The App-Runx1 Region Is Critical for Birth Defects and Electrocardiographic Dysfunctions Observed in a Down Syndrome Mouse Model

Down syndrome (DS) leads to complex phenotypes and is the main genetic cause of birth defects and heart diseases. The Ts65Dn DS mouse model is trisomic for the distal part of mouse chromosome 16 and displays similar features with post-natal lethality and cardiovascular defects. In order to better understand these defects, we defined electrocardiogram (ECG) with a precordial set-up, and we found conduction defects and modifications in wave shape, amplitudes, and durations in Ts65Dn mice. By using a genetic approach consisting of crossing Ts65Dn mice with Ms5Yah mice monosomic for the App-Runx1 genetic interval, we showed that the Ts65Dn viability and ECG were improved by this reduction of gene copy number. Whole-genome expression studies confirmed gene dosage effect in Ts65Dn, Ms5Yah, and Ts65Dn/Ms5Yah hearts and showed an overall perturbation of pathways connected to post-natal lethality (Coq7, Dyrk1a, F5, Gabpa, Hmgn1, Pde10a, Morc3, Slc5a3, and Vwf) and heart function (Tfb1m, Adam19, Slc8a1/Ncx1, and Rcan1). In addition cardiac connexins (Cx40, Cx43) and sodium channel sub-units (Scn5a, Scn1b, Scn10a) were found down-regulated in Ts65Dn atria with additional down-regulation of Cx40 in Ts65Dn ventricles and were likely contributing to conduction defects. All these data pinpoint new cardiac phenotypes in the Ts65Dn, mimicking aspects of human DS features and pathways altered in the mouse model. In addition they highlight the role of the App-Runx1 interval, including Sod1 and Tiam1, in the induction of post-natal lethality and of the cardiac conduction defects in Ts65Dn. These results might lead to new therapeutic strategies to improve the care of DS people

The ERP signature of the contextual diversity effect in visual word recognition

Behavioral experiments have revealed that words appearing in many different contexts are responded to faster than words that appear in few contexts. Although this contextual diversity (CD) effect has been found to be stronger than the word-frequency (WF) effect, it is a matter of debate whether the facilitative effects of CD and WF reflect the same underlying mechanisms. The analysis of the electrophysiological correlates of CD may shed some light on this issue. This experiment is the first to examine the ERPs to high- and low-CD words when WF is controlled for. Results revealed that while high-CD words produced faster responses than low-CD words, their ERPs showed larger negativities (225-325 ms) than low-CD words. This result goes in the opposite direction of the ERP WF effect (high-frequency words elicit smaller N400 amplitudes than low-frequency words). The direction and scalp distribution of the CD effect resembled the ERP effects associated with "semantic richness." Thus, while apparently related, CD and WF originate from different sources during the access of lexical-semantic representations.The research reported in this article has been partially funded by Grants PSI2011-26924 (Spanish Ministry of Economy and Competitiveness) and GV/2014/067 (Conselleria d'Educacio, Investigacio, Cultura i Esport de la Generalitat Valenciana).info:eu-repo/semantics/publishedVersio

Residential Transience and Depression: Does the Relationship Exist for Men and Women?

Residential transience may contribute to adverse mental health. However, to date, this relationship has not been well-investigated among urban, impoverished populations. In a sample of drug users and their social network members (n = 1,024), we assessed the relationship between transience (frequently moving in the past 6 months) and depressive symptoms, measured by the CES-D, among men and women. Even after adjusting for homelessness, high levels of depressive symptoms were 2.29 [95%CI = 1.29–4.07] times more likely among transient men compared to nontransient men and 3.30 [95% CI = 1.10–9.90] times more common among transient women compared to nontransient women. Stable housing and mental health services need to be available, easily accessible, and designed so that they remain amenable to utilization under transient circumstances

Efficient and rapid generation of large genomic variants in rats and mice using CRISMERE

Modelling Down syndrome (DS) in mouse has been crucial for the understanding of the disease and the evaluation of therapeutic targets. Nevertheless, the modelling so far has been limited to the mouse and, even in this model, generating duplication of genomic regions has been labour intensive and time consuming. We developed the CRISpr MEdiated REarrangement (CRISMERE) strategy, which takes advantage of the CRISPR/Cas9 system, to generate most of the desired rearrangements from a single experiment at much lower expenses and in less than 9 months. Deletions, duplications, and inversions of genomic regions as large as 24.4 Mb in rat and mouse founders were observed and germ line transmission was confirmed for fragment as large as 3.6 Mb. Interestingly we have been able to recover duplicated regions from founders in which we only detected deletions. CRISMERE is even more powerful than anticipated it allows the scientific community to manipulate the rodent and probably other genomes in a fast and efficient manner which was not possible before