Design patterns for the construction of computational biological models.

Computational biological models have proven to be an invaluable tool for understanding and predicting the behaviour of many biological systems. While it may not be too challenging for experienced researchers to construct such models from scratch, it is not a straightforward task for early stage researchers. Design patterns are well-known techniques widely applied in software engineering as they provide a set of typical solutions to common problems in software design. In this paper, we collect and discuss common patterns that are usually used during the construction and execution of computational biological models. We adopt Petri nets as a modelling language to provide a visual illustration of each pattern; however, the ideas presented in this paper can also be implemented using other modelling formalisms. We provide two case studies for illustration purposes and show how these models can be built up from the presented smaller modules. We hope that the ideas discussed in this paper will help many researchers in building their own future models.

Veterinary systems biology for bridging the phenotype-genotype gap via computational modeling for disease epidemiology and animal welfare.

Veterinary systems biology is an innovative approach that integrates biological data at the molecular and cellular levels, allowing for a more extensive understanding of the interactions and functions of complex biological systems in livestock and veterinary science. It has tremendous potential to integrate multi-omics data with the support of vetinformatics resources for bridging the phenotype-genotype gap via computational modeling. To understand the dynamic behaviors of complex systems, computational models are frequently used. It facilitates a comprehensive understanding of how a host system defends itself against a pathogen attack or operates when the pathogen compromises the host's immune system. In this context, various approaches, such as systems immunology, network pharmacology, vaccinology and immunoinformatics, can be employed to effectively investigate vaccines and drugs. By utilizing this approach, we can ensure the health of livestock. This is beneficial not only for animal welfare but also for human health and environmental well-being. Therefore, the current review offers a detailed summary of systems biology advancements utilized in veterinary sciences, demonstrating the potential of the holistic approach in disease epidemiology, animal welfare and productivity.

Experimental measurement and computational prediction of bacterial Hanks-type Ser/Thr signaling system regulatory targets.

Bacteria possess diverse classes of signaling systems that they use to sense and respond to their environments and execute properly timed developmental transitions. One widespread and evolutionarily ancient class of signaling systems are the Hanks-type Ser/Thr kinases, also sometimes termed "eukaryotic-like" due to their homology with eukaryotic kinases. In diverse bacterial species, these signaling systems function as critical regulators of general cellular processes such as metabolism, growth and division, developmental transitions such as sporulation, biofilm formation, and virulence, as well as antibiotic tolerance. This multifaceted regulation is due to the ability of a single Hanks-type Ser/Thr kinase to post-translationally modify the activity of multiple proteins, resulting in the coordinated regulation of diverse cellular pathways. However, in part due to their deep integration with cellular physiology, to date, we have a relatively limited understanding of the timing, regulatory hierarchy, the complete list of targets of a given kinase, as well as the potential regulatory overlap between the often multiple kinases present in a single organism. In this review, we discuss experimental methods and curated datasets aimed at elucidating the targets of these signaling pathways and approaches for using these datasets to develop computational models for quantitative predictions of target motifs. We emphasize novel approaches and opportunities for collecting data suitable for the creation of new predictive computational models applicable to diverse species.

Zebrafish Behavior: Opportunities and Challenges.

A great challenge in neuroscience is understanding how activity in the brain gives rise to behavior. The zebrafish is an ideal vertebrate model to address this challenge, thanks to the capacity, at the larval stage, for precise behavioral measurements, genetic manipulations, and recording and manipulation of neural activity noninvasively and at single-neuron resolution throughout the whole brain. These techniques are being further developed for application in freely moving animals and juvenile stages to study more complex behaviors including learning, decision making, and social interactions. We review some of the approaches that have been used to study the behavior of zebrafish and point to opportunities and challenges that lie ahead.

Deep models of superficial face judgments.

The diversity of human faces and the contexts in which they appear gives rise to an expansive stimulus space over which people infer psychological traits (e.g., trustworthiness or alertness) and other attributes (e.g., age or adiposity). Machine learning methods, in particular deep neural networks, provide expressive feature representations of face stimuli, but the correspondence between these representations and various human attribute inferences is difficult to determine because the former are high-dimensional vectors produced via black-box optimization algorithms. Here we combine deep generative image models with over 1 million judgments to model inferences of more than 30 attributes over a comprehensive latent face space. The predictive accuracy of our model approaches human interrater reliability, which simulations suggest would not have been possible with fewer faces, fewer judgments, or lower-dimensional feature representations. Our model can be used to predict and manipulate inferences with respect to arbitrary face photographs or to generate synthetic photorealistic face stimuli that evoke impressions tuned along the modeled attributes.

Integrating bioinformatic strategies in spatial life science research.

As space exploration programs progress, manned space missions will become more frequent and farther away from Earth, putting a greater emphasis on astronaut health. Through the collaborative efforts of researchers from various countries, the effect of the space environment factors on living systems is gradually being uncovered. Although a large number of interconnected research findings have been produced, their connection seems to be confused, and many unknown effects are left to be discovered. Simultaneously, several valuable data resources have emerged, accumulating data measuring biological effects in space that can be used to further investigate the unknown biological adaptations. In this review, the previous findings and their correlations are sorted out to facilitate the understanding of biological adaptations to space and the design of countermeasures. The biological effect measurement methods/data types are also organized to provide references for experimental design and data analysis. To aid deeper exploration of the data resources, we summarized common characteristics of the data generated from longitudinal experiments, outlined challenges or caveats in data analysis and provided corresponding solutions by recommending bioinformatics strategies and available models/tools.

Scoring personalized molecular portraits identify Systemic Lupus Erythematosus subtypes and predict individualized drug responses, symptomatology and disease progression.

OBJECTIVES: Systemic Lupus Erythematosus is a complex autoimmune disease that leads to significant worsening of quality of life and mortality. Flares appear unpredictably during the disease course and therapies used are often only partially effective. These challenges are mainly due to the molecular heterogeneity of the disease, and in this context, personalized medicine-based approaches offer major promise. With this work we intended to advance in that direction by developing MyPROSLE, an omic-based analytical workflow for measuring the molecular portrait of individual patients to support clinicians in their therapeutic decisions. METHODS: Immunological gene-modules were used to represent the transcriptome of the patients. A dysregulation score for each gene-module was calculated at the patient level based on averaged z-scores. Almost 6100 Lupus and 750 healthy samples were used to analyze the association among dysregulation scores, clinical manifestations, prognosis, flare and remission events and response to Tabalumab. Machine learning-based classification models were built to predict around 100 different clinical parameters based on personalized dysregulation scores. RESULTS: MyPROSLE allows to molecularly summarize patients in 206 gene-modules, clustered into nine main lupus signatures. The combination of these modules revealed highly differentiated pathological mechanisms. We found that the dysregulation of certain gene-modules is strongly associated with specific clinical manifestations, the occurrence of relapses or the presence of long-term remission and drug response. Therefore, MyPROSLE may be used to accurately predict these clinical outcomes. CONCLUSIONS: MyPROSLE (https://myprosle.genyo.es) allows molecular characterization of individual Lupus patients and it extracts key molecular information to support more precise therapeutic decisions.

Review on predicting pairwise relationships between human microbes, drugs and diseases: from biological data to computational models.

In recent years, with the rapid development of techniques in bioinformatics and life science, a considerable quantity of biomedical data has been accumulated, based on which researchers have developed various computational approaches to discover potential associations between human microbes, drugs and diseases. This paper provides a comprehensive overview of recent advances in prediction of potential correlations between microbes, drugs and diseases from biological data to computational models. Firstly, we introduced the widely used datasets relevant to the identification of potential relationships between microbes, drugs and diseases in detail. And then, we divided a series of a lot of representative computing models into five major categories including network, matrix factorization, matrix completion, regularization and artificial neural network for in-depth discussion and comparison. Finally, we analysed possible challenges and opportunities in this research area, and at the same time we outlined some suggestions for further improvement of predictive performances as well.

Population trends in human rib cross-sectional shapes.

Rib fractures remain the most frequent thoracic injury in motor vehicle crashes. Computational human body models (HBMs) can be used to simulate these injuries and design mitigation strategies, but they require adequately detailed geometry to replicate such fractures. Due to a lack of rib cross-sectional shape data availability, most commercial HBMs use highly simplified rib sections extracted from a single individual during original HBM development. This study provides human rib shape data collected from chest CT scans of 240 females and males across the full adult age range. A cortical bone mapping algorithm extracted cross-sectional geometry from scans in terms of local periosteal position with respect to the central rib axis and local cortex thickness. Principal component analysis was used to reduce the dimensionality of these cross-sectional shape data. Linear regression found significant associations between principal component scores and subject demographics (sex, age, height, and weight) at all rib levels, and predicted scores were used to explore the expected rib cross-sectional shapes across a wide range of subject demographics. The resulting detailed rib cross-sectional shapes were quantified in terms of their total cross-sectional area and their cortical bone cross-sectional area. Average-sized female ribs were smaller in total cross-sectional area than average-sized male ribs by between 20% and 36% across the rib cage, with the greatest differences seen in the central portions of rib 6. This trend persisted although to smaller differences of 14%-29% when comparing females and males of equal intermediate weight and stature. Cortical bone cross-sectional areas were up to 18% smaller in females than males of equivalent height and weight but also reached parity in certain regions of the rib cage. Increased age from 25 to 80 years was associated with reductions in cortical bone cross-sectional area (up to 37% in females and 26% in males at mid-rib levels). Total cross-sectional area was also seen to reduce with age in females but to a lesser degree (of up to 17% in mid-rib regions). Similar regions saw marginal increases in total cross-sectional area for male ribs, indicating age affects rib cortex thickness moreso than overall rib cross-sectional size. Increased subject height was associated with increased rib total and cortical bone cross-sectional areas by approximately 25% and 15% increases, respectively, in mid-rib sections for a given 30 cm increase in height, although the magnitudes of these associations varied by sex and rib location. Increased weight was associated with approximately equal changes in both cortical bone and total cross-sectional areas in males. These effects were most prominent (around 25% increases for an addition of 50 kg) toward lower ribs in the rib cage and had only modest effects (less than 12% change) in ribs 2-4. Females saw greater increases with weight in total rib area compared to cortical bone area, of up to 21% at the eighth rib level. Results from this study show the expected shapes of rib cross-sections across the adult rib cage and across a broad range of demographics. This detailed geometry can be used to produce accurate rib models representing widely varying populations.

Don't throw the associative baby out with the Bayesian bathwater: Children are more associative when reasoning retrospectively under information processing demands.

Causal reasoning is a fundamental cognitive ability that enables individuals to learn about the complex interactions in the world around them. However, the mechanisms that underpin causal reasoning are not well understood. For example, it remains unresolved whether children's causal inferences are best explained by Bayesian inference or associative learning. The two experiments and computational models reported here were designed to examine whether 5- and 6-year-olds will retrospectively reevaluate objects-that is, adjust their beliefs about the causal status of some objects presented at an earlier point in time based on the observed causal status of other objects presented at a later point in time-when asked to reason about 3 and 4 objects and under varying degrees of information processing demands. Additionally, the experiments and models were designed to determine whether children's retrospective reevaluations were best explained by associative learning, Bayesian inference, or some combination of both. The results indicated that participants retrospectively reevaluated causal inferences under minimal information-processing demands (Experiment 1) but failed to do so under greater information processing demands (Experiment 2) and that their performance was better captured by an associative learning mechanism, with less support for descriptions that rely on Bayesian inference. RESEARCH HIGHLIGHTS: Five- and 6-year-old children engage in retrospective reevaluation under minimal information-processing demands (Experiment 1). Five- and 6-year-old children do not engage in retrospective reevaluation under more extensive information-processing demands (Experiment 2). Across both experiments, children's retrospective reevaluations were better explained by a simple associative learning model, with only minimal support for a simple Bayesian model. These data contribute to our understanding of the cognitive mechanisms by which children make causal judgements.

The ReCoDe addiction research consortium: Losing and regaining control over drug intake-Findings and future perspectives.

Substance use disorders (SUDs) are seen as a continuum ranging from goal-directed and hedonic drug use to loss of control over drug intake with aversive consequences for mental and physical health and social functioning. The main goals of our interdisciplinary German collaborative research centre on Losing and Regaining Control over Drug Intake (ReCoDe) are (i) to study triggers (drug cues, stressors, drug priming) and modifying factors (age, gender, physical activity, cognitive functions, childhood adversity, social factors, such as loneliness and social contact/interaction) that longitudinally modulate the trajectories of losing and regaining control over drug consumption under real-life conditions. (ii) To study underlying behavioural, cognitive and neurobiological mechanisms of disease trajectories and drug-related behaviours and (iii) to provide non-invasive mechanism-based interventions. These goals are achieved by: (A) using innovative mHealth (mobile health) tools to longitudinally monitor the effects of triggers and modifying factors on drug consumption patterns in real life in a cohort of 900 patients with alcohol use disorder. This approach will be complemented by animal models of addiction with 24/7 automated behavioural monitoring across an entire disease trajectory; i.e. from a naïve state to a drug-taking state to an addiction or resilience-like state. (B) The identification and, if applicable, computational modelling of key molecular, neurobiological and psychological mechanisms (e.g., reduced cognitive flexibility) mediating the effects of such triggers and modifying factors on disease trajectories. (C) Developing and testing non-invasive interventions (e.g., Just-In-Time-Adaptive-Interventions (JITAIs), various non-invasive brain stimulations (NIBS), individualized physical activity) that specifically target the underlying mechanisms for regaining control over drug intake. Here, we will report on the most important results of the first funding period and outline our future research strategy.

A guide to ERK dynamics, part 1: mechanisms and models.

Extracellular signal-regulated kinase (ERK) has long been studied as a key driver of both essential cellular processes and disease. A persistent question has been how this single pathway is able to direct multiple cell behaviors, including growth, proliferation, and death. Modern biosensor studies have revealed that the temporal pattern of ERK activity is highly variable and heterogeneous, and critically, that these dynamic differences modulate cell fate. This two-part review discusses the current understanding of dynamic activity in the ERK pathway, how it regulates cellular decisions, and how these cell fates lead to tissue regulation and pathology. In part 1, we cover the optogenetic and live-cell imaging technologies that first revealed the dynamic nature of ERK, as well as current challenges in biosensor data analysis. We also discuss advances in mathematical models for the mechanisms of ERK dynamics, including receptor-level regulation, negative feedback, cooperativity, and paracrine signaling. While hurdles still remain, it is clear that higher temporal and spatial resolution provide mechanistic insights into pathway circuitry. Exciting new algorithms and advanced computational tools enable quantitative measurements of single-cell ERK activation, which in turn inform better models of pathway behavior. However, the fact that current models still cannot fully recapitulate the diversity of ERK responses calls for a deeper understanding of network structure and signal transduction in general.

Instance theory predicts categorization decisions in the absence of categorical structure: A computational analysis of artificial grammar learning without a grammar.

Theories of categorization have historically focused on the stimulus characteristics to which people are sensitive. Artificial grammar learning (AGL) provides a clear example of this phenomenon, with theorists debating between knowledge of rules, fragments, whole strings, and so on as the basis of categorization decisions (i.e., stimulus-driven explanations). We argue that this focus loses sight of the more important question of how participants make categorization decisions on a mechanistic level (i.e., process-driven explanations). To address the problem, we derived predictions from an instance-based model of human memory in a pseudo-AGL task in which all study and test strings were generated randomly, a task that stimulus-driven explanations of AGL would have difficulty accommodating. We conducted a standard AGL experiment with human participants using the same strings. The model's predictions corresponded to participants' decisions well, even in the absence of any experimenter-generated structure and regardless of whether test stimuli contained any incidental structure. We argue that theories of categorization ought to continue shifting towards the goal of modeling categorization at the level of cognitive processes rather than primarily attempting to identify the stimulus characteristics to which participants are drawn.

Neurocomputational Models of Interval Timing: Seeing the Forest for the Trees.

Extracting temporal regularities and relations from experience/observation is critical for organisms' adaptiveness (communication, foraging, predation, prediction) in their ecological niches. Therefore, it is not surprising that the internal clock that enables the perception of seconds-to-minutes-long intervals (interval timing) is evolutionarily well-preserved across many species of animals. This comparative claim is primarily supported by the fact that the timing behavior of many vertebrates exhibits common statistical signatures (e.g., on-average accuracy, scalar variability, positive skew). These ubiquitous statistical features of timing behaviors serve as empirical benchmarks for modelers in their efforts to unravel the processing dynamics of the internal clock (namely answering how internal clock "ticks"). In this chapter, we introduce prominent (neuro)computational approaches to modeling interval timing at a level that can be understood by general audience. These models include Treisman's pacemaker accumulator model, the information processing variant of scalar expectancy theory, the striatal beat frequency model, behavioral expectancy theory, the learning to time model, the time-adaptive opponent Poisson drift-diffusion model, time cell models, and neural trajectory models. Crucially, we discuss these models within an overarching conceptual framework that categorizes different models as threshold vs. clock-adaptive models and as dedicated clock/ramping vs. emergent time/population code models.

Association of aerobic glycolysis with the structural connectome reveals a benefit-risk balancing mechanism in the human brain.

Aerobic glycolysis (AG), that is, the nonoxidative metabolism of glucose, contributes significantly to anabolic pathways, rapid energy generation, task-induced activity, and neuroprotection; yet high AG is also associated with pathological hallmarks such as amyloid-ß deposition. An important yet unresolved question is whether and how the metabolic benefits and risks of brain AG is structurally shaped by connectome wiring. Using positron emission tomography and magnetic resonance imaging techniques as well as computational models, we investigate the relationship between brain AG and the macroscopic connectome. Specifically, we propose a weighted regional distance-dependent model to estimate the total axonal projection length of a brain node. This model has been validated in a macaque connectome derived from tract-tracing data and shows a high correspondence between experimental and estimated axonal lengths. When applying this model to the human connectome, we find significant associations between the estimated total axonal projection length and AG across brain nodes, with higher levels primarily located in the default-mode and prefrontal regions. Moreover, brain AG significantly mediates the relationship between the structural and functional connectomes. Using a wiring optimization model, we find that the estimated total axonal projection length in these high-AG regions exhibits a high extent of wiring optimization. If these high-AG regions are randomly rewired, their total axonal length and vulnerability risk would substantially increase. Together, our results suggest that high-AG regions have expensive but still optimized wiring cost to fulfill metabolic requirements and simultaneously reduce vulnerability risk, thus revealing a benefit-risk balancing mechanism in the human brain.

How much data do we need to estimate computational models of decision-making? The COMPASS toolbox.

How much data are needed to obtain useful parameter estimations from a computational model? The standard approach to address this question is to carry out a goodness-of-recovery study. Here, the correlation between individual-participant true and estimated parameter values determines when a sample size is large enough. However, depending on one's research question, this approach may be suboptimal, potentially leading to sample sizes that are either too small (underpowered) or too large (overcostly or unfeasible). In this paper, we formulate a generalized concept of statistical power and use this to propose a novel approach toward determining how much data is needed to obtain useful parameter estimates from a computational model. We describe a Python-based toolbox (COMPASS) that allows one to determine how many participants are needed to fit one specific computational model, namely the Rescorla-Wagner model of learning and decision-making. Simulations revealed that a high number of trials per person (more than the number of persons) are a prerequisite for high-powered studies in this particular setting.

A systematic review of computational models for the design of spinal cord stimulation therapies: from neural circuits to patient-specific simulations.

Seventy years ago, Hodgkin and Huxley published the first mathematical model to describe action potential generation, laying the foundation for modern computational neuroscience. Since then, the field has evolved enormously, with studies spanning from basic neuroscience to clinical applications for neuromodulation. Computer models of neuromodulation have evolved in complexity and personalization, advancing clinical practice and novel neurostimulation therapies, such as spinal cord stimulation. Spinal cord stimulation is a therapy widely used to treat chronic pain, with rapidly expanding indications, such as restoring motor function. In general, simulations contributed dramatically to improve lead designs, stimulation configurations, waveform parameters and programming procedures and provided insight into potential mechanisms of action of electrical stimulation. Although the implementation of neural models are relentlessly increasing in number and complexity, it is reasonable to ask whether this observed increase in complexity is necessary for improved accuracy and, ultimately, for clinical efficacy. With this aim, we performed a systematic literature review and a qualitative meta-synthesis of the evolution of computational models, with a focus on complexity, personalization and the use of medical imaging to capture realistic anatomy. Our review showed that increased model complexity and personalization improved both mechanistic and translational studies. More specifically, the use of medical imaging enabled the development of patient-specific models that can help to transform clinical practice in spinal cord stimulation. Finally, we combined our results to provide clear guidelines for standardization and expansion of computational models for spinal cord stimulation.

Computational modelling in disorders of consciousness: Closing the gap towards personalised models for restoring consciousness.

Disorders of consciousness are complex conditions characterised by persistent loss of responsiveness due to brain injury. They present diagnostic challenges and limited options for treatment, and highlight the urgent need for a more thorough understanding of how human consciousness arises from coordinated neural activity. The increasing availability of multimodal neuroimaging data has given rise to a wide range of clinically- and scientifically-motivated modelling efforts, seeking to improve data-driven stratification of patients, to identify causal mechanisms for patient pathophysiology and loss of consciousness more broadly, and to develop simulations as a means of testing in silico potential treatment avenues to restore consciousness. As a dedicated Working Group of clinicians and neuroscientists of the international Curing Coma Campaign, here we provide our framework and vision to understand the diverse statistical and generative computational modelling approaches that are being employed in this fast-growing field. We identify the gaps that exist between the current state-of-the-art in statistical and biophysical computational modelling in human neuroscience, and the aspirational goal of a mature field of modelling disorders of consciousness; which might drive improved treatments and outcomes in the clinic. Finally, we make several recommendations for how the field as a whole can work together to address these challenges.

From phenomenological to biophysical models of seizures.

Epilepsy is a complex disease that requires various approaches for its study. This short review discusses the contribution of theoretical and computational models. The review presents theoretical frameworks that underlie the understanding of certain seizure properties and their classification based on their dynamical properties at the onset and offset of seizures. Dynamical system tools are valuable resources in the study of seizures. These tools can provide insights into seizure mechanisms and offer a framework for their classification, by analyzing the complex, dynamic behavior of seizures. Additionally, computational models have high potential for clinical applications, as they can be used to develop more accurate diagnostic and personalized medicine tools. We discuss various modeling approaches that span different scales and levels, while also questioning the neurocentric view, emphasizing the importance of considering glial cells. Finally, we explore the epistemic value provided by this type of approach.

Italian, European, and international neuroinformatics efforts: An overview.

Neuroinformatics is a research field that focusses on software tools capable of identifying, analysing, modelling, organising and sharing multiscale neuroscience data. Neuroinformatics has exploded in the last two decades with the emergence of the Big Data phenomenon, characterised by the so-called 3Vs (volume, velocity and variety), which provided neuroscientists with an improved ability to acquire and process data faster and more cheaply thanks to technical improvements in clinical, genomic and radiological technologies. This situation has led to a 'data deluge', as neuroscientists can routinely collect more study data in a few days than they could in a year just a decade ago. To address this phenomenon, several neuroimaging-focussed neuroinformatics platforms have emerged, funded by national or transnational agencies, with the following goals: (i) development of tools for archiving and organising analytical data (XNAT, REDCap and LabKey); (ii) development of data-driven models evolving from reductionist approaches to multidimensional models (RIN, IVN, HBD, EuroPOND, E-DADS and GAAIN BRAIN); and (iii) development of e-infrastructures to provide sufficient computational power and storage resources (neuGRID, HBP-EBRAINS, LONI and CONP). Although the scenario is still fragmented, there are technological and economical attempts at both national and international levels to introduce high standards for open and Findable, Accessible, Interoperable and Reusable (FAIR) neuroscience worldwide.