This study describes a novel series of UDP-N-acetylglucosamine acyltransferase (LpxA) inhibitors that was identified through affinity-mediated selection from a DNA-encoded compound library. The original hit was a selective inhibitor of Pseudomonas aeruginosa LpxA with no activity against Escherichia coli LpxA. The biochemical potency of the series was optimized through an X-ray crystallography-supported medicinal chemistry program, resulting in compounds with nanomolar activity against P. aeruginosa LpxA (best half-maximal inhibitory concentration (IC50) <5 nM) and cellular activity against P. aeruginosa (best minimal inhibitory concentration (MIC) of 4 μg/mL). Lack of activity against E. coli was maintained (IC50 > 20 μM and MIC > 128 μg/mL). The mode of action of analogues was confirmed through genetic analyses. As expected, compounds were active against multidrug-resistant isolates. Further optimization of pharmacokinetics is needed before efficacy studies in mouse infection models can be attempted. To our knowledge, this is the first reported LpxA inhibitor series with selective activity against P. aeruginosa.
International audienceIn this chapter, we will introduce the basic research questions spanning all chapters in this volume: How do we ‘encode’ complex thoughts into linguistic signals, how do we interpret such signals in appropriate ways, and to what extent is what we encode constrained at the outset by the particular language we grow up with? We will introduce recent developments of an experimental approach to linguistics and argue for the necessity of cross-linguistic experimental paradigms for linguistic research at the interface of syntax, semantics and pragmatics
Syntactic language features of word problems have often been identified by assessment studies and interview studies as potential obstacles in word problem solving. However, students' processes of noticing and interpreting these features have only rarely been investigated in depth because noticing is hard to investigate. Eye-tracking methodology has already been shown to be a suitable methodology for analyzing noticing other word problem features, but not yet for syntactic features. The longitudinal eye-tracking study presented here analyzes fifth graders' processes of noticing and interpreting of syntactic word problems before and after an intervention on word problem solving. Based on the eye-mind hypothesis, the study captures students' noticing through eyetracking, whereas interpreting can be captured by their solutions. The analysis of pre-intervention data reveals that long fixations cannot be identified with successful noticing and vice versa. But when comparing the net dwell time (i.e., the time that students look at the words indicating syntactic structures) before and after the intervention, an interesting decrease is revealed. This decrease occurs for both expected and less expected syntactic structures, regardless of the accuracy of mathematization. Meanwhile, analyzing the revisits of students indicates differences between items with more or less expected structures and correctly or incorrectly mathematized items. Methodologically, the article contributes to understanding which eye-tracking measures are relevant for capturing changes in students' processes of noticing syntactic language features: The revisits and scan paths reveal more insights than the net dwell time.
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Much of how we sequence events in speech mirrors the order of their natural occurrence. While event chains that conform to chronology may be easier to process, languages offer substantial freedom to manipulate temporal order. This article explores to what extent digressions from chronology are attributable to differences in grammatical aspect systems. We compared reverse order reports (RORs) in event descriptions elicited from native speakers of four languages, two with (Spanish, Modern Standard Arabic [MSA]) and two without grammatical aspect (German, Hungarian). In the Arabic group, all participants were highly competent MSA speakers from Palestine and Jordan. Standardized frequency counts showed significantly more RORs expressed by non-aspect groups than by aspect groups. Adherence to chronology changing as a function of contrast in grammatical aspect signal that languages without obligatory marking of ongoingness may provide more flexibility for event reordering. These findings bring novel insights about the dynamic interplay between language structure and temporal sequencing in the discourse stream.
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