N-Alkyl-α-amino acids in Nature and their biocatalytic preparation

PWS would like to acknowledge the European Union for his current funding: “This project has received funding from the European Union’s Horizon 2020 research and innovation programme under Marie Skłodowska-Curie grant agreement No 665919”.N-alkylated-α-amino acids are useful building blocks for the pharmaceutical and fine chemical industries. Enantioselective methods of N-alkylated-α-amino acid synthesis are therefore highly valuable and widely investigated. While there are a variety of chemical methods for their synthesis, they often employ stoichiometric quantities of hazardous reagents such as pyrophoric metal hydrides or genotoxic alkylating agents, whereas biocatalytic routes can provide a greener and cleaner alternative to existing methods. This review highlights the occurrence of the N-alkyl-α-amino acid motif and its role in nature, important applications towards human health and biocatalytic methods of preparation. Several enzyme classes that can be used to access chiral N-alkylated-α-amino acids and their substrate selectivities are detailed.PostprintPeer reviewe

Constraints on narrow exotic states from K+p and K0_Lp scattering data

We consider the effect of exotic S=+1 resonances Theta+ and Theta++ on K+p elastic scattering data (total cross section) and the process K0_Lp-->K0_Sp. Data near the observed Theta+(1540) are examined for evidence of additional states. The width limit for a Theta++ state is reconsidered and shown to be much less than 1 MeV.Comment: 4 pages, 3 eps figures; minor corrections, one fig adde

Actin polymerization in cellular oxidant injury

Microfilaments undergo an ATP-dependent disruption into shortened bundles following cellular exposure to oxidants. This phenomenon does not require a net change in the amount of polymerized actin. However, increased amounts of polymerized actin have been detected in oxidant-injured cells and it was the purpose of this study to determine the conditions under which the actin polymerization may occur. Utilizing the formation of oxidized glutathione (GSSG) as an indicator of cellular sulfhydryl oxidation, conditions were chosen to accentuate sulfhydryl oxidation within the target P388D1 cell line following exposure to the oxidants, H2O2 and diamide. Using the DNase I and flow cytometric assays of actin polymerization, significant polymerization of actin was detected only under conditions in which sulfhydryl oxidation occurred after exposure to the two oxidizing agents. Greater sulfhydryl oxidation early in the course of injury was associated with a greater rate and extent of actin polymerization in the injured cells. Experiments with cells depleted of glutathione (GSH) demonstrated that neither loss of GSH nor absolute levels of GSSG formed during oxidant exposure were responsible for the polymerization of actin. The data presented are consistent with the hypothesis that oxidizing conditions which induce significant sulfhydryl oxidation in target cells are correlated with assembly of polymerized actin and that this represents a process which is distinct and separate from the ATP-dependent gross disruption of microfilaments.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29200/1/0000254.pd

Surface-reconstructed Icosahedral Structures for Lead Clusters

We describe a new family of icosahedral structures for lead clusters. In general, structures in this family contain a Mackay icosahedral core with a reconstructed two-shell outer-layer. This family includes the anti-Mackay icosahedra, which have have a Mackay icosahedral core but with most of the surface atoms in hexagonal close-packed positions. Using a many-body glue potential for lead, we identify two icosahedral structures in this family which have the lowest energies of any known structure in the size range from 900 to 15000 lead atoms. We show that these structures are stabilized by a feature of the many-body glue part of the interatomic potential.Comment: 9 pages, 8 figure

Coalescence of nanoscale metal clusters: Molecular-dynamics study

We study the coalescence of nanoscale metal clusters in an inert-gas atmosphere using constant-energy molecular dynamics. The coalescence proceeds via atomic diffusion with the release of surface energy raising the temperature. If the temperature exceeds the melting point of the coalesced cluster, a molten droplet forms. If the temperature falls between the melting point of the larger cluster and those of the smaller clusters, a metastable molten droplet forms and freezes.Comment: 5 figure

Z^* Resonances: Phenomenology and Models

We explore the phenomenology of, and models for, the Z^* resonances, the lowest of which is now well established, and called the Theta. We provide an overview of three models which have been proposed to explain its existence and/or its small width, and point out other relevant predictions, and potential problems, for each. The relation to what is known about KN scattering, including possible resonance signals in other channels, is also discussed.Comment: 29 pages, uses RevTeX4; expanded version (published form

Wild-type sTREM2 blocks Aβ aggregation and neurotoxicity, but the Alzheimer's R47H mutant increases Aβ aggregation.

TREM2 is a pattern recognition receptor, expressed on microglia and myeloid cells, detecting lipids and Aβ and inducing an innate immune response. Missense mutations (e.g., R47H) of TREM2 increase risk of Alzheimer's disease (AD). The soluble ectodomain of wild-type TREM2 (sTREM2) has been shown to protect against AD in vivo, but the underlying mechanisms are unclear. We show that Aβ oligomers bind to cellular TREM2, inducing shedding of the sTREM2 domain. Wild-type sTREM2 bound to Aβ oligomers (measured by single-molecule imaging, dot blots, and Bio-Layer Interferometry) inhibited Aβ oligomerization and disaggregated preformed Aβ oligomers and protofibrils (measured by transmission electron microscopy, dot blots, and size-exclusion chromatography). Wild-type sTREM2 also inhibited Aβ fibrillization (measured by imaging and thioflavin T fluorescence) and blocked Aβ-induced neurotoxicity (measured by permeabilization of artificial membranes and by loss of neurons in primary neuronal-glial cocultures). In contrast, the R47H AD-risk variant of sTREM2 is less able to bind and disaggregate oligomeric Aβ but rather promotes Aβ protofibril formation and neurotoxicity. Thus, in addition to inducing an immune response, wild-type TREM2 may protect against amyloid pathology by the Aβ-induced release of sTREM2, which blocks Aβ aggregation and neurotoxicity. In contrast, R47H sTREM2 promotes Aβ aggregation into protofibril that may be toxic to neurons. These findings may explain how wild-type sTREM2 apparently protects against AD in vivo and why a single copy of the R47H variant gene is associated with increased AD risk.European Unio