Recursive Numeral Systems Optimize the Trade-off Between Lexicon Size and Average Morphosyntactic Complexity.

Human languages vary in terms of which meanings they lexicalize, but this variation is constrained. It has been argued that languages are under two competing pressures: the pressure to be simple (e.g., to have a small lexicon) and to allow for informative (i.e., precise) communication, and that which meanings get lexicalized may be explained by languages finding a good way to trade off between these two pressures. However, in certain semantic domains, languages can reach very high levels of informativeness even if they lexicalize very few meanings in that domain. This is due to productive morphosyntax and compositional semantics, which may allow for construction of meanings which are not lexicalized. Consider the semantic domain of natural numbers: many languages lexicalize few natural number meanings as monomorphemic expressions, but can precisely convey very many natural number meanings using morphosyntactically complex numerals. In such semantic domains, lexicon size is not in direct competition with informativeness. What explains which meanings are lexicalized in such semantic domains? We will propose that in such cases, languages need to solve a different kind of trade-off problem: the trade-off between the pressure to lexicalize as few meanings as possible (i.e, to minimize lexicon size) and the pressure to produce as morphosyntactically simple utterances as possible (i.e, to minimize average morphosyntactic complexity of utterances). To support this claim, we will present a case study of 128 natural languages' numeral systems, and show computationally that they achieve a near-optimal trade-off between lexicon size and average morphosyntactic complexity of numerals. This study in conjunction with previous work on communicative efficiency suggests that languages' lexicons are shaped by a trade-off between not two but three pressures: be simple, be informative, and minimize average morphosyntactic complexity of utterances.

The SlyD metallochaperone targets iron-sulfur biogenesis pathways and the TCA cycle.

IMPORTANCE: Correct folding of proteins represents a crucial step for their functions. Among the chaperones that control protein folding, the ubiquitous PPIases catalyze the cis/trans-isomerization of peptidyl-prolyl bonds. Only few protein targets of PPIases have been reported in bacteria. To fill this knowledge gap, we performed a large-scale two-hybrid screen to search for targets of the Escherichia coli and Helicobacter pylori SlyD PPIase-metallochaperone. SlyD from both organisms interacts with enzymes (i) containing metal cofactors, (ii) from the central metabolism tricarboxylic acid (TCA) cycle, and (iii) involved in the formation of the essential and ancestral Fe-S cluster cofactor. E. coli and H. pylori ∆slyD mutants present similar phenotypes of diminished susceptibility to antibiotics and to oxidative stress. In H. pylori, measurements of the intracellular ATP content, proton motive force, and activity of TCA cycle proteins suggest that SlyD regulates TCA cycle enzymes by controlling the formation of their indispensable Fe-S clusters.

8-Hydroxyquinolylnitrones as multifunctional ligands for the therapy of neurodegenerative diseases.

We describe the development of quinolylnitrones (QNs) as multifunctional ligands inhibiting cholinesterases (ChEs: acetylcholinesterase and butyrylcholinesterase-hBChE) and monoamine oxidases (hMAO-A/B) for the therapy of neurodegenerative diseases. We identified QN 19, a simple, low molecular weight nitrone, that is readily synthesized from commercially available 8-hydroxyquinoline-2-carbaldehyde. Quinolylnitrone 19 has no typical pharmacophoric element to suggest ChE or MAO inhibition, yet unexpectedly showed potent inhibition of hBChE (IC50 = 1.06 ± 0.31 nmol/L) and hMAO-B (IC50 = 4.46 ± 0.18 µmol/L). The crystal structures of 19 with hBChE and hMAO-B provided the structural basis for potent binding, which was further studied by enzyme kinetics. Compound 19 acted as a free radical scavenger and biometal chelator, crossed the blood-brain barrier, was not cytotoxic, and showed neuroprotective properties in a 6-hydroxydopamine cell model of Parkinson's disease. In addition, in vivo studies showed the anti-amnesic effect of 19 in the scopolamine-induced mouse model of AD without adverse effects on motoric function and coordination. Importantly, chronic treatment of double transgenic APPswe-PS1δE9 mice with 19 reduced amyloid plaque load in the hippocampus and cortex of female mice, underscoring the disease-modifying effect of QN 19.

Pseudo-irreversible butyrylcholinesterase inhibitors: Structure-activity relationships, computational and crystallographic study of the N-dialkyl O-arylcarbamate warhead.

Alongside reversible butyrylcholinesterase inhibitors, a plethora of covalent butyrylcholinesterase inhibitors have been reported in the literature, typically pseudo-irreversible carbamates. For these latter, however, most cases lack full confirmation of their covalent mode of action. Additionally, the available reports regarding the structure-activity relationships of the O-arylcarbamate warhead are incomplete. Therefore, a follow-up on a series of pseudo-irreversible covalent carbamate human butyrylcholinesterase inhibitors and the structure-activity relationships of the N-dialkyl O-arylcarbamate warhead are presented in this study. The covalent mechanism of binding was tested by IC50 time-dependency profiles, and sequentially and increasingly confirmed by kinetic analysis, whole protein LC-MS, and crystallographic analysis. Computational studies provided valuable insights into steric constraints and identified problematic, bulky carbamate warheads that cannot reach and carbamoylate the catalytic Ser198. Quantum mechanical calculations provided further evidence that steric effects appear to be a key factor in determining the covalent binding behaviour of these carbamate cholinesterase inhibitors and their duration of action. Additionally, the introduction of a clickable terminal alkyne moiety into one of the carbamate N-substituents and in situ derivatisation with azide-containing fluorophore enabled fluorescent labelling of plasma human butyrylcholinesterase. This proof-of-concept study highlights the potential of this novel approach and for these compounds to be further developed as clickable molecular probes for investigating tissue localisation and activity of cholinesterases.

Indefinite Pronouns Optimize the Simplicity/Informativeness Trade-Off.

The vocabulary of human languages has been argued to support efficient communication by optimizing the trade-off between simplicity and informativeness. The argument has been originally based on cross-linguistic analyses of vocabulary in semantic domains of content words, such as kinship, color, and number terms. The present work applies this analysis to a category of function words: indefinite pronouns (e.g., someone, anyone, no one). We build on previous work to establish the meaning space and featural make-up for indefinite pronouns, and show that indefinite pronoun systems across languages optimize the simplicity/informativeness trade-off. This demonstrates that pressures for efficient communication shape both content and function word categories. In doing so, our work aligns with several concurrent studies exploring the simplicity/informativeness trade-off in functional vocabulary. Importantly, we further argue that the trade-off may explain some of the universal properties of indefinite pronouns, thus reducing the explanatory load for linguistic theories.

The influence of polarity items on inferential judgments.

Polarity items are linguistic expressions such as any, at all, some, which are acceptable in some linguistic environments but not others. Crucially, whether a polarity item is acceptable in a given environment is argued to depend on the inferences (in the reasoning sense) that this environment allows. We show that the inferential judgments reported for a given environment are modified in the presence of polarity items. Hence, there is a two-way influence between linguistic and reasoning abilities: the linguistic acceptability of polarity items is dependent on reasoning facts and, conversely, reasoning judgments can be altered by the mere addition of seemingly innocuous polarity items.

A novel mode of control of nickel uptake by a multifunctional metallochaperone.

Cellular metal homeostasis is a critical process for all organisms, requiring tight regulation. In the major pathogen Helicobacter pylori, the acquisition of nickel is an essential virulence determinant as this metal is a cofactor for the acid-resistance enzyme, urease. Nickel uptake relies on the NixA permease and the NiuBDE ABC transporter. Till now, bacterial metal transporters were reported to be controlled at their transcriptional level. Here we uncovered post-translational regulation of the essential Niu transporter in H. pylori. Indeed, we demonstrate that SlyD, a protein combining peptidyl-prolyl isomerase (PPIase), chaperone, and metal-binding properties, is required for the activity of the Niu transporter. Using two-hybrid assays, we found that SlyD directly interacts with the NiuD permease subunit and identified a motif critical for this contact. Mutants of the different SlyD functional domains were constructed and used to perform in vitro PPIase activity assays and four different in vivo tests measuring nickel intracellular accumulation or transport in H. pylori. In vitro, SlyD PPIase activity is down-regulated by nickel, independently of its C-terminal region reported to bind metals. In vivo, a role of SlyD PPIase function was only revealed upon exposure to high nickel concentrations. Most importantly, the IF chaperone domain of SlyD was shown to be mandatory for Niu activation under all in vivo conditions. These data suggest that SlyD is required for the active functional conformation of the Niu permease and regulates its activity through a novel mechanism implying direct protein interaction, thereby acting as a gatekeeper of nickel uptake. Finally, in agreement with a central role of SlyD, this protein is essential for the colonization of the mouse model by H. pylori.

Review: Pathogenesis of Helicobacter pylori infection.

The original strategies developed by Helicobacter pylori to persistently colonise its host and to deregulate its cellular functions make this bacterium an outstanding model to study host-pathogen interaction and the mechanisms responsible for bacterial-induced carcinogenesis. During the last year, significant results were obtained on the role of bacterial factors essential for gastric colonisation such as spiral shape maintenance, orientation through chemotaxis and the formation of bacteria clonal population islands inside the gastric glands. Particularities of the H pylori cell surface, a structure important for immune escape, were demonstrated. New insights in the bacterial stress response revealed the importance of DNA methylation-mediated regulation. Further findings were reported on H pylori components that mediate natural transformation and mechanisms of bacterial DNA horizontal transfer which maintain a high level of H pylori genetic variability. Within-host evolution was found to be niche-specific and probably associated with physiological differences between the antral and oxyntic gastric mucosa. In addition, with the progress of CryoEM, high-resolution structures of the major virulence factors, VacA and CagT4SS, were obtained. The use of gastric organoid models fostered research revealing, preferential accumulation of bacteria at the site of injury during infection. Several studies further characterised the role of CagA in the oncogenic properties of H pylori, identifying the activation of novel CagA-dependent pathways, leading to the promotion of genetic instabilities, epithelial-to-mesenchymal transition and finally carcinogenesis. Recent studies also highlight that microRNA-mediated regulation and epigenetic modifications, through DNA methylation, are key events in the H pylori-induced tumorigenesis process.

The σB signalling activation pathway in the enteropathogen Clostridioides difficile.

Clostridium difficile is the main cause of antibiotic-associated diarrhoea. Inside the gut, C. difficile must adapt to the stresses it copes with, by inducing protection, detoxification and repair systems that belong to the general stress response involving σB . Following stresses, σB activation requires a PP2C phosphatase to dephosphorylate the anti-anti-sigma factor RsbV that allows its interaction with the anti-sigma factor RsbW and the release of σB . In this work, we studied the signalling pathway responsible for the activation of σB in C. difficile. Contrary to other firmicutes, the expression of sigB in C. difficile is constitutive and not autoregulated. We confirmed the partner switching mechanism that involved RsbV, RsbW and σB . We also showed that CD2685, renamed RsbZ, and its phosphatase activity are required for RsbV dephosphorylation triggering σB activation. While CD0007 and CD0008, whose genes belong to the sigB operon, are not involved in σB activity, depletion of the essential iron-sulphur flavoprotein, CD2684, whose gene forms an operon with rsbZ, prevents σB activation. Finally, we observed that σB is heterogeneously active in a subpopulation of C. difficile cells from the exponential phase, likely leading to a 'bet-hedging' strategy allowing a better chance for the cells to survive adverse conditions.