Atypical local brain connectivity in pediatric autism spectrum disorder? A coordinate-based meta-analysis of regional homogeneity studies.

Despite decades of massive neuroimaging research, the comprehensive characterization of short-range functional connectivity in autism spectrum disorder (ASD) remains a major challenge for scientific advances and clinical translation. From the theoretical point of view, it has been suggested a generalized local over-connectivity that would characterize ASD. This stance is known as the general local over-connectivity theory. However, there is little empirical evidence supporting such hypothesis, especially with regard to pediatric individuals with ASD (age [Formula: see text] 18 years old). To explore this issue, we performed a coordinate-based meta-analysis of regional homogeneity studies to identify significant changes of local connectivity. Our analyses revealed local functional under-connectivity patterns in the bilateral posterior cingulate cortex and superior frontal gyrus (key components of the default mode network) and in the bilateral paracentral lobule (a part of the sensorimotor network). We also performed a functional association analysis of the identified areas, whose dysfunction is clinically consistent with the well-known deficits affecting individuals with ASD. Importantly, we did not find relevant clusters of local hyper-connectivity, which is contrary to the hypothesis that ASD may be characterized by generalized local over-connectivity. If confirmed, our result will provide a valuable insight into the understanding of the complex ASD pathophysiology.

Incidence, prevalence, and global burden of autism spectrum disorder from 1990 to 2019 across 204 countries.

Autism spectrum disorder (ASD) substantially contributes to the burden of mental disorders. Improved awareness and changes in diagnostic criteria of ASD may have influenced the diagnostic rates of ASD. However, while data on trends in diagnostic rates in some individual countries have been published, updated estimates of diagnostic rate trends and ASD-related disability at the global level are lacking. Here, we used the Global Burden of Diseases, Injuries, and Risk Factors Study data to address this gap, focusing on changes in prevalence, incidence, and disability-adjusted life years (DALYs) of ASD across the world. From 1990 to 2019, overall age-standardized estimates remained stable globally. Both prevalence and DALYs increased in countries with high socio-demographic index (SDI). However, the age-standardized incidence decreased in some low SDI countries, indicating a need to improve awareness. The male/female ratio decreased between 1990 and 2019, possibly accounted for by increasing clinical attention to ASD in females. Our results suggest that ASD detection in low SDI countries is suboptimal, and that ASD prevention/treatment in countries with high SDI should be improved, considering the increasing prevalence of the disorder. Additionally, growing attention is being paid to ASD diagnosis in females, who might have been left behind by ASD epidemiologic and clinical research previously. ASD burden estimates are underestimated as GBD does not account for mortality in ASD.

Expanding the clinical phenotype of the ultra-rare Skraban-Deardorff syndrome: Two novel individuals with WDR26 loss-of-function variants and a literature review.

De novo variants in the WDR26 gene leading to haploinsufficiency have recently been associated with Skraban-Deardorff syndrome. This condition is an ultra-rare autosomal dominant neurodevelopmental disorder characterized by a broad range of clinical signs, including intellectual disability (ID), developmental delay (DD), seizures, abnormal facial features, feeding difficulties, and minor skeletal anomalies. Currently, 18 cases have been reported in the literature and for only 15 of them a clinical description is available. Here, we describe a child with Skraban-Deardorff syndrome associated with the WDR26 pathogenic de novo variant NM_025160.6:c.69dupC, p.(Gly24ArgfsTer48), and an adult associated with the pathogenic de novo variant c.1076G > A, p.(Trp359Ter). The adult patient was a 29-year-old female with detailed information on clinical history and pharmacological treatments since birth, providing an opportunity to map disease progression and patient management. By comparing our cases with published reports of Skraban-Deardorff syndrome, we provide a genetic and clinical summary of this ultrarare condition, describe the clinical management from childhood to adult age, and further expand on the clinical phenotype.

The loss of flight in ant workers enabled an evolutionary redesign of the thorax for ground labour.

BACKGROUND: Explanations for the ecological dominance of ants generally focus on the benefits of division of labour and cooperation during foraging. However, the principal innovation of ants relative to their wasp ancestors was the evolution of a new phenotype: a wingless worker caste optimized for ground labour. Ant workers are famous for their ability to lift and carry heavy loads, but we know surprisingly little about the morphological basis of their strength. Here we examine the consequences of the universal loss of flight in ant workers on skeletomuscular adaptations in the thorax for enhanced foraging on six legs. RESULTS: Using X-ray microcomputed tomography and 3D segmentation, we compared winged queens and wingless workers in Euponera sikorae (subfamily Ponerinae) and Cataglyphis savignyi (subfamily Formicinae). Workers are characterized by five major changes to their thorax: i) fusion of the articulated flight thorax (queens) into a rigid box optimized to support the muscles that operate the head, legs and abdomen, ii) redesign of internal cuticular structures for better bracing and muscle attachment, iii) substantial enlargement of the neck muscles for suspending and moving the head, iv) lengthening of the external trochanter muscles, predominant for the leg actions that lift the body off the ground, v) modified angle of the petiole muscles that are key for flexion of the abdomen. We measured volumes and pennation angles for a few key muscles to assess their increased efficacy. Our comparisons of additional workers across five genera in subfamilies Dorylinae and Myrmicinae show these modifications in the wingless thorax to be consistent. In contrast, a mutillid wasp showed a different pattern of muscle adaptations resulting from the lack of wing muscles. CONCLUSIONS: Rather than simply a subtraction of costly flight muscles, we propose the ant worker thorax evolved into a power core underlying stronger mandibles, legs, and sting. This contrasts with solitary flightless insects where the lack of central place foraging generated distinct selective pressures for rearranging the thorax. Stronger emphasis is needed on morphological innovations of social insects to further our understanding of the evolution of social behaviours.

The morphometric co-atrophy networking of schizophrenia, autistic and obsessive spectrum disorders.

By means of a novel methodology that can statistically derive patterns of co-alterations distribution from voxel-based morphological data, this study analyzes the patterns of brain alterations of three important psychiatric spectra-that is, schizophrenia spectrum disorder (SCZD), autistic spectrum disorder (ASD), and obsessive-compulsive spectrum disorder (OCSD). Our analysis provides five important results. First, in SCZD, ASD, and OCSD brain alterations do not distribute randomly but, rather, follow network-like patterns of co-alteration. Second, the clusters of co-altered areas form a net of alterations that can be defined as morphometric co-alteration network or co-atrophy network (in the case of gray matter decreases). Third, within this network certain cerebral areas can be identified as pathoconnectivity hubs, the alteration of which is supposed to enhance the development of neuronal abnormalities. Fourth, within the morphometric co-atrophy network of SCZD, ASD, and OCSD, a subnetwork composed of eleven highly connected nodes can be distinguished. This subnetwork encompasses the anterior insulae, inferior frontal areas, left superior temporal areas, left parahippocampal regions, left thalamus and right precentral gyri. Fifth, the co-altered areas also exhibit a normal structural covariance pattern which overlaps, for some of these areas (like the insulae), the co-alteration pattern. These findings reveal that, similarly to neurodegenerative diseases, psychiatric disorders are characterized by anatomical alterations that distribute according to connectivity constraints so as to form identifiable morphometric co-atrophy patterns.

Skeletomuscular adaptations of head and legs of Melissotarsus ants for tunnelling through living wood.

BACKGROUND: While thousands of ant species are arboreal, very few are able to chew and tunnel through living wood. Ants of the genus Melissotarsus (subfamily Myrmicinae) inhabit tunnel systems excavated under the bark of living trees, where they keep large numbers of symbiotic armoured scale insects (family Diaspididae). Construction of these tunnels by chewing through healthy wood requires tremendous power, but the adaptations that give Melissotarsus these abilities are unclear. Here, we investigate the morphology of the musculoskeletal system of Melissotarsus using histology, scanning electron microscopy, X-ray spectrometry, X-ray microcomputed tomography (micro-CT), and 3D modelling. RESULTS: Both the head and legs of Melissotarsus workers contain novel skeletomuscular adaptations to increase their ability to tunnel through living wood. The head is greatly enlarged dorsoventrally, with large mandibular closer muscles occupying most of the dorsal half of the head cavity, while ventrally-located opener muscles are also exceptionally large. This differs from the strong closing: opening asymmetry typical of most mandibulated animals, where closing the mandibles requires more force than opening. Furthermore, the mandibles are short and cone-shaped with a wide articulatory base that concentrates the force generated by the muscles towards the tips. The increased distance between the axis of mandibular rotation and the points of muscle insertion provides a mechanical advantage that amplifies the force from the closer and opener muscles. We suggest that the uncommonly strong opening action is required to move away crushed plant tissues during tunnelling and allow a steady forward motion. X-ray spectrometry showed that the tip of the mandibles is reinforced with zinc. Workers in this genus have aberrant legs, including mid- and hindlegs with hypertrophied coxae and stout basitarsi equipped with peg-like setae, and midleg femura pointed upward and close to the body. This unusual design famously prevents them from standing and walking on a normal two-dimensional surface. We reinterpret these unique traits as modifications to brace the body during tunnelling rather than locomotion per se. CONCLUSIONS: Melissotarsus represents an extraordinary case study of how the adaptation to - and indeed engineering of - a novel ecological niche can lead to the evolutionary redesign of core biomechanical systems.

Autism, epilepsy, and synaptopathies: a not rare association.

Autism spectrum disorders (ASD) are neurodevelopmental disorders typically diagnosed in childhood, characterized by core social dysfunction, rigid and repetitive behaviors, restricted interests, and abnormal sensorial sensitivity. ASD belong to multifactorial diseases: both genetic and environmental factors have been considered as potential risk factors for their onset. ASD are often associated with neurological conditions: the co-occurrence of epilepsy is well documented and there is also evidence of a higher prevalence of EEG abnormalities with 4-86% of individuals with ASD presenting epileptiform or not epileptiform EEG abnormalities. The presence of epilepsy in people with ASD may be determined by several structural alterations, genetic conditions, or metabolic dysfunctions, known to play a role in the emergence of both epilepsy and autism. The purpose of this article is to discuss precisely such latter cause of the autism-epilepsy association, focusing specifically on those "synaptic genes," whose mutation predisposes to both the diseases.

A novel 3q29 deletion associated with autism, intellectual disability, psychiatric disorders, and obesity.

Copy number variation (CNV) has been associated with a variety of neuropsychiatric disorders, including intellectual disability/developmental delay (ID/DD), autism spectrum disorder (ASD), and schizophrenia (SCZ). Often, individuals carrying the same pathogenic CNV display high clinical variability. By array-CGH analysis, we identified a novel familial 3q29 deletion (1.36 Mb), centromeric to the 3q29 deletion region, which manifests with variable expressivity. The deletion was identified in a 3-year-old girl diagnosed with ID/DD and autism and segregated in six family members, all affected by severe psychiatric disorders including schizophrenia, major depression, anxiety disorder, and personality disorder. All individuals carrying the deletion were overweight or obese, and anomalies compatible with optic atrophy were observed in three out of four cases examined. Amongst the 10 genes encompassed by the deletion, the haploinsufficiency of Optic Atrophy 1 (OPA1), associated with autosomal dominant optic atrophy, is likely responsible for the ophthalmological anomalies. We hypothesize that the haploinsufficiency of ATPase type 13A4 (ATP13A4) and/or Hairy/Enhancer of Split Drosophila homolog 1 (HES1) contribute to the neuropsychiatric phenotype, while HES1 deletion might underlie the overweight/obesity. In conclusion, we propose a novel contiguous gene syndrome due to a proximal 3q29 deletion variably associated with autism, ID/DD, psychiatric traits and overweight/obesity.

Concordance of white matter and gray matter abnormalities in autism spectrum disorders: a voxel-based meta-analysis study.

There are at least two fundamental unanswered questions in the literature on autism spectrum disorders (ASD): Are abnormalities in white (WM) and gray matter (GM) consistent with one another? Are WM morphometric alterations consistent with alterations in the GM of regions connected by these abnormal WM bundles and vice versa? The aim of this work is to bridge this gap. After selecting voxel-based morphometry and diffusion tensor imaging studies comparing autistic and normally developing groups of subjects, we conducted an activation likelihood estimation (ALE) meta-analysis to estimate consistent brain alterations in ASD. Multidimensional scaling was used to test the similarity of the results. The ALE results were then analyzed to identify the regions of concordance between GM and WM areas. We found statistically significant topological relationships between GM and WM abnormalities in ASD. The most numerous were negative concordances, found bilaterally but with a higher prevalence in the right hemisphere. Positive concordances were found in the left hemisphere. Discordances reflected the spatial distribution of negative concordances. Thus, a different hemispheric contribution emerged, possibly related to pathogenetic factors affecting the right hemisphere during early developmental stages. Besides, WM fiber tracts linking the brain structures involved in social cognition showed abnormalities, and most of them had a negative concordance with the connected GM regions. We interpreted the results in terms of altered brain networks and their role in the pervasive symptoms dramatically impairing communication and social skills in ASD patients.

Effects of Executive Functions Training in Primary School Students with Borderline Intellectual Functioning Through a Multi-Method, Multi-Informant Intervention: A Pilot Study.

Objective: Borderline Intellectual Functioning (BIF) impacts cognitive functioning and adaptive behavior. Recent studies have demonstrated the efficacy of Executive Functions trainings to support daily-living skills in several clinical populations. However, although the relationship between Executive Functions and BIF has been studied, few studies have explored the effects of cognitive enhancement training for BIF children. Given the pivotal significance of Executive Functions in learning, orchestrating cognitive processes, and modulating affective and behavioral responses, our study aimed to evaluate the efficacy of cognitive enhancement training targeting Executive Functions in a group of 23 children diagnosed with Borderline Intellectual Functioning devoid of neurodevelopmental impairments. Method: We included a multiple assessment based on several informants (children, teachers, parents, and tutors) and provided individualized cognitive enhancement training focused on Executive Functions through both digital and analog activities. The training was highly customized, structured and monitored at various stages of the process activities. The training was composed of 20 sessions, each lasting 2 hours, held twice a week for each child. Results: The obtained results confirmed the efficacy of cognitive enhancement training in improving Executive Functions, the primary target of the intervention, particularly in attention, verbal fluency, planning, inhibitory control, working memory, and flexibility. Furthermore, improvements were observed by all the informants in other cognitive functions, learning, and adaptive behaviors. Conclusions: Our study contributes to the understanding of BIF, emphasizing the efficacy of neuropsychological enhancement through personalized training for EF.

Disentangling the role of gray matter volume and concentration in autism spectrum disorder: A meta-analytic investigation of 25 years of voxel-based morphometry research.

Despite over two decades of neuroimaging research, a unanimous definition of the pattern of structural variation associated with autism spectrum disorder (ASD) has yet to be found. One potential impeding issue could be the sometimes ambiguous use of measurements of variations in gray matter volume (GMV) or gray matter concentration (GMC). In fact, while both can be calculated using voxel-based morphometry analysis, these may reflect different underlying pathological mechanisms. We conducted a coordinate-based meta-analysis, keeping apart GMV and GMC studies of subjects with ASD. Results showed distinct and non-overlapping patterns for the two measures. GMV decreases were evident in the cerebellum, while GMC decreases were mainly found in the temporal and frontal regions. GMV increases were found in the parietal, temporal, and frontal brain regions, while GMC increases were observed in the anterior cingulate cortex and middle frontal gyrus. Age-stratified analyses suggested that such variations are dynamic across the ASD lifespan. The present findings emphasize the importance of considering GMV and GMC as distinct yet synergistic indices in autism research.

Autonomic and hedonic response to affective touch in autism spectrum disorder.

Interpersonal touch plays a crucial role in shaping relationships and encouraging social connections. Failure in processing tactile input or abnormal tactile sensitivity may hamper social behaviors and have severe consequences in individuals' relational lives. Autism Spectrum Disorder (ASD) is characterized by both sensory disruptions and social impairments, making affective touch an ideal meeting point for understanding these features in ASD individuals. By integrating behavioral and physiological measures, we investigated the effects of affective touch on adult individuals with ASD from both an implicit and explicit perspective. Specifically, at an implicit level, we investigated whether and how receiving an affective touch influenced participants' skin conductance tonic and phasic components. At the explicit level, we delved into the affective and unpleasant features of affective touch. Overall, we observed lower skin conductance level in ASD compared to TD subjects. Interestingly, the typically developing (TD) group showed an increased autonomic response for affective touch compared to a control touch, while ASD subjects' autonomic response did not differ between the two conditions. Furthermore, ASD participants provided higher ratings for both the affective and unpleasant components of the touch, compared to TD subjects. Our results reveal a noteworthy discrepancy in ASD population between the subjective experience, characterized by amplified hedonic but also unpleasant responses, and the physiological response, marked by a lack of autonomic activation related to affective touch. This insightful dissociation seems crucial for a deeper understanding of the distinctive challenges characterizing people with ASD and may have implications for diagnosis and therapeutic approaches.

Investigating the impact of disposable surgical face-masks on face identity and emotion recognition in adults with autism spectrum disorder.

With the outburst of the COVID-19 pandemic, disposable surgical face-masks (DSFMs) have been widely adopted as a preventive measure. DSFMs hide the bottom half of the face, thus making identity and emotion recognition very challenging, both in typical and atypical populations. Individuals with autism spectrum disorder (ASD) are often characterized by face processing deficits; thus, DSFMs could pose even a greater challenge for this population compared to typically development (TD) individuals. In this study, 48 ASDs of level 1 and 110 TDs underwent two tasks: (i) the Old-new face memory task, which assesses whether DSFMs affect face learning and recognition, and (ii) the Facial affect task, which explores DSFMs' effect on emotion recognition. Results from the former show that, when faces were learned without DSFMs, identity recognition of masked faces decreased for both ASDs and TDs. In contrast, when faces were first learned with DSFMs, TDs but not ASDs benefited from a "context congruence" effect, that is, faces wearing DSFMs were better recognized if learned wearing DSFMs. In addition, results from the Facial affect task show that DSFMs negatively impacted specific emotion recognition in both TDs and ASDs, although differentially between the two groups. DSFMs negatively affected disgust, happiness and sadness recognition in TDs; in contrast, ASDs performance decreased for every emotion except anger. Overall, our study demonstrates a general, although different, disruptive effect on identity and emotion recognition both in ASD and TD population.

Revealing the Selectivity of Neuroanatomical Alteration in Autism Spectrum Disorder via Reverse Inference.

BACKGROUND: Although neuroimaging research has identified atypical neuroanatomical substrates in individuals with autism spectrum disorder (ASD), it is at present unclear whether and to what extent disorder-selective gray matter alterations occur in this spectrum of conditions. In fact, a growing body of evidence shows a substantial overlap between the pathomorphological changes across different brain diseases, which may complicate identification of reliable neural markers and differentiation of the anatomical substrates of distinct psychopathologies. METHODS: Using a novel data-driven and Bayesian methodology with published voxel-based morphometry data (849 peer-reviewed experiments and 22,304 clinical subjects), this study performs the first reverse inference investigation to explore the selective structural brain alteration profile of ASD. RESULTS: We found that specific brain areas exhibit a >90% probability of gray matter alteration selectivity for ASD: the bilateral precuneus (Brodmann area 7), right inferior occipital gyrus (Brodmann area 18), left cerebellar lobule IX and Crus II, right cerebellar lobule VIIIA, and right Crus I. Of note, many brain voxels that are selective for ASD include areas that are posterior components of the default mode network. CONCLUSIONS: The identification of these spatial gray matter alteration patterns offers new insights into understanding the complex neurobiological underpinnings of ASD and opens attractive prospects for future neuroimaging-based interventions.

Diagnostic assessment, therapeutic care and education pathways in persons with autism spectrum disorder in transition from childhood to adulthood: the Italian National Ev.A Longitudinal Project.

INTRODUCTION: The transition from childhood to adulthood is one of the main critical points in the network of services for taking care of people with autism spectrum disorder (ASD). Within the framework of the national research programs on autism, an exploratory longitudinal multicentre study was conducted. This research program, called "Ev.A Project (Developmental and Adult Age)", was proposed by the Italian National Institute of Health (Istituto Superiore di Sanità, ISS) and the aim was the development and testing of a diagnostic, therapeutic, assistance and educational pathway (PDTAE) for autism. AIM: The present study aimed to evaluate two impact outcomes of the care protocol: the response obtained by the ASD person, and the perception of the change in the family context. METHODS: Participants underwent an initial clinical evaluation and then after one year. Over the course of the year, participants undertook a program of intervention. The measures of adaptive functioning, need for support, psychiatric symptomatology and family quality of life were used for the outcome assessment. Linear mixed models were constructed for each measure to estimate the explanatory/predictive behavior of the intensity of the interventions, adjusted for the participant's level of symptom severity. RESULTS: The results estimate a main effect of Intervention Group (b=-27.22, p<0.001) and severity level (b=-41.87, p<0.001) on the adaptive functioning of the ASD person, but no effect on performance on the dimension of Family Quality of Life (b=0.523, p=0.455). CONCLUSIONS: The most significant predictor of the impact on the ASD person is the activation of the service network, which must take into account the level of severity of the presented symptoms.

Pregnancy in autistic women and social medical considerations: scoping review and meta- synthesis.

Introduction: This article addresses a topic that has been largely overlooked by scientific literature, namely pregnancy in autistic women. Generally, the issue of sexuality in disability, particularly in disabled women, autistic or otherwise, has been underexplored. However, it is necessary to scientifically investigate this topic to propose adequate social and health policies. Therefore, we chose to conduct a scoping review to answer three main questions: "What does it mean for an autistic woman to be pregnant?"; "How do these two conditions coexist?"; "Are health services prepared to receive this population adequately or does autism become a stigma for pregnant women?" Methods: We conducted a systematic review and qualitative thematic synthesis following the Preferred Reporting Guidelines for Systematic Reviews and Meta-Analyses on autistic women and pregnancy in the last 10 years. Results: The studies included in our review are 7, extremely diverse in terms of methodologies and sample sizes. Despite the heterogeneity of samples and methodologies, all research tends to highlight the following results. For autistic women during pregnancy, three areas seem to be the most difficult: sensory issues, mood disorders, and relationships with specialists. Discussion: Our study found that women with ASD face unique challenges during childbirth that differ from those of neurotypical women. Participants often felt belittled, ignored, and uninformed about the care they received, and being placed at the centre of attention was often seen as negative and hindering rather than positive. However, the research shows us how some "expected" results, such as difficulties in breastfeeding, have been disproven.

Genetic variants in DDX53 contribute to Autism Spectrum Disorder associated with the Xp22.11 locus.

Autism Spectrum Disorder (ASD) exhibits an ~4:1 male-to-female sex bias and is characterized by early-onset impairment of social/communication skills, restricted interests, and stereotyped behaviors. Disruption of the Xp22.11 locus has been associated with ASD in males. This locus includes the three-exon PTCHD1 gene, an adjacent multi-isoform long noncoding RNA (lncRNA) named PTCHD1-AS (spanning ~1Mb), and a poorly characterized single-exon RNA helicase named DDX53 that is intronic to PTCHD1-AS. While the relationship between PTCHD1/PTCHD1-AS and ASD is being studied, the role of DDX53 has not been examined, in part because there is no apparent functional murine orthologue. Through clinical testing, here, we identified 6 males and 1 female with ASD from 6 unrelated families carrying rare, predicted-damaging or loss-of-function variants in DDX53. Then, we examined databases, including the Autism Speaks MSSNG and Simons Foundation Autism Research Initiative, as well as population controls. We identified 24 additional individuals with ASD harboring rare, damaging DDX53 variations, including the same variants detected in two families from the original clinical analysis. In this extended cohort of 31 participants with ASD (28 male, 3 female), we identified 25 mostly maternally-inherited variations in DDX53, including 18 missense changes, 2 truncating variants, 2 in-frame variants, 2 deletions in the 3' UTR and 1 copy number deletion. Our findings in humans support a direct link between DDX53 and ASD, which will be important in clinical genetic testing. These same autism-related findings, coupled with the observation that a functional orthologous gene is not found in mouse, may also influence the design and interpretation of murine-modelling of ASD.

Evolutionary history of the recruitment of conserved developmental genes in association to the formation and diversification of a novel trait.

BACKGROUND: The origin and modification of novel traits are important aspects of biological diversification. Studies combining concepts and approaches of developmental genetics and evolutionary biology have uncovered many examples of the recruitment, or co-option, of genes conserved across lineages for the formation of novel, lineage-restricted traits. However, little is known about the evolutionary history of the recruitment of those genes, and of the relationship between them -for example, whether the co-option involves whole or parts of existing networks, or whether it occurs by redeployment of individual genes with de novo rewiring. We use a model novel trait, color pattern elements on butterfly wings called eyespots, to explore these questions. Eyespots have greatly diversified under natural and sexual selection, and their formation involves genetic circuitries shared across insects. RESULTS: We investigated the evolutionary history of the recruitment and co-recruitment of four conserved transcription regulators to the larval wing disc region where circular pattern elements develop. The co-localization of Antennapedia, Notch, Distal-less, and Spalt with presumptive (eye)spot organizers was examined in 13 butterfly species, providing the largest comparative dataset available for the system. We found variation between families, between subfamilies, and between tribes. Phylogenetic reconstructions by parsimony and maximum likelihood methods revealed an unambiguous evolutionary history only for Antennapedia, with a resolved single origin of eyespot-associated expression, and many homoplastic events for Notch, Distal-less, and Spalt. The flexibility in the (co-)recruitment of the targeted genes includes cases where different gene combinations are associated with morphologically similar eyespots, as well as cases where identical protein combinations are associated with very different phenotypes. CONCLUSIONS: The evolutionary history of gene (co-)recruitment is consistent with both divergence from a recruited putative ancestral network, and with independent co-option of individual genes. The diversity in the combinations of genes expressed in association with eyespot formation does not parallel diversity in characteristics of the adult phenotype. We discuss these results in the context of inferring homology. Our study underscores the importance of widening the representation of phylogenetic, morphological, and genetic diversity in order to establish general principles about the mechanisms behind the evolution of novel traits.

The Effect of Sleep-Wake Routines on the Negative Emotional States and Aggressive Behaviors in Adults with Autism Spectrum Disorders (ASD) during the COVID-19 Outbreak.

Disruption in routine may be related to experiencing negative emotional states and to aggressive behaviors in individuals with Autism Spectrum Disorder (ASD). The lockdown because of COVID-19 contributed to the disruption of individuals' routines, including the sleep−wake cycle. The current study tested a relationship between the adherence to the sleep−wake routine and aggressive behaviors via the mediation role of negative emotional states (i.e., anxiety and anger). Forty-three parents of adults with ASD completed a web-based questionnaire about their life condition during the first lockdown (April−May 2020). Preliminary analyses showed a worsening in the adults' aggressive behaviors during the lockdown in comparison to before it (Z = −3.130; p = 0.002). In the mediation models, the relationship between the adherence to the sleep−wake routines and aggressive behaviors was significant. The models showed the hypothesized mediated relationships among the adherence to the sleep−wake routines, negative emotional states, and aggressive behaviors (Model 1: F (1, 41) = 10.478, p < 0.001; Model 2: F(1, 41) = 9.826, p = 0.003). The findings confirmed the potential protective role of the adherence to the sleep−wake routines for the emotional and behavioral adjustment of adults with autism. Theoretical and practical contributions of the study were discussed; indeed, our results may inform parent-coaching as well as intervention programs for individuals with ASD given that adequate sleep hygiene may contribute to improvements in internalizing/externalizing behaviors.

Efficacy and Safety of Q10 Ubiquinol With Vitamins B and E in Neurodevelopmental Disorders: A Retrospective Chart Review.

Increased oxidative stress and defective mitochondrial functioning are shared features among many brain disorders. The aim of this study was to verify retrospectively the clinical efficacy and safety of a metabolic support therapy with Q10 ubiquinol, vitamin E and complex-B vitamins in various neurodevelopmental disorders. This retrospective chart review study included 59 patients (mean age 10.1 ± 1.2 y.o., range 2.5-39 years; M:F = 2.47:1), diagnosed with Autism Spectrum Disorder (n = 17), Autism Spectrum Disorder with co-morbid Intellectual Disability (n = 19), Intellectual Disability or Global Developmental Delay (n = 15), Attention-Deficit/Hyperactivity Disorder (n = 3) and Intellectual Disability in Phelan-McDermid syndrome due to chr. 22q13.33 deletion (n = 5). After a minimum of 3 months of therapy, a positive outcome was recorded in 45/59 (76.27%) patients, with Clinical Global Impression-Improvement scores ranging between 1 ("very much improved") and 3 ("minimally improved"). The most widespread improvements were recorded in cognition (n = 26, 44.1%), adaptative functioning (n = 26, 44.1%) and social motivation (n = 19, 32.2%). Improvement rates differed by diagnosis, being observed most consistently in Phelan-McDermid Syndrome (5/5, 100%), followed by Intellectual Disability/Global Developmental Delay (13/15, 86.7%), Autism Spectrum Disorder with co-morbid Intellectual Disability (15/19, 78.9%), Autism Spectrum Disorder (11/17, 64.7%) and ADHD (1/3, 33.3%). No significant adverse event or side effect leading to treatment discontinuation were recorded. Mild side effects were reported in 18 (30.5%) patients, with the most frequent being increased hyperactivity (9/59, 15.3%). This retrospective chart review suggests that metabolic support therapy with Q10 ubiquinol, vitamin E and complex-B vitamins is well tolerated and produces some improvement in the majority of patients with neurodevelopmental disorders, especially in the presence of intellectual disability. Randomized controlled trials for each single neurodevelopmental disorder are now warranted to conclusively demonstrate the efficacy of these mitochondrial bioenergetic and antioxidant agents and to estimate their therapeutic effect size.