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A Lipid-Raft Theory of Alzheimer's Disease. 阿尔茨海默病的脂质筏理论
IF 12.1 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-30 DOI: 10.1146/annurev-biochem-052024-115455
Ari Rappoport

I present a theory of Alzheimer's disease (AD) that explains its symptoms, pathology, and risk factors. To do this, I introduce a new theory of brain plasticity that elucidates the physiological roles of AD-related agents. New events generate synaptic and branching candidates competing for long-term enhancement. Competition resolution crucially depends on the formation of membrane lipid rafts, which requires astrocyte-produced cholesterol. Sporadic AD is caused by impaired formation of plasma-membrane lipid rafts, preventing the conversion of short- to long-term memory and yielding excessive tau phosphorylation, intracellular cholesterol accumulation, synaptic dysfunction, and neurodegeneration. Amyloid β (Aβ) production is promoted by cholesterol during the switch to competition resolution, and cholesterol accumulation stimulates chronic Aβ production, secretion, and aggregation. The theory addresses all of the major established facts known about the disease and is supported by strong evidence.

我提出了阿尔茨海默病(AD)的理论,解释了它的症状、病理和风险因素。为此,我提出了一种新的大脑可塑性理论,阐明了与阿尔茨海默病有关的物质的生理作用。新事件产生的突触和分支候选物在竞争中获得长期增强。竞争的解决关键取决于膜脂筏的形成,这需要星形胶质细胞产生的胆固醇。散发性注意力缺失症是由血浆膜脂质筏的形成受损引起的,阻碍了短期记忆向长期记忆的转换,并导致过度的 tau 磷酸化、细胞内胆固醇积聚、突触功能障碍和神经变性。淀粉样蛋白 β(Aβ)的产生在向竞争解析转换的过程中受到胆固醇的促进,胆固醇的积累会刺激 Aβ 的长期产生、分泌和聚集。该理论涉及有关该疾病的所有已知主要事实,并得到有力证据的支持。
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引用次数: 0
Inositol Pyrophosphates as Versatile Metabolic Messengers. 作为多功能代谢信使的肌醇焦磷酸盐
IF 12.1 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 DOI: 10.1146/annurev-biochem-030222-121901
Latika Nagpal, Sining He, Feng Rao, Solomon H Snyder

Discovered in 1993, inositol pyrophosphates are evolutionarily conserved signaling metabolites whose versatile modes of action are being increasingly appreciated. These include their emerging roles as energy regulators, phosphodonors, steric/allosteric regulators, and G protein-coupled receptor messengers. Through studying enzymes that metabolize inositol pyrophosphates, progress has also been made in elucidating the various cellular and physiological functions of these pyrophosphate-containing, energetic molecules. The two main forms of inositol pyrophosphates, 5-IP7 and IP8, synthesized respectively by inositol-hexakisphosphate kinases (IP6Ks) and diphosphoinositol pentakisphosphate kinases (PPIP5Ks), regulate phosphate homeostasis, ATP synthesis, and several other metabolic processes ranging from insulin secretion to cellular energy utilization. Here, we review the current understanding of the catalytic and regulatory mechanisms of IP6Ks and PPIP5Ks, as well as their counteracting phosphatases. We also highlight the genetic and cellular evidence implicating inositol pyrophosphates as essential mediators of mammalian metabolic homeostasis.

肌醇焦磷酸盐于 1993 年被发现,是一种进化保守的信号代谢物,其多种作用模式正日益受到重视。这些作用包括作为能量调节剂、磷定子、立体/立体调节剂和 G 蛋白偶联受体信使的新角色。通过研究代谢肌醇焦磷酸盐的酶,在阐明这些含焦磷酸盐的高能分子的各种细胞和生理功能方面也取得了进展。肌醇焦磷酸盐的两种主要形式--5-IP7 和 IP8--分别由肌醇六磷酸激酶(IP6Ks)和二磷酸肌醇五磷酸激酶(PPIP5Ks)合成,它们调节磷酸盐平衡、ATP 合成以及从胰岛素分泌到细胞能量利用等多个代谢过程。在此,我们回顾了目前对 IP6Ks 和 PPIP5Ks 及其抗衡磷酸酶的催化和调控机制的理解。我们还重点介绍了肌醇焦磷酸盐作为哺乳动物代谢稳态重要介质的遗传和细胞证据。
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引用次数: 0
The Nicotinic Acetylcholine Receptor and Its Pentameric Homologs: Toward an Allosteric Mechanism of Signal Transduction at the Atomic Level. 烟碱乙酰胆碱受体及其五聚体同源物:在原子水平上实现信号转导的异构机制。
IF 12.1 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-07-02 DOI: 10.1146/annurev-biochem-030122-033116
Marco Cecchini, Pierre-Jean Corringer, Jean-Pierre Changeux

The nicotinic acetylcholine receptor has served, since its biochemical identification in the 1970s, as a model of an allosteric ligand-gated ion channel mediating signal transition at the synapse. In recent years, the application of X-ray crystallography and high-resolution cryo-electron microscopy, together with molecular dynamic simulations of nicotinic receptors and homologs, have opened a new era in the understanding of channel gating by the neurotransmitter. They reveal, at atomic resolution, the diversity and flexibility of the multiple ligand-binding sites, including recently discovered allosteric modulatory sites distinct from the neurotransmitter orthosteric site, and the conformational dynamics of the activation process as a molecular switch linking these multiple sites. The model emerging from these studies paves the way for a new pharmacology based, first, upon the occurrence of an original mode of indirect allosteric modulation, distinct from a steric competition for a single and rigid binding site, and second, the design of drugs that specifically interact with privileged conformations of the receptor such as agonists, antagonists, and desensitizers. Research on nicotinic receptors is still at the forefront of understanding the mode of action of drugs on the nervous system.

烟碱乙酰胆碱受体自 20 世纪 70 年代被生化鉴定以来,一直是突触中介导信号转换的异位配体门控离子通道的模型。近年来,X 射线晶体学和高分辨率冷冻电镜技术的应用,以及对烟碱受体和同源物的分子动力学模拟,为人们了解神经递质的通道门控开辟了新纪元。它们以原子分辨率揭示了多个配体结合位点的多样性和灵活性,包括最近发现的有别于神经递质正交位点的异位调节位点,以及作为连接这些多个位点的分子开关的激活过程的构象动力学。这些研究得出的模型为建立新的药理学铺平了道路,首先,这种间接异位调节模式是独创的,有别于对单一刚性结合位点的立体竞争;其次,可以设计出与受体的特殊构象发生特异性相互作用的药物,如激动剂、拮抗剂和脱敏剂。在了解药物对神经系统的作用模式方面,对烟碱受体的研究仍处于前沿。预计《生物化学年刊》第 93 卷的最终在线出版日期为 2024 年 6 月。修订后的预计日期请参见 http://www.annualreviews.org/page/journal/pubdates。
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引用次数: 0
Signaling from RAS to RAF: The Molecules and Their Mechanisms. 从 RAS 到 RAF 的信号传递:分子及其机制。
IF 12.1 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-07-02 DOI: 10.1146/annurev-biochem-052521-040754
Hyesung Jeon, Emre Tkacik, Michael J Eck

RAF family protein kinases are a key node in the RAS/RAF/MAP kinase pathway, the signaling cascade that controls cellular proliferation, differentiation, and survival in response to engagement of growth factor receptors on the cell surface. Over the past few years, structural and biochemical studies have provided new understanding of RAF autoregulation, RAF activation by RAS and the SHOC2 phosphatase complex, and RAF engagement with HSP90-CDC37 chaperone complexes. These studies have important implications for pharmacologic targeting of the pathway. They reveal RAF in distinct regulatory states and show that the functional RAF switch is an integrated complex of RAF with its substrate (MEK) and a 14-3-3 dimer. Here we review these advances, placing them in the context of decades of investigation of RAF regulation. We explore the insights they provide into aberrant activation of the pathway in cancer and RASopathies (developmental syndromes caused by germline mutations in components of the pathway).

RAF家族蛋白激酶是RAS/RAF/MAP激酶通路中的一个关键节点,RAS/RAF/MAP激酶通路是控制细胞增殖、分化和存活的信号级联,可对细胞表面的生长因子受体的参与做出反应。在过去几年中,结构和生化研究使人们对 RAF 的自动调节、RAS 和 SHOC2 磷酸酶复合物对 RAF 的激活以及 RAF 与 HSP90-CDC37 合子复合物的接合有了新的认识。这些研究对该通路的药物靶向具有重要意义。它们揭示了处于不同调控状态的 RAF,并表明 RAF 的功能开关是 RAF 与其底物(MEK)和 14-3-3 二聚体的综合复合物。在此,我们回顾了这些研究进展,并将其置于数十年来对 RAF 调控的研究背景中。我们将探讨它们为癌症和 RAS 病(由该通路成分的种系突变引起的发育综合征)中该通路的异常激活提供的启示。预计《生物化学年刊》第 93 卷的最终在线出版日期为 2024 年 6 月。修订后的预计日期请参见 http://www.annualreviews.org/page/journal/pubdates。
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引用次数: 0
A Life of Translocations. 易位的一生。
IF 12.1 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-07-02 DOI: 10.1146/annurev-biochem-030122-040444
Tom A Rapoport

Writing a career retrospective for this prestigious series is a huge challenge. Is my story really of that much interest? One thing that is different about my life in science is the heavy influence of the turmoil of the past century. Born in the US, raised in East Germany, and returning to the US relatively late in life, I experienced research under both suboptimal and privileged conditions. My scientific story, like the political winds that blew me from one continent to the next, involved shifts into different fields. For advice to young scientists, I would suggest: Don't be afraid to start something new, it pays to be persistent, and science is a passion. In addition to telling my own story, this article also provides the opportunity to express my gratitude to my trainees and colleagues and to convey my conviction that we have the best job on earth.

为这个著名的系列节目撰写职业回顾是一个巨大的挑战。我的故事真的那么有趣吗?在我的科学生涯中,有一件事是不同的,那就是上个世纪的动荡对我的影响很大。我出生在美国,在东德长大,很晚才回到美国,经历了次优和特权条件下的研究。我的科学经历,就像把我从一个大陆吹到另一个大陆的政治之风,涉及到不同领域的转变。对于年轻科学家的建议,我建议:不要害怕开始新事物,坚持不懈是值得的,科学是一种激情。除了讲述我自己的故事外,这篇文章还提供了一个机会来表达我对我的学员和同事的感激之情,并传达我的信念:我们拥有世界上最好的工作。预计《生物化学年度评论》第93卷的最终在线出版日期是2024年6月。修订后的估计数请参阅http://www.annualreviews.org/page/journal/pubdates。
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引用次数: 0
Eukaryotic Ribosome Assembly. 真核核糖体组装。
IF 12.1 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-07-02 DOI: 10.1146/annurev-biochem-030222-113611
Arnaud Vanden Broeck, Sebastian Klinge

During the last ten years, developments in cryo-electron microscopy have transformed our understanding of eukaryotic ribosome assembly. As a result, the field has advanced from a list of the vast array of ribosome assembly factors toward an emerging molecular movie in which individual frames are represented by structures of stable ribosome assembly intermediates with complementary biochemical and genetic data. In this review, we discuss the mechanisms driving the assembly of yeast and human small and large ribosomal subunits. A particular emphasis is placed on the most recent findings that illustrate key concepts of ribosome assembly, such as folding of preribosomal RNA, the enforced chronology of assembly, enzyme-mediated irreversible transitions, and proofreading of preribosomal particles.

过去十年间,冷冻电镜技术的发展改变了我们对真核核糖体组装的认识。因此,该领域已经从大量核糖体组装因子的列表向新兴的分子电影迈进,其中单个框架由稳定的核糖体组装中间体结构和补充的生化和遗传数据来表示。在这篇综述中,我们讨论了驱动酵母和人类大小核糖体亚基组装的机制。我们特别强调说明核糖体组装关键概念的最新发现,如前核糖体 RNA 的折叠、组装的强制时序、酶介导的不可逆转换以及前核糖体颗粒的校对。
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引用次数: 0
Lipid Quality Control and Ferroptosis: From Concept to Mechanism. 脂质控制与铁下垂:从概念到机制。
IF 12.1 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-07-02 DOI: 10.1146/annurev-biochem-052521-033527
Zhipeng Li, Mike Lange, Scott J Dixon, James A Olzmann

Cellular quality control systems sense and mediate homeostatic responses to prevent the buildup of aberrant macromolecules, which arise from errors during biosynthesis, damage by environmental insults, or imbalances in enzymatic and metabolic activity. Lipids are structurally diverse macromolecules that have many important cellular functions, ranging from structural roles in membranes to functions as signaling and energy-storage molecules. As with other macromolecules, lipids can be damaged (e.g., oxidized), and cells require quality control systems to ensure that nonfunctional and potentially toxic lipids do not accumulate. Ferroptosis is a form of cell death that results from the failure of lipid quality control and the consequent accumulation of oxidatively damaged phospholipids. In this review, we describe a framework for lipid quality control, using ferroptosis as an illustrative example to highlight concepts related to lipid damage, membrane remodeling, and suppression or detoxification of lipid damage via preemptive and damage-repair lipid quality control pathways.

细胞质量控制系统感知和介导稳态反应,以防止异常大分子的积累,这些异常大分子是由生物合成过程中的错误、环境损害或酶和代谢活动的不平衡引起的。脂质是结构多样的大分子,具有许多重要的细胞功能,从膜的结构作用到信号和能量储存分子。与其他大分子一样,脂质会被破坏(如氧化),细胞需要质量控制系统来确保无功能和潜在毒性的脂质不会积聚。铁死亡是一种细胞死亡形式,由脂质控制失败和氧化损伤磷脂的积累引起。在这篇综述中,我们描述了一个脂质控制的框架,以铁下沉为例,强调与脂质损伤、膜重塑以及通过先发制人和损伤修复脂质控制途径抑制或解毒脂质损伤相关的概念。预计《生物化学年度评论》第93卷的最终在线出版日期是2024年6月。修订后的估计数请参阅http://www.annualreviews.org/page/journal/pubdates。
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引用次数: 0
Racial Stress, Racial Trauma, and Evidence-Based Strategies for Coping and Empowerment. 种族压力、种族创伤和以证据为基础的应对和赋权策略。
IF 12.1 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-01 Epub Date: 2024-07-02 DOI: 10.1146/annurev-clinpsy-081122-020235
Samantha C Holmes, Manzar Zare, Angela M Haeny, Monnica T Williams

Racial stress and racial trauma refer to psychological, physiological, and behavioral responses to race-based threats and discriminatory experiences. This article reviews the evidence base regarding techniques for coping with racial stress and trauma. These techniques include self-care, self-compassion, social support, mindfulness, cognitive restructuring, cognitive defusion, identity-affirming practices and development of racial/ethnic identity, expressive writing, social action and activism, and psychedelics. These strategies have shown the potential to mitigate psychological symptoms and foster a sense of empowerment among individuals affected by racial stress and trauma. While the ultimate goal should undoubtedly be to address the root cause of racism, it is imperative to acknowledge that until then, implementing these strategies can effectively provide much-needed support for individuals affected by racism.

种族压力和种族创伤是指对种族威胁和歧视经历的心理、生理和行为反应。本文回顾了应对种族压力和创伤技巧的证据基础。这些技巧包括自我保健、自我同情、社会支持、正念、认知重组、认知消解、身份确认实践和种族/民族身份的发展、表达性写作、社会行动和激进主义以及迷幻剂。这些策略已经显示出缓解受种族压力和创伤影响的个人的心理症状和培养他们的自强意识的潜力。虽然最终目标无疑应该是解决种族主义的根源,但必须承认,在此之前,实施这些策略可以有效地为受种族主义影响的个人提供急需的支持。临床心理学年度评论》第20卷的最终在线出版日期预计为2024年5月。有关修订后的预计日期,请参阅 http://www.annualreviews.org/page/journal/pubdates。
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引用次数: 0
Impact of Acute Alcohol Consumption on Sexuality: A Look at Psychological Mechanisms. 急性饮酒对性行为的影响:心理机制研究
IF 12.1 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-01 Epub Date: 2024-07-02 DOI: 10.1146/annurev-clinpsy-080921-075423
William H George, Jessica A Blayney, Kelly Cue Davis

Alcohol's link with sexuality is long-standing and prominent. While research continues to document robust associations between drinking and sexual behavior, scientific attention now centers primarily on evaluating mechanisms and attendant theoretical frameworks to advance our understanding of how alcohol exerts a causal impact. We describe four domains with reliable evidence of alcohol effects: sexualized social perceptions, sexual arousal, sexual risk taking, and sexual assault. We consider three contextual frames: distal factors associated with encountering opportunities for alcohol-involved sex, proximal factors associated with alcohol's acute effects, and distal-proximal interactions. We then examine the empirical support for mechanisms embedded within four theoretical frameworks: alcohol disinhibition, alcohol expectancy, alcohol myopia, and emotion regulation. Support for disinhibition mechanisms is evident with sexual arousal only. Expectancy and myopia mechanisms enjoy support across domains and make up bases for integrative expectancy-myopia causal explanations. Emotion regulation mechanisms evidence preliminary support in risk taking and sexual assault. Implications and future directions are considered.

酒精与性行为的联系由来已久,而且十分突出。尽管研究继续记录了饮酒与性行为之间的紧密联系,但现在的注意力主要集中在评估机制和相应的理论框架上,以促进我们对酒精如何产生因果影响的理解。我们描述了有可靠证据表明酒精影响的四个领域:性社会认知、性唤起、性冒险和性侵犯。我们考虑了三个背景框架:与遭遇酒精性行为机会相关的远端因素、与酒精的急性效应相关的近端因素,以及远端与近端之间的相互作用。然后,我们研究了四种理论框架下的机制的实证支持:酒精抑制、酒精预期、酒精近视和情绪调节。仅在性唤起方面,对抑制机制的支持是显而易见的。期望和近视机制在各个领域都得到了支持,并构成了期望-近视综合因果解释的基础。情绪调节机制在风险承担和性侵犯中得到初步支持。研究还考虑了影响和未来发展方向。临床心理学年度评论》第 20 卷的最终在线出版日期预计为 2024 年 5 月。修订后的预计日期请参见 http://www.annualreviews.org/page/journal/pubdates。
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引用次数: 0
The Scientific Basis for the Regulation of Flavors in Tobacco Products. 烟草制品中香料监管的科学依据》。
IF 12.1 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-01 Epub Date: 2024-07-02 DOI: 10.1146/annurev-clinpsy-080921-075624
Krysten W Bold, Grace Kong, Stephanie S O'Malley

Effective tobacco policies are important for reducing the harm of tobacco use and can have a broad impact at the population level. This review provides an overview of how clinical science can inform tobacco policies with a focus on policies related to flavored tobacco products, using menthol cigarettes as an illustrative example. Specifically, this review summarizes the role of flavors in tobacco use and the history of regulation of flavored tobacco products by the US Food and Drug Administration (FDA), provides an overview of clinical research methods used to contribute to the scientific evidence to inform FDA tobacco policies, discusses key findings related to menthol tobacco products using these methods, and proposes future directions for clinical research. As the tobacco marketplace continues to evolve with new products and flavor chemicals, ongoing clinical science will be essential for establishing evidence-based policies to protect public health and reduce tobacco-related health disparities.

有效的烟草政策对于减少烟草使用的危害非常重要,并能在人群层面产生广泛影响。本综述概述了临床科学如何为烟草政策提供依据,并以薄荷卷烟为例重点介绍了与香料烟草制品相关的政策。具体而言,本综述概述了香料在烟草使用中的作用以及美国食品药品管理局(FDA)对香料烟草制品的监管历史,概述了用于为FDA烟草政策提供科学依据的临床研究方法,讨论了使用这些方法对薄荷烟草制品进行研究的主要发现,并提出了临床研究的未来方向。随着烟草市场不断出现新产品和风味化学品,持续的临床科学研究对于制定循证政策以保护公众健康和减少烟草相关的健康差异至关重要。临床心理学年度综述》第 20 卷的最终在线出版日期预计为 2024 年 5 月。修订后的预计日期请参见 http://www.annualreviews.org/page/journal/pubdates。
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引用次数: 0
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Annual review of biochemistry
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