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"Jennings, Michael"
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MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition
Inhibition of the NLRP3 inflammasome is a promising strategy for the development of new treatments for inflammatory diseases. MCC950 is a potent and specific small-molecule inhibitor of the NLRP3 pathway, but its molecular target is not defined. Here, we show that MCC950 directly interacts with the Walker B motif within the NLRP3 NACHT domain, thereby blocking ATP hydrolysis and inhibiting NLRP3 activation and inflammasome formation.
MCC950, a small-molecule inhibitor of the NLRP3 inflammasome, interacts directly with NLRP3 at the Walker B motif that hydrolyzes ATP, as defined by a protease-susceptibility assay, mutational analysis, and surface plasmon resonance analysis.
Journal Article
Glycointeractions in bacterial pathogenesis
Many important interactions between bacterial pathogens and their hosts are highly specific binding events that involve host or pathogen carbohydrate structures (glycans). Glycan interactions can mediate adhesion, invasion and immune evasion and can act as receptors for toxins. Several bacterial pathogens can also enzymatically alter host glycans to reveal binding targets, degrade the host cell glycans or alter the function of host glycoproteins. In recent years, high-throughput screening technologies, such as lectin, glycan and mucin microarrays, have transformed the field by identifying new bacterial–host glycointeractions, which are crucial for colonization, persistence and disease. In this Review, we discuss interactions involving both host and bacterial glycans that have a role in bacterial pathogenesis. We also highlight recent technological advances that have illuminated the glycoscience of microbial pathogenesis.
Journal Article
Policy agendas in British politics
\"Through a unique dataset covering half a century of policy-making in Britain, this book traces how topics like the economy, international affairs, and crime have changed in their importance to government. The data concerns key venues of decision-making - the Queen's Speech, laws and budgets - which are compared to the media and public opinion. These trends are conveyed through accessible figures backed up by a series of examples of important policies. As a result, the book throws new light on the key points of change in British politics, such as Thatcherism and New Labour and explores different approaches to agenda setting helping to account for these changes: incrementalism, the issue attention cycle and the punctuated equilibrium model. What results is the development of a new approach to agenda setting labelled focused adaptation whereby policy-makers respond to structural shifts in the underlying pattern of attention\"-- Provided by publisher.
Book
Role of transporters in regulating mammalian intracellular inorganic phosphate
This review summarizes the current understanding of the role of plasma membrane transporters in regulating intracellular inorganic phosphate ([Pi] In ) in mammals. Pi influx is mediated by SLC34 and SLC20 Na + -Pi cotransporters. In non-epithelial cells other than erythrocytes, Pi influx via SLC20 transporters PiT1 and/or PiT2 is balanced by efflux through XPR1 (xenotropic and polytropic retrovirus receptor 1). Two new pathways for mammalian Pi transport regulation have been described recently: 1) in the presence of adequate Pi, cells continuously internalize and degrade PiT1. Pi starvation causes recycling of PiT1 from early endosomes to the plasma membrane and thereby increases the capacity for Pi influx; and 2) binding of inositol pyrophosphate InsP8 to the SPX domain of XPR1 increases Pi efflux. InsP8 is degraded by a phosphatase that is strongly inhibited by Pi. Therefore, an increase in [Pi] In decreases InsP8 degradation, increases InsP8 binding to SPX, and increases Pi efflux, completing a feedback loop for [Pi] In homeostasis. Published data on [Pi] In by magnetic resonance spectroscopy indicate that the steady state [Pi] In of skeletal muscle, heart, and brain is normally in the range of 1–5 mM, but it is not yet known whether PiT1 recycling or XPR1 activation by InsP8 contributes to Pi homeostasis in these organs. Data on [Pi] In in cultured cells are variable and suggest that some cells can regulate [Pi] better than others, following a change in [Pi] Ex . More measurements of [Pi] In , influx, and efflux are needed to determine how closely, and how rapidly, mammalian [Pi] In is regulated during either hyper- or hypophosphatemia.
Journal Article
One-way street
\"One-Way Street is a thoroughfare unlike anything else in literature--by turns exhilarating and bewildering, requiring mental agility and a special kind of urban literacy. Presented here in a new edition with expanded notes, this genre-defying meditation on the semiotics of late-1920s Weimar culture offers a fresh opportunity to encounter Walter Benjamin at his most virtuosic and experimental, writing in a vein that anticipates later masterpieces such as 'On the Concept of History' and The Arcades Project. Composed of sixty short prose pieces that vary wildly in style and theme, One-Way Street evokes a dense cityscape of shops, cafes, and apartments, alive with the hubbub of social interactions and papered over with public inscriptions of all kinds: advertisements, signs, posters, slogans. Benjamin avoids all semblance of linear narrative, presenting readers with a seemingly random sequence of aphorisms, reminiscences, jokes, off-the-cuff observations, dreamlike fantasias, serious philosophical inquiries, apparently unserious philosophical parodies, and trenchant political commentaries. Providing remarkable insight into the occluded meanings of everyday things, Benjamin time and again proves himself the unrivalled interpreter of what he called 'the soul of the commodity.' Despite the diversity of its individual sections, Benjamin's text is far from formless. Drawing on the avant-garde aesthetics of Dada, Constructivism, and Surrealism, its unusual construction implies a practice of reading that cannot be reduced to simple formulas. Still refractory, still radical, One-Way Street is a work in perpetual progress.\"--Provided by publisher.
Book
Ga2O3 and Related Ultra-Wide Bandgap Power Semiconductor Oxides: New Energy Electronics Solutions for CO2 Emission Mitigation
Currently, a significant portion (~50%) of global warming emissions, such as CO2, are related to energy production and transportation. As most energy usage will be electrical (as well as transportation), the efficient management of electrical power is thus central to achieve the XXI century climatic goals. Ultra-wide bandgap (UWBG) semiconductors are at the very frontier of electronics for energy management or energy electronics. A new generation of UWBG semiconductors will open new territories for higher power rated power electronics and solar-blind deeper ultraviolet optoelectronics. Gallium oxide—Ga2O3 (4.5–4.9 eV), has recently emerged pushing the limits set by more conventional WBG (~3 eV) materials, such as SiC and GaN, as well as for transparent conducting oxides (TCO), such asIn2O3, ZnO and SnO2, to name a few. Indeed, Ga2O3 as the first oxide used as a semiconductor for power electronics, has sparked an interest in oxide semiconductors to be investigated (oxides represent the largest family of UWBG). Among these new power electronic materials, AlxGa1-xO3 may provide high-power heterostructure electronic and photonic devices at bandgaps far beyond all materials available today (~8 eV) or ZnGa2O4 (~5 eV), enabling spinel bipolar energy electronics for the first time ever. Here, we review the state-of-the-art and prospects of some ultra-wide bandgap oxide semiconductor arising technologies as promising innovative material solutions towards a sustainable zero emission society.
Journal Article
Staphylococcus aureus LukAB cytotoxin kills human neutrophils by targeting the CD11b subunit of the integrin Mac-1
Staphylococcus aureus causes diseases ranging from superficial wound infections to more invasive manifestations like osteomyelitis and endocarditis. The evasion of host phagocytes recruited to the site of infection is essential to the success of S. aureus as a pathogen. A single S. aureus strain can produce up to five different bicomponent pore-forming leukotoxins that lyse immune cells by forming pores in the cellular plasma membrane. Although these leukotoxins have been considered redundant due to their cytotoxic activity toward human neutrophils, each toxin displays varied species and cell-type specificities. This suggests that cellular factors may influence which cells each toxin targets. Here we describe the identification of CD11b, the α subunit of the αM/β2 integrin (CD11b/CD18), macrophage-1 antigen, or complement receptor 3, as a cellular receptor for leukocidin A/B (LukAB), an important toxin that contributes to S. aureus killing of human neutrophils. We demonstrate that CD11b renders human neutrophils susceptible to LukAB-mediated killing by purified LukAB as well as during S. aureus infection ex vivo. LukAB directly interacts with human CD11b by binding to the I domain, a property that determines the species specificity exhibited by this toxin. Identification of a LukAB cellular target has broad implications for the use of animal models to study the role of LukAB in S. aureus pathogenesis, explains the toxin’s tropism toward human neutrophils and other phagocytes, and provides a cellular therapeutic target to block the effect of LukAB toward human neutrophils.
Journal Article