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The present study aimed to clarify the development of motor unit (MU) firing properties and the association between those neural properties and force steadiness (FS)/neurological tests in 6- to 12-year-old children. Fifty-eight school-aged children performed maximal voluntary knee extension contraction, a submaximal FS test at 10% of maximal voluntary knee extension contraction, knee extension reaction time to light stimulus test, and single-leg standing test, and data from 38 children who passed the criteria were subject to analysis. During the FS test, high-density surface electromyography was recorded from the vastus lateralis muscle to identify individual MU firing activity. FS was improved with an increase in age (r = −.540, P <.001). The MU firing rate (MUFR) was significantly decreased with an increase in age (r = −.343, P =.035). MUFR variability was not associated with age. Although there was no significant correlation between FS and MUFR, FS was significantly correlated with MUFR variability even after adjustment for the effect of age (r =.551, P =.002). Neither the reaction time nor the single-leg standing test was correlated with any MU firing properties. These findings suggest that MUFR variability makes an important contribution to precise force control in children but does not naturally develop with age. [ABSTRACT FROM AUTHOR]

This systematic review synthesized current literature regarding the effect of physical activity (PA) interventions on brain structure (BS) and brain function (BF) in healthy children. This review followed the Preferred Reporting Items for Systematic Reviews protocols and used the Rayyan web for data extraction. Eleven experimental studies were included. Specifically, six studies conducted chronic PA interventions, and the others applied acute PA interventions. Evidence from five articles (45.45%) confirmed that PA interventions had beneficial effects on brain structure and function in healthy children, including enhancing brain activation and microstructural plasticity. These articles shared a study protocol and were conducted in school settings, indicating homogeneity. Due to the technical complexity and limitations involved, there are few studies on brain health and development. Future research is necessary to validate and evaluate the effectiveness of PA interventions on brain structure and function in healthy children. [ABSTRACT FROM AUTHOR]

Background: Early childhood stunting affects around 150 million young children worldwide and leads to suboptimal human potential in later life. However, there is limited data on the effects of early childhood stunting and catch-up growth on brain morphometry. Methods: We evaluated childhood brain volumes at nine years of age in a community-based birth-cohort follow-up study in Vellore, south India among four groups based on anthropometric assessments at two, five, and nine years namely 'Never Stunted' (NS), 'Stunted at two years and caught up by five years' (S2N5), 'Stunted at two and five years and caught up by nine years' (S2N9), and 'Always Stunted' (AS). T1-weighted magnetic resonance imaging (MRI) images were acquired using a 3T MRI scanner, and brain volumes were quantified using FreeSurfer software. Analysis of Variance (ANOVA) was used to determine the differences in brain volumetry between the stunting groups, with age and sex as covariates. The effect size ANOVA models was evaluated using Eta squared. Findings: Amongst 251 children from the initial cohort, 178 children with a mean age of 9.54 underwent neuroimaging and considered for further analysis. The total brain volume, subcortical volume, bilateral cerebellar white matter, and posterior corpus callosum showed a declining trend from NS to AS. Regional cortical brain analysis showed significant lower bilateral lateral occipital volumes, right pallidum, bilateral caudate, and right thalamus volumes between NS and AS. Interpretation: To the best of our knowledge, this first neuroimaging analysis to investigate the effects of persistent childhood stunting and catch-up growth on brain volumetry indicates impairment at different brain levels involving total brain and subcortical volumes, networking/connecting centres (thalamus, basal ganglia, callosum, cerebellum) and visual processing area of lateral occipital cortex. [ABSTRACT FROM AUTHOR]

Recognizing the systemic exclusion of structurally oppressed groups from academic awards, the ENRRICH (Excellence in Neurodevelopment and Rehabilitation Research In Child Health) summer studentship emphasized the inclusion of structurally oppressed groups. Herein, we outline the processes in creating this funding opportunity, and plans for improvement, including enhanced representation among supervisors. [ABSTRACT FROM AUTHOR]

This review evaluates in-vitro models for studying how maternal influences during pregnancy impact the development of offspring microglia, the immune cells of the central nervous system. The models examined include primary microglia cultures, microglia cell lines, iPSC-derived microglia, PBMC-induced microglia-like cells, 3D brain organoids derived from iPSCs, and Hofbauer cells. Each model is assessed for its ability to replicate the in-vivo environment of the developing brain, with a focus on their strengths, limitations, and practical challenges. Key factors such as scalability, genetic and epigenetic fidelity, and physiological relevance are highlighted. Microglia cell lines are highly scalable but lack genetic and epigenetic fidelity. iPSC-derived microglia provide moderate physiological relevance and patient-specific genetic insights but face operational and epigenetic challenges inherent to reprogramming. 3D brain organoids, derived from iPSCs, offer an advanced platform for studying complex neurodevelopmental processes but require extensive resources and technical expertise. Hofbauer cells, which are fetal macrophages located in the placenta and share a common developmental origin with microglia, are uniquely exposed to prenatal maternal factors and, depending on fetal barrier maturation, exhibit variable epigenetic fidelity. This makes them particularly useful for exploring the impact of maternal influences on fetal programming of microglial development. The review concludes that no single model comprehensively captures all aspects of maternal influences on microglial development, but it offers guidance on selecting the most appropriate model based on specific research objectives and experimental constraints. [ABSTRACT FROM AUTHOR]

RNA abundance is controlled by rates of synthesis and degradation. Although mis-regulation of RNA turnover is linked to neurodevelopmental disorders, how it contributes to cortical development is largely unknown. Here, we discover the landscape of RNA stability regulation in the cerebral cortex and demonstrate that intact RNA decay machinery is essential for corticogenesis in vivo. We use SLAM-seq to measure RNA half-lives transcriptome-wide across multiple stages of cortical development. Leveraging these data, we discover cis-acting features associated with RNA stability and probe the relationship between RNA half-life and developmental expression changes. Notably, RNAs that are up-regulated across development tend to be more stable, while down-regulated RNAs are less stable. Using compound mouse genetics, we discover CNOT3, a core component of the CCR4-NOT deadenylase complex linked to neurodevelopmental disease, is essential for cortical development. Conditional knockout of Cnot3 in neural progenitors and their progeny in the developing mouse cortex leads to severe microcephaly due to altered cell fate and p53-dependent apoptosis. Finally, we define the molecular targets of CNOT3, revealing it controls expression of poorly expressed, non-optimal mRNAs in the cortex, including cell cycle-related transcripts. Collectively, our findings demonstrate that fine-tuned control of RNA turnover is crucial for brain development. Dysregulation of RNA stability is linked to neurodevelopmental disorders, but how it contributes to cortical development is not well understood. This study profiles the RNA stability landscape of the cortex across development and reveals that the CCR4-NOT deadenylase complex is essential for corticogenesis in vivo. [ABSTRACT FROM AUTHOR]

Introduction: Learning and memory allow individuals to adapt to their environmental needs and survive. Fish have the ability to solve complex learning tasks, associative learning, and flexible spatial memory. The proto-oncogene fos (c-fos) has been reported to be involved in brain development, learning and memory in mammals. However, whether the c-fos plays a vital role in learning and memory in fish is unclear. Methods: Almost all fish have two paralogues of c-fos named fosaa and fosab. We used CRISPR/Cas9 technology to generate fosaa and fosab knockout zebrafish models. Results: In this study, we discovered the brain weight marked reduction in fosaa −/− and fosab −/− zebrafish compared with the wild-type (WT) (AB strain) zebrafish. In the T-maze behavioral assay, the fosab −/− zebrafish took significantly more than the average time to complete the assigned trial as the increase in the days compared to WT zebrafish, while the fosaa −/− zebrafish did not show a notable variance. The average time to complete the trial in fosab −/− zebrafish was significantly higher than in WT zebrafish. The relative mRNA expression level of c- jun in fosab −/− zebrafish was significantly higher than that in WT zebrafish, while the fosaa −/− zebrafish has no discernible trend. Additionally, the phylogenetic and multiple amino acid alignment results indicated that fish fosab has a higher identity with mammals Fos. Discussion: By integrating the above results, we found that fosab , but not fosaa, may possess a learning and memory function in fish. For the first time, we illustrated the role of fosaa and fosab in learning and memory via c-fos knockout in fish, which can provide new insights into environmental adaptation. [ABSTRACT FROM AUTHOR]

Brain macrophages encompass two major populations: microglia in the parenchyma and border-associated macrophages (BAMs) in the extra-parenchymal compartments. These cells play crucial roles in maintaining brain homeostasis and immune surveillance. Microglia and BAMs are phenotypically and epigenetically distinct and exhibit highly specialized functions tailored to their environmental niches. Intriguingly, recent studies have shown that both microglia and BAMs originate from the same myeloid progenitor during yolk sac hematopoiesis, but their developmental fates diverge within the brain. Several works have partially unveiled the mechanisms orchestrating the development of microglia and BAMs in both mice and humans; however, many questions remain unanswered. Defining the molecular underpinnings controlling the transcriptional and epigenetic programs of microglia and BAMs is one of the upcoming challenges for the field. In this review, we outline current knowledge on ontogeny, phenotypic diversity, and the factors shaping the ecosystem of brain macrophages. We discuss insights garnered from human studies, highlighting similarities and differences compared to mice. Lastly, we address current research gaps and potential future directions in the field. Understanding how brain macrophages communicate with their local environment and how the tissue instructs their developmental trajectories and functional features is essential to fully comprehend brain physiology in homeostasis and disease. [ABSTRACT FROM AUTHOR]

Understanding cortical inhibition and its diverse roles remains a key challenge in neurophysiological research. Traditionally, inhibition has been recognized for controlling the stability and rhythmicity of network dynamics, or refining the spatiotemporal properties of cortical representations. In this perspective, we propose that specific types of interneurons may play a complementary role, by modulating the computational properties of neural networks. We review experimental and theoretical evidence, mainly from rodent sensory cortices, that supports this view. Additionally, we explore how dysfunctions in these interneurons may disrupt the network's ability to switch between computational modes, impacting the flexibility of cortical processing and potentially contributing to various neurodevelopmental and psychiatric disorders. [ABSTRACT FROM AUTHOR]

The function of the nervous system is intimately tied to its complex and highly interconnected architecture. Precise control of dendritic branching in individual neurons is central to building the complex structure of the nervous system. Here, we show that the kinetochore protein KNL-1 and its associated KMN (Knl1/Mis12/Ndc80 complex) network partners, typically known for their role in chromosome-microtubule coupling during mitosis, control dendrite branching in the Caenorhabditis elegans mechanosensory PVD neuron. KNL-1 restrains excess dendritic branching and promotes contact-dependent repulsion events, ensuring robust sensory behavior and preventing premature neurodegeneration. Unexpectedly, KNL-1 loss resulted in significant alterations of the actin cytoskeleton alongside changes in microtubule dynamics within dendrites. We show that KNL-1 modulates F-actin dynamics to generate proper dendrite architecture and that its N-terminus can initiate F-actin assembly. These findings reveal that the postmitotic neuronal KMN network acts to shape the developing nervous system by regulating the actin cytoskeleton and provide new insight into the mechanisms controlling dendrite architecture. [ABSTRACT FROM AUTHOR]

Understanding the cellular and genetic mechanisms driving human-specific features of cortical development remains a challenge. We generated a cell-type resolved atlas of transcriptome and chromatin accessibility in the developing macaque and mouse prefrontal cortex (PFC). Comparing with published human data, our findings demonstrate that although the cortex cellular composition is overall conserved across species, progenitor cells show significant evolutionary divergence in cellular properties. Specifically, human neural progenitors exhibit extensive transcriptional rewiring in growth factor and extracellular matrix (ECM) pathways. Expression of the human-specific progenitor marker ITGA2 in the fetal mouse cortex increases the progenitor proliferation and the proportion of upper-layer neurons. These transcriptional divergences are primarily driven by altered activity in the distal regulatory elements. The chromatin regions with human-gained accessibility are enriched with human-specific sequence changes and polymorphisms linked to intelligence and neuropsychiatric disorders. Our results identify evolutionary changes in neural progenitors and putative gene regulatory mechanisms shaping primate brain evolution. [Display omitted] • Cross-species comparison of developing prefrontal cortex at cell-type resolution • Primate RG cells show transcriptomic changes in growth factor and ECM pathways • ITGA2 is a human-specific progenitor marker that boosts progenitor proliferation • Human-gained accessible regions are linked to intelligence and brain disorders Liu et al. conducted a cross-species comparison of the developing prefrontal cortex at single-cell resolution, and they identified human-specific transcriptomic and epigenomic changes in neural progenitors that contribute to evolutionary changes in regulatory mechanisms shaping human brain development. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is a prevalent and highly fatal primary malignant brain tumor. N6-methyladenosine (m6A) modification plays a critical role in the development of brain tumor. WTAP and ZC3H13 have been identified across various species. Immune contexture, which includes the tumor microenvironment (TME), plays a significant role in cancer progression and treatment. This study aimed to explore the potential impact between WTAP and ZC3H13 on the immunological characteristics of GBM. We utilized data from TCGA-GBM, GEO and CGGA datasets to obtain platform and probe data. Patients with GBM were stratified into two clusters based on the expression of WTAP and ZC3H13 using consensus clustering approach. Immune infiltration within the tumor microenvironment was assessed using ESTIMATE, CIBERSORT and ssGSEA methodologies. Functional disparities were determined through gene set enrichment analysis (GSEA). Tumor mutation burden (TMB) and immune checkpoint inhibitors (ICIs) were also analyzed. Co-expression network analysis (WGCNA) was used to identify genes associated with WTAP/ZC3H13 and immunity. Validation was performed using GEO and CGGA datasets. Our analysis revealed that cluster1 exhibited higher WTAP expression but lower ZC3H13 expression compared to cluster2. Cluster1 showed higher levels of immune infiltration and TMB compared to cluster2. WGCNA identified 15 genes closely associated with WTAP/ZC3H13 expression and immune scores, notably CTLA4, CD27, ICOS, and LAG3. Our results suggested that WTAP and ZC3H13 influence on immune contexture of GBM, providing new insights into tumor immunity in GBM. [ABSTRACT FROM AUTHOR]

Dendritic branching and synaptic organization shape single-neuron and network computations. How they emerge simultaneously during brain development as neurons become integrated into functional networks is still not mechanistically understood. Here, we propose a mechanistic model in which dendrite growth and the organization of synapses arise from the interaction of activity-independent cues from potential synaptic partners and local activity-dependent synaptic plasticity. Consistent with experiments, three phases of dendritic growth – overshoot, pruning, and stabilization – emerge naturally in the model. The model generates stellate-like dendritic morphologies that capture several morphological features of biological neurons under normal and perturbed learning rules, reflecting biological variability. Model-generated dendrites have approximately optimal wiring length consistent with experimental measurements. In addition to establishing dendritic morphologies, activity-dependent plasticity rules organize synapses into spatial clusters according to the correlated activity they experience. We demonstrate that a trade-off between activity-dependent and -independent factors influences dendritic growth and synaptic location throughout development, suggesting that early developmental variability can affect mature morphology and synaptic function. Therefore, a single mechanistic model can capture dendritic growth and account for the synaptic organization of correlated inputs during development. Our work suggests concrete mechanistic components underlying the emergence of dendritic morphologies and synaptic formation and removal in function and dysfunction, and provides experimentally testable predictions for the role of individual components. [ABSTRACT FROM AUTHOR]

Objective: To assess whether specific parent media practices are associated with the consumption of R-rated (restricted) movies and mature-rated video game use in early adolescents. Methods: Data from the Adolescent Brain Cognitive Development (ABCD) Study (N = 10,054, 12–13 years, Year 3, 2019–2021) were analyzed. Ordinal logistic regression models were used to assess associations among media parenting practices and R-rated movies or mature-rated video game use, adjusting for potential confounders. Results: Parental allowance of bedroom screen use (adjusted odds ratio [AOR] 1.44, 95% confidence interval [CI] 1.36–1.53), family mealtime screen use (AOR 1.19, 95% CI 1.13–1.25), and parent screen use (AOR 1.11, 95% CI 1.03–1.20) were positively associated with watching R-rated movies. Parental allowance of bedroom screen use (AOR 1.44, 95% CI 1.36–1.52), family mealtime screen use (AOR 1.26, 95% CI 1.19–1.32), and parent screen use (AOR 1.11, 95% CI 1.02–1.20) were positively associated with playing mature-rated video games. Greater parental monitoring and limiting of screen time were negatively associated with watching R-rated movies (AOR 0.81, 95% CI 0.77–0.85 and AOR 0.73, 95% CI 0.68–0.79 respectively) and playing mature-rated video games (AOR 0.81, 95% CI 0.77–0.86 and AOR 0.72, 95% CI 0.67–0.77). Restricting screen time as a punishment for misbehavior was linked to a higher odds of watching R-rated movies (AOR 1.06, 95% CI 1.01–1.11) and playing mature-rated video games (AOR 1.12, 95% CI 1.07–1.17) while offering screen time to reward for good behavior was negatively associated with watching R-rated movies (AOR 0.95, 95% CI 0.90–0.99). Conclusions: Media parenting practices such as monitoring or limiting screen use are significantly associated with playing mature-rated video games and watching R-rated movies. Punitive measures, such as restricting screen time as a punishment are slightly associated with increased engagement with such content. These findings highlight the importance of intentional and thoughtful parental strategies in managing children's media consumption effectively. [ABSTRACT FROM AUTHOR]

Down Syndrome (DS) is a genetic disorder caused by the presence of an extra copy of chromosome 21, and leading to various developmental and cognitive defects. A critical feature of DS is the occurrence of oxidative distress particularly in the brain, which exacerbates neurodevelopmental processes. Mitochondria play a crucial role in cell energy metabolism and their impairment is one of the major causes of oxidative distress in several pathologies. Hence, this study investigates mitochondrial proteostasis by the mean of the mitochondrial Unfolded Protein Response (UPRmt) and the mitochondrial protein quality control (MQC) mechanisms in the context of DS, focusing on their implications in redox homeostasis in brain development. We analyzed key UPRmt markers and mitochondrial function in the frontal cortex isolated fromTs2Cje mice, a model for DS, across different developmental stages. Our results demonstrate significant alterations in UPRmt markers, particularly at postnatal day 0 (P0) and 1 month (1M). These changes indicate early UPRmt activation, primarily driven by the ATF5/GRP75 axis, although compromised by reduced levels of other components. Impaired UPRmt correlates with decreased mitochondrial activity, evidenced by reduced oxygen consumption rates and altered expression of OXPHOS complexes. Additionally, elevated oxidative stress markers such as 3-nitrotyrosine (3-NT), 4-hydroxynonenal (HNE), and protein carbonyls (PC) were observed, linking mitochondrial dysfunction to increased oxidative damage. Defects of MQC, including disrupted biogenesis, increased fission, and the activation of mitophagy were evident mostly at P0 and 1M consistent with UPRmt activation. Principal Component Analysis revealed distinct phenotypic differences between Ts2Cje and control mice, driven by these molecular alterations. Our findings underscore the critical role of UPRmt and MQC in DS brain development, highlighting potential therapeutic targets to mitigate mitochondrial dysfunction and oxidative distress, thereby alleviating some of the neurodevelopmental and cognitive impairments associated with DS. [Display omitted] • UPRmt activation is compromised in Ts2Cje mice brain. • Defects of Mitochodrial Quality Control (MQC) occur in Ts2Cje mice brain. • Dysfunctional UPRmt and MQC alter mitochondrial energy production. • Mitochondrial damage is responsible for oxidative distress in Ts2Cje mice brain. • These alterations are evident since P0 likely affecting brain development. [ABSTRACT FROM AUTHOR]

Brain plasticity is the ability of the nervous system to change its structure and functioning in response to experiences. These changes occur mainly at synaptic connections, and this plasticity is named synaptic plasticity. During postnatal development, environmental influences trigger changes in synaptic plasticity that will play a crucial role in the formation and refinement of brain circuits and their functions in adulthood. One of the greatest challenges of present neuroscience is to try to explain how synaptic connections change and cortical maps are formed and modified to generate the most suitable adaptive behavior after different external stimuli. Adenosine is emerging as a key player in these plastic changes at different brain areas. Here, we review the current knowledge of the mechanisms responsible for the induction and duration of synaptic plasticity at different postnatal brain development stages in which adenosine, probably released by astrocytes, directly participates in the induction of long-term synaptic plasticity and in the control of the duration of plasticity windows at different cortical synapses. In addition, we comment on the role of the different adenosine receptors in brain diseases and on the potential therapeutic effects of acting via adenosine receptors. [ABSTRACT FROM AUTHOR]

Animals can navigate through complex environments with amazing flexibility and efficiency: they forage over large areas, quickly learning rewarding behavior and changing their plans when necessary. Some insights into the neural mechanisms supporting this ability can be found in the hippocampus (HPC)—a brain structure involved in navigation, learning, and memory. Neuronal activity in the HPC provides a hierarchical representation of space, representing an environment at multiple scales. In addition, it has been observed that when memory-consolidation processes in the HPC are inactivated, animals can still plan and navigate in a familiar environment but not in new environments. Findings like these suggest three useful principles: spatial learning is hierarchical, learning a hierarchical world-model is intrinsically valuable, and action planning occurs as a downstream process separate from learning. Here, we demonstrate computationally how an agent could learn hierarchical models of an environment using off-line replay of trajectories through that environment and show empirically that this allows computationally efficient planning to reach arbitrary goals within a reinforcement learning setting. Using the computational model to simulate hippocampal damage reproduces navigation behaviors observed in rodents with hippocampal inactivation. The approach presented here might help to clarify different interpretations of some spatial navigation studies in rodents and present some implications for future studies of both machine and biological intelligence. [ABSTRACT FROM AUTHOR]

Thyroid hormones (THs) regulate metabolism in a homeostatic state in an adult organism. During the prenatal period, prior to the establishment of homeostatic mechanisms, THs assume additional functions as key regulators of brain development. Here, we focus on reviewing the role of THs in orchestrating cellular dynamics in a developing brain. The evidence from the reviewed scientific literature suggests that the developmental roles of the hormones are predominantly mediated by non-genomic mitochondrial effects of THs due to attenuation of genomic effects of THs that antagonise non-genomic impacts. We argue that the key function of TH signalling during brain development is to orchestrate the tempo of self-organisation of neural progenitor cells. Further, evidence is provided that major neurodevelopmental consequences of hypothyroidism stem from an altered tempo of cellular self-organisation. [ABSTRACT FROM AUTHOR]

Emerging evidence suggests that DNA methylation is crucial in the mental disorder pathophysiology. The current study attempted to identify the dysregulation of DNA methylation patterns in adolescent patients suffering from depressive episodes (DE) while considering the impact of various subtypes, including psychotic symptoms and a history of childhood trauma. The study included 67 patients with DE and 30 healthy controls (HCs) subjects. Severe depressive episode (SDE) patients were grouped according to psychotic symptoms, such as SDE with vs. SDE without psychotic symptoms (cases 29 vs. 21). The Childhood Trauma Questionnaire-Short Form helped assess childhood trauma among all patients. Thus, all the patients were divided into adolescent DE experiencing ≥ two trauma types vs. experiencing ≤ one trauma type (cases, 50 vs. 17). Methylome-wide analysis was conducted on peripheral blood to identify methylation differences in CpG sites for three comparisons: DE vs. HCs, SDE patients with vs. without psychotic symptoms, and DE patients having 0–1 type of childhood trauma vs. those having ≥two types of childhood trauma. Adolescent DE patients demonstrated a predominant trend of lower methylation levels than HCs, with 259 hypermethylated and 3956 hypomethylated sites. Differentially hypomethylated sites involve related genes such as FKBP5 , BDNF , NR3C1 , GABRB3 , SHANK1 , SLC38A1 , SLC6A18 , CHRNB1 , CTNNA2 , CTTNBP2 , etc. All these genes could be involved in DE pathogenesis. Significant DNA methylation differences could be observed in SDE subgroups with and without psychotic symptoms (e.g., genes like DTNB , CNTN1 , CTNNA2), along with those DE patients having 0–1 type of childhood trauma compared to those with ≥2 types (e.g., VWA3B , SYT10 , SDK2 , CAMSAP3). Many significant methylated sites were associated with genes involved in brain development, highlighting the potential pathophysiological mechanisms linked with DE and its subtypes, such as psychotic symptoms and childhood trauma. Our findings suggest that differential DNA methylation is associated with the pathophysiology of DE, as well as the presence of psychotic symptoms and a history of childhood trauma. These blood-based methylation patterns may serve as biomarkers for DE and shed light on underlying mechanisms across these subtypes. • Explore DNA methylation linked to adolescent DE, SDE with psychotic symptoms, and DE with a history of childhood trauma. • Genes associated with differentially methylated sites in adolescent DE pathogenesis include FKBP5 , BDNF , and NR3C1 , etc. • Significantly methylated sites linked to SDE with psychotic symptoms were annotated in genes like DTNB , CNTN1 , and TOX , etc. • Significantly methylated sites associated with childhood trauma were annotated in genes such as VWA3B , SYT10 , and SDK2 , etc. • Many significant methylated sites were associated with genes involved in neuron projection, dendrite development, etc. [ABSTRACT FROM AUTHOR]

Objectives: To establish and validate a non-invasive deep learning (DL) model based on contrast-enhanced ultrasound (CEUS) to predict vessels encapsulating tumor clusters (VETC) patterns in hepatocellular carcinoma (HCC). Materials and methods: This retrospective study included consecutive HCC patients with preoperative CEUS images and available tissue specimens. Patients were randomly allocated into the training and test cohorts. CEUS images were analyzed using the ResNet-18 convolutional neural network for the development and validation of the VETC predictive model. The predictive value for postoperative early recurrence (ER) of the proposed model was further evaluated. Results: A total of 242 patients were enrolled finally, including 195 in the training cohort (54.6 ± 11.2 years, 178 males) and 47 in the test cohort (55.1 ± 10.6 years, 40 males). The DL model (DL signature) achieved favorable performance in both the training cohort (area under the receiver operating characteristics curve [AUC]: 0.92, 95% confidence interval [CI]: 0.88–0.96) and test cohort (AUC: 0.90, 95% CI: 0.82–0.99). The stratified analysis demonstrated good discrimination of DL signature regardless of tumor size. Moreover, the DL signature was found independently correlated with postoperative ER (hazard ratio [HR]: 1.99, 95% CI: 1.29–3.06, p = 0.002). C-indexes of 0.70 and 0.73 were achieved when the DL signature was used to predict ER independently and combined with clinical features. Conclusion: The proposed DL signature provides a non-invasive and practical method for VETC-HCC prediction, and contributes to the identification of patients with high risk of postoperative ER. Clinical relevance statement: This DL model based on contrast-enhanced US displayed an important role in non-invasive diagnosis and prognostication for patients with VETC-HCC, which was helpful in individualized management. Key Points: Preoperative biopsy to determine VETC status in HCC patients is limited. The contrast-enhanced DL model provides a non-invasive tool for the prediction of VETC-HCC. The proposed deep-learning signature assisted in identifying patients with a high risk of postoperative ER. [ABSTRACT FROM AUTHOR]

• Maternal immune activation decreased ATP8A2 expression in the offspring's mPFC. • Upregulation of ATP8A2 restored synapse-associated protein levels. • Upregulation of ATP8A2 improved behavioural performance. • Upregulation of ATP8A2 eliminated microglial phagocytosis of synaptophysin. • Upregulation of ATP8A2 eliminated phosphatidylserine exposure. Prenatal virus infection-induced maternal immune activation (MIA) is linked to a greater risk of neurodevelopmental disorders in offspring. Prenatal exposure to poly(I:C) in pregnant mice is a well-established approach to mimic virus infection-induced MIA, leading to neuropsychiatric disorders and aberrant brain development, especially in the medial prefrontal cortex (mPFC). ATPase phospholipid flippase 8A2 (ATP8A2) is the main phospholipid lipase, expressed in the mPFC and is crucial for maintaining cell membrane stability by flipping phosphatidylserine from the outer leaflet to the inner leaflet of the cell membrane. Atp8a2 knockout or mutation causes a series of phenotypes, including impaired neuronal cell survival, neuroinflammation, altered synaptic plasticity, and behavioral abnormalities. These findings suggest that ATP8A2 expression in the mPFC may be impaired in MIA offspring and that the decrease in ATP8A2 expression may be involved in the development of MIA-induced neuropsychiatric disorders in offspring. No reports addressing this issue have been published. Here, after confirming abnormal affective-/social-related behaviors in adulthood and reduced synapse-associated protein expression on the birth day (P0) and the fourth postnatal day (P4) in the mPFC of MIA offspring that were born to dams exposed prenatally to a single dose of poly(I:C) (10 mg/kg, i.p.), decreased ATP8A2 expression was also observed in the mPFC of MIA offspring at P0 and P4. Upregulating ATP8A2 in the mPFC restored synapse-associated protein levels, along with a partial improvement in the behavioral performance of MIA offspring. Upregulation of ATP8A2 also blocked neuronal phosphatidylserine externalization and eliminated the excitation/inhibition (E/I) imbalance in the mPFC of MIA offspring. This study revealed that the low expression of ATP8A2 following MIA exposure may play a role in mediating abnormal brain development and function in offspring. ATP8A2 potentially represents a novel molecule involved in MIA-induced neuropsychiatric disorders in offspring, and may serve as a novel therapeutic target for the intervention of psychiatric disorders. [ABSTRACT FROM AUTHOR]

This scoping review aims to synthesise what is known about professional collaboration among schools, healthcare and social care for children with neurodevelopmental disorders. Papers (N = 29; discussions, theoretical, empirical; 2003–2022) were selected in early 2023 from seven databases and supplemented by manual search. The analysis was conducted using qualitative content analysis. The results revealed the forms, underpinning factors and benefits of collaboration. Collaboration was seen as important in assessment and interventions, evaluation, support planning, co-therapy, service coordination and school transitions, and when carrying out these, teamwork and consultation were seen as essential. Collaborative competencies, shared understanding and dialogic interactions were suggested to promote collaboration. The main challenges were professional competition, time shortage, legal constraints and difficulty in accessing information. This review suggests that there is a vital need for functional, professional collaboration in supporting children with neurodevelopmental disorders. This necessitates systemic changes, such as restructured organisations, active parental involvement, effective and open communication and collaborative competencies among professionals. Schools should play a central role in providing support through collaborative action. [ABSTRACT FROM AUTHOR]

The original description of cerebral palsy (CP) contained case histories suggesting that perinatal environmental stressors resulted in brain injury and neurodevelopmental disability. While there are clear associations between environmental impact on brain development and CP, recent studies indicate an 11% to 40% incidence of monogenic conditions in patients given a diagnosis of CP. A genetic diagnosis supports the delivery of personalized medicine. In this review, we describe how the Wnt pathway exemplifies our understanding of pathophysiology related to a gene variant (CTNNB1) found in some children diagnosed with CP. We cover studies undertaken to establish the baseline prevalence of monogenic conditions in populations attending CP clinics. We list factors indicating increased likelihood of a genomic diagnosis; and we highlight the need for a comprehensive, accurate, genotype–phenotype reference data set to aid variant interpretation in CP cohorts. We also consider the wider societal implications of genomic management of CP including significance of the diagnostic label, benefits and pitfalls of a genetic diagnosis, logistics, and cost. [ABSTRACT FROM AUTHOR]

Maternal prenatal depression can affect child brain and behavioral development. Specifically, altered limbic network structure and function is a likely mechanism through which prenatal depression impacts the life-long mental health of exposed children. While developmental trajectories are influenced by many factors that exacerbate risk or promote resiliency, the role of child age and sex in the relationship between prenatal depression and the child brain remains unclear. Here, we review studies of associations between prenatal depression and brain structure and function, with a focus on the role of age and sex in these relationships. After exposure to maternal prenatal depression, altered amygdala, hippocampal, and frontal cortical structure, as well as changes in functional and structural connectivity within the limbic network, are evident during the fetal, infant, preschool, childhood, and adolescent stages of development. Sex appears to play a key role in this relationship, with evidence of differential findings particularly in infants, with males showing smaller and females larger hippocampal and amygdala volumes following prenatal depression. Longitudinal studies in this area have only begun to emerge within the last 5 years and will be key to understanding critical windows of opportunity. Future research focused on the role of age and sex in this relationship is essential to further inform screening, policy, and interventions for children exposed to prenatal depression, interrupt the intergenerational transmission of depression, and ultimately support healthy brain development. [ABSTRACT FROM AUTHOR]

Summary: Since climate change affects psychiatric, neurological and neuropsychological disorders, as well as brain development, the Irish Doctors for the Environment working group on mental health has changed its title and remit to brain health. Mental health professionals need to respond coherently and effectively to the climate crisis. This need challenges traditional professional, disciplinary and academic boundaries and demands a holistic, person-centred approach. We propose that meeting this challenge is vital if the public, policy-makers and legislators are to grasp the full extent of the significance of climate's impact on brain health. [ABSTRACT FROM AUTHOR]

The brain of adult honeybee (Apis mellifera) workers is larger than that of queens, facilitating behavioural differentiation between the castes. This brain diphenism develops during the pharate‐adult stage and is driven by a caste‐specific gene expression cascade in response to unique hormonal milieus. Previous molecular screening identified minibrain (mnb; DYRK1A) as a potential regulator in this process. Here, we used RNAi approach to reduce mnb transcript levels and test its role on brain diphenism development in honeybees. White‐eyed unpigmented cuticle worker pupae were injected with dsRNA for mnb (Mnb‐i) or gfp, and their phenotypes were assessed two and 8 days later using classic histological and transcriptomic analyses. After 2 days of the injections, Mnb‐i bees showed 98% of downregulation of mnb transcripts. After 8 days, the brain of Mnb‐i bees showed reduction in total volume and in the volume of the mushroom bodies (MB), antennal, and optic lobes. Additionally, signs of apoptosis were observed in the Kenyon cells region of the MB, and the cohesion of the brain tissues was affected. Our transcriptomic analyses revealed that 226 genes were affected by the knockdown of mnb transcripts, most of which allowing axonal fasciculation. These results suggest the evolutionary conserved mnb gene has been co‐opted for promoting hormone‐mediated developmental brain morphological plasticity generating caste diphenism in honeybees. [ABSTRACT FROM AUTHOR]

Down syndrome (DS) and autism spectrum disorder (ASD) are two neurodevelopmental disorders characterized by impairments in language. Most studies do not consider the possible role sex differences may play in language profiles. Thus, the current study aimed to evaluate whether parent-reported structural and pragmatic language vary as a function of sex in youth with DS (n = 37), ASD (n = 106), and typical development (TD; n = 61). Findings suggest a female advantage in both structural and pragmatic language in DS; in contrast, no sex differences were found for either ASD or TD. Results suggest that males with DS may require more extensive interventions for language. Future research should investigate how age, IQ, and mode of measurement may impact the nature of these observations. [ABSTRACT FROM AUTHOR]

• The reviewed studies exhibit significant heterogeneity in the EEG parameters and brain MRI measurements in preterm infants. • Reduced discontinuity in EEG and higher Burdjalov scores are associated with improved structural brain development. • Clarifying how EEG and brain MRI are related can aid in the advancement of brain-oriented care strategies in the NICU. To systematically review the literature on the associations between electroencephalogram (EEG) and brain magnetic resonance imaging (MRI) measures in preterm infants (gestational age < 37 weeks). A comprehensive search was performed in PubMed and EMBASE databases up to February 12th, 2024. Non-relevant studies were eliminated following the PRISMA guidelines. Ten out of 991 identified studies were included. Brain MRI metrics used in these studies include volumes, cortical features, microstructural integrity, visual assessments, and cerebral linear measurements. EEG parameters were classified as qualitative (Burdjalov maturity score, seizure burden, and background activity) or quantitative (discontinuity, spectral content, amplitude, and connectivity). Among them, discontinuity and the Burdjalov score were most frequently examined. Higher discontinuity was associated with reduced brain volume, cortical surface, microstructural integrity, and linear measurements. The Burdjalov score related to brain maturation qualitatively assessed on MRI. No other consistent correlations could be established due to the variability across studies. The reviewed studies utilized a variety of EEG and MRI measurements, while discontinuity and the Burdjalov score stood out as significant indicators of structural brain development. This review, for the first time, provides an extensive overview of EEG-MRI associations in preterm infants, potentially facilitating their clinical application. [ABSTRACT FROM AUTHOR]

The purpose of the study was to investigate the association between discrimination by multiple sources (ie, teachers, students, and other adults) and early adolescents' behavioral problems (ie, internalizing, externalizing, and attention problems), also considering the protective role of parental warmth in the association. Cross-sectional analyses were conducted with 3,245 early adolescents of color obtained from the Adolescent Brain Cognitive Development Study (ABCD Study) at year 1 follow-up (Y1), a large and diverse sample of children (mean age = 9.48 years) in the United States. Racially–ethnically minoritized adolescents reported sources of discrimination, parental warmth, and symptoms of psychopathology. Regression with interaction terms was conducted to investigate the associations among sources of discrimination, parental warmth, and behavioral problems among racially–ethnically minority adolescents. Sensitivity analyses were conducted to examine (1) race/ethnicity and sex/gender variations; (2) whether the associations between different sources of discrimination and behavioral problems were reliably different; and (3) effects of discrimination, parental warmth, and their interplay at Y1 in predicting adolescents' behavioral problems at year 2 follow-up. Early adolescents experiencing interpersonal racial–ethnic discrimination by multiple sources, including teachers, students, and other adults, reported higher levels of attention, internalizing, and externalizing problems. Parental warmth was protective for the association between interpersonal racial–ethnic discrimination and early adolescents' behavioral problems. Experiencing interpersonal racial–ethnic discrimination from teachers, peers, and other adults is related to heightened attention, internalizing, and externalizing problems among racially–ethnically minoritized early adolescents. Parental warmth may reduce the risk of developing behavioral problems among early adolescents who experience interpersonal racial–ethnic discrimination from students, teachers, and other adults outside of school. In this cross sectional analysis of 3,245 early adolescents of color obtained from the Adolescent Brain Cognitive Development (ABCD) Study, the authors found that early adolescents experiencing interpersonal racial-ethnic discrimination from multiple sources, including teachers, students, and other adults, reported higher levels of behavioral problems (ie, internalizing, externalizing, and attention problems). Parental warmth was found to be protective for the association between interpersonal racial-ethnic discrimination and early adolescents' behavioral problems. These findings emphasize the importance of assessing experiences of interpersonal racial-ethnic discrimination among racially-ethnically minoritized early adolescents and contribute to the understanding of parental warmth as a protective factor for early adolescents to cope with such experiences. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. One or more of the authors of this paper received support from a program designed to increase minority representation in science. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. While citing references scientifically relevant for this work, we also actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our reference list. We actively worked to promote sex and gender balance in our author group. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list. [ABSTRACT FROM AUTHOR]

Key Points: Question: Does adolescent cannabis initiation contribute to changes in psychosis spectrum symptoms, reflect a shared vulnerability for both cannabis use and psychosis risk, or suggest efforts to self-medicate symptoms? Findings: This cohort study of 11 868 adolescents found that adolescents who used cannabis at any point during the study period reported a greater number of psychosis spectrum symptoms and more distress from symptoms relative to those who never used cannabis, providing evidence for shared vulnerability. Additionally, consistent with a self-medication hypothesis, the number of psychosis spectrum symptoms and distress from symptoms increased in the time leading up to cannabis initiation, whereas mixed evidence was observed for an increase in psychosis symptoms after cannabis initiation (ie, contributing risk). Meaning: These findings underscore the importance of accounting for shared vulnerability and self-medication effects when modeling cannabis–psychosis risk associations, particularly in adolescence. This cohort study assesses associations between cannabis use and psychosis symptoms among adolescents. Importance: Adolescent cannabis use has been consistently posited to contribute to the onset and progression of psychosis. However, alternative causal models may account for observed associations between cannabis use and psychosis risk, including shared vulnerability for both cannabis use and psychosis or efforts to self-medicate distress from psychosis spectrum symptomology. Objective: To test 3 hypotheses that may explain cannabis–psychosis risk associations by modeling psychosis spectrum symptom trajectories prior to and after cannabis initiation across adolescent development (approximately 10-15 years of age). Design, Setting, and Participants: This cohort study used data from 5 waves across 4 years of follow-up from the Adolescent Brain Cognitive Development (ABCD) Study. The ABCD study is an ongoing large-scale, longitudinal study of brain development and mental and physical health of children in the US launched in June 2016. Data are collected from 21 research sites. The study included data from 11 868 adolescents aged 9 to 10 years at baseline. Three participants were excluded from the present analysis owing to missing data. Data analysis was performed from September 2023 to July 2024. Main Outcomes and Measures: Discontinuous growth curve modeling was used to assess trajectories of psychosis spectrum symptoms before and after cannabis initiation. Control variables considered for this investigation were age, sex, internalizing and externalizing symptoms, socioeconomic status, parental mental health, and other substance use. Results: Among the 11 858 participants at wave 1, the mean (SD) age was 9.5 (0.5) years; 6182 (52%) participants were male. Consistent with a shared vulnerability hypothesis, adolescents who used cannabis at any point during the study period reported a greater number of psychosis spectrum symptoms (B, 0.86; 95% CI, 0.68-1.04) and more distress (B, 1.17; 95% CI, 0.96-1.39) from psychosis spectrum symptoms relative to those who never used cannabis. Additionally, consistent with a self-medication hypothesis, the number of psychosis spectrum symptoms (B, 0.16; 95% CI, 0.12-0.20) and distress (B, 0.23; 95% CI, 0.21-0.26) from psychosis spectrum symptoms increased in the time leading up to cannabis initiation. We observed mixed evidence for an increase in psychosis symptoms after cannabis initiation (ie, contributing risk hypothesis). Conclusion and Relevance: The findings underscore the importance of accounting for shared vulnerability and self-medication effects when modeling cannabis–psychosis risk associations. [ABSTRACT FROM AUTHOR]

Background: Neonatal appendicitis (NA) is a rare condition with an estimated incidence of 0.04% to 0.2%. It is more prevalent in male preterm infants, with a mortality rate of 20% to 25%. It is usually misdiagnosed as neonatal necrotizing enterocolitis (NEC) owing to its diverse diagnostic challenges. Poor perfusion, hypoxia, anemia, or any other condition that impairs intestinal blood supply is a risk factor for bowel injury, which could explain the physiopathology of NA. Clinical Findings: We describe an interesting case of a preterm infant with recurrent episodes of abdominal distension and persistent anemia who was finally diagnosed with NA. Primary Diagnosis: The patient was treated with exploratory laparotomy and appendicectomy, with further symptom resolution. The diagnosis was confirmed by pathological examination. Interventions: Surgery for acute abdomen secondary to perforated appendicitis. Outcomes: Improved recurrent abdominal distension and persistent anemia and achieved full enteral nutrition. Patients with other diseases such as Hirschsprung's disease were ruled out. Practice Recommendations: This case demonstrates that identifying the early signs and symptoms of NA requires a high index of suspicion. Anemia may play a significant role in the etiology of intestinal injury, increasing the risk of NA and NEC. Further studies are needed to explore the association between anemia and intestinal injury and its implications for neurodevelopment. [ABSTRACT FROM AUTHOR]

The central nervous system (CNS) requires specialized blood vessels to support neural function within specific microenvironments. During neurovascular development, endothelial Wnt/β-catenin signaling is required for BBB development within the brain parenchyma, whereas fenestrated blood vessels that lack BBB properties do not require Wnt/β-catenin signaling. Here, we used zebrafish to further characterize this phenotypic heterogeneity of the CNS vasculature. Using transgenic reporters of Wnt/β-catenin transcriptional activity, we found an inverse correlation between activated Wnt/β-catenin signaling in endothelial cells (ECs) versus non-ECs within these distinct microenvironments. Our results indicated that the level of Wnt/β-catenin signaling in non-ECs may regulate Wnt/β-catenin activity in adjacent ECs. To further test this concept, we generated a transgenic Tet-On inducible system to drive constitutively active β-catenin expression in neural progenitor cells (NPCs). We found that dose-dependent activation of Wnt/β-catenin in NPCs caused severe deficiency in CNS angiogenesis and BBB development. Additionally, we discovered a significant increase in the proliferation of microglia and infiltration of peripheral neutrophils indicative of a stereotypical neuroinflammatory response. In conclusion, our results demonstrate the importance of proper Wnt/β-catenin signaling within specific CNS microenvironments and highlights the potentially deleterious consequences of aberrant Wnt activation. [ABSTRACT FROM AUTHOR]

AbstractPurpose: Children with limited speech and motor function, frequently subsequent to neurodevelopmental conditions, often require augmentative and alternative communication (AAC). Assessment practices to inform effective AAC interventions for these children can be challenging because of the considerable heterogeneity and range of factors that require consideration. An improved understanding of current assessment practices is imperative to optimize the provision of AAC.Materials and Methods: We conducted a scoping review to identify the assessment practices used with children with limited speech and motor function subsequent to neurodevelopmental conditions (birth to 18 years) within the Participation Model of AAC.Results: In total, 171 assessment practices were identified. Almost all were related to access supports and barriers, of which the majority focused on children’s capabilities. Relatively few methods were identified to support the assessment of children’s participation patterns and communication needs or opportunity supports and barriers. Twenty-three percent of identified formal assessment practices required modifications to established procedures, and 10% could not be completed by all child participants.Conclusion: Identified assessment practices focused primarily on children and their abilities, whereas very few focused on external factors (e.g., environmental and opportunity supports and barriers). Additionally, identified assessment practices may inaccurately measure the abilities of children with limited speech and motor function, as the procedures often required modification.IMPLICATIONS FOR REHABILITATIONWithout adequate practices to assess all areas of the Participation Model, clinicians may have difficulty providing comprehensive AAC servicesFuture research should focus on developing practices to assess children’s opportunity and environmental supports and barriersThere is a need for practices that are more accessible to children with limited speech and motor functionWithout adequate practices to assess all areas of the Participation Model, clinicians may have difficulty providing comprehensive AAC servicesFuture research should focus on developing practices to assess children’s opportunity and environmental supports and barriersThere is a need for practices that are more accessible to children with limited speech and motor function [ABSTRACT FROM AUTHOR]

Complex structural and functional changes occurring in typical and atypical development necessitate multidimensional approaches to better understand the risk of developing psychopathology. Here, we simultaneously examined structural and functional brain network patterns in relation to dimensions of psychopathology in the Adolescent Brain Cognitive Development (ABCD) dataset. Several components were identified, recapitulating the psychopathology hierarchy, with the general psychopathology (p) factor explaining most covariance with multimodal imaging features, while the internalizing, externalizing, and neurodevelopmental dimensions were each associated with distinct morphological and functional connectivity signatures. Connectivity signatures associated with the p factor and neurodevelopmental dimensions followed the sensory-to-transmodal axis of cortical organization, which is related to the emergence of complex cognition and risk for psychopathology. Results were consistent in two separate data subsamples and robust to variations in analytical parameters. Although model parameters yielded statistically significant brain–behavior associations in unseen data, generalizability of the model was rather limited for all three latent components (r change from within- to out-of-sample statistics: LC1within = 0.36, LC1out = 0.03; LC2within = 0.34, LC2out = 0.05; LC3within = 0.35, LC3out = 0.07). Our findings help in better understanding biological mechanisms underpinning dimensions of psychopathology, and could provide brain-based vulnerability markers. [ABSTRACT FROM AUTHOR]

[Display omitted] • Mercaptomethylimidazole (MMI) affects the evolution of total neonatal development. • Hypothyroidism alter neonatal expression of neuronal and inducible nitric oxide synthases. • Changes of perinatal nitic oxide synthase expression influence protein nitration. • Thyroid hormones are crucial for nitric oxide production during postnatal development. Thyroid hormones play an important morphogenetic role during the fetal and neonatal periods and regulate numerous metabolic processes. In the central nervous system, they control myelination and overall brain development, regional gene expression, and regulation of oxygen consumption. Their deficiency in the fetal and neonatal periods causes severe mental retardation, due to lack of thyroid function, or to iodine deficiency. At the same time, nitric oxide is an atypical neurotransmitter that also has special relevance in neuronal development and plasticity and functions as a vasodilator, regulating cerebral blood flow. Although under physiological conditions it functions as a neuroprotector, in excess it can be neurotoxic. We have studied, by immunocytochemical and Western blot techniques, the evolution of the expression of neuronal and inducible isoforms of the enzyme nitric oxide synthase, and of nitrotyrosine as a marker of protein nitration produced by the presence of nitric oxide, during the early stages of postnatal brain development. We induced hypothyroidism by administering mercaptomethylimidazole to pregnant mothers, from the seventh day of gestation until the sacrifice of the offspring. The results show a delay in the evolution of the expression of the two isoforms of the enzyme nitric oxide synthase in hypothyroid animals, followed by an anomalous overexpression in later stages. Finally, the expression of nitrotyrosine follows an evolution that is synchronized with that shown by both isoenzymes in control and hypothyroid animals. [ABSTRACT FROM AUTHOR]

The intracellular protozoan Toxoplasma gondii manipulates host cell signaling to avoid targeting by autophagosomes and lysosomal degradation. Epidermal Growth Factor Receptor (EGFR) is a mediator of this survival strategy. However, EGFR expression is limited in the brain and retina, organs affected in toxoplasmosis. This raises the possibility that T. gondii activates a signaling mechanism independently of EGFR to avoid autophagic targeting. We report T. gondii activates Src to promote parasite survival even in cells that lack EGFR. Blockade of Src triggered LC3 and LAMP-1 recruitment around the parasitophorous vacuole (PV) and parasite killing dependent on the autophagy protein, ULK1, and lysosomal enzymes. Src promoted PI3K activation and recruitment of activated Akt to the PV membrane. T. gondii promoted Src association with PTEN, and PTEN phosphorylation at Y240, S380, T382, and T383, hallmarks of an inactive PTEN conformation known to maintain Akt activation. Blockade of parasite killing was dependent of activated Akt. Src knockdown or treatment with the Src family kinase inhibitor, Saracatinib, impaired these events, leading to PTEN accumulation around the PV and a reduction in activated Akt recruitment at this site. Saracatinib treatment in mice with pre-established cerebral and ocular toxoplasmosis promoted PTEN recruitment around tachyzoites in neural tissue impairing recruitment of activated Akt, profoundly reducing parasite load and neural histopathology that were dependent of the autophagy protein, Beclin 1. Our studies uncovered an EGFR-independent pathway activated by T. gondii that enables its survival and is central to the development of neural toxoplasmosis. Author summary: Toxoplasma gondii, a causative agent of retinitis and encephalitis, survives within host cells by avoiding autophagy-dependent degradation by the lysosome. While T. gondii activates EGFR to avoid autophagic killing, EGFR expression is limited in neural tissue. We uncovered that, independently of EGFR, T. gondii activates the ubiquitous molecule, Src, resulting in PTEN inhibition and decoration of the parasite-containing vacuole with activated Akt (negative regulator of autophagy). Inhibition of Src impaired this cascade, leading to autophagic killing of T. gondii demonstrated by autophagosomal and lysosomal marker recruitment and parasite killing dependent on ULK1 and lysosomal enzymes. The Src family kinase inhibitor, Saracatinib, induced PTEN recruitment around parasites in neural tissue and impaired recruitment of activated Akt, causing a striking reduction in parasite load and histopathology in mice with ocular and cerebral toxoplasmosis. Autophagy-deficient mice treated with Saracatinib did not have improved parasite load or histopathology supporting the pivotal role of this pathway for parasite survival and development of toxoplasmosis. [ABSTRACT FROM AUTHOR]

Psychiatric disorders are influenced by genetic and environmental factors. However, their study is hindered by limitations on precisely characterizing human behavior. New technologies such as wearable sensors show promise in surmounting these limitations in that they measure heterogeneous behavior in a quantitative and unbiased fashion. Here, we analyze wearable and genetic data from the Adolescent Brain Cognitive Development (ABCD) study. Leveraging >250 wearable-derived features as digital phenotypes, we show that an interpretable AI framework can objectively classify adolescents with psychiatric disorders more accurately than previously possible. To relate digital phenotypes to the underlying genetics, we show how they can be employed in univariate and multivariate genome-wide association studies (GWASs). Doing so, we identify 16 significant genetic loci and 37 psychiatric-associated genes, including ELFN1 and ADORA3 , demonstrating that continuous, wearable-derived features give greater detection power than traditional case-control GWASs. Overall, we show how wearable technology can help uncover new linkages between behavior and genetics. [Display omitted] • Uniform processing of wearable and genomic data and integration with AI modeling and GWAS • AI framework uses wearable digital phenotypes to better predict psychiatric disorders • Univariate and multivariate digital phenotypes can act as a continuous response for GWAS • Wearable GWAS detects a larger number of loci compared with traditional case-control GWAS Complex disorders require precise strategies for their characterization. AI-based digital phenotypes from biosensors can be used to predict psychiatric disorders and identify GWAS loci. [ABSTRACT FROM AUTHOR]

AbstractPurposeMethodResultConclusionWhile there is evidence for the effectiveness of programmes targeting cyberbullying in general adolescent populations, less is known for adolescents with neurodevelopmental disorders, who are at heightened risk of involvement in cyberbullying. This scoping review aimed to identify and map the evidence in relation to managing cyberbullying among adolescents aged 10–19 with neurodevelopmental disorders.The following databases were searched: ProQuest (including dissertations and theses), PsychInfo, MEDLINE, Scopus, and Google Scholar. Two independent reviewers screened the studies in two stages: Title and abstract, and full text.Twenty-nine studies were included; 19 involved exploring existing strategies used by adolescents with neurodevelopmental disorders, their parents, teachers, or service providers, to manage cyberbullying. The remaining 10 papers implemented and evaluated the effectiveness of cyberbullying prevention and/or intervention programmes.While there is some emerging evidence for the efficacy of cyberbullying programs for adolescents with neurodevelopmental disorders, the literature is sparse. Future research should explore the efficacy of programmes delivered at classroom, small group, and individual levels and examine how adolescents with a range of neurodevelopmental disorders and diverse learning needs respond to such programmes. Critically, this may help reduce cyberbullying incidents and the subsequent impact on mental health among adolescents with neurodevelopmental disorders. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM), the most malignant primary brain tumor in adults, has poor prognosis irrespective of therapeutic advances due to its radio-resistance and infiltrative growth into brain tissue. The present study assessed functions and putative druggability of BRCA1-associated ATM activator 1 (BRAT1) as a crucial factor driving key aspects of GBM, including enhanced DNA damage response and tumor migration. By a stable depletion of BRAT1 in GBM and glioma stem-like (GSC) cell lines, we observed a delay in DNA double-strand break repair and increased sensitivity to radiation treatment, corroborated by in vitro and in vivo studies demonstrating impaired tumor growth and invasion. Proteomic and phosphoproteomic analyses further emphasize the role of BRAT1's cell migration and invasion capacity, with a notable proportion of downregulated proteins associated with these processes. In line with the genetic manipulation, we found that treatment with the BRAT1 inhibitor Curcusone D (CurD) significantly reduced GSC migration and invasion in an ex vivo slice culture model, particularly when combined with irradiation, resulting in a synergistic inhibition of tumor growth and infiltration. Our results reveal that BRAT1 contributes to GBM growth and invasion and suggest that therapeutic inhibition of BRAT1 with CurD or similar compounds might constitute a novel approach for anti-GBM directed treatments. [ABSTRACT FROM AUTHOR]

Kruppel-like factor 15 (KLF15), a member of the KLF family, is closely involved in many biological processes. However, the mechanism by which KLF15 regulates neural development is still unclear. Considering the complexity and importance of neural network development, in this study, we investigated the potent regulatory role of KLF15 in neural network development. KLF15 was detected highly expressed in the cerebellum and enriched in Purkinje cells, with a significant increase in KLF15 expression between 15 and 20 days of neural development. Knockdown of KLF15 led to loss of Purkinje cells and impaired motility in mice. Therefore, our study aims to elucidate the relationship between KLF15 and Purkinje cells in mice, may provide a new research idea for the developmental mechanism of the mouse cerebellum. [ABSTRACT FROM AUTHOR]

Although chromatin remodelers are among the most important risk genes associated with neurodevelopmental disorders (NDDs), the roles of these complexes during brain development are in many cases unclear. Here, we focused on the recently discovered ChAHP chromatin remodeling complex. The zinc finger and homeodomain transcription factor ADNP is a core subunit of this complex, and de novo ADNP mutations lead to intellectual disability and autism spectrum disorder. However, germline Adnp knockout mice were previously shown to exhibit early embryonic lethality, obscuring subsequent roles for the ChAHP complex in neurogenesis. To circumvent this early developmental arrest, we generated a conditional Adnp mutant allele. Using single-cell transcriptomics, cut&run-seq, and histological approaches, we show that during neocortical development, Adnp orchestrates the production of late-born, upper-layer neurons through a two-step process. First, Adnp is required to sustain progenitor proliferation specifically during the developmental window for upper-layer cortical neurogenesis. Accordingly, we found that Adnp recruits the ChAHP subunit Chd4 to genes associated with progenitor proliferation. Second, in postmitotic differentiated neurons, we define a network of risk genes linked to NDDs that are regulated by Adnp and Chd4. Taken together, these data demonstrate that ChAHP is critical for driving the expansion of upper-layer cortical neurons and for regulating neuronal gene expression programs, suggesting that these processes may potentially contribute to NDD etiology. [ABSTRACT FROM AUTHOR]

Axon guidance is a key event in neural circuit development that drives the correct targeting of axons to their targets through long distances and unique patterns. Exosomes, extracellular vesicles that are smaller than 100 nm, are secreted by most cell types in the brain. Regulation of cell-cell communication, neuroregeneration, and synapse formation by exosomes have been extensively studied. However, the interaction between exosomes and axon guidance molecules is poorly understood. This review summarizes the relationship between exosomes and canonical and non-canonical guidance cues and hypothesizes a possible model for exosomes mediating axon guidance between cells. The roles of exosomes in axon outgrowth, regeneration, and neurodevelopmental disorders are also reviewed, to discuss exosome-guidance interactions as potential clinical therapeutic targets. [ABSTRACT FROM AUTHOR]

Once believed to be the culprits of epileptogenic activity, the functional properties of balloon/giant cells (BC/GC), commonly found in some malformations of cortical development including focal cortical dysplasia type IIb (FCDIIb) and tuberous sclerosis complex (TSC), are beginning to be unraveled. These abnormal cells emerge during early brain development as a result of a hyperactive mTOR pathway and may express both neuronal and glial markers. A paradigm shift occurred when our group demonstrated that BC/GC in pediatric cases of FCDIIb and TSC are unable to generate action potentials and lack synaptic inputs. Hence, their role in epileptogenesis remained obscure. In this review, we provide a detailed characterization of abnormal non-neuronal cells including BC/GC, intermediate cells, and dysmorphic/reactive astrocytes found in FCDIIb and TSC cases, with special emphasis on electrophysiological and morphological assessments. Regardless of pathology, the electrophysiological properties of abnormal cells appear more glial-like, while others appear more neuronal-like. Their morphology also differs in terms of somatic size, shape, and dendritic elaboration. A common feature of these types of non-neuronal cells is their inability to generate action potentials. Thus, despite their distinct properties and etiologies, they share a common functional feature. We hypothesize that, although the exact role of abnormal non-neuronal cells in FCDIIb and TSC remains mysterious, it can be suggested that cells displaying more glial-like properties function in a similar way as astrocytes do, i.e., to buffer K+ ions and neurotransmitters, while those with more neuronal properties, may represent a metabolic burden due to high energy demands but inability to receive or transmit electric signals. In addition, due to the heterogeneity of these cells, a new classification scheme based on morphological, electrophysiological, and gene/protein expression in FCDIIb and TSC cases seems warranted. [ABSTRACT FROM AUTHOR]

Introduction: Grafts with alcohol-associated liver disease (ALD) subjected to prolonged cold ischaemia from donors after brain death (DBD) are typically unsuitable for transplantation. Here, we investigated the role of growth hormone (GH) in livers with ALD from DBDs and its relationship with vascular endothelial growth factor A (VEGFA) and VEGFB. Methods: Livers from rats fed ethanol for 6 weeks and with brain death (BD) were cold stored for 24 h and subjected to ex vivo reperfusion. Hepatic damage and proliferative and inflammatory parameters were analysed after BD, before graft retrieval, and after reperfusion. Survival was monitored using an in vivo transplantation model. Results: In DBDs, the administration of GH, which increased the levels in the intestine but not in the liver, induced the generation of both VEGFA and VEGFB in the intestine and protected against hepatic damage caused by BD before retrieving liver grafts from donors. However, VEGFA was the only factor that protected against damage after cold ischemia and reperfusion, which also increased the survival of the recipients. Discussion: In conclusion, the signalling pathway and beneficial properties of the GH-VEGFA/VEGFB pathway, in which the intestine-liver axis plays a key role, were disrupted when grafts with ALD from DBDs were retrieved from donors and subjected to cold ischemia and reperfusion. [ABSTRACT FROM AUTHOR]