A Systems Approach to Stress, Stressors and Resilience in Humans

The paper focuses on the biology of stress and resilience and their biomarkers in humans from the system science perspective. A stressor pushes the physiological system away from its baseline state towards a lower utility state. The physiological system may return towards the original state in one attractor basin but may be shifted to a state in another, lower utility attractor basin. While some physiological changes induced by stressors may benefit health, there is often a chronic wear and tear cost due to implementing changes to enable the return of the system to its baseline state and maintain itself in the high utility baseline attractor basin following repeated perturbations. This cost, also called allostatic load, is the utility reduction associated with both a change in state and with alterations in the attractor basin that affect system responses following future perturbations. This added cost can increase the time course of the return to baseline or the likelihood of moving into a different attractor basin following a perturbation. Opposite to this is the system’s resilience which influences its ability to return to the high utility attractor basin following a perturbation by increasing the likelihood and/or speed of returning to the baseline state following a stressor. This review paper is a qualitative systematic review; it covers areas most relevant for moving the stress and resilience field forward from a more quantitative and neuroscientific perspective

System Dynamics Modeling for Traumatic Brain Injury: Mini-review of Applications

Traumatic brain injury (TBI) is a highly complex phenomenon involving a cascade of disruptions across biomechanical, neurochemical, neurological, cognitive, emotional, and social systems. Researchers and clinicians urgently need a rigorous conceptualization of brain injury that encompasses nonlinear and mutually causal relations among the factors involved, as well as sources of individual variation in recovery trajectories. System dynamics, an approach from systems science, has been used for decades in fields such as management and ecology to model nonlinear feedback dynamics in complex systems. In this mini-review, we summarize some recent uses of this approach to better understand acute injury mechanisms, recovery dynamics, and care delivery for TBI. We conclude that diagram-based approaches like causal-loop diagramming have the potential to support the development of a shared paradigm of TBI that incorporates social support aspects of recovery. When developed using adequate data from large-scale studies, simulation modeling presents opportunities for improving individualized treatment and care delivery

System Dynamics Modeling for Cancer Prevention and Control: A systematic review

Cancer prevention and control requires consideration of complex interactions between multilevel factors. System dynamics modeling, which consists of diagramming and simulation approaches for understanding and managing such complexity, is being increasingly applied to cancer prevention and control, but the breadth, characteristics, and quality of these studies is not known. We searched PubMed, Scopus, APA PsycInfo, and eight peer-reviewed journals to identify cancer-related studies that used system dynamics modeling. A dual review process was used to determine eligibility. Included studies were assessed using quality criteria adapted from prior literature and mapped onto the cancer control continuum. Characteristics of studies and models were abstracted and qualitatively synthesized. 32 studies met our inclusion criteria. A mix of simulation and diagramming approaches were used to address diverse topics, including chemotherapy treatments (16%), interventions to reduce tobacco or e-cigarettes use (16%), and cancer risk from environmental contamination (13%). Models spanned all focus areas of the cancer control continuum, with treatment (44%), prevention (34%), and detection (31%) being the most common. The quality assessment of studies was low, particularly for simulation approaches. Diagramming-only studies more often used participatory approaches. Involvement of participants, description of model development processes, and proper calibration and validation of models showed the greatest room for improvement. System dynamics modeling can illustrate complex interactions and help identify potential interventions across the cancer control continuum. Prior efforts have been hampered by a lack of rigor and transparency regarding model development and testing. Supportive infrastructure for increasing awareness, accessibility, and further development of best practices of system dynamics for multidisciplinary cancer research is needed

Mapping Mental Models Through an Improved Method for Identifying Causal Structures in Qualitative Data

Qualitative data are commonly used in the development of system dynamicsmodels, but methods for systematically identifying causal structures in qualita-tive data have not been widely established. This article presents a modifiedprocess for identifying causal structures (e.g., feedback loops) that are commu-nicated implicitly or explicitly and utilizes software to make coding, tracking,and model rendering more efficient. This approach draws from existingmethods, system dynamics best practice, and qualitative data analysis tech-niques. Steps of this method are presented along with a description of causalstructures for an audience new to system dynamics. The method is applied to aset of interviews describing mental models of clinical practice transformationfrom an implementation study of screening and treatment for unhealthy alco-hol use in primary care. This approach has the potential to increase rigour andtransparency in the use of qualitative data for model building and to broadenthe user base for causal-loop diagramming

Introduction of an agent-based multi-scale modular architecture for dynamic knowledge representation of acute inflammation

<p>Abstract</p> <p>Background</p> <p>One of the greatest challenges facing biomedical research is the integration and sharing of vast amounts of information, not only for individual researchers, but also for the community at large. Agent Based Modeling (ABM) can provide a means of addressing this challenge via a unifying translational architecture for dynamic knowledge representation. This paper presents a series of linked ABMs representing multiple levels of biological organization. They are intended to translate the knowledge derived from in vitro models of acute inflammation to clinically relevant phenomenon such as multiple organ failure.</p> <p>Results and Discussion</p> <p>ABM development followed a sequence starting with relatively direct translation from in-vitro derived rules into a cell-as-agent level ABM, leading on to concatenated ABMs into multi-tissue models, eventually resulting in topologically linked aggregate multi-tissue ABMs modeling organ-organ crosstalk. As an underlying design principle organs were considered to be functionally composed of an epithelial surface, which determined organ integrity, and an endothelial/blood interface, representing the reaction surface for the initiation and propagation of inflammation. The development of the epithelial ABM derived from an in-vitro model of gut epithelial permeability is described. Next, the epithelial ABM was concatenated with the endothelial/inflammatory cell ABM to produce an organ model of the gut. This model was validated against in-vivo models of the inflammatory response of the gut to ischemia. Finally, the gut ABM was linked to a similarly constructed pulmonary ABM to simulate the gut-pulmonary axis in the pathogenesis of multiple organ failure. The behavior of this model was validated against in-vivo and clinical observations on the cross-talk between these two organ systems</p> <p>Conclusion</p> <p>A series of ABMs are presented extending from the level of intracellular mechanism to clinically observed behavior in the intensive care setting. The ABMs all utilize cell-level agents that encapsulate specific mechanistic knowledge extracted from in vitro experiments. The execution of the ABMs results in a dynamic representation of the multi-scale conceptual models derived from those experiments. These models represent a qualitative means of integrating basic scientific information on acute inflammation in a multi-scale, modular architecture as a means of conceptual model verification that can potentially be used to concatenate, communicate and advance community-wide knowledge.</p

Deletion of individual Ku subunits in mice causes an NHEJ-independent phenotype potentially by altering apurinic/apyrimidinic site repair

Ku70 and Ku80 form a heterodimer called Ku that forms a holoenzyme with DNA dependent-protein kinase catalytic subunit (DNA-PKCS) to repair DNA double strand breaks (DSBs) through the nonhomologous end joining (NHEJ) pathway. As expected mutating these genes in mice caused a similar DSB repair-defective phenotype. However, ku70-/- cells and ku80 -/- cells also appeared to have a defect in base excision repair (BER). BER corrects base lesions, apurinic/apyrimidinic (AP) sites and single stand breaks (SSBs) utilizing a variety of proteins including glycosylases, AP endonuclease 1 (APE1) and DNA Polymerase β (Pol β). In addition, deleting Ku70 was not equivalent to deleting Ku80 in cells and mice. Therefore, we hypothesized that free Ku70 (not bound to Ku80) and/or free Ku80 (not bound to Ku70) possessed activity that influenced BER. To further test this hypothesis we performed two general sets of experiments. The first set showed that deleting either Ku70 or Ku80 caused an NHEJ-independent defect. We found ku80-/- mice had a shorter life span than dna-pkcs-/- mice demonstrating a phenotype that was greater than deleting the holoenzyme. We also found Ku70-deletion induced a p53 response that reduced the level of small mutations in the brain suggesting defective BER. We further confirmed that Ku80-deletion impaired BER via a mechanism that was not epistatic to Pol β. The second set of experiments showed that free Ku70 and free Ku80 could influence BER. We observed that deletion of either Ku70 or Ku80, but not both, increased sensitivity of cells to CRT0044876 (CRT), an agent that interferes with APE1. In addition, free Ku70 and free Ku80 bound to AP sites and in the case of Ku70 inhibited APE1 activity. These observations support a novel role for free Ku70 and free Ku80 in altering BER. © 2014 Choi et al

A Functional Variant in MicroRNA-146a Promoter Modulates Its Expression and Confers Disease Risk for Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with a strong genetic predisposition, characterized by an upregulated type I interferon pathway. MicroRNAs are important regulators of immune homeostasis, and aberrant microRNA expression has been demonstrated in patients with autoimmune diseases. We recently identified miR-146a as a negative regulator of the interferon pathway and linked the abnormal activation of this pathway to the underexpression of miR-146a in SLE patients. To explore why the expression of miR-146a is reduced in SLE patients, we conducted short parallel sequencing of potentially regulatory regions of miR-146a and identified a novel genetic variant (rs57095329) in the promoter region exhibiting evidence for association with SLE that was replicated independently in 7,182 Asians (Pmeta = 2.74×10−8, odds ratio = 1.29 [1.18–1.40]). The risk-associated G allele was linked to reduced expression of miR-146a in the peripheral blood leukocytes of the controls. Combined functional assays showed that the risk-associated G allele reduced the protein-binding affinity and activity of the promoter compared with those of the promoter containing the protective A allele. Transcription factor Ets-1, encoded by the lupus-susceptibility gene ETS1, identified in recent genome-wide association studies, binds near this variant. The manipulation of Ets-1 levels strongly affected miR-146a promoter activity in vitro; and the knockdown of Ets-1, mimicking its reduced expression in SLE, directly impaired the induction of miR-146a. We also observed additive effects of the risk alleles of miR-146a and ETS1. Our data identified and confirmed an association between a functional promoter variant of miR-146a and SLE. This risk allele had decreased binding to transcription factor Ets-1, contributing to reduced levels of miR-146a in SLE patients

Physics Design Requirements for the National Spherical Torus Experiment Liquid Lithium Divertor

Recent NSTX high power divertor experiments have shown significant and recurring benefits of solid lithium coatings on PFC's to the performance of divertor plasmas in both L- and H- mode confinement regimes heated by high-power neutral beams. The next step in this work is installation of a liquid lithium divertor (LLD) to achieve density control for inductionless current drive capability (e.g., about a 15-25% ne decrease from present highest non-inductionless fraction discharges which often evolve toward the density limit, ne/nGW~1), to enable ne scan capability (x2) in the H-mode, to test the ability to operate at significantly lower density for future ST-CTF reactor designs (e.g., ne/nGW = 0.25), and eventually to investigate high heat-flux power handling (10 MW/m2) with longpulse discharges (>1.5s). The first step (LLD-1) physics design encompasses the desired plasma requirements, the experimental capabilities and conditions, power handling, radial location, pumping capability, operating temperature, lithium filling, MHD forces, and diagnostics for control and characterization