Development Of Neurological Disorders Research Articles

A national survey of iodine nutrition in children aged 3-6 years in China and its relationship with children's physical growth.

Iodine, an essential trace element for the human body, plays a pivotal role in sustaining health. Malnutrition has emerged as a pressing public health concern, posing a significant threat to human well-being. Iodine deficiency poses a substantial threat to the development of children, potentially leading to neurological developmental disorders and mental retardation. Conversely, excessive iodine intake can result in structural and functional abnormalities in the thyroid gland. In this study, we selected children aged 3-6 years through a stratified cluster sampling approach in six regions across China to explore the correlation between iodine nutrition and their physical growth. A total of 5920 preschool children participated in this study, with a median urinary iodine concentration (UIC) of 177.33 [107.06, 269.92] μg/L. Among these children, 250 (4.2%) exhibited stunting, 180 (3.0%) were underweight, 198 (3.3%) experienced wasting, 787 (3.3%) were overweight and 414 (7.0%) were classified as obese. The multivariate linear regression revealed that UIC exhibited a positive correlation with body mass index z-Score (BMIZ) in overweight children (β = 0.038; 95% CI: 0.001, 0.075). In normally growing children, the associations between UIC and height-for-age z-score, weight-for-age z-score and BMIZ displayed nonlinear patterns. Our findings suggest that iodine nutrition is adequate for Chinese children aged 3-6 years. Furthermore, iodine nutrition is intricately linked to the growth and development of these children. Consequently, it is imperative to implement decisive measures to prevent both iodine deficiency and excess.

Exploring the Effects of Repetitive Transcranial Magnetic Stimulation on Comorbid Sleep Disorders in Preschool Children with Attention-Deficit Hyperactivity Disorder.

Attention-deficit hyperactivity disorder (ADHD) is one of the most common neurological developmental disorders in children, and sleep disorders (SDs) are a common comorbidity in children with ADHD. There are currently no pharmacological treatment options for SD in children with ADHD of preschool age (4-6 years). Repetitive transcranial magnetic stimulation (rTMS) is a novel, non-invasive neuromodulation technique. This study explores the effectiveness of rTMS for comorbid SDs in preschool-aged children with ADHD. Thirty-five children of preschool age with ADHD and comorbid SDs were recruited for this study. The children were divided into a parent behavior management training (PBMT) group (n = 19) and a repetitive transcranial magnetic stimulation combined with parent behavior management training group (n = 16). Both groups underwent 8 weeks of treatment. The children's SD scores were assessed using the Chinese Children's Sleep Habits Questionnaire, were measured before the start, at the end, and 4 weeks after the end of the intervention, and were used to measure the effects. Within-group differences were compared using a repeated-measures analysis of variance, and between-group differences were compared using an independent samples t-test and Mann-Whitney U-test. Both the PBMT group and the rTMS combined with the PBMT group significantly improved the SDs of preschool-aged children with ADHD (P < .001), but the effect of the intervention was more pronounced in the rTMS combined with the PBMT group (P < .001) and lasted longer than the PBMT group (P = .004). Repetitive transcranial magnetic stimulation is a promising non-pharmacological therapy to improve SD in preschool-aged children with ADHD.

Future Prospects for Assessment of General Movements in Developing Countries

The well-being of children is crucial for a nation’s demographic, economic, and intellectual prospects. Developing countries face an increasing number of children with disabilities, primarily attributed to congenital developmental defects, neurological disorders, and other health issues. Neurological disorders pose significant challenges to realizing the full potential of children and society. Early intervention is essential for improving functional outcomes in infants with neurological impairments. General Movements (GM) assessment, a predictor of subsequent neurological outcomes, plays a vital role in early detection. However, its widespread implementation in developing countries is limited. This article explores the history of GM assessment, its current state in developing countries, and the potential for mobile applications to revolutionize early assessments and interventions in developing countries.

Brain organoids: A revolutionary tool for modeling neurological disorders and development of therapeutics.

Brain organoids are self-organized, three-dimensional (3D) aggregates derived from pluripotent stem cells that have cell types and cellular architectures resembling those of the developing human brain. The current understanding of human brain developmental processes and neurological disorders has advanced significantly with the introduction of this in vitro model. Brain organoids serve as a translational link between two-dimensional (2D) cultures and in vivo models which imitate the neural tube formation at the early and late stages and the differentiation of neuroepithelium with whole-brain regionalization. In addition, the generation of region-specific brain organoids made it possible to investigate the pathogenic and etiological aspects of acquired and inherited brain disease along with drug discovery and drug toxicity testing. In this review article, we first summarize an overview of the existing methods and platforms used for generating brain organoids and their limitations and then discuss the recent advancement in brain organoid technology. In addition, we discuss how brain organoids have been used to model aspects of neurodevelopmental and neurodegenerative diseases, including autism spectrum disorder (ASD), Rett syndrome, Zika virus-related microcephaly, Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD).

A Rare Case of Arnold Chiari Malformation Evident after a Streptococcal Throat Infection in a Young Female

Arnold Chiari malformation is a rare neurological developmental disorder that presents at birth. No such cases have been reported in support of microbial infections causing Chiari malformation yet there is evidence how microorganisms can lead to brain abscess, brain empyema, and meningoencephalitis.

Agomelatine: A Potential Multitarget Compound for Neurodevelopmental Disorders.

Agomelatine (AGM) is one of the latest atypical antidepressants, prescribed exclusively for the treatment of depression in adults. AGM belongs to the pharmaceutical class of melatonin agonist and selective serotonin antagonist ("MASS"), as it acts both as a selective agonist of melatonin receptors MT1 and MT2, and as a selective antagonist of 5-HT2C/5-HT2B receptors. AGM is involved in the resynchronization of interrupted circadian rhythms, with beneficial effects on sleep patterns, while antagonism on serotonin receptors increases the availability of norepinephrine and dopamine in the prefrontal cortex, with an antidepressant and nootropic effect. The use of AGM in the pediatric population is limited by the scarcity of data. In addition, few studies and case reports have been published on the use of AGM in patients with attention deficit and hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Considering this evidence, the purpose of this review is to report the potential role of AGM in neurological developmental disorders. AGM would increase the expression of the cytoskeleton-associated protein (ARC) in the prefrontal cortex, with optimization of learning, long-term memory consolidation, and improved survival of neurons. Another important feature of AGM is the ability to modulate glutamatergic neurotransmission in regions associated with mood and cognition. With its synergistic activity a melatoninergic agonist and an antagonist of 5-HT2C, AGM acts as an antidepressant, psychostimulant, and promoter of neuronal plasticity, regulating cognitive symptoms, resynchronizing circadian rhythms in patients with autism, ADHD, anxiety, and depression. Given its good tolerability and good compliance, it could potentially be administered to adolescents and children.

The effectiveness of compassion-focused therapy in helping attitudes and work-related flow of autism child mentors

Introduction: Autism spectrum disorder (ASD) is a developmental neurological disorder that threatens individuals’ social interactions and communication by limiting their activities and personal interests. Aim: The present study aimed to assess the effectiveness of compassion-focused therapy in helping attitudes and the work-related flow of autism child mentors in the rehabilitation centers of Mazandaran, Iran. Method: The research method was a quasi-experimental study with a pretest-posttest, control group, follow-up design. The sample population included all male and female mentors of autistic children in the rehabilitation centers of Mazandaran in 2020. In total, 30 mentors were selected by voluntary sampling and divided into a test and a control group by simple random sampling (15 per group). Eight sessions of therapeutic intervention were provided to the study groups. Post-test and follow-ups were conducted for both groups after therapy. Data were collected using Nickell’s Helping Attitude Scale (1998) and Bakker’s Work-Related Flow Scale (2008). Data analysis covariance analysis was performed in SPSS version 25. Results: Findings demonstrated a significant difference between the mean scores of the test and control groups regarding helping attitudes and work-related flow among autism child mentors in the post-test stage (p&lt;0.01). Further, compassion-focused therapy was effective in helping attitudes (0.84) and work-related flow (0.91) of autism child mentors. Conclusion: Results indicate that compassion-focused therapy can potentially improve helping attitudes and the work-related flow of autism mentors in different situations. Therefore, incorporating this educational intervention into the rehabilitation agenda of these mentors appears to be quite beneficial.

The global prevalence of ADHD in children and adolescents: a systematic review and meta-analysis

BackgroundAttention-Deficit / Hyperactivity Disorder is a developmental neurological disorder that has three basic characteristics: Attention Deficit, Hyperactivity, and impulsivity. This study aimed to investigate the prevalence of ADHD in children and adolescents.MethodsThis investigation was carried out using the meta-analysis method under PRISMA guidelines. Until October 2020, the articles were gathered by scanning PubMed, Scopus, WOS, and Science Direct databases. The second version of Comprehensive Meta-Analysis software was used to run analyses after extracting data from chosen papers. At a significance level of 0.05, the I2 test was used to analyze study heterogeneity, and the Egger test was used to assess publication bias.ResultsThis analysis includes 61 cross-sectional research, with 53 research used to determine the prevalence of ADHD in children, 7.6% of 96,907 children aged 3 to 12 years had ADHD (95% confidence interval: 6.1–9.4%), and 5.6% of teenagers aged 12 to 18 years have ADHD (95% confidence interval: 4.8-7%). The prevalence of ADHD in children and adolescents according to the DSM-V criterion is also higher than previous diagnostic criteria, according to studies.ConclusionThe findings of this study based on meta-analysis show the high prevalence of attention deficit hyperactivity disorder (ADHD). The findings of this study demonstrate the importance of management and policy in the treatment and control of ADHD in children and adolescents.

A retrospective analysis of MS/MS screening for IEM in high-risk areas

Inborn errors of metabolism (IEM) can lead to severe motor and neurological developmental disorders and even disability and death in children due to untimely treatment. In this study, we used tandem mass spectrometry (MS/MS) for primary screening and recall of those with positive primary screening for rescreening. Further diagnosis was based on biochemical tests, imaging and clinical presentation as well as accurate genetic testing using multi-gene panel with high-throughput sequencing of 130 IEM-related genes. The screening population was 16,207 newborns born between July 1, 2019, and December 31, 2021. Based on the results, 8 newborns were diagnosed with IEM, constituting a detection rate of 1:2,026. Phenylketonuria was the most common form of IEM. In addition, seven genes associated with IEM were detected in these eight patients. All eight patients received standardized treatment starting in the neonatal period, and the follow-up results showed good growth and development. Therefore, our study suggests that MS/MS rescreening for IEM pathogenic variants in high-risk areas, combined with a sequencing validation strategy, can be highly effective in the early detection of affected children. This strategy, combined with early intervention, can be effective in preventing neonatal morbidity and improving population quality.

The use of data independent acquisition based proteomic analysis and machine learning to reveal potential biomarkers for autism spectrum disorder

Autism spectrum disorder (ASD) is a complex neurological developmental disorder in children, and is associated with social isolation and restricted interests. The etiology of this disorder is still unknown. There is neither any confirmed laboratory test nor any effective therapeutic strategy to diagnose or cure it. We performed data independent acquisition (DIA) and multiple reaction monitoring (MRM) analysis of plasma from children with ASD and controls. The result showed that 45 differentially expressed proteins (DEPs) were identified between autistic subjects and controls. Among these, only one DEP was down-regulated in ASD; other DEPs were up-regulated in ASD children's plasma. These proteins are found associated with complement and coagulation cascades, vitamin digestion and absorption, cholesterol metabolism, platelet degranulation, selenium micronutrient network, extracellular matrix organization and inflammatory pathway, which have been reported to be related to ASD. After MRM verification, five key proteins in complement pathway (PLG, SERPINC1, and A2M) and inflammatory pathway (CD5L, ATRN, SERPINC1, and A2M) were confirmed to be significantly up-regulated in ASD group. Through the screening of machine learning model and MRM verification, we found that two proteins (biotinidase and carbonic anhydrase 1) can be used as early diagnostic markers of ASD (AUC = 0.8, p = 0.0001). SignificanceASD is the fastest growing neurodevelopmental disorder in the world and has become a major public health problem worldwide. Its prevalence has been steadily increasing, with a global prevalence rate of 1%. Early diagnosis and intervention can achieve better prognosis. In this study, data independent acquisition (DIA) and multiple reaction monitoring (MRM) analysis was applied to analyze the plasma proteome of ASD patients (31 (±5) months old), and 378 proteins were quantified. 45 differentially expressed proteins (DEPs) were identified between the ASD group and the control group. They mainly were associated with platelet degranulation, ECM proteoglycar, complement and coagulation cascades, selenium micronutrient network, regulation of insulin-like growth factor (IGF) transport and uptake by insulin-like growth factor binding proteins (IGFBPs), cholesterol metabolism, vitamin metabolism, and inflammatory pathway. Through the integrated machine learning methods and the MRM verification of independent samples, it is considered that biotinidase and carbon anhydrase 1 have the potential to become biomarkers for the early diagnosis of ASD. These results complement proteomics database of the ASD patients, broaden our understanding of ASD, and provide a panel of biomarkers for the early diagnosis of ASD.

Analysis of Mouse Brain Sections by Live-cell Time-lapse Confocal Microscopy.

The developing cerebral cortex of mammals is generated from nascent pyramidal neurons, which radially migrate from their birthplace in the ventral part of the neural tube to the cortical surface. Subtle aberrations in this process may cause significant changes in cortical structure and lead to developmental neurological disorders. During pyramidal neuron migration, we recently showed that the migrating neuron, which bypasses its last preceding neuron, is critical for its proper positioning and contributes to cerebral cortex thickness. Studying this process requires an imaging system with single-cell resolution and a prolonged observation window. Therefore, we built a system to maintain an organotypic brain slice on the stage of a Leica SP5 confocal microscope, which facilitated high-resolution imaging over a 12-hour time-lapse observation period of cellular events during neuron migration. Here, we share our protocol along with guidelines for overcoming difficulties during the setup. This protocol facilitates the observation of, but is not limited to, neurodevelopmental and pathological processes occurring during neuron migration.

Psychometric Properties of the Persian Version of the 47-item Mobility Questionnaire in Children with Cerebral Palsy

Background: Cerebral palsy (CP) is a developmental-neurological disorder that is common in children. As children with CP have several problems and limitations regarding locomotion and mobility, accessing an assessment tool for measuring mobility is crucial. Objectives: This study aims to evaluate the psychometric properties of the Persian version of the 47-item mobility questionnaire in Iranian children with cerebral palsy between 6 and 12 years of age in Tehran, Iran September 2019. Methods: In this psychometric study, 202 participants (84 girls and 118 boys, with a mean age of 95.92 months ± 23.73), 15 parents, and nine occupational therapists participated. A multistage sampling method was used. Content, construct, convergent, and face validity were estimated. Internal validity and test-retest reliability were studied, too. The convergent validity of MobQ was studied according to the gross motor functions classification scale (GMFCS). Results: The results showed that all items of the 47-item mobility questionnaire had a content validity higher than the minimum acceptable value (0.78 for CVR and 0.79 for CVI). Further, based on the opinions of 9 experts and 15 persons completing the questionnaire, an understandable and unambiguous questionnaire was reported regarding face validity. The evaluation of the intragroup correlation coefficient's reliability in this study also showed that ICC was 0.998 and Cronbach's alpha coefficient value was 0.996. A Spearman correlation coefficient of 0.937 was obtained to assess the convergent validity of the Persian version of the "Mobility Questionnaire" and the Gross Motor Skills Classification Scale. Conclusions: The results of this study, therefore, showed that the Persian version of the 47-item mobility questionnaire had good psychometric characteristics for children with CP between 6 and 12 years of age. Therefore, this questionnaire can be suitable for measuring children's mobility in research and clinical studies.

A Preliminary Study of Telepractice Prelinguistic Milieu Teaching for Children with Autism Spectrum Disorders

Background: Autism Spectrum Disorder (ASD) is a developmental neurological disorder characterized by impaired social interactions. The aim of study was to examine the telepractice Prelinguistic Milieu Teaching (PMT) for ASD children.&#x0D; Methods: This study followed a pretest–posttest design. 11 mothers of children with ASD aged 26-71 months (mean=47.09 months, SD=14) were included. Mothers were given the necessary training on the PMT for 12 one-hour weekly sessions, through the WhatsApp software. The self-reported McArthur-Bates communication development inventories (CDIs) was the main outcome measure. The data were analyzed using Wilcoxon test.&#x0D; Results: Mean scores of expressive and perceptive words significantly improved after treatment with large effects sizes (Cohen’s d &gt;0.8). The activity and gestures section scores showed significant improvements after treatment in the areas of communication gestures, play and routines, working with objects and imitation of adult activities (Cohen’s d &gt;0.8).&#x0D; Conclusion: This study provides preliminary evidence that the telepractice of PMT is effective for children with autism spectrum disorder. Further study with a rigours design is warranted.

Genomic Basis for Individual Differences in Susceptibility to the Neurotoxic Effects of Diesel Exhaust.

Air pollution is a known environmental health hazard. A major source of air pollution includes diesel exhaust (DE). Initially, research on DE focused on respiratory morbidities; however, more recently, exposures to DE have been associated with neurological developmental disorders and neurodegeneration. In this study, we investigated the effects of sub-chronic inhalation exposure to DE on neuroinflammatory markers in two inbred mouse strains and both sexes, including whole transcriptome examination of the medial prefrontal cortex. We exposed aged male and female C57BL/6J (B6) and DBA/2J (D2) mice to DE, which was cooled and diluted with HEPA-filtered compressed air for 2 h per day, 5 days a week, for 4 weeks. Control animals were exposed to HEPA-filtered air on the same schedule as DE-exposed animals. The prefrontal cortex was harvested and analyzed for proinflammatory cytokine gene expression (Il1β, Il6, Tnfα) and transcriptome-wide response by RNA-seq. We observed differential cytokine gene expression between strains and sexes in the DE-exposed vs. control-exposed groups for Il1β, Tnfα, and Il6. For RNA-seq, we identified 150 differentially expressed genes between air and DE treatment related to natural killer cell-mediated cytotoxicity per Kyoto Encyclopedia of Genes and Genomes pathways. Overall, our data show differential strain-related effects of DE on neuroinflammation and neurotoxicity and demonstrate that B6 are more susceptible than D2 to gene expression changes due to DE exposures than D2. These results are important because B6 mice are often used as the default mouse model for DE studies and strain-related effects of DE neurotoxicity warrant expanded studies.

The role of intellectual disability with autism spectrum disorder and the documented cooccurring conditions: A population-based study.

Previous research has identified that patterns of cooccurring conditions (CoCs) associated with autism spectrum disorder (ASD) differ based on the presence of intellectual disability (ID). This study explored the association of documented CoCs among 8-year-old children with ASD and ID (ASD+ID, n=2416) and ASD without ID (ASD-ID, n=5372) identified by the Autism and Developmental Disabilities Monitoring Network, surveillance years (SYs) 2012 and 2014. After adjusting for demographic variables, record source, surveillance site, and SY, children with ASD+ID, as compared with children with ASD-ID, were more likely to have histories of nonspecific developmental delays and neurological disorders documented in their records but were less likely to have behavioral and psychiatric disorders. ID plays a key role on how children with ASD would experience other CoCs. Our results emphasize how understanding the pattern of CoCs in ASD+ID and ASD-ID can inform comprehensive and multidisciplinary approaches in assessment and management of children in order to develop targeted interventions to reduce possible CoCs or CoCs-related impairments.

Novel Ensemble Model Recommendation Approach for the Detection of Dyslexia.

There are a large number of neurological disorders being explored regarding possible management and treatment, with dyslexia being one of the disorders that affect children at the onset of their learning process. Dyslexia is a developmental neurological disorder that prevents children from learning. The disorder has a prevalence of around 10% across the globe, as reported by most of the literature on dyslexia. The early detection and management of dyslexia is one of the primary pursuits among different research. One such domain that leads this pursuit of the early detection and management of dyslexia is artificial intelligence. With so much effort being expended to explore the applicability of artificial intelligence to address the problem of dyslexia detection, in this work, an ensemble model for the early detection of dyslexia is proposed and recommend. The work experimentally considers a pool of ensembles with rigorous validation on a large sized dataset. The final ensemble model recommendation for detection is expressed after evaluating all of the ensemble frameworks based on a number of evaluation parameters. Our experiments reveal that the subspace discriminant ensemble showed superiority for the detection of dyslexia with an accuracy of 90% on five-fold cross validation with the least training time. An accuracy of 90.90% was achieved using boosted trees with a holdout validation of 30%, while with no validation the subspace K-Nearest Neighbor (KNN) outperformed the other ensembles with an accuracy of 99.9%.

Changes to the Gut Microbiome in Young Children Showing Early Behavioral Signs of Autism.

The human gut microbiome has increasingly been associated with autism spectrum disorder (ASD), which is a neurological developmental disorder, characterized by impairments to social interaction. The ability of the gut microbiota to signal across the gut-brain-microbiota axis with metabolites, including short-chain fatty acids, impacts brain health and has been identified to play a role in the gastrointestinal and developmental symptoms affecting autistic children. The fecal microbiome of older children with ASD has repeatedly shown particular shifts in the bacterial and fungal microbial community, which are significantly different from age-matched neurotypical controls, but it is still unclear whether these characteristic shifts are detectable before diagnosis. Early microbial colonization patterns can have long-lasting effects on human health, and pre-emptive intervention may be an important mediator to more severe autism. In this study, we characterized both the microbiome and short-chain fatty acid concentrations of fecal samples from young children between 21 and 40 months who were showing early behavioral signs of ASD. The fungal richness and acetic acid concentrations were observed to be higher with increasing autism severity, and the abundance of several bacterial taxa also changed due to the severity of ASD. Bacterial diversity and SCFA concentrations were also associated with stool form, and some bacterial families were found with differential abundance according to stool firmness. An exploratory analysis of the microbiome associated with pre-emptive treatment also showed significant differences at multiple taxonomic levels. These differences may impact the microbial signaling across the gut-brain-microbiota axis and the neurological development of the children.

Med12 is Essential for Skeletal Muscle Development

Tight regulation of tissue‐ and cell‐specific gene expression is essential for healthy physiological development. Mediator is a multisubunit protein complex that links basal transcriptional machinery, transcription factors, and epigenetic modifiers to gene targets to coordinate transcriptional regulation during development. One subunit, MED12, controls tissue‐ and cell‐specific gene expression. Some mutations in MED12 cause neurological developmental disorders, while others are associated with uterine leiomyomas. In addition to these diseases, human MED12 mutations have been linked to muscle disorders such as skeletal muscle hypotonia and congenital heart defects, but the function of MED12 in muscle and muscle cell development has not been elucidated. The objective in this study was to discover a molecular role of MED12 in transcriptional control of muscle development. We hypothesized that MED12 is required for healthy muscle development, and that MED12 helps recruit myogenic transcription factors (TFs) to Mediator at the Pre‐Initiation Complex (PIC) to achieve transcriptional control. Our lab generated a conditional skeletal muscle‐specific Med12 knockout mouse model (Med12mKO) driven by a Myogenin‐Cre transgene that is expressed during embryonic muscle development. Med12mKOmice have a runted phenotype, smaller muscles, disorganized muscle architecture, and suffer premature death, compared to littermate controls. Gene expression analysis by RNA‐sequencing (RNA‐seq) of muscle from 1‐day old Med12mKO and control mice revealed that Med12 deletion dysregulates metabolic and structural genes, including several myosin genes. MED12 is a transcriptional regulator, but does not directly bind DNA. To identify putative candidate TFs that regulate muscle gene expression in a MED12‐dependent manner we performed Upstream Regulator Analysis (URA) of dysregulated genes in Med12mKO muscle. Multiple TFs that regulate muscle gene expression were predicted to do so via MED12, including SRF, which is known to regulate expression of many myosin genes. Using differentiating C2C12 mouse myoblasts as a cell model of myogenesis, knockdown of Med12by shRNA resulted in diminished myotube size and reduced expression of myosin genes, recapitulating the gene expression and muscle phenotype observed in the Med12mKOmodel. However, no interaction was detected between SRF and MED12 in C2C12 myoblasts by Co‐Immunoprecipitation (Co‐IP), which did not support our hypothesis of muscle gene expression regulation through a MED12‐SRF mechanism. To further investigate how loss of MED12 dysregulates muscle gene expression, we used an unbiased approach to identify TFs that interact with MED12. We immunoprecipitated MED12 from C2C12 myoblasts and identified interacting TFs using mass spectrometry. We are currently investigating other TFs through which MED12 could be regulating gene expression during muscle development. We conclude that Med12 is required for normal skeletal muscle development, including normal gene expression of structural and metabolic genes during myogenesis.

LIS1 and NDEL1 Regulate Axonal Trafficking of Mitochondria in Mature Neurons.

Defective mitochondrial dynamics in axons have been linked to both developmental and late-onset neurological disorders. Axonal trafficking is in large part governed by the microtubule motors kinesin-1 and cytoplasmic dynein 1 (dynein). Dynein is the primary retrograde transport motor in axons, and mutations in dynein and many of its regulators also cause neurological diseases. Depletion of LIS1, famous for linking dynein deregulation to lissencephaly (smooth brain), in adult mice leads to severe neurological phenotypes, demonstrating post-developmental roles. LIS1 stimulates retrograde transport of acidic organelles in cultured adult rat dorsal root ganglion (DRG) axons but findings on its role in mitochondrial trafficking have been inconsistent and have not been reported for adult axons. Here we report that there is an increased number of mitochondria in cross-sections of sciatic nerve axons from adult LIS1+/– mice. This is probably related to reduced dynein activity as axons from adult rat nerves exposed to the dynein inhibitor, ciliobrevin D also had increased numbers of mitochondria. Moreover, LIS1 overexpression (OE) in cultured adult rat DRG axons stimulated retrograde mitochondrial transport while LIS1 knockdown (KD) or expression of a LIS1 dynein-binding mutant (LIS1-K147A) inhibited retrograde transport, as did KD of dynein heavy chain (DHC). These findings are consistent with our report on acidic organelles. However, KD of NDEL1, a LIS1 and dynein binding protein, or expression of a LIS1 NDEL1-binding mutant (LIS1-R212A) also dramatically impacted retrograde mitochondrial transport, which was not the case for acidic organelles. Manipulations that disrupted retrograde mitochondrial transport also increased the average length of axonal mitochondria, suggesting a role for dynein in fusion or fission events. Our data point to cargo specificity in NDEL1 function and raise the possibility that defects in the LIS1/NDEL1 dynein regulatory pathway could contribute to mitochondrial diseases with axonal pathologies.

A Combined Proteomics and Metabolomics Profiling to Investigate the Genetic Heterogeneity of Autistic Children.

Autism spectrum disorder (ASD) has become one of the most common neurological developmental disorders in children. However, the study of ASD diagnostic markers faces significant challenges due to the existence of heterogeneity. In this study, genetic testing was performed on children who were clinically diagnosed with ASD. Children with ASD susceptibility genes and healthy controls were studied. The proteomics of plasma and peripheral blood mononuclear cells (PBMCs) as well as plasma metabolomics were carried out. The results showed that although there was genetic heterogeneity in children with ASD, the differentially expressed proteins (DEPs) in plasma, peripheral blood mononuclear cells, and differential metabolites in plasma could still effectively distinguish autistic children from controls. The mechanism associated with them focuses on several common and previously reported mechanisms of ASD. The biomarkers for ASD diagnosis could be found by taking differentially expressed proteins and differential metabolites into consideration. Integrating omics data, glycerophospholipid metabolism and N-glycan biosynthesis might play a critical role in the pathogenesis of ASD.