David Yue (1957-2014).

Abstract

Dr David Yue died suddenly and tragically in his laboratory on 23 December 2014. We write as his friends and colleagues to express our deepest sympathy to his family, while acknowledging his stellar accomplishments as a scientist, teacher, mentor and programme leader. Dr Yue studied for his undergraduate degree in Biochemistry at Harvard College and then earned an MD and PhD from Johns Hopkins University. As a Faculty member in Bioengineering and Neurosciences at Johns Hopkins University, Dr Yue earned an international reputation as one of the world's most innovative and accomplished cellular and molecular physiologists/biophysicists/bioengineers. The consistent and very important goal of his work was to obtain an understanding of the molecular details of key aspects of Ca2+ fluxes and [Ca2+]i homeostasis in mammalian cells, and thus discover fundamental physiological mechanisms. Some of his early work was done on cardiac muscle, using a combination of experimental protocols and bioengineering approaches to measure [Ca2+]i and force production. This work resulted in an improved and novel understanding of the relationship between [Ca2+]i and active force generation that governs the mechanical properties of the mammalian ventricle. Later, Dr Yue's major scientific focus was on the molecular physiology, biophysics and pharmacology of selected Ca2+ channels, with an emphasis on molecular mechanisms and their modulation by calmodulin. An excellent series of papers over a 15 year period collectively stand out as being one of the most innovative, creative and rigorous bodies of work done by any cell physiology laboratory worldwide. This was recognized when Dr. Yue received the prestigious Kenneth Cole Award from the Biophysical Society in 2011. The Yue laboratory was the first to draw attention to the fact that the C-terminal segment of the L-type Ca2+ channel can itself significantly modulate Ca2+ channel function. In addition, a clever and complex combination and application of electrophysiological principles, optical techniques and applied mathematics allowed the Yue group significantly to advance the understanding of the functional role of calmodulin in mammalian cells. In these studies, Dr Yue and his trainees identified and then demonstrated key aspects of Ca2+ signalling in mechanistic detail. They found that there are two very different functional roles for two molecular domains on the calmodulin molecule. One module senses Ca2+ and regulates downstream signalling using a signal transmission mode that, by analogy to a stereo system, would be considered frequency modulated. In contrast, a second lobe of the same molecule operates mainly as an amplitude sensor. In combination, these two calmodulin-based signals explain essential aspects of short-term and long-term regulation by Ca2+ of fundamental neurophysiological processes, such as long-term potentiation and depression, and transcriptional regulation. In addition to these remarkable, in fact unique, scientific contributions, Dr David Yue was well known and much respected as a mentor of graduate students and postdoctoral fellows and as a commi-tted and exceptionally effective teacher. Both his students and his Faculty colleagues rank his commitment to and effectiveness in teaching, mentoring and programme development as being equal to his very impressive scientific record. Many of the papers in this supplemental issue of The Journal of Physiology are based on or relate importantly to fundamental mechanisms for regulation of intracellular Na+ and Ca2+ in the mammalian heart. These physiological principles and resulting pathophysiological sequelae, e.g. ventricular arrhythmias, relate closely to some of the most recent work from the Yue laboratory (Ben-Johny et al. 2014; Ben-Johny & Yue, 2014). Indeed, David Yue and his colleagues were very well positioned to make further significant advances concerning Ca2+- and calmodulin-mediated mechanisms of cardiac arrhythmias (Limpitikul et al. 2014; Park et al. 2014). David Yue was an exceptional scientist and academic leader. The untimely interruption of his extremely productive and impactful career leaves a very significant void in fields such as cellular and molecular physiology. We recognize, however, that the most tragic aspect of the passing of David Yue is the loss of this committed father, husband and mentor.