Mining Symbionts of a Spider-Transmitted Fungus Illuminates Uncharted Biosynthetic Pathways to Cytotoxic Benzolactones

A spider-transmitted fungus (Rhizopus microsporus) that was isolated from necrotic human tissue was found to harbor endofungal bacteria (Burkholderia sp.). Metabolic profiling of the symbionts revealed a complex of cytotoxic agents (necroximes). Their structures were characterized as oxime-substituted benzolactone enamides with a peptidic side chain. The potently cytotoxic necroximes are also formed in symbiosis with the fungal host and could have contributed to the necrosis. Genome sequencing and computational analyses revealed a novel modular PKS/NRPS assembly line equipped with several non-canonical domains. Based on gene-deletion mutants, we propose a biosynthetic model for bacterial benzolactones. We identified specific traits that serve as genetic handles to find related salicylate macrolide pathways (lobatamide, oximidine, apicularen) in various other bacterial genera. Knowledge of the biosynthetic pathway enables biosynthetic engineering and genome-mining approaches.     

Synthesis and Diversification of Macrocyclic Alkynediyl Sulfide Peptides

The synthesis of rare macrocyclic alkynediyl sulfides by a Cu-catalyzed C_sp−S cross-coupling is presented. The catalytic protocol (Cu(MeCN)₄PF₆/dtbbpy) promotes macrocyclization of peptides, dipeptides and tripeptides at ambient temperature (14 examples, 23→73 % yields) via thiols and bromoalkynes, and is chemoselective with regards to terminal alkynes. Importantly, the underexplored alkynediyl sulfide functionality incorporates a rigidifying structural element and opens new opportunities for diversification of macrocyclic frameworks through S oxidation, halide addition and azide–alkyne cycloaddition chemistries to integrate sulfones, halides or valuable fluorophores (7 examples, 37→92 % yields).     

Immunology of O-glycosylated proteins: approaches to the design of a MUC1 glycopeptide-based tumor vaccine

Until about 1990 there was general consent about the assumption that only protein and peptide antigens have the capacity of CD4(+) or CD8(+) T-cell stimulation. Since about ten years evidence is now accumulating that carbohydrate-peptide epitopes do play a role in classical MHC-mediated immune responses. This holds true for glycopeptides, where the glycan chain is short and not located at an "anchor residue" needed for MHC interaction. T-cell recognition of O-glycosylated peptides is potentially of high biomedical significance, because it can mediate the immune protection against microorganisms, the vaccination in anti-tumor therapies, but also some aspects of autoimmunity. The epithelial type 1 transmembrane mucin MUC1 is established as a marker for monitoring recurrence of breast cancer and is a promising target for immunotherapeutic strategies to treat cancer by active specific immunization. Natural human immune responses to the tumor-associated glycoforms of the mucin indicate that antibody reactivities are more directed to glycopeptide than to non-glycosylated peptide epitopes. To overcome the weak immunogenicity of the natural target, heavily O-glycosylated MUC1, the question was addressed whether O-linked glycans remain intact during processing in the MHC class II pathway and interfere with endosomal processing and peptide presentation. Attempts were made to define on a biochemical level the structural requirements for an efficient endosomal proteolysis catalyzed by cathepsin L in antigen-presenting cells. Evidence based on work with CD4(+) T-hybridomas confirms that O-glycopeptides can be effectively presented to T-cells and that glycans can form integral parts of the TCR defined epitopes. Similar approaches are currently followed in the MHC class I pathway which aim at the identification of immunogenic glycopeptides generated by immunoproteasomes.     

Constraints on two-lepton two-quark operators

Physics from beyond the Standard Model, such as leptoquarks, can induce four fermion operators involving a quark, an anti-quark, a lepton and an anti-lepton. We update the (flavour-dependent) constraints on the coefficients of such interactions, arising from collider searches for contact interactions, meson decays and other rare processes. We then make naive estimates for the magnitude of the coefficients, as could arise in texture models or from inverse hierarchies in the kinetic term coefficients. These “expectations” suggest that rare kaon decays could be a good place to look for such operators.     

Mean field loops versus quantum anti-crossing nets in trapped Bose-Einstein condensates

We study a Bose-Einstein condensate trapped in an asymmetric double well potential. Solutions of the time-independent Gross-Pitaevskii equation reveal intrinsic loops in the energy (or chemical potential) level behavior when the shape of the potential is varied. We investigate the corresponding behavior of the quantum (many-body) energy levels. Applying the two-mode approximation to the bosonic field operators, we show that the quantum energy levels create an anti-crossing net inside the region bounded by the loop of the mean field solution. Received 6 March 2002 / Received in final form 19 September 2002 Published online 15 November 2002 RID="a" ID="a"e-mail: smerzi@cnls.lanl.gov     

Driven Rydberg atoms reveal quartic level repulsion

The dynamics of Rydberg states of a hydrogen atom subjected simultaneously to uniform static electric field and two microwave fields with commensurate frequencies is considered in the range of small field amplitudes. In the certain range of the parameters of the system the classical secular motion of the electronic ellipse reveals chaotic behavior. Quantum mechanically, when the fine structure of the atom is taken into account, the energy level statistics obey predictions appropriate for the symplectic Gaussian random matrix ensemble.     

Initial stages of water adsorption on NaCl (100) studied by scanning polarization force microscopy

Scanning polarization force microscopy was used to study the topography, polarizability, and contact potential of cleaved NaCl(100) as a function of the relative humidity (RH) between < 5% and 40%. In this humidity range there are reversible changes in surface potential and polarizability, while large scale modifications in step topography and irreversible ion redistribution occur above 40% RH. In dry conditions the surface contact potential was more negative near atomic steps than over flat terraces. As humidity was increased, changes were observed in the local polarizability of the steps due to ionic solvation, and the contact potential of the terraces became more negative. At 40% RH surface-potential differences between steps and terraces could no longer be detected. These results are interpreted in terms of preferential anion solvation, initially localized near steps, and later spreading over the entire surface.