Polymeric materials

Summary The Polymer Section of the Santa Barbara Workshop on Modeling of Materials is briefly reviewed. Motivation and need for modeling in polymer-based materials are outlined and the recommendations resulting from the workshop reported.     

Buchbesprechungen

Ohne Zusammenfassung     

Molecular basis and species specificity of high affinity binding of vasoactive intestinal polypeptide by the rat secretin receptor

The affinity and specificity of the binding interaction between ligands and their receptors are key for appropriate hormonal regulation of target tissues. However, it is now apparent that vasoactive intestinal polypeptide (VIP) binds to the rat secretin receptor with similar affinity to that for its natural ligand, secretin (Holtmann et al., 1995). In this report, we establish that this is not a characteristic of the human secretin receptor, and use rat-human secretin receptor chimeras, site mutants and truncated receptor constructs to establish the molecular basis for this unusual binding interaction. Of note, isolated N-terminal domains of the rat secretin and the VIP receptors are capable of high affinity binding of VIP. In the recently recognized secretin family of receptors, this domain has six conserved cysteine residues and disulfide bonds that are likely important to achieve the complex conformation critical for this binding. A single acidic residue (Asp98) present in the rat secretin receptor appears to be critical, because a site-mutant changing this to the polar, but uncharged residue present in that position in the human receptor (Asn) eliminates the high affinity binding of VIP. Of interest, a previously identified critical basic residue in VIP (Lys15) provides a candidate for charge-pairing with this residue, potentially aligning the peptide ligand in a nonproductive orientation within this receptor.     

Immunological identification of candidate proteins involved in regulating active shape changes of outer hair cells

By employing immunological methods, it has been demonstrated that myosin, myosin light chain (MLC) and myosin light chain kinase (MLCK) proteins in outer hair cells (OHC) are immunologically different from isoforms in platelets, smooth muscle and heart muscle, and are probably more related to isoforms found in red blood cells (RBC). Moreover, proteins related to band 3 protein (b3p) and protein 4.1 (p 4.1), ankyrin as well as fodrin and spectrin, but not glycophorin, have been identified in isolated OHCs. Both OHCs and RBC differ from other motile non-muscle cells in their lack of smooth muscle isoforms of actin, their common high levels of spectrin-, ankyrin- and band 3-like proteins, as well as the expression of the 80 kDa protein 4.1 isoform. The data support the notion that motility of OHC may be based upon regulation of the b3p/p 4.1/ankyrin complex, and thus may be reminiscent to the active shape changes in RBC.     

Verminderung des Gehaltes von Blei und anderen Elementen in Wein mit Hilfe von Pectins?ure

Zusammenfassung Der Bleigehalt von Wein kann durch Zusatz von Pectinsäure (PS) vermindert werden. Die Wirksamkeit der Bleiverminderung durch PS hängt von der Qualitätsstufe des Weines ab. In Auslesewein (Wein A) senkten 6250 mg PS/1 den Bleigehalt in 24 h von 0,88 mg/l auf 0,28 mg/l und in Spätlese (Wein B) von 0,83 mg/l auf 0,06 mg/1. Unter den gleichen Bedingungen nahm in Wein A der Gehalt an Fe, Zn und Cu von 8,85 mg/l auf 7,05 mg/1, von 4,75 mg/l auf 1,25 mg/l and von 0,67 mg/l auf 0.57 mg/l ab; bei Wein B reduzierte sich der Gehalt von Fe, Zn und Cu von 6,70 mg/l auf 5,41 mg/1, von 1,17 mg/l auf 0,28 mg/l und von 0,46 mg/l auf 0,28 mg/1. Durch Filtration des Weines wurde PS nahezu quantitativ entfernt. Eine geschmackliche Beeinträchtigung des Weines durch PS ist bei 750 mg and 1500 mg PS/1 nicht feststellbar, jedoch bei 6 250 mg PS/1 nicht auszuschließen. Aufgrund ihrer hohen Bindungsaffinität zu Blei scheint PS geeignet, Blei auch aus anderen flüssi-gen Lebensmitteln zu entfernen.

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Reduction of lead content and of other metals in wine by means of pectic acid

Summary A procedure for reducing the Pb content in wines containing high levels of Pb is described. The reduction of Pb by means of pectic acid (PA) depends on the quality grade of the wine. In Auslese (wine A) 6250 mg PA/l diminished Pb content in 24 h from 0.88 mg/l to 0.28 mg/1; in Spatlese (wine B) from 0.83 mg/l to 0.06 mg/1. Under the same conditions the content of Fe, Zn, Cu decreased in wine A from 8.85 mg/l to 7.05 mg/1, from 4.75 mg/l to 1.25 mg/1, from 0.67 mg/l to 0.57 mg/l and in wine B from 6.70 mg/l to 5.41 mg/1, from 1.17 mg/l to 0.28 mg, 0.46 mg/l to 0.28 mg/l, respectively. PA is removed almost quantitatively by filtration. Sensory properties of treated wines were unchanged with concentrations of PA of 750 mg and 1500 mg/l. A slight effect on taste at 6250 mg PA/l wine cannot be excluded. On account of its high affinity to Pb, PA will probably remove Pb from other liquid foods as well.

     

Polycyclic Aromatic Hydrocarbons Activate the Aryl Hydrocarbon Receptor and the Constitutive Androstane Receptor to Regulate Xenobiotic Metabolism in Human Liver Cells

Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants produced by incomplete combustion of organic matter. They induce their own metabolism by upregulating xenobiotic-metabolizing enzymes such as cytochrome P450 monooxygenase 1A1 (CYP1A1) by activating the aryl hydrocarbon receptor (AHR). However, previous studies showed that individual PAHs may also interact with the constitutive androstane receptor (CAR). Here, we studied ten PAHs, different in carcinogenicity classification, for their potential to activate AHR- and CAR-dependent luciferase reporter genes in human liver cells. The majority of investigated PAHs activated AHR, while non-carcinogenic PAHs tended to activate CAR. We further characterized gene expression, protein abundancies and activities of the AHR targets CYP1A1 and 1A2, and the CAR target CYP2B6 in human HepaRG hepatoma cells. Enzyme induction patterns strongly resembled the profiles obtained at the receptor level, with AHR-activating PAHs inducing CYP1A1/1A2 and CAR-activating PAHs inducing CYP2B6. In summary, this study provides evidence that beside well-known activation of AHR, some PAHs also activate CAR, followed by subsequent expression of respective target genes. Furthermore, we found that an increased PAH ring number is associated with AHR activation as well as the induction of DNA double-strand breaks, whereas smaller PAHs activated CAR but showed no DNA-damaging potential.     

Structure-Activity Relationships of Benzamides and Isoindolines Designed as SARS-CoV Protease Inhibitors Effective against SARS-CoV-2

Inhibition of coronavirus (CoV)-encoded papain-like cysteine proteases (PL^pro) represents an attractive strategy to treat infections by these important human pathogens. Herein we report on structure-activity relationships (SAR) of the noncovalent active-site directed inhibitor (R)-5-amino-2-methyl-N-(1-(naphthalen-1-yl)ethyl) benzamide ( 2 b ), which is known to bind into the S3 and S4 pockets of the SARS-CoV PL^pro. Moreover, we report the discovery of isoindolines as a new class of potent PL^pro inhibitors. The studies also provide a deeper understanding of the binding modes of this inhibitor class. Importantly, the inhibitors were also confirmed to inhibit SARS-CoV-2 replication in cell culture suggesting that, due to the high structural similarities of the target proteases, inhibitors identified against SARS-CoV PL^pro are valuable starting points for the development of new pan-coronaviral inhibitors.     

Luminescent Amphiphilic Aminoglycoside Probes to Study Transfection

We report the characterization of amphiphilic aminoglycoside conjugates containing luminophores with aggregation-induced emission properties as transfection reagents. These inherently luminescent transfection vectors are capable of binding plasmid DNA through electrostatic interactions; this binding results in an emission “on” signal due to restriction of intramolecular motion of the luminophore core. The luminescent cationic amphiphiles effectively transferred plasmid DNA into mammalian cells (HeLa, HEK 293T), as proven by expression of a red fluorescent protein marker. The morphologies of the aggregates were investigated by microscopy as well as ζ-potential and dynamic light-scattering measurements. The transfection efficiencies using luminescent cationic amphiphiles were similar to that of the gold-standard transfection reagent Lipofectamine® 2000.