Solution Structure of a Hexitol Nucleic Acid Duplex with Four Consecutive T⋅T Base Pairs

The structure of the hexitol nucleic acid (HNA) h(GCGCTTTTGCGC) was determined by NMR spectroscopy. This unnatural nucleic acid was developed as a mimic for A‐RNA. In solution, the studied sequence is forming a symmetric double‐stranded structure with four central consecutive T⋅T wobble pairs flanked by G⋅C Watson‐Crick base pairs. The stem regions adopt an A‐type helical structure. Discrete changes in backbone angles are altering the course of the helix axis in the internal loop region. Two H‐bonds are formed in each wobble pair, and base stacking is preserved in the duplex, explaining the stability of the duplex. This structure elucidation provides information about the influence of a (T)₄ fragment on local helix geometries as well as on the nature of the T⋅T mismatch base pairing in a TTTT tract.     

Toric Aspects of the First Eigenvalue

In this paper we study the smallest non-zero eigenvalue \(\lambda _1\) of the Laplacian on toric Kähler manifolds. We find an explicit upper bound for \(\lambda _1\) in terms of moment polytope data. We show that this bound can only be attained for \(\mathbb C\mathbb P^n\) endowed with the Fubini–Study metric and therefore \(\mathbb C\mathbb P^n\) endowed with the Fubini–Study metric is spectrally determined among all toric Kähler metrics. We also study the equivariant counterpart of \(\lambda _1\) which we denote by \(\lambda _1^T\). It is the smallest non-zero eigenvalue of the Laplacian restricted to torus-invariant functions. We prove that \(\lambda _1^T\) is not bounded among toric Kähler metrics thus generalizing a result of Abreu–Freitas on \(S^2\). In particular, \(\lambda _1^T\) and \(\lambda _1\) do not coincide in general.     

Divide and conquer: rat liver tissue proteomics based on the analysis of purified constituents

Comparative proteome data of normal and diseased tissue samples are difficult to interpret. Proteins detected in tissues are derived from different cell types and blood constituents. Pathologic or toxicant-induced aberrations may affect the proteome profile of tissues in several ways since different cell types may respond in very different and highly specific manners. The aim of this study was to analyze the proteome profiles of purified rat liver primary cells and of blood plasma in comparison to liver whole tissue. Moreover, we investigated alterations of these profiles induced by the liver toxicant N-nitrosomorpholine (NNM) used as a model compound. Whole liver samples, pure hepatocytes and Kupffer cells as well as blood plasma were obtained from saline- or NNM-treated rats. Proteins were separated by 2-D PAGE and their amounts were estimated by fluorography. Selected proteins were identified by MS analysis of tryptic digests. Among them we identified proteins exclusively expressed in the analysed constituents. Several of these proteins were assigned in the proteome profile of whole-tissue homogenates. Furthermore, we identified several proteins that were modified, up-regulated or down-regulated due to NNM treatment in total liver homogenates. Some of these protein alterations were specifically detected in primary cells isolated from NNM-treated rats. Thus, we demonstrated the successful assignment of NNM-induced proteome alterations in rat liver to the cell type of origin. The currently applied approach may help to better understand pathologic processes at a whole-tissue level.     

The Kalimantacin Polyketide Antibiotics Inhibit Fatty Acid Biosynthesis in Staphylococcus aureus by Targeting the Enoyl‐Acyl Carrier Protein Binding Site of FabI

The enoyl‐acyl carrier protein reductase enzyme FabI is essential for fatty acid biosynthesis in Staphylococcus aureus and represents a promising target for the development of novel, urgently needed anti‐staphylococcal agents. Here, we elucidate the mode of action of the kalimantacin antibiotics, a novel class of FabI inhibitors with clinically‐relevant activity against multidrug‐resistant S. aureus. By combining X‐ray crystallography with molecular dynamics simulations, in vitro kinetic studies and chemical derivatization experiments, we characterize the interaction between the antibiotics and their target, and we demonstrate that the kalimantacins bind in a unique conformation that differs significantly from the binding mode of other known FabI inhibitors. We also investigate mechanisms of acquired resistance in S. aureus and identify key residues in FabI that stabilize the binding of the antibiotics. Our findings provide intriguing insights into the mode of action of a novel class of FabI inhibitors that will inspire future anti‐staphylococcal drug development.     

Evaluating noise in social context: the effect of procedural unfairness on noise annoyance judgments

General dosage-response curves typically over- or underestimate the actual prevalence of noise annoyance for specific groups of individuals. The present study applies a social psychological approach to noise annoyance that helps to understand and predict collective deflections from the curve. The approach holds that being exposed to man-made sound is more than mere exposure; it is a social experience, too: You expose Me. In effect, social aspects of the situation, like the evaluation of the sound management procedure, influence the evaluation of sound. The laboratory experiment (N=90) investigates the effect of procedural unfairness on noise annoyance. The sound management procedure is varied systematically: Participants are promised they will listen to the sound of their choice (i.e., bird song, radio sound, or aircraft sound) but receive aircraft sound despite their expressed preference (unfair procedure), or they are simply told they will listen to aircraft sound (neutral procedure). All are exposed to aircraft sound (50 or 70 dBA Leq). A collective rise in noise annoyance is predicted in the unfair relative to the neutral procedure conditions. Results show that noise annoyance ratings are significantly higher in the unfair relative to the neutral conditions. Consequences for theory and practice are discussed.     

Structural characterization and biological evaluation of small interfering RNAs containing cyclohexenyl nucleosides

CeNA is an oligonucleotide where the (deoxy)ribose sugars have been replaced by cyclohexenyl moieties. We have determined the NMR structure of a CeNA:RNA duplex and have modeled this duplex in the crystal structure of a PIWI protein. An N puckering of the ribose nucleosides, a 2H3 conformation of the cyclohexenyl nucleosides, and an A-like helix conformation of the backbone, which deviates from the standard A-type helix by a larger twist and a smaller slide, are observed. The model of the CeNA:RNA duplex bound to the PIWI protein does not show major differences in the interaction of the guide CeNA with the protein when compared with dsRNA, suggesting that CeNA modified oligonucleotides might be useful as siRNAs. Incorporation of one or two CeNA units in the sense or antisense strands of dsRNA led to similar or enhanced activity compared to unmodified siRNAs. This was tested by targeting inhibition of expression of the MDR1 gene with accompanying changes in P-glycoprotein expression, drug transport, and drug resistance.     

Synthesis of Nicotinamide Adenine Dinucleotide (NAD) Analogues with a Sugar Modified Nicotinamide Moiety

The synthesis of nicotinamide adenine dinucleotide (NAD) analogues in which the ribose unit of the nicotinamide moiety is replaced by a hexitol, altritol, and cyclohexenyl sugar mimic is described.     

Preparation and thermal stability of Al2O3-clay and Fe2O3-clay nanocomposites, with potential application as remediation of radioactive effluents

In the last years metal/clays, aluminosilicates with properties and characteristics of microporous materials, have received more attention, due to the possibility of their use as matrix for nanoparticles encapsulation and stabilization processes. Some types of clays were comparatively evaluated for treating the simulated radioactive wastewater. The raw clay from Valea Chioarului Romania and its pillared forms with Al, Fe, pillars for decontamination of waste-waters with medium and low radioactivity were used. Characterization of the obtained materials was carried out using techniques such as X-ray diffraction, Fourier transform infrared spectroscopy, BET analyses and thermogravimetric analysis (DTG-TG), respectively. Also, the thermal stability of nanocomposites was highly superior to native clay due to the presence of the well-dispersed clay nanolayer, which has a barrier property in a composite system. Clay nanocomposite sample materials were obtained with good thermal stability after calcination. Clay nanocomposites samples were evaluated for remediation of radioactive effluents by treating the radioactive wastes streams. The ion-exchange characteristics and the abilities to uptake radioisotopes of indigene clay from Valea Chioarului area-Romania were examined. The results showed that the precursor used in sample preparation influenced the structural and textural properties of nanocomposites and also capability of prepared modified clay samples by pillaring to be potential candidates for use in connection with environmental protection, remediation of radioactive effluents, respectively.     

Influence of the nucleobase and anchimeric assistance of the carboxyl acid groups in the hydrolysis of amino acid nucleoside phosphoramidates

Nucleoside phosphoramidates (NPs) are a class of nucleotide analogues that has been developed as potential antiviral/antitumor prodrugs. Recently, we have shown that some amino acid nucleoside phosphoramidates (aaNPs) can act as substrates for viral polymerases like HIV‐1 RT. Herein, we report the synthesis and hydrolysis of a series of new aaNPs, containing either natural or modified nucleobases to define the basis for their differential reactivity. Aqueous stability, kinetics, and hydrolysis pathways were studied by NMR spectroscopy at different solution pD values (5–7) and temperatures. It was observed that the kinetics and mechanism (P? N and/or P? O bond cleavage) of the hydrolysis reaction largely depend on the nature of the nucleobase and amino acid moieties. Aspartyl NPs were found to be more reactive than Gly or β‐Ala NPs. For aspartyl NPs, the order of reactivity of the nucleobase was 1‐deazaadenine>7‐deazaadenine>adenine>thymine≥3‐deazaadenine. Notably, neutral aqueous solutions of Asp‐1‐deaza‐dAMP degraded spontaneously even at 4 °C through exclusive P? O bond hydrolysis (a 50‐fold reactivity difference for Asp‐1‐deaza‐dAMP vs. Asp‐3‐deaza‐dAMP at pD 5 and 70 °C). Conformational studies by NMR spectroscopy and molecular modeling suggest the involvement of the protonated N3 atom in adenine and 1‐ and 7‐deazaadenine in the intramolecular catalysis of the hydrolysis reaction through the rare syn conformation.