Biophysical Society Bulletin | November 2025

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Know the Editor Brian Salzberg

Editor’s Pick

University of Pennsylvania Editor, Channels, Transporters, and Receptors Biophysical Journal

Brian Salzberg

What has been your most exciting discovery as a biophysicist?

Certainly, my most exciting discovery as a biophysicist was the finding of voltage-sensitive dyes, notably Merocyanine 540, with Larry Cohen and Vicencio Davila in 1972. I still remember the thrill that I experienced when, in the process of assaying fluorescent molecules for voltage sensitivity by applying depolarizing and hyperpolarizing steps to a volt age-clamped squid giant axon and measuring the attendant fluorescence changes, we needed to reduce the oscilloscope gain three clicks to accommodate the fluorescence signal on the oscilloscope screen. This was followed, many years later, by finding, in the course of looking for molecular indicators of membrane potential, that rapid changes in light scatter ing arising from mammalian nerve terminals in response to the action potential revealed angstrom-scale changes in the terminal diameter. At a cocktail party of non-scientists, how would you explain what you do? Very many, if not most, cellular processes depend upon changes in either the voltage across the membrane or rapid changes in intracellular calcium. We discovered how to mon itor these events by optical means, introducing molecular in dicators of both voltage (potentiometric dyes with Cohen and Davila) and changes in intracellular calcium (first the calcium indicator Arsenazo, with Joel Brown , Paul Deweer , Cohen, and others). Optical techniques tend to be noninvasive, and I have worked to improve these, particularly the use of voltage-sen sitive dyes and light scattering.

Biophysical Journal Bayesian analysis and efficient algorithms for single-molecule fluorescence data and step counting Chiara Mattamira, Alyssa Ward, Sriram Tiruvadi Krishnan, Rajan Lamichhane, Francisco N. Barrera, and Ioannis Sgouralis “Who amongst us has not felt a secret shame when Yale Gold man passes by in his Miata convertible with that ‘No Ensem ble Averaging’ sign emblazoned on the door (photo available upon request)? We all use ensemble averaging when single molecule techniques might give us more information, but frankly the latter are a nuisance. How do you sift through noise to find those step-like intensity changes from photo bleaching of individual molecules? The beauty of ensemble techniques like FPR/FRAP and FCS is that they pull signal out of the noise without pulling hair out of the head. A new paper in Biophysical Journal simplifies all this by pulling signal out of noise through a Bayesian nonparametric framework, with no a priori assumptions about molecular dynamics (unlike Hidden Markov Models) and no subjective bias from manual analysis. Markov Chain Monte Carlo sampling enables robust counting of photobleaching steps in noisy data, even in high-through put, low signal-to-noise data applications. The paper has a beautiful demonstration of the technology on clustering of a receptor tyrosine kinase protein and clear instructions on how to make this work with a signal-to-noise ratio near 1. Give this a try and hold your head high when that feared Miata next drives into your lab!”

Version of Record Published August 20, 2025 DOI: https:/doi.org/10.1016/j.bpj.2025.08.014

November 2025

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