Search Results (670)

Background: Signaling pathways like those depending on cAMP/PKA, calcium/calmodulin/CaMK, MEK-1/MAPK or PI3K/Akt have been described to modulate suprachiasmatic nucleus (SCN) neuronal signaling via influencing transcription factors like CREB. Here, we analyzed the effect of cyclic nucleotide phosphodiesterase inhibitors and structurally similar substances commonly used as autophagy modulators on a cell line stably expressing a cyclic nucleotide element-driven luciferase reporter. Methods: We used an SCN cell line stably transfected with a CRE-luciferase reporter (SCNCRE) to evaluate signaling and vitality responses to various isoform-selective PDE inhibitors and autophagy modulators to evaluate the mechanism of action of the latter. Results: In this study the different impacts of common PDE inhibitors and autophagy modulators on CRE-luciferase activity applied alone and in combination with known CRE-luciferase activating agents showed that (1) PDE3, 4 and 5 are present in SCNCRE cells, with (2) PDE3 being the most active and (3) the autophagy inhibitor 3-Methyladenin (3-MA) displaying PDE inhibitor-like behavior. Conclusions: Experiments provide evidence that, in addition to the extracellular signaling pathways components shown before to be involved in CRE-luciferase activity regulation like cAMP analogs, adenylate cyclase activators and beta-adrenoceptor agonists, cyclic nucleotide metabolism as realized by phosphodiesterase activity, or molecule/agents influencing processes like autophagy or inflammation, modulate transcriptional CRE-dependent activity in these cells. Specifically, we provide evidence that the autophagy inhibitor 3-MA, given that PDEs are expressed, may also act as a PDE inhibitor and inducer of CRE-mediated transcriptional activity. Full article

Precision neurosurgery is rapidly evolving as a medical specialty by merging genomic medicine, multi-omics technologies, and artificial intelligence (AI) technology, while at the same time, society is shifting away from the traditional, anatomic model of care to consider a more precise, molecular model of care. The general purpose of this review is to contemporaneously reflect on how these advances will impact neurosurgical care by providing us with more precise diagnostic and treatment pathways. We hope to provide a relevant review of the recent advances in genomics and multi-omics in the context of clinical practice and highlight their transformational opportunities in the existing models of care, where improved molecular insights can support improvements in clinical care. More specifically, we will highlight how genomic profiling, CRISPR-Cas9, and multi-omics platforms (genomics, transcriptomics, proteomics, and metabolomics) are increasing our understanding of central nervous system (CNS) disorders. Achievements obtained with transformational technologies such as single-cell RNA sequencing and intraoperative mass spectrometry are exemplary of the molecular diagnostic possibilities in real-time molecular diagnostics to enable a more directed approach in surgical options. We will also explore how identifying specific biomarkers (e.g., IDH mutations and MGMT promoter methylation) became a tipping point in the care of glioblastoma and allowed for the establishment of a new taxonomy of tumors that became applicable for surgeons, where a change in practice enjoined a different surgical resection approach and subsequently stratified the adjuvant therapies undertaken after surgery. Furthermore, we reflect on how the novel genomic characterization of mutations like DEPDC5 and SCN1A transformed the pre-surgery selection of surgical candidates for refractory epilepsy when conventional imaging did not define an epileptogenic zone, thus reducing resective surgery occurring in clinical practice. While we are atop the crest of an exciting wave of advances, we recognize that we also must be diligent about the challenges we must navigate to implement genomic medicine in neurosurgery—including ethical and technical challenges that could arise when genomic mutation-based therapies require the concurrent application of multi-omics data collection to be realized in practice for the benefit of patients, as well as the constraints from the blood–brain barrier. The primary challenges also relate to the possible gene privacy implications around genomic medicine and equitable access to technology-based alternative practice disrupting interventions. We hope the contribution from this review will not just be situational consolidation and integration of knowledge but also a stimulus for new lines of research and clinical practice. We also hope to stimulate mindful discussions about future possibilities for conscientious and sustainable progress in our evolution toward a genomic model of precision neurosurgery. In the spirit of providing a critical perspective, we hope that we are also adding to the larger opportunity to embed molecular precision into neuroscience care, striving to promote better practice and better outcomes for patients in a global sense. Full article

Sudden Unexpected Death in Epilepsy (SUDEP) is a leading cause of mortality among individuals with epilepsy, particularly those with drug-resistant forms. This review explores the complex multisystem mechanisms underpinning SUDEP, integrating recent findings on brain, cardiac, and pulmonary dysfunctions. Background/Objectives: The main objective of this review is to elucidate how seizures disrupt critical physiological systems, especially the brainstem, heart, and lungs, contributing to SUDEP, with emphasis on respiratory control failure and autonomic instability. Methods: The literature from experimental models, clinical observations, neuroimaging studies, and genetic analyses was systematically examined. Results: SUDEP is frequently preceded by generalized tonic–clonic seizures, which trigger central and obstructive apnea, hypoventilation, and cardiac arrhythmias. Brainstem dysfunction, particularly in areas such as the pre-Bötzinger complex and nucleus tractus solitarius, plays a central role. Genetic mutations affecting ion channels (e.g., SCN1A, KCNQ1) and neurotransmitter imbalances (notably serotonin and GABA) exacerbate autonomic dysregulation. Risk is compounded by a prone sleeping position, reduced arousal capacity, and impaired ventilatory responses. Conclusions: SUDEP arises from a cascade of interrelated failures in respiratory and cardiac regulation initiated by seizure activity. The recognition of modifiable risk factors, implementation of monitoring technologies, and targeted therapies such as serotonergic agents may reduce mortality. Multidisciplinary approaches integrating neurology, cardiology, and respiratory medicine are essential for effective prevention strategies. Full article

Background: Hemiplegic migraine (HM) is a rare and severe subtype of migraine with a complex genetic basis. Although pathogenic variants in CACNA1A, ATP1A2, and SCN1A explain some familial cases, a significant proportion of patients remain genetically undiagnosed. Increasing evidence points to an overlap between migraine and cerebral small vessel disease (SVD), implicating vascular dysfunction in HM pathophysiology. Objective: This study aimed to identify rare or novel variants in genes associated with SVD in a cohort of patients clinically diagnosed with HM who tested negative for known familial hemiplegic migraine (FHM) pathogenic variants. Methods: We conducted a case-control association analysis of whole exome sequencing (WES) data from 184 unrelated HM patients. A targeted panel of 34 SVD-related genes was assessed. Variants were prioritised based on rarity (MAF ≤ 0.05), location (exonic/splice site), and predicted pathogenicity using in silico tools. Statistical comparisons to gnomAD’s Non-Finnish European population were made using chi-square tests. Results: Significant variants were identified in several SVD-related genes, including LRP1 (p.Thr4077Arg), COL4A1 (p.Pro54Leu), COL4A2 (p.Glu1123Gly), and TGFBR2 (p.Met148Leu and p.Ala51Pro). The LRP1 variant showed the strongest association (p < 0.001). All key variants demonstrated pathogenicity predictions in multiple computational models, implicating them in vascular dysfunction relevant to migraine mechanisms. Conclusions: This study provides new insights into the genetic architecture of hemiplegic migraine, identifying rare and potentially deleterious variants in SVD-related genes. These findings support the hypothesis that vascular and cellular maintenance pathways contribute to migraine susceptibility and may offer new targets for diagnosis and therapy. Full article

The hydropower unit is the core of the hydropower station, and maintaining the safety and stability of the hydropower unit is the first essential priority of the operation of the hydropower station. However, the complex environment increases the probability of the failure of hydropower units. Therefore, aiming at the complex diversity of hydropower unit faults and the imbalance of fault data, this paper proposes a fault identification method based on modified fractional-order hierarchical fluctuation dispersion entropy (MFHFDE) and AdaBoost-stochastic configuration networks (AdaBoost-SCN). First, the modified hierarchical entropy and fractional-order theory are incorporated into the multiscale fluctuation dispersion entropy (MFDE) to enhance the responsiveness of MFDE to various fault signals and address its limitation of overlooking the high-frequency components of signals. Subsequently, the Euclidean distance is used to select the fractional order. Then, a novel method for evaluating the complexity of time-series signals, called MFHFDE, is presented. In addition, the AdaBoost algorithm is used to integrate stochastic configuration networks (SCN) to establish the AdaBoost-SCN strong classifier, which overcomes the problem of the weak generalization ability of SCN under the condition of an unbalanced number of signal samples. Finally, the features extracted via MFHFDE are fed into the classifier to accomplish pattern recognition. The results show that this method is more robust and effective compared with other methods in the anti-noise experiment and the feature extraction experiment. In the six kinds of imbalanced experimental data, the recognition rate reaches more than 98%. Full article

Timely and accurate detection of wind turbine blade surface defects is crucial for ensuring operational safety and improving maintenance efficiency with respect to large-scale wind farms. However, existing methods often suffer from poor generalization, background interference, and inadequate real-time performance. To overcome these limitations, we developed an end-to-end defect recognition framework, structured as a three-stage process: blade localization using YOLOv5, robust feature extraction via the large vision model DINOv2, and defect classification using a Stochastic Configuration Network (SCN). Unlike conventional CNN-based approaches, the use of DINOv2 significantly improves the capability for representation under complex textures. The experimental results reveal that the proposed method achieved a classification accuracy of 97.8% and an average inference time of 19.65 ms per image, satisfying real-time requirements. Compared to traditional methods, this framework provides a more scalable, accurate, and efficient solution for the intelligent inspection and maintenance of wind turbine blades. Full article

Alzheimer’s Disease (AD) is the most common type of dementia. The circadian system, which is controlled by the master clock in the Suprachiasmatic Nucleus (SCN) of the hypothalamus, is crucial for various physiological processes. Studies have shown that changes in the circadian rhythms can deteriorate neurodegenerative diseases. Changes in the SCN are associated with cognitive decline in AD. The cognitive impairments in AD, especially memory dysfunctions, may be related to Circadian Rhythm Disturbances (CRDs). Moreover, rhythmic expression of clock genes is disrupted in AD patients. There is a circadian pattern of inflammatory processes in AD, and dysregulation of core clock genes promotes neuroinflammation. The present narrative review addresses the intricate link between CRDs and AD, revisiting the relevant cellular and molecular mechanisms. The association between CRDs and AD highlights the need for further investigation of the underlying mechanisms. Full article

Lycopene exhibits a broad spectrum of biological activities with potential therapeutic applications. Despite its established antioxidant and anti-inflammatory properties, the molecular basis for its pharmacological actions remains incompletely defined. Here we investigated the molecular targets, pharmacodynamic feasibility, and tissue-specific expression of lycopene targets using a computational pharmacology approach combined with affinity and protein–protein interaction (PPI) analyses. Lycopene-associated human protein targets were predicted using a Swiss target screening platform. Molecular docking was used to estimate binding affinities, and concentration-affinity (CA) ratios were calculated based on physiologically relevant plasma concentrations (75–210 nM). PPI networks of lycopene targets were constructed to identify highly connected targets, and tissue expression analysis was assessed for high-affinity targets using protein-level data from the Human Protein Atlas database. Of the 94 predicted targets, 37% were nuclear receptors and 18% were Family A G Protein Coupled Receptors (GPCRs). Among the top 15 high-affinity targets, nuclear receptors and GPCRs comprised 40% and 26.7%, respectively. Twenty targets had affinities < 10 μM, with six key targets (MAP2K2, SCN2A, SLC6A5, SCN3A, TOP2A, and TRIM24) showing submicromolar binding. CA ratio analysis identified MAP2K2, SCN2A, and SLC6A5 as pharmacodynamically feasible targets (CA > 1). PPI analysis revealed 32 targets with high interaction and 9 with significant network connectivity. Seven targets (TRIM24, GRIN1, NTRK1, FGFR1, NTRK3, CHRNB4, and PIK3CD) showed both high affinity and centrality in the interaction network. The expression profiling of submicromolar targets revealed widespread tissue distribution for MAP2K2 and SCN3A, while SCN2A, TOP2A, and TRIM24 showed more restricted expression patterns. This integrative analysis identifies a subset of lycopene targets with both high affinity and pharmacological feasibility, particularly MAP2K2, SCN2A, and TRIM24. Lycopene appears to exert its biological effects through modulation of interconnected signalling networks involving nuclear receptors, GPCRs, and ion channels. These findings support the potential of lycopene as a multi-target therapeutic agent and provide a rationale for future experimental and clinical validation. Full article

Background: HM is a rare, severe form of migraine with aura, characterised by motor weakness and strongly influenced by genetic factors affecting the brain. While pathogenic variants in CACNA1A, ATP1A2, and SCN1A genes have been implicated in familial HM, approximately 75% of cases lack known pathogenic variants in these genes, suggesting a more complex genetic basis. Methods: To advance our understanding of HM, we applied a variant prioritisation approach using whole-exome sequencing (WES) data from patients referred for HM diagnosis (n = 184) and utilised PathVar, a bioinformatics pipeline designed to identify pathogenic variants. Our analysis incorporated two strategies for association testing: (1) PathVar-identified single nucleotide variants (SNVs) and (2) PathVar SNVs combined with missense and rare variants. Principal component analysis (PCA) was performed to adjust for ancestral and other unknown differences between cases and controls. Results: Our results reveal a sequential reduction in the number of genes significantly associated with HM, from 20 in the first strategy to 11 in the second, which highlights the unique contribution of PathVar SNVs to the genetic architecture of HM. PathVar SNVs were more distinctive in the case cohort, suggesting a closer link to the functional changes underlying HM compared to controls. Notably, novel genes, such as SLC38A10, GCOM1, and NXPH2, which were previously not implicated in HM, are now associated with the disorder, advancing our understanding of its genetic basis. Conclusions: By prioritising PathVar SNVs, we identified a broader set of genes potentially contributing to HM. Given that HM is a rare condition, our findings, utilising a sample size of 184, represent a unique contribution to the field. This iterative analysis demonstrates that integrating diverse variant schemes provides a more comprehensive view of the genetic factors driving HM. Full article

Guvermectin, a Streptomyces-derived purine nucleoside compound, exhibits dual bioactivities as a plant growth regulator and an antibacterial agent. While its biosynthetic gene cluster (BGC) is regulated by the cluster-situated activator GvmR and the adjacent repressor GvmR2, the role of distal transcriptional regulators (TRs) in guvermectin biosynthesis remains unexplored. Here, we identified ScnR1, a highly conserved LacI-family TR located far from the guvermectin BGC, which is directly activated by GvmR. Overexpression of scnR1 significantly suppressed guvermectin biosynthesis. Further investigations revealed that ScnR1 competitively binds to the gvmR, gvmA, and O1 promoters (overlapping with the GvmR-binding sites), thereby inhibiting the guvermectin BGC transcription. Moreover, ScnR1 formed a reciprocal feedback loop with the adjacent repressor GvmR2, where each repressor inhibits the other’s expression. These findings reveal a multi-layered regulatory mechanism wherein LacI-family TRs fine-tune guvermectin biosynthesis through competitive DNA binding and reciprocal feedback control. This study offers new perspectives on the hierarchical control of secondary metabolism in Streptomyces and provides valuable theoretical guidance for the engineering of strains with enhanced natural product production. Full article

Soybean cyst nematodes (SCNs) are a significant disease that causes yield loss and reducing seed quality in soybeans (Glycine max). Developing SCN-resistant soybean varieties can minimize the need for insecticide use and reduce yield loss. Cinnamate-4-hydroxylase (C4H) and laccase (Lac) are key enzymes in the lignin synthesis pathway. In this study, SCN stress significantly promoted lignin accumulation in soybean roots and upregulated the expression of lignin signaling pathway genes GmC4H (Glyma.02G236500), GmLac55 (Glyma.13G076900), and GmLac85 (Glyma.20G051900). Using Agrobacterium rhizogenes-mediated transformation, the pNI900 expression vector was introduced into the soybean cultivar Williams 82 to generate GmLac55-overexpressing plants. The overexpression of GmLac55 enhanced soybean roots resistance to SCN and inhibited the further development of J2 larvae. Our study presents a strategy for increasing SCN resistance in soybean through Agrobacterium-mediated targeted mutagenesis of the GmLac55 gene. Full article

The leading causes of pediatric arterial ischemic stroke (PAIS) are arteriopathies, which refer to pathologies of the arterial walls in the brain. Since traditional risk factors for cardiovascular diseases in children play a smaller role than in adults, it can be supposed that genetic factors may be of particular importance in this age group. Therefore, this study aimed to identify mutations affecting the formation of vascular wall pathologies, which can subsequently lead to ischemic stroke. The study used a database of 92 Caucasian children diagnosed with ischemic stroke. From this group, 25 children with arteriopathies were selected. The study had an exploratory and descriptive design, with the aim of characterizing rare genetic variants in a selected cohort, without attempting formal statistical association testing. The sequencing was performed using the Illumina NextSeq 550 platform. A panel of 161 genes known to be associated with stroke or arteriopathies was selected for further analysis. We identified 10 pathogenic or likely pathogenic mutations in 15 patients. Among these, three are likely monogenic causes of stroke (ELN, SCN5A, and VHL genes), two are considered risk factors (FV and ADAMTS13), two have conflicting interpretations (ACAD9 and ENG), and three are most likely benign (CBS, PMM2, and PKD1). The frequency of genetic variants underlying ischemic stroke or acting as risk factors for the disease in the studied group is significantly higher than the estimated frequency of monogenic forms of stroke in young adults and higher than in the general population. NGS testing is worth considering, especially in patients who exhibit certain symptoms that may suggest the presence of mutations. Full article

Fertilization management constitutes a critical determinant of agroecosystem productivity. Reasonable fertilization can increase the organic matter content in soil; however, the potential mechanism of how different fertilization regimes impact soil carbon sequestration is unclear. We hypothesized that the combined application of biochar and organic fertilizer would enhance soil carbon sequestration by improving soil physicochemical conditions, increasing microbial activity, and promoting the accumulation of stable forms of carbon. This study systematically investigated different regimes, including the application of chemical fertilizer alone (SCN), chemical fertilizer with biochar (SCB), chemical fertilizer with organic fertilizer (SCO), and chemical fertilizer with both biochar and organic fertilizer (SCBO), on soil physiochemical properties, enzyme activities, labile organic carbon fractions, microbial carbon fixation gene expression, and community composition. The results demonstrated that (1) the application of organic materials significantly enhanced soil nutrient levels and enzyme activities, with the best performance from SCBO; (2) the organic materials increased the labile soil organic carbon (SOC) content and the carbon pool management index, with SCO showing the highest at 69.82%; (3) SCB and SCBO improved the stability of soil carbon components by increasing the proportion of Aromatic C; and (4) the carbon fixation genes ACAT and sdhA exhibited the highest abundance in SCBO. In parallel, the relative abundance of Actinomycetota increased with the application of organic materials, reaching its peak in SCBO. Mantel testing revealed a strong correlation between microbial community composition and SOC, emphasizing the importance of SOC in microbial growth and metabolism. Moreover, the strong correlation between carbon fixation genes and aromatic carbon suggested that specific carbon forms, particularly aromatic structures, played a critical role in driving microbial carbon fixation processes. Full article

In order to elucidate the factors regulating nutrient dynamics in plant–soil interactions across various latitudes within the karst climax community, this study focused on the karst forest climax community in Guizhou Province, Southwest China. We analyzed and compared the differences in carbon, nitrogen, and phosphorus content, as well as stoichiometry, in plant leaves and soils under various growing conditions. Additionally, redundancy analyses were conducted to investigate the stoichiometric correlations between plants and soil. The research findings indicate the following: (1) Leaf carbon content (LCC) and the carbon-to-nitrogen ratio (LCN) exhibit significant differences across various latitudes, with the lowest values observed in high-latitude regions. (2) Soil organic carbon (SOC) and the carbon-to-nitrogen ratio (SCN) also show significant variations across latitudes, with the lowest concentrations found in high-latitude regions and the highest in low-latitude regions. (3) The variability in leaf nutrient element ratios among karst region climax communities is greatest in low-latitude areas. This study found that the carbon content (LCC), nitrogen content (LNC), and carbon-to-nitrogen ratio (LCN) of leaves in karst climax community plants decrease as latitude increases. This suggests that plants regulate the nutrient utilization efficiency of carbon content (LCC), nitrogen content (LNC), and phosphorus content (LPC) in their leaves to maintain the nutrients necessary for their growth and development along the latitudinal gradient. The sensitivity of soil organic carbon (SOC), carbon-to-nitrogen (SCN), and carbon-to-phosphorus (SCP) ratios to latitudinal changes were particularly pronounced in the karst climax community. Additionally, plant leaf stoichiometry was significantly influenced by soil phosphorus content (SPC) in mid- and high-latitude regions, while factors other than soil nitrogen content (SNC) had a more substantial impact on plant leaf stoichiometry in low-latitude areas. The findings of this study are highly significant for guiding nutrient management in karst forest ecosystems and for the restoration of degraded karst forest vegetation. Full article

The structural parameters and electronic structures of Sc- and Y-based nitride semiconductors that adopted hexagonal BN-like atomic sheets were investigated with calculations based on density functional theory (DFT). A hybrid exchange-correlation functional and spin–orbit coupling were employed for studies on the band structures. A strong variation in the band gap type, as well as the width, was revealed not only between the monolayer and bulk materials but also between the multilayer systems. An exceptionally wide range of band gaps from 1.39 (bulk) up to 3.59 eV (three layers) was obtained for two-dimensional materials based on ScN. This finding is related to two phenomena: significant contributions of subsurface ions into bands that formed a valence band maximum and pronounced shifts in conduction band positions with respect to the Fermi energy between the multilayer systems. The relatively low values of the work function (below 2.36 eV) predicted for the few-layer YN materials might be considered for applications in electron emission. In spite of the fact that the band gaps of two-dimensional materials predicted with hybrid DFT calculations may be overestimated to some extent, the electronic structure of homo- and heterostructures formed by rare earth nitride semiconductors seems to be an interesting subject for further experimental research. Full article