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Reprogramming of fibroblasts into cancer-associated fibroblasts via IGF2-mediated autophagy promotes metastasis of lung cancer cells 通过 IGF2 介导的自噬作用将成纤维细胞重编程为癌症相关成纤维细胞，促进肺癌细胞的转移

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience

Pub Date : 2024-10-28 DOI: 10.1016/j.isci.2024.111269

Limin Cao , Bingbing Li , Sijia Zheng , Qicheng Zhang , Yongmei Qian , Yinghui Ren , Huimin Wang , Min Wang , Xiang Wu , Jiayi Zhang , Ke Xu

Cancer-associated fibroblasts (CAFs) are major component of stromal cells. Growing evidence suggests that CAFs promote tumor growth and metastasis; however, the reprogramming of normal fibroblasts (NFs) into CAFs by tumor cells still remains largely unknown. In this study, we found that non-small cell lung cancer (NSCLC) cells activated NFs into CAFs via autophagy induction. Insulin-like growth factor 2 (IGF2) secreted by NSCLC cells mediated NSCLC cells’ effect on autophagy induction and CAFs activation. Importantly, the activated CAFs promoted NSCLC cells growth, migration, and invasion. Further study showed that the activated CAFs facilitated NSCLC cells invasion via promoting epithelial-mesenchymal transition (EMT) process, upregulating metastasis-related genes, releasing CXCL12, and activating its downstream AKT serine/threonine kinase 1 (AKT)/ nuclear factor κB (NF-κB) signaling pathway. These findings revealed that IGF2-mediated autophagy plays a critical role in CAFs activation and suggested the IGF2-autophagy cascade in fibroblasts could be a potential target for lung cancer therapy.

癌症相关成纤维细胞（CAFs）是基质细胞的主要组成部分。越来越多的证据表明，CAFs 可促进肿瘤生长和转移；然而，肿瘤细胞将正常成纤维细胞（NFs）重编程为 CAFs 的过程在很大程度上仍不为人知。在这项研究中，我们发现非小细胞肺癌（NSCLC）细胞通过自噬诱导将 NFs 活化为 CAFs。NSCLC细胞分泌的胰岛素样生长因子2（IGF2）介导了NSCLC细胞对自噬诱导和CAFs活化的影响。重要的是，活化的CAFs促进了NSCLC细胞的生长、迁移和侵袭。进一步的研究表明，活化的CAFs通过促进上皮-间质转化（EMT）过程、上调转移相关基因、释放CXCL12以及激活其下游的AKT丝氨酸/苏氨酸激酶1（AKT）/核因子κB（NF-κB）信号通路来促进NSCLC细胞的侵袭。这些发现揭示了IGF2介导的自噬在CAFs活化中起着关键作用，并表明成纤维细胞中的IGF2自噬级联可能是肺癌治疗的潜在靶点。

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引用次数: 0

Anti-disturbance control of CPG bionic reflection in pneumatic muscle actuator 气动肌肉推杆中 CPG 仿生反射的抗干扰控制

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience

Pub Date : 2024-10-28 DOI: 10.1016/j.isci.2024.111264

Lina Wang , Zeling Chen , Xiaofeng Wang , Binrui Wang

Addressing the joint control problem of pneumatic muscle-driven robots, this study aims to design a bionic reflex mechanism to enhance the robots’ adaptive capacity to various disturbances. Based on the biological reflex mechanism, we developed a spindle reflex and deep tendon reflex control system based on CPG (central pattern generator) to mitigate the sudden impact on the hip joint and the continuous blocking force on the knee joint, respectively. The spindle reflex controller incorporates the fast response of sliding mode control to effectively minimize the trajectory deviation of the hip joint under impact disturbances. The deep tendon reflex controller integrates RBF neural network adaptive control and the Tegotae framework to suppress excessive tension in the knee joint and augment the system’s adaptability to the blocking force disturbances. The experimental results confirm that the two reflex mechanisms significantly enhance the robustness and flexibility of the pneumatic muscle-driven robot in motion.

针对气动肌肉驱动机器人的关节控制问题，本研究旨在设计一种仿生反射机制，以增强机器人对各种干扰的适应能力。在生物反射机制的基础上，我们开发了基于中央模式发生器（CPG）的主轴反射和深腱反射控制系统，以分别减轻对髋关节的突然冲击和对膝关节的持续阻挡力。主轴反射控制器结合了滑动模式控制的快速响应特性，可有效减少髋关节在冲击干扰下的轨迹偏差。深筋腱反射控制器整合了 RBF 神经网络自适应控制和 Tegotae 框架，以抑制膝关节的过度张力，增强系统对阻挡力干扰的适应性。实验结果证实，这两种反射机制显著增强了气动肌肉驱动机器人在运动中的鲁棒性和灵活性。

引用次数: 0

Dietary caloric restriction protects experimental autoimmune uveitis by regulating Teff/Treg balance 饮食热量限制通过调节Teff/Treg平衡保护实验性自身免疫性葡萄膜炎

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience

Pub Date : 2024-10-28 DOI: 10.1016/j.isci.2024.111279

Zhaohuai Li , Runping Duan , Qi Jiang , Jiaying Liu , Jialing Chen , Loujing Jiang , Tianfu Wang , He Li , Yihan Zhang , Xuening Peng , Zhaohao Huang , Lei Zhu , Wenjun Zou , Ying Lin , Wenru Su

Uveitis, an autoimmune disease, often leads to blindness. CD4⁺ T cells, including regulatory T cells (Tregs) and effector T cells (Th1 and Th17), play a critical role in its pathogenesis. Caloric restriction (CR) has been shown to alleviate autoimmune diseases. However, careful characterization of the impact of CR on experimental autoimmune uveitis (EAU) is poorly understood. This study used single-cell RNA sequencing to analyze cervical draining lymph nodes in mice under ad libitum (AL) and CR diets, with or without EAU. CR increased Tregs, altered immune cell metabolism, reduced EAU symptoms, and downregulated inflammatory and glycolysis genes. Flow cytometry confirmed CR’s inhibitory effect on Th1 and Th17 proliferation and its promotion of Treg proliferation. CR also balanced CD4⁺ T cells by inhibiting the PI3K/AKT/c-Myc pathway and reducing GM-CSF in Th17 cells. These findings suggest CR as a potential therapeutic strategy for autoimmune diseases.

葡萄膜炎是一种自身免疫性疾病，通常会导致失明。CD4+ T细胞，包括调节性T细胞（Tregs）和效应T细胞（Th1和Th17），在其发病机制中起着至关重要的作用。热量限制（CR）已被证明可以缓解自身免疫性疾病。然而，人们对热量限制对实验性自身免疫性葡萄膜炎（EAU）的影响还知之甚少。本研究使用单细胞 RNA 测序分析了小鼠在自由饮食（AL）和 CR 饮食条件下，有或没有 EAU 的颈部引流淋巴结。CR增加了Tregs，改变了免疫细胞代谢，减轻了EAU症状，并下调了炎症和糖酵解基因。流式细胞术证实了CR对Th1和Th17增殖的抑制作用以及对Treg增殖的促进作用。CR 还通过抑制 PI3K/AKT/c-Myc 通路和减少 Th17 细胞中的 GM-CSF 来平衡 CD4+ T 细胞。这些发现表明，CR 是治疗自身免疫性疾病的一种潜在策略。

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引用次数: 0

The first interneuron of the mouse visual system is tailored to the natural environment through morphology and electrical coupling 小鼠视觉系统的第一个中间神经元通过形态和电耦合适应自然环境

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience

Pub Date : 2024-10-28 DOI: 10.1016/j.isci.2024.111276

Matteo Spinelli , Alejandra Acevedo Harnecker , Christoph T. Block , Lucia Lindenthal , Fabian Schuhmann , Martin Greschner , Ulrike Janssen-Bienhold , Karin Dedek , Christian Puller

The topographic complexity of the mouse retina has long been underestimated. However, functional gradients exist, which reflect the non-uniform statistics of the visual environment. Horizontal cells are the first visual interneurons that shape the receptive fields of down-stream neurons. We asked whether regional specializations are present in terms of horizontal cell density distributions, morphological properties, localization of gap junction proteins, and the spatial extent of electrical coupling. These key features were asymmetrically organized along the dorsoventral axis. Dorsal cells were less densely distributed, had larger dendritic trees, and electrical coupling was more extensive than in ventral cells. The steepest change occurred at the visual horizon. Our results show that the cellular and synaptic organization of the mouse visual system are adapted to the visual environment at the earliest possible level and that horizontal cells are suited to form the substrate for the global gradient of ganglion cell receptive fields.

长期以来，人们一直低估了小鼠视网膜的地形复杂性。然而，功能梯度是存在的，它反映了视觉环境的非均匀统计。水平细胞是塑造下行神经元感受野的第一视觉中间神经元。我们从水平细胞的密度分布、形态特性、缝隙连接蛋白的定位以及电耦合的空间范围等方面探讨了区域特化是否存在。这些关键特征沿背腹轴呈非对称组织。与腹侧细胞相比，背侧细胞的分布密度较低，树突树较大，电耦合更为广泛。最陡峭的变化发生在视平线处。我们的研究结果表明，小鼠视觉系统的细胞和突触组织在尽可能早的水平上适应了视觉环境，水平细胞适合形成神经节细胞感受野全球梯度的基质。

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引用次数: 0

Dietary or pharmacological inhibition of insulin-like growth factor-1 protects from renal ischemia-reperfusion injury in mice 膳食或药物抑制胰岛素样生长因子-1可防止小鼠肾缺血再灌注损伤

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience

Pub Date : 2024-10-28 DOI: 10.1016/j.isci.2024.111256

Arnaud Lyon , Thomas Agius , Michael R. Macarthur , Kevin Kiesworo , Louis Stavart , Florent Allagnat , Sarah J. Mitchell , Leonardo V. Riella , Korkut Uygun , Heidi Yeh , Sebastien Déglise , Déla Golshayan , Alban Longchamp

One-week protein restriction (PR) limits ischemia-reperfusion (IR) damages and improves metabolic fitness. Similarly, longer-term calory restriction results in increased lifespan, partly via reduced insulin-like growth factor (IGF)-1. However, the influence of short-term PR on IGF-1 and its impact on IR are unknown. PR was achieved in mice via one-week carbohydrate loading and/or through a low-protein diet. PR decreased IGF-1 circulating levels as well as renal and hepatic expression. Upon renal IR, serum IGF-1 positively correlated with renal dysfunction and tissular damages, independently of sex and age. Exogenous IGF-1 administration abrogated PR benefits during IR, while IGF-1 receptor inhibition with linsitinib was protective. IGF-1 was associated with a reduction in forkhead box O (FoxO), and AMP-activated protein kinase (AMPK) signaling pathways previously demonstrated to improve IR resilience in various organs. These data support dietary or pharmacological reduction of IGF-1 signaling to mitigate IR injury prior to solid organ transplantation and beyond.

为期一周的蛋白质限制（PR）可限制缺血再灌注（IR）损伤并改善代谢健康。同样，长期热量限制会延长寿命，部分原因是胰岛素样生长因子（IGF）-1 减少。然而，短期PR对IGF-1的影响及其对IR的影响尚不清楚。小鼠通过一周的碳水化合物负荷和/或低蛋白饮食来实现 PR。PR降低了IGF-1的循环水平以及肾脏和肝脏表达。肾脏IR时，血清IGF-1与肾功能障碍和组织损伤呈正相关，与性别和年龄无关。服用外源性IGF-1会减弱IR期间的PR益处，而使用林西替尼抑制IGF-1受体则具有保护作用。IGF-1与叉头框O（FoxO）和AMP激活蛋白激酶（AMPK）信号通路的减少有关，这些信号通路以前曾被证明能提高各种器官的红外适应能力。这些数据支持通过饮食或药物减少 IGF-1 信号传导，以减轻实体器官移植前和移植后的红外损伤。

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引用次数: 0

Vitamin D alleviates HFD-induced hepatic fibrosis by inhibiting DNMT1 to affect the TGFβ1/Smad3 pathway 维生素 D 通过抑制 DNMT1 来影响 TGFβ1/Smad3 通路，从而减轻高密度脂蛋白胆固醇诱导的肝纤维化

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience

Pub Date : 2024-10-28 DOI: 10.1016/j.isci.2024.111262

Yueqing Liang , Xueyi Jiang , Xinfeng Zhao , Tiantian Tang , Xiuqin Fan , Rui Wang , Mengyi Yang , Kemin Qi , Yi Zhang , Ping Li

Increasing evidence points toward vitamin D (VD) having lipometabolism and immune-related properties to protect against related metabolic diseases through influencing DNA methylation with inconsistent results. Simultaneously, its relatively precise molecular metabolism on the progression of metabolic-associated fatty liver disease (MAFLD) remains uncertain. Here, we report an unprecedented role and possible mechanism for VD supplementation on the alleviation of high-fat diet (HFD)-induced MAFLD. Over time, our results demonstrated that metabolic disorders in the HFD-induced MAFLD were aggravated with a certain time-response dependence and accompanied by reduced VD metabolites. All these could be alleviated under sufficient VD supplementation in vivo and vitro. It was partially by inhibiting the expressions of DNMT1 to reverse the epigenetic patterns on the VD metabolism genes and TGFβR1, which ultimately triggered the TGFβ1/Smad3 pathway to result in the development of MAFLD. Furthermore, the protective effects of VD were weakened by the treatment with gene silencing of DNMT1.

越来越多的证据表明，维生素 D（VD）具有脂肪代谢和免疫相关特性，可通过影响 DNA 甲基化来预防相关代谢性疾病，但结果并不一致。同时，维生素 D 对代谢相关性脂肪肝（MAFLD）进展的相对精确的分子代谢作用仍不确定。在此，我们报告了补充 VD 在缓解高脂饮食（HFD）诱导的 MAFLD 方面前所未有的作用和可能机制。我们的研究结果表明，随着时间的推移，高脂饮食诱导的 MAFLD 代谢紊乱会加剧，并具有一定的时间反应依赖性，同时伴有 VD 代谢物的减少。在体内和体外补充足够的 VD 后，所有这些问题都可以得到缓解。这部分是通过抑制 DNMT1 的表达，逆转 VD 代谢基因和 TGFβR1 的表观遗传模式，最终触发 TGFβ1/Smad3 通路，导致 MAFLD 的发生。此外，通过基因沉默 DNMT1 的处理削弱了 VD 的保护作用。

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引用次数: 0

The ghost of ice ages past: Impact of Last Glacial Maximum landscapes on modern biodiversity 过去冰河时代的幽灵末次冰川极盛时期地貌对现代生物多样性的影响

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience

Pub Date : 2024-10-28 DOI: 10.1016/j.isci.2024.111272

Jeffrey C. Nekola , Jan Divíšek , Michal Horsák

Modeled modern and Last Glacial Maximum (LGM) climate ranges for 47 genetically confirmed small Holarctic land snails documented profound landscape dynamism over the last 21,000 years. Following deglaciation, range areas tended to increase by 50% while isolating barrier widths were cut in half. At the same time, the nature of isolating barriers underwent profound change, with the North American continental ice sheet becoming as important in the LGM as the Atlantic Ocean is today in separating Nearctic and Palearctic faunas. Because appropriate modern climate occurs for these species throughout the Holarctic, with no clear barriers being present—especially for such efficient passive dispersers—the current >90% turnover observed between Eurasian and North American species pools appears at least in part related to the LGM landscape. Understanding current and predicting potential future biodiversity patterns thus requires consideration of the landscape template across at least 15,000 years time scales.

47 种经基因确认的全北极陆地小蜗牛的现代和末次冰川极盛时期（LGM）气候范围模型记录了过去 21,000 年间地貌的巨大变化。在冰川退化之后，分布区的面积增加了 50%，而隔离屏障的宽度却减少了一半。与此同时，隔离屏障的性质也发生了深刻的变化，北美大陆冰盖在远古时期的重要性不亚于今天大西洋在分隔近地动物群和古北动物群方面的重要性。由于这些物种适宜的现代气候出现在整个全北极地区，没有明显的屏障，特别是对于这种高效的被动扩散者来说，目前在欧亚和北美物种库之间观察到的90%的更替率似乎至少在一定程度上与LGM地貌有关。因此，要了解当前和预测未来潜在的生物多样性模式，需要考虑至少 15000 年时间尺度上的地貌模板。

引用次数: 0

IFRD1 is required for maintenance of bladder epithelial homeostasis 维持膀胱上皮稳态需要 IFRD1

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience

Pub Date : 2024-10-28 DOI: 10.1016/j.isci.2024.111282

Bisiayo E. Fashemi , Amala K. Rougeau , Arnold M. Salazar , Steven J. Bark , Rayvanth Chappidi , Jeffrey W. Brown , Charles J. Cho , Jason C. Mills , Indira U. Mysorekar

The maintenance of homeostasis and rapid regeneration of the urothelium following stress are critical for bladder function. Here, we identify a key role for IFRD1 in maintaining urothelial homeostasis in a mouse model. We demonstrate that the murine bladder expresses IFRD1 at homeostasis, particularly in the urothelium, and its loss alters the global transcriptome with significant accumulation of endolysosomes and dysregulated uroplakin expression pattern. We show that IFRD1 interacts with mRNA-translation-regulating factors in human urothelial cells. Loss of Ifrd1 leads to disrupted proteostasis, enhanced endoplasmic reticulum (ER stress) with activation of the PERK arm of the unfolded protein response pathway, and increased oxidative stress. Ifrd1-deficient bladders exhibit urothelial cell apoptosis/exfoliation, enhanced basal cell proliferation, reduced differentiation into superficial cells, increased urothelial permeability, and aberrant voiding behavior. These findings highlight a crucial role for IFRD1 in urothelial homeostasis, suggesting its potential as a therapeutic target for bladder dysfunction.

膀胱功能的关键在于维持尿路上皮的稳态并在应激后迅速再生。在这里，我们确定了 IFRD1 在小鼠模型中维持尿路上皮平衡的关键作用。我们证明，小鼠膀胱在平衡状态下表达 IFRD1，尤其是在尿路上皮细胞中，而 IFRD1 的缺失会改变全局转录组，导致内溶酶体的显著积累和尿棘蛋白表达模式的失调。我们发现，IFRD1 与人尿路细胞中的 mRNA 翻译调节因子相互作用。Ifrd1的缺失会导致蛋白稳态紊乱、内质网（ER）应激增强（未折叠蛋白反应途径的PERK臂被激活）以及氧化应激增加。Ifrd1缺陷的膀胱表现出尿路上皮细胞凋亡/脱落、基底细胞增殖增强、表层细胞分化减少、尿路上皮通透性增加以及排尿行为异常。这些发现凸显了 IFRD1 在尿路神经元稳态中的关键作用，表明它有可能成为膀胱功能障碍的治疗靶点。

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引用次数: 0

TCCbuilder: An open-source tool for the analysis of thermal switches, thermal diodes, thermal regulators, and thermal control circuits TCCbuilder：用于分析热敏开关、热敏二极管、热调节器和热敏控制电路的开源工具

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience

Pub Date : 2024-10-28 DOI: 10.1016/j.isci.2024.111263

Katja Vozel , Katja Klinar , Nada Petelin , Andrej Kitanovski

In the area of thermal management, thermal control elements (TCEs) and thermal control circuits (TCCs) are proving to be innovative solutions to the challenges of temperature control and heat dissipation in various applications, ranging from electronic cooling to energy conversion and temperature control in buildings. Their integration promises to improve power density, energy efficiency, system reliability and system life expectancy. With the aim of connecting researchers in the field of thermal management and accelerating the development of TCEs and TCCs, we have developed an open-source TCC simulation tool called TCCbuilder that enables a quick and easy time-dependent 1D numerical analysis of the behavior of TCEs and TCCs. It uses the heat conduction equation to solve temperature profiles in different devices. The TCCbuilder application offers features not previously available with any other TCC modeling tool: a large adjacent library of materials and TCEs as well as a user-friendly graphical user interface (GUI).

在热管理领域，热控制元件（TCE）和热控制电路（TCC）被证明是应对各种应用中温度控制和散热挑战的创新解决方案，这些应用包括电子冷却、能源转换和建筑物温度控制等。它们的集成有望提高功率密度、能源效率、系统可靠性和系统寿命。为了将热管理领域的研究人员联系起来，加速 TCE 和 TCC 的开发，我们开发了一款名为 TCCbuilder 的开源 TCC 仿真工具，该工具可对 TCE 和 TCC 的行为进行快速、简便的随时间变化的一维数值分析。它使用热传导方程来求解不同器件中的温度曲线。TCCbuilder 应用程序具有其他 TCC 建模工具所不具备的功能：邻近的大型材料和 TCE 库以及用户友好的图形用户界面 (GUI)。

引用次数: 0

Communication subspace dynamics of the canonical olfactory pathway 典型嗅觉通路的通信子空间动力学

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience

Pub Date : 2024-10-28 DOI: 10.1016/j.isci.2024.111275

Joaquín Gonzalez , Pablo Torterolo , Kevin A. Bolding , Adriano B.L. Tort

Understanding how different brain areas communicate is crucial for elucidating the mechanisms underlying cognition. A possible way for neural populations to interact is through a communication subspace, a specific region in the state-space enabling the transmission of behaviorally relevant spiking patterns. In the olfactory system, it remains unclear if different populations employ such a mechanism. Our study reveals that neuronal ensembles in the main olfactory pathway (olfactory bulb to olfactory cortex) interact through a communication subspace, which is driven by nasal respiration and allows feedforward and feedback transmission to occur segregated along the sniffing cycle. Moreover, our results demonstrate that subspace communication depends causally on the activity of both areas, is hindered during anesthesia, and transmits a low-dimensional representation of odor.

了解不同脑区如何进行交流对于阐明认知的内在机制至关重要。神经群相互作用的一种可能方式是通过通信子空间，即状态空间中能够传输与行为相关的尖峰模式的特定区域。在嗅觉系统中，不同的神经群是否采用了这种机制仍不清楚。我们的研究揭示了主要嗅觉通路（嗅球到嗅皮层）中的神经元集合通过通信子空间相互作用，该子空间由鼻呼吸驱动，允许前馈和反馈传输沿着嗅觉周期发生分离。此外，我们的研究结果表明，子空间通信与两个区域的活动有因果关系，在麻醉期间会受到阻碍，并传输低维的气味表征。

引用次数: 0

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