PLoS Computational Biology最新文献

{"title":"Real-time forecasting of COVID-19-related hospital strain in France using a non-Markovian mechanistic model.","authors":"Alexander Massey, C. Boennec, C. X. Restrepo-Ortiz, Christophe Blanchet, Samuel Alizon, Mircea T. Sofonea","doi":"10.1371/journal.pcbi.1012124","DOIUrl":"https://doi.org/10.1371/journal.pcbi.1012124","url":null,"abstract":"Projects such as the European Covid-19 Forecast Hub publish forecasts on the national level for new deaths, new cases, and hospital admissions, but not direct measurements of hospital strain like critical care bed occupancy at the sub-national level, which is of particular interest to health professionals for planning purposes. We present a sub-national French framework for forecasting hospital strain based on a non-Markovian compartmental model, its associated online visualisation tool and a retrospective evaluation of the real-time forecasts it provided from January to December 2021 by comparing to three baselines derived from standard statistical forecasting methods (a naive model, auto-regression, and an ensemble of exponential smoothing and ARIMA). In terms of median absolute error for forecasting critical care unit occupancy at the two-week horizon, our model only outperformed the naive baseline for 4 out of 14 geographical units and underperformed compared to the ensemble baseline for 5 of them at the 90% confidence level (n = 38). However, for the same level at the 4 week horizon, our model was never statistically outperformed for any unit despite outperforming the baselines 10 times spanning 7 out of 14 geographical units. This implies modest forecasting utility for longer horizons which may justify the application of non-Markovian compartmental models in the context of hospital-strain surveillance for future pandemics.","PeriodicalId":49688,"journal":{"name":"PLoS Computational Biology","volume":"5 11","pages":"e1012124"},"PeriodicalIF":4.3,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140963817","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}

{"title":"Ten simple rules for teaching an introduction to R","authors":"Ava M. Hoffman, Carrie Wright","doi":"10.1371/journal.pcbi.1012018","DOIUrl":"https://doi.org/10.1371/journal.pcbi.1012018","url":null,"abstract":"","PeriodicalId":49688,"journal":{"name":"PLoS Computational Biology","volume":"19 7","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141052879","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}

{"title":"Evolutionary analyses of intrinsically disordered regions reveal widespread signals of conservation.","authors":"Marc D Singleton, Michael B. Eisen","doi":"10.1371/journal.pcbi.1012028","DOIUrl":"https://doi.org/10.1371/journal.pcbi.1012028","url":null,"abstract":"Intrinsically disordered regions (IDRs) are segments of proteins without stable three-dimensional structures. As this flexibility allows them to interact with diverse binding partners, IDRs play key roles in cell signaling and gene expression. Despite the prevalence and importance of IDRs in eukaryotic proteomes and various biological processes, associating them with specific molecular functions remains a significant challenge due to their high rates of sequence evolution. However, by comparing the observed values of various IDR-associated properties against those generated under a simulated model of evolution, a recent study found most IDRs across the entire yeast proteome contain conserved features. Furthermore, it showed clusters of IDRs with common \"evolutionary signatures,\" i.e. patterns of conserved features, were associated with specific biological functions. To determine if similar patterns of conservation are found in the IDRs of other systems, in this work we applied a series of phylogenetic models to over 7,500 orthologous IDRs identified in the Drosophila genome to dissect the forces driving their evolution. By comparing models of constrained and unconstrained continuous trait evolution using the Brownian motion and Ornstein-Uhlenbeck models, respectively, we identified signals of widespread constraint, indicating conservation of distributed features is mechanism of IDR evolution common to multiple biological systems. In contrast to the previous study in yeast, however, we observed limited evidence of IDR clusters with specific biological functions, which suggests a more complex relationship between evolutionary constraints and function in the IDRs of multicellular organisms.","PeriodicalId":49688,"journal":{"name":"PLoS Computational Biology","volume":"90 10","pages":"e1012028"},"PeriodicalIF":4.3,"publicationDate":"2024-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140654809","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}

{"title":"A weak coupling mechanism for the early steps of the recovery stroke of myosin VI: A free energy simulation and string method analysis.","authors":"Florian E C Blanc, A. Houdusse, Marco Cecchini","doi":"10.1371/journal.pcbi.1012005","DOIUrl":"https://doi.org/10.1371/journal.pcbi.1012005","url":null,"abstract":"Myosin motors use the energy of ATP to produce force and directed movement on actin by a swing of the lever arm. ATP is hydrolysed during the off-actin re-priming transition termed recovery stroke. To provide an understanding of chemo-mechanical transduction by myosin, it is critical to determine how the reverse swing of the lever arm and ATP hydrolysis are coupled. Previous studies concluded that the recovery stroke of myosin II is initiated by closure of the Switch II loop in the nucleotide-binding site. Recently, we proposed that the recovery stroke of myosin VI starts with the spontaneous re-priming of the converter domain to a putative pre-transition state (PTS) intermediate that precedes Switch II closing and ATPase activation. Here, we investigate the transition from the pre-recovery, post-rigor (PR) state to PTS in myosin VI using geometric free energy simulations and the string method. First, our calculations rediscover the PTS state agnostically and show that it is accessible from PR via a low free energy transition path. Second, separate path calculations using the string method illuminate the mechanism of the PR to PTS transition with atomic resolution. In this mechanism, the initiating event is a large movement of the converter/lever-arm region that triggers rearrangements in the Relay-SH1 region and the formation of the kink in the Relay helix with no coupling to the active site. Analysis of the free-energy barriers along the path suggests that the converter-initiated mechanism is much faster than the one initiated by Switch II closure, which supports the biological relevance of PTS as a major on-pathway intermediate of the recovery stroke in myosin VI. Our analysis suggests that lever-arm re-priming and ATP hydrolysis are only weakly coupled, so that the myosin recovery stroke is initiated by thermal fluctuations and stabilised by nucleotide consumption via a ratchet-like mechanism.","PeriodicalId":49688,"journal":{"name":"PLoS Computational Biology","volume":"30 3","pages":"e1012005"},"PeriodicalIF":4.3,"publicationDate":"2024-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140657693","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}

{"title":"Validity conditions of approximations for a target-mediated drug disposition model: A novel first-order approximation and its comparison to other approximations.","authors":"Jong Hyuk Byun, Hye Seon Jeon, Hwi‐yeol Yun, Jae Kyoung Kim","doi":"10.1371/journal.pcbi.1012066","DOIUrl":"https://doi.org/10.1371/journal.pcbi.1012066","url":null,"abstract":"Target-mediated drug disposition (TMDD) is a phenomenon characterized by a drug's high-affinity binding to a target molecule, which significantly influences its pharmacokinetic profile within an organism. The comprehensive TMDD model delineates this interaction, yet it may become overly complex and computationally demanding in the absence of specific concentration data for the target or its complexes. Consequently, simplified TMDD models employing quasi-steady state approximations (QSSAs) have been introduced; however, the precise conditions under which these models yield accurate results require further elucidation. Here, we establish the validity of three simplified TMDD models: the Michaelis-Menten model reduced with the standard QSSA (mTMDD), the QSS model reduced with the total QSSA (qTMDD), and a first-order approximation of the total QSSA (pTMDD). Specifically, we find that mTMDD is applicable only when initial drug concentrations substantially exceed total target concentrations, while qTMDD can be used for all drug concentrations. Notably, pTMDD offers a simpler and faster alternative to qTMDD, with broader applicability than mTMDD. These findings are confirmed with antibody-drug conjugate real-world data. Our findings provide a framework for selecting appropriate simplified TMDD models while ensuring accuracy, potentially enhancing drug development and facilitating safer, more personalized treatments.","PeriodicalId":49688,"journal":{"name":"PLoS Computational Biology","volume":"59 11","pages":"e1012066"},"PeriodicalIF":4.3,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140665957","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}

{"title":"Neutral competition explains the clonal composition of neural organoids.","authors":"Florian G. Pflug, Simon Haendeler, Christopher Esk, Dominik Lindenhofer, Jurgen Knoblich, A. von Haeseler","doi":"10.1371/journal.pcbi.1012054","DOIUrl":"https://doi.org/10.1371/journal.pcbi.1012054","url":null,"abstract":"Neural organoids model the development of the human brain and are an indispensable tool for studying neurodevelopment. Whole-organoid lineage tracing has revealed the number of progenies arising from each initial stem cell to be highly diverse, with lineage sizes ranging from one to more than 20,000 cells. This high variability exceeds what can be explained by existing stochastic models of corticogenesis and indicates the existence of an additional source of stochasticity. To explain this variability, we introduce the SAN model which distinguishes Symmetrically diving, Asymmetrically dividing, and Non-proliferating cells. In the SAN model, the additional source of stochasticity is the survival time of a lineage's pool of symmetrically dividing cells. These survival times result from neutral competition within the sub-population of all symmetrically dividing cells. We demonstrate that our model explains the experimentally observed variability of lineage sizes and derive the quantitative relationship between survival time and lineage size. We also show that our model implies the existence of a regulatory mechanism which keeps the size of the symmetrically dividing cell population constant. Our results provide quantitative insight into the clonal composition of neural organoids and how it arises. This is relevant for many applications of neural organoids, and similar processes may occur in other developing tissues both in vitro and in vivo.","PeriodicalId":49688,"journal":{"name":"PLoS Computational Biology","volume":"5 4","pages":"e1012054"},"PeriodicalIF":4.3,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140672772","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}

{"title":"Temperature-driven coordination of circadian transcriptional regulation.","authors":"Bingxian Xu, D. Hwangbo, Sumit Saurabh, C. Rosensweig, Ravi Allada, William L. Kath, Rosemary Braun","doi":"10.1371/journal.pcbi.1012029","DOIUrl":"https://doi.org/10.1371/journal.pcbi.1012029","url":null,"abstract":"The circadian clock is an evolutionarily-conserved molecular oscillator that enables species to anticipate rhythmic changes in their environment. At a molecular level, the core clock genes induce circadian oscillations in thousands of genes in a tissue-specific manner, orchestrating myriad biological processes. While previous studies have investigated how the core clock circuit responds to environmental perturbations such as temperature, the downstream effects of such perturbations on circadian regulation remain poorly understood. By analyzing bulk-RNA sequencing of Drosophila fat bodies harvested from flies subjected to different environmental conditions, we demonstrate a highly condition-specific circadian transcriptome: genes are cycling in a temperature-specific manner, and the distributions of their phases also differ between the two conditions. Further employing a reference-based gene regulatory network (Reactome), we find evidence of increased gene-gene coordination at low temperatures and synchronization of rhythmic genes that are network neighbors. We report that the phase differences between cycling genes increase as a function of geodesic distance in the low temperature condition, suggesting increased coordination of cycling on the gene regulatory network. Our results suggest a potential mechanism whereby the circadian clock mediates the fly's response to seasonal changes in temperature.","PeriodicalId":49688,"journal":{"name":"PLoS Computational Biology","volume":"50 7","pages":"e1012029"},"PeriodicalIF":4.3,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140676072","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}

{"title":"Non-invasive assessment of stroke volume and cardiovascular parameters based on peripheral pressure waveform.","authors":"Kamil Wołos, L. Pstras, M. Debowska, Wojciech Dabrowski, Dorota Siwicka-Gieroba, Jan Poleszczuk","doi":"10.1371/journal.pcbi.1012013","DOIUrl":"https://doi.org/10.1371/journal.pcbi.1012013","url":null,"abstract":"Cardiovascular diseases are the leading cause of death globally, making the development of non-invasive and simple-to-use tools that bring insights into the state of the cardiovascular system of utmost importance. We investigated the possibility of using peripheral pulse wave recordings to estimate stroke volume (SV) and subject-specific parameters describing the selected properties of the cardiovascular system. Peripheral pressure waveforms were recorded in the radial artery using applanation tonometry (SphygmoCor) in 35 hemodialysis (HD) patients and 14 healthy subjects. The pressure waveforms were then used to estimate subject-specific parameters of a mathematical model of pulse wave propagation coupled with the elastance-based model of the left ventricle. Bioimpedance cardiography measurements (PhysioFlow) were performed to validate the model-estimated SV. Mean absolute percentage error between the simulated and measured pressure waveforms was 4.0% and 2.8% for the HD and control group, respectively. We obtained a moderate correlation between the model-estimated and bioimpedance-based SV (r = 0.57, p<0.05, and r = 0.58, p<0.001, for the control group and HD patients, respectively). We also observed a correlation between the estimated end-systolic elastance of the left ventricle and the peripheral systolic pressure in both HD patients (r = 0.84, p<0.001) and the control group (r = 0.70, p<0.01). These preliminary results suggest that, after additional validation and possibly further refinement to increase accuracy, the proposed methodology could support non-invasive assessment of stroke volume and selected heart function parameters and vascular properties. Importantly, the proposed method could be potentially implemented in the existing devices measuring peripheral pressure waveforms.","PeriodicalId":49688,"journal":{"name":"PLoS Computational Biology","volume":" 4","pages":"e1012013"},"PeriodicalIF":4.3,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140689568","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}

{"title":"Precise cortical contributions to sensorimotor feedback control during reactive balance.","authors":"Scott Boebinger, Aiden M. Payne, Giovanni Martino, Kennedy Kerr, Jasmine L Mirdamadi, J. L. McKay, Michael R Borich, Lena H Ting","doi":"10.1371/journal.pcbi.1011562","DOIUrl":"https://doi.org/10.1371/journal.pcbi.1011562","url":null,"abstract":"The role of the cortex in shaping automatic whole-body motor behaviors such as walking and balance is poorly understood. Gait and balance are typically mediated through subcortical circuits, with the cortex becoming engaged as needed on an individual basis by task difficulty and complexity. However, we lack a mechanistic understanding of how increased cortical contribution to whole-body movements shapes motor output. Here we use reactive balance recovery as a paradigm to identify relationships between hierarchical control mechanisms and their engagement across balance tasks of increasing difficulty in young adults. We hypothesize that parallel sensorimotor feedback loops engaging subcortical and cortical circuits contribute to balance-correcting muscle activity, and that the involvement of cortical circuits increases with balance challenge. We decomposed balance-correcting muscle activity based on hypothesized subcortically- and cortically-mediated feedback components driven by similar sensory information, but with different loop delays. The initial balance-correcting muscle activity was engaged at all levels of balance difficulty. Its onset latency was consistent with subcortical sensorimotor loops observed in the lower limb. An even later, presumed, cortically-mediated burst of muscle activity became additionally engaged as balance task difficulty increased, at latencies consistent with longer transcortical sensorimotor loops. We further demonstrate that evoked cortical activity in central midline areas measured using electroencephalography (EEG) can be explained by a similar sensory transformation as muscle activity but at a delay consistent with its role in a transcortical loop driving later cortical contributions to balance-correcting muscle activity. These results demonstrate that a neuromechanical model of muscle activity can be used to infer cortical contributions to muscle activity without recording brain activity. Our model may provide a useful framework for evaluating changes in cortical contributions to balance that are associated with falls in older adults and in neurological disorders such as Parkinson's disease.","PeriodicalId":49688,"journal":{"name":"PLoS Computational Biology","volume":"170 4","pages":"e1011562"},"PeriodicalIF":4.3,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140693413","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}

{"title":"CoVar: A generalizable machine learning approach to identify the coordinated regulators driving variational gene expression.","authors":"Satyaki Roy, S. Sheikh, T. Furey","doi":"10.1371/journal.pcbi.1012016","DOIUrl":"https://doi.org/10.1371/journal.pcbi.1012016","url":null,"abstract":"Network inference is used to model transcriptional, signaling, and metabolic interactions among genes, proteins, and metabolites that identify biological pathways influencing disease pathogenesis. Advances in machine learning (ML)-based inference models exhibit the predictive capabilities of capturing latent patterns in genomic data. Such models are emerging as an alternative to the statistical models identifying causative factors driving complex diseases. We present CoVar, an ML-based framework that builds upon the properties of existing inference models, to find the central genes driving perturbed gene expression across biological states. Unlike differentially expressed genes (DEGs) that capture changes in individual gene expression across conditions, CoVar focuses on identifying variational genes that undergo changes in their expression network interaction profiles, providing insights into changes in the regulatory dynamics, such as in disease pathogenesis. Subsequently, it finds core genes from among the nearest neighbors of these variational genes, which are central to the variational activity and influence the coordinated regulatory processes underlying the observed changes in gene expression. Through the analysis of simulated as well as yeast expression data perturbed by the deletion of the mitochondrial genome, we show that CoVar captures the intrinsic variationality and modularity in the expression data, identifying key driver genes not found through existing differential analysis methodologies.","PeriodicalId":49688,"journal":{"name":"PLoS Computational Biology","volume":" 12","pages":"e1012016"},"PeriodicalIF":4.3,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140690733","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}