Development Of Nervous System Research Articles

Transcriptomics and biochemical evidence of trigonelline ameliorating learning and memory decline in the senescence-accelerated mouse prone 8 (SAMP8) model by suppressing proinflammatory cytokines and elevating neurotransmitter release

In recent years, exploring natural compounds with functional properties to ameliorate aging-associated cognitive decline has become a research priority to ensure healthy aging. In the present study, we investigated the effects of Trigonelline (TG), a plant alkaloid, on memory and spatial learning in 16-week-old senescence-accelerated mouse model SAMP8 using an integrated approach for cognitive and molecular biology aspects. After 30 days of oral administration of TG at the dose of 5 mg/kg/day, the mice were trained in Morris Water Maze task. TG-treated SAMP8 mice exhibited significant improvement in the parameters of escape latency, distance moved, and annulus crossing index. Next, we performed a whole-genome transcriptome profiling of the mouse hippocampus using microarrays. Gene ontology analyses showed that a wide range of biological processes, including nervous system development, mitochondrial function, ATP synthesis, and several signaling pathways related to inflammation, autophagy, and neurotransmitter release, were significantly enriched in TG-treated SAMP8 compared to nontreated. Further, a nonlinear dimensionality reduction technique, Uniform Manifold Approximation and Projection (UMAP), was applied to identify clusters of functions that revealed TG primarily regulated pathways related to inflammation, followed by those involved in neurotransmitter release. In addition, a protein–protein interaction network analysis indicated that TG may exert its biological effects through negatively modulating Traf6-mediated NF-κB activation. Finally, ELISA test showed that TG treatment significantly decreased proinflammatory cytokines- TNFα and IL6 and increased neurotransmitters- dopamine, noradrenaline, and serotonin in mouse hippocampus. Altogether, our integrated bio-cognitive approach highlights the potential of TG in alleviating age-related memory and spatial impairment.

Whole-genome resequencing reveals genetic diversity and selection signals in warm temperate and subtropical Sillago sinica populations

BackgroundGenetic diversity and heterogeneous genomic signatures in marine fish populations may result from selection pressures driven by the strong effects of environmental change. Nearshore fishes are often exposed to complex environments and human activities, especially those with small ranges. However, studies on genetic diversity and population selection signals in these species have mostly been based on a relatively small number of genetic markers. As a newly recorded species of Sillaginidae, the population genetics and genomic selection signals of Sillago sinica are fragmented or even absent.ResultsTo address this theoretical gap, we performed whole-genome resequencing of 43 S. sinica individuals from Dongying (DY), Qingdao (QD) and Wenzhou (WZ) populations and obtained 4,878,771 high-quality SNPs. Population genetic analysis showed that the genetic diversity of S. sinica populations was low, but the genetic diversity of the WZ population was higher than that of the other two populations. Interestingly, the three populations were not strictly clustered within the group defined by their sampling location but showed an obvious geographic structure signal from the warm temperate to the subtropics. With further analysis, warm-temperate populations exhibited strong selection signals in genomic regions related to nervous system development, sensory function and immune function. However, subtropical populations showed more selective signalling for environmental tolerance and stress signal transduction.ConclusionsGenome-wide SNPs provide high-quality data to support genetic studies and localization of selection signals in S. sinica populations. The reduction in genetic diversity may be related to the bottleneck effect. Considering that low genetic diversity leads to reduced environmental adaptability, conservation efforts and genetic diversity monitoring of this species should be increased in the future. Differences in genomic selection signals between warm temperate and subtropical populations may be related to human activities and changes in environmental complexity. This study deepened the understanding of population genetics and genomic selection signatures in nearshore fishes and provided a theoretical basis for exploring the potential mechanisms of genomic variation in marine fishes driven by environmental selection pressures.

Duration of fetoscopic spina bifida repair does not affect the central nervous system in fetal lambs

Prenatal spina bifida aperta (SBA) repair improves neurologic outcomes, yet comes with a significant risk of prematurity and uterine scar-related complications. To reduce those, different fetoscopic techniques, e.g. with varying number of ports, are being explored. This has an impact on the duration of the procedure, potentially affecting central nervous system (CNS) development. Both the condition and anesthesia can impact the CNS, particularly the hippocampus, a region vital for prospective and episodic memory. Previous animal studies have shown the potential influence of anesthesia, premature delivery, and maternal surgery during pregnancy on this area. To compare the effects of 2- versus 3-port fetoscopic SBA repair in the fetal lamb model using neuron count of the hippocampus as primary outcome. Based on the hippocampal neuron count from previous lamb experiments, we calculated that we required five animals per group to achieve a statistical power of ≥ 80%. A SBA defect was created in fetal lambs at 75 days of gestation (term: 145 days). At 100 days, fetuses underwent either a 2-port or 3-port fetoscopic repair. At 143 days, all surviving fetuses were delivered by cesarean section, anesthetized and transcardially perfused with a mixture of formaldehyde and gadolinium. Next, they underwent neonatal brain and spine MRI following which these organs were harvested for histology. Hippocampus, frontal cortex, caudate nucleus, and cerebellum samples were immunostained to identify neurons, astrocytes, microglia, and markers associated with cell proliferation, myelination, and synapses. The degree of hindbrain herniation and the ventricular diameter were measured on MRI images and volumes of relevant brain and medulla areas were segmented. Both treatment groups included five fetuses and nine unoperated littermates served as normal controls. The durations for both skin-to-skin (341 ± 31 vs 287 ± 40 min; P=0.04) and fetal surgery (183 ± 30 vs 128 ± 22; P=0.01) were longer for the 2-port than for the 3-port approach. There were no significant differences in neuron density in the hippocampus, frontal cortex and cerebellum. In the caudate nucleus, the neuron count was higher in the 2-port group (965 ± 156 vs. 767 ± 92 neurons/mm2, P=0.04). There were neither differences in proliferation, astrogliosis, synaptophysin, or myelin. The tip of the cerebellar vermis was closer to the foramen magnum in 2-port animals compared to 3-port animals (-0.72 ± 0.67 mm vs. -2.47 ± 0.91 mm, P=0.009). There were no significant differences in the ratio of hippocampus, caudate nucleus, or cerebellar volume to body weight. For the spine, no differences were noted in spine volume/body weight ratio for the lower (L1/L2), mid (L3/L4), and higher (L5/6) levels. Compared to controls, in repaired animals the cerebellar vermis tip lays closer to the foramen magnum, parietal ventricles were enlarged and medulla volumes were reduced. In the experimental spina bifida fetal lamb model, a 2-port repair took 40% longer than a 3-port repair. There was however no indication of any relevant morphologic differences in the fetal brain.

Identification of exosomal microRNA panel as diagnostic and prognostic biomarker for small cell lung cancer

BackgroundSmall cell lung cancer (SCLC) has an exceptionally poor prognosis; as most of the cases are initially diagnosed as extensive disease with hematogenous metastasis. Therefore, the early diagnosis of SCLC is very important and may improve its prognosis.MethodsTo investigate the feasibility of early diagnosis of SCLC, we examined exosomal microRNAs (miRNAs) present in serum obtained from patients with SCLC. First, exosomes were isolated in serum from patients with SCLC and healthy individuals and were characterized using particle size and protein markers. Additionally, miRNA array was performed to define SCLC-specific exosomal miRNAs. Second, the obtained miRNAs were further validated employing a large cohort. Finally, the ability to diagnose SCLC was estimated by area under the curve (AUC), and intracellular mRNA change patterns were verified through validated miRNAs.ResultsFrom the miRNA array results, we selected 51-miRNAs based on p-values and top 10 differentially expressed genes, and 25-miRNAs were validated using quantitative reverse transcription-polymerase chain reaction. The 25-miRNAs were further validated employing a large cohort. Among them, 7-miRNAs showed significant differences. Furthermore, 6-miRNAs (miR-3565, miR-3124-5p, miR-200b-3p, miR-6515, miR-3126-3p and miR-9-5p) were up-regulated and 1-miRNA (miR-92b-5p) was down-regulated. The AUC value of each miRNA sets between 0.64 and 0.76, however the combined application of 3-miRNAs (miR-200b-3p, miR-3124-5p and miR-92b-5p) remarkably improved the diagnostic value (AUC = 0.93). Gene ontology analysis revealed that the 3-miRNA panel is linked to various oncogene pathways and nervous system development. When the 3-miRNAs were introduced to cells, the resulting changes in total mRNA expression strongly indicated the presence of lung diseases, including lung cancer. In addition, the 3-miRNA panel was significantly associated with a poorer prognosis, although individual miRNAs have not been validated as prognostic markers.ConclusionOur study identified SCLC-specific exosomal miRNAs, and the 3-miRNAs panel (miR-200b-3p, miR-3124-5p and miR-92b-5p) may serve as a diagnostic and prognostic marker for SCLC.Graphical abstract

Replenished microglia partially rescue schizophrenia-related stress response.

Microglia play an important role in the maintenance of brain and behavioral homeostasis. The protective effect of microglial replenishment was reported in neurological diseases, but whether microglial therapy would benefit psychiatric disorders such as schizophrenia has been unclear. As schizophrenia is a stress-vulnerable disorder and psychosocial stress promotes inflammation and microglial activation, we aim to understand how microglial replenishment works in stress-associated schizophrenia. We used a CSF1R-mediated pharmacological approach to study repopulated microglia (repMg) in a cohort of mice (n = 10/group) undergoing chronic unpredictable stress (CUS). We further studied a cohort of first-episode schizophrenia (FES, n = 74) patients who had higher perceived stress scores (PSS) than healthy controls (HCs, n = 68). Reborn microglia attenuated CUS-induced learned hopelessness and social withdrawal but not anxiety in mice. Compared to control, CUS- or repMg-induced differentially expressed genes (DEGs) in the prefrontal cortex regulated nervous system development and axonal guidance. CUS also caused microglial hyper-ramification and increased engulfment of synaptophysin and vesicular glutamate transporter-2 by microglia and astrocytes, which were recovered in CUS + repMg (all p < 0.05). Moreover, FES patients had smaller hippocampal fimbria than HCs (p < 1e-7), which were negatively associated with PSS (r = -0.397, p = 0.003). Blood DEGs involved in immune system development were also associated with PSS and the right fimbria more prominently in FES patients than HCs (Zr, p < 0.0001). The KCNQ1 was a partial mediator between PSS and fimbria size (β = -0.442, 95% CI: -1.326 ~ -0.087). Microglial replenishment may potentially benefit psychiatric disorders such as schizophrenia.

Longitudinal scRNA-seq analysis in mouse and human informs optimization of rapid mouse astrocyte differentiation protocols.

Macroglia (astrocytes and oligodendrocytes) are required for normal development and function of the central nervous system, yet many questions remain about their emergence during the development of the brain and spinal cord. Here we used single-cell/single-nucleus RNA sequencing (scRNA-seq/snRNA-seq) to analyze over 298,000 cells and nuclei during macroglia differentiation from mouse embryonic and human-induced pluripotent stem cells. We computationally identify candidate genes involved in the fate specification of glia in both species and report heterogeneous expression of astrocyte surface markers across differentiating cells. We then used our transcriptomic data to optimize a previous mouse astrocyte differentiation protocol, decreasing the overall protocol length and complexity. Finally, we used multi-omic, dual single-nuclei (sn)RNA-seq/snATAC-seq analysis to uncover potential genomic regulatory sites mediating glial differentiation. These datasets will enable future optimization of glial differentiation protocols and provide insight into human glial differentiation.

Long-term effects of prenatal magnesium sulfate exposure on nervous system development in preterm-born children.

This study used structural magnetic resonance imaging to analyze changes in the gray matter volume (GMV) of preterm-born (PTB) and term-born (TB) children to help elucidate the influence of magnesium sulfate treatment on the nervous system development. A total of 51 subjects were recruited, including 28 PTB and 23 TB children. The intelligence scale and MRI scan were completed at the corrected age of 10 to 16 years. A whole-brain voxel-wise analysis tested the main effect of the status (PTB without magnesium, PTB with magnesium, and TB) using a factorial design in SPM8. The mean volumes of the regions that showed significant group effects on the GMV after the FDR correction were extracted in the common space for each subject. Verbal and full-scale intelligence quotient scores were significantly lower for PTB children without magnesium than for TB children; however, the scores of PTB children with magnesium and TB children were almost identical. Compared with TB children, PTB children had significantly reduced left straight gyrus and left inferior frontal gyrus GMVs; however, the volumes of PTB children with magnesium were closer to those of TB children. Changes in the GMV of the left inferior frontal gyrus were significantly correlated with full-scale and verbal intelligence quotient scores, whereas the lower gestational age at the time of mgsou4 treatment led to a larger GMV of the left inferior frontal gyrus. Brain structural abnormalities could exist in PTB children. The GMVs of the left straight gyrus and left inferior frontal gyrus were significantly reduced in these children. The influence of magnesium sulfate treatment was not significant, but the cognitive levels of these children were significantly increased and almost identical to those of TB children. Initiation of magnesium sulfate treatment during gestation is negatively correlated with the left inferior frontal gyrus GMV.

Contemporary Understanding of the Central Autonomic Nervous System in Fetal-Neonatal Transition

THE CRITICAL ROLE OF THE CENTRAL AUTONOMIC NERVOUS SYSTEM IN FETAL-NEONATAL TRANSITION: Sarah B. Mulkey, Adre dú Plessis Seminars in Pediatric Neurology Volume 28, December 2018, Pages 29-37 The objective of this article is to understand the complex role of the central autonomic nervous system in normal and complicated fetal-neonatal transition and how autonomic nervous system dysfunction can lead to brain injury. The central autonomic nervous system supports coordinated fetal transitional cardiovascular, respiratory, and endocrine responses to provide safe transition of the fetus at delivery. Fetal and maternal medical and environmental exposures can disrupt normal maturation of the autonomic nervous system in utero, cause dysfunction, and complicate fetal-neonatal transition. Brain injury may both be caused by autonomic nervous system failure and contribute directly to autonomic nervous system dysfunction in the fetus and newborn. The central autonomic nervous system has multiple roles in supporting transition of the fetus. Future studies should aim to improve real-time monitoring of fetal autonomic nervous system function and in supporting typical autonomic nervous system development even under complicated conditions.

Ontogeny of working memory and behavioural flexibility in the free movement pattern (FMP) Y-maze in zebrafish

The acquisition of executive skills such as working memory, decision-making and adaptive responding occur at different stages of central nervous system development. Zebrafish (Danio rerio) are increasingly used in behavioural neuroscience for complex behavioural tasks, and there is a critical need to understand the ontogeny of their executive functions. Zebrafish across developmental stages (4, 7, 14, 30 and 90 days post fertilisation (dpf)), were assessed to track development of working memory (WM) and behavioural flexibility (BF) using the free movement pattern Y-maze (FMP Y-maze). Several differences in both WM and BF were identified during the transition from yolk-dependent to independent feeding. Specifically, WM is evident in all age groups, even from 4 dpf. However, BF is not developed until larvae start free feeding, and show significant improvement thereafter, with young adults (90 dpf) demonstrating the most well-defined BF. We demonstrate, for the first time, objective WM processes in 4 dpf zebrafish larvae. This suggests that those wishing to study WM in zebrafish may be able to do so from 4 dpf, thus drastically increasing throughput. In addition, we show that zebrafish follow distinct stages of cognitive development and age-related changes during the early developmental period. Finally, our findings indicate distinct WM and BF mechanisms, which may be useful to study for translational purposes.

CUT homeobox genes: transcriptional regulation of neuronal specification and beyond.

CUT homeobox genes represent a captivating gene class fulfilling critical functions in the development and maintenance of multiple cell types across a wide range of organisms. They belong to the larger group of homeobox genes, which encode transcription factors responsible for regulating gene expression patterns during development. CUT homeobox genes exhibit two distinct and conserved DNA binding domains, a homeodomain accompanied by one or more CUT domains. Numerous studies have shown the involvement of CUT homeobox genes in diverse developmental processes such as body axis formation, organogenesis, tissue patterning and neuronal specification. They govern these processes by exerting control over gene expression through their transcriptional regulatory activities, which they accomplish by a combination of classic and unconventional interactions with the DNA. Intriguingly, apart from their roles as transcriptional regulators, they also serve as accessory factors in DNA repair pathways through protein-protein interactions. They are highly conserved across species, highlighting their fundamental importance in developmental biology. Remarkably, evolutionary analysis has revealed that CUT homeobox genes have experienced an extraordinary degree of rearrangements and diversification compared to other classes of homeobox genes, including the emergence of a novel gene family in vertebrates. Investigating the functions and regulatory networks of CUT homeobox genes provides significant understanding into the molecular mechanisms underlying embryonic development and tissue homeostasis. Furthermore, aberrant expression or mutations in CUT homeobox genes have been associated with various human diseases, highlighting their relevance beyond developmental processes. This review will overview the well known roles of CUT homeobox genes in nervous system development, as well as their functions in other tissues across phylogeny.

P04.10.A ASSESSMENT OF VDR STATUS BY IMMUNOHISTOCHEMISTRY IN CHILDHOOD MALIGNANCIES - VDR EXPRESSION PATTERN OF CNS TUMORS

Abstract BACKGROUND Childhood cancers, including CNS tumors, the second most prevalent entities after hematological malignancies cannot generally be prevented or identified through screening, the disease is often diagnosed at advanced stages, and this obviously affects patient outcomes negatively. There is an urgent need for identifying prognostic and therapeutic biomarkers. Our previous work has shown a correlation between lower vitamin D levels in children with cancer and adverse prognosis. VDR expression in childhood solid tumors has been linked to tumor characteristics and patient survival only in few studies, moreover literature found that VDR plays a role in the development of the central nervous system. METHODS For this study, 177 children with solid tumors were selected whose biopsies and tumor tissue formalin-fixed, paraffin-embedded tissue blocks were available for immunohistochemical (IHC) analysis at Semmelweis University, Budapest (Hungary). To investigate the association between the presence of VDR in the tumor tissue and outcome, tumor samples and the survival dataset of 110 children were available. RESULTS We found that minor VDR expression was associated with a significantly less favorable prognosis (p = 0.0061) in the examined childhood solid tumors. The rate of VDR expression differed significantly between tumor types (p &amp;lt;0.0001). In case of CNS tumors pathological observations on VDR expression characteristics partly not correlated with previous literature. In some ependymoma samples an utterly novel VDR pattern was observed. CONCLUSION In conclusion, VDR expression measured by IHC staining is inversely associated with aggressive characteristics in different childhood cancers. The downregulation of VDR expression in more aggressive childhood cancers suggests that functional vitamin D activity may slow or block cancer progression. The presence of VDR may have prognostic and therapeutic implications for CNS malignancies. Knowledge of the VDR status in childhood solid tumors provides clinicians with a valuable biomarker and based on this, additional therapy (vitamin D, and analogs) to use alongside conventional first-line oncotherapy.

Coordination of alternative splicing and alternative polyadenylation revealed by targeted long read sequencing

Nervous system development is associated with extensive regulation of alternative splicing (AS) and alternative polyadenylation (APA). AS and APA have been extensively studied in isolation, but little is known about how these processes are coordinated. Here, the coordination of cassette exon (CE) splicing and APA in Drosophila was investigated using a targeted long-read sequencing approach we call Pull-a-Long-Seq (PL-Seq). This cost-effective method uses cDNA pulldown and Nanopore sequencing combined with an analysis pipeline to quantify inclusion of alternative exons in connection with alternative 3’ ends. Using PL-Seq, we identified genes that exhibit significant differences in CE splicing depending on connectivity to short versus long 3’UTRs. Genomic long 3’UTR deletion was found to alter upstream CE splicing in short 3’UTR isoforms and ELAV loss differentially affected CE splicing depending on connectivity to alternative 3’UTRs. This work highlights the importance of considering connectivity to alternative 3’UTRs when monitoring AS events.

MBMethPred: a computational framework for the accurate classification of childhood medulloblastoma subgroups using data integration and AI-based approaches.

Childhood medulloblastoma is a malignant form of brain tumor that is widely classified into four subgroups based on molecular and genetic characteristics. Accurate classification of these subgroups is crucial for appropriate treatment, monitoring plans, and targeted therapies. However, misclassification between groups 3 and 4 is common. To address this issue, an AI-based R package called MBMethPred was developed based on DNA methylation and gene expression profiles of 763 medulloblastoma samples to classify subgroups using machine learning and neural network models. The developed prediction models achieved a classification accuracy of over 96% for subgroup classification by using 399 CpGs as prediction biomarkers. We also assessed the prognostic relevance of prediction biomarkers using survival analysis. Furthermore, we identified subgroup-specific drivers of medulloblastoma using functional enrichment analysis, Shapley values, and gene network analysis. In particular, the genes involved in the nervous system development process have the potential to separate medulloblastoma subgroups with 99% accuracy. Notably, our analysis identified 16 genes that were specifically significant for subgroup classification, including EP300, CXCR4, WNT4, ZIC4, MEIS1, SLC8A1, NFASC, ASCL2, KIF5C, SYNGAP1, SEMA4F, ROR1, DPYSL4, ARTN, RTN4RL1, and TLX2. Our findings contribute to enhanced survival outcomes for patients with medulloblastoma. Continued research and validation efforts are needed to further refine and expand the utility of our approach in other cancer types, advancing personalized medicine in pediatric oncology.

Prenatal and adolescent alcohol exposure, neuroinflammation, and Alzheimer’s disease: a network meta analysis approach

Abstract Objectives This review aims to determine the connection between developmental alcohol exposure and its potential impact on Alzheimer's disease (AD) later in life. We employ a network meta-analysis approach and examine gene fold changes from literature and Gene Expression Omnibus (GEO) datasets. Our goal is to investigate whether prenatal alcohol exposure (PAE) and/or adolescent alcohol exposure (AAE) could activate specific neuroinflammatory genes, potentially increasing the risk of AD development. Content We conducted a comprehensive analysis of brain datasets using a network meta-analysis approach. By synthesizing gene fold changes from literature and GEO datasets, we examined the potential impact of developmental alcohol exposure on increased risk of developing AD in the future. Summary Our findings reveal significant associations between alcohol exposure and critical functional categories and diseases in the brain. Alcohol exposure was strongly linked to the “Inflammatory Response” and “Nervous System Development and Function” categories, indicative of inflammatory reactions in the brain and detrimental effects on nervous system integrity. Furthermore, we observed links with “Organismal Injury and Abnormalities” and “Cell Death and Survival.” Pathway analysis revealed dysregulation in neuroinflammatory, ERK/MAPK signaling, amyloid processing, IL-1 signaling and calcium signaling pathways, suggesting their potential involvement in alcohol-induced neurotoxicity. Outlook This review highlights the necessity of recognizing developmental alcohol exposure as a potential risk factor for AD and shed light on the underlying mechanisms that may contribute to alcohol-induced neurotoxicity. By expanding our understanding of these mechanisms, we can better address the complex relationship between developmental alcohol exposure and neurodegenerative disorders like AD.

Activity based restorative therapy considerations for children: medical and therapeutic perspectives for the pediatric population.

Well-established scientific evidence demonstrates that activity is essential for the development and repair of the central nervous system, yet traditional rehabilitation approaches target muscles only above the lesion as a means of compensation. Activity-Based Rehabilitation (ABR) represents an evolving paradigm shift in neurorehabilitation targeting activation of the neuromuscular system below the lesion. Based on activity-dependent plasticity, ABR offers high intensity activation of the nervous system to optimize the capacity for recovery, while working to offset the chronic complications that occur as a result of neurologic injury. Treatment focus shifts from compensatory training to promotion of restoration of function with special emphasis on normalizing sensory cues and movement kinematics. ABR in children carries special considerations for a developing nervous system and the focus is not just restoring functions but advancing functions in line with typical development. Application of activity-based interventions includes traditional rehabilitation strategies at higher intensity and frequency than in traditional models, including locomotor training, functional electrical stimulation, massed practice, and task specific training, applied across the continuum of care from early intervention to the chronic condition.

A guide to complement biology, pathology and therapeutic opportunity.

Complement has long been considered a key innate immune effector system that mediates host defence and tissue homeostasis. Yet, growing evidence has illuminated a broader involvement of complement in fundamental biological processes extending far beyond its traditional realm in innate immunity. Complement engages in intricate crosstalk with multiple pattern-recognition and signalling pathways both in the extracellular and intracellular space. Besides modulating host-pathogen interactions, this crosstalk guides early developmental processes and distinct cell trajectories, shaping tissue immunometabolic and regenerative programmes in different physiological systems. This Review provides a guide to the system-wide functions of complement. It highlights illustrative paradigm shifts that have reshaped our understanding of complement pathobiology, drawing examples from evolution, development of the central nervous system, tissue regeneration and cancer immunity. Despite its tight spatiotemporal regulation, complement activation can be derailed, fuelling inflammatory tissue pathology. The pervasive contribution of complement to disease pathophysiology has inspired a resurgence of complement therapeutics with major clinical developments, some of which have challenged long-held dogmas. We thus highlight major therapeutic concepts and milestones in clinical complement intervention.

Associative gene networks reveal novel candidates important for ADHD and dyslexia comorbidity

BackgroundAttention deficit hyperactivity disorder (ADHD) is commonly associated with developmental dyslexia (DD), which are both prevalent and complicated pediatric neurodevelopmental disorders that have a significant influence on children’s learning and development. Clinically, the comorbidity incidence of DD and ADHD is between 25 and 48%. Children with DD and ADHD may have more severe cognitive deficiencies, a poorer level of schooling, and a higher risk of social and emotional management disorders. Furthermore, patients with this comorbidity are frequently treated for a single condition in clinical settings, and the therapeutic outcome is poor. The development of effective treatment approaches against these diseases is complicated by their comorbidity features. This is often a major problem in diagnosis and treatment. In this study, we developed bioinformatical methodology for the analysis of the comorbidity of these two diseases. As such, the search for candidate genes related to the comorbid conditions of ADHD and DD can help in elucidating the molecular mechanisms underlying the comorbid condition, and can also be useful for genotyping and identifying new drug targets.ResultsUsing the ANDSystem tool, the reconstruction and analysis of gene networks associated with ADHD and dyslexia was carried out. The gene network of ADHD included 599 genes/proteins and 148,978 interactions, while that of dyslexia included 167 genes/proteins and 27,083 interactions. When the ANDSystem and GeneCards data were combined, a total of 213 genes/proteins for ADHD and dyslexia were found. An approach for ranking genes implicated in the comorbid condition of the two diseases was proposed. The approach is based on ten criteria for ranking genes by their importance, including relevance scores of association between disease and genes, standard methods of gene prioritization, as well as original criteria that take into account the characteristics of an associative gene network and the presence of known polymorphisms in the analyzed genes. Among the top 20 genes with the highest priority DRD2, DRD4, CNTNAP2 and GRIN2B are mentioned in the literature as directly linked with the comorbidity of ADHD and dyslexia. According to the proposed approach, the genes OPRM1, CHRNA4 and SNCA had the highest priority in the development of comorbidity of these two diseases. Additionally, it was revealed that the most relevant genes are involved in biological processes related to signal transduction, positive regulation of transcription from RNA polymerase II promoters, chemical synaptic transmission, response to drugs, ion transmembrane transport, nervous system development, cell adhesion, and neuron migration.ConclusionsThe application of methods of reconstruction and analysis of gene networks is a powerful tool for studying the molecular mechanisms of comorbid conditions. The method put forth to rank genes by their importance for the comorbid condition of ADHD and dyslexia was employed to predict genes that play key roles in the development of the comorbid condition. The results can be utilized to plan experiments for the identification of novel candidate genes and search for novel pharmacological targets.

The role of microRNAs in neurobiology and pathophysiology of the hippocampus.

MicroRNAs (miRNAs) are short non-coding and well-conserved RNAs that are linked to many aspects of development and disorders. MicroRNAs control the expression of genes related to different biological processes and play a prominent role in the harmonious expression of many genes. During neural development of the central nervous system, miRNAs are regulated in time and space. In the mature brain, the dynamic expression of miRNAs continues, highlighting their functional importance in neurons. The hippocampus, as one of the crucial brain structures, is a key component of major functional connections in brain. Gene expression abnormalities in the hippocampus lead to disturbance in neurogenesis, neural maturation and synaptic formation. These disturbances are at the root of several neurological disorders and behavioral deficits, including Alzheimer's disease, epilepsy and schizophrenia. There is strong evidence that abnormalities in miRNAs are contributed in neurodegenerative mechanisms in the hippocampus through imbalanced activity of ion channels, neuronal excitability, synaptic plasticity and neuronal apoptosis. Some miRNAs affect oxidative stress, inflammation, neural differentiation, migration and neurogenesis in the hippocampus. Furthermore, major signaling cascades in neurodegeneration, such as NF-Kβ signaling, PI3/Akt signaling and Notch pathway, are closely modulated by miRNAs. These observations, suggest that microRNAs are significant regulators in the complicated network of gene regulation in the hippocampus. In the current review, we focus on the miRNA functional role in the progression of normal development and neurogenesis of the hippocampus. We also consider how miRNAs in the hippocampus are crucial for gene expression mechanisms in pathophysiological pathways.

A genomic estimated breeding value-assisted reduction method of single nucleotide polymorphism sets: a novel approach for determining the cutoff thresholds in genome-wide association studies and best linear unbiased prediction

ABSTRACT Traditionally, the p-value is the criterion for the cutoff threshold to determine significant markers in genome-wide association studies (GWASs). Choosing the best subset of markers for the best linear unbiased prediction (BLUP) for improved prediction ability (PA) has become an interesting issue. However, when dealing with many traits having the same marker information, the p-values’ themselves cannot be used as an obvious solution for having a confidence in GWAS and BLUP. We thus suggest a genomic estimated breeding value-assisted reduction method of the single nucleotide polymorphism (SNP) set (GARS) to address these difficulties. GARS is a BLUP-based SNP set decision presentation. The samples were Landrace pigs and the traits used were back fat thickness (BF) and daily weight gain (DWG). The prediction abilities (PAs) for BF and DWG for the entire SNP set were 0.8 and 0.8, respectively. By using the correlation between genomic estimated breeding values (GEBVs) and phenotypic values, selecting the cutoff threshold in GWAS and the best SNP subsets in BLUP was plausible as defined by GARS method. 6,000 SNPs in BF and 4,000 SNPs in DWG were considered as adequate thresholds. Gene Ontology (GO) analysis using the GARS results of the BF indicated neuron projection development as the notable GO term, whereas for the DWG, the main GO terms were nervous system development and cell adhesion.

Low-dose Cu exposure enhanced α-synuclein accumulation associates with mitochondrial impairments in mice model of Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disorder that mainly affects the elder population, and its etiology is enigmatic. Both environmental risks and genetics may influence the development of PD. Excess copper causes neurotoxicity and accelerates the progression of neurodegenerative diseases. However, the underlying mechanisms of copper-induced neurotoxicity remain controversial. In this study, A53T transgenic α-synuclein (A53T) mice and their matching wild-type (WT) mice were treated with a low dose of copper (0.13 ppm copper chlorinated drinking water, equivalent to the copper exposure of human daily copper intake dose) for 4 months, and copper poisoning was performed on human A53T mutant SHSY5Y cells overexpressed with α-synuclein (dose of 1/4 IC50), to test the effects of copper exposure on the body. The results of the open field test showed that the moto function of Cu-treated mice was impaired. Proteomics revealed changes in neurodevelopment, transport function, and mitochondrial membrane-related function in Cu-treated WT mice, which were associated with reduced expression of mitochondrial complex (NDUFA10, ATP5A), dopamine neurons (TH), and dopamine transporter (DAT). Mitochondrial function, nervous system development, synaptic function, and immune response were altered in Cu-treated A53T mice. These changes were associated with increased mitochondrial splitting protein (Drp1), decreased mitochondrial fusion protein (OPA1, Mfn1), abnormalities in mitochondrial autophagy protein (LC3BII/I, P62), decreased dopamine neuron (TH) expression, increased α-synuclein expression, inflammatory factors (IL-6, IL-1β, and TNF-α) release and microglia (Iba1) activation. In addition, we found that Cu2+ (30 μM) induced excessive ROS production and reduced mitochondrial ATP production in human A53T mutant α-synuclein overexpressing SHSY5Y cells by in vitro experiments. In conclusion, low-dose copper treatment altered critical proteins involved in mitochondrial, neurodevelopmental, and inflammatory responses and affected mitochondria's ROS and ATP production levels.