Search Results (1,635)

Background/Objectives: Real-world evidence shows alarmingly suboptimal utilization of guideline directed medical therapy (GDMT) in heart failure with reduced ejection fraction (HFrEF). One of the barriers of GDMT implementation appears to be concerns about the potential development of drug-related adverse events (AEs), particularly in high-risk patients. This study aimed to evaluate whether advanced HFrEF (AHF) patients can be up-titrated safely and whether AHF predisposes individuals to the occurrence of putatively drug-related AEs. Methods: A total of 373 HFrEF patients with documented baseline, 2 months, and 12 months visits were analyzed for utilization and target dosages (TDs) of HF drugs. Successful up-titration and AEs were evaluated for different stages of HF reflected by N-terminal pro-B type natriuretic peptide (NT-proBNP) (<1000 pg/mL, 1000–2000 pg/mL, >2000 pg/mL). Results: A stepwise increase in HF medications was observed for all drug classes during follow-up. At 12 months, 73%, 75%, 62%, 86%, and 45% of patients received ≥90% of TDs of beta-blockers (BBs), renin–angiotensin system inhibitors (RASis), mineralocorticoid receptor antagonists (MRAs), sodium–glucose cotransporter-2 inhibitors (SGLT2 i), and triple-therapy, respectively. Predictors of successful up-titration in logistic regression were baseline HF drug TDs, estimated glomerular filtration rate (eGFR), and potassium, but not NT-proBNP or age. The development of AEs was rare, with hyperkalemia as the most common event (34% at 12 months). AEs were comparable in all stages of HF. However, the development of hyperkalemia was more frequent in patients with higher NT-proBNP and also accounted for most cases of incomplete up-titration. Conclusions: This study suggests that with dedicated protocols and frequent visits, GDMT can be successfully implemented across all stages of HFrEF, including patients with AHF. Full article

A hetero-disubstituted sugarcane bagasse (HDSB) was prepared by simultaneous one-pot chemical modification of sugarcane bagasse with succinic and phthalic anhydrides. HDSB was used in batch mode for the removal of the cationic dyes auramine-O (AO) and safranin-T (ST) from spiked aqueous solutions. Adsorption of the dyes in mono- and bicomponent systems was investigated as a function of HDSB dosage, pH, contact time, and initial dye concentration. Maximum adsorption capacities for AO and ST on HDSB, at pH 7.0, were 1.37 mmol g⁻¹ (367.7 mg g⁻¹) and 0.93 mmol g⁻¹ (293.3 mg g⁻¹), respectively. In the bicomponent system, ST was preferentially adsorbed on HDSB, revealing an antagonistic effect of ST on AO adsorption. Changes in the enthalpy of the adsorption as a function of HDSB surface coverage were determined by isothermal titration calorimetry, with Δ_adsH° values for AO and ST equal to −22.1 ± 0.3 kJ mol⁻¹ and −23.44 ± 0.01 kJ mol⁻¹, respectively. Under standard conditions, the adsorption of the dyes on HDSB was exergonic and enthalpically driven. Desorption removed ~50% of the adsorbed dyes, and subsequent re-adsorption showed that HDSB could be reused, with non-desorbed dye molecules acting as new binding sites. The interaction between AO and ST with HDSB was elucidated by molecular dynamics simulations with atomistic modeling. Full article

Botulinum neurotoxins (BoNTs) are known to inhibit synaptic transmission by targeting SNARE proteins, but their selectivity toward central excitatory and inhibitory pathways is not yet fully understood. In this study, the interaction of serotypes A (BoNT/A) and B (BoNT/B) with the glutamatergic and GABAergic systems has been investigated using a pharmacological approach in an animal model of inflammatory pain, i.e., the formalin test in mice. BoNTs were administered intracerebroventricularly, three days before testing, followed 15 min before testing by systemic administration of sub-analgesic doses of MK801, an NMDA receptor antagonist, or muscimol, a GABA_A receptor agonist. BoNT/A reduced the second phase of the formalin test without affecting both the first phase and the interphase, suggesting a selective action on excitatory glutamatergic circuits while sparing GABAergic inhibition. Co-administration of MK801 with BoNT/A did not enhance analgesia, and muscimol did not further reduce interphase, confirming preserved GABAergic transmission. In contrast, BoNT/B abolished the interphase, consistent with impaired GABA release. Co-administration of MK801 or muscimol with BoNT/B restored the interphase, indicating compensatory rebalancing of excitatory-inhibitory networks. These results demonstrate that BoNT/A and BoNT/B exert distinct effects on central neurotransmission and support the hypothesis that BoNT/A preferentially targets excitatory synapses, while BoNT/B targets inhibitory synapses. This work contributes to a deeper understanding of anti-inflammatory mechanisms of BoNTs and their selective interaction with central pain pathways. Full article

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by venous and arterial thrombosis and obstetric complications, driven by antiphospholipid antibodies (APLAs). This review synthesizes the latest advancements and current understanding, diagnosis, and treatment of APS. APLAs, including lupus anticoagulant (LAC), anticardiolipin (aCL), and anti-β2-glycoprotein I (aβ2-GPI), interfere with coagulation and endothelial function, as well as with placental health. APS can be primary or secondary; it is often associated with systemic autoimmune diseases like lupus. The pathogenesis of APS remains only partially understood. APLAs promote thrombosis through endothelial damage, platelet activation, and inflammatory signaling pathways. Laboratory diagnosis relies on persistent positivity for APLAs and LAC through tests like ELISA and clotting assays, following a three-step confirmation process. New integrated test systems have been introduced to improve standardization. Classification criteria have evolved, with the 2023 EULAR-ACR criteria providing a weighted, domain-based scoring system, enhancing diagnostic precision. Catastrophic APS (CAPS) is a severe, rare manifestation of APS, characterized by multi-organ failure due to rapid, widespread microthrombosis and systemic inflammation, which requires urgent anticoagulation. Seronegative APS is proposed for patients with clinical features of APS but negative standard antibody tests, possibly due to non-criteria antibodies or transient immunosuppression. Treatment primarily involves long-term anticoagulation with vitamin K antagonists; direct oral anticoagulants are generally not recommended. APS diagnosis and management remain complex due to clinical heterogeneity and laboratory challenges. Continued refinement of diagnostic tools and criteria is essential for improving outcomes in this life-threatening condition. Full article

The worldwide agriculture industry is facing increasing problems due to rapid population increase and increasingly unfavorable weather patterns. In order to reach the projected food production targets, which are essential for guaranteeing global food security, innovative and sustainable agricultural methods must be adopted. Conventional approaches, including traditional breeding procedures, often cannot handle the complex and simultaneous effects of biotic pressures such as pest infestations, disease attacks, and nutritional imbalances, as well as abiotic stresses including heat, salt, drought, and heavy metal toxicity. Applying phytohormonal approaches, particularly those involving hormonal crosstalk, presents a viable way to increase crop resilience in this context. Abscisic acid (ABA), gibberellins (GAs), auxin, cytokinins, salicylic acid (SA), jasmonic acid (JA), ethylene, and GA are among the plant hormones that control plant stress responses. In order to precisely respond to a range of environmental stimuli, these hormones allow plants to control gene expression, signal transduction, and physiological adaptation through intricate networks of antagonistic and constructive interactions. This review focuses on how the principal hormonal signaling pathways (in particular, ABA-ET, ABA-JA, JA-SA, and ABA-auxin) intricately interact and how they affect the plant stress response. For example, ABA-driven drought tolerance controls immunological responses and stomatal behavior through antagonistic interactions with ET and SA, while using SnRK2 kinases to activate genes that react to stress. Similarly, the transcription factor MYC2 is an essential node in ABA–JA crosstalk and mediates the integration of defense and drought signals. Plants’ complex hormonal crosstalk networks are an example of a precisely calibrated regulatory system that strikes a balance between growth and abiotic stress adaptation. ABA, JA, SA, ethylene, auxin, cytokinin, GA, and BR are examples of central nodes that interact dynamically and context-specifically to modify signal transduction, rewire gene expression, and change physiological outcomes. To engineer stress-resilient crops in the face of shifting environmental challenges, a systems-level view of these pathways is provided by a combination of enrichment analyses and STRING-based interaction mapping. These hormonal interactions are directly related to the United Nations Sustainable Development Goals (SDGs), particularly SDGs 2 (Zero Hunger), 12 (Responsible Consumption and Production), and 13 (Climate Action). This review emphasizes the potential of biotechnologies to use hormone signaling to improve agricultural performance and sustainability by uncovering the molecular foundations of hormonal crosstalk. Increasing our understanding of these pathways presents a strategic opportunity to increase crop resilience, reduce environmental degradation, and secure food systems in the face of increasing climate unpredictability. Full article

The serotonergic system, originating in the raphe nuclei, differentially modulates the dorsal and ventral hippocampus, which are implicated in cognition and emotion, respectively. Emerging evidence from rodent models (e.g., neonatal ventral hippocampal lesion, pharmacological NMDA receptor antagonist exposure) and human postmortem studies indicates dorsoventral serotonergic alterations in schizophrenia. These data include elevated 5-HT1A receptor expression in the dorsal hippocampus, linking serotonergic hypofunction to cognitive deficits, and hyperactive 5-HT2A/3 receptor signaling and denser serotonergic innervation in the ventral hippocampus driving local hyperexcitability associated with psychosis and stress responsivity. These dorsoventral serotonergic alterations are shown to disrupt the excitation–inhibition balance, impair synaptic plasticity, and disturb network oscillations, as established by in vivo electrophysiology and functional imaging. Synthesizing these multi-level findings, we propose a novel “dorsoventral serotonin imbalance” model of schizophrenia, in which ventral hyperactivation predominantly contributes to psychotic symptoms and dorsal hypoactivity underlies cognitive deficits. We further highlight promising preclinical evidence that selective targeting of region- and receptor-specific targeting, using both pharmacological agents and emerging delivery technologies, may offer novel therapeutic opportunities enabling symptom-specific strategies in schizophrenia. Full article

Adenosine receptors (ARs) are G protein-coupled receptors that are widely expressed across tissues, traditionally associated with cardiovascular, neurological, and immune regulation. Recent studies, however, have highlighted their non-canonical functions, revealing critical roles in metabolism, immunometabolism, and epigenetic regulation. AR subtypes, particularly A2A and A2B, modulate glucose and lipid metabolism, mitochondrial activity, and energy homeostasis. In immune cells, AR signaling influences metabolic reprogramming and polarization through key regulators such as mTOR, AMPK, and HIF-1α, contributing to immune tolerance or activation depending on the context. Additionally, ARs have been implicated in epigenetic modulation, affecting DNA methylation, histone acetylation, and non-coding RNA expression via metabolite-sensitive mechanisms. Therapeutically, AR-targeting agents are being explored for cancer and chronic inflammatory diseases. While clinical trials with A2A antagonists in oncology show encouraging results, challenges remain due to receptor redundancy, systemic effects, and the need for tissue-specific selectivity. Future strategies involve biased agonism, allosteric modulators, and combination therapies guided by biomarker-based patient stratification. Overall, ARs are emerging as integrative hubs connecting extracellular signals with cellular metabolic and epigenetic machinery. Understanding these non-canonical roles may unlock novel therapeutic opportunities across diverse disease landscapes. Full article

Background: The endogenous opioid system plays a pivotal role in numerous physiological processes and is implicated in a range of diseases, including atherosclerosis, a condition contributing to nearly 50% of deaths in Western societies. Objectives: This study investigates the effects of opioid receptor blockade, using naloxone, on the plasma lipid profile and atherosclerosis progression. Methods: ApoE^−/− mice with advanced atherosclerosis were treated with naloxone for seven days, and the effects on atherosclerotic plaque development and liver steatosis were evaluated. Results: A proteomic analysis of liver samples post-treatment identified 38 proteins with altered abundance. The results revealed that naloxone treatment led to an increase in HDL cholesterol, a lipid fraction associated with protective cardiovascular effects. Furthermore, naloxone did not influence the progression of atherosclerotic plaques or the development of liver steatosis. Conclusions: In conclusion, while short-term naloxone treatment in mice with advanced atherosclerosis does not alter overall atherosclerotic plaque progression or liver steatosis, the observed elevation in HDL cholesterol and the extensive changes in liver protein abundance underscore the complex and multifaceted role of the opioid system in lipid metabolism and cardiovascular health. These findings provide a foundation for further exploration of opioid receptor antagonists as modulators of lipid profiles and potential contributors to cardiovascular therapy. Full article

Petroleum oily sludge (OLS), a hazardous by-product of the petroleum industry, and high-alkali lignite (HAL), an underutilized low-rank coal, pose significant challenges to sustainable waste management and resource efficiency. This study systematically investigated the combustion behavior, reaction pathways, and gaseous-pollutant-release mechanisms across varying blend ratios, utilizing integrated thermogravimetric-mass spectrometry analysis (TG-MS), interaction analysis, and kinetic modeling. The key findings reveal that co-combustion significantly enhances the combustion performance compared to individual fuels. This is evidenced by reduced ignition and burnout temperatures, as well as an improved comprehensive combustion index. Notably, an interaction analysis revealed coexisting synergistic and antagonistic effects, with the synergistic effect peaking at a blending ratio of 50% OLS due to the complementary properties of the fuels. The activation energy was found to be at its minimum value of 32.5 kJ/mol at this ratio, indicating lower reaction barriers. Regarding gas emissions, co-combustion at a 50% OLS blending ratio reduces incomplete combustion products while increasing CO₂, indicating a more complete reaction. Crucially, sulfur-containing pollutants (SO₂, H₂S) are suppressed, whereas nitrogen-containing emissions (NH₃, NO₂) increase but remain controllable. This study provides novel insights into the synergistic mechanisms between OLS and HAL during co-combustion, offering foundational insights for the optimization of OLS-HAL combustion systems toward efficient energy recovery and sustainable industrial waste management. Full article

Protecting the soil ecosystem’s functioning is one of the main goals of recent regulations of chemicals. It is important to take soil biodiversity into account when designing cropping systems and measuring their impacts. Our main objective was to evaluate the effects of an organic amendment on soil nematode biodiversity compared to two years of fumigation. The plot-trial was conducted on tomato and lettuce plants under greenhouse, and free-living nematodes were used as bio-indicators of soil health. Treatments included a soil fumigant (applied once or twice over time), water control, and an organic substance. Soil samplings were carried out to determine the Meloidogyne incognita reproduction factor and the soil nematode community analysis using soil biological indicators. Data showed that soil fumigation clearly made the soil increasingly dependent on chemicals. Furthermore, fumigants suppressed pests and pathogens as well as their natural antagonists, causing a lack of biodiversity. While soils treated with organic matter respond slowly to stressors, they are progressively more suppressive thanks to biodiversity enrichment. Nematodes have proven to be useful indicators of the soil biota in response to biotic or abiotic disturbances. Their species richness and functional diversity make them valid bioindicators of soil management impact. Full article

The floral transition in Chinese cabbage (Brassica rapa ssp. pekinensis) is governed by a complex interplay of gene expression and hormonal regulation. Temporal transcriptome profiling was conducted across three developmental stages: pre-bolting (PBS), bolting (BS), and flowering stages (FS), to investigate the underlying molecular mechanisms. A total of 7092 differentially expressed genes (DEGs) were identified, exhibiting distinct expression trajectories during the transition. Moreover, functional enrichment analyses revealed strong associations with plant hormone signaling, MAPK pathways, and developmental regulation processes. Key flowering-related genes, such as BrFLM, BrAP2, BrFD, BrFT, and BrSOC1s displayed antagonistic expression patterns. Hormonal pathways involving auxin, ABA, ET, BR, GA, JA, CK, and SA showed stage-dependent modulation. Further, orphan genes (OGs), especially EARLY FLOWERING 1 (EF1), showed significant upregulation during the transition, which exhibited 1.84-fold and 1.93-fold increases at BS and FS compared to PBS, respectively (p < 0.05). Functional validation through EF1 overexpression (EF1OE) in Arabidopsis consistently promoted early flowering. The expression levels of AtFT and AtSOC1 were significantly upregulated in EF1OE lines compared to wild-type (WT) plants. The findings contribute to understanding the coordinated genetic and hormonal events driving floral development in Chinese cabbage, suggesting EF1 as a candidate for bolting resistance breeding. This work also expands the existing regulatory framework through the successful integration of OGs into the complex floral induction system of Brassica crops. Full article

Hepatitis B virus (HBV) specifically infects hepatocytes and has a complex life cycle owing to the stabilization and pooling of covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes. We previously reported that the suppression of dedicator of cytokinesis 11 (DOCK11) decreases cccDNA and HBV-DNA levels and identified it as a new HBV therapeutic target. The DOCK11-associated gene, Wnt/β-catenin signaling regulator tankyrase (TNKS), was identified using in vitro methods; however, its function in the HBV life cycle remains unknown. Here, we used various inhibitors, antagonists, and short-hairpin RNA treatments related to TNKS signaling in HBV-infected hepatocytes. The role of TNKS-related Wnt/β-catenin signaling in the HBV life cycle was evaluated using immunoprecipitation assays with DOCK11 and bulk RNA sequencing methods. TNKS and Wnt/β-catenin signaling inhibitors significantly repressed cccDNA and HBV-DNA levels. Conversely, certain Wnt/β-catenin signaling agonists enhanced the HBV life cycle. DOCK11 directly binds to β-catenin to regulate HBV using its nuclear transport system. SKL2001, normally used as a Wnt/β-catenin signaling agonist, strongly reduced cccDNA in HBV-infected hepatocytes and in combination with entecavir predominantly eradicated HBV without cytotoxicity. Therefore, DOCK11 and other Wnt/β-catenin signaling molecules may be therapeutic targets to prevent persistent HBV infection. Full article

There is a present need to develop alternative biotherapeutic drugs to mitigate the exacerbated inflammatory immune responses characteristic of sepsis. The potent endotoxin lipopolysaccharide (LPS), a major component of Gram-negative bacterial outer membrane, activates the immune system via Toll-like receptor 4 (TLR4), triggering macrophages and a persistent cascade of inflammatory mediators. Our previous studies have demonstrated that Fh15, a recombinant member of the Fasciola hepatica fatty acid binding protein family, can significantly increase the survival rate by suppressing many inflammatory mediators induced by LPS in a septic shock mouse model. Although Fh15 has been proposed as a TLR4 antagonist, the specific mechanisms underlying its immunomodulatory effect remained unclear. In the present study, we employed a quantitative proteomics approach using tandem mass tag (TMT) followed by LC-MS/MS analysis to identify and quantify differentially expressed proteins that participate in signaling pathways downstream TLR4 of macrophages, which can be dysregulated by Fh15. Data are available via ProteomeXchange with identifier PXD065520. Based on significant fold change (FC) cut-off of 1.5 and p-value ≤ 0.05 criteria, we focused our attention to 114 proteins that were upregulated by LPS and downregulated by Fh15. From these proteins, TNFα, IL-1α, Lck, NOS2, SOD2 and CD36 were selected for validation by Western blot on murine bone marrow-derived macrophages due to their relevant roles in the NF-κB, iNOS, oxidative stress, and phagosome signaling pathways, which are closely associated with sepsis pathogenesis. These results suggest that Fh15 exerts a broad spectrum of action by simultaneously targeting multiple downstream pathways activated by TLR4, thereby modulating various aspects of the inflammatory responses during sepsis. Full article

In this study, a novel shape memory alloy actuated bearing active preload system (SMA-BAPS) was proposed and experimentally demonstrated. SMA actuators placed in a single or antagonistic configuration were employed to drive the screw pair and thus fulfill one-way or bidirectional preload adjustment. Moreover, the self-locking screw pair was used to maintain the bearing preload without external energy input. To determine the parameters of screw pair and SMA actuators, a detailed design process was conducted based on analytical models of the proposed system. Finally, a screw pair with a lead of 3 mm and SMA actuators with a diameter of 0.5 mm and a length of 130 mm were adopted. Prototype tests were conducted to validate and evaluate the performance of the preload adjustment with the SMA-BAPS. The resistive torque and the natural frequency of spindles were recorded to represent the preload level of the bearing. Through the performance tests, the SMA-BAPS induced a maximum 47% variation in the resistive torque and a 20% variation in the spindle’s natural frequency. The response time of the SMA-BAPS was less than 5 s when the heating current of 5 A was applied on the SMA actuator. This design highlighted the compact size, quick response, as well as the bidirectional preload adjustment, representing its potential use in aerospace mechanisms and advanced motors. Full article

Background/Objectives: The overuse of short-acting β₂-agonists (SABAs) has been associated with increased asthma morbidity and mortality, prompting changes in treatment guidelines. However, the role of frequent short-acting muscarinic antagonists (SAMAs) use remains poorly defined and unaddressed in current recommendations. This study offers the first real-world analysis of SAMA overuse in asthma, quantifying its association with exacerbation risk and healthcare utilization and comparing its predictive value to that of SABAs. Methods: A retrospective multicenter cohort study analyzed electronic health records (EHRs) from 132 adults with asthma in the Spanish National Health System (SNS). Associations between annual SAMA use and clinical outcomes were assessed using negative binomial regression and 5000-sample bootstrap simulations. Interaction and threshold models were applied to explore how SAMA use affected outcomes and identify clinically actionable cutoffs. Results: SAMA use was independently associated with a 19.2% increase in exacerbation frequency per canister and a nearly sixfold increase in the odds of experiencing ≥1 exacerbation (OR = 5.97; 95% CI: 2.43–14.66). An inflection point at 2.5 canisters/year marked the threshold beyond which annual exacerbations exceeded one. Increased SAMA use was also associated with a higher number of respiratory consultations and with more frequent prescriptions of systemic corticosteroids and antibiotics. The risk increased more sharply with SAMAs than with SABAs, and the lack of correlation between them suggests distinct clinical patterns underlying their use. Conclusions: SAMA use emerges as a digitally traceable and clinically meaningful indicator of asthma instability. While the associations observed are robust and consistent across multiple outcomes, they should be considered provisional due to the study’s retrospective design and limited sample size. Replication in larger and more diverse cohorts is needed to confirm external validity. These findings support the integration of SAMA tracking into asthma management tools—alongside SABAs—to enable the earlier identification of uncontrolled disease and guide therapeutic adjustment. Full article