Hybrid Equation/Agent-Based Model of Ischemia-Induced Hyperemia and Pressure Ulcer Formation Predicts Greater Propensity to Ulcerate in Subjects with Spinal Cord Injury

Pressure ulcers are costly and life-threatening complications for people with spinal cord injury (SCI). People with SCI also exhibit differential blood flow properties in non-ulcerated skin. We hypothesized that a computer simulation of the pressure ulcer formation process, informed by data regarding skin blood flow and reactive hyperemia in response to pressure, could provide insights into the pathogenesis and effective treatment of post-SCI pressure ulcers. Agent-Based Models (ABM) are useful in settings such as pressure ulcers, in which spatial realism is important. Ordinary Differential Equation-based (ODE) models are useful when modeling physiological phenomena such as reactive hyperemia. Accordingly, we constructed a hybrid model that combines ODEs related to blood flow along with an ABM of skin injury, inflammation, and ulcer formation. The relationship between pressure and the course of ulcer formation, as well as several other important characteristic patterns of pressure ulcer formation, was demonstrated in this model. The ODE portion of this model was calibrated to data related to blood flow following experimental pressure responses in non-injured human subjects or to data from people with SCI. This model predicted a higher propensity to form ulcers in response to pressure in people with SCI vs. non-injured control subjects, and thus may serve as novel diagnostic platform for post-SCI ulcer formation. © 2013 Solovyev et al

Metallothionein I as a direct link between therapeutic hematopoietic stem/progenitor cells and cerebral protection in stroke

National Institutes of Health/National Heart, Lung, and blood Institute (NIH/NHLBI (HL125572-01A1)); Malcolm Feist Cardiovascular Fellowship program; National Institute of General Medical Sciences COBRE Grant (P30- GM110703) and Japan Society for the Promotion of Science (Grants-in-Aid for Scientific Research- KAKENHI, 16H07356)

Beyond element-wise interactions: identifying complex interactions in biological processes

Background: Biological processes typically involve the interactions of a number of elements (genes, cells) acting on each others. Such processes are often modelled as networks whose nodes are the elements in question and edges pairwise relations between them (transcription, inhibition). But more often than not, elements actually work cooperatively or competitively to achieve a task. Or an element can act on the interaction between two others, as in the case of an enzyme controlling a reaction rate. We call “complex” these types of interaction and propose ways to identify them from time-series observations. Methodology: We use Granger Causality, a measure of the interaction between two signals, to characterize the influence of an enzyme on a reaction rate. We extend its traditional formulation to the case of multi-dimensional signals in order to capture group interactions, and not only element interactions. Our method is extensively tested on simulated data and applied to three biological datasets: microarray data of the Saccharomyces cerevisiae yeast, local field potential recordings of two brain areas and a metabolic reaction. Conclusions: Our results demonstrate that complex Granger causality can reveal new types of relation between signals and is particularly suited to biological data. Our approach raises some fundamental issues of the systems biology approach since finding all complex causalities (interactions) is an NP hard problem

Expression quantitative trait loci are highly sensitive to cellular differentiation state

Blood cell development from multipotent hematopoietic stem cells to specialized blood cells is accompanied by drastic changes in gene expression for which the triggers remain mostly unknown. Genetical genomics is an approach linking natural genetic variation to gene expression variation, thereby allowing the identification of genomic loci containing gene expression modulators (eQTLs). In this paper, we used a genetical genomics approach to analyze gene expression across four developmentally close blood cell types collected from a large number of genetically different but related mouse strains. We found that, while a significant number of eQTLs (365) had a consistent “static” regulatory effect on gene expression, an even larger number were found to be very sensitive to cell stage. As many as 1,283 eQTLs exhibited a “dynamic” behavior across cell types. By looking more closely at these dynamic eQTLs, we show that the sensitivity of eQTLs to cell stage is largely associated with gene expression changes in target genes. These results stress the importance of studying gene expression variation in well-defined cell populations. Only such studies will be able to reveal the important differences in gene regulation between different ce

Mathematical modeling of solid cancer growth with angiogenesis

<p>Abstract</p> <p>Background</p> <p>Cancer arises when within a single cell multiple malfunctions of control systems occur, which are, broadly, the system that promote cell growth and the system that protect against erratic growth. Additional systems within the cell must be corrupted so that a cancer cell, to form a mass of any real size, produces substances that promote the growth of new blood vessels. Multiple mutations are required before a normal cell can become a cancer cell by corruption of multiple growth-promoting systems.</p> <p>Methods</p> <p>We develop a simple mathematical model to describe the solid cancer growth dynamics inducing angiogenesis in the absence of cancer controlling mechanisms.</p> <p>Results</p> <p>The initial conditions supplied to the dynamical system consist of a perturbation in form of pulse: The origin of cancer cells from normal cells of an organ of human body. Thresholds of interacting parameters were obtained from the steady states analysis. The existence of two equilibrium points determine the strong dependency of dynamical trajectories on the initial conditions. The thresholds can be used to control cancer.</p> <p>Conclusions</p> <p>Cancer can be settled in an organ if the following combination matches: better fitness of cancer cells, decrease in the efficiency of the repairing systems, increase in the capacity of sprouting from existing vascularization, and higher capacity of mounting up new vascularization. However, we show that cancer is rarely induced in organs (or tissues) displaying an efficient (numerically and functionally) reparative or regenerative mechanism.</p

A Computational Approach to Understand In Vitro Alveolar Morphogenesis

Primary human alveolar type II (AT II) epithelial cells maintained in Matrigel cultures form alveolar-like cysts (ALCs) using a cytogenesis mechanism that is different from that of other studied epithelial cell types: neither proliferation nor death is involved. During ALC formation, AT II cells engage simultaneously in fundamentally different, but not fully characterized activities. Mechanisms enabling these activities and the roles they play during different process stages are virtually unknown. Identifying, characterizing, and understanding the activities and mechanisms are essential to achieving deeper insight into this fundamental feature of morphogenesis. That deeper insight is needed to answer important questions. When and how does an AT cell choose to switch from one activity to another? Why does it choose one action rather than another? We report obtaining plausible answers using a rigorous, multi-attribute modeling and simulation approach that leveraged earlier efforts by using new, agent and object-oriented capabilities. We discovered a set of cell-level operating principles that enabled in silico cells to self-organize and generate systemic cystogenesis phenomena that are quantitatively indistinguishable from those observed in vitro. Success required that the cell components be quasi-autonomous. As simulation time advances, each in silico cell autonomously updates its environment information to reclassify its condition. It then uses the axiomatic operating principles to execute just one action for each possible condition. The quasi-autonomous actions of individual in silico cells were sufficient for developing stable cyst-like structures. The results strengthen in silico to in vitro mappings at three levels: mechanisms, behaviors, and operating principles, thereby achieving a degree of validation and enabling answering the questions posed. We suggest that the in silico operating principles presented may have a biological counterpart and that a semiquantitative mapping exists between in silico causal events and in vitro causal events

FADS2 Genetic Variance in Combination with Fatty Acid Intake Might Alter Composition of the Fatty Acids in Brain

Multiple lines of evidence suggest that fatty acids (FA) play an important role in cognitive function. However, little is known about the functional genetic pathways involved in cognition. The main goals of this study were to replicate previously reported interaction effects between breast feeding (BF) and FA desaturase (FADS) genetic variation on IQ and to investigate the possible mechanisms by which these variants might moderate BF effect, focusing on brain expression. Using a sample of 534 twins, we observed a trend in the moderation of BF effects on IQ by FADS2 variation. In addition, we made use of publicly available gene expression databases from both humans (193) and mice (93) and showed that FADS2 variants also correlate with FADS1 brain expression (P-value<1.1E-03). Our results provide novel clues for the understanding of the genetic mechanisms regulating FA brain expression and improve the current knowledge of the FADS moderation effect on cognition

Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty

Sensorimotor adaptation as a behavioural biomarker of early spinocerebellar ataxia type 6.

Early detection of the behavioural deficits of neurodegenerative diseases may help to describe the pathogenesis of such diseases and establish important biomarkers of disease progression. The aim of this study was to identify how sensorimotor adaptation of the upper limb, a cerebellar-dependent process restoring movement accuracy after introduction of a perturbation, is affected at the pre-clinical and clinical stages of spinocerebellar ataxia type 6 (SCA6), an inherited neurodegenerative disease. We demonstrate that initial adaptation to the perturbation was significantly impaired in the eighteen individuals with clinical motor symptoms but mostly preserved in the five pre-clinical individuals. Moreover, the amount of error reduction correlated with the clinical symptoms, with the most symptomatic patients adapting the least. Finally both pre-clinical and clinical individuals showed significantly reduced de-adaptation performance after the perturbation was removed in comparison to the control participants. Thus, in this large study of motor features in SCA6, we provide novel evidence for the existence of subclinical motor dysfunction at a pre-clinical stage of SCA6. Our findings show that testing sensorimotor de-adaptation could provide a potential predictor of future motor deficits in SCA6

Preference Transitivity and Symbolic Representation in Capuchin Monkeys (Cebus apella)

BACKGROUND: Can non-human animals comprehend and employ symbols? The most convincing empirical evidence comes from language-trained apes, but little is known about this ability in monkeys. Tokens can be regarded as symbols since they are inherently non-valuable objects that acquire an arbitrarily assigned value upon exchange with an experimenter. Recent evidence suggested that capuchin monkeys, which diverged from the human lineage 35 million years ago, can estimate, represent and combine token quantities. A fundamental and open question is whether monkeys can reason about symbols in ways similar to how they reason about real objects. METHODOLOGY/PRINCIPAL FINDINGS: Here we examined this broad question in the context of economic choice behavior. Specifically, we assessed whether, in a symbolic context, capuchins' preferences satisfy transitivity--a fundamental trait of rational decision-making. Given three options A, B and C, transitivity holds true if A > or = B, B > or = C and A > or = C (where > or = indicates preference). In this study, we trained monkeys to exchange three types of tokens for three different foods. We then compared choices monkeys made between different types of tokens with choices monkeys made between the foods. Qualitatively, capuchins' preferences revealed by the way of tokens were similar to those measured with the actual foods. In particular, when choosing between tokens, monkeys displayed strict economic preferences and their choices satisfied transitivity. Quantitatively, however, values measured by the way of tokens differed systematically from those measured with the actual foods. In particular, for any pair of foods, the relative value of the preferred food increased when monkeys chose between the corresponding tokens. CONCLUSIONS/SIGNIFICANCE: These results indicate that indeed capuchins are capable of treating tokens as symbols. However, as they do so, capuchins experience the cognitive burdens imposed by symbolic representation