Immune responses to ISCOM (R) formulations in animal and primate models

ISCOMs(R) are typically 40 nm cage-like structures comprising antigen, saponin, cholesterol and phospholipid. ISCOMs(R) have been shown to induce antibody responses and activate T helper cells and cyrolytic T lymphocytes in a number of animal species, including non-human primates. Recent clinical studies have demonstrated that ISCOMs(R) are also able to induce antibody and cellular immune responses in humans. This review describes the current understanding of the ability of ISCOMs(R) to induce immune responses and the mechanisms underlying this property. Recent progress in the characterisation and manufacture of ISCOMs(R) will also be discussed. (C) 2001 Elsevier Science Ltd. All rights reserved.

H-1 NMR study of the states of water in equilibrium Poly(HEMA-co-THFMA) hydrogels

The spin-spin relaxation times, T-2, of hydrated samples of poly(hydroxymethyl methacrylate), PHEMA, poly(tetrahydrofurfuryl methacrylate),PTHFMA, and the,corresponding HEMA-THFMA copolymers have been examined to probe the states of,the imbibed water in these polymers. The decay in the transverse magnetization of water. in fully hydrated samples of PHEMA, PTHFMA, and copolymers of HEMA and THFMA was described by a multiexponential function. The short component of T-2 was interpreted as water molecules that were strongly interacting with the polymer chains. The intermediate component of T-2 was assigned to water residing in the porous structure of the samples. The long component of T-2 was believed to arise from water residing in the remnants of cracks formed in the polymer network during water sorption.

PFG-NMR measurements of the self-diffusion coefficients of water in equilibrium poly(HEMA-co-THFMA) hydrogels

The self-diffusion coefficients for water in a series of copolymers of 2-hydroxyethyl methacrylate, HEMA, and tetrahydrofurfuryl methacrylate, THFMA, swollen with water to their equilibrium states have been studied at 310 K using PFG-NMR. The self-diffusion coefficients calculated from the Stejskal-Tanner equation, D-obs, for all of the hydrated polymers were found to be dependent on the NMR storage time, as a result of spin exchange between the proton reservoirs of the water and the polymers, reaching an equilibrium plateau value at long storage times. The true values of the diffusion coefficients were calculated from the values of D-obs, in the plateau regions by applying a correction for the fraction of water protons present, obtained from the equilibrium water contents of the gels. The true self-diffusion coefficient for water in polyHEMA obtained at 310 K by this method was 5.5 x 10(-10) m(2) s(-1). For the copolymers containing 20% HEMA or more a single value of the self-diffusion coefficient was found, which was somewhat larger than the corresponding values obtained for the macroscopic diffusion coefficient from sorption measurements. For polyTHFMA and copolymers containing less than 20% HEMA, the PFG-NMR stimulated echo attenuation decay curves and the log-attenuation plots were characteristic of the presence of two diffusing water species. The self-diffusion coefficients of water in the equilibrium-hydrated copolymers were found to be dependent on the copolymer composition, decreasing with increasing THFMA content.

On the overabundance of light rare earth elements in terrestrial zircons and its implication for Earth's earliest magmatic differentiation

We present whole-rock and zircon rare earth element (REE) data from two early Archaean gneisses (3.81 Ga and 3.64 Ga) from the Itsaq gneiss complex, south-west Greenland. Both gneisses represent extremely rare examples of unaltered, fresh and relatively undeformed igneous rocks of such antiquity. Cathodoluminescence imaging of their zircons indicates a single crystallisation episode with no evidence for either later metamorphic and/or anatectic reworking or inheritance of earlier grains. Uniform, single-population U/Pb age data confirm the structural simplicity of these zircons. One sample, a 3.64 Ga granodioritic gneiss from the Gothabsfjord, yields a chondrite-normalised REE pattern with a positive slope from La to Lu as well as substantial positive Ce and slight negative Eu anomalies, features generally considered to be typical of igneous zircon. In contrast, the second sample, a 3.81 Ga tonalite from south of the Isua Greenstone Belt, has variable but generally much higher light REE abundances, with similar middle to heavy REE. Calculation of zircon/melt distribution coefficients (D-REE(zircon/melt)) from each sample yields markedly different values for the trivalent REE (i.e. Ce and Eu omitted) and simple application of one set of D-REE(zircon/melt) to model the melt composition for the other sample yields concentrations that are in error by up to two orders of magnitude for the light REE (La-Nd). The observed light REE overabundance in the 3.81 Ga tonalite is a commonly observed feature in terrestrial zircons for which a number of explanations ranging from lattice strain to disequilibrium crystallisation have been proposed and are further investigated herein. Regardless of the cause of light REE overabundance, our study shows that simple application of zircon/melt distribution coefficients is not an unambiguous method for ascertaining original melt composition. In this context, recent studies that use REE data to claim that > 4.3 Ga Hadean detrital zircons originally crystallised from an evolved magma, in turn suggesting the operation of geological processes in the early Earth analogous to those of the present day (e.g. subduction and melting of hydrated oceanic crust), must be regarded with caution. Indeed, comparison of terrestrial Hadean and > 3.9 Ga lunar highland zircons shows remarkable similarities in the light REE, even though subduction processes that have been used to explain the terrestrial zircons have never operated on the Moon. (C) 2002 Elsevier Science B.V. All rights reserved.

Fluid-mobile trace element constraints on the role of slab melting and implications for Archaean crustal growth models

We use published and new trace element data to identify element ratios which discriminate between arc magmas from the supra-subduction zone mantle wedge and those formed by direct melting of subducted crust (i.e. adakites). The clearest distinction is obtained with those element ratios which are strongly fractionated during refertilisation of the depleted mantle wedge, ultimately reflecting slab dehydration. Hence, adakites have significantly lower Pb/Nd and B/Be but higher Nb/Ta than typical arc magmas and continental crust as a whole. Although Li and Be are also overenriched in continental crust, behaviour of Li/Yb and Be/Nd is more complex and these ratios do not provide unique signatures of slab melting. Archaean tonalite-trondhjemite-granodiorites (TTGs) strongly resemble ordinary mantle wedge-derived arc magmas in terms of fluid-mobile trace element content, implying that they-did not form by slab melting but that they originated from mantle which was hydrated and enriched in elements lost from slabs during prograde dehydration. We suggest that Archaean TTGs formed by extensive fractional crystallisation from a mafic precursor. It is widely claimed that the time between the creation and subduction of oceanic lithosphere was significantly shorter in the Archaean (i.e. 20 Ma) than it is today. This difference was seen as an attractive explanation for the presumed preponderance of adakitic magmas during the first half of Earth's history. However, when we consider the effects of a higher potential mantle temperature on the thickness of oceanic crust, it follows that the mean age of oceanic lithosphere has remained virtually constant. Formation of adakites has therefore always depended on local plate geometry and not on potential mantle temperature.

Effect of type of grain and oil supplement on the performance, blood lipoproteins, egg cholesterol and fatty ccids of laying hens

The effects of type of grain (wheat vs. sorghum) and oil supplement/kg diet [0, 20g olive oil (OL), 20g safflower oil (SO), 10 g OL plus 10 g SO (OLSO)], over a 12-week period on the performance, plasma and lipoproteins lipids [cholesterol (C), triglycerides (TG), phospholipid (P)], and yolk C and fatty acids concentrations of laying hens were studied. Hens fed on the sorghum diet had significantly (P

Annexin II regulates multivesicular endosome biogenesis in the degradation pathway of animal cells

Proteins of the annexin family are believed to be involved in membrane-related processes, but their precise functions remain unclear. Here, we have made use of several experimental approaches, including pathological conditions, RNA interference and in vitro transport assays, to study the function of annexin II in the endocytic pathway. We find that annexin II is required for the biogenesis of multivesicular transport intermediates destined for late endosomes, by regulating budding from early endosomes-but not the membrane invagination process. Hence, the protein appears to be a necessary component of the machinery controlling endosomal membrane dynamics and multivesicular endosome biogenesis. We also find that annexin II interacts with cholesterol and that its subcellular distribution is modulated by the subcellular distribution of cholesterol, including in cells from patients with the cholesterol-storage disorder Niemann-Pick C. We conclude that annexin II forms cholesterol-containing platforms on early endosomal membranes, and that these platforms regulate the onset of the degradation pathway in animal cells.

Cytotoxic iron chelators: Characterization of the structure, solution chemistry and redox activity of ligands and iron complexes of the di-2-pyridyl ketone isonicotinoyl hydrazone (HPKIH) analogues

Di-2-pyridyl ketone isonicotinoyl hydrazone (HPKIH) and a range of its analogues comprise a series of monobasic acids that are capable of binding iron (Fe) as tridentate (N,N,O) ligands. Recently, we have shown that these chelators are highly cytotoxic, but show selective activity against cancer cells. Particularly interesting was the fact that cytotoxicity of the HPKIH analogues is maintained even after complexation with Fe. To understand the potent anti-tumor activity of these compounds, we have fully characterized their chemical properties. This included examination of the solution chemistry and X-ray crystal structures of both the ligands and Fe complexes from this class and the ability of these complexes to mediate redox reactions. Potentiometric titrations demonstrated that all chelators are present predominantly in their charge-neutral form at physiological pH (7.4), allowing access across biological membranes. Keto-enol tautomerism of the ligands was identified, with the tautomers exhibiting distinctly different protonation constants. Interestingly, the chelators form low-spin (diamagnetic) divalent Fe complexes in solution. The chelators form distorted octahedral complexes with Fe-II, with two tridentate ligands arranged in a meridional fashion. Electrochemistry of the Fe complexes in both aqueous and non-aqueous solutions revealed that the complexes are oxidized to their ferric form at relatively high potentials, but this oxidation is coupled to a rapid reaction with water to form a hydrated (carbinolamine) derivative, leading to irreversible electrochemistry. The Fe complexes of the HPKIH analogues caused marked DNA degradation in the presence of hydrogen peroxide. This observation confirms that Fe complexes from the HPKIH series mediate Fenton chemistry and do not repel DNA. Collectively, studies on the solution chemistry and structure of these HPKIH analogues indicate that they can bind cellular Fe and enhance its redox activity, resulting in oxidative damage to vital biomolecules.