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Buoyancy regulation in insects. 昆虫的浮力调节
IF 5.3 2区 医学 Q1 PHYSIOLOGY Pub Date : 2024-09-25 DOI: 10.1152/physiol.00017.2024
Philip G D Matthews

Multiple insect lineages have successfully reinvaded the aquatic environment, evolving to complete either part or all of their life cycle submerged in water. While these insects vary in their reliance on atmospheric oxygen, with many having the ability to extract dissolved oxygen directly from the water, all retain an internal air-filled respiratory system, their tracheal system, due to their terrestrial origins. However, carrying air within their tracheal system, and even augmenting this volume with additional air bubbles carried on their body, dramatically increases their buoyancy which can make it challenging to remain submerged. But by manipulating this air volume a few aquatic insects can deliberately alter or regulate their position in the water column. Unlike cephalopods and teleost fish that control the volume of gas within their hydrostatic organs by either using osmosis to pull liquid from a rigid chamber or secreting oxygen at high pressure to inflate a flexible chamber, insects have evolved hydrostatic control mechanisms that rely either on the temporary stabilization of a compressible air-bubble volume using O2 unloaded from hemoglobin, or the mechanical expansion and contraction of a gas-filled volume with rigid, gas-permeable walls. The ability to increase their buoyancy while submerged separates aquatic insects from the buoyancy compensation achieved by other air-breathing aquatic animals which also use air within their respiratory systems to offset their submerged weight. The mechanisms they have evolved to achieve this are unique and provide new insights into the function and evolution of mechanochemical systems.

多个昆虫品系已经成功地重新进入水生环境,进化到可以在水中完成部分或全部生命周期。虽然这些昆虫对大气中氧气的依赖程度各不相同,许多昆虫能够直接从水中提取溶解氧,但由于它们的陆生起源,所有昆虫都保留了内部充满空气的呼吸系统--气管系统。然而,在气管系统中携带空气,甚至在身体上携带额外的气泡来增加空气量,会大大增加它们的浮力,这可能会使它们在水中保持沉默具有挑战性。但是,通过操纵这种气量,一些水生昆虫可以有意改变或调节它们在水体中的位置。头足类和远摄鱼类通过利用渗透作用从一个坚硬的腔体中抽取液体或分泌高压氧气使一个柔性腔体膨胀来控制其静水器官中的气体体积,而昆虫则不同,它们进化出了静水控制机制,这种机制要么依赖于利用从血红蛋白中释放的氧气暂时稳定可压缩的气泡体积,要么依赖于具有坚硬的透气壁的充满气体的体积的机械膨胀和收缩。水生昆虫在水下增加浮力的能力使它们与其他呼吸空气的水生动物所获得的浮力补偿区分开来,后者也是利用呼吸系统中的空气来抵消水下重量。它们为实现这一目标而进化出的机制是独一无二的,为机械化学系统的功能和进化提供了新的视角。
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引用次数: 0
ROLE OF RANKL SIGNALING IN BONE HOMEOSTASIS. rankl信号在骨平衡中的作用。
IF 5.3 2区 医学 Q1 PHYSIOLOGY Pub Date : 2024-09-10 DOI: 10.1152/physiol.00031.2024
Cristina Sobacchi, Ciro Menale, Laura Crisafulli, Francesca Ficara

RANKL and its cognate receptor RANK are crucial regulators of bone metabolism in physiological as well as in pathological conditions. Here we go through the works that unveiled the paramount role of this signaling pathway. We focus on the RANKL cytokine, whose alterations are responsible for rare and common bone diseases. We describe recent insights on the regulation of RANKL expression, which provide new hints for the pharmacological regulation of this molecule. Based on the multiple functions exerted by RANKL (within and outside the bone tissue), we advise caution regarding potential unintended consequences of its inhibition.

RANKL 及其同源受体 RANK 是生理和病理状态下骨代谢的关键调节因子。在此,我们将介绍揭示这一信号通路重要作用的研究成果。我们重点关注 RANKL 细胞因子,它的改变是罕见和常见骨病的罪魁祸首。我们描述了最近对 RANKL 表达调控的深入研究,这为该分子的药理调控提供了新的线索。基于 RANKL 的多种功能(在骨组织内外),我们建议谨慎对待抑制 RANKL 可能带来的意外后果。
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引用次数: 0
Beyond ATP: Metabolite networks as regulators of erythroid differentiation. 超越 ATP:作为红细胞分化调节器的代谢物网络
IF 5.3 2区 医学 Q1 PHYSIOLOGY Pub Date : 2024-09-03 DOI: 10.1152/physiol.00035.2024
Axel Joly, Arthur Schott, Ira Phadke, Pedro Gonzalez-Menendez, Sandrina Kinet, Naomi Taylor

Hematopoietic stem cells (HSCs) possess the capacity for self-renewal and the sustained production of all mature blood cell lineages. It has been well established that a metabolic rewiring controls the switch of HSCs from a self-renewal state to a more differentiated state but it is only recently that we have appreciated the importance of metabolic pathways in regulating the commitment of progenitors to distinct hematopoietic lineages. In the context of erythroid differentiation, an extensive network of metabolites - including amino acids, sugars, nucleotides, fatty acids, vitamins, and iron - is required for red blood cell (RBC) maturation. In this review, we will highlight the multi-faceted roles via which metabolites regulate physiological erythropoiesis as well as the effects of metabolic perturbations on erythroid lineage commitment and differentiation. Of note, the erythroid differentiation process is associated with an exceptional breadth of SLC metabolite transporter upregulation. Finally, we will discuss how recent research, revealing the critical impact of metabolic reprogramming in diseases of disordered and ineffective erythropoiesis, has created opportunities for the development of novel metabolic-centered therapeutic strategies.

造血干细胞(HSCs)具有自我更新和持续产生所有成熟血细胞系的能力。造血干细胞从自我更新状态向分化状态的转换是由新陈代谢线路控制的,这一点已得到公认,但直到最近,我们才认识到新陈代谢途径在调节祖细胞向不同造血系的承诺方面的重要性。在红细胞分化的过程中,红细胞(RBC)的成熟需要大量的代谢物,包括氨基酸、糖类、核苷酸、脂肪酸、维生素和铁。在这篇综述中,我们将重点介绍代谢物调节生理性红细胞生成的多方面作用,以及代谢紊乱对红细胞系的承诺和分化的影响。值得注意的是,红细胞分化过程与 SLC 代谢物转运体的广泛上调有关。最后,我们将讨论最近的研究如何揭示代谢重编程在红细胞生成障碍和无效疾病中的关键影响,从而为开发以代谢为中心的新型治疗策略创造机会。
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引用次数: 0
Mitochondrial Calcium Regulation of Cardiac Metabolism in Health and Disease. 线粒体钙对健康和疾病中心脏代谢的调节。
IF 5.3 2区 医学 Q1 PHYSIOLOGY Pub Date : 2024-09-01 Epub Date: 2024-05-07 DOI: 10.1152/physiol.00014.2024
Enrique Balderas, Sandra H J Lee, Neeraj K Rai, David M Mollinedo, Hannah E Duron, Dipayan Chaudhuri

Oxidative phosphorylation is regulated by mitochondrial calcium (Ca2+) in health and disease. In physiological states, Ca2+ enters via the mitochondrial Ca2+ uniporter and rapidly enhances NADH and ATP production. However, maintaining Ca2+ homeostasis is critical: insufficient Ca2+ impairs stress adaptation, and Ca2+ overload can trigger cell death. In this review, we delve into recent insights further defining the relationship between mitochondrial Ca2+ dynamics and oxidative phosphorylation. Our focus is on how such regulation affects cardiac function in health and disease, including heart failure, ischemia-reperfusion, arrhythmias, catecholaminergic polymorphic ventricular tachycardia, mitochondrial cardiomyopathies, Barth syndrome, and Friedreich's ataxia. Several themes emerge from recent data. First, mitochondrial Ca2+ regulation is critical for fuel substrate selection, metabolite import, and matching of ATP supply to demand. Second, mitochondrial Ca2+ regulates both the production and response to reactive oxygen species (ROS), and the balance between its pro- and antioxidant effects is key to how it contributes to physiological and pathological states. Third, Ca2+ exerts localized effects on the electron transport chain (ETC), not through traditional allosteric mechanisms but rather indirectly. These effects hinge on specific transporters, such as the uniporter or the Na+/Ca2+ exchanger, and may not be noticeable acutely, contributing differently to phenotypes depending on whether Ca2+ transporters are acutely or chronically modified. Perturbations in these novel relationships during disease states may either serve as compensatory mechanisms or exacerbate impairments in oxidative phosphorylation. Consequently, targeting mitochondrial Ca2+ holds promise as a therapeutic strategy for a variety of cardiac diseases characterized by contractile failure or arrhythmias.

在健康和疾病状态下,氧化磷酸化受线粒体钙(Ca2+)的调节。在生理状态下,Ca2+ 通过线粒体 Ca2+ 单通道进入线粒体,并迅速增强 NADH 和 ATP 的生成。然而,维持 Ca2+ 的平衡至关重要:Ca2+ 不足会影响应激适应,而 Ca2+ 过载则会引发细胞死亡。在这篇综述中,我们将深入探讨进一步明确线粒体 Ca2+ 动态与氧化磷酸化之间关系的最新见解。我们的重点是这种调节如何影响健康和疾病中的心脏功能,包括心力衰竭、缺血再灌注、心律失常、儿茶酚胺能多形性室性心动过速、线粒体心肌病、巴特综合征和弗里德里希共济失调。最近的数据提出了几个主题。首先,线粒体 Ca2+ 调节对燃料底物选择、代谢产物输入和 ATP 供需匹配至关重要。其次,线粒体 Ca2+ 调节活性氧(ROS)的产生和反应,其促氧化作用和抗氧化作用之间的平衡是线粒体 Ca2+ 如何促进生理和病理状态的关键。第三,Ca2+ 对电子传递链(ETC)产生局部效应,但不是通过传统的异构机制,而是间接的。这些影响取决于特定的转运体,如单向转运体或 Na+-Ca2+ 交换体,而且在急性期可能并不明显,表型的形成取决于 Ca2+ 转运体是急性改变还是慢性改变。在疾病状态下,这些新型关系的紊乱可能会成为一种补偿机制,也可能会加剧氧化磷酸化的损伤。因此,以线粒体 Ca2+ 为靶点有望成为以收缩功能衰竭或心律失常为特征的多种心脏疾病的治疗策略。
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引用次数: 0
Nrf2-Keap1 in Cardiovascular Disease: Which Is the Cart and Which the Horse? 心血管疾病中的 Nrf2-Keap1:哪个是车,哪个是马?
IF 5.3 2区 医学 Q1 PHYSIOLOGY Pub Date : 2024-09-01 Epub Date: 2024-04-30 DOI: 10.1152/physiol.00015.2024
Neha Dhyani, Changhai Tian, Lie Gao, Tara L Rudebush, Irving H Zucker

High levels of oxidant stress in the form of reactive oxidant species are prevalent in the circulation and tissues in various types of cardiovascular disease including heart failure, hypertension, peripheral arterial disease, and stroke. Here we review the role of nuclear factor erythroid 2-related factor 2 (Nrf2), an important and widespread antioxidant and anti-inflammatory transcription factor that may contribute to the pathogenesis and maintenance of cardiovascular diseases. We review studies showing that downregulation of Nrf2 exacerbates heart failure, hypertension, and autonomic function. Finally, we discuss the potential for using Nrf2 modulation as a therapeutic strategy for cardiovascular diseases and autonomic dysfunction.

在各种类型的心血管疾病(包括心力衰竭、高血压、外周动脉疾病和中风)中,血液循环和组织中普遍存在以活性氧化物(ROS)形式存在的高水平氧化应激。核因子红细胞 2 相关因子 2(Nrf2)是一种重要而广泛的抗氧化和抗炎转录因子,可能有助于心血管疾病的发病和维持。我们回顾的研究表明,Nrf2 的下调会加剧心力衰竭、高血压和自律神经功能。最后,我们讨论了使用 Nrf2 调节作为心血管疾病和自主神经功能障碍治疗策略的潜力。
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引用次数: 0
New Insights into IGF-1 Signaling in the Heart. IGF-1 信号在心脏中的新发现。
IF 5.3 2区 医学 Q1 PHYSIOLOGY Pub Date : 2024-09-01 Epub Date: 2024-05-07 DOI: 10.1152/physiol.00003.2024
Wang-Soo Lee, E Dale Abel, Jaetaek Kim

Insulin-like growth factor-1 (IGF-1) signaling has multiple physiological roles in cellular growth, metabolism, and aging. Myocardial hypertrophy, cell death, senescence, fibrosis, and electrical remodeling are hallmarks of various heart diseases and contribute to the progression of heart failure. This review highlights the critical role of IGF-1 and its cognate receptor in cardiac hypertrophy, aging, and remodeling.

胰岛素样生长因子(IGF)-1 信号在细胞生长、新陈代谢和衰老过程中发挥着多种生理作用。心肌肥厚、细胞死亡、衰老、纤维化和电重塑是各种心脏病的标志,也是心力衰竭的诱因。本综述强调了 IGF-1 及其同源受体在心肌肥厚、衰老和重塑中的关键作用。
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引用次数: 0
ECM Microenvironment in Vascular Homeostasis: New Targets for Atherosclerosis. 血管稳态中的 ECM 微环境:动脉粥样硬化的新目标。
IF 5.3 2区 医学 Q1 PHYSIOLOGY Pub Date : 2024-09-01 DOI: 10.1152/physiol.00028.2023
Lu Zhang, Qianqian Feng, Wei Kong

Alterations in vascular extracellular matrix (ECM) components, interactions, and mechanical properties influence both the formation and stability of atherosclerotic plaques. This review discusses the contribution of the ECM microenvironment in vascular homeostasis and remodeling in atherosclerosis, highlighting Cartilage oligomeric matrix protein (COMP) and its degrading enzyme ADAMTS7 as examples, and proposes potential avenues for future research aimed at identifying novel therapeutic targets for atherosclerosis based on the ECM microenvironment.

血管细胞外基质(ECM)成分、相互作用和机械特性的改变会影响动脉粥样硬化斑块的形成和稳定性。本综述以软骨低聚基质蛋白(COMP)及其降解酶 ADAMTS7 为例,讨论了 ECM 微环境在动脉粥样硬化的血管稳态和重塑过程中的作用,并提出了未来研究的潜在途径,旨在根据 ECM 微环境确定动脉粥样硬化的新型治疗靶点。
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引用次数: 0
Physiology in Perspective. 透视生理学
IF 5.3 2区 医学 Q1 PHYSIOLOGY Pub Date : 2024-09-01 DOI: 10.1152/physiol.00033.2024
Nikki Forrester
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引用次数: 0
Factors contributing to heat tolerance in humans & experimental models. 导致人类和实验模型耐热性的因素。
IF 5.3 2区 医学 Q1 PHYSIOLOGY Pub Date : 2024-08-27 DOI: 10.1152/physiol.00028.2024
Orlando Laitano, Kentaro Oki, Nisha Charkoudian

Understanding physiological mechanisms of tolerance to heat exposure, and potential ways to improve such tolerance, is increasingly important in the context of ongoing climate change. We discuss the concept of heat tolerance in humans and experimental models (primarily rodents), including intracellular mechanisms and improvements in tolerance with heat acclimation.

在当前气候变化的背景下,了解耐受热暴露的生理机制以及提高这种耐受性的潜在方法变得越来越重要。我们将讨论人类和实验模型(主要是啮齿类动物)耐热性的概念,包括细胞内机制和耐热性的改善。
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引用次数: 0
Harnessing Deep Learning Methods for Voltage-Gated Ion Channel Drug Discovery. 利用深度学习方法发现电压门控离子通道药物。
IF 5.3 2区 医学 Q1 PHYSIOLOGY Pub Date : 2024-08-27 DOI: 10.1152/physiol.00029.2024
Diego Lopez Mateos, Brandon John Harris, Adriana Hernández González, Kush Narang, Vladimir Yarov-Yarovoy

Voltage-gated ion channels (VGICs) are pivotal in regulating electrical activity in excitable cells and are critical pharmaceutical targets for treating many diseases including cardiac arrhythmia and neuropathic pain. Despite their significance, challenges such as achieving target selectivity persist in VGIC drug development. Recent progress in deep learning, particularly diffusion models, has enabled the computational design of protein binders for any clinically relevant protein based solely on its structure. These developments coincide with a surge in experimental structural data for VGICs, providing a rich foundation for computational design efforts. This review explores the recent advancements in computational protein design using deep learning and diffusion methods, focusing on their application in designing protein binders to modulate VGIC activity. We discuss the potential use of these methods to computationally design protein binders targeting different regions of VGICs, including the pore domain, voltage-sensing domains, and interface with auxiliary subunits. We provide a comprehensive overview of the different design scenarios, discuss key structural considerations, and address the practical challenges in developing VGIC-targeting protein binders. By exploring these innovative computational methods, we aim to provide a framework for developing novel strategies that could significantly advance VGIC pharmacology and lead to the discovery of effective and safe therapeutics.

电压门控离子通道(VGIC)在调节可兴奋细胞的电活动中起着关键作用,是治疗心律失常和神经性疼痛等多种疾病的关键药物靶点。尽管其意义重大,但在 VGIC 药物开发过程中,实现目标选择性等挑战依然存在。深度学习(尤其是扩散模型)领域的最新进展使人们能够完全根据临床相关蛋白质的结构,为其计算设计蛋白质结合剂。这些进展与 VGIC 实验结构数据的激增不谋而合,为计算设计工作提供了丰富的基础。本综述探讨了利用深度学习和扩散方法进行计算蛋白质设计的最新进展,重点是这些方法在设计调节 VGIC 活性的蛋白质结合剂中的应用。我们讨论了这些方法在计算设计针对 VGIC 不同区域(包括孔结构域、电压感应结构域以及与辅助亚基的接口)的蛋白质结合剂方面的潜在用途。我们全面概述了不同的设计方案,讨论了关键的结构考虑因素,并探讨了开发 VGIC 靶向蛋白结合剂的实际挑战。通过探索这些创新的计算方法,我们旨在为开发新的策略提供一个框架,这些策略将大大推动 VGIC 药理学的发展,并促进有效、安全疗法的发现。
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引用次数: 0
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Physiology
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