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A better understanding of the inner structural features (watermarks and chain line/wire intervals) of the manuscript papers of Leonardo da Vinci (1452-1519) can provide valuable information regarding chronology, geographic origins, and studio practice. For valid conclusions, however, clear representations of watermarks and chain line/wires are required. While the easient way to capture these unique physical characteristics of paper is via transmitted light, they can be difficult to decipher when writing and other surface marks found on the recto (front/obverse) and the verso (back/reverse) of the sheet obscure them. Using Leonardo's Codex Leicester (Bill Gates Collection), complied circa 1508-1510, as a case study, a computational approach was designed to minimize surface writing to enhance the watermarks and chain lines/wires detectable in the paper, by subtracting out diffuse specular (normal) light images of the recto and verso sides from the transmitted light image. This is accomplished by posing the problem as a mathematical optimization problem, and solving for the optimal weights is fast and robust. 

Human pluripotent stem cell (hPSC)-derived neural organoids display unprecedented emergent properties. Yet in contrast to the singular neuroepithelial tube from which the entire central nervous system (CNS) develops in vivo, current organoid protocols yield tissues with multiple neuroepithelial units, a.k.a. neural rosettes, each acting as independent morphogenesis centers and thereby confounding coordinated, reproducible tissue development. Here, we discover that controlling initial tissue morphology can effectively (>80%) induce single neural rosette emergence within hPSC-derived forebrain and spinal tissues. Notably, the optimal tissue morphology for observing singular rosette emergence was distinct for forebrain versus spinal tissues due to previously unknown differences in ROCK-mediated cell contractility. Following release of geometric confinement, the tissues displayed radial outgrowth with maintenance of a singular neuroepithelium and peripheral neuronal differentiation. Thus, we have identified neural tissue morphology as a critical biophysical parameter for controlling in vitro neural tissue morphogenesis furthering advancement towards biomanufacture of CNS tissues with biomimetic anatomy and physiology.