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The largest impact on mainstream improvement of results was probably due to making ML (Maximum likelihood)-based 2D and 3D classification including Bayesian statistics practically feasible by clever implementation on today's computer hardware. While earlier work was indispensable to point the way, only later algorithms were optimized enough for practical use (Frealign, Relion, EMAN2, Frealing/cisTEM, Spire, and cryoSPARC).
(Murata., 2018) Cryo-electron microscopy for structural analysis of dynamic biological macromolecules. Biochemica et Biophysica Acta (BBA).