors include activation-induced deaminase (AID), which acts only at regions of single-stranded DNA (ssDNA). Recent work leads to a model involving the tethering of AID to the nascent RNA as it emerges from the RNA polymerase. This mechanism may have relevance in class switch recombination (CSR) and somatic hypermutation (SHM), as well as broader relevance for other DNA enzymes.

在 B 细胞瘤反复发生的易位中,有两种染色体断裂现象,其中一种往往是由于重组激活基因复合物(RAG 复合物)在末端连接之前释放了 DNA 末端。另一种断裂发生在非抗原受体基因位点上 20-600 bp 的脆弱区内,这种狭窄的脆弱区有一系列更复杂、更耐人寻味的机理因素。这些因素包括活化诱导脱氨酶(AID),它只作用于单链 DNA(ssDNA)区域。最近的研究提出了一个模型,涉及 AID 在新生 RNA 从 RNA 聚合酶中产生时与新生 RNA 的系链。这种机制可能与类开关重组(CSR)和体细胞超突变(SHM)有关,也与其他 DNA 酶有关。
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引用次数: 0
Dilation of ion selectivity filters in cation channels 阳离子通道中离子选择性过滤器的扩张。
IF 13.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-05-01 DOI: 10.1016/j.tibs.2024.02.004
Kate Huffer , Xiao-Feng Tan , Ana I. Fernández-Mariño , Surbhi Dhingra , Kenton J. Swartz

Ion channels establish the voltage gradient across cellular membranes by providing aqueous pathways for ions to selectively diffuse down their concentration gradients. The selectivity of any given channel for its favored ions has conventionally been viewed as a stable property, and in many cation channels, it is determined by an ion-selectivity filter within the external end of the ion-permeation pathway. In several instances, including voltage-activated K+ (Kv) channels, ATP-activated P2X receptor channels, and transient receptor potential (TRP) channels, the ion-permeation pathways have been proposed to dilate in response to persistent activation, dynamically altering ion permeation. Here, we discuss evidence for dynamic ion selectivity, examples where ion selectivity filters exhibit structural plasticity, and opportunities to fill gaps in our current understanding.

离子通道通过为离子提供沿着浓度梯度选择性扩散的水通道,在细胞膜上形成电压梯度。任何特定通道对其偏爱离子的选择性通常被视为一种稳定的特性,在许多阳离子通道中,它是由离子渗透途径外部端的离子选择性过滤器决定的。在一些情况下,包括电压激活的 K+ (Kv) 通道、ATP 激活的 P2X 受体通道和瞬时受体电位(TRP)通道,离子渗透途径被认为会随着持续激活而扩张,从而动态地改变离子渗透。在此,我们将讨论动态离子选择性的证据、离子选择性过滤器表现出结构可塑性的例子,以及填补我们目前认识空白的机会。
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引用次数: 0
Mitochondria in disease: changes in shapes and dynamics 疾病中的线粒体:形状和动态变化。
IF 13.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-04-01 DOI: 10.1016/j.tibs.2024.01.011
Brenita C. Jenkins , Kit Neikirk , Prasanna Katti , Steven M. Claypool , Annet Kirabo , Melanie R. McReynolds , Antentor Hinton Jr.

Mitochondrial structure often determines the function of these highly dynamic, multifunctional, eukaryotic organelles, which are essential for maintaining cellular health. The dynamic nature of mitochondria is apparent in descriptions of different mitochondrial shapes [e.g., donuts, megamitochondria (MGs), and nanotunnels] and crista dynamics. This review explores the significance of dynamic alterations in mitochondrial morphology and regulators of mitochondrial and cristae shape. We focus on studies across tissue types and also describe new microscopy techniques for detecting mitochondrial morphologies both in vivo and in vitro that can improve understanding of mitochondrial structure. We highlight the potential therapeutic benefits of regulating mitochondrial morphology and discuss prospective avenues to restore mitochondrial bioenergetics to manage diseases related to mitochondrial dysfunction.

线粒体的结构往往决定了这些高度动态、多功能真核细胞器的功能,而线粒体对维持细胞健康至关重要。线粒体的动态特性在不同线粒体形状(如甜甜圈、巨线粒体(MG)和纳米隧道)和嵴动态的描述中显而易见。本综述探讨了线粒体形态动态变化的意义以及线粒体和嵴形态的调节因素。我们将重点放在跨组织类型的研究上,并介绍了用于检测体内和体外线粒体形态的新显微镜技术,这些技术可提高对线粒体结构的认识。我们强调了调节线粒体形态的潜在治疗效果,并讨论了恢复线粒体生物能以控制线粒体功能障碍相关疾病的前景。
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引用次数: 0
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Trends in Biochemical Sciences
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