Senescent cells are characterized by a stable proliferation arrest and a senescence-associated secretory phenotype or SASP. Although these cells can have some beneficial effects, including protecting Show more
Senescent cells are characterized by a stable proliferation arrest and a senescence-associated secretory phenotype or SASP. Although these cells can have some beneficial effects, including protecting from tumor formation, their accumulation is deleterious during aging as it promotes age-related diseases, including cancer initiation and progression. Although the SASP has a critical role, its composition, regulation and dual role in cancer remain largely misunderstood. Here, we show that ANGPTL4 is one of the rare secreted factors induced in many different types of senescent cells. Importantly, ANGPTL4 knockdown during senescence or its constitutive expression, respectively inhibits or induces classical proinflammatory SASP factors, such as IL1A, IL6 and IL8. The latter effect is mediated upstream of IL1A, an early SASP factor, suggesting an upstream role of ANGPTL4 in SASP induction. This ANGPTL4-dependent proinflammatory SASP can promote human neutrophil activation in ex vivo assays, or tumor initiation in a KRAS-dependent lung tumorigenesis model in mice. This upstream activity of ANGPTL4 in regulating the proinflammatory SASP depends on its upregulation following a hypoxia-like response and HIF2A activation, and its proteolytic processing by the FURIN proprotein convertase. Altogether these findings shed light on a two-step activation of ANGPTL4 by HIF2A and FURIN in senescent cells and its upstream role in promoting the proinflammatory SASP, cancer and potentially other senescence-associated diseases. Show less
Prediction has become a key concept for understanding language comprehension, language production, and more recently reading. Recent studies suggest that predictive mechanisms in reading may be relate Show more
Prediction has become a key concept for understanding language comprehension, language production, and more recently reading. Recent studies suggest that predictive mechanisms in reading may be related to domain-general statistical learning (SL) abilities that support the extraction of regularities from sequential input. Both mechanisms have been discussed in relation to developmental dyslexia. Some suggest that SL is impaired in dyslexia with negative effects on the ability to make linguistic predictions. Others suggest that dyslexic readers rely to a greater extent on semantic and syntactic predictions to compensate for lower-level deficits. Here, we followed these two research questions in a single study. We therefore assessed the effects of semantic and syntactic prediction in reading and SL abilities in a population of university students with dyslexia and a group of typical readers using fMRI. The SL task was a serial reaction time (SRT) task that was performed inside and outside the scanner. The predictive reading task was performed in the scanner and used predictive versus nonpredictive semantic and syntactic contexts. Our results revealed distinct neural networks underlying semantic and syntactic predictions in reading, group differences in predictive processing in the left precentral gyrus and right anterior insula, and an association between predictive reading and SL, particularly in dyslexic readers. These findings contribute to our understanding of the interplay between SL, predictive processing, and compensation in dyslexia, providing new insights into the neural mechanisms that support reading. Show less