Search Results (20,088)

(1) Background: The characteristics of rare diseases (RDs) vary considerably—not only between different disease types but also between individual patients with the same condition. In the Roma community, we analyzed the most frequent rare genetic disorders related to the founder effect. (2) Methods: This retrospective study, conducted between January 2019 and January 2025 at the Clinical Genetics and Metabolics Outpatient Clinic in Košice, included 61 patients aged from infancy to 25 years diagnosed with hypomyelinating leukodystrophy 14, pontocerebellar hypoplasia type 1B, neuronal ceroid lipofuscinosis 7, or TMEM70 deficiency. (3) Results: This study includes the largest known cohort of patients with hypomyelinating leukodystrophy 14 caused by the UFM1 c.-273_-271delTCA mutation, predominantly affecting males (n = 17). The disorder is severe, with most patients dying before one year of age, and is characterized by inspiratory stridor, axial hypotonia, spastic quadriparesis, pseudobulbar signs, and microcephaly. In a separate group with pontocerebellar hypoplasia type 1B, six Roma patients (three males, three females) shared the same EXOSC3 mutation. Diagnosis occurred at an average age of 8.8 months, and most children did not survive beyond three years. Common features included microcephaly, severe hypotonia, and spastic quadriplegia. Thirteen children from eight families were diagnosed with neuronal ceroid lipofuscinosis 7, all carrying the same MFSD8 mutation. Symptoms typically began with psychomotor regression between ages 3 and 4, along with intellectual disability and seizures, which were more frequent in males. The mean age at diagnosis was 4.5 years, and eight children died before age nine. Finally, 25 patients with TMEM70 deficiency associated with Roma ancestry were identified, predominantly females, with a mean age of 9.95 years and the oldest patient aged 25. Four children died due to severe metabolic crises. Common findings included intellectual disability, global hypotonia, hypertrophic cardiomyopathy, epilepsy, and failure to thrive. (4) Conclusions: Most rare diseases are genetic and carry high morbidity and mortality, with no targeted therapies currently available. Their increased prevalence in the Roma population reflects founder effects and high consanguinity. Prenatal and newborn screening, along with voluntary carrier testing for couples, is essential for proactive health management. Full article

Background/Objectives: Intracerebral hemorrhage (ICH) is a severe subtype of stroke characterized by extensive secondary brain injury driven by oxidative stress, inflammation, and progressive neuronal loss, leading to poor neurological outcomes. Thymoquinone, a bioactive compound derived from Nigella sativa, has demonstrated potent antioxidant and neuroprotective properties, but its integrated effects in hemorrhagic stroke remain insufficiently explored. This study aimed to evaluate the antioxidant and neuroregenerative effects of thymoquinone in a rat model of ICH. Methods: Male Wistar rats with experimentally induced ICH were randomized into untreated controls and two treatment groups receiving thymoquinone (150 mg/kg and 250 mg/kg) for three consecutive days. Oxidative injury and antioxidant responses were assessed using membrane blebbing, malondialdehyde (MDA), superoxide dismutase (SOD) activity, and nuclear factor erythroid 2-related factor 2 (NRF2) expression, while neuroprotection was evaluated by neuronal counts in perihematomal tissue. Results: Thymoquinone treatment significantly reduced membrane blebbing and MDA levels, while markedly increasing SOD activity and NRF2 expression in a dose-dependent manner. These biochemical improvements were accompanied by significant preservation of neuronal morphology and increased neuronal survival, with the 250 mg/kg dose showing the strongest effects. Conclusions: In conclusion, thymoquinone confers robust antioxidant and neuroprotective benefits in experimental ICH and represents a promising candidate for mitigating secondary brain injury following intracerebral hemorrhage. Full article

Nesfatin-1 and ghrelin O-acyltransferase (GOAT) have established roles in metabolic regulation and neuronal excitability, yet their relationship in epilepsy remains conflicted. This cross-sectional study compared 22 adolescent epilepsy patients (13.1 ± 2.0 years; 11 women/11 men) with 20 age-matched healthy controls (HCs) (12.3 ± 2.2 years; 8 women/12 men). Serum and salivary nesfatin-1 and GOAT levels were measured by enzyme-linked immunosorbent assay; Spearman’s rank correlation assessed inter-neuropeptide relationships. Serum nesfatin-1 was markedly elevated in patients with epilepsy compared to HCs (44.04 (interquartile range 38.19–76.72) vs. 8.65 (interquartile range 7.82–9.01) ng/mL, p < 0.001; ~5-fold). Serum GOAT was similarly elevated (4.90 (interquartile range 4.17–6.66) vs. 1.41 (interquartile range 1.21–1.79) ng/mL, p < 0.001; 3.5-fold). A significant inverse correlation between serum nesfatin-1 and GOAT levels was identified in patients with epilepsy (rho = −0.68, 95% CI [−0.86, −0.36], p < 0.001) but not in HCs (p = 0.53) and remained independent of age, sex, body mass index and epilepsy type. This inverse correlation was significant in women (rho = −0.68, p = 0.021) with a similar trend in men (rho = −0.53, p = 0.096). Salivary nesfatin-1 mirrored serum patterns (2.3-fold increase; p < 0.001), while salivary GOAT showed a 9-fold reduction (p < 0.001). This study provides the first evidence of an inverse nesfatin-1/GOAT correlation in adolescent epilepsy, suggesting disease-specific neuroendocrine dysregulation. These exploratory findings support the potential of these neuropeptides as candidate biomarkers warranting further validation and offer new insights into the metabolic-excitability axis in epilepsy. Full article

Depression is a common mental disorder that substantially impairs patients’ daily life and work. To identify natural and safe preventive options, we investigated the preventive effect and underlying mechanism of the Ganoderma lucidum and Rosa roxburghii Tratt formula (GLRRTF) on depression. A total of 72 chemical components in GLRRTF were identified by UHPLC-ESI-Q-Exactive Plus Orbitrap-MS Analysis. GLRRTF (containing 400 mg/kg of G. lucidum extract and 800 mg/kg of R. roxburghii extract per day), administered as a 1-week preventive intervention followed by 4 weeks of co-administration with chronic unpredictable mild stress, prevented the development of depression-like behaviors in male C57BL/6J mice and reduced neuronal damage in the hippocampus. Airflow-assisted desorption electrospray ionization mass spectrometry imaging and enzyme-linked immunosorbent assays showed that GLRRTF corrected abnormalities in neurotransmitter levels. The 16S rRNA sequencing indicated that GLRRTF restored dysbiosis of the gut microbiota. Metabolomic profiling revealed that GLRRTF increased the level of tryptophan and promoted tryptophan metabolism towards the 5-HT and indole pathways in feces and the brain. Western blot demonstrated that GLRRTF increased 5-HT production from tryptophan in the brain by regulating tryptophan hydroxylase 2 and DOPA decarboxylase. GLRRTF activated the PI3K/AKT pathway by regulating brain-derived neurotrophic factor and its receptor tropomyosin receptor kinase B. This research provides a comprehensive mechanistic understanding of GLRRTF’s preventive effect against depression, highlighting its potential as a novel, safe, and preventive functional food formulation. Full article

Alzheimer’s disease (AD) is increasingly recognized as a multisystem neurodegenerative disorder in which sensory dysfunction accompanies cognitive decline. As an accessible extension of the central nervous system, the retina provides a valuable window for investigating early neurodegenerative processes; however, the cellular mechanisms underlying AD-associated retinal pathology remain incompletely understood. Here, using the APP/PS1 mouse model, we systematically examined structural, functional, and glial alterations in the retina across disease stages. Despite robust age-dependent amyloid plaque accumulation in visual-related brain regions, no plaque-like β-amyloid (Aβ) deposits were detected in the retina even at advanced ages. Nevertheless, young APP/PS1 mice exhibited early thinning of inner retinal layers, impaired retinal electrophysiological responses, and reduced excitatory synaptic inputs to retinal ganglion cells (RGCs), preceding overt neuronal loss. These neuronal changes were accompanied by pronounced Müller glial activation, characterized by upregulation of gliosis markers and extensive morphological remodeling. Functional analyses further revealed dynamic alterations in glial homeostasis, including early elevation followed by age-dependent decline of glutamine synthetase activity, together with increased expression and disrupted perivascular polarity of aquaporin-4. Consistently, transcriptomic profiling of young AD retinas identified coordinated dysregulation of genes involved in amino acid metabolism, transport, and oxidative stress responses. Together, our findings identify Müller glial remodeling as an early feature of AD-associated retinal pathology that coincides with synaptic vulnerability of RGCs and occurs independently of local Aβ plaque deposition, highlighting retinal glia as potential early indicators and modulators of neurodegeneration. Full article

Model-based reinforcement learning (MBRL) is a promising approach for achieving high sample efficiency in learning control policies. The existing world models in MBRL typically represent the environment’s state as a single global latent vector. However, such representations limit the model’s ability to capture object interactions and reason about individual objects—capabilities that are critical for visual object-oriented tasks—and may lead to lower sample efficiency. To address this limitation, we propose Kuramoto Object-Centric Reinforcement Learning (KORL), a model-based agent that learns an object-centric world model. Our approach introduces a novel Kuramoto Slot Attention for Video (KSAVi) model that integrates Kuramoto oscillatory neurons with the Slot Attention module to robustly extract object representations. We design a world model that leverages these structured object-centric latents and predicts dynamics using graph neural networks, thereby incorporating an inductive bias for modeling object interactions. We evaluate KORL on a suite of visually diverse object-oriented robotic manipulation tasks and demonstrate that our method outperforms object-centric model-free and model-based approaches. Full article

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive cognitive decline and neuropathological hallmarks such as amyloid-β plaques and neurofibrillary tangles. In recent years, chronic neuroinflammation has emerged as a central mechanism linking genetic, metabolic, and immune dysfunctions in AD. Activated microglia and astrocytes release pro-inflammatory cytokines and reactive oxygen species that exacerbate synaptic and neuronal injury, while impaired clearance mechanisms and blood–brain barrier disruption further sustain inflammation. A growing body of research highlights the role of immunometabolism—the bidirectional interaction between immune activation and cellular metabolism—in shaping glial phenotypes and disease progression. Dysregulation of glucose, lipid, and amino acid metabolism, together with alterations in key metabolites such as lactate, NAD⁺, and reactive oxygen species, promotes a maladaptive inflammatory state. Genetic factors including APOE4 and TREM2 variants affect microglial lipid handling pathways, while systemic metabolic disorders and gut microbiota alterations amplify neuroinflammatory cascades. Natural bioactive compounds, particularly polyphenols, have gained attention for their ability to modulate immunometabolic pathways. By activating AMPK and SIRT1 and inhibiting mTOR and NLRP3 inflammasome signaling, polyphenols may tune mitochondrial function, redox homeostasis, and autophagy, promoting adaptation to chronic metabolic stress. Therefore, metabolic-immune interactions represent pleiotropic therapeutic avenues for AD. Understanding how immunometabolites and nutrient-sensing pathways regulate compartmentalized inflammation in the CNS may pave the way for novel interventions that combine metabolic precision with neuroprotective efficacy. Full article

Artificial intelligence is typically formulated as an information-processing system composed of artificial neurons, where computation is understood as recursive operations connecting inputs and outputs. However, real neural systems are materially embodied and continuously reconfigured by metabolic and physical processes, suggesting that computation cannot be reduced to fixed causal structures. In this paper, we propose a theoretical framework that captures the interplay between informational and material processes as the interaction between two computational schemes: a vertical scheme, representing fixed cause–effect relations, and a horizontal scheme, representing transformations between such relations. We show that the vertical scheme corresponds to Bayesian inference, which updates probability distributions over a fixed hypothesis space, and is consistent with the free-energy minimization principle. In contrast, the horizontal scheme is formalized as inverse Bayesian inference, which modifies the hypothesis space itself by updating likelihood structures based on experienced data. We further demonstrate that the interplay between these schemes can be expressed algebraically as a process of continuously gluing Boolean algebras. This construction yields a non-distributive orthomodular lattice, i.e., quantum logic, without invoking Hilbert space formalism. In this view, quantum logic emerges not as a static logical system but as a structural consequence of dynamically reconfiguring causal contexts. This framework provides a unified perspective in which inference is understood not only as optimization within a fixed model but also as a process that generates and transforms the model itself. It offers a formal basis for describing open-ended computation and suggests a connection to approaches such as unconventional computing and Natural Born Intelligence, where computational structures evolve through interaction with material processes. Unlike existing approaches, this framework derives quantum-logic-like structure from the continual reconfiguration of causal contexts rather than from Hilbert-space assumptions or optimization within a fixed hypothesis space. Full article

Excessive activation of the sympathetic nervous system is a prominent contributor linked to heart failure (HF) progression. Pathological remodeling of the central nervous system represents a plausible upstream event associated with central sympathetic hyperactivity, whereas dysfunction of the brain–heart axis may act as a pivotal hub involved in this pathological process. This review systematically summarizes the functional characteristics of major sympathetic regulatory nuclei under HF, including the subfornical organ (SFO), paraventricular nucleus of the hypothalamus (PVN), rostral ventrolateral medulla (RVLM), and nucleus tractus solitarius (NTS). Following the pathological logic from upstream initiation to inter-organ closed-loop responses, seven interconnected pathological mechanisms are analyzed: glial cell activation and neuroinflammation, endoplasmic reticulum stress, renin–angiotensin system (RAS) imbalance, abnormal signaling pathways and transcription factors, impaired neuronal microenvironment homeostasis, dysregulated post-transcriptional and post-translational modifications, and extracellular vesicle-mediated inter-organ signal transmission. Their cross-regulation and positive feedback amplification effects are highlighted. Multidimensional central-targeted intervention strategies established on this basis possess important fundamental significance and translational potential. This review also discusses current scientific challenges and prospects for interdisciplinary frontiers, providing theoretical references and practical insights for central regulation research in HF and its precise clinical translation. Full article

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder. It is characterized by the accumulation of misfolded α-synuclein (α-syn) and progressive loss of dopaminergic neurons in the substantia nigra. Due to the limitations of current therapies, mesenchymal stromal cell (MSC) transplantation has emerged as a promising neuroprotective strategy. This study evaluated the neuroprotective potential of decidua-derived mesenchymal stromal cells (DMSCs) in vitro using a human neuroblastoma cell line (NB69) exposed to the neurotoxin 1-methyl-4-phenylpyridinium (MPP+) as a PD model. The NB69 cells were differentiated into a mature dopaminergic phenotype using dibutyryl cyclic adenosine monophosphate (dbcAMP) and then exposed to MPP+. In proliferative NB69 cells, the effect of DMSCs was masked by their inherent antitumor activity against the neuroblastoma phenotype. Conversely, in the differentiated NB69 model, DMSCs demonstrated a significant protective role against MPP+-induced cytotoxicity. Interestingly, the mechanism by which DMSCs might exert a neuroprotective effect against MPP+ damage in differentiated NB69 cells appears to involve improving mitochondrial function by reducing free radicals. In summary, these findings suggest that DMSCs exert a neuroprotective effect in a dopaminergic-like context and highlight the importance of using differentiated cell models to accurately evaluate cell-based therapies for PD in the striatum. Full article

Compensatory mechanisms are thought to maintain sufficient dopamine (DA) signaling to mitigate locomotor impairment during progressive nigrostriatal neuron loss in Parkinson’s disease (PD). Recent evidence indicated augmented DA tissue content in the substantia nigra (SN), not striatum, compensates for tyrosine hydroxylase (TH) and neuronal loss, and alleviates the severity of hypokinesia during neuronal loss. Here, we determined if increased extracellular DA in the SN may also be a compensatory mechanism to augment DA signaling. Following unilateral 6-hydroxydopamine (6-OHDA) lesion or sham-operation, we contemporaneously evaluated extracellular DA against both DA tissue and TH levels in striatum and SN at 7 and 28 days. At 7 days post-lesion, TH loss exceeded ~90% in striatum, and ~70% in the SN. The severity of DA tissue loss coincided with TH protein loss only in striatum (>90%) on both days after lesion, whereas in the SN, DA loss was absent on day 7 and significantly less than TH loss by day 28. Whereas there was a robust increase in extracellular DA in striatum in our sham-operation group, the severe TH and DA tissue loss in striatum practically abolished KCl (K⁺)-stimulated extracellular DA by day 7. In contrast, whereas striatal K⁺-stimulation had no effect on extracellular DA in the SN in sham-operation group, extracellular DA levels increased in the SN 7 days after nigrostriatal lesion: an increase no longer apparent by day 28. Thus, despite significant loss of TH protein loss in the SN, extracellular and tissue DA tissue levels were augmented during neuronal loss. These results build upon evidence that compensatory mechanisms to augment DA signaling are not engaged in striatum, and point to the SN as the locus of augmented DA signaling to offset loss of TH during nigrostriatal neuron loss. Full article

Introduction: The relationship between epilepsy and alcohol use is complex and clinically significant. Alcohol acts as a neurochemical modulator capable of lowering the seizure threshold during both intoxication and withdrawal, while chronic misuse may contribute to epileptogenesis through neuronal injury, metabolic stress, and neurotransmitter dysregulation. However, the long-term impact of alcohol use on mortality among people with epilepsy (PWE) remains insufficiently characterized. The purpose of this study was to assess all-cause mortality risk among individuals with epilepsy based on alcohol use history, stratified by race/ethnicity. Methods: Data from the 2008–2018 National Health Interview Survey (NHIS) were linked to mortality outcomes on 31 December 2019 from the National Death Index (NDI) for U.S. adults aged 18 years and older. PWE and alcohol use were determined using self-reported data. Survival probabilities were estimated using weighted Kaplan–Meier methods, and hazard ratios were calculated using Cox proportional hazards models adjusted for demographic and clinical covariates. Results: Our results indicated that among PWE, alcohol use was associated with increased all-cause mortality. The unadjusted hazard ratio (HR) for alcohol use among individuals with epilepsy was 1.30, increasing to 1.40 after multivariable adjustment. In contrast, alcohol use alone without epilepsy was not associated with elevated mortality risk after adjustment. When stratified by race, the combined effect of epilepsy and alcohol use was significantly associated with increased mortality among Black individuals but not White individuals. Conclusions: In this nationally representative cohort, the combined presence of epilepsy and alcohol use was associated with higher all-cause mortality compared with alcohol use alone. Racial differences were observed, underscoring the need for integrated clinical care and further research into genetic, biological, and social determinants influencing epilepsy outcomes. Full article

This article explores the complex interplay between the process of protein translation and DNA methylation, discussing their combined involvement in brain development. We will emphasize on DNA methylation and related proteins such as DNMTs, TETs, and MeCP2, the latter being the prototype of DNA methyl-binding proteins. Collectively, DNA methylation machinery may be involved in controlling the cell fate commitment of brain cells, as well as their neuronal and glial lineage specification. We aim to summarize current knowledge on the dynamics of protein translation, ribosome biogenesis, and relevant cellular pathways, including the mTOR signaling, in the context of brain development. Special attention is given to MeCP2 because of its unique role as an epigenetic factor that influences the chromatin states with a link to protein translation and its relevance to human disease. We also discuss the impact of DNA methylation-mediated chromatin regulation and protein translation in neurodevelopmental disorders. Our discussions include multi-omics techniques and integrative mechanisms that connect DNA methylation with protein translation. Full article

Background/Objectives: Fibromyalgia (FM) syndrome is characterised by constant and pervasive musculoskeletal pain and may be comorbid with obesity. Glucagon Peptide-1 Receptor Agonists (GLP-1RAs) are relatively new pharmacotherapies developed for the treatment of type 2 diabetes mellitus (T2DM) and have been repurposed for the treatment of obesity. In addition to their well-established impact on glucose balance, new evidence indicates that GLP-1RAs may have anti-inflammatory properties beyond glycaemic regulation. The use of GLP-1RAs has been proposed to modulate the central pain pathways in patients with FM; however, few studies have directly evaluated their effects on central pain. Hence, the purpose of this study is to review the relationship between FM and obesity and to explore the potential role of GLP-1RAs in the management of FM. Methods: A literature search was conducted across four databases—PubMed/Medline, Cochrane, Google Scholar, and PEDro—up to May 2025. The literature was sparse, and no formal evaluation process was performed; however, papers were excluded if they failed to address either FM or GLP-1RAs. The key characteristics of each study were extracted and summarised in table form to enable efficient narrative synthesis. Results: Of the 56 included studies, 24 were preclinical reviews, 16 were clinical reviews, 8 examined preclinical animal models, and only 8 focused on human data, limited to retrospective analyses of data and self-reporting. There is some evidence that GLP-1RAs may reduce neuronal excitability, inhibit pain signalling, and decrease inflammation. Conclusions: However, no clinical trials directly evaluating GLP-1RAs in FM were identified, and therefore no conclusions can be drawn regarding clinical efficacy in FM, including in patients with comorbid obesity. Full article

Opioid-induced constipation (OIC) represents a prevalent adverse effect of opioid analgesics, affecting 60–90% of patients and ssignificantly compromising quality of life. This review delineates the multifactorial pathogenesis of OIC. Peripheral μ-opioid receptor (MOR) activation suppresses enteric neuronal excitability, inhibits intestinal motility and secretion, and impairs rectoanal function. Notably, the colon appears to exhibit a distinctive lack of tolerance to opioids. Enteric glial cell activation has been implicated in neuroinflammation, while interstitial cells of Cajal show impaired pacemaker function. Central mechanisms are increasingly recognized to involve the brain–gut axis. Furthermore, opioid-induced barrier disruption, microbiota dysbiosis, and LPS/TLR4-mediated inflammation are proposed to interact and may contribute to a self-reinforcing cycle. Animal models have been instrumental in dissecting these mechanisms. However, they present limitations in reproducibility, clinical phenotype fidelity, and translational validity, particularly regarding microbiome composition and neuroimmune responses. Future research should prioritize the development of standardized, physiologically relevant animal models incorporating multi-omics approaches, and validate mechanism-based therapeutic strategies, including peripherally acting MOR antagonists and microbiota-targeted interventions, for precision management of OIC. Full article