Understanding cells as integrated systems is central to modern biology. Although fluorescence microscopy can resolve subcellular structure in living cells, it is expensive, is slow, and can damage cells. We present a label-free method for predicting three-dimensional fluorescence directly from transmitted-light images and demonstrate that it can be used to generate multi-structure, integrated images. The method can also predict immunofluorescence (IF) from electron micrograph (EM) inputs, extending the potential applications.

One contribution of 11 to a Theme Issue 'Towards the virtual physiological human: mathematical and computational case studies'. Ongoing developments in cardiac modelling have resulted, in particular, in the development of advanced and increasingly complex computational frameworks for simulating cardiac tissue electrophysiology. The goal of these simulations is often to represent the detailed physiology and pathologies of the heart using codes that exploit the computational potential of high-performance computing architectures. These developments have rapidly progressed the simulation capacity of cardiac virtual physiological human style models; however, they have also made it increasingly challenging to verify that a given code provides a faithful representation of the purported governing equations and corresponding solution techniques. This study provides the first cardiac tissue electrophysiology simulation benchmark to allow these codes to be verified. The benchmark was successfully evaluated on 11 simulation platforms to generate a consensus gold-standard converged solution. The benchmark definition in combination with the gold-standard solution can now be used to verify new simulation codes and numerical methods in the future.

Maleckar MM, Greenstein JL, Giles WR, Trayanova NA. K ϩ current changes account for the rate dependence of the action potential in the human atrial myocyte. Am J Physiol Heart Circ Physiol 297: H1398 -H1410, 2009. First published July 24, 2009 doi:10.1152/ajpheart.00411.2009.-Ongoing investigation of the electrophysiology and pathophysiology of the human atria requires an accurate representation of the membrane dynamics of the human atrial myocyte. However, existing models of the human atrial myocyte action potential do not accurately reproduce experimental observations with respect to the kinetics of key repolarizing currents or rate dependence of the action potential and fail to properly enforce charge conservation, an essential characteristic in any model of the cardiac membrane. In addition, recent advances in experimental methods have resulted in new data regarding the kinetics of repolarizing currents in the human atria. The goal of this study was to develop a new model of the human atrial action potential, based on the Nygren et al. model of the human atrial myocyte and newly available experimental data, that ensures an accurate representation of repolarization processes and reproduction of action potential rate dependence and enforces charge conservation. Specifically, the transient outward K ϩ current (It) and ultrarapid rectifier K ϩ current (IKur) were newly formulated. The inwardly recitifying K ϩ current (IK1) was also reanalyzed and implemented appropriately. Simulations of the human atrial myocyte action potential with this new model demonstrated that early repolarization is dependent on the relative conductances of I t and IKur, whereas densities of both I Kur and IK1 underlie later repolarization. In addition, this model reproduces experimental measurements of rate dependence of I t, IKur, and action potential duration. This new model constitutes an improved representation of excitability and repolarization reserve in the human atrial myocyte and, therefore, provides a useful computational tool for future studies involving the human atrium in both health and disease. ionic model; repolarization; potassium current ACCURATE REPRESENTATION of the ionic currents of the human atrial myocyte is essential for the ongoing investigation of human atrial electrophysiology and pathophysiology. It is now well established that the elucidation of mechanisms underlying the complex phenomena that occur in highly integrative systems, such as atrial tissue, requires that experimental data be incorporated such that models are both accurate and biophysically based.Within the past decade, advances in experimental methods have resulted in a much-improved characterization of repolarizing currents in the human atria (21, 50, 59 -61). New insights into the underlying channel isoforms responsible for these K ϩ currents are also now available (32,41,53,54,56). However, findings regarding essential repolarization processes in the human atria have been incorporated into none of the available mathematical models of the actio...

Atrial fibrosis has been implicated in the development and maintenance of atrial arrhythmias, and is characterized by expansion of the extracellular matrix and an increased number of fibroblasts (Fbs). Electrotonic coupling between atrial myocytes and Fbs may contribute to the formation of an arrhythmogenic substrate. However, the role of these cell-cell interactions in the function of both normal and diseased atria remains poorly understood. The goal of this study was to gain mechanistic insight into the role of electrotonic Fb-myocyte coupling on myocyte excitability and repolarization. To represent the system, a human atrial myocyte (hAM) coupled to a variable number of Fbs, we employed a new ionic model of the hAM, and a variety of membrane representations for atrial Fbs. Simulations elucidated the effects of altering the intercellular coupling conductance, electrophysiological Fb properties, and stimulation rate on the myocyte action potential. The results demonstrate that the myocyte resting potential and action potential waveform are modulated strongly by the properties and number of coupled Fbs, the degree of coupling, and the pacing frequency. Our model provides mechanistic insight into the consequences of heterologous cell coupling on hAM electrophysiology, and can be extended to evaluate these implications at both tissue and organ levels.