👤 Eddy Cavalli

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

Glioblastoma (GBM) is a highly lethal type of cancer. GBM recurrence following chemoradiation is typically attributed to the regrowth of invasive and resistant cells. Therefore, there is a pressing need to gain a deeper understanding of the mechanisms underlying GBM resistance to chemoradiation and its ability to infiltrate. Using a combination of transcriptomic, proteomic, and phosphoproteomic analyses, longitudinal imaging, organotypic cultures, functional assays, animal studies, and clinical data analyses, we demonstrate that chemoradiation and brain vasculature induce cell transition to a functional state named VC-Resist (vessel co-opting and resistant cell state). This cell state is midway along the transcriptomic axis between proneural and mesenchymal GBM cells and is closer to the AC/MES1-like state. VC-Resist GBM cells are highly vessel co-opting, allowing significant infiltration into the surrounding brain tissue and homing to the perivascular niche, which in turn induces even more VC-Resist transition. The molecular and functional characteristics of this FGFR1-YAP1-dependent GBM cell state, including resistance to DNA damage, enrichment in the G2M phase, and induction of senescence/stemness pathways, contribute to its enhanced resistance to chemoradiation. These findings demonstrate how vessel co-option, perivascular niche, and GBM cell plasticity jointly drive resistance to therapy during GBM recurrence. Show less

We examined the reliance on phonological decoding and morpho-orthographic decomposition strategies in developing and skilled readers of French. A lexical decision experiment was conducted where the critical stimuli were four types of nonwords, all derived from the same base word, such as the French word visage (face) in the following examples: (a) pseudo-homophone (PsH) nonwords (e.g., visaje), (b) orthographic controls for PsH nonwords (e.g., visape), (c) pseudo-morphemic (PsM) nonwords (e.g., visageable), and (d) orthographic controls for PsM nonwords (e.g., visagealle, where alle is not a suffix in French). Responses to PsH and PsM nonwords and their controls were studied in three groups of school children (Grades 1, 2, and 5) and one group of skilled adult readers. PsH interference effects (i.e., more errors to PsH nonwords than to the corresponding controls) decreased during reading acquisition to become nonsignificant in skilled readers. Interestingly, the opposite pattern was seen in PsM interference effects (also measured in terms of accuracy), which were already significant in Grade 1 and increased during reading development to reach their maximum in skilled readers. These results point toward opposing learning trajectories in the use of phonological and morphological information when learning to silently read for meaning. Show less

It has been argued that university students with dyslexia compensate for their reading deficits by a neural re-organization of the typical reading network, where the lexical representations of words are (re-)structured according to semantic rather than orthographic information. To investigate the re-organization of neural word representations more directly, we used multivariate representational similarity analyses (RSA) to find out which brain regions of the reading network respond to orthographic and semantic similarity between 544 pairs of words and whether there were any differences between typical and dyslexic readers. In accordance with the re-organization hypothesis, we predicted greater similarity (i.e., correlation of neural dissimilarity matrices) in adult dyslexic than in typical readers in regions associated with semantic processing and weaker similarity in regions associated with orthographic processing. Our results did not confirm these predictions. First, we found sensitivity to semantic similarity in all three subparts of the fusiform gyrus (FG1, FG2, and FG3) bilaterally. Adults with dyslexia showed less (rather than more) sensitivity to semantic similarity in the posterior subpart of fusiform gyrus (FG1) in the left hemisphere. Second, in typical readers, sensitivity to orthographic information was not only found in the left fusiform gyrus (FG1, FG2, and FG3) but also in left inferior frontal gyrus (IFG). Adults with dyslexia, in contrast, did not show sensitivity to orthographic information in left IFG. However, they showed increased sensitivity to orthographic information in the right hemisphere FG1. Together, the results show abnormal orthographic processing in left IFG and right FG1 and reduced semantic information in left FG1. While we found evidence for compensatory re-organization in adult dyslexia, the present results do not support the hypothesis according to which adults with dyslexia rely more heavily on semantic information. Instead, they revealed atypical hemispheric organization of the reading network that is not restricted to the typical left language hemisphere. Show less

The FADS1 and FADS2 genes in the FADS cluster encode the rate-limiting enzymes in the synthesis of long-chain polyunsaturated fatty acids (LC-PUFAs). Genetic variation in this region has been associated with a large number of diseases and traits many of them correlated to differences in metabolism of PUFAs. However, the causative variants leading to these associations have not been identified. Here we find that the multiallelic rs174557 located in an AluYe5 element in intron 1 of FADS1 is functional and lies within a PATZ1 binding site. The derived allele of rs174557, which is the common variant in most populations, diminishes binding of PATZ1, a transcription factor conferring allele-specific downregulation of FADS1. The PATZ1 binding site overlaps with a SP1 site. The competitive binding between the suppressive PATZ1 and the activating complex of SP1 and SREBP1c determines the enhancer activity of this region, which regulates expression of FADS1. Show less

Menopause is associated with changes in lipid levels resulting in increased risk of atherosclerosis and cardiovascular events. Hormone therapy (HT) and atorvastatin have been used to improve lipid profile in postmenopausal women. Effects of HT, atorvastatin and APOE polymorphisms on serum lipids and APOE and LXRA expression were evaluated in 87 hypercholesterolemic postmenopausal women, randomly selected for treatment with atorvastatin (AT, n=17), estrogen or estrogen plus progestagen (HT, n=34) and estrogen or estrogen plus progestagen associated with atorvastatin (HT+AT, n=36). RNA was extracted from peripheral blood mononuclear cells (PBMC) and mRNA expression was measured by TaqMan(®) PCR. APOE ɛ2/ɛ3/ɛ4 genotyping was performed using PCR-RFLP. Total cholesterol (TC), LDL-c and apoB were reduced after each treatment (p<0.001). Triglycerides, VLDL-c and apoAI were reduced only after atorvastatin (p<0.05), whereas triglycerides and VLDL-c were increased after HT (p=0.01). HT women had lower reduction on TC, LDL-c and apoB than AT and HT+AT groups (p<0.05). APOE mRNA expression was reduced after atorvastatin treatment (p=0.03). Although LXRA gene expression was not modified by atorvastatin, it was correlated with APOE mRNA before and after treatments. Basal APOE mRNA expression was not influenced by gene polymorphisms, however the reduction on APOE expression was more pronounced in ɛ3ɛ3 than in ɛ3ɛ4 carriers. Atorvastatin down-regulates APOE mRNA expression and it is modified by APOE genotypes in PBMC from postmenopausal women. Show less

Decreased cardiac contractility and beta-adrenergic responsiveness have been observed in cirrhotic cardiomyopathy, but their molecular mechanisms remain unclear. To study beta-adrenergic-stimulated contractility and beta-adrenergic gene expression patterns, 20 Wistar Kyoto rats were treated with carbon tetrachloride to induce cirrhosis and 20 rats were used as controls. Left ventricular contractility was recorded in electrically driven isolated hearts perfused at constant flow with isoproterenol (10(-10) to 10(-6) M). A cardiac gene expression profile was obtained using a microarray for the myocyte adrenergic pathway. The cardiac contractility maximal response to isoproterenol was significantly reduced in cirrhotic rats in comparison to control rats, whereas the half-maximal effective concentration was not different. In cirrhotic rats, cardiac gene expression analysis showed a significant overexpression of G protein alpha-inhibiting subunit 2 (Galpha(i2)), cyclic nucleotide phosphodiesterase (PDE2a), regulator of G-protein signaling 2 (RGS2), and down-expression of adenylate cyclase (Adcy3). These results indicate that overexpression of Galpha(i2), PDE2a, and RGS2 down-regulates the beta-adrenergic signaling pathway, thus contributing to the pathogenesis of cirrhotic cardiomyopathy. Show less