Mechanism of Islet Amyloid Polypeptide Fibrillation at Lipid Interfaces Studied by Infrared Reflection Absorption Spectroscopy

AbstractIslet amyloid polypeptide (IAPP) is a pancreatic hormone and one of a number of proteins that are involved in the formation of amyloid deposits in the islets of Langerhans of type II diabetes mellitus patients. Though IAPP-membrane interactions are known to play a major role in the fibrillation process, the mechanism and the peptide's conformational changes involved are still largely unknown. To obtain new insights into the conformational dynamics of IAPP upon its aggregation at membrane interfaces and to relate these structures to its fibril formation, we studied the association of IAPP at various interfaces including neutral as well as charged phospholipids using infrared reflection absorption spectroscopy. The results obtained reveal that the interaction of human IAPP with the lipid interface is driven by the N-terminal part of the peptide and is largely driven by electrostatic interactions, as the protein is able to associate strongly with negatively charged lipids only. A two-step process is observed upon peptide binding, involving a conformational transition from a largely α-helical to a β-sheet conformation, finally forming ordered fibrillar structures. As revealed by simulations of the infrared reflection absorption spectra and complementary atomic force microscopy studies, the fibrillar structures formed consist of parallel intermolecular β-sheets lying parallel to the lipid interface but still contain a significant number of turn structures. We may assume that these dynamical conformational changes observed for negatively charged lipid interfaces play an important role as the first steps of IAPP-induced membrane damage in type II diabetes

Spurious Symmetry Enhancement and Interaction-Induced Topology in Magnons

Linear spin wave theory (LSWT) is the standard technique to compute the spectra of magnetic excitations in quantum materials. In this paper, we show that LSWT, even under ordinary circumstances, may fail to implement the symmetries of the underlying ordered magnetic Hamiltonian leading to spurious degeneracies. In common with pseudo-Goldstone modes in cases of quantum order-by-disorder these degeneracies tend to be lifted by magnon-magnon interactions. We show how, instead, the correct symmetries may be restored at the level of LSWT. In the process we give examples, supported by nonperturbative matrix product based time evolution calculations, where symmetries dictate that there should be a topological magnon gap but where LSWT fails to open up this gap. We also comment on possible spin split magnons in MnF$_2$ and similar rutiles by analogy to recently proposed altermagnets

SuperDRUG2: a one stop resource for approved/marketed drugs

Regular monitoring of drug regulatory agency web sites and similar resources for information on new drug approvals and changes to legal status of marketed drugs is impractical. It requires navigation through several resources to find complete information about a drug as none of the publicly accessible drug databases provide all features essential to complement in silico drug discovery. Here, we propose SuperDRUG2 (http://cheminfo.charite.de/superdrug2) as a comprehensive knowledge-base of approved and marketed drugs. We provide the largest collection of drugs (containing 4587 active pharmaceutical ingredients) which include small molecules, biological products and other drugs. The database is intended to serve as a one-stop resource providing data on: chemical structures, regulatory details, indications, drug targets, side-effects, physicochemical properties, pharmacokinetics and drug-drug interactions. We provide a 3D-superposition feature that facilitates estimation of the fit of a drug in the active site of a target with a known ligand bound to it. Apart from multiple other search options, we introduced pharmacokinetics simulation as a unique feature that allows users to visualise the 'plasma concentration versus time' profile for a given dose of drug with few other adjustable parameters to simulate the kinetics in a healthy individual and poor or extensive metabolisers

Chalcone-based Selective Inhibitors of a C4 Plant Key Enzyme as Novel Potential Herbicides

Weeds are a challenge for global food production due to their rapidly evolving resistance against herbicides. We have identified chalcones as selective inhibitors of phosphoenolpyruvate carboxylase (PEPC), a key enzyme for carbon fixation and biomass increase in the C4 photosynthetic pathway of many of the world’s most damaging weeds. In contrast, many of the most important crop plants use C3 photosynthesis. Here, we show that 2′,3′,4′,3,4-Pentahydroxychalcone (IC50 = 600 nM) and 2′,3′,4′-Trihydroxychalcone (IC50 = 4.2 μM) are potent inhibitors of C4 PEPC but do not affect C3 PEPC at a same concentration range (selectivity factor: 15–45). Binding and modeling studies indicate that the active compounds bind at the same site as malate/aspartate, the natural feedback inhibitors of the C4 pathway. At the whole plant level, both substances showed pronounced growth-inhibitory effects on the C4 weed Amaranthus retroflexus, while there were no measurable effects on oilseed rape, a C3 plant. Growth of selected soil bacteria was not affected by these substances. Our chalcone compounds are the most potent and selective C4 PEPC inhibitors known to date. They offer a novel approach to combat C4 weeds based on a hitherto unexplored mode of allosteric inhibition of a C4 plant key enzyme

Topological Magnons in Kitaev Magnets at High Fields

We study the Kitaev-Heisenberg-$\Gamma$-$\Gamma'$ model that describes the magnetism in strong spin-orbit coupled honeycomb lattice Mott insulators. In strong $[111]$ magnetic fields that bring the system into the fully polarized paramagnetic phase, we find that the spin wave bands carry nontrivial Chern numbers over large regions of the phase diagram implying the presence of chiral magnon edge states. In contrast to other topological magnon systems, the topological nontriviality of these systems results from the presence of magnon number non-conserving terms in the Hamiltonian. Since the effects of interactions are suppressed by $J/h$, the validity of the single particle picture is tunable making paramagnetic phases particularly suitable for the exploration of this physics. Using time dependent DMRG and interacting spin wave theory, we demonstrate the presence of the chiral edge mode and its evolution with field.Comment: 16 pages (main text + supplementary material), 10 figure

MEDIC: a practical disease vocabulary used at the Comparative Toxicogenomics Database

The Comparative Toxicogenomics Database (CTD) is a public resource that promotes understanding about the effects of environmental chemicals on human health. CTD biocurators manually curate a triad of chemical–gene, chemical–disease and gene–disease relationships from the scientific literature. The CTD curation paradigm uses controlled vocabularies for chemicals, genes and diseases. To curate disease information, CTD first had to identify a source of controlled terms. Two resources seemed to be good candidates: the Online Mendelian Inheritance in Man (OMIM) and the ‘Diseases’ branch of the National Library of Medicine's Medical Subject Headers (MeSH). To maximize the advantages of both, CTD biocurators undertook a novel initiative to map the flat list of OMIM disease terms into the hierarchical nature of the MeSH vocabulary. The result is CTD’s ‘merged disease vocabulary’ (MEDIC), a unique resource that integrates OMIM terms, synonyms and identifiers with MeSH terms, synonyms, definitions, identifiers and hierarchical relationships. MEDIC is both a deep and broad vocabulary, composed of 9700 unique diseases described by more than 67 000 terms (including synonyms). It is freely available to download in various formats from CTD. While neither a true ontology nor a perfect solution, this vocabulary has nonetheless proved to be extremely successful and practical for our biocurators in generating over 2.5 million disease-associated toxicogenomic relationships in CTD. Other external databases have also begun to adopt MEDIC for their disease vocabulary. Here, we describe the construction, implementation, maintenance and use of MEDIC to raise awareness of this resource and to offer it as a putative scaffold in the formal construction of an official disease ontology