The complex physiology of Parkinson's disease (PD) and its limited response to conventional therapies make it a challenging condition to manage. Evidence suggests that both environmental and genetic variables play essential roles in the progression of PD. However, the possible interplay between environment and genetics in PD etiology remains mostly unresolved. Brain-derived neurotrophic factor (BDNF) is a neurotrophin widely distributed and intensively investigated in the mammalian brain. BDNF modulates dopaminergic neurotransmission via neuronal differentiation regulation. BDNF communicates with the Tropomyosin receptor kinase B (TrkB) and activates Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) which can subsequently phosphorylate downstream CREB protein at ser133 residue. Research suggests that numerous health advantages, including significant protections for PD, have been linked to olives, a specific component of the Mediterranean diet. OLE is effective in the treatment of a variety of neurological conditions, including PD. Changes in gene expression patterns induced by aberrant histone acetylation can also aid in the causes of PD. Thus, in the context of neurological diseases, comprehending the epigenetic regulation of the neuronal survival gene is thought to be essential. OLE was first administered intraperitoneally as a pretreatment for seven days. Thereafter, OLE was administered one hour after the rotenone injection for 5 weeks. Herein, we have observed the neuroprotective role of OLE in the cellular signalling cascade associated with neuronal survival through the BDNF/ERK/CREB pathway. Subsequently, we examined the effect of OLE on the enrichment of histone acetylation AcH3K9 in the neuro-survival gene promoter region in PD cases. The data suggest that OLE regulates at both cellular and epigenomic levels by promoting the enrichment of acetylated H3K9 on the neuro-survival gene promoter region in the nigrostriatal region of PD mice.
Quantitative reverse transcription polymerase chain reaction (RT-qPCR) requires stable reference genes (RGs) to ensure accurate target gene normalization. Plant growth regulators like abscisic acid (ABA) and gibberellins (GA3) play critical roles in plant reproductive transitions, yet validated RGs for Coffea arabica under these specific treatments remain scarce. This study aimed to evaluate the expression stability of eight candidate RGs in coffee leaves subjected to various hormonal concentrations. The stability of CaACT, CaGAPDH, CaEFA1, CaTUB, CaAP47, CaMDH, CaRPL39, and CaUBQ2 was evaluated in leaf tissues of Coffea arabica during the reproductive stage under different ABA and GA3 treatments using five statistical algorithms: geNorm, NormFinder, BestKeeper, Delta-Ct, and RefFinder. The expression profiles of the candidate genes varied among treatments, with CaEFA1, CaGAPDH, CaMDH, and CaACT showing higher and more stable expression levels, whereas CaTUB and CaAP47 were consistently ranked as the least stable genes. Pearson correlation analysis revealed high correlations among CaRPL39, CaUBQ2, CaMDH, CaGAPDH, CaEFA1, and CaACT, while CaAP47 and CaTUB showed the lowest correlation coefficients. Validation analysis using the flowering-related gene CaTFL1 demonstrated that normalization with stable RGs (CaACT and CaMDH) produced more consistent expression profiles and narrower confidence intervals than normalization using unstable RGs. CaACT and CaMDH are the most suitable RGs for RT-qPCR normalization in leaf tissues of Coffea arabica during the reproductive stage under ABA and GA3 treatments. These findings provide a reliable basis for future studies involving hormonal regulation and reproductive development in coffee plants and reinforce the importance of validating RGs for specific experimental conditions.
Although reproductive vaccines are essential in swine herd health programs, evidence on their safety across different physiological stages remains limited. This study evaluated the clinical and reproductive safety of Porcilis® EPL in sows and gilts under commercial field conditions. In a randomized, blinded, controlled trial, 200 females were allocated to treated or control groups within five physiological categories, of which 190 completed the study. Sows received a single dose and gilts a two-dose protocol. Clinical parameters (body condition, rectal temperature, general health, feed intake) and injection-site reactions were monitored for 14 days post-vaccination. Reproductive outcomes, including conception, litter size, stillbirths, mummification, and neonatal viability, were recorded. PCR testing for PCV2, PCV3, and PPV was performed on non-viable piglets. The vaccine was well tolerated, with no systemic adverse reactions and only mild, self-limiting injection-site swellings in some treated females. Body condition and temperature profiles remained within physiological limits. Reproductive performance did not differ between groups (p > 0.05). Pathogen detection frequencies were similar across treatments, indicating that vaccination did not measurably alter fetal susceptibility to endemic PCV2, PCV3, or PPV. Porcilis® EPL showed excellent clinical and reproductive safety when administered during different physiological stages in sows and gilts. The vaccine did not affect fertility, gestational outcomes, or perinatal survival and did not measurably alter pathogen detection under field conditions with natural pathogen exposure, supporting its safe integration into breeding herd vaccination programs. PCR detection of PCV2, PCV3, and PPV was included as an exploratory epidemiological assessment to distinguish vaccine-specific effects from endemic pathogen circulation. No differences were observed between groups, supporting that Porcilis® EPL did not influence susceptibility to non-target pathogens. This study provides a comprehensive, randomized, blinded field evaluation of the clinical and reproductive safety of Porcilis® EPL administered to sows and gilts at different physiological stages under real commercial conditions. By integrating detailed clinical monitoring, thermophysiological responses, body condition dynamics, reproductive performance, and molecular diagnostics of non-viable piglets, the study offers a multidimensional assessment of vaccine safety. The findings indicate that Porcilis® EPL is clinically well tolerated, does not compromise fertility or perinatal outcomes, and did not measurably alter pathogen detection under field conditions, including herds with endemic circulation of PCV2, PCV3, and PPV. This work helps address an important knowledge gap regarding the use of reproductive vaccines during sensitive gestational windows and supports evidence-based vaccination strategies for modern swine production systems.
The spatial suppression of a high-probability distractor location (HPDL) acquired through statistical learning critically reduces its attentional priority. The present study conducted four experiments to systematically investigate the mechanisms underlying how this learned suppression generalizes to novel tasks. Specifically, we focused on how generalization is influenced by the priority-enhancing attentional capture of a salient target and the competing demands of a newly introduced suppression process. Following training, Experiments 1 and 2 employed a salient color singleton target to test attentional capture. Experiment 1 reused training stimuli, whereas Experiment 2 introduced novel shapes to determine if the capture effect of novel stimuli would completely override the learned suppression. Experiment 3 introduced a new suppression process to evaluate the impact of competing suppression demands. Finally, Experiment 4 utilized a feature search paradigm as a test task devoid of color singletons to eliminate these interfering factors. The results revealed that the intense capture effect of novel stimuli in Experiment 2 completely masked the generalization. Furthermore, sliding window analyses in Experiments 1 and 3 uncovered a dynamic process where generalization only manifested during the middle of the test phase, indicating a competition between these newly introduced factors and the previously acquired suppression. Conversely, eliminating all interference in Experiment 4 yielded a highly stable and persistent generalization of the HPDL suppression. These findings demonstrate that novel interfering factors drive a dynamic adjustment of the HPDL weight within the priority map, revealing the highly flexible and adaptive nature of human attentional control.
Cleaner wrasse (Labroides dimidiatus) undergoes sex reversal to male, and the two sexes exhibit distinctive cleaning behavior mediated by vision. As a keystone cleaner species in coral reef ecosystems, this fish plays an indispensable ecological role. Yet, the visual regulatory mechanisms underlying its sex-specific cleaning behaviors remain unknown. Through genome annotation and phylogenetic analysis, visual opsin genes were identified in the cleaner wrasse genome. Gene expression levels were quantified by RT-qPCR to examine sexual dimorphism. Additionally, 4 C-seq coupled with dual-luciferase reporter assays was employed to identify and validate putative enhancers regulating opsin gene expression. Eight visual opsin genes in five families were identified: rhodopsin (RH1), green-sensitive (RH2), ultraviolet-sensitive (SWS1), blue-sensitive (SWS2), and red-sensitive (LWS). Notably, RH2 has undergone diversification into four genes, indicating a high degree of functional specialization in hue resolution. All opsins maintain high homology in conserved motifs and functional domains, while also possessing distinct regions that may facilitate adaptation to complex photic environments. RT-qPCR revealed significant sexual dimorphism in opsin expression. Females exhibited higher expression of SWS1, SWS2B and RH2 family genes, consistent with their primary role as cleaners, which requires precise visual discrimination of client fish coloration and ectoparasites. In contrast, males showed significantly higher expression of RH1 and LWS, likely reflecting adaptation for territorial patrol and social competition following sex change. Furthermore, using 4 C-seq coupled with dual-luciferase reporter assays, we identified and validated active enhancers upstream of RH1 and RH2-1 genes. RH1 was found to be regulated by multiple enhancers acting in concert, suggesting a capacity for robust environmental responsiveness and developmental stage-specific modulation. In contrast, RH2-1 appears to be under the control of a single enhancer binding to transcription factors. These findings help elucidate the molecular basis of visual system adaptation in cleaner wrasse and provide preliminary insights into the potential links between visual opsin gene regulation, cleaning behavior, and ecological adaptation.
Prior research found differences in the perceived safety benefits from firearm exposure among diverse gun owners. More women have bought firearms in recent years, resulting in a growing proportion of women who own guns. To examine differences in perceptions of safety among US women, including women who personally own firearms. This descriptive survey study used data from the nationally representative National Survey of Gun Policy, fielded January 6 to 24, 2025. Participants included members of the AmeriSpeak panel who were invited to, and completed, the survey (survey completion rate, 69.8%; N = 2977) online or by telephone in English or Spanish. This study focused specifically on women respondents. Women respondents were stratified by whether they personally owned a gun, lived in a home with a gun that did not belong to them, or had no guns in the home. The main outcome was differences in respondents affirming whether "personally owning a gun will make me safer" and "I would feel safer if more people were allowed to legally carry guns." These perceptions were also examined across racial and ethnic subgroups of gun-owning women and by whether protection in or out of the home were important reasons for ownership. Differences were assessed using survey-weighted logistic regression models. A total of 1411 women completed the survey. The mean (SE) age of women respondents was 48.4 (0.6) years; 12.8% self-identified as non-Hispanic Black, 17.4% as Hispanic, 60.3% as non-Hispanic White, and 9.5% as non-Hispanic other race. Overall, 41.1% (95% CI, 37.7%-44.4%) of women affirmed that personally owning a gun would make them safer, and 21.3% (95% CI, 18.5%-24.0%) agreed they would feel safer if more people were allowed to legally carry guns. Affirmations were significantly higher among gun-owning women (69.7% [95% CI, 63.0%-76.3%] and 35.3% [95% CI, 28.6%-42.0%], respectively), compared with those living in homes with guns (48.9% [95% CI, 40.6%-57.1%] and 22.2% [95% CI, 15.1%-29.3%]) and gun-free homes (26.0% [95% CI, 22.5%-29.6%] and 14.8% [95% CI, 11.9%-17.8%]). Among gun owners, agreement with perceived safety gains from ownership ranged from 63.2% (95% CI, 36.7%-89.8%) among non-Hispanic other to 72.6% (95% CI, 56.1%-89.1%) among Hispanic respondents, and perceived safety from others carrying from 20.1% (95% CI, 9.4%-30.9%) among Black to 40.5% (95% CI, 13.4%-67.6%) among non-Hispanic other respondents, with no significant differences by racial and ethnic groups. There were no significant differences when comparing those who did vs did not report that protection in the home or out of the home were important reasons for ownership. In this survey study of US women, more than half of overall respondents perceived they would not feel safer with greater exposure to firearms, although results varied by personal gun ownership. As gun ownership diversifies, these findings highlight the importance of attending to perceptions of safety in discussions of interventions to reduce gun violence.
To evaluate the efficacy of maintenance iron therapy focused on the menstrual period in preventing anaemia recurrence in women of reproductive age and to examine the accuracy of red cell distribution width (RDW) change in predicting recurrence. To evaluate the efficacy of low-dose iron supplementation administered only during menstruation in preventing recurrence of iron deficiency anaemia and to assess the predictive value of RDW dynamics for early detection of relapse. One hundred and twenty-four female patients who had completed treatment for iron deficiency anaemia (IDA) were divided into maintenance (n = 62) and control (n = 62) groups using Propensity Score Matching (PSM). The maintenance group received only 100 mg of elemental iron during menstruation; the control group was followed without treatment. Patients were followed up for 12 months in terms of haematological parameters. At the end of the twelve-month follow-up, the anaemia recurrence rate was determined to be 8.1% in the maintenance group and 32.3% in the control group (p < 0.001). The maintenance strategy reduced the risk of recurrence by 78% (HR: 0.22; 95% CI: 0.08-0.58). While a progressive decrease in ferritin levels and a marked increase in RDW values were observed in the control group, the parameters remained stable in the maintenance group. ROC analysis determined that a ≥ 0.8% relative increase in RDW predicted anaemia recurrence (Hb < 12 g/dL) approximately three months in advance with 82% sensitivity and 90% specificity (AUC: 0.89). In multivariate analysis, not receiving maintenance therapy and a baseline RDW > 14.8% were identified as independent risk factors. Low-dose maintenance iron therapy synchronised with the menstrual cycle is highly effective in preventing IDA recurrence. RDW, a routine haematological parameter, is a dynamic and inexpensive biomarker that reflects depletion of iron stores months before a decrease in haemoglobin. This proactive approach offers clinicians an important intervention opportunity in the management of chronic iron deficiency.
This study aimed to evaluate the clinical outcomes and identify risk factors for failure of pneumatic retinopexy (PR) using pure air. A retrospective analysis was conducted on 199 eyes from 199 patients with uncomplicated RRD who underwent PR at a single institution between 2019 and 2024. All patients were followed for at least 6 months, with specific follow-up intervals at 1 week and 1, 3, and 6 months. The primary outcome was the anatomical success rate. Statistical analyses, including univariate and multivariate logistic regression, were performed to identify preoperative risk factors for surgical failure. A machine learning model (Random Forest) was also developed to predict surgical success. The single-operation anatomical success rate was 83.9% (167/199). Following repeated gas injection in select cases, the final success rate increased to 89.4% (178/199). Multivariate analysis identified younger age (< 50 years) (Odds Ratio [OR] 2.66; P < 0.05), the presence of a round hole (as opposed to a horseshoe tear) (OR 2.35; P < 0.05) as independent risk factors for primary PR failure. Additionally, lattice degeneration in the attached retina emerged as a potential risk factor with borderline statistical significance (OR 2.49, P = 0.046). A Random Forest model employed for predicting surgical success yielded favorable outcomes, with an accuracy of 0.88 and an AUC of 0.819. Pneumatic retinopexy using intravitreal air is an effective treatment for uncomplicated RRD, achieving high final anatomical success rates. However, surgeons should be aware of a higher risk of failure in younger patients and in eyes with round retinal holes or lattice degeneration in the attached retina. Machine learning models show promise for preoperatively predicting surgical outcomes.
Rush immunotherapy (RIT) accelerates the induction phase of allergen-specific immunotherapy treatment (ASIT) by administering incrementally increasing allergen doses over a single day. This approach reduces the time required to maintenance dosing. Safety information in cats with atopic skin syndrome (FASS) remains limited. The objective of the study was to evaluate the safety of RIT in cats with hypersensitivity disease compatible with FASS and to describe the frequency and nature of adverse events. Forty-seven client-owned cats that underwent RIT. A multicentre medical record review from 2019 to 2024 was performed to identify cats that met at least six of 10 criteria for non-flea-induced hypersensitivity dermatitis and were therefore considered consistent with a diagnosis of FASS. All included cats received documented flea prevention and underwent elimination diet trials. Data collected included signalment, medical history, concurrent medications, RIT protocol details, monitoring findings and follow-up communication. Adverse events (AEs) were recorded. In three of 47 cats (6.4%), AEs were observed including tachypnoea, behavioural distress and increased pruritus. In one cat, RIT was discontinued before protocol completion. All affected cats transitioned to maintenance ASIT without recurrence of AEs. Rush immunotherapy appears to be safe in cats with FASS when performed with clinical monitoring. Adverse events were infrequent, mild and self-limiting, supporting use of accelerated induction protocols in appropriately selected patients.
Bethesda IV thyroid nodules remain a major diagnostic challenge because cytology cannot reliably distinguish benign from malignant follicular-patterned lesions, often leading to diagnostic surgery for ultimately benign disease. This study evaluated whether ultrasound radiomics combined with machine learning could improve preoperative risk stratification in this setting. We conducted a retrospective monocentric study including 69 surgically treated patients with Bethesda IV thyroid nodules and definitive histopathology. Ultrasound images acquired between 2019 and 2020 were manually segmented, and radiomic features were extracted using LIFEx software. After preprocessing and removal of non-informative features, the dataset was split into training (n = 48) and a held-out test set (n = 21), isolated prior to any modelling procedure. Dimensionality reduction was performed with principal component analysis analysis (20 components, 99.5% explained variance). Three supervised machine-learning models were developed and compared: K-nearest neighbors (KNN), Random Forest (RF), and Extreme Gradient Boosting (XGBoost). Internal validation was performed by leave-one-out cross-validation on the training set, with StandardScaler and PCA fitted inside each fold. Final performance was assessed once on the held-out test set. All metrics are reported with 95% confidence intervals. Model performance was assessed using cross-validation and leave-one-out cross-validation, with evaluation of accuracy, F1-score, sensitivity, specificity, and ROC-AUC. Final histology showed malignancy in 39/69 nodules (56.5%). On the held-out test set, RF (n = 50 estimators, depth = 10) achieved the best overall performance: AUC 0.735 (95% CI 0.513-0.956), sensitivity 0.714 (95% CI 0.454-0.883), specificity 0.571 (95% CI 0.250-0.842), and accuracy 0.667 (95% CI 0.454-0.828). KNN (k = 3) achieved AUC 0.602 (95% CI 0.359-0.845). XGBoost did not generalise to the test set (AUC 0.378, 95% CI 0.094-0.661). Leave-one-out cross-validation estimates were modest across all models (AUC range 0.397-0.588), with confidence intervals overlapping 0.50, reflecting the limited statistical power of the training set at n = 48. Ultrasound radiomics combined with Random Forest shows preliminary discriminative ability for distinguishing benign from malignant Bethesda IV thyroid nodules. The wide confidence intervals observed highlight the need for a larger prospective validation cohort. These findings establish a methodological framework and provide sample size benchmarks for a powered confirmatory study.
To investigate the specific role and underlying mechanisms of individual herbs in Qingda Granule (QDG) in attenuating hypertension and inhibiting proliferation of vascular smooth muscle cells (VSMCs). Spontaneously hypertensive rats (SHRs) and angiotensin II (Ang II)-stimulated VSMCs were treated with QDG or its individual herbs. SHRs were divided into groups using a completely randomized design: SHRs, valsartan (Val), QDG, Gastrodia elata Blume (Tianma, Gas), Uncaria rhynchophylla Miz. ex Havil. (Gouteng, Unc), Scutellaria baicalensis Georgi (Huangqin, Scu), and Nelumbo nucifera Gaertn (Lianzixin, Nel), 6 in each group. All treatments were administered via intragastric gavage once daily for 10 weeks. Vascular function and pathological changes were evaluated by ultrasonography and HE staining. The proliferation of VSMCs was assayed by cell counting kit-8, immunohistochemistry (IHC), and Western blot. RNA sequencing was performed to identify differentially expressed transcripts (DETs) in the abdominal aorta. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was performed to identify the key signaling pathways, and the expression of pathway-related proteins was subsequently verified by IHC and Western blot. QDG and its individual herb treatments significantly attenuated the increase in pulse wave velocity and aortic wall thickness in SHRs. QDG inhibited the increased PCNA expression and cell viability in VSMCs. Unc, Scu, and Nel exhibited effects similar to QDG, while Gas did not show these effects. RNA sequencing analysis identified DETs in abdominal aortic tissues. KEGG analysis based on the DETs revealed that multiple common and unique signaling pathways were enriched. Among them, the MAPK pathway was enriched in the QDG, Unc, Scu, and Nel groups, but not in the Gas group, and the cAMP pathway was significantly enriched in all groups. IHC and Western blot analysis verified that compared with the SHR group, the QDG, Unc, Scu, and Nel groups inhibited MAPK pathway activation and promoted cAMP pathway activation in the abdominal aorta of SHR and Ang II-stimulated A7R5s (P<0.05). However, Gas only inhibited the activation of the p38 MAPK pathway and promoted the activation of the cAMP pathway (P<0.05). The herbs in QDG exert significant antihypertensive effects by regulating common and unique pathways. Specifically, Unc, Scu, and Nel inhibit ERK and JNK pathway activation, which likely underlies QDG's suppression of VSMCs proliferation.
Robot-assisted distal pancreatectomy is increasingly recognized as an important minimally invasive option for lesions of the pancreatic body and tail. Given the technical complexity inherent to distal pancreatectomy, including deep operative planes, vascular dissection, splenic vessel management, and the persistent risk of postoperative pancreatic fistula, robotic systems may offer specific advantages in selected settings. However, although the number of relevant publications has continued to rise, the overall research landscape and thematic development of this field remain insufficiently and unsystematically characterized. The present study was designed to assess the global research status, knowledge structure, and evolving hotspots in the field of robot-assisted distal pancreatectomy through bibliometric and visualization analysis. A total of 254 eligible publications indexed in the Web of Science Core Collection between January 1, 2007 and December 31, 2025, including 210 articles and 44 reviews, were analyzed using Bibliometrix, VOSviewer, CiteSpace, and Scimago Graphica. The yearly publication output demonstrated a general increasing pattern, with more marked growth from the mid-2010s onward and the highest output recorded in 2025. Italy together with the United States remained the principal contributors across much of the study period, while China showed sustained growth in recent years. The United States ranked first in citation impact. Several institutions, including the University of Amsterdam, University of Verona, and University of Pisa, emerged as major contributors. Among the leading publication venues were Surgical Endoscopy and Other Interventional Techniques, Annals of Surgical Oncology, and Journal of Robotic Surgery. Citation and co-citation analyses showed that the intellectual structure of the field has been shaped mainly by studies focusing on surgical technique, perioperative outcomes, and comparisons with laparoscopic distal pancreatectomy. Keyword analysis indicated that spleen preservation, pancreatic fistula, laparoscopic comparison, learning curve, clinical outcomes, and multicenter evaluation are among the main research themes, with recent attention increasingly directed toward preservation strategies, outcome assessment, and more refined clinical application. In conclusion, research on robot-assisted distal pancreatectomy has expanded steadily and is moving from early feasibility-focused exploration toward a more specialized and clinically oriented stage. Future progress in this field will likely depend on stronger multicenter collaboration, more indication-specific evaluation, and more standardized evidence generation.
Non-small cell lung cancer (NSCLC) with KRASG12C mutation is associated with poor prognosis and resistance to standard therapies. Sotorasib, a KRASG12C tyrosine kinase inhibitor, has shown clinical efficacy, yet its interaction with different irradiation modalities remains unclear. This study aimed to evaluate the potential radiosensitizing effect of Sotorasib in such mutated cells exposed to X-rays or carbon-ion (C-ions) irradiation. Two human NSCLC cell lines (H358, KRASG12C; and A549, KRASG12S) were treated with Sotorasib alone or in combination with X-rays or C-ions irradiation (1-8 Gy). Cell viability, clonogenic survival, and sphere-forming ability and cytokines were assessed. Sotorasib alone specifically reduced the clonogenic capacity of H358 cells to ~ 30% while no effect was observed with A549 cells. Interestingly, Sotorasib combined with X-ray irradiation decreased clonogenic survival compared with either treatment alone, without evidence of synergy. In contrast, a synergistic effect was observed with C-ions in H358 cells (β = -0.36, 95% CI [- 0.52 to - 0.20], p < 0.001; enhancement ratio = 4.21 at SF2). C-ions irradiation alone markedly reduced sphere formation in both cell lines, whereas sotorasib showed no additional impact. GM-CSF expression was downregulated with sotorasib alone while IP-10 was upregulated when H358 cells were irradiated with sotorasib, suggesting an immune-specific modulatory response. A specific radiosensitization of KRASG12C -mutated NSCLC cells was observed when associating Sotorasib with C-ions. This represents the first evidence of synergistic enhanced cytotoxicity from combining KRASG12C inhibition with high-LET radiation. These findings support further in vivo and translational studies exploring C-ions therapy as a promising strategy for KRASG12C-mutated NSCLC.
This study presents a multi-faceted investigation into the structural, electronic, and therapeutic profiles of the crown and chair conformers of CPRA, 2HPRA, 3HPRA, and 4HPRA macrocycles. A dispersion corrected standard density functional theory (DFT/B3LYP-D3) calculations were utilized for geometric optimization, Mulliken atomic charge analysis, and to evaluate conformational stability based on relative energy values. Frontier Molecular Orbital (FMO) analysis, global reactivity descriptors, and dipole moments reveal that the crown conformers exhibit significantly elevated chemical reactivity compared to their chair counterparts. Thermodynamic assessments further delineate the reaction pathways, confirming the kinetic and thermodynamic stability of the products. These theoretical insights are corroborated by topological mapping include Molecular Electrostatic Potential (MESP), Electron Localization Function (ELF), and Localization of Electron Density (LOL) analyses which map the reactive sites, electron distribution, and intramolecular hydrogen bonding networks. Experimentally, the macrocycles were rapidly synthesized within 30-60 min, and their crown-chair conformations were confirmed via 1H-NMR and 13C-NMR spectroscopy. UV-Visible and fluorescence analyses indicate that phenyl and hydroxyphenyl substitutions on the methine bridges pivotally modulate charge-transfer and proton-transfer transitions, yielding distinct photophysical properties and Stokes shift values. Biologically, blind molecular docking (CB-Dock2) underscores the medicinal potential of these macrocycles, demonstrating high binding affinity and specific interactions with the p53 cellular tumor antigen. Furthermore, phosphomolybdate and Kirby-Bauer assays reveal potent antioxidant and antibacterial activities against both Gram-positive and Gram-negative bacteria. Collectively, these computational and experimental findings position these macrocycles as promising candidates for novel anticancer and antibacterial drug development, as well as high-sensitivity molecular probes for advanced photophysical sensing.
Inflammatory bone loss is a frequent complication of chronic inflammatory and immune-associated disorders. In this review, we synthesize the osteoimmune mechanisms through which persistent inflammation disrupts coupled bone remodeling, with emphasis on RANKL-dependent osteoclastogenesis, suppressed osteoblast-supportive signaling, cytokine networks, immune-cell plasticity, and lesion microenvironment. We distinguish canonical inflammatory bone-loss settings, such as rheumatoid arthritis, periodontitis, and inflammatory osteolysis, from supportive models, including diabetic, ovariectomy-associated, osteoarthritis-related, and steroid-associated bone pathology. We further discuss local versus systemic bone loss and the emerging concept that osteoclasts arising in inflammatory environments may differ from those in physiological remodeling. Natural small molecules are reviewed as multifunctional candidates, but their therapeutic potential is evaluated cautiously in light of model heterogeneity, limited clinical data, pharmacokinetic constraints, and uncertain lesion-specific exposure. Finally, delivery platforms are considered as disease-context-dependent tools for improving local retention, formulation stability, and potentially lesion-specific exposure to natural small molecules.
The interplay between glymphatic function and sleep quality is crucial for brain health and cognitive longevity in late adulthood. Beyond chronological age, whether brain age has specific effects on the associations between glymphatic function, sleep quality, and cognition are understudied in cognitive unimpaired adults. Structural and diffusion magnetic resonance imaging (MRI) data from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) project (N = 582, age range 18-87 years) were used to calculate brain age metrics and the diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index. Brain age metrics comprised estimated brain age and the brain predicted age difference (brain-PAD). Subjective sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). Cognitive assessments included accuracy, reaction time, intraindividual variability of reaction time, and fluid intelligence. Leftward asymmetry of the DTI-ALPS index was consistently observed across brain age-specific groups. The brain-PAD score was significantly correlated with a lower left DTI-ALPS index. Adults with a positive brain-PAD score exhibited a robust correlation between DTI-ALPS indices and sleep quality features, whereas those with a negative brain-PAD score showed a reliable correlation between DTI-ALPS indices and cognition. Mediation analyses further revealed that the relationship between left DTI-ALPS index and sleep efficiency was mediated by brain age. This study provides the first demonstration that lateral differences in the DTI-ALPS index vary according to brain ageing statuses. The two distinct profiles of the sleep-glymphatic function-cognition connections observed in relation to brain-PAD scores suggest that a preserved brain age may serve as a protective factor against age-related decline in glymphatic function. These findings may underscore the translational potential of brain age models as both clinical biomarkers and modifiable targets for interventions aimed at promoting healthy longevity and brain resilience.
BackgroundThe standard metric to assess the benefit of cancer screening is reduction in cancer-specific mortality. However, patients may benefit from downstaging of disease due to screening, even among those who would have survived late-stage disease absent screening.MethodsWe developed a model of stage and survival in the absence and presence of screening. Within each stage/survival category without screening, there are transition probabilities to various stage/survival and mode of detection (screen detected or not) categories under screening. The model includes rules for allowable transitions; for example, stage and survival are unchanged for non-screen detected cancers, and survival status changing from dying to surviving requires downstaging. A two-stage (early/late) model was fit to National Lung Screening Trial (NLST) data. The low-dose computed tomography (LDCT) arm was considered the screening arm and the chest radiograph arm the control (non-screening) arm.ResultsThere were 1032 and 993 lung cancer cases in the NLST LDCT and control arm, respectively. 15.2% of control arm cases were late-stage (III/IV) survivors. Their rate of transitioning to early-stage (I/II) survivors under screening was 18.4%, resulting in 2.8% (15.2% * 18.4%) of all cases transitioning from late-stage survivors under no screening to early-stage survivors with screening. 47.1% of late-stage control arm cases did not survive; their rate of transitioning to early-stage survivors under screening was 21.5%, resulting in 10.1% (47.1% * 21.5%) of all cases under no screening with that transition.ConclusionsModeling the effects of screening on stage and survival can help elucidate a more holistic set of screening benefits.
To identify independent risk factors and predictors for botulinum toxin type A (BTA) reinjection within 6 months in acute acquired concomitant esotropia (AACE) patients, providing a scientific foundation for risk-stratified clinical management. In this case-control study, AACE patients enrolled at Beijing Tongren Hospital (July 2021-January 2025) receiving initial BTA treatment were categorized into reinjection (n = 56) and nonreinjection (n = 61) groups based on the need for a second injection within 6 months. All participants underwent comprehensive ophthalmic and binocular vision assessments at baseline (T0), 1 month (T1), and 3 months (T2). Binary logistic regression analyses were performed to identify predictors. Baseline characteristics were comparable between groups, except that anisometropia (≥ 1.0 D) was significantly more prevalent in the reinjection group. Multivariable analysis revealed that baseline anisometropia (≥ 1.0 D) was an independent risk factor for reinjection (OR = 2.789, 95% CI: 1.183-6.576). Incorporating postoperative measures, the dynamic prediction model further identified residual distance deviation at 3 months (T2), measured with full refractive correction, as a significant predictor (OR = 1.315 per prism diopter increase, 95% CI: 1.069-1.619). A prediction model combining these factors achieved an area under the curve of 0.810 (95% CI: 0.732-0.887). A cutoff of > 5.23 prism diopters for residual deviation at T2 predicted reinjection with 82.0% specificity. Anisometropia is a robust baseline predictor for BTA reinjection in AACE. Residual distance deviation at 3 months postoperatively serves as a critical dynamic indicator of treatment response and reinjection risk, enabling early identification of high-risk patients.
Simultaneous digestive and metabolic disorders in pregnant dairy cows present significant diagnostic challenges, especially during the dry period when physiological adaptations obscure clinical signs. The concurrent occurrence of left displaced abomasum (LDA), liver abscessation, and traumatic reticuloperitonitis (TRP) is uncommon and highlights the diagnostic challenges associated with non-specific clinical signs during the dry period. A six-year-old Holstein cow, in her fourth lactation and at 276 days of gestation, presented with lethargy, diarrhea, and reduced feed intake. Clinical examination confirmed LDA, while blood biochemistry indicated hepatic dysfunction with elevated gamma-glutamyl transferase (GGT) and aspartate aminotransferase (AST) activities. A right-sided omentopexy was performed; however, the cow's condition deteriorated, requiring an emergency cesarean section. Despite intervention, the animal failed to improve and was euthanized. Postmortem examination revealed a large hepatic abscess (21 cm in diameter) containing approximately 5 L of purulent material, TRP caused by a 4-cm nail embedded in the reticulum, and acute abomasitis. The coexistence of these conditions suggests a possible association between traumatic, inflammatory, and metabolic processes; however, the exact sequence of disease development could not be definitively established. This case highlights the diagnostic complexity of concurrent metabolic and infectious disorders in late-gestation dairy cows. The findings emphasize the importance of early recognition, careful interpretation of clinical and laboratory findings, and comprehensive diagnostic evaluation in dry cows, where physiological adaptations and reduced monitoring intensity may delay detection of severe underlying disease.
Hip fracture is the most severe complication of osteoporosis. We followed up patients with hip fracture for up to 7 years. Compared with the general population, the overall mortality rate ratio was approximately 9.27 over the follow-up period. Our findings justify the need for urgent improvement of osteoporosis and hip-fracture care. Hip fracture is the most severe complication of osteoporosis, being associated with substantial morbidity, loss of independence, and increased long-term mortality. Data on excess mortality after hip fracture in the population from Eastern Europe is very limited. The objective of the study is to quantify excess mortality after hip fracture by comparing observed with expected mortality derived from age-specific population data for the largest urban region in Romania. We performed a longitudinal observational cohort study including patients hospitalized with hip fracture followed longitudinally up to 7 years after the fracture. A total of 1977 hip fracture patients (1452 women) aged ≥ 40 years were included. Between 2018 and 2024, 1460 deaths occurred (overall mortality 73.85); the overall crude mortality rate in the cohort was 215.6 per 1000 person-years. Compared with the general population, the overall age-specific mortality rate ratio (RR) was approximately 9.27 over the follow-up period. Cohort crude mortality rates were highest in the first post-fracture year and then decreased but remained elevated all across follow-up with overall annual cohort-to-population RRs of 5.74 to 18.10. In univariate Cox regression analyses, female sex was associated with a lower risk of mortality (HR 0.84, 95% CI 0.75-0.94, p = 0.002), while conservative management was associated with a markedly increased risk of death compared with surgical treatment (HR 1.95, 95% CI 1.72-2.21, p < 0.001). In multivariate Cox proportional hazards analysis, conservative management remained independently associated with an increased risk of all-cause mortality (HR 2.01, 95% CI 1.77-2.28, p < 0.001), female sex remains independently associated with improved survival (HR 0.67, 95% CI 0.60-0.76, p < 0.001), and also increasing age is a strong independent predictor of mortality (HR 1.33, 95% CI 1.28-1.37, p < 0.001). Hip fracture is associated with a high and lasting mortality burden in Romanian patients. These findings justify the need for urgent improvement of osteoporosis care and hip fracture systems, aiming to improve survival and quality of life for this patient population.