A Modular Workflow for Model Building, Analysis, and Parameter Estimation in Systems Biology and Neuroscience

Neuroscience incorporates knowledge from a range of scales, from single molecules to brain wide neural networks. Modeling is a valuable tool in understanding processes at a single scale or the interactions between two adjacent scales and researchers use a variety of different software tools in the model building and analysis process. Here we focus on the scale of biochemical pathways, which is one of the main objects of study in systems biology. While systems biology is among the more standardized fields, conversion between different model formats and interoperability between various tools is still somewhat problematic. To offer our take on tackling these shortcomings and by keeping in mind the FAIR (findability, accessibility, interoperability, reusability) data principles, we have developed a workflow for building and analyzing biochemical pathway models, using pre-existing tools that could be utilized for the storage and refinement of models in all phases of development. We have chosen the SBtab format which allows the storage of biochemical models and associated data in a single file and provides a human readable set of syntax rules. Next, we implemented custom-made MATLAB® scripts to perform parameter estimation and global sensitivity analysis used in model refinement. Additionally, we have developed a web-based application for biochemical models that allows simulations with either a network free solver or stochastic solvers and incorporating geometry. Finally, we illustrate convertibility and use of a biochemical model in a biophysically detailed single neuron model by running multiscale simulations in NEURON. Using this workflow, we can simulate the same model in three different simulators, with a smooth conversion between the different model formats, enhancing the characterization of different aspects of the model.

Molecular Mechanisms of the Toll-Like Receptor, STING, MAVS, Inflammasome, and Interferon Pathways

Pattern recognition receptors (PRRs) form the front line of defense against pathogens. Many of the molecular mechanisms that facilitate PRR signaling have been characterized in detail, which is critical for the development of accurate PRR pathway models at the molecular interaction level.

Eye Movement Indices of Post-Saccadic Task Under Cognitive Load: A Path Analysis to Predict Individual’s Performance

Purpose: The evidence on the linear relationship between cognitive load, saccade, fixation, and task performance was uncertain. We tested pathway models for degraded task performance resulting from changes in saccadic and post-saccadic fixation under cognitive load. Methods: Participants' (n = 38) eye movements were recorded using a post-saccadic discrimination task without and with arithmetic operations to impose cognitive load, validated through recording heart rate variability and subjective measurement. Results: Results showed that cognitive load led to longer latencies of saccade and fixation; more inaccurate responses and fewer secondary saccades (P<0.001). Longer saccade latencies influenced task performance indirectly via increases in fixation latency, thereby, longer reaction times and higher response errors were observed due to limited fixation duration on desired target. Conclusion: We suggest that latency and duration of fixation indicate efficiency of information processing and can predict the speed and accuracy of task performance under cognitive load.

Physical Demands of Women's Soccer Matches: A Perspective Across the Developmental Spectrum

Female soccer players are exposed to specific physical demands during matches, which vary according to the standard of play. Existing studies have largely focused on quantifying the distances covered for professional and international level players. This approach is limited in scope regarding the broader aspects around physical demands and is detached from development pathway models. An understanding of the demands across all standards will provide valuable insights about appropriate player development and help ensure physical readiness for the demands of the sport. The aim of this perspective paper is to describe the physical demands experienced during women's soccer matches across the developmental spectrum. A combination of evidence from the literature and data from the author's research (JDV) is presented. Specifically highlighted are the trends for locomotor distances, acceleration and deceleration frequency, and metabolic power metrics for youth (≤U17), college (NCAA/U20), professional (domestic) and international standards of women's soccer. In addition, the changes in match demands between levels of play are used to help illustrate gaps that must be overcome in order to successfully achieve physical readiness to compete at higher levels. The evidence demonstrates the importance of training appropriate attributes to prepare female soccer players who are striving to play at progressively higher standards.

Using Pathway Modeling to Evaluation and Improve Student-Centered Teaching Practices in Co-Taught College Science Courses

Student-centered teaching practices such as active learning continue to gain momentum in college science education. Many instructors committed to these innovative practices transform their classroom beyond the standard lecture. Nevertheless, widespread implementation of these practices is limited because the learning benefits for students are often attained through increased instructional complexity to which many instructors cannot commit. When co-instructors are teaching the course, the level of commitment to building a student-centered classroom may be even more profound. For these reasons, new tools are needed to help instructors and co-instructors plan, organize, evaluate, and communicate their classroom innovations. Pathway modeling is a tool with potential to fill this gap. Unlike curriculum mapping -- which identifies academic content gaps, redundancies, and misalignments by examining a series of courses within a plan of study &ndash; course pathway modeling creates a visual map of a single course and reveals how teaching practices influence short-, mid-, and long-term student learning outcomes. This essay demonstrates how course pathway modeling can help co-instructors better represent the complexity of student-centered teaching practices. We include guides for creating course pathway models and discuss how this approach offers the potential to improve curricular design, course evaluation, student assessment, and communication between co-instructors.

Multipath: An R Package to Generate Integrated Reproducible Pathway Models

Biological pathway data integration has become a topic of interest in the past years. This interest originates essentially from the continuously increasing size of existing prior knowledge as well as from the many challenges scientists face when studying biological pathways. Multipath is a framework that aims at helping re-trace the use of specific pathway knowledge in specific publications, and easing the data integration of multiple pathway types and further influencing knowledge sources. Multipath thus helps scientists to increase the reproducibility of their code and analysis by allowing the integration of numerous data sources and documentation of their integration steps while doing so. In this paper, we present the package Multipath, and we describe how it can be used for data integration and tracking pathway modifications. We present a multilayer model built from the Wnt Pathway as a demonstration.

Do Social Support and Strain Mediate the Relationship Between Childhood Exposures and Frailty in Later Life?

Previous studies have identified the early origins of physical frailty, notably poor childhood health and socioeconomic status, but relatively few studies examine whether social support in later life mitigates the influence of early noxious exposures on frailty. Given the established relationship between health and social relationships in older adults, this research uses data from the Health and Retirement study (2004-2016) to examine whether social support and strain mediate the effect of childhood exposures on frailty in later life. A series of linear regression and pathway models were estimated to test whether childhood exposures, including socioeconomic status, infectious and chronic diseases, impairments, and risky adolescent parental behaviors, were associated with phenotypic frailty (Fried et al. 2001). After adjusting for demographic and adult factors, accumulated childhood misfortune was directly (b=0.015, p&lt;.01) and indirectly (b=0.007, p&lt;.001) associated with more frailty. Average social support, but not strain, from one’s spouse, children, family and friends significantly mediated the relationship between accumulated misfortune and frailty (b= -.002, p&lt;.01). Path analysis revealed that social support reduces later life frailty directly (b=-0.106 ,p&lt;.001) and indirectly through a reduction in adult morbidity (b=-0.031, p&lt;.001). However, counterintuitively we found that accumulated misfortune was associated with more social support. Supplemental analyses reveal that one or more infectious diseases in childhood were responsible for the positive relationship (b= 0.393, p&lt;.001). These results have implications for how we may reduce the burden of frailty on those who have experienced misfortune early in life.

WikiPathways: connecting communities

WikiPathways (https://www.wikipathways.org) is a biological pathway database known for its collaborative nature and open science approaches. With the core idea of the scientific community developing and curating biological knowledge in pathway models, WikiPathways lowers all barriers for accessing and using its content. Increasingly more content creators, initiatives, projects and tools have started using WikiPathways. Central in this growth and increased use of WikiPathways are the various communities that focus on particular subsets of molecular pathways such as for rare diseases and lipid metabolism. Knowledge from published pathway figures helps prioritize pathway development, using optical character and named entity recognition. We show the growth of WikiPathways over the last three years, highlight the new communities and collaborations of pathway authors and curators, and describe various technologies to connect to external resources and initiatives. The road toward a sustainable, community-driven pathway database goes through integration with other resources such as Wikidata and allowing more use, curation and redistribution of WikiPathways content.

A Modular Workflow for Model Building, Analysis, and Parameter Estimation in Systems Biology and Neuroscience

Neuroscience incorporates knowledge from a range of scales from molecular dynamics to neural networks. Modeling is a valuable tool in understanding processes at a single scale or the interactions between two adjacent scales and researchers use a variety of different software tools in the model building and analysis process. Systems biology, for instance, is among the more standardized fields. However, conversion between different model formats and interoperability between various tools is still somewhat problematic. To offer our take on tackling these shortcomings and by keeping in mind the FAIR (findability, accessibility, interoperability, reusability) data principles, we have developed a workflow for building and analyzing biochemical pathway models using pre-existing tools that could be utilized for the storage and refinement of models in all phases of development. We have chosen the SBtab format which allows the storage of biochemical models and associated data in a single file and provides a human readable set of syntax rules. Next, we implement custom-made MATLAB® scripts to perform parameter estimation and sensitivity analysis used in model refinement. Additionally, we have developed a web-based application for biochemical models that allows simulations with either a network free solver or stochastic solvers and incorporating geometry. Finally, we illustrate convertibility and use of a biochemical model in a biophysically detailed single neuron model by running multiscale simulations in NEURON. By this we can simulate the same model in three principally different simulators, describing different aspects of the system, and with a smooth conversion between the different model formats.