Search Results (2,109)

Bisphenol AF (BPAF) exposure is increasingly linked to metabolic disorders, yet the molecular initiating events (MIE) and key events (KE) leading to hepatic steatosis remain unclear. We constructed an adverse outcome pathway (AOP) to mechanistically connect BPAF-triggered macrophage–hepatocyte crosstalk to liver fat accumulation. Male C57BL/6 mice received daily oral gavage of 0, 0.5, 4, or 32 mg kg⁻¹ BPAF for 90 d, and Transwell co-cultures of RAW264.7 macrophages and AML12 hepatocytes were used for in vitro validation. Targeted metabolomics, western blotting, and lipid staining quantified succinate, pathway proteins, and steatosis. BPAF dose-dependently increased serum succinate (BMD = 6901.95 nM) and hepatic triglyceride (TG) (BMD = 874.26 nM). Cryo-EM docking revealed BPAF binding to SUCNR1 at 2.9 Å, disrupting the inactive-state conformation. In co-culture, BPAF-exposed macrophages released succinate that bound hepatocyte SUCNR1, suppressed Akt phosphorylation, and activated JNK. These KEs led to a 40% increase in lipid droplets and elevated TG, total cholesterol (TC), and free fatty acids (FFA) without liver weight gain. We propose the first AOP for BPAF-induced hepatic steatosis: BPAF–SUCNR1 binding (MIE) → macrophage succinate release (KE1) → SUCNR1-mediated Akt inhibition/JNK activation (KE2–4) → hepatic lipid accumulation (KE5) → steatosis (AO). These findings provide mechanistic insight for chemical risk assessment of BPAF and structurally related bisphenols. Full article

Particle accelerators are powerful tools in fundamental research, medicine, and industry that provide high-energy beams that can be used to study matter and to enable advanced applications. The state-of-the-art particle accelerators are fundamentally constructed from superconducting radio-frequency (SRF) cavities, which act as resonant structures for the acceleration of charged particles. The performance of such cavities is governed by inherent superconducting material properties such as the transition temperature, critical fields, penetration depth, and other related parameters and material quality. For the last few decades, bulk niobium has been the preferred material for SRF cavities, enabling accelerating gradients on the order of ~50 MV/m; however, its intrinsic limitations, high cost, and complicated manufacturing have motivated the search for alternative strategies. Among these, sputter-deposited superconducting thin films offer a promising route to address these challenges by reducing costs, improving thermal stability, and providing access to numerous high-T_c superconductors. This review focuses on progress in sputtered superconducting materials for SRF applications, in particular Nb, NbN, NbTiN, Nb₃Sn, Nb₃Al, V₃Si, Mo–Re, and MgB₂. We review how deposition process parameters such as deposition pressure, substrate temperature, substrate bias, duty cycle, and reactive gas flow influence film microstructure, stoichiometry, and superconducting properties, and link these to RF performance. High-energy deposition techniques, such as HiPIMS, have enabled the deposition of dense Nb and nitride films with high transition temperatures and low surface resistance. In contrast, sputtering of Nb₃Sn offers tunable stoichiometry when compared to vapour diffusion. Relatively new material systems, such as Nb₃Al, V₃Si, Mo-Re, and MgB₂, are just a few of the possibilities offered, but challenges with impurity control, interface engineering, and cavity-scale uniformity will remain. We believe that future progress will depend upon energetic sputtering, multilayer architectures, and systematic demonstrations at the cavity scale. Full article

Drug–radiopharmaceutical interactions can significantly alter radiotracer biodistribution, complicating diagnostic accuracy. This case report describes a 64-year-old male who underwent a Technetium-99m-methoxyisobutyl isonitrile (^99mTc-MIBI) parathyroid scan for suspected primary hyperparathyroidism. Initially, the patient was asked to discontinue his medications for his chronic illnesses for 24 h prior to the scan. However, the images revealed significantly reduced counts/tracer uptake in the thyroid, parathyroid and cardiac tissues in both the early and delayed phases. After a detailed review of his medication profile, it was postulated that there were potential interactions involving multiple P-glycoprotein (P-gp) substrates with specific emphasis on amlodipine, atorvastatin and telmisartan. The patient was advised to discontinue all medications for 72 h prior to the date of a repeat scan which was scheduled for two weeks after his initial scan. The repeat scan successfully detected a small focus of marked tracer retention in the left inferior parathyroid bed, suggestive of a small parathyroid adenoma. Post-surgery, the focus identified on the scan was removed and histologically confirmed to be a parathyroid adenoma. This is the first report of its kind among nuclear medicine patients in Jamaica. It highlights the importance of reviewing medication history prior to nuclear imaging, particularly when using radiotracers affected by P-gp mechanisms. This is crucial for mitigating against false-negative results, thus ensuring accurate diagnosis and appropriate clinical management. Full article

Background/Objectives: The presence of distant metastases is the main cause of death in medullary thyroid carcinoma (MTC). However, due to the rarity of this cancer, few studies have thoroughly analyzed the variables influencing the development of distant metastases. The objective of this study was to evaluate, in patients with MTC, the factors associated with the occurrence of synchronous and metachronous distant metastases. Methods: An analytical, observational, retrospective cohort study was conducted at a tertiary hospital. Patients with histologically confirmed MTC, both sporadic and familial (MEN2 syndrome), were included. The influence of epidemiological variables, heredity, complementary tests, surgical factors, histological features, staging, and disease progression was assessed. A univariate comparative analysis was first performed, followed by a multivariate analysis using logistic regression. Results: This study included 146 patients, of whom 75% (n = 109) had familial MTC. Lymph node involvement at diagnosis was observed in 36% (n = 52). During follow-up, distant metastases developed in 14% (n = 21) of patients, including five cases present at the time of diagnosis. The median follow-up was 214 months (IQR 106–289). The presence of distant metastases was associated with an increased risk of mortality. Factors associated with distant metastases included age, calcitonin level, hereditary status, lymph node involvement, and overall stage. In multivariate analysis, the lymph node ratio (LNR) remained the only significant predictor (OR 29.124). Conclusions: Several variables were related to the presence of distant metastases. Among them, the LNR emerged as the independent predictor of both synchronous and metachronous distant metastases. Full article

Background: B7-H3, an immunoregulatory protein of the B7 family, has been associated with both anti-cancer immunity and tumor promotion, with its expression commonly correlated with poor prognosis. Although it is frequently expressed across cancers, its heterogeneity may limit the effectiveness of B7-H3-targeted therapies. Consequently, a sensitive and non-invasive method is needed to assess B7-H3 expression for patient selection and stratification. Single-domain antibody fragments (sdAbs) offer a promising platform for developing such a diagnostic tool. Methods: To generate B7-H3 sdAbs, two Ilamas were immunized with the recombinant human B7-H3 protein. Positive clones were selected through Phage biopanning and characterized for thermal stability, binding specificity, and affinity to human and murine B7-H3 proteins. Selected sdAbs were radiolabeled with Technetium-99m (^99mTc) and evaluated for B7-H3 detection in two xenograft tumor models using micro-SPECT/CT imaging and dissection studies. Results: Sixteen purified sdAbs bound specifically to recombinant B7-H3 proteins and cells expressing native B7-H3 antigens, with nanomolar affinities. The four best-performing sdAbs bound promiscuously to tested mouse and human B7-H3 isoforms. Lead sdAb C51 labeled with ^99mTc displayed specific accumulation across two human B7-H3⁺ tumor models, achieving high contrast with a tumor-to-blood ratio of up to 10 ± 3.16, and a tumor uptake of up to 4.96 ± 1.4%IA/g at 1.5 h post injection. Conclusions: The lead sdAb enabled rapid, specific, and non-invasive imaging of human B7-H3⁺ tumors. Its isoform promiscuity supports broad applicability across cancers expressing different human B7-H3 isoforms. These results support further development for clinical translation to enable patient selection and improved B7-H3-targeted therapies. Full article

Background: Parathyromatosis, an exceptional clinical and pathological entity, involves multiple small nodules of hyper-functional parathyroid tissue scattered throughout the neck and/or mediastinum, in relationship with a prior parathyroidectomy (mostly) or embryologic remnant. Since its first identification in 1975, many aspects of this condition have remained a matter of debate. Objective: We introduce an updated perspective on parathyromatosis covering the main clinical points for everyday practice, from diagnosis to management, as well as the current level of pathogenic understanding. Methods: A narrative review. Results: A total of 22 patients were identified, with the following characteristics: an age range of 33–68 (mean 46.18) years; 4/22 subjects <40 years; female-to-male ratio = 14:8. Of the 22 subjects, 21 had undergone previous parathyroidectomy for primary (n = 14) or secondary (n = 7) hyperparathyroidism. One case was a surgically naïve patient. Analysis of the surgical procedures (seeding circumstances) revealed the following: parathyroid cyst removal, left/right parathyroidectomy; removal of 3.5 parathyroids ± self-transplantation, VATS for mediastinal parathyroid tumours. Parathyroidectomy was accompanied by thyroid surgery (n = 3 patients), specifically hemi-thyroidectomy, partial left-thyroid lobectomy, and partial thyroidectomy. The shortest timeframe from parathyroidectomy to parathyromatosis-related hyperparathyroidism recognition was 1 year, and the longest was 17 years. The highest number of previous surgeries was four. The recognition of parathyromatosis was due to the clinical picture of associated hyperparathyroidism, except for in 2/21 cases with incidental detection. The implant sites coincided with the prior surgical area, but also with unusual locations (clavicle, pleura, mediastinum, sternocleidomastoid muscle and forearm, thyroid). The imaging evaluation included ultrasound plus CT plus 99m-Tc sestamibi scintigraphy, as well as (variable rates) neck MRI, SPECT/CT, 11-Choline PET-CT, Gallium-68 DOTATATE, and 4D CT. Surgery implied serial procedures in some cases (e.g., up to seven). The surgery spectrum largely varied, including not only cervicotomy, but also thoracoscopy, VATS, pericardial adipose tissue excision and thymectomy, etc. Conclusions: Awareness remains a key factor when approaching such an unusual ailment underlying little-understood pathogenic loops, which, if left unrecognized and untreated, might impair patients’ quality of life and the overall parathyroid disease burden. Full article

Objective: Vitamin D deficiency (VDD) is common in pregnancy and may affect lipid metabolism. The underlying mechanisms are multifactorial, but most evidence so far comes from non-pregnant populations. This study aims to identify metabolites and metabolic patterns associated with VDD in early pregnancy and to evaluate their relationships with maternal lipid profiles. Methods: A nested case–control research was carried out in the Zhoushan Pregnant Women Cohort (ZPWC). Cases were defined as women with VDD (25(OH)D < 20 ng/mL), and controls (≥20 ng/mL) were matched 1:1 using propensity scores based on age, pre-pregnancy BMI, gestational week, and calendar year at blood sampling. The untargeted metabolomics of first-trimester maternal plasma were measured. Metabolic profiles were analyzed using partial least squares-discriminant analysis (PLS-DA). Principal component analysis (PCA) was applied to visualize group separation, and metabolite set enrichment analysis (MSEA) was performed to reveal biologically relevant metabolic patterns. Associations between VDD-related metabolite components in early pregnancy and lipid levels in mid-pregnancy were assessed using linear regression models. Results: 44 cases and 44 controls were selected for the study. There were 60 metabolites identified as being connected to VDD. Among these, 26 metabolites, primarily glycerophospholipids and fatty acyls, exhibited decreased levels in the VDD group. In contrast, 34 metabolites showed increased levels, mainly comprising benzene derivatives, carboxylic acids, and organooxygen compounds. PCA based on these metabolites explained 52.8% of the total variance (R²X = 0.528) across the first six principal components (PC1: 16.4%, PC2: 10.6%, PC3: 9.2%, PC4: 6.3%, PC5: 5.7%, PC6: 4.6%). PC2, dominated by lineolic acids and derivatives, was negatively associated with total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) (all p < 0.01). PC3, dominated by glycerophosphocholines, was negatively associated with TC, TG, and high-density lipoprotein cholesterol (HDL-C) (all p < 0.05). MSEA revealed significant enrichment of the pantothenate and CoA biosynthesis pathway after multiple testing correction (FDR < 0.05). Conclusions: This study reveals distinct metabolic alterations linked to VDD and suggests potential mechanisms underlying its association with maternal lipid metabolism in early pregnancy. Full article

Objectives: This study focuses on the regulatory mechanism of Schisandrin B (Sch B) on the lipid metabolism and apoptosis of AML-12 liver cells, with a particular emphasis on its potential therapeutic effect and mechanism of action in preventing and treating metabolic-associated fatty liver disease (MAFLD) by activating the PPARγ signaling pathway. Methods: An MAFLD cell model was established by inducing AML-12 cells with a mixture of oleic acid (OA) and palmitic acid (PA) (2:1). AML-12 cells were divided into a control group, a model group, and 20 μM and 40 μM Sch B groups. The cells were lysed and prepared into the cell suspension, then the cell suspension was centrifuged to obtain its supernatant, and the levels of total cholesterol (TC), triglycerides (TG), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) in the supernatant were detected according to the instructions of the kits. Effects of Sch B on the pathological changes of AML-12 cells were observed by Oil Red O staining. The key targets were screened through network pharmacology, and relevant targets were verified through molecular docking simulation. The activity of PPARγ was detected using a dual luciferase reporter plasmid, and the level of cell apoptosis was detected using the Annexin V-FITC/PI double staining method. The Western blot method was used to analyze the expression of genes related to lipid metabolism and apoptosis pathways. Results: Sch B could regulate lipid metabolism disorders in OA+PA-induced MAFLD cell model. The activation of PPARγ-PCK1/Aspase is a key step in the action of Sch B, which can effectively block fatty acid synthesis, improve fatty acid oxidation, and reduce lipid droplet aggregation in liver cells, thereby alleviating lipid metabolism abnormalities in the MAFLD cell model and inhibiting cell apoptosis. Conclusions: This finding may lay an important theoretical foundation and open a new research direction for the deep development and application of Schisandra chinensis. Full article

Epoxy resins are valuable in aerospace, electronics, and high-performance industries; however, their inherently low thermal conductivity (TC) limits applications requiring effective heat dissipation. Recent reports suggest that certain liquid crystalline or partially crystalline epoxy formulations can achieve higher TC, even exceeding 1 W/(m·K). To investigate this, 17 epoxy formulations were prepared, including the commonly used diglycidyl ether of bisphenol A (DGEBA) and two custom-synthesized diepoxides: TME4, which contains rigid aromatic ester linkages with a C4 aliphatic spacer, and LCE-DP, featuring rigid imine bonds. Thermal conductivity was measured using four techniques: laser flash analysis (LFA), modified transient plane source (MTPS), time-domain thermoreflectance (TDTR), and displacement thermo-optic phase spectroscopy (D-TOPS). Additionally, small-angle and wide-angle X-ray scattering (SAXS/WAXS) were performed to detect crystalline or liquid crystalline domains. All formulations exhibited TC values ranging from 0.13 to 0.32 W/(m·K). The TME4–DDS systems, previously reported to be near 1 W/(m·K), consistently measured between 0.26 and 0.30 W/(m·K). Thus, under our synthesis and curing conditions, the elevated TC reported in prior studies was not reproduced, and no strong evidence of crystallinity was observed; indications of local ordering did not translate into higher conductivity. Variations in TC among methods often matched or exceeded the gains attributed to mesophase formation. More broadly, evidence for crystallinity in epoxy thermosets appears weak, consistent with the notion that crosslinking suppresses long-range ordering. Full article

The aim of the study was to evaluate the feasibility of using exhaust gases as a CO₂ source in the cultivation of Tetraselmis subcordiformis microalgae for biomass and hydrogen production. It was shown that the growth rate of T. subcordiformis biomass and its biochemical composition depended on the CO₂ source. The highest growth rate of 286 ± 15 mgVS/L-d and a final biomass concentration of 2710 ± 180 mgVS/L were achieved in the variant where exhaust gases from a coal and biomass supplementary combustion plant were the CO₂ source (V2). The highest CO₂ reduction efficiency of 90.3 ± 3.2% was achieved in the case where waste gases from biogas combustion were the CO₂ source (V1). In V2, the highest CO₂ utilization efficiency was achieved (CO₂UE = 46.7 ± 2.4%). Analyzing the biomass composition confirmed differences in total carbon content (TC) and polysaccharide fraction. The highest H₂ production efficiency and rate, which were 70.9 ± 2.7 mL/gVS and 2.27 ± 0.08 mL/gVS·h, respectively, were obtained in V2. The results obtained indicate the possibility of integrating fuel combustion processes with the cultivation of T. subcordiformis and photobiological H₂ production, which is a promising solution in the context of climate neutrality and the implementation of circular economy postulates. This approach demonstrates a sustainable strategy for linking industrial CO₂ emissions with the production of renewable biohydrogen and thus contributes to climate protection and the promotion of circular economy concepts. Full article

Background/Objectives: In a previous study, we observed significantly prolonged hepatic and pulmonary first-pass transit times (TTs) for ^99mTc-pertechnetate absorbed through the colorectal mucosa during per-rectal portal scintigraphy (PRPS). This decrease in radiotracer flow velocity was not seen when ^99mTc-pertechnetate was administered into the spleen during trans-splenic portal scintigraphy or injected intravenously in radionuclide angiocardiography. We hypothesized that ^99mTc-pertechnetate, an artificial compound, is recognized during colorectal absorption as a potentially hazardous chemical (PHC), with its hepatic and pulmonary slowdown aiding elimination. A similar sudden decrease in portal flow occurs during early metastasis of colorectal cancer (CRC), as shown by a pathological rise in the hepatic perfusion index. We aimed to study the hepatic and pulmonary vasoactive responses triggered by PHCs after they pass through the gut mucosa and evaluate the potential activation of this mechanism in early CRC metastasis. Methods: We measured transit times to determine whether hepatic and pulmonary vasoconstriction occur in response to radiotracers administered at different sites. We performed PRPS with in vivo ^99mTc-labelled RBC to evaluate the liver transit time (LTT) and right heart to liver circulation time (RHLT). Liver angioscintigraphy (LAS) was used to assess RHLT following the intravenous injection of ^99mTc-pertechnetate and ^99mTc-HDP (hydroxyethylene-diphosphate). Lower rectum transmucosal dynamic scintigraphy (LR-TMDS) was conducted to measure RHLT of ^99mTc-pertechnetate delivered into the lower rectum submucosa. LAS was performed to assess LTT for ^99mTc-HDP intravenously injected and delivered to the gut mucosa via arterial flow. Results: In healthy volunteers, PRPS showed notably increased LTT, ranging from 23.5 to 25.5 s, and RHLT (between 39.5 and 42.5 s) for in vivo ^99mTc-labelled RBC. Significantly lower RHLT values ranging from 9 to 13.5 were observed for ^99mTc-pertechnetate and ^99mTc-HDP administered intravenously during LAS, as well as for ^99mTc-pertechnetate at LR–TMDS (between 12 and 15 s). The LTT assessed at LAS for ^99mTc-HDP ranged from 22 to 27 s. Conclusions: An intense vasoconstriction occurs in the liver and lungs in response to substances recognized by the body as PHCs when they pass through the gut mucosa, aiding their elimination. Full article

To express and purify staphylococcal enterotoxin M (SEM) using immobilized metal affinity chromatography (IMAC), a signal peptide-truncated (ΔNsp) wild-type SEM (SEM_WT) was N-terminally fused in pET-28a(+) to a polyhistidine tag (His_6×-) and thrombin cleavage site (TCS; LVPR↓GS), generating His_6×-TCS-ΔNspSEM_WT. Unexpectedly, 4 °C desalting reduced the fusion protein’s molecular weight by ~2.0 kDa on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). N-terminal sequencing and mass spectrometry identified cleavage specifically at the arginine (R) and glycine (G) peptide bond (R–G bond) within the TCS motif. AlphaFold 3 revealed an exposed serine protease catalytic triad: histidine 172, serine 178, and aspartic acid 212 (H₁₇₂/S₁₇₈/D₂₁₂) in the β-grasp domain, suggesting intrinsic thrombin-like activity (TLA). Sequential IMAC and size-exclusion high-performance liquid chromatography (SE-HPLC) purification eliminated contaminant concerns, while chromogenic substrate S-2238 (S-2238) assays demonstrated increasing specific activity and purification fold, supporting intrinsic TLA. Critically, the mutation of serine at position 178 to alanine (His_6×-TCS-ΔNspSEM_S178A) abolished TLA but preserved the secondary/tertiary structure, confirming the activity’s origin within the wild-type construct. Molecular dynamics (MD) simulations probed the atomistic mechanism for specific R–G bond cleavage. This work establishes a foundation for understanding ΔNspSEM_WT’s TLA. Full article

Background/Objectives: Macrophages with the M2 phenotype are an immune population with great relevance for tumor development. We have previously demonstrated that mesenchymal stromal cells (MSCs) from cervical cancer (CeCa-MSCs) enhance the immunomodulatory activity of CeCa cells on T lymphocytes; however, the effect of these cells on the ability of tumor cells to polarize macrophages had not been evaluated to date. Methods: To address this, we set out to analyze the effect of normal cervix (NCx) and CeCa-MSCs interacting with CeCa tumor cells (TCs) to polarize macrophages in a coculture system. Results: Our results show that macrophages from TC/NCx-MSC cocultures decreased CD163 expression. In turn, we observed that macrophages from TC/CeCa-MSC cocultures, in contrast to those in the presence of TCs/NCx-MSCs, increased the intracellular production of IDO, IL-4, and IL-10; decreased T lymphocyte proliferation; and increased the presence of soluble IL-10. Interestingly, coculture in the presence of TCs/NCx-MSCs decreased the capacity of macrophages to generate regulatory T lymphocyte populations, as well as their phagocytic capacity, and increased IL-6 secretion, unlike the coculture of macrophages in the presence of TCs/CeCa-MSCs. Our results show that TCs/CeCa-MSCs in cocultures, unlike TCs/NCx-MSCs, have a greater capacity to polarize macrophages to an M2 phenotype and that such macrophages have a greater immunosuppressive potential. Conclusions: This in vitro study suggests that intracellular communication between MSCs and tumor cells in CeCa may promote tumor growth through the polarization of macrophages with increased immunosuppressive activity. Full article

The fast-paced lifestyle of modern people has changed their dietary structure and increased the prevalence of obesity, of which a high-fat diet is the main cause. Therefore, this study investigates whether reducing fat intake can improve obesity and physical health. We induced an obese model with a 60 kcal% fat diet (HFD) for 12 weeks, followed by an intervention with a 4.9 kcal% fat diet (regular chow diet, RD) for 20 weeks. We found that after 20 weeks of RD, various indicators were significantly reduced compared with the HFD group, including dietary intake (3.26 ± 0.38 g, p < 0.01), Lee index (385.24 ± 14.22, p < 0.0001), blood glucose (8.75 ± 2.44 mmol/L, p < 0.01), blood lipids (TC: 2.60 ± 0.63 mmol/L, p < 0.001; TG: 0.72 ± 0.08 mmol/L, p < 0.001; and LDL-C: 0.57 ± 0.30 mmol/L, p < 0.0001), and inflammatory status (IL-6: 32.70 ± 7.55 pg/mL, p < 0.05). In addition, increasing dietary intake also indirectly increased fiber intake, which could promote intestinal microbiota diversity. Changing the diet of obese mice from HFD to RD still maintained the abundance of the probiotics Akkermansia, Parabacteroides, Alloprevotella, and Porphyromonadaceae, among which fiber intake played an important role. Therefore, we found that only reducing dietary fat intake was effective for weight loss, and dietary fiber intake helped maintain a healthy intestinal microbiota balance. Full article

Amyloidosis is characterized by the tissue deposition of insoluble fibrils derived from misfolded proteins. This case report describes a Hispanic man diagnosed with both monoclonal gammopathy of undetermined significance (MGUS) and wild-type transthyretin amyloidosis (ATTR) cardiac amyloidosis. The diagnosis was made using a combination of serological tests and multimodality cardiac imaging. The report highlights the importance of multimodality imaging in diagnosing cardiac amyloidosis, especially in cases where MGUS is also present. The patient presented with shortness of breath and was found to have cardiac abnormalities through electrocardiogram, echocardiogram, and cardiac magnetic resonance (CMR). A technetium-99m pyrophosphate (Tc-99m PYP) scan confirmed the presence of ATTR cardiac amyloidosis. Bone marrow biopsy confirmed MGUS. The patient was treated with diuretics and remained asymptomatic during follow-up. The report emphasizes the need for accurate diagnosis to differentiate between AL, ATTR, and MGUS due to their distinct clinical courses and treatments. Full article