Pub Date : 2024-08-02eCollection Date: 2024-08-01DOI: 10.1371/journal.pcbi.1012256
Einar Bjarki Gunnarsson, Seungil Kim, Brandon Choi, J Karl Schmid, Karn Kaura, Heinz-Josef Lenz, Shannon M Mumenthaler, Jasmine Foo
Patient-derived tumor organoids (PDTOs) are novel cellular models that maintain the genetic, phenotypic and structural features of patient tumor tissue and are useful for studying tumorigenesis and drug response. When integrated with advanced 3D imaging and analysis techniques, PDTOs can be used to establish physiologically relevant high-throughput and high-content drug screening platforms that support the development of patient-specific treatment strategies. However, in order to effectively leverage high-throughput PDTO observations for clinical predictions, it is critical to establish a quantitative understanding of the basic properties and variability of organoid growth dynamics. In this work, we introduced an innovative workflow for analyzing and understanding PDTO growth dynamics, by integrating a high-throughput imaging deep learning platform with mathematical modeling, incorporating flexible growth laws and variable dormancy times. We applied the workflow to colon cancer organoids and demonstrated that organoid growth is well-described by the Gompertz model of growth. Our analysis showed significant intrapatient heterogeneity in PDTO growth dynamics, with the initial exponential growth rate of an organoid following a lognormal distribution within each dataset. The level of intrapatient heterogeneity varied between patients, as did organoid growth rates and dormancy times of single seeded cells. Our work contributes to an emerging understanding of the basic growth characteristics of PDTOs, and it highlights the heterogeneity in organoid growth both within and between patients. These results pave the way for further modeling efforts aimed at predicting treatment response dynamics and drug resistance timing.
{"title":"Understanding patient-derived tumor organoid growth through an integrated imaging and mathematical modeling framework.","authors":"Einar Bjarki Gunnarsson, Seungil Kim, Brandon Choi, J Karl Schmid, Karn Kaura, Heinz-Josef Lenz, Shannon M Mumenthaler, Jasmine Foo","doi":"10.1371/journal.pcbi.1012256","DOIUrl":"10.1371/journal.pcbi.1012256","url":null,"abstract":"<p><p>Patient-derived tumor organoids (PDTOs) are novel cellular models that maintain the genetic, phenotypic and structural features of patient tumor tissue and are useful for studying tumorigenesis and drug response. When integrated with advanced 3D imaging and analysis techniques, PDTOs can be used to establish physiologically relevant high-throughput and high-content drug screening platforms that support the development of patient-specific treatment strategies. However, in order to effectively leverage high-throughput PDTO observations for clinical predictions, it is critical to establish a quantitative understanding of the basic properties and variability of organoid growth dynamics. In this work, we introduced an innovative workflow for analyzing and understanding PDTO growth dynamics, by integrating a high-throughput imaging deep learning platform with mathematical modeling, incorporating flexible growth laws and variable dormancy times. We applied the workflow to colon cancer organoids and demonstrated that organoid growth is well-described by the Gompertz model of growth. Our analysis showed significant intrapatient heterogeneity in PDTO growth dynamics, with the initial exponential growth rate of an organoid following a lognormal distribution within each dataset. The level of intrapatient heterogeneity varied between patients, as did organoid growth rates and dormancy times of single seeded cells. Our work contributes to an emerging understanding of the basic growth characteristics of PDTOs, and it highlights the heterogeneity in organoid growth both within and between patients. These results pave the way for further modeling efforts aimed at predicting treatment response dynamics and drug resistance timing.</p>","PeriodicalId":20241,"journal":{"name":"PLoS Computational Biology","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11324155/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141879306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-02eCollection Date: 2024-08-01DOI: 10.1371/journal.pcbi.1012288
Ulysse Rançon, Timothée Masquelier, Benoit R Cottereau
Sounds are temporal stimuli decomposed into numerous elementary components by the auditory nervous system. For instance, a temporal to spectro-temporal transformation modelling the frequency decomposition performed by the cochlea is a widely adopted first processing step in today's computational models of auditory neural responses. Similarly, increments and decrements in sound intensity (i.e., of the raw waveform itself or of its spectral bands) constitute critical features of the neural code, with high behavioural significance. However, despite the growing attention of the scientific community on auditory OFF responses, their relationship with transient ON, sustained responses and adaptation remains unclear. In this context, we propose a new general model, based on a pair of linear filters, named AdapTrans, that captures both sustained and transient ON and OFF responses into a unifying and easy to expand framework. We demonstrate that filtering audio cochleagrams with AdapTrans permits to accurately render known properties of neural responses measured in different mammal species such as the dependence of OFF responses on the stimulus fall time and on the preceding sound duration. Furthermore, by integrating our framework into gold standard and state-of-the-art machine learning models that predict neural responses from audio stimuli, following a supervised training on a large compilation of electrophysiology datasets (ready-to-deploy PyTorch models and pre-processed datasets shared publicly), we show that AdapTrans systematically improves the prediction accuracy of estimated responses within different cortical areas of the rat and ferret auditory brain. Together, these results motivate the use of our framework for computational and systems neuroscientists willing to increase the plausibility and performances of their models of audition.
声音是一种时间刺激,被听觉神经系统分解成许多基本组成部分。例如,在当今的听觉神经反应计算模型中,从时间到频谱-时间的转换模拟耳蜗进行的频率分解是广泛采用的第一个处理步骤。同样,声音强度的增减(即原始波形本身或其频谱带)构成了神经代码的关键特征,具有高度的行为意义。然而,尽管科学界对听觉关闭反应的关注与日俱增,但它们与瞬时开启、持续反应和适应的关系仍不清楚。在这种情况下,我们提出了一种基于一对线性滤波器的新通用模型,名为 AdapTrans,它能在一个统一且易于扩展的框架内捕捉到持续和瞬时的 ON 和 OFF 反应。我们证明,使用 AdapTrans 对音频耳蜗图进行过滤,可以准确呈现在不同哺乳动物身上测量到的神经反应的已知特性,例如关断反应对刺激物下落时间和前面声音持续时间的依赖性。此外,在对大量电生理学数据集(可随时部署的 PyTorch 模型和公开共享的预处理数据集)进行监督训练后,我们将我们的框架集成到预测音频刺激神经反应的黄金标准和最先进的机器学习模型中,结果表明 AdapTrans 系统地提高了大鼠和雪貂听觉大脑不同皮质区域内估计反应的预测准确性。这些结果共同推动了我们的框架在计算和系统神经科学家中的应用,使他们愿意提高其听觉模型的可信度和性能。
{"title":"A general model unifying the adaptive, transient and sustained properties of ON and OFF auditory neural responses.","authors":"Ulysse Rançon, Timothée Masquelier, Benoit R Cottereau","doi":"10.1371/journal.pcbi.1012288","DOIUrl":"10.1371/journal.pcbi.1012288","url":null,"abstract":"<p><p>Sounds are temporal stimuli decomposed into numerous elementary components by the auditory nervous system. For instance, a temporal to spectro-temporal transformation modelling the frequency decomposition performed by the cochlea is a widely adopted first processing step in today's computational models of auditory neural responses. Similarly, increments and decrements in sound intensity (i.e., of the raw waveform itself or of its spectral bands) constitute critical features of the neural code, with high behavioural significance. However, despite the growing attention of the scientific community on auditory OFF responses, their relationship with transient ON, sustained responses and adaptation remains unclear. In this context, we propose a new general model, based on a pair of linear filters, named AdapTrans, that captures both sustained and transient ON and OFF responses into a unifying and easy to expand framework. We demonstrate that filtering audio cochleagrams with AdapTrans permits to accurately render known properties of neural responses measured in different mammal species such as the dependence of OFF responses on the stimulus fall time and on the preceding sound duration. Furthermore, by integrating our framework into gold standard and state-of-the-art machine learning models that predict neural responses from audio stimuli, following a supervised training on a large compilation of electrophysiology datasets (ready-to-deploy PyTorch models and pre-processed datasets shared publicly), we show that AdapTrans systematically improves the prediction accuracy of estimated responses within different cortical areas of the rat and ferret auditory brain. Together, these results motivate the use of our framework for computational and systems neuroscientists willing to increase the plausibility and performances of their models of audition.</p>","PeriodicalId":20241,"journal":{"name":"PLoS Computational Biology","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11324186/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141879302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-02eCollection Date: 2024-08-01DOI: 10.1371/journal.pcbi.1012048
Janani Ravi, Kewalin Samart, Jason Zwolak
Budding yeast, Saccharomyces cerevisiae, is widely used as a model organism to study the genetics underlying eukaryotic cellular processes and growth critical to cancer development, such as cell division and cell cycle progression. The budding yeast cell cycle is also one of the best-studied dynamical systems owing to its thoroughly resolved genetics. However, the dynamics underlying the crucial cell cycle decision point called the START transition, at which the cell commits to a new round of DNA replication and cell division, are under-studied. The START machinery involves a central cyclin-dependent kinase; cyclins responsible for starting the transition, bud formation, and initiating DNA synthesis; and their transcriptional regulators. However, evidence has shown that the mechanism is more complicated than a simple irreversible transition switch. Activating a key transcription regulator SBF requires the phosphorylation of its inhibitor, Whi5, or an SBF/MBF monomeric component, Swi6, but not necessarily both. Also, the timing and mechanism of the inhibitor Whi5's nuclear export, while important, are not critical for the timing and execution of START. Therefore, there is a need for a consolidated model for the budding yeast START transition, reconciling regulatory and spatial dynamics. We built a detailed mathematical model (START-BYCC) for the START transition in the budding yeast cell cycle based on established molecular interactions and experimental phenotypes. START-BYCC recapitulates the underlying dynamics and correctly emulates key phenotypic traits of ~150 known START mutants, including regulation of size control, localization of inhibitor/transcription factor complexes, and the nutritional effects on size control. Such a detailed mechanistic understanding of the underlying dynamics gets us closer towards deconvoluting the aberrant cellular development in cancer.
{"title":"Modeling the START transition in the budding yeast cell cycle.","authors":"Janani Ravi, Kewalin Samart, Jason Zwolak","doi":"10.1371/journal.pcbi.1012048","DOIUrl":"10.1371/journal.pcbi.1012048","url":null,"abstract":"<p><p>Budding yeast, Saccharomyces cerevisiae, is widely used as a model organism to study the genetics underlying eukaryotic cellular processes and growth critical to cancer development, such as cell division and cell cycle progression. The budding yeast cell cycle is also one of the best-studied dynamical systems owing to its thoroughly resolved genetics. However, the dynamics underlying the crucial cell cycle decision point called the START transition, at which the cell commits to a new round of DNA replication and cell division, are under-studied. The START machinery involves a central cyclin-dependent kinase; cyclins responsible for starting the transition, bud formation, and initiating DNA synthesis; and their transcriptional regulators. However, evidence has shown that the mechanism is more complicated than a simple irreversible transition switch. Activating a key transcription regulator SBF requires the phosphorylation of its inhibitor, Whi5, or an SBF/MBF monomeric component, Swi6, but not necessarily both. Also, the timing and mechanism of the inhibitor Whi5's nuclear export, while important, are not critical for the timing and execution of START. Therefore, there is a need for a consolidated model for the budding yeast START transition, reconciling regulatory and spatial dynamics. We built a detailed mathematical model (START-BYCC) for the START transition in the budding yeast cell cycle based on established molecular interactions and experimental phenotypes. START-BYCC recapitulates the underlying dynamics and correctly emulates key phenotypic traits of ~150 known START mutants, including regulation of size control, localization of inhibitor/transcription factor complexes, and the nutritional effects on size control. Such a detailed mechanistic understanding of the underlying dynamics gets us closer towards deconvoluting the aberrant cellular development in cancer.</p>","PeriodicalId":20241,"journal":{"name":"PLoS Computational Biology","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11324117/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141879304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-31eCollection Date: 2024-07-01DOI: 10.1371/journal.pcbi.1012354
Nan Wu, Isabel Valera, Fabian Sinz, Alexander Ecker, Thomas Euler, Yongrong Qiu
Neural population responses in sensory systems are driven by external physical stimuli. This stimulus-response relationship is typically characterized by receptive fields, which have been estimated by neural system identification approaches. Such models usually require a large amount of training data, yet, the recording time for animal experiments is limited, giving rise to epistemic uncertainty for the learned neural transfer functions. While deep neural network models have demonstrated excellent power on neural prediction, they usually do not provide the uncertainty of the resulting neural representations and derived statistics, such as most exciting inputs (MEIs), from in silico experiments. Here, we present a Bayesian system identification approach to predict neural responses to visual stimuli, and explore whether explicitly modeling network weight variability can be beneficial for identifying neural response properties. To this end, we use variational inference to estimate the posterior distribution of each model weight given the training data. Tests with different neural datasets demonstrate that this method can achieve higher or comparable performance on neural prediction, with a much higher data efficiency compared to Monte Carlo dropout methods and traditional models using point estimates of the model parameters. At the same time, our variational method provides us with an effectively infinite ensemble, avoiding the idiosyncrasy of any single model, to generate MEIs. This allows us to estimate the uncertainty of stimulus-response function, which we have found to be negatively correlated with the predictive performance at model level and may serve to evaluate models. Furthermore, our approach enables us to identify response properties with credible intervals and to determine whether the inferred features are meaningful by performing statistical tests on MEIs. Finally, in silico experiments show that our model generates stimuli driving neuronal activity significantly better than traditional models in the limited-data regime.
{"title":"Probabilistic neural transfer function estimation with Bayesian system identification.","authors":"Nan Wu, Isabel Valera, Fabian Sinz, Alexander Ecker, Thomas Euler, Yongrong Qiu","doi":"10.1371/journal.pcbi.1012354","DOIUrl":"10.1371/journal.pcbi.1012354","url":null,"abstract":"<p><p>Neural population responses in sensory systems are driven by external physical stimuli. This stimulus-response relationship is typically characterized by receptive fields, which have been estimated by neural system identification approaches. Such models usually require a large amount of training data, yet, the recording time for animal experiments is limited, giving rise to epistemic uncertainty for the learned neural transfer functions. While deep neural network models have demonstrated excellent power on neural prediction, they usually do not provide the uncertainty of the resulting neural representations and derived statistics, such as most exciting inputs (MEIs), from in silico experiments. Here, we present a Bayesian system identification approach to predict neural responses to visual stimuli, and explore whether explicitly modeling network weight variability can be beneficial for identifying neural response properties. To this end, we use variational inference to estimate the posterior distribution of each model weight given the training data. Tests with different neural datasets demonstrate that this method can achieve higher or comparable performance on neural prediction, with a much higher data efficiency compared to Monte Carlo dropout methods and traditional models using point estimates of the model parameters. At the same time, our variational method provides us with an effectively infinite ensemble, avoiding the idiosyncrasy of any single model, to generate MEIs. This allows us to estimate the uncertainty of stimulus-response function, which we have found to be negatively correlated with the predictive performance at model level and may serve to evaluate models. Furthermore, our approach enables us to identify response properties with credible intervals and to determine whether the inferred features are meaningful by performing statistical tests on MEIs. Finally, in silico experiments show that our model generates stimuli driving neuronal activity significantly better than traditional models in the limited-data regime.</p>","PeriodicalId":20241,"journal":{"name":"PLoS Computational Biology","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11318871/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141860656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-31eCollection Date: 2024-07-01DOI: 10.1371/journal.pcbi.1012311
Yiu-Chung Lau, Songwei Shan, Dong Wang, Dongxuan Chen, Zhanwei Du, Eric H Y Lau, Daihai He, Linwei Tian, Peng Wu, Benjamin J Cowling, Sheikh Taslim Ali
Like other tropical and subtropical regions, influenza viruses can circulate year-round in Hong Kong. However, during the COVID-19 pandemic, there was a significant decrease in influenza activity. The objective of this study was to retrospectively forecast influenza activity during the year 2020 and assess the impact of COVID-19 public health social measures (PHSMs) on influenza activity and hospital admissions in Hong Kong. Using weekly surveillance data on influenza virus activity in Hong Kong from 2010 to 2019, we developed a statistical modeling framework to forecast influenza virus activity and associated hospital admissions. We conducted short-term forecasts (1-4 weeks ahead) and medium-term forecasts (1-13 weeks ahead) for the year 2020, assuming no PHSMs were implemented against COVID-19. We estimated the reduction in transmissibility, peak magnitude, attack rates, and influenza-associated hospitalization rate resulting from these PHSMs. For short-term forecasts, mean ambient ozone concentration and school holidays were found to contribute to better prediction performance, while absolute humidity and ozone concentration improved the accuracy of medium-term forecasts. We observed a maximum reduction of 44.6% (95% CI: 38.6% - 51.9%) in transmissibility, 75.5% (95% CI: 73.0% - 77.6%) in attack rate, 41.5% (95% CI: 13.9% - 55.7%) in peak magnitude, and 63.1% (95% CI: 59.3% - 66.3%) in cumulative influenza-associated hospitalizations during the winter-spring period of the 2019/2020 season in Hong Kong. The implementation of PHSMs to control COVID-19 had a substantial impact on influenza transmission and associated burden in Hong Kong. Incorporating information on factors influencing influenza transmission improved the accuracy of our predictions.
{"title":"Forecasting of influenza activity and associated hospital admission burden and estimating the impact of COVID-19 pandemic on 2019/20 winter season in Hong Kong.","authors":"Yiu-Chung Lau, Songwei Shan, Dong Wang, Dongxuan Chen, Zhanwei Du, Eric H Y Lau, Daihai He, Linwei Tian, Peng Wu, Benjamin J Cowling, Sheikh Taslim Ali","doi":"10.1371/journal.pcbi.1012311","DOIUrl":"10.1371/journal.pcbi.1012311","url":null,"abstract":"<p><p>Like other tropical and subtropical regions, influenza viruses can circulate year-round in Hong Kong. However, during the COVID-19 pandemic, there was a significant decrease in influenza activity. The objective of this study was to retrospectively forecast influenza activity during the year 2020 and assess the impact of COVID-19 public health social measures (PHSMs) on influenza activity and hospital admissions in Hong Kong. Using weekly surveillance data on influenza virus activity in Hong Kong from 2010 to 2019, we developed a statistical modeling framework to forecast influenza virus activity and associated hospital admissions. We conducted short-term forecasts (1-4 weeks ahead) and medium-term forecasts (1-13 weeks ahead) for the year 2020, assuming no PHSMs were implemented against COVID-19. We estimated the reduction in transmissibility, peak magnitude, attack rates, and influenza-associated hospitalization rate resulting from these PHSMs. For short-term forecasts, mean ambient ozone concentration and school holidays were found to contribute to better prediction performance, while absolute humidity and ozone concentration improved the accuracy of medium-term forecasts. We observed a maximum reduction of 44.6% (95% CI: 38.6% - 51.9%) in transmissibility, 75.5% (95% CI: 73.0% - 77.6%) in attack rate, 41.5% (95% CI: 13.9% - 55.7%) in peak magnitude, and 63.1% (95% CI: 59.3% - 66.3%) in cumulative influenza-associated hospitalizations during the winter-spring period of the 2019/2020 season in Hong Kong. The implementation of PHSMs to control COVID-19 had a substantial impact on influenza transmission and associated burden in Hong Kong. Incorporating information on factors influencing influenza transmission improved the accuracy of our predictions.</p>","PeriodicalId":20241,"journal":{"name":"PLoS Computational Biology","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11318919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141860653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-31eCollection Date: 2024-07-01DOI: 10.1371/journal.pcbi.1011820
Wilfredo Blanco, Joel Tabak, Richard Bertram
The pulsatile activity of gonadotropin-releasing hormone neurons (GnRH neurons) is a key factor in the regulation of reproductive hormones. This pulsatility is orchestrated by a network of neurons that release the neurotransmitters kisspeptin, neurokinin B, and dynorphin (KNDy neurons), and produce episodic bursts of activity driving the GnRH neurons. We show in this computational study that the features of coordinated KNDy neuron activity can be explained by a neural network in which connectivity among neurons is modular. That is, a network structure consisting of clusters of highly-connected neurons with sparse coupling among the clusters. This modular structure, with distinct parameters for intracluster and intercluster coupling, also yields predictions for the differential effects on synchronization of changes in the coupling strength within clusters versus between clusters.
促性腺激素释放激素神经元(GnRH 神经元)的脉动活动是调节生殖激素的一个关键因素。这种脉动性是由神经元网络协调的,这些神经元释放神经递质吻肽、神经激肽 B 和达因啡肽(KNDy 神经元),并产生驱动 GnRH 神经元的偶发性突发性活动。我们在这项计算研究中表明,KNDy 神经元协调活动的特征可以用神经元之间的连接是模块化的神经网络来解释。也就是说,这种网络结构由高度连接的神经元群组成,而神经元群之间的耦合稀疏。这种模块化结构具有不同的簇内耦合参数和簇间耦合参数,还能预测簇内和簇间耦合强度的变化对同步的不同影响。
{"title":"Population bursts in a modular neural network as a mechanism for synchronized activity in KNDy neurons.","authors":"Wilfredo Blanco, Joel Tabak, Richard Bertram","doi":"10.1371/journal.pcbi.1011820","DOIUrl":"10.1371/journal.pcbi.1011820","url":null,"abstract":"<p><p>The pulsatile activity of gonadotropin-releasing hormone neurons (GnRH neurons) is a key factor in the regulation of reproductive hormones. This pulsatility is orchestrated by a network of neurons that release the neurotransmitters kisspeptin, neurokinin B, and dynorphin (KNDy neurons), and produce episodic bursts of activity driving the GnRH neurons. We show in this computational study that the features of coordinated KNDy neuron activity can be explained by a neural network in which connectivity among neurons is modular. That is, a network structure consisting of clusters of highly-connected neurons with sparse coupling among the clusters. This modular structure, with distinct parameters for intracluster and intercluster coupling, also yields predictions for the differential effects on synchronization of changes in the coupling strength within clusters versus between clusters.</p>","PeriodicalId":20241,"journal":{"name":"PLoS Computational Biology","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11318907/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141860655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-31eCollection Date: 2024-07-01DOI: 10.1371/journal.pcbi.1011728
Jonas Verhellen, Kosio Beshkov, Sebastian Amundsen, Torbjørn V Ness, Gaute T Einevoll
The human brain operates at multiple levels, from molecules to circuits, and understanding these complex processes requires integrated research efforts. Simulating biophysically-detailed neuron models is a computationally expensive but effective method for studying local neural circuits. Recent innovations have shown that artificial neural networks (ANNs) can accurately predict the behavior of these detailed models in terms of spikes, electrical potentials, and optical readouts. While these methods have the potential to accelerate large network simulations by several orders of magnitude compared to conventional differential equation based modelling, they currently only predict voltage outputs for the soma or a select few neuron compartments. Our novel approach, based on enhanced state-of-the-art architectures for multitask learning (MTL), allows for the simultaneous prediction of membrane potentials in each compartment of a neuron model, at a speed of up to two orders of magnitude faster than classical simulation methods. By predicting all membrane potentials together, our approach not only allows for comparison of model output with a wider range of experimental recordings (patch-electrode, voltage-sensitive dye imaging), it also provides the first stepping stone towards predicting local field potentials (LFPs), electroencephalogram (EEG) signals, and magnetoencephalography (MEG) signals from ANN-based simulations. While LFP and EEG are an important downstream application, the main focus of this paper lies in predicting dendritic voltages within each compartment to capture the entire electrophysiology of a biophysically-detailed neuron model. It further presents a challenging benchmark for MTL architectures due to the large amount of data involved, the presence of correlations between neighbouring compartments, and the non-Gaussian distribution of membrane potentials.
人脑在从分子到电路的多个层次上运行,要了解这些复杂的过程需要综合的研究努力。模拟生物物理上的精细神经元模型是研究局部神经回路的一种计算昂贵但有效的方法。最近的创新表明,人工神经网络(ANN)可以准确预测这些详细模型在尖峰、电位和光学读数方面的行为。虽然与传统的基于微分方程的建模相比,这些方法有可能将大型网络模拟的速度提高几个数量级,但它们目前只能预测神经元体或少数几个神经元区的电压输出。我们的新方法基于多任务学习(MTL)的增强型先进架构,可同时预测神经元模型每个区室的膜电位,速度比传统模拟方法快两个数量级。通过同时预测所有膜电位,我们的方法不仅可以将模型输出与更广泛的实验记录(贴片电极、电压敏感染料成像)进行比较,而且还为通过基于 ANN 的模拟预测局部场电位(LFP)、脑电图(EEG)信号和脑磁图(MEG)信号提供了第一块基石。虽然 LFP 和 EEG 是重要的下游应用,但本文的重点在于预测每个隔室中的树突电压,以捕捉生物物理上精细的神经元模型的整个电生理学。由于涉及大量数据、相邻隔室之间存在相关性以及膜电位的非高斯分布,它进一步为 MTL 架构提出了一个具有挑战性的基准。
{"title":"Multitask learning of a biophysically-detailed neuron model.","authors":"Jonas Verhellen, Kosio Beshkov, Sebastian Amundsen, Torbjørn V Ness, Gaute T Einevoll","doi":"10.1371/journal.pcbi.1011728","DOIUrl":"10.1371/journal.pcbi.1011728","url":null,"abstract":"<p><p>The human brain operates at multiple levels, from molecules to circuits, and understanding these complex processes requires integrated research efforts. Simulating biophysically-detailed neuron models is a computationally expensive but effective method for studying local neural circuits. Recent innovations have shown that artificial neural networks (ANNs) can accurately predict the behavior of these detailed models in terms of spikes, electrical potentials, and optical readouts. While these methods have the potential to accelerate large network simulations by several orders of magnitude compared to conventional differential equation based modelling, they currently only predict voltage outputs for the soma or a select few neuron compartments. Our novel approach, based on enhanced state-of-the-art architectures for multitask learning (MTL), allows for the simultaneous prediction of membrane potentials in each compartment of a neuron model, at a speed of up to two orders of magnitude faster than classical simulation methods. By predicting all membrane potentials together, our approach not only allows for comparison of model output with a wider range of experimental recordings (patch-electrode, voltage-sensitive dye imaging), it also provides the first stepping stone towards predicting local field potentials (LFPs), electroencephalogram (EEG) signals, and magnetoencephalography (MEG) signals from ANN-based simulations. While LFP and EEG are an important downstream application, the main focus of this paper lies in predicting dendritic voltages within each compartment to capture the entire electrophysiology of a biophysically-detailed neuron model. It further presents a challenging benchmark for MTL architectures due to the large amount of data involved, the presence of correlations between neighbouring compartments, and the non-Gaussian distribution of membrane potentials.</p>","PeriodicalId":20241,"journal":{"name":"PLoS Computational Biology","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11318869/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141860654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-30eCollection Date: 2024-07-01DOI: 10.1371/journal.pcbi.1012271
Andres J Nevarez, Anusorn Mudla, Sabrina A Diaz, Nan Hao
Melanoma showcases a complex interplay of genetic alterations and intra- and inter-cellular morphological changes during metastatic transformation. While pivotal, the role of specific mutations in dictating these changes still needs to be fully elucidated. Telomerase promoter mutations (TERTp mutations) significantly influence melanoma's progression, invasiveness, and resistance to various emerging treatments, including chemical inhibitors, telomerase inhibitors, targeted therapy, and immunotherapies. We aim to understand the morphological and phenotypic implications of the two dominant monoallelic TERTp mutations, C228T and C250T, enriched in melanoma metastasis. We developed isogenic clonal cell lines containing the TERTp mutations and utilized dual-color expression reporters steered by the endogenous Telomerase promoter, giving us allelic resolution. This approach allowed us to monitor morpholomic variations induced by these mutations. TERTp mutation-bearing cells exhibited significant morpholome differences from their wild-type counterparts, with increased allele expression patterns, augmented wound-healing rates, and unique spatiotemporal dynamics. Notably, the C250T mutation exerted more pronounced changes in the morpholome than C228T, suggesting a differential role in metastatic potential. Our findings underscore the distinct influence of TERTp mutations on melanoma's cellular architecture and behavior. The C250T mutation may offer a unique morpholomic and systems-driven advantage for metastasis. These insights provide a foundational understanding of how a non-coding mutation in melanoma metastasis affects the system, manifesting in cellular morpholome.
{"title":"Using deep learning to decipher the impact of telomerase promoter mutations on the dynamic metastatic morpholome.","authors":"Andres J Nevarez, Anusorn Mudla, Sabrina A Diaz, Nan Hao","doi":"10.1371/journal.pcbi.1012271","DOIUrl":"10.1371/journal.pcbi.1012271","url":null,"abstract":"<p><p>Melanoma showcases a complex interplay of genetic alterations and intra- and inter-cellular morphological changes during metastatic transformation. While pivotal, the role of specific mutations in dictating these changes still needs to be fully elucidated. Telomerase promoter mutations (TERTp mutations) significantly influence melanoma's progression, invasiveness, and resistance to various emerging treatments, including chemical inhibitors, telomerase inhibitors, targeted therapy, and immunotherapies. We aim to understand the morphological and phenotypic implications of the two dominant monoallelic TERTp mutations, C228T and C250T, enriched in melanoma metastasis. We developed isogenic clonal cell lines containing the TERTp mutations and utilized dual-color expression reporters steered by the endogenous Telomerase promoter, giving us allelic resolution. This approach allowed us to monitor morpholomic variations induced by these mutations. TERTp mutation-bearing cells exhibited significant morpholome differences from their wild-type counterparts, with increased allele expression patterns, augmented wound-healing rates, and unique spatiotemporal dynamics. Notably, the C250T mutation exerted more pronounced changes in the morpholome than C228T, suggesting a differential role in metastatic potential. Our findings underscore the distinct influence of TERTp mutations on melanoma's cellular architecture and behavior. The C250T mutation may offer a unique morpholomic and systems-driven advantage for metastasis. These insights provide a foundational understanding of how a non-coding mutation in melanoma metastasis affects the system, manifesting in cellular morpholome.</p>","PeriodicalId":20241,"journal":{"name":"PLoS Computational Biology","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11288469/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141856288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-29eCollection Date: 2024-07-01DOI: 10.1371/journal.pcbi.1012300
Diogo Melo, Luisa F Pallares, Julien F Ayroles
Finding communities in gene co-expression networks is a common first step toward extracting biological insight from these complex datasets. Most community detection algorithms expect genes to be organized into assortative modules, that is, groups of genes that are more associated with each other than with genes in other groups. While it is reasonable to expect that these modules exist, using methods that assume they exist a priori is risky, as it guarantees that alternative organizations of gene interactions will be ignored. Here, we ask: can we find meaningful communities without imposing a modular organization on gene co-expression networks, and how modular are these communities? For this, we use a recently developed community detection method, the weighted degree corrected stochastic block model (SBM), that does not assume that assortative modules exist. Instead, the SBM attempts to efficiently use all information contained in the co-expression network to separate the genes into hierarchically organized blocks of genes. Using RNAseq gene expression data measured in two tissues derived from an outbred population of Drosophila melanogaster, we show that (a) the SBM is able to find ten times as many groups as competing methods, that (b) several of those gene groups are not modular, and that (c) the functional enrichment for non-modular groups is as strong as for modular communities. These results show that the transcriptome is structured in more complex ways than traditionally thought and that we should revisit the long-standing assumption that modularity is the main driver of the structuring of gene co-expression networks.
{"title":"Reassessing the modularity of gene co-expression networks using the Stochastic Block Model.","authors":"Diogo Melo, Luisa F Pallares, Julien F Ayroles","doi":"10.1371/journal.pcbi.1012300","DOIUrl":"10.1371/journal.pcbi.1012300","url":null,"abstract":"<p><p>Finding communities in gene co-expression networks is a common first step toward extracting biological insight from these complex datasets. Most community detection algorithms expect genes to be organized into assortative modules, that is, groups of genes that are more associated with each other than with genes in other groups. While it is reasonable to expect that these modules exist, using methods that assume they exist a priori is risky, as it guarantees that alternative organizations of gene interactions will be ignored. Here, we ask: can we find meaningful communities without imposing a modular organization on gene co-expression networks, and how modular are these communities? For this, we use a recently developed community detection method, the weighted degree corrected stochastic block model (SBM), that does not assume that assortative modules exist. Instead, the SBM attempts to efficiently use all information contained in the co-expression network to separate the genes into hierarchically organized blocks of genes. Using RNAseq gene expression data measured in two tissues derived from an outbred population of Drosophila melanogaster, we show that (a) the SBM is able to find ten times as many groups as competing methods, that (b) several of those gene groups are not modular, and that (c) the functional enrichment for non-modular groups is as strong as for modular communities. These results show that the transcriptome is structured in more complex ways than traditionally thought and that we should revisit the long-standing assumption that modularity is the main driver of the structuring of gene co-expression networks.</p>","PeriodicalId":20241,"journal":{"name":"PLoS Computational Biology","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11309492/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141793177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-29eCollection Date: 2024-07-01DOI: 10.1371/journal.pcbi.1011879
Vivienne Leech, Fiona N Kenny, Stefania Marcotti, Tanya J Shaw, Brian M Stramer, Angelika Manhart
Collective alignment of cell populations is a commonly observed phenomena in biology. An important example are aligning fibroblasts in healthy or scar tissue. In this work we derive and simulate a mechanistic agent-based model of the collective behaviour of actively moving and interacting cells, with a focus on understanding collective alignment. The derivation strategy is based on energy minimisation. The model ingredients are motivated by data on the behaviour of different populations of aligning fibroblasts and include: Self-propulsion, overlap avoidance, deformability, cell-cell junctions and cytoskeletal forces. We find that there is an optimal ratio of self-propulsion speed and overlap avoidance that maximises collective alignment. Further we find that deformability aids alignment, and that cell-cell junctions by themselves hinder alignment. However, if cytoskeletal forces are transmitted via cell-cell junctions we observe strong collective alignment over large spatial scales.
{"title":"Derivation and simulation of a computational model of active cell populations: How overlap avoidance, deformability, cell-cell junctions and cytoskeletal forces affect alignment.","authors":"Vivienne Leech, Fiona N Kenny, Stefania Marcotti, Tanya J Shaw, Brian M Stramer, Angelika Manhart","doi":"10.1371/journal.pcbi.1011879","DOIUrl":"10.1371/journal.pcbi.1011879","url":null,"abstract":"<p><p>Collective alignment of cell populations is a commonly observed phenomena in biology. An important example are aligning fibroblasts in healthy or scar tissue. In this work we derive and simulate a mechanistic agent-based model of the collective behaviour of actively moving and interacting cells, with a focus on understanding collective alignment. The derivation strategy is based on energy minimisation. The model ingredients are motivated by data on the behaviour of different populations of aligning fibroblasts and include: Self-propulsion, overlap avoidance, deformability, cell-cell junctions and cytoskeletal forces. We find that there is an optimal ratio of self-propulsion speed and overlap avoidance that maximises collective alignment. Further we find that deformability aids alignment, and that cell-cell junctions by themselves hinder alignment. However, if cytoskeletal forces are transmitted via cell-cell junctions we observe strong collective alignment over large spatial scales.</p>","PeriodicalId":20241,"journal":{"name":"PLoS Computational Biology","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11309491/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141793175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}