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The morphology of cell spheroids in simple shear flow 简单剪切流中的球形细胞形态
Pub Date : 2024-04-11 DOI: arxiv-2404.07528
Rosalia Ferraro, Jasmin Di Franco, Sergio Caserta, Stefano Guido
Cell spheroids are a widely used model to investigate cell-cell andcell-matrix interactions in a 3D microenvironment in vitro. Most research oncell spheroids has been focused on their response to various stimuli understatic conditions. Recently, the effect of flow on cell spheroids has beeninvestigated in the context of tumor invasion in interstitial space. Inparticular, microfluidic perfusion of cell spheroids embedded in a collagenmatrix has been shown to modulate cell-cell adhesion and to represent apossible mechanism promoting tumor invasion by interstitial flow. However,studies on the effects of well-defined flow fields on cell spheroids arelacking in the literature. Here, we apply simple shear flow to cell spheroidsin a parallel plate apparatus while observing their morphology by opticalmicroscopy. By using image analysis techniques, we show that cell spheroidsrotate under flow as rigid particles. As time goes on, cells from the outerlayer detach from the sheared cell spheroids and are carried away by the flow.Hence, the size of cell spheroids declines with time at a rate increasing withthe external shear stress, which can be used to estimate cell-cell adhesion.The technique proposed in this work allows one to correlate flow-inducedeffects with microscopy imaging of cell spheroids in a well-established shearflow field, thus providing a method to obtain quantitative results which arerelevant in the general field of mechanobiology.
细胞球是一种广泛使用的模型,用于研究体外三维微环境中细胞-细胞和细胞-基质之间的相互作用。大多数关于细胞球的研究都集中在它们对各种刺激和静态条件的反应上。最近,在肿瘤侵入间质空间的背景下,人们研究了流动对细胞球的影响。特别是,对嵌入胶原基质的细胞球体进行微流体灌注已被证明能调节细胞与细胞之间的粘附力,是间质流动促进肿瘤侵袭的可能机制。然而,文献中缺乏关于定义明确的流场对细胞球体影响的研究。在这里,我们在平行板装置中对细胞球体施加简单的剪切流,同时用光学显微镜观察它们的形态。通过图像分析技术,我们发现细胞球体在流动过程中会像刚性颗粒一样旋转。随着时间的推移,外层细胞会从剪切的细胞球体上脱离并被流动带走。因此,细胞球体的大小会随着时间的推移而减小,减小的速度随着外部剪切应力的增大而增大,这可以用来估计细胞与细胞之间的粘附力。这项工作中提出的技术可以将流动诱导效应与细胞球体在成熟的剪切流场中的显微成像联系起来,从而提供了一种获得定量结果的方法,这些定量结果与一般的机械生物学领域相关。
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引用次数: 0
Nonlinear dynamics of confined cell migration -- modeling and inference 封闭细胞迁移的非线性动力学--建模与推理
Pub Date : 2024-04-10 DOI: arxiv-2404.07390
Pedrom Zadeh, Brian A. Camley
The motility of eukaryotic cells is strongly influenced by their environment,with confined cells often developing qualitatively different motility patternsfrom those migrating on simple two-dimensional substrates. Recent experiments,coupled with data-driven methods to extract a cell's equation of motion, showedthat cancerous MDA-MB-231 cells persistently hop in a limit cycle when placedon two-state adhesive micropatterns (two large squares connected by a narrowbridge), while they remain stationary on average in rectangular confinements.In contrast, healthy MCF10A cells migrating on the two-state micropattern arebistable, i.e., they settle into either basin on average with onlynoise-induced hops between the two states. We can capture all these behaviorswith a single computational phase field model of a crawling cell, under theassumption that contact with non-adhesive substrate inhibits the cell front.Our model predicts that larger and softer cells are more likely to persistentlyhop, while smaller and stiffer cells are more likely to be bistable. Other keyfactors controlling cell migration are the frequency of protrusions and theirmagnitude of noise. Our results show that relatively simple assumptions abouthow cells sense their geometry can explain a wide variety of different cellbehaviors, and show the power of data-driven approaches to characterize bothexperiment and simulation.
真核细胞的运动受环境影响很大,封闭的细胞与在简单的二维基质上迁移的细胞通常会形成质的不同的运动模式。最近的实验以及提取细胞运动方程的数据驱动方法表明,癌细胞 MDA-MB-231 放置在双态粘合微图案(由窄桥连接的两个大正方形)上时,会在极限循环中持续跳跃,而在矩形封闭环境中则平均保持静止、与此相反,健康的 MCF10A 细胞在双态微模式下迁移时是可变的,即它们平均会定居在任一盆地中,两种状态之间只有噪声引起的跳跃。我们可以用一个爬行细胞的单一计算相场模型来捕捉所有这些行为,前提是与非粘性基底的接触会抑制细胞前沿。我们的模型预测,较大和较软的细胞更有可能持续跳跃,而较小和较硬的细胞更有可能双稳态。控制细胞迁移的其他关键因素是突起的频率及其噪声的大小。我们的研究结果表明,关于细胞如何感知其几何形状的相对简单的假设可以解释各种不同的细胞行为,并展示了数据驱动方法在实验和模拟两方面进行表征的能力。
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引用次数: 0
Blood lipoproteins shape the phenotype and lipid content of early atherosclerotic lesion macrophages: a dual-structured mathematical model 血脂蛋白决定早期动脉粥样硬化病变巨噬细胞的表型和脂质含量:双结构数学模型
Pub Date : 2024-04-10 DOI: arxiv-2404.07051
Keith L Chambers, Mary R Myerscough, Michael G Watson, Helen M Byrne
Macrophages in atherosclerotic lesions exhibit a spectrum of behaviours orphenotypes. The phenotypic distribution of monocyte-derived macrophages (MDMs),its correlation with MDM lipid content, and relation to blood lipoproteindensities are not well understood. Of particular interest is the balancebetween low density lipoproteins (LDL) and high density lipoproteins (HDL),which carry bad and good cholesterol respectively. To address these issues, wehave developed a mathematical model for early atherosclerosis in which the MDMpopulation is structured by phenotype and lipid content. The model admits asimpler, closed subsystem whose analysis shows how lesion composition becomesmore pathological as the blood density of LDL increases relative to the HDLcapacity. We use asymptotic analysis to derive a power-law relationship betweenMDM phenotype and lipid content at steady-state. This relationship enables usto understand why, for example, lipid-laden MDMs have a more inflammatoryphenotype than lipid-poor MDMs when blood LDL lipid density greatly exceeds HDLcapacity. We show further that the MDM phenotype distribution always attains alocal maximum, while the lipid content distribution may be unimodal, adopt aquasi-uniform profile or decrease monotonically. Pathological lesions exhibit alocal maximum in both the phenotype and lipid content MDM distributions, withthe maximum at an inflammatory phenotype and near the lipid content capacityrespectively. These results illustrate how macrophage heterogeneity arises inearly atherosclerosis and provide a framework for future model validationthrough comparison with single-cell RNA sequencing data.
动脉粥样硬化病变中的巨噬细胞表现出多种行为或表型。单核细胞衍生巨噬细胞(MDM)的表型分布、其与MDM脂质含量的相关性以及与血液脂蛋白密度的关系尚不十分清楚。尤其令人感兴趣的是低密度脂蛋白(LDL)和高密度脂蛋白(HDL)之间的平衡,它们分别携带坏胆固醇和好胆固醇。为了解决这些问题,我们建立了一个早期动脉粥样硬化的数学模型,其中 MDM 群体是由表型和脂质含量构成的。该模型包含一个更简单的封闭子系统,其分析表明了病变组成如何随着血液中低密度脂蛋白密度相对于高密度脂蛋白容量的增加而变得更加病态。我们利用渐进分析推导出稳态时 MDM 表型与脂质含量之间的幂律关系。这种关系使我们能够理解,例如,当血液中低密度脂蛋白脂质密度大大超过高密度脂蛋白容量时,为什么脂质含量高的 MDM 比脂质含量低的 MDM 具有更强的炎症表型。我们进一步研究发现,MDM 表型分布总是达到局部最大值,而脂质含量分布可能是单峰的,也可能是水均匀分布或单调递减。病理病变的 MDM 表型和脂质含量分布都显示出局部最大值,最大值分别位于炎症表型和脂质含量容量附近。这些结果说明了巨噬细胞的异质性是如何在早期动脉粥样硬化中产生的,并通过与单细胞 RNA 测序数据的比较为未来的模型验证提供了一个框架。
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引用次数: 0
Does nematic order allow groups of elongated cells to sense electric fields better? 向列有序是否能让拉长的细胞群更好地感知电场?
Pub Date : 2024-04-06 DOI: arxiv-2404.04723
Kurmanbek Kaiyrbekov, Brian A. Camley
Collective response to external directional cues like electric fields plays apivotal role in processes such as tissue development, regeneration, and woundhealing. In this study we focus on the impact of anisotropy in cell shape andlocal cell alignment on the collective response to electric fields. We modelelongated cells that have a different accuracy sensing the field depending ontheir orientation with respect to the field. Elongated cells often line up withtheir long axes in the same direction - "nematic order" - does this help thegroup of cells sense the field more accurately? We use simulations of a simplemodel to show that if cells orient themselves perpendicular to their averagevelocity, alignment of a cell's long axis to its nearest neighbors' orientationcan enhance the directional response to electric fields. However, for cells tobenefit from aligning, their accuracy of sensing must be strongly dependent oncell orientation. We also show that cell-cell adhesion modulates the accuracyof cells in the group.
对电场等外部定向线索的集体反应在组织发育、再生和伤口愈合等过程中起着至关重要的作用。在这项研究中,我们重点研究了细胞形状的各向异性和局部细胞排列对电场集体响应的影响。我们将拉长的细胞制成模式,根据它们相对于电场的方向不同,它们对电场的感应精度也不同。拉长的细胞通常与其长轴朝同一方向排列--这就是 "向列序"--这是否有助于细胞群更准确地感知电场?我们利用一个简单模型的模拟结果表明,如果细胞的方向与其平均速度垂直,细胞长轴与其近邻的方向一致就能增强对电场的定向响应。然而,要使细胞从对齐中获益,其感应的准确性必须与细胞方向密切相关。我们还发现,细胞间的粘附会调节细胞群的精确度。
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引用次数: 0
Emergent Simplicities in the Living Histories of Individual Cells 单个细胞生命历程中的新兴简单性
Pub Date : 2024-04-02 DOI: arxiv-2404.01682
Charles S. Wright, Kunaal Joshi, Rudro R. Biswas, Srividya Iyer-Biswas
Organisms maintain the status quo, holding key physiological variablesconstant to within an acceptable tolerance, and yet adapt with precision andplasticity to dynamic changes in externalities. What organizational principlesensure such exquisite yet robust control of systems-level "state variables" incomplex systems with an extraordinary number of moving parts and fluctuatingvariables? Here we focus on these issues in the specific context of intra- andintergenerational life histories of individual bacterial cells, whosebiographies are precisely charted via high-precision dynamic experiments usingthe SChemostat technology. We highlight intra- and intergenerational scalinglaws and other "emergent simplicities" revealed by these high-precision data.In turn, these facilitate a principled route to dimensional reduction of theproblem, and serve as essential building blocks for phenomenological andmechanistic theory. Parameter-free data-theory matches for multiple organismsvalidate theory frameworks, and explicate the systems physics of stochastichomeostasis and adaptation.
生物体维持现状,将关键的生理变量保持在可接受的容差范围内,同时又能精确地、可塑性地适应外部环境的动态变化。在具有大量运动部件和波动变量的复杂系统中,什么样的组织原则才能确保对系统级 "状态变量 "进行如此精细而稳健的控制?在这里,我们以单个细菌细胞的代内和代际生命史为特定背景,重点讨论了这些问题。我们利用 SChemostat 技术,通过高精度动态实验精确绘制了这些细胞的生命史。我们强调了这些高精度数据所揭示的代内和代际缩放规律及其他 "突现的简单性"。反过来,这些数据又促进了问题降维的原则性途径,并成为现象学和机理理论的重要基石。多个生物体的无参数数据理论匹配验证了理论框架,并解释了随机稳态和适应的系统物理学。
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引用次数: 0
Healing Regimes for Microscopic Wounds in the Vertex Model of Cell Tissues 细胞组织顶点模型中显微伤口的愈合机制
Pub Date : 2024-03-21 DOI: arxiv-2403.14501
R. F. Almada, N. A. M. Araujo, P. Patricio
Wounds in epithelial tissues compromise their vital role in homeostasis. Arapid and efficient wound healing encompasses different mechanisms, whichincludes the formation of a contractile actin-myosin cable around its edge,known as the purse-string mechanism. We combine mean-field calculations andnumerical simulations of the Vertex model to study the interplay between tissueproperties and the purse-string mechanism and its impact on the healingprocess. We find different regimes, where the wound opens, closes partially orcompletely. We also derive an analytic expression for the closure time which isvalidated by numerical simulations. This study establishes under whichconditions the purse-string mechanism suffices for closure, providing ananalytical mean-field expression for the respective thresholds.
上皮组织的伤口会损害其在平衡中的重要作用。快速高效的伤口愈合包含不同的机制,其中包括在伤口边缘形成收缩的肌动蛋白-肌球蛋白索,即所谓的 "荷包绳机制"。我们结合顶点模型的均场计算和数值模拟,研究了组织特性与荷包绳机制之间的相互作用及其对愈合过程的影响。我们发现了伤口张开、部分闭合或完全闭合的不同状态。我们还推导出了闭合时间的解析表达式,并通过数值模拟进行了验证。这项研究确定了在哪些条件下,荷包绳机制足以使伤口闭合,并提供了相应阈值的平均场分析表达式。
{"title":"Healing Regimes for Microscopic Wounds in the Vertex Model of Cell Tissues","authors":"R. F. Almada, N. A. M. Araujo, P. Patricio","doi":"arxiv-2403.14501","DOIUrl":"https://doi.org/arxiv-2403.14501","url":null,"abstract":"Wounds in epithelial tissues compromise their vital role in homeostasis. A\u0000rapid and efficient wound healing encompasses different mechanisms, which\u0000includes the formation of a contractile actin-myosin cable around its edge,\u0000known as the purse-string mechanism. We combine mean-field calculations and\u0000numerical simulations of the Vertex model to study the interplay between tissue\u0000properties and the purse-string mechanism and its impact on the healing\u0000process. We find different regimes, where the wound opens, closes partially or\u0000completely. We also derive an analytic expression for the closure time which is\u0000validated by numerical simulations. This study establishes under which\u0000conditions the purse-string mechanism suffices for closure, providing an\u0000analytical mean-field expression for the respective thresholds.","PeriodicalId":501321,"journal":{"name":"arXiv - QuanBio - Cell Behavior","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140202586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Transfer Learning for T-Cell Response Prediction 用于 T 细胞反应预测的迁移学习
Pub Date : 2024-03-18 DOI: arxiv-2403.12117
Josua StadelmaierUniversity of Tübingen, Brandon MaloneNEC OncoImmunity, Ralf EggelingUniversity of Tübingen
We study the prediction of T-cell response for specific given peptides, whichcould, among other applications, be a crucial step towards the development ofpersonalized cancer vaccines. It is a challenging task due to limited,heterogeneous training data featuring a multi-domain structure; such dataentail the danger of shortcut learning, where models learn generalcharacteristics of peptide sources, such as the source organism, rather thanspecific peptide characteristics associated with T-cell response. Using a transformer model for T-cell response prediction, we show that thedanger of inflated predictive performance is not merely theoretical but occursin practice. Consequently, we propose a domain-aware evaluation scheme. We thenstudy different transfer learning techniques to deal with the multi-domainstructure and shortcut learning. We demonstrate a per-source fine tuningapproach to be effective across a wide range of peptide sources and furthershow that our final model outperforms existing state-of-the-art approaches forpredicting T-cell responses for human peptides.
我们研究了针对特定多肽的 T 细胞反应预测,除其他应用外,这可能是开发个性化癌症疫苗的关键一步。由于具有多域结构的异构训练数据有限,这是一项具有挑战性的任务;此类数据存在捷径学习的危险,即模型学习的是肽源的一般特征,如源生物,而不是与 T 细胞反应相关的特定肽特征。通过使用 T 细胞反应预测的转换器模型,我们发现预测性能膨胀的危险不仅存在于理论上,而且在实践中也时有发生。因此,我们提出了一种领域感知评估方案。然后,我们研究了不同的迁移学习技术,以处理多领域结构和捷径学习。我们证明了按来源进行微调的方法在广泛的肽来源中是有效的,并进一步证明了我们的最终模型在预测人类肽的 T 细胞反应方面优于现有的最先进方法。
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引用次数: 0
Modeling iPSC-derived Endothelial Cell Transition in Tumor Angiogenesis using Petri Nets 利用 Petri 网模拟肿瘤血管生成过程中的 iPSC 衍生内皮细胞转换
Pub Date : 2024-03-11 DOI: arxiv-2403.06555
Adéla Šterberová, Andreea Dincu, Stijn Oudshoorn, Vincent van Duinen, Lu Cao
Tumor angiogenesis concerns the development of new blood vessels supplyingthe necessary nutrients for the further development of existing tumor cells.The entire process is complex, involving the production and consumption ofchemicals, endothelial cell transitions as well as cell interactions,divisions, and migrations. Microfluidic cell culture platform has been used tostudy angiogenesis of endothelial cells derived from human induced pluripotentstem cells (iPSC-ECs) for a physiological relevant micro-environment. In thispaper, we elaborate on how to define a pipeline for simulating thetransformation and process that an iPSC-derived endothelial cell goes throughin this biological scenario. We leverage the robustness and simplicity of Petrinets for modeling the cell transformation and associated constraints. Theenvironmental and spacial factors are added using custom 2-dimensional grids.Although the pipeline does not capture the entire complexity of tumorangiogenesis, we are able to capture the essence of endothelial celltransitions in tumor angiogenesis using this conceptually simplified solution.
整个过程十分复杂,涉及化学物质的产生和消耗、内皮细胞的转换以及细胞的相互作用、分裂和迁移。微流控细胞培养平台已被用于研究由人诱导多能干细胞(iPSC-ECs)衍生的内皮细胞在生理相关微环境中的血管生成。在本文中,我们将详细阐述如何定义一个管道,用于模拟 iPSC 内皮细胞在这种生物场景中的转化和过程。我们利用 Petrinets 的鲁棒性和简易性对细胞转化和相关约束进行建模。虽然该管道不能捕捉到肿瘤血管生成的全部复杂性,但我们能够利用这种概念上简化的解决方案捕捉到肿瘤血管生成过程中内皮细胞转化的本质。
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引用次数: 0
Properties of Hagen-Poiseuille flows in channel networks 渠道网络中哈根-普瓦耶流的特性
Pub Date : 2024-02-29 DOI: arxiv-2402.19185
A. F. Valente, R. Almeida, R. Dilão
We derive the main properties of adaptive Hagen-Poiseuille flows in elasticmicrochannel networks akin to biological veins in organisms. We show thatadaptive Hagen-Poiseuille flows successfully simulate key features oftextit{Physarum polycephalum} networks, replicating physiologicalout-of-equilibrium phenomena like peristalsis and shuttle streaming, associatedwith the mechanism of nutrient transport in textit{Physarum}. A newtopological steady state has been identified for asynchronous adaptation,supporting out-of-equilibrium laminar fluxes. Adaptive Hagen-Poiseuille flowsshow saturation effects on the fluxes in contractile veins, as observed inanimal and artificial contractile veins.
我们推导了弹性微通道网络(类似于生物体内的生物静脉)中自适应哈根-普瓦耶流的主要特性。我们的研究表明,自适应哈根-普绪耶流成功地模拟了textit{Physarum polycephalum}网络的主要特征,复制了与textit{Physarum}营养物质运输机制相关的生理失衡现象,如蠕动和穿梭流。为异步适应确定了一种新的表观稳态,支持失衡层流。正如在动物和人工收缩静脉中观察到的那样,适应性哈根-普瓦斯维尔流对收缩静脉中的通量显示出饱和效应。
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引用次数: 0
Why Attention Graphs Are All We Need: Pioneering Hierarchical Classification of Hematologic Cell Populations with LeukoGraph 为什么我们只需要注意图?利用 LeukoGraph 率先对血液细胞群进行分级分类
Pub Date : 2024-02-28 DOI: arxiv-2402.18610
Fatemeh Nassajian Mojarrad, Lorenzo Bini, Thomas Matthes, Stéphane Marchand-Maillet
In the complex landscape of hematologic samples such as peripheral blood orbone marrow, cell classification, delineating diverse populations into ahierarchical structure, presents profound challenges. This study presentsLeukoGraph, a recently developed framework designed explicitly for this purposeemploying graph attention networks (GATs) to navigate hierarchicalclassification (HC) complexities. Notably, LeukoGraph stands as a pioneeringeffort, marking the application of graph neural networks (GNNs) forhierarchical inference on graphs, accommodating up to one million nodes andmillions of edges, all derived from flow cytometry data. LeukoGraph intricatelyaddresses a classification paradigm where for example four different cellpopulations undergo flat categorization, while a fifth diverges into twodistinct child branches, exemplifying the nuanced hierarchical structureinherent in complex datasets. The technique is more general than this example.A hallmark achievement of LeukoGraph is its F-score of 98%, significantlyoutclassing prevailing state-of-the-art methodologies. Crucially, LeukoGraph'sprowess extends beyond theoretical innovation, showcasing remarkable precisionin predicting both flat and hierarchical cell types across flow cytometrydatasets from 30 distinct patients. This precision is further underscored byLeukoGraph's ability to maintain a correct label ratio, despite the inherentchallenges posed by hierarchical classifications.
在外周血或骨髓等血液样本的复杂环境中,细胞分类、将不同种群划分为层次结构等工作面临着巨大挑战。本研究介绍了LeukoGraph,它是最近开发的一个框架,专门为此目的而设计,采用图注意网络(GAT)来驾驭分层分类(HC)的复杂性。值得注意的是,LeukoGraph 是一项开创性的工作,它标志着图神经网络(GNN)在图层次推断中的应用,可容纳多达一百万个节点和数百万条边,所有这些都来自流式细胞仪数据。LeukoGraph复杂地处理了一个分类范例,例如,四个不同的细胞群进行平面分类,而第五个细胞群则分化为两个不同的子分支,体现了复杂数据集中固有的细微层次结构。LeukoGraph 的一个标志性成就是它的 F 分数高达 98%,大大超过了目前最先进的方法。最重要的是,LeukoGraph 的优势不仅限于理论创新,它在预测来自 30 位不同患者的流式细胞仪数据集中的扁平和分层细胞类型方面都表现出了非凡的精确性。LeukoGraph 还能保持正确的标记比例,这进一步突出了它的精确性,尽管分层分类本身就存在挑战。
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引用次数: 0
期刊
arXiv - QuanBio - Cell Behavior
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