An Executive Functioning Perspective in Neurofibromatosis Type 1: From ADHD and Autism Spectrum Disorder to Research Domains

Purpose: Neurofibromatosis type 1 (NF1) is a rare monogenic disorder associated with executive function (EF) deficits and heightened risk for attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). The goal of this paper is to understand how EFs provide a common foundation to understand vulnerabilities for ADHD and ASD within NF1. Methods: A literature review and synthesis was conducted. Results: EF difficulties in working memory, inhibitory control, cognitive flexibility, and planning are evident in NF1, ADHD, and ASD. However, relatively little is known about the heterogeneity of EFs and ADHD and ASD outcomes in NF1. Assessment of ADHD and ASD in NF1 is based on behavioral symptoms without understanding neurobiological contributions. Recent efforts are promoting the use of dimensional and multidisciplinary methods to better understand normal and abnormal behavior, including integrating information from genetics to self-report measures. Conclusion: NF1 is a monogenic disease with well-developed molecular and phenotypic research as well as complementary animal models. NF1 presents an excellent opportunity to advance our understanding of the neurobiological impact of known pathogenic variation in normal and abnormal neural pathways implicated in human psychopathology. EFs are core features of NF1, ADHD, and ASD, and these neurodevelopmental outcomes are highly prevalent in NF1. We propose a multilevel approach for understanding EFs in patients with NF1.This is essential to advance targeted interventions for NF1 patients and to advance the exciting field of research in this condition

When Walls are No Longer Barriers: Perception of Wall Height in Parkour

Through training, skilled parkour athletes (traceurs) overcome everyday obstacles, such as walls, that are typically insurmountable. Traceurs and untrained novices estimated the height of walls and reported their anticipated ability to climb the wall. The traceurs perceived the walls as shorter than did novices. This result suggests that perception is scaled by the perceiver’s anticipated ability to act, and is consistent with the action-specific account of perception

Action-Specific Effects Underwater

Action-specific effects on perception are apparent in terrestrial environments. For example, targets that require more effort to walk, jump, or throw to look farther away than when the targets require less effort. Here, we examined whether action-specific effects would generalize to an underwater environment. Instead, perception might be geometrically precise, rather than action-specific, in an environment that is novel from an evolutionary perspective. We manipulated ease to swim by giving participants swimming flippers or taking them away. Those who estimated distance while wearing the flippers judged underwater targets to be closer than did participants who had taken them off. In addition, participants with better swimming ability judged the targets to be closer than did those with worse swimming ability. These results suggest perceived distance underwater is a function of the perceiver’s ability to swim to the targets

Neurofibromatosis Type 1 Implicates Ras Pathways in the Genetic Architecture of Neurodevelopmental Disorders

The genetic architecture of neurodevelopmental disorders is largely polygenic, non-specific, and pleiotropic. This complex genetic architecture makes the search for specific etiological mechanisms that contribute to neurodevelopmental risk more challenging. Monogenic disorders provide an opportunity to focus in on how well-articulated signaling pathways contribute to risk for neurodevelopmental outcomes. This paper will focus on neurofbromatosis type 1 (NF1), a rare monogenic disorder that is associated with varied neurodevelopmental outcomes. Specifically, this paper will provide a brief overview of NF1 and its phenotypic associations with autism spectrum disorder, attention-deficit/hyperactivity disorder, and specific learning disorders, describe how variation within the NF1 gene increases risk for neurodevelopmental disorders via altered Ras signaling, and provide future directions for NF1 research to help elucidate the genetic architecture of neurodevelopmental disorders in the general population

ASAS-SSR Triennnial Reproduction Symposium: Looking Back and Moving Forward—How Reproductive Physiology has Evolved: Fetal origins of impaired muscle growth and metabolic dysfunction: Lessons from the heat-stressed pregnant ewe

Intrauterine growth restriction (IUGR) is the second leading cause of perinatal mortality and predisposes offspring to metabolic disorders at all stages of life. Muscle-centric fetal adaptations reduce growth and yield metabolic parsimony, beneficial for IUGR fetal survival but detrimental to metabolic health after birth. Epidemiological studies have reported that IUGRborn children experience greater prevalence of insulin resistance and obesity, which progresses to diabetes, hypertension, and other metabolic disorders in adulthood that reduce quality of life. Similar adaptive programming in livestock results in decreased birth weights, reduced and inefficient growth, decreased carcass merit, and substantially greater mortality rates prior to maturation. High rates of glucose consumption and metabolic plasticity make skeletal muscle a primary target for nutrient-sparing adaptations in the IUGR fetus, but at the cost of its contribution to proper glucose homeostasis after birth. Identifying the mechanisms underlying IUGR pathophysiology is a fundamental step in developing treatments and interventions to improve outcomes in IUGR-born humans and livestock. In this review, we outline the current knowledge regarding the adaptive restriction of muscle growth and alteration of glucose metabolism that develops in response to progressively exacerbating intrauterine conditions. In addition, we discuss the evidence implicating developmental changes in β adrenergic and inflammatory systems as key mechanisms for dysregulation of these processes. Lastly, we highlight the utility and importance of sheep models in developing this knowledge

Sustained maternal inflammation during the early third trimester yields fetal adaptations that impair subsequent skeletal muscle growth and glucose metabolism in sheep

Intrauterine growth restriction (IUGR) is linked to metabolic dysfunction in offspring, but the mediating mechanisms are still under investigation (Barker et al., 1993). IUGR fetuses adapt to their poor intrauterine environment by repartitioning nutrients to organs critical for survival (i.e., brain, heart) at the expense of tissues such as muscle (Yates et al., 2012c). These developmental adaptations help the fetus to survive in utero but have lifelong consequences in offspring; persistent reduction of highly metabolic muscle mass is detrimental to glucose homeostasis (DeFronzo et al., 1981). Glucose metabolism is regulated primarily by insulin, and nutrient depravation is associated with impaired β-cell mass, insulin secretion, and insulin action in the IUGR fetus (Limesand et al., 2006). Moreover, inflammation disrupts insulin action and aids in the development of insulin resistance (Bach et al., 2013). We recently showed that inflammatory cytokines acutely stimulate glucose metabolism despite their antagonistic effects on insulin signaling (Cadaret et al., 2017b). However, we hypothesize that chronic exposure alters responsiveness to cytokines and results in basal cytokine concentrations having a greater inhibitory tone. Furthermore, chronic maternal inflammation may induce fetal inflammatory adaptations that impair muscle growth and metabolism. Therefore, our objective was to determine the effects of sustained maternal inflammation on fetal growth, islet function, and muscle glucose metabolism

Sustained maternal inflammation during the early third trimester yields fetal adaptations that impair subsequent skeletal muscle growth and glucose metabolism in sheep

Intrauterine growth restriction (IUGR) is linked to metabolic dysfunction in offspring, but the mediating mechanisms are still under investigation (Barker et al., 1993). IUGR fetuses adapt to their poor intrauterine environment by repartitioning nutrients to organs critical for survival (i.e., brain, heart) at the expense of tissues such as muscle (Yates et al., 2012c). These developmental adaptations help the fetus to survive in utero but have lifelong consequences in offspring; persistent reduction of highly metabolic muscle mass is detrimental to glucose homeostasis (DeFronzo et al., 1981). Glucose metabolism is regulated primarily by insulin, and nutrient depravation is associated with impaired β-cell mass, insulin secretion, and insulin action in the IUGR fetus (Limesand et al., 2006). Moreover, inflammation disrupts insulin action and aids in the development of insulin resistance (Bach et al., 2013). We recently showed that inflammatory cytokines acutely stimulate glucose metabolism despite their antagonistic effects on insulin signaling (Cadaret et al., 2017b). However, we hypothesize that chronic exposure alters responsiveness to cytokines and results in basal cytokine concentrations having a greater inhibitory tone. Furthermore, chronic maternal inflammation may induce fetal inflammatory adaptations that impair muscle growth and metabolism. Therefore, our objective was to determine the effects of sustained maternal inflammation on fetal growth, islet function, and muscle glucose metabolism

Bridging Indigenous and science-based knowledge in coastal and marine research, monitoring, and management in Canada

This work is licensed under a Creative Commons Attribution 4.0 International License.Background Drawing upon multiple types of knowledge (e.g., Indigenous knowledge, local knowledge, science-based knowledge) strengthens the evidence-base for policy advice, decision making, and environmental management. While the benefits of incorporating multiple types of knowledge in environmental research and management are many, doing so has remained a challenge. This systematic map examined the extent, range, and nature of the published literature (i.e., commercially published and grey) that seeks to respectively bridge Indigenous and science-based knowledge in coastal and marine research and management in Canada. Methods This systematic map applied standardized search terms across four databases focused on commercially published literature, carefully selected specialist websites, and two web-based search engines. In addition, reference sections of relevant review articles were cross-checked to identify articles that may not have been found using the search strategy. Search results were screened in two sequential stages; (1) at title and abstract; and (2) at full text following a published protocol. All case studies included were coded using a standard questionnaire. A narrative synthesis approach was used to identify trends in the evidence, knowledge gaps, and knowledge clusters. Results A total of 62 articles that spanned 71 Canadian case studies were included in the systematic map. Studies across the coastal and marine regions of Inuit Nunangat accounted for the majority of the studies. Whether the focus is on management and decision making or research and monitoring, the predominant ecological scale was at the species level, accounting for over two-thirds of the included studies. There were 24 distinct coastal and marine species of central focus across the studies. Nunavut had the greatest taxonomic coverage as studies conducted to date cover 13 different genera. The predominant methodology employed for combining and/or including Indigenous knowledge was case study design, which accounted for over half of the studies. Other methodologies employed for combining and/or including different ways of knowing included: (i) community-based participatory research; (ii) mixed methods; (iii) ethnography; and (iv) simulation modelling. There are a suite of methods utilized for documenting and translating Indigenous knowledge and an equally diverse tool box of methods used in the collection of scientific data. Over half of the case studies involved Indigenous knowledge systems of the Inuit, while another significant proportion involved Indigenous knowledge systems of First Nations, reflecting 21 unique nations. We found that demographics of knowledge holders were generally not reported in the articles reviewed. Conclusions The results of this systematic map provide key insights to inform and improve future research. First, a variety of methodologies and methods are used in these types of studies. Therefore, there is a need to consider in more detail how Indigenous and science-based knowledge systems can be respectively bridged across subjects while also recognizing specific place-based needs of Indigenous communities. Second, the work highlights the need to better report the demographics of knowledge holders. Further inquiry focused on the extent of knowledge co-production and assessing Indigenous participation across different stages of the research process would serve the research community well to improve future research and monitoring in support of, and to strengthen, evidence-based environmental management

Increased prevalence of dhfr and dhps mutants at delivery in Malawian pregnant women receiving intermittent preventive treatment for malaria

In the context of an Intermittent preventive treatment (IPTp) trial for pregnant women in Malawi, P. falci-parum samples from 85 women at enrollment and 35 women at delivery were genotyped for mutations associated with sulfadoxine-pyrimethamine resistance. The prevalence of the highly resistant haplotype with mutations at codons 51 and 108 of dihydrofolate reductase (dhfr) and codons 437 and 540 of dihydropteroate synthase (dhps) increased from 81% at enrollment to 100% at delivery (p=0.01). Pregnant women who were smear-positive at enrollment were more likely to have P. falciparum parasitemia at delivery. These results lend support to concerns that IPTp use may lead to increased drug resistance in pregnant women during pregnancy and emphasize the importance of screening pregnant women for malaria parasites in areas with prevalent SP resistance even when they are already on IPTp

Extended Functional Connectivity of Convergent Structural Alterations Among Individuals with PTSD: A Neuroimaging Meta-Analysis

Background: Post-traumatic stress disorder (PTSD) is a debilitating disorder defined by the onset of intrusive, avoidant, negative cognitive or affective, and/or hyperarousal symptoms after witnessing or experiencing a traumatic event. Previous voxel-based morphometry studies have provided insight into structural brain alterations associated with PTSD with notable heterogeneity across these studies. Furthermore, how structural alterations may be associated with brain function, as measured by task-free and task-based functional connectivity, remains to be elucidated. Methods: Using emergent meta-analytic techniques, we sought to first identify a consensus of structural alterations in PTSD using the anatomical likelihood estimation (ALE) approach. Next, we generated functional profiles of identified convergent structural regions utilizing resting-state functional connectivity (rsFC) and meta-analytic co-activation modeling (MACM) methods. Finally, we performed functional decoding to examine mental functions associated with our ALE, rsFC, and MACM brain characterizations. Results: We observed convergent structural alterations in a single region located in the medial prefrontal cortex. The resultant rsFC and MACM maps identified functional connectivity across a widespread, whole-brain network that included frontoparietal and limbic regions. Functional decoding revealed overlapping associations with attention, memory, and emotion processes. Conclusions: Consensus-based functional connectivity was observed in regions of the default mode, salience, and central executive networks, which play a role in the tripartite model of psychopathology. Taken together, these findings have important implications for understanding the neurobiological mechanisms associated with PTSD