Structural and functional evidence for membrane docking and disruption sites on phospholipase A2-like proteins revealed by complexation with the inhibitor suramin

Local myonecrosis resulting from snakebite envenomation is not efficiently neutralized by regular antivenom administration. This limitation is considered to be a significant health problem by the World Health Organization. Phospholipase A2-like (PLA2-like) proteins are among the most important proteins related to the muscle damage resulting from several snake venoms. However, despite their conserved tertiary structure compared with PLA2s, their biological mechanism remains incompletely understood. Different oligomeric conformations and binding sites have been identified or proposed, leading to contradictory data in the literature. In the last few years, a comprehensive hypothesis has been proposed based on fatty-acid binding, allosteric changes and the presence of two different interaction sites. In the present study, a combination of techniques were used to fully understand the structural-functional characteristics of the interaction between suramin and MjTX-II (a PLA2-like toxin). In vitro neuromuscular studies were performed to characterize the biological effects of the protein-ligand interaction and demonstrated that suramin neutralizes the myotoxic activity of MjTX-II. The high-resolution structure of the complex identified the toxin-ligand interaction sites. Calorimetric assays showed two different binding events between the protein and the inhibitor. It is demonstrated for the first time that the inhibitor binds to the surface of the toxin, obstructing the sites involved in membrane docking and disruption according to the proposed myotoxic mechanism. Furthermore, higher-order oligomeric formation by interaction with interfacial suramins was observed, which may also aid the inhibitory process. These results further substantiate the current myotoxic mechanism and shed light on the search for efficient inhibitors of the local myonecrosis phenomenon.Peer Reviewe

Electrical control of glass-like dynamics in vanadium dioxide for data storage and processing

Metal–oxide–semiconductor junctions are the building blocks of modern electronics and can provide a variety of functionalities, from memory to computing. The technology, however, faces constraints in terms of further miniaturization and compatibility with post–von Neumann computing architectures. Manipulation of structural—rather than electronic—states could provide a path to ultrascaled low-power functional devices, but the electrical control of such states is challenging. Here we report electronically accessible long-lived structural states in vanadium dioxide that can provide a scheme for data storage and processing. The states can be arbitrarily manipulated on short timescales and tracked beyond 10,000 s after excitation, exhibiting features similar to glasses. In two-terminal devices with channel lengths down to 50 nm, sub-nanosecond electrical excitation can occur with an energy consumption as small as 100 fJ. These glass-like functional devices could outperform conventional metal–oxide–semiconductor electronics in terms of speed, energy consumption and miniaturization, as well as provide a route to neuromorphic computation and multilevel memories

Do cancer cells undergo phenotypic switching? The case for imperfect cancer stem cell markers

The identification of cancer stem cells in vivo and in vitro relies on specific surface markers that should allow to sort cancer cells in phenotypically distinct subpopulations. Experiments report that sorted cancer cell populations after some time tend to express again all the original markers, leading to the hypothesis of phenotypic switching, according to which cancer cells can transform stochastically into cancer stem cells. Here we explore an alternative explanation based on the hypothesis that markers are not perfect and are thus unable to identify all cancer stem cells. Our analysis is based on a mathematical model for cancer cell proliferation that takes into account phenotypic switching, imperfect markers and error in the sorting process. Our conclusion is that the observation of reversible expression of surface markers after sorting does not provide sufficient evidence in support of phenotypic switching

Room-Temperature Ballistic Transport in III-Nitride Heterostructures

Room-temperature (RT) ballistic transport of electrons is experimentally observed and theoretically investigated in III-nitrides. This has been largely investigated at low temperatures in low band gap III–V materials due to their high electron mobilities. However, their application to RT ballistic devices is limited by their low optical phonon energies, close to KT at 300 K. In addition, the short electron mean-free-path at RT requires nanoscale devices for which surface effects are a limitation in these materials. We explore the unique properties of wide band-gap III-nitride semiconductors to demonstrate RT ballistic devices. A theoretical model is proposed to corroborate experimentally their optical phonon energy of 92 meV, which is ∼4× larger than in other III–V semiconductors. This allows RT ballistic devices operating at larger voltages and currents. An additional model is described to determine experimentally a characteristic dimension for ballistic transport of 188 nm. Another remarkable property is their short carrier depletion at device sidewalls, down to 13 nm, which allows top-down nanofabrication of very narrow ballistic devices. These results open a wealth of new systems and basic transport studies possible at RT.United States. Defense Advanced Research Projects Agency. Nitride Electronic NeXt-Generation Technology (NEXT) ProgramUnited States. Office of Naval Research. Young Investigator Progra

Senescent Cells in Growing Tumors: Population Dynamics and Cancer Stem Cells

Tumors are defined by their intense proliferation, but sometimes cancer cells turn senescent and stop replicating. In the stochastic cancer model in which all cells are tumorigenic, senescence is seen as the result of random mutations, suggesting that it could represent a barrier to tumor growth. In the hierarchical cancer model a subset of the cells, the cancer stem cells, divide indefinitely while other cells eventually turn senescent. Here we formulate cancer growth in mathematical terms and obtain predictions for the evolution of senescence. We perform experiments in human melanoma cells which are compatible with the hierarchical model and show that senescence is a reversible process controlled by survivin. We conclude that enhancing senescence is unlikely to provide a useful therapeutic strategy to fight cancer, unless the cancer stem cells are specifically targeted