Identifying components required for OMP biogenesis as novel targets for antiinfective drugs

The emergence of multiresistant Gram-negative bacteria requires new therapies for combating bacterial infections. Targeting the biogenesis of virulence factors could be an alternative strategy instead of killing bacteria with antibiotics. The outer membrane (OM) of Gram-negative bacteria acts as a physical barrier. At the same time it facilitates the exchange of molecules and harbors a multitude of proteins associated with virulence. In order to insert proteins into the OM, an essential oligomeric membrane-associated protein complex, the ss-barrel assembly machinery (BAM) is required. Being essential for the biogenesis of outer membrane proteins (OMPs) the BAM and also periplasmic chaperones may serve as attractive targets to develop novel antiinfective agents. Herein, we aimed to elucidate which proteins belonging to the OMP biogenesis machinery have the most important function in granting bacterial fitness, OM barrier function, facilitating biogenesis of dedicated virulence factors and determination of overall virulence. To this end we used the enteropathogen Yersinia enterocolitica as a model system. We individually knocked out all non-essential components of the BAM (BamB, C and E) as well as the periplasmic chaperones DegP, SurA and Skp. In summary, we found that the most profound phenotypes were produced by the loss of BamB or SurA with both knockouts resulting in significant attenuation or even avirulence of Ye in a mouse infection model. Thus, we assume that both BamB and SurA are promising targets for the development of new antiinfective drugs in the future.Peer reviewe

Situating language register across the ages, languages, modalities, and cultural aspects: Evidence from complementary methods

In the present review paper by members of the collaborative research center “Register: Language Users' Knowledge of Situational-Functional Variation” (CRC 1412), we assess the pervasiveness of register phenomena across different time periods, languages, modalities, and cultures. We define “register” as recurring variation in language use depending on the function of language and on the social situation. Informed by rich data, we aim to better understand and model the knowledge involved in situation- and function-based use of language register. In order to achieve this goal, we are using complementary methods and measures. In the review, we start by clarifying the concept of “register”, by reviewing the state of the art, and by setting out our methods and modeling goals. Against this background, we discuss three key challenges, two at the methodological level and one at the theoretical level: (1) To better uncover registers in text and spoken corpora, we propose changes to established analytical approaches. (2) To tease apart between-subject variability from the linguistic variability at issue (intra-individual situation-based register variability), we use within-subject designs and the modeling of individuals' social, language, and educational background. (3) We highlight a gap in cognitive modeling, viz. modeling the mental representations of register (processing), and present our first attempts at filling this gap. We argue that the targeted use of multiple complementary methods and measures supports investigating the pervasiveness of register phenomena and yields comprehensive insights into the cross-methodological robustness of register-related language variability. These comprehensive insights in turn provide a solid foundation for associated cognitive modeling.Peer Reviewe

The influence of Nature and Nurture on speaker-specific parameters in twins speech

Die Dissertation thematisiert sprecherspezifische Variabilität bei ein- und zweieiigen Zwillingen hinsichtlich Artikulation, Akustik und Perzeption. Die zentrale Fragestellung ist, ob sprecherspezifische Charakteristika auf physiologisch-biologischen Differenzen der Sprecher beruhen (BIOLOGIE), oder sich auf gelernte, umweltabhängige Unterschiede zurückführen lassen (UMWELT). Artikulatorische und akustische Daten wurden von 4 eineiigen Zwillingspaaren (EZ, 100% genetische Übereinstimmung) und 3 zweieiigen Zwillingspaaren (ZZ, 50% genetische Übereinstimmung) analysiert. Zusätzlich wurde ein Perzeptionstest zur auditiven Ähnlichkeit der Zwillinge durchgeführt. Auf einen großen Einfluss des Faktors BIOLOGIE lässt sich schließen, wenn sich EZ ähnlicher sind als ZZ. Sind sich aber ZZ genauso ähnlich wie EZ, zeigt sich die Wichtigkeit der gleichen Lernumgebung (UMWELT). Die Ergebnisse weisen auf einen großen Einfluss des Faktors UMWELT und stützen die Hypothese, dass sprachliche Ziele gelernt sind und sich am auditiven Feedback orientieren. Darüber hinaus wurden drei Faktoren gefunden, die den Einfluss der BIOLOGIE intensivieren: a) Lautklasse, b) Wortakzent und c) Koartikulation. Plosive und Sibilanten sind aufgrund des stärker ausgeprägten linguo-palatalen Kontaktes mehr durch die individuelle Physiologie beeinflusst als Vokale. Außerdem wurde ein größerer Effekt des Faktors BIOLOGIE in unbetonten als in betonten Silben gefunden. Zusätzlich stellten sich koartikulatorische Prozesse als wichtig heraus: dynamische Parameter – artikulatorische Gesten und akustische Transitionen – sind stärker durch die Physiologie beeinflusst als statische Parameter – artikulatorische Ziele und stabile akustische Regionen. Sowohl der Faktor BIOLOGIE als auch der Faktor UMWELT sind einflussreiche Größen hinsichtlich sprecherspezifischer Variabilität. Welcher der beiden Faktoren die übergeordnete Rolle übernimmt, hängt von den spezifischen Charakteristika des untersuchten Parameters ab.This dissertation examines inter-speaker variability in monozygotic (MZ) and dizygotic (DZ) twin pairs in regard to articulation, acoustics and perception. The aim of the study is to evaluate whether speaker-specific variability reflects physiological differences between speakers (NATURE) or bases on learned variation due to social environmental influences (NURTURE). Articulatory and acoustic data was analyzed from 4 MZ twin pairs (100% identical genes) and 3 DZ twin pairs (50 % identical genes). Additionally, a perception experiment was carried out to explore the perceived auditory similarity. The effect of NATURE should have a larger impact than the effect of NURTURE, if a parameter differs more in DZ than in MZ twin pairs. If MZ and DZ twins show the same amount of inter-speaker variability, NURTURE seems to be crucial. Results point to the importance of NURTURE and shared social environment. Nevertheless, three factors were found that intensify the effect of NATURE: a) phoneme class, b) lexical stress, and c) degree of coarticulation. Somatosensory feedback plays a larger role for consonants than for vowels, and thus individual physiology was found to shape articulation more in sibilants and stops than in vowels. Additionally, a stronger impact of NATURE was found in parameters that are auditorily less salient: unstressed syllables were more similar in MZ than in DZ twins, while for stressed syllables this was not the case. Moreover, coarticulation turned out to be essential: dynamic parameters – articulatory gestures and acoustic transitions – were more influenced by physiological constraints (NATURE) than static parameters – articulatory targets and stable acoustic regions. Thus, both NATURE and NURTURE are crucial influencing factors in speaker-specific variability. However, the relative importance of the two factors is highly dependent on the specific characteristics of the investigated parameter

Articulatory and acoustic inter-speaker variability in the production of German vowels

This study examines articulatory and acoustic inter-speaker variability in the production of the German vowels /i/, /u/ and /a/. Our subjects are 3 monozygotic twin pairs (2 female and 1 male pair) and 2 dizygotic female twin pairs. All of them were born, raised and are still living in Berlin and see their twin brother or sister regularly. We assume that monozygotic twins that are genetically identical and share the same physiology should be more similar in their articulation than dizygotic twins but that the shared time and social environment of twins, regardless of their genetic similarity, also plays a crucial role in the acoustic similarity of twins. Articulatory measurements were made with EMA (Electromagnetic Articulography) and the target positions of the produced vowels were analyzed. Additionally, the formants F1-F4 of each vowel were measured and compared within the twin pairs. Our data seems to point out the importance of a shared environment and the strong influence of learning over the anatomical identity of the monozygotic twins regarding the production of vowels. But, additional results suggest (1) the impact of physiology on the production of a vowel following a velar consonant and (2) the interaction of physiology and stress in inter-speaker variability