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      Progranulin improves neural development via the PI3K/Akt/GSK-3β pathway in the cerebellum of a VPA-induced rat model of ASD

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          Abstract

          Autism spectrum disorder (ASD) is a neurodevelopmental disease featuring social interaction deficits and repetitive/stereotyped behaviours; the prevalence of this disorder has continuously increased. Progranulin (PGRN) is a neurotrophic factor that promotes neuronal survival and differentiation. However, there have not been sufficient studies investigating its effect in animal models of autism. This study investigated the effects of PGRN on autistic phenotypes in rats treated with valproic acid (VPA) and assessed the underlying molecular mechanisms. PGRN was significantly downregulated in the cerebellum at postnatal day 14 (PND14) and PND35 in VPA-exposed rats, which simultaneously showed defective social preference, increased repetitive behaviours, and uncoordinated movements. When human recombinant PGRN (r-PGRN) was injected into the cerebellum of newborn ASD model rats (PND10 and PND17), some of the behavioural defects were alleviated. r-PGRN supplementation also reduced cerebellar neuronal apoptosis and rescued synapse formation in ASD rats. Mechanistically, we confirmed that PGRN protects neurodevelopment via the PI3K/Akt/GSK-3β pathway in the cerebellum of a rat ASD model. Moreover, we found that prosaposin (PSAP) promoted the internalisation and neurotrophic activity of PGRN. These results experimentally demonstrate the therapeutic effects of PGRN on a rat model of ASD for the first time and provide a novel therapeutic strategy for autism.

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          Ror2 signaling regulates Golgi structure and transport through IFT20 for tumor invasiveness

          Signaling through the Ror2 receptor tyrosine kinase promotes invadopodia formation for tumor invasion. Here, we identify intraflagellar transport 20 (IFT20) as a new target of this signaling in tumors that lack primary cilia, and find that IFT20 mediates the ability of Ror2 signaling to induce the invasiveness of these tumors. We also find that IFT20 regulates the nucleation of Golgi-derived microtubules by affecting the GM130-AKAP450 complex, which promotes Golgi ribbon formation in achieving polarized secretion for cell migration and invasion. Furthermore, IFT20 promotes the efficiency of transport through the Golgi complex. These findings shed new insights into how Ror2 signaling promotes tumor invasiveness, and also advance the understanding of how Golgi structure and transport can be regulated.
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            Motor coordination in autism spectrum disorders: a synthesis and meta-analysis.

            Are motor coordination deficits an underlying cardinal feature of Autism Spectrum Disorders (ASD)? Database searches identified 83 ASD studies focused on motor coordination, arm movements, gait, or postural stability deficits. Data extraction involved between-group comparisons for ASD and typically developing controls (N = 51). Rigorous meta-analysis techniques including random effects models, forest and funnel plots, I (2), publication bias, fail-safe analysis, and moderator variable analyses determined a significant standardized mean difference effect equal to 1.20 (SE = 0.144; p <0.0001; Z = 10.49). This large effect indicated substantial motor coordination deficits in the ASD groups across a wide range of behaviors. The current overall findings portray motor coordination deficits as pervasive across diagnoses, thus, a cardinal feature of ASD.
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              The Changing Epidemiology of Autism Spectrum Disorders

              Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with lifelong impacts. Genetic and environmental factors contribute to ASD etiology, which remains incompletely understood. Research on ASD epidemiology has made significant advances in the past decade. Current prevalence is estimated to be at least 1.5% in developed countries, with recent increases primarily among those without comorbid intellectual disability. Genetic studies have identified a number of rare de novo mutations and gained footing in the areas of polygenic risk, epigenetics, and gene-by-environment interaction. Epidemiologic investigations focused on nongenetic factors have established advanced parental age and preterm birth as ASD risk factors, indicated that prenatal exposure to air pollution and short interpregnancy interval are potential risk factors, and suggested the need for further exploration of certain prenatal nutrients, metabolic conditions, and exposure to endocrine-disrupting chemicals. We discuss future challenges and goals for ASD epidemiology as well as public health implications.
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                Author and article information

                Contributors
                chendi@cqmu.edu.cn
                Journal
                Transl Psychiatry
                Transl Psychiatry
                Translational Psychiatry
                Nature Publishing Group UK (London )
                2158-3188
                22 March 2022
                22 March 2022
                2022
                : 12
                : 114
                Affiliations
                [1 ]GRID grid.203458.8, ISNI 0000 0000 8653 0555, Cerebrovascular Diseases Laboratory, Institute of Neuroscience, , Chongqing Medical University, ; Chongqing, 400016 China
                [2 ]GRID grid.24696.3f, ISNI 0000 0004 0369 153X, Advanced Innovation Center for Human Brain Protection, , Capital Medical University, ; Beijing, 100070 China
                [3 ]GRID grid.24696.3f, ISNI 0000 0004 0369 153X, China National Clinical Research Center for Neurological Diseases, , Beijing Tiantan Hospital, Capital Medical University, ; Beijing, 100070 China
                [4 ]Present Address: Qujiang No. 2 Middle School, Xi’an, 710000 China
                [5 ]GRID grid.452642.3, Present Address: Department of Nuclear Medicine, , Nanchong Central Hospital, The Second Clinical College of North Sichuan Medical College, ; Nanchong, 637000 China
                Author information
                http://orcid.org/0000-0002-5528-1378
                Article
                1875
                10.1038/s41398-022-01875-4
                8941112
                35318322
                a085bb3e-84f6-4e8e-92c3-2cf2dfdbb964
                © The Author(s) 2022

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 16 November 2021
                : 22 February 2022
                : 24 February 2022
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100007957, Chongqing Municipal Education Commission (Chongqing Municipality Education Commission);
                Award ID: KJQN202000410
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);
                Award ID: 81801506
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100004374, Chongqing Medical University (CQMU);
                Award ID: SRIEP202003
                Award Recipient :
                Categories
                Article
                Custom metadata
                © The Author(s) 2022

                Clinical Psychology & Psychiatry
                molecular neuroscience,pharmacodynamics
                Clinical Psychology & Psychiatry
                molecular neuroscience, pharmacodynamics

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