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The small GTPases H, K, and NRAS are molecular switches indispensable for proper regulation of cellular proliferation and growth. Several mutations in the genes encoding members of this protein family are associated with cancer and result in aberrant activation of signaling processes caused by a deregulated recruitment of downstream effector proteins. In this study, we engineered variants of the Ras-binding domain (RBD) of the C-Raf proto-oncogene, Ser/Thr kinase (CRAF). These variants bound with high affinity with the effector-binding site of Ras in an active conformation. Structural characterization disclosed how the newly identified RBD mutations cooperate and thereby enhance affinity with the effector-binding site in Ras compared with WT RBD. The engineered RBD variants closely mimicked the interaction mode of naturally occurring Ras effectors and acted as dominant-negative affinity reagents that block Ras signal transduction. Experiments with cancer cells showed that expression of these RBD variants inhibits Ras signaling, reducing cell growth and inducing apoptosis. Using these optimized RBD variants, we stratified patient-derived colorectal cancer organoids with known Ras mutational status according to their response to Ras inhibition. These results revealed that the presence of Ras mutations was insufficient to predict sensitivity to Ras inhibition, suggesting that not all of these tumors required Ras signaling for proliferation. In summary, by engineering the Ras/Raf interface of the CRAF-RBD, we identified potent and selective inhibitors of Ras in its active conformation that outcompete binding of Ras-signaling effectors.
Using data taken at 23 center-of-mass energies between 4.0 and 4.6 GeV with the BESIII detector at the BEPCII collider and with a total integrated luminosity of approximately 15 fb−1, the process e+e−→2(pp¯) is studied for the first time. The Born cross sections for e+e−→2(pp¯) are measured, and no significant structure is observed in the lineshape. The baryon pair (pp and p¯p¯) invariant mass spectra are consistent with phase space, therefore no hexaquark or di-baryon state is found.
Treatment of relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT) remains a great challenge. Aiming to evaluate the combination of venetoclax and hypomethylating agents (HMAClax) for the treatment of relapse of myeloid malignancies after alloHSCT, we retrospectively collected data from 32 patients treated at 11 German centers. Venetoclax was applied with azacitidine (n = 13) or decitabine (n = 19); 11 patients received DLI in addition. HMAClax was the first salvage therapy in 8 patients. The median number of cycles per patient was 2 (1–19). All but 1 patient had grade 3/4 neutropenia. Hospital admission for grade 3/4 infections was necessary in 23 patients (72%); 5 of these were fatal. In 30 evaluable patients, overall response rate (ORR) was 47% (14/30, 3 CR MRDneg, 5 CR, 2 CRi, 1 MLFS, 3 PR). ORR was 86% in first salvage patients versus 35% in later salvage patients (p = 0.03). In 6 patients with molecular relapse (MR), ORR was 67% versus 42% in patients with hematological relapse (HR) (n = 24, p = n.s.). After a median follow-up of 8.4 months, 25 patients (78%) had died and 7 were alive. Estimated median overall survival was 3.7 months. Median survival of patients with HMAClax for first versus later salvage therapy was 5.7 and 3.4 months (p = n.s.) and for patients with MR (not reached) compared to HR (3.4 months, p = 0.024). This retrospective case series shows that venetoclax is utilized in various different combinations, schedules, and doses. Toxicity is substantial and patients who receive venetoclax/HMA combinations for MR or as first salvage therapy derive the greatest benefit.
We present an analysis of multiple question fronting in a restricted variant of the HPSG formalism (DELPH-IN) where unification is the only natively defined operation. Analysing multiple fronting in this formalism is challenging, because it requires carefully handling list appends, something that HPSG analyses of question fronting heavily rely on. Our analysis uses the append list type to address this challenge. We focus the testing of our analysis on Russian, although we also integrate it into the Grammar Matrix customization system where it serves as a basis for cross-linguistic modeling. In this context, we discuss the relationship of our analysis to lexical threading and conclude that, while lexical threading has its advantages, modeling multiple extraction cross-linguistically is easier without the lexical threading assumption.
The Smurf comics series is, among others, famous for the so-called "smurf language", in which words or parts of words can be replaced by "smurf". We will argue that this "smurfing" has the properties of placeholding. Based on data from German translations of Smurf comics, we will provide a formalization of smurfing in German which can be generalized to a theory of placeholder expressions.
This paper sketches an analysis in Lexical Resource Semantics of adverbial and adjectival modification in nominal projections which is extensible to modification of other syntactic categories. It combines insights into the syntax-semantics interface of recursive modification in HPSG with underspecified semantics and type-logical meaning representations in the tradition of Montague grammar. The analysis is phrased in such a way that it receives a direct implementation in the Constraint Language of Lexical Resource Semantics as part of the TRALE system.
The indigenous languages of North America have played a critical role in discussions of the universality of part-of-speech distinctions. In this paper, we show that Oneida does not include a grammatical distinction between nouns and verbs. Rather, Oneida inflecting lexical items are subject to two cross-cutting semantic classifications, one that concerns the sort of entities they describe, the other the sort of semantic relation they include in their content. Labels such as ‘noun' and ‘verb' can still be used for cross-linguistic comparison, as the semantic partition of lexical items corresponds to canonical nouns and verbs according to morphologists and some typologists. But the meta-grammatical status of these labels is quite distinct from the status of corresponding labels in Indo-European languages like English.
This paper presents an incremental approach to verb clusters in German which radically differs from standard HPSG accounts. While the common assumption is that the verbs in subordinate clauses form clusters and accumulate all their valence requirements on a SUBCAT list, the assumption in this paper is that the arguments in verb final clauses are encapsulated incrementally into syntactic and semantic structures before the verbs are attached. The proposed analysis is in line with psycholinguistic findings. A grammar fragment of German demonstrating an implementation of the analysis is presented.
This paper proposes an account for the four auxiliaries in Kazakh that express the imperfective aspect. The main factors – the auxiliary, the main verb, their inflections and the aspectual specifications reveal a complicated system, which can be captured with an appropriate monotonic, multiple inheritance type hierarchy using online-type construction with the implementation of Pāṇinian competition. This analysis sheds light to a very different auxiliary system that we find in Indo-European languages.
Unrealized arguments in SBCG
(2020)
In null instantiation (NI) an optionally unexpressed argument receives either anaphoric or existential interpretation (Fillmore, 1986; Mauner & Koenig, 2000; Kay, 2002; Ruppenhofer & Michaelis, 2010, 2014). Examples include Lexically licensed NI (Nixon resigned.), Contextual accessibility NI (Can I see?), Labelese (Contains alcohol), Diary NI (Got up, got out of bed, dragged a comb across my head), Generic-habitual NI (The police only arrest (people) when there's probable cause). We think of a predicator as having NI potential when one or more of its frame elements may remain unexpressed under certain conditions. While one cannot accurately predict a predicator's NI potential based either on semantic factors (e.g., Aktionsart class of the verb, as in Hovav & Levin (1998)) or pragmatic factors (e.g., relative discourse prominence of arguments, as in Goldberg (2006)), NI potential, while highly constrained, is not simply lexical idiosyncrasy, but is instead the product of both lexical and constructional licensing. In the latter case, a construction can endow a verb with NI potential that it would not otherwise have. Using representational tools of Sign Based Construction Grammar (Sag 2012, a.o), we offer a lexical treatment of null instantiation that covers both distinct patterns of construal of null instantiated arguments and the difference between listeme-based and contextually licensed, thus construction-based, null complementation