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Coupled osteogenesis and angiogenesis on 3D-printed highly porous PCL/magnesium/laponite nanocomposite scaffold
Detection of risk levels in optical mark recognition exams using categorical feature-based machine learning models
The solute-binding proteins DppA1–5 of Pseudomonas aeruginosa have distinct substrate profiles
Abstract Pseudomonas aeruginosa is an opportunistic pathogen with high antibiotic resistance that infects immunocompromised patients. Its survival in diverse environments relies on nutrient uptake systems such as the dipeptide permease (Dpp), an ATP-binding cassette transporter that imports di- and tripeptides. Unlike other bacteria, whose Dpp includes a single solute-binding protein that binds substrates in the periplasm, P. aeruginosa encodes five paralogs (DppA1–5), the functional significance of which remains unclear. Here, we systematically profile the ligand specificities of all five DppA proteins using Differential Scanning Fluorimetry with a library of 281 di- and tripeptides. We find that DppA1 and DppA3 preferentially bind dipeptides, whereas DppA2 and DppA4 favor tripeptides. DppA5 shows no detectable binding, suggesting a divergent function. Ligand binding is highly structure-sensitive and distinct across DppA paralogs. A comparative reanalysis of published nutrient utilization data for dppA1–5 suggests that previous studies underestimated this functional specialization. In contrast, our findings indicate that P. aeruginosa encodes multiple DppA paralogs to expand Dpp substrate scope and enhance nutrient acquisition. This work provides a foundation for further exploration of the Dpp in bacterial signaling and its exploitation for drug delivery via Trojan Horse antimicrobials.
Awareness, attitude and practice of Indian population regarding probiotic foods in everyday life
Sox11 overexpression restores embryonic pro-growth transcription in mature corticospinal tract neurons
Research on ground pressure control modes in a subsea mine by physical model test and numerical simulation analysis
Differences of respiratory tract flora and metabonomic characteristics of lung lavage fluid in pneumoconiosis model rats
Validated Erythrosin B spectrofluorimetric method for ganciclovir bioanalysis in rabbit plasma following valganciclovir bioconversion and Pharmacokinetic application
Abstract A novel, environmentally sustainable spectrofluorimetric method was developed and validated for sensitive determination of ganciclovir in rabbit plasma following valganciclovir administration. The method is based on fluorescence quenching of Erythrosin B probe through static complex formation with ganciclovir, as confirmed by comprehensive spectroscopic characterization using UV-visible absorption and fluorescence spectroscopy. Furthermore, temperature-dependent Stern-Volmer analysis revealed static quenching mechanism with Stern-Volmer constants decreasing from 3.77 × 10 5 to 2.79 × 10 5 M − 1 upon temperature increase from 298 to 313 K. Moreover, thermodynamic studies demonstrated spontaneous, exothermic interactions with negative Gibbs free energy and enthalpy changes, while positive entropy indicated favorable complex formation. Additionally, Job’s method confirmed 1:1 stoichiometry, while semiempirical PM3 quantum mechanical calculations identified halogen bonding and electrostatic interactions as primary binding mechanisms. Experimental conditions were systematically optimized to achieve maximum quenching efficiency at pH 5.0 with 10 µg/mL Erythrosin B concentration and 5-minute reaction time. The method demonstrated excellent analytical performance with good linearity (r 2 = 0.9991) over 0.05–3.0 µg/mL range and adequate sensitivity for therapeutic monitoring applications. Furthermore, comprehensive validation according to ICH M10 guidelines confirmed method reliability with accuracy ranging from 96.04% to 104.76% and precision below 4.61% RSD across all quality control levels. Subsequently, successful pharmacokinetic application in New Zealand white rabbits provided key parameters including C max of 4.25 µg/mL, half-life of 2.94 h, and AUC ₀₋∞ of 21.6 µg·h/mL, consistent with published clinical data. Finally, environmental sustainability assessment using four complementary evaluation tools confirmed favorable green analytical chemistry and analytical practicality traits with scores of 0.71, 76%, 70.0, and 65% for AGREE, MoGAPI, BAGI, and CACI, respectively. In conclusion, the developed spectrofluorimetric method offers significant advantages including cost-effectiveness, minimal waste generation, and elimination of derivatization steps, positioning it as an attractive alternative to conventional methods.
Social familiarity shapes collective decision-making in response to looming stimuli in Medaka fish
Abstract Social familiarity within groups promotes behavioural synchrony and facilitates information transfer. Whether it shapes collective decision-making under predator threat is unknown. Here groups of six medaka ( Oryzias latipes ) familiarised for one month were used to test whether familiarisation promotes instantaneous collective decision-making in response to a looming stimulus (LS) mimicking a predator attack. First, we analysed behavioural transitions, defined as changes among three behavioural states: high-speed, normal and freezing-like before, during, and after LS in groups of six individuals. Individuals showing high-speed state in response to LS typically tended to shift to freezing-like state afterwards, whereas non-responders were more likely to maintain normal state. Group-level analysis revealed a bimodal distribution in the number of individuals exhibiting freezing-like state, with peaks at zero and six individuals, corresponding to ‘all non-freezing’ and ‘all-freezing’. Clustering analysis further identified three consistent group profiles: ‘freezing-dominant’, ‘non-freezing-dominant’, and ‘mixed-type’ based on behavioural tendencies across 10 trials. In contrast, in unfamiliar groups assembled immediately before testing, the ‘freezing-dominant’ profile was absent, and the distribution in the number of individuals exhibiting freezing-like state shifted to unimodal. In these groups, even at the individual level, responses more often showed a transition from high-speed state to normal state rather than freezing-like state. The results indicate that social familiarity promotes synchronous freezing-like state and consensus decisions under looming threat. Our study presents a behavioural assay for predator-evoked collective decision-making in a genetic model fish, providing a framework for future efforts to link behavioural ethology with neuroscience.
In-silico studies, synthesis, and pharmacological screening of novel multitarget diphenylpyrazole scaffold as EGFR/BRAF and cyclooxygenase-2 inhibitors
Resilience assessment and spatiotemporal evolution analysis of water resources system in the provinces along the Yellow River
Deep learning-based model for analyzing student engagement in activities
Responding to climate change: assessing the current situation and influencing factors of forest carbon sinks in China
Nuclear eNOS Interacts With and <i>S</i> -Nitrosates ADAR1 to Modulate Type I Interferon Signaling and Endothelial Function
BACKGROUND: Nitric oxide (NO), generated by the endothelial NO synthase (eNOS), regulates vascular tone and endothelial homeostasis to counteract vascular inflammation. Most eNOS is localized at the cell membrane or in the Golgi apparatus, but the enzyme is also present in the endothelial cell nucleus. Here, we assessed the relevance of nuclear eNOS and NO signaling for endothelial cell function. METHODS: eNOS loss-of-function approaches were combined with confocal microscopy and biochemical, histological, and multiomics analyses. The pathophysiological relevance of the findings was assessed in murine models of atherogenesis (hypercholesterolemia and partial carotid ligation) as well as in samples from patients with atherosclerosis. RESULTS: eNOS was present in the nucleus of unstimulated human and murine endothelial cells (in vitro and ex vivo) and stimulation with VEGF (vascular endothelial growth factor) enhanced its nuclear localization. Coimmunoprecipitation studies coupled with proteomics revealed the association of nuclear eNOS with 81 proteins involved in RNA binding and processing. Among the latter was ADAR1 (double-stranded RNA-specific adenosine deaminase), an enzyme involved in editing double-stranded RNA via the deamination of A to I. ADAR1 was S -nitrosated in human endothelial cells, and the knockdown of eNOS resulted in altered ADAR1-mediated A-to-I editing and an increase in double-stranded RNA. The latter phenomenon elicited aggregation of MAVS (mitochondrial antiviral signaling protein), activation of the type I IFN (interferon) signaling pathway and a marked downregulation of cell cycle–related genes. ADAR1 depletion elicited similar effects on the activation of type I IFN signaling. As a result, growth factor–stimulated cell proliferation was abrogated, and basal as well as stimulated cell death were increased in endothelial cells lacking eNOS. Endothelial dysfunction in mice as well as in subjects with atherosclerosis was accompanied by accumulation of double-stranded RNA and activation of type I IFN signaling. Preserving NO bioavailability in vivo (Tyr657Phe eNOS mice) prevented these effects. CONCLUSIONS: Our findings uncovered a novel mechanism linking nuclear eNOS-derived NO with the activity of ADAR1 to maintain vascular homeostasis. Reduced NO bioavailability results in previously unrecognized activation of a type I IFN response in the endothelium, which contributes to atherogenesis.
Short-Term Anticoagulation Versus Dual Antiplatelet Therapy for Preventing Device Thrombosis Following Left Atrial Appendage Closure: The ANDES Randomized Clinical Trial
BACKGROUND: The optimal antithrombotic treatment after transcatheter left atrial appendage closure (LAAC) remains to be determined. The objective of this trial was to compare anticoagulation and antiplatelet therapy for preventing device-related thrombosis (DRT) after LAAC. METHODS: This was a prospective multicenter international randomized trial comparing 2 different antithrombotic strategies for preventing DRT after LAAC in patients with nonvalvular atrial fibrillation. Patients were randomized (1:1) to receive direct oral anticoagulants (DOACs) or dual antiplatelet therapy (DAPT; aspirin+clopidogrel) for 60 days. Patients underwent transesophageal echocardiography at 60 days, and the images were analyzed in a central echocardiography laboratory by experienced echocardiographers blinded to the allocated treatment. The primary outcome was DRT as determined by transesophageal echocardiography 60 days after LAAC in patients receiving the allocated treatment at the time of transesophageal echocardiography (per-protocol analysis). The safety outcome included all-cause mortality, stroke, bleeding, or site-reported DRT within 60 days after LAAC in all randomized patients (intention-to-treat analysis). RESULTS: A total of 510 patients (mean age 77±9 years, 35% women) were included between October 2018 and May 2025, and 253 and 257 patients were randomized to the DOAC and DAPT groups, respectively. Of these, 399 patients underwent transesophageal echocardiography and were receiving the allocated treatment at 60 days after LAAC. The primary outcome occurred in 3 patients (1.5%) in the DOAC group compared with 8 patients (4.1%) in the DAPT group (difference, −2.7% [95% CI, −6.0% to 0.6%]; P =0.110). The safety outcome occurred in 52 patients (22.5%) in the DOAC group compared with 82 patients (34.9%) in the DAPT group (difference, −12.4% [95% CI, −20.6% to −4.2%]; P =0.003), and differences were mainly driven by a lower rate of bleeding events in the DOAC group (44 patients [17.4%] versus 64 patients [24.9%]; difference, −7.5% [95% CI, −14.6% to −0.4%]; P =0.038). CONCLUSIONS: The use of DOACs after LAAC failed to reduce DRT compared with DAPT, but it was associated with an improved safety profile. The results of this study should be interpreted with caution because of statistical power issues related to the narrower-than-expected between-group differences and will need confirmation in future larger studies. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03568890.
Challenges of Clinical Trials in Cardio-Oncology: Navigating Surrogate Outcomes and Identifying Patients at Risk of Late Cardiovascular Complications
Coronary Artery Revascularization in the Older Adult Population: A Scientific Statement From the American Heart Association
The United States is facing a demographic shift as the population of older adults grows rapidly, with the proportion of Americans ≥65 years of age projected to double by 2060. This aging trend will have far-reaching effects on health care systems, especially because aging is a primary risk factor for cardiovascular disease. Age-related cardiovascular changes, such as increased arterial stiffness, endothelial dysfunction, and reduced elasticity, increase the risk for hypertension, atherosclerosis, and other risk factors. Older adults often experience additional complications, including obesity, diabetes, and metabolic diseases, further increasing their cardiovascular risk. Every year, >720 000 Americans experience myocardial infarction or coronary artery disease–related deaths, with older adults disproportionately affected. Individuals ≥75 years of age account for 30% to 40% of all acute coronary syndrome hospitalizations, often presenting with complex coronary disease and associated geriatric syndromes, such as frailty, cognitive impairment, and multimorbidity, complicating revascularization strategies. American College of Cardiology/American Heart Association guidelines for coronary revascularization primarily focus on younger populations, leaving substantial gaps for older adults with geriatric complexities. This scientific statement highlights the need for individualized approaches that consider geriatric syndromes, patient preferences, cognitive function, and life expectancy. This scientific statement outlines key aims: to review age-related cardiovascular changes and geriatric syndromes, provide pragmatic revascularization strategies, and advocate for shared decision-making. Addressing these knowledge gaps is essential for optimizing cardiovascular care for older adults, ensuring that treatment aligns with patient goals and accounts for the unique risks they face.
Sacubitril-Valsartan for the Prevention of Anthracycline Cardiotoxicity in Patients With Elevated Cardiac Troponin I Concentration During Chemotherapy: A Double-Blind Randomized Placebo-Controlled Clinical Trial: The SARAH Trial
BACKGROUND: The clinical effects of sacubitril-valsartan, an angiotensin receptor-neprilysin inhibitor, on anthracycline-induced cardiotoxicity remain unknown. Experimental evidence suggests cardioprotective properties. This study evaluated the efficacy of sacubitril-valsartan in reducing cardiotoxicity in patients with increased cardiac troponin I concentrations during anthracycline chemotherapy. METHODS: This randomized, double-blind, placebo-controlled trial enrolled 114 patients with elevated cardiac troponin I levels during anthracycline treatment. Participants were randomized 1:1 to receive either sacubitril-valsartan or placebo for 6 months, with a target dose of 97/103 mg twice daily. The primary end point was the occurrence of a >15% reduction in the global longitudinal strain from baseline to 6 months. Secondary end points included changes in biomarkers, echocardiographic and cardiac magnetic resonance parameters, and adverse events. This trial was initially conceptualized as a pilot investigation because of its exploratory nature. Data were analyzed according to the intention-to-treat principle. RESULTS: Among the randomized patients, 90% were women, and 80.7% had breast cancer. The primary end point occurred in 4 patients (7%) in the sacubitril-valsartan group and 14 patients (25%) in the placebo group (odds ratio, 0.23 [95% CI, 0.07–0.75]; P= 0.015). The sacubitril-valsartan group showed a 2.5% improvement in global longitudinal strain, whereas the placebo group experienced a 7.6% decline ( P <0.001). No significant differences in changes in cardiac troponin I or NT-proBNP (N-terminal pro-B-type natriuretic peptide) were observed. Hypotension (systolic blood pressure <100 mm Hg) occurred more frequently in the sacubitril-valsartan group than in the placebo group (8 cases versus 1 case; P =0.032). CONCLUSIONS: The SARAH trial (Sacubitril-Valsartan for the Prevention of Anthracycline Cardiotoxicity in Patients With Elevated hs-cTnI Concentrations During Chemotherapy) demonstrated the potential of sacubitril-valsartan therapy to reduce the incidence of left ventricular dysfunction, as assessed by global longitudinal strain, in patients with elevated high-sensitivity cardiac troponin I after anthracycline treatment. REGISTRATION: URL: https://ensaiosclinicos.gov.br/rg/RBR-5q4gm5b ; UTN code: U1111-1274-1961.