Understanding how nanoparticles with different shapes interact with cell membranes is important in drug and gene delivery, but this interaction remains poorly studied. Using computer simulations, we investigate the physical translocation processes of nanoparticles with different shapes (for example, spheres, ellipsoids, rods, discs and pushpin-like particles) and volumes across a lipid bilayer. We find that the shape anisotropy and initial orientation of the particle are crucial to the nature of the interaction between the particle and lipid bilayer. The penetrating capability of a nanoparticle across a lipid bilayer is determined by the contact area between the particle and lipid bilayer, and the local curvature of the particle at the contact point. Particle volume affects translocation indirectly, and particle rotation can complicate the penetration process. Our results provide a practical guide to geometry considerations when designing nanoscale cargo carriers.

SUMMARY The altered metabolism of tumor cells confers a selective advantage for survival and proliferation, and studies have shown that targeting such metabolic shifts may be a useful therapeutic strategy. We developed an intensely fluorescent, rapidly responsive, pH-resistant, genetically encoded sensor of wide dynamic range, denoted SoNar, for tracking cytosolic NAD+ and NADH redox states in living cells and in vivo. SoNar responds to subtle perturbations of various pathways of energy metabolism in real-time, and allowed high-throughput screening for new agents targeting tumor metabolism. Among > 5,500 unique compounds, we identified KP372-1 as a potent NQO1-mediated redox cycling agent that produced extreme oxidative stress, selectively induced cancer cell apoptosis and effectively decreased tumor growth in vivo. This study demonstrates that genetically encoded sensor-based metabolic screening could serve as a valuable approach for drug discovery.

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The nucleolus is a prominent subnuclear compartment, where ribosome biosynthesis takes place. Recently, the nucleolus has gained attention for its novel role in the regulation of cellular stress. Nucleolar stress is emerging as a new concept, which is characterized by diverse cellular insultinduced abnormalities in nucleolar structure and function, ultimately leading to activation of p53 or other stress signaling pathways and alterations in cell behavior. Despite a number of comprehensive reviews on this concept, straightforward and clear-cut way criteria for a nucleolar stress state, regarding the factors that elicit this state, the morphological and functional alterations as well as the rationale for p53 activation are still missing. Based on literature of the past two decades, we herein summarize the evolution of the concept and provide hallmarks of nucleolar stress. Along with updated information and thorough discussion of existing confusions in the field, we pay particular attention to the current understanding of the sensing mechanisms, i.e., how stress is integrated by p53. In addition, we propose our own emphasis regarding the role of nucleolar protein NPM1 in the hallmarks of nucleolar stress and sensing mechanisms. Finally, the links of nucleolar stress to human diseases are briefly and selectively introduced.