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Divergence unveils further distinct phenotypic traits of human brain connectomics fingerprint 发散进一步揭示了人类大脑连接组指纹的明显表型特征
IF 4.1 2区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Pub Date : 2025-12-01 DOI: 10.1016/j.isci.2025.114282
Md Kaosar Uddin , Nghi Nguyen , Huajun Huang , Duy Duong-Tran , Jingyi Zheng
The accurate identification of individuals from functional connectomes (FCs) is central to individualized neuro/psychiatric assessment. Traditional metrics (Pearson and Euclidean) fail to capture the non-Euclidean geometry of FCs, and geodesic metrics (affine-invariant and Log-Euclidean) require task- and scale-specific regularization and degrade in high-dimensional settings. To address these challenges, we propose the Alpha-Z Bures-Wasserstein divergence, a geometry-aware divergence for FC comparison that operates effectively without meticulous parameter tuning. Across Human Connectome Project tasks, scan lengths, and spatial resolutions, we benchmark Alpha-Z against classical and state-of-the-art manifold-based distances and quantify how varying regularization influences geodesic performance. Alpha-Z yields consistently higher identification rates, with pronounced advantages in rank-deficient regimes, and preserves performance across parcellations and conditions. We further verify generalization across resting-state and task fMRI under multiple parcellation schemes. These results position Alpha-Z as a reliable, robust, and scalable framework for functional connectivity analysis, improving sensitivity to cognitive and behavioral patterns and offering strong potential for individualized clinical neuroscience.
从功能性连接体(FCs)中准确识别个体是个体化神经/精神评估的核心。传统度量(Pearson和Euclidean)无法捕获fc的非欧几里得几何,测地线度量(仿射不变和对数欧几里得)需要特定于任务和规模的正则化,并且在高维设置中会降级。为了解决这些挑战,我们提出了Alpha-Z Bures-Wasserstein散度,这是一种用于FC比较的几何感知散度,无需细致的参数调整即可有效运行。在人类连接组项目任务、扫描长度和空间分辨率方面,我们将Alpha-Z与经典和最先进的基于流形的距离进行基准测试,并量化不同的正则化如何影响测地性能。Alpha-Z的识别率始终较高,在等级缺乏的情况下具有明显的优势,并且在不同的包裹和条件下保持性能。我们进一步验证了在多个分割方案下静息状态和任务fMRI的泛化。这些结果将Alpha-Z定位为功能连接分析的可靠、健壮和可扩展的框架,提高了对认知和行为模式的敏感性,并为个性化临床神经科学提供了强大的潜力。
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引用次数: 0
Bridged artificial neurons based on memristor circuit for spiking propagation network and coincidence detection 基于忆阻电路的桥接人工神经元尖峰传播网络与重合检测
IF 4.1 2区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Pub Date : 2025-12-01 DOI: 10.1016/j.isci.2025.114294
Wei Zhao , Chenwei Fu , Dengwang Yuan , Yongkang Deng , Yufan Guan , Jidong Li
The biological nervous system relies on precise temporal integration for efficient information processing and perception. Among these, spiking propagation and coincidence detection play a crucial role in neural coding and signal processing. Here, we proposed a bridged artificial neuron unit based on a memristor emulator circuit, capable of mimicking ion-channel-like spiking behavior, including spike generation and refractory periods. These units can be connected in series to form chains or networks for spike propagation and interaction, enabling reliable unidirectional action potential transmission and coincidence detection. As a proof of concept, we developed a bioinspired auditory processing system that emulates the interaural time difference-processing mechanism of the barn owl. The system achieves microsecond-level sound localization with outstanding noise resistance. These findings demonstrate the potential of bridged artificial neuron units for advancing neuromorphic computing, bioinspired perception systems, and high-precision biosensing applications.
生物神经系统依赖于精确的时间整合来进行有效的信息处理和感知。其中,尖峰传播和符合检测在神经编码和信号处理中起着至关重要的作用。在这里,我们提出了一个基于忆阻器仿真电路的桥接人工神经元单元,能够模拟离子通道样的尖峰行为,包括尖峰产生和不应期。这些单元可以串联起来,形成链或网络,用于尖峰传播和相互作用,实现可靠的单向动作电位传输和巧合检测。为了验证这一概念,我们开发了一种仿生听觉处理系统,该系统模拟了仓鸮的耳间时差处理机制。该系统实现了微秒级的声音定位,具有优异的抗噪性能。这些发现证明了桥接人工神经元单元在推进神经形态计算、生物感知系统和高精度生物传感应用方面的潜力。
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引用次数: 0
AKG-TET axis is central to senescence plasticity AKG-TET轴是衰老可塑性的核心
IF 4.1 2区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Pub Date : 2025-12-01 DOI: 10.1016/j.isci.2025.114298
Shin Akakura , Siamak Tabibzadeh
Cellular senescence, a state of stable cell-cycle arrest associated with aging, is characterized by a distinct pro-inflammatory secretome. This study systematically interrogates the critical role of the α-ketoglutarate (AKG)-Ten-eleven translocation (TET) axis in regulating senescence in human somatic cells. Downregulating TET expression and activity, either genetically (siRNA) or pharmacologically (via C35), or limiting AKG bioavailability through a targeting peptide, trigger widespread epigenetic reprogramming, amplify pro-inflammatory signaling, and enhance the senescence-associated secretory phenotype (SASP), ultimately driving cells toward replicative senescence. Conversely, augmenting AKG bioavailability or TET expression and activity significantly enhances cellular resilience to stress, effectively preventing and reversing senescent phenotypes. These findings not only position the AKG-TET axis as a critical regulatory nexus of cellular senescence but also challenge the traditional view of senescence as a fixed endpoint, revealing its dynamic and plastic nature susceptible to therapeutic intervention.
细胞衰老是一种与衰老相关的稳定的细胞周期停滞状态,其特征是具有独特的促炎分泌组。本研究系统探讨了α-酮戊二酸(AKG)- 10 - 11易位(TET)轴在调节人体细胞衰老中的关键作用。通过基因(siRNA)或药理学(通过C35)下调TET的表达和活性,或通过靶向肽限制AKG的生物利用度,触发广泛的表观遗传重编程,放大促炎信号,增强衰老相关分泌表型(SASP),最终驱动细胞走向复制性衰老。相反,增加AKG的生物利用度或TET的表达和活性可以显著增强细胞对压力的恢复能力,有效地预防和逆转衰老表型。这些发现不仅将AKG-TET轴定位为细胞衰老的关键调控关系,而且挑战了衰老是固定终点的传统观点,揭示了其动态性和可塑性,易受治疗干预的影响。
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引用次数: 0
GSK3β/HIF-1α signaling-dependent anti-parasite effect of Cynanchi atrati Radix 白芍GSK3β/HIF-1α信号依赖性抗寄生虫作用
IF 4.1 2区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Pub Date : 2025-12-01 DOI: 10.1016/j.isci.2025.114292
Fei-Fei Gao , Guan-Hao Hong , Xin-Cheng Wang , Jia-hui Zeng , Yu-Sun Yun , In-Wook Choi , Jae-Min Yuk , Wei Zhou , Xin-tian Chen , Gang Min Hur , Guang-Ho Cha
Medicinal plants yield bioactive compounds with potential for parasite control. We examined Cynanchi atrati Radix (C. atrati) and its component 4′-hydroxyacetophenone (4′HAP) for activity against Toxoplasma gondii (T. gondii) using cultured cells and mouse infection models. C. atrati extracts limited parasite growth with minimal host-cell toxicity. Chemical screening pinpointed 4′HAP as the active constituent that suppresses T. gondii proliferation in vitro and in vivo. Mechanistically, C. atrati and 4′HAP activated GSK3β, destabilized HIF-1α, and curtailed parasite fitness; pharmacologic GSK3β inhibition restored parasite growth, whereas HIF-1α depletion further reduced survival, highlighting the GSK3β/HIF-1α axis as a host pathway that constrains infection. These results identify a plant-derived small molecule and its mechanistic target for host-directed antiparasitic therapy and provide a framework for developing treatments for toxoplasmosis.
药用植物产生具有控制寄生虫潜力的生物活性化合物。本文采用培养细胞和小鼠感染模型,检测了红参及其成分4′-羟基苯乙酮(4′hap)对刚地弓形虫(T. gondii)的抗虫活性。天竺葵提取物限制寄生虫生长,对宿主细胞的毒性最小。化学筛选确定4′hap为抑制弓形虫体外和体内增殖的活性成分。在机制上,C. atrati和4'HAP激活GSK3β,破坏HIF-1α的稳定,并降低寄生虫的适应性;药理学抑制GSK3β恢复了寄生虫的生长,而HIF-1α的缺失进一步降低了寄生虫的存活,这表明GSK3β/HIF-1α轴是抑制感染的宿主途径。这些结果确定了一种植物源性小分子及其宿主抗寄生虫治疗的机制靶点,并为弓形虫病的治疗提供了一个框架。
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引用次数: 0
Constructing the spatiotemporal atlas of single-cell lineage trajectories in stereotypic biological structures 构建单细胞谱系轨迹的时空图谱在刻板的生物结构
IF 4.1 2区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Pub Date : 2025-12-01 DOI: 10.1016/j.isci.2025.114307
Ran Wang , Xianfa Yang , Chengfei Lian , Jianjie Wang , Jiehui Chen , Yun Qian , Yaochen Xu , Liantang Wang , John C. Marioni , Patrick P.L. Tam , Naihe Jing
Spatial transcriptomics technologies have emerged as instrumental tools for elucidating cellular heterogeneity and molecular regulation within the complex tissue microenvironment, but are constrained by insufficient gene recovery or an inability to achieve intact single-cell resolution. By integrating spatial transcriptomics and single-cell RNA sequencing technologies, we develop a mathematical method of single-cell resolved spatiotemporal (SCST) mapping that comprises tiered algorithms for constructing the spatial molecular atlas of the biospecimen at single-cell resolution across a timeline of development. The embedded spatial-smoothing algorithm in SCST significantly enhances the spatial mapping accuracy of single cells, thereby improving the fidelity of the annotation of cell identity to the equivalent in vivo cell type. Through 3D mathematical modeling, SCST facilitates the spatial reconstruction of a single-cell molecular atlas and the delineation of cellular heterogeneity. When integrated with temporal data, SCST can also delineate the spatiotemporal lineage trajectory at single-cell resolution in a developing biological entity.
空间转录组学技术已成为阐明复杂组织微环境中的细胞异质性和分子调控的工具,但受到基因恢复不足或无法实现完整单细胞分辨率的限制。通过整合空间转录组学和单细胞RNA测序技术,我们开发了一种单细胞分辨率时空(SCST)制图的数学方法,该方法包括分层算法,用于在发育时间轴上以单细胞分辨率构建生物标本的空间分子图谱。SCST中嵌入的空间平滑算法显著提高了单细胞的空间映射精度,从而提高了细胞身份标注对体内等效细胞类型的保真度。通过三维数学建模,SCST有助于单细胞分子图谱的空间重建和细胞异质性的描绘。当与时间数据相结合时,SCST还可以在发育中的生物实体中以单细胞分辨率描绘时空谱系轨迹。
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引用次数: 0
Context-dependent NMDA receptor dysfunction predicts seizure treatment in mice with human GluN1 variant 上下文依赖的NMDA受体功能障碍预测人类GluN1变异小鼠的癫痫治疗
IF 4.1 2区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Pub Date : 2025-12-01 DOI: 10.1016/j.isci.2025.114301
Sridevi Venkatesan , Daria Nazarkina , Megan T. Sullivan , Yao-Fang Tan , Sarah Qu , Amy J. Ramsey , Evelyn K. Lambe
Mutations in N-methyl-D-aspartate receptors (NMDARs) cause epilepsy and profound cognitive impairment, though the underlying subunit-specific vulnerabilities remain unclear. We investigate the impact of a severe human variant in the lurcher motif of obligate GluN1 NMDAR subunit using transgenic mice, revealing unexpected context-dependent phenotypes. We show that the GluN1 Y647S variant significantly reduces current flow through pharmacologically isolated synaptic NMDARs in prefrontal neurons. Yet in intact local circuits, this loss-of-function paradoxically extends NMDAR-dependent dendritic integration, causing prolonged circuit-wide excitation that promotes seizures. Mutant receptors appear deficient in engaging opposing dendritic ion channels that normally curtail NMDAR-dependent excitation. Boosting SK channel activity normalizes dendritic integration, whereas slight decreases in extracellular magnesium further extend abnormally prolonged integration in mutant mice. We find that magnesium supplementation successfully treats seizures in vivo in the transgenic mice, despite loss-of-function of NMDARs. Overall, we disentangle a GluN1 variant’s receptor-level effects and its dendritic impact to treat seizures effectively.
n -甲基- d -天冬氨酸受体(NMDARs)的突变导致癫痫和严重的认知障碍,尽管潜在的亚基特异性脆弱性尚不清楚。我们使用转基因小鼠研究了GluN1 NMDAR亚基专性lurcher基的严重人类变异的影响,揭示了意想不到的上下文依赖性表型。我们发现GluN1 Y647S变异显著降低了通过药理学分离的前额叶神经元突触NMDARs的电流。然而,在完整的局部电路中,这种功能丧失反而延长了nmdar依赖的树突整合,导致长时间的全回路兴奋,从而促进癫痫发作。突变受体似乎缺乏参与对立的树突离子通道,通常限制nmdar依赖的兴奋。增强SK通道活性使树突整合正常化,而细胞外镁的轻微减少进一步延长了突变小鼠异常延长的整合。我们发现,尽管NMDARs的功能丧失,但镁补充剂成功地治疗了转基因小鼠体内的癫痫发作。总的来说,我们解开了GluN1变体的受体水平效应及其对有效治疗癫痫发作的树突影响。
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引用次数: 0
A pilot study: Incorporating Treponema pallidum antigens into machine learning models for accurate syphilis treatment outcome assessment 一项试点研究:将梅毒螺旋体抗原纳入机器学习模型,以准确评估梅毒治疗结果
IF 4.1 2区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Pub Date : 2025-12-01 DOI: 10.1016/j.isci.2025.114275
Jiangchen Yao , Dingfa Deng , Han Yu , Junxia Duan , Shuyun Xia , Xunyu Cao , Yafeng Xie , Bibo Xie , Peng Ling , Feijun Zhao
As the reliability of nontreponemal tests for evaluating syphilis treatment efficacy is increasingly questioned, we propose an optimized approach using Treponema pallidum (Tp) antigens (Tp0134, Tp0768, Tp0971, Tp0462, and Tp92) combined with a machine learning (ML) model. Analysis of 509 serum samples (including paired pre- and post-treatment samples) employed an established ELISA assay to dynamically monitor antibody changes. Results demonstrated that post-treatment antibody reduction for potential infection-stage-dependent antigens (pIDAs) (especially Tp0134 and Tp0768) was markedly higher than for the non-infection-stage-dependent antigen Tp92 and traditional methods. Utilizing nested cross-validation to train an array of ML models, ultimately chosen random forest model (AUC = 0.815) demonstrated enhanced efficacy in accurately distinguishing between infection and cure. Specifically, Tp0768, Tp92, and Tp0134 were identified as the pivotal features. Combining Tp antigens with ML provides a more accurate and dynamic tool for treatment efficacy assessment, enabling a more effective evaluation of syphilis treatment outcomes in the future.
随着非梅毒螺旋体检测评估梅毒治疗效果的可靠性受到越来越多的质疑,我们提出了一种利用梅毒螺旋体(Tp)抗原(Tp0134、Tp0768、Tp0971、Tp0462和Tp92)结合机器学习(ML)模型的优化方法。509份血清样本(包括配对的治疗前和治疗后样本)的分析采用已建立的ELISA法动态监测抗体变化。结果表明,治疗后对潜在感染期依赖性抗原(pIDAs)(特别是Tp0134和Tp0768)的抗体降低率明显高于非感染期依赖性抗原Tp92和传统方法。利用嵌套交叉验证训练一系列ML模型,最终选择的随机森林模型(AUC = 0.815)在准确区分感染和治愈方面表现出更高的功效。具体而言,Tp0768、Tp92和Tp0134被确定为关键特征。Tp抗原与ML的结合为治疗疗效评估提供了更准确、更动态的工具,可以在未来更有效地评价梅毒的治疗效果。
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引用次数: 0
EMT-induced stem cell and mesenchymal programs can be decoupled via cell division and ESRP1-dependent mechanisms emt诱导的干细胞和间充质程序可以通过细胞分裂和esrp1依赖机制解耦
IF 4.1 2区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Pub Date : 2025-12-01 DOI: 10.1016/j.isci.2025.114284
Petra den Hollander , Maria Castaneda , Suhas V. Vasaikar , Joanna Joyce Maddela , Claire Gould , Breanna R. Demestichas , Robiya Joseph , Shivangi Agarwal , Abhijeet P. Deshmukh , Alvina Zia , Shruti Shah , Tieling Zhou , Geraldine Raja , Paul Allegakoen , Nick A. Kuburich , Mika Pietila , Chunxiao Fu , Jeffrey Chang , Chad J. Creighton , William F. Symmans , Sendurai A. Mani
Epithelial-to-mesenchymal transition (EMT) is known to induce both stemness and mesenchymal properties, and our findings reveal that these two programs can be uncoupled. During EMT, epithelial cells transition from symmetric divisions producing differentiated daughter cells to self-renewing daughter cells. When we block cell division and induce EMT, cells gain mesenchymal properties but not stemness, suggesting the importance of cell division for gaining stemness. We identified ESRP1 as a key regulator of EMT-driven stemness, which get downregulated during EMT in a cell division-dependent manner. Overexpression of ESRP1 prevents the gain of stemness without affecting the mesenchymal program. Only the stemness and not the mesenchymal signature, induced during EMT, correlates with poor prognosis. All cancer cells with stemness properties exhibit mesenchymal properties, but not all mesenchymal cells exhibit stemness properties. In summary, during EMT the stemness program is controlled by cell division and ESRP1, and this program predicts poor prognosis.
上皮-间充质转化(Epithelial-to-mesenchymal transition, EMT)可以诱导干细胞和间充质特性,我们的研究结果表明这两个程序可以分离。在EMT过程中,上皮细胞从对称分裂产生分化的子细胞转变为自我更新的子细胞。当我们阻断细胞分裂并诱导EMT时,细胞获得了间质特性,但没有获得干性,这表明细胞分裂对获得干性的重要性。我们发现ESRP1是EMT驱动的干性的关键调节因子,在EMT期间以细胞分裂依赖的方式下调。ESRP1的过表达在不影响间质程序的情况下阻止了干性的获得。在EMT期间,只有干性而非间充质特征与不良预后相关。所有具有干性的癌细胞都表现出间充质特性,但并非所有间充质细胞都表现出干性特性。综上所述,在EMT期间,干细胞程序由细胞分裂和ESRP1控制,该程序预示着不良预后。
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引用次数: 0
Multilayer innovation network resilience: A framework for digital economy vulnerability assessment 多层创新网络弹性:数字经济脆弱性评估框架
IF 4.1 2区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Pub Date : 2025-12-01 DOI: 10.1016/j.isci.2025.114295
Hongjuan Zhang , Haibing Liu , Rongkai Chen
Innovation networks drive technological progress, yet their multilayer structures remain poorly understood in digital economy vulnerability contexts. This study develops a comprehensive framework for assessing multilayer innovation network resilience, analyzing interdependencies and disruption scenarios using China’s digital economy as a representative empirical context. We construct coupled multilayer networks implementing four integrated attack strategies to identify cascading vulnerability mechanisms. Results reveal asymmetric patterns: collaboration networks show significant fragility to targeted attacks, while knowledge networks demonstrate higher resilience, especially during mature stages. Cascade failure analysis establishes that knowledge network disruptions propagate severe ecosystem-wide effects, whereas collaboration network perturbations generate limited cross-layer impacts. This asymmetry advances multilayer innovation network theory and provides practical insights for vulnerability assessment. The framework indicates that protecting critical technological knowledge should prioritize over maintaining collaborative arrangements when resources are limited, as knowledge networks constitute the essential integrative mechanism within innovation systems.
创新网络推动技术进步,但在数字经济脆弱性背景下,人们对其多层结构仍知之甚少。本研究开发了一个综合框架,用于评估多层创新网络弹性,分析相互依赖关系和中断情景,并以中国数字经济为代表性实证背景。我们构建了耦合的多层网络,实现了四种集成的攻击策略来识别级联漏洞机制。结果揭示了不对称模式:协作网络对目标攻击表现出明显的脆弱性,而知识网络表现出更高的弹性,尤其是在成熟阶段。级联失效分析表明,知识网络中断传播严重的生态系统影响,而协作网络扰动产生有限的跨层影响。这种不对称性促进了多层创新网络理论的发展,并为脆弱性评估提供了实践见解。该框架表明,在资源有限的情况下,保护关键技术知识应优先于维持协作安排,因为知识网络构成了创新系统内部必不可少的整合机制。
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引用次数: 0
Convolvulus pluricaulis confers antidepressant and antioxidant effects through conserved metabolic and molecular pathways in Drosophila 旋花在果蝇体内通过保守的代谢和分子途径具有抗抑郁和抗氧化作用
IF 4.1 2区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Pub Date : 2025-12-01 DOI: 10.1016/j.isci.2025.114296
Shreyasi Mitra , Amit Kumar , Manish Pandey , Aman Gill , Meenakshi Sharma , Shivani Pundir , Mansi Jangir , Geetanjali Chawla
Convolvulus pluricaulis (shankhpushpi) is a traditional herb used to treat depression and anxiety. Using Drosophila melanogaster as a model, we identified conserved metabolic and molecular pathways mediating its neuroprotective effects. Metabolomic profiling of flies fed C. pluricaulis revealed altered levels of ascorbic acid, glucose, and adenine monophosphate in the head tissue. Gene expression analysis showed significant modulation of Glut1 (glucose transporter 1), CG6293 (ascorbate transporter), Rdl (resistant to dieldrin), GABA-B-R1 (GABA-B receptor 1), and Sod1 (superoxide dismutase 1). Dietary C. pluricaulis reduced depression-like behavior in a stress-induced model and elevated head ascorbate levels. Knockdown of CG6293, Sod1, Glut1, or GABA-B-R1 abolished the antioxidant effects, and knockdown of CG6293 eliminated the antidepressant effects, implicating these genes as key downstream effectors. Supplementation with L-ascorbic acid mimicked the behavioral and oxidative resilience conferred by C. pluricaulis. Together, these findings reveal conserved antioxidant and anxiolytic mechanisms underlying the pharmacological effects of C. pluricaulis in Drosophila.
旋花(shankhpushpi)是一种用于治疗抑郁和焦虑的传统草药。以黑腹果蝇为模型,我们确定了介导其神经保护作用的保守代谢和分子途径。饲喂多角蝇的果蝇代谢组学分析显示,头部组织中抗坏血酸、葡萄糖和单磷酸腺嘌呤的水平发生了变化。基因表达分析显示,Glut1(葡萄糖转运蛋白1)、CG6293(抗坏血酸转运蛋白)、Rdl(抗狄德灵)、GABA-B- r1 (GABA-B受体1)和Sod1(超氧化物歧化酶1)均有显著调节。在应激诱导的模型中,饮食中的多毛霉可以减少抑郁样行为,并提高头部抗坏血酸水平。CG6293、Sod1、Glut1或GABA-B-R1的敲低可消除抗氧化作用,而CG6293的敲低可消除抗抑郁作用,提示这些基因是关键的下游效应基因。补充l -抗坏血酸模拟了C. pluricaulis赋予的行为和氧化恢复能力。总之,这些发现揭示了隐球菌对果蝇的药理作用的保守的抗氧化和抗焦虑机制。
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