Putting endotoxin to work for us: Monophosphoryl lipid A as a safe and effective vaccine adjuvant

The development of non-infectious subunit vaccines greatly increases the safety of prophylactic immunization, but also reinforces the need for a new generation of immunostimulatory adjuvants. Because adverse effects are a paramount concern in prophylactic immunization, few new adjuvants have received approval for use anywhere in the developed world. The vaccine adjuvant monophosphoryl lipid A is a detoxified form of the endotoxin lipopolysaccharide, and is among the first of a new generation of Toll-like receptor agonists likely to be used as vaccine adjuvants on a mass scale in human populations. Much remains to be learned about this compound’s mechanism of action, but recent developments have made clear that it is unlikely to be simply a weak version of lipopolysaccharide. Instead, monophosphoryl lipid A’s structure seems to have fortuitously retained several functions needed for stimulation of adaptive immune responses, while shedding those associated with pro-inflammatory side effects. Received 25 April 2008; received after revision 05 June 2008; accepted 10 June 2008     

A Cenozoic record of the equatorial Pacific carbonate compensation depth

Atmospheric carbon dioxide concentrations and climate are regulated on geological timescales by the balance between carbon input from volcanic and metamorphic outgassing and its removal by weathering feedbacks; these feedbacks involve the erosion of silicate rocks and organic-carbon-bearing rocks. The integrated effect of these processes is reflected in the calcium carbonate compensation depth, which is the oceanic depth at which calcium carbonate is dissolved. Here we present a carbonate accumulation record that covers the past 53 million years from a depth transect in the equatorial Pacific Ocean. The carbonate compensation depth tracks long-term ocean cooling, deepening from 3.0-3.5?kilometres during the early Cenozoic (approximately 55?million years ago) to 4.6 kilometres at present, consistent with an overall Cenozoic increase in weathering. We find large superimposed fluctuations in carbonate compensation depth during the middle and late Eocene. Using Earth system models, we identify changes in weathering and the mode of organic-carbon delivery as two key processes to explain these large-scale Eocene fluctuations of the carbonate compensation depth.     

A positive feedback mechanism governs the polarity and motion of motile cilia

Ciliated epithelia produce fluid flow in many organ systems, ranging from the respiratory tract where it clears mucus to the ventricles of the brain where it transports cerebrospinal fluid. Human diseases that disable ciliary flow, such as primary ciliary dyskinesia, can compromise organ function or the ability to resist pathogens, resulting in recurring respiratory infections, otitis, hydrocephaly and infertility. To create a ciliary flow, the cilia within each cell need to be polarized coordinately along the planar axis of the epithelium, but how polarity is established in any ciliated epithelia is not known. Here we analyse the developmental mechanisms that polarize cilia, using the ciliated cells in the developing Xenopus larval skin as a model system. We show that cilia acquire polarity through a sequence of events, beginning with a polar bias set by tissue patterning, followed by a refinement phase. Our results indicate that during refinement, fluid flow is both necessary and sufficient in determining cilia polarity. These findings reveal a novel mechanism in which tissue patterning coupled with fluid flow act in a positive feedback loop to direct the planar polarity of cilia.     

High-temperature metal-organic magnets

For over two decades there have been intense efforts aimed at the development of alternatives to conventional magnets, particularly materials comprised in part or wholly of molecular components. Such alternatives offer the prospect of realizing magnets fabricated through controlled, low-temperature, solution-based chemistry, as opposed to high-temperature metallurgical routes, and also the possibility of tuning magnetic properties through synthesis. However, examples of magnetically ordered molecular materials at or near room temperature are extremely rare, and the properties of these materials are often capricious and difficult to reproduce. Here we present a versatile solution-based route to a new class of metal-organic materials exhibiting magnetic order well above room temperature. Reactions of the metal (M) precursor complex bis(1,5-cyclooctadiene)nickel with three different organics A-TCNE (tetracyanoethylene), TCNQ (7,7,8,8-tetracyanoquinodimethane) or DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone)--proceed via electron transfer from nickel to A and lead to materials containing Ni(II) ions and reduced forms of A in a 2:1 Ni:A ratio--that is, opposite to that of conventional (low Curie temperature) MA(2)-type magnets. These materials also contain oxygen-based species within their architectures. Magnetic characterization of the three compounds reveals spontaneous field-dependent magnetization and hysteresis at room temperature, with ordering temperatures well above ambient. The unusual stoichiometry and striking magnetic properties highlight these three compounds as members of a class of stable magnets that are at the interface between conventional inorganic magnets and genuine molecule-based magnets.     

Insect hemolymph clotting

The clot’s appearance in different large-bodied insects has been described, but until recently, little was known about any insect clot’s molecular makeup, and few experiments could directly test its function. Techniques have been developed in Drosophila (fruit fly) larvae to identify clotting factors that can then be tested for effects on hemostasis, healing, and immunity. This has revealed unanticipated complexity in the hemostatic mechanisms in these larvae. While the clot’s molecular structure is not yet fully understood, progress is being made, and the loss of clotting factors has been shown to cause subtle immune defects. The few similarities between coagulation in different insect species and life stages, and the current state of knowledge about coagulation in insects are discussed.     

What's nu? A re-examination of Maxwell's ‘ratio-of-units’ argument,from the mechanical theory of the electromagnetic field to ‘On the elementary relations between electrical measurements’

This re-examination of the earliest version of Maxwell's most important argument for the electromagnetic theory of light—the equality between the speed of wave propagation in the electromagnetic ether and the ratio of electrostatic to electromagnetic measures of electrical quantity—establishes unforeseen connections between Maxwell's theoretical electrical metrology and his mechanical theory of the electromagnetic field. Electrical metrology was not neutral with respect to field-theoretic versus action-at-a-distance conceptions of electro-magnetic interaction. Mutual accommodation between these conceptions was reached by Maxwell on the British Association for the Advancement of Science (BAAS) Committee on Electrical Standards by exploiting the measurement of the medium parameters—electric inductive capacity and magnetic permeability—on an arbitrary scale. While he always worked within this constraint in developing the ‘ratio-of-units’ argument mathematically, I maintain that Maxwell came to conceive of the ratio ‘as a velocity’ by treating the medium parameters as physical quantities that could be measured absolutely, which was only possible via the correspondences between electrical and mechanical quantities established in the mechanical theory. I thereby correct two closely-related misconceptions of the ratio-of-units argument—the counterintuitive but widespread notion that the ratio is naturally a speed, and the supposition that Maxwell either inferred or proved this from its dimensional formula.     

IP<Subscript>3</Subscript> receptor signaling and endothelial barrier function

The endothelium, a monolayer of endothelial cells lining vessel walls, maintains tissue-fluid homeostasis by restricting the passage of the plasma proteins and blood cells into the interstitium. The ion Ca²⁺, a ubiquitous secondary messenger, initiates signal transduction events in endothelial cells that is critical to control of vascular tone and endothelial permeability. The ion Ca²⁺ is stored inside the intracellular organelles and released into the cytosol in response to environmental cues. The inositol 1,4,5-trisphosphate (IP₃) messenger facilitates Ca²⁺ release through IP₃ receptors which are Ca²⁺-selective intracellular channels located within the membrane of the endoplasmic reticulum. Binding of IP₃ to the IP₃Rs initiates assembly of IP₃R clusters, a key event responsible for amplification of Ca²⁺ signals in endothelial cells. This review discusses emerging concepts related to architecture and dynamics of IP₃R clusters, and their specific role in propagation of Ca²⁺ signals in endothelial cells.     

Voltage-gated sodium channel-associated proteins and alternative mechanisms of inactivation and block

Voltage-gated sodium channels mediate inward current of action potentials upon membrane depolarization of excitable cells. The initial transient sodium current is restricted to milliseconds through three distinct channel-inactivating and blocking mechanisms. All pore-forming alpha subunits of sodium channels possess structural elements mediating fast inactivation upon depolarization and recovery within milliseconds upon membrane repolarization. Accessory subunits modulate fast inactivation dynamics, but these proteins can also limit current by contributing distinct inactivation and blocking particles. A-type isoforms of fibroblast growth factor homologous factors (FHFs) bear a particle that induces long-term channel inactivation, while sodium channel subunit Navβ4 employs a blocking particle that rapidly dissociates upon membrane repolarization to generate resurgent current. Despite their different physiological functions, the FHF and Navβ4 particles have similarity in amino acid composition and mechanisms for docking within sodium channels. The three competing channel-inactivating and blocking processes functionally interact to regulate a neuron’s intrinsic excitability.     

Genome-wide association study identifies FCGR2A as a susceptibility locus for Kawasaki disease

Kawasaki disease is a systemic vasculitis of unknown etiology, with clinical observations suggesting a substantial genetic contribution to disease susceptibility. We conducted a genome-wide association study and replication analysis in 2,173 individuals with Kawasaki disease and 9,383 controls from five independent sample collections. Two loci exceeded the formal threshold for genome-wide significance. The first locus is a functional polymorphism in the IgG receptor gene FCGR2A (encoding an H131R substitution) (rs1801274; P = 7.35 × 10(-11), odds ratio (OR) = 1.32), with the A allele (coding for histadine) conferring elevated disease risk. The second locus is at 19q13, (P = 2.51 × 10(-9), OR = 1.42 for the rs2233152 SNP near MIA and RAB4B; P = 1.68 × 10(-12), OR = 1.52 for rs28493229 in ITPKC), which confirms previous findings(1). The involvement of the FCGR2A locus may have implications for understanding immune activation in Kawasaki disease pathogenesis and the mechanism of response to intravenous immunoglobulin, the only proven therapy for this disease.