Search Results (392)

The growing disconnection between humans and nature—particularly in urban environments—has been associated with declining well-being and lower engagement in pro-environmental behavior. Although the Connectedness with Nature Scale (CNS) has been widely used internationally to measure this relationship, there is a lack of evidence on its validity and reliability in Latin American contexts, especially in urban and rural settings. This study aims to address this gap by examining the psychometric properties of the CNS in a sample of 956 Colombian participants. Using exploratory and confirmatory factor analyses, we tested two versions of the scale (14-item and 12-item models), both showing good fit and high internal consistency (α > 0.90). Convergent validity was confirmed through strong correlations with the Environmental Identity and Pro-environmental Behavior Scales. These findings support the CNS as a valid and reliable tool to assess the human–nature connection in Colombia and highlight its potential for informing urban sustainability initiatives, environmental education, and public policy in diverse sociocultural contexts. Full article

Neurodegenerative diseases (NDDs) such as Alzheimer’s, Parkinson’s, ALS, and Huntington’s pose a growing global challenge due to their complex pathobiology and aging demographics. Once considered as cellular debris, small extracellular vesicles (sEVs) are now recognized as active mediators of intercellular signaling in NDD progression. These nanovesicles (~30–150 nm), capable of crossing the blood–brain barrier, carry pathological proteins, RNAs, and lipids, facilitating the spread of toxic species like Aβ, tau, TDP-43, and α-synuclein. sEVs are increasingly recognized as valuable diagnostic tools, outperforming traditional CSF biomarkers in early detection and disease monitoring. On the therapeutic front, engineered sEVs offer a promising platform for CNS-targeted delivery of siRNAs, CRISPR tools, and neuroprotective agents, demonstrating efficacy in preclinical models. However, translational hurdles persist, including standardization, scalability, and regulatory alignment. Promising solutions are emerging, such as CRISPR-based barcoding, which enables high-resolution tracking of vesicle biodistribution; AI-guided analytics to enhance quality control; and coordinated regulatory efforts by the FDA, EMA, and ISEV aimed at unifying identity and purity criteria under forthcoming Minimal Information for Studies of Extracellular Vesicles (MISEV) guidelines. This review critically examines the mechanistic roles, diagnostic potential, and therapeutic applications of sEVs in NDDs, and outlines key strategies for clinical translation. Full article

A 12-membered pyridinophane scaffold containing two pyridine and two tertiary amine residues is examined as a prototype ligand (^tBuN4) for supporting nitrene transfer to olefins. The known [(^tBuN4)M^II(MeCN)₂]²⁺ (M = Mn, Fe, Co, and Ni) and [(^tBuN4)Cu^I(MeCN)]⁺ cations are synthesized with the hexafluorophosphate counteranion. The aziridination of para-substituted styrenes with PhI=NTs (Ts = tosyl) in various solvents proved to be high yielding for the Cu(I) and Cu(II) reagents, in contrast to the modest efficacy of all other metals. For α-substituted styrenes, aziridination is accompanied by products of aziridine ring opening, especially in chlorinated solvents. Bulkier β-substituted styrenes reduce product yields, largely for the Cu(II) reagent. Aromatic olefins are more reactive than aliphatic congeners by a significant margin. Mechanistic studies (Hammett plots, KIE, and stereochemical scrambling) suggest that both copper reagents operate via sequential formation of two N–C bonds during the aziridination of styrene, but with differential mechanistic parameters, pointing towards two distinct catalytic manifolds. Computational studies indicate that the putative copper nitrenes derived from Cu(I) and Cu(II) are each associated with closely spaced dual spin states, featuring high spin densities on the nitrene N atom. The computed electrophilicity of the Cu(I)-derived nitrene reflects the faster operation of the Cu(I) manifold. Full article

Calcium channel blockers (CCBs), originally developed for cardiovascular indications, have gained attention for their therapeutic potential in neuropsychiatric, endocrine, and pain-related disorders. In neuropsychiatry, nimodipine and isradipine, both L-type CCBs, show mood-stabilizing and neuroprotective effects, with possible benefits in depression, bipolar disorder, and schizophrenia. In endocrinology, verapamil, a non-dihydropyridine L-type blocker, has been associated with the preservation of pancreatic β-cell function and reduced insulin dependence in diabetes. CCBs may also aid in managing primary aldosteronism and pheochromocytoma, particularly in patients with calcium signaling mutations. In pain medicine, α2δ ligands and selective blockers of N-type and T-type channels demonstrate efficacy in neuropathic and inflammatory pain. However, their broader use is limited by challenges in central nervous system (CNS) penetration, off-target effects, and heterogeneous trial outcomes. Future research should focus on pharmacogenetic stratification, novel delivery platforms, and combination strategies to optimize repurposing of CCBs across disciplines. Full article

Wilson’s disease (WD) is an autosomal recessive disorder of copper metabolism caused by mutations in the ATP7B gene. While hepatic manifestations are frequent, psychiatric symptoms occur in up to 30% of patients and may precede neurological signs. This study was the first to assess the relationship between oxidative stress, selected genetic polymorphisms, and psychiatric symptoms in WD. A total of 464 patients under the care of the Institute of Psychiatry and Neurology in Warsaw were studied. Genotyping for GPX1 (rs1050450), SOD2 (rs4880), and CAT (rs1001179) was performed, along with biochemical analyses of copper metabolism, oxidative DNA, lipid and protein damage, and systemic antioxidant capacity. Among the most important observations are the following: the homozygous GPX1 rs1050450 TT and SOD2 rs4880 CC genotypes were associated with the lowest prevalence of psychiatric symptoms. The CAT rs1001179 TT genotype was linked to a delayed onset of psychiatric symptoms by 6.0–8.5 years. Patients with or without psychiatric symptoms did not differ significantly in saliva 8-OHdG, total antioxidant capacity, serum glutathione (GSH), catalase, and MnSOD; however, patients reporting psychiatric symptoms had significantly higher prostaglandin F2α 8-epimer (8-iso-PGF2α) concentrations and tended to have lower serum glutathione peroxidase (Gpx) concentrations compared to those without such symptoms. Our data firstly provide consistent evidence that oxidative stress balance associated with copper overload in the CNS may be associated with CNS damage and the development of psychiatric symptoms of WD. In particular, our findings of increased oxidative lipid damage together with decreased Gpx activity indirectly suggest that damage to neuronal membrane lipids, which may be potentially related to abnormalities in GSH metabolism, may have an etiological role in CNS damage and related symptoms. Full article

Medulloblastoma (MB) is the most common malignant brain tumor in children and typically arises in the cerebellum, likely due to disruptions in neuronal precursor development. The primary inhibitory neurotransmitter in the central nervous system (CNS), γ-aminobutyric acid (GABA), exerts its effects through GABA_A, GABA_B, and GABA_C receptors. GABA receptor activity regulates the development and function of cerebellar neurons, including glutamatergic cerebellar granule cells (CGCs). Beyond the nervous system, GABA is also a common metabolite in non-neuronal cell types. An increasing body of evidence indicates that GABA can influence cell proliferation, differentiation, and migration in several types of adult solid tumors, including brain cancers. GABA and GABA_A receptor agonists can impair the viability and survival of MB cells, primarily acting on GABA_A receptors containing the α5 subunit. A marked expression of the gene encoding the α5 subunit is found across all MB tumor molecular subgroups, particularly Group 3 MB, which has a poor prognosis. Importantly, high levels of the γ-aminobutyric acid type A receptor subunit α5 (GABRA5) gene are associated with shorter patient overall survival in Group 3 and Group 4 MB. In contrast, high γ-aminobutyric acid type A receptor subunit β1 (GABRB1) gene expression is related to longer survival in all MB subgroups. The GABAergic system may, therefore, regulate MB cell function and tumor progression and influence patient prognosis, and is worthy of further investigation as a biomarker and therapeutic target in MB. Full article

Background/Objectives: This research reports the synthesis and evaluation of novel charged thienobenzo-triazoles as non-selective cholinesterase inhibitors (AChEs and BChEs), their anti-inflammatory properties, and a computational study. Methods: Fifteen derivatives were created through photochemical cyclization and quaternization of the triazole core. The compounds were tested for AChE and BChE inhibition. They showed greater potency and selectivity toward BChE. Results: The most potent compound, derivative 14, inhibited BChE with an IC₅₀ of 98 nM, while derivative 9 also displayed significant anti-inflammatory activity by inhibiting LPS-induced TNF-α production (IC₅₀ = 0.66 µM). Molecular docking revealed that triazolinium salts form key π-π and electrostatic interactions within enzyme active sites. In silico predictions indicated favorable ADME-Tox properties for compounds 9 and 11, including low mutagenicity and moderate CNS permeability. Conclusions: These findings highlight the potential of new charged triazolinium salts as peripherally selective cholinesterase inhibitors with additional anti-inflammatory potential. Full article

Ionotropic glutamate receptors—including N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate receptors—play a pivotal role in excitatory signaling in the central nervous system (CNS), which is particularly important for learning and memory processes. Among them, AMPA and kainate receptors (known as ‘non-NMDA’ receptors) have gained increasing attention as therapeutic targets for various CNS disorders. Positive allosteric modulators (PAMs) of these receptors enhance their activity without directly activating them, offering a promising strategy to fine-tune glutamatergic signaling with potentially fewer side effects compared to orthosteric agonists. This review presents a comprehensive overview of recent advances in the development of AMPA and kainate receptor PAMs. We classify the most relevant modulators into main chemotype groups and discuss their binding modes, structure–activity relationships, and efficacy as determined through in vitro and in vivo studies. Additionally, we provide an overview of AMPA receptor PAMs that have entered into clinical trials over the past few decades. The increasing interest in kainate receptor PAMs is also mentioned, underlining their emerging role in future neuropharmacological strategies. Full article

Chronic pain affects approximately 20% of the global adult population, posing significant healthcare and economic challenges. Effective management requires addressing both biological and psychosocial factors, with emerging therapies such as antioxidants and marine algae offering promising new treatment avenues. Marine algae synthesize bioactive compounds, including polyphenols, carotenoids, and sulfated polysaccharides, which modulate oxidative stress, inflammation, and neuroimmune signaling pathways implicated in pain. Both preclinical and clinical studies support their potential application in treating inflammatory, neuropathic, muscular, and chronic pain conditions. Notable constituents include polyphenols, carotenoids (such as fucoxanthin), vitamins, minerals, and sulfated polysaccharides. These compounds modulate oxidative stress and inflammatory pathways, particularly by reducing reactive oxygen species (ROS) and downregulating cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). Brown and red algae produce phlorotannins and fucoidans that alleviate pain and inflammation in preclinical models. Carotenoids like fucoxanthin demonstrate neuroprotective effects by influencing autophagy and inflammatory gene expression. Algal-derived vitamins (C and E) and minerals (magnesium, selenium, and zinc) contribute to immune regulation and pain modulation. Additionally, sulfated polysaccharides suppress microglial activation in the central nervous system (CNS). Marine algae represent a promising natural source of bioactive compounds with potential applications in pain management. Although current evidence, primarily derived from preclinical studies, indicates beneficial effects in various pain models, further research is necessary to confirm their efficacy, safety, and mechanisms in human populations. These findings advocate for the continued exploration of marine algae as complementary agents in future therapeutic strategies. Full article

We present high-angular resolution observations, conducted with the Atacama Large Millimeter/Submillimeter Array (ALMA) in Band 6, of high-excitation molecular lines of ${\mathrm{CH}}_3\mathrm{CN}$, CH₃OH, and the H29$\alpha$ radio recombination line, towards the G333.6-0.2 ultracompact (UC) H ii region. Our observations reveal three hot molecular cores: A, B, and C, where emission is detected in ten components of the $J=14\to 13$ rotational ladder of ${\mathrm{CH}}_3\mathrm{CN}$ and in the CH₃OH $J=5_{1,4}\to 4_{1,3}$ transition. Rotational diagram analysis of ${\mathrm{CH}}_3\mathrm{CN}$ reveals excitation temperatures ranging from 380 to 430 K. First-order moment maps of ${\mathrm{CH}}_3\mathrm{CN}$ and CH₃OH reveal distinct velocity gradients in all cores, suggesting rotating structures, with core A also showing evidence of expansion motions. The H29$\alpha$ recombination line shows a linewidth of $30.2\pm 0.12$ km s⁻¹, dominated by dynamical and thermal broadening, indicative of large-scale motions in ionized gas. Analysis of the ionized gas properties yields an electron density of $(4.8\pm 0.4)\times {10}^5$ cm⁻³, an emission measure of $(1.23\pm 0.06)\times {10}^9$ pc cm⁻⁶, and a Lyman continuum photon flux consistent with an O5–O6 V (Zero-Age Main Sequence; ZAMS) star. Our results suggest that G333.6-0.2 is in an intermediate evolutionary stage between hypercompact (HC) and ultracompact (UC) H ii regions, hosting active high-mass star formation with rotating hot cores and ionized gas dynamics. Full article

The central nervous system (CNS) is highly susceptible to damage due to its limited ability to regenerate. Injuries to the CNS, whether from trauma, ischemia, or neurodegenerative diseases, disrupt both cellular and vascular structures, leading to immediate (primary) and subsequent (secondary) damage. Primary damage involves the physical disruption of cells and blood vessels, weakening the blood–brain barrier (BBB) and triggering excitotoxicity and calcium overload. Secondary damage develops over hours to days and is marked by ionic imbalance, mitochondrial dysfunction, oxidative stress, and chronic inflammation, which further aggravates tissue damage. Inflammation plays a dual role: acute inflammation helps in repair, while chronic inflammation accelerates neurodegeneration. Microglia and astrocytes play key roles in this inflammatory response, with M1-like microglia promoting pro-inflammatory responses and M2-like microglia supporting anti-inflammatory and repair processes. Neurodegenerative diseases are characterized by the accumulation of misfolded proteins such as Tau, amyloid-beta, TDP-43, and α-synuclein, which impair cellular function and lead to neuronal loss. Neurodegenerative diseases are characterized by the accumulation of misfolded proteins and influenced by genetic risk factors (e.g., APOE4, TARDBP). Despite the CNS’s limited regenerative abilities, processes like synaptogenesis, neurogenesis, axonal regeneration, and remyelination offer potential for recovery. Therapeutic approaches aim to target inflammatory pathways, enhance repair mechanisms, and develop neuroprotective treatments to counter excitotoxicity, oxidative stress, and apoptosis. Advances in stem cell therapy, gene therapy, and personalized medicine hold promise for improving outcomes. Future research should focus on combining strategies, utilizing advanced technologies, and conducting translational studies to bridge the gap between preclinical research and clinical application. By better understanding and leveraging the complex processes of CNS injury and repair, researchers hope to develop effective therapies to restore function and enhance the quality of life for individuals with CNS disorders. Full article

The occurrence of demyelination in the central nervous system (CNS) causes neurodegenerative lesions. The occurrence and development of demyelination involve multiple pathological mechanisms, including the generation of reactive oxygen species (ROS) caused by mitochondrial dysfunction in microglia and subsequent neuroinflammation. Scutellarin is a natural flavonoid drug with significant neuroprotective effects, including antioxidant, anti-inflammatory, and anti-apoptotic properties, and is widely used in the treatment of neurological diseases. However, the protective effects and mechanisms of scutellarin on demyelination have not yet been elucidated. This study aims to investigate the neuroprotective effects of scutellarin on demyelination and its underlying molecular mechanisms. Our results showed that treatment with scutellarin significantly alleviated Cuprizone-induced myelin damage, neuronal apoptosis, and neurological deficits in mice. In in vitro experiments, scutellarin significantly reduced Cuprizone–copper-induced pro-inflammatory microglia formation and inhibited the secretion of TNF-α, thereby reducing myelin cell damage. Mechanism studies revealed that scutellarin inhibited the secretion of TNF-α by microglia and alleviated myelin cell damage by reducing the excessive production of mitochondrial reactive oxygen species (Mito-ROS), reactive oxygen species (ROS), and malondialdehyde (MDA) induced by Cuprizone–copper in microglia. Finally, scutellarin improved mitochondrial dysfunction in microglia and significantly alleviated myelin cell damage by inhibiting the expression of p38MAPK. In conclusion, our findings demonstrate that scutellarin exerts significant neuroprotective effects on Cuprizone-induced mice by improving mitochondrial dysfunction in microglia, thereby reducing inflammatory responses. This effect is closely associated with the inhibition of the p38MAPK pathway. Full article

T lymphocytes infiltrate the CNS in response to murine cytomegalovirus (MCMV) infection and form a pool of long-lived brain tissue-resident memory T-cells (bT_RMs), which display markers of residency (i.e., CD103, CD69, CD49a). However, the functional role of these bT_RMs is still unknown. By 30 days postinfection, a latent viral brain infection was established, as indicated by absence of viral transcripts (IE1, E1, and gB) produced during productive infection. Following intracerebroventricular injection of either depleting α-CD8 Ab (clone YTS169.4) or α-CD103-sap (clone IT50) into the brain, 90–95% T-cell depletion was achieved. Using luciferase-expressing mice, we observed recommenced imaging signals indicative of de novo MCMV IE promoter activity in depleted animals. Surprisingly, using an explant assay, we efficiently recovered reactivatable, infectious virus from untreated, latent animals, but not from those depleted of bT_RMs (viral recovery in explants was reduced from 100% to 50% by day 21). We identified Lgals3 (galectin 3), Gpnmb (glycoprotein nonmetastatic melanoma protein B) and Hmox1 (heme oxygenase 1) as genes that were most upregulated in bT_RM-depleted groups. When bT_RMs were depleted, there was transient expression of viral IE genes which resulted in antiviral microglia with a phagocytic, disease-associated (DAM) or neurodegenerative (MGnD) phenotype. These data provide new insights into the role of bT_RMs in controlling both CNS reactivation and driving microglial phenotypes. Full article

Mastitis significantly impacts both the yield and quality of milk. The somatic cell count (SCC) and differential somatic cell count (DSCC), which are related to immune cells, are primary indicators for assessing mammary gland health. In this study, eight previously established mid-infrared spectroscopy models were utilized to predict the content of milk protein fractions (αs1-CN, β-CN, κ-CN, total CN, α-LA, β-LG, IgG, and LF) in milk samples from 21,388 lactating cows across 33 herds. Four linear mixed models were applied to analyze the secretion patterns of milk protein fractions by days in milk (DIM) and parity, their variations under different mastitis conditions, and their associations with the somatic cell score (SCS), DSCC, and immune cell counts (PMN + LYM score (PMN + LYMS) and MAC score (MACS)). The primary findings of the investigation comprised the following: (1) IgG was higher in early lactation, decreased with advancing lactation days, and slightly increased in late lactation, while seven other protein factions decreased from early to peak lactation and increased during mid-to-late lactation. Parity influenced all milk protein fractions except αs1-CN, with total CN, β-CN, and α-LA decreasing and κ-CN, β-LG, IgG, and LF increasing as parity increased (p < 0.05). (2) Mastitis significantly reduced the milk yield, fat percentage, protein percentage, and the contents of total CN, β-CN, κ-CN, and α-LA while increasing β-LG, IgG, and LF. (3) The SCS was negatively correlated with milk yield and α-LA but positively correlated with the fat percentage, protein percentage, κ-CN, β-LG, IgG, and LF. (4) When the DSCC increased to 50%, the milk yield decreased, while the milk protein percentage and κ-CN content significantly increased (p < 0.05). When the DSCC exceeded 50%, the fat percentage, protein percentage, total casein, αs1-CN, β-CN, κ-CN, β-LG, IgG, and LF decreased, while the α-LA content increased (p < 0.05). (5) When the PMN + LYMS increased, the milk yield and α-LA content rose, while the milk fat percentage, the milk protein percentage, and the contents of αs1-CN, β-CN, κ-CN, total CN, β-LG, IgG, and LF decreased (p < 0.05). Conversely, when the MACS increased, the milk yield and α-LA content declined, whereas the milk fat percentage, the milk protein percentage, and the contents of αs1-CN, β-CN, κ-CN, total CN, β-LG, IgG, and LF increased (p < 0.05). This study offers valuable insights into enhancing milk product quality, advancing the early diagnosis and mechanistic research of bovine mastitis, and the sustainable development of the dairy farming industry. Full article

Cognitive dysfunction represents one of the most persistent and disabling features of Long COVID, yet its molecular underpinnings remain incompletely understood. This narrative review synthesizes current evidence on the pathophysiological mechanisms linking SARS-CoV-2 infection to long-term neurocognitive sequelae. Key processes include persistent neuroinflammation, blood–brain barrier (BBB) disruption, endothelial dysfunction, immune dysregulation, and neuroendocrine imbalance. Microglial activation and cytokine release (e.g., IL-6, TNF-α) promote synaptic dysfunction and neuronal injury, while activation of inflammasomes such as NLRP3 amplifies CNS inflammation. Vascular abnormalities, including microthrombosis and BBB leakage, facilitate the infiltration of peripheral immune cells and neurotoxic mediators. Hypothalamic–pituitary–adrenal axis dysfunction and reduced vagal tone further exacerbate systemic inflammation and autonomic imbalance. Biomarkers such as GFAP, NFL, IL-6, and S100B have been associated with both neuroinflammation and cognitive symptoms. Notably, transcriptomic signatures in Long COVID overlap with those observed in Alzheimer’s disease, highlighting shared pathways involving tau dysregulation, oxidative stress, and glial reactivity. Understanding these mechanisms is critical for identifying at-risk individuals and developing targeted therapeutic strategies. This review underscores the need for longitudinal research and integrative biomarker analysis to elucidate the molecular trajectory of cognitive impairment in Long COVID. Full article