Mathematical Model of Innate and Adaptive Immunity of Sepsis: A Modeling and Simulation Study of Infectious Disease

Citation: Shi, Z. Z., Wu, C. H. J., Ben-Arieh, D., & Simpson, S. Q. (2015). Mathematical Model of Innate and Adaptive Immunity of Sepsis: A Modeling and Simulation Study of Infectious Disease. Biomed Research International, 31. doi:10.1155/2015/504259Sepsis is a systemic inflammatory response (SIR) to infection. In this work, a system dynamics mathematical model (SDMM) is examined to describe the basic components of SIR and sepsis progression. Both innate and adaptive immunities are included, and simulated results in silico have shown that adaptive immunity has significant impacts on the outcomes of sepsis progression. Further investigation has found that the intervention timing, intensity of anti- inflammatory cytokines, and initial pathogen load are highly predictive of outcomes of a sepsis episode. Sensitivity and stability analysis were carried out using bifurcation analysis to explore system stability with various initial and boundary conditions. The stability analysis suggested that the system could diverge at an unstable equilibrium after perturbations if r(t2max) (maximum release rate of Tumor Necrosis Factor- (TNF-) alpha by neutrophil) falls below a certain level. This finding conforms to clinical findings and existing literature regarding the lack of efficacy of anti- TNF antibody therapy

An Agent-Based Model of a Hepatic Inflammatory Response to Salmonella: A Computational Study under a Large Set of Experimental Data

Citation: Shi, Z. Z., Chapes, S. K., Ben-Arieh, D., & Wu, C. H. (2016). An Agent-Based Model of a Hepatic Inflammatory Response to Salmonella: A Computational Study under a Large Set of Experimental Data. Plos One, 11(8), 39. doi:10.1371/journal.pone.0161131We present an agent-based model (ABM) to simulate a hepatic inflammatory response (HIR) in a mouse infected by Salmonella that sometimes progressed to problematic proportions, known as "sepsis". Based on over 200 published studies, this ABM describes interactions among 21 cells or cytokines and incorporates 226 experimental data sets and/or data estimates from those reports to simulate a mouse HIR in silico. Our simulated results reproduced dynamic patterns of HIR reported in the literature. As shown in vivo, our model also demonstrated that sepsis was highly related to the initial Salmonella dose and the presence of components of the adaptive immune system. We determined that high mobility group box-1, C-reactive protein, and the interleukin-10: tumor necrosis factor-a ratio, and CD4+ T cell: CD8+ T cell ratio, all recognized as biomarkers during HIR, significantly correlated with outcomes of HIR. During therapy-directed silico simulations, our results demonstrated that anti-agent intervention impacted the survival rates of septic individuals in a time-dependent manner. By specifying the infected species, source of infection, and site of infection, this ABM enabled us to reproduce the kinetics of several essential indicators during a HIR, observe distinct dynamic patterns that are manifested during HIR, and allowed us to test proposed therapy-directed treatments. Although limitation still exists, this ABM is a step forward because it links underlying biological processes to computational simulation and was validated through a series of comparisons between the simulated results and experimental studies

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Automated Optical Surface Strain Measurement System to Determine the Transfer Length in Pretensioned Concrete Railroad Ties

This report documents the advances that have been made to determine the transfer length of pretensioned concrete railroad ties using non-contact surface displacement measurements by digital image correlation. The work has culminated with two fully-functional devices that address specific needs of the industry. The first device utilizes a multi-camera method for measuring the surface strain profile on a railroad tie and determining the associated transfer length to within +/- 1.5 in. with as few as 5 independent measurements of surface strain. The work represents a practical step towards the continuous monitoring of in-plant prestressed railroad tie production, using transfer length as a quality control parameter. The second device is capable of making measurements of strain in a real-time continuously scanning/traversing (CST) manner over the entire distance range of interest on the tie associated with transfer-length development. It was shown to be capable of a strain measurement resolution of nominally about ± 20 microstrain, at traversing speeds of up to several inches per second

Use of 3D Non-Contact Profilometry to Quantify Indent Characteristics of Prestressing Wires Used in Pretensioned Concrete Railroad Ties

The objective of this research was to investigate possible correlation between prestressing wire indent geometry and the performance of pretensioned concrete members fabricated with these same reinforcements. Thirteen (13) commercially available and twelve (12) custom-made reinforcement wires were evaluated. A new non-contact indent profiling system was developed to collect detailed surface profiles of the prestressing steel. New geometrical feature measurements and processing algorithms were developed to provide detailed measurement of prestressing steel according to the dimensioning and tolerancing guidelines of ASME Y14.5-2009. These geometrical features were found to have significant correlation with the transfer length and fracture propensity of concrete crossties. Models were created to predict the transfer length of concrete crossties based on the extracted indent characteristics

A Comprehensive Study of Prestressing Steel and Concrete Variables Affecting Transfer Length in Pre-Tensioned Concrete Crossties

A comprehensive study was conducted to determine the variation of transfer length in pretensioned prestressed concrete railroad ties with varying prestressing steel types and concrete parameters. The in-depth evaluation included eighteen different prestressing reinforcement types that are employed in concrete railroad ties worldwide. The study consisted of two phases: Lab- Phase and Plant-Phase. Throughout the study, transfer lengths were determined from surface strain measurements on pre-tensioned concrete members. During the Lab-Phase, pre-tensioned concrete prisms were fabricated to replicate plant manufactured crossties. A special jacking arrangement was employed to ensure that each of the reinforcements was tensioned to the same force. Later, during the Plant-Phase, pre-tensioned concrete railroad ties were fabricated at a concrete crosstie manufacturing plant using the same reinforcements. In addition, a long-term study was conducted on plant-manufactured crossties to determine the variation of transfer length due to in-track loading

Using Tensioned Pullout Tests to Determine the Bond-Slip Relationship and Splitting-Propensity of Reinforcements Used in Pretensioned Concrete Railroad Ties

A study was conducted to evaluate the bond and splitting propensity characteristics of 12 different 5.32-mm-diameter prestressing wires used in the production of prestressed concrete railroad ties. Establishment of the bond-slip relationship of these wires at both transfer of prestress (transfer bond) and under flexural loading (flexural bond) was necessary to enable the accurate modeling of these ties using finite elements. Transfer bond and flexural bond of various indent patterns were tested using tensioned pullout tests. Specimens of various sizes with single or multiple wires were tested to determine the effects of cover and wire quantity on bond. Results from the testing program showed 1) the tensioned pullout tests could be used to predict the transfer length of prisms made with the same reinforcement, 2) the indent geometry depth and side-wall angle are good indicators of the likelihood of specimen splitting cracks, and 3) the importance of adequate concrete cover to eliminate potential splitting cracks

Effect of Concrete Properties and Prestressing Steel Reinforcement Type on the Development Length in Pretensioned Concrete Railroad ties

A study was conducted to determine the effect of different concrete properties and prestressing steel reinforcement type on the development length and flexural capacity of prestressed concrete railroad ties. Thirteen different 5.32-mm-diameter prestressing wires and six different strands (four 7-wire strands and two 3-wire strands) were used to fabricate 4-tendon pretensioned prisms with a square cross section. A consistent concrete mixture utilizing Type III cement and a water-to-cementitious ratio of 0.32 was used for all prisms. The prisms were detensioned at concrete compressive strengths of 3500 psi, 4500 psi, and 6000 psi. Load tests revealed that there is a large difference in the development length for different wire/strand types as well as with different concrete release strengths. Additionally, cyclic load tests revealed that there is also a significant difference in the bond performance of these reinforcement types under repeated loadings