Anion receptor chemistry: highlights from 2011 and 2012

This review covers advances in anion complexation in the years 2011 and 2012. The review covers both organic and inorganic systems and also highlights the applications to which anion receptors can be applied such as self-assembly and molecular architecture, sensing, catalysis and anion transport

Highly effective yet simple transmembrane anion transporters based upon ortho-phenylenediamine bis-ureas

Simple, highly fluorinated receptors are shown to function as highly effective transmembrane anion antiporters with the most active transporters rivalling the transport efficacy of natural anion transporter prodigiosin for bicarbonate

Thiosquaramides: pH switchable anion transporters

The transport of anions across cellular membranes is an important biological function governed by specialised proteins. In recent years, many small molecules have emerged that mimick the anion transport behaviour of these proteins, but only a few of these synthetic molecules also display the gating/switching behaviour seen in biological systems. A small series of thiosquar-amides was synthesised and their pH-dependent chloride binding and anion transport behaviour was investigated using 1H NMR titrations, single crystal X-ray diffraction and a variety of vesicle-based techniques. Spectrophotometric titrations and DFT calculations revealed that the thiosquaramides are significantly more acidic than their oxosquaramide analogues, with pKa values between 4.0 and 9.0. This led to the observation that at pH 7.2 the anion transport ability of the thiosquaramides is fully switched OFF due to deprotonation of the receptor, but is completely switched ON at lower pH

Words cluster phonetically beyond phonotactic regularities

Recent evidence suggests that cognitive pressures associated with language acquisition and use could affect the organization of the lexicon. On one hand, consistent with noisy channel models of language (e.g., Levy, 2008), the phonological distance between wordforms should be maximized to avoid perceptual confusability (a pressure for dispersion). On the other hand, a lexicon with high phonological regularity would be simpler to learn, remember and produce (e.g., Monaghan et al., 2011) (a pressure for clumpiness). Here we investigate wordform similarity in the lexicon, using measures of word distance (e.g., phonological neighborhood density) to ask whether there is evidence for dispersion or clumpiness of wordforms in the lexicon. We develop a novel method to compare lexicons to phonotactically-controlled baselines that provide a null hypothesis for how clumpy or sparse wordforms would be as the result of only phonotactics. Results for four languages, Dutch, English, German and French, show that the space of monomorphemic wordforms is clumpier than what would be expected by the best chance model according to a wide variety of measures: minimal pairs, average Levenshtein distance and several network properties. This suggests a fundamental drive for regularity in the lexicon that conflicts with the pressure for words to be as phonologically distinct as possible. Keywords: Linguistics; Lexical design; Communication; Phonotactic

Full elucidation of the transmembrane anion transport mechanism of squaramides using in silico investigations

A comprehensive experimental and theoretical investigation of the transmembrane chloride transport promoted by four series of squaramide derivatives, with different degrees of fluorination, number of convergent N-H binding units and conformational shapes, is reported. The experimental chloride binding and transport abilities of these small synthetic molecules in liposomes were rationalised with quantum descriptors and molecular dynamics simulations in POPC bilayers. The tripodal tren-based compounds, with three squaramide binding motifs, have high chloride affinity, isolating the anion from water molecules within the membrane model and preventing its release to the aqueous phase, in agreement with the absence of experimental transport activity. In contrast, the symmetrical monosquaramides, with moderate chloride binding affinity, are able to bind and release chloride either in the aqueous phase or at the membrane interface level, in line with experimentally observed high transport activity. The PMF profiles associated with the diffusion of these free transporters and their chloride complexes across phospholipid bilayers show that the assisted chloride translocation is thermodynamically favoured

Acylthioureas as anion transporters: the effect of intramolecular hydrogen bonding

Small molecule synthetic anion transporters may have potential application as therapeutic agents for the treatment of diseases including cystic fibrosis and cancer. Understanding the factors that can dictate the anion transport activity of such transporters is a crucial step towards their application in biological systems. In this study a series of acylthiourea anion transporters were synthesised and their anion binding and transport properties in POPC bilayers have been investigated. The transport activity of these receptors is dominated by their lipophilicity, which is in turn dependent on both substituent effects and the formation and strength of an intramolecular hydrogen bond as inferred from DFT calculations. This is in contrast to simpler thiourea systems, in which the lipophilicity depends predominantly on substituent effects alone

Molecular Mimicry of Human Cytochrome P450 by Hepatitis C Virus at the Level of Cytotoxic T Cell Recognition

Hepatitis C virus (HCV) is thought to be involved in the pathogenesis of autoimmune hepatitis (AIH) type 2, which is defined by the presence of type I antiliver kidney microsome autoantibodies directed mainly against cytochrome P450 (CYP)2D6 and by autoreactive liver infiltrating T cells. Virus-specific CD8+ cytotoxic T lymphocytes (CTLs) that recognize infected cells and contribute to viral clearance and tissue injury during HCV infection could be involved in the induction of AIH. To explore whether the antiviral cellular immunity may turn against self-antigens, we characterized the primary CTL response against an HLA-A*0201–restricted HCV-derived epitope, i.e., HCV core 178–187, which shows sequence homology with human CYP2A6 and CYP2A7 8–17. To determine the relevance of these homologies for the pathogenesis of HCV-associated AIH, we used synthetic peptides to induce primary CTL responses in peripheral blood mononuclear cells of healthy blood donors and patients with chronic HCV infection. We found that the naive CTL repertoire of both groups contains cross-reactive CTLs inducible by the HCV peptide recognizing both CYP2A6 and CYP2A7 peptides as well as endogenously processed CYP2A6 protein. Importantly, we failed to induce CTLs with the CYP-derived peptides that showed a lower capacity to form stable complexes with the HLA-A2 molecule. These findings demonstrate the potential of HCV to induce autoreactive CD8+ CTLs by molecular mimicry, possibly contributing to virus-associated autoimmunity

[18F]fluorination/decarbonylation: New route to aryl [18F]fluorides

A new route to aryl [18F]fluorides without electron withdrawing ring substituents has been developed. [18F]Fluorobenzaldehydes, prepared from no-carrier-added (NCA) [18F]fluoride using nucleophilic aromatic substitution of fluoro or nitro groups, were decarbonylated using palladium on charcoal (Pd-C). By this approach 2-methoxy-4-nitrobenzaldehyde was converted to NCA 3-[18F]fluorophenol (25-30%, EOB) and 4-fluoro-2-methoxy-5-methylbenzaldehyde to carrier-added (CA) 3-[18F]fluoro-4-methylphenol (30-40%, EOB). Overall synthesis time was about 2 h. Since the 4-fluoro-2-methoxy-5-methylbenzaldehyde was in turn prepared by methylation and regiospecific formylation of 3-fluoro-4-methylphenol, the overall process represents use of a removable activating group for nucleophilic aromatic substitution with [18F]fluoride for preparation of CA and NCA aryl [18F]fluorides.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29665/1/0000754.pd

Gender Gap in Parental Leave Intentions: Evidence from 37 Countries

Despite global commitments and efforts, a gender-based division of paid and unpaid work persists. To identify how psychological factors, national policies, and the broader sociocultural context contribute to this inequality, we assessed parental-leave intentions in young adults (18–30 years old) planning to have children (N = 13,942; 8,880 identified as women; 5,062 identified as men) across 37 countries that varied in parental-leave policies and societal gender equality. In all countries, women intended to take longer leave than men. National parental-leave policies and women’s political representation partially explained cross-national variations in the gender gap. Gender gaps in leave intentions were paradoxically larger in countries with more gender-egalitarian parental-leave policies (i.e., longer leave available to both fathers and mothers). Interestingly, this cross-national variation in the gender gap was driven by cross-national variations in women’s (rather than men’s) leave intentions. Financially generous leave and gender-egalitarian policies (linked to men’s higher uptake in prior research) were not associated with leave intentions in men. Rather, men’s leave intentions were related to their individual gender attitudes. Leave intentions were inversely related to career ambitions. The potential for existing policies to foster gender equality in paid and unpaid work is discussed