The early-stage detection of alpha-synuclein (alpha-Syn), a hallmark biomarker of Parkinson's disease, is critical for timely diagnosis and therapeutic intervention. Herein, we report on a metal-enhanced fluorescence (MEF) immuno-biosensor constructed from a nanohybrid comprising glutathione (GSH)-capped CdSe/In2S3Se quantum dots (QDs), multishaped AuCu alloy nanoparticles (NPs) and reduced graphene oxide (rGO). The QDs-AuCu alloy NP-rGO nanohybrid was prepared via solution-phase assembly and anti-alpha-Syn antibodies (Ab) were immobilized via physical adsorption. Target alpha-syn interaction triggered fluorescence amplification, which was further supported by finite difference time domain (FDTD) simulations revealing localized electric field enhancement at the QDs-AuCu alloy NP-rGO interface. Notably, the QDs-AuCu alloy NP-rGO nanohybrid exhibited enhanced redox currents and reduced impedance, reflecting a synergistic contribution from the QDs, plasmon-active AuCu NPs and conductive rGO scaffold in facilitating efficient charge transport and interfacial electron transfer. Density functional theory (DFT) calculations revealed that introducing an In2S3Se shell around GSH-CdSe QDs led to a significant reduction in the HOMO-LUMO energy gap from 0.323 eV to 0.013 eV which was accompanied by a downward shift in the Fermi level from-1.99 eV to-4.10 eV. Post-self-consistent field (SCF) analysis of electron density and electrostatic potential (ESP) maps confirmed increased electron delocalization and a stronger internal dipole moment in CdSe/In2S3Se QDs compared to CdSe, as evidenced by compact density contours and intensified polarity in the ESP profiles. These changes were driven by increased orbital delocalization and stronger interfacial electronic coupling between core and shell atoms, thus confirming the role of the core/shell architecture in enhancing charge transfer and electronic conductivity. The QDs-AuCu alloy NP-rGO-Ab immunosensor achieved a wide dynamic detection range from 0.01 to 100 pg/mL, a limit of detection of 5.6 fg/mL and high recovery rates (94.0-99.4%) in spiked human serum. In addition, cytotoxicity assessment using HEK293T cells demonstrated that the QDs and QDs-AuCu alloy NP-rGO nanohybrid retained high cell viability across all tested concentrations whilst stability studies conducted in acidic buffers (pH 1 to pH 5) and in biologically relevant media, showed that the QDs remained structurally stable with no observable degradation or loss of optical performance.
In biomedical research, accurate longitudinal biomarker and disease progression analysis is essential, particularly for personalized risk assessment. Joint models of longitudinal biomarkers and multi-state survival processes provide a natural framework, but parameter estimation becomes unstable in high-dimensional settings. This study introduces a novel extension that incorporates shrinkage estimation into joint longitudinal-multi-state models, reducing variability by pulling estimates toward a structured target. Also, determine the asymptotic distributional hazards and biases of the suggested estimators and examine how well they perform in comparison to the unrestricted maximum likelihood estimator. The strategy connects classical shrinkage estimation with modern joint modeling, providing a principled approach to stabilize inference in complex multi-state biomedical settings. Simulation studies show that the proposed shrinkage joint model achieves lower bias and mean squared error than the standard approach. The developed framework offers a robust tool for biomedical applications, such as cancer, where integrating biomarker trajectories with disease-state transitions can improve prognostic precision and support personalized treatment strategies.
This study evaluates the seismic fragility of high-rise steel storage racks under long-distance and short-distance earthquake excitations using Incremental Dynamic Analysis (IDA). Two representative sites were selected to represent long- and short-distance earthquake scenarios. A numerical model of the high-rise rack system was developed and validated against substructure experimental results and benchmark data reported in the literature. The IDA results show that the earthquake scenario significantly influenced the seismic response of the investigated rack. Long-distance ground motions generally resulted in severe damage and collapse at lower seismic intensity levels, particularly for global deformation responses. Long-distance excitation also resulted in a more abrupt transition from severe damage to collapse, indicating a limited deformation reserve once severe damage was reached. In contrast, short-distance ground motions produced more localized damage and a more gradual progression toward collapse. In addition, serviceability assessments showed a higher susceptibility to residual misalignment under long-distance ground motions, highlighting potential risks to automated warehouse operations even at relatively low seismic intensities. Overall, the results indicate greater vulnerability of the investigated high-rise rack to long-distance ground motions in terms of global deformation, damage progression, and residual misalignment.
Background Metabolic dysfunction–associated steatotic liver disease (MASLD) is highly prevalent and frequently undiagnosed, despite liver fibrosis being the strongest predictor of liver-related morbidity and mortality. We aimed to quantify Fibrosis-4 (FIB-4) index-based fibrosis risk and to evaluate guideline-recommended follow-up—FIB-4 documentation, confirmatory testing, and specialist referral—in a large US cohort. Methods We conducted a retrospective study of electronic health record data from the US All of Us Research Program. Among adults aged 35 years or older with sufficient laboratory data, FIB-4 scores were calculated from routinely captured biomarkers, classified as low (<1.3), indeterminate (1.3–2.67; 2.0–2.67 if aged ≥65 years), or high risk (>2.67), and described across sociodemographic and metabolic subgroups; associations with incident major adverse liver outcomes (MALO) were assessed with Cox proportional-hazards regression. We examined FIB-4 documentation, confirmatory testing, and specialty referrals within 365 days of the index FIB-4 date. Findings Among 136,004 participants (mean age 60.8 years [SD 13.5]; 79,365 [58.4%] female; 81,420 [59.9%] White, 21,779 [16.0%] Hispanic or Latino, 20,076 [14.8%] Black), 26,971 (19.8%, 95% CI 19.6–20.0) had indeterminate and 11,217 (8.2%, 8.1–8.4) high FIB-4–based fibrosis risk. Elevated risk was more frequent with cardiovascular disease (41.7% vs 25.6%), hypertension (30.7% vs 23.4%), and type 2 diabetes (29.7% vs 27.4%), rising from 25.6% with no metabolic comorbidities to 36.6% with four. FIB-4 documentation was rare, and fewer than 1% of high-risk participants underwent confirmatory testing or referral; referral was low across risk categories (0.19% high, 0.19% indeterminate, 0.25% low risk). MALO occurred in 1308 (11.7%) high-risk vs 830 (0.8%) low-risk participants (adjusted hazard ratio 19.68, 95% CI 17.88–21.67). Interpretation Routinely collected laboratory data identify substantial liver fibrosis risk in this volunteer US cohort, yet guideline-recommended follow-up is uncommon. Implementation strategies such as automated risk calculation and reflex-based testing pathways could reduce missed opportunities for earlier diagnosis and intervention. Funding No specific funding was received for this study.
