1. Bajikar SS, Anderson AG, Zhou J, Durham MA, Trostle AJ, Wan YW, Liu Z, Zoghbi HY. MeCP2 regulates Gdf11, a dosage-sensitive gene critical for neurological function. Elife;2023 (Feb 27);12

Loss- and gain-of-function of MeCP2 causes Rett syndrome (RTT) and MECP2 duplication syndrome (MDS), respectively. MeCP2 binds methyl-cytosines to finely tune gene expression in the brain, but identifying genes robustly regulated by MeCP2 has been difficult. By integrating multiple transcriptomics datasets, we revealed that MeCP2 finely regulates growth differentiation factor 11 (Gdf11). Gdf11 is down-regulated in RTT mouse models and, conversely, up-regulated in MDS mouse models. Strikingly, genetically normalizing Gdf11 dosage levels improved several behavioral deficits in a mouse model of MDS. Next, we discovered that losing one copy of Gdf11 alone was sufficient to cause multiple neurobehavioral deficits in mice, most notably hyperactivity and decreased learning and memory. This decrease in learning and memory was not due to changes in proliferation or numbers of progenitor cells in the hippocampus. Lastly, loss of one copy of Gdf11 decreased survival in mice, corroborating its putative role in aging. Our data demonstrate that Gdf11 dosage is important for brain function.

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2. Chen YJ, Duku E, Zaidman-Zait A, Szatmari P, Smith IM, Ungar WJ, Zwaigenbaum L, Vaillancourt T, Kerns C, Bennett T, Elsabbagh M, Thompson A, Georgiades S. Variable patterns of daily activity participation across settings in autistic youth: A latent profile transition analysis. Autism;2023 (Feb 28):13623613231154729.

What people do or engage in in their daily lives, or daily life participation, is often linked to their state of being happy and healthy, as well as potential for living independently. To date, little research has been conducted on daily activity participation by autistic youth at home, at school or in the community. Learning more about individual differences in participation levels and what might influence them can help to create custom supports for autistic youth and their families. In this study, 158 caregivers of autistic youth were asked how often their children took part in 25 common activities at two assessments, about one year apart. The analysis showed three profiles for each of the home and school settings and two profiles for the community setting. These profiles reflected distinct patterns in how often autistic youth took part in various daily activities, particularly in doing homework, school club activities and community gatherings. Most autistic youth were in profiles marked by often taking part at home but less often at school and in the community, and about three-fourths of them tended to stay in the same profile over time. Autistic youth with limited participation profiles were more likely to have lower scores on measures of cognitive ability and daily life skills and more challenging behaviour, and faced more barriers in their environment. These findings show how important it is to think about each autistic person’s strengths and weaknesses, and changing needs, to better support their daily life participation.

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3. Çolak H, Sarıyer ET, Noğay NH. The Effect of Nutritional Interventions Reducing Oxidative Stress on Behavioral and Gastrointestinal Problems in Autism Spectrum Disorder. Int J Dev Neurosci;2023 (Feb 26)

BACKGROUND AND AIMS: Although the exact cause of autism spectrum disorder, which is a neurodevelopmental disorder, is not known, it is thought that environmental factors are also effective in addition to genetic risk factors. Studies are showing an increase in oxidative stress markers and a decrease in some antioxidant enzymes in individuals with autism. This study aims to try to explain the effect of nutritional interventions that reduce oxidative stress on behavioral and gastrointestinal problems in ASD based on a literature review. METHODS: All relevant studies from 2000 to 2021 were identified through a systematic search in the PubMed and Web of Science databases by using key search terms. A systematic search of the electronic databases resulted in a total of 3235 potential articles, and data were extracted from 24 studies. RESULTS: There were nine clinical trials and 15 animal studies. Most studies find statistically significant results for nutritional supplementation compared to placebo ASD symptoms. CONCLUSION: Most studies on the interventions of nutritional supplements that reduce oxidative stress in individuals with ASD have found improving effects on ASD symptoms, and no serious side effects have been observed. However, more interventional studies are needed to determine the precise effects of oxidative stress-reducing nutritional supplementation.

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4. Czech H. Response to Tatzer et al: Their paper on what Asperger knew about Nazi « child euthanasia » does not provide a rigorous assessment of the available evidence. Acta Paediatr;2023 (Feb 27)

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5. Del Rosario C, Nixon E, Quigley J, Whitehouse AJO, Maybery MT. Parent-child interaction and developmental outcomes in children with typical and elevated likelihood of autism. Infant Behav Dev;2023 (Feb 25);71:101830.

BACKGROUND: Early parent-child interactions have a critical impact on the developmental outcomes of the child. It has been reported that infants with a family history of autism and their parents may engage in different patterns of behaviours during interaction compared to those without a family history of autism. This study investigated the association of parent-child interactions with child developmental outcomes of those with typical and elevated likelihood of autism. METHOD: This longitudinal study investigated the relationship between global attributes of parent-child interaction and the developmental outcomes of infant siblings with elevated likelihood (EL: n = 29) or typical likelihood (TL: n = 39) of developing autism. Parent-child interactions were recorded during a session of free-play when the infants were six months of age. Developmental assessments were carried out when the children were 12 and 24 months of age. RESULTS: The intensity of mutuality was significantly higher in the TL group than in the EL group, and developmental outcomes were poorer in the EL group when compared to the TL group. Positive associations between parent-child interaction scores at six months and developmental outcomes at 12 months were observed only in the TL group. However, in the EL group, higher levels of infant positive affect and attentiveness paid to the caregiver is associated with lower autism symptoms. Due to the sample size and design of the study, the findings must be viewed as indicative. CONCLUSION: This preliminary investigation demonstrated differences in the association between parent-child interaction quality and developmental outcomes for children with typical and elevated likelihood for autism. Future studies should combine micro-analytic and macro-analytic approaches to parent-child interaction to further examine the nature of this relationship.

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6. Feil D, Abrishamcar S, Christensen GM, Vanker A, Koen N, Kilanowski A, Hoffman N, Wedderburn CJ, Donald KA, Kobor MS, Zar HJ, Stein DJ, Hüls A. DNA methylation as a potential mediator of the association between indoor air pollution and neurodevelopmental delay in a South African birth cohort. Clin Epigenetics;2023 (Feb 28);15(1):31.

BACKGROUND: Exposure to indoor air pollution during pregnancy has been linked to neurodevelopmental delay in toddlers. Epigenetic modification, particularly DNA methylation (DNAm), may explain this link. In this study, we employed three high-dimensional mediation analysis methods (HIMA, DACT, and gHMA) followed by causal mediation analysis to identify differentially methylated CpG sites and genes that mediate the association between indoor air pollution and neurodevelopmental delay. Analyses were performed using data from 142 mother to child pairs from a South African birth cohort, the Drakenstein Child Health Study. DNAm from cord blood was measured using the Infinium MethylationEPIC and HumanMethylation450 arrays. Neurodevelopment was assessed at age 2 years using the Bayley Scores of Infant and Toddler Development, 3rd edition across four domains (cognitive development, general adaptive behavior, language, and motor function). Particulate matter with an aerodynamic diameter of 10 μm or less (PM(10)) was measured inside participants’ homes during the second trimester of pregnancy. RESULTS: A total of 29 CpG sites and 4 genes (GOPC, RP11-74K11.1, DYRK1A, RNMT) were identified as significant mediators of the association between PM(10) and cognitive neurodevelopment. The estimated proportion mediated (95%-confidence interval) ranged from 0.29 [0.01, 0.86] for cg00694520 to 0.54 [0.11, 1.56] for cg05023582. CONCLUSIONS: Our findings suggest that DNAm may mediate the association between prenatal PM(10) exposure and cognitive neurodevelopment. DYRK1A and several genes that our CpG sites mapped to, including CNKSR1, IPO13, IFNGR1, LONP2, and CDH1, are associated with biological pathways implicated in cognitive neurodevelopment and three of our identified CpG sites (cg23560546 [DAPL1], cg22572779 [C6orf218], cg15000966 [NT5C]) have been previously associated with fetal brain development. These findings are novel and add to the limited literature investigating the relationship between indoor air pollution, DNAm, and neurodevelopment, particularly in low- and middle-income country settings and non-white populations.

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7. Fuselier MN, Guzick AG, Bakhshaie J, Wood JJ, Kendall PC, Kerns CM, Small BJ, Goodman WK, Storch EA. Examining the Relationship Between Anxiety Severity and Autism-Related Challenges During Cognitive Behavioral Therapy for Children with Autism. J Autism Dev Disord;2023 (Feb 27)

PURPOSE: Using data from a randomized clinical trial evaluating cognitive behavioral therapy (CBT) for children with autism and co-occurring anxiety, this study examined the relationship between autism features and anxiety symptoms throughout CBT. METHODS: Two multilevel mediation analyses were run which examined the mediating role of changes in anxiety for changes in two core features of autism, (a) repetitive and restrictive behaviors (RRBs) and (b) social communication/interaction impairments, between pre- and post-treatment. RESULTS: Indirect effects between time and autism characteristics were significant for both models, indicating that as anxiety changes, so do RRBs and social communication/interaction as the outcomes respectively. CONCLUSION: Findings suggest a bidirectional relationship between anxiety and autism features. Implications of these findings are discussed.

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8. Garcia Torres M, Magaña S, Balcazar F. Brief report: Evaluation of an adapted youth version of Parents Taking Action for parents of pre/adolescents with autism spectrum disorder in Colombia. Autism;2023 (Feb 27):13623613231155773.

We evaluated the efficacy of the youth version of the program Parents Taking Action in Bogota, Colombia. This program aims to provide information, resources, and strategies about topics of puberty, sexuality, and adolescence for parents of preadolescents with autism spectrum disorder. We examined whether parents in the treatment groups would improve in levels of knowledge, empowerment, self-efficacy, and use of strategies compared to the control group. We recruited two groups of Colombian parents of pre/adolescent with autism spectrum disorder between the ages of 10 and 17 in the city of Bogota, Colombia, through a community-based organization. One of the groups received the intervention and the other served as a control group. Parents in the control group received the intervention after the 4-month follow-up. The intervention included four 3-h weekly sessions in which the curriculum with nine topic areas was delivered providing parents with a space to practice strategies, learn from others, and set goals. Parents in the intervention group reported significantly greater knowledge, self-efficacy, use of strategies, and empowerment compared to the control/waitlist group. Parents were also highly satisfied with the content, materials, and peer connections that the program offered. The program has potential for high impact as information is scarce and parents do not have resources related to the complicated developmental stages of pre/adolescence. The program shows promise as an efficacious tool for community organizations and health providers to provide extra support to families of youth with autism spectrum disorder.

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9. Giuliani A, Sabbatinelli J, Amatori S, Graciotti L, Silvestrini A, Matacchione G, Ramini D, Mensà E, Prattichizzo F, Babini L, Mattiucci D, Busilacchi EM, Bacalini MG, Espinosa E, Lattanzio F, Procopio AD, Olivieri F, Poloni A, Fanelli M, Rippo MR. MiR-422a promotes adipogenesis via MeCP2 downregulation in human bone marrow mesenchymal stem cells. Cell Mol Life Sci;2023 (Feb 27);80(3):75.

Methyl-CpG binding protein 2 (MeCP2) is a ubiquitous transcriptional regulator. The study of this protein has been mainly focused on the central nervous system because alterations of its expression are associated with neurological disorders such as Rett syndrome. However, young patients with Rett syndrome also suffer from osteoporosis, suggesting a role of MeCP2 in the differentiation of human bone marrow mesenchymal stromal cells (hBMSCs), the precursors of osteoblasts and adipocytes. Here, we report an in vitro downregulation of MeCP2 in hBMSCs undergoing adipogenic differentiation (AD) and in adipocytes of human and rat bone marrow tissue samples. This modulation does not depend on MeCP2 DNA methylation nor on mRNA levels but on differentially expressed miRNAs during AD. MiRNA profiling revealed that miR-422a and miR-483-5p are upregulated in hBMSC-derived adipocytes compared to their precursors. MiR-483-5p, but not miR-422a, is also up-regulated in hBMSC-derived osteoblasts, suggesting a specific role of the latter in the adipogenic process. Experimental modulation of intracellular levels of miR-422a and miR-483-5p affected MeCP2 expression through direct interaction with its 3′ UTR elements, and the adipogenic process. Accordingly, the knockdown of MeCP2 in hBMSCs through MeCP2-targeting shRNA lentiviral vectors increased the levels of adipogenesis-related genes. Finally, since adipocytes released a higher amount of miR-422a in culture medium compared to hBMSCs we analyzed the levels of circulating miR-422a in patients with osteoporosis-a condition characterized by increased marrow adiposity-demonstrating that its levels are negatively correlated with T- and Z-scores. Overall, our findings suggest that miR-422a has a role in hBMSC adipogenesis by downregulating MeCP2 and its circulating levels are associated with bone mass loss in primary osteoporosis.

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10. Grönniger B, Fritschka E, Fahrig I, Danzer A, Sadowski G. Water Sorption in Rubbery and Glassy Polymers, Nifedipine, and Their ASDs. Mol Pharm;2023 (Feb 27)

Polymers like poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA) or hydroxypropyl methylcellulose acetate succinate (HPMCAS) are commonly used as a matrix for amorphous solid dispersions (ASDs) to enhance the bioavailability of the active pharmaceutical ingredients (APIs). The stability of ASDs is strongly influenced by the water sorption in the ASD from the surrounding air. In this work, the water sorption in the neat polymers PVPVA and HPMCAS, in the neat API nifedipine (NIF), and in their ASDs of different drug loads was measured above and below the glass-transition temperature. The equilibrium water sorption was predicted using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) combined with the Non-Equilibrium Thermodynamics of Glassy Polymers (NET-GP).The water-sorption kinetics were modeled using the Maxwell-Stefan approach whereas the thermodynamic driving force was calculated using PC-SAFT and NET-GP. The water diffusion coefficients in the polymers, NIF, or ASDs were determined using the Free-Volume Theory. Using the water-sorption kinetics of the pure polymers and of NIF, the water-sorption kinetics of the ASDs were successfully predicted, thus providing the water diffusion coefficients in the ASD as a function of relative humidity and of the water concentration in polymers or ASDs.

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11. Guo P, Yang X, Guo X, Yang H, Pan J, Li Y. Dietary fish oil improves autistic behaviors and gut homeostasis by altering the gut microbial composition in a mouse model of fragile X syndrome. Brain Behav Immun;2023 (Feb 28);110:140-151.

Fragile X syndrome (FXS) is the most common inherited intellectual disability, caused by a lack of the fragile X mental retardation protein (FMRP). Individuals with neurodevelopmental disorders frequently experience gastrointestinal problems that are primarily linked to gut microbial dysbiosis, inflammation, and increased intestinal permeability. Omega-3 polyunsaturated fatty acids (omega-3 PUFAs) are non-pharmacological agents that exert potential therapeutic effects against neurological disorders. However, it is unclear whether omega-3 PUFAs improve autistic behaviors in fragile X syndrome (FXS) by altering the gut microbial composition. Here, we describe gastrointestinal problems in Fmr1 knockout (KO) mice. FMRP deficiency causes intestinal homeostasis dysfunction in mice. Fish oil (FO) as a source of omega-3 PUFAs reduces intestinal inflammation but increases the mRNA and protein levels of TJP3 in the colon of juvenile Fmr1 KO mice. Fecal microbiota transplantation from FO-fed Fmr1 KO mice increased the gut abundance of Akkermansia and Gordonibacter in recipient Fmr1 KO mice and improved gut homeostasis and autistic behaviors. Our findings demonstrate that omega-3 PUFAs improve autistic behaviors and gut homeostasis in FMRP-deficient mice by suppressing gut microbiota dysbiosis, thereby presenting a novel therapeutic approach for juvenile FXS treatment.

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12. Hajikhezri Z, Kaira Y, Schubert E, Darweesh M, Svensson C, Akusjärvi G, Punga T. Fragile X-Related Protein FXR1 Controls Human Adenovirus Capsid mRNA Metabolism. J Virol;2023 (Feb 28);97(2):e0153922.

Human adenoviruses (HAdVs) are widespread pathogens causing a variety of diseases. A well-controlled expression of virus capsid mRNAs originating from the major late transcription unit (MLTU) is essential for forming the infectious virus progeny. However, regulation of the MLTU mRNA metabolism has mainly remained enigmatic. In this study, we show that the cellular RNA-binding protein FXR1 controls the stability of the HAdV-5 MLTU mRNAs, as depletion of FXR1 resulted in increased steady-state levels of MLTU mRNAs. Surprisingly, the lack of FXR1 reduced viral capsid protein accumulation and formation of the infectious virus progeny, indicating an opposing function of FXR1 in HAdV-5 infection. Further, the long FXR1 isoform interfered with MLTU mRNA translation, suggesting FXR1 isoform-specific functions in virus-infected cells. We also show that the FXR1 protein interacts with N6-methyladenosine (m(6)A)-modified MLTU mRNAs, thereby acting as a novel m(6)A reader protein in HAdV-5 infected cells. Collectively, our study identifies FXR1 as a regulator of MLTU mRNA metabolism in the lytic HAdV-5 life cycle. IMPORTANCE Human adenoviruses (HAdVs) are common pathogens causing various self-limiting diseases, such as the common cold and conjunctivitis. Even though adenoviruses have been studied for more than 6 decades, there are still gaps in understanding how the virus interferes with the host cell to achieve efficient growth. In this study, we identified the cellular RNA-binding protein FXR1 as a factor manipulating the HAdV life cycle. We show that the FXR1 protein specifically interferes with mRNAs encoding essential viral capsid proteins. Since the lack of the FXR1 protein reduces virus growth, we propose that FXR1 can be considered a novel cellular proviral factor needed for efficient HAdV growth. Collectively, our study provides new detailed insights about the HAdV-host interactions, which might be helpful when developing countermeasures against pathogenic adenovirus infections and for improving adenovirus-based therapies.

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13. Hensley JL, Beydoun HA. Quasi-experimental Controlled Study on the Effect of Autism Resource Clinic Guardian Attendance at a Military Treatment Facility. Mil Med;2023 (Feb 28)

INTRODUCTION: Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that requires multidisciplinary care. Evidence-based practice indicates that early intervention may improve long-term ASD outcomes. The Autism Resource Clinic (ARC) provides an educational session for guardians empowering them to build a personalized ASD team for their child. We examined the impact of guardian attendance of an ARC at a Military Treatment Facility on time to initiation of patient services and guardian stress level. MATERIALS AND METHODS: A quasi-experimental controlled study was conducted comparing a group of guardians attending the ARC with a group of guardians not attending the ARC following a child’s initial ASD diagnosis. ARC speakers included medical, county/state, community/military, and advocacy experts. Surveys were completed at diagnosis, 1, 2, and 3 mo postdiagnosis. Initiation of patient services and Parental Stress Scale scores were compared between groups using independent samples t-test, chi-square tests, or nonparametric tests, as appropriate. RESULTS: Use of Applied Behavioral Analysis was significantly higher among ARC attendees vs. nonattendees (73.3% vs. 33.3%, P = 0.028). County early intervention was more frequent among ARC attendees versus nonattendees (40% vs. 13.3%, P = 0.09). Of borderline significance, median time to initiation of genetics services was greater in ARC attendees vs. nonattendees (106 vs. 65.5, P = 0.10). The two groups did not differ on changes in Parental Stress Scale score from baseline to follow-up months 1, 2, or 3. CONCLUSIONS: Although ARC did not influence time to initiation of patient services or guardian stress level, attendance of ARC was associated with more frequent use of Applied Behavioral Analysis services and county early intervention services. This pilot study is unique as it targets guardians of ASD patients within military treatment facilities. Study limitations include data collection during the coronavirus disease 2019 pandemic, sequential evaluation of experimental and control groups, sample size and generalizability. A large, multicenter, randomized controlled trial is required to better assess the impact of this educational opportunity among military populations.

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14. Huang M, Qi Q, Xu T. Targeting Shank3 deficiency and paresthesia in autism spectrum disorder: A brief review. Front Mol Neurosci;2023;16:1128974.

Autism spectrum disorder (ASD) includes a group of multifactorial neurodevelopmental disorders characterized by impaired social communication, social interaction, and repetitive behaviors. Several studies have shown an association between cases of ASD and mutations in the genes of SH3 and multiple ankyrin repeat domain protein 3 (SHANK3). These genes encode many cell adhesion molecules, scaffold proteins, and proteins involved in synaptic transcription, protein synthesis, and degradation. They have a profound impact on all aspects of synaptic transmission and plasticity, including synapse formation and degeneration, suggesting that the pathogenesis of ASD may be partially attributable to synaptic dysfunction. In this review, we summarize the mechanism of synapses related to Shank3 in ASD. We also discuss the molecular, cellular, and functional studies of experimental models of ASD and current autism treatment methods targeting related proteins.

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15. Hudson M, Santavirta S, Putkinen V, Seppälä K, Sun L, Karjalainen T, Karlsson HK, Hirvonen J, Nummenmaa L. Neural responses to biological motion distinguish autistic and schizotypal traits. Soc Cogn Affect Neurosci;2023 (Feb 27)

Difficulties in social interactions characterize both autism and schizophrenia, and are correlated in the neurotypical population. It is unknown whether this represents a shared etiology or superficial phenotypic overlap. Both conditions exhibit atypical neural activity in response to the perception of social stimuli and decreased neural synchronization between individuals. This study investigated if neural activity and neural synchronization associated with biological motion perception are differentially associated with autistic and schizotypal traits in the neurotypical population. Participants viewed naturalistic social interactions whilst hemodynamic brain activity was measured with fMRI, which was modelled against a continuous measure of the extent of biological motion. General Linear Model analysis revealed that biological motion perception was associated with neural activity across the action-observation network. However, inter-subject phase synchronization analysis revealed neural activity to be synchronized between individuals in occipital and parietal areas, but de-synchronized in temporal and frontal regions. Autistic traits were associated with decreased neural activity (precuneus, middle cingulate gyrus) and schizotypal traits were associated with decreased neural synchronization (middle and inferior frontal gyri). Biological motion perception elicits divergent patterns of neural activity and synchronization, which dissociate autistic and schizotypal traits in the general population, suggesting they originate from different neural mechanisms.

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16. Hughes MM, Shaw KA, Patrick ME, DiRienzo M, Bakian AV, Bilder DA, Durkin MS, Hudson A, Spivey MH, DaWalt LS, Salinas A, Schwenk YD, Lopez M, Baroud TM, Maenner MJ. Adolescents With Autism Spectrum Disorder: Diagnostic Patterns, Co-occurring Conditions, and Transition Planning. J Adolesc Health;2023 (Feb 25)

PURPOSE: The objectives of this study were to describe child characteristics associated with later autism spectrum disorder (ASD) identification and the health status and educational transition plans of adolescents with ASD. METHODS: Longitudinal population-based surveillance cohort from the Autism Developmental Disabilities Monitoring Network during 2002-2018 in five catchment areas in the United States. Participants included 3,148 children born in 2002 whose records were first reviewed for ASD surveillance in 2010. RESULTS: Of the 1,846 children identified in the community as an ASD case, 11.6% were first identified after age 8 years. Children who were more likely to have ASD identified at older ages were Hispanic; were born with low birth weight; were verbal; had high intelligence quotient or adaptive scores; or had certain co-occurring neuropsychological conditions by age 8 years. By age 16 years, neuropsychological conditions were common with more than half of the adolescents with ASD having a diagnosis of attention-deficit/hyperactivity disorder or anxiety. Intellectual disability (ID) status was unchanged for the majority (>80%) of children from ages 8-16 years. A transition plan was completed for over 94% of adolescents, but disparities were observed in planning by ID status. DISCUSSION: A high percentage of adolescents with ASD have co-occurring neuropsychological conditions, markedly higher than at age 8. While most adolescents had transition planning, this occurred less often for those with ID. Ensuring access to services for all people with ASD during adolescence and transition to adulthood may help to promote overall health and quality of life.

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17. Hustyi KM, Ryan AH, Hall SS. A Scoping Review of Behavioral Interventions for Promoting Social Gaze in Individuals with Autism Spectrum Disorder and Other Developmental Disabilities. Res Autism Spectr Disord;2023 (Feb);100

BACKGROUND: Individuals diagnosed with autism spectrum disorder (ASD) commonly experience difficulties maintaining social gaze with others during interactions. Although behavioral interventions targeted to promote social gaze in ASD are evident in the literature, to our knowledge, no review of the literature has been conducted to summarize and evaluate the evidence for these interventions. METHODS: We reviewed and summarized behavioral intervention studies designed to promote social gaze in individuals diagnosed with ASD and other developmental disabilities published in English between 1977 and January 2022 using PsychINFO and PubMed databases. RESULTS: 41 studies met the inclusion criteria describing interventions conducted on 608 individuals. A variety of intervention strategies were employed to promote social gaze in these individuals including discrete trial instruction, prompting, modeling, and imitation. Most studies employed single-case research designs and reported successful outcomes, but limited data were available concerning the generalization, maintenance and social validity of these interventions. An increasing number of studies utilized technology-based procedures including computer application gameplay, gaze-contingent eye tracking devices and humanoid robots. CONCLUSIONS: The present review indicates that behavioral interventions can be successfully employed to promote social gaze in individuals with ASD and other developmental disabilities. However, future research is needed to establish the generalization, maintenance and social validity of these interventions. There are also important ethical issues to be addressed given the increasing divide between treatment advocates and proponents of the neurodiversity movement.

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18. Ivanoff AE, Ivanoff CS. Ring chromosome 14 syndrome: what the dentist should know to manage children with r(14) effec-tively. Folia Med (Plovdiv);2023 (Feb 28);65(1):20-29.

INTRODUCTION: Ring chromosome 14 syndrome, or r(14), is a rare genetic disorder characterized by distinctive facial features, intractable epilepsy, delayed development, intellectual disability, and autism spectrum disorder. With less than 100 documented cases worldwide, the disease is not well known or fully studied. Furthermore, the literature offers little guidance to aid dentists in the management of these patients as r(14) remains undocumented in the dental literature. AIM: To investigate the manifestations and challenges faced by a group of subjects suffering from r(14), to raise awareness of this syndrome, and to provide tips and suggestions that dentists may find helpful to manage r(14) children effectively. MATERIALS AND METHODS: A voluntary survey was administered to the caretakers of 13 r(14) patients who, as of 2019, were registered in the NORD (National Organization for Rare Diseases) global data bank (Ring 14 USA Outreach). The patients were assessed for age, gender, geographic distribution, phenotype, physical appearance, maxillofacial characteristics, presence of oral conditions and abnormalities, malocclusion, epileptic seizures, cognitive abilities, speech, muscle tone, nutrition, autism, and other developmental and behavioral points of interest. RESULTS: Of the 13 patients queried, 7 were male and 6 were female. The age of the patients ranged from 5 to 49 years. Ten patients were of European ancestry and three were Hispanic, all residing across the U.S. The majority of patients were diagnosed as infants, shortly after commencement of uncontrollable seizures. All the patients had microcephaly and presented with Class II malocclusions. More frequent occlusal anomalies and conditions included diastemata of the anterior teeth, congenitally missing teeth, crowding, and drooling. The majority of subjects was unable to speak, suffered from intractable seizures, and frequently exhibited behavioral outbursts. CONCLUSIONS: A child with r(14) may present a considerable challenge to the dentist and staff, but the dental problems of r(14) children are, for the most part, like those of any other patient and can often be handled by the dentist. Depending on the severity of symptoms, some children with r(14) may be as treatable in the dental office as any other child.

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19. Loan A, Leung JW, Cook DP, Ko C, Vanderhyden BC, Wang J, Chan HM. Prenatal low-dose methylmercury exposure causes premature neuronal differentiation and autism-like behaviors in a rodent model. iScience;2023 (Mar 17);26(3):106093.

Aberrant neurodevelopment is a core deficit of autism spectrum disorder (ASD). Here we ask whether a non-genetic factor, prenatal exposure to the environmental pollutant methylmercury (MeHg), is a contributing factor in ASD onset. We showed that adult mice prenatally exposed to non-apoptotic MeHg exhibited key ASD characteristics, including impaired communication, reduced sociability, and increased restrictive repetitive behaviors, whereas in the embryonic cortex, prenatal MeHg exposure caused premature neuronal differentiation. Further single-cell RNA sequencing (scRNA-seq) analysis disclosed that prenatal exposure to MeHg resulted in cortical radial glial precursors (RGPs) favoring asymmetric differentiation to directly generate cortical neurons, omitting the intermediate progenitor stage. In addition, MeHg exposure in cultured RGPs increased CREB phosphorylation and enhanced the interaction between CREB and CREB binding protein (CBP). Intriguingly, metformin, an FDA-approved drug, can reverse MeHg-induced premature neuronal differentiation via CREB/CBP repulsion. These findings provide insights into ASD etiology, its underlying mechanism, and a potential therapeutic strategy.

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20. Min S, Gandal MJ, Kopp RF, Liu C, Chen C. No Increased Detection of Nucleic Acids of CNS-related Viruses in the Brains of Patients with Schizophrenia, Bipolar Disorder, and Autism Spectrum Disorder. Schizophr Bull;2023 (Feb 28)

BACKGROUND AND HYPOTHESIS: Viral infections are increasingly recognized in the etiology of psychiatric disorders based on epidemiological and serological studies. Few studies have analyzed viruses directly within the brain and no comprehensive investigation of viral infection within diseased brains has been completed. This study aims to determine whether viral infection in brain tissues is a risk factor for 3 major psychiatric disorders, including schizophrenia, bipolar disorder, and autism spectrum disorder. STUDY DESIGN: This study directly evaluated the presence of viral DNA or RNA in 1569 brains of patients and controls using whole-genome sequencing and RNA sequencing data with 4 independent cohorts. The PathSeq tool was used to identify known human viruses in the genome and transcriptome of patients and controls. STUDY RESULTS: A variety of DNA and RNA viruses related to the central nervous system were detected in the brains of patients with major psychiatric disorders, including viruses belonging to Herpesviridae, Polyomaviridae, Retroviridae, Flaviviridae, Parvoviridae, and Adenoviridae. However, no consistent significant differences were found between patients and controls in terms of types and amount of virus detected at both DNA and RNA levels. CONCLUSIONS: The findings of this study do not suggest an association between viral infection in postmortem brains and major psychiatric disorders.

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21. Palmer M, Chandler S, Carter Leno V, Mgaieth F, Yorke I, Hollocks M, Pickles A, Slonims V, Scott S, Charman T, Simonoff E. Factors associated with mental health symptoms among UK autistic children and young people and their parents during the COVID-19 pandemic. Autism;2023 (Feb 27):13623613231153694.

What is already known about the topic: The COVID-19 pandemic and the associated restrictions impacted all of society. There is emerging evidence showing a range of impacts on autistic children and young people and their families. Further research that looks at how individuals coped during the pandemic while considering how they were doing before the pandemic is needed.What this paper adds: This article explores whether how well autistic youth were doing before the pandemic influenced how they coped during the pandemic. It also looked at how well their parents were doing during the pandemic and whether any pre-pandemic factors influenced how they coped. Samples of both primary-school-aged autistic children and autistic teenagers and their parents were surveyed to answer these questions. More engagement and enjoyment in education provision during the pandemic and getting outside more were linked with better child and parental mental health during the pandemic. More attention deficit hyperactivity disorder before the pandemic was linked with more attention deficit hyperactivity disorder and behavioural problems during the pandemic in primary-school-aged autistic children, and more emotional problems during the pandemic in autistic teenagers. Parents with more mental health problems during the pandemic had more mental health problems before the pandemic.Implications for practice, research or policy: Encouraging engagement and enjoyment in education and promoting physical exercise are key intervention targets. Ensuring access to attention deficit hyperactivity disorder medication and support is important, especially if this is managed jointly across school and home.

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22. Rodgers J, Goodwin J, Nielsen E, Bhattarai N, Heslop P, Kharatikoopaei E, O’Connor RC, Ogundimu E, Ramsay SE, Steele K, Townsend E, Vale L, Walton E, Wilson C, Cassidy S. Adapted suicide safety plans to address self-harm, suicidal ideation, and suicide behaviours in autistic adults: protocol for a pilot randomised controlled trial. Pilot Feasibility Stud;2023 (Feb 28);9(1):31.

BACKGROUND: Suicide prevention is a national priority for the UK government. Autistic people are at greater risk of experiencing self-harm and suicidal thoughts and behaviours than the general population. Safety plans are widely used in suicide prevention but have not yet been designed with and for autistic people. We developed the first safety plan specifically targeting suicidality in autistic adults: the Autism Adapted Safety Plan (AASP). It consists of a prioritised list of hierarchical steps that can be used prior to or during a crisis to mitigate risk of self-harm and suicidal behaviour. This is a pilot study that aims to assess the feasibility and acceptability of the AASPs and the research processes, including the response rates, potential barriers and reach of AASPs, methods of recruitment, what comprises usual care, and economic evaluation methods/tools. METHODS: This is an external pilot randomised controlled trial of a suicide prevention tool aimed at mitigating the risk of self-harm and suicidal behaviour in autistic adults: AASPs. Participants will be assessed at baseline and followed up 1 month and 6 months later. Assessments include questions about self-harm, suicidality, service use, and their experience of the AASP/taking part in the study. Autistic adults who have a clinical autism diagnosis and self-reported history of self-harm, suicidal thoughts, or suicidal behaviours within the last 6 months will be invited to take part in the study. Informed consent will be obtained. Participants will be recruited via community and third sector services (including community settings, autism charities, and mental health charities). They may also « self-refer » into the study through social media recruitment and word of mouth. Ninety participants will be randomised to either develop an AASP or receive their usual care in a 1:1 ratio. DISCUSSION: The present study will provide an evaluation of the suitability of the processes that would be undertaken in a larger definitive study, including recruitment, randomisation, methods, questionnaires, outcome measures, treatment, and follow-up assessments. TRIAL REGISTRATION: ISRCTN70594445, Protocol v4: 8/2/22.

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23. Saha S, Chatterjee M, Dutta N, Sinha S, Mukhopadhyay K. Analysis of neurotransmitters validates the importance of the dopaminergic system in autism spectrum disorder. World J Pediatr;2023 (Feb 27)

BACKGROUND: The reasons behind the cardinal symptoms of communication deficits and repetitive, stereotyped behaviors that characterize autism spectrum disorder (ASD) remain unknown. The dopamine (DA) system, which regulates motor activity, goal-directed behaviors, and reward function, is believed to play a crucial role in ASD, although the exact mechanism is still unclear. Investigations have shown an association of the dopamine receptor D4 (DRD4) with various neurobehavioral disorders. METHODS: We analyzed the association between ASD and four DRD4 genetic polymorphisms, 5′ flanking 120-bp duplication (rs4646984), rs1800955 in the promoter, exon 1 12 bp duplication (rs4646983), and exon 3 48 bp repeats. We also examined plasma DA and its metabolite levels, DRD4 mRNA expression, and correlations of the studied polymorphisms with these parameters by case-control comparative analyses. The expression of DA transporter (DAT), which is important in regulating the circulating DA level, was also evaluated. RESULTS: A significantly higher occurrence of rs1800955 « T/TT » was observed in the probands. ASD traits were affected by rs1800955 « T » and the higher repeat alleles of the exon 3 48 bp repeats, rs4646983 and rs4646984. ASD probands exhibited lower DA and norepinephrine levels together with higher homovanillic acid levels than the control subjects. DAT and DRD4 mRNA expression were down-regulated in the probands, especially in the presence of DAT rs3836790 « 6R » and rs27072 « CC » and DRD4 rs4646984 higher repeat allele and rs1800955 « T ». CONCLUSION: This pioneering investigation revealed a positive correlation between genetic variants, hypodopaminergic state, and impairment in socio-emotional and communication reciprocity in Indian subjects with ASD, warranting further in-depth analysis.

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24. Spackman E, Smillie LD, Frazier TW, Hardan AY, Alvares GA, Whitehouse A, Uljarević M. Profiles of circumscribed interests in autistic youth. Front Behav Neurosci;2023;17:1037967.

Circumscribed interests (CI) encompass a range of different interests and related behaviors that can be characterized by either a high intensity but otherwise usual topic [referred to as restricted interests (RI)] or by a focus on topics that are not salient outside of autism [referred to as unusual interests (UI)]. Previous research has suggested that there is pronounced variability across individuals in terms of the endorsement of different interests, however, this variability has not been quantified using formal subtyping approaches. Therefore, using Latent Profile Analysis in a sample of 1,892 autistic youth (M(age) = 10.82, SD(age) = 4.14; 420 females), this study aimed to identify subgroups based on the RU and UI profiles. Three profiles of autistic individuals were identified. They were characterized as Low CI, Predominantly RI, and Predominantly UI. Importantly, profiles differed on several key demographic and clinical variables, including age, sex composition, IQ, language level, social and communication abilities, anxiety, and obsessive-compulsive behaviors. Although replication across other samples is needed, the profiles identified in this study are potentially promising for future research given their distinct profiles of RI and UI and unique patterns of associations with key cognitive and clinical variables. Therefore, this study represents an important initial step towards more individualized assessment and support for diverse presentations of CI in autistic youth.

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25. Talantseva OI, Romanova RS, Shurdova EM, Dolgorukova TA, Sologub PS, Titova OS, Kleeva DF, Grigorenko EL. The global prevalence of autism spectrum disorder: A three-level meta-analysis. Front Psychiatry;2023;14:1071181.

Autism spectrum disorder (ASD) is one the most disabling developmental disorders, imposing an extremely high economic burden. Obtaining as accurate prevalence estimates as possible is crucial to guide governments in planning policies for identification and intervention for individuals with ASD and their relatives. The precision of prevalence estimates can be heightened by summative analyses of the data collected around the world. To that end, we conducted a three-level mixed-effects meta-analysis. A systematic search of the Web of Science, PubMed, EMBASE, and PsycINFO databases from 2000 up to 13 July 2020 was performed, and reference lists of previous reviews and existing databases of prevalence studies were screened. Overall, 79 studies were included in the analysis of ASD and 59-in the analysis of previously existing relevant diagnoses: 30 for Autistic Disorder (AD), 15 for Asperger Syndrome (AS), and 14 for Atypical Autism (AA) and Pervasive Developmental Disorder – Not Otherwise Specified (PDD-NOS); these research reports covered the period from 1994 to 2019. Pooled prevalence estimates were 0.72% (95% CI = 0.61-0.85) for ASD, 0.25% (95% CI = 0.18-0.33) for AD, 0.13% (95% CI = 0.07-0.20) for AS, and 0.18% (95% CI = 0.10-0.28) for the combined group of AA and PDD-NOS. Estimates were higher (1) for the studies that used records-review surveillance rather than other designs; (2) in North America compared with other geographical regions; and (3) in high-income compared with lower-income countries. The highest prevalence estimates were registered in the USA. There was an increase in autism prevalence estimates over time. The prevalence was also significantly higher for children aged between 6 and 12 years compared to children under the age of 5 and over the age of 13 years. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42019131525, identifier CRD42019131525.

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26. Xiao L, Feng J, Zhang W, Pan J, Wang M, Zhang C, Li L, Su X, Yao P. Autism-like behavior of murine offspring induced by prenatal exposure to progestin is associated with gastrointestinal dysfunction due to claudin-1 suppression. FEBS J;2023 (Feb 28)

Autism spectrum disorders (ASD) are associated with the contribution of many prenatal risk factors; in particular, the sex hormone progestin and vitamin D receptor (VDR) are associated with gastrointestinal (GI) symptoms in ASD development, although the related mechanism remains unclear. We investigated the possible role and mechanism of progestin 17-hydroxyprogesterone caproate (17-OHPC) exposure-induced GI dysfunction and autism-like behaviors (ALB) in mouse offspring. An intestine-specific VDR deficient mouse model was established for prenatal treatment, while transplantation of hematopoietic stem cells (HSCT) with related gene manipulation were used for postnatal treatment for 17-OHPC exposure-induced GI dysfunction and ALB in mouse offspring. The in vivo mouse experiments found that VDR deficiency mimics prenatal 17-OHPC exposure-mediated GI dysfunction, but has no effect on 17-OHPC-mediated autism-like behaviors (ALB) in mouse offspring. Furthermore, prenatal 17-OHPC exposure induces CLDN1 suppression in intestine epithelial cells, and transplantation of hematopoietic stem cells (HSCT) with CLDN1 expression ameliorates prenatal 17-OHPC exposure-mediated GI dysfunction, but has no effect on 17-OHPC-mediated ALB in offspring. In conclusion, prenatal 17-OHPC exposure triggers GI dysfunction in autism-like mouse offspring via CLDN1 suppression, providing a possible explanation for the involvement of CLDN1 and VDR in prenatal 17-OHPC exposure-mediated GI dysfunction with ASD.

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27. Xu B, Ho Y, Fasolino M, Medina J, O’Brien WT, Lamonica JM, Nugent E, Brodkin ES, Fuccillo MV, Bucan M, Zhou Z. Allelic contribution of Nrxn1α to autism-relevant behavioral phenotypes in mice. PLoS Genet;2023 (Feb 27);19(2):e1010659.

Copy number variations (CNVs) in the Neurexin 1 (NRXN1) gene, which encodes a presynaptic protein involved in neurotransmitter release, are some of the most frequently observed single-gene variants associated with autism spectrum disorder (ASD). To address the functional contribution of NRXN1 CNVs to behavioral phenotypes relevant to ASD, we carried out systematic behavioral phenotyping of an allelic series of Nrxn1 mouse models: one carrying promoter and exon 1 deletion abolishing Nrxn1α transcription, one carrying exon 9 deletion disrupting Nrxn1α protein translation, and one carrying an intronic deletion with no observable effect on Nrxn1α expression. We found that homozygous loss of Nrxn1α resulted in enhanced aggression in males, reduced affiliative social behaviors in females, and significantly altered circadian activities in both sexes. Heterozygous or homozygous loss of Nrxn1α affected the preference for social novelty in male mice, and notably, enhanced repetitive motor skills and motor coordination in both sexes. In contrast, mice bearing an intronic deletion of Nrxn1 did not display alterations in any of the behaviors assessed. These findings demonstrate the importance of Nrxn1α gene dosage in regulating social, circadian, and motor functions, and the variables of sex and genomic positioning of CNVs in the expression of autism-related phenotypes. Importantly, mice with heterozygous loss of Nrxn1, as found in numerous autistic individuals, show an elevated propensity to manifest autism-related phenotypes, supporting the use of models with this genomic architecture to study ASD etiology and assess additional genetic variants associated with autism.

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28. Zhang L, Bang S, He Q, Matsuda M, Luo X, Jiang YH, Ji RR. SHANK3 in vagal sensory neurons regulates body temperature, systemic inflammation, and sepsis. Front Immunol;2023;14:1124356.

Excessive inflammation has been implicated in autism spectrum disorder (ASD), but the underlying mechanisms have not been fully studied. SHANK3 is a synaptic scaffolding protein and mutations of SHANK3 are involved in ASD. Shank3 expression in dorsal root ganglion sensory neurons also regulates heat pain and touch. However, the role of Shank3 in the vagus system remains unknown. We induced systemic inflammation by lipopolysaccharide (LPS) and measured body temperature and serum IL-6 levels in mice. We found that homozygous and heterozygous Shank3 deficiency, but not Shank2 and Trpv1 deficiency, aggravates hypothermia, systemic inflammation (serum IL-6 levels), and sepsis mortality in mice, induced by lipopolysaccharide (LPS). Furthermore, these deficits can be recapitulated by specific deletion of Shank3 in Nav1.8-expressing sensory neurons in conditional knockout (CKO) mice or by selective knockdown of Shank3 or Trpm2 in vagal sensory neurons in nodose ganglion (NG). Mice with Shank3 deficiency have normal basal core temperature but fail to adjust body temperature after perturbations with lower or higher body temperatures or auricular vagus nerve stimulation. In situ hybridization with RNAscope revealed that Shank3 is broadly expressed by vagal sensory neurons and this expression was largely lost in Shank3 cKO mice. Mechanistically, Shank3 regulates the expression of Trpm2 in NG, as Trpm2 but not Trpv1 mRNA levels in NG were significantly reduced in Shank3 KO mice. Our findings demonstrated a novel molecular mechanism by which Shank3 in vagal sensory neurons regulates body temperature, inflammation, and sepsis. We also provided new insights into inflammation dysregulation in ASD.

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29. Zhao W, Johnston KG, Ren H, Xu X, Nie Q. Inferring neuron-neuron communications from single-cell transcriptomics through NeuronChat. Nat Commun;2023 (Feb 28);14(1):1128.

Neural communication networks form the fundamental basis for brain function. These communication networks are enabled by emitted ligands such as neurotransmitters, which activate receptor complexes to facilitate communication. Thus, neural communication is fundamentally dependent on the transcriptome. Here we develop NeuronChat, a method and package for the inference, visualization and analysis of neural-specific communication networks among pre-defined cell groups using single-cell expression data. We incorporate a manually curated molecular interaction database of neural signaling for both human and mouse, and benchmark NeuronChat on several published datasets to validate its ability in predicting neural connectivity. Then, we apply NeuronChat to three different neural tissue datasets to illustrate its functionalities in identifying interneural communication networks, revealing conserved or context-specific interactions across different biological contexts, and predicting communication pattern changes in diseased brains with autism spectrum disorder. Finally, we demonstrate NeuronChat can utilize spatial transcriptomics data to infer and visualize neural-specific cell-cell communication.

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