Environmental and genetic influences on neurocognitive development: the importance of multiple methodologies and time-dependent intervention

Genetic mutations and environmental factors dynamically influence gene expression and developmental trajectories at the neural, cognitive, and behavioral levels. The examples in this article cover different periods of neurocognitive development—early childhood, adolescence, and adulthood—and focus on studies in which researchers have used a variety of methodologies to illustrate the early effects of socioeconomic status and stress on brain function, as well as how allelic differences explain why some individuals respond to intervention and others do not. These studies highlight how similar behaviors can be driven by different underlying neural processes and show how a neurocomputational model of early development can account for neurodevelopmental syndromes, such as autism spectrum disorders, with novel implications for intervention. Finally, these studies illustrate the importance of the timing of environmental and genetic factors on development, consistent with our view that phenotypes are emergent, not predetermined

Rab4 Orchestrates a Small GTPase Cascade for Recruitment of Adaptor Proteins to Early Endosomes

SummaryBackgroundEarly, sorting endosomes are a major crossroad of membrane traffic, at the intersection of the endocytic and exocytic pathways. The sorting of endosomal cargo for delivery to different subcellular destinations is mediated by a number of distinct coat protein complexes, including adaptor protein 1 (AP-1), AP-3, and Golgi-localized, gamma adaptin ear-containing, Arf-binding (GGAs) protein. Ultrastructural studies suggest that these coats assemble onto tubular subdomains of the endosomal membrane, but the mechanisms of coat recruitment and assembly at this site remain poorly understood.ResultsHere we report that the endosomal Rab protein Rab4 orchestrates a GTPase cascade that results in the sequential recruitment of the ADP-ribosylation factor (Arf)-like protein Arl1; the Arf-specific guanine nucleotide exchange factors BIG1 and BIG2; and the class I Arfs, Arf1 and Arf3. Knockdown of Arf1, or inhibition of BIG1 and BIG2 activity with brefeldin A results in the loss of AP-1, AP-3, and GGA-3, but not Arl1, from endosomal membranes and the formation of elongated tubules. In contrast, depletion of Arl1 randomizes the distribution of Rab4 on endosomal membranes, inhibits the formation of tubular subdomains, and blocks recruitment of BIG1 and BIG2, Arfs, and adaptor protein complexes to the endosome.ConclusionsTogether these findings indicate that Arl1 links Rab4-dependent formation of endosomal sorting domains with downstream assembly of adaptor protein complexes that constitute the endosomal sorting machinery

Stress and stressors experienced by the parents of high-risk neonates admitted in neonatal intensive care unit: Systematic review and meta-analysis evidence available from India

The aim of the systematic review and meta-analysis is to determine the stress and stressors experienced by the parents of high-risk neonates admitted to the neonatal intensive care unit (NICU) in India. We included both quantitative and qualitative studies. The Joanna Briggs Institute Critical Appraisal Checklist and Critical Appraisal Skill Programme checklist were used to assess the quality of included studies. A systematic search was conducted in PubMed, EMBASE, SCOPUS, EBSCOhost, Web of Science, ProQuest, Microsoft Academic, DOAJ, Indian Citation Index, and J-Gate to identify relevant studies. Additionally, online hand searching was performed on Indian websites of relevant institutions, women and child health departments, repositories, registries, and paediatric journals. Twelve of the 21 quantitative studies found that maternal stress was higher than fathers due to the separation from their babies and the medical condition of the neonate. One qualitative study reported that financial burden, alterations in the parenting role, and concern over domestic issues are significant causes of fathers' stress. A meta-analysis of the included studies assessed the prevalence of maternal, paternal, and parental stress and reported that mothers experienced higher stress levels than fathers across all subscales. The most typical stressors for parents were changes in neonatal looks, behaviour, and altered parental roles. Beyond the immediate NICU care and interactions, other triggering factors of stress among parents must be considered to design multicomponent interventions in a local (Indian) context. Moreover, parental psychological support and regular counselling can be incorporated into the standard neonatal intensive care policy

A Genome-Wide Screen Identifies Genes That Affect Somatic Homolog Pairing in Drosophila

In Drosophila and other Dipterans, homologous chromosomes are in close contact in virtually all nuclei, a phenomenon known as somatic homolog pairing. Although homolog pairing has been recognized for over a century, relatively little is known about its regulation. We performed a genome-wide RNAi-based screen that monitored the X-specific localization of the male-specific lethal (MSL) complex, and we identified 59 candidate genes whose knockdown via RNAi causes a change in the pattern of MSL staining that is consistent with a disruption of X-chromosomal homolog pairing. Using DNA fluorescent in situ hybridization (FISH), we confirmed that knockdown of 17 of these genes has a dramatic effect on pairing of the 359 bp repeat at the base of the X. Furthermore, dsRNAs targeting Pr-set7, which encodes an H4K20 methyltransferase, cause a modest disruption in somatic homolog pairing. Consistent with our results in cultured cells, a classical mutation in one of the strongest candidate genes, pebble (pbl), causes a decrease in somatic homolog pairing in developing embryos. Interestingly, many of the genes identified by our screen have known roles in diverse cell-cycle events, suggesting an important link between somatic homolog pairing and the choreography of chromosomes during the cell cycle

Optimal Reachability for Weighted Timed Games

Weighted timed automata are timed automata annotated with costs on locations and transitions. The optimal game-reachability problem for these automata is to find the best-cost strategy of supplying the inputs so as to ensure reachability of a target set within a specified number of iterations. The only known complexity bound for this problem is a doubly-exponential upper bound. We establish a singly-exponential upper bound and show that there exist automata with exponentially many states in a single region with pair-wise distinct optimal strategies

Algorithm for normal random numbers

We propose a simple algorithm for generating normally distributed pseudo random numbers. The algorithm simulates N molecules that exchange energy among themselves following a simple stochastic rule. We prove that the system is ergodic, and that a Maxwell like distribution that may be used as a source of normally distributed random deviates follows when N tends to infinity. The algorithm passes various performance tests, including Monte Carlo simulation of a finite 2D Ising model using Wolff's algorithm. It only requires four simple lines of computer code, and is approximately ten times faster than the Box-Muller algorithm.Comment: 5 pages, 3 encapsulated Postscript Figures. Submitted to Phys.Rev.Letters. For related work, see http://pipe.unizar.es/~jf

Long and short paths in uniform random recursive dags

In a uniform random recursive k-dag, there is a root, 0, and each node in turn, from 1 to n, chooses k uniform random parents from among the nodes of smaller index. If S_n is the shortest path distance from node n to the root, then we determine the constant \sigma such that S_n/log(n) tends to \sigma in probability as n tends to infinity. We also show that max_{1 \le i \le n} S_i/log(n) tends to \sigma in probability.Comment: 16 page

Risk of criminal justice system interactions in young adults with attention-deficit/hyperactivity disorder: findings from a national birth cohort

Objective: To examine criminal justice system (CJS) interactions and pathways through the justice system for young adults with ADHD compared to young adults without ADHD. Method: Nationwide 3-year birth cohort study using linked health and CJS data. Cox proportional hazards models were employed to examine associations between ADHD and police proceedings, court charges, court convictions, and incarcerations. Results: Young adults with ADHD were significantly more likely to interact with the CJS including police proceedings (hazard ratio [HR], 2.1 95% CI [2.0, 2.2]) court charges (HR, 2.2 95% CI [2.1, 2.3]), court convictions (HR, 2.3 95% CI [2.2, 2.4]), and incarceration (HR, 4.8 95% CI [4.3, 5.4]). Conclusions: Young adults with ADHD are overrepresented at all stages of the CJS. Results highlight the importance of early identification and responsivity to ADHD within the CJS and suggest that the NZ justice system may require changes to both areas to ensure that young individuals with ADHD receive equitable access to, and treatment within, the CJS