Beyond the Baroreflex: A New Measure of Autonomic Regulation Based on the Time-Frequency Assessment of Variability, Phase Coherence and Couplings

For decades the role of autonomic regulation and the baroreflex in the generation of the respiratory sinus arrhythmia (RSA) - modulation of heart rate by the frequency of breathing - has been under dispute. We hypothesized that by using autonomic blockers we can reveal which oscillations and their interactions are suppressed, elucidating their involvement in RSA as well as in cardiovascular regulation more generally. R-R intervals, end tidal CO2, finger arterial pressure, and muscle sympathetic nerve activity (MSNA) were measured simultaneously in 7 subjects during saline, atropine and propranolol infusion. The measurements were repeated during spontaneous and fixed-frequency breathing, and apnea. The power spectra, phase coherence and couplings were calculated to characterise the variability and interactions within the cardiovascular system. Atropine reduced R-R interval variability (p \u3c 0.05) in all three breathing conditions, reduced MSNA power during apnea and removed much of the significant coherence and couplings. Propranolol had smaller effect on the power of oscillations and did not change the number of significant interactions. Most notably, atropine reduced R-R interval power in the 0.145–0.6 Hz interval during apnea, which supports the hypothesis that the RSA is modulated by a mechanism other than the baroreflex. Atropine also reduced or made negative the phase shift between the systolic and diastolic pressure, indicating the cessation of baroreflex-dependent blood pressure variability. This result suggests that coherent respiratory oscillations in the blood pressure can be used for the non-invasive assessment of autonomic regulation

Cancer Biomarker Discovery: The Entropic Hallmark

Background: It is a commonly accepted belief that cancer cells modify their transcriptional state during the progression of the disease. We propose that the progression of cancer cells towards malignant phenotypes can be efficiently tracked using high-throughput technologies that follow the gradual changes observed in the gene expression profiles by employing Shannon's mathematical theory of communication. Methods based on Information Theory can then quantify the divergence of cancer cells' transcriptional profiles from those of normally appearing cells of the originating tissues. The relevance of the proposed methods can be evaluated using microarray datasets available in the public domain but the method is in principle applicable to other high-throughput methods. Methodology/Principal Findings: Using melanoma and prostate cancer datasets we illustrate how it is possible to employ Shannon Entropy and the Jensen-Shannon divergence to trace the transcriptional changes progression of the disease. We establish how the variations of these two measures correlate with established biomarkers of cancer progression. The Information Theory measures allow us to identify novel biomarkers for both progressive and relatively more sudden transcriptional changes leading to malignant phenotypes. At the same time, the methodology was able to validate a large number of genes and processes that seem to be implicated in the progression of melanoma and prostate cancer. Conclusions/Significance: We thus present a quantitative guiding rule, a new unifying hallmark of cancer: the cancer cell's transcriptome changes lead to measurable observed transitions of Normalized Shannon Entropy values (as measured by high-throughput technologies). At the same time, tumor cells increment their divergence from the normal tissue profile increasing their disorder via creation of states that we might not directly measure. This unifying hallmark allows, via the the Jensen-Shannon divergence, to identify the arrow of time of the processes from the gene expression profiles, and helps to map the phenotypical and molecular hallmarks of specific cancer subtypes. The deep mathematical basis of the approach allows us to suggest that this principle is, hopefully, of general applicability for other diseases

Introduction to chronotaxic systems – systems far from thermodynamics equilibrium that adjust their clocks

The complex, fluctuating dynamics that abounds in nature is now easily monitored and analysed, applying either stochastic or deterministic methods. It has been demonstrated that complex systems far from thermodynamic equilibrium, especially living systems, often exhibit time-varying dynamics. To date they have been usually treated as stochastic. Here we focus on the non-autonomous properties of complex systems and propose a new class of dynamical systems. Namely, we assume that a basic dynamical unit which inherently possesses an internal source of energy, is continuously perturbed by the environment and maintains its stability by adjusting the rate of exchange of energy and matter with the environment. We provide a mathematical formalism for such systems, combining the recent theory of pullback attractors with the theory of self-sustained oscillators. We name the new class of systems as chronotaxic and, based on measured data, show that the heart possesses properties characteristic of chronotaxic systems. This means that its dynamics is largely deterministic, which opens new possibilities for diagnosis and prediction. We expect that many complex systems will be identified as chronotaxic and that their models will become much simpler and more realistic

Chronotaxic systems with separable amplitude and phase dynamics

Until recently, deterministic non-autonomous oscillatory systems with stable amplitudes and time-varying frequencies were not recognised as such and have often been mistreated as stochastic. These systems, named chronotaxic, were introduced in \emph{Phys. Rev. Lett.} \textbf{111}, 024101 (2013). In contrast to conventional limit cycle models of self-sustained oscillators, these systems posses a time-dependent point attractor or steady state. This allows oscillations with time-varying frequencies to resist perturbations, a phenomenon which is ubiquitous in living systems. In this work a detailed theory of chronotaxic systems is presented, specifically in the case of separable amplitude and phase dynamics. The theory is extended by the introduction of chronotaxic amplitude dynamics. The wide applicability of chronotaxic systems to a range of fields from biological and condensed matter systems to robotics and control theory is discussed

Beyond the Baroreflex: A New Measure of Autonomic Regulation Based on the Time-Frequency Assessment of Variability, Phase Coherence and Couplings

For decades the role of autonomic regulation and the baroreflex in the generation of the respiratory sinus arrhythmia (RSA) - modulation of heart rate by the frequency of breathing - has been under dispute. We hypothesized that by using autonomic blockers we can reveal which oscillations and their interactions are suppressed, elucidating their involvement in RSA as well as in cardiovascular regulation more generally. R-R intervals, end tidal CO2, finger arterial pressure, and muscle sympathetic nerve activity (MSNA) were measured simultaneously in 7 subjects during saline, atropine and propranolol infusion. The measurements were repeated during spontaneous and fixed-frequency breathing, and apnea. The power spectra, phase coherence and couplings were calculated to characterise the variability and interactions within the cardiovascular system. Atropine reduced R-R interval variability (p &amp;lt; 0.05) in all three breathing conditions, reduced MSNA power during apnea and removed much of the significant coherence and couplings. Propranolol had smaller effect on the power of oscillations and did not change the number of significant interactions. Most notably, atropine reduced R-R interval power in the 0.145–0.6 Hz interval during apnea, which supports the hypothesis that the RSA is modulated by a mechanism other than the baroreflex. Atropine also reduced or made negative the phase shift between the systolic and diastolic pressure, indicating the cessation of baroreflex-dependent blood pressure variability. This result suggests that coherent respiratory oscillations in the blood pressure can be used for the non-invasive assessment of autonomic regulation.</jats:p

The inverse approach to chronotaxic systems for single-variable time series

Following the development of a new class of self-sustained oscillators with a time-varying but stable frequency, the inverse approach to these systems is now formulated. We show how observed data arranged in a single-variable time series can be used to recognise such systems. This approach makes use of time-frequency domain information using the wavelet transform as well as the recently-developed method of Bayesian-based inference. In addition, a new set of methods, named phase fluctuation analysis, is introduced to detect the defining properties of the new class of systems by directly analysing the statistics of the observed perturbations. We apply these methods to numerical examples but also elaborate further on the cardiac system

Assembly of 43 human Y chromosomes reveals extensive complexity and variation

The uploaded file contains Supplementary Tables S1-S61 for the manuscript "Assembly of 43 human Y chromosomes reveals extensive complexity and variation

Assembly of 43 human Y chromosomes reveals extensive complexity and variation

The uploaded file contains Supplementary Tables S1-S61 for the manuscript "Assembly of 43 human Y chromosomes reveals extensive complexity and variation