1. Adolph KE, West KL. Autism: The face value of eye contact. Curr Biol;2022 (Jun 20);32(12):R577-R580.

Inattention to faces in clinical assessments is a robust marker for autism. However, a new study distinguishes diagnostic marker from behavioral mechanism, showing that face looking in everyday activity is equally rare in autistic and neurotypical children and not required for joint attention in either group.

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2. Coburn KL, Kurtz MR, Rivera D, Kana RK. Behavioral and neurobiological evidence for the effects of reading interventions on autistic children: A systematic review. Neurosci Biobehav Rev;2022 (Jun 18);139:104748.

This study systematically reviewed the literature on reading interventions for autistic children. Peer-reviewed articles that reported behavioral and/or neurobiological effects of reading intervention were identified in five online databases. After screening, 15 studies met the inclusion criteria for this review. These studies focus on interventions targeted towards improving specific reading skills: comprehension, vocabulary, fluency, and phonological awareness. Studied interventions included interactive and shared reading, visualization strategies, vocabulary and main idea instruction, video modeling, and interventions supported by tablet-based technology. Overall, the studies identified in this review reported improvements to each of the targeted reading skills and changes to neural activation and connectivity. In addition, changes at the brain level were associated with improvements in reading. Specifically, frontal, temporal, and occipital regions associated with visual and language processing showed increased activation and functional connectivity following intervention. This review provides important insights into the landscape of reading intervention studies in autism and into the neurobiological underpinnings of reading skills and how interventions affect those processes.

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3. Elgen SKF, Røiseland MA, Bircow EI, Vollsæter M, Hysing M. Correction to: Symptoms and antecedents of autism in children born extremely premature: a national population-based study. Eur Child Adolesc Psychiatry;2022 (Jun 21)

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4. Gomez A, Lio G, Costa M, Sirigu A, Demily C. Dissociation of early and late face-related processes in autism spectrum disorder and Williams syndrome. Orphanet J Rare Dis;2022 (Jun 22);17(1):244.

BACKGROUND: Williams syndrome (WS) and Autism Spectrum Disorders (ASD) are neurodevelopmental conditions associated with atypical but opposite face-to-face interactions patterns: WS patients overly stare at others, ASD individuals escape eye contact. Whether these behaviors result from dissociable visual processes within the occipito-temporal pathways is unknown. Using high-density electroencephalography, multivariate signal processing algorithms and a protocol designed to identify and extract evoked activities sensitive to facial cues, we investigated how WS (N = 14), ASD (N = 14) and neurotypical subjects (N = 14) decode the information content of a face stimulus. RESULTS: We found two neural components in neurotypical participants, both strongest when the eye region was projected onto the subject’s fovea, simulating a direct eye contact situation, and weakest over more distant regions, reaching a minimum when the focused region was outside the stimulus face. The first component peaks at 170 ms, an early signal known to be implicated in low-level face features. The second is identified later, 260 ms post-stimulus onset and is implicated in decoding salient face social cues. Remarkably, both components were found distinctly impaired and preserved in WS and ASD. In WS, we could weakly decode the 170 ms signal based on our regressor relative to facial features, probably due to their relatively poor ability to process faces’ morphology, while the late 260 ms component was highly significant. The reverse pattern was observed in ASD participants who showed neurotypical like early 170 ms evoked activity but impaired late evoked 260 ms signal. CONCLUSIONS: Our study reveals a dissociation between WS and ASD patients and points at different neural origins for their social impairments.

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5. Han Y, Jin S, Liu L, Qu Z, Gao L, Li P, Xiong W, Zhang X. Exploring associations between urine levels of phthalates and autism spectrum disorder symptoms: a case-control study in Tianjin, China. Environ Sci Pollut Res Int;2022 (Jun 21)

Autism spectrum disorder (ASD) comprises a group of neurodevelopmental disorders. The etiology of autism remains unclear, but a growing body of evidence indicates that phthalates play a role in its pathogenesis. The aim of this study was to compare the urine levels of phthalates in children with ASD and healthy children. We also explored whether phthalates have an effect on ASD symptoms. The participants in this study included 101 children with ASD (79 boys and 22 girls) and 101 sex- and age-matched controls. The levels of phthalates were analyzed by gas chromatography-mass spectrometry (GC-MS). We detected significant differences in monoethyl phthalate (MEP) levels between the severe ASD and control groups (p < 0.05). Mono-n-butyl phthalate (MBP) concentration was positively correlated with language skill impairment in ASD (β: 0.387, p = 0.041). MEP levels were associated with the CARS "Imitation" score in all children (OR: 1.470). MBP levels were associated with the "Nonverbal Communication" score among boys (OR: 1.233), and MEP levels were associated with the "Nonverbal Communication" score among girls (OR: 2.648). MEP levels were related to the CARS total score after adjustment for sex (β: 1.524, p = 0.047). Compared with the reference mono(2-ethylhexyl) phthalate (MEHP) group, children with ASD in the medium-exposure group had an OR of 3.370 for aggravating ASD severity. These results suggested that increased exposure to phthalates contributes to more ASD symptoms and that there are potentially sex-specific associations. These findings warrant further confirmation.

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6. Hwang YH, Hayward BE, Zafarullah M, Kumar J, Durbin Johnson B, Holmans P, Usdin K, Tassone F. Both cis and trans-acting genetic factors drive somatic instability in female carriers of the FMR1 premutation. Sci Rep;2022 (Jun 21);12(1):10419.

The fragile X mental retardation (FMR1) gene contains an expansion-prone CGG repeat within its 5′ UTR. Alleles with 55-200 repeats are known as premutation (PM) alleles and confer risk for one or more of the FMR1 premutation (PM) disorders that include Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), Fragile X-associated Primary Ovarian Insufficiency (FXPOI), and Fragile X-Associated Neuropsychiatric Disorders (FXAND). PM alleles expand on intergenerational transmission, with the children of PM mothers being at risk of inheriting alleles with > 200 CGG repeats (full mutation FM) alleles) and thus developing Fragile X Syndrome (FXS). PM alleles can be somatically unstable. This can lead to individuals being mosaic for multiple size alleles. Here, we describe a detailed evaluation of somatic mosaicism in a large cohort of female PM carriers and show that 94% display some evidence of somatic instability with the presence of a series of expanded alleles that differ from the next allele by a single repeat unit. Using two different metrics for instability that we have developed, we show that, as with intergenerational instability, there is a direct relationship between the extent of somatic expansion and the number of CGG repeats in the originally inherited allele and an inverse relationship with the number of AGG interruptions. Expansions are progressive as evidenced by a positive correlation with age and by examination of blood samples from the same individual taken at different time points. Our data also suggests the existence of other genetic or environmental factors that affect the extent of somatic expansion. Importantly, the analysis of candidate single nucleotide polymorphisms (SNPs) suggests that two DNA repair factors, FAN1 and MSH3, may be modifiers of somatic expansion risk in the PM population as observed in other repeat expansion disorders.

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7. Kar K. A Computational Probe into the Behavioral and Neural Markers of Atypical Facial Emotion Processing in Autism. J Neurosci;2022 (Jun 22);42(25):5115-5126.

Despite ample behavioral evidence of atypical facial emotion processing in individuals with autism spectrum disorder (ASD), the neural underpinnings of such behavioral heterogeneities remain unclear. Here, I have used brain-tissue mapped artificial neural network (ANN) models of primate vision to probe candidate neural and behavior markers of atypical facial emotion recognition in ASD at an image-by-image level. Interestingly, the image-level behavioral patterns of the ANNs better matched the neurotypical subjects ‘behavior than those measured in ASD. This behavioral mismatch was most remarkable when the ANN behavior was decoded from units that correspond to the primate inferior temporal (IT) cortex. ANN-IT responses also explained a significant fraction of the image-level behavioral predictivity associated with neural activity in the human amygdala (from epileptic patients without ASD), strongly suggesting that the previously reported facial emotion intensity encodes in the human amygdala could be primarily driven by projections from the IT cortex. In sum, these results identify primate IT activity as a candidate neural marker and demonstrate how ANN models of vision can be used to generate neural circuit-level hypotheses and guide future human and nonhuman primate studies in autism.SIGNIFICANCE STATEMENT Moving beyond standard parametric approaches that predict behavior with high-level categorical descriptors of a stimulus (e.g., level of happiness/fear in a face image), in this study, I demonstrate how an image-level probe, using current deep-learning-based ANN models, allows identification of more diagnostic stimuli for autism spectrum disorder enabling the design of more powerful experiments. This study predicts that IT cortex activity is a key candidate neural marker of atypical facial emotion processing in people with ASD. Importantly, the results strongly suggest that ASD-related atypical facial emotion intensity encodes in the human amygdala could be primarily driven by projections from the IT cortex.

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8. Kouroupa A, Laws KR, Irvine K, Mengoni SE, Baird A, Sharma S. The use of social robots with children and young people on the autism spectrum: A systematic review and meta-analysis. PLoS One;2022;17(6):e0269800.

BACKGROUND: Robot-mediated interventions show promise in supporting the development of children on the autism spectrum. OBJECTIVES: In this systematic review and meta-analysis, we summarize key features of available evidence on robot-interventions for children and young people on the autism spectrum aged up to 18 years old, as well as consider their efficacy for specific domains of learning. DATA SOURCES: PubMed, Scopus, EBSCOhost, Google Scholar, Cochrane Library, ACM Digital Library, and IEEE Xplore. Grey literature was also searched using PsycExtra, OpenGrey, British Library EThOS, and the British Library Catalogue. Databases were searched from inception until April (6th) 2021. SYNTHESIS METHODS: Searches undertaken across seven databases yielded 2145 articles. Forty studies met our review inclusion criteria of which 17 were randomized control trials. The methodological quality of studies was conducted with the Quality Assessment Tool for Quantitative Studies. A narrative synthesis summarised the findings. A meta-analysis was conducted with 12 RCTs. RESULTS: Most interventions used humanoid (67%) robotic platforms, were predominantly based in clinics (37%) followed home, schools and laboratory (17% respectively) environments and targeted at improving social and communication skills (77%). Focusing on the most common outcomes, a random effects meta-analysis of RCTs showed that robot-mediated interventions significantly improved social functioning (g = 0.35 [95%CI 0.09 to 0.61; k = 7). By contrast, robots did not improve emotional (g = 0.63 [95%CI -1.43 to 2.69]; k = 2) or motor outcomes (g = -0.10 [95%CI -1.08 to 0.89]; k = 3), but the numbers of trials were very small. Meta-regression revealed that age accounted for almost one-third of the variance in effect sizes, with greater benefits being found in younger children. CONCLUSIONS: Overall, our findings support the use of robot-mediated interventions for autistic children and youth, and we propose several recommendations for future research to aid learning and enhance implementation in everyday settings. PROSPERO REGISTRATION: Our methods were preregistered in the PROSPERO database (CRD42019148981).

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9. Lim HK, Yoon JH, Song M. Autism Spectrum Disorder Genes: Disease-Related Networks and Compensatory Strategies. Front Mol Neurosci;2022;15:922840.

The mammalian brain comprises structurally and functionally distinct regions. Each of these regions has characteristic molecular mechanisms that mediate higher-order tasks, such as memory, learning, emotion, impulse, and motor control. Many genes are involved in neuronal signaling and contribute to normal brain development. Dysfunction of essential components of neural signals leads to various types of brain disorders. Autism spectrum disorder is a neurodevelopmental disorder characterized by social deficits, communication challenges, and compulsive repetitive behaviors. Long-term genetic studies have uncovered key genes associated with autism spectrum disorder, such as SH3 and multiple ankyrin repeat domains 3, methyl-CpG binding protein 2, neurexin 1, and chromodomain helicase DNA binding protein 8. In addition, disease-associated networks have been identified using animal models, and the understanding of the impact of these genes on disease susceptibility and compensation is deepening. In this review, we examine rescue strategies using key models of autism spectrum disorder.

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10. Lucaci AG, Notaras MJ, Kosakovsky Pond SL, Colak D. The evolution of BDNF is defined by strict purifying selection and prodomain spatial coevolution, but what does it mean for human brain disease?. Transl Psychiatry;2022 (Jun 22);12(1):258.

Brain-Derived Neurotrophic Factor (BDNF) is an essential mediator of brain assembly, development, and maturation. BDNF has been implicated in a variety of brain disorders such as neurodevelopmental disorders (e.g., autism spectrum disorder), neuropsychiatric disorders (e.g., anxiety, depression, PTSD, and schizophrenia), and various neurodegenerative disorders (e.g., Parkinson’s, Alzheimer’s, etc.). To better understand the role of BDNF in disease, we sought to define the evolution of BDNF within Mammalia. We conducted sequence alignment and phylogenetic reconstruction of BDNF across a diverse selection of >160 mammalian species spanning ~177 million years of evolution. The selective evolutionary change was examined via several independent computational models of codon evolution including FEL (pervasive diversifying selection), MEME (episodic selection), and BGM (structural coevolution of sites within a single molecule). We report strict purifying selection in the main functional domain of BDNF (NGF domain, essentially comprising the mature BDNF protein). Additionally, we discover six sites in our homologous alignment which are under episodic selection in early regulatory regions (i.e. the prodomain) and 23 pairs of coevolving sites that are distributed across the entirety of BDNF. Coevolving BDNF sites exhibited complex spatial relationships and geometric features including triangular relations, acyclic graph networks, double-linked sites, and triple-linked sites, although the most notable pattern to emerge was that changes in the mature region of BDNF tended to coevolve along with sites in the prodomain. Thus, we propose that the discovery of both local and distal sites of coevolution likely reflects ‘evolutionary fine-tuning’ of BDNF’s underlying regulation and function in mammals. This tracks with the observation that BDNF’s mature domain (which encodes mature BDNF protein) is largely conserved, while the prodomain (which is linked to regulation and its own unique functionality) exhibits more pervasive and diversifying evolutionary selection. That said, the fact that negative purifying selection also occurs in BDNF’s prodomain also highlights that this region also contains critical sites of sensitivity which also partially explains its disease relevance (via Val66Met and other prodomain variants). Taken together, these computational evolutionary analyses provide important context as to the origins and sensitivity of genetic changes within BDNF that may help to deconvolute the role of BDNF polymorphisms in human brain disorders.

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11. Malara M, Lutz AK, Incearap B, Bauer HF, Cursano S, Volbracht K, Lerner JJ, Pandey R, Delling JP, Ioannidis V, Arévalo AP, von Bernhardi JE, Schön M, Bockmann J, Dimou L, Boeckers TM. SHANK3 deficiency leads to myelin defects in the central and peripheral nervous system. Cell Mol Life Sci;2022 (Jun 20);79(7):371.

Mutations or deletions of the SHANK3 gene are causative for Phelan-McDermid syndrome (PMDS), a syndromic form of autism spectrum disorders (ASDs). We analyzed Shank3Δ11(-/-) mice and organoids from PMDS individuals to study effects on myelin. SHANK3 was found to be expressed in oligodendrocytes and Schwann cells, and MRI analysis of Shank3Δ11(-/-) mice revealed a reduced volume of the corpus callosum as seen in PMDS patients. Myelin proteins including myelin basic protein showed significant temporal and regional differences with lower levels in the CNS but increased amounts in the PNS of Shank3Δ11(-/-) animals. Node, as well as paranode, lengths were increased and ultrastructural analysis revealed region-specific alterations of the myelin sheaths. In PMDS hiPSC-derived cerebral organoids we observed an altered number and delayed maturation of myelinating cells. These findings provide evidence that, in addition to a synaptic deregulation, impairment of myelin might profoundly contribute to the clinical manifestation of SHANK3 deficiency.

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12. Marsack-Topolewski CN. Comparison of Perceptions of Activities of Daily Living of Adult Children with Autism Among Three Groups of Aging Caregivers. J Appl Gerontol;2022 (Jun 22):7334648221111392.

Many aging parents care for adult children with autism spectrum disorder (ASD) and an additional loved one. This exploratory study compared differences among compound 1 (caring for an additional family member), compound 2 (caring for a typically developing minor child), and noncompound (solely caring for an adult child with ASD) caregivers on perceptions of the degree of support that care recipients need to perform specific types activities of daily living (ADL) that care recipients need assistance to complete. Each caregiver cared for at least one adult child with ASD. Results from a web-based survey completed by 320 aging caregivers were examined using Kruskal-Wallis ANOVA tests for independent samples. Compound 1 and noncompound caregivers were more likely to be involved in assisting their adult children with some ADLs when compared with compound 2 caregivers. Findings provide insight into the realities of caregivers with regard to ADL needs of their adult children.

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13. Meng J, Han L, Zheng N, Wang T, Xu H, Jiang Y, Wang Z, Liu Z, Zheng Q, Zhang X, Luo H, Can D, Lu J, Zhang YW. Microglial Tmem59 Deficiency Impairs Phagocytosis of Synapse and Leads to Autism-Like Behaviors in Mice. J Neurosci;2022 (Jun 22);42(25):4958-4979.

Synaptic abnormality is an important pathologic feature of autism spectrum disorders (ASDs) and responsible for various behavioral defects in these neurodevelopmental disorders. Microglia are the major immune cells in the brain and also play an important role in synapse refinement. Although dysregulated synaptic pruning by microglia during the brain development has been associated with ASDs, the underlying mechanism has yet to be fully elucidated. Herein, we observed that expression of Transmembrane protein 59 (TMEM59), a protein recently shown to regulate microglial function, was decreased in autistic patients. Furthermore, we found that both male and female mice with either complete or microglia-specific loss of Tmem59 developed ASD-like behaviors. Microglial TMEM59-deficient mice also exhibited enhanced excitatory synaptic transmission, increased dendritic spine density, and elevated levels of excitatory synaptic proteins in synaptosomes. TMEM59-deficient microglia had impaired capacity for synapse engulfment both in vivo and in vitro. Moreover, we demonstrated that TMEM59 interacted with the C1q receptor CD93 and TMEM59 deficiency promoted CD93 protein degradation in microglia. Downregulation of CD93 in microglia also impaired synapse engulfment. These findings identify a crucial role of TMEM59 in modulating microglial function on synapse refinement during brain development and suggest that TMEM59 deficiency may contribute to ASDs through disrupting phagocytosis of excitatory synapse and thus distorting the excitatory-inhibitory (E/I) neuronal activity balance.SIGNIFICANCE STATEMENT Microglia play an important role in synapse refinement. Dysregulated synaptic pruning by microglia during brain development has been associated with autism spectrum disorders (ASDs). However, the underlying mechanism has yet to be fully elucidated. Herein, we observe that the expression of Transmembrane protein 59 (TMEM59), an autophagy-related protein, is decreased in autistic patients. Moreover, we find ASD-like behaviors in mice with complete loss and with microglia-specific loss of Tmem59 Mechanistic studies reveal that TMEM59 deficiency in microglia impairs their synapse engulfment ability likely through destabilizing the C1q receptor CD93, thereby leading to enhanced excitatory neurotransmission and increased dendritic spine density. Our findings demonstrate a crucial role of microglial TMEM59 in early neuronal development and provide new insight into the etiology of ASDs.

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14. Remec N, Zhou J, Shida-Tokeshi J, Pickering TA, Vanderbilt DL, Smith BA. Outcomes and Hand Use of Reaching Attempts: Comparison of Infants at Risk for Developmental Disability and Infants With Typical Development. Front Psychol;2022;13:712252.

BACKGROUND: Infants at risk for developmental disabilities often show signs of motor delay. Reaching is a skill that can help us identify atypical motor trajectories in early infancy. Researchers have studied performance after onset of reaching, but none have followed infants at risk from pre-reaching to skilled reaching. AIMS: We assessed differences in reaching outcomes and hand use as reaching skill emerged in infants at risk for developmental disabilities and with typical development. METHODS AND PROCEDURES: We followed infants at risk for developmental disabilities (n = 11) and infants with typical development (n = 21) longitudinally as they developed reaching skill. Infants reached for a toy at midline while sitting in the caregiver’s lap. Video data were coded for reach outcome (miss, touch, partial grasp, and whole-hand grasp) and hand use (right, left, and bilateral). OUTCOMES AND RESULTS: Infants at risk had a larger proportion of missed reaches across visits compared to infants with typical development. Infants at risk also showed less variability in hand use when grasping over the study period. CONCLUSION AND IMPLICATIONS: Our results provide information to support early differences in reaching performance to inform identification of typical and atypical developmental trajectories. Future studies should assess how the missed reaches are different and consider other quantitative measures of movement variability in infants at risk.

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15. Rinaldi LJ, Simner J, Koursarou S, Ward J. Autistic traits, emotion regulation, and sensory sensitivities in children and adults with Misophonia. J Autism Dev Disord;2022 (Jun 21)

Misophonia is an unusually strong aversion to everyday sounds such as chewing, crunching, or breathing. Previous studies have suggested that rates of autism might be elevated in misophonia, and here we examine this claim in detail. We present a comprehensive review of the relevant literature, and two empirical studies examining children and adults with misophonia. We tested 142 children and 379 adults for traits associated with autism (i.e., attention-to-detail, attention-switching, social processing, communication, imagination, emotion regulation, and sensory sensitivity across multiple domains). Our data show that autistic traits are indeed elevated in misophonics compared to controls. We discuss our findings in relation to models of the interface between autism, sensory sensitivities, and the specific features of misophonia.

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16. Sanchez-Martin I, Magalhães P, Ranjzad P, Fatmi A, Richard F, Manh TPV, Saurin AJ, Feuillet G, Denis C, Woolf AS, Schanstra JP, Zürbig P, Caubit X, Fasano L. Haploinsufficiency of the mouse Tshz3 gene leads to kidney defects. Hum Mol Genet;2022 (Jun 22);31(12):1921-1945.

Renal tract defects and autism spectrum disorder (ASD) deficits represent the phenotypic core of the 19q12 deletion syndrome caused by the loss of one copy of the TSHZ3 gene. Although a proportion of Tshz3 heterozygous (Tshz3+/lacZ) mice display ureteral defects, no kidney defects have been reported in these mice. The purpose of this study was to characterize the expression of Tshz3 in adult kidney as well as the renal consequences of embryonic haploinsufficiency of Tshz3 by analyzing the morphology and function of Tshz3 heterozygous adult kidney. Here, we described Tshz3 expression in the smooth muscle and stromal cells lining the renal pelvis, the papilla and glomerular endothelial cells (GEnCs) of the adult kidney as well as in the proximal nephron tubules in neonatal mice. Histological analysis showed that Tshz3+/lacZ adult kidney had an average of 29% fewer glomeruli than wild-type kidney. Transmission electron microscopy of Tshz3+/lacZ glomeruli revealed a reduced thickness of the glomerular basement membrane and a larger foot process width. Compared to wild type, Tshz3+/lacZ mice showed lower blood urea, phosphates, magnesium and potassium at 2 months of age. At the molecular level, transcriptome analysis identified differentially expressed genes related to inflammatory processes in Tshz3+/lacZ compare to wild-type (control) adult kidneys. Lastly, analysis of the urinary peptidome revealed 33 peptides associated with Tshz3+/lacZ adult mice. These results provide the first evidence that in the mouse Tshz3 haploinsufficiency leads to cellular, molecular and functional abnormalities in the adult mouse kidney.

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17. Schaaf ZA, Tat L, Cannizzaro N, Green R, Rülicke T, Hippenmeyer S, Zarbalis KS. WDFY3 mutation alters laminar position and morphology of cortical neurons. Mol Autism;2022 (Jun 22);13(1):27.

BACKGROUND: Proper cerebral cortical development depends on the tightly orchestrated migration of newly born neurons from the inner ventricular and subventricular zones to the outer cortical plate. Any disturbance in this process during prenatal stages may lead to neuronal migration disorders (NMDs), which can vary in extent from focal to global. Furthermore, NMDs show a substantial comorbidity with other neurodevelopmental disorders, notably autism spectrum disorders (ASDs). Our previous work demonstrated focal neuronal migration defects in mice carrying loss-of-function alleles of the recognized autism risk gene WDFY3. However, the cellular origins of these defects in Wdfy3 mutant mice remain elusive and uncovering it will provide critical insight into WDFY3-dependent disease pathology. METHODS: Here, in an effort to untangle the origins of NMDs in Wdfy3(lacZ) mice, we employed mosaic analysis with double markers (MADM). MADM technology enabled us to genetically distinctly track and phenotypically analyze mutant and wild-type cells concomitantly in vivo using immunofluorescent techniques. RESULTS: We revealed a cell autonomous requirement of WDFY3 for accurate laminar positioning of cortical projection neurons and elimination of mispositioned cells during early postnatal life. In addition, we identified significant deviations in dendritic arborization, as well as synaptic density and morphology between wild type, heterozygous, and homozygous Wdfy3 mutant neurons in Wdfy3-MADM reporter mice at postnatal stages. LIMITATIONS: While Wdfy3 mutant mice have provided valuable insight into prenatal aspects of ASD pathology that remain inaccessible to investigation in humans, like most animal models, they do not a perfectly replicate all aspects of human ASD biology. The lack of human data makes it indeterminate whether morphological deviations described here apply to ASD patients or some of the other neurodevelopmental conditions associated with WDFY3 mutation. CONCLUSIONS: Our genetic approach revealed several cell autonomous requirements of WDFY3 in neuronal development that could underlie the pathogenic mechanisms of WDFY3-related neurodevelopmental conditions. The results are also consistent with findings in other ASD animal models and patients and suggest an important role for WDFY3 in regulating neuronal function and interconnectivity in postnatal life.

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18. Schwartz A, Hwang IT. Supporting young adults with intellectual/developmental disabilities to deliver a peer mentoring intervention: Evaluating fidelity and resources required. J Appl Res Intellect Disabil;2022 (Jun 22)

BACKGROUND: Peer-delivered interventions are a best practice in mental health, yet no such intervention exists for young adults (YA) with intellectual/developmental disabilities with co-occurring mental health conditions. We evaluated YA with intellectual/developmental disabilities’ ability to deliver a novel peer mentoring intervention with fidelity and the supports received. METHODS: We coded audio-recorded mentoring sessions to evaluate if 4 mentors adhered to ‘content’ (e.g., psychoeducation) and ‘quality’ (e.g., validation) fidelity criteria (codes: yes/no). We conducted content analysis of mentor support logs and interviews with mentors’, mentors’ parents and teachers to describe the supports mentors received. RESULTS: Average fidelity for content criteria (M = 73.3%) was higher than quality criteria (M = 60.0%). Weekly support addressed logistics, delivering content, interpersonal interactions, emotional support, professionalism, and organisation. Family members and teachers rarely provided additional support. CONCLUSIONS: With support, YA can deliver a peer mentoring intervention addressing mental health. Additional training activities will be developed to improve fidelity.

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19. Shiota Y, Hirosawa T, Yoshimura Y, Tanaka S, Hasegawa C, Iwasaki S, Sano M, An KM, Yokoyama S, Kikuchi M. Effect of CNTNAP2 polymorphism on receptive language in children with autism Spectrum disorder without language developmental delay. Neuropsychopharmacol Rep;2022 (Jun 22)

AIM: The receptive language ability of individuals with autism spectrum disorder (ASD) seems to lag behind expressive language ability. Several autism-related genes may influence this developmental delay. Polymorphism of one such gene, namely, the contactin-associated protein-like 2 gene (CNTNAP2), affects receptive language in individuals with language delay. However, the association between CNTNAP2 polymorphism and receptive language in individuals with no language delay remains unclear. METHODS: We included 59 children with ASD and 57 children with typical development in this study and investigated this association using coarse-grained exact matching. RESULTS: We present the first evidence of an association between CNTNAP2 rs2710102 (A-allele carrier) and reduced receptive language ability in children with ASD whose language development was not delayed. Similarly, among children with typical development, A-allele carriers had lower receptive language ability, but the difference was non-significant. CONCLUSIONS: It is possible that the effect of rs2710102 on receptive language ability is larger in the presence of autism-related genes. Consequently, we speculate that the effect of rs2710102 on receptive language ability would be exerted in combination with other genes. These findings provide new insights into the genetic interactions between mutations associated with common language disorders and ASD and identify molecular mechanisms and risk alleles that contribute to receptive vocabulary. These findings also provide practical guidance in terms of providing candidate genetic markers that may provide opportunities for targeted early intervention to stratify risk and improve prognosis for poor receptive language development in children with ASD.

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20. Torres A, Montiel-Nava C. Clinical and demographic differences by sex in autistic Venezuelan children: A cross-sectional study. Res Dev Disabil;2022 (Jun 18);128:104276.

BACKGROUND: Sex differences in symptom severity and adaptive function in children with ASD have been historically inconsistent and studies are predominantly from American- and European-residing populations. Alike, there is limited information on the complex interplay between sex, intelligence, adaptive function, and autism symptom severity; this is crucial to identify given their predictive value for health outcomes in autism AIM: This study aimed to identify sex differences in autism symptom severity and adaptive function in a sample of Venezuelan children. METHOD: One-hundred-and-three Venezuelan children ages 3-7 completed a comprehensive assessment for symptom severity, adaptive functioning, and intelligence. RESULTS: Sex differences were not present in any autism diagnostic domain or adaptive function.Symptom severity was not a significant predictor for adaptive function, which contrasts with studies sampling American children. CONCLUSION: This study corroborates other findings based on non-American children, where symptom severity was not a function of adaptive function. Awareness of the interplay of culture, sex-related standards, and autism symptomatology will result in better identification and diagnosis of autism regardless of sex or cultural background. What this paper adds? This paper aids the current literature on sex difference on both autism symptom severity and adaptive function. It also provides a snapshot of the relationship between symptom severity, adaptive function, and other psychological variables that influence the outcome of children with ASD.

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21. Wolbert F, Nikoleit K, Steinbrink M, Luebbert C, Sadowski G. The Shelf Life of ASDs: 1. Measuring the Crystallization Kinetics at Humid Conditions. Mol Pharm;2022 (Jun 21)

Amorphous solid dispersions (ASDs), where an active pharmaceutical ingredient (API) is dissolved in a polymer, are a favored formulation technique to achieve sufficient bioavailability of poorly water-soluble APIs. The shelf life of such ASDs is often limited by API crystallization. Crystallization depends strongly on the storage conditions (relative humidity and temperature) and the polymer selected for generating the ASD. Determining the crystallization kinetics of ASDs under various conditions requires suitable analytical methods. In this work, two different analytical methods were compared and cross-validated: The first builds on water-sorption measurements combined with thermodynamic predictions ( Eur. J. Pharm. Biopharm. 2018, 127, 183-193, DOI: 10.1016/j.toxrep.2018.11.002), whereas the second applies Raman spectroscopy. Using the two independent methods, factors influencing the crystallization kinetics of ASDs containing the API griseofulvin were investigated quantitatively. It was found that crystallization kinetics increases with increasing temperature and relative humidity. Additionally, the influence of different polymers (poly(vinylpyrrolidone-co-vinyl acetate) and Soluplus) on crystallization kinetics were investigated. The experimentally obtained crystallization kinetics were described using the Johnson-Mehl-Avrami-Kolmogorov model and are the basis for future shelf life predictions at desired storage conditions.

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22. Zhang A, Sokolova I, Domissy A, Davis J, Rao L, Hana Utami K, Wang Y, Hagerman RJ, Pouladi MA, Sanna P, Boland MJ, Loring JF. Maturation Delay of Human GABAergic Neurogenesis in Fragile X Syndrome Pluripotent Stem Cells. Stem Cells Transl Med;2022 (Jun 22);11(6):613-629.

Fragile X Syndrome (FXS), the leading monogenic cause of intellectual disability and autism spectrum disorder, is caused by expansion of a CGG trinucleotide repeat in the 5′-UTR of the Fragile X Mental Retardation-1 (FMR1) gene. Epigenetic silencing of FMR1 results in loss of the Fragile X Mental Retardation Protein (FMRP). Although most studies to date have focused on excitatory neurons, recent evidence suggests that GABAergic inhibitory networks are also affected. To investigate human GABAergic neurogenesis, we established a method to reproducibly derive inhibitory neurons from multiple FXS and control human pluripotent stem cell (hPSC) lines. Electrophysiological analyses suggested that the developing FXS neurons had a delay in the GABA functional switch, a transition in fetal development that converts the GABAA channel’s function from depolarization to hyperpolarization, with profound effects on the developing brain. To investigate the cause of this delay, we analyzed 14 400 single-cell transcriptomes from FXS and control cells at 2 stages of GABAergic neurogenesis. While control and FXS cells were similar at the earlier time point, the later-stage FXS cells retained expression of neuroblast proliferation-associated genes and had lower levels of genes associated with action potential regulation, synapses, and mitochondria compared with controls. Our analysis suggests that loss of FMRP prolongs the proliferative stage of progenitors, which may result in more neurons remaining immature during the later stages of neurogenesis. This could have profound implications for homeostatic excitatory-inhibitory circuit development in FXS, and suggests a novel direction for understanding disease mechanisms that may help to guide therapeutic interventions.

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23. Zuniga-Kennedy M, Davoren M, Shuffrey LC, Luna RA, Savidge T, Prasad V, Anderson GM, Veenstra-VanderWeele J, Williams KC. Intestinal Predictors of Whole Blood Serotonin Levels in Children With or Without Autism. J Autism Dev Disord;2022 (Jun 21)

Hyperserotonemia, or elevated levels of whole blood serotonin (WB5-HT), was the first biomarker linked to autism spectrum disorder (ASD). Despite numerous studies investigating the etiology of hyperserotonemia, results have been inconsistent. Recent findings suggest a relationship between the immune system and hyperserotonemia. The current study investigated whether intestinal 5-HT levels, 5-HT gene expression, or intestinal cell types predict WB5-HT. Participants included thirty-one males aged 3-18 who were classified into one of three groups: ASD and functional GI issues, typically developing with GI issues, and typically developing without GI issues. Samples from a lower endoscopy were analyzed to examine the pathways in predicting WB-5HT. Results demonstrated an association between T-Lymphocytes and WB5-HT.

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