NKT cell-dependent glycolipid–peptide vaccines with potent anti-tumour activity

It is known that T cells can eliminate tumour cells through recognition of unique or aberrantly expressed antigens presented as peptide epitopes by major histocompatibility complex (MHC) molecules on the tumour cell surface. With recent advances in defining tumour-associated antigens, it should now be possible to devise therapeutic vaccines that expand specific populations of anti-tumour T cells. However there remains a need to develop simpler efficacious synthetic vaccines that possess clinical utility. We present here the synthesis and analysis of vaccines based on conjugation of MHC-binding peptide epitopes to α-galactosylceramide, a glycolipid presented by the nonpolymorphic antigen-presenting molecule CD1d to provoke the stimulatory activity of type I natural killer T (NKT) cells. The chemical design incorporates an enzymatically cleavable linker that effects controlled release of the active components in vivo. Chemical and biological analysis of different linkages with different enzymatic targets enabled selection of a synthetic vaccine construct with potent therapeutic anti-tumour activity in mice, and marked in vitro activity in human blood.     

Diagonal-preserving ring ⁎-isomorphisms of Leavitt path algebras

The graph groupoids of directed graphs E and F are topologically isomorphic if and only if there is a diagonal-preserving ring ?-isomorphism between the Leavitt path algebras of E and F.     

Surface tensor estimation from linear sections

From Crofton's formula for Minkowski tensors we derive stereological estimators of translation invariant surface tensors of convex bodies in the n‐dimensional Euclidean space. The estimators are based on one‐dimensional linear sections. In a design based setting we suggest three types of estimators. These are based on isotropic uniform random lines, vertical sections, and non‐isotropic random lines, respectively. Further, we derive estimators of the specific surface tensors associated with a stationary process of convex particles in the model based setting.     

Cu(I) catalysed cyclopropanation with enantiopure scorpionate type ligands derived from (+)-camphor or (-)-menthone

One-pot syntheses of three new enantiopure heteroscorpionate ligands derived from (+)-camphor or (-)-menthone are described. The ligands are obtained by reacting pyrazoles derived from (+)-camphor or (-)-menthone with sodium hydride and thionyl chloride. Subsequent reactions with pyridine and various aldehydes afford the tripod ligands in multi-gram amounts. Especially the menthopyrazole based ligand 6 showed encouraging ee values up to 69% in the Cu(I) catalysed enantioselective cyclopropanation of styrene with ethyl diazoacetate.     

Eu(3+)-mediated polymerization of benzenetetracarboxylic acid studied by spectroscopy, temperature-dependent calorimetry, and density functional theory

Thermodynamic parameters for the complexation of Eu(3+) with pyromellitic acid (1,2,4,5-benzenetetracarboxylic acid, BTC) as a model system for polymerizable metal-complexing humic acids were determined using temperature-dependent time-resolved laser-induced fluorescence spectroscopy (TRLFS) and isothermal titration calorimetry (ITC). At low metal and ligand concentrations (<50 μM Eu(3+), <1 mM BTC), a 1:1 monomeric Eu-BTC complex was identified in the range of 25-60 °C. At elevated concentrations (>500 μM Eu(3+) and BTC) a temperature-dependent polymerization was observed, where BTC monomers are linked via coordinating shared Eu(3+) ions. The two methods lead to comparable thermodynamic data (ΔH = 18.5 ± 1.5/16.5 ± 0.1 kJ mol(-1); ΔS = 152 ± 5/130 ± 5 J mol(-1) K(-1); TRLFS/ITC) in the absence of polymerization. With the onset of polymerization, TRLFS reveals the water coordination number of the lanthanide, whereas calorimetry is superior in determining the thermodynamic data in this regime. Evaluating the heat uptake kinetics, the monomer and polymer formation steps could be separated by "time-resolved" ITC, revealing almost identical binding enthalpies for the sequential reactions. Structural features of the complexes were studied by Fourier-transform infrared (FTIR) spectroscopy in combination with density functional theory (DFT) calculations showing predominantly chelating coordination with two carboxylate groups in the monomeric complex and monodentate binding of a single carboxylate group in the polymeric complex of the polycarboxylate with Eu(3+). The data show that pyromellitic acid is a suitable model for the study of metal-mediated polymerization as a crucial factor in determining the effect of humic acids on the mobility of heavy metals in the environment.     

First fluorescence spectroscopic investigation of Am(III) complexation with an organic carboxylic ligand, pyromellitic acid

For the first time Am(III) complexation with a small organic ligand could be identified and characterized with time-resolved laser-induced fluorescence spectroscopy (TRLFS) at room temperature and trace metal concentration. With pyromellitic acid (1,2,4,5-benzene-tetracarboxylic acid, BTC) as ligand spectroscopic characteristics for the Am-BTC complex system were determined at pH 5.0, an ionic strength of 0.1 M (NaClO4) and room temperature. The fluorescence lifetimes were determined to be 23.2±2.2 ns for Am3+(aq) and 27.2±1.2 ns for the Am-BTC 1:1 complex; the emission maximum for the 5D1-(7)F1 transition is 691 nm for both species. The complex stability constant for the Am-BTC 1:1 complex was calculated to be logβ110=5.42±0.16.     

Inclusive excitation-energy distributions of hot nuclei from 44 MeV/nucleon Ar- and 32 MeV/nucleon Kr-induced reactions

Inclusive neutron multiplicity distributions were measured by means of 4π liquid-scintillator detectors for Ar and Kr-induced reactions at 44 MeV/nucleon and 32 MeV/nucleon, respectively. For all the systems studied, the observed distributions exhibit a bump structure at large multiplicity, corresponding to highly dissipative collisions. For Ar-induced reactions, the excitation energies necessary to explain the most probable neutron multiplicity associated with these dissipative collisions are estimated, the correspondence between excitation energy and neutron multiplicity being calculated in the framework of the statistical model. The so-obtained values of excitation energies, which are systematically lower than those predicted using the massive-transfer picture, are discussed.     

An unprecedented tetranuclear niobium aqua ion with a capping mu4-sulfido ligand

The aqueous solution chemistry of niobium is rather unexplored, and well characterized aqua complexes are scarce. In this work, a new niobium aqua ion is obtained upon treatment of Zn-reduced ethanolic solutions of NbCl5 with HCl in the presence of a sulfide source. The red aqua ion, obtained upon cation-exchange chromatography, forms readily the thiocyanate complex which has been crystallized as Cs(4.26)Na(1.74)[Nb4SO5(NCS)10] . 0.33H2O. X-ray crystallography revealed an unprecedented metal-metal bonded tetranuclear Nb4(mu4-S)(mu2-O)5(4+) core with a capping mu4-S ligand.     

Advances in photolithographically fabricated ENFET membranes

A photolithographically fabricated membrane for enzyme immobilisation based on an Ion Sensitive Field Effect Transistor (ISFET) is described. The preparation of an Enzyme-FET (ENFET) containing urease was successful. The ENFET has been used for the determination of urea and pesticides; this depends on the chosen enzyme level in the membrane and can be employed in a flow-injection system. The urea sensitive sensor (high enzyme load) has a wide linear range (1–500 mmol/l) a fast response (t₉₅=20 s) and a lifetime greater than 30 days. The application of this sensor to the determination of urea in the waste water from a fertilizer plant and in blood serum is discussed. The second sensor (low enzyme level) was able to detect pesticides in water based on the inhibition of urease. The detection limit was found to be 0.1 µg/l for Carbofuran (10 minutes incubation time, without preconcentration).