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CXCL12-CXCR4 signaling controls multiple physiological processes and its dysregulation is associated with cancers and inflammatory diseases. To discover as-yet-unknown endogenous ligands of CXCR4, we screened a blood-derived peptide library for inhibitors of CXCR4-tropic HIV-1 strains. This approach identified a 16 amino acid fragment of serum albumin as an effective and highly specific CXCR4 antagonist. The endogenous peptide, termed EPI-X4, is evolutionarily conserved and generated from the highly abundant albumin precursor by pH-regulated proteases. EPI-X4 forms an unusual lasso-like structure and antagonizes CXCL12-induced tumor cell migration, mobilizes stem cells, and suppresses inflammatory responses in mice. Furthermore, the peptide is abundant in the urine of patients with inflammatory kidney diseases and may serve as a biomarker. Our results identify EPI-X4 as a key regulator of CXCR4 signaling and introduce proteolysis of an abundant precursor protein as an alternative concept for chemokine receptor regulation.
The frequency of intensional and non-first-order definable operators in natural languages constitutes a challenge for automated reasoning with the kind of logical translations that are deemed adequate by formal semanticists. Whereas linguists employ expressive higher-order logics in their theories of meaning, the most successful logical reasoning strategies with natural language to date rely on sophisticated first-order theorem provers and model builders. In order to bridge the fundamental mathematical gap between linguistic theory and computational practice, we present a general translation from a higher-order logic frequently employed in the linguistics literature, two-sorted Type Theory, to first-order logic under Henkin semantics. We investigate alternative formulations of the translation, discuss their properties, and evaluate the availability of linguistically relevant inferences with standard theorem provers in a test suite of inference problems stated in English. The results of the experiment indicate that translation from higher-order logic to first-order logic under Henkin semantics is a promising strategy for automated reasoning with natural languages.
As a surrogate of live cells, proteo-lipobeads are presented, encapsulating functional membrane proteins in a strict orientation into a lipid bilayer. Assays can be performed just as on live cells, for example using fluorescence measurements. As a proof of concept, we have demonstrated proton transport through cytochrome c oxidase.