Search Results (250)

Schizophrenia, depression, and bipolar disorder may represent neurodegenerative conditions involving both degeneration and aberrant regeneration of monoaminergic axons. Negative and cognitive symptoms could arise from monoaminergic axon degeneration, whereas positive symptoms and manic states might result from excessive axonal regeneration and sprouting. The molecular mechanisms driving these opposing processes remain largely unclear. This review considers the possible role of calcium-independent phospholipase A₂ (iPLA2) in regulating monoamine axon degeneration and hyper-regeneration in schizophrenia. Emerging evidence suggests that pro-inflammatory signaling mediated by cytosolic PLA₂ (cPLA2) may promote monoamine axon degeneration, while anti-inflammatory iPLA2 activity could facilitate regeneration and sprouting. Overactivation of iPLA2 might lead to aberrant axonal sprouting, potentially contributing to positive symptoms through hyperdopaminergic states in the medial prefrontal cortex (mPFC). Conversely, axon degeneration in the same region may underlie negative and cognitive symptoms. The review also discusses a potential interplay between dopamine and N-methyl-D-aspartate (NMDA) receptor signaling in distinct neuronal populations of the mPFC and suggests that targeting iPLA2 and its pathways could represent a promising therapeutic strategy. Viewing schizophrenia and related disorders through the lens of monoamine axon pathology may eventually improve diagnostic precision and inform the development of treatments aimed at restoring the balance between degeneration and regeneration. Full article

Background/Objectives: Cerebellar cognitive affective syndrome (CCAS) is a well-recognized postoperative complication in children following resection of brain tumors involving cerebellar midline structures. The fastigial nucleus is regarded as relevant, but the underlying neural mechanisms remain incompletely understood. This study uses an oddball paradigm designed to model attentional and learning processes relevant to CCAS to investigate how early-life lesions of the fastigial nucleus in rats affect cognitive performance and neural information processing in the medial prefrontal cortex (mPFC) in adulthood. Methods: Fastigial lesions were induced stereotaxically in 23-day-old male Sprague Dawley rats [n = 9]. Naïve [n = 9] and sham-lesioned rats [n = 6] served as controls. As adults, all rats were trained in an oddball paradigm requiring discrimination of a rare target tone from a rare distractor and a frequent standard tone. Local field potentials (LFPs) were recorded from electrodes implanted in the mPFC during oddball testing and event-related potentials (ERPs) were analyzed. Results: Rats with fastigial lesions required significantly more training days to reach ≥70% correct performance criterion. In fully trained rats, analysis of neural recordings during behavioral testing revealed reduced ERP amplitudes and prolonged latencies of late ERP components after target stimuli. Developmental fastigial lesions lead to lasting deficits in cognitive learning capacity and neural mPFC processing, highlighting the integrative role of cerebellar midline structures in higher-order cognitive function and sensory discrimination. Conclusions: This rodent model provides a valuable translational platform for further investigating the neural basis of CCAS and may inform neurosurgical strategies aimed at minimizing cognitive sequelae in children undergoing cerebellar tumor resection. Full article

Cognitive flexibility, the ability to adapt behavior to changing environmental demands, is a core deficit in schizophrenia (SZ), that predicts disease progression. This review synthesizes findings on the neural substates of cognitive flexibility by using a framework that distinguishes animal model tasks by their motivational valence: aversive versus appetitive. While human studies using tasks like the Wisconsin Card Sorting Test (WCST) reveal significant cognitive inflexibility in SZ, particularly in set shifting, rodent models provide important mechanistic insights. The current literature suggests that aversive tasks, such as water mazes, and appetitive tasks, such as the Birrel–Brown discrimination task, engage distinct neural circuits, despite assessing supposedly similar cognitive processes. Aversive paradigms primarily rely on hippocampal–medial prefrontal cortex (mPFC) pathways, whereas appetitive tasks heavily involve orbitofrontal cortex (OFC)–striatal circuits, with significant modulation by dopamine and serotonin. Both valences seem to require an intact balance of glutamate and GABA transmission within prefrontal regions. This framework helps clarify inconsistencies in the literature and underscores how motivational context shapes the neural substrates of cognitive flexibility. Full article

Background: Pain is a complex phenomenon characterized by unpleasant experiences with profound heterogeneity influenced by biological, psychological, and social factors. According to the National Health Interview Survey, 50.2 million U.S. adults (20.5%) experience pain on most days, with the annual cost of prescription medication for pain reaching approximately USD 17.8 billion. Theranostic pain nanomedicine therefore emerges as an attractive analgesic strategy with the potential for increased efficacy, reduced side-effects, and treatment personalization. Theranostic nanomedicine combines drug delivery and diagnostic features, allowing for real-time monitoring of analgesic efficacy in vivo using molecular imaging. However, clinical translation of these nanomedicines are challenging due to complex manufacturing methodologies, lack of standardized quality control, and potentially high costs. Quality by Design (QbD) can navigate these challenges and lead to the development of an optimal pain nanomedicine. Our lab previously reported a macrophage-targeted perfluorocarbon nanoemulsion (PFC NE) that demonstrated analgesic efficacy across multiple rodent pain models in both sexes. Here, we report PFC-free, biphasic nanoemulsions formulated with a biocompatible and non-immunogenic plant-based coconut oil loaded with a COX-2 inhibitor and a clinical-grade, indocyanine green (ICG) near-infrared fluorescent (NIRF) dye for parenteral theranostic analgesic nanomedicine. Methods: Critical process parameters and material attributes were identified through the FMECA (Failure, Modes, Effects, and Criticality Analysis) method and optimized using a 3 × 2 full-factorial design of experiments. We investigated the impact of the oil-to-surfactant ratio (w/w) with three different surfactant systems on the colloidal properties of NE. Small-scale (100 mL) batches were manufactured using sonication and microfluidization, and the final formulation was scaled up to 500 mL with microfluidization. The colloidal stability of NE was assessed using dynamic light scattering (DLS) and drug quantification was conducted through reverse-phase HPLC. An in vitro drug release study was conducted using the dialysis bag method, accompanied by HPLC quantification. The formulation was further evaluated for cell viability, cellular uptake, and COX-2 inhibition in the RAW 264.7 macrophage cell line. Results: Nanoemulsion droplet size increased with a higher oil-to-surfactant ratio (w/w) but was no significant impact by the type of surfactant system used. Thermal cycling and serum stability studies confirmed NE colloidal stability upon exposure to high and low temperatures and biological fluids. We also demonstrated the necessity of a solubilizer for long-term fluorescence stability of ICG. The nanoemulsion showed no cellular toxicity and effectively inhibited PGE2 in activated macrophages. Conclusions: To our knowledge, this is the first instance of a celecoxib-loaded theranostic platform developed using a plant-derived hydrocarbon oil, applying the QbD approach that demonstrated COX-2 inhibition. Full article

Refractory high-entropy alloys (HEAs) are promising candidates for next-generation nuclear applications, particularly fusion reactors, due to their excellent high-temperature mechanical properties and irradiation resistance. Here, the microstructure and mechanical behavior were investigated for an equimolar WTaTiVZr HEA, designed from a palette of low-activation elements. The as-cast alloy exhibited a dendritic microstructure composed of W-Ta rich dendrites and Zr-Ti-V rich inter-dendritic regions, both possessing a body-centered cubic (BCC) crystal structure. Room temperature bulk compression tests showed ultra-high strength of around 1.6 GPa and plastic strain ~6%, with fracture surfaces showing cleavage facets. The alloy also demonstrated excellent high-temperature strength of ~650 MPa at 500 °C. Scratch-based fracture toughness was ~38 MPa√m for the as-cast WTaTiVZr HEA compared to ~25 MPa√m for commercially used pure tungsten. This higher value of fracture toughness indicates superior damage tolerance relative to commercially used pure tungsten. These results highlight the alloy’s potential as a low-activation structural material for high-temperature plasma-facing components (PFCs) in fusion reactors. Full article

Social anxiety disorder (SAD) is characterized by fear and avoidance of social situations. Considering the reduced availability of conventional therapies, we aimed to improve our understanding of the biological mechanisms in SAD by evaluating gamma-aminobutyric acid (GABA) and other neurometabolites (including glutamate + glutamine/glutamix (Glx), N-acetyl aspartate (NAA), myo-inositol (mI), total choline (tCho), and total creatine (tCr) in the dorsomedial prefrontal cortex/anterior cingulate cortex (dmPFC/ACC), dorsolateral prefrontal cortex (dlPFC), and the insula). In this pilot study, we recruited 26 (age: 25.3 ± 5.0 years; 61.5% female) individuals with SAD and 26 (age: 25.1 ± 4.4 years; 61.5% female) sex-age-matched controls. Using proton magnetic resonance spectroscopy, we found that compared to the controls, GABA+ macromolecular signal (GABA+) in dlPFC (t = 2.63; p = 0.012) and Glx in the insula (Mann–Whitney U = 178.3; p = 0.024) were higher in the participants with SAD. However, no between-group differences were observed in dmPFC/ACC (t = 0.39; p = 0.699). Increased GABA+ in dlPFC could be explained by aberrant GABA transporters. In the insula, increased Glx may be associated with the dysfunction of glutamate transporters or decreased activity of glutamic acid decarboxylase in the GABAergic inhibitory neurons. However, these proposed mechanisms need to be further investigated in SAD. Full article

This study addresses the unclear mechanisms by which preferential flow channels (PFCs), formed during long-term waterflooding, affect nano-gel microsphere (NGM) flooding efficiency, utilizing CMG reservoir numerical simulation software. A dynamic evolution model of PFCs was established by coupling CROCKTAB (stress–porosity hysteresis) and CROCKTABW (water saturation-driven permeability evolution), and the deep flooding mechanism of NGMs (based on their gel properties such as swelling, elastic deformation, and adsorption, and characterized by a “plugging-migration-replugging” process) was integrated. The results demonstrate that neglecting PFCs overestimates recovery by 8.7%, while NGMs reduce permeability by 33% (from 12 to 8 mD) in high-conductivity zones via “bridge-plug-filter cake” structures, diverting flow to low-permeability layers (+33% permeability, from 4.5 to 6 mD). Field application in a Chang 6 tight reservoir (permeability variation coefficient 0.82) confirms a >10-year effective period with 0.84% incremental recovery (from 7.31% to 8.15%) and favorable economics (ROI ≈ 10:1), providing a theoretical and engineering framework for gel-based conformance control in analogous reservoirs. Full article

Transcranial direct current stimulation (tDCS) modulates cortical excitability, thus inducing improvements in motor learning of simple tasks. In this study, we aimed to evaluate the effect of different tDCS conditions—anodal stimulation over the motor cortex (M1), anodal and cathodal stimulation over the prefrontal cortex (PFC), and sham—on the online and offline learning of a complex accuracy task (golf-putting) in novice golfers. Methods: A total of 40 young, healthy subjects (24 men, 16 women) without previous golf experience were randomly distributed in four groups receiving sham, anodal M1, anodal PFC or cathodal PFC tDCS. All subjects participated in two consecutive sessions. In the first session, they performed 15 blocks of 10 golf-putting along with tDCS stimulation. After 24 h, they performed the same task without tDCS. Results: Repeated measures ANOVA revealed a significant improvement in performance during the two consecutive golf-putting sessions regardless of the site and the stimulation conditions. Conclusion: Our findings suggest that tDCS over M1 or PFC does not confer additional benefits in the acquisition of complex, full-body motor skills such as golf-putting. Full article

Objective: Burning mouth syndrome (BMS) is a chronic and often debilitating orofacial pain condition characterized by a burning sensation in the oral mucosa without clear abnormal lesions. While its etiology is considered multifactorial, the underlying pathophysiology remains unclear. This narrative review aims to synthesize existing functional magnetic resonance imaging (fMRI) studies to shed light on the central neural mechanisms contributing to BMS. Methods: A focused electronic search was conducted across the PubMed and J-STAGE databases for relevant articles published in English from January 2000 to May 2025. The review prioritized studies investigating brain structure and function using fMRI in individuals with BMS. Results: Our synthesis of the literature consistently demonstrated that the brains of individuals with BMS exhibit augmented connectivity within the medial pain system and a diminished gray matter volume in the medial prefrontal cortex (mPFC). These findings suggest a crucial role for altered brain circuitry, particularly a reduction in the output of the basal ganglia dopamine system, in the experience of BMS pain. Conclusions: The consistent fMRI findings strongly indicate that BMS involves significant functional and structural brain alterations. The observed changes in the mPFC and its connections to the basal ganglia dopamine system highlight this pathway as a potential target for both pharmacological and non-pharmacological neurological interventions for individuals with BMS. Full article

In order to examine the fracture development law of overlying strata in goafs and to reasonably lay out a high gas-drainage roadway under gob-side entry retaining with roadside filling, the 91–105 working face of the Wangzhuang Coal Mine was selected as the engineering case study. The failure laws and fracture development characteristics of the overlying strata in both the strike and dip directions using gob-side entry retaining and roadside filling were studied through rock mechanic tests and PFC numerical simulations. The optimal layout of the high gas-drainage roadway was determined through theoretical analysis and coupled Fluent–PFC numerical simulations, and on-site monitoring was conducted to evaluate the extraction effects. The results indicate that the first weighting interval of the 91–105 working face was 40 m, while the periodic weighting interval was approximately 14 m. The height of the falling zone was 14.4 m, and the height of the gas-conducting fracture zone was 40.7 m. In the dip direction, compared with coal pillar retaining, gob-side entry retaining with roadside filling formed an inverted trapezoid secondary breaking zone above the retaining roadway. Using this method, the span of the separation zone increased to 30 m, and the collapse angle decreased to 52°, resulting in a shift in the separation zone—the primary space for gas migration—toward the goaf. It was determined that the optimal location of the high gas-drainage roadway was 28 m above the coal roof and 30 m horizontally from the return air roadway. Compared with the 8105 working face, this position was 10 m closer toward the goaf. On-site gas extraction monitoring data indicate that, at this optimized position, the gas concentration in the high gas-drainage roadway increased by 22%, and the net gas flow increased by 18%. Full article

Depression and obesity are comorbid conditions linked through shared neuroinflammatory and immune mechanisms. This study examined the effects of chronic cannabidiol (CBD) treatment on behavior and neuroinflammatory gene expression in female rats exposed to a combined model of high-fat diet (HFD) and unpredictable chronic mild stress (UCMS). Rats were subjected to an acute HFD for 2 weeks, followed by 4 weeks of UCMS. CBD (10 mg/kg, i.p.) or vehicle was administered during the final 2 weeks of UCMS. Specifically, mRNA levels of nuclear factor kappa B1 (NF-κB1), tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and IL-6 were measured in the ventromedial prefrontal cortex (vmPFC) and CA1. CBD’s effects varied depending on the type of stressor. It promoted coping behavior, increased locomotion, reduced freezing, and restored UCMS-induced depressive-like behavior in a splash test. In the vmPFC, CBD normalized the HFD- and UCMS-induced increase in il1β, and downregulated nfkb1 and tnfa expression. In the CA1, it normalized stress-induced downregulation in nfkb1 expression. These findings suggest that the efficacy of CBD in modulating both behavior and neuroinflammation is contingent upon the nature of the stress exposure, highlighting its potential as a targeted treatment for stress-related neuropsychiatric disorders in females. Full article

Shallow landslides are one of the main geological hazards that occur during heavy rainfall in Yuexi County every year, posing potential risks to the personal and property safety of local residents. A rainfall-induced shallow landslide named Baishizu No. 15 landslide in Yuexi Country was taken as a case study. Based on the field geological investigation, combined with physical and mechanical experiments in laboratory as well as numerical simulation, the failure mechanism induced by rainfall infiltration was studied, and the movement process after landslide failure was inverted. The results show that the pore-water pressure within 2 m of the landslide body increases significantly and the factory of safety (F_s) has a good corresponding relationship with rainfall, which decreased to 0.978 after the heavy rainstorm on July 5 and July 6 in 2020. The maximum shear strain and displacement are concentrated at the foot and front edge of the landslide, which indicates a “traction type” failure mode of the Baishizu No. 15 landslide. In addition, the maximum displacement during landslide instability is about 0.5 m. The residual strength of soils collected from the soil–rock interface shows significant rate-strengthening, which ensures that the Baishizu No. 15 landslide will not exhibit high-speed and long runout movement. The rate-dependent friction coefficient of sliding surface was considered to simulate the movement process of the Baishizu No. 15 landslide by using PFC^2D. The simulation results show that the movement velocity exhibited obvious oscillatory characteristics. After the movement stopped, the landslide formed a slip cliff at the rear edge and deposited as far as the platform at the front of the slope foot but did not block the road ahead. The final deposition state is basically consistent with the on-site investigation. The research results of this paper can provide valuable references for the disaster prevention, mitigation, and risk assessment of shallow landslides on residual soil slopes in the Dabie mountainous region. Full article

In cold-region rock engineering, freeze–thaw cycle-induced crack propagation in fractured rock masses serves as a major cause of disasters such as slope instability. Existing studies primarily focus on the influence of individual fissure parameters, yet lack a systematic analysis of the crack propagation mechanisms under the coupled action of multiple parameters. To address this, we establish three groups of slope models with different rock bridge distances (d), rock bridge angles (α), and fissure angles (β) based on the PFC2D discrete element method. Frost heave loads are simulated by incorporating the volumetric expansion during water–ice phase change. The Parallel Bond Model (PBM) is used to capture the mechanical behavior between particles and the bond fracture process. This reveals the crack evolution laws under freeze–thaw cycles. The results show that, at a short rock bridge distance of d = 60 m, stress concentrates in the fracture zone. This easily leads to the rapid penetration of main cracks and triggers sudden instability. At a long rock bridge distance where d ≥ 100 m, the degree of stress concentration decreases. Meanwhile, the stress distribution range expands, promoting multiple crack initiation points and the development of branch cracks. The number of cracks increases as the rock bridge distance grows. In cases where the rock bridge angle is α ≤ 60°, stress is more likely to concentrate in the fracture zone. The crack propagation exhibits strong synergy, easily forming a penetration surface. When α = 75°, the stress concentration areas become dispersed and their distribution range expands. Cracks initiate earliest at this angle, with the largest number of cracks forming. Cumulative damage is significant under this condition. When the fissure angle is β = 60°, stress concentration areas gather around the fissures. Their distribution range expands, making cracks easier to propagate. Crack propagation becomes more dispersed in this case. When β = 30°, the main crack rapidly penetrates due to stress concentration, inhibiting the development of branch cracks, and the number of cracks is the smallest after freeze–thaw cycles. When β = 75°, the freeze–thaw stress dispersion leads to insufficient driving force, and the number of cracks is 623. The research findings provide a theoretical foundation for assessing freeze–thaw damage in fractured rock masses of cold regions and for guiding engineering stability control from a multi-parameter perspective. Full article

Prenatal cannabis exposure (PCE) has been associated with altered prefrontal cortex (PFC) activity and connectivity in adulthood, potentially increasing the risk of psychopathology later in life. This risk is thought to involve a complex interplay between the endocannabinoid and dopaminergic systems. We investigated the transcriptional regulation of genes associated with these systems in an animal model of PCE during adolescence, focusing on DNA methylation and specific microRNAs (miRNAs). Our study revealed increased mRNA levels of dopamine D1 and D2 receptors (Drd1 and Drd2) in the PFC, with a notable effect on Drd2 in male offspring. Notably, we observed a consistent reduction in Drd2 DNA methylation levels in PCE male rats. Both Drd1 and Drd2 expressions were regulated by selective miRNAs. Accordingly, we found changes in the excitability of PFC pyramidal neurons in male adolescent PCE offspring, along with alterations in the Netrin-1/DCC guidance cue system. Our findings highlight PCE-induced modifications of the PFC dopaminergic system while maintaining stable gene expression of the endocannabinoid system in male offspring. Changes in this complex interaction during sensitive developmental periods like adolescence might lead to sex-dependent divergent behavioral outcomes induced by PCE. Full article

Background/Objectives: While the presence of inflammatory processes in stenotic aortic valves is acknowledged, no systematic characterization of the systemic immune reaction upon aortic valve stenosis (AS) has been performed yet. The hypothesis of this study was that AS induces a systemic inflammatory reaction linked with local processes in the heart. Methods: Murine wire injury (WI) to induce AS, or sham surgery, were performed prior to the 4-week assessment of AS severity, left ventricular (LV) function and hypertrophy with echocardiography (echo). Organ weights, levels of leukocytes, cytokines and costimulatory molecules in blood, heart, and peripheral immune organs (spleen, liver, lymph nodes), and immune cell uptake of Cy5-labelled perfluorocarbon nanoemulsions were measured. Results: Trends towards correlation were found between organ weights, myocardial immune cells and echo. Cytokine mRNA levels trended mainly towards an increase in heart and regional lymph nodes and a reduction in spleen and liver, and correlation with echo was more homogeneous after WI. Unchanged cytokine protein levels in myocardium and plasma trended to correlate with echo. A homogeneous pattern was found for echo and costimulatory molecule correlation, while PFC uptake by lymphatic cells was reduced upon AS. Conclusions: The results suggest a link between number and activation state of leukocytes in peripheral organs and cardiac processes in AS. Considering the pathological value of inflammation, it is crucial that future studies investigate if a modulation of the systemic inflammatory reaction relieves severity of AS and opposes development of heart failure. Full article