Partial agreement between task and BRIEF-P-based EF measures depends on school socioeconomic status.

Executive functions (EF), either conceptualized as skills involved in regulation of cognition and emotion in service of goal-oriented behavior, or reductively as working memory, flexibility and inhibitory control, are commonly invoked constructs in developmental science. Two main traditions on EFs measurement prevail, one consisting of ratings obtained through questionnaires that inquire on behavior in common situations, the other based on performance in laboratory tasks. Whether both types of assessment actually refer to the same constructs is not consensual. Further, the role of school context in the degree of correspondence between both types of measures remains largely unexplored. Here, we show in a sample of over 220 children (age M = 5.6, SD = 0.4 years), by means of multilevel models, that whether EF tasks can predict BRIEF-P ratings and vice-versa, depends on the process considered and on the school SES. Inhibitory control, planning, and global executive functioning are associated with BRIEF-P ratings in all schools. In contrast, we found no association among measures of flexibility independently of school SES. For working memory, we found that questionnaire rating predicts span only in high SES schools, but span predicts behaviors across schools. Our findings contribute to a growing body of literature that proposes constructs assessed by questionnaires and tasks only partially overlap and suggests that school SES may be a relevant factor to consider when questionnaires are answered by teachers.

Food Restriction Ameliorates the Development of Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by the accumulation of kidney cysts that ultimately leads to loss of renal function and kidney failure. At present, the treatment for ADPKD is largely supportive. Multiple studies have focused on pharmacologic approaches to slow the development of the cystic disease; however, little is known about the role of nutrition and dietary manipulation in PKD. Here, we show that food restriction (FR) effectively slows the course of the disease in mouse models of ADPKD. Mild to moderate (10%-40%) FR reduced cyst area, renal fibrosis, inflammation, and injury in a dose-dependent manner. Molecular and biochemical studies in these mice indicate that FR ameliorates ADPKD through a mechanism involving suppression of the mammalian target of the rapamycin pathway and activation of the liver kinase B1/AMP-activated protein kinase pathway. Our data suggest that dietary interventions such as FR, or treatment that mimics the effects of such interventions, may be potential and novel preventive and therapeutic options for patients with ADPKD.

Cardiomyopathy and Worsened Ischemic Heart Failure in SM22-α Cre-Mediated Neuropilin-1 Null Mice: Dysregulation of PGC1α and Mitochondrial Homeostasis.

OBJECTIVE: Neuropilin-1 (NRP-1) is a multidomain membrane receptor involved in angiogenesis and development of neuronal circuits, however, the role of NRP-1 in cardiovascular pathophysiology remains elusive. APPROACH AND RESULTS: In this study, we first observed that deletion of NRP-1 induced peroxisome proliferator-activated receptor γ coactivator 1α in cardiomyocytes and vascular smooth muscle cells, which was accompanied by dysregulated cardiac mitochondrial accumulation and induction of cardiac hypertrophy- and stress-related markers. To investigate the role of NRP-1 in vivo, we generated mice lacking Nrp-1 in cardiomyocytes and vascular smooth muscle cells (SM22-α-Nrp-1 KO), which exhibited decreased survival rates, developed cardiomyopathy, and aggravated ischemia-induced heart failure. Mechanistically, we found that NRP-1 specifically controls peroxisome proliferator-activated receptor γ coactivator 1 α and peroxisome proliferator-activated receptor γ in cardiomyocytes through crosstalk with Notch1 and Smad2 signaling pathways, respectively. Moreover, SM22-α-Nrp-1 KO mice exhibited impaired physical activities and altered metabolite levels in serum, liver, and adipose tissues, as demonstrated by global metabolic profiling analysis. CONCLUSIONS: Our findings provide new insights into the cardioprotective role of NRP-1 and its influence on global metabolism.

Deleted in breast cancer 1 (DBC1) protein regulates hepatic gluconeogenesis.

Liver gluconeogenesis is essential to provide energy to glycolytic tissues during fasting periods. However, aberrant up-regulation of this metabolic pathway contributes to the progression of glucose intolerance in individuals with diabetes. Phosphoenolpyruvate carboxykinase (PEPCK) expression plays a critical role in the modulation of gluconeogenesis. Several pathways contribute to the regulation of PEPCK, including the nuclear receptor Rev-erbα and the histone deacetylase SIRT1. Deleted in breast cancer 1 (DBC1) is a nuclear protein that binds to and regulates both Rev-erbα and SIRT1 and, therefore, is a candidate to participate in the regulation of PEPCK. In this work, we provide evidence that DBC1 regulates glucose metabolism and the expression of PEPCK. We show that DBC1 levels decrease early in the fasting state. Also, DBC1 KO mice display higher gluconeogenesis in a normal and a high-fat diet. DBC1 absence leads to an increase in PEPCK mRNA and protein expression. Conversely, overexpression of DBC1 results in a decrease in PEPCK mRNA and protein levels. DBC1 regulates the levels of Rev-erbα, and manipulation of Rev-erbα activity or levels prevents the effect of DBC1 on PEPCK. In addition, Rev-erbα levels decrease in the first hours of fasting. Finally, knockdown of the deacetylase SIRT1 eliminates the effect of DBC1 knockdown on Rev-erbα levels and PEPCK expression, suggesting that the mechanism of PEPCK regulation is, at least in part, dependent on the activity of this enzyme. Our results point to DBC1 as a novel regulator of gluconeogenesis.

DBC1 (Deleted in Breast Cancer 1) modulates the stability and function of the nuclear receptor Rev-erbα.

The nuclear receptor Rev-erbα has been implicated as a major regulator of the circadian clock and integrates circadian rhythm and metabolism. Rev-erbα controls circadian oscillations of several clock genes and Rev-erbα protein degradation is important for maintenance of the circadian oscillations and also for adipocyte differentiation. Elucidating the mechanisms that regulate Rev-erbα stability is essential for our understanding of these processes. In the present paper, we report that the protein DBC1 (Deleted in Breast Cancer 1) is a novel regulator of Rev-erbα. Rev-erbα and DBC1 interact in cells and in vivo, and DBC1 modulates the Rev-erbα repressor function. Depletion of DBC1 by siRNA (small interfering RNA) in cells or in DBC1-KO (knockout) mice produced a marked decrease in Rev-erbα protein levels, but not in mRNA levels. In contrast, DBC1 overexpression significantly enhanced Rev-erbα protein stability by preventing its ubiquitination and degradation. The regulation of Rev-erbα protein levels and function by DBC1 depends on both the N-terminal and C-terminal domains of DBC1. More importantly, in cells depleted of DBC1, there was a dramatic decrease in circadian oscillations of both Rev-erbα and BMAL1. In summary, our data identify DBC1 as an important regulator of the circadian receptor Rev-erbα and proposes that Rev-erbα could be involved in mediating some of the physiological effects of DBC1.

The Long and Winding Road to Real-Life Experiments: Remote Assessment of Executive Functions with Computerized Games-Results from 8 Years of Naturalistic Interventions.

Mate Marote is an open-access cognitive training software aimed at children between 4 and 8 years old. It consists of a set of computerized games specifically tailored to train and evaluate Executive Functions (EF), a class of processes critical for purposeful, goal-directed behavior, including working memory, planning, flexibility, and inhibitory control. Since 2008, several studies were performed with this software at children's own schools in interventions supervised in-person by cognitive scientists. After 2015, we incorporated naturalistic, yet controlled, interventions with children's own teachers' help. The platform includes a battery of standardized tests, disguised as games, to assess children's EF. The main question that emerges is whether the results, obtained with these traditional tasks but conducted without the presence of researchers, are comparable to those widely reported in the literature, that were obtained in more supervised settings. In this study, we were able to replicate the expected difficulty and age effects in at least one of the analyzed dependent variables of each employed test. We also report important discrepancies between the expected and the observed response time patterns, specifically for time-constrained tasks. We hereby discuss the benefits and setbacks of a new possible strategy for this type of assessment in naturalistic settings. We conclude that this battery of established EF tasks adapted for its remote usage is appropriate to measure the expected mental processes in naturalistic settings, enriching opportunities to upscale cognitive training interventions at schools. These types of tools can constitute a concerted strategy to bring together educational neuroscience research and real-life practice.

Role of deleted in breast cancer 1 (DBC1) protein in SIRT1 deacetylase activation induced by protein kinase A and AMP-activated protein kinase.

The NAD(+)-dependent deacetylase SIRT1 is a key regulator of several aspects of metabolism and aging. SIRT1 activation is beneficial for several human diseases, including metabolic syndrome, diabetes, obesity, liver steatosis, and Alzheimer disease. We have recently shown that the protein deleted in breast cancer 1 (DBC1) is a key regulator of SIRT1 activity in vivo. Furthermore, SIRT1 and DBC1 form a dynamic complex that is regulated by the energetic state of the organism. Understanding how the interaction between SIRT1 and DBC1 is regulated is therefore essential to design strategies aimed to activate SIRT1. Here, we investigated which pathways can lead to the dissociation of SIRT1 and DBC1 and consequently to SIRT1 activation. We observed that PKA activation leads to a fast and transient activation of SIRT1 that is DBC1-dependent. In fact, an increase in cAMP/PKA activity resulted in the dissociation of SIRT1 and DBC1 in an AMP-activated protein kinase (AMPK)-dependent manner. Pharmacological AMPK activation led to SIRT1 activation by a DBC1-dependent mechanism. Indeed, we found that AMPK activators promote SIRT1-DBC1 dissociation in cells, resulting in an increase in SIRT1 activity. In addition, we observed that the SIRT1 activation promoted by PKA and AMPK occurs without changes in the intracellular levels of NAD(+). We propose that PKA and AMPK can acutely activate SIRT1 by inducing dissociation of SIRT1 from its endogenous inhibitor DBC1. Our experiments provide new insight on the in vivo mechanism of SIRT1 regulation and a new avenue for the development of pharmacological SIRT1 activators targeted at the dissociation of the SIRT1-DBC1 complex.

Early and late calcium waves during wound healing in corneal endothelial cells.

Immediately after wounding, bovine corneal endothelial cells develop a fast calcium wave that propagates from the wound border to the rest of the monolayer and extinguishes in approximately 5 minutes. One hour after wounding, a late, slow calcium wave (SCW) develops concomitantly to the depolarization of the plasma membrane potential of the border cells. The incorporation of inhibitors of the epithelial sodium channel and of the sodium-calcium exchanger produces inhibition of the membrane depolarization and the SCW, and diminishes the rate of wound healing. The L-type calcium channel blocker nimodipine does not have any effect on the SCW. The reversible inhibition of the fast calcium wave does not affect the SCW and only slightly decreases the velocity of healing. Our results suggest that the SCW is at least partially produced by the coupling of the epithelial sodium channel and the sodium-calcium exchanger functioning in reverse mode. They also suggest that the SCW may play a role in the overall healing process.

Socioeconomic status differences in children's affective decision-making: The role of awareness in the Children's Gambling Task.

Future-oriented decision-making is an important adaptive behavior. In the present study, we examined whether decision-making varies as a function of socioeconomic status (SES) using the Children's Gambling task (CGT). We administered the CGT to 227 children (49% female, 48% low SES) between the ages of 5 and 7 years. After completing the CGT, we assessed children's knowledge of the reward/loss contingencies. Data analysis was conducted through multilevel modeling. Fluid intelligence, as measured by the Test of Nonverbal Intelligence, was included as a covariate in the analysis. Overall performance differed between SES groups. Children from middle/high-SES backgrounds learned to choose more from the deck with higher future reward. In contrast, children in the low-SES group did not act in a full future-oriented manner. No differences were found in the level of explicit understanding of the task reached by the two SES groups. Whereas middle/high-SES children with higher knowledge of the game performed better on the last blocks of the task in comparison with their same-SES peers with no understanding, low-SES children with higher explicit knowledge did not exhibit an improvement in their decision-making strategy in comparison with their same-SES low-awareness counterparts. Fluid intelligence did not predict CGT performance, suggesting that SES differences were not mediated by reasoning capabilities. The finding that children from low-SES families continued exhibiting an immediate reward-oriented strategy despite being aware of deck contingencies fits with (although speculatively) the evolutionary-developmental framework. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

HDAC3 is negatively regulated by the nuclear protein DBC1.

HDAC3 is a member of the class I histone deacetylase family that regulates gene expression by deacetylation of histones and non-histone proteins. HDAC3 activity has been shown to be modulated by interaction with the co-repressors NCoR and SMRT. Here, we present evidence that the nuclear protein DBC1 is an endogenous inhibitor of HDAC3. DBC1 has been previously identified as a regulator of some nuclear receptors, the methyltransferase SUV39H1, and the NAD-dependent deacetylase SIRT1. Furthermore, DBC1 has been shown to influence transcription regulation and apoptosis, and it may also act as a tumor suppressor. We found that DBC1 interacts and specifically inhibits the deacetylase HDAC3. This interaction depends on the N terminus of DBC1 and the C terminus of HDAC3. Expression of DBC1 not only inhibited HDAC3 activity but also altered its subcellular distribution. In addition, knockdown of endogenous DBC1 in cells and knock-out in mouse tissues increased HDAC3 deacetylase activity. Together, these results identify DBC1 as a new regulator of HDAC3 and demonstrate that DBC1 is a negative regulator of two key distinct deacetylases, SIRT1 and HDAC3. These findings may lead to a better understanding of the biological roles of DBC1 and HDAC3 in metabolic diseases and cancer.