Mutational Spectrum in Holoprosencephaly Shows That FGF is a New Major Signaling Pathway.

Holoprosencephaly (HPE) is the most common congenital cerebral malformation in humans, characterized by impaired forebrain cleavage and midline facial anomalies. It presents a high heterogeneity, both in clinics and genetics. We have developed a novel targeted next-generation sequencing (NGS) assay and screened a cohort of 257 HPE patients. Mutations with high confidence in their deleterious effect were identified in approximately 24% of the cases and were held for diagnosis, whereas variants of uncertain significance were identified in 10% of cases. This study provides a new classification of genes that are involved in HPE. SHH, ZIC2, and SIX3 remain the top genes in term of frequency with GLI2, and are followed by FGF8 and FGFR1. The three minor HPE genes identified by our study are DLL1, DISP1, and SUFU. Here, we demonstrate that fibroblast growth factor signaling must now be considered a major pathway involved in HPE. Interestingly, several cases of double mutations were found and argue for a polygenic inheritance of HPE. Altogether, it supports that the implementation of NGS in HPE diagnosis is required to improve genetic counseling.

A multicomponent exploration of verbal short-term storage deficits in normal aging and Alzheimer's disease.

Although many studies have shown diminished performance in verbal short-term memory tasks in normal aging and Alzheimer's disease (AD), the cognitive processes responsible for this verbal short-term storage (STS) impairment are still unclear for both populations. We explored verbal STS functioning in patients with AD, elderly participants, and young participants, by investigating a series of processes that could underlie STS impairments in normal elderly and AD populations. The processes we investigated were (a) the influence of lexical and sublexical language knowledge on short-term storage performance, (b) functioning of the phonological loop component via word length and phonological similarity effects, and (c) executive control processes (coordination and integration). For the AD and elderly groups, the influence of language knowledge on verbal STS performance and the functioning of the phonological loop were preserved. In contrast, the AD group showed deficits for coordination and integration processes. Our results suggest that the verbal STS deficit observed in AD patients is related to impaired executive control processes. On the other hand, language-related processes underlying passive storage capacity seem to be preserved.

Genotoxicity assessment of deoxynivalenol in the Caco-2 cell line model using the Comet assay.

The genotoxic risk associated with deoxynivalenol (DON), a prevalent trichothecene mycotoxin which contaminates cereal-based products has not yet been deeply explored. In this work, the alkaline version of the Comet assay was used to evaluate DNA damage stemming from DON exposure in both dividing and differentiated Caco-2 cells, an epithelial intestinal cell line. To avoid false positive results, cytotoxic and apoptotic thresholds were firstly established using the MTS and neutral red assays and the Hoestch staining method, respectively. Dividing cells were found to be more sensitive to DON than differentiated cells and the lowest IC(10) (0.5 microM) obtained for dividing cells exposed for 72 h was used as the highest working concentration in the genotoxicity study. Both differentiated and dividing cells responded with a dose-dependent relationship to DON in terms of DNA damage in the 0.01-0.5 microM range. These results demonstrated the existence of a genotoxic potential for DON at low concentrations compatible with actual exposure situations and calls for additional studies to determine the functional consequences which could be taken into account for the risk assessment of this food contaminant.

Involvement of both prefrontal and inferior parietal cortex in dual-task performance.

This PET study explored the neural substrate of both dual-task management and integration task using single tasks that are known not to evoke any prefrontal activation. The paradigm included two simple (visual and auditory) discrimination tasks, a dual task and an integration task (requiring simultaneous visual and auditory discrimination), and baseline tasks (passive viewing and hearing). Data were analyzed using SPM99. As predicted, the comparison of each single task to the baseline task showed no activity in prefrontal areas. The comparison of the dual task to the single tasks demonstrated left-sided foci of activity in the frontal gyrus (BA 9/46, BA 10/47 and BA 6), inferior parietal gyrus (BA 40), and cerebellum. By reference to previous neuroimaging studies, BA 9/46 was associated with the coordinated manipulation of simultaneously presented information, BA 10/47 with selection processes, BA 6 with articulatory rehearsal, and BA 40 with attentional shifting. Globally similar regions were found for the integration task, except that the inferior parietal gyrus was not recruited. These results confirm the hypothesis that the left prefrontal cortex is implicated in dual-task performance. Moreover, the involvement of a parietal area in the dual task is in keeping with the hypothesis that a parieto-frontal network sustains executive functioning.