We study stationary distributions in the context of stochastic reaction networks. In particular, we are interested in complex balanced reaction networks and reduction of such networks by assuming a set of species (called non-interacting species) are degraded fast (and therefore essentially absent in the 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 network obtained by algebraic elimination of the non-interacting species. In general, the limiting stationary distribution might differ from the stationary distribution of the reduced reaction network. We identify various sufficient conditions for when these two distributions are the same, including when the reaction network is detailed balanced and when the set of non-interacting species consists of intermediate species. In the latter case, the limiting stationary distribution essentially retains the form of the complex balanced distribution. This finding is particularly surprising given that the reduced reaction network might be non-weakly reversible and exhibit unconventional kinetics.
{"title":"Asymptotic analysis for stationary distributions of scaled reaction networks","authors":"Linard Hoessly, Carsten Wiuf, Panqiu Xia","doi":"arxiv-2402.02276","DOIUrl":"https://doi.org/arxiv-2402.02276","url":null,"abstract":"We study stationary distributions in the context of stochastic reaction\u0000networks. In particular, we are interested in complex balanced reaction\u0000networks and reduction of such networks by assuming a set of species (called\u0000non-interacting species) are degraded fast (and therefore essentially absent in\u0000the network), implying some reaction rates are large compared to others.\u0000Technically, we assume these reaction rates are scaled by a common parameter\u0000$N$ and let $Ntoinfty$. The limiting stationary distribution as $Ntoinfty$\u0000is compared to the stationary distribution of the reduced reaction network\u0000obtained by algebraic elimination of the non-interacting species. In general,\u0000the limiting stationary distribution might differ from the stationary\u0000distribution of the reduced reaction network. We identify various sufficient\u0000conditions for when these two distributions are the same, including when the\u0000reaction network is detailed balanced and when the set of non-interacting\u0000species consists of intermediate species. In the latter case, the limiting\u0000stationary distribution essentially retains the form of the complex balanced\u0000distribution. This finding is particularly surprising given that the reduced\u0000reaction network might be non-weakly reversible and exhibit unconventional\u0000kinetics.","PeriodicalId":501325,"journal":{"name":"arXiv - QuanBio - Molecular Networks","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139758441","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}
The exponential factor of Arrhenius satisfactorily quantifies the energetic restriction of chemical reactions but is still awaiting a rigorous basis. Assuming that the Arrhenius equation should be based on statistical mechanics and is probabilistic in nature, two structures for this equation are compared, depending on whether the reactant energies are viewed as the mean values of specific energy distributions or as particular levels in a global energy distribution. In the first version, the Arrhenius exponential factor would be a probability that depends once on temperature, while in the second it is a ratio of probabilities that depends twice on temperature. These concurrent equations are tested using experimental data for the isomerization of 2-butene. This comparison reveals the fundamental structure of the Arrhenius law in isothermal systems and overlooked properties resulting from the introduction of reactant energies into the equation.
{"title":"Test of the formal basis of Arrhenius law with heat capacities","authors":"Denis Michel","doi":"arxiv-2402.00900","DOIUrl":"https://doi.org/arxiv-2402.00900","url":null,"abstract":"The exponential factor of Arrhenius satisfactorily quantifies the energetic\u0000restriction of chemical reactions but is still awaiting a rigorous basis.\u0000Assuming that the Arrhenius equation should be based on statistical mechanics\u0000and is probabilistic in nature, two structures for this equation are compared,\u0000depending on whether the reactant energies are viewed as the mean values of\u0000specific energy distributions or as particular levels in a global energy\u0000distribution. In the first version, the Arrhenius exponential factor would be a\u0000probability that depends once on temperature, while in the second it is a ratio\u0000of probabilities that depends twice on temperature. These concurrent equations\u0000are tested using experimental data for the isomerization of 2-butene. This\u0000comparison reveals the fundamental structure of the Arrhenius law in isothermal\u0000systems and overlooked properties resulting from the introduction of reactant\u0000energies into the equation.","PeriodicalId":501325,"journal":{"name":"arXiv - QuanBio - Molecular Networks","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139772840","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}
Isolated sarcoplasmic reticulum vesicles in the presence of Mg(2+) and absence of Ca(2+) retain significant ATP hydrolytic activity that can be attributed to the Ca(2+)-ATPase protein. At neutral pH and the presence of 5 mM Mg(2+), the dependence of the hydrolysis rate on a linear ATP concentration scale can be fitted by a single hyperbolic function. MgATP hydrolysis is inhibited by either free Mg(2+) or free ATP. The rate of ATP hydrolysis is not perturbed by vanadate, whereas the rate of p-nitrophenyl phosphate hydrolysis is not altered by a nonhydrolyzable ATP analog. ATP binding affinity at neutral pH and in a Ca(2+)-free medium is increased by Mg(2+) but decreased by vanadate when Mg(2+) is present. It is suggested that MgATP hydrolysis in the absence of Ca(2+) requires some optimal adjustment of the enzyme cytoplasmic domains. The Ca(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。
{"title":"Functional approach to the catalytic site of the sarcoplasmic reticulum Ca(2+)-ATPase: binding and hydrolysis of ATP in the absence of Ca(2+)","authors":"A Lax, F Soler, F Fernandez Belda","doi":"arxiv-2401.17382","DOIUrl":"https://doi.org/arxiv-2401.17382","url":null,"abstract":"Isolated sarcoplasmic reticulum vesicles in the presence of Mg(2+) and\u0000absence of Ca(2+) retain significant ATP hydrolytic activity that can be\u0000attributed to the Ca(2+)-ATPase protein. At neutral pH and the presence of 5 mM\u0000Mg(2+), the dependence of the hydrolysis rate on a linear ATP concentration\u0000scale can be fitted by a single hyperbolic function. MgATP hydrolysis is\u0000inhibited by either free Mg(2+) or free ATP. The rate of ATP hydrolysis is not\u0000perturbed by vanadate, whereas the rate of p-nitrophenyl phosphate hydrolysis\u0000is not altered by a nonhydrolyzable ATP analog. ATP binding affinity at neutral\u0000pH and in a Ca(2+)-free medium is increased by Mg(2+) but decreased by vanadate\u0000when Mg(2+) is present. It is suggested that MgATP hydrolysis in the absence of\u0000Ca(2+) requires some optimal adjustment of the enzyme cytoplasmic domains. The\u0000Ca(2+)-independent activity is operative at basal levels of cytoplasmic Ca(2+)\u0000or when the Ca(2+) binding transition is impeded.","PeriodicalId":501325,"journal":{"name":"arXiv - QuanBio - Molecular Networks","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139657430","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}
Sarcoplasmic reticulum vesicles and purified Ca$^{2+}$-ATPase hydrolyze acetyl phosphate both in the presence and absence of Ca$^{2+}$. The Ca$^{2+}$-independent activity was fully sensitive to vanadate, insensitive to thapsigargin, and proceeded without accumulation of phosphorylated enzyme. Acetyl phosphate hydrolysis in the absence of Ca$^{2+}$ was activated by dimethyl sulfoxide. The Ca$^{2+}$-dependent activity was partially sensitive to vanadate, fully sensitive to thapsigargin, and associated with steady phosphoenzyme accumulation. The Ca$^{2+}$/P(i) coupling ratio at neutral pH sustained by 10 mm acetyl phosphate was 0.57. Addition of 30% dimethyl sulfoxide completely blocked Ca$^{2+}$ transport and partially inhibited the hydrolysis rate. Uncoupling induced by dimethyl sulfoxide included the accumulation of vanadate-insensitive phosphorylated enzyme. When acetyl phosphate was the substrate, the hydrolytic pathway was dependent on experimental conditions that might or might not allow net Ca$^{2+}$ transport. The interdependence of both Ca$^{2+}$-dependent and Ca$^{2+}$-independent hydrolytic activities was demonstrated.
{"title":"Dissecting the Hydrolytic Activities of Sarcoplasmic Reticulum ATPase in the Presence of Acetyl Phosphate","authors":"F Soler, MI Fortea, A Lax, F Fernandez Belda","doi":"arxiv-2401.17375","DOIUrl":"https://doi.org/arxiv-2401.17375","url":null,"abstract":"Sarcoplasmic reticulum vesicles and purified Ca$^{2+}$-ATPase hydrolyze\u0000acetyl phosphate both in the presence and absence of Ca$^{2+}$. The\u0000Ca$^{2+}$-independent activity was fully sensitive to vanadate, insensitive to\u0000thapsigargin, and proceeded without accumulation of phosphorylated enzyme.\u0000Acetyl phosphate hydrolysis in the absence of Ca$^{2+}$ was activated by\u0000dimethyl sulfoxide. The Ca$^{2+}$-dependent activity was partially sensitive to\u0000vanadate, fully sensitive to thapsigargin, and associated with steady\u0000phosphoenzyme accumulation. The Ca$^{2+}$/P(i) coupling ratio at neutral pH\u0000sustained by 10 mm acetyl phosphate was 0.57. Addition of 30% dimethyl\u0000sulfoxide completely blocked Ca$^{2+}$ transport and partially inhibited the\u0000hydrolysis rate. Uncoupling induced by dimethyl sulfoxide included the\u0000accumulation of vanadate-insensitive phosphorylated enzyme. When acetyl\u0000phosphate was the substrate, the hydrolytic pathway was dependent on\u0000experimental conditions that might or might not allow net Ca$^{2+}$ transport.\u0000The interdependence of both Ca$^{2+}$-dependent and Ca$^{2+}$-independent\u0000hydrolytic activities was demonstrated.","PeriodicalId":501325,"journal":{"name":"arXiv - QuanBio - Molecular Networks","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139657561","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}
Nearly all circadian clocks maintain a period that is insensitive to temperature changes, a phenomenon known as temperature compensation (TC). Yet, it is unclear whether there is any common feature among different systems that exhibit TC. From a general timescale invariance, we show that TC relies on existence of certain period-lengthening reactions wherein the period of the system increases strongly with the rates in these reactions. By studying several generic oscillator models, we show that this counter-intuitive dependence is nonetheless a common feature of oscillators in the nonlinear (far-from-onset) regime where the oscillation can be separated into fast and slow phases. The increase of the period with the period-lengthening reaction rates occurs when the amplitude of the slow phase in the oscillation increases with these rates while the progression-speed in the slow phase is controlled by other rates of the system. The positive dependence of the period on the period-lengthening rates balances its inverse dependence on other kinetic rates in the system, which gives rise to robust TC in a wide range of parameters. We demonstrate the existence of such period-lengthening reactions and their relevance for TC in all four model systems we considered. Theoretical results for a model of the Kai system are supported by experimental data. A study of the energy dissipation also shows that better TC performance requires higher energy consumption. Our study unveils a general mechanism by which a biochemical oscillator achieves TC by operating at regimes far from the onset where 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。
{"title":"Temperature Compensation through Kinetic Regulation in Biochemical Oscillators","authors":"Haochen Fu, Chenyi Fei, Qi Ouyang, Yuhai Tu","doi":"arxiv-2401.13960","DOIUrl":"https://doi.org/arxiv-2401.13960","url":null,"abstract":"Nearly all circadian clocks maintain a period that is insensitive to\u0000temperature changes, a phenomenon known as temperature compensation (TC). Yet,\u0000it is unclear whether there is any common feature among different systems that\u0000exhibit TC. From a general timescale invariance, we show that TC relies on\u0000existence of certain period-lengthening reactions wherein the period of the\u0000system increases strongly with the rates in these reactions. By studying\u0000several generic oscillator models, we show that this counter-intuitive\u0000dependence is nonetheless a common feature of oscillators in the nonlinear\u0000(far-from-onset) regime where the oscillation can be separated into fast and\u0000slow phases. The increase of the period with the period-lengthening reaction\u0000rates occurs when the amplitude of the slow phase in the oscillation increases\u0000with these rates while the progression-speed in the slow phase is controlled by\u0000other rates of the system. The positive dependence of the period on the\u0000period-lengthening rates balances its inverse dependence on other kinetic rates\u0000in the system, which gives rise to robust TC in a wide range of parameters. We\u0000demonstrate the existence of such period-lengthening reactions and their\u0000relevance for TC in all four model systems we considered. Theoretical results\u0000for a model of the Kai system are supported by experimental data. A study of\u0000the energy dissipation also shows that better TC performance requires higher\u0000energy consumption. Our study unveils a general mechanism by which a\u0000biochemical oscillator achieves TC by operating at regimes far from the onset\u0000where period-lengthening reactions exist.","PeriodicalId":501325,"journal":{"name":"arXiv - QuanBio - Molecular Networks","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139581460","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}
David Murrugarra, Alan Veliz-Cuba, Elena Dimitrova, Claus Kadelka, Matthew Wheeler, Reinhard Laubenbacher
The concept of control is central to understanding and applications of biological network models. Some of their key structural features relate to control functions, through gene regulation, signaling, or metabolic mechanisms, and computational models need to encode these. Applications of models often focus on model-based control, such as in biomedicine or metabolic engineering. This paper presents an approach to model-based control that exploits two common features of biological networks, namely their modular structure and canalizing features of their regulatory mechanisms. The paper focuses on intracellular regulatory networks, represented by Boolean network models. A main result of this paper is that control strategies can be identified by focusing on one module at a time. This paper also presents a criterion based on canalizing features of the regulatory rules to identify modules that do not contribute to network control and can be excluded. For even moderately sized networks, finding global control inputs is computationally very challenging. The modular approach presented here leads to a highly efficient approach to solving this problem. This approach is applied to a published Boolean network model of blood cancer large granular lymphocyte (T-LGL) leukemia to identify a minimal control set that achieves a desired control objective.
{"title":"Modular Control of Biological Networks","authors":"David Murrugarra, Alan Veliz-Cuba, Elena Dimitrova, Claus Kadelka, Matthew Wheeler, Reinhard Laubenbacher","doi":"arxiv-2401.12477","DOIUrl":"https://doi.org/arxiv-2401.12477","url":null,"abstract":"The concept of control is central to understanding and applications of\u0000biological network models. Some of their key structural features relate to\u0000control functions, through gene regulation, signaling, or metabolic mechanisms,\u0000and computational models need to encode these. Applications of models often\u0000focus on model-based control, such as in biomedicine or metabolic engineering.\u0000This paper presents an approach to model-based control that exploits two common\u0000features of biological networks, namely their modular structure and canalizing\u0000features of their regulatory mechanisms. The paper focuses on intracellular\u0000regulatory networks, represented by Boolean network models. A main result of\u0000this paper is that control strategies can be identified by focusing on one\u0000module at a time. This paper also presents a criterion based on canalizing\u0000features of the regulatory rules to identify modules that do not contribute to\u0000network control and can be excluded. For even moderately sized networks,\u0000finding global control inputs is computationally very challenging. The modular\u0000approach presented here leads to a highly efficient approach to solving this\u0000problem. This approach is applied to a published Boolean network model of blood\u0000cancer large granular lymphocyte (T-LGL) leukemia to identify a minimal control\u0000set that achieves a desired control objective.","PeriodicalId":501325,"journal":{"name":"arXiv - QuanBio - Molecular Networks","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139558884","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}
Chuanbo Liu, Yu Fu, Lu Lin, Elliot L. Elson, Jin Wang
Noise plays a crucial role in the regulation of cellular and organismal function and behavior. Exploring noise's impact is key to understanding fundamental biological processes, such as gene expression, signal transduction, and the mechanisms of development and evolution. Currently, a comprehensive method to quantify dynamical behavior of cellular noise within these biochemical systems is lacking. In this study, we introduce an optically-controlled perturbation system utilizing the light-sensitive Phytochrome B (PhyB) from textit{Arabidopsis thaliana}, which enables precise noise modulation with high spatial-temporal resolution. Our system exhibits exceptional sensitivity to light, reacting consistently to pulsed light signals, distinguishing it from other photoreceptor-based promoter systems that respond to a single light wavelength. To characterize our system, we developed a stochastic model for phytochromes that accounts for photoactivation/deactivation, thermal reversion, and the dynamics of the light-activated gene promoter system. To precisely control our system, we determined the rate constants for this model using an omniscient deep neural network that can directly map rate constant combinations to time-dependent state joint distributions. By adjusting the activation rates through light intensity and degradation rates via N-terminal mutagenesis, we illustrate that out optical-controlled perturbation can effectively modulate molecular expression level as well as noise. Our results highlight the potential of employing an optically-controlled gene perturbation system as a noise-controlled stimulus source. This approach, when combined with the analytical capabilities of a sophisticated deep neural network, enables the accurate estimation of rate constants from observational data in a broad range of biochemical reaction networks.
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。
{"title":"Understanding Cellular Noise with Optical Perturbation and Deep Learning","authors":"Chuanbo Liu, Yu Fu, Lu Lin, Elliot L. Elson, Jin Wang","doi":"arxiv-2401.12498","DOIUrl":"https://doi.org/arxiv-2401.12498","url":null,"abstract":"Noise plays a crucial role in the regulation of cellular and organismal\u0000function and behavior. Exploring noise's impact is key to understanding fundamental biological\u0000processes, such as gene expression, signal transduction, and the mechanisms of\u0000development and evolution. Currently, a comprehensive method to quantify dynamical behavior of cellular\u0000noise within these biochemical systems is lacking. In this study, we introduce an optically-controlled perturbation system\u0000utilizing the light-sensitive Phytochrome B (PhyB) from textit{Arabidopsis\u0000thaliana}, which enables precise noise modulation with high spatial-temporal\u0000resolution. Our system exhibits exceptional sensitivity to light, reacting consistently\u0000to pulsed light signals, distinguishing it from other photoreceptor-based\u0000promoter systems that respond to a single light wavelength. To characterize our system, we developed a stochastic model for phytochromes\u0000that accounts for photoactivation/deactivation, thermal reversion, and the\u0000dynamics of the light-activated gene promoter system. To precisely control our system, we determined the rate constants for this\u0000model using an omniscient deep neural network that can directly map rate\u0000constant combinations to time-dependent state joint distributions. By adjusting the activation rates through light intensity and degradation\u0000rates via N-terminal mutagenesis, we illustrate that out optical-controlled\u0000perturbation can effectively modulate molecular expression level as well as\u0000noise. Our results highlight the potential of employing an optically-controlled gene\u0000perturbation system as a noise-controlled stimulus source. This approach, when combined with the analytical capabilities of a\u0000sophisticated deep neural network, enables the accurate estimation of rate\u0000constants from observational data in a broad range of biochemical reaction\u0000networks.","PeriodicalId":501325,"journal":{"name":"arXiv - QuanBio - Molecular Networks","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139558881","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}
Nikolaos Ntetsikas, Styliana Kyriakoudi, Antonis Kirmizis, Bige Deniz Unluturk, Andreas Pitsillides, Ian F. Akyildiz, Marios Lestas
Although continuous advances in theoretical modelling of Molecular Communications (MC) are observed, there is still an insuperable gap between theory and experimental testbeds, especially at the microscale. In this paper, the development of the first testbed incorporating engineered yeast cells is reported. Different from the existing literature, eukaryotic yeast cells are considered for both the sender and the receiver, with {alpha}-factor molecules facilitating the information transfer. The use of such cells is motivated mainly by the well understood biological mechanism of yeast mating, together with their genetic amenability. In addition, recent advances in yeast biosensing establish yeast as a suitable detector and a neat interface to in-body sensor networks. The system under consideration is presented first, and the mathematical models of the underlying biological processes leading to an end-to-end (E2E) system are given. The experimental setup is then described and used to obtain experimental results which validate the developed mathematical models. Beyond that, the ability of the system to effectively generate output pulses in response to repeated stimuli is demonstrated, reporting one event per two hours. However, fast RNA fluctuations indicate cell responses in less than three minutes, demonstrating the potential for much higher rates in the future.
{"title":"Engineering Yeast Cells to Facilitate Information Exchange","authors":"Nikolaos Ntetsikas, Styliana Kyriakoudi, Antonis Kirmizis, Bige Deniz Unluturk, Andreas Pitsillides, Ian F. Akyildiz, Marios Lestas","doi":"arxiv-2401.13712","DOIUrl":"https://doi.org/arxiv-2401.13712","url":null,"abstract":"Although continuous advances in theoretical modelling of Molecular\u0000Communications (MC) are observed, there is still an insuperable gap between\u0000theory and experimental testbeds, especially at the microscale. In this paper,\u0000the development of the first testbed incorporating engineered yeast cells is\u0000reported. Different from the existing literature, eukaryotic yeast cells are\u0000considered for both the sender and the receiver, with {alpha}-factor molecules\u0000facilitating the information transfer. The use of such cells is motivated\u0000mainly by the well understood biological mechanism of yeast mating, together\u0000with their genetic amenability. In addition, recent advances in yeast\u0000biosensing establish yeast as a suitable detector and a neat interface to\u0000in-body sensor networks. The system under consideration is presented first, and\u0000the mathematical models of the underlying biological processes leading to an\u0000end-to-end (E2E) system are given. The experimental setup is then described and\u0000used to obtain experimental results which validate the developed mathematical\u0000models. Beyond that, the ability of the system to effectively generate output\u0000pulses in response to repeated stimuli is demonstrated, reporting one event per\u0000two hours. However, fast RNA fluctuations indicate cell responses in less than\u0000three minutes, demonstrating the potential for much higher rates in the future.","PeriodicalId":501325,"journal":{"name":"arXiv - QuanBio - Molecular Networks","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139581552","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}
Sebastian Lobentanzer, Pablo Rodriguez-Mier, Stefan Bauer, Julio Saez-Rodriguez
Correlation is not causation. As simple as this widely agreed-upon statement may seem, scientifically defining causality and using it to drive our modern biomedical research is immensely challenging. In this perspective, we attempt to synergise the partly disparate fields of systems biology, causal reasoning, and machine learning, to inform future approaches in the field of systems biology and molecular networks.
{"title":"Molecular causality in the advent of foundation models","authors":"Sebastian Lobentanzer, Pablo Rodriguez-Mier, Stefan Bauer, Julio Saez-Rodriguez","doi":"arxiv-2401.09558","DOIUrl":"https://doi.org/arxiv-2401.09558","url":null,"abstract":"Correlation is not causation. As simple as this widely agreed-upon statement\u0000may seem, scientifically defining causality and using it to drive our modern\u0000biomedical research is immensely challenging. In this perspective, we attempt\u0000to synergise the partly disparate fields of systems biology, causal reasoning,\u0000and machine learning, to inform future approaches in the field of systems\u0000biology and molecular networks.","PeriodicalId":501325,"journal":{"name":"arXiv - QuanBio - Molecular Networks","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139497392","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}
Ting-He Zhang, Sumin Jo, Michelle Zhang, Kai Wang, Shou-Jiang Gao, Yufei Huang
N6-methyladenosine (m6A) is the most abundant mRNA modification within mammalian cells, holding pivotal significance in the regulation of mRNA stability, translation, and splicing. Furthermore, it plays a critical role in the regulation of RNA degradation by primarily recruiting the YTHDF2 reader protein. However, the selective regulation of mRNA decay of the m6A-methylated mRNA through YTHDF2 binding is poorly understood. To improve our understanding, we developed m6A-BERT-Deg, a BERT model adapted for predicting YTHDF2-mediated degradation of m6A-methylated mRNAs. We meticulously assembled a high-quality training dataset by integrating multiple data sources for the HeLa cell line. To overcome the limitation of small training samples, we employed a pre-training-fine-tuning strategy by first performing a self-supervised pre-training of the model on 427,760 unlabeled m6A site sequences. The test results demonstrated the importance of this pre-training strategy in enabling m6A-BERT-Deg to outperform other benchmark models. We further conducted a comprehensive model interpretation and revealed a surprising finding that the presence of co-factors in proximity to m6A sites may disrupt YTHDF2-mediated mRNA degradation, subsequently enhancing mRNA stability. We also extended our analyses to the HEK293 cell line, shedding light on the context-dependent YTHDF2-mediated mRNA degradation.
{"title":"Understanding YTHDF2-mediated mRNA Degradation By m6A-BERT-Deg","authors":"Ting-He Zhang, Sumin Jo, Michelle Zhang, Kai Wang, Shou-Jiang Gao, Yufei Huang","doi":"arxiv-2401.08004","DOIUrl":"https://doi.org/arxiv-2401.08004","url":null,"abstract":"N6-methyladenosine (m6A) is the most abundant mRNA modification within\u0000mammalian cells, holding pivotal significance in the regulation of mRNA\u0000stability, translation, and splicing. Furthermore, it plays a critical role in\u0000the regulation of RNA degradation by primarily recruiting the YTHDF2 reader\u0000protein. However, the selective regulation of mRNA decay of the m6A-methylated\u0000mRNA through YTHDF2 binding is poorly understood. To improve our understanding,\u0000we developed m6A-BERT-Deg, a BERT model adapted for predicting YTHDF2-mediated\u0000degradation of m6A-methylated mRNAs. We meticulously assembled a high-quality\u0000training dataset by integrating multiple data sources for the HeLa cell line.\u0000To overcome the limitation of small training samples, we employed a\u0000pre-training-fine-tuning strategy by first performing a self-supervised\u0000pre-training of the model on 427,760 unlabeled m6A site sequences. The test\u0000results demonstrated the importance of this pre-training strategy in enabling\u0000m6A-BERT-Deg to outperform other benchmark models. We further conducted a\u0000comprehensive model interpretation and revealed a surprising finding that the\u0000presence of co-factors in proximity to m6A sites may disrupt YTHDF2-mediated\u0000mRNA degradation, subsequently enhancing mRNA stability. We also extended our\u0000analyses to the HEK293 cell line, shedding light on the context-dependent\u0000YTHDF2-mediated mRNA degradation.","PeriodicalId":501325,"journal":{"name":"arXiv - QuanBio - Molecular Networks","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139481746","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}
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