Search Results (6,583)

Hormone-dependent breast cancer, particularly in its treatment-resistant forms, remains a significant therapeutic challenge. In this study, we applied a fully computational strategy to design steroid-based compounds capable of simultaneously targeting three key receptors involved in disease progression: progesterone receptor (PR), estrogen receptor alpha (ER-α), and HER2. Using a robust 3D-QSAR model (R² = 0.86; Q²_LOO = 0.86) built from 52 steroidal structures, we identified molecular features associated with high anticancer potential, specifically increased polarizability and reduced electronegativity. From a virtual library of 271 DFT-optimized analogs, 31 compounds were selected based on predicted potency (pIC₅₀ > 7.0) and screened via molecular docking against PR (PDB 2W8Y), HER2 (PDB 7JXH), and ER-α (PDB 6VJD). Seven candidates showed strong binding affinities (ΔG ≤ −9 kcal/mol for at least two targets), with Estero-255 emerging as the most promising. This compound demonstrated excellent conformational stability, a robust hydrogen-bonding network, and consistent multitarget engagement. Molecular dynamics simulations over 100 nanoseconds confirmed the structural integrity of the top ligands, with low RMSD values, compact radii of gyration, and stable binding energy profiles. Key interactions included hydrophobic contacts, π–π stacking, halogen–π interactions, and classical hydrogen bonds with conserved residues across all three targets. These findings highlight Estero-255, alongside Estero-261 and Estero-264, as strong multitarget candidates for further development. By potentially disrupting the PI3K/AKT/mTOR signaling pathway, these compounds offer a promising strategy for overcoming resistance in hormone-driven breast cancer. Experimental validation, including cytotoxicity assays and ADME/Tox profiling, is recommended to confirm their therapeutic potential. Full article

Steel is an important product in many engineering sectors; however, steelmaking remains one of the largest ${\mathrm{CO}}_2$ emitters. Therefore, new governmental policies drive the steelmaking industry toward a cleaner and more sustainable operation such as the gas-based direct reduction–electric arc furnace process. To become carbon neutral, utilizing more scrap is one of the feasible solutions to achieve this goal. Addressing knowledge gaps regarding scrap heterogeneity (size, shape, and composition) is essential to evaluate the effects of increased scrap ratios in basic oxygen furnace (BOF) operations. This review systematically examines heat and mass transfer correlations relevant to scrap melting in BOF steelmaking, with a focus on low Prandtl number fluids (thick thermal boundary layer) and dense particulate systems. Notably, a majority of these correlations are designed for fluids with high Prandtl numbers. Even for the ones tailored for low Prandtl, they lack the introduction of the porosity effect which alters the melting behavior in such high temperature systems. The review is divided into two parts. First, it surveys heat transfer correlations for single elements (rods, spheres, and prisms) under natural and forced convection, emphasizing their role in predicting melting rates and estimating maximum shell size. Second, it introduces three numerical modeling approaches, highlighting that the computational fluid dynamics–discrete element method (CFD–DEM) offers flexibility in modeling diverse scrap geometries and contact interactions while being computationally less demanding than particle-resolved direct numerical simulation (PR-DNS). Nevertheless, the review identifies a critical gap: no current CFD–DEM framework simultaneously captures shell formation (particle growth) and non-isotropic scrap melting (particle shrinkage), underscoring the need for improved multiphase models to enhance BOF operation. Full article

Internal fins are commonly utilized as a passive technique to enhance natural convection, but their efficiency depends on complex interplay between fin design, material properties, and convective strength. This study presents an extensive numerical analysis of buoyancy-driven flow in square cavities containing a single horizontal fin on the hot wall. Over 9000 simulations were conducted, methodically varying the Rayleigh number (Ra = 10 to 10⁵), Prandtl number (Pr = 0.1 to 10), and fin characteristics, such as length, vertical position, thickness, and the thermal conductivity ratio (up to 1000), to assess their overall impact on thermal efficiency. Thermal enhancements compared to scenarios without fins are quantified using local and average Nusselt numbers, as well as a Nusselt number ratio (NNR). The results reveal that, contrary to conventional beliefs, long fins positioned centrally can actually decrease heat transfer by up to 11.8% at high Ra and Pr due to the disruption of thermal plumes and diminished circulation. Conversely, shorter fins located near the cavity’s top and bottom wall edges can enhance the Nusselt numbers for the hot wall by up to 8.4%, thereby positively affecting the development of thermal boundary layers. A U-shaped Nusselt number distribution related to fin placement appears at Ra ≥ 10³, where edge-aligned fins consistently outperform those positioned mid-height. The benefits of high-conductivity fins become increasingly nonlinear at larger Ra, with advantages limited to designs that minimally disrupt core convective patterns. These findings challenge established notions regarding passive thermal enhancement and provide a predictive thermogeometric framework for designing enclosures. The results can be directly applied to passive cooling systems in electronics, battery packs, solar thermal collectors, and energy-efficient buildings, where optimizing heat transfer is vital without employing active control methods. Full article

Powdery mildew (PM), caused by Sphaerotheca phaseoli, severely threatens mungbean (Vigna radiata) productivity and quality, yet the molecular basis of resistance remains poorly defined. This study employed transcriptome profiling to compare defense responses in a resistant genotype, SUPER5, and a susceptible variety, CN84-1, following pathogen infection. A total of 1755 differentially expressed genes (DEGs) were identified, with SUPER5 exhibiting strong upregulation of genes encoding pathogenesis-related (PR) proteins, disease resistance proteins, and key transcription factors. Notably, genes involved in phenylpropanoid and flavonoid biosynthesis, pathways associated with antimicrobial compound and lignin production, were markedly induced in SUPER5. In contrast, CN84-1 showed limited activation of defense genes and downregulation of essential regulators such as MYB14. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses highlighted the involvement of plant–pathogen interaction pathways, MAPK signaling, and reactive oxygen species (ROS) detoxification in the resistant response. Quantitative real-time PCR validated 11 candidate genes, including PAL3, PR2, GSO1, MLO12, and P21, which function in pathogen recognition, signaling, the biosynthesis of antimicrobial metabolites, the production of defense proteins, defense regulation, and the reinforcement of the cell wall. Co-expression network analysis revealed three major gene modules linked to flavonoid metabolism, chitinase activity, and responses to both abiotic and biotic stresses. These findings offer valuable molecular insights for breeding PM-resistant mungbean varieties. Full article

Triple-negative breast cancer (TNBC) is a clinically and molecularly heterogeneous subtype defined by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. In this study, tumor specimens from 104 TNBC patients were analyzed to characterize molecular and clinicopathological features and to assess the expression and therapeutic potential of four key surface markers: epidermal growth factor receptor (EGFR), epithelial cell adhesion molecule (EpCAM), tissue factor (TF), and trophoblast cell surface antigen (TROP2). Multiplex immunofluorescence (mIF) demonstrated elevated EGFR and TROP2 expression in the majority of samples. Significant positive correlations were observed between EGFR and TF, as well as between TROP2 and both TF and EpCAM. Expression analyses revealed increased EGFR and TF levels with advancing tumor stage, whereas EpCAM expression declined in advanced-stage tumors. TROP2 and TF expression were significantly elevated in higher-grade tumors. Additionally, EGFR and EpCAM levels were significantly higher in patients with elevated Ki-67 indices. Binding specificity assays using single-chain variable fragment (scFv-SNAP) fusion proteins confirmed robust targeting efficacy, particularly for EGFR and TROP2. These findings underscore the therapeutic relevance of EGFR and TROP2 as potential biomarkers and targets in TNBC. Full article

Phosphatidylinositol-3-kinase (PI3K) inhibition has emerged as a therapeutic option against indolent lymphoma, including relapsed follicular lymphoma (FL). While inhibition of active signaling in the lymphoma cell represents the primary mode of action, PI3K inhibition also exerts immunomodulatory effects. Here we have analyzed 17 consecutive advanced treatment line FL patients treated with the delta-selective PI3K inhibitor idelalisib in a retrospective single-center observational study, with a specific focus on response and immune effects. Eleven patients achieved complete remission (CR) or partial remission (PR) with median response duration of 22 (11–88) months following a median idelalisib exposure of 15 (4–88) months. Disease response persisted in three patients for a median of 37 (21–63) months following cessation of idelalisib without another therapy being initiated. Autoimmune side effects occurred in eight of the eleven patients who responded, compared to none in six patients whose disease did not respond. In conclusion, a time-limited exposure to idelalisib may induce sustained remissions in a portion of patients with recurrent and/or refractory (r/r) FL, suggesting immunomodulatory effects of PI3K inhibition to be involved in the control of the disease. Full article

Background: Breast cancer remains a major public health challenge in Latin America, where access to personalized risk assessment tools is still limited. This study aimed to evaluate the implementation of a polygenic risk score (PRS)-based stratification model combined with remote genomic counseling in Colombian women with sporadic breast cancer and healthy women. Methods: In 2023, an embedded mixed-methods observational study was conducted in Medellín involving 1997 women aged 40–75 years who underwent clinical PRS testing. The intervention integrated PRS-based risk categorization with individualized risk factor assessment and lifestyle recommendations delivered through a remote counseling platform. Results: PRS analysis classified 9.7% of women as high risk and 46% as low risk. Healthier lifestyle patterns were significantly associated with lower PRS categories (p = 0.034). Physical activity showed a protective effect (OR = 0.60, 95% CI: 0.5–0.8), while prior smoking, elevated BMI, and sedentary behavior were associated with higher risk. The counseling model achieved high delivery (93%) and satisfaction (85%) rates. Qualitative insights revealed improved understanding of genomic risk and greater engagement in preventive behaviors. Only one new case of breast cancer was detected among intermediate-risk participants, with a diagnostic lead time of 12 months. Conclusions: These findings support the feasibility, acceptability, and potential impact of integrating PRS and genomic counseling in cancer prevention strategies in middle-income settings. Full article

Background: Left bundle branch block (LBBB) following trans-catheter aortic valve implantation (TAVI) has been excluded from same-day discharge. Early identification of patients with stable LBBB can help facilitate same-day discharge. We aim to assess the role of 6-hour ECG to determine development of LBBB in patients undergoing TAVI. Methods: This is a prospective single-centre study of patients who have LBBB following elective TAVI procedures. All patients underwent ECGs pre-TAVI, as well as immediately, 6 h, and 24 h post-TAVI. Changes in ECG were compared at 6 and 24 h with the one immediately post TAVI. Results: The study included 115 patients with uncomplicated procedures. The mean age was 81 ± 7 years, with 54% male. A self-expanding valve was used in 67% of patients. Following TAVI, prolongations of PR interval and QRS duration were dynamic and reduced at 6 h. The change in PR interval at 6 and 24 h was comparable [−11 (−20 to 3) vs. −2 (−24 to 16) ms, p = 0.18]. Similarly, there was no statistical difference in the change of QRS duration at 6 and 24 h compared to the ECG immediately post-TAVI [−10 (−40 to −2) vs. −7 (−34 to 0) ms, p = 0.055]. Changes in ECG were also comparable in patients undergoing balloon-expandable and self-expanding valves. Conclusions: The current study supports that 6-hour ECG has the potential to reduce the need for prolonged continuous monitoring post-TAVI. ECG at 6 h can help optimise patient flow and facilitate early discharge. Future studies with larger sample sizes are required to confirm our findings. Full article

The design and adjustable properties of nanoporous materials are important for current and future technological applications, research, and development. In addition, nanoporous ferroelectric materials have the potential to achieve competitive ferroelectric, dielectric, and piezoelectric characteristics. In this work, using the phase-field model, we found that the shape of pores in barium titanite ceramics governs the formation of the ferroelectric domain structure and the switching hysteresis loop. A remanent polarization-coercive field (P_r-E_c) diagram is introduced to denote the shape of the hysteresis loops. We performed a fundamental study in understanding how the domain structures affect the properties of domain-engineered porous ferroelectrics. Simulation results show that the hysteresis loop of porous ferroelectrics can be designed by controlling the shape/orientation of the ellipse-shaped pores. Numerical simulations also verify that the dielectric/piezoelectric properties can be improved with artificially designed porous structures. These phase-field results may be useful in the development of highly performing lead-free ferroelectric/piezoelectric materials. Full article

The alloy Pr${}_2$Fe${}_{16.75}$Ni${}_{0.25}$ has been examined to investigate its structural properties, critical behavior, and magnetocaloric effects. Rietveld’s refinement of X-ray diffraction patterns has revealed a rhombohedral structure with an $R\overline{3}m$ space group. Pr${}_2$Fe${}_{16.9}$Ni${}_{0.25}$ also demonstrates a direct magnetocaloric effect near room temperature, accompanied by a moderate magnetic entropy change ($-\Delta S_M^{\max }$ = 5.5 J kg${}^{-1}$ K${}^{-1}$ at ${\mu }_0\Delta H=5$ T) and a broad working temperature range. Furthermore, the Relative Cooling Power (RCP) is approximately 89% of the widely recognized gadolinium (Gd) for ${\mu }_0\Delta H=2$ T. This compound exhibits a commendable magnetocaloric response, on par with or even surpassing that of numerous other intermetallic alloys. Critical behavior was analyzed using thermo-magnetic measurements, employing methods such as the modified Arrott plot, critical isotherm analysis, and Kouvel-Fisher techniques. The obtained critical exponents ($\beta$, $\gamma$, and $\delta$) exhibit similarities to those of the 3D-Ising model, characterized explicitly by intermediate range interactions. Full article

This research addresses the challenges of proactive scheduling and routing in manufacturing systems governed by the Material Requirement Planning (MRP) method. Such systems often face capacity constraints, difficulties in resource balancing, and limited traceability of component requirements. The lack of seamless integration between customer orders and production tasks, combined with the manual and time-consuming nature of schedule adjustments, highlights the need for an automated and optimized scheduling method. We propose a novel optimization-based approach that leverages mixed-integer linear programming (MILP) combined with a proprietary procedure for reducing the size of the modeled problem to generate feasible and/or optimal production schedules. The model incorporates dynamic routing, partial resource utilization, limited additional resources (e.g., tools, workers), technological breaks, and time quantization. Key results include determining order feasibility, identifying unfulfilled order components, minimizing costs, shortening deadlines, and assessing feasibility in the absence of available resources. By automating the generation of data from MRP/ERP systems, constructing an optimization model, and exporting the results back to the MRP/ERP structure, this method improves decision-making and competes with expensive Advanced Planning and Scheduling (APS) systems. The proposed innovation solution—the integration of MILP-based optimization with the proprietary PT (data transformation) and PR (model-size reduction) procedures—not only increases operational efficiency but also enables demand source tracking and offers a scalable and economical alternative for modern production environments. Experimental results demonstrate significant reductions in production costs (up to 25%) and lead times (more than 50%). Full article

Background and Objectives: Emerging evidence indicates that individuals exposed to adverse childhood experiences (ACEs) face elevated risks for various chronic illnesses. However, the association between ACEs and osteoporosis risk remains underexplored, particularly regarding potential modifications by genetic susceptibility. This prospective cohort study aims to examine the relationship of ACEs with incident osteoporosis and investigate interactions with polygenic risk score (PRS). Materials and Methods: This study analyzed 124,789 UK Biobank participants initially free of osteoporosis. Cumulative ACE burden (emotional neglect, emotional abuse, physical neglect, physical abuse, sexual abuse) was ascertained through validated questionnaires. Multivariable-adjusted Cox proportional hazards models assessed osteoporosis risk during a median follow-up of 12.8 years. Moderation analysis examined genetic susceptibility interactions using a standardized PRS incorporating osteoporosis-related SNPs. Results: Among 2474 incident osteoporosis cases, cumulative ACEs showed dose–response associations with osteoporosis risk (adjusted hazard ratio [HR]_{per one-unit increase} = 1.07, 95% confidence interval [CI] 1.04–1.11; high ACEs [≥3 types] vs. none: HR = 1.26, 1.10–1.43). Specifically, emotional neglect (HR = 1.14, 1.04–1.25), emotional abuse (HR = 1.14, 1.03–1.27), physical abuse (HR = 1.17, 1.05–1.30), and sexual abuse (HR = 1.15, 1.01–1.31) demonstrated comparable effect sizes. Sex-stratified analysis revealed stronger associations in women. Joint exposure to high ACEs/high PRS tripled osteoporosis risk (HR = 3.04, 2.46–3.76 vs. low ACEs/low PRS) although G × E interaction was nonsignificant (P-interaction = 0.10). Conclusions: These results suggest that ACEs conferred incremental osteoporosis risk independent of genetic predisposition. These findings support the inclusion of ACE screening in osteoporosis prevention strategies and highlight the need for targeted bone health interventions for youth exposed to ACEs. Full article

Plant pathogenesis-related (PR) proteins are a large and diverse family of proteins with antimicrobial activity, often induced by pathogen attack. Traditionally, PR proteins were thought to mainly participate in plant defense mechanisms against biotic stress. However, in recent years, increasing evidence has shown that these proteins also play important roles in the response to abiotic stress in plants. In the present review, we provide a summary of the latest findings on PR proteins and focus on their response to various abiotic stresses, the mechanism by which PR proteins are activated by external and internal signals, and their biological functions in plant responses to abiotic stresses. In addition, the existing challenges and future applications are also summarized, aiming to provide a reference for further research on PR proteins in the context of plant physiology. Full article

Anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) is a heterogeneous group of small-vessel vasculitides, characterized by the presence of antibodies binding to myeloperoxidase (MPO) and proteinase-3 (PR3) found in neutrophil granules. Apart from being the target of ANCA, neutrophils actively contribute to the vicious cycle of inflammation and vascular damage in AAV. On the other hand, platelets have recently been recognized as essential for thrombosis and as inflammatory effectors that collaborate with neutrophils, reinforcing the generation of reactive oxygen species (ROS) and the formation of neutrophil extracellular traps (NETs) in those diseases. Neutrophils exhibit morphological and functional heterogeneity in AAV, reflecting the complexity of their contribution to disease pathogenesis. Since long-term immunosuppression may be related to serious infections and malignancies, there is an urgent need for reliable biomarkers of disease activity to optimize the management of AAV. This review summarizes the current understanding of the role of neutrophils and platelets in the pathogenesis of granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), focusing on their crosstalk, and highlights the potential for identifying novel biomarkers relevant for predicting the disease course and its relapses. Full article

This study analyzes the lacustrine hydrocarbon source rocks of the Lower Cretaceous in the Erdengsumu sag of the Erlian Basin, evaluating their characteristics and identifying areas with oil resource potential, while also investigating the ancient lake environment, material source input, and controlling factors, ultimately developing a sedimentary model for lacustrine hydrocarbon source rocks. The findings suggest the following: (1) The lower Tengger Member (K₁bt₁) and the Aershan Formation (K₁ba) are the primary oil-producing strata, with an effective hydrocarbon source rock exhibiting a lower limit of total organic carbon (TOC) at 0.95%. The Ro value typically remains below 0.8%, indicating that high-maturity oil production has not yet been attained. (2) The oil generation threshold depths for the Dalestai and Sayinhutuge sub-sags are 1500 m and 1214 m, respectively. The thickness of the effective hydrocarbon source rock surpasses 200 m, covering areas of 42.48 km² and 88.71 km², respectively. The cumulative hydrocarbon generation intensity of wells Y1 and Y2 is 486 × 10⁴ t/km² and 26 × 10⁴ t/km², respectively, suggesting that the Dalestai sub-sag possesses considerable petroleum potential. The Aershan Formation in the Chagantala sub-sag has a maximum burial depth of merely 1800 m, insufficient to attain the oil generation threshold depth. (3) The research area’s productive hydrocarbon source rocks consist of organic matter types I and II₁. The Pr/Ph range is extensive (0.33–2.07), signifying a reducing to slightly oxidizing sedimentary environment. This aligns with the attributes of small fault lake basins, characterized by shallow water and robust hydrodynamics. (4) The low ratio of ∑nC₂₁₋/∑nC₂₂₊ (0.36–0.81), high CPI values (>1.49), and high C₂₉ sterane concentration suggest a substantial terrestrial contribution, with negligible input from aquatic algae–bacterial organic matter. Moreover, as sedimentation duration extends, the contribution from higher plants progressively increases. (5) The ratio of the width of the deep depression zone to the width of the depression in the Erdengsumu sag is less than 0.25. The boundary fault scale is small, its activity is low, and there is not much input from the ground. Most of the source rocks are in the reducing sedimentary environment of the near-lying gently sloping zone. Full article