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The microscope’s 3-dimensional blurring function, finite optical resolution due to light diffraction, finite pixel resolution, and complex\nmorphological manifestations of the structures, all contribute to GT-hardness. Unsupervised segmentation approaches are quite inaccurate. Manual segmentation relying of heuristics and experience therefore remains the preferred approach. Nonetheless, this process is tedious, with 100s of structures present inside a single cell. Thus, generating analytic across large population of cells or performing advanced artificial intelligence (AI) tasks such as tracking is greatly limited. We bring modeling and deep learning to a nexus for solving this GT-hard problem, improving both the accuracy and speed of sub-cellular segmentation. We introduce the approach of simulation-supervision empowered with physics-based GT. 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