The role of selenoproteins in neurodevelopment and neurological function: Implications in autism spectrum disorder.

Selenium and selenoproteins play a role in many biological functions, particularly in brain development and function. This review outlines the role of each class of selenoprotein in human brain function. Most selenoproteins play a large antioxidant role within the brain. Autism spectrum disorder (ASD) has been shown to correlate with increased oxidative stress, and the presumption of selenoproteins as key players in ASD etiology are discussed. Further, current literature surrounding selenium in ASD and selenium supplementation studies are reviewed. Finally, perspectives are given for future directions of selenoprotein research in ASD.

Isotopic composition of serum zinc and copper in healthy children and children with autism spectrum disorder in North America.

To better understand zinc and copper regulation and their involvement in various biochemical pathways as it relates to autism spectrum disorder (ASD), isotopic composition of serum zinc and copper were evaluated in both healthy children and children with ASD in North America. No significant difference in isotopic composition of serum zinc or copper with respect to healthy controls and ASD children were identified. However, the isotopic composition of serum copper in boys was found to be enriched in 65Cu in comparison to previously published healthy adult copper isotopic composition. Furthermore, in both boys and girls, the average isotopic composition of serum zinc is heavier than previously published healthy adult isotopic zinc composition. There was also a negative association between total zinc concentrations in serum and the zinc isotopic composition of serum in boys. Finally, children with heavier isotopic composition of copper also showed a high degree of variability in their zinc isotopic composition. While numerous studies have measured the isotopic composition of serum zinc and copper in adults, this is one of the first studies which measured the isotopic composition of serum copper and zinc in children, specifically those diagnosed with ASD. The results of this study showed that age and gender specific normal ranges of isotopic composition must be established to effectively use isotopic composition analysis in studying various diseases including ASD.

Eating disorders and intrasexual competition: testing an evolutionary hypothesis among young women.

The sexual competition hypothesis (SCH) contends that intense female intrasexual competition (ISC) is the ultimate cause of eating disorders. The SCH explains the phenomenon of the pursuit of thinness as an adaptation to ISC in the modern environment. It argues that eating disorders are pathological phenomena that arise from the mismatch between the modern environment and the inherited female adaptations for ISC. The present study has two aims. The first is to examine the relationship between disordered eating behavior (DEB) and ISC in a sample of female undergraduates. The second is to establish whether there is any relationship between disordered eating behavior and life history (LH) strategy. Participants completed a battery of questionnaires examining eating-related attitudes and behaviors, ISC, and LH strategy. A group of 206 female undergraduates were recruited. A structural equation model was constructed to analyze the data. ISC for mates was significantly associated with DEB, as predicted by the SCH. DEB was found to be predicted by fast LH strategy, which was only partially mediated by the SCH. The results of this study are supportive of the SCH and justify research on a clinical sample.

Fetal Alcohol Spectrum Disorder and Iron Homeostasis.

Prenatal alcohol exposure results in a spectrum of behavioral, cognitive, and morphological abnormalities collectively referred to as fetal alcohol spectrum disorder (FASD). FASD presents with significant phenotypic variability and may be modified by gestational variables such as maternal nutritional status. Iron serves a critical function in the development of and processes within central nervous system (CNS) structures. Gestational iron deficiency alters CNS development and may contribute to neurodevelopmental impairment in FASD. This review explores the relationship between iron deficiency and fetal alcohol spectrum disorder as described in small animal and human studies. Consideration is given to the pathophysiologic mechanisms linking iron homeostasis and prenatal alcohol exposure. Existing data suggest that iron deficiency contributes to the severity of FASD and provide a mechanistic explanation linking these two conditions.

Corrigendum: Evaluation of Zn, Cu, and Se Levels in the North American Autism Spectrum Disorder Population.

[This corrects the article DOI: 10.3389/fnmol.2021.665686.].

Evaluation of Zn, Cu, and Se Levels in the North American Autism Spectrum Disorder Population.

Metal ion dyshomeostasis and disparate levels of biometals like zinc (Zn), copper (Cu), and selenium (Se) have been implicated as a potential causative factor for Autism Spectrum Disorder (ASD). In this study, we have enrolled 129 children (aged 2-4 years) in North America, of which 64 children had a diagnosis of ASD and 65 were controls. Hair, nail, and blood samples were collected and quantitatively analyzed for Zn, Cu and Se using inductively coupled plasma mass spectrometry (ICP-MS). Of the analyzed biometals, serum Se (116.83 ± 14.84 mcg/mL) was found to be significantly lower in male ASD cases compared to male healthy controls (128.21 ± 9.11 mcg/mL; p < 0.005). A similar trend was found for nail Se levels in ASD (1.01 ± 0.15 mcg/mL) versus that of controls (1.11 ± 0.17 mcg/mL) with a p-value of 0.0132 using a stratified Wilcoxon rank sum testing. The level of Se in ASD cohort was co-analyzed for psychometric correlation and found a negative correlation between total ADOS score and serum Se levels. However, we did not observe any significant difference in Zn, Cu, and Zn/Cu ratio in ASD cases versus controls in this cohort of North American children. Further studies are recommended to better understand the biology of the relationship between Se and ASD status.

Sec15, a component of the exocyst, promotes notch signaling during the asymmetric division of Drosophila sensory organ precursors.

Asymmetric division of sensory organ precursors (SOPs) in Drosophila generates different cell types of the mature sensory organ. In a genetic screen designed to identify novel players in this process, we have isolated a mutation in Drosophila sec15, which encodes a component of the exocyst, an evolutionarily conserved complex implicated in intracellular vesicle transport. sec15(-) sensory organs contain extra neurons at the expense of support cells, a phenotype consistent with loss of Notch signaling. A vesicular compartment containing Notch, Sanpodo, and endocytosed Delta accumulates in basal areas of mutant SOPs. Based on the dynamic traffic of Sec15, its colocalization with the recycling endosomal marker Rab11, and the aberrant distribution of Rab11 in sec15 clones, we propose that a defect in Delta recycling causes cell fate transformation in sec15(-) sensory lineages. Our data indicate that Sec15 mediates a specific vesicle trafficking event to ensure proper neuronal fate specification in Drosophila.

Sec15 interacts with Rab11 via a novel domain and affects Rab11 localization in vivo.

Sec15, a component of the exocyst, recognizes vesicle-associated Rab GTPases, helps target transport vesicles to the budding sites in yeast and is thought to recruit other exocyst proteins. Here we report the characterization of a 35-kDa fragment that comprises most of the C-terminal half of Drosophila melanogaster Sec15. This C-terminal domain was found to bind a subset of Rab GTPases, especially Rab11, in a GTP-dependent manner. We also provide evidence that in fly photoreceptors Sec15 colocalizes with Rab11 and that loss of Sec15 affects rhabdomere morphology. Determination of the 2.5-A crystal structure of the C-terminal domain revealed a novel fold consisting of ten alpha-helices equally distributed between two subdomains (N and C subdomains). We show that the C subdomain, mainly via a single helix, is sufficient for Rab binding.

Abnormal Levels of Metal Micronutrients and Autism Spectrum Disorder: A Perspective Review.

The aim of the present review is to summarize the prevalence of abnormal levels of various metal micronutrients including copper (Cu), iron (Fe), magnesium (Mg), zinc (Zn), and selenium (Se) in Autism Spectrum Disorder (ASD) using hair, nail and serum samples. A correlation of selected abnormal metal ions with known neurodevelopmental processes using Gene Ontology (GO) term was also conducted. Data included in this review are derived from ASD clinical studies performed globally. Metal ion disparity data is also analyzed and discussed based on gender (Male/Female) to establish any gender dependent correlation. Finally, a rational perspective and possible path to better understand the role of metal micronutrients in ASD is suggested.

Association of Comorbid Mood and Anxiety Disorders With Autism Spectrum Disorder.

Importance: It is critical to evaluate the risk of comorbid psychiatric diagnoses to meet the needs of individuals with autism spectrum disorder (ASD). Objective: To examine whether individuals with ASD are at greater risk for comorbid diagnoses of depression, anxiety, or bipolar disorder. Design, Setting, and Participants: This cohort study used data from a population-based birth cohort of 31 220 individuals born in Olmsted County, Minnesota, from January 1, 1976, to December 31, 2000. Patients with research-identified ASD were previously identified using a multistep process that evaluated signs and symptoms abstracted from medical and educational records. For each of the 1014 patients with ASD, 2 age- and sex-matched referents who did not meet criteria for ASD were randomly selected from the birth cohort (n = 2028). Diagnosis codes for anxiety, depression, and bipolar disorders were electronically obtained using the Rochester Epidemiological Project records-linkage system. Data analysis was performed from July 1, 2018, to April 1, 2019. Main Outcomes and Measures: Cumulative incidence of clinically diagnosed depression, anxiety, and bipolar disorder through early adulthood in individuals with ASD compared with referents. Results: A total of 1014 patients with ASD (median age at last follow-up, 22.8 years [interquartile range, 18.4-28.0 years]; 747 [73.7%] male; 902 [89.0%] white) and 2028 referents (median age at last follow-up, 22.4 years [interquartile range, 18.8-26.2 years]; 1494 [73.7%] male; 1780 [87.8%] white) participated in the study. Patients with ASD were significantly more likely to have clinically diagnosed bipolar disorder (hazard ratio [HR], 9.34; 95% CI, 4.57-19.06), depression (HR, 2.81; 95% CI, 2.45-3.22), and anxiety (HR, 3.45; 95% CI, 2.96-4.01) compared with referents. Among individuals with ASD, the estimates of cumulative incidence by 30 years of age were 7.3% (95% CI, 4.8%-9.7%) for bipolar disorder, 54.1% (95% CI, 49.8%-58.0%) for depression, and 50.0% (95% CI, 46.0%-53.7%) for anxiety. Among referents, cumulative incidence estimates by 30 years of age were 0.9% (95% CI, 0.1%-1.7%) for bipolar disorder, 28.9% (95% CI, 25.7%-32.0%) for depression, and 22.2% (95% CI, 19.3%-25.0%) for anxiety. Conclusions and Relevance: The findings suggest that individuals with ASD may be at increased risk for clinically diagnosed depression, anxiety, and bipolar disorder compared with age- and sex-matched referents. This study supports the importance of early, ongoing surveillance and targeted treatments to address the psychiatric needs of individuals with ASD.

Mutations in Drosophila sec15 reveal a function in neuronal targeting for a subset of exocyst components.

The exocyst is a complex of proteins originally identified in yeast that has been implicated in polarized secretion. Components of the exocyst have been implicated in neurite outgrowth, cell polarity, and cell viability. We have isolated an exocyst component, sec15, in a screen for genes required for synaptic specificity. Loss of sec15 causes a targeting defect of photoreceptors that coincides with mislocalization of specific cell adhesion and signaling molecules. Additionally, sec15 mutant neurons fail to localize other exocyst members like Sec5 and Sec8, but not Sec6, to neuronal terminals. However, loss of sec15 does not cause cell lethality in contrast to loss of sec5 or sec6. Our data suggest a role of Sec15 in an exocyst-like subcomplex for the targeting and subcellular distribution of specific proteins. The data also show that functions of other exocyst components persist in the absence of sec15, suggesting that different exocyst components have separable functions.

Activity-independent prespecification of synaptic partners in the visual map of Drosophila.

Specifying synaptic partners and regulating synaptic numbers are at least partly activity-dependent processes during visual map formation in all systems investigated to date . In Drosophila, six photoreceptors that view the same point in visual space have to be sorted into synaptic modules called cartridges in order to form a visuotopically correct map . Synapse numbers per photoreceptor terminal and cartridge are both precisely regulated . However, it is unknown whether an activity-dependent mechanism or a genetically encoded developmental program regulates synapse numbers. We performed a large-scale quantitative ultrastructural analysis of photoreceptor synapses in mutants affecting the generation of electrical potentials (norpA, trp;trpl), neurotransmitter release (hdc, syt), vesicle endocytosis (synj), the trafficking of specific guidance molecules during photoreceptor targeting (sec15), a specific guidance receptor required for visual map formation (Dlar), and 57 other novel synaptic mutants affecting 43 genes. Remarkably, in all these mutants, individual photoreceptors form the correct number of synapses per presynaptic terminal independently of cartridge composition. Hence, our data show that each photoreceptor forms a precise and constant number of afferent synapses independently of neuronal activity and partner accuracy. Our data suggest cell-autonomous control of synapse numbers as part of a developmental program of activity-independent steps that lead to a "hard-wired" visual map in the fly brain.

Drosophila NMNAT maintains neural integrity independent of its NAD synthesis activity.

Wallerian degeneration refers to a loss of the distal part of an axon after nerve injury. Wallerian degeneration slow (Wld(s)) mice overexpress a chimeric protein containing the NAD synthase NMNAT (nicotinamide mononucleotide adenylyltransferase 1) and exhibit a delay in axonal degeneration. Currently, conflicting evidence raises questions as to whether NMNAT is the protecting factor and whether its enzymatic activity is required for such a possible function. Importantly, the link between nmnat and axon degeneration is at present solely based on overexpression studies of enzymatically active protein. Here we use the visual system of Drosophila as a model system to address these issues. We have isolated the first nmnat mutations in a multicellular organism in a forward genetic screen for synapse malfunction in Drosophila. Loss of nmnat causes a rapid and severe neurodegeneration that can be attenuated by blocking neuronal activity. Furthermore, in vivo neuronal expression of mutated nmnat shows that enzymatically inactive NMNAT protein retains strong neuroprotective effects and rescues the degeneration phenotype caused by loss of nmnat. Our data indicate an NAD-independent requirement of NMNAT for maintaining neuronal integrity that can be exploited to protect neurons from neuronal activity-induced degeneration by overexpression of the protein.

A multiple lines of evidence approach for identifying geologic heterogeneities in conceptual site models for performance assessments.

Model-based decision making is commonly used in performance assessments to assure water resource protection for both human health and the environment for hundreds of years into the future. To make decisions regarding aquifer protection against potential contamination, a conceptual site model (CSM) describing the hydrodynamic behavior needs to account for subsurface heterogeneities in sufficient detail. When site-specific data are sparse, larger-scale geologic descriptions are adopted with the consequence of losing small-scale features (at the cm scale) that can control contaminant transport. In this study, a multiple lines of evidence approach is used to construct vadose zone CSMs based on an evaluation of several types of data, including geologic logs, borehole moisture content and concentration data, geophysical spectral gamma logging data, and groundwater concentration data for a tank farm at the Hanford Site in southeastern Washington State. The resulting CSMs of the unsaturated zone represent a synthesis of what is known about flow and transport processes at the site-scale and maintain consistency with knowledge that has been accumulated at the regional scale. Through a process of extensive data analyses, a systematic approach is described to create an evidence base that supports the evaluation and development of CSMs. Numerical models are then used to evaluate the impact that smaller-scale heterogeneities have on contaminant transport through the vadose zone for a performance assessment on waste tank closure. Together, the field data and the numerical experiments suggest that although small-scale features close to source releases can have an impact on horizontal spreading, overall there is a relatively minor impact on transport for the site under study as evaluated by differences in peak fluxes and arrival times for historical leak events, and for potential releases resulting from waste tank closure. Use of alternative CSMs, developed through careful examination of available characterization and monitoring data, provides confidence that geologic heterogeneities do not impact contaminant transport behavior significantly enough to alter the assessment of risk for closure at this site.

Synaptojanin is recruited by endophilin to promote synaptic vesicle uncoating.

We describe the isolation and characterization of Drosophila synaptojanin (synj) mutants. synj encodes a phosphatidylinositol phosphatase involved in clathrin-mediated endocytosis. We show that Synj is specifically localized to presynaptic terminals and is associated with synaptic vesicles. The electrophysiological and ultrastructural defects observed in synj mutants are strikingly similar to those found in endophilin mutants, and Synj and Endo colocalize and interact biochemically. Moreover, synj; endo double mutant synaptic terminals exhibit properties that are very similar to terminals of each single mutant, and overexpression of Endophilin can partially rescue the functional defects in partial loss-of-function synj mutants. Interestingly, Synj is mislocalized and destabilized at synapses devoid of Endophilin, suggesting that Endophilin recruits and stabilizes Synj on newly formed vesicles to promote vesicle uncoating. Our data also provide further evidence that kiss-and-run is able to maintain neurotransmitter release when synapses are not extensively challenged.

Ondansetron for acute gastroenteritis in children.

QUESTION: In my pediatric practice I see many children with acute gastroenteritis. Their parents ask for antiemetic medications. Ondansetron has been well tolerated when used to control nausea and vomiting in patients receiving chemotherapy. Is there a role for it in managing acute gastroenteritis in children? ANSWER: Use of antiemetics is not indicated for treatment of acute gastroenteritis. Some evidence suggests ondansetron is clinically more effective and better tolerated and has a better side effect profile than other antiemetics, but does not suggest that it reduces hospital admission rates. Use of ondansetron, as with other antiemetics, continues to be at treating physicians' discretion, and potential adverse events should be considered before administration.

An E-mail for Your Thoughts.

Engaging adolescents is one of many challenges facing Child and Adolescent Mental Health Services today. However, taking advantage of the technology available can bring professionals a step closer to their patients by providing an alternative means of interaction. In this article we explore the use of e-mail as a method of engaging adolescents. The advantages and disadvantages of e-mailing patients are discussed along with recommendations for its safe use.