Shaping Single Photons through Multimode Optical Fibers using Mechanical Perturbations

The capacity of information delivered by single photons is boosted by encoding high-dimensional quantum dits in their transverse shape. Transporting such high-dimensional quantum dits in optical networks may be accomplished using multimode optical fibers, which support the low-loss transmission of multiple spatial modes over existing infrastructure. However, when photons propagate through a multimode fiber their transverse shape gets scrambled because of mode mixing and modal interference. This is usually corrected using free-space spatial light modulators, inhibiting a robust all-fiber operation. In this work, we demonstrate an all-fiber approach for controlling the shape of single photons and the spatial correlations between entangled photon pairs, using carefully controlled mechanical perturbations of the fiber. We optimize these perturbations to localize the spatial distribution of a single photon or the spatial correlations of photon pairs in a single spot, enhancing the signal in the optimized spot by over an order of magnitude. Using the same approach we show a similar enhancement for coupling light from a multimode fiber into a single-mode fiber

Impact of 2-hydroxypropyl-β-cyclodextrin inclusion complex formation on dopamine receptor-ligand interaction – A case study

The octanol–water distribution coefficient (logP), used as a measure of lipophilicity, plays a major role in the drug design and discovery processes. While average logP values remain unchanged in approved oral drugs since 1983, current medicinal chemistry trends towards increasingly lipophilic compounds that require adapted analytical workflows and drug delivery systems. Solubility enhancers like cyclodextrins (CDs), especially 2-hydroxypropyl-β-CD (2-HP-β-CD), have been studied in vitro and in vivo investigating their ADMET (adsorption, distribution, metabolism, excretion and toxicity)-related properties. However, data is scarce regarding the applicability of CD inclusion complexes (ICs) in vitro compared to pure compounds. In this study, dopamine receptor (DR) ligands were used as a case study, utilizing a combined in silico/in vitro workflow. Media-dependent solubility and IC stoichiometry were investigated using HPLC. NMR was used to observe IC formation-caused chemical shift deviations while in silico approaches utilizing basin hopping global minimization were used to propose putative IC binding modes. A cell-based in vitro homogeneous time-resolved fluorescence (HTRF) assay was used to quantify ligand binding affinity at the DR subtype 2 (D2R). While all ligands showed increased solubility using 2-HP-β-CD, they differed regarding IC stoichiometry and receptor binding affinity. This case study shows that IC-formation was ligand-dependent and sometimes altering in vitro binding. Therefore, IC complex formation can’t be recommended as a general means of improving compound solubility for in vitro studies as they may alter ligand binding

Isolation and Functional Characterization of the Novel Clostridium botulinum Neurotoxin A8 Subtype

Botulism is a severe neurological disease caused by the complex family of botulinum neurotoxins (BoNT). Based on the different serotypes known today, a classification of serotype variants termed subtypes has been proposed according to sequence diversity and immunological properties. However, the relevance of BoNT subtypes is currently not well understood. Here we describe the isolation of a novel Clostridium botulinum strain from a food-borne botulism outbreak near Chemnitz, Germany. Comparison of its botulinum neurotoxin gene sequence with published sequences identified it to be a novel subtype within the BoNT/A serotype designated BoNT/A8. The neurotoxin gene is located within an ha-orfX+ cluster and showed highest homology to BoNT/A1, A2, A5, and A6. Unexpectedly, we found an arginine insertion located in the HC domain of the heavy chain, which is unique compared to all other BoNT/A subtypes known so far. Functional characterization revealed that the binding characteristics to its main neuronal protein receptor SV2C seemed unaffected, whereas binding to membrane-incorporated gangliosides was reduced in comparison to BoNT/A1. Moreover, we found significantly lower enzymatic activity of the natural, full-length neurotoxin and the recombinant light chain of BoNT/A8 compared to BoNT/A1 in different endopeptidase assays. Both reduced ganglioside binding and enzymatic activity may contribute to the considerably lower biological activity of BoNT/A8 as measured in a mouse phrenic nerve hemidiaphragm assay. Despite its reduced activity the novel BoNT/A8 subtype caused severe botulism in a 63-year-old male. To our knowledge, this is the first description and a comprehensive characterization of a novel BoNT/A subtype which combines genetic information on the neurotoxin gene cluster with an in-depth functional analysis using different technical approaches. Our results show that subtyping of BoNT is highly relevant and that understanding of the detailed toxin function might pave the way for the development of novel therapeutics and tailor-made antitoxins

Revision of the absolute configurations of chelocardin and amidochelocardin

Even with the aid of the available methods, the configurational assignment of natural products can be a challenging task that is prone to errors, and it sometimes needs to be corrected after total synthesis or single-crystal X-ray diffraction (XRD) analysis. Herein, the absolute configuration of amidochelocardin is revised using a combination of XRD, NMR spectroscopy, experimental ECD spectra, and time-dependent density-functional theory (TDDFT)-ECD calculations. As amidochelocardin was obtained via biosynthetic engineering of chelocardin, we propose the same absolute configuration for chelocardin based on the similar biosynthetic origins of the two compounds and result of TDDFT-ECD calculations. The evaluation of spectral data of two closely related analogues, 6-desmethyl-chelocardin and its semisynthetic derivative 1, also supports this conclusion

The European Butterfly Indicator for grassland species: 1990-2013

This report presents the fifth version of the European Grassland Butterfly Indicator, one of the EU biodiversity indicators of the European Environment Agency

Exploiting the biosynthetic potential of myxobacteria for natural product discovery

Myxobakterien sind eine der vielversprechendsten Quellen für neue Naturstoffe, die eine hervorragende Basis für die Entwicklung neuer Pharmazeutika darstellen. Mittels einer aktivitätsgeleiteten Isolierungsstrategie und durch die Anwendung von „genome mining“ Technologien konnten drei neuartige Naturstoffklassen, die Myxoquaterine, die Myxoglucamide und die Myxopentacine entdeckt werden. Alle drei Naturstoffklassen zeichnen sich durch neuartige strukturelle Merkmal aus und zusätzlich zeigen die Myxoquaterine eine vielversprechende zytotoxische Bioaktivität. Die Analyse der Biosynthesewege konnte zeigen, dass bei jeder Naturstoffklasse jeweils Reaktionen auftreten, die bisher nur in sehr wenig anderen Biosynthesen gefunden wurden.Myxobacteria are one of the most prolific sources for new natural products. In general, natural products are an excellent base for the development of new pharmaceuticals. Using an activity guided isolation strategy and genome mining technologies, three new natural product classes, the myxoquaterines, the myxoglucamides and the myxopentacines were discovered. These three compound classes show new structural features and in addition, the myxoquaterines posses a promising cytotoxic bioactivity. Analysis of the biosynthetic pathways showed that in the synthesis of each compound class untypical reactions occur that were rarely found in othe

Myxobacteria of the <i>Cystobacterineae</i> Suborder Are Producers of New Vitamin K₂ Derived Myxoquinones

Vitamin K is an essential, lipid soluble vitamin that plays an important role in the human blood coagulation cascade as well as in the life cycle of bacteria and plants. In this study, we report the isolation and structure elucidation of unprecedented polyhydroxylated menaquinone variants named myxoquinones that are produced by myxobacteria and structurally belong to the Vitamin K family. We analyze the occurrence of myxoquinones across an LC-MS data collection from myxobacterial extracts and shed light on the distribution of myxoquinone-type biosynthetic gene clusters among publicly available myxobacterial genomes. Our findings indicate that myxoquinones are specifically produced by strains of the Cystobacterineae suborder within myxobacteria. Furthermore, bioinformatic analysis of the matching gene clusters allowed us to propose a biosynthetic model for myxoquinone formation. Due to their increased water-solubility, the myxoquinones could be a suitable starting point for the development of a better bioavailable treatment of vitamin K deficiency

Structure and Biosynthesis of Myxofacyclines: Unique Myxobacterial Polyketides Featuring Varying and Unprecedented Heterocycles

A metabolome-guided screening approach in the novel myxobacterium Corallococcus sp. MCy9072 resulted in the isolation of the unprecedented natural product myxofacycline A featuring a rare isoxazole substructure. Identification and genomic investigation of additional producers alongside targeted gene inactivation experiments and heterologous expression of the corresponding biosynthetic gene cluster in the host Myxococcus xanthus DK1622 confirmed a noncanonical megaenzyme complex as the biosynthetic origin of myxofacycline A. Induced expression of the respective genes led to significantly increased production titers enabling the identification of six further members of the myxofacycline natural product family. Whereas myxofacycline A–D display an isoxazole substructure, myxofacycline E and F intriguingly were found to contain 4 pyrimidinole, a heterocycle unprecedented in natural products. Lastly, myxofacycline G features another rare 1,2 dihydropyrol-3-one moiety. In addition to the full structure elucidation, we report the underlying biosynthetic machinery and present a rationale for the formation of all myxofacyclines. Unexpectedly, an extraordinary polyketide synthase-nonribosomal peptide synthetase hybrid was found to produce all three types of heterocycles in these natural products

Thiamyxins: Structure and Biosynthesis of Myxobacterial RNA-Virus-Inhibitors

During our search for novel myxobacterial natural products, we discovered the Thiamyxins: thiazole- and thiazoline-rich non-ribosomal peptide-polyketide hybrids with potent antiviral activity. We isolated two cyclized and two open-chain congeners of this unprecedented natural product family, whereof the non-cyclized Thiamyxin D was found to be fused to a glycerol unit attached to the C-terminal carboxyl function. Alongside their structure elucidation and absolute stereochemistry, we present the biosynthetic origin of the Thiamyxins supported by a concise biosynthesis model based on biosynthetic gene cluster analysis and feeding experiments with isotope labelled precursors. We report an unprecedented incorporation of a 2-(hydroxymethyl)-4-methylpent-3-enoic acid moiety originating from the involved polyketide synthase featuring a rare GCN5-related N-acetyltransferase-like decarboxylase domain. The Thiamyxins showed potent inhibition of different RNA-viruses as analysed in cell culture models of corona, zika and dengue virus infection. Their potency up to a half maximal inhibitory concentration of 560 nM combined with milder cytotoxic effects on human cell lines indicate a potential for further development of the Thiamyxins as broad-spectrum antivirals targeting RNA-viruses