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Antibiotic resistance is a global public health concern. Bacteria have evolved resistance to most antibiotics, which means that for any given bacterial infection, the bacteria may be resistant to one or several antibiotics. It has been suggested that genomic sequencing and machine learning (ML) could make resistance testing more accurate and cost-effective. Given that ML is likely to become an ever more important tool in medicine, we believe that it is important for pre-health students and others in the life sciences to learn to use ML tools. This paper provides a step-by-step tutorial to train 4 different ML models (logistic regression, random forests, extreme gradient-boosted trees, and neural networks) to predict drug resistance for Escherichia coli isolates and to evaluate their performance using different metrics and cross-validation techniques. We also guide the user in how to load and prepare the data used for the ML models. The tutorial is accessible to beginners and does not require any software to be installed as it is based on Google Colab notebooks and provides a basic understanding of the different ML models. The tutorial can be used in undergraduate and graduate classes for students in Biology, Public Health, Computer Science, or related fields.

Antibiotic resistance is a global public health concern. Bacteria have evolved resistance to most antibiotics, which means that for any given bacterial infection, the bacteria may be resistant to one or several antibiotics. It has been suggested that genomic sequencing and machine learning (ML) could make resistance testing more accurate and cost-effective. Given that ML is likely to become an ever more important tool in medicine, we believe that it is important for pre-health students and others in the life sciences to learn to use ML tools. This paper provides a step-by-step tutorial to train 4 different ML models (logistic regression, random forests, extreme gradient-boosted trees, and neural networks) to predict drug resistance for Escherichia coli isolates and to evaluate their performance using different metrics and cross-validation techniques. We also guide the user in how to load and prepare the data used for the ML models. The tutorial is accessible to beginners and does not require any software to be installed as it is based on Google Colab notebooks and provides a basic understanding of the different ML models. The tutorial can be used in undergraduate and graduate classes for students in Biology, Public Health, Computer Science, or related fields. [ABSTRACT FROM AUTHOR]

Author summary: 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. [ABSTRACT FROM AUTHOR]

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.].

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. Author summary: Computational researchers have a responsibility to ensure that the software they write stands up to the same scientific scrutiny as traditional research studies. These 10 simple rules make doing so easier by enhancing usability, reproducibility, transparency, and other crucial characteristics that aren't taught in most computer science or research methods curricula. [ABSTRACT FROM AUTHOR]

"There is no problem that a library card can't solve" according to author Eleanor Brown [[1]]. Is it a research article, written to present new data and the authors' interpretation of those data? Rule 5: Understand the formatting intentions Just like the overall intent of the article (discussed in Rule 2), the intent of each section within a research article can guide your interpretation. Twitter and other social media platforms have become excellent resources for discussing papers with other scientists, the public or your nonscientist friends, or even the paper's author(s). [Extracted from the article]

The article presents several rules for restructuring papers to avoid losing readers. Authors are instructed to focus their papers on a central contribution and to concentrate on the context-content-conclusion (C-C-C) scheme. They are also advised to optimize a paper's logical flow by avoiding zig-zag and using parallelism and to include complete story in the abstract.

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]

The article offers several rules for writing a reply paper. It mentions that before writing a reply determine if it is appropriate to write and writing a perspectives papers are applicable for annual reviews or for journals. It states that one should not overawe with bid data or big name like genomics, proteomics and GenBank, and highlights that always follow facts rather than being personal while writing a reply paper.

The author discusses the factors which should be considered by researchers while writing research papers. Topics discussed include analyzing the logical flow of experiments, choosing a target audience or a right journal for delivering main messages of the research to them, and discussion of various aspects of a hypothesis pursued in the research. Also mentioned are a Nobel-Prize-winning paper on the DNA double helix structure, and objective reading of reviews of the papers.

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]

This paper describes and validates an algorithm to solve optimal control problems for agent-based models (ABMs). For a given ABM and a given optimal control problem, the algorithm derives a surrogate model, typically lower-dimensional, in the form of a system of ordinary differential equations (ODEs), solves the control problem for the surrogate model, and then transfers it back to the original ABM. It applies to quite general ABMs and offers several options for the ODE structure, depending on what information about the ABM is to be used. There is a broad range of applications for such an algorithm, since ABMs are used widely in the life sciences, such as ecology, epidemiology, and biomedicine and healthcare, areas where optimal control is an important purpose for modeling, such as for medical digital twin technology. Author summary: The motivation for the work reported in this paper is the development of mathematical tools for medical digital twin development. Based on a computational model of some aspects of human biology, there is a two-way interaction between the physical twin (the patient) and the digital twin (the model). In one direction, the model is periodically calibrated with patient-derived data to evolve together with the patient, making the model into a digital twin, and in the other direction, optimal interventions derived from the digital twin are administered to the patient. In many cases, the underlying computational model does not readily provide optimal control methods to identify interventions. Model types such as agent-based models (ABMs) are often more suitable than models consisting of ordinary differential equations (ODEs). In this paper, we present an algorithm that takes as input a general ABM, together with an optimal control problem and provides as output a solution. This is accomplished by first constructing a surrogate ODE model, solving the optimal control problem, and then lifting it to the ABM. The algorithm provides for several different types of surrogate models, ranging from those that implement mechanistic features of the ABM to purely phenomenological models. The algorithm is validated by applying it to a predator-prey ABM and a metabolic network represented as an ABM. [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]

Measles is an important infectious disease system both for its burden on public health and as an opportunity for studying nonlinear spatio-temporal disease dynamics. Traditional mechanistic models often struggle to fully capture the complex nonlinear spatio-temporal dynamics inherent in measles outbreaks. In this paper, we first develop a high-dimensional feed-forward neural network model with spatial features (SFNN) to forecast endemic measles outbreaks and systematically compare its predictive power with that of a classical mechanistic model (TSIR). We illustrate the utility of our model using England and Wales measles data from 1944-1965. These data present multiple modeling challenges due to the interplay between metapopulations, seasonal trends, and nonlinear dynamics related to demographic changes. Our results show that while the TSIR model yields similarly performant short-term (1 to 2 biweeks ahead) forecasts for highly populous cities, our neural network model (SFNN) consistently achieves lower root mean squared error (RMSE) across other forecasting windows. Furthermore, we show that our spatial-feature neural network model, without imposing mechanistic assumptions a priori, can uncover gravity-model-like spatial hierarchy of measles spread in which major cities play an important role in driving regional outbreaks. We then turn our attention to integrative approaches that combine mechanistic and machine learning models. Specifically, we investigate how the TSIR can be utilized to improve a state-of-the-art approach known as Physics-Informed-Neural-Networks (PINN) which explicitly combines compartmental models and neural networks. Our results show that the TSIR can facilitate the reconstruction of latent susceptible dynamics, thereby enhancing both forecasts in terms of mean absolute error (MAE) and parameter inference of measles dynamics within the PINN. In summary, our results show that appropriately designed neural network-based models can outperform traditional mechanistic models for short to long-term forecasts, while simultaneously providing mechanistic interpretability. Our work also provides valuable insights into more effectively integrating machine learning models with mechanistic models to enhance public health responses to measles and similar infectious disease systems. Author summary: Mechanistic models have been foundational in developing an understanding of the transmission dynamics of infectious diseases including measles. In contrast to their mechanistic counterparts, machine learning techniques including neural networks have primarily focused on improving forecasting accuracy without explicitly inferring transmission dynamics. Effectively integrating these two modeling approaches remains a central challenge. In this paper, we first develop a high-dimensional neural network model to forecast spatiotemporal endemic measles outbreaks and systematically compare its predictive power with that of a classical mechanistic model (TSIR). We illustrate the utility of our model using a detailed dataset describing measles outbreaks in England and Wales from 1944–1965, one of the best-documented and most-studied nonlinear infectious disease systems. Our results show that overall, our neural network model outperforms the TSIR in all forecasting windows. Furthermore, we show that our neural network model can uncover the mechanism of hierarchical spread of measles where major cities drive regional outbreaks. We then develop an integrative approach that explicitly and effectively combines mechanistic and machine learning models, improving simultaneously both forecasting and inference. In summary, our work offers valuable insights into the effective utilization of machine learning models, and integration with mechanistic models, for enhancing outbreak responses to measles and similar infectious disease systems. [ABSTRACT FROM AUTHOR]

Animals can adapt their preferences for different types of reward according to physiological state, such as hunger or thirst. To explain this ability, we employ a simple multi-objective reinforcement learning model that learns multiple values according to different reward dimensions such as food or water. We show that by weighting these learned values according to the current needs, behaviour may be flexibly adapted to present preferences. This model predicts that individual dopamine neurons should encode the errors associated with some reward dimensions more than with others. To provide a preliminary test of this prediction, we reanalysed a small dataset obtained from a single primate in an experiment which to our knowledge is the only published study where the responses of dopamine neurons to stimuli predicting distinct types of rewards were recorded. We observed that in addition to subjective economic value, dopamine neurons encode a gradient of reward dimensions; some neurons respond most to stimuli predicting food rewards while the others respond more to stimuli predicting fluids. We also proposed a possible implementation of the model in the basal ganglia network, and demonstrated how the striatal system can learn values in multiple dimensions, even when dopamine neurons encode mixtures of prediction error from different dimensions. Additionally, the model reproduces the instant generalisation to new physiological states seen in dopamine responses and in behaviour. Our results demonstrate how a simple neural circuit can flexibly guide behaviour according to animals' needs. Author summary: Animals and humans can search for different resources depending on their needs. For example, when you are thirsty at work, you may go to a common room where hopefully coffee or water is available, while if you are hungry, you would rather go to a canteen. Such ability to seek different resources based on a physiological state is so fundamental to survival, that is present also in simple animals. This paper proposes how this ability could arise from a simple neural circuit that can be mapped on evolutionary older parts of the vertebrate brain, called the basal ganglia. The model suggests that this circuit learns the availability of different reward types, and then combines them according to the physiological state to control behaviour. [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]

A correction to the article "Ten Simple Rules for Structuring Papers," that appeared in the 2017 issue is presented.

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]

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]

Repetition is a classic mechanism for the evolution of cooperation. The standard way to study repeated games is to assume that there is an exogenous probability with which every interaction is repeated. If it is sufficiently likely that interactions are repeated, then reciprocity and cooperation can evolve together in repeated prisoner's dilemmas. Who individuals interact with can however also be under their control, or at least to some degree. If we change the standard model so that it allows for individuals to terminate the interaction with their current partner, and find someone else to play their prisoner's dilemmas with, then this limits the effectiveness of disciplining each other within the partnership, as one can always leave to escape punishment. The option to leave can however also be used to get away from someone who is not cooperating, which also has a disciplining effect. We find that the net effect of introducing the option to leave on cooperation is positive; with the option to leave, the average amount of cooperation that evolves in simulations is substantially higher than without. One of the reasons for this increase in cooperation is that partner choice creates endogenous phenotypic assortment. Compared to the standard models for the co-evolution of reciprocity and cooperation, and models of kin selection, our model thereby produces a better match with many forms of human cooperation in repeated settings. Individuals in our model end up interacting, not with random others that they cannot separate from, once matched, or with others that they are genetically related to, but with partners that they choose to stay with, and that are similarly dependable not to play defect as they are themselves. Author summary: The two mechanisms studied most in the literature on the evolution of cooperation are population structure (or kin selection), and repetition, which can allow for reciprocity to evolve. In the literature on repeated games, it is typically assumed that the matching is random and exogenous. However, not all human interactions in which there is scope for cooperation take place between individuals that have no say in who they play with, or between individuals that are genetically related. In many interactions, individuals can decide to stay with their partner, or leave and find someone else to play their repeated games with. We show that if we include the option to leave in an otherwise classical setting of repeated interactions, partner choice can evolve and maintain higher levels of cooperation than reciprocity does in the standard setting, where individuals cannot leave their partner. This points to the power of partner choice. [ABSTRACT FROM AUTHOR]

The "similarity of dissimilarities" is an emerging paradigm in biomedical science with significant implications for protein function prediction, machine learning (ML), and personalized medicine. In protein function prediction, recognizing dissimilarities alongside similarities provides a more detailed understanding of evolutionary processes, allowing for a deeper exploration of regions that influence biological functionality. For ML models, incorporating dissimilarity measures helps avoid misleading results caused by highly correlated or similar data, addressing confounding issues like the Doppelgänger Effect. This leads to more accurate insights and a stronger understanding of complex biological systems. In the realm of personalized AI and precision medicine, the importance of dissimilarities is paramount. Personalized AI builds local models for each sample by identifying a network of neighboring samples. However, if the neighboring samples are too similar, it becomes difficult to identify factors critical to disease onset for the individual, limiting the effectiveness of personalized interventions or treatments. This paper discusses the "similarity of dissimilarities" concept, using protein function prediction, ML, and personalized AI as key examples. Integrating this approach into an analysis allows for the design of better, more meaningful experiments and the development of smarter validation methods, ensuring that the models learn in a meaningful way. [ABSTRACT FROM AUTHOR]

This study introduces a novel neuromechanical model employing a detailed spiking neural network to explore the role of axial proprioceptive sensory feedback, namely stretch feedback, in salamander locomotion. Unlike previous studies that often oversimplified the dynamics of the locomotor networks, our model includes detailed simulations of the classes of neurons that are considered responsible for generating movement patterns. The locomotor circuits, modeled as a spiking neural network of adaptive leaky integrate-and-fire neurons, are coupled to a three-dimensional mechanical model of a salamander with realistic physical parameters and simulated muscles. In open-loop simulations (i.e., without sensory feedback), the model replicates locomotor patterns observed in-vitro and in-vivo for swimming and trotting gaits. Additionally, a modular descending reticulospinal drive to the central pattern generation network allows to accurately control the activation, frequency and phase relationship of the different sections of the limb and axial circuits. In closed-loop swimming simulations (i.e. including axial stretch feedback), systematic evaluations reveal that intermediate values of feedback strength increase the tail beat frequency and reduce the intersegmental phase lag, contributing to a more coordinated, faster and energy-efficient locomotion. Interestingly, the result is conserved across different feedback topologies (ascending or descending, excitatory or inhibitory), suggesting that it may be an inherent property of axial proprioception. Moreover, intermediate feedback strengths expand the stability region of the network, enhancing its tolerance to a wider range of descending drives, internal parameters' modifications and noise levels. Conversely, high values of feedback strength lead to a loss of controllability of the network and a degradation of its locomotor performance. Overall, this study highlights the beneficial role of proprioception in generating, modulating and stabilizing locomotion patterns, provided that it does not excessively override centrally-generated locomotor rhythms. This work also underscores the critical role of detailed, biologically-realistic neural networks to improve our understanding of vertebrate locomotion. Author summary: In this paper, we developed a computational model to investigate how salamanders move, both while swimming and walking. Unlike previous studies that often oversimplified the dynamics of these complex neural networks, our model includes detailed simulations of the classes of neurons that are considered responsible for generating movement patterns. The locomotor circuits, modeled as a spiking neural network, are coupled to a three-dimensional mechanical model of a salamander with realistic physical parameters and simulated muscles. The neural model integrates axial proprioceptive sensory feedback from the body's movements to modulate the locomotor gaits. Our simulations suggest that this sensory feedback plays a major role in controlling the rhythm and coordination of movements. This has implications for understanding not only how salamanders move but also provides insights into the evolution of locomotion in vertebrates. By investigating how central and sensory mechanisms interact to produce efficient and adaptable movement, our work contributes to the broader field of neuroscience and robotics, offering potential strategies for designing more effective biomimetic robots. [ABSTRACT FROM AUTHOR]

Transfer learning aims to integrate useful information from multi-source datasets to improve the learning performance of target data. This can be effectively applied in genomics when we learn the gene associations in a target tissue, and data from other tissues can be integrated. However, heavy-tail distribution and outliers are common in genomics data, which poses challenges to the effectiveness of current transfer learning approaches. In this paper, we study the transfer learning problem under high-dimensional linear models with t-distributed error (Trans-PtLR), which aims to improve the estimation and prediction of target data by borrowing information from useful source data and offering robustness to accommodate complex data with heavy tails and outliers. In the oracle case with known transferable source datasets, a transfer learning algorithm based on penalized maximum likelihood and expectation-maximization algorithm is established. To avoid including non-informative sources, we propose to select the transferable sources based on cross-validation. Extensive simulation experiments as well as an application demonstrate that Trans-PtLR demonstrates robustness and better performance of estimation and prediction when heavy-tail and outliers exist compared to transfer learning for linear regression model with normal error distribution. Data integration, Variable selection, T distribution, Expectation maximization algorithm, Genotype-Tissue Expression, Cross validation. Author summary: Many genetic loci have been shown to be associated with the mechanisms of important disease onset. Therefore, studying the expression of important genes contributes to the diagnosis and treatment of diseases. However, limited target gene expression data poses challenges to studying gene regulation. How to effectively integrate gene expression data from multiple sources is a key issue that needs to be addressed. In this study, we propose a robust transfer learning method aimed at improving the estimation and prediction performance of target gene expression data by integrating information from multiple data sources. By introducing a high-dimensional linear regression model with t-error distribution, our method addresses the shortcomings of previous transfer learning methods faced with heavy-tail distributions and outliers in genomics, providing robustness to complex data features. Extensive simulation experiments and an application demonstrate that our method exhibits better estimation and prediction performance when dealing with gene expression data with heavy-tail distributions and outliers. [ABSTRACT FROM AUTHOR]

Computational models are complex scientific constructs that have become essential for us to better understand the world. Many models are valuable for peers within and beyond disciplinary boundaries. However, there are no widely agreed-upon standards for sharing models. This paper suggests 10 simple rules for you to both (i) ensure you share models in a way that is at least "good enough," and (ii) enable others to lead the change towards better model-sharing practices. [ABSTRACT FROM AUTHOR]

Phylogenies depicting the evolutionary history of genetically heterogeneous subpopulations of cells from the same cancer, i.e., cancer phylogenies, offer valuable insights about cancer development and guide treatment strategies. Many methods exist that reconstruct cancer phylogenies using point mutations detected with bulk DNA sequencing. However, these methods become inaccurate when reconstructing phylogenies with more than 30 mutations, or, in some cases, fail to recover a phylogeny altogether. Here, we introduce Orchard, a cancer phylogeny reconstruction algorithm that is fast and accurate using up to 1000 mutations. Orchard samples without replacement from a factorized approximation of the posterior distribution over phylogenies, a novel result derived in this paper. Each factor in this approximate posterior corresponds to a conditional distribution for adding a new mutation to a partially built phylogeny. Orchard optimizes each factor sequentially, generating a sequence of incrementally larger phylogenies that ultimately culminate in a complete tree containing all mutations. Our evaluations demonstrate that Orchard outperforms state-of-the-art cancer phylogeny reconstruction methods in reconstructing more plausible phylogenies across 90 simulated cancers and 14 B-progenitor acute lymphoblastic leukemias (B-ALLs). Remarkably, Orchard accurately reconstructs cancer phylogenies using up to 1,000 mutations. Additionally, we demonstrate that the large and accurate phylogenies reconstructed by Orchard are useful for identifying patterns of somatic mutations and genetic variations among distinct cancer cell subpopulations. Author summary: Somatic mutations accumulate during cancer progression, leading to genetically distinct subpopulations of cancer cells. Understanding the evolutionary relationships among these subpopulations reveals critical events and offers clinical insights for treatment. We developed a novel machine learning algorithm, Orchard, which uses point mutations detected via bulk DNA sequencing to reconstruct phylogenies depicting the genetic evolution of an individual cancer. We evaluated Orchard on 90 simulated cancers and 14 B-progenitor acute lymphoblastic leukemias. Our results demonstrate that Orchard is fast and accurate at reconstructing phylogenies with up to 1,000 mutations detected in 100 cancer samples. Orchard's ability to reconstruct large phylogenies motivated a novel approach: applying agglomerative clustering to these trees to identify clusters of mutations that co-occur in cells. Our results show that this new clustering approach accurately identifies mutation clusters in real data, often outperforming state-of-the-art methods. [ABSTRACT FROM AUTHOR]

For the vast majority of genes in sequenced genomes, there is limited understanding of how they are regulated. Without such knowledge, it is not possible to perform a quantitative theory-experiment dialogue on how such genes give rise to physiological and evolutionary adaptation. One category of high-throughput experiments used to understand the sequence-phenotype relationship of the transcriptome is massively parallel reporter assays (MPRAs). However, to improve the versatility and scalability of MPRAs, we need a "theory of the experiment" to help us better understand the impact of various biological and experimental parameters on the interpretation of experimental data. These parameters include binding site copy number, where a large number of specific binding sites may titrate away transcription factors, as well as the presence of overlapping binding sites, which may affect analysis of the degree of mutual dependence between mutations in the regulatory region and expression levels. To that end, in this paper we create tens of thousands of synthetic gene expression outputs for bacterial promoters using both equilibrium and out-of-equilibrium models. These models make it possible to imitate the summary statistics (information footprints and expression shift matrices) used to characterize the output of MPRAs and thus to infer the underlying regulatory architecture. Specifically, we use a more refined implementation of the so-called thermodynamic models in which the binding energies of each sequence variant are derived from energy matrices. Our simulations reveal important effects of the parameters on MPRA data and we demonstrate our ability to optimize MPRA experimental designs with the goal of generating thermodynamic models of the transcriptome with base-pair specificity. Further, this approach makes it possible to carefully examine the mapping between mutations in binding sites and their corresponding expression profiles, a tool useful not only for developing a theory of transcription, but also for exploring regulatory evolution. Author summary: With the rapid advancement of sequencing technology, there has been an exponential increase in the amount of genomic sequence data available from diverse organisms. Nevertheless, deciphering the genotype-phenotype mapping of this data remains a formidable task, especially when dealing with non-coding sequences such as the promoter. In current databases, annotations for transcription factor binding sites are sorely lacking, which creates a challenge for developing a systematic theory of transcriptional regulation. To address this gap in knowledge, high-throughput methods such as massively parallel reporter assays (MPRAs) have been employed to decipher the regulatory genome. In this work, we make use of thermodynamic models to computationally simulate MPRAs in the context of transcriptional regulation and produce thousands of synthetic MPRA datasets for bacterial promoters. We examine how well typical experimental and data analysis procedures of MPRAs are able to recover common regulatory architectures under different sets of experimental and biological parameters. By establishing a dialogue between high-throughput experiments and a physical theory of transcription, our efforts serve to both improve current experimental procedures and enhancing our broader understanding of the sequence-function landscape of regulatory sequences. [ABSTRACT FROM AUTHOR]

Neuroblastoma is the most common extra-cranial solid tumour in children. Over half of all high-risk cases are expected to succumb to the disease even after chemotherapy, surgery, and immunotherapy. Although the importance of MYCN amplification in this disease is indisputable, the mechanistic details remain enigmatic. Here, we present a multicellular model of neuroblastoma comprising a continuous automaton, discrete cell agents, and a centre-based mechanical model, as well as the simulation results we obtained with it. The continuous automaton represents the tumour microenvironment as a grid-like structure, where each voxel is associated with continuous variables such as the oxygen level therein. Each discrete cell agent is defined by several attributes, including its cell cycle position, mutations, gene expression pattern, and more with behaviours such as cell cycling and cell death being stochastically dependent on these attributes. The centre-based mechanical model represents the properties of these agents as physical objects, describing how they repel each other as soft spheres. By implementing a stochastic simulation algorithm on modern GPUs, we simulated the dynamics of over one million neuroblastoma cells over a period of months. Specifically, we set up 1200 heterogeneous tumours and tracked the MYCN-amplified clone's dynamics in each, revealed the conditions that favour its growth, and tested its responses to 5000 drug combinations. Our results are in agreement with those reported in the literature and add new insights into how the MYCN-amplified clone's reproductive advantage in a tumour, its gene expression profile, the tumour's other clones (with different mutations), and the tumour's microenvironment are inter-related. Based on the results, we formulated a hypothesis, which argues that there are two distinct populations of neuroblastoma cells in the tumour; the p53 protein is pro-survival in one and pro-apoptosis in the other. It follows that alternating between inhibiting MDM2 to restore p53 activity and inhibiting ARF to attenuate p53 activity is a promising, if unorthodox, therapeutic strategy. The multicellular model has the advantages of modularity, high resolution, and scalability, making it a potential foundation for creating digital twins of neuroblastoma patients. Author summary: Neuroblastoma is the most common extra-cranial solid tumour in children. Although very low–risk, low-risk, and intermediate-risk cases have good survival rates, most high-risk patients succumb to the disease or relapse despite modern therapies. Neuroblastoma biology is still full of unanswered questions and successful treatment is likely to require a personalised approach. Mathematical and computational modelling could contribute to a better understanding of its origin and nature, as well as the ongoing effort to advance patient-specific therapies, partly because of the potential for integration with other emerging technologies such as multi-omics, medical imaging, data mining, machine learning, and high-performance computing. During the PRIMAGE project, we built, calibrated, and validated, to the best of our knowledge, the first multicellular computational model of neuroblastoma. As we reported in an earlier paper, this was integrated into a multi-scale orchestrated computational framework. Here, we describe how we used the multicellular computational model as a standalone component, to gain new insights into neuroblastoma. Armed with it, we carried out large-scale computer simulations involving over a million independent cell agents in the most expensive case and 5000 hypothetical drug combinations. Our results confirm and add new insights into the non-linear dynamics spanning the intracellular, intercellular, and microenvironmental scales of neuroblastoma. They also indicate that an unconventional therapy targeting a frequently overlooked role of p53 (DNA repair) is promising. On the basis of these results, we believe that our model will be useful for the in silico medicine community. We hope that it will one day become the foundation of a virtual neuroblastoma. [ABSTRACT FROM AUTHOR]

Data clustering is a core data science approach widely used and referenced in the scientific literature. Its algorithms are often intuitive and can lead to exciting, insightful results that are easy to interpret. For these reasons, data clustering techniques could be the first method encountered in data science training. This paper proposes a hands-on approach to data clustering training suitable for introductory courses. The education approach features problem-based training that starts with the data and gradually introduces various data processing and analysis methods, illustrating them through visual representations of data and models. The proposed training is suitable for a general audience, does not require a background in statistics, mathematics, or computer science, and aims to engage the audience through practical examples, an exploratory approach to data analysis with visual analysis, experimentation, and a gentle learning curve. The manuscript details the pedagogical units of the training, motivates them through the sequence of methods introduced, and proposes data sets and data analysis workflows to be explored in the class. Author summary: The highest satisfaction for any instructor comes from an engaged audience, a motivated class that pays attention, and student questions that open up new venues for exploring the planned material. Any introduction to data science deserves such an audience, while the burden is on the instructor to prepare an exciting lesson that covers the planned material and keeps students engaged with just the right mix of theory and practice. We could think of no better topic to cover in this way than an introduction to machine learning and no better way to introduce this field than through data clustering. Of course, by including the necessary ingredients to assist instructors: use cases to explore, a visual analytics environment to use in the classroom, and a set of problems to intuitively introduce concepts ranging from data representation, similarity scoring, clustering methods, to evaluation and explanation of the resulting models. In the manuscript, we propose the ingredients of such training and offer them in a form ready to be explored by instructors in practical, hands-on courses. [ABSTRACT FROM AUTHOR]