Search Results (184)

Background/Objectives: Neurodegenerative diseases (NDs) such as Alzheimer’s (AD), Parkinson’s (PD), Huntington’s (HD), and Amyotrophic Lateral Sclerosis (ALS) are clinically distinct but share overlapping molecular mechanisms. Methods: To identify conserved systemic signatures, we analyzed blood RNA-Seq datasets using Weighted Gene Co-Expression Network Analysis (WGCNA), differential expression, pathway enrichment, and miRNA–mRNA network mapping. Results: Two modules, the red and turquoise, showed strong preservation across diseases. The red module was enriched for cytoskeletal and metabolic regulation, while the turquoise module involved immune, stress-response, and proteostatic pathways. Discussion: Key hub genes, such as HMGCR, ACTR2, MYD88, PTEN, EP300, and regulatory miRNAs like miR-29, miR-132, and miR-146a, formed interconnected networks reflecting shared molecular vulnerabilities. The absence of classical heat shock proteins in preserved blood modules highlights tissue-specific expression differences between blood and neural systems. Several hub genes overlap with known pharmacological targets, suggesting potential in translational relevance. Conclusions: Together, these findings reveal conserved blood-based transcriptional modules that suggest parallel central neurodegenerative processes and may support future biomarker development and possible therapeutic exploration. Full article

Autism Spectrum Disorder (ASD) is a complex and multifactorial neurodevelopmental condition whose pathogenesis remains only partially elucidated. Earlier accounts of oxidative stress in ASD often relied on the reductive paradigm of an imbalance between oxidants and antioxidants. In contrast, this narrative review, based on a systematic examination of 1102 publications indexed in scientific databases from 2002 to July 2025, reframes the discussion in terms of redox system dysfunction, a broader and more integrative construct. Here, reactive oxidant species, molecular targets, and reducing/antioxidant counterparts are considered elements of a dynamic circuitry whose maladaptation progressively undermines homeostasis. The sequence of events unfolds in three stages. The first is primary redox dysfunction, manifesting as alterations in metabolic, signaling, and defense pathways. From this disturbance, a second stage arises, marked by functional derailment of cellular compartments—from membranes and cytosol to organelles and nuclei—including mitochondrial and peroxisomal deficits. Ultimately, a third stage emerges, defined by neurodevelopmental alterations such as impaired neurotransmission, synaptic dysfunction, abnormal plasticity, morphogenetic defects, neuroinflammation, and gut–brain–microbiota disarrangements. This progression situates the redox system as a central hub at the interface between human cells and the microbiota, resonating with the ecological and evolutionary principles of the holobiont and the One Health framework. By weaving dispersed evidence into a coherent perspective, this review advances beyond previous analyses, offering a unifying paradigm that connects biochemical dysfunction to clinical heterogeneity in ASD and opens new directions for interdisciplinary research. Full article

Over the past two decades, immune–inflammatory dysregulation has emerged as a central paradigm in the biology of mood disorders. Patients with major depression (MDD) and bipolar disorder (BD) frequently display low-grade systemic inflammation. Elevated C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) identify clinically relevant subgroups of patients characterized by greater severity, cognitive impairment, and poor treatment response. Changes in the gut microbiota and disruptions of the blood–brain barrier (BBB) act as important gateways through which systemic immune activity can influence the brain. At the intracellular level, pattern-recognition receptors activate convergent hubs including NF-κB, JAK/STAT, and MAPK cascades, while the NLRP3 inflammasome integrates mitochondrial dysfunction and oxidative stress with IL-1β release and pyroptosis. These pathways converge on glial dysregulation, impaired BDNF/TrkB signaling, and kynurenine pathway (KP) alterations, fostering excitotoxicity and synaptic deficits. Translational studies demonstrate that elevated CRP and IL-6 predict poor antidepressant outcomes. Anti-inflammatory agents such as infliximab and celecoxib show efficacy in specific subgroups of patients. Emerging multi-omics approaches identify immuno-metabolic biotypes, supporting the rationale for biomarker-guided stratification. These findings define an ‘inflammatory biotype’ of mood disorders and highlight the need for biomarkers and precision-based trials to guide treatment. Full article

Glioblastoma multiforme (GBM) is an aggressive brain cancer characterized by highly invasive growth driven by glial-mesenchymal transition (GMT). Given the urgent need for effective therapies targeting this process, we aimed to discover potential GMT inhibitors using transcriptomic-based repurposing applied to both approved and experimental drugs. Deep bioinformatic analysis of transcriptomic data from GBM patient tumors and GBM cell lines with mesenchymal phenotype using gene set variation analysis (GSVA), weighted gene co-expression network analysis (WGCNA), reconstruction of GMT-related gene association networks, gene set enrichment analysis (GSEA), and the search for correlation with transcriptomic profiles of known GMT markers, revealed a novel 31-gene GMT signature applicable as relevant input data for the connectivity map-based drug repurposing study. Using this gene signature, a number of small-molecule compounds were predicted as potent anti-GMT agents. Further ranking according to their blood–brain barrier permeability, as well as structural and transcriptomic similarities to known anti-GBM drugs, revealed SP600125, vemurafenib, FG-7142, dibenzoylmethane, and phensuximide as the most promising for GMT inhibition. In vitro validation showed that SP600125, which is most closely associated with GMT-related hub genes, effectively inhibited TGF-β1- and chemical hypoxia-induced GMT in U87 GBM cells by reducing morphological changes, migration, vasculogenic mimicry, and mesenchymal marker expression. These results clearly demonstrate the applicability of connectivity mapping as a powerful tool to accelerate the discovery of effective GMT-targeting therapies for GBM and significantly expand our understanding of the antitumor potential of SP600125. Full article

Bone immunity represents a dynamic interface where skeletal homeostasis intersects with systemic immune regulation. We synthesize emerging paradigms by contrasting two functionally distinct microenvironments: the marrow cavity, a hematopoietic and immune cell reservoir, and cancellous bone, a metabolically active hub orchestrating osteoimmune interactions. The marrow cavity not only generates innate and adaptive immune cells but also preserves long-term immune memory through stromal-derived chemokines and survival factors, while cancellous bone regulates bone remodeling via macrophage-osteoclast crosstalk and cytokine gradients. Breakthroughs in lymphatic vasculature identification challenge traditional views, revealing cortical and lymphatic networks in cancellous bone that mediate immune surveillance and pathological processes such as cancer metastasis. Central to bone immunity is the neuro–immune–endocrine axis, where sympathetic and parasympathetic signaling bidirectionally modulate osteoclastogenesis and macrophage polarization. Gut microbiota-derived metabolites, including short-chain fatty acids and polyamines, reshape bone immunity through epigenetic and receptor-mediated pathways, bridging systemic metabolism with local immune responses. In disease contexts, dysregulated immune dynamics drive osteoporosis via RANKL/IL-17 hyperactivity and promote leukemic evasion through microenvironmental immunosuppression. We further propose the “brain–gut–bone axis” as a systemic regulatory framework, wherein vagus nerve-mediated gut signaling enhances osteogenic pathways, while leptin and adipokine circuits link marrow adiposity to inflammatory bone loss. These insights redefine bone as a multidimensional immunometabolic organ, integrating neural, endocrine, and microbial inputs to maintain homeostasis. By elucidating the mechanisms of immune-driven bone pathologies, this work highlights therapeutic opportunities through biomaterial-mediated immunomodulation and microbiota-targeted interventions, paving the way for next-generation treatments in osteoimmune disorders. Full article

Given the strong coupling between electricity flow and carbon flow, promoting the low-carbon transformation of the energy sector is a crucial measure to actively responding to climate challenges. As a pivotal hub linking the electricity market with the carbon market, promoting electricity–carbon coordinated scheduling of Virtual Power Plants (VPPs) is of great significance in expediting the energy transition process. Based on the introduction of carbon potential, this manuscript constructs a VPP electricity–carbon coordinated scheduling model that incorporates various typical elements, including renewable energy units and demand response. Furthermore, this paper utilizes Brain Storm Optimization (BSO) to improve the Snow Ablation Optimizer (SAO) algorithm and applies the improved algorithm to solve the model developed in this manuscript. Finally, an analysis was conducted using a small-scale VPP project in eastern China, and the results are the following: Firstly, the SAO improved by BSO demonstrates a significant enhancement in solution efficiency. In particular, for the cases presented in this manuscript, the algorithm’s convergence speed increased by 42.85%. Secondly, under the multi-market conditions and with real-time carbon potential, VPPs will possess greater flexibility in scheduling optimization and stronger incentives to fully explore their emission reduction potential through collaborative electricity–carbon scheduling, thereby improving both economic and environmental performance. However, constrained by factors such as the currently low carbon price level, the extent of improvement in VPPs’ performance under real-time carbon potential, compared to fixed carbon potential, remains relatively limited, with a 1.07% increase in economic benefits and a 2.63% reduction in carbon emissions. Thirdly, an increase in carbon prices can incentivize VPPs to continuously tap into their emission reduction potential, but beyond a certain threshold (120 CNY/t in this case study), the marginal contribution of further carbon price increases to emission reductions will progressively decline. Specifically, for every 20-yuan increase in the carbon price, the carbon emission reduction rate of VPPs drops below 1%. Full article

Language, a uniquely human cognitive faculty, is fundamentally characterized by its capacity for complex thoughts and structured expressions. This review examines two critical measures of linguistic performance: idea density (ID) and grammatical complexity (GC). ID quantifies the richness of information conveyed per unit of language, reflecting semantic efficiency and conceptual processing. GC, conversely, measures the structural sophistication of syntax, indicative of hierarchical organization and rule-based operations. We explore the neurobiological underpinnings of these measures, identifying key brain regions and white matter pathways involved in their generation and comprehension. This includes linking ID to a distributed network of semantic hubs, like the anterior temporal lobe and temporoparietal junction, and GC to a fronto-striatal procedural network encompassing Broca’s area and the basal ganglia. Moreover, a central theme is the integration of Chomsky’s theories of Universal Grammar (UG), which posits an innate human linguistic endowment, with their neurobiological correlates. This integration analysis bridges foundational models that first mapped syntax (Friederici’s work) to distinct neural pathways with contemporary network-based theories that view grammar as an emergent property of dynamic, inter-regional neural oscillations. Furthermore, we examine the genetic factors influencing ID and GC, including genes implicated in neurodevelopmental and neurodegenerative disorders. A comparative anatomical perspective across human and non-human primates illuminates the evolutionary trajectory of the language-ready brain. Also, we emphasize that, clinically, ID and GC serve as sensitive neurocognitive markers whose power lies in their often-dissociable profiles. For instance, the primary decline of ID in Alzheimer’s disease contrasts with the severe grammatical impairment in nonfluent aphasia, aiding in differential diagnosis. Importantly, as non-invasive and scalable metrics, ID and GC also provide a critical complement to gold-standard but costly biomarkers like CSF and PET. Finally, the review considers the emerging role of AI and Natural Language Processing (NLP) in automating these linguistic analyses, concluding with a necessary discussion of the critical challenges in validation, ethics, and implementation that must be addressed for these technologies to be responsibly integrated into clinical practice. Full article

Refractory neuropathic pain of the head and neck remains a major clinical challenge, particularly when mediated through the cervicotrigeminal complex (CTC), a unique anatomical hub integrating trigeminal and upper cervical nociceptive inputs. This narrative review synthesizes neuroanatomical, pathophysiological, and clinical evidence to provide a unifying framework for diagnosis and management. A structured search of PubMed, Scopus, and Web of Science identified English-language clinical and mechanistic studies addressing CTC-mediated pain, with case reports excluded unless mechanistically informative. We propose multidimensional refractoriness criteria that integrate pharmacological non-response, failed interventional strategies, and objective functional impairment. Current treatments span pharmacotherapy, peripheral interventions (nerve blocks, radiofrequency ablation), and neuromodulation at multiple network levels (occipital nerve stimulation, spinal cord stimulation, motor cortex stimulation, deep brain stimulation). Non-invasive approaches such as rTMS, tDCS, and vagus nerve stimulation are emerging but remain investigational. Advances in imaging and neurophysiological biomarkers now permit greater precision in detecting CTC dysfunction and tailoring therapy. By combining anatomical precision, mechanistic insight, and multidisciplinary strategies, this review proposes a clinically actionable definition of refractoriness and supports a stepwise, mechanism-based approach to therapy. CTC emerges as a targetable hub for diagnostic and therapeutic strategies in refractory head and neck pain. Full article

Temperature stress is a major cause of mortality in aquaculture, yet the molecular mechanisms underlying cold adaptation in commercially important fish such as the silver pomfret (Pampus argenteus) remain poorly understood. In this study, we used integrated miRNA and mRNA transcriptomics to analyze brain tissue responses of silver pomfret under gradient cold exposure conditions (28 °C control, 18 °C moderate, 13 °C extreme). We identified 85 differentially expressed miRNAs (DEmiRs), with 22 altered under moderate cold and 68 altered in extreme cold, demonstrating that miRNA regulatory activity intensifies with decreasing temperature. Combined miRNA target prediction and expression correlation analysis revealed 8 and 247 differentially expressed target genes (DETGs), which formed cold-adaptive regulatory networks with corresponding DEmiRs. Functional analysis showed enrichment of pathways related to circadian rhythm (e.g., PER targeted by miR-429-y and miR-181-z), immunity (e.g., JUN-miR-10545-x cluster), and endocrine function (e.g., NHERF1-miR-181-z). Notably, miR-181-z was identified as a central regulatory hub, interacting with 13.2% nodes in BE network. Our study provides the first comprehensive miRNA-mRNA network resource for cold stress response in silver pomfret, offering valuable molecular biomarkers for breeding cold-resilient strains and enhancing sustainable aquaculture practices. Full article

Objectives: Individuals with Autism Spectrum Disorder (ASD) exhibit difficulties in the social use of language, regardless of age, cognitive abilities, and symptom severity. The left Broca’s area and adjacent cortex are crucial for socio-pragmatic language, particularly in retrieving and integrating context-dependent words. Neuroimaging studies in ASD have shown hypoactivation of the Broca’s area and an aberrant pattern of functional connectivity between language-related regions, suggesting their potential involvement in socio-communicative deficits. Given the potential of tDCS to modulate brain activity, its application targeting Broca’s areas in addition to psychological intervention may represent a promising approach for enhancing socio-communicative skills in ASD. Thus, this study aims to investigate the effect of concomitant anodal tDCS and cognitive behavioral-oriented training (CBT) on pragmatic and communicative skills in young adults with ASD. Methods: A sample of 10 ASD individuals (18–25 years) underwent treatment with both active and sham tDCS targeting the left Broca’s area during concomitant CBT. Each condition was delivered for five consecutive days, and the order of the conditions was blindly randomized. Results: Active tDCS significantly improved global communicative and pragmatic abilities compared to sham. A negative correlation was observed between communicative skills improvement and Intelligence Quotient (IQ); no significant association was found between IQ and ASD symptoms’ severity. Conclusions: Multisession tDCS targeting the left Broca’s area, combined with CBT, may enhance social language in terms of both production and comprehension of non-literal meanings, supporting Broca’s area as a central neural hub for social language. Full article

In recent years, research has focused on biomarkers as key tools to predict clinical outcomes and guide therapeutic decisions in Multiple Sclerosis (MS). MicroRNAs (miRs)—small non-coding RNA molecules that regulate gene expression at the post-transcriptional level—have emerged as promising biomarkers in MS due to their accessibility in biological fluids. This study investigates the role of specific serum miRs mainly involved in immune response regulation as potential prognostic biomarkers in MS, focusing on young patients with recent diagnosis. The study had a prospective design, involving a cohort of patients followed in the Hub and Spoke MS network of Verona province. Fifty-one patients (33F) aged 18–40 years with recent MS diagnosis (≤2 years; 45 relapsing-remitting, 6 primary progressive) were consecutively enrolled. At baseline, serum samples were collected for miR analysis alongside clinical-demographic and MRI data, including T2 lesion volume, normalized brain volume (NBV), gray matter volume, white matter volume (WMV) calculated at baseline and annual percentage brain volume change (PBVC) and occurrence of new T2 or gadolinium-enhancing (Gd+) lesions on follow-up scans. Candidate miRs were chosen based on their potential biological role in MS pathogenesis reported in the literature. miRs assays were done using real-time PCR and expressed as a ratio relative to a normalizer (i.e., miR-425-5p). Levels of miR-34a-5p were significantly higher in patients with Gd+ lesions (p < 0.001) and correlated to lower NBV (rho = −0.454, p = 0.001) and WMV (rho = −0.494, p < 0.001). Conversely, miR-140-5p exhibited a protective effect against occurrence of new T2 or Gd+ lesions over time (HR 0.43; IC 95% 0.19–0.99; p = 0.048). Additionally, miR-30b-5p correlated directly with PBVC (adjusted rho = −0.646; p < 0.001). These findings support the potential of serum miR-34a-5p, miR-140-5p, and miR-30b-5p as markers of disease activity and progression in patients with recently diagnosed MS. Full article

Background/Objectives: Sequence learning, the ability to pick up on regularities in our environment to facilitate behavior, is critically dependent on striatal structures in the brain, with the putamen emerging as a critical hub for implicit sequence learning. As the putamen is known to shrink with age, and age-related declines in sequence learning abilities are common, it has been hypothesized that the structural integrity of the putamen is likely related to sequence learning outcomes. However, the structural literature is sparse. One reason may be that traditional structural imaging measures, like volume, are not sufficiently sensitive to measure changes that are related to performance outcomes. We propose that magnetic resonance elastography (MRE), an emerging neuroimaging tool that provides quantitative measures of microstructural integrity, may fill this gap. Methods: In this study, both sequence learning abilities and the structural integrity of the putamen were assessed in 61 cognitively healthy middle-aged and older adults (range: 45–78 years old). Sequence learning was measured via performance on the Serial Reaction Time Task. Putamen integrity was assessed in two ways: first, via standard structural volume assessments, and second, via MRE measures of tissue integrity. Results: Age significantly correlated with both putamen volume and stiffness but not sequence learning scores. While sequence learning scores did not correlate with volume, MRE-derived measures of putamen stiffness were significantly correlated with learning outcomes such that individuals with stiffer putamen showed higher learning scores. A series of control analyses were performed to highlight the specificity and sensitivity of this putamen stiffness–sequence learning relationship. Conclusions: Together these data indicate that microstructural changes that occur in the putamen as we age may contribute to changes in sequence learning outcomes. Full article

Background: The red nucleus (RN) is a phylogenetically conserved structure within the midbrain that is traditionally associated with general motor coordination; however, its specific role in controlling directional movement remains poorly understood. Methods: This study systematically investigates the function and mechanism of RN neurons in directional movement by combining stereotactic brain injections, fiber photometry recordings, multi-unit in vivo electrophysiological recordings, optogenetic manipulation, and anterograde trans-synaptic tracing. Results: We analyzed mice performing standardized T-maze turning tasks and revealed that anatomically distinct RN neuronal ensembles exhibit direction-selective activity patterns. These neurons demonstrate preferential activation during ipsilateral turning movements, with activity onset consistently occurring after movement initiation. We establish a causal relationship between RN neuronal activity and directional motor control: selective activation of RN glutamatergic neurons facilitates ipsilateral turning, whereas temporally precise inhibition significantly impairs the execution of these movements. Anterograde trans-synaptic tracing using H129 reveals that RN neurons selectively project to spinal interneuron populations responsible for ipsilateral flexion and coordinated limb movements. Conclusions: These findings offer a framework for understanding asymmetric motor control in the brain. This work redefines the RN as a specialized hub within midbrain networks that mediate lateralized movements and offers new avenues for neuromodulatory treatments for neurodegenerative and post-injury motor disorders. Full article

Type 10 17β-hydroxysteroid dehydrogenase (17β-HSD10) is the HSD17B10 gene product. It plays an appreciable part in the carcinogenesis and pathogenesis of neurodegeneration, such as Alzheimer’s disease and infantile neurodegeneration. This mitochondrial, homo-tetrameric protein is a central hub in various metabolic pathways, e.g., branched-chain amino acid degradation and neurosteroid metabolism. It can bind to other proteins carrying out diverse physiological functions, e.g., tRNA maturation. It has also previously been proposed to be an Aβ-binding alcohol dehydrogenase (ABAD) or endoplasmic reticulum-associated Aβ-binding protein (ERAB), although those reports are controversial due to data analyses. For example, the reported k_m value of some substrate of ABAD/ERAB was five times higher than its natural solubility in the assay employed to measure k_m. Regarding any reported “one-site competitive inhibition” of ABAD/ERAB by Aβ, the k_i value estimations were likely impacted by non-physiological concentrations of 2-octanol at high concentrations of vehicle DMSO and, therefore, are likely artefactual. Certain data associated with ABAD/ERAB were found not reproducible, and multiple experimental approaches were undertaken under non-physiological conditions. In contrast, 17β-HSD10 studies prompted a conclusion that Aβ inhibited 17β-HSD10 activity, thus harming brain cells, replacing a prior supposition that “ABAD” mediates Aβ neurotoxicity. Furthermore, it is critical to find answers to the question as to why elevated levels of 17β-HSD10, in addition to Aβ and phosphorylated Tau, are present in the brains of AD patients and mouse AD models. Addressing this question will likely prompt better approaches to develop treatments for Alzheimer’s disease. Full article

The neurobiology of chronic pain is complex and multifaceted, intertwining with the mesocorticolimbic system to regulate the behavioral and perceptional response to adverse stimuli. Specifically, the ventral tegmental area (VTA), the dopaminergic hub of the reward pathways located deep within the midbrain, is crucial for regulating the release of dopamine (DA) throughout the central nervous system (CNS). To better understand the nuances among chronic pain, VTA response, and therapeutics, implementing progressive approaches for mapping and visualizing the deep brain in real time during nociceptive stimulation is crucial. In this study, we utilize a fluorescence imaging platform with a genetically encoded calcium indicator (GCaMP6s) to directly visualize activity in the VTA during acute nociceptive stimulation in both healthy adult mice and adult mice with partial nerve ligation (PNL)-induced neuropathic pain. We also investigate the visualization of the analgesic properties of morphine. Deep brain imaging using our self-fabricated µ-complementary metal–oxide–semiconductor (CMOS) imaging device allows the tracking of the VTA’s response to adverse stimuli. Our findings show that nociceptive stimulation is associated with a reduction in VTA fluorescence activity, supporting the potential of this platform for visualizing pain-related responses in the central nervous system. Additionally, treatment with morphine significantly reduces the neuronal response caused by mechanical stimuli and is observable using the CMOS imaging platform, demonstrating a novel way to potentially assess and treat neuropathic pain. Full article