Enantiospecific Synthesis and Cytotoxicity Evaluation of Oximidine II Analogues

Analogues of the anticancer natural product oximidine II were prepared and evaluated for cytotoxicity. One analogue of oximidine II that carries a C15 allylic amide side chain as well as two analogues with C15 vinyl sulfone side chains were found to lack cytotoxicity against the cancer cell line SK‐Mel‐5, thereby confirming the necessity of the C15 enamide side chain of oximidine II for cytotoxicity. Four analogues, designed by comparative molecular similarity index analysis (CoMSIA), that feature a less complex macrolactone scaffold were prepared and tested. The two analogues carrying a C15 vinyl sulfone group and the two analogues with a C15 oximidine II enamide side chain showed weak cytotoxicity against the SK‐Mel‐5 cell line and other cell lines, indicating that the designed simplified macrocycles cannot replace the oximidine II macrocycle.     

Chemical-Shift Perturbations Reflect Bile Acid Binding to Norovirus Coat Protein: Recognition Comes in Different Flavors

Bile acids have been reported as important cofactors promoting human and murine norovirus (NoV) infections in cell culture. The underlying mechanisms are not resolved. Through the use of chemical shift perturbation (CSP) NMR experiments, we identified a low-affinity bile acid binding site of a human GII.4 NoV strain. Long-timescale MD simulations reveal the formation of a ligand-accessible binding pocket of flexible shape, allowing the formation of stable viral coat protein–bile acid complexes in agreement with experimental CSP data. CSP NMR experiments also show that this mode of bile acid binding has a minor influence on the binding of histo-blood group antigens and vice versa. STD NMR experiments probing the binding of bile acids to virus-like particles of seven different strains suggest that low-affinity bile acid binding is a common feature of human NoV and should therefore be important for understanding the role of bile acids as cofactors in NoV infection.     

Refining Genotypes and Phenotypes in KCNA2-Related Neurological Disorders

Pathogenic variants in KCNA2, encoding for the voltage-gated potassium channel K_v1.2, have been identified as the cause for an evolving spectrum of neurological disorders. Affected individuals show early-onset developmental and epileptic encephalopathy, intellectual disability, and movement disorders resulting from cerebellar dysfunction. In addition, individuals with a milder course of epilepsy, complicated hereditary spastic paraplegia, and episodic ataxia have been reported. By analyzing phenotypic, functional, and genetic data from published reports and novel cases, we refine and further delineate phenotypic as well as functional subgroups of KCNA2-associated disorders. Carriers of variants, leading to complex and mixed channel dysfunction that are associated with a gain- and loss-of-potassium conductance, more often show early developmental abnormalities and an earlier onset of epilepsy compared to individuals with variants resulting in loss- or gain-of-function. We describe seven additional individuals harboring three known and the novel KCNA2 variants p.(Pro407Ala) and p.(Tyr417Cys). The location of variants reported here highlights the importance of the proline(405)–valine(406)–proline(407) (PVP) motif in transmembrane domain S6 as a mutational hotspot. A novel case of self-limited infantile seizures suggests a continuous clinical spectrum of KCNA2-related disorders. Our study provides further insights into the clinical spectrum, genotype–phenotype correlation, variability, and predicted functional impact of KCNA2 variants.     

(S)-Reutericyclin: Susceptibility Testing and In Vivo Effect on Murine Fecal Microbiome and Volatile Organic Compounds

We aimed to assess the in vitro antimicrobial activity and the in vivo effect on the murine fecal microbiome and volatile organic compound (VOC) profile of (S)-reutericyclin. The antimicrobial activity of (S)-reutericyclin was tested against Clostridium difficile, Listeria monocytogenes, Escherichia coli, Enterococcus faecium, Staphylococcus aureus, Staphylococcus (S.) epidermidis, Streptococcus agalactiae, Pseudomonas aeruginosa and Propionibacterium acnes. Reutericyclin or water were gavage fed to male BALBc mice for 7 weeks. Thereafter stool samples underwent 16S based microbiome analysis and VOC analysis by gas chromatography mass spectrometry (GC-MS). (S)-reutericyclin inhibited growth of S. epidermidis only. Oral (S)-reutericyclin treatment caused a trend towards reduced alpha diversity. Beta diversity was significantly influenced by reutericyclin. Linear discriminant analysis Effect Size (LEfSe) analysis showed an increase of Streptococcus and Muribaculum as well as a decrease of butyrate producing Ruminoclostridium, Roseburia and Eubacterium in the reutericyclin group. VOC analysis revealed significant increases of pentane and heptane and decreases of 2,3-butanedione and 2-heptanone in reutericyclin animals. The antimicrobial activity of (S)-reutericyclin differs from reports of (R)-reutericyclin with inhibitory effects on a multitude of Gram-positive bacteria reported in the literature. In vivo (S)-reutericyclin treatment led to a microbiome shift towards dysbiosis and distinct alterations of the fecal VOC profile.     

Large-scale parallel arrays of silicon nanowires via block copolymer directed self-assembly

Extending the resolution and spatial proximity of lithographic patterning below critical dimensions of 20 nm remains a key challenge with very-large-scale integration, especially if the persistent scaling of silicon electronic devices is sustained. One approach, which relies upon the directed self-assembly of block copolymers by chemical-epitaxy, is capable of achieving high density 1?:?1 patterning with critical dimensions approaching 5 nm. Herein, we outline an integration-favourable strategy for fabricating high areal density arrays of aligned silicon nanowires by directed self-assembly of a PS-b-PMMA block copolymer nanopatterns with a L(0) (pitch) of 42 nm, on chemically pre-patterned surfaces. Parallel arrays (5 × 10(6) wires per cm) of uni-directional and isolated silicon nanowires on insulator substrates with critical dimension ranging from 15 to 19 nm were fabricated by using precision plasma etch processes; with each stage monitored by electron microscopy. This step-by-step approach provides detailed information on interfacial oxide formation at the device silicon layer, the polystyrene profile during plasma etching, final critical dimension uniformity and line edge roughness variation nanowire during processing. The resulting silicon-nanowire array devices exhibit Schottky-type behaviour and a clear field-effect. The measured values for resistivity and specific contact resistance were ((2.6 ± 1.2) × 10(5)Ωcm) and ((240 ± 80) Ωcm(2)) respectively. These values are typical for intrinsic (un-doped) silicon when contacted by high work function metal albeit counterintuitive as the resistivity of the starting wafer (～10 Ωcm) is 4 orders of magnitude lower. In essence, the nanowires are so small and consist of so few atoms, that statistically, at the original doping level each nanowire contains less than a single dopant atom and consequently exhibits the electrical behaviour of the un-doped host material. Moreover this indicates that the processing successfully avoided unintentional doping. Therefore our approach permits tuning of the device steps to contact the nanowires functionality through careful selection of the initial bulk starting material and/or by means of post processing steps e.g. thermal annealing of metal contacts to produce high performance devices. We envision that such a controllable process, combined with the precision patterning of the aligned block copolymer nanopatterns, could prolong the scaling of nanoelectronics and potentially enable the fabrication of dense, parallel arrays of multi-gate field effect transistors.     

MS Binding Assays for D1 and D5 Dopamine Receptors

MS Binding Assays are a label‐free alternative to radioligand binding assays. They provide basically the same capabilities as the latter, but an unlabeled reporter ligand is used instead of a radioligand. The study presented herein describes the development of MS Binding Assays that address D₁ and D₅ dopamine receptors. A highly sensitive, rapid and robust LC–ESI‐MS/MS quantification method for the selective D₁ dopamine receptor antagonist SCH23390 ((5R)‐8‐chloro‐3‐methyl‐5‐phenyl‐1,2,4,5‐tetrahydro‐3‐benzazepin‐7‐ol) was established and validated, using its 8‐bromo analogue SKF83566 as an internal standard. This quantification method proved to be suitable for the characterization of SCH23390 binding to human D₁ and D₅ receptors. Following the concept of MS Binding Assays, saturation experiments for D₁ and D₅ receptors were performed, as well as competition experiments for D₁ receptors. The results obtained are in good agreement with results from radioligand binding assays and therefore indicate that the established MS Binding Assays addressing D₁ and D₅ receptors are well‐suited substitutes for radioligand binding assays, the technique that has so far dominated affinity determinations toward these targets.     

Tetraacylgermanes as highly efficient photoinitiators for visible light cured dimethacrylate resins and dental composites

Tetrabenzoylgermane 1 and various substituted tetrabenzoylgermanes 2 – 7 were investigated as visible light (VL) photoinitiators (PIs) for dental dimethacrylate resins and dimethacrylate‐based composites. The tetrabenzoylgermanes 1 – 7 show a very strong VL absorption between 400 and 450 nm. Substituents on the benzoyl chromophore strongly influence their properties such as melting point, solubility, absorption behavior, or PI reactivity. A good photobleaching behavior and a very high reactivity as VL PI was found in photo‐differential scanning calorimeter experiments for selected tetrabenzoylgermanes. Composite pastes containing only ～0.1 wt % of Ge‐PI exhibited a sufficient photocuring due to the high PI‐reactivity of the tetraacylgermanes. Among the investigated germane PIs, tetrakis(2‐methylbenzoyl)germane 2 shows the best performance as VL PI for restorative composites and enables the composites to be photocured using an LED with an emission maximum of 500 nm. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018 , 135, 46115.     

Reproducible Measurement Results in Organic Solvent Nanofiltration with Ceramic Membranes

Ceramic membranes are still quite innovative to organic solvent nanofiltration. Nevertheless, flux and rejection results obtained in filtration measurements seem to depend largely on the experimental procedure, membrane production batch and setup. Therefore, an experimental approach is described, which proved to provide reproducible and reliable results that may be used as data set to derive parameters in model development.     

Silica nanotubes and hollow silica nanofibers: Gas phase mineralization,polymerization catalysis and in-situ polyethylene nanocomposites

Gas phase mineralization and mesoscopic replication of polyvinyl alcohol (PVA) nanofibers represents an attractive route to the preparation of silica nanotubes and hollow fibers with independent control of pore diameter and wall size. In the sol/gel gas phase process, PVA nanofibers, produced by electrospinning of aqueous PVA, were encapsulated in a thin silica shell by repeated sequenced feed of SiCl₄ and H₂O vapors, followed by thermal degradation of the PVA core at 550 °C. The hollow fiber wall thickness was governed by the number of SiCl₄/H₂O cycles with an average increase of the wall size of 0.7 nm per cycle. In contrast to conventional sol/gel electrospinning and wet sol/gel dip coating, shearing of such hollow silicate nanofibers afforded single silica nanotubes with an average length of a few microns. Aqueous silica sols added together with PVA gave control of the inner pore architectures. Methylalumoxane (MAO) activated silica nanotubes were used as supports for half sandwich chromium (III) (Cr) and post metallocene (Fe) catalysts for ethylene polymerization and in-situ nanocomposite formation with uniform dispersion of silica nanotubes within the polyethylene matrix. A blend of Cr and Fe was supported on silica nanotubes to produce melt processable polyethylene nanocomposites with bimodal molecular weight distributions.