The ubiquitin system is complex, multifaceted, and is crucial for the modulation of a vast number of cellular processes. Ubiquitination is tightly regulated at different levels by a range of enzymes including E1s, E2s, and E3s, and an array of DUBs. The UPS directs protein degradation through the proteasome, and regulates a wide array of cellular processes including transcription and epigenetic factors as well as key oncoproteins. Ubiquitination is key to the dynamic regulation of programmed cell death. Notably, the TNF signaling pathway is controlled by competing ubiquitin conjugation and deubiquitination, which governs both proteasomal degradation and signaling complex formation. In the inflammatory response, ubiquitination is capable of both activating and dampening inflammasome activation through the control of either protein stability, complex formation, or, in some cases, directly affecting receptor activity. In this review, we discuss the enzymes and targets in the ubiquitin system that regulate fundamental cellular processes regulating cell death, and inflammation, as well as disease consequences resulting from their dysregulation. Finally, we highlight several pre-clinical and clinical compounds that regulate ubiquitin system enzymes, with the aim of restoring homeostasis and ameliorating diseases.

The electrical double layer (EDL) at the amorphous silica−aqueous electrolyte interface is of longstanding scientific interest and current technological relevance. Using extensive molecular dynamics simulations, we have studied this EDL as a function of salt concentration for a silica surface charge density of −0.82e/nm 2 (e = electron charge). The simulation results can be captured with a simple model by breaking the double-layer region into three zones: an inner region in which the Na + counterion population is independent of [NaCl] and there are no Cl − co-ions, an intermediate region which hosts a population of nonexchangeable Na + plus another group of Na + and Cl − ions whose population is described by a Langmuir adsorption model, and an outer region where the ion distribution is well-described using the Poisson−Boltzmann theory. When the asymptotic [NaCl] >0.17 M, the adsorption of Na + in the intermediate zone leads to an overcompensation of the negatively charged silica surface. Nonlinear spectroscopic experiments on the water−amorphous silica interface have been interpreted by others using the Gouy−Chapman model at low salt concentration and the constant capacitance model at high salt concentration. We discuss the applicability of these and other models and the implications for interpretation of the results of second harmonic and sum frequency generation experiments.

Four new alpha-methylene-gamma-lactone-bearing cembranoids, 20-acetylsinularolide B (6), presinularolide B (7), 3-dehydroxylpresinularolide B (8), and 3-dehydroxyl-20-acetylpresinularolide B (9), together with five known analogues, sinularolides B-E (1- 4) and 20-acetylsinularolide C (5), were isolated from a South China Sea soft coral Lobophytum crassum. Their structures and relative stereochemistry were established by a combination of detailed spectroscopic data analysis and chemical correlations. The structures of 1- 9 were further confirmed by an X-ray diffraction study on a single crystal of sinularolide B (1). The absolute configurations of sinularolide B (1) and presinularolide B (7) were determined by a novel solid-state CD/TDDFT approach and by a modified Mosher's method, respectively. This study also revealed that the coupling constant between the lactonic methine protons ((3) J 1,2) varies considerably with different functional groups on the cembrane ring and that the determination of the stereochemistry of lactone ring fusion based on this coupling constant is risky. In a bioassay, sinularolides B and C (1 and 2) and new cembranoids 7 and 8 showed in vitro cytotoxicity against the tumor cell lines A-549 and P-388.