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Assessing the effect of model specification and prior sensitivity on Bayesian tests of temporal signal. 评估模型规范和先验敏感性对贝叶斯时间信号检验的影响。
IF 3.8 2区 生物学
PLoS Computational Biology Pub Date : 2024-11-06 DOI: 10.1371/journal.pcbi.1012371
John H Tay, Arthur Kocher, Sebastian Duchene
{"title":"Assessing the effect of model specification and prior sensitivity on Bayesian tests of temporal signal.","authors":"John H Tay, Arthur Kocher, Sebastian Duchene","doi":"10.1371/journal.pcbi.1012371","DOIUrl":"https://doi.org/10.1371/journal.pcbi.1012371","url":null,"abstract":"<p><p>Our understanding of the evolution of many microbes has been revolutionised by the molecular clock, a statistical tool to infer evolutionary rates and timescales from analyses of biomolecular sequences. In all molecular clock models, evolutionary rates and times are jointly unidentifiable and 'calibration' information must therefore be used. For many organisms, sequences sampled at different time points can be employed for such calibration. Before attempting to do so, it is recommended to verify that the data carry sufficient information for molecular dating, a practice referred to as evaluation of temporal signal. Recently, a fully Bayesian approach, BETS (Bayesian Evaluation of Temporal Signal), was proposed to overcome known limitations of other commonly used techniques such as root-to-tip regression or date randomisation tests. BETS requires the specification of a full Bayesian phylogenetic model, posing several considerations for untangling the impact of model choice on the detection of temporal signal. Here, we aimed to (i) explore the effect of molecular clock model and tree prior specification on the results of BETS and (ii) provide guidelines for improving our confidence in molecular clock estimates. Using microbial molecular sequence data sets and simulation experiments, we assess the impact of the tree prior and its hyperparameters on the accuracy of temporal signal detection. In particular, highly informative priors that are inconsistent with the data can result in the incorrect detection of temporal signal. In consequence, we recommend: (i) using prior predictive simulations to determine whether the prior generates a reasonable expectation of parameters of interest, such as the evolutionary rate and age of the root node, (ii) conducting prior sensitivity analyses to assess the robustness of the posterior to the choice of prior, and (iii) selecting a molecular clock model that reasonably describes the evolutionary process.</p>","PeriodicalId":20241,"journal":{"name":"PLoS Computational Biology","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142591134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A computational analysis of the oncogenic and anti-tumor immunity role of P4HA3 in human cancers. 通过计算分析 P4HA3 在人类癌症中的致癌和抗肿瘤免疫作用。
IF 3.8 2区 生物学
PLoS Computational Biology Pub Date : 2024-11-06 DOI: 10.1371/journal.pcbi.1012284
Hong Yan Huang, Fu Wei Zhang, Jie Yu, Yan Hong Xiao, Di Zhu, XiaoLin Yi, XiaoHua Lin, Ming Jin, Hai Yun Jin, Yong Sheng Huang, Shu Wei Ren
{"title":"A computational analysis of the oncogenic and anti-tumor immunity role of P4HA3 in human cancers.","authors":"Hong Yan Huang, Fu Wei Zhang, Jie Yu, Yan Hong Xiao, Di Zhu, XiaoLin Yi, XiaoHua Lin, Ming Jin, Hai Yun Jin, Yong Sheng Huang, Shu Wei Ren","doi":"10.1371/journal.pcbi.1012284","DOIUrl":"https://doi.org/10.1371/journal.pcbi.1012284","url":null,"abstract":"<p><p>Prolyl-4-hydroxylase subunit alpha3 (P4HA3) is a triple helical procollagen synthesis protein. The role of P4HA3 in cancer development is not well known and lacks comprehensive analyses among human cancers. This study aimed to investigate the relationship between P4HA3 expression and anti-tumor immunity and its prognostic value in pan-cancer. P4HA3 expression was analyzed from TIMER2.0, GTEx, GEPIA2.0 and TCGA databases. Genetic and DNA methylation alterations, survival analysis and proteins co-expression analysis of P4HA3 in cBio Cancer Genomics Portal, TCGA, GSCA and TIMER2.0. The correlation between P4HA3 expression and immune infiltration was analyzed by TIDE, XCELL, MCPCOUNTER, and EPIC. We performed EdU and transwell experiments to evaluate the influence of P4HA3 on the proliferation, migration and invasion abilities of different tumors. Patients derived xenograft (PDX) and subcutaneous transplantation models were utilized to explore the correlation between P4HA3 and immunotherapy response in triple-negative breast cancer (TNBC). Among 33 types of cancers, P4HA3 had generally different expression between different tumors, further analysis showed that the expression of P4HA3 was correlated with the cells infiltration of the tumor microenvironment (TME). The expression of P4HA3 was positively with the cell proliferation markers and epithelial-mesenchymal transition (EMT) markers. Moreover, P4HA3 deficiency inhibited the proliferation, migration and invasion abilities of tumor cells, and promoted anti-tumor immunotherapy of PD-1/PD-L1 inhibitor. This pan-cancer analysis of P4HA3 provides a comprehensive understanding of its oncogenic and prognosis role in different cancers, P4HA3 abnormal expression could be a useful biomarker for predicting the effectiveness of immunotherapy in cancer patients.</p>","PeriodicalId":20241,"journal":{"name":"PLoS Computational Biology","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142591131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
During haptic communication, the central nervous system compensates distinctly for delay and noise. 在触觉交流过程中,中枢神经系统会对延迟和噪音进行明显的补偿。
IF 3.8 2区 生物学
PLoS Computational Biology Pub Date : 2024-11-06 DOI: 10.1371/journal.pcbi.1012037
Jonathan Eden, Ekaterina Ivanova, Etienne Burdet
{"title":"During haptic communication, the central nervous system compensates distinctly for delay and noise.","authors":"Jonathan Eden, Ekaterina Ivanova, Etienne Burdet","doi":"10.1371/journal.pcbi.1012037","DOIUrl":"https://doi.org/10.1371/journal.pcbi.1012037","url":null,"abstract":"<p><p>Physically connected humans have been shown to exploit the exchange of haptic forces and tactile information to improve their performance in joint action tasks. As human interactions are increasingly mediated through robots and networks it is important to understand the impact that network features such as lag and noise may have on human behaviour. In this paper, we investigated interaction with a human-like robot controller that provides similar haptic communication behaviour as human-human interaction and examined the influence and compensation mechanisms for delay and noise on haptic communication. The results of our experiments show that participants can perceive a difference between noise and delay, and make use of compensation mechanisms to preserve performance in both cases. However, while noise is compensated for by increasing co-contraction, delay compensation could not be explained by this strategy. Instead, computational modelling suggested that a distinct mechanism is used to compensate for the delay and yield an efficient haptic communication.</p>","PeriodicalId":20241,"journal":{"name":"PLoS Computational Biology","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142591144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Structure-aware annotation of leucine-rich repeat domains. 富亮氨酸重复域的结构感知注释。
IF 3.8 2区 生物学
PLoS Computational Biology Pub Date : 2024-11-05 DOI: 10.1371/journal.pcbi.1012526
Boyan Xu, Alois Cerbu, Christopher J Tralie, Daven Lim, Ksenia Krasileva
{"title":"Structure-aware annotation of leucine-rich repeat domains.","authors":"Boyan Xu, Alois Cerbu, Christopher J Tralie, Daven Lim, Ksenia Krasileva","doi":"10.1371/journal.pcbi.1012526","DOIUrl":"10.1371/journal.pcbi.1012526","url":null,"abstract":"<p><p>Protein domain annotation is typically done by predictive models such as HMMs trained on sequence motifs. However, sequence-based annotation methods are prone to error, particularly in calling domain boundaries and motifs within them. These methods are limited by a lack of structural information accessible to the model. With the advent of deep learning-based protein structure prediction, existing sequenced-based domain annotation methods can be improved by taking into account the geometry of protein structures. We develop dimensionality reduction methods to annotate repeat units of the Leucine Rich Repeat solenoid domain. The methods are able to correct mistakes made by existing machine learning-based annotation tools and enable the automated detection of hairpin loops and structural anomalies in the solenoid. The methods are applied to 127 predicted structures of LRR-containing intracellular innate immune proteins in the model plant Arabidopsis thaliana and validated against a benchmark dataset of 172 manually-annotated LRR domains.</p>","PeriodicalId":20241,"journal":{"name":"PLoS Computational Biology","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A mechanistic model of in vitro plasma activation to evaluate therapeutic kallikrein-kinin system inhibitors. 体外血浆活化机理模型,用于评估治疗性 Kallikrein-kinin 系统抑制剂。
IF 3.8 2区 生物学
PLoS Computational Biology Pub Date : 2024-11-04 DOI: 10.1371/journal.pcbi.1012552
Alireza Rezvani-Sharif, Hadi Lioe, Steven K Dower, Matthias Pelzing, Con Panousis, Dalton J E Harvie, Ineke L Muir
{"title":"A mechanistic model of in vitro plasma activation to evaluate therapeutic kallikrein-kinin system inhibitors.","authors":"Alireza Rezvani-Sharif, Hadi Lioe, Steven K Dower, Matthias Pelzing, Con Panousis, Dalton J E Harvie, Ineke L Muir","doi":"10.1371/journal.pcbi.1012552","DOIUrl":"https://doi.org/10.1371/journal.pcbi.1012552","url":null,"abstract":"<p><strong>Background: </strong>The kallikrein-kinin system (KKS) is a complex biochemical pathway that plays a crucial role in regulating several physiological processes, including inflammation, coagulation, and blood pressure. Dysregulation of the KKS has been associated with several pathological conditions such as hereditary angioedema (HAE), hypertension, and stroke. Developing an accurate quantitative model of the KKS may provide a better understanding of its role in health and disease and facilitate the rapid and targeted development of effective therapies for KKS-related disorders.</p><p><strong>Objectives: </strong>Here, we present a novel, detailed mechanistic model of the plasma KKS, elucidating the processes of Factor XII (FXII) activation, the kallikrein feedback loop, cleavage of high molecular weight kininogen leading to bradykinin (BK) production, and the impact of inhibitors.</p><p><strong>Methods: </strong>The model incorporates both surface and solution-phase reactions of all proteins in the KKS, describing how binding site concentration affects the rate of surface reactions. The model was calibrated and validated using a variety of published and in-house experimental datasets, which encompass a range of dextran sulphate (DXS) concentrations to initiate contact activation and various KKS inhibitors to block bradykinin production.</p><p><strong>Results: </strong>Our mathematical model showed that a trace amount of activated FXII is required for subsequent FXII activation. The model also reveals a bell-shaped curve relationship between the activation of the KKS and the number of DXS surface binding sites. Simulations of BK generation in healthy and HAE plasma demonstrated the impact of C1 esterase inhibitor (C1inh) deficiency via increased peak BK levels and accelerated formation in HAE plasma. The efficacy of KKS inhibitors, such as CSL312, ecallantide, and C1inh, was also evaluated, with CSL312 showing the most potent inhibition of BK generation.</p><p><strong>Conclusions: </strong>The present model represents a valuable framework for studying the intricate interactions within the plasma KKS and provides a better understanding of the mechanism of action of various KKS-targeted therapies.</p>","PeriodicalId":20241,"journal":{"name":"PLoS Computational Biology","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142576459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Harnessing the optimization of enzyme catalytic rates in engineering of metabolic phenotypes. 在代谢表型工程中利用酶催化率的优化。
IF 3.8 2区 生物学
PLoS Computational Biology Pub Date : 2024-11-04 DOI: 10.1371/journal.pcbi.1012576
Zahra Razaghi-Moghadam, Fayaz Soleymani Babadi, Zoran Nikoloski
{"title":"Harnessing the optimization of enzyme catalytic rates in engineering of metabolic phenotypes.","authors":"Zahra Razaghi-Moghadam, Fayaz Soleymani Babadi, Zoran Nikoloski","doi":"10.1371/journal.pcbi.1012576","DOIUrl":"https://doi.org/10.1371/journal.pcbi.1012576","url":null,"abstract":"<p><p>The increasing availability of enzyme turnover number measurements from experiments and of turnover number predictions from deep learning models prompts the use of these enzyme parameters in precise metabolic engineering. Yet, there is no computational approach that allows the prediction of metabolic engineering strategies that rely on the modification of turnover numbers. It is also unclear if modifications of turnover numbers without alterations in the host's transcriptional regulatory machinery suffice to increase the production of chemicals of interest. Here, we present a constraint-based modeling approach, termed Overcoming Kinetic rate Obstacles (OKO), that uses enzyme-constrained metabolic models to predict in silico strategies to increase the production of a given chemical, while ensuring specified cell growth. We demonstrate that the application of OKO to enzyme-constrained metabolic models of Escherichia coli and Saccharomyces cerevisiae results in strategies that can at least double the production of over 40 compounds with little penalty to growth. Interestingly, we show that the overproduction of compounds of interest does not entail only an increase in the values of turnover numbers. Lastly, we demonstrate that a refinement of OKO, allowing also for manipulation of enzyme abundance, facilitates the usage of the available compendia and deep learning models of turnover numbers in the design of precise metabolic engineering strategies. Our results expand the usage of genome-scale metabolic models toward the identification of targets for protein engineering, allowing their direct usage in the generation of innovative metabolic engineering designs for various biotechnological applications.</p>","PeriodicalId":20241,"journal":{"name":"PLoS Computational Biology","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142576462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Synapses learn to utilize stochastic pre-synaptic release for the prediction of postsynaptic dynamics. 突触学会利用突触前的随机释放来预测突触后的动态。
IF 3.8 2区 生物学
PLoS Computational Biology Pub Date : 2024-11-04 eCollection Date: 2024-11-01 DOI: 10.1371/journal.pcbi.1012531
David Kappel, Christian Tetzlaff
{"title":"Synapses learn to utilize stochastic pre-synaptic release for the prediction of postsynaptic dynamics.","authors":"David Kappel, Christian Tetzlaff","doi":"10.1371/journal.pcbi.1012531","DOIUrl":"10.1371/journal.pcbi.1012531","url":null,"abstract":"<p><p>Synapses in the brain are highly noisy, which leads to a large trial-by-trial variability. Given how costly synapses are in terms of energy consumption these high levels of noise are surprising. Here we propose that synapses use noise to represent uncertainties about the somatic activity of the postsynaptic neuron. To show this, we developed a mathematical framework, in which the synapse as a whole interacts with the soma of the postsynaptic neuron in a similar way to an agent that is situated and behaves in an uncertain, dynamic environment. This framework suggests that synapses use an implicit internal model of the somatic membrane dynamics that is being updated by a synaptic learning rule, which resembles experimentally well-established LTP/LTD mechanisms. In addition, this approach entails that a synapse utilizes its inherently noisy synaptic release to also encode its uncertainty about the state of the somatic potential. Although each synapse strives for predicting the somatic dynamics of its postsynaptic neuron, we show that the emergent dynamics of many synapses in a neuronal network resolve different learning problems such as pattern classification or closed-loop control in a dynamic environment. Hereby, synapses coordinate themselves to represent and utilize uncertainties on the network level in behaviorally ambiguous situations.</p>","PeriodicalId":20241,"journal":{"name":"PLoS Computational Biology","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11534197/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142576466","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}
引用次数: 0
Enhancing insights in sexually transmitted infection mapping: Syphilis in Forsyth County, North Carolina, a case study. 提高性传播感染绘图的洞察力:北卡罗来纳州福塞斯县梅毒案例研究。
IF 3.8 2区 生物学
PLoS Computational Biology Pub Date : 2024-10-31 DOI: 10.1371/journal.pcbi.1012464
Lani Fox, William C Miller, Dionne Gesink, Irene Doherty, Marc Serre
{"title":"Enhancing insights in sexually transmitted infection mapping: Syphilis in Forsyth County, North Carolina, a case study.","authors":"Lani Fox, William C Miller, Dionne Gesink, Irene Doherty, Marc Serre","doi":"10.1371/journal.pcbi.1012464","DOIUrl":"10.1371/journal.pcbi.1012464","url":null,"abstract":"<p><p>In 2008-2011 Forsyth County, North Carolina experienced a four-fold increase in syphilis rising to over 35 cases per 100,000 mirroring the 2021 state syphilis rate. Our methodology extends current models with: 1) donut geomasking to enhance resolution while protecting patient privacy; 2) a moving window uniform grid to control the modifiable area unit problem, edge effect and remove kriging islands; and 3) mitigating the \"small number problem\" with Uniform Model Bayesian Maximum Entropy. Data is 2008-2011 early syphilis cases reported to the NC Department of Health and Human Services for Forsyth County. Results were assessed using latent rate theory cross validation. We show combining a moving window and a UMBME analysis with geomasked data effectively predicted the true or latent syphilis rate 5% to 26% more accurate than the traditional, geopolitical boundary method. It removed kriging islands, reduced background incidence rate to 0, relocated nine outbreak hotspots to more realistic locations, and elucidated hotspot connectivity producing more realistic geographical patterns for targeted insights. Using the Forsyth outbreak as a case study showed how the outbreak emerged from endemic areas spreading through sexual core transmitters and contextualizing the outbreak to current and past outbreaks. As the dynamics of sexually transmitted infections spread have changed to online partnership selection and demographically to include more women, partnership selection continues to remain highly localized. Furthermore, it is important to present methods to increase interpretability and accuracy of visual representations of data.</p>","PeriodicalId":20241,"journal":{"name":"PLoS Computational Biology","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Structural influences on synaptic plasticity: The role of presynaptic connectivity in the emergence of E/I co-tuning. 结构对突触可塑性的影响:突触前连接在 E/I 协同调谐中的作用
IF 3.8 2区 生物学
PLoS Computational Biology Pub Date : 2024-10-31 eCollection Date: 2024-10-01 DOI: 10.1371/journal.pcbi.1012510
Emmanouil Giannakakis, Oleg Vinogradov, Victor Buendía, Anna Levina
{"title":"Structural influences on synaptic plasticity: The role of presynaptic connectivity in the emergence of E/I co-tuning.","authors":"Emmanouil Giannakakis, Oleg Vinogradov, Victor Buendía, Anna Levina","doi":"10.1371/journal.pcbi.1012510","DOIUrl":"10.1371/journal.pcbi.1012510","url":null,"abstract":"<p><p>Cortical neurons are versatile and efficient coding units that develop strong preferences for specific stimulus characteristics. The sharpness of tuning and coding efficiency is hypothesized to be controlled by delicately balanced excitation and inhibition. These observations suggest a need for detailed co-tuning of excitatory and inhibitory populations. Theoretical studies have demonstrated that a combination of plasticity rules can lead to the emergence of excitation/inhibition (E/I) co-tuning in neurons driven by independent, low-noise signals. However, cortical signals are typically noisy and originate from highly recurrent networks, generating correlations in the inputs. This raises questions about the ability of plasticity mechanisms to self-organize co-tuned connectivity in neurons receiving noisy, correlated inputs. Here, we study the emergence of input selectivity and weight co-tuning in a neuron receiving input from a recurrent network via plastic feedforward connections. We demonstrate that while strong noise levels destroy the emergence of co-tuning in the readout neuron, introducing specific structures in the non-plastic pre-synaptic connectivity can re-establish it by generating a favourable correlation structure in the population activity. We further show that structured recurrent connectivity can impact the statistics in fully plastic recurrent networks, driving the formation of co-tuning in neurons that do not receive direct input from other areas. Our findings indicate that the network dynamics created by simple, biologically plausible structural connectivity patterns can enhance the ability of synaptic plasticity to learn input-output relationships in higher brain areas.</p>","PeriodicalId":20241,"journal":{"name":"PLoS Computational Biology","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Spatiotemporal orchestration of calcium-cAMP oscillations on AKAP/AC nanodomains is governed by an incoherent feedforward loop. AKAP/AC 纳米域上钙-CAMP 振荡的时空协调是由一个不连贯的前馈环路控制的。
IF 3.8 2区 生物学
PLoS Computational Biology Pub Date : 2024-10-31 eCollection Date: 2024-10-01 DOI: 10.1371/journal.pcbi.1012564
Lingxia Qiao, Michael Getz, Ben Gross, Brian Tenner, Jin Zhang, Padmini Rangamani
{"title":"Spatiotemporal orchestration of calcium-cAMP oscillations on AKAP/AC nanodomains is governed by an incoherent feedforward loop.","authors":"Lingxia Qiao, Michael Getz, Ben Gross, Brian Tenner, Jin Zhang, Padmini Rangamani","doi":"10.1371/journal.pcbi.1012564","DOIUrl":"10.1371/journal.pcbi.1012564","url":null,"abstract":"<p><p>The nanoscale organization of enzymes associated with the dynamics of second messengers is critical for ensuring compartmentation and localization of signaling molecules in cells. Specifically, the spatiotemporal orchestration of cAMP and Ca2+ oscillations is critical for many cellular functions. Previous experimental studies have shown that the formation of nanodomains of A-kinase anchoring protein 79/150 (AKAP150) and adenylyl cyclase 8 (AC8) on the surface of pancreatic MIN6 β cells modulates the phase of Ca2+-cAMP oscillations from out-of-phase to in-phase. In this work, we develop computational models of the Ca2+/cAMP pathway and AKAP/AC nanodomain formation that give rise to the two important predictions: instead of an arbitrary phase difference, the out-of-phase Ca2+/cAMP oscillation reaches Ca2+ trough and cAMP peak simultaneously, which is defined as inversely out-of-phase; the in-phase and inversely out-of-phase oscillations associated with Ca2+-cAMP dynamics on and away from the nanodomains can be explained by an incoherent feedforward loop. Factors such as cellular surface-to-volume ratio, compartment size, and distance between nanodomains do not affect the existence of in-phase or inversely out-of-phase Ca2+/cAMP oscillation, but cellular surface-to-volume ratio and compartment size can affect the time delay for the inversely out-of-phase Ca2+/cAMP oscillation while the distance between two nanodomains does not. Finally, we predict that both the Turing pattern-generated nanodomains and experimentally measured nanodomains demonstrate the existence of in-phase and inversely out-of-phase Ca2+/cAMP oscillation when the AC8 is at a low level, consistent with the behavior of an incoherent feedforward loop. These findings unveil the key circuit motif that governs cAMP and Ca2+ oscillations and advance our understanding of how nanodomains can lead to spatial compartmentation of second messengers.</p>","PeriodicalId":20241,"journal":{"name":"PLoS Computational Biology","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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