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Asymptotic analysis for stationary distributions of scaled reaction networks 比例反应网络静态分布的渐近分析
Pub Date : 2024-02-03 DOI: arxiv-2402.02276
Linard Hoessly, Carsten Wiuf, Panqiu Xia
We study stationary distributions in the context of stochastic reactionnetworks. In particular, we are interested in complex balanced reactionnetworks and reduction of such networks by assuming a set of species (callednon-interacting species) are degraded fast (and therefore essentially absent inthe network), implying some reaction rates are large compared to others.Technically, we assume these reaction rates are scaled by a common parameter$N$ and let $Ntoinfty$. The limiting stationary distribution as $Ntoinfty$is compared to the stationary distribution of the reduced reaction networkobtained by algebraic elimination of the non-interacting species. In general,the limiting stationary distribution might differ from the stationarydistribution of the reduced reaction network. We identify various sufficientconditions for when these two distributions are the same, including when thereaction network is detailed balanced and when the set of non-interactingspecies consists of intermediate species. In the latter case, the limitingstationary distribution essentially retains the form of the complex balanceddistribution. This finding is particularly surprising given that the reducedreaction network might be non-weakly reversible and exhibit unconventionalkinetics.
我们研究随机反应网络中的静态分布。特别是,我们对复杂的平衡反应网络和通过假设一组物种(称为非相互作用物种)快速降解(因此在网络中基本上不存在)来还原此类网络感兴趣,这意味着一些反应速率与其他反应速率相比很大。我们将 $Ntoinfty$ 时的极限静止分布与代数消除非相互作用物种后得到的还原反应网络的静止分布进行比较。一般来说,极限静止分布可能与还原反应网络的静止分布不同。我们确定了这两种分布相同的各种充分条件,包括当反应网络详细平衡时,以及当非相互作用物种集由中间物种组成时。在后一种情况下,极限静态分布基本上保留了复杂平衡分布的形式。鉴于还原反应网络可能是非弱可逆的,并表现出非传统的动力学,这一发现尤其令人惊讶。
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引用次数: 0
Test of the formal basis of Arrhenius law with heat capacities 用热容量检验阿伦尼乌斯定律的形式基础
Pub Date : 2024-01-31 DOI: arxiv-2402.00900
Denis Michel
The exponential factor of Arrhenius satisfactorily quantifies the energeticrestriction of chemical reactions but is still awaiting a rigorous basis.Assuming that the Arrhenius equation should be based on statistical mechanicsand is probabilistic in nature, two structures for this equation are compared,depending on whether the reactant energies are viewed as the mean values ofspecific energy distributions or as particular levels in a global energydistribution. In the first version, the Arrhenius exponential factor would be aprobability that depends once on temperature, while in the second it is a ratioof probabilities that depends twice on temperature. These concurrent equationsare tested using experimental data for the isomerization of 2-butene. Thiscomparison reveals the fundamental structure of the Arrhenius law in isothermalsystems and overlooked properties resulting from the introduction of reactantenergies into the equation.
假设阿伦尼乌斯方程应以统计力学为基础,并具有概率性质,那么根据反应物能量是被视为特定能量分布的平均值,还是被视为全局能量分布中的特定水平,我们对该方程的两种结构进行了比较。在第一个版本中,阿伦尼乌斯指数因子是一个取决于温度一次的概率,而在第二个版本中,它是一个取决于温度两次的概率比。我们使用 2-丁烯异构化的实验数据对这些并行方程进行了检验。这一比较揭示了等温系统中阿伦尼乌斯定律的基本结构,以及在方程中引入反应物能量所产生的被忽视的性质。
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引用次数: 0
Functional approach to the catalytic site of the sarcoplasmic reticulum Ca(2+)-ATPase: binding and hydrolysis of ATP in the absence of Ca(2+) 肌浆网 Ca(2+)-ATP 酶催化位点的功能研究:Ca(2+)缺失时 ATP 的结合和水解
Pub Date : 2024-01-30 DOI: arxiv-2401.17382
A Lax, F Soler, F Fernandez Belda
Isolated sarcoplasmic reticulum vesicles in the presence of Mg(2+) andabsence of Ca(2+) retain significant ATP hydrolytic activity that can beattributed to the Ca(2+)-ATPase protein. At neutral pH and the presence of 5 mMMg(2+), the dependence of the hydrolysis rate on a linear ATP concentrationscale can be fitted by a single hyperbolic function. MgATP hydrolysis isinhibited by either free Mg(2+) or free ATP. The rate of ATP hydrolysis is notperturbed by vanadate, whereas the rate of p-nitrophenyl phosphate hydrolysisis not altered by a nonhydrolyzable ATP analog. ATP binding affinity at neutralpH and in a Ca(2+)-free medium is increased by Mg(2+) but decreased by vanadatewhen Mg(2+) is present. It is suggested that MgATP hydrolysis in the absence ofCa(2+) requires some optimal adjustment of the enzyme cytoplasmic domains. TheCa(2+)-independent activity is operative at basal levels of cytoplasmic Ca(2+)or when the Ca(2+) binding transition is impeded.
分离的肌质网囊泡在有 Mg(2+)和无 Ca(2+)的条件下仍具有显著的 ATP 水解活性,这种活性可归因于 Ca(2+)-ATP 酶蛋白。在中性 pH 值和 5 mMMg(2+)存在的条件下,水解速率对线性 ATP 浓度标度的依赖性可以用一个双曲线函数来拟合。MgATP 的水解受到游离 Mg(2+) 或游离 ATP 的抑制。ATP 的水解速率不受钒酸盐的干扰,而对硝基苯磷酸的水解速率则不受不可水解的 ATP 类似物的影响。在中性pH和不含 Ca(2+)的介质中,Mg(2+)会增加 ATP 的结合亲和力,但当 Mg(2+)存在时,香草酸盐会降低 ATP 的结合亲和力。这表明,在没有 Ca(2+)的情况下,MgATP 的水解需要对酶的细胞质结构域进行某种优化调整。在细胞质 Ca(2+) 的基础水平或 Ca(2+) 结合转换受阻时,Ca(2+) 依赖性活性发挥作用。
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引用次数: 0
Dissecting the Hydrolytic Activities of Sarcoplasmic Reticulum ATPase in the Presence of Acetyl Phosphate 剖析肉质网 ATP 酶在乙酰磷酸存在下的水解活动
Pub Date : 2024-01-30 DOI: arxiv-2401.17375
F Soler, MI Fortea, A Lax, F Fernandez Belda
Sarcoplasmic reticulum vesicles and purified Ca$^{2+}$-ATPase hydrolyzeacetyl phosphate both in the presence and absence of Ca$^{2+}$. TheCa$^{2+}$-independent activity was fully sensitive to vanadate, insensitive tothapsigargin, and proceeded without accumulation of phosphorylated enzyme.Acetyl phosphate hydrolysis in the absence of Ca$^{2+}$ was activated bydimethyl sulfoxide. The Ca$^{2+}$-dependent activity was partially sensitive tovanadate, fully sensitive to thapsigargin, and associated with steadyphosphoenzyme accumulation. The Ca$^{2+}$/P(i) coupling ratio at neutral pHsustained by 10 mm acetyl phosphate was 0.57. Addition of 30% dimethylsulfoxide completely blocked Ca$^{2+}$ transport and partially inhibited thehydrolysis rate. Uncoupling induced by dimethyl sulfoxide included theaccumulation of vanadate-insensitive phosphorylated enzyme. When acetylphosphate was the substrate, the hydrolytic pathway was dependent onexperimental conditions that might or might not allow net Ca$^{2+}$ transport.The interdependence of both Ca$^{2+}$-dependent and Ca$^{2+}$-independenthydrolytic activities was demonstrated.
肉质网囊泡和纯化的 Ca$^{2+}$-ATPase 在 Ca$^{2+}$ 存在和不存在的情况下都能水解磷酸乙酰。不依赖于 Ca$^{2+}$ 的活性对钒酸盐完全敏感,对硫代甘氨不敏感,并且没有磷酸化酶的积累。钙^{2+}$依赖性活性对瓦那酸盐部分敏感,对硫辛加精完全敏感,并与稳定的磷酸酶积累有关。在中性 pH 值下,由 10 毫米磷酸乙酰基维持的 Ca$^{2+}$/P(i) 耦合比为 0.57。加入 30% 的二甲基亚砜完全阻断了 Ca$^{2+}$ 的运输,并部分抑制了水解速率。二甲基亚砜诱导的解偶联包括对钒酸盐不敏感的磷酸化酶的积累。当以乙酰磷酸为底物时,水解途径取决于可能允许或不允许 Ca$^{2+}$ 净运输的实验条件。
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引用次数: 0
Temperature Compensation through Kinetic Regulation in Biochemical Oscillators 通过生化振荡器中的动力学调节进行温度补偿
Pub Date : 2024-01-25 DOI: arxiv-2401.13960
Haochen Fu, Chenyi Fei, Qi Ouyang, Yuhai Tu
Nearly all circadian clocks maintain a period that is insensitive totemperature changes, a phenomenon known as temperature compensation (TC). Yet,it is unclear whether there is any common feature among different systems thatexhibit TC. From a general timescale invariance, we show that TC relies onexistence of certain period-lengthening reactions wherein the period of thesystem increases strongly with the rates in these reactions. By studyingseveral generic oscillator models, we show that this counter-intuitivedependence is nonetheless a common feature of oscillators in the nonlinear(far-from-onset) regime where the oscillation can be separated into fast andslow phases. The increase of the period with the period-lengthening reactionrates occurs when the amplitude of the slow phase in the oscillation increaseswith these rates while the progression-speed in the slow phase is controlled byother rates of the system. The positive dependence of the period on theperiod-lengthening rates balances its inverse dependence on other kinetic ratesin the system, which gives rise to robust TC in a wide range of parameters. Wedemonstrate the existence of such period-lengthening reactions and theirrelevance for TC in all four model systems we considered. Theoretical resultsfor a model of the Kai system are supported by experimental data. A study ofthe energy dissipation also shows that better TC performance requires higherenergy consumption. Our study unveils a general mechanism by which abiochemical oscillator achieves TC by operating at regimes far from the onsetwhere period-lengthening reactions exist.
几乎所有的昼夜节律钟都能保持一个对温度变化不敏感的周期,这种现象被称为温度补偿(TC)。然而,目前还不清楚不同系统之间是否存在表现出温度补偿的共同特征。从一般时标不变量出发,我们证明了温度补偿依赖于某些周期延长反应的存在,在这些反应中,系统的周期随着反应速率的增加而强烈增加。通过研究几种一般振荡器模型,我们发现这种反常的依赖性是非线性(远离起始点)振荡器的共同特征,在这种振荡器中,振荡可以分为快慢两个阶段。当振荡中慢相的振幅随着这些速率的增加而增加,而慢相的进速度受系统的其他速率控制时,周期就会随着周期延长反应速率的增加而增加。周期对周期延长速率的正向依赖性平衡了其对系统中其他动力学速率的反向依赖性,从而在广泛的参数范围内产生了稳健的 TC。我们证明了这种周期延长反应的存在,以及它们在我们所考虑的所有四个模型系统中与 TC 的相关性。实验数据支持了 Kai 系统模型的理论结果。对能量耗散的研究还表明,更好的热电偶性能需要更高的能量消耗。我们的研究揭示了一种普遍机制,即生化振荡器通过在远离周期延长反应存在的起始状态下运行来实现 TC。
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引用次数: 0
Modular Control of Biological Networks 生物网络的模块化控制
Pub Date : 2024-01-23 DOI: arxiv-2401.12477
David Murrugarra, Alan Veliz-Cuba, Elena Dimitrova, Claus Kadelka, Matthew Wheeler, Reinhard Laubenbacher
The concept of control is central to understanding and applications ofbiological network models. Some of their key structural features relate tocontrol functions, through gene regulation, signaling, or metabolic mechanisms,and computational models need to encode these. Applications of models oftenfocus on model-based control, such as in biomedicine or metabolic engineering.This paper presents an approach to model-based control that exploits two commonfeatures of biological networks, namely their modular structure and canalizingfeatures of their regulatory mechanisms. The paper focuses on intracellularregulatory networks, represented by Boolean network models. A main result ofthis paper is that control strategies can be identified by focusing on onemodule at a time. This paper also presents a criterion based on canalizingfeatures of the regulatory rules to identify modules that do not contribute tonetwork control and can be excluded. For even moderately sized networks,finding global control inputs is computationally very challenging. The modularapproach presented here leads to a highly efficient approach to solving thisproblem. This approach is applied to a published Boolean network model of bloodcancer large granular lymphocyte (T-LGL) leukemia to identify a minimal controlset that achieves a desired control objective.
控制的概念是理解和应用生物网络模型的核心。它们的一些关键结构特征与控制功能有关,如基因调控、信号传导或代谢机制,而计算模型需要对这些功能进行编码。模型的应用通常侧重于基于模型的控制,如在生物医学或代谢工程中的应用。本文介绍了一种基于模型的控制方法,它利用了生物网络的两个共同特征,即模块化结构和调控机制的渠化特征。本文的重点是以布尔网络模型为代表的细胞内调控网络。本文的一个主要结果是,可以通过一次只关注一个模块来确定控制策略。本文还提出了一种基于调控规则渠化特征的标准,用于识别无助于网络控制并可被排除的模块。即使对于中等规模的网络,寻找全局控制输入在计算上也非常具有挑战性。本文介绍的模块化方法是解决这一问题的高效方法。本文将这种方法应用于已发表的血癌大颗粒淋巴细胞(T-LGL)白血病布尔网络模型,以确定能实现预期控制目标的最小控制集。
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引用次数: 0
Understanding Cellular Noise with Optical Perturbation and Deep Learning 用光学扰动和深度学习理解细胞噪声
Pub Date : 2024-01-23 DOI: arxiv-2401.12498
Chuanbo Liu, Yu Fu, Lu Lin, Elliot L. Elson, Jin Wang
Noise plays a crucial role in the regulation of cellular and organismalfunction and behavior. Exploring noise's impact is key to understanding fundamental biologicalprocesses, such as gene expression, signal transduction, and the mechanisms ofdevelopment and evolution. Currently, a comprehensive method to quantify dynamical behavior of cellularnoise within these biochemical systems is lacking. In this study, we introduce an optically-controlled perturbation systemutilizing the light-sensitive Phytochrome B (PhyB) from textit{Arabidopsisthaliana}, which enables precise noise modulation with high spatial-temporalresolution. Our system exhibits exceptional sensitivity to light, reacting consistentlyto pulsed light signals, distinguishing it from other photoreceptor-basedpromoter systems that respond to a single light wavelength. To characterize our system, we developed a stochastic model for phytochromesthat accounts for photoactivation/deactivation, thermal reversion, and thedynamics of the light-activated gene promoter system. To precisely control our system, we determined the rate constants for thismodel using an omniscient deep neural network that can directly map rateconstant combinations to time-dependent state joint distributions. By adjusting the activation rates through light intensity and degradationrates via N-terminal mutagenesis, we illustrate that out optical-controlledperturbation can effectively modulate molecular expression level as well asnoise. Our results highlight the potential of employing an optically-controlled geneperturbation system as a noise-controlled stimulus source. This approach, when combined with the analytical capabilities of asophisticated deep neural network, enables the accurate estimation of rateconstants from observational data in a broad range of biochemical reactionnetworks.
噪声在调控细胞和生物体的功能与行为方面起着至关重要的作用。探索噪声的影响是理解基因表达、信号转导以及发育和进化机制等基本生物过程的关键。目前,还缺乏一种全面的方法来量化这些生化系统中细胞噪声的动态行为。在这项研究中,我们利用拟南芥中对光敏感的植物色素B(PhyB)引入了一种光控扰动系统,该系统能以高时空分辨率对噪声进行精确调制。我们的系统对光的敏感度极高,能对脉冲光信号做出一致的反应,这使它有别于其他只对单一波长的光做出反应的基于光感受器的启动子系统。为了描述我们的系统,我们开发了一个植物色素随机模型,该模型考虑了光激活/去激活、热还原以及光激活基因启动子系统的动力学。为了精确控制我们的系统,我们使用全知的深度神经网络确定了该模型的速率常数,该网络可以直接将速率常数组合映射到随时间变化的状态联合分布上。通过光照强度调整激活率,并通过 N 端突变调整降解率,我们证明了光控扰动可以有效调节分子表达水平和噪声。我们的研究结果凸显了采用光控基因扰动系统作为噪声控制刺激源的潜力。这种方法与复杂的深度神经网络的分析能力相结合,可以在广泛的生化反应网络中从观测数据中准确估计速率常数。
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引用次数: 0
Engineering Yeast Cells to Facilitate Information Exchange 酵母细胞工程促进信息交流
Pub Date : 2024-01-23 DOI: arxiv-2401.13712
Nikolaos Ntetsikas, Styliana Kyriakoudi, Antonis Kirmizis, Bige Deniz Unluturk, Andreas Pitsillides, Ian F. Akyildiz, Marios Lestas
Although continuous advances in theoretical modelling of MolecularCommunications (MC) are observed, there is still an insuperable gap betweentheory and experimental testbeds, especially at the microscale. In this paper,the development of the first testbed incorporating engineered yeast cells isreported. Different from the existing literature, eukaryotic yeast cells areconsidered for both the sender and the receiver, with {alpha}-factor moleculesfacilitating the information transfer. The use of such cells is motivatedmainly by the well understood biological mechanism of yeast mating, togetherwith their genetic amenability. In addition, recent advances in yeastbiosensing establish yeast as a suitable detector and a neat interface toin-body sensor networks. The system under consideration is presented first, andthe mathematical models of the underlying biological processes leading to anend-to-end (E2E) system are given. The experimental setup is then described andused to obtain experimental results which validate the developed mathematicalmodels. Beyond that, the ability of the system to effectively generate outputpulses in response to repeated stimuli is demonstrated, reporting one event pertwo hours. However, fast RNA fluctuations indicate cell responses in less thanthree minutes, demonstrating the potential for much higher rates in the future.
尽管分子通信(MC)的理论建模不断取得进展,但理论与实验平台之间仍存在不可逾越的鸿沟,尤其是在微观尺度上。本文报告了首个结合工程酵母细胞的实验平台的开发情况。与现有文献不同的是,真核酵母细胞被视为发送方和接收方,{α}因子分子为信息传递提供了便利。使用这种细胞的主要原因是酵母交配的生物机制已被充分理解,而且它们的遗传性也很好。此外,酵母生物传感技术的最新进展证明,酵母是一种合适的检测器,也是体内传感器网络的一个简便接口。首先介绍了所考虑的系统,并给出了导致端到端(E2E)系统的基本生物过程的数学模型。然后介绍了实验装置,并利用实验结果验证了所建立的数学模型。除此以外,实验还证明了该系统在重复刺激下有效产生输出脉冲的能力,每两小时报告一次事件。然而,快速的 RNA 波动表明细胞在不到三分钟的时间内就会做出反应,这表明未来有可能实现更高的反应速度。
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引用次数: 0
Molecular causality in the advent of foundation models 基础模型出现时的分子因果关系
Pub Date : 2024-01-17 DOI: arxiv-2401.09558
Sebastian Lobentanzer, Pablo Rodriguez-Mier, Stefan Bauer, Julio Saez-Rodriguez
Correlation is not causation. As simple as this widely agreed-upon statementmay seem, scientifically defining causality and using it to drive our modernbiomedical research is immensely challenging. In this perspective, we attemptto synergise the partly disparate fields of systems biology, causal reasoning,and machine learning, to inform future approaches in the field of systemsbiology and molecular networks.
相关性不是因果关系。尽管这一广为认同的说法看似简单,但科学地定义因果关系并用它来推动现代生物医学研究却极具挑战性。在这一视角中,我们试图将系统生物学、因果推理和机器学习这几个互不相关的领域协同起来,为系统生物学和分子网络领域未来的研究方法提供参考。
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引用次数: 0
Understanding YTHDF2-mediated mRNA Degradation By m6A-BERT-Deg 了解 m6A-BERT-Deg 介导的 YTHDF2- mRNA 降解
Pub Date : 2024-01-15 DOI: arxiv-2401.08004
Ting-He Zhang, Sumin Jo, Michelle Zhang, Kai Wang, Shou-Jiang Gao, Yufei Huang
N6-methyladenosine (m6A) is the most abundant mRNA modification withinmammalian cells, holding pivotal significance in the regulation of mRNAstability, translation, and splicing. Furthermore, it plays a critical role inthe regulation of RNA degradation by primarily recruiting the YTHDF2 readerprotein. However, the selective regulation of mRNA decay of the m6A-methylatedmRNA through YTHDF2 binding is poorly understood. To improve our understanding,we developed m6A-BERT-Deg, a BERT model adapted for predicting YTHDF2-mediateddegradation of m6A-methylated mRNAs. We meticulously assembled a high-qualitytraining dataset by integrating multiple data sources for the HeLa cell line.To overcome the limitation of small training samples, we employed apre-training-fine-tuning strategy by first performing a self-supervisedpre-training of the model on 427,760 unlabeled m6A site sequences. The testresults demonstrated the importance of this pre-training strategy in enablingm6A-BERT-Deg to outperform other benchmark models. We further conducted acomprehensive model interpretation and revealed a surprising finding that thepresence of co-factors in proximity to m6A sites may disrupt YTHDF2-mediatedmRNA degradation, subsequently enhancing mRNA stability. We also extended ouranalyses to the HEK293 cell line, shedding light on the context-dependentYTHDF2-mediated mRNA degradation.
N6-甲基腺苷(m6A)是哺乳动物细胞内最丰富的mRNA修饰,在调控mRNA稳定性、翻译和剪接方面具有关键意义。此外,它还主要通过招募 YTHDF2 阅读蛋白在 RNA 降解调控中发挥关键作用。然而,人们对 m6A 甲基化 mRNA 通过 YTHDF2 结合选择性调控 mRNA 降解还知之甚少。为了加深理解,我们开发了 m6A-BERT-Deg,这是一个用于预测 YTHDF2 介导的 m6A 甲基化 mRNA 降解的 BERT 模型。为了克服训练样本少的限制,我们采用了预训练-微调策略,首先在 427,760 个未标记的 m6A 位点序列上对模型进行了自监督预训练。测试结果表明了这种预训练策略在使m6A-BERT-Deg超越其他基准模型方面的重要性。我们进一步进行了全面的模型解释,发现了一个惊人的发现,即在 m6A 位点附近存在辅助因子可能会破坏 YTHDF2 介导的 mRNA 降解,从而增强 mRNA 的稳定性。我们还将分析扩展到了 HEK293 细胞系,揭示了 YTHDF2- 介导的 mRNA 降解的环境依赖性。
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引用次数: 0
期刊
arXiv - QuanBio - Molecular Networks
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