Catalyst-Controlled Transannular Polyketide Cyclization Cascades: Selective Folding of Macrocyclic Polyketides

The biomimetic synthesis of aromatic polyketides from macrocyclic substrates by means of catalyst-controlled transannular cyclization cascades is described. The macrocyclic substrates, which feature increased stability and fewer conformational states, were thereby transformed into several distinct polyketide scaffolds. The catalyst-controlled transannular cyclizations selectively led to aromatic polyketides with a defined folding and oxygenation pattern, thus emulating β-keto-processing steps of polyketide biosynthesis

Atroposelective synthesis of tetra-ortho-substituted biaryls by catalyst-controlled non-canonical polyketide cyclizations

The cyclization of poly-β-carbonyl-substrates controlled by polyketide synthases intricately governs the biosynthesis of a wide range of aromatic polyketides. Analogous small-molecule-catalysed processes would conceivably induce selective cyclizations of non-canonical polycarbonyl substrates to provide products distinct from natural polyketides. Here, we report a secondary amine-catalysed twofold cyclization of non-canonical hexacarbonyl substrates, furnishing enantioenriched tetra-ortho-substituted binaphthalenes. The substrates were prepared by a fourfold ozonolysis of dicinnamyl biindenes and converted under catalyst control with high atroposelectivity. Privileged catalysts, helicenes and ligands are readily accessible from the binaphthalene products stemming from the non-canonical polyketide cyclizations

Catalytic Arene-forming Aldol Condensation: Stereoselective Synthesis of Rotationally Restricted Aromatic Compounds

By taking inspiration from the fascinating biosynthetic machinery that creates aromatic polyketides, our group investigates analogous reactions catalyzed by small molecules. We are particularly captivated by the prospects of intramolecular aldol condensation reactions to generate different rotationally restricted aromatic compounds. In a first project of our independent research group, a highly stereoselective amine catalyzed synthesis of axially chiral biaryls, tertiary aromatic amides and oligo-1,2-naphthylenes has been developed. In this article, we outline the twists and turns for our escape from the aromatic flatland to structurally intriguing chiral arene scaffolds relevant for various fields of application

Insights from birthing experiences of fistula survivors in North-central Nigeria: Interplay of structural violence

Obstetric Fistula is an abnormal opening between the vagina and rectum resulting from prolonged and obstructed labour. Studies indicate that delays in accessing maternal care and home birth contribute to the development of fistula. Survivors are usually women of low socioeconomic status residing in rural locations. This study explores the birthing experiences of 15 fistula survivors through a narrative inquiry approach at a repair centre in North-central Nigeria. Using structural violence as a lens, it describes the role of social, political and health systems in the inequitable access to care for women. For women opting for home births, preference for home delivery was mainly due to lack of finances, poor health systems and cultural practices. Rural location inhibited access as, women seeking facility delivery faced transfer delays to referral centres when complications developed. Inequitable maternal health services in rural locations in Nigeria are inherently linked to access to health care; and these contribute to the increased incidences of fistulae. Structural intervention is a health policy priority to address poor health systems and achieve universal health coverage to address maternal health issues in Nigeria

First Observation of Self-Amplified Spontaneous Emission in a Free-Electron Laser at 109 nm Wavelength

We present the first observation of Self-Amplified Spontaneous Emission (SASE) in a free-electron laser (FEL) in the Vacuum Ultraviolet regime at 109 nm wavelength (11 eV). The observed free-electron laser gain (approx. 3000) and the radiation characteristics, such as dependency on bunch charge, angular distribution, spectral width and intensity fluctuations all corroborate the existing models for SASE FELs.Comment: 6 pages including 6 figures; e-mail: [email protected]

Molecular dynamics simulations reveal that AEDANS is an inert fluorescent probe for the study of membrane proteins

Computer simulations were carried out of a number of AEDANS-labeled single cysteine mutants of a small reference membrane protein, M13 major coat protein, covering 60% of its primary sequence. M13 major coat protein is a single membrane-spanning, α-helical membrane protein with a relatively large water-exposed region in the N-terminus. In 10-ns molecular dynamics simulations, we analyze the behavior of the AEDANS label and the native tryptophan, which were used as acceptor and donor in previous FRET experiments. The results indicate that AEDANS is a relatively inert environmental probe that can move unhindered through the lipid membrane when attached to a membrane protein

The surfactant protein C mutation A116D alters cellular processing, stress tolerance, surfactant lipid composition, and immune cell activation

<p>Abstract</p> <p>Background</p> <p>Surfactant protein C (SP-C) is important for the function of pulmonary surfactant. Heterozygous mutations in <it>SFTPC</it>, the gene encoding SP-C, cause sporadic and familial interstitial lung disease (ILD) in children and adults. Mutations mapping to the BRICHOS domain located within the SP-C proprotein result in perinuclear aggregation of the proprotein. In this study, we investigated the effects of the mutation A116D in the BRICHOS domain of SP-C on cellular homeostasis. We also evaluated the ability of drugs currently used in ILD therapy to counteract these effects.</p> <p>Methods</p> <p>SP-C^A116Dwas expressed in MLE-12 alveolar epithelial cells. We assessed in vitro the consequences for cellular homeostasis, immune response and effects of azathioprine, hydroxychloroquine, methylprednisolone and cyclophosphamide.</p> <p>Results</p> <p>Stable expression of SP-C^A116Din MLE-12 alveolar epithelial cells resulted in increased intracellular accumulation of proSP-C processing intermediates. SP-C^A116Dexpression further led to reduced cell viability and increased levels of the chaperones Hsp90, Hsp70, calreticulin and calnexin. Lipid analysis revealed decreased intracellular levels of phosphatidylcholine (PC) and increased lyso-PC levels. Treatment with methylprednisolone or hydroxychloroquine partially restored these lipid alterations. Furthermore, SP-C^A116Dcells secreted soluble factors into the medium that modulated surface expression of CCR2 or CXCR1 receptors on CD4⁺lymphocytes and neutrophils, suggesting a direct paracrine effect of SP-C^A116Don neighboring cells in the alveolar space.</p> <p>Conclusions</p> <p>We show that the A116D mutation leads to impaired processing of proSP-C in alveolar epithelial cells, alters cell viability and lipid composition, and also activates cells of the immune system. In addition, we show that some of the effects of the mutation on cellular homeostasis can be antagonized by application of pharmaceuticals commonly applied in ILD therapy. Our findings shed new light on the pathomechanisms underlying SP-C deficiency associated ILD and provide insight into the mechanisms by which drugs currently used in ILD therapy act.</p