An exploration of knowledge-organizing technologies to advance transdisciplinary back pain research.

Chronic low back pain (LBP) is influenced by a broad spectrum of patient-specific factors as codified in domains of the biopsychosocial model (BSM). Operationalizing the BSM into research and clinical care is challenging because most investigators work in silos that concentrate on only one or two BSM domains. Furthermore, the expanding, multidisciplinary nature of BSM research creates practical limitations as to how individual investigators integrate current data into their processes of generating impactful hypotheses.

Theoretical Schemas to Guide Back Pain Consortium (BACPAC) Chronic Low Back Pain Clinical Research.

Background: Chronic low back pain (cLBP) is a complex with a heterogenous clinical presentation. A better understanding of the factors that contribute to cLBP is needed for accurate diagnosis, optimal treatment, and identification of mechanistic targets for new therapies. The Back Pain Consortium (BACPAC) Research Program provides a unique opportunity in this regard, as it will generate large clinical datasets, including a diverse set of harmonized measurements.

Utilizing virtual experiments to increase understanding of discrepancies involving in vitro-to-in vivo predictions of hepatic clearance.

Predictions of xenobiotic hepatic clearance in humans using in vitro-to-in vivo extrapolation methods are frequently inaccurate and problematic. Multiple strategies are being pursued to disentangle responsible mechanisms. The objective of this work is to evaluate the feasibility of using insights gained from independent virtual experiments on two model systems to begin unraveling responsible mechanisms.

Biomedical research models in the science of fracture healing - Pitfalls & promises.

Development of intervention strategies to stimulate fracture healing has long been a focus of musculoskeletal research. Considerable investment in empirical research has led to the discovery of several genes and signaling pathways that are involved in skeletal development and regeneration. However, there are currently very few biologic interventions that can efficiently be used to enhance fracture healing in clinical practice.

Contrasting model mechanisms of alanine aminotransferase (ALT) release from damaged and necrotic hepatocytes as an example of general biomarker mechanisms.

Interpretations of elevated blood levels of alanine aminotransferase (ALT) for drug-induced liver injury often assume that the biomarker is released passively from dying cells. However, the mechanisms driving that release have not been explored experimentally. The usefulness of ALT and related biomarkers will improve by developing mechanism-based explanations of elevated levels that can be expanded and elaborated incrementally.

Nocturnal torpor by superb fairy-wrens: a key mechanism for reducing winter daily energy expenditure.

Many passerine birds are small and require a high mass-specific rate of resting energy expenditure, especially in the cold. The energetics of thermoregulation is, therefore, an important aspect of their ecology, yet few studies have quantified thermoregulatory patterns in wild passerines. We used miniature telemetry to record the skin temperature ( T) of free-living superb fairy-wrens ( Malurus cyaneus, 8.

Propagation of Pericentral Necrosis During Acetaminophen-Induced Liver Injury: Evidence for Early Interhepatocyte Communication and Information Exchange.

Acetaminophen (APAP)-induced liver injury is clinically significant, and APAP overdose in mice often serves as a model for drug-induced liver injury in humans. By specifying that APAP metabolism, reactive metabolite formation, glutathione depletion, and mitigation of mitochondrial damage within individual hepatocytes are functions of intralobular location, an earlier virtual model mechanism provided the first concrete multiattribute explanation for how and why early necrosis occurs close to the central vein (CV). However, two characteristic features could not be simulated consistently: necrosis occurring first adjacent to the CV, and subsequent necrosis occurring primarily adjacent to hepatocytes that have already initiated necrosis.

The Spectrum of Mechanism-Oriented Models and Methods for Explanations of Biological Phenomena.

Developing and improving mechanism-oriented computational models to better explain biological phenomena is a dynamic and expanding frontier. As the complexity of targeted phenomena has increased, so too has the diversity in methods and terminologies, often at the expense of clarity, which can make reproduction challenging, even problematic. To encourage improved semantic and methodological clarity, we describe the spectrum of Mechanism-oriented Models being used to develop explanations of biological phenomena.

A Model Mechanism-Based Explanation of an In Vitro-In Vivo Disconnect for Improving Extrapolation and Translation.

An improved understanding of in vivo-to-in vitro hepatocyte changes is crucial to interpreting in vitro data correctly and further improving hepatocyte-based in vitro-to-in vivo extrapolations to human targets. We demonstrate using virtual experiments as a means of helping to untangle plausible causes of inaccurate extrapolations. We start with virtual mice that use biomimetic software livers.

Simulation enabled search for explanatory mechanisms of the fracture healing process.

A significant portion of bone fractures fail to heal properly, increasing healthcare costs. Advances in fracture management have slowed because translation barriers have limited generation of mechanism-based explanations for the healing process. When uncertainties are numerous, analogical modeling can be an effective strategy for developing plausible explanations of complex phenomena.

Competing Mechanistic Hypotheses of Acetaminophen-Induced Hepatotoxicity Challenged by Virtual Experiments.

Acetaminophen-induced liver injury in mice is a model for drug-induced liver injury in humans. A precondition for improved strategies to disrupt and/or reverse the damage is a credible explanatory mechanism for how toxicity phenomena emerge and converge to cause hepatic necrosis. The Target Phenomenon in mice is that necrosis begins adjacent to the lobule's central vein (CV) and progresses outward.

Virtual Experiments Enable Exploring and Challenging Explanatory Mechanisms of Immune-Mediated P450 Down-Regulation.

Hepatic cytochrome P450 levels are down-regulated during inflammatory disease states, which can cause changes in downstream drug metabolism and hepatotoxicity. Long-term, we seek sufficient new insight into P450-regulating mechanisms to correctly anticipate how an individual's P450 expressions will respond when health and/or therapeutic interventions change. To date, improving explanatory mechanistic insight relies on knowledge gleaned from in vitro, in vivo, and clinical experiments augmented by case reports.

A cell-centered, agent-based framework that enables flexible environment granularities.

Background: Mechanistic explanations of cell-level phenomena typically adopt an observer perspective. Explanations developed from a cell's perspective may offer new insights. Agent-based models lend themselves to model from an individual perspective, and existing agent-based models generally utilize a regular lattice-based environment.

In silico, experimental, mechanistic model for extended-release felodipine disposition exhibiting complex absorption and a highly variable food interaction.

The objective of this study was to develop and explore new, in silico experimental methods for deciphering complex, highly variable absorption and food interaction pharmacokinetics observed for a modified-release drug product. Toward that aim, we constructed an executable software analog of study participants to whom product was administered orally. The analog is an object- and agent-oriented, discrete event system, which consists of grid spaces and event mechanisms that map abstractly to different physiological features and processes.

Toward modular biological models: defining analog modules based on referent physiological mechanisms.

Background: Currently, most biomedical models exist in isolation. It is often difficult to reuse or integrate models or their components, in part because they are not modular. Modular components allow the modeler to think more deeply about the role of the model and to more completely address a modeling project's requirements.

Tuneable resolution as a systems biology approach for multi-scale, multi-compartment computational models.

The use of multi-scale mathematical and computational models to study complex biological processes is becoming increasingly productive. Multi-scale models span a range of spatial and/or temporal scales and can encompass multi-compartment (e.g.

Novel wave intensity analysis of arterial pulse wave propagation accounting for peripheral reflections.

We present a novel analysis of arterial pulse wave propagation that combines traditional wave intensity analysis with identification of Windkessel pressures to account for the effect on the pressure waveform of peripheral wave reflections. Using haemodynamic data measured in vivo in the rabbit or generated numerically in models of human compliant vessels, we show that traditional wave intensity analysis identifies the timing, direction and magnitude of the predominant waves that shape aortic pressure and flow waveforms in systole, but fails to identify the effect of peripheral reflections. These reflections persist for several cardiac cycles and make up most of the pressure waveform, especially in diastole and early systole.

Agent-based modeling: a systematic assessment of use cases and requirements for enhancing pharmaceutical research and development productivity.

A crisis continues to brew within the pharmaceutical research and development (R&D) enterprise: productivity continues declining as costs rise, despite ongoing, often dramatic scientific and technical advances. To reverse this trend, we offer various suggestions for both the expansion and broader adoption of modeling and simulation (M&S) methods. We suggest strategies and scenarios intended to enable new M&S use cases that directly engage R&D knowledge generation and build actionable mechanistic insight, thereby opening the door to enhanced productivity.

Individualized, discrete event, simulations provide insight into inter- and intra-subject variability of extended-release, drug products.

Objective: Develop and validate particular, concrete, and abstract yet plausible in silico mechanistic explanations for large intra- and interindividual variability observed for eleven bioequivalence study participants. Do so in the face of considerable uncertainty about mechanisms.

Methods: We constructed an object-oriented, discrete event model called subject (we use small caps to distinguish computational objects from their biological counterparts).

Haemodynamics in the mouse aortic arch computed from MRI-derived velocities at the aortic root.

Mice are widely used to investigate atherogenesis, which is known to be influenced by stresses related to blood flow. However, numerical characterization of the haemodynamic environment in the commonly studied aortic arch has hitherto been based on idealizations of inflow into the aorta. Our purpose in this work was to numerically characterize the haemodynamic environment in the mouse aortic arch using measured inflow velocities, and to relate the resulting shear stress patterns to known locations of high- and low-lesion prevalence.

Relational grounding facilitates development of scientifically useful multiscale models.

We review grounding issues that influence the scientific usefulness of any biomedical multiscale model (MSM). Groundings are the collection of units, dimensions, and/or objects to which a variable or model constituent refers. To date, models that primarily use continuous mathematics rely heavily on absolute grounding, whereas those that primarily use discrete software paradigms (e.

Enabling clearance predictions to emerge from in silico actions of quasi-autonomous hepatocyte components.

We demonstrate the feasibility of using in silico hepatocyte cultures (ISHCs) to provide predictions of the intrinsic clearance (CL) of compounds in hepatocyte cultures. We compare results with predictions obtained using a multiple linear regression method. Our expectation is that the method can be extended to predict in vivo clearance of new compounds in humans.

MDCK cystogenesis driven by cell stabilization within computational analogues.

The study of epithelial morphogenesis is fundamental to increasing our understanding of organ function and disease. Great progress has been made through study of culture systems such as Madin-Darby canine kidney (MDCK) cells, but many aspects of even simple morphogenesis remain unclear. For example, are specific cell actions tightly coupled to the characteristics of the cell's environment or are they more often cell state dependent? How does the single lumen, single cell layer cyst consistently emerge from a variety of cell actions? To improve insight, we instantiated in silico analogues that used hypothesized cell behavior mechanisms to mimic MDCK cystogenesis.

Cloud computing and validation of expandable in silico livers.

Background: In Silico Livers (ISLs) are works in progress. They are used to challenge multilevel, multi-attribute, mechanistic hypotheses about the hepatic disposition of xenobiotics coupled with hepatic responses. To enhance ISL-to-liver mappings, we added discrete time metabolism, biliary elimination, and bolus dosing features to a previously validated ISL and initiated re-validated experiments that required scaling experiments to use more simulated lobules than previously, more than could be achieved using the local cluster technology.

Computational experiments reveal plausible mechanisms for changing patterns of hepatic zonation of xenobiotic clearance and hepatotoxicity.

No concrete, causal, mechanistic theory is available to explain how different hepatic zonation patterns of P450 isozyme levels and hepatotoxicity emerge following dosing with different compounds. We used the synthetic method of modeling and simulation to discover, explore, and experimentally challenge concrete mechanisms that show how and why biomimetic zonation patterns can emerge and change within agent-based analogues, expecting that those mechanisms may have counterparts in rats. Mobile objects map to compounds.