Mitochondrial chaotic dynamics: Redox-energetic behavior at the edge of stability

Mitochondria serve multiple key cellular functions, including energy generation, redox balance, and regulation of apoptotic cell death, thus making a major impact on healthy and diseased states. Increasingly recognized is that biological network stability/instability can play critical roles in determining health and disease. We report for the first-time mitochondrial chaotic dynamics, characterizing the conditions leading from stability to chaos in this organelle. Using an experimentally validated computational model of mitochondrial function, we show that complex oscillatory dynamics in key metabolic variables, arising at the “edge” between fully functional and pathological behavior, sets the stage for chaos. Under these conditions, a mild, regular sinusoidal redox forcing perturbation triggers chaotic dynamics with main signature traits such as sensitivity to initial conditions, positive Lyapunov exponents, and strange attractors. At the “edge” mitochondrial chaos is exquisitely sensitive to the antioxidant capacity of matrix Mn superoxide dismutase as well as to the amplitude and frequency of the redox perturbation. These results have potential implications both for mitochondrial signaling determining health maintenance, and pathological transformation, including abnormal cardiac rhythms.publishedVersionKembro, Jackelyn Melissa. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; Argentina.Kembro, Jackelyn Melissa. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones Biológicas y Tecnológicas; Argentina.Cortassa, Sonia. National Institutes of Health. NIH · NIA Intramural Research Program; Estados Unidos.Lloyd, David. Cardiff University. School of Biosciences 1; Inglaterra.Sollot, Steven. Johns Hopkins University. Laboratory of Cardiovascular Science; Estados Unidos.Sollot, Steven. Johns Hopkins University. Laboratory of Cardiovascular Science; Estados Unidos

A verified solution of friction factor in compression test based on its sample\u27s shape changes

The friction factor is a key input for "barrel compression test" and for a meaningful interpretation of the test data. Despite its widespread use, due to the complexity of the problem, there are very few solutions available for the test, la alone for the friction factor. Extended-Avitzur (EA) model has serious known limitations to calculate the friction factor. To estimate the friction factor more reliably, a closed-form solution of the friction factor has been proposed here. The solution is based on the "Exponential Profile Model" (EPM) and provides an instantaneous value for the friction factor. It simply relies on the sample's initial and deformed dimensions. Unlike existing experimental procedures, the proposed solution integrates the test results and friction factor identification based on a single set of experimental load-displacement-barreling data. Merits of the model and its solution were highlighted and compared to those of the conventional Cylindrical Profile Models (CPM5). A finite element model was developed as the reference to produce pseudo-experimental test data and to verify the presented solution. The deformation data were used in the EPM and the EA model to calculate the friction factors by each model and to compare them with the reference data as the benchmark. Contrary to EA's estimated friction factors, those identified by the EPM were in good agreement with the reference values. Recommendations were provided to identify a deformation zone at which the EPM's friction factor can be estimated meaningfully

Abstract 13376: Sleep-Disordered Breathing is Associated With Larger Ventricular Repolarization Instability

Byline: Soroosh Solhjoo, Johns Hopkins Univ Sch of Medicine, Baltimore, MD; Mark C Haigney, F. Edward HȨbert Sch of Medicine, Bethesda, MD; Trishul Siddharthan, Univ of Miami Miller Sch of Medicine, Miami, FL; Abigail L Koch, Univ of Miami Miller Sch of Medicine, Miami, FL; Ciprian M Crainiceanu, Johns Hopkins Bloomberg Sch of Public Health, Baltimore, MD; Naresh M Punjabi, Univ of Miami Miller Sch of Medicine, Miami, FL Introduction: Sleep-disordered breathing (SDB) is a common disorder in the general population that is associated with adverse cardiovascular events, such as sudden cardiac death, but the underlying mechanisms are unclear. Hypothesis: Ventricular repolarization instability is greater in those with severe SDB than those without SDB, independent of other risk factors. Methods: Among the participants of the Sleep Heart Health Study (SHHS), we identified those with SDB who had no diagnosed cardiovascular disease or other factors that could affect cardiac repolarization. Severe SDB was defined as having a respiratory disturbance index (RDI) > 33 events/hour (top 95%ile of the SHHS cohort). We also identified a group of participants matched to the severe SDB group on age, sex, BMI, and race and had RDI < 1.33 events/hour (bottom 25%ile; without SDB). Each group consisted of 61 (45 M and 16 F) participants. Oxygen saturation levels (SpO2) were used to measure hypoxemia burden as the percentage of sleep time with SpO2 < 90% (T90). Heart rate (HR), heart rate variability (SDNN), and QT variability index (QTVI, a measure of ventricular repolarization instability) were calculated from one-lead ECG recordings. Student's t-test was used to assess statistical associations. Results: The SDB group had a larger T90 than those without SDB (11.39 Ø 1.42% vs 1.32 Ø 0.61%, P < 0.001). Participants with SDB also had greater mean HR (P = 0.028), SDNN (P = 0.017), and QTVI (P = 0.027) than those without SDB. Based on a multivariable linear model that included hypoxemia burden, age, BMI, and smoking status, T90 was the only independent predictor of QTVI (P = 0.022). Conclusion: SDB is associated with higher HR, HRV, and QTVI, an indicator of increased instability in ventricular repolarization leading to increased risk for cardiac arrhythmias and sudden cardiac death. The severity of the destabilizing effect of SDB on ventricular repolarization appears to be modified by hypoxemia burden.Professiona

Abstract 12538: Intermittent Hypoxemia Progressively Destabilizes Ventricular Repolarization in Healthy Awake Subjects

Byline: Soroosh Solhjoo, Johns Hopkins Univ Sch of Medicine, Baltimore, MD; Naresh M Punjabi, Univ of Miami Miller Sch of Medicine, Miami, FL; Trishul Siddharthan, Univ of Miami Miller Sch of Medicine, Miami, FL; Abigail L Koch, Univ of Miami Miller Sch of Medicine, Miami, FL; Ciprian M Crainiceanu, Johns Hopkins Bloomberg Sch of Public Health, Baltimore, MD; Mark C Haigney, F. Edward HȨbert Sch of Medicine, Bethesda, MD Introduction : Obstructive sleep apnea (OSA) is highly prevalent in the general population. OSA is associated with adverse cardiovascular events, including sudden cardiac death, but the mechanism is unclear. Intermittent hypoxemia, a pathognomonic feature of OSA, could increase the propensity for abnormal ventricular repolarization. We previously found that short-term exposure of awake healthy subjects to recurrent hypoxic episodes increased their heart rate (HR) and HR variability. Hypothesis: Exposure to intermittent hypoxia increases ventricular repolarization instability in awake healthy subjects. Methods: Healthy adults (N = 19) were exposed to either intermittent hypoxia or air for 4 hours on two different days in a randomized order. Intermittent hypoxia was induced with exposure to hypoxic gas (95% N2 and 5% O2) or ambient air in an alternative fashion at a frequency of üô 25 times/hour, mimicking moderate to severe OSA. Repolarization stability was assessed using the QT variability index (QTVI), a validated predictor of cardiac arrhythmias and mortality. HR and QTVI were measured from one-lead ECG over consecutive 5-min epochs. Paired sample t-test was used to assess statistical associations. Results: Mean oxygen saturation levels were lower during exposure to intermittent hypoxia (90.86 Ø 0.19%) versus normoxia (97.37 Ø 0.20%, P < 10-13). Electrocardiographic measures at baseline were similar between the two conditions. No changes in these measures were noted during the conditions of normoxia. However, with intermittent hypoxia, mean HR and QTVI steadily increased (HR: 63.31 Ø 1.51 initial, 69.21 Ø 2.14 final, P < 0.001; QTVI: -1.85 Ø 0.04 initial, -1.64 Ø 0.07 final, P = 0.016). By the end of the 4-hour experiment, QTVI was greater in hypoxia vs. normoxia (final QTVI in hypoxia: -1.64 Ø 0.07, in normoxia: -1.86 Ø 0.06, P = 0.021). Conclusion: Four hours of intermittent hypoxia in awake normal healthy subjects progressively destabilized ventricular repolarization. Chronic exposure to recurrent periods of intermittent hypoxemia in OSA can increase ventricular repolarization and contribute to the OSA-associated adverse cardiovascular events, including sudden cardiac death.Professiona

Tumor microenvironment: Interactions and therapy

Tumor microenvironment (TME) is a host for a complex network of heterogeneous stromal cells with overlapping or opposing functions depending on the dominant signals within this milieu. Reciprocal paracrine interactions between cancer cells with cells within the tumor stroma often reshape the TME in favor of the promotion of tumor. These complex interactions require more sophisticated approaches for cancer therapy, and, therefore, advancing knowledge about dominant drivers of cancer within the TME is critical for designing therapeutic schemes. This review will provide knowledge about TME architecture, multiple signaling, and cross communications between cells within this milieu, and its targeting for immunotherapy of cancer. © 2018 Wiley Periodicals, Inc