A unified theory of calcium alternans in ventricular myocytes.

Intracellular calcium (Ca2+) alternans is a dynamical phenomenon in ventricular myocytes, which is linked to the genesis of lethal arrhythmias. Iterated map models of intracellular Ca2+ cycling dynamics in ventricular myocytes under periodic pacing have been developed to study the mechanisms of Ca2+ alternans. Two mechanisms of Ca2+ alternans have been demonstrated in these models: one relies mainly on fractional sarcoplasmic reticulum Ca2+ release and uptake, and the other on refractoriness and other properties of Ca2+ sparks. Each of the two mechanisms can partially explain the experimental observations, but both have their inconsistencies with the experimental results. Here we developed an iterated map model that is composed of two coupled iterated maps, which unifies the two mechanisms into a single cohesive mathematical framework. The unified theory can consistently explain the seemingly contradictory experimental observations and shows that the two mechanisms work synergistically to promote Ca2+ alternans. Predictions of the theory were examined in a physiologically-detailed spatial Ca2+ cycling model of ventricular myocytes

R-from-T as a common mechanism of arrhythmia initiation in long QT syndromes

Background: Long QT syndromes (LQTS) arise from many genetic and nongenetic causes with certain characteristic ECG features preceding polymorphic ventricular tachyarrhythmias (PVTs). However, how the many molecular causes result in these characteristic ECG patterns and how these patterns are mechanistically linked to the spontaneous initiation of PVT remain poorly understood. Methods: Anatomic human ventricle and simplified tissue models were used to investigate the mechanisms of spontaneous initiation of PVT in LQTS. Results: Spontaneous initiation of PVT was elicited by gradually ramping up I-Ca,I-L to simulate the initial phase of a sympathetic surge or by changing the heart rate, reproducing the different genotype-dependent clinical ECG features. In LQTS type 2 (LQT2) and LQTS type 3 (LQT3), T-wave alternans was observed followed by premature ventricular complexes (PVCs). Compensatory pauses occurred resulting in short-long-short sequences. As I-Ca,I-L increased further, PVT episodes occurred, always preceded by a short-long-short sequence. However, in LQTS type 1 (LQT1), once a PVC occurred, it always immediately led to an episode of PVT. Arrhythmias in LQT2 and LQT3 were bradycardia dependent, whereas those in LQT1 were not. In all 3 genotypes, PVCs always originated spontaneously from the steep repolarization gradient region and manifested on ECG as R-on-T. We call this mechanism R-from-T, to distinguish it from the classic explanation of R-on-T arrhythmogenesis in which an exogenous PVC coincidentally encounters a repolarizing region. In R-from-T, the PVC and the T wave are causally related, where steep repolarization gradients combined with enhanced I-Ca,I-L lead to PVCs emerging from the T wave. Since enhanced I-Ca,I-L was required for R-from-T to occur, suppressing window I-Ca,I-L effectively prevented arrhythmias in all 3 genotypes. Conclusions: Despite the complex molecular causes, these results suggest that R-from-T is likely a common mechanism for PVT initiation in LQTS. Targeting I-Ca,I-L properties, such as suppressing window I-Ca,I-L or preventing excessive I-Ca,I-L increase, could be an effective unified therapy for arrhythmia prevention in LQTS

The alchemy of ideas

This article presents an assessment of the power of ideas and their role in initiating change and progress. The enormous potential cascade effect is illustrated by examining the movement of Modernism in the arts. Next, the immense scope and capabilities of the modern scientific endeavor—with robotic space exploration at the scale of 10⁹ meters at one extreme and the wonders of nanoscience at the scale of 10⁻⁹ m at the other—are examined. The attitudes and philosophies of neurological surgery are related to those involved in the Modernist movement and placed on the defined scale of contemporary scientific activity

Stability of grid amplifiers

We present a stability model for quasi-optical grid amplifiers. This model is useful for predicting and suppressing the common-mode oscillations that often occur in amplifier grids. Three stabilization techniques will be discussed. The first technique uses a capacitor to stabilize the grid. The second approach employs resistance to suppress the oscillations. The final technique stabilizes the grid by reducing the on-chip common-mode resistance, allowing greatly increased amplifier efficiencies. Experimental evidence will be presented to confirm the validity of our stability model

A 100-Element MODFET Grid Amplifier

A 100-element quasi-optical amplifier is presented. The active devices are custom-fabricated modulation-doped field-effect transistors (MODFETs). Common-mode oscillations were suppressed using resistors in the input gate leads. The grid has 9 dB of gain at 10.1 GHz. The 3-dB bandwidth is 1.2 GHz. We present a model for the gain of the grid versus frequency and compare measurement with theory

Silicon Waveguides and Ring Resonators at 5.5 {\mu}m

We demonstrate low loss ridge waveguides and the first ring resonators for the mid-infrared, for wavelengths ranging from 5.4 to 5.6 {\mu}m. Structures were fabricated using electron-beam lithography on the silicon-on-sapphire material system. Waveguide losses of 4.0 +/- 0.7 dB/cm are achieved, as well as Q-values of 3.0 k.Comment: 4 pages, 4 figures, includes supplemental material

Global Analysis of Nucleon Strange Form Factors at Low Q2Q^2

We perform a global analysis of all recent experimental data from elastic parity-violating electron scattering at low $Q^2$. The values of the electric and magnetic strange form factors of the nucleon are determined at $Q^2 = 0.1$ GeV/$c^2$ to be $G^s_E = -0.008 \pm 0.016$ and $G^s_M = 0.29 \pm 0.21$.Comment: 8 pages, 1 figur

Gain and Stability Models for HBT Grid Amplifiers

A 16-element heterojunction bipolar transistor (HBT) grid amplifier has been fabricated with a peak gain of 11 dB at 9.9 GHz with a 3-dB bandwidth of 350 MHz. We report a gain analysis model for the grid and give a comparison of the measurement and theory. The measured patterns show the evidence of a common-mode oscillation. A stability model for the common-mode oscillation is developed. Based on the stability model, a lumped capacitor gives suitable phase shift of the circular function, thus stabilizing the grid. A second 18-element grid was fabricated, using this theory, with improved stability