Search Results (3,320)

Background: Relapsed/refractory acute myeloid leukemia (R/R AML) remains a therapeutic challenge due to disease heterogeneity, resistance mechanisms, and poor tolerability to intensive regimens. Venetoclax (VEN), a BCL-2 inhibitor, has shown promise in combination with hypomethylating agents (HMAs), but data on response timing in the R/R setting are limited. The aim of this study was to assess the efficacy, safety, and kinetics of response to HMA-VEN therapy in a real-world cohort of R/R AML patients, with particular focus on early versus late responders. Methods: This prospective single-center study included 33 adult patients with R/R AML treated with VEN plus either azacitidine (AZA) or decitabine (DEC) from 2018 to 2021. The primary endpoint was the composite complete remission (cCR) rate and the rate of early and late response, respectively, occurring within two cycles of therapy or later; secondary endpoints included overall survival (OS), relapse-free survival (RFS), time to relapse (TTR), and safety. Results: The cCR was 58%, with complete remission (CR) or CR with incomplete recovery (CRi) achieved in 52% of patients. Median OS was 9 months. No significant differences in OS or TTR were observed between early (≤2 cycles) and late (>2 cycles) responders. Eight responders (42%) underwent allogeneic hematopoietic stem cell transplantation (HSCT), with comparable transplant rates in both groups of responders. Toxicity was manageable. Grade 3–4 neutropenia occurred in all patients, and febrile neutropenia occurred in 44% of patients. An Eastern Cooperative Oncology Group (ECOG) score >2 was associated with inferior response and shorter treatment duration. Conclusions: HMA-VEN therapy is effective and safe in R/R AML, including for patients with delayed responses. The absence of a prognostic disadvantage for late responders supports flexible treatment schedules and suggests that the continuation of therapy may be beneficial even without early blast clearance. Tailored approaches based on performance status and comorbidities are warranted, and future studies should incorporate minimal residual disease (MRD)-based monitoring to refine response assessment. Full article

Accurate State of Charge (SOC) estimation for retired power batteries remains a critical challenge due to their degraded electrochemical properties and heterogeneous aging mechanisms. Traditional methods relying solely on electrical parameters (e.g., voltage and current) exhibit significant errors, as aged batteries experience altered internal resistance, capacity fade, and uneven heat generation, which distort the relationship between electrical signals and actual SOC. To address these limitations, this study proposes a surface temperature-assisted SOC estimation method, leveraging the distinct thermal characteristics of retired batteries. By employing infrared thermal imaging, key temperature feature regions—the positive/negative tabs and central area—are identified, which exhibit strong correlations with SOC dynamics under varying operational conditions. A Gated Recurrent Unit (GRU) neural network is developed to integrate multi-region temperature data with electrical parameters, capturing spatial–temporal thermal–electrical interactions unique to retired batteries. The model is trained and validated using experimental data collected under constant current discharge conditions, demonstrating superior accuracy compared to conventional methods. Specifically, our method achieves 64.3–68.1% lower RMSE than traditional electrical-parameter-only approaches (V-I inputs) across 0.5 C–2 C discharge rates. Results show that the proposed method reduces SOC estimation errors compared to traditional voltage-based models, achieving RMSE values below 1.04 across all tested rates. This improvement stems from the model’s ability to decode localized heating patterns and their hysteresis effects, which are particularly pronounced in aged batteries. The method’s robustness under high-rate operations highlights its potential for enhancing the reliability of retired battery management systems in secondary applications such as energy storage. Full article

Introduction: The combination of ceftazidime−avibactam (CAZ-AVI) with aztreonam (ATM) may be an option for the treatment of infections due to metallo-β-lactamases (MBLs) producing bacteria, as recommended by current guidelines. MBLs protect the pathogen from any available β-lactam/β-lactamase inhibitor (BL/BLI). Moreover, in vitro and clinical data suggest that double carbapenem therapy (DCT) may be an option for such infections. Materials and Methods: This retrospective study was conducted in two mixed intensive care units (ICUs) at the University Hospital of Larissa, Thessaly, Greece, and the General Hospital of Larissa, Thessaly, Greece, during a three-year period (2022−2024). Mechanically ventilated patients with bloodstream infection (BSI) caused by K. pneumoniae resistant to all BL/BLI combinations were studied. Patients were divided into three groups: in the first, patients were treated with CAZ-AVI + ATM; in the second, with DCT; and in the third, with antibiotics other than BL/BLIs that presented in vitro susceptibility. The primary outcome of the study was the change in Sequential Organ Failure Assessment (SOFA) score between the onset of infection and the fourth day of antibiotic treatment. Secondary outcomes were SOFA score evolution during the treatment period, total duration of mechanical ventilation (MV), ICU length of stay (LOS), and ICU mortality. Results: A total of 95 patients were recruited. Among them, 23 patients received CAZ-AVI + AZT, 22 received DCT, and 50 patients received another antibiotic regimen which was in vitro active against the pathogen. The baseline characteristics were similar. The mean (SE) overall age was 63.2 (1.3) years. Mean (SE) Acute Physiology and Chronic Health Evaluation II (APACHE II) and SOFA scores were 16.3 (0.6) and 7.6 (0.3), respectively. The Charlson Index was similar between groups. The control group presented a statistically lower SOFA score on day 4 compared to the other two groups [mean (SE) 8.9 (1) vs. 7.4 (0.9) vs. 6.4 (0.5) for CAZ-AVI + ATM, DCT and control group, respectively (p = 0.045)]. The duration of mechanical ventilation, ICU LOS, and mortality were similar between the groups (p > 0.05). Comparison between survivors and non-survivors revealed that survivors had a lower SOFA score on the day of BSI, higher PaO₂/FiO₂ ratio, higher platelet counts, and lower lactate levels (p < 0.05). Septic shock was more frequent among non-survivors (60.3%) in comparison to survivors (27%) (p = 0.0015). Independent factors for mortality were PaO₂/FiO₂ ratio and lactate levels (p < 0.05). None of the antibiotic regimens received by the patients was independently associated with survival. Conclusions: Treatment with CAZ-AVI + ATM or DCT may offer similar clinical outcomes for patients suffering from BSI caused by K. pneumoniae strains resistant to all available BL/BLIs. However, larger studies are required to confirm the findings. Full article

Antibiotic resistance is considered to be one of the most complex health obstacles of our time. Methicillin-resistant Staphylococcus aureus (MRSA) represents a global health challenge due to its broad treatment resistance capacity, resulting in high mortality rates. The shikimate pathway (SP) is responsible for the biosynthesis of chorismate from glycolysis and pentose phosphate pathway intermediates. This pathway plays a crucial role in producing aromatic amino acids, folates, ubiquinone, and other secondary metabolites in bacteria. Notably, SP is absent in humans, which makes it a specific and potential therapeutic target to explore for discovering new antibiotics against MRSA. The present study characterized in vitro and in silico natural products as inhibitors of the shikimate dehydrogenase from methicillin-resistant S. aureus (SaSDH). The results showed that, from the set of compounds studied, phloridzin, rutin, and caffeic acid were the most potent inhibitors of SaSDH, with IC₅₀ values of 140, 160, and 240 µM, respectively. Furthermore, phloridzin showed a mixed-type inhibition mechanism, whilst rutin and caffeic acid showed non-competitive mechanisms. The structural characterization of the SaSDH–inhibitor complex indicated that these compounds interacted with amino acids from the catalytic site and formed stable complexes. In biological activity studies against MRSA, caffeic acid showed an MIC of 2.2 mg/mL. Taken together, these data encourage using these compounds as a starting point for developing new antibiotics based on natural products against MRSA. Full article

Background/Objectives: Antimicrobial resistance (AMR) contributes to millions of deaths globally each year, creating an urgent need for new therapeutic agents. Antimicrobial peptides (AMPs) have emerged as promising candidates due to their potential to combat AMR pathogens. This study aimed to evaluate the antimicrobial activity of an AMP from a soil-derived bacterial isolate against Gram-negative bacteria. Method: Soil bacteria were isolated and screened for antimicrobial activity. The bioactive peptide was purified and determined its structure and antimicrobial efficacy. Genomic analysis was conducted to predict the biosynthetic gene clusters (BGCs) responsible for AMP production. Results: Genomic analysis identified the isolate as Paenibacillus sp. Na14, which exhibited low genomic similarity (61.0%) to other known Paenibacillus species, suggesting it may represent a novel species. The AMP from the Na14 strain exhibited heat stability up to 90 °C for 3 h and retained its activity across a broad pH range from 3 to 11. Structural analysis revealed that the Na14 peptide consisted of 14 amino acid residues, adopting an α-helical structure. This peptide exhibited bactericidal activity at concentrations of 2–4 µg/mL within 6–12 h, and its killing rate was concentration-dependent. The peptide was found to disrupt the bacterial membranes. The Na14 peptide shared 64.29% sequence similarity with brevibacillin 2V, an AMP from Brevibacillus sp., which also belongs to the Paenibacillaceae family. Genomic annotation identified BGCs associated with secondary metabolism, with a particular focus on non-ribosomal peptide synthetase (NRPS) gene clusters. Structural modeling of the predicted NRPS enzymes showed high similarity to known NRPS modules in Brevibacillus species. These genomic findings provide evidence supporting the similarity between the Na14 peptide and brevibacillin 2V. Conclusions: This study highlights the discovery of a novel AMP with potent activity against Gram-negative pathogens and provides new insight into conserved AMP biosynthetic enzymes within the Paenibacillaceae family. Full article

In the process of producing ferroalloys, a large amount of secondary raw materials is formed, including slag, aspiration dusts and sludge. The recycling of secondary raw materials can create resources and bring environmental and economic benefits. Wet secondary raw materials (WSRMs) are characterized by a high chromium oxide content (averaging 24%), but due to their high moisture levels, they cannot be directly used in arc furnaces. As a strategic approach, mixing WSRMs with drier, more chromium-rich dusts (up to 45% Cr₂O₃) has been proposed. This not only reduces the overall moisture content of the mixture but also enhances the metallurgical value of the charge material. This paper presents the results of laboratory studies on the agglomeration of secondary wet raw materials using briquetting, extrusion and pelletizing methods. The main factors influencing the quality of the resulting product were analyzed, including the method of agglomeration, the composition of the mixture, as well as the type and dosage of the binder component. The strength characteristics of the finished agglomerated samples were evaluated in terms of resistance to splitting, impact loads and falling. Notably, the selected binders are organic and polymer substances capable of complete combustion under metallurgical smelting conditions. Full article

The secondary metabolites of the fungus Penicillium thymicola, fumiquinazolines F and G, have antibacterial and antifungal characteristics; however, their potential anti-tumor action against human cancer cells remains unknown. The goal of our study was to determine the biological efficacy of fumiquinazolines F and G on breast and prostate cancer cells. Cancer cell proliferation and migration were monitored in real time using xCELLigence technology and flow cytometry. Alterations in mRNA and protein expression were assessed by RT-qPCR, ELISA, and Western blotting. Our data indicate that fumiquinazolines F and G are more effective in inhibiting breast cancer cell proliferation than prostate cancer cells. Fumiquinazoline F is active against both hormone-dependent epithelial MCF-7 (IC₅₀ 48 μM) and hormone-resistant triple-negative mesenchymal MDA-MB-231 breast cancer cells (IC₅₀ 54.1 μM). The metabolite has low cytotoxicity but slows cell cycle progression. In fumiquinazoline F-treated MDA-MB-231 cells, the levels of proteins implicated in epithelial–mesenchymal transition (EMT) (such as E-cadherin, vimentin, and CD44) fluctuate, resulting in a decrease in cell migratory rate and adhesion to a hyaluronic acid-coated substrate. Thus, fumiquinazolines F and G exhibit anticancer activity by inhibiting EMT, cell proliferation, and migration, hence reverting malignant cells to a less pathogenic phenotype. The compound’s multi-target anticancer profile underscores its potential for further exploration of novel EMT-regulating pathways. Full article

This study examines the moral agency of French secondary school headteachers through the lens of the theory of conventions. Using qualitative data from interviews with fifteen headteachers involved in professional development, this study explores how these leaders justify their practices within a centralized, bureaucratic, and hierarchical education system. It identifies a variety of conventions—civic, domestic, industrial, project, market, inspired, and fame—that headteachers draw on to navigate institutional constraints, manage professional relationships, and foster pedagogical and organizational change. Particular attention is given to how civic and domestic conventions shape leadership discourse and practices, especially regarding trust building, decision making, and reform implementation. We also compare the French context with international examples from the International Successful School Principalship Project (ISSPP), focusing on Nordic countries, where leadership emphasizes democratic participation, professional trust, and shared responsibility. This study underscores the uniqueness of the French leadership model, which resists managerial and market logics while remaining rooted in republican and egalitarian ideals. It concludes by advocating for a more context-aware, ethically grounded, and dialogical approach to school leadership. Full article

The extensive use of pesticides has significant implications for public health and the environment. Breeding crop plants is the most effective and environmentally friendly approach to improve the plants’ resistance. However, it is time-consuming and costly, and it is sometimes difficult to achieve satisfactory results. Plants induce defense responses to natural elicitors by interpreting multiple genes that encode proteins, including enzymes, secondary metabolites, and pathogenesis-related (PR) proteins. These responses characterize systemic acquired resistance. Humic substances trigger positive local and systemic physiological responses through a complex network of hormone-like signaling pathways and can be used to induce biotic and abiotic stress resistance. This study aimed to assess the effect of humic substances on the activity of phenylalanine ammonia-lyase (PAL), peroxidase (POX), and β-1,3-glucanase (GLU) used as a resistance marker in various plant species, including orange, coffee, sugarcane, soybeans, maize, and tomato. Seedlings were treated with a dilute aqueous suspension of humic substances (4 mM C L⁻¹) as a foliar spray or left untreated (control). Leaf tissues were collected for enzyme assessment two days later. Humic substances significantly promoted the systemic acquired resistance marker activities compared to the control in all independent assays. Overall, all enzymes studied in this work, PAL, GLUC, and POX, showed an increase in activity by 133%, 181%, and 149%, respectively. Among the crops studied, citrus and coffee achieved the highest activity increase in all enzymes, except for POX in coffee, which showed a decrease of 29% compared to the control. GLUC exhibited the highest response to HS treatment, the enzyme most prominently involved in increasing enzymatic activity in all crops. Plants can improve their resistance to pathogens through the exogenous application of HSs as this promotes the activity of enzymes related to plant resistance. Finally, we consider the potential use of humic substances as a natural chemical priming agent to boost plant resistance in agriculture Full article

Early blight, caused by the pathogen Alternaria solani, is a major fungal disease impacting potato production globally, with reported yield losses of up to 40% in susceptible varieties. As one of the most common diseases affecting potatoes, its incidence has been steadily increasing year after year. This study aimed to elucidate the molecular mechanisms underlying resistance to early blight by comparing gene expression profiles in resistant (B1) and susceptible (D30) potato seedlings. Transcriptome sequencing was conducted at three time points post-infection (3, 7, and 10 dpi) to identify differentially expressed genes (DEGs). Weighted Gene Co-expression Network Analysis (WGCNA) and pathway enrichment analyses were performed to explore resistance-associated pathways and hub genes. Over 11,537 DEGs were identified, with the highest number observed at 10 dpi. Genes such as LOC102603761 and LOC102573998 were significantly differentially expressed across multiple comparisons. In the resistant B1 variety, upregulated genes were enriched in plant–pathogen interaction, MAPK signaling, hormonal signaling, and secondary metabolite biosynthesis pathways, particularly flavonoid biosynthesis, which likely contributes to biochemical defense against A. solani. WGCNA identified 24 distinct modules, with hub transcription factors (e.g., WRKY33, MYB, and NAC) as key regulators of resistance. These findings highlight critical molecular pathways and candidate genes involved in early blight resistance, providing a foundation for further functional studies and breeding strategies to enhance potato resilience. Full article

The southeastern Yunnan region in the southwestern Nanpanjiang Basin is one of the most important manganese enrichment zones in China. Manganese mineralization is mainly confined to marine mud–sand–carbonate interbeds of the Middle Triassic Ladinian Falang Formation (T₂f), which contains several medium to large deposits such as Dounan, Baixian, and Yanzijiao. However, the geological processes that control manganese mineralization in this region remain insufficiently understood. Understanding the tectonic evolution of the basin is therefore essential to unravel the mechanisms of Middle Triassic metallogenesis. This study investigates how rift-related tectonic activity influences manganese ore formation. This study integrates global gravity and magnetic field models (WGM2012, EMAG2v3), audio-frequency magnetotelluric (AMT) profiles, and regional geological data to investigate ore-controlling structures. A distinct gravity low–magnetic high belt is delineated along the basin axis, indicating lithospheric thinning and enhanced mantle-derived heat flow. Structural interpretation reveals a rift system with a checkerboard pattern formed by intersecting NE-trending major faults and NW-trending secondary faults. Four hydrothermal plume centers are identified at these fault intersections. AMT profiles show that manganese ore bodies correspond to stable low-resistivity zones, suggesting fluid-rich, hydrothermally altered horizons. These findings demonstrate a strong spatial coupling between hydrothermal activity and mineralization. This study provides the first identification of the internal rift architecture within the Nanpanjiang Basin. The basin-scale rift–graben system exerts first-order control on sedimentation and manganese metallogenesis, supporting a trinity model of tectonic control, hydrothermal fluid transport, and sedimentary enrichment. These insights not only improve our understanding of rift-related manganese formation in southeastern Yunnan but also offer a methodological framework applicable to similar rift basins worldwide. Full article

Deep coalbed methane (CBM) reservoirs are characterized by high hydrocarbon content and are considered an important strategic resource. Due to their inherently low permeability and porosity, horizontal well drilling is commonly employed to enhance production, with the length of the horizontal section playing a critical role in determining CBM output. However, during extended horizontal drilling, wellbore instability frequently occurs as a result of drilling fluid invasion into the coal formation, posing significant safety challenges. This instability is primarily caused by the physical intrusion of drilling fluids and their interactions with the coal seam, which alter the mechanical integrity of the formation. To address these challenges, interpenetrating and semi-interpenetrating network (IPN/s-IPN) hydrogels have gained attention due to their superior physicochemical properties. This material offers enhanced sealing and support performance across fracture widths ranging from micrometers to millimeters, making it especially suited for plugging applications in deep CBM reservoirs. A self-degradable interpenetrating double-network hydrogel particle plugging agent (SSG) was developed in this study, using polyacrylamide (PAM) as the primary network and an ionic polymer as the secondary network. The SSG demonstrated excellent thermal stability, remaining intact for at least 40 h in simulated formation water at 120 °C with a degradation rate as high as 90.8%, thereby minimizing potential damage to the reservoir. After thermal aging at 120 °C, the SSG maintained strong plugging performance and favorable viscoelastic properties. A drilling fluid containing 2% SSG achieved an invasion depth of only 2.85 cm in an 80–100 mesh sand bed. The linear viscoelastic region (LVR) ranged from 0.1% to 0.98%, and the elastic modulus reached 2100 Pa, indicating robust mechanical support and deformation resistance. Full article

The barbel chub (Squaliobarbus curriculus) exhibits remarkable resistance to grass carp reovirus (GCRV), a devastating pathogen in aquaculture. To reveal the molecular basis of this resistance, we investigated complement factor D (DF)—a rate-limiting serine protease governing alternative complement pathway activation. Molecular cloning revealed that the barbel chub DF (ScDF) gene encodes a 1251-bp cDNA sequence translating into a 250-amino acid protein. Crucially, bioinformatic characterization identified a unique N-glycosylation site at Asn¹³⁹ in ScDF, representing a structural divergence absent in grass carp (Ctenopharyngodon idella) DF (CiDF). While retaining a conserved Tryp_SPc domain harboring the catalytic triad (His⁶¹, Asp¹⁰⁹, and Ser²⁰⁴) and substrate-binding residues (Asp¹⁹⁸, Ser²¹⁹, and Gly²²¹), sequence and phylogenetic analyses confirmed ScDF’s evolutionary conservation, displaying 94.4% amino acid identity with CiDF and clustering within the Cyprinidae. Expression profiling revealed constitutive ScDF dominance in the liver, and secondary prominence was observed in the heart. Upon GCRV challenge in S. curriculus kidney (SCK) cells, ScDF transcription surged to a 438-fold increase versus uninfected controls at 6 h post-infection (hpi; p < 0.001)—significantly preceding the 168-hpi response peak documented for CiDF in grass carp. Functional validation showed that ScDF overexpression suppressed key viral capsid genes (VP2, VP5, and VP7) and upregulated the interferon regulator IRF9. Moreover, recombinant ScDF protein incubation induced interferon pathway genes and complement C3 expression. Collectively, ScDF’s rapid early induction (peaking at 6 hpi) and multi-pathway coordination may contribute to barbel chub’s GCRV resistance. These findings may provide molecular insights into the barbel chub’s high GCRV resistance compared to grass carp and novel perspectives for anti-GCRV breeding strategies in fish. Full article

This study applies Computational Fluid Dynamics (CFD) and mathematical modeling to examine uterine and umbilical arterial blood flow during pregnancy, providing a more detailed understanding of hemodynamic changes across gestation. Statistical analysis of Doppler ultrasound data from a large cohort of more than 200 pregnant women (in the second and third trimesters) reveals significant increases in the umbilical arterial peak systolic velocity ($PSV$) between the 22nd and 30th weeks, while uterine artery velocities remain relatively stable, suggesting adaptations in vascular resistance during pregnancy. By combining the Navier–Stokes equations with Doppler ultrasound-derived inlet velocity profiles, we quantify several key fluid dynamics parameters, including time-averaged wall shear stress ($TAWSS$), oscillatory shear index ($OSI$), relative residence time ($RRT$), Reynolds number ($Re$), and Dean number ($De$), evaluating laminar flow stability in the uterine artery and secondary flow patterns in the umbilical artery. Since blood exhibits shear-dependent viscosity and complex rheological behavior, modeling it as a non-Newtonian fluid is essential to accurately capture pulsatile flow dynamics and wall shear stresses in these vessels. Unlike conventional imaging techniques, CFD offers enhanced visualization of blood flow characteristics such as streamlines, velocity distributions, and instantaneous particle motion, providing insights that are not easily captured by Doppler ultrasound alone. Specifically, CFD reveals secondary flow patterns in the umbilical artery, which interact with the primary flow, a phenomenon that is challenging to observe with ultrasound. These findings refine existing hemodynamic models, provide population-specific reference values for clinical assessments, and improve our understanding of the relationship between umbilical arterial flow dynamics and fetal growth restriction, with important implications for maternal and fetal health monitoring. Full article

To investigate temporal deformation mechanisms of hydraulic asphalt concrete slope flow under evolving temperatures, this study developed a novel temperature-controlled slope flow intelligent test apparatus. Using this apparatus, slope flow tests were conducted at four temperature levels: 20 °C, 35 °C, 50 °C, and 70 °C. By applying nonlinear dynamics theory, the temporal evolution of slope flow deformation and its nonlinear mechanical characteristics under varying temperatures were thoroughly analyzed. Results indicate that the thermal stability of hydraulic asphalt concrete is synergistically governed by the phase-transition behavior between asphalt binder and aggregates. Temporal evolution of slope flow exhibits a distinct three-stage pattern as follows: rapid growth (0~12 h), where sharp temperature rise disrupts the primary skeleton of coarse aggregates; decelerated growth (12~24 h), where an embryonic secondary skeleton forms and progressively resists deformation; stabilization (>24 h), where reorganization of coarse aggregates is completed, establishing structural equilibrium. The thermal stability temperature influence factor (δ) shows a nonlinear concave growth trend with increasing test temperature. Dynamically, this process transitions sequentially through critical stability, nonlinear stability, period-doubling oscillatory stability, and unsteady states. Full article