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A game of rock-paper-scissors is an interesting example of an interaction where none of the pure strategies strictly dominates all others, leading to a cyclic pattern. In this work, we consider an unstable version of rock-paper-scissors dynamics and allow individuals to make behavioural mistakes during the strategy execution. We show that such an assumption can break a cyclic relationship leading to a stable equilibrium emerging with only one strategy surviving. We consider two cases: completely random mistakes when individuals have no bias towards any strategy and a general form of mistakes. Then, we determine conditions for a strategy to dominate all other strategies. However, given that individuals who adopt a dominating strategy are still prone to behavioural mistakes in the observed behaviour, we may still observe extinct strategies. That is, behavioural mistakes in strategy execution stabilise evolutionary dynamics leading to an evolutionary stable and, potentially, mixed co-existence equilibrium.

Papers describing software are an important part of computational fields of scientific research. These "software papers" are unique in a number of ways, and they require special consideration to improve their impact on the scientific community and their efficacy at conveying important information. Here, we discuss 10 specific rules for writing software papers, covering some of the different scenarios and publication types that might be encountered, and important questions from which all computational researchers would benefit by asking along the way.

Conferences are great venues for disseminating algorithmic bioinformatics results, but they unfortunately do not offer an opportunity to make major revisions in the way that journals do. As a result, it is not possible for authors to fix mistakes that might be easily correctable but nevertheless can cause the paper to be rejected. As a reviewer, I wish that I had the opportunity to tell the authors, "Hey, you forgot to do this really important thing, without which it is hard to accept the paper, but if you could go back and fix it, you might have a great paper for the conference." This lack of a back and forth can be especially problematic for first-time submitters or those from outside the field, e.g., biologists. In this article, I outline Ten Simple Rules to follow when writing an algorithmic bioinformatics conference paper to avoid having it rejected.

[This corrects the article DOI: 10.1371/journal.pcbi.1005619.].

A game of rock-paper-scissors is an interesting example of an interaction where none of the pure strategies strictly dominates all others, leading to a cyclic pattern. In this work, we consider an unstable version of rock-paper-scissors dynamics and allow individuals to make behavioural mistakes during the strategy execution. We show that such an assumption can break a cyclic relationship leading to a stable equilibrium emerging with only one strategy surviving. We consider two cases: completely random mistakes when individuals have no bias towards any strategy and a general form of mistakes. Then, we determine conditions for a strategy to dominate all other strategies. However, given that individuals who adopt a dominating strategy are still prone to behavioural mistakes in the observed behaviour, we may still observe extinct strategies. That is, behavioural mistakes in strategy execution stabilise evolutionary dynamics leading to an evolutionary stable and, potentially, mixed co-existence equilibrium. Author summary: A game of rock-paper-scissors is more than just a children's game. This type of interactions is often used to describe competition among animals or humans. A special feature of such an interaction is that none of the pure strategies dominates, resulting in a cyclic pattern. However, in wild communities such interactions are rarely observed by biologists. Our results suggest that this lack of cyclicity may stem from imperfectness of interacting individuals. In other words, we show analytically that heterogeneity in behavioural patterns may break a cyclic relationship and lead to a stable equilibrium in pure or mixed strategies. [ABSTRACT FROM AUTHOR]

A common feature of morphogenesis is the formation of three-dimensional structures from the folding of two-dimensional epithelial sheets, aided by cell shape changes at the cellular-level. Changes in cell shape must be studied in the context of cell-polarised biomechanical processes within the epithelial sheet. In epithelia with highly curved surfaces, finding single-cell alignment along a biological axis can be difficult to automate in silico. We present 'Origami', a MATLAB-based image analysis pipeline to compute direction-variant cell shape features along the epithelial apico-basal axis. Our automated method accurately computed direction vectors denoting the apico-basal axis in regions with opposing curvature in synthetic epithelia and fluorescence images of zebrafish embryos. As proof of concept, we identified different cell shape signatures in the developing zebrafish inner ear, where the epithelium deforms in opposite orientations to form different structures. Origami is designed to be user-friendly and is generally applicable to fluorescence images of curved epithelia. Author summary: During embryonic development, two-dimensional epithelial sheets bend and fold into complex three-dimensional structures–like paper in the origami art form. The genetic and biomechanical processes driving epithelial folding can be polarised in the epithelium, leading to asymmetric shape changes at the single cell level. Defects in such epithelial shaping have been linked to many developmental anomalies and diseases. It is, therefore, important not only to quantify shape change at the single cell level, but also to orientate these asymmetrical changes along an epithelial axis of polarity when studying morphogenetic processes. Origami is a MATLAB-based software that has been developed to automatically extract such single-cell asymmetrical shape features along the epithelial apico-basal axis from fluorescence microscopy images of folding epithelia. Origami provides a solution to computing directional vectors along the epithelial apico-basal axis followed by extracting direction-variant shape features of each segmented cell. It is generally applicable to epithelial structures regardless of complexity or direction of folding and is robust to imaging conditions. As proof of concept, Origami successfully differentiated between different cell shape signatures in highly curved structures at different developmental timepoints in the zebrafish inner ear. [ABSTRACT FROM AUTHOR]

Reverse epidemiology is a mathematical modelling tool used to ascertain information about the source of a pathogen, given the spatial and temporal distribution of cases, hospitalisations and deaths. In the context of a deliberately released pathogen, such as Bacillus anthracis (the disease-causing organism of anthrax), this can allow responders to quickly identify the location and timing of the release, as well as other factors such as the strength of the release, and the realized wind speed and direction at release. These estimates can then be used to parameterise a predictive mechanistic model, allowing for estimation of the potential scale of the release, and to optimise the distribution of prophylaxis. In this paper we present two novel approaches to reverse epidemiology, and demonstrate their utility in responding to a simulated deliberate release of B. anthracis in ten locations in the UK and compare these to the standard grid-search approach. The two methods—a modified MCMC and a Recurrent Convolutional Neural Network—are able to identify the source location and timing of the release with significantly better accuracy compared to the grid-search approach. Further, the neural network method is able to do inference on new data significantly quicker than either the grid-search or novel MCMC methods, allowing for rapid deployment in time-sensitive outbreaks. Author summary: In this paper we demonstrate three methods for estimating the source location and timing of a deliberate release of Bacillus anthracis based on the temporal and spatial distribution of cases. Two of our proposed methods, a modified MCMC approach and a neural network based approach, provide significant improvements over previous methods by directly addressing the problematic parameter-likelihood surface, and, in the case of the neural network approach, addressing the slow deployment speeds of existing methods. Our results represent a major step forward in the accuracy and speed of epidemiological back-calculation. [ABSTRACT FROM AUTHOR]

In silico clinical trials (ISCTs) are an emerging method in modeling and simulation where medical interventions are evaluated using computational models of patients. ISCTs have the potential to provide cost-effective, time-efficient, and ethically favorable alternatives for evaluating the safety and effectiveness of medical devices. However, ensuring the credibility of ISCT results is a significant challenge. This paper aims to identify unique considerations for assessing the credibility of ISCTs and proposes an ISCT credibility assessment workflow based on recently published model assessment frameworks. First, we review various ISCTs described in the literature, carefully selected to showcase the range of methodological options available. These studies cover a wide variety of devices, reasons for conducting ISCTs, patient model generation approaches including subject-specific versus 'synthetic' virtual patients, complexity levels of devices and patient models, incorporation of clinician or clinical outcome models, and methods for integrating ISCT results with real-world clinical trials. We next discuss how verification, validation, and uncertainty quantification apply to ISCTs, considering the range of ISCT approaches identified. Based on our analysis, we then present a hierarchical workflow for assessing ISCT credibility, using a general credibility assessment framework recently published by the FDA's Center for Devices and Radiological Health. Overall, this work aims to promote standardization in ISCTs and contribute to the wider adoption and acceptance of ISCTs as a reliable tool for evaluating medical devices. Author summary: A new method for evaluating a medical device is an in silico clinical trial, where the device performance is tested using computational models representing a cohort of patients. Demonstrating that in silico clinical trials are reliable is clearly of paramount importance. However, little information is available on how to ensure this. In this paper we present a workflow for evaluating an in silico clinical trial. This workflow was developed by considering a wide-ranging sample of previously published in silico clinical trials, together with a detailed assessment of how specific model evaluation activities apply to in silico clinical trials. [ABSTRACT FROM AUTHOR]

The rapid development of vaccines to combat the spread of COVID-19, caused by the SARS-CoV-2 virus, is a great scientific achievement. Before the development of the COVID-19 vaccines, most studies capitalized on the available data that did not include pharmaceutical measures. Such studies focused on the impact of non-pharmaceutical measures such as social distancing, sanitation, use of face masks, and lockdowns to study the spread of COVID-19. In this study, we used the SIDARTHE-V model, an extension of the SIDARTHE model, which includes vaccination rollouts. We studied the impact of vaccination on the severity of the virus, specifically focusing on death rates, in African countries. The SIRDATHE-V model parameters were extracted by simultaneously fitting the COVID-19 cumulative data of deaths, recoveries, active cases, and full vaccinations reported by the governments of Ghana, Kenya, Mozambique, Nigeria, South Africa, Togo, and Zambia. Using South Africa as a case study, our analysis showed that the cumulative death rates declined drastically with the increased extent of vaccination drives. Whilst the infection rates sometimes increased with the arrival of new coronavirus variants, the death rates did not increase as they did before vaccination. Author summary: The onset of the COVID-19 pandemic prompted swift global responses. These included non-pharmaceutical control measures at the beginning of the pandemic such as social distancing, masks, and the later development of vaccines. In our first paper, we studied the evolution of the pandemic in the African continent by fitting the observed data with the SIRDATHE model in the first year (March 2020—March 2021) of the pandemic, before vaccination. We examined the impact of non-pharmaceutical control measures on COVID-19 transmission in the first year of the pandemic. As vaccination campaigns commenced, we extended our model to SIDARTHE-V model, which included the vaccination component. The SIRDATHE-V model assumes total immunity in the vaccinated population. However, our observations revealed breakthrough infections even amongst the vaccinated population. Therefore, in our application of the SIRDATHE-V model, we considered the fact that even the vaccinated could become infected. In this study, we investigated the impact of COVID-19 vaccination in Africa. We analysed COVID-19 data from seven African countries: Ghana, Kenya, Mozambique, Nigeria, South Africa, Togo, and Zambia over approximately two years, from March 2020 to March 2022. Considering variations in vaccination programs in each country, for example, the use of different vaccines and different starting dates, this study focused on the impact of vaccination on the death rates. Our findings showed a decline in cumulative death rates due to COVID-19 when vaccination drives were coupled with non-pharmaceutical control measures. We therefore conclude that in combating the spread of acute viral infections with dynamics similar to COVID-19, a comprehensive strategy involving both pharmaceutical (vaccination) and non-pharmaceutical (social measures) interventions is crucial. [ABSTRACT FROM AUTHOR]

A recent paper claimed that t-SNE and UMAP embeddings of single-cell datasets are "specious" and fail to capture true biological structure. The authors argued that such embeddings are as arbitrary and as misleading as forcing the data into an elephant shape. Here we show that this conclusion was based on inadequate and limited metrics of embedding quality. More appropriate metrics quantifying neighborhood and class preservation reveal the elephant in the room: while t-SNE and UMAP embeddings of single-cell data do not preserve high-dimensional distances, they can nevertheless provide biologically relevant information. [ABSTRACT FROM AUTHOR]

We discuss the invasion of the Omicron BA.1 variant into England as a paradigm for real-time model fitting and projection. Here we use a mixture of simple SIR-type models, analysis of the early data and a more complex age-structure model fit to the outbreak to understand the dynamics. In particular, we highlight that early data shows that the invading Omicron variant had a substantial growth advantage over the resident Delta variant. However, early data does not allow us to reliably infer other key epidemiological parameters—such as generation time and severity—which influence the expected peak hospital numbers. With more complete epidemic data from January 2022 are we able to capture the true scale of the epidemic in terms of both infections and hospital admissions, driven by different infection characteristics of Omicron compared to Delta and a substantial shift in estimated precautionary behaviour during December. This work highlights the challenges of real time forecasting, in a rapidly changing environment with limited information on the variant's epidemiological characteristics. Author summary: One of the key challenges for modellers at the start of any outbreak is to predict its likely scale and the associated burden on the health systems. This was the scenario in December of 2021, when the UK was faced with the invasion of the Omicron (BA.1) variant. For the Omicron BA.1 wave the peak in hospital admission was initially overestimated due to the simplifying assumption that Omicron would behave like a faster spreading version of the Delta variant, and that there would be little or no change to population behaviour during the wave. In this paper, we use a range of models and analyses to understand the challenges of correctly predicting the peak. Compared with forecasts made from the earliest data, the peak was reduced by the shorter infectious period of Omicron, its lower severity but mostly by changes in behaviour and testing over the Christmas holiday season. Historic projections made in December of 2021 that assumed a set of imposed mitigation measures were therefore more accurate than those that assumed no controls, although in practice the controls were largely self-imposed. This paper therefore highlights the challenges of forecasting the likely scale of outbreaks and the importance of understanding the population response to public health messaging. [ABSTRACT FROM AUTHOR]

We study the problem of mass screening of heterogeneous populations under limited testing budget. Mass screening is an essential tool that arises in various settings, e.g., the COVID-19 pandemic. The objective of mass screening is to classify the entire population as positive or negative for a disease as efficiently and accurately as possible. Under limited budget, testing facilities need to allocate a portion of the budget to target sub-populations (i.e., proactive screening) while reserving the remaining budget to screen for symptomatic cases (i.e., reactive screening). This paper addresses this decision problem by taking advantage of accessible population-level risk information to identify the optimal set of sub-populations for proactive/reactive screening. The framework also incorporates two widely used testing schemes: Individual and Dorfman group testing. By leveraging the special structure of the resulting bilinear optimization problem, we identify key structural properties, which in turn enable us to develop efficient solution schemes. Furthermore, we extend the model to accommodate customized testing schemes across different sub-populations and introduce a highly efficient heuristic solution algorithm for the generalized model. We conduct a comprehensive case study on COVID-19 in the US, utilizing geographically-based data. Numerical results demonstrate a significant improvement of up to 52% in total misclassifications compared to conventional screening strategies. In addition, our case study offers valuable managerial insights regarding the allocation of proactive/reactive measures and budget across diverse geographic regions. Author summary: The problem of mass screening of heterogeneous populations is challenging, especially when we do not have enough tests to check everyone all at once. Therefore, under limited testing budget, testing facilities need to allocate a portion of the testing budget to target sub-populations (i.e., proactive screening) while reserving the remaining budget to screen for symptomatic cases (i.e., reactive screening). Our study provides a strategy to make those decision efficiently by taking advantage of risk information and utilizing optimization models. We conduct a comprehensive case study on COVID-19 in the US and numerical results demonstrate a significant improvement compared to conventional screening strategies. The results of this paper will benefit health administrators and policy-makers by providing managerial insights regarding optimal allocation of testing kits and testing designs across diverse geographic regions. [ABSTRACT FROM AUTHOR]

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. Author summary: Our research focuses on cutting-edge techniques in computational neuroscience. We specifically make use of simulations of biophysically detailed neuron models. Traditionally these methods are computationally intensive, but recent advancements using artificial neural networks (ANNs) have shown promise in predicting neural behavior with remarkable accuracy. However, existing ANNs fall short in providing comprehensive predictions across all compartments of a neuron model and only provide information on the activity of a limited number of locations along the extent of a neuron. In our study, we introduce a novel approach leveraging state-of-the-art multitask learning architectures. This approach allows us to simultaneously predict membrane potentials in every compartment of a neuron model. By distilling the underlying electrophysiology into an ANN, we significantly outpace conventional simulation methods. By accurately capturing voltage outputs across the neuron's structure, our method invites comparisons with experimental data and paves the way for predicting complex aggregate signals such as local field potentials and EEG signals. Our findings not only advance our understanding of neural dynamics but also present a significant benchmark for future research in computational neuroscience. [ABSTRACT FROM AUTHOR]

Capillary plexus cultivation is crucial in tissue engineering and regenerative medicine. Theoretical simulations have been conducted to supplement the expensive experimental works. However, the mechanisms connecting mechanical and chemical stimuli remained undefined, and the functions of the different VEGF forms in the culture environment were still unclear. In this paper, we developed a hybrid model for simulating short-term in vitro capillary incubations. We used the Cellular Potts model to predict individual cell migration, morphology change, and continuum mechanics to quantify biogel deformation and VEGF transport dynamics. By bridging the mechanical regulation and chemical stimulation in the model, the results showed good agreement between the predicted network topology and experiments, in which elongated cells connected, forming the network cords and round cells gathered, creating cobblestone-like aggregates. The results revealed that the capillary-like networks could develop in high integrity only when the mechanical and chemical couplings worked adequately, with the cell morphology and haptotaxis driven by the soluble and bound forms of VEGF, respectively, functioning simultaneously. Author summary: Microvascular incubation is crucial in regenerative medicine and tissue engineering because of its connection between engineered organizations and the living body. Static incubation in a Petri dish provides an effective way to observe the cell migration during blood vessel formation and record the cell behaviors in different environments: various coating substrates on the Petri dish surface and multiple additives in the culture medium. In this paper, we built a mathematical model based on the interactions between the endothelial cells, the biogel components, and the specific chemicals that regulate blood vessel development. Our simulation results showed good agreement with the literature experiments, both in the single cell shape and overall cell arrangement, revealing that the stable capillary network resulted from the mechanical attachment and traction between cells and substrate materials and the chemical stimulations by spatial signals. [ABSTRACT FROM AUTHOR]

As of now, more than 60 years have passed since the first determination of protein structures through crystallography, and a significant portion of protein structures can be predicted by computers. This is due to the groundbreaking enhancement in protein structure prediction achieved through neural network training utilizing extensive sequence and structure data. However, substantial challenges persist in structure prediction due to limited data availability, with antibody structure prediction standing as one such challenge. In this paper, we propose a novel neural network architecture that effectively enables structure prediction by reflecting the inherent combinatorial nature involved in protein structure formation. The core idea of this neural network architecture is not solely to track and generate a single structure but rather to form a community of multiple structures and pursue accurate structure prediction by exchanging information among community members. Applying this concept to antibody CDR H3 loop structure prediction resulted in improved structure sampling. Such an approach could be applied in the structural and functional studies of proteins, particularly in exploring various physiological processes mediated by loops. Moreover, it holds potential in addressing various other types of combinatorial structure prediction and design problems. Author summary: In this paper, we propose a new architecture that aims to improve upon protein structure prediction algorithms like AlphaFold or RoseTTAFold by considering the combinatorial nature of protein structure formation. Such an architecture, reflecting the physical principles of nature, is expected to yield beneficial results, particularly in scenarios with limited structure and sequence information. Named ComMat, this architecture does not focus on a single structure but rather on a set of multiple structures—a community—simultaneously. In this process, combinatorial exploration of protein structure is encouraged through information exchange among community members. ComMat is an instance that integrates this idea within the structure module of AlphaFold. Applying ComMat to antibody CDR H3 loop structure prediction yielded outstanding results in structure sampling and prediction when tested on the IgFold set and compared with IgFold and AlphaFold-Multimer. It confirmed that improved structure sampling stems from effective structural exploration. The proposed concept here could potentially be used in the development of various other combinatorial protein structure prediction and protein design methods. [ABSTRACT FROM AUTHOR]

Computable biomedical knowledge (CBK) is: "the result of an analytic and/or deliberative process about human health, or affecting human health, that is explicit, and therefore can be represented and reasned upon using logic, formal standards, and mathematical approaches." Representing biomedical knowledge in a machine-interpretable, computable form increases its ability to be discovered, accessed, understood, and deployed. Computable knowledge artifacts can greatly advance the potential for implementation, reproducibility, or extension of the knowledge by users, who may include practitioners, researchers, and learners. Enriching computable knowledge artifacts may help facilitate reuse and translation into practice. Following the examples of 10 Simple Rules papers for scientific code, software, and applications, we present 10 Simple Rules intended to make shared computable knowledge artifacts more useful and reusable. These rules are mainly for researchers and their teams who have decided that sharing their computable knowledge is important, who wish to go beyond simply describing results, algorithms, or models via traditional publication pathways, and who want to both make their research findings more accessible, and to help others use their computable knowledge. These rules are roughly organized into 3 categories: planning, engineering, and documentation. Finally, while many of the following examples are of computable knowledge in biomedical domains, these rules are generalizable to computable knowledge in any research domain. Author summary: Computable biomedical knowledge, including algorithms, models, and evidence, is already impacting—and will likely transform—health research and healthcare delivery. Representing this knowledge in formats that can be discovered and processed by computers increases its potential for use at scale. Similarly, making these algorithms, models, etc. (aka computable knowledge artifacts) understandable and reusable by others can help facilitate reuse and translation into practice. However, as with other types of scientific software or research data, creating artifacts that are usable by and useful to others requires intentionality, and often additional time and effort. We've developed over 100 computable knowledge artifacts in diverse areas of health research and healthcare and we've learned a few things along the way. We've distilled these lessons learned into 10 Simple Rules to help researchers who would like to make their computational research products available and useful to others. Our work centers on knowledge in the biomedical domain, but we believe these 10 Simple Rules are generalizable and valuable as design principles for any researcher wishing to share computational research products. [ABSTRACT FROM AUTHOR]

Periplasmic binding proteins (PBPs) are bacterial proteins commonly used as scaffolds for substrate-detecting biosensors. In these biosensors, effector proteins (for example fluorescent proteins) are inserted into a PBP such that the effector protein's output changes upon PBP-substate binding. The insertion site is often determined by comparison of PBP apo/holo crystal structures, but random insertion libraries have shown that this can miss the best sites. Here, we present a PBP biosensor design method based on residue contact analysis from molecular dynamics. This computational method identifies the best previously known insertion sites in the maltose binding PBP, and suggests further previously unknown sites. We experimentally characterise fluorescent protein insertions at these new sites, finding they too give functional biosensors. Furthermore, our method is sufficiently flexible to both suggest insertion sites compatible with a variety of effector proteins, and be applied to binding proteins beyond PBPs. Author summary: "Biosensors" are microscopic tools that can detect specific molecules of interest and are made of biological building blocks, such as proteins. Upon coming into contact with their target molecule, such as a marker of a specific disease, biosensors change shape and their properties are altered. For example, upon contact with a disease marker, a biosensor could glow brightly to work as a diagnostic, or perhaps it could produce a chemical signal that can be detected by the immune system. Understanding how biosensors change shape in response to their target is key to developing more biosensors with complex responses. In this paper, we use computer simulations of a biosensor component to understand what parameters are important for biosensor design. We use these parameters to generate new biosensors that respond to their target molecule by producing light, but put forward a case that the lesson learned are generalisable enough to inform more complex sensor outputs as well. [ABSTRACT FROM AUTHOR]

Although adaptive cancer therapy shows promise in integrating evolutionary dynamics into treatment scheduling, the stochastic nature of cancer evolution has seldom been taken into account. Various sources of random perturbations can impact the evolution of heterogeneous tumors, making performance metrics of any treatment policy random as well. In this paper, we propose an efficient method for selecting optimal adaptive treatment policies under randomly evolving tumor dynamics. The goal is to improve the cumulative "cost" of treatment, a combination of the total amount of drugs used and the total treatment time. As this cost also becomes random in any stochastic setting, we maximize the probability of reaching the treatment goals (tumor stabilization or eradication) without exceeding a pre-specified cost threshold (or a "budget"). We use a novel Stochastic Optimal Control formulation and Dynamic Programming to find such "threshold-aware" optimal treatment policies. Our approach enables an efficient algorithm to compute these policies for a range of threshold values simultaneously. Compared to treatment plans shown to be optimal in a deterministic setting, the new "threshold-aware" policies significantly improve the chances of the therapy succeeding under the budget, which is correlated with a lower general drug usage. We illustrate this method using two specific examples, but our approach is far more general and provides a new tool for optimizing adaptive therapies based on a broad range of stochastic cancer models. Author summary: Tumor heterogeneities provide an opportunity to improve therapies by leveraging complex (often competitive) interactions of different types of cancer cells. These interactions are usually stochastic due to both individual cell differences and random events affecting the patient as a whole. The new generation of cancer models strive to account for this inherent stochasticity, and adaptive treatment plans need to reflect it as well. In optimizing such treatment, the most common approach is to maximize the probability of eventually stabilizing or eradicating the tumor. In this paper, we consider a more nuanced version of success, maximizing the probability of reaching these therapy goals before the cumulative burden from the disease and treatment exceed a chosen threshold. Importantly, our method allows computing such optimal treatment plans efficiently and for a range of thresholds at once. If used on a high-fidelity personalized model, our general approach could potentially be used by clinicians to choose the most suitable threshold after a detailed discussion of a specific patient's goals (e.g., to include the trade-offs between toxicity and quality of life). [ABSTRACT FROM AUTHOR]

Astrocytes are a ubiquitous and enigmatic type of non-neuronal cell and are found in the brain of all vertebrates. While traditionally viewed as being supportive of neurons, it is increasingly recognized that astrocytes play a more direct and active role in brain function and neural computation. On account of their sensitivity to a host of physiological covariates and ability to modulate neuronal activity and connectivity on slower time scales, astrocytes may be particularly well poised to modulate the dynamics of neural circuits in functionally salient ways. In the current paper, we seek to capture these features via actionable abstractions within computational models of neuron-astrocyte interaction. Specifically, we engage how nested feedback loops of neuron-astrocyte interaction, acting over separated time-scales, may endow astrocytes with the capability to enable learning in context-dependent settings, where fluctuations in task parameters may occur much more slowly than within-task requirements. We pose a general model of neuron-synapse-astrocyte interaction and use formal analysis to characterize how astrocytic modulation may constitute a form of meta-plasticity, altering the ways in which synapses and neurons adapt as a function of time. We then embed this model in a bandit-based reinforcement learning task environment, and show how the presence of time-scale separated astrocytic modulation enables learning over multiple fluctuating contexts. Indeed, these networks learn far more reliably compared to dynamically homogeneous networks and conventional non-network-based bandit algorithms. Our results fuel the notion that neuron-astrocyte interactions in the brain benefit learning over different time-scales and the conveyance of task-relevant contextual information onto circuit dynamics. Author summary: Astrocytes, a non-neuronal cell type, constitute a significant portion of all cells in the brain, yet our understanding of their involvement in neural computation remains limited. In this paper, we use computational modeling to examine how astrocytes may interact with neurons to expand the types of activity and, ultimately, computations that neurons can produce. Two features of astrocytes make them interesting in this context. First, a single astrocyte is able to modulate dozens of neurons and synaptic connections between them. Furthermore, this modulation occurs at slower temporal scales than the neural activity itself, thus meaning that astrocytes could have long-lasting effects on neural activity and connectivity. Our computational models capture both of these features. Using these models, we show that networks with astrocytes can more readily adapt to slowly varying task parameters versus those with neurons alone. We further analyze the models to understand, in mathematical terms, why such effects may arise. Our results shed light on the potential computational role of this common, but enigmatic type of brain cell. [ABSTRACT FROM AUTHOR]

In ischaemic stroke, a large reduction in blood supply can lead to the breakdown of the blood-brain barrier and to cerebral oedema after reperfusion therapy. The resulting fluid accumulation in the brain may contribute to a significant rise in intracranial pressure (ICP) and tissue deformation. Changes in the level of ICP are essential for clinical decision-making and therapeutic strategies. However, the measurement of ICP is constrained by clinical techniques and obtaining the exact values of the ICP has proven challenging. In this study, we propose the first computational model for the simulation of cerebral oedema following acute ischaemic stroke for the investigation of ICP and midline shift (MLS) relationship. The model consists of three components for the simulation of healthy blood flow, occluded blood flow and oedema, respectively. The healthy and occluded blood flow components are utilized to obtain oedema core geometry and then imported into the oedema model for the simulation of oedema growth. The simulation results of the model are compared with clinical data from 97 traumatic brain injury patients for the validation of major model parameters. Midline shift has been widely used for the diagnosis, clinical decision-making, and prognosis of oedema patients. Therefore, we focus on quantifying the relationship between ICP and midline shift (MLS) and identify the factors that can affect the ICP-MLS relationship. Three major factors are investigated, including the brain geometry, blood-brain barrier damage severity and the types of oedema (including rare types of oedema). Meanwhile, the two major types (stress and tension/compression) of mechanical brain damage are also presented and the differences in the stress, tension, and compression between the intraparenchymal and periventricular regions are discussed. This work helps to predict ICP precisely and therefore provides improved clinical guidance for the treatment of brain oedema. Author summary: Midline shift has been widely employed in clinical settings to estimate the severity of post-stroke brain oedema. However, the midline shift is affected by many factors and its relationship with intracranial pressure has been proven to vary among patients. In this paper, we utilise a computational tool to investigate the midline shift under large brain deformation from a mechanical perspective. The Augmented Lagrange Method is for the first time employed to solve the large deformation of oedema brains with midline shifts over 5 mm. In the model validation, a reasonable agreement between clinical data and simulation results are obtained. This paper models three different factors that can affect midline shift during oedema development, including brain geometry, blood-brain barrier damage severity and type of oedema. Meanwhile, we discuss the scenarios that can lead to unexpectedly small midline shifts and present quantitative results for a better understanding of brain mechanics during oedema. [ABSTRACT FROM AUTHOR]

Quantifying fungal growth underpins our ability to effectively treat severe fungal infections. Current methods quantify fungal growth rates from time-course morphology-specific data, such as hyphal length data. However, automated large-scale collection of such data lies beyond the scope of most clinical microbiology laboratories. In this paper, we propose a mathematical model of fungal growth to estimate morphology-specific growth rates from easy-to-collect, but indirect, optical density (OD600) data of Aspergillus fumigatus growth (filamentous fungus). Our method accounts for OD600 being an indirect measure by explicitly including the relationship between the indirect OD600 measurements and the calibrating true fungal growth in the model. Therefore, the method does not require de novo generation of calibration data. Our model outperformed reference models at fitting to and predicting OD600 growth curves and overcame observed discrepancies between morphology-specific rates inferred from OD600 versus directly measured data in reference models that did not include calibration. Author summary: Quantifying fungal growth is essential for antifungal drug discovery and monitoring antifungal resistance. As fungal growth is complex, with fungal morphology (shape) dynamically changing over time, previous studies have quantified fungal growth by estimating growth rates during specific fungal morphologies (morphology-specific growth rates) or by mathematically modelling fungal growth. However, collecting time-series data that captures the morphological information required for mathematical model fitting or estimating morphology-specific growth rates is prohibitively time consuming for large-scale drug testing in most microbiology laboratories. Alternatively, fungal growth can be quickly, although indirectly, quantified by measuring the optical density (OD) of a broth culture. However, changes in OD are not always reflective of true changes in fungal growth because OD is an indirect measure. This paper proposes a method to model fungal growth and estimate a morphology-specific growth rate from indirect OD600 measurements of the major mould pathogen, Aspergillus fumigatus. We explicitly model the relationship between measured indirect OD600 data and true fungal growth (calibration). The presented work serves as the much-needed foundation for estimating and comparing morphology-specific fungal growth rates in varying antifungal drug concentrations using only OD600 data. [ABSTRACT FROM AUTHOR]

We introduce an innovative, data-driven topological data analysis (TDA) technique for estimating the state spaces of dynamically changing functional human brain networks at rest. Our method utilizes the Wasserstein distance to measure topological differences, enabling the clustering of brain networks into distinct topological states. This technique outperforms the commonly used k-means clustering in identifying brain network state spaces by effectively incorporating the temporal dynamics of the data without the need for explicit model specification. We further investigate the genetic underpinnings of these topological features using a twin study design, examining the heritability of such state changes. Our findings suggest that the topology of brain networks, particularly in their dynamic state changes, may hold significant hidden genetic information. Author summary: The paper introduces a new data-driven topological data analysis (TDA) method for studying dynamically changing human functional brain networks obtained from the resting-state functional magnetic resonance imaging (rs-fMRI). Leveraging persistent homology, a multiscale topological approach, we present a framework that incorporates the temporal dimension of brain network data. This allows for a more robust estimation of the topological features of dynamic brain networks. The method employs the Wasserstein distance to measure the topological differences between networks and demonstrates greater efficiency and performance than the commonly used k-means clustering in defining the state spaces of dynamic brain networks. Our method maintains robust performance across different scales and is especially suited for dynamic brain networks. In addition to the methodological advancement, the paper applies the proposed technique to analyze the heritability of overall brain network topology using a twin study design. The study investigates whether the dynamic pattern of brain networks is a genetically influenced trait, an area previously underexplored. By examining the state change patterns in twin brain networks, we make significant strides in understanding the genetic factors underlying dynamic brain network features. Furthermore, the paper makes its method accessible by providing MATLAB codes, contributing to reproducibility and broader application. [ABSTRACT FROM AUTHOR]

This paper extends the FAIR (Findable, Accessible, Interoperable, Reusable) guidelines to provide criteria for assessing if software conforms to best practices in open source. By adding "USE" (User-Centered, Sustainable, Equitable), software development can adhere to open source best practice by incorporating user-input early on, ensuring front-end designs are accessible to all possible stakeholders, and planning long-term sustainability alongside software design. The FAIR-USE4OS guidelines will allow funders and researchers to more effectively evaluate and plan open-source software projects. There is good evidence of funders increasingly mandating that all funded research software is open source; however, even under the FAIR guidelines, this could simply mean software released on public repositories with a Zenodo DOI. By creating FAIR-USE software, best practice can be demonstrated from the very beginning of the design process and the software has the greatest chance of success by being impactful. Author summary: This research builds on the FAIR principles to ensure research software adheres to open-source development best practice, which includes community engagement and early planning for long-term sustainability. By creating guidelines ("FAIR-USE4OS") that can be followed, funders and researchers are in a stronger position to evaluate and create research software with maximal chance of success. This research is important as open-source software that is not "FAIR-USE" has a lower probability of long-term impact. These guidelines will help benefit and impact society once they are widely accepted by researchers and funders, which could happen within a relatively short time period given good evidence that funders are actively including and updating open source policies, which directly impact upon how research is conducted. [ABSTRACT FROM AUTHOR]

To optimize proteins for particular traits holds great promise for industrial and pharmaceutical purposes. Machine Learning is increasingly applied in this field to predict properties of proteins, thereby guiding the experimental optimization process. A natural question is: How much progress are we making with such predictions, and how important is the choice of regressor and representation? In this paper, we demonstrate that different assessment criteria for regressor performance can lead to dramatically different conclusions, depending on the choice of metric, and how one defines generalization. We highlight the fundamental issues of sample bias in typical regression scenarios and how this can lead to misleading conclusions about regressor performance. Finally, we make the case for the importance of calibrated uncertainty in this domain. Author summary: Supervised machine learning is increasingly used to predict the function and properties of proteins. The performance obtained with these methods relies on a multitude of factors including how data is represented, how observations are distributed, how training is conducted, and how performance is measured. In this paper, we systematically assess the importance of these different components in a protein regression pipeline. We discuss the benefits of using representations extracted from protein language models, the impact of the choice of regression algorithm, and the role of uncertainty. Finally, to avoid misleading performance claims, we stress the need for carefully aligning the train/test setup to reflect the setting in which the prediction algorithm will ultimately be applied. [ABSTRACT FROM AUTHOR]

Biological cells replicate their genomes in a well-planned manner. The DNA replication program of an organism determines the timing at which different genomic regions are replicated, with fundamental consequences for cell homeostasis and genome stability. In a growing cell culture, genomic regions that are replicated early should be more abundant than regions that are replicated late. This abundance pattern can be experimentally measured using deep sequencing. However, a general quantitative theory linking this pattern to the replication program is still lacking. In this paper, we predict the abundance of DNA fragments in asynchronously growing cultures from any given stochastic model of the DNA replication program. As key examples, we present stochastic models of the DNA replication programs in budding yeast and Escherichia coli. In both cases, our model results are in excellent agreement with experimental data and permit to infer key information about the replication program. In particular, our method is able to infer the locations of known replication origins in budding yeast with high accuracy. These examples demonstrate that our method can provide insight into a broad range of organisms, from bacteria to eukaryotes. Author summary: Biological cells replicate their genome in a planned manner. One way of obtaining experimental information about this plan is by deep sequencing a growing culture of cells. The idea underlying these experiments is that genomic regions that are replicated earlier would be present in higher abundances than regions replicated at a later stage. In this paper, we make use of this idea to obtain precise quantitative information on replication programs from sequencing. As a main application, we infer the locations of origins of replication in budding yeast from sequencing data. Our inference is consistent with direct experimental evidences on the locations of these origins. Our method can be in principle be applied to any organism that can be cultured and sequenced, and has therefore the potential to shed light on the replication program of a broad class of organisms. [ABSTRACT FROM AUTHOR]

This article discusses the Ten Simple Rules and Quick Tips collections in PLOS Computational Biology. The Ten Simple Rules collection was started in 2006 and has since grown to include over 250 papers. Quick Tips articles were introduced in 2013 as a more specific and focused format compared to Ten Simple Rules articles. The authors provide ten rules for writing a Quick Tips article, including giving tips instead of rules, minimizing overlap with other articles, making each tip a declarative statement, being concise, being creative with the number of tips, presenting tips logically, using visuals, being an empathic instructor, asking for feedback before writing the manuscript, and helping the editors by suggesting potential reviewers. The authors emphasize the importance of minimizing overlap and amplifying new insights in Quick Tips articles. They also note that both collections are valuable resources for teaching and learning. The article concludes by reminding potential authors that there are no publication charges for Quick Tips and Ten Simple Rules articles in PLOS Computational Biology. [Extracted from the article]

For many emerging scientists, research experiences for undergraduates (REU) programs are an important gateway to graduate school and a career in science, technology, engineering, and mathematics (STEM). REUs provide guided mentorship and learning experiences in a summer-long program where students develop research skills, build scientific knowledge, and strengthen their scientific identity. While the benefits of REUs are abundant, the process is not always easy to navigate, especially for students who come from first-generation and/or low-income (FLI) backgrounds. This paper provides two-fold guidance for undergraduate students interested in participating in REUs. Rules 1 to 5 focus on demystifying the application process from beginning to end, and Rules 6 to 10 guide students who are on the other side of the application process. Thus, this paper will be most helpful for undergraduate students who are either considering applying for an REU or have been accepted into one and want to learn more about what to expect. It can also be a shareable resource for faculty, staff, and mentors who work directly with STEM undergraduates. [ABSTRACT FROM AUTHOR]

Multiplex panel tests identify many individual pathogens at once, using a set of component tests. In some panels the number of components can be large. If the panel is detecting causative pathogens for a single syndrome or disease then we might estimate the burden of that disease by combining the results of the panel, for example determining the prevalence of pneumococcal pneumonia as caused by many individual pneumococcal serotypes. When we are dealing with multiplex test panels with many components, test error in the individual components of a panel, even when present at very low levels, can cause significant overall error. Uncertainty in the sensitivity and specificity of the individual tests, and statistical fluctuations in the numbers of false positives and false negatives, will cause large uncertainty in the combined estimates of disease prevalence. In many cases this can be a source of significant bias. In this paper we develop a mathematical framework to characterise this issue, we determine expressions for the sensitivity and specificity of panel tests. In this we identify a counter-intuitive relationship between panel test sensitivity and disease prevalence that means panel tests become more sensitive as prevalence increases. We present novel statistical methods that adjust for bias and quantify uncertainty in prevalence estimates from panel tests, and use simulations to test these methods. As multiplex testing becomes more commonly used for screening in routine clinical practice, accumulation of test error due to the combination of large numbers of test results needs to be identified and corrected for. Author summary: During analysis of pneumococcal incidence data obtained from serotype specific multiplex urine antigen testing, we identified that despite excellent test sensitivity and specificity, the small error rate in each individual serotype test has the potential to compound and cause large uncertainty in the resulting estimates of pneumococcal prevalence, obtained by combining individual results. This limits the accuracy of estimates of the burden of disease caused by vaccine preventable pneumococcal serotypes, and in certain situations can produce marked bias. [ABSTRACT FROM AUTHOR]

One of the key problems the brain faces is inferring the state of the world from a sequence of dynamically changing stimuli, and it is not yet clear how the sensory system achieves this task. A well-established computational framework for describing perceptual processes in the brain is provided by the theory of predictive coding. Although the original proposals of predictive coding have discussed temporal prediction, later work developing this theory mostly focused on static stimuli, and key questions on neural implementation and computational properties of temporal predictive coding networks remain open. Here, we address these questions and present a formulation of the temporal predictive coding model that can be naturally implemented in recurrent networks, in which activity dynamics rely only on local inputs to the neurons, and learning only utilises local Hebbian plasticity. Additionally, we show that temporal predictive coding networks can approximate the performance of the Kalman filter in predicting behaviour of linear systems, and behave as a variant of a Kalman filter which does not track its own subjective posterior variance. Importantly, temporal predictive coding networks can achieve similar accuracy as the Kalman filter without performing complex mathematical operations, but just employing simple computations that can be implemented by biological networks. Moreover, when trained with natural dynamic inputs, we found that temporal predictive coding can produce Gabor-like, motion-sensitive receptive fields resembling those observed in real neurons in visual areas. In addition, we demonstrate how the model can be effectively generalized to nonlinear systems. Overall, models presented in this paper show how biologically plausible circuits can predict future stimuli and may guide research on understanding specific neural circuits in brain areas involved in temporal prediction. Author summary: While significant advances have been made in the neuroscience of how the brain processes static stimuli, the time dimension has often been relatively neglected. However, time is crucial since the stimuli perceived by our senses typically dynamically vary in time, and the cortex needs to make sense of these changing inputs. This paper describes a computational model of cortical networks processing temporal stimuli. This model is able to infer and track the state of the environment based on noisy inputs, and predict future sensory stimuli. By ensuring that these predictions match the incoming stimuli, the model is able to learn the structure and statistics of its temporal inputs and produces responses of neurons resembling those in the brain. The model may help in further understanding neural circuits in sensory cortical areas. [ABSTRACT FROM AUTHOR]

Using the CRISPR-Cas9 system to perform base substitutions at the target site is a typical technique for genome editing with the potential for applications in gene therapy and agricultural productivity. When the CRISPR-Cas9 system uses guide RNA to direct the Cas9 endonuclease to the target site, it may misdirect it to a potential off-target site, resulting in an unintended genome editing. Although several computational methods have been proposed to predict off-target effects, there is still room for improvement in the off-target effect prediction capability. In this paper, we present an effective approach called CRISPR-M with a new encoding scheme and a novel multi-view deep learning model to predict the sgRNA off-target effects for target sites containing indels and mismatches. CRISPR-M takes advantage of convolutional neural networks and bidirectional long short-term memory recurrent neural networks to construct a three-branch network towards multi-views. Compared with existing methods, CRISPR-M demonstrates significant performance advantages running on real-world datasets. Furthermore, experimental analysis of CRISPR-M under multiple metrics reveals its capability to extract features and validates its superiority on sgRNA off-target effect predictions. Author summary: Genome editing using the CRISPR-Cas9 system, particularly base substitutions directed by guide RNA, holds immense potential for applications in gene therapy and agricultural productivity. However, the risk of unintended off-target effects poses a challenge, as misdirection of the Cas9 endonuclease can lead to unintended genome alterations. While computational methods exist for predicting off-target effects, there remains a need for encoding methods with more representation space and deep learning models with generalization capability and the adaptability. This paper introduces CRISPR-M, an innovative approach addressing the limitations of existing methods in predicting off-target effects, especially for target sites with indels and mismatches. CRISPR-M employs a novel encoding scheme and a multi-view deep learning model, combining convolutional neural networks and bidirectional long short-term memory recurrent neural networks. The three-branch network structure enhances the prediction accuracy by considering multiple perspectives. Compared with previous representative methods, CRISPR-M exhibits remarkable performance advantages when applied to real-world datasets. The experimental evaluation of CRISPR-M, assessed by various metrics such as ROC, PRC, GC content and melting temperature, demonstrates its ability to extract meaningful features and establishes its superiority in predicting off-target effects of sgRNA. [ABSTRACT FROM AUTHOR]

From mathematical models of growth to computer simulations of pigmentation, the study of shell formation has given rise to an abundant number of models, working at various scales. Yet, attempts to combine those models have remained sparse, due to the challenge of combining categorically different approaches. In this paper, we propose a framework to streamline the process of combining the molecular and tissue scales of shell formation. We choose these levels as a proxy to link the genotype level, which is better described by molecular models, and the phenotype level, which is better described by tissue-level mechanics. We also show how to connect observations on shell populations to the approach, resulting in collections of molecular parameters that may be associated with different populations of real shell specimens. The approach is as follows: we use a Quality-Diversity algorithm, a type of black-box optimization algorithm, to explore the range of concentration profiles emerging as solutions of a molecular model, and that define growth patterns for the mechanical model. At the same time, the mechanical model is simulated over a wide range of growth patterns, resulting in a variety of spine shapes. While time-consuming, these steps only need to be performed once and then function as look-up tables. Actual pictures of shell spines can then be matched against the list of existing spine shapes, yielding a potential growth pattern which, in turn, gives us matching molecular parameters. The framework is modular, such that models can be easily swapped without changing the overall working of the method. As a demonstration of the approach, we solve specific molecular and mechanical models, adapted from available theoretical studies on molluscan shells, and apply the multiscale framework to evaluate the characteristics of spines from three distinct populations of Turbo sazae. Author summary: Connecting genotype to phenotype is a fundamental goal in developmental biology. While many studies examine this link in model organisms for which gene regulatory networks are well known, for non-model organisms, different techniques are required, and multiscale computational modeling offers a promising direction. In this paper, we develop a framework linking molecular-scale interactions to tissue-level growth and mechanics to organ-level characteristics in order to investigate spine formation in T. sazae, a species of mollusc that displays remarkable phenotypic plasticity in spine form. Our analysis uncovers a subtle but statistically significant difference in spine form between shell specimens collected from three different localities in Japan. Moreover, by tracing the difference in form through parametric differences in the multiscale framework, we provide mechanistic insight as to how environmental differences may translate to a change in form. The methodology we present may readily be extended to more detailed modeling of this system, and the conceptual framework is amenable for multiscale analysis in other systems. [ABSTRACT FROM AUTHOR]

Natural eye movements have primarily been studied for over-learned activities such as tea-making, sandwich-making, and hand-washing, which have a fixed sequence of associated actions. These studies demonstrate a sequential activation of low-level cognitive schemas facilitating task completion. However, whether these action schemas are activated in the same pattern when a task is novel and a sequence of actions must be planned in the moment is unclear. Here, we recorded gaze and body movements in a naturalistic task to study action-oriented gaze behavior. In a virtual environment, subjects moved objects on a life-size shelf to achieve a given order. To compel cognitive planning, we added complexity to the sorting tasks. Fixations aligned with the action onset showed gaze as tightly coupled with the action sequence, and task complexity moderately affected the proportion of fixations on the task-relevant regions. Our analysis revealed that gaze fixations were allocated to action-relevant targets just in time. Planning behavior predominantly corresponded to a greater visual search for task-relevant objects before the action onset. The results support the idea that natural behavior relies on the frugal use of working memory, and humans refrain from encoding objects in the environment to plan long-term actions. Instead, they prefer just-in-time planning by searching for action-relevant items at the moment, directing their body and hand to it, monitoring the action until it is terminated, and moving on to the following action. Author summary: Eye movements in the natural environment have primarily been studied for over-learned and habitual everyday activities (tea-making, sandwich-making, hand-washing) with a fixed sequence of associated actions. These studies show eye movements correspond to a specific order of actions learned over time. In this study, we were interested in how humans plan and execute actions for tasks that do not have an inherent action sequence. To that end, we asked subjects to sort objects based on object features on a life-size shelf in a virtual environment as we recorded their eye and body movements. We investigated the general characteristics of gaze behavior while acting under natural conditions. Our paper provides a comprehensive approach to preprocess naturalistic gaze data in virtual reality. Furthermore, we provide a data-driven method of analyzing the different action-oriented functions of gaze. The results show that bereft of a predefined action sequence, humans prefer to plan only their immediate actions, where eye movements are used to search for the target object to immediately act on, then to guide the hand towards it and monitor the action until it is terminated. Such a simplistic approach ensures that humans choose sub-optimal behavior over planning under sustained cognitive load. [ABSTRACT FROM AUTHOR]

Conventional approaches to enhance movement coordination, such as providing instructions and visual feedback, are often inadequate in complex motor tasks with multiple degrees of freedom (DoFs). To effectively address coordination deficits in such complex motor systems, it becomes imperative to develop interventions grounded in a model of human motor learning; however, modeling such learning processes is challenging due to the large DoFs. In this paper, we present a computational motor learning model that leverages the concept of motor synergies to extract low-dimensional learning representations in the high-dimensional motor space and the internal model theory of motor control to capture both fast and slow motor learning processes. We establish the model's convergence properties and validate it using data from a target capture game played by human participants. We study the influence of model parameters on several motor learning trade-offs such as speed-accuracy, exploration-exploitation, satisficing, and flexibility-performance, and show that the human motor learning system tunes these parameters to optimize learning and various output performance metrics. Author summary: Examining the learning and acquisition of motor skills in humans when facing complex, high-dimensional tasks is vital for understanding human motor learning, optimizing the performance of human-in-the-loop systems, improving learning outcomes, and facilitating rehabilitation. Toward this goal, we develop a normative model of human motor learning in high-dimensional novel motor tasks and show that it explains experimental data reasonably well. Further, through a model-based investigation, we examine various motor learning trade-offs, such as exploration-exploitation, speed-accuracy, satisficing, and flexibility-performance. These findings provide a foundational insight into how the human brain may balance these trade-offs during learning. [ABSTRACT FROM AUTHOR]

RNA molecules, essential for viruses and living organisms, derive their pivotal functions from intricate 3D structures. To understand these structures, one can analyze torsion and pseudo-torsion angles, which describe rotations around bonds, whether real or virtual, thus capturing the RNA conformational flexibility. Such an analysis has been made possible by RNAtango, a web server introduced in this paper, that provides a trigonometric perspective on RNA 3D structures, giving insights into the variability of examined models and their alignment with reference targets. RNAtango offers comprehensive tools for calculating torsion and pseudo-torsion angles, generating angle statistics, comparing RNA structures based on backbone torsions, and assessing local and global structural similarities using trigonometric functions and angle measures. The system operates in three scenarios: single model analysis, model-versus-target comparison, and model-versus-model comparison, with results output in text and graphical formats. Compatible with all modern web browsers, RNAtango is accessible freely along with the source code. It supports researchers in accurately assessing structural similarities, which contributes to the precision and efficiency of RNA modeling. [ABSTRACT FROM AUTHOR]

Machine learning-based approaches are particularly suitable for identifying essential genes as they allow the generation of predictive models trained on features from multi-source data. Gene essentiality is neither binary nor static but determined by the context. The databases for essential gene annotation do not permit the personalisation of the context, and their update can be slower than the publication of new experimental data. We propose HELP (Human Gene Essentiality Labelling & Prediction), a computational framework for labelling and predicting essential genes. Its double scope allows for identifying genes based on dependency or not on experimental data. The effectiveness of the labelling method was demonstrated by comparing it with other approaches in overlapping the reference sets of essential gene annotations, where HELP demonstrated the best compromise between false and true positive rates. The gene attributes, including multi-omics and network embedding features, lead to high-performance prediction of essential genes while confirming the existence of essentiality nuances. Author summary: Essential genes (EGs) are commonly defined as those required for an organism or cell's growth and survival. The essentiality is strictly dependent on both environmental and genetic conditions, determining a difference between those considered common EGs (cEGs), essential in most of the contexts considered, and those essential specifically to one or few contexts (context-specific EGs, csEGs). In this paper, we present a library of tools and methodologies to address the identification and prediction of cEGs and csEGs. Furthermore, we attempt to experimentally explore the statement that essentiality is not a binary property by identifying, predicting and analysing an intermediate class between the Essential (E) and Not Essential (NE) genes. Among the multi-source data used to predict the EGs, we found the best attributes combination to capture the essentiality. We demonstrated that the additional class of genes we defined as "almost Essential" shows differences in these attributes from the E and NE genes. We believe that investigating the context-specificity and the dynamism of essentiality is particularly relevant to unravelling crucial insights into biological mechanisms and suggesting new candidates for precision medicine. [ABSTRACT FROM AUTHOR]

Triploidy is very useful in both aquaculture and some cultivated plants as the induced sterility helps to enhance growth and product quality, as well as acting as a barrier against the contamination of wild populations by escapees. To use genetic information from triploids for academic or breeding purposes, an efficient and robust method to genotype triploids is needed. We developed such a method for genotype calling from SNP arrays, and we implemented it in the R package named GenoTriplo. Our method requires no prior information on cluster positions and remains unaffected by shifted luminescence signals. The method relies on starting the clustering algorithm with an initial higher number of groups than expected from the ploidy level of the samples, followed by merging groups that are too close to each other to be considered as distinct genotypes. Accurate classification of SNPs is achieved through multiple thresholds of quality controls. We compared the performance of GenoTriplo with that of fitPoly, the only published method for triploid SNP genotyping with a free software access. This was assessed by comparing the genotypes generated by both methods for a dataset of 1232 triploid rainbow trout genotyped for 38,033 SNPs. The two methods were consistent for 89% of the genotypes, but for 26% of the SNPs, they exhibited a discrepancy in the number of different genotypes identified. For these SNPs, GenoTriplo had >95% concordance with fitPoly when fitPoly genotyped better. On the contrary, when GenoTriplo genotyped better, fitPoly had less than 50% concordance with GenoTriplo. GenoTriplo was more robust with less genotyping errors. It is also efficient at identifying low-frequency genotypes in the sample set. Finally, we assessed parentage assignment based on GenoTriplo genotyping and observed significant differences in mismatch rates between the best and second-best couples, indicating high confidence in the results. GenoTriplo could also be used to genotype diploids as well as individuals with higher ploidy level by adjusting a few input parameters. Author summary: To cultivate plants, fish and shellfish more profitable for both farmers and consumers, one can utilize individuals with three chromosome sets instead of the two found in fertile populations that are diploids. These individuals, called triploids, are generally sterile and then often exhibit higher growth and quality of products, such as seedless fruits or better flesh quality for fish and shellfish. To be able to improve performances of the sterile triploids by selective breeding, it is important to know the versions of the genes present in the three chromosome sets of triploids. Until now, few methods existed to identify these three versions, and none have been demonstrated as sufficiently effective. It is the reason why we developed the GenoTriplo software. We demonstrate in this paper the possibility to accurately genotype triploids, as well as how it can be used to reconstruct pedigree information of triploid progeny. Ultimately, we expect that it can help select for reproduction the parents that have the best triploid progeny for the traits of interest such as growth, vigour or product quality. [ABSTRACT FROM AUTHOR]

The goal of dimension reduction tools is to construct a low-dimensional representation of high-dimensional data. These tools are employed for a variety of reasons such as noise reduction, visualization, and to lower computational costs. However, there is a fundamental issue that is discussed in other modeling problems that is often overlooked in dimension reduction—overfitting. In the context of other modeling problems, techniques such as feature-selection, cross-validation, and regularization are employed to combat overfitting, but rarely are such precautions taken when applying dimension reduction. Prior applications of the two most popular non-linear dimension reduction methods, t-SNE and UMAP, fail to acknowledge data as a combination of signal and noise when assessing performance. These methods are typically calibrated to capture the entirety of the data, not just the signal. In this paper, we demonstrate the importance of acknowledging noise when calibrating hyperparameters and present a framework that enables users to do so. We use this framework to explore the role hyperparameter calibration plays in overfitting the data when applying t-SNE and UMAP. More specifically, we show previously recommended values for perplexity and n_neighbors are too small and overfit the noise. We also provide a workflow others may use to calibrate hyperparameters in the presence of noise. Author summary: In our infinitely complex world, perfect data rid of noise is an unattainable ambition. Hence, our goal is to coerce meaningful information, or the signal, from data inevitably riddled with unwanted, random variation. Advances in technology have allowed us to collect and process biological data of increasing size and complexity, so it is now more important than ever to acknowledge noise in our analyses to ensure random structures are not confused for significant patterns. Many algorithms and ideas have been suggested, some more cognizant of noise than others, but it is still unclear how noise should be handled in various situations. Our experiments, however, indicate typical calibrations of popular analysis methods are inadequately handling noisy, complex biological data. In response, we show and explain how alternate calibrations perform better in the presence of noise and lead to results more faithful to the data. By providing evidence of mishandled noise and presenting solutions, we hope to further the discussion on handling noise in biological data. [ABSTRACT FROM AUTHOR]

Large-scale studies of gene expression are commonly influenced by biological and technical sources of expression variation, including batch effects, sample characteristics, and environmental impacts. Learning the causal relationships between observable variables may be challenging in the presence of unobserved confounders. Furthermore, many high-dimensional regression techniques may perform worse. In fact, controlling for unobserved confounding variables is essential, and many deconfounding methods have been suggested for application in a variety of situations. The main contribution of this article is the development of a two-stage deconfounding procedure based on Bow-free Acyclic Paths (BAP) search developed into the framework of Structural Equation Models (SEM), called SEMbap(). In the first stage, an exhaustive search of missing edges with significant covariance is performed via Shipley d-separation tests; then, in the second stage, a Constrained Gaussian Graphical Model (CGGM) is fitted or a low dimensional representation of bow-free edges structure is obtained via Graph Laplacian Principal Component Analysis (gLPCA). We compare four popular deconfounding methods to BAP search approach with applications on simulated and observed expression data. In the former, different structures of the hidden covariance matrix have been replicated. Compared to existing methods, BAP search algorithm is able to correctly identify hidden confounding whilst controlling false positive rate and achieving good fitting and perturbation metrics. Author summary: Directed acyclic graphs (DAGs) directed graph, with variables at the vertices and direct causal connections at the edges, can be used to illustrate the causal structure of the SEM, but this does not always mean that all significant factors are considered. We examine a class of models that may include some hidden variables. Specifically, we consider that the graph represents a bow-free acyclic path diagram (BAP), where the directed edges signify direct causal effects, while the bidirected edges suggest hidden confounders. In this paper, we provide a two-step deconfounding technique based on BAP search, which is included into the SEM framework via the SEMbap() function implemented in the R package SEMgraph. Secondly, we want to offer a significant evaluation of the most advanced deconfounding techniques using both synthetic and real data, as well as knowledge of a biological signaling pathway encoded in a DAG, in terms of (i) SEM fitting, (ii) system perturbation, and (iii) recovery performance metrics. The BAP search algorithm outperforms current techniques in accurately detecting hidden confounding, regulating false positive rate, and producing well-fitting and perturbation metrics. [ABSTRACT FROM AUTHOR]

Genomic surveillance of pathogen evolution is essential for public health response, treatment strategies, and vaccine development. In the context of SARS-COV-2, multiple models have been developed including Multinomial Logistic Regression (MLR) describing variant frequency growth as well as Fixed Growth Advantage (FGA), Growth Advantage Random Walk (GARW) and Piantham parameterizations describing variant Rt. These models provide estimates of variant fitness and can be used to forecast changes in variant frequency. We introduce a framework for evaluating real-time forecasts of variant frequencies, and apply this framework to the evolution of SARS-CoV-2 during 2022 in which multiple new viral variants emerged and rapidly spread through the population. We compare models across representative countries with different intensities of genomic surveillance. Retrospective assessment of model accuracy highlights that most models of variant frequency perform well and are able to produce reasonable forecasts. We find that the simple MLR model provides ∼0.6% median absolute error and ∼6% mean absolute error when forecasting 30 days out for countries with robust genomic surveillance. We investigate impacts of sequence quantity and quality across countries on forecast accuracy and conduct systematic downsampling to identify that 1000 sequences per week is fully sufficient for accurate short-term forecasts. We conclude that fitness models represent a useful prognostic tool for short-term evolutionary forecasting. Author summary: Over the course of the COVID-19 pandemic, SARS-CoV-2 evolved into many different genetic variants such as the well known Alpha, Beta, Gamma and Delta variants in early 2021 and the Omicron variant in late 2021. These genetic variants could more easily spread from person to person and so outcompeted previous versions of the virus. Even if they aren't being given Greek letter names, new variants are still arising with recent waves of COVID-19 caused by variants such as XBB and JN.1. Predicting which variants will increase in frequency and which variants will decrease in frequency is important for public health, particularly in terms of updating the formulation of the annual COVID-19 vaccine. In this paper, we investigate statistical models that use observed frequencies of different variants in the past weeks to estimate the frequency of different variants today and to forecast the frequency of different variants in 30 days time. We find that in countries with sufficient amounts and timeliness of genetic sequence data, that models forecast well and can be a useful tool for public health. [ABSTRACT FROM AUTHOR]

Compartmental models provide simple and efficient tools to analyze the relevant transmission processes during an outbreak, to produce short-term forecasts or transmission scenarios, and to assess the impact of vaccination campaigns. However, their calibration is not straightforward, since many factors contribute to the rapid change of the transmission dynamics. For example, there might be changes in the individual awareness, the imposition of non-pharmacological interventions and the emergence of new variants. As a consequence, model parameters such as the transmission rate are doomed to vary in time, making their assessment more challenging. Here, we propose to use Physics-Informed Neural Networks (PINNs) to track the temporal changes in the model parameters and the state variables. PINNs recently gained attention in many engineering applications thanks to their ability to consider both the information from data (typically uncertain) and the governing equations of the system. The ability of PINNs to identify unknown model parameters makes them particularly suitable to solve ill-posed inverse problems, such as those arising in the application of epidemiological models. Here, we develop a reduced-split approach for the implementation of PINNs to estimate the temporal changes in the state variables and transmission rate of an epidemic based on the SIR model equation and infectious data. The main idea is to split the training first on the epidemiological data, and then on the residual of the system equations. The proposed method is applied to five synthetic test cases and two real scenarios reproducing the first months of the Italian COVID-19 pandemic. Our results show that the split implementation of PINNs outperforms the joint approach in terms of accuracy (up to one order of magnitude) and computational times (speed up of 20%). Finally, we illustrate that the proposed PINN-method can also be adopted to produced short-term forecasts of the dynamics of an epidemic. Author summary: During the recent COVID-19 pandemic, we all became familiar with the reproduction number, a crucial quantity to determine if the number of infections is going to increase or decrease. Understanding the past changes of this quantity is fundamental to produce realistic forecasts of the epidemic and to plan possible containment strategies. There are several methods to infer the values of the reproduction number and, thus, the number of new infections. Statistical methods are based on the analysis of the collected epidemiological data. Instead, modeling approaches (such as the popular SIR model) attempt constructing a set of mathematical equations whose solution aims at approximating the dynamics underlying the data. In this paper, we explore the use of a recently developed technique called Physics-Informed Neural Network, which tries to combine the two approaches and to simultaneously fit the data, infer the dynamics of the unknown parameters, and solve the model equations. The proposed PINN implementations are tested in different scenarios using both synthetic and real-world data referred to the COVID-19 pandemic outbreak in Italy. The promising results can pave the way for a wider use of PINNs in epidemiological applications. [ABSTRACT FROM AUTHOR]

Single-cell ATAC-seq sequencing data (scATAC-seq) has been widely used to investigate chromatin accessibility on the single-cell level. One important application of scATAC-seq data analysis is differential chromatin accessibility (DA) analysis. However, the data characteristics of scATAC-seq such as excessive zeros and large variability of chromatin accessibility across cells impose a unique challenge for DA analysis. Existing statistical methods focus on detecting the mean difference of the chromatin accessible regions while overlooking the distribution difference. Motivated by real data exploration that distribution difference exists among cell types, we introduce a novel composite statistical test named "scaDA", which is based on zero-inflated negative binomial model (ZINB), for performing differential distribution analysis of chromatin accessibility by jointly testing the abundance, prevalence and dispersion simultaneously. Benefiting from both dispersion shrinkage and iterative refinement of mean and prevalence parameter estimates, scaDA demonstrates its superiority to both ZINB-based likelihood ratio tests and published methods by achieving the highest power and best FDR control in a comprehensive simulation study. In addition to demonstrating the highest power in three real sc-multiome data analyses, scaDA successfully identifies differentially accessible regions in microglia from sc-multiome data for an Alzheimer's disease (AD) study that are most enriched in GO terms related to neurogenesis and the clinical phenotype of AD, and AD-associated GWAS SNPs. Author summary: Understanding the cis-regulatory elements that control the fundamental gene regulatory process is important to basic biology. scATAC-seq data offers an unprecedented opportunity to investigate chromatin accessibility on the single-cell level and explore cell heterogeneity to reveal the dynamic changes of cis-regulatory elements among different cell types. To understand the dynamic change of gene regulation using scATAC-seq data, differential chromatin accessibility (DA) analysis, which is one of the most fundamental analyses for scATAC-seq data, can enable the identification of differentially accessible regions between cell types or between multiple conditions. Subsequently, DA analysis has many applications such as identifying cell type-specific chromatin accessible regions to reveal the cell type-specific gene regulatory program, assessing disease-associated changes in chromatin accessibility to detect potential biomarkers, and linking differentially accessible regions to differentially expressed genes for building a comprehensive gene regulatory map. This paper proposes a novel statistical method named "scaDA" to improve the detection of differentially accessible regions by performing differential distribution analysis. scaDA is believed to benefit the research community of single-cell genomics. [ABSTRACT FROM AUTHOR]

The article offers suggestions for preparing pre-submission inquiries for submissions to the journal "PLOS Computational Biology," including summarizing the problem domain and its relevance to the general readership of the journal, providing details of an innovation, and explaining the validation of the method.

The analysis of neurons that exhibit receptive fields dependent on an organism's spatial location, such as grid, place or boundary cells typically begins by mapping their activity in space using firing rate maps. However, mapping approaches are varied and depend on multiple tuning parameters that are usually chosen qualitatively by the experimenter and thus vary significantly across studies. Small changes in parameters such as these can impact results significantly, yet, to date a quantitative investigation of firing rate maps has not been attempted. Using simulated datasets, we examined how tuning parameters, recording duration and firing field size affect the accuracy of spatial maps generated using the most widely used approaches. For each approach we found a clear subset of parameters which yielded low-error firing rate maps and isolated the parameters yielding 1) the least error possible and 2) the Pareto-optimal parameter set which balanced error, computation time, place field detection accuracy and the extrapolation of missing values. Smoothed bivariate histograms and averaged shifted histograms were consistently associated with the fastest computation times while still providing accurate maps. Adaptive smoothing and binning approaches were found to compensate for low positional sampling the most effectively. Kernel smoothed density estimation also compensated for low sampling well and resulted in accurate maps, but it was also among the slowest methods tested. Overall, the bivariate histogram, coupled with spatial smoothing, is likely the most desirable method in the majority of cases. Author summary: Spatially modulated neurons in the brain increase their activity when an animal visits specific regions of its environment. Studying these neurons often begins with the creation of a firing rate map: a statistical representation of the cell's activity in space. Different methods, relying on different parameters, are commonly used to generate these maps. These parameters can have a huge impact on the maps created and, in turn, any results derived from them. Yet, very little quantification of these parameters has been attempted and they are almost universally chosen based on qualitative, study-dependent assessments. In this paper we quantify the 'best' combinations of parameters for each method and provide a way for researchers to calculate these for their own data. Using parameters that are both consistent across studies and quantifiably demonstrated to be the most accurate will reduce the variability between future studies while improving the validity of their results. [ABSTRACT FROM AUTHOR]

The extent to which dengue virus has been circulating globally and especially in Africa is largely unknown. Testing available blood samples from previous cross-sectional serological surveys offers a convenient strategy to investigate past dengue infections, as such serosurveys provide the ideal data to reconstruct the age-dependent immunity profile of the population and to estimate the average per-capita annual risk of infection: the force of infection (FOI), which is a fundamental measure of transmission intensity. In this study, we present a novel methodological approach to inform the size and age distribution of blood samples to test when samples are acquired from previous surveys. The method was used to inform SERODEN, a dengue seroprevalence survey which is currently being conducted in Ghana among other countries utilizing samples previously collected for a SARS-CoV-2 serosurvey. The method described in this paper can be employed to determine sample sizes and testing strategies for different diseases and transmission settings. Author summary: The historical circulation of dengue virus is still poorly understood in many parts of the world, and age-stratified seroprevalence surveys can provide the data to quantify population exposure to dengue and its transmission intensity. In this work, we developed a simulation-based method that can be used to identify the sample sizes and age-distribution of the samples needed to obtain informative estimates of dengue force of infection from existing blood samples. We apply this method to data obtained from a SARS-CoV-2 serological survey, previously conducted in three cities in Ghana. The methods and code developed in this paper can be used to design serological surveys for dengue and other pathogens when using existing blood samples with accompanying information on age and location. [ABSTRACT FROM AUTHOR]