Journal of Theoretical Biology最新文献

英文中文

JTB Editorial for Professor Denise Kirschner 为 Denise Kirschner 教授撰写的 JTB 编辑文章。

IF 1.9 4区数学 Q2 BIOLOGY

Journal of Theoretical Biology

Pub Date : 2024-10-18 DOI: 10.1016/j.jtbi.2024.111976

Mark Chaplain (Journal of Theoretical Biology co-Chief Editor), Akira Sasaki (Journal of Theoretical Biology co-Chief Editor), Joshua Weitz (Journal of Theoretical Biology co-Chief Editor)

引用次数: 0

Probabilistic analysis of tumor growth inhibition models to Support trial design 肿瘤生长抑制模型的概率分析，支持试验设计。

IF 1.9 4区数学 Q2 BIOLOGY

Journal of Theoretical Biology

Pub Date : 2024-10-18 DOI: 10.1016/j.jtbi.2024.111969

Marcus Baaz , Tim Cardilin , Torbjörn Lundh , Mats Jirstrand

A large enough sample size of patients is required to statistically show that one treatment is better than another. However, too large a sample size is expensive and can also result in findings that are statistically significant, but not clinically relevant. How sample sizes should be chosen is a well-studied problem in classical statistics and analytical expressions can be derived from the appropriate test statistic. However, these expressions require information regarding the efficacy of the treatment, which may not be available, particularly for newly developed drugs. Tumor growth inhibition (TGI) models are frequently used to quantify the efficacy of newly developed anticancer drugs. In these models, the tumor growth dynamics are commonly described by a set of ordinary differential equations containing parameters that must be estimated using experimental data.

One widely used endpoint in clinical trials is the proportion of patients in different response categories determined using the Response Evaluation Criteria In Solid Tumors (RECIST) framework. From the TGI model, we derive analytical expressions for the probability of patient response to combination therapy. The probabilistic expressions are used together with classical statistics to derive a parametric model for the sample size required to achieve a certain significance level and test power when comparing two treatments.

Furthermore, the probabilistic expressions are used to generalize the Tumor Static Exposure concept to be more suitable for predicting clinical response. The derivatives of the probabilistic expressions are used to derive two additional expressions characterizing the exposure and its sensitivity. Finally, our results are illustrated using parameters obtained from calibrating the model to preclinical data.

要从统计学角度证明一种治疗方法优于另一种治疗方法，需要足够大的患者样本量。然而，样本量过大不仅成本高昂，还可能导致研究结果具有统计学意义，但与临床无关。如何选择样本量是经典统计学中一个经过深入研究的问题，可以从适当的检验统计量得出分析表达式。然而，这些表达式需要有关疗效的信息，而这些信息可能无法获得，尤其是新开发的药物。肿瘤生长抑制（TGI）模型常用于量化新开发抗癌药物的疗效。在这些模型中，肿瘤生长动态通常由一组常微分方程来描述，其中包含的参数必须使用实验数据来估算。临床试验中广泛使用的一个终点是根据实体瘤反应评估标准（RECIST）框架确定的不同反应类别患者的比例。根据 TGI 模型，我们推导出了患者对联合疗法产生反应的概率分析表达式。将概率表达式与经典统计学方法结合使用，可推导出参数模型，用于比较两种治疗方法时达到一定显著性水平和检验功率所需的样本量。此外，概率表达式还用于推广肿瘤静态暴露概念，使其更适用于预测临床反应。概率表达式的导数被用来推导出另外两个表达式，以表征暴露及其敏感性。最后，我们使用根据临床前数据校准模型所获得的参数对结果进行了说明。

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引用次数: 0

A bulk-surface mechanobiochemical modelling approach for single cell migration in two-space dimensions 二维空间中单细胞迁移的体表机械生物化学建模方法。

IF 1.9 4区数学 Q2 BIOLOGY

Journal of Theoretical Biology

Pub Date : 2024-10-16 DOI: 10.1016/j.jtbi.2024.111966

David Hernandez-Aristizabal , Diego-Alexander Garzon-Alvarado , Carlos-Alberto Duque-Daza , Anotida Madzvamuse

In this work, we present a mechanobiochemical model for two-dimensional cell migration which couples mechanical properties of the cell cytosol with biochemical processes taking place near or on the cell plasma membrane. The modelling approach is based on a recently developed mathematical formalism of evolving bulk-surface partial differential equations of reaction–diffusion type. We solve these equations using finite element methods within a moving-mesh framework derived from the weak formulation of the evolving bulk-surface PDEs. In the present work, the cell cytosol interior (bulk) dynamics are coupled to the cell membrane (surface) dynamics through non-homogeneous Dirichlet boundary conditions. The modelling approach exhibits both directed cell migration in response to chemical cues as well as spontaneous migration in the absence of such cues. As a by-product, the approach shows fundamental characteristics associated with single cell migration such as: (i) cytosolic and membrane polarisation, (ii) actin dependent protrusions, and (iii) continuous shape deformation of the cell during migration.

Cell migration is an ubiquitous process in life that is mainly triggered by the dynamics of the actin cytoskeleton and therefore is driven by both mechanical and biochemical processes. It is a multistep process essential for mammalian organisms and is closely linked to a vast diversity of processes; from embryonic development to cancer invasion. Experimental, theoretical and computational studies have been key to elucidate the mechanisms underlying cell migration. On one hand, rapid advances in experimental techniques allow for detailed experimental measurements of cell migration pathways, while, on the other, computational approaches allow for the modelling, analysis and understanding of such observations. The bulk-surface mechanobiochemical modelling approach presented in this work, set premises to study single cell migration through complex non-isotropic environments in two- and three-space dimensions.

在这项研究中，我们提出了一种二维细胞迁移的机械生物化学模型，该模型将细胞胞体的机械特性与发生在细胞质膜附近或细胞质膜上的生化过程结合起来。建模方法基于最近开发的反应-扩散型体表偏微分方程演化数学形式。我们使用有限元方法，在由不断演化的体表偏微分方程的弱公式推导出的移动网格框架内求解这些方程。在本研究中，细胞胞体内部（体）动力学与细胞膜（表面）动力学通过非均质 Dirichlet 边界条件耦合在一起。这种建模方法既显示了细胞在化学线索作用下的定向迁移，也显示了细胞在无化学线索作用下的自发迁移。作为副产品，该方法显示了与单细胞迁移相关的基本特征，例如(i) 细胞质和细胞膜极化，(ii) 依靠肌动蛋白的突起，以及 (iii) 迁移过程中细胞形状的持续变形。细胞迁移是生命中无处不在的过程，主要由肌动蛋白细胞骨架的动态触发，因此由机械和生化过程共同驱动。它是哺乳动物生物体必不可少的一个多步骤过程，与从胚胎发育到癌症侵袭等多种过程密切相关。实验、理论和计算研究是阐明细胞迁移机制的关键。一方面，实验技术的飞速发展使我们能够对细胞迁移途径进行详细的实验测量；另一方面，计算方法使我们能够对这些观察结果进行建模、分析和理解。本研究提出的体表机械生物化学建模方法，为研究单细胞在二维和三维复杂的非各向同性环境中的迁移提供了前提条件。

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引用次数: 0

Bayesian parameter inference for epithelial mechanics 上皮力学的贝叶斯参数推断。

IF 1.9 4区数学 Q2 BIOLOGY

Journal of Theoretical Biology

Pub Date : 2024-10-10 DOI: 10.1016/j.jtbi.2024.111960

Xin Yan , Goshi Ogita , Shuji Ishihara , Kaoru Sugimura

Cell-based mechanical models, such as the Cell Vertex Model (CVM), have proven useful for studying the mechanical control of epithelial tissue dynamics. We recently developed a statistical method called image-based parameter inference for formulating CVM model functions and estimating their parameters from image data of epithelial tissues. In this study, we employed Bayesian statistics to improve the utility and flexibility of image-based parameter inference. Tests on synthetic data confirmed that both our non-hierarchical and hierarchical Bayesian models provide accurate estimates of model parameters. By applying this method to Drosophila wings, we demonstrated that the reliability of parameter estimation is closely linked to the mechanical anisotropies present in the tissue. Moreover, we revealed that the cortical elasticity term is dispensable for explaining force-shape correlations in vivo. We anticipate that the flexibility of the Bayesian statistical framework will facilitate the integration of various types of information, thereby contributing to the quantitative dissection of the mechanical control of tissue dynamics.

基于细胞的机械模型，如细胞顶点模型（CVM），已被证明有助于研究上皮组织动态的机械控制。我们最近开发了一种称为基于图像的参数推断的统计方法，用于制定 CVM 模型函数，并从上皮组织的图像数据中估计其参数。在这项研究中，我们采用了贝叶斯统计方法来提高基于图像的参数推断的实用性和灵活性。对合成数据的测试证实，我们的非分层贝叶斯模型和分层贝叶斯模型都能准确估计模型参数。通过将这种方法应用于果蝇翅膀，我们证明了参数估计的可靠性与组织中存在的机械各向异性密切相关。此外，我们还揭示了皮层弹性项对于解释体内力-形状相关性是不可或缺的。我们预计贝叶斯统计框架的灵活性将有助于整合各种类型的信息，从而为定量分析组织动力学的机械控制做出贡献。

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引用次数: 0

Choice of landscape discretisation method affects the inferred rate of spread in wildlife disease spread models 景观离散化方法的选择会影响野生动物疾病传播模型的推断传播速度。

IF 1.9 4区数学 Q2 BIOLOGY

Journal of Theoretical Biology

Pub Date : 2024-10-09 DOI: 10.1016/j.jtbi.2024.111963

Mossa Merhi Reimert, Maya Katrin Gussmann, Anette Ella Boklund, Matt Denwood

Disease modelling at the livestock-wildlife interface is an important topic for which discrete-space models are used for the wildlife component. One prominent example is African Swine Fever, where wild boar play an influential role as reservoirs of disease spillover into domestic pig farms. In this paper, we present a simulation study that demonstrates the impact of seemingly arbitrary choices of landscape discretisation method on the inferred rate of spread within the model. We use an ordinary differential equation model to implement a simplified model of disease transmission between discrete groups of wild boar with spillover into domestic pig farms contained within a homogeneous landscape. We examine a range of scenarios whereby the landscape is discretised into wild boar patches of varying size and shape, and compare the rate of spread between domestic pig farms placed at fixed points on the landscape. Our results demonstrate a non-monotonic relationship between patch size and rate of spread, which is particularly unstable and unpredictable for square and triangular shaped patches. Discretisation of the landscape into hexagons appears to produce a more stable relationship between patch size and rate of spread for the three types of transmission kernel we investigated. Although the rate of disease spread does converge to a stable value, this occurs at patch sizes that are much smaller than would be used in practice for wild boar. We conclude that outputs of disease models containing a wildlife component should not be considered to be robust to arbitrary choices for patch size and placement, but rather as a source of uncertainty to be examined using sensitivity analysis. Furthermore, we strongly recommend the use of hexagons rather than squares or right triangles for landscape discretisation.

家畜与野生动物交界处的疾病建模是一个重要课题，其中野生动物部分采用离散空间模型。其中一个突出的例子是非洲猪瘟，野猪作为疫病传播源对国内养猪场的影响很大。在本文中，我们介绍了一项模拟研究，展示了看似任意选择的景观离散化方法对模型内推断传播速度的影响。我们使用常微分方程模型来实现离散野猪群之间的疾病传播简化模型，并将其外溢到包含在同质景观中的家猪场。我们研究了将地貌离散为大小和形状各异的野猪斑块的一系列方案，并比较了位于地貌上固定点的家猪场之间的传播速度。我们的研究结果表明，斑块大小与扩散速度之间存在非单调关系，尤其是正方形和三角形斑块的扩散速度不稳定，难以预测。对于我们研究的三种传播内核，将地形离散化为六边形似乎能在斑块大小和传播速度之间产生更稳定的关系。虽然疾病传播率确实趋近于一个稳定值，但这是在斑块大小远小于野猪实际使用的情况下发生的。我们的结论是，包含野生动物成分的疾病模型的输出结果不应被视为对任意选择的斑块大小和位置具有稳健性，而应被视为不确定性的来源，并使用敏感性分析进行研究。此外，我们强烈建议使用六边形而不是正方形或直角三角形进行景观离散化。

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引用次数: 0

A model for transcription-dependent R-loop formation at double-stranded DNA breaks: Implications for their detection and biological effects 双链 DNA 断裂处转录依赖性 R 环形成模型：对其检测和生物效应的影响

IF 1.9 4区数学 Q2 BIOLOGY

Journal of Theoretical Biology

Pub Date : 2024-10-09 DOI: 10.1016/j.jtbi.2024.111962

Boris P. Belotserkovskii, Philip C. Hanawalt

R-loops are structures containing an RNA-DNA duplex and an unpaired DNA strand. During R-loop formation an RNA strand invades the DNA duplex, displacing the homologous DNA strand and binding the complementary DNA strand. Here we analyze a model for transcription-dependent R-loop formation at double-stranded DNA breaks (DSBs). In this model, R-loop formation is preceded by detachment of the non-template DNA strand from the RNA polymerase (RNAP). Then, strand exchange is initiated between the nascent RNA and the non-template DNA strand. During that strand exchange the length of the R-loop could either increase, or decrease in a biased random-walk fashion, in which the bias would depend upon the DNA sequence. Eventually, the restoration of the DNA duplex would completely displace the RNA. However, as long as the RNAP remains bound to the template DNA strand it prevents that displacement. Thus, according to the model, RNAPs stalled at DSBs can increase the lifespan of R-loops, increasing their detectability in experiments, and perhaps enhancing their biological effects.

R 环是包含 RNA-DNA 双链和未配对 DNA 链的结构。在 R 环形成过程中，RNA 链侵入 DNA 双链，取代同源 DNA 链并结合互补 DNA 链。在这里，我们分析了双链DNA断裂（DSB）处依赖转录的R环形成模型。在该模型中，R 环形成之前，非模板 DNA 链会从 RNA 聚合酶（RNAP）上分离。然后，新生 RNA 和非模板 DNA 链之间开始进行链交换。在链交换过程中，R 环的长度可能会增加，也可能会以有偏差的随机漫步方式减少，而偏差取决于 DNA 序列。最终，DNA 双链的恢复将完全取代 RNA。但是，只要 RNAP 仍与模板 DNA 链结合，就会阻止这种位移。因此，根据该模型，停滞在 DSB 上的 RNAP 可以延长 R 环的寿命，提高它们在实验中的可检测性，或许还能增强它们的生物效应。

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引用次数: 0

An immuno-epidemiological model with non-exponentially distributed disease stage on complex networks 复杂网络上非指数分布疾病阶段的免疫流行病学模型。

IF 1.9 4区数学 Q2 BIOLOGY

Journal of Theoretical Biology

Pub Date : 2024-10-09 DOI: 10.1016/j.jtbi.2024.111964

Junyuan Yang , Xinyi Duan , Guiquan Sun

Most of epidemic models assume that duration of the disease phase is distributed exponentially for the simplification of model formulation and analysis. Actually, the exponentially distributed assumption on the description of disease stages is hard to accurately approximate the interplay of drug concentration and viral load within host. In this article, we formulate an immuno-epidemiological epidemic model on complex networks, which is composed of ordinary differential equations and integral equations. The linkage of within- and between-host is connected by setting that the death caused by the disease is an increasing function in viral load within host. Mathematical analysis of the model includes the existence of the solution to the epidemiological model on complex networks, the existence and stability of equilibrium, which are completely determined by the basic reproduction number of the between-host system. Numerical analysis are shown that the non-exponentially distributions and the topology of networks have significant roles in the prediction of epidemic patterns.

大多数流行病模型都假设疾病阶段的持续时间呈指数分布，以简化模型的表述和分析。实际上，对疾病阶段描述的指数分布假设很难准确近似宿主体内药物浓度和病毒载量的相互作用。本文建立了一个由常微分方程和积分方程组成的复杂网络免疫流行病学模型。通过设定疾病导致的死亡是宿主体内病毒载量的递增函数，将宿主体内和宿主之间的联系联系起来。模型的数学分析包括复杂网络流行病学模型解的存在性、平衡的存在性和稳定性，这些完全由宿主间系统的基本繁殖数决定。数值分析表明，非指数分布和网络拓扑结构对流行模式的预测具有重要作用。

引用次数: 0

The development of drug resistance in metastatic tumours under chemotherapy: An evolutionary perspective 化疗下转移性肿瘤耐药性的发展：从进化角度看

IF 1.9 4区数学 Q2 BIOLOGY

Journal of Theoretical Biology

Pub Date : 2024-10-05 DOI: 10.1016/j.jtbi.2024.111957

Federica Padovano , Chiara Villa

We present a mathematical model of the evolutionary dynamics of a metastatic tumour under chemotherapy, comprising non-local partial differential equations for the phenotype-structured cell populations in the primary tumour and its metastasis. These equations are coupled with a physiologically-based pharmacokinetic model of drug administration and distribution, implementing a realistic delivery schedule. The model is carefully calibrated from the literature, focusing on BRAF-mutated melanoma treated with Dabrafenib as a case study. By means of long-time asymptotic and global sensitivity analyses, as well as numerical simulations, we explore the impact of cell migration from the primary to the metastatic site, physiological aspects of the tumour tissues and drug dose on the development of chemoresistance and treatment efficacy. Our findings provide a possible explanation for empirical evidence indicating that chemotherapy may foster metastatic spread and that metastases may be less impacted by the chemotherapeutic agent.

我们提出了一个化疗下转移性肿瘤演变动态的数学模型，其中包括原发肿瘤及其转移瘤中表型结构细胞群的非局部偏微分方程。这些方程与基于生理学的给药和分布药代动力学模型相结合，实现了现实的给药时间表。该模型根据文献进行了仔细校准，并以使用达拉非尼治疗的 BRAF 突变黑色素瘤为案例进行了研究。通过长期渐近分析和全局敏感性分析以及数值模拟，我们探讨了细胞从原发部位向转移部位迁移、肿瘤组织的生理方面以及药物剂量对化疗耐药性的发展和治疗效果的影响。我们的研究结果为经验证据提供了一种可能的解释，即化疗可能会促进转移扩散，而转移灶受到化疗药物的影响可能较小。

引用次数: 0

Global stability of coexistence equilibria for n-species models of facultative mutualism n种互惠模式共存平衡的全局稳定性。

IF 1.9 4区数学 Q2 BIOLOGY

Journal of Theoretical Biology

Pub Date : 2024-10-03 DOI: 10.1016/j.jtbi.2024.111961

Paul Georgescu , Hong Zhang

We further pursue an investigation on an abstract model characterizing the dynamics of a general class of

n

-species facultative mutualisms that was initiated in Georgescu et al. (2017), establishing biologically relevant sufficient conditions for the global asymptotic stability of the coexistence equilibria. These conditions are given in terms of per-species limits of growth-to-loss ratios computed at higher population densities, complemented by either monotonicity or sublinearity inequalities, and are observed to hold for

n

-species versions of mutualistic models in current use. The specific modeling details that require either of these conditions being satisfied are outlined and discussed. As mutualisms can enhance species diversification and facilitate stable coexistence via a plethora of mechanisms, it is then important to understand the stability of speciose mutualisms, our results being of potential interest to theoretical ecologists studying the coexistence of many interacting species and to conservationists aiming for rare species preservation.

我们进一步研究了一个抽象模型，该模型描述了 Georgescu 等人（2017 年）提出的一般 n 种亲缘互惠关系的动态特征，为共存均衡的全局渐进稳定性建立了生物学相关的充分条件。这些条件是以在较高种群密度下计算的每物种生长-损失比的极限值给出的，并辅以单调性或亚线性不等式，据观察，这些条件在目前使用的 n 种互生模型中都是成立的。本文概述并讨论了需要满足上述任一条件的具体建模细节。由于互惠关系可以通过多种机制提高物种多样性并促进稳定共存，因此了解物种互惠关系的稳定性非常重要，我们的研究结果对于研究多种相互作用物种共存的理论生态学家和旨在保护稀有物种的保护主义者具有潜在的意义。

引用次数: 0

Exploring the treatment of SARS-CoV-2 with modified vesicular stomatitis virus 探索用改良水泡性口炎病毒治疗 SARS-CoV-2

IF 1.9 4区数学 Q2 BIOLOGY

Journal of Theoretical Biology

Pub Date : 2024-10-02 DOI: 10.1016/j.jtbi.2024.111959

Nishnath Polavarapu , Madison Doty , Hana M. Dobrovolny

SARS-CoV-2 caused a global pandemic and is now an endemic virus that will require continued antiviral and vaccine development. A possible new treatment modality was recently suggested that would use vesicular stomatitis virus (VSV) modified to express the ACE2 receptor. Since the modified VSV expresses the cell surface receptor that is used by the SARS-CoV-2 spike protein, the thought is that SARS-CoV-2 virions would bind to the modified VSV and thus be neutralized. Additionally, since SARS-CoV-2 infected cells also express the spike protein, the modified VSV could potentially infect these cells, allowing for its own replication, but also potentially interfering with replication of SARS-CoV-2. This idea has not yet been tested experimentally, but we can investigate the feasibility of this possible treatment theoretically. In this manuscript, we develop a mathematical model of this suggested treatment and explore conditions under which it might be effective. We find that treatment with modified VSV does little to change the SARS-CoV-2 time course except when the treatment is applied at the onset of the SARS-CoV-2 infection at very high doses. In this case, VSV reduces the peak SARS-CoV-2 viral load, but lengthens the duration of the SARS-CoV-2 infection. Thus, we find that modified VSV treatment is unlikely to be effective largely because it does not prevent infection of cells by SARS-CoV-2.

SARS-CoV-2 造成了全球大流行，现在已成为一种地方性病毒，需要继续开发抗病毒药物和疫苗。最近有人提出了一种可能的新治疗方法，即使用经修饰的水泡性口炎病毒（VSV）来表达 ACE2 受体。由于改造后的 VSV 表达的细胞表面受体是 SARS-CoV-2 棘突蛋白所使用的，因此人们认为 SARS-CoV-2 病毒会与改造后的 VSV 结合，从而被中和。此外，由于受 SARS-CoV-2 感染的细胞也表达尖峰蛋白，经过修饰的 VSV 有可能感染这些细胞，从而实现自身复制，但也有可能干扰 SARS-CoV-2 的复制。这一想法尚未得到实验验证，但我们可以从理论上研究这种可能的治疗方法的可行性。在本手稿中，我们建立了这一建议疗法的数学模型，并探讨了其可能有效的条件。我们发现，使用改良 VSV 治疗对 SARS-CoV-2 的时间进程几乎没有影响，除非在 SARS-CoV-2 感染开始时使用非常高的剂量进行治疗。在这种情况下，VSV 会降低 SARS-CoV-2 病毒载量的峰值，但会延长 SARS-CoV-2 感染的持续时间。因此，我们发现改良的 VSV 治疗不可能有效，主要是因为它不能阻止细胞感染 SARS-CoV-2。

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