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In this study, we investigate the three-dot sign as a discourse marker (DM) with textual, subjective and intersubjective discourse functions. As a graphical marker that is used across languages, the three-dot sign is especially suitable for comparative studies and dynamics in language contact. Our corpus study targeting instant messages of different languages (English, German, Greek, Russian, Turkish) and speaker groups (monolinguals and bilingual heritage speakers) suggests that graphical DMs are prone to cross-linguistic influence. This depends on the specific contact situation and does not seem to be a general effect of bilingualism. The societal status of a language might further influence the use of such markers in digital informal writing. Language-specific developments that relate to emerging functions indicate that functional versatility promotes frequent use of (graphical) DMs.

Pancreatic ductal adenocarcinoma (PDAC) still presents with a dismal prognosis despite intense research. Better understanding of cellular homeostasis could identify druggable targets to improve therapy. Here we propose RAD50-interacting protein 1 (RINT1) as an essential mediator of cellular homeostasis in PDAC. In a cohort of resected PDAC, low RINT1 protein expression correlated significantly with better survival. Accordingly, RINT1 depletion caused severe growth defects in vitro associated with accumulation of DNA double-strand breaks (DSB), G2 cell cycle arrest, disruption of Golgi–endoplasmic reticulum homeostasis, and cell death. Time-resolved transcriptomics corroborated by quantitative proteome and interactome analyses pointed toward defective SUMOylation after RINT1 loss, impairing nucleocytoplasmic transport and DSB response. Subcutaneous xenografts confirmed tumor response by RINT1 depletion, also resulting in a survival benefit when transferred to an orthotopic model. Primary human PDAC organoids licensed RINT1 relevance for cell viability. Taken together, our data indicate that RINT1 loss affects PDAC cell fate by disturbing SUMOylation pathways. Therefore, a RINT1 interference strategy may represent a new putative therapeutic approach.Significance:These findings provide new insights into the aggressive behavior of PDAC, showing that RINT1 directly correlates with survival in patients with PDAC by disturbing the SUMOylation process, a crucial modification in carcinogenesis.

Contains a more detailed method section as well as all additional supplementary figures S1 to S8

Dieser Beitrag widmet sich der Beschreibung des Korpus Deutsch in Namibia (DNam), das uber die Datenbank fur Gesprochenes Deutsch (DGD) frei zuganglich ist. Bei diesem Korpus handelt es sich um eine neue digitale Ressource, die den Sprachgebrauch der deutschsprachigen Minderheit in Namibia sowie die zugehorigen Spracheinstellungen umfassend und systematisch dokumentiert. Wir beschreiben die Datenerhebung und die dabei angewandten Methoden (freie Gesprache, „Sprachsituationen“, semi-strukturierte Interviews), die Datenaufbereitung inklusive Transkription, Normalisierung und Tagging sowie die Eigenschaften des verfugbaren Korpus (Umfang, verfugbare Metadaten usw.) und einige grundlegende Funktionalitaten im Rahmen der DGD. Erste Forschungsergebnisse, die mithilfe der neuen Ressource erzielt wurden, veranschaulichen die vielseitige Nutzbarkeit des Korpus fur Fragestellungen aus den Bereichen Kontakt-, Variations- und Soziolinguistik.

Pancreatic ductal adenocarcinoma (PDAC) still presents with a dismal prognosis despite intense research. Better understanding of cellular homeostasis could identify druggable targets to improve therapy. Here we propose RAD50-interacting protein 1 (RINT1) as an essential mediator of cellular homeostasis in PDAC. In a cohort of resected PDAC, low RINT1 protein expression correlated significantly with better survival. Accordingly, RINT1 depletion caused severe growth defects in vitro associated with accumulation of DNA double-strand breaks (DSB), G2 cell cycle arrest, disruption of Golgi–endoplasmic reticulum homeostasis, and cell death. Time-resolved transcriptomics corroborated by quantitative proteome and interactome analyses pointed toward defective SUMOylation after RINT1 loss, impairing nucleocytoplasmic transport and DSB response. Subcutaneous xenografts confirmed tumor response by RINT1 depletion, also resulting in a survival benefit when transferred to an orthotopic model. Primary human PDAC organoids licensed RINT1 relevance for cell viability. Taken together, our data indicate that RINT1 loss affects PDAC cell fate by disturbing SUMOylation pathways. Therefore, a RINT1 interference strategy may represent a new putative therapeutic approach. Significance: These findings provide new insights into the aggressive behavior of PDAC, showing that RINT1 directly correlates with survival in patients with PDAC by disturbing the SUMOylation process, a crucial modification in carcinogenesis.

Recent findings from spoken language use outside formal standard German provide evidence for linearizations that violate the V2 constraint, suggesting that there might be extensions of V2 in German to a more liberal forefield that can also accommodate V3. Evidence for this was first reported from Kiezdeutsch, an urban dialect from informal peer-group settings in multilingual contexts, and has subsequently also been found in more monolingual settings of German. Findings point to a specific pattern that allows both frame setters and topics to appear together in the left periphery. This chapter contains results from a cross-linguistic study that further explored such an information-structural motive. The investigation was inspired by a seminal study by Goldin-Meadow et al. (2008) that revealed language-independent preferences for the serialization of thematic roles, a ‘natural order of events’. The study investigates a possible ‘natural order of information’ in three typologically different languages, namely German, English, and Turkish: were speakers more likely to place verbs in a position after frame setter plus topic (supporting V3) if language-specific grammatical restrictions were removed? Results indicate an information-structural motivation of V3 that holds across speakers of different linguistic backgrounds (German, English, Turkish), even in violation of language-specific word order options.

[Background]: Organotypic cultures derived from pancreatic ductal adenocarcinoma (PDAC) termed pancreatic ductal cancer organoids (PDOs) recapitulate the primary cancer and can be derived from primary or metastatic biopsies. Although isolation and culture of patient-derived pancreatic organoids were established several years ago, pros and cons for individualized medicine have not been comprehensively investigated to date., [Methods]: We conducted a feasibility study, systematically comparing head-to-head patient-derived xenograft tumor (PDX) and PDX-derived organoids by rigorous immunohistochemical and molecular characterization. Subsequently, a drug testing platform was set up and validated in vivo. Patient-derived organoids were investigated as well., [Results]: First, PDOs faithfully recapitulated the morphology and marker protein expression patterns of the PDXs. Second, quantitative proteomes from the PDX as well as from corresponding organoid cultures showed high concordance. Third, genomic alterations, as assessed by array-based comparative genomic hybridization, revealed similar results in both groups. Fourth, we established a small-scale pharmacotyping platform adjusted to operate in parallel considering potential obstacles such as culture conditions, timing, drug dosing, and interpretation of the results. In vitro predictions were successfully validated in an in vivo xenograft trial. Translational proof-of-concept is exemplified in a patient with PDAC receiving palliative chemotherapy., [Conclusion]: Small-scale drug screening in organoids appears to be a feasible, robust and easy-to-handle disease modeling method to allow response predictions in parallel to daily clinical routine. Therefore, our fast and cost-efficient assay is a reasonable approach in a predictive clinical setting., The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Main funding is provided by the German Cancer Aid grant to A. Kleger (111879). Additional funding came from the Deutsche Forschungsgemeinschaft (DFG, K.L. 2544/1-1, and 1-2; GRK 2254/1 to T. Seufferlein), the BIU fund (Böhringer Ingelheim), the NDIMED-Verbund PancChip, and the Else-Kröner-Fresenius Memorial funding to A. Kleger. AK receives also funding from the DFG within the Heisenberg program and from the Baden-Württemberg Foundation via ExPo Chip. This project was also funded by ANR-DFG collaborative research project (ANR-18-CE92-0031, DFG KL 2544/5-1) to CJ and AK and via additional DFG funding KL 2544/6-1, KL 2544/7-1, KL 2544/1-1, and KL 2544/1-2 to AK. L. Perkhofer is funded by Bausteinprogramm of the Ulm University hospital. This work was supported by a project grant for André Lechel (Deutsche Krebshilfe/111264), for Patrick C. Hermann (Max Eder Fellowship 111746, Projektnummer 316249678 – SFB 1279, and Hector Foundation Cancer Research grant M65.1). Reinhild Rösler and parts of proteomics method development were funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – SFB 1074. Bruno Sainz Jr was funded by a Ramón y Cajal Merit Award from the Ministerio de Economía y Competitividad, Spain and a coordinated grant from the Fundación Asociación Española Contra el Cáncer (AECC).

The PI3K/Akt pathway promotes skeletal muscle growth and myogenic differentiation. Although its importance in skeletal muscle biology is well documented, many of its substrates remain to be identified. We here studied PI3K/Akt signaling in contracting skeletal muscle cells by quantitative phosphoproteomics. We identified the extended basophilic phosphosite motif RxRxxp[S/T]xxp[S/T] in various proteins including filamin-C (FLNc). Importantly, this extended motif, located in a unique insert in Ig-like domain 20 of FLNc, is doubly phosphorylated. The protein kinases responsible for this dual-site phosphorylation are Akt and PKCα. Proximity proteomics and interaction analysis identified filamin A-interacting protein 1 (FILIP1) as direct FLNc binding partner. FILIP1 binding induces filamin degradation, thereby negatively regulating its function. Here, dual-site phosphorylation of FLNc not only reduces FILIP1 binding, providing a mechanism to shield FLNc from FILIP1-mediated degradation, but also enables fast dynamics of FLNc necessary for its function as signaling adaptor in cross-striated muscle cells., Reimann, Schwäble et al. perform quantitative proteomics to study PI3K/Akt signaling in contracting myotubes. They identify a dual-site phosphorylation motif in the actin cross-linker and signaling adaptor filamin C, which regulates its degradation and mobility, suggesting the importance of dual phosphorylation for filamin C function in striated muscle cells.

This article investigates a public debate in Germany that put a special spotlight on the interaction of standard language ideologies with social dichotomies, centering on the question of whether Kiezdeutsch, a new way of speaking in multilingual urban neighbourhoods, is a legitimate German dialect. Based on a corpus of emails and postings to media websites, I analyse central topoi in this debate and an underlying narrative on language and identity. Central elements of this narrative are claims of cultural elevation and cultural unity for an idealised standard language High German', a view of German dialects as part of a national folk culture, and the construction of an exclusive in-group of German' speakers who own this language and its dialects. The narrative provides a potent conceptual frame for the Othering of Kiezdeutsch and its speakers, and for the projection of social and sometimes racist deliminations onto the linguistic plane., Postprints der Universität Potsdam : Philosophische Reihe, 157

This paper investigates evidence for linguistic coherence in new urban dialects that evolved in multiethnic and multilingual urban neighbourhoods. We propose a view of coherence as an interpretation of empirical observations rather than something that would be "out there in the data", and argue that this interpretation should be based on evidence of systematic links between linguistic phenomena, as established by patterns of covariation between phenomena that can be shown to be related at linguistic levels. In a case study, we present results from qualitative and quantitative analyses for a set of phenomena that have been described for Kiezdeutsch, a new dialect from multilingual urban Germany. Qualitative analyses point to linguistic relationships between different phenomena and between pragmatic and linguistic levels. Quantitative analyses, based on corpus data from KiDKo (www.kiezdeutschkorpus.de), point to systematic advantages for the Kiezdeutsch data from a multiethnic and multilingual context provided by the main corpus (KiDKo/Mu), compared to complementary corpus data from a mostly monoethnic and monolingual (German) context (KiDKo/Mo). Taken together, this indicates patterns of covariation that support an interpretation of coherence for this new dialect: ourfindings point to an interconnected linguistic system, rather than to a mere accumulation of individual features. In addition to this internal coherence, the data also points to external coherence: Kiezdeutsch is not disconnected on the outside either, but fully integrated within the general domain of German, an integration that defies a distinction of "autochthonous" and "allochthonous" German, not only at the level of speakers, but also at the level of linguistic systems. (C) 2015 Elsevier B.V. All rights reserved.

We discuss an intervention programme for kindergarten and school teachers' continuing education in Germany that targets biases against language outside a perceived monolingual ‘standard’ and its speakers. The programme combines anti-bias methods relating to linguistic diversity with objectives of raising critical language awareness. Evaluation through teachers' workshops in Berlin and Brandenburg points to positive and enduring attitudinal changes in participants, but not in control groups that did not attend workshops, and effects were independent of personal variables gender and teaching subject and only weakly associated with age. We relate these effects to such programme features as indirect and inclusive methods that foster active engagement, and the combination of ‘safer’ topics targeting attitudes towards linguistic structures with more challenging ones dealing with the discrimination of speakers. Der Beitrag diskutiert ein Interventionsprogramm fur die Weiterbildung von Lehrer/inne/n und Erzieher/inne/n, das Vorurteile gegenuber sprachlichen Praktiken auserhalb eines vermeintlichen monolingualen „Standarddeutschen“ und seinen Sprecher/inne/n fokussiert (www.deutsch-ist-vielseitig.de). Das Programm verbindet Anti-bias -Methoden zur sprachlichen Vielfalt mit solchen, die auf eine Verstarkung kritischer Sprachbewusstheit abheben. Die Evaluation der Materialien in Lehrerfortbildungen in Berlin und Brandenburg weist auf positive und anhaltende Einstellungsveranderungen bei den Teilnehmer/inne/n, aber nicht bei Mitgliedern einer Kontrollgruppe, die nicht an den Fortbildungen teilnahm; die Effekte waren unabhangig von den personenbezogen Variablen Geschlecht und Lehrfach und nur schwach mit Alter assoziiert. Wir diskutieren diese Effekte im Zusammenhang mit Eigenschaften des Programms wie der Verwendung indirekter und inklusiver Methoden, die eine aktive Auseinandersetzung fordern, und der Verbindung von weniger „bedrohlichen“ Themen, die sich auf Einstellungen gegenuber sprachlichen Strukturen beziehen, mit solchen, die die Diskrimierung von Sprecher/inne/n behandeln und daher eine grosere Herausforderung darstellen

We used event-related potentials (ERPs) to investigate the neurocognitive mechanisms associated with processing light verb constructions such as “give a kiss”. These constructions consist of a semantically underspecified light verb (“give”) and an event nominal that contributes most of the meaning and also activates an argument structure of its own (“kiss”). This creates a mismatch between the syntactic constituents and the semantic roles of a sentence. Native speakers read German verb-final sentences that contained light verb constructions (e.g., “Julius gave Anne a kiss”), non-light constructions (e.g., “Julius gave Anne a rose”), and semantically anomalous constructions (e.g., *“Julius gave Anne a conversation”). ERPs were measured at the critical verb, which appeared after all its arguments. Compared to non-light constructions, the light verb constructions evoked a widely distributed, frontally focused, sustained negative-going effect between 500 and 900 ms after verb onset. We interpret this effect as reflecting working memory costs associated with complex semantic processes that establish a shared argument structure in the light verb constructions.

The Z-disc is a protein-rich structure critically important for the development and integrity of myofibrils, which are the contractile organelles of cross-striated muscle cells. We here used mouse C2C12 myoblast, which were differentiated into myotubes, followed by electrical pulse stimulation (EPS) to generate contracting myotubes comprising mature Z-discs. Using a quantitative proteomics approach, we found significant changes in the relative abundance of 387 proteins in myoblasts versus differentiated myotubes, reflecting the drastic phenotypic conversion of these cells during myogenesis. Interestingly, EPS of differentiated myotubes to induce Z-disc assembly and maturation resulted in increased levels of proteins involved in ATP synthesis, presumably to fulfill the higher energy demand of contracting myotubes. Because an important role of the Z-disc for signal integration and transduction was recently suggested, its precise phosphorylation landscape further warranted in-depth analysis. We therefore established, by global phosphoproteomics of EPS-treated contracting myotubes, a comprehensive site-resolved protein phosphorylation map of the Z-disc and found that it is a phosphorylation hotspot in skeletal myocytes, underscoring its functions in signaling and disease-related processes. In an illustrative fashion, we analyzed the actin-binding multiadaptor protein filamin C (FLNc), which is essential for Z-disc assembly and maintenance, and found that PKCα phosphorylation at distinct serine residues in its hinge 2 region prevents its cleavage at an adjacent tyrosine residue by calpain 1. Fluorescence recovery after photobleaching experiments indicated that this phosphorylation modulates FLNc dynamics. Moreover, FLNc lacking the cleaved Ig-like domain 24 exhibited remarkably fast kinetics and exceedingly high mobility. Our data set provides research community resource for further identification of kinase-mediated changes in myofibrillar protein interactions, kinetics, and mobility that will greatly advance our understanding of Z-disc dynamics and signaling.

Language can strongly influence the emotional state of the recipient. In contrast to the broad body of experimental and neuroscientific research on semantic information and prosodic speech, the emotional impact of grammatical structure has rarely been investigated. One reason for this might be, that measuring effects of syntactic structure involves the use of complex stimuli, for which the emotional impact of grammar is difficult to isolate. In the present experiment we examined the emotional impact of structural parallelisms, that is, repetitions of syntactic features, on the emotion-sensitive "late positive potential" (LPP) with a cross-modal priming paradigm. Primes were auditory presented nonsense sentences which included grammatical-syntactic parallelisms. Visual targets were positive, neutral, and negative faces, to be classified as emotional or non-emotional by the participants. Electrophysiology revealed diminished LPP amplitudes for positive faces following parallel primes. Thus, our findings suggest that grammatical structure creates an emotional context that facilitates processing of positive emotional information.

YchF is an evolutionarily conserved ATPase of unknown function. In humans, the YchF homologue hOla1 appears to influence cell proliferation and was found to be up-regulated in many tumors. A possible involvement in regulating the oxidative stress response was also suggested, but details on the underlying mechanism are lacking. For gaining insight into YchF function, we used Escherichia coli as a model organism and found that YchF overexpression resulted in H(2)O(2) hypersensitivity. This was not caused by transcriptional or translational down-regulation of H(2)O(2)-scavenging enzymes. Instead, we observed YchF-dependent inhibition of catalase activity and a direct interaction with the major E. coli catalase KatG. KatG inhibition was dependent on the ATPase activity of YchF and was regulated by post-translational modifications, most likely including an H(2)O(2)-dependent dephosphorylation. We furthermore showed that YchF expression is repressed by the transcription factor OxyR and further post-translationally modified in response to H(2)O(2). In summary, our data show that YchF functions as a novel negative regulator of the oxidative stress response in E. coli. Considering the available data on hOla1, YchF/Ola1 most likely execute similar functions in bacteria and humans, and their up-regulation inhibits the ability of the cells to scavenge damaging reactive oxygen species.

This paper discusses a hitherto undescribed usage of the particle so as a dedicated focus marker in contemporary German. I discuss grammatical and pragmatic characteristics of this focus marker, supporting my account with natural linguistic data and with controlled experimental evidence showing that so has a significant influence on speakers' understanding of what the focus expression in a sentence is. Against this background, I sketch a possible pragmaticalization path from referential usages of so via hedging to a semantically bleached focus marker, which, unlike particles such as auch 'also'/'too' or nur 'only', does not contribute any additional meaning.

The serine/threonine kinase mammalian target of rapamycin (mTOR) governs growth, metabolism, and aging in response to insulin and amino acids (aa), and is often activated in metabolic disorders and cancer. Much is known about the regulatory signaling network that encompasses mTOR, but surprisingly few direct mTOR substrates have been established to date. To tackle this gap in our knowledge, we took advantage of a combined quantitative phosphoproteomic and interactomic strategy. We analyzed the insulin- and aa-responsive phosphoproteome upon inhibition of the mTOR complex 1 (mTORC1) component raptor, and investigated in parallel the interactome of endogenous mTOR. By overlaying these two datasets, we identified acinus L as a potential novel mTORC1 target. We confirmed acinus L as a direct mTORC1 substrate by co-immunoprecipitation and MS-enhanced kinase assays. Our study delineates a triple proteomics strategy of combined phosphoproteomics, interactomics, and MS-enhanced kinase assays for the de novo-identification of mTOR network components, and provides a rich source of potential novel mTOR interactors and targets for future investigation.

Functional gains : a cross-linguistic case study of three particles in Swedish, Norwegian and German

Osmotic stress as well as silicon (Si) improve the resistance of barley (Hordeum vulgare cv. Ingrid) against barley powdery mildew (Blumeria graminis f. sp. hordei Speer). Nothing is known about interactions, particularly whether Si is necessary for pathogen resistance induced by osmotic stress. In this paper, we show that Si nutrition was not necessary for osmotic-stress-induced pathogen resistance. Si-mediated resistance could, however, be enhanced by osmotic stress and vice versa. Even at maximum Si-mediated resistance, further enhancement of pathogen resistance by osmotic stress was possible. The fungus was controlled by the formation of effective papillae in both treatments. The combined effect of Si and osmotic stress was as strong as the calculated addition of the Si and the osmotic-stress effect. Our data clearly show that the effect of osmotic stress and Si is not competitive but additive. A synergistic action of both treatments cannot be supported by our data. It is assumed that the basal pathogen resistance of barley is enhanced by Si due to strengthening of papillae in addition to the increased formation of effective papillae induced by osmotic stress. Therefore, the addition of Si increases pathogen resistance equally at all investigated NaCl concentrations. A function of Si in pathogen defense exceeding the strengthening of papillae is not supported by our data. Osmotischer Stress und Silizium erhohen die Pathogenresistenz von Gerste gegen Gerstenmehltau auf additive Weise Sowohl osmotischer Stress als auch Silizium (Si) verbessern die Resistenz von Gerste (Hordeum vulgare cv. Ingrid) gegen Gerstenmehltau (Blumeria graminis f. sp. hordei Speer). Dabei ist unbekannt, ob es eine Interaktion zwischen beiden Faktoren gibt und ob Si fur die durch osmotischen Stress induzierte Pathogenresistenz benotigt wird. Die hier dargestellten Ergebnisse zeigen, dass osmotischer Stress auch ohne Si-Ernahrung eine Pathogenresistenz induziert. Die durch Si erhohte Pathogenresistenz konnte durch osmotischen Stress weiter gesteigert werden und umgekehrt. Selbst wenn die durch Si erhohte Resistenz maximal war, steigerte osmotischer Stress diese weiter. Bei beiden Behandlungen wurde der Pilz durch die Bildung effektiver Papillen abgewehrt. Der kombinierte Effekt von Si und osmotischem Stress war genauso stark wie der berechnete additive Effekt dieser beiden Faktoren, was eine additive Wirkung der Behandlungen zeigt. Eine synergistische Wirkung beider Behandlungen konnte nicht nachgewiesen werden. Es ist zu vermuten, dass Si die basale Pathogenresistenz durch die Verstarkung der Papillen erhoht. Dieser Effekt addiert sich zu dem Effekt der durch osmotischen Stress erhohten Zahl effektiver Papillen. Daher erhohte die Zugabe von Si bei allen getesteten NaCl-Konzentrationen die Pathogenresistenz in demselben Mase. Eine uber die Verstarkung der Papillen hinaus gehende Funktion von Si in der Pathogenabwehr wird durch unsere Daten nicht gezeigt.