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Computational inference of chemokine-mediated roles for the vagus nerve in modulating intra- and inter-tissue inflammation 通过计算推断迷走神经介导的趋化因子在调节组织内和组织间炎症中的作用
Pub Date : 2024-02-15 DOI: 10.3389/fsysb.2024.1266279
Ashti M. Shah, R. Zamora, Derek A. Barclay, Jinling Yin, Fayten el-Dehaibi, M. Addorisio, T. Tsaava, A. Tynan, Kevin Tracey, Sangeeta Chavan, Y. Vodovotz
Introduction: The vagus nerve innervates multiple organs, but its role in regulating cross-tissue spread of inflammation is as yet unclear. We hypothesized that the vagus nerve may regulate cross-tissue inflammation via modulation of the putatively neurally regulated chemokine IP-10/CXCL10.Methods: Rate-of-change analysis, dynamic network analysis, and dynamic hypergraphs were used to model intra- and inter-tissue trends, respectively, in inflammatory mediators from mice that underwent either vagotomy or sham surgery.Results: This analysis suggested that vagotomy primarily disrupts the cross-tissue attenuation of inflammatory networks involving IP-10 as well as the chemokines MIG/CXCL9 and CCL2/MCP-1 along with the cytokines IFN-γ and IL-6. Computational analysis also suggested that the vagus-dependent rate of expression of IP-10 and MIG/CXCL9 in the spleen impacts the trajectory of chemokine expression in other tissues. Perturbation of this complex system with bacterial lipopolysaccharide (LPS) revealed a vagally regulated role for MIG in the heart. Further, LPS-stimulated expression of IP-10 was inferred to be vagus-independent across all tissues examined while reducing connectivity to IL-6 and MCP-1, a hypothesis supported by Boolean network modeling.Discussion: Together, these studies define novel spatiotemporal dimensions of vagus-regulated acute inflammation.
引言迷走神经支配多个器官,但它在调节炎症跨组织扩散方面的作用尚不清楚。我们假设迷走神经可能通过调节可能受神经调节的趋化因子 IP-10/CXCL10 来调节跨组织炎症:方法:使用变化率分析、动态网络分析和动态超图分别模拟小鼠接受迷走神经切断术或假手术后组织内和组织间炎症介质的变化趋势:结果:分析表明,迷走神经切断术主要破坏了涉及 IP-10、趋化因子 MIG/CXCL9 和 CCL2/MCP-1 以及细胞因子 IFN-γ 和 IL-6 的炎症网络的跨组织衰减。计算分析还表明,脾脏中依赖迷走神经的 IP-10 和 MIG/CXCL9 的表达率会影响其他组织中趋化因子的表达轨迹。细菌脂多糖(LPS)对这一复杂系统的干扰揭示了 MIG 在心脏中受迷走神经调控的作用。此外,据推断,LPS 刺激的 IP-10 在所有受检组织中的表达都与迷走神经无关,同时减少了与 IL-6 和 MCP-1 的连接,布尔网络建模支持了这一假设:这些研究共同定义了迷走神经调控急性炎症的新时空维度。
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引用次数: 0
Computational inference of chemokine-mediated roles for the vagus nerve in modulating intra- and inter-tissue inflammation 通过计算推断迷走神经介导的趋化因子在调节组织内和组织间炎症中的作用
Pub Date : 2024-02-15 DOI: 10.3389/fsysb.2024.1266279
Ashti M. Shah, R. Zamora, Derek A. Barclay, Jinling Yin, Fayten el-Dehaibi, M. Addorisio, T. Tsaava, A. Tynan, Kevin Tracey, Sangeeta Chavan, Y. Vodovotz
Introduction: The vagus nerve innervates multiple organs, but its role in regulating cross-tissue spread of inflammation is as yet unclear. We hypothesized that the vagus nerve may regulate cross-tissue inflammation via modulation of the putatively neurally regulated chemokine IP-10/CXCL10.Methods: Rate-of-change analysis, dynamic network analysis, and dynamic hypergraphs were used to model intra- and inter-tissue trends, respectively, in inflammatory mediators from mice that underwent either vagotomy or sham surgery.Results: This analysis suggested that vagotomy primarily disrupts the cross-tissue attenuation of inflammatory networks involving IP-10 as well as the chemokines MIG/CXCL9 and CCL2/MCP-1 along with the cytokines IFN-γ and IL-6. Computational analysis also suggested that the vagus-dependent rate of expression of IP-10 and MIG/CXCL9 in the spleen impacts the trajectory of chemokine expression in other tissues. Perturbation of this complex system with bacterial lipopolysaccharide (LPS) revealed a vagally regulated role for MIG in the heart. Further, LPS-stimulated expression of IP-10 was inferred to be vagus-independent across all tissues examined while reducing connectivity to IL-6 and MCP-1, a hypothesis supported by Boolean network modeling.Discussion: Together, these studies define novel spatiotemporal dimensions of vagus-regulated acute inflammation.
引言迷走神经支配多个器官,但它在调节炎症跨组织扩散方面的作用尚不清楚。我们假设迷走神经可能通过调节可能受神经调节的趋化因子 IP-10/CXCL10 来调节跨组织炎症:方法:使用变化率分析、动态网络分析和动态超图分别模拟小鼠接受迷走神经切断术或假手术后组织内和组织间炎症介质的变化趋势:结果:分析表明,迷走神经切断术主要破坏了涉及 IP-10、趋化因子 MIG/CXCL9 和 CCL2/MCP-1 以及细胞因子 IFN-γ 和 IL-6 的炎症网络的跨组织衰减。计算分析还表明,脾脏中依赖迷走神经的 IP-10 和 MIG/CXCL9 的表达率会影响其他组织中趋化因子的表达轨迹。细菌脂多糖(LPS)对这一复杂系统的干扰揭示了 MIG 在心脏中受迷走神经调控的作用。此外,据推断,LPS 刺激的 IP-10 在所有受检组织中的表达都与迷走神经无关,同时减少了与 IL-6 和 MCP-1 的连接,布尔网络建模支持了这一假设:这些研究共同定义了迷走神经调控急性炎症的新时空维度。
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引用次数: 0
Editorial: Combining mechanistic modeling with machine learning to study multiscale biological processes 社论:将机理建模与机器学习相结合,研究多尺度生物过程
Pub Date : 2024-02-02 DOI: 10.3389/fsysb.2024.1367549
S. Peirce-Cottler, Y. Vodovotz
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引用次数: 0
Editorial: Combining mechanistic modeling with machine learning to study multiscale biological processes 社论:将机理建模与机器学习相结合,研究多尺度生物过程
Pub Date : 2024-02-02 DOI: 10.3389/fsysb.2024.1367549
S. Peirce-Cottler, Y. Vodovotz
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引用次数: 0
Genome-scale flux balance analysis reveals redox trade-offs in the metabolism of the thermoacidophile Methylacidiphilum fumariolicum under auto-, hetero-and methanotrophic conditions 基因组尺度的通量平衡分析揭示了嗜热菌 Methylacidiphilum fumariolicum 在自养、异养和甲烷养分条件下的新陈代谢中的氧化还原权衡问题
Pub Date : 2024-01-29 DOI: 10.3389/fsysb.2024.1291612
Alexis Saldivar, Patricia Ruiz-Ruiz, Sergio Revah, C. Zuñiga
Members of the genus Methylacidiphilum are thermoacidophile methanotrophs with optimal growth temperatures between 50°C and 60°C, and pH between 1.0 and 3.0. These microorganisms, as well as other extremophile bacteria, offer an attractive platform for environmental and industrial biotechnology because of their robust operating conditions and capacity to grow using low-cost substrates. In this study, we isolated Methylacidiphilum fumariolicum str. Pic from a crater lake located in the state of Chiapas, Mexico. We sequenced the genome and built a genome-scale metabolic model. The manually curated model contains 667 metabolites, 729 reactions, and 473 genes. Predicted flux distributions using flux balance analysis identified changes in redox trade-offs under methanotrophic and autotrophic conditions (H2+CO2). This was also predicted under heterotrophic conditions (acetone, isopropanol, and propane). Model validation was performed by testing the capacity of the strains to grow using four substrates: CH4, acetone, isopropanol, and LP-Gas. The results suggest that the metabolism of M. fumariolicum str. Pic is limited by the regeneration of redox equivalents such as NAD(P)H and reduced cytochromes.
Methylacidiphilum 属的成员是嗜热甲烷菌,其最佳生长温度为 50°C 至 60°C,pH 值为 1.0 至 3.0。这些微生物和其他嗜极细菌一样,因其稳健的操作条件和使用低成本底物生长的能力,为环境和工业生物技术提供了一个极具吸引力的平台。在本研究中,我们从位于美国加利福尼亚州的火山口湖中分离出了 Methylacidiphilum fumariolicum str.Pic。我们对其基因组进行了测序,并建立了一个基因组尺度的代谢模型。经人工编辑的模型包含 667 个代谢物、729 个反应和 473 个基因。利用通量平衡分析预测的通量分布确定了甲烷营养和自养条件(H2+CO2)下氧化还原权衡的变化。在异养条件(丙酮、异丙醇和丙烷)下也能预测到这种变化。通过测试菌株在四种底物条件下的生长能力,对模型进行了验证:CH4、丙酮、异丙醇和液化石油气。结果表明,M. fumariolicum str.Pic 的新陈代谢受到氧化还原当量(如 NAD(P)H 和还原型细胞色素)再生的限制。
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引用次数: 0
A framework for multi-scale intervention modeling: virtual cohorts, virtual clinical trials, and model-to-model comparisons 多尺度干预建模框架:虚拟队列、虚拟临床试验和模型间比较
Pub Date : 2024-01-22 DOI: 10.3389/fsysb.2023.1283341
Christian T. Michael, Sayed A. Almohri, J. Linderman, Denise E. Kirschner
Computational models of disease progression have been constructed for a myriad of pathologies. Typically, the conceptual implementation for pathology-related in silico intervention studies has been ad hoc and similar in design to experimental studies. We introduce a multi-scale interventional design (MID) framework toward two key goals: tracking of disease dynamics from within-body to patient to population scale; and tracking impact(s) of interventions across these same spatial scales. Our MID framework prioritizes investigation of impact on individual patients within virtual pre-clinical trials, instead of replicating the design of experimental studies. We apply a MID framework to develop, organize, and analyze a cohort of virtual patients for the study of tuberculosis (TB) as an example disease. For this study, we use HostSim: our next-generation whole patient-scale computational model of individuals infected with Mycobacterium tuberculosis. HostSim captures infection within lungs by tracking multiple granulomas, together with dynamics occurring with blood and lymph node compartments, the compartments involved during pulmonary TB. We extend HostSim to include a simple drug intervention as an example of our approach and use our MID framework to quantify the impact of treatment at cellular and tissue (granuloma), patient (lungs, lymph nodes and blood), and population scales. Sensitivity analyses allow us to determine which features of virtual patients are the strongest predictors of intervention efficacy across scales. These insights allow us to identify patient-heterogeneous mechanisms that drive outcomes across scales.
人们已经为各种病症构建了疾病进展的计算模型。通常情况下,与病理学相关的硅学干预研究的概念实施是临时性的,在设计上与实验研究类似。我们引入了多尺度干预设计(MID)框架,以实现两个关键目标:追踪从体内到患者再到人群的疾病动态;以及追踪干预措施在这些相同空间尺度上的影响。我们的 MID 框架优先考虑在虚拟临床前试验中调查对单个患者的影响,而不是复制实验研究的设计。我们应用 MID 框架来开发、组织和分析虚拟患者队列,以肺结核(TB)为例进行研究。在这项研究中,我们使用了 HostSim:我们的下一代结核分枝杆菌感染者全病人尺度计算模型。HostSim 通过跟踪多个肉芽肿以及肺结核期间涉及的血液和淋巴结区的动态变化来捕捉肺部感染情况。我们对 HostSim 进行了扩展,将一种简单的药物干预作为我们方法的一个实例,并使用我们的 MID 框架来量化治疗对细胞和组织(肉芽肿)、患者(肺、淋巴结和血液)以及人群的影响。通过敏感性分析,我们可以确定虚拟患者的哪些特征是各尺度干预效果的最强预测因素。这些洞察力使我们能够确定驱动各尺度结果的患者异质性机制。
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引用次数: 0
Metabolic perturbation studies using a Nash Equilibrium model of liver machine perfusion: modeling oxidative stress and effect of glutathione supplementation 利用肝机灌注纳什平衡模型进行代谢扰动研究:模拟氧化应激和谷胱甘肽补充剂的影响
Pub Date : 2024-01-08 DOI: 10.3389/fsysb.2023.1260315
Angelo Lucia, Korkut Uygun
The current clinical standard of Static Cold Storage (SCS) which involves preservation on ice (about +4°C) in a hypoxic state limits storage to a few hours for metabolically active tissues such as the liver and the heart. This period of hypoxia during can generate superoxide and other free radicals from purine metabolism, a well-established component of ischemia/reperfusion injury (IRI). Machine perfusion is at the cutting edge of organ preservation, which provides a functional, oxygenated preservation modality that can avoid/attenuate IRI. In clinical application, perfusion usually follows a period of SCS. This presentation of oxygen following hypoxia can lead to superoxide and hydrogen peroxide generation, but machine perfusion also allows manipulation of the temperature profiles and supply of antioxidant treatments, which could be used to minimize such issues. However, metabolomic data is difficult to gather, and there are currently no mathematical models present to allow rational design of experiments or guide clinical practice. In this article, the effects of a gradual warming temperature policy and glutathione supplementation to minimize oxidative stress are studied. An optimal gradual warming temperature policy for mid-thermic machine perfusion of a liver metabolic model is determined using a combination of Nash Equilibrium and Monte Carlo optimization. Using this optimal gradual warming temperature policy, minimum GSH requirements to maintain hydrogen peroxide concentrations in the normal region are calculated using a different Monte Carlo optimization methodology. In addition, the dynamic behavior of key metabolites and cofactors are determined. Results show that the minimum GSH requirement increases and that the ratio of GSH/GSSG decreases with increasing hydrogen peroxide concentration. In addition, at high concentrations of hydrogen peroxide it is shown that cytochrome C undergoes dysfunction leading to a decrease in useful oxygen consumption and ATP synthesis from the electron transport chain and an overall reduction in the energy charge for the liver cells.
目前的临床标准是静态冷藏(SCS),即在缺氧状态下置于冰上(约 +4°C)保存,这就将肝脏和心脏等代谢活跃组织的保存时间限制在几小时之内。这一时期的缺氧会产生超氧化物和其他来自嘌呤代谢的自由基,这是缺血/再灌注损伤(IRI)的一个公认组成部分。机器灌注是器官保存的最前沿技术,它提供了一种功能性氧合保存方式,可以避免/减轻 IRI。在临床应用中,灌注通常是在一段时间的 SCS 之后进行。缺氧后氧气的出现会导致超氧化物和过氧化氢的产生,但机器灌注还可以控制温度曲线和提供抗氧化剂治疗,从而最大限度地减少此类问题。然而,代谢组学数据很难收集,目前也没有数学模型来合理设计实验或指导临床实践。本文研究了逐渐升温的温度策略和补充谷胱甘肽对减少氧化应激的影响。采用纳什均衡和蒙特卡洛优化相结合的方法,确定了肝脏代谢模型中期热机灌注的最佳渐进升温温度策略。利用这种最佳渐进升温温度策略,采用不同的蒙特卡洛优化方法计算了将过氧化氢浓度维持在正常区域的最低 GSH 要求。此外,还确定了关键代谢物和辅助因子的动态行为。结果表明,随着过氧化氢浓度的增加,最低 GSH 需求量增加,GSH/GSSG 比率降低。此外,在高浓度的过氧化氢条件下,细胞色素 C 会发生功能障碍,导致电子传递链的有用耗氧量和 ATP 合成减少,肝细胞的能量负荷总体下降。
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引用次数: 0
Crosstalking with Dendritic Cells: A Path to Engineer Advanced T Cell Immunotherapy. 与树突状细胞串联:设计先进 T 细胞免疫疗法的途径。
Pub Date : 2024-01-01 Epub Date: 2024-04-29 DOI: 10.3389/fsysb.2024.1372995
Sogand Schafer, Kaige Chen, Leyuan Ma

Crosstalk between dendritic cells (DCs) and T cells plays a crucial role in modulating immune responses in natural and pathological conditions. DC-T cell crosstalk is achieved through contact-dependent (i.e., immunological synapse) and contact-independent mechanisms (i.e., cytokines). Activated DCs upregulate co-stimulatory signals and secrete proinflammatory cytokines to orchestrate T cell activation and differentiation. Conversely, activated T helper cells "license" DCs towards maturation, while regulatory T cells (Tregs) silence DCs to elicit tolerogenic immunity. Strategies to efficiently modulate the DC-T cell crosstalk can be harnessed to promote immune activation for cancer immunotherapy or immune tolerance for the treatment of autoimmune diseases. Here, we review the natural crosstalk mechanisms between DC and T cells. We highlight bioengineering approaches to modulate DC-T cell crosstalk, including conventional vaccines, synthetic vaccines, and DC-mimics, and key seminal studies leveraging these approaches to steer immune response for the treatment of cancer and autoimmune diseases.

树突状细胞(DC)和 T 细胞之间的串联在调节自然和病理条件下的免疫反应中起着至关重要的作用。DC-T细胞之间的串联是通过依赖接触的机制(即免疫突触)和不依赖接触的机制(即细胞因子)实现的。活化的 DC 上调共刺激信号并分泌促炎细胞因子,以协调 T 细胞的活化和分化。相反,活化的 T 辅助细胞会 "许可 "DC 走向成熟,而调节性 T 细胞(Tregs)则会抑制 DC 以激发耐受性免疫。有效调节DC-T细胞串扰的策略可用于促进癌症免疫疗法的免疫激活或治疗自身免疫性疾病的免疫耐受。在此,我们回顾了 DC 和 T 细胞之间的天然串联机制。我们重点介绍了调节直流-T 细胞串联的生物工程方法,包括传统疫苗、合成疫苗和直流模拟物,以及利用这些方法引导免疫反应以治疗癌症和自身免疫性疾病的重要开创性研究。
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引用次数: 0
Editorial: Integrative systems biology and big data for agricultural improvement and understanding 社论:综合系统生物学和大数据促进农业改良和理解
Pub Date : 2023-12-20 DOI: 10.3389/fsysb.2023.1347323
Liliana Fadul-Pacheco, Antony T. Vincent, Eric R. Paquet
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引用次数: 0
The development of an ingestible biosensor for the characterization of gut metabolites related to major depressive disorder: hypothesis and theory 开发用于描述与重度抑郁障碍有关的肠道代谢物特征的可摄取生物传感器:假设与理论
Pub Date : 2023-12-05 DOI: 10.3389/fsysb.2023.1274184
Amanda Densil, Mya Elisabeth George, Hala Mahdi, Andrew Chami, Alyssa Mark, Chantal Luo, Yifan Wang, Aribah Ali, Pengpeng Tang, Audrey Yihui Dong, Sin Yu Pao, Rubani Singh Suri, Isabella Valentini, Lila Al-Arabi, Fanxiao Liu, Alesha Singh, Linda Wu, Helen Peng, Anjana Sudharshan, Zoha Naqvi, Jayda Hewitt, Catherine Andary, Vincent Leung, Paul Forsythe, Jianping Xu
The diagnostic process for psychiatric conditions is guided by the Diagnostic and Statistical Manual of Mental Disorders (DSM) in North America. Revisions of the DSM over the years have led to lowered diagnostic thresholds across the board, incurring increased rates of both misdiagnosis and over-diagnosis. Coupled with stigma, this ambiguity and lack of consistency exacerbates the challenges that clinicians and scientists face in the clinical assessment and research of mood disorders such as Major Depressive Disorder (MDD). While current efforts to characterize MDD have largely focused on qualitative approaches, the broad variations in physiological traits, such as those found in the gut, suggest the immense potential of using biomarkers to provide a quantitative and objective assessment. Here, we propose the development of a probiotic Escherichia coli (E. coli) multi-input ingestible biosensor for the characterization of key gut metabolites implicated in MDD. DNA writing with CRISPR based editors allows for the molecular recording of signals while riboflavin detection acts as a means to establish temporal and spatial specificity for the large intestine. We test the feasibility of this approach through kinetic modeling of the system which demonstrates targeted sensing and robust recording of metabolites within the large intestine in a time- and dose- dependent manner. Additionally, a post-hoc normalization model successfully controlled for confounding factors such as individual variation in riboflavin concentrations, producing a linear relationship between actual and predicted metabolite concentrations. We also highlight indole, butyrate, tetrahydrofolate, hydrogen peroxide, and tetrathionate as key gut metabolites that have the potential to direct our proposed biosensor specifically for MDD. Ultimately, our proposed biosensor has the potential to allow for a greater understanding of disease pathophysiology, assessment, and treatment response for many mood disorders.
在北美,精神疾病的诊断过程由《精神疾病诊断和统计手册》(DSM)指导。多年来,DSM的修订导致了诊断门槛的全面降低,导致误诊和过度诊断率的增加。再加上耻辱感,这种模糊性和缺乏一致性加剧了临床医生和科学家在重度抑郁症(MDD)等情绪障碍的临床评估和研究中面临的挑战。虽然目前表征重度抑郁症的努力主要集中在定性方法上,但生理特征的广泛变化,例如在肠道中发现的生理特征,表明使用生物标志物提供定量和客观评估的巨大潜力。在这里,我们建议开发一种益生菌大肠杆菌(E. coli)多输入可摄取生物传感器,用于表征与MDD相关的关键肠道代谢物。使用基于CRISPR的编辑器编写DNA允许对信号进行分子记录,而核黄素检测则是建立大肠时间和空间特异性的一种手段。我们通过系统的动力学建模来测试这种方法的可行性,该系统以时间和剂量依赖的方式展示了对大肠内代谢物的靶向传感和稳健记录。此外,一个事后归一化模型成功地控制了核黄素浓度的个体差异等混杂因素,在实际代谢物浓度和预测代谢物浓度之间产生了线性关系。我们还强调吲哚、丁酸盐、四氢叶酸、过氧化氢和四硫酸盐是关键的肠道代谢物,它们有可能指导我们提出的MDD生物传感器。最终,我们提出的生物传感器有潜力允许对许多情绪障碍的疾病病理生理学,评估和治疗反应有更深入的了解。
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引用次数: 0
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Frontiers in systems biology
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