Search Results (148)

Conjugated linolenic acids (CLnAs) are emerging as promising agents to trigger ferroptosis, a cell death driven by excessive lipid peroxidation, in cancer cells. Given the aggressive nature and treatment resistance of malignant melanoma, exploring CLnAs as therapeutic agents may offer a novel strategy to overcome these challenges. Here, we investigated the toxicity of four CLnA isomers on human (A375, WM266.4) and zebrafish (ZMEL1) melanoma cell lines. We observed a dose-dependent reduction in cell viability across all three tested cell lines. While human melanoma cells were more sensitive to CLnAs than ZMEL1 cells, treatment with ferroptosis inhibitors mitigated cell death in all models, confirming ferroptosis as the consistent primary mechanism of cell death. In addition, chemical inhibitors of ACSL4 and GPX4 modulated CLnA toxicity, further substantiating the ferroptotic mechanism by highlighting the role of these key regulators. Furthermore, fatty acid analysis revealed that CLnAs were effectively incorporated into phospholipids, generating substrates for lethal lipid peroxidation. At the transcriptional level, CLnA treatment significantly upregulated the pro-ferroptotic gene acsl4a in ZMEL1 cells. Overall, our study identifies specific CLnAs as potent ferroptosis inducers in both human and zebrafish melanoma cells and underscores the translational relevance of the zebrafish model based on a shared ferroptotic mechanism. Full article

Background: Cerliponase alfa is currently the only approved disease-modifying therapy for neuronal ceroid lipofuscinosis type 2 (CLN2) disease and requires lifelong intracerebroventricular (ICV) infusion, traditionally via a scalp-sited ventricular access device (VAD). Chest-sited port (chest port) for intracerebroventricular access using a tunneled central venous access device is described as an alternative, though data remain limited. Methods: We present an anonymized caregiver narrative perspective describing two pediatric patients with CLN2 disease receiving cerliponase alfa infusions via different ICV access strategies: one patient who transitioned from a scalp-based ventricular access device to a chest port and one patient who initiated therapy with a chest port. A semi-structured caregiver interview was used to capture experiential insights related to decision-making, procedural burden, safety considerations, and psychosocial adaptation. Results: The caregiver identified key advantages of chest ports for ICV infusion, including durability of the device, enhanced securement, and smooth long-term routine integration. The transition from a scalp VAD to a chest port was described as proactive, well-coordinated, and associated with high caregiver satisfaction. Noted considerations included increased visibility of the access needle to the child, proximity to oral secretions, and potential misidentification of the port by emergency medical services. Families implemented mitigation strategies through labeling, education, and coordination with the care team. Conclusions: This caregiver-centered case report highlights how access device choice meaningfully shapes treatment burden, safety planning, and daily life for families managing CLN2 disease. As chest-port methodologies become adopted, incorporating caregiver and patient perspectives is essential to developing patient-centered treatment options for long-term intracerebroventricular therapy. Full article

Neuronal ceroid lipofuscinosis type 6 (CLN6) is a fatal, autosomal recessive neurodegenerative disorder characterized by cognitive/motor impairment, vision loss, as well as neuronal loss and gliosis in the brain, and premature death. Onset typically occurs in childhood. No approved pharmacological treatments exist that halt or reverse disease progression. A novel flupirtine benzyl carbamate was orally administered to male and female Cln6^nclf mice from 4 to 28 weeks of age to evaluate its neuroprotective and antispastic effects. Drug treatment produced significant, sex-dependent phenotypic improvements. Treated mice of both sexes exhibited reduced hindlimb spasticity, but only treated males demonstrated diminution in locomotor hyperactivity and recovery of visuospatial performance. In the brains of male and female Cln6^nclf mice, flupirtine benzyl carbamate significantly decreased astrocytosis, microgliosis and mitochondrial ATP synthase subunit C (SCMAS) accumulation, increased neuronal marker expression and reduced the number of TUNEL-positive cells. The treatment failed to rescue photoreceptor loss or clear retinal SCMAS storage. These outcomes result in distinct sex-specific differences in neuronal vulnerability and drug responsiveness. Overall, these findings demonstrate that flupirtine benzyl carbamate diminishes key motor, visual and pathological deficits in CLN6 disease, highlighting its promise as a potential disease-modifying therapy for CLN6 in humans despite sex-specific differences. Full article

Background: Cerliponase alfa is an intracerebroventricular (ICV) enzyme replacement therapy (ERT) and the only approved treatment for neuronal ceroid lipofuscinosis type 2 (CLN2) disease. While generally well tolerated, infusion-associated reactions (IARs), including hypersensitivity events and anaphylaxis, remain a recognized safety consideration. Methods: This single-center, retrospective study describes the incidence and management of IARs in pediatric patients with CLN2 receiving long-term ICV cerliponase alfa at Great Ormond Street Hospital, London, United Kingdom. Results: Over a 10-year period (2014–2024), 31 patients received approximately 2705 ICV infusions. Eleven patients experienced at least one IAR. Most reactions were mild and transient, typically consisting of pyrexia, vomiting, or rash, and were managed conservatively with antipyretics and antihistamines. Four patients required steroid intervention following recurrent or more pronounced symptoms, which led to improved infusion tolerance. One patient experienced a single episode of anaphylaxis that required treatment with intramuscular adrenaline and intravenous hydrocortisone. Therapy was continued with a revised pre-medication regime, with no further severe reactions. Conclusions: These findings demonstrate that IARs to ICV cerliponase alfa are typically mild and readily manageable within a multidisciplinary framework. They highlight the importance of structured infusion protocols, vigilant monitoring strategies, and a coordinated management approach to ensure the long-term safety of ERT for children with CLN2 disease. Full article

We report the crystallization and single-crystal X-ray analysis of the monohydrate hydrochloride salt of chloroquine(CQ), abbreviated CQHCl·H₂O, an antimalarial drug with the formula C₁₈H₂₆ClN₃. The crystal structure reveals a well-defined supramolecular architecture stabilized by an extensive hydrogen-bonding network involving CQH⁺ cations, chloride anions, and water molecules. Notably, this study provides the first crystallographic characterization of a monoprotonated chloroquine salt. Additionally, our findings demonstrate the feasibility of isolating pseudo-polymorphic forms of a commercially available CQ salt via heterogeneous crystallization. Full article

Colorectal cancer (CRC) is the third most common malignant tumor worldwide, with morbidity and mortality rates increasing annually. Consequently, the development of safe and effective natural anti-tumor drugs has become a critical research focus. Lignin, a polyphenolic polymer abundant in nature, possesses a unique chemical structure that imparts antioxidant, anti-inflammatory, and tumor cell-related bioactivities, demonstrating remarkable potential in the prevention and treatment of CRC. In this study, we investigated the anti-tumor cell effects of coffee grounds lignin nanoparticles (CLN), prepared using aqueous ethanol extraction from coffee waste, against three CRC cell lines (HCT116, HT29, SW620). The results indicated that CLN potently inhibited the proliferation of all three CRC cell lines mentioned above. This research supports the transformation of lignin from natural products into innovative anti-colorectal cancer agent, offering new insights for the development of novel therapeutic strategies characterized by low toxicity and high efficacy. As research advances and technology continues to innovate, lignin-based nanoparticles emerge as key natural products in CRC therapy, offering new hope for patients and paving the way for the application of natural products in cancer therapy. Full article

¹⁸F-Florbetapir PET imaging is widely used to assess amyloid-β (Aβ) burden in the brain, particularly in the context of Alzheimer’s disease (AD). Conventional assessments typically rely on selected individual slices, which may limit spatial accuracy and are prone to image blurring. In the present study, we introduce novel techniques to enhance the spatial resolution and clarity of Aβ signal visualization in individuals pretreated with ¹⁸F-florbetapir. PET scans were retrospectively obtained from the Imaging and Data Archive for twelve individuals, including six cognitively unimpaired subjects and six diagnosed with AD. Each dataset consisted of 346 raw images, comprising 90 axial, 128 coronal, and 128 sagittal slices. Images were reconstructed into a single 3D volume using the 3D Slicer platform. Crucially, we applied artificial intelligence or AI-driven signal enhancement techniques to suppress background noise and amplify Aβ signals. This AI-enhanced processing improved image clarity and enabled visualization of subtle and spatially organized signal patterns. To verify anatomical location, Aβ PET signals were registered with MRI. This integrated workflow allowed us to visualize Aβ signals across regions of interest, including the brain parenchyma, skull, and cervical tissues. Our analytical approaches revealed that Aβ signals are highly concentrated and confined within non-CNS fluid compartments, forming canal-like networks that extend from the brain parenchyma toward the skull base, particularly the occipital clivus, and connect to the cervical lymph nodes. Additional Aβ signals were observed along the internal carotid plexus. These findings suggest that, when reconstruction in 3D and enhanced with AI, ¹⁸F-florbetapir PET imaging may not only reflect Aβ plaque burden in the brain but also visualize soluble Aβ species concentrated within anatomical clearance pathways leading to the peripheral lymphatic system. This approach offers a new dimension to PET signal interpretation and highlights the potential of AI-enhanced 3D in advancing neuroimaging analysis. Full article

The development of smart sustainable cities is closely linked to the advancement of city manufacturing, which aims to meet local demand while maintaining economic, social, and environmental balance. This concept is realised in large cities through City Multifloor Manufacturing Clusters (CMFMCs) equipped with City Logistics Nodes (CLNs) that manage intra- and extra-cluster logistics. These flows depend on supplies arriving via Intermodal Logistics Nodes (ILNs) located on city outskirts, where disruptions caused by intermodal supply chain uncertainty can significantly affect production continuity and urban sustainability. This study aims to develop a stochastic inventory management model for city manufacturing clusters operating under intermodal supply chain uncertainty. The model is designed to ensure stable and resilient material supply to city manufacturers by optimising buffer stock (BS) levels, reducing delivery delays, and improving transport and storage efficiency. Based on the Multi-Layer Bayesian Network Method (MLBNM), the model integrates probabilistic reasoning and resilience principles to support decision-making under uncertainty. A simulation-based case study of a representative CMFMC system was used for model verification and validation. The results show that the MLBNM-based approach enhances Sustainable Supply Chain Resilience (SSCR), improves inventory flexibility, and reduces environmental impacts. The study contributes to theory and practice by providing a quantitative framework for ensuring resilient and sustainable inventory management in city manufacturing systems. Full article

Background: Despite repeated re-emergence of Sudan ebolavirus (SUDV), its long-term human toll remains under-characterised. We assessed multisystem clinical, biochemical, and psychosocial outcomes ~25 years after the 2000 Gulu outbreak. Methods: We conducted a cross-sectional evaluation of 45 survivors of laboratory-confirmed SUDV and 30 age- and gender-matched community controls from the same region. Symptoms were assessed as current at the study visit using a structured checklist; for each symptom present, we recorded severity and duration from onset to the visit date. Standardised clinical examinations, haematological and biochemical assessments, anxiety and depression screening, and structured interviews on social support and stigma were performed. Group comparisons were assessed with Wilcoxon rank-sum and χ²/Fisher’s exact tests; correlations were assessed with Spearman’s ρ. Findings: Core physiological indices (vital signs, BMI, blood pressure, and body temperature) and mental health were comparable between survivors and controls. Nevertheless, survivors reported ongoing symptoms, including joint pain and visual impairment each in 36% (16/45), fatigue in 18% (8/45), and neurological symptoms in 13% (6/45). Subclinical laboratory deviations centred on hepatic and platelet biology: elevated total bilirubin occurred in 14% of survivors versus 6.7% of controls; thrombocytopenia or platelet morphological abnormalities in 12% versus 3.3%; haemoglobin abnormalities in 6% versus 0%. Among survivors, albumin and mean platelet volume declined with age (both p ≤ 0.03). Psychological morbidity was low (normal anxiety 82% (37/45; and normal depression 80% (36/45). Yet a social paradox emerged, despite universal post-outbreak support, 98% (44/45) described enduring stigma. To minimise differential recall bias, symptom inventories were not collected from controls; consequently, between-group comparisons for symptom prevalence were not performed, and symptom inferences are restricted to survivors and framed descriptively. Interpretation: A quarter-century after infection, SUDV survivors show preserved systemic physiology but carry chronic musculoskeletal, sensory, and neurological sequelae, alongside a discrete subclinical profile implicating hepatic function and platelet biology. Psychological resilience coexists with near-universal, persistent stigma, indicating that material support did not achieve full psychosocial reintegration. Given the lack of virological and deep immune profiling, proposed pathogenetic mechanisms, such as antigen persistence or immune-mediated injury, remain speculative and hypotheses-generating only. These findings argue for survivor-centred long-term care, embedded with epidemic preparedness frameworks that integrate musculoskeletal rehabilitation, ophthalmic and neurological services with comprehensive mental health care, and sustained anti-stigma community engagement. This dissociation, including short-lived support alongside enduring stigma, indicates that humanitarian relief alone does not secure durable psychosocial reintegration and should be complemented by long-horizon, survivor-centred services and community engagement. Funding: This study was supported by the Coalition for Epidemic Preparedness Innovations (CEPI) under the Universal Protocol for Standardising Assays and Advancing Vaccine Immunogenicity Assessments for Emerging and Re-emerging Viral Threats, implemented through the Uganda Virus Research Institute (UVRI) as part of CEPI’s Centralised Laboratory Network (CLN). Full article

Lithium Niobate (LiNbO₃, LN) crystals are multifunctional optical materials with excellent electro-optical, acousto-optical, and nonlinear optical properties, and their broad spectral transparency makes them widely used in electro-optical modulators, tunable filters, and beam deflectors. Near Stoichiometric Lithium Niobate (NSLN) crystals have a lithium to niobium ratio ([Li]/[Nb]) close to 1:1,demonstrate superior performance characteristics compared to composition lithium niobate (Congruent Lithium Niobate (CLN), [Li]/[Nb] = 48.5:51.5) crystals. NSLN crystals have a lower coercive field (~4 kV/mm), higher electro-optic coefficient (${\gamma }_{33}$ = 38.3 pm/V), and better nonlinear optical properties. This paper systematically reviews the research progress on preparation methods, the physical properties of LN and NSLN crystals, and their applications in devices such as electro-optical modulators, optical micro-ring resonators, and holographic storage. Finally, the future development direction of NSLN crystals in the preparation process (large-size single-crystal growth and defect control) and new electro-optical devices (low voltage deflectors based on domain engineering) is envisioned. Full article

Scandium(III) (Sc(III)) is the smallest among the trivalent ions in Group 3, which includes yttrium(III) and lanthanides (III) with a hydration number of 8 and 8–9, respectively. The hydration number of Sc(III) in aqueous solutions reported so far varies from six to ten and remains an open question. In general, applying pressure and temperature to aqueous solutions perturbs the water structure and ion solvation, providing insight into the nature of ion solvation. In the present study, we perform neutron scattering measurements of a 1 m (mol/kg) ScCl₃ aqueous solution in D₂O (hereafter H is used to symbolize the hydrogen atom instead of D) under the thermodynamic conditions from 0.1 MPa/298 K to 4 GPa/523 K. Using the empirical potential structure refinement (EPSR) method, the neutron scattering data are analyzed to extract the site–site pair distribution functions, coordination number distributions, angle distributions, and spatial density functions (3D structure). A predominant Sc(III) species is [Sc(OH₂)₇]³⁺ with a distorted pentagonal bipyramidal geometry together with appreciable amounts of contact ion pair species [ScCl_n(OH₂)_(6−n)]⁽³⁻ⁿ⁾⁺ (n = 1–3) and [Sc(OH₂)₈]³⁺ with mean Sc–Cl and Sc–OH₂ distances of 2.42 and 2.11 Å, respectively. An aqua chloride ion is surrounded on average by 7.8 and 10.9 water molecules with a Cl–H₂O distance of 3.10 Å at 0.1 MPa/298 K and 4 GPa/523 K, respectively. Applying GPa pressure transforms the tetrahedral network structure of water under ambient conditions to a dense, randomly packed structure with a mean coordination number of 12.6, resulting in an increase in the first-neighbor distance from 2.77 to 2.89 Å. The hydrogen bonds between water molecules remain linear but are largely distorted at high temperatures and high pressures. The present results provide a hint for understanding the underlying mechanism of high-pressure and temperature coordination chemistry and in applied fields, such as processes in geochemistry of the Earth’s upper mantle and pressure-induced protein denaturation. Full article

This study explores the potential application of lignin nanoparticles and chitosan–lignin nanoparticles (CLNs) as hydrophobic barrier coatings for paperboard. The lignin nanoparticles were initially prepared using a mixed solvent of ethanol and acetone. Their characteristics were examined via scanning electron microscopy (SEM) and dynamic light scattering, which revealed particle sizes in the range of 180–400 nm. The results indicated that the coatings with pure lignin nanoparticles failed to impart hydrophobicity to the paperboard, whereas the CLN coatings significantly enhanced hydrophobicity and reduced water absorption. The water contact angle increased from 109° to over 128° after the first CLN coating, remained at 127° with the second and third coating layers, and was maintained at 119° with four layers. Multilayer coatings were applied to improve barrier performance; however, no further enhancement in hydrophobicity was observed. The CLN-coated paper exhibited a significantly improved surface smoothness, as confirmed by SEM. The results indicate that a single-layer CLN coating is effective for imparting water-barrier properties to paperboard. In contrast, the coating with pure lignin nanoparticles resulted in cracked surfaces and inconsistent coating thicknesses. Full article

Credit-linked notes (CLNs) are vital for transferring and diversifying credit risks in asset securitization, yet their application in China remains limited despite policy support. This paper optimizes China’s CLN pricing mechanism by developing the structured model incorporating the dynamic default boundary and the probability of government implicit guarantees. The model transforms the pricing problem into a semi-unbounded problem via partial differential methods, yielding an explicit pricing solution through Poisson’s formula. Empirical analysis reveals that government implicit guarantees are observed in systemically important institutions in the domestic CLN market and significantly reduce credit risk premiums, with Monte Carlo simulations indicating an approximately positive linear correlation between guarantee probability and CLN prices. Our results demonstrate the dual impact of implicit guarantees—lowering risk premiums while potentially hindering market discipline. This research advances China’s credit derivative pricing theory, offering institutions a pricing tool and further providing policy and practical suggestions for regulatory authorities. Full article

Neuronal ceroid lipofuscinoses (NCLs) are paediatric neurodegenerative disorders that primarily affect the central nervous system (CNS). The high prevalence of gastrointestinal (GI) symptoms has prompted researchers and clinicians to move beyond an exclusively “brain-centric” perspective. At the molecular level, mutations in CLN genes lead to lysosomal dysfunction and impaired autophagy, resulting in intracellular accumulation of storage material that disrupts both central and enteric neuronal homeostasis. To systematically examine current clinical and preclinical knowledge on gut involvement in NCLs, with a focus on recent findings related to the enteric nervous system and gut microbiota. We conducted a systematic review following the PRISMA guidelines using PubMed as the sole database. Both clinical (human) and preclinical (animal) studies were included. A total of 18 studies met the inclusion criteria, focusing on gastrointestinal dysfunction, nervous system involvement, and gut microbiota. We found that the nature of GI symptoms was multifactorial in NCLs, involving not only the CNS but also the autonomic and enteric nervous systems, which were affected early by lysosomal deposits and enteric neuron degeneration. Of note, preclinical studies showed that gene therapy could improve not only CNS manifestations but also GI ones, which may have beneficial implications for patient care. While the role of the ENS seems to be clearer, that of gut microbiota needs to be further clarified. Current evidence from preclinical models highlighted alterations in the composition of the microbiota and suggested a possible influence on the progression and modulation of neurological symptoms. However, these results need to be confirmed by further studies demonstrating the causality of this relationship. GI involvement is a key feature of NCLs, with early impact on the enteric nervous system and possible links to gut microbiota. Although preclinical findings—particularly on gene therapy—are encouraging due to their dual impact on both CNS and GI manifestations, the causal role of the gut microbiota remains to be fully elucidated. In this context, the development of sensitive and specific outcome measures to assess GI symptoms in clinical trials is crucial for evaluating the efficacy of future therapeutic interventions. Full article

CLN2 disease (neuronal ceroid lipofuscinosis type 2) is an ultra-rare lysosomal storage disorder caused by mutations in the TPP1/CLN2 gene, resulting in impaired tripeptidyl peptidase 1 (TPP1) activity. The timely initiation of enzyme replacement therapy is pivotal for attenuating progressive and irreversible neurodegeneration. This study aimed to benchmark the performance of Oxford Nanopore long-read sequencing (ONT-LRS) for targeted TPP1 mutation detection in a Turkish CLN2 cohort and to assess its concordance with orthogonal validation methods, including Sanger sequencing and enzymatic activity assays. Using a custom-designed primer panel, the entire TPP1 gene (6846 bp) was sequenced on the Oxford Nanopore (ONT) MinIon platform in seven clinically confirmed CLN2 index patients and sixteen unaffected family members. Detected variants were validated via Sanger sequencing and correlated with TPP1 enzyme activity in leucocytes and dried blood spots. Four pathogenic or likely pathogenic TPP1 variants were identified: c.622C>T (p.Arg208*), c.857A>G (p.Asn286Ser), c.1204G>T (p.Glu402*), and c.225A>G (p.Gln75=), along with fourteen additional benign variants. Variant allele frequencies were 50% for c.622C>T, 28.6% for c.1204G>T, 14.3% for c.857A>G, and 7.1% for c.225A>G. Notably, this is the first report to document the homozygous state of the c.857A>G variant and the compound heterozygous configuration of the c225A>G and c.622C>T variants in CLN2 patients, thereby expanding the known mutational landscape. In contrast, the globally common variant c.509-1G>C was not observed, suggesting regional variation in TPP1 mutation patterns. Consistent with the prior Turkish studies, c.622C>T (p.Arg208*) was the most prevalent variant, followed by c.1204G>T (p.Glu402*). TPP1 enzymatic activity was significantly reduced in all affected individuals (p < 0.0001), supporting the functional relevance of the identified variants. ONT-LRS offers a robust, cost-effective platform for high-resolution analysis of the TPP1 gene. Integrating molecular and biochemical data improves diagnostic precision and supports timely, targeted interventions for CLN2 disease, particularly in regions with high consanguinity and limited diagnostic infrastructure. Full article