Spatial communication systems across languages reflect universal action constraints

The extent to which languages share properties reflecting the non-linguistic constraints of the speakers who speak them is key to the debate regarding the relationship between language and cognition. A critical case is spatial communication, where it has been argued that semantic universals should exist, if anywhere. Here, using an experimental paradigm able to separate variation within a language from variation between languages, we tested the use of spatial demonstratives—the most fundamental and frequent spatial terms across languages. In n = 874 speakers across 29 languages, we show that speakers of all tested languages use spatial demonstratives as a function of being able to reach or act on an object being referred to. In some languages, the position of the addressee is also relevant in selecting between demonstrative forms. Commonalities and differences across languages in spatial communication can be understood in terms of universal constraints on action shaping spatial language and cognition

Up-regulation of MDR1 and induction of doxorubicin resistance by histone deacetylase inhibitor depsipeptide (FK228) and ATRA in acute promyelocytic leukemia cells

The multidrug resistance 1 (MDR1) gene product P-glycoprotein (P-gp) is frequently implicated in cross-resistance of tumors to chemotherapeutic drugs. In contrast, acute promyelocytic leukemia (APL) cells do not express MDR1 and are highly sensitive to anthracyclines. The combination of ATRA and the novel histone deacetylase inhibitor (HDACI) depsipeptide (FK228) induced P-gp expression and prevented growth inhibition and apoptosis in NB4 APL cells subsequently exposed to doxorubicin (DOX). ATRA/FK228 treatment after exposure to DOX, however, enhanced apoptosis. Both agents, ATRA or FK228, induced MDR1 mRNA. This effect was significantly enhanced by ATRA/FK228 administered in combination, due in part to increased H4 and H3-Lys9 acetylation of the MDR1 promoter and recruitment of the nuclear transcription factor Y alpha (NFYA) transcription activator to the CCAAT box. Cotreatment with specific P-gp inhibitor PSC833 reversed cytoprotective effects of ATRA/FK228. G1 cell-cycle arrest and p21 mRNA induction were also observed in response to ATRA/FK228, which may restrict DOX-induced apoptosis of cells in G2 phase. These results indicate that epigenetic mechanisms involving NF-YA transcription factor recruitment and histone acetylation are activated by ATRA and HDACI, induce MDR1 in APL cells, and point to the critical importance of mechanism-based sequential therapy in future clinical trials that combine HDAC inhibitors, ATRA, and anthracyclines