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Increasing antibiotic resistance in Gram-negative bacteria, particularly in Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae, presents a global medical challenge. No new antibiotics will be available for these ‘superbugs’ in the near future due to the dry antibiotic discovery pipeline. Colistin and polymyxin B are increasingly used as the last-line therapeutic options for treatment of infections caused by multidrug-resistant Gram-negative bacteria. This article surveys the significant progress over the last decade in understanding polymyxin chemistry, mechanisms of antibacterial activity and resistance, structure–activity relationships and pharmacokinetics/pharmacodynamics. In the ‘Bad Bugs, No Drugs’ era, we must pursue structure–activity relationship-based approaches to develop novel polymyxin-like lipopeptides targeting polymyxin-resistant Gram-negative ‘superbugs’. Before new antibiotics become available, we must optimize the clinical use of polymyxins through the application of pharmacokinetic/pharmacodynamic principles, thereby minimizing the development of resistance.

The electron's spin angular momentum is one of several alternative state variables under consideration on the International Technology Roadmap for Semiconductors (ITRS) for processing information in the fundamentally new ways that will be required beyond the ultimate scaling limits of silicon-based complementary metal-oxide-semiconductor technology 1 . Electrical injection/transport of spin-polarized carriers is prerequisite for developing such an approach 2,3 . Although significant progress has been realized in GaAs (ref. 4), little progress has been made in Si, despite its overwhelming dominance of the semiconductor industry. Here, we report successful injection of spin-polarized electrons from an iron film through an Al 2 O 3 tunnel barrier into Si(001). The circular polarization of the electroluminescence resulting from radiative recombination in Si and in GaAs (in Si/AlGaAs/GaAs structures) tracks the Fe magnetization, confirming that these spin-polarized electrons originate from the Fe contact. The polarization reflects Fe majority spin. We determine a lower bound for the Si electron spin polarization of 10%, and obtain an estimate of ∼30% at 5 K, with significant polarization extending to at least 125 K. We further demonstrate spin transport across the Si/AlGaAs interface.The manipulation of carrier spin angular momentum in semiconductors offers enhanced functionality and a new paradigm for device operation 2-4 . Recent calculations 5 indicate that spinbased field-effect transistors can exhibit lower leakage currents and switching energies than those projected for end-of-roadmap complementary metal-oxide-semiconductor devices, significantly reducing heat dissipation, which has been identified as one of the grand challenges facing scaled complementary metal-oxidesemiconductors 1 . Several fundamental properties of Si make it an ideal host for spin-based functionality. Spin-orbit effects producing spin relaxation are much smaller in Si than in GaAs owing to the lower atomic mass and the inversion symmetry of the crystal structure itself. The dominant naturally occurring isotope, Si 28 , has no nuclear spin, suppressing hyperfine interactions. Consequently, spin lifetimes are expected to be relatively long, as demonstrated by electron paramagnetic resonance work on donor-bound electrons 6 and more recent work on free electrons in Si (refs 7,8). In addition, silicon's mature technology base and overwhelming dominance of the semiconductor industry make it an obvious choice for implementing spin-based functionality. Several spin-based Si devices have indeed been proposed, including transistor structures 9,10 and elements for application in quantum computation/information technology 11 .Despite these advantages, efficient electrical spin injection and transport in Si have yet to be demonstrated. Here, we electrically inject spin-polarized electrons from a thin ferromagnetic Fe film through an Al 2 O 3 tunnel barrier into a Si(001) n−i−p doped heterostructure, and observe circular polarization of the electrolumin...

Approximately 2% of mammalian genes encode proteases. Comparative genomics reveals that those involved in immunity and reproduction show the most interspecies diversity and evidence of positive selection during evolution. This is particularly true of granzymes, the cytotoxic proteases of natural killer cells and CD8+ T cells. There are 5 granzyme genes in humans and 10 in mice, and it is suggested that granzymes evolve to meet species-specific immune challenge through gene duplication and more subtle alterations to substrate specificity. We show that mouse and human granzyme B have distinct structural and functional characteristics. Specifically, mouse granzyme B is 30 times less cytotoxic than human granzyme B and does not require Bid for killing but regains cytotoxicity on engineering of its active site cleft. We also show that mouse granzyme A is considerably more cytotoxic than human granzyme A. These results demonstrate that even “orthologous” granzymes have species-specific functions, having evolved in distinct environments that pose different challenges.