Computational Analysis of Complex Beat-to-Beat Dynamics in Heart Cells

Contrary to the popular belief that the heart maintains a regular rhythm, healthy heartbeats fluctuate in a chaotic way. We now know that the fluctuations do not display uncorrelated randomness, but they contain long-range correlations and can be characterized by a fractal. This behavior supports the adaptability of the heart and may thus protect it from external stress. The fractal complexity is also found in the smallest parts of the heart: the cells. In the dawn of advanced pluripotent stem cell technology, producing independently beating cardiomyocytes in a laboratory, the beat-rate fluctuations of heart cells can be directly studied. In this thesis, we investigate the complex fluctuations in the field potentials generated by clusters of human cardiomyocytes. We show that the heart cells exhibit similar correlation properties in the beat-to-beat intervals and field potential durations comparable to RR and QT intervals, i.e., time between consecutive R waves and time from Q wave to the end of T wave, respectively, in an electrocardiogram of a heart. The cells are studied under conditions resembling real-life situations such as cardiac disorders, application of cardioactive drugs, and injuries. The results show significant alteration of the scaling properties in the beat rates, reflecting the changes in the intrinsic mechanism at the cellular level. By employing a set of nonlinear time series analysis tools, we explore their powerful applicability as well as their limitations. Our main method of choice throughout the work is detrended fluctuation analysis, which is designed to detect the degree of correlation in nonstationary time series. We demonstrate that detrended fluctuation analysis and its extensions are extremely useful in dealing with the field potential data of the heart cells despite the presence of abnormalities and irregular trends. The study of heartbeat dynamics at the cellular level using computational methods has important advantages. In particular, the methods provide non-invasive and versatile ways to improve our understanding of the intrinsic firing patterns of the heart cells, which play a crucial role in the future applications of in vitro human cardiomyocytes

Distinct Climate Response to Radiative Cooling Over North Asia and North America

Department of Urban and Environmental Engineering (Environmental Science and Engineering)We contrast the patterns of tropical climate response to localized radiative cooling forcing over different two continents in an atmospheric model coupled to a slab ocean and a fully coupled model with an ocean dynamics. Without ocean dynamics, atmospheric heat transport compensates most of the forcing. The slab ocean model produces similar patterns of tropical climate responses that are nearly insensitive of the longitudinal forcing location. Common patterns of interhemispheric temperature contrast accompany a southward shift of the Intertropical Convergence Zone. In contrast, the fully coupled model produces distinct spatial distributions of tropical precipitation responses depending on the forcing location. The change of surface pressure pattern affects the climatological northeasterly wind over the tropical Pacific Ocean. It determines the efficiency of ocean circulation components: Wind-driven shallow overturning circulation or Deep overturning circulation. A strengthening of the Atlantic Meridional Overturning Circulation to an imposed North America cooling effectively brings the heat and explains most of the ocean heat transport response. However, Pacific trade winds tend to be weakened in response to anomalous low-pressure over the Northern Pacific Ocean, hence the influence of Indo-Pacific Ocean heat transport is very small. North Asia cooling produces comparable contribution of ocean heat transport in both the Atlantic and Indo-Pacific Ocean. High-pressure anomaly over the Northern Pacific Ocean induces a strengthening of the equatorial Pacific trade winds, the northward Ekman transport, and the subtropical cell in the Northern Hemisphere. It is a major contributor to the experimental difference of ocean compensation, in turn, it causes different patterns of tropical precipitation response.clos

Ubiquitination Enzymes

Posttranslational protein modifications by mono- or polyubiquitination are involved in diverse cellular signaling pathways and tightly regulated to ensure proper function of cellular processes. Three types of enzymes, namely ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin-protein ligases (E3), contribute to ubiquitination. Combinations of E2 and E3 enzymes determine ∼ the fate of their substrates via ubiquitination. The seven lysine residues of ubiquitin, Lys6, Lys11, Lys27, Lys29, Lys33, Lys48, and Lys63, can serve as attachment sites for other ubiquitin molecules. Lys48 (K48)-linked polyubiquitination facilitates recognition of the conjugated protein by proteasome molecules and subsequent proteolytic degradation of the target protein. By contrast, Lys63 (K63)-linked polyubiquitination appears to be involved in polyubiquitin signaling in critical cellular processes, such as DNA repair, regulation of the I-kappaB kinase/NF-kappaB cascade, or T cell receptor signaling, but not protein degradation. In this review, we describe the properties of ubiquitin modification enzymes and the structural interplay among these proteins

The Effects of Pharmacological Compounds on Beat Rate Variations in Human Long QT-Syndrome Cardiomyocytes

Healthy human heart rate fluctuates overtime showing long-range fractal correlations. In contrast, various cardiac diseases and normal aging show the breakdown of fractal complexity. Recently, it was shown that human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) intrinsically exhibit fractal behavior as in humans. Here, we investigated the fractal complexity of hiPSC-derived long QT-cardiomyocytes (LQT-CMs). We recorded extracellular field potentials from hiPSC-CMs at baseline and under the effect of various compounds including β-blocker bisoprolol, ML277, a specific and potent IKs current activator, as well as JNJ303, a specific IKs blocker. From the peak-to-peak-intervals, we determined the long-range fractal correlations by using detrended fluctuation analysis. Electrophysiologically, the baseline corrected field potential durations (cFPDs) were more prolonged in LQT-CMs than in wildtype (WT)-CMs. Bisoprolol did not have significant effects to the cFPD in any CMs. ML277 shortened cFPD in a dose-dependent fashion by 11 % and 5-11 % in WT- and LQT-CMs, respectively. JNJ303 prolonged cFPD in a dose-dependent fashion by 22 % and 7-13 % in WT- and LQT-CMs, respectively. At baseline, all CMs showed fractal correlations as determined by short-term scaling exponent α. However, in all CMs, the α was increased when pharmacological compounds were applied indicating of breakdown of fractal complexity. These findings suggest that the intrinsic mechanisms contributing to the fractal complexity are not altered in LQT-CMs. The modulation of IKs channel and β1-adrenoreceptors by pharmacological compounds may affect the fractal complexity of the hiPSC-CMs

Association between ambient particulate matter concentration and fetal growth restriction stratified by maternal employment

Background Fetal growth has been known to be associated with particulate matter (PM) air pollution during gestation. Given that regular working may deviate outdoor air pollution exposure, the association between air pollution and fetal growth restriction can be different across maternal working status. This study was to assess possible effect modification by maternal employment in the association between exposure to PM during pregnancy and fetal growth restriction. Methods Using hourly PM less than or equal to 10 and 2.5 μm in diameter (PM10 and PM2.5) regulatory monitoring data for 2001–2012 and 2008–2012, respectively, and birth certificate data for 2002–2012, we computed maternal exposures with district-level averages of PM10 and PM2.5 during one year before birth, entire pregnancy, and the 1st, 2nd and 3rd trimesters. The outcomes of fetal growth restriction were assessed by small for gestational age (SGA, weighted <10th percentile in the same gestational age) as well as low birth weight (LBW, < 2.5 kg) at term. We performed logistic regression to examine the association between PM and each of fetal growth restriction outcomes adjusting for individual risk factors. For effect modification by maternal employment, we estimated adjusted odds ratio (OR) of SGA or LBW for interquartile (IQR) increases in PM10 or PM2.5 stratified by employed and non-employed mothers. We also computed relative excess risk due to interaction (RERI) to investigate additive interaction. Results Among 824,011 singleton term births, 34.0% (279,856) were employed and 66.0% (544,155) were non-employed mothers. Proportions of LBW were 1.5% in employed and 1.6% in non-employed (P < 0.001). SGA occurred in 12.7% of employed and 12.8% of non- employed (P = 0.124) mothers. For non-employed mothers, we observed increased odds of SGA per IQR increase in PM10 for one year before birth (OR = 1.02, 95% confidence intervals (CI): 1.00–1.04, P = 0.028). ORs of SGA for full pregnancy period and the 3rd trimester were also positive but did not reach statistical significance. We did not observe positive association for PM2.5. RERI was not significant both for PM10 and PM2.5. Conclusions We did not observe evidence of effect modification by maternal employment in the association between ambient PM and fetal growth restriction. Future studies using more refined exposure measures should confirm this finding.This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2013R1A6A3A04059017, 2016R1D1A1B03933410, 2018R1A2B6004608 and 2018R1D1A1B07048821) and the National Cancer Center of Korea (NCC-1810220-01). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscrip

Large-scale climate response to regionally confined extratropical cooling: effect of ocean dynamics

This study investigates the effect of ocean dynamics on the tropical climate response to localized radiative cooling over three northern extratropical land regions using hierarchical model simulations that vary in the degree of ocean coupling. Without ocean dynamics, the tropical climate response is independent of the extratropical forcing location, characterized by a southward tropical precipitation shift with a high degree of zonal symmetry, a reduced zonal sea surface temperature gradient along the equatorial Pacific, and the eastward-shifted Walker circulation. When ocean dynamical adjustments are allowed, the zonal-mean tropical precipitation shift is damped primarily via Eulerian-mean ocean heat transport. The oceanic damping effect is strongest (weakest) for North Asian (American) cooling, associated with the largest (smallest) Eulerian-mean ocean heat transport across the equatorial Pacific. The cross-equatorial ocean heat transport in the Pacific is anchored to the North Pacific subtropical high, the response of which can be inferred from the corresponding slab ocean simulations. Hence, the slab ocean simulations provide useful a priori prediction for oceanic damping efficiency. Ocean dynamics also modulates the spatial pattern of climate response in a distinct manner depending on the zonal distribution of imposed forcing. North Asian forcing induces a pronounced eastern equatorial Pacific cooling extending to the western basin, accompanying the westward shifted Walker circulation. European forcing causes cooling confined to the eastern equatorial Pacific and strengthens the Walker circulation. The tropical precipitation response in these two cases exhibits large zonal variations with a high degree of equatorial symmetry, being essentially uncorrelated with the corresponding slab ocean simulations. By contrast, North American forcing induces a sufficiently strong inter-hemispheric contrast in the tropical Pacific SST response, due to the relatively weak oceanic damping effect, producing a weaker but spatially similar tropical response to that in the slab ocean simulation. This study demonstrates that the effect of ocean dynamics in modulating the tropical climate response depends on the extratropical forcing location. The results are relevant for understanding the distinct climate response induced by aerosols from different continental sites

Wolff-Parkinson-White Syndrome in a Patient With Mitochondrial Encephalopathy, Lactic Acidosis and Stroke-Like Episodes Syndrome

Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome is a multisystem disorder, which is clinically characterized by encephalopathy, dementia, seizures and stroke-like episodes. Multiple organs can be affected and cardiac involvement often dominates the clinical picture because of its high energy requirement. We report a case of a 21-year-old woman with MELAS syndrome who had pre-excitation ECG and one episode of tachycardia attack

Transcriptional control of hydrogen peroxide homeostasis regulates ground tissue patterning in the Arabidopsis root

In multicellular organisms, including higher plants, asymmetric cell divisions (ACDs) play a crucial role in generating distinct cell types. The Arabidopsis root ground tissue initially has two layers: endodermis (inside) and cortex (outside). In the mature root, the endodermis undergoes additional ACDs to produce the endodermis itself and the middle cortex (MC), located between the endodermis and the pre-existing cortex. In the Arabidopsis root, gibberellic acid (GA) deficiency and hydrogen peroxide (H2O2) precociously induced more frequent ACDs in the endodermis for MC formation. Thus, these findings suggest that GA and H2O2 play roles in regulating the timing and extent of MC formation. However, details of the molecular interaction between GA signaling and H2O2 homeostasis remain elusive. In this study, we identified the PEROXIDASE 34 (PRX34) gene, which encodes a class III peroxidase, as a molecular link to elucidate the interconnected regulatory network involved in H2O2- and GA-mediated MC formation. Under normal conditions, prx34 showed a reduced frequency of MC formation, whereas the occurrence of MC in prx34 was restored to nearly WT levels in the presence of H2O2. Our results suggest that PRX34 plays a role in H2O2-mediated MC production. Furthermore, we provide evidence that SCARECROW-LIKE 3 (SCL3) regulates H2O2 homeostasis by controlling transcription of PRX34 during root ground tissue maturation. Taken together, our findings provide new insights into how H2O2 homeostasis is achieved by SCL3 to ensure correct radial tissue patterning in the Arabidopsis root