Search Results (3,180)

An enantioselective Mannich reaction of 2-(2-nitrophenylsulfenylimino)acetamide is described. Under the optimized conditions using proline, triethylamine, and diarylthiourea additives, the initially formed Mannich adduct undergoes irreversible cyclization to afford cyclic hemiaminal products in 21–58% yield, with diastereomeric ratios ranging from 53:47 to 83:17. Enantioselectivity reaches up to 97% ee. The presence of N–H functionality of the substrate is crucial for this cyclization; in its absence, the Mannich adduct undergoes facile decomposition. Subsequent reduction in this intermediate efficiently furnished the corresponding homoserine derivative. Full article

G-quadruplex (G4) DNA structures have recently emerged as promising chiral scaffolds for enantioselective catalysis. This study investigates how thymidine loop modifications influence the catalytic performance of the telomeric G4 sequence HT21 in the asymmetric sulfoxidation of thioanisole. To this end, several singly or doubly modified HT21 derivatives were synthesized by using β-L-2′-deoxythymidine, 5-hydroxymethyl-2′-deoxyuridine, and 5-bromo-2′-deoxyuridine instead of a T residue, or β-L-2′-deoxyadonesine instead of an A residue, in specific positions within the TTA loops. The catalytic activity of these analogues was evaluated in the Cu(II)-mediated oxidation of thioanisole using hydrogen peroxide as oxidant. All modified sequences maintained complete substrate conversion, but their enantioselectivities varied markedly. Whereas the highest enantiomeric excess (84% ee) had previously been achieved with the HT21 analogue bearing a β-L-2′-deoxyadenosine in the first loop, the thymidine-based modifications, either alone or in combination, resulted in lower ee values, suggesting that loop alterations critically affect the chiral microenvironment, not all loop positions are functionally equivalent, and single substitutions within the same loop can result in different enantioselectivities. These findings highlight new insights on how individual loop residues contribute to asymmetric induction and offer further details for tuning G4-based catalytic scaffolds. Full article

The combination of supported lipid bilayers (SLBs) with the Quartz Crystal Microbalance with Dissipation monitoring (QCM-D) has been proven to be a powerful tool to simultaneously monitor mass and viscoelastic changes related to membrane binding-events. In this work, the above methodology is employed for the study of the interaction of the Early Endosomal Antigen 1 (EEA1) to a model lipid bilayer that mimics the early endosome (EE) membrane, focusing on the membrane composition. Starting with the formation of a lipid bilayer through the vesicles fusion technique, we investigated the formation of SLBs that incorporate phosphatidylinositol 3-phosphate (PI(3)P), a key component for EEA1 binding, in combination with other lipids, e.g., (1,2-dioleoyl-sn-glycero-3)-phosphocholine (DOPC), -phosphoserine (DOPS), -phosphoethanolamine (DOPE), and cholesterol (Chol). The interaction of the full-length coiled-coil EEA1 to the formed SLBs was further studied in real time with the QCM-D and characterized with respect to the lipid composition and pH. Our findings confirm that PI(3)P is essential for the EEA1–membrane interaction, while it was shown that Chol and phosphatidylserine greatly influence the binding event. In fact, including 30% Chol in a PI(3)P (3%):PS (6%) SLB resulted in almost double EEA1 binding than in the absence of Chol. Moreover, we employed the QCM-viscoelastic model available to analyze the QCM-D data with emphasis on the study of the protein conformation. Our results showed that, in our in vitro system, EEA1 is not fully extended and/or highly packed, but is mainly in a bent, distorted conformation with an average size close to 100 nm. This study complements previous works employing in vitro assays, also demonstrating the ability to reconstitute more complex biomimetic EE membranes containing inositol phospholipids on a QCM surface for the study of EEA1 binding. Full article

This study reports the fabrication of chitosan/carboxymethyl cellulose (C/M) nanocomposites by electrolyte gelation–spray drying and the evaluation of their antibacterial performance as carriers for the antibiotic ampicillin. Chitosan (C), a cationic biopolymer derived from chitin, was combined with the anionic polysaccharide carboxymethyl cellulose (M) at different mass ratios to form stable nanocomposites via electrostatic interactions and then collected in a spray dryer. The resulting particles exhibited mean diameters ranging from 800 to 1500 nm and zeta potentials varying from +90 to −40 mV, depending on the C/M ratio. The optimal formulation (C/M = 2:1 ratio) achieved a high recovery yield (71.1%), lower PDI (0.52), and ampicillin encapsulation efficiency EE (82.4%). Fourier transform infrared spectroscopy (FTIR) confirmed the presence of hydrogen bonding and ionic interactions among C/M, and ampicillin within the nanocomposite matrix. The nanocomposites demonstrated controlled ampicillin release and pronounced antibacterial activity against Staphylococcus aureus, with minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values of 3.2 µg/mL and 5.3 µg/mL, respectively, which were lower than those of free ampicillin. These results indicate that the chitosan/carboxymethyl cellulose nanocomposites are promising, eco-friendly carriers for antibiotic delivery and antibacterial applications. Full article

Background: Cleft palate (CP) is a prevalent craniofacial malformation, with the TGFβ pathway playing a critical role. Recent evidence links autophagy to regulating mouse embryonic palatal mesenchyme (MEPM) cells, but its interaction with TGFβ-activated phosphorylation cascades remains largely unknown. Here, we investigated the interplay between these pathways during palatogenesis. Methods: H&E and IHC analyses revealed increased expression of Beclin 1 and LC3 during the critical period of palatal shelf elevation and fusion (E13.5–E15.5). Bulk RNA sequencing (Bulk RNA-seq) further revealed enrichment of autophagy-related pathways and their interaction with TGFβ signaling. TMT-based phosphoproteomics was performed on TGFβ2-treated MEPM cells. Results: We identified 23,471 peptides and 3952 proteins, including 6339 phosphopeptides corresponding to 2195 phosphoproteins. Differential analysis found 477 phosphopeptides with increased abundance and 53 with decreased abundance, revealing the enrichment of seven serine (p-Ser) motifs (RxxS, SDxD, SDxE, SP, SxDE, SxEE, SxxxxD) and one threonine (p-Thr) motif (TP). Notably, kinase-substrate enrichment analysis identified CSNK2A as a previously unrecognized phosphorylation regulator, together with MAPKs and CDKs. Functional enrichment showed significant involvement of mTOR, MAPK, and autophagy/mitophagy pathways. Conclusions: Our findings revealed that TGFβ2 reshapes the MEPM phosphoproteome through Smad-independent pathway, expanding the palate-specific phospho-signaling atlas beyond the canonical Smad cascade. Full article

High-energy methods dominate the development of lipid nanoparticles but often require specialized equipment that increases production costs. Low-energy approaches, particularly those free of organic solvents, offer a promising alternative. This study aimed to obtain nanostructured lipid carriers (NLCs) using a solvent-free, low-energy process combining microemulsification and phase inversion. Cetearyl alcohol and PEG-40 hydrogenated castor oil were selected as the solid lipid and surfactant, respectively; the formulation and process were optimized through a Box–Behnken Design. Incorporation of the ionic surfactant extended colloidal stability, while the poloxamer in the aqueous phase enhanced steric stabilization. Resveratrol was efficiently encapsulated (E.E. = 98%), contributing to reduced particle size (291 nm), improved homogeneity (PDI = 0.25), and positive surface charge (+43 mV). Scale-up yielded stable particles carrying resveratrol with a mean size of 507 nm, PDI = 0.24, and ZP = +52 mV. The optimized formulation remained stable for 90 days at 8 °C. In vitro release demonstrated a sustained and controlled release profile, with significantly lower resveratrol release compared to the free compound. Thermal analysis confirmed drug incorporation within the lipid matrix, while transmission electron microscopy (TEM) revealed spherical particles (~200 nm) and SAXS indicated a nanostructure of ~50 nm. Overall, this study demonstrates that solvent-free, low-energy processing can produce stable and scalable NLC formulations, successfully encapsulating resveratrol with favorable physicochemical properties and controlled release behavior. These findings highlight a simple, cost-effective strategy for developing lipid-based nanocarriers with potential applications in drug delivery. Full article

Exudative epidermitis (EE), caused by Staphylococcus hyicus, represents an issue for swine production, particularly due to antimicrobial resistance. In this project, we isolated bacteriophages using S. hyicus as host and studied them as a potential alternative to antibiotic treatment in Quebec, Canada. Three phages, STAE-4, STAF-3, and STAM-1, were isolated from swine farm samples using a single S. hyicus strain (SC366) as the host. Transmission electron microscopy revealed that all three phages exhibited a siphovirus-like morphology, and RAPD-PCR profiling indicated that the phages were genetically distinct. Whole genome sequencing confirmed these differences and showed that the three phages were closely related to each other, and, more importantly, highly similar to phages previously described as infecting Staphylococcus chromogenes, a species closely related to S. hyicus. Host range analysis confirmed that the three phages preferentially infected the S. chromogenes strains included in the study, exhibiting minimal to no lytic activity against other strains of S. hyicus or Staphylococcus agnetis, another closely related species. The only exception was the host S. hyicus strain SC366, which was effectively infected by all three phages, albeit less efficiently than the most sensitive S. chromogenes strain (SC385). Adsorption tests further supported these observations, showing that phages bound to strain SC366 much more quickly than to SC385, despite the lower lytic activity observed. Taken together, these results highlight that while the phages retain some capacity to infect S. hyicus, their biological properties point to a stronger adaptation to S. chromogenes, indicating that they are not suitable candidates for controlling EE. Full article

Leukocyte-specific protein 1 (LSP1) is known as an endothelial gatekeeper because it controls endothelial permeability and transendothelial cell migration, including that of leukocytes and potentially metastatic cancer cells. In endothelial cells, LSP1 is predominantly in the nucleus under resting conditions but translocates to extranuclear compartments upon stimulation with TNF-α. The discrepancy between its predicted molecular weight (~37 kDa) and its observed migration on SDS-PAGE (≥52 kDa), along with its dynamic subcellular distribution, suggests a possible post-translational modification by SUMOylation. To investigate this, we examined endogenous LSP1 in murine primary endothelial cells and overexpressed recombinant LSP1 in murine endothelial (SVEC4-10EE2) and HEK293T cells. Our results demonstrate that LSP1 is SUMOylated by SUMO1, with Ubc9 serving as the conjugating enzyme and SENP1 as the deSUMOylating protease. Site-directed mutagenesis of lysines K270 and K318 abolished SUMOylation, resulting in a marked reduction in LSP1 steady-state levels. This reduction was attributed to enhanced ubiquitination and accelerated proteasomal degradation of LSP1 in the SUMOylation-deficient state. Furthermore, deSUMOylation impaired the TNF-α-induced translocation of LSP1 from the nucleus to extranuclear compartments, particularly the cytoskeleton. In summary, our findings establish that LSP1 is a SUMO1-modified protein. SUMOylation stabilizes LSP1 by preventing proteasomal degradation and is essential for its proper subcellular trafficking in endothelial cells in response to inflammatory stimuli. Full article

Background/Objectives: Under general anesthesia, maintaining patients’ blood pressure (BP) is important to prevent organ ischemia. When bleeding occurs, it is sometimes difficult to increase BP with boluses of fluids or transfusions, and vasoconstrictors must be administered. This study investigated circulatory dynamic changes in patients who bled during surgery and were administered phenylephrine, particularly left ventricular end-diastolic volume (EDV), effective arterial elastance (Ea), and left ventricular end-systolic elastance (Ees), calculating each value from the left ventricular–arterial coupling (Ees/Ea). Methods: We calculated Ees/Ea using electrocardiograms, arterial pressure waveforms, and phonocardiograms using an esophageal stethoscope. We investigated the changes in patients’ EDV, Ea, and Ees during two periods: phenylephrine administration and after BP elevation. Results: The seven participants comprised three men and four women. Between the two periods, linear mixed-model analysis revealed that mean arterial pressure (MAP), Ea, and Ees significantly increased over time (MAP; β = 8.7, p < 0.01, Ea; β = 0.22, p < 0.05, Ees; β = 0.73, p < 0.05), while no significant changes were observed in other parameters such as heart rate and EDV. Conventional parameters demonstrated that stroke volume variation significantly decreased (β = −2.0, p = 0.01), systemic vascular resistance index significantly increased (β = 200, p < 0.01), while no significant change was observed in cardiac index (β = −0.03, p = 0.7). In patients administered phenylephrine due to BP decrease from bleeding, significant changes in afterload and cardiac contractility occurred without changes in preload. Conclusions: Our noninvasive method for calculating EDV, Ea, and Ees can be valuable for monitoring hemodynamics under anesthesia. Full article

This paper presents an extended investigation into deep learning-based cryptanalysis of block ciphers by introducing and evaluating a multi-server attack environment. Building upon our prior work in centralized settings, we explore the practicality and scalability of deploying such attacks across multiple distributed edge servers. We assess the vulnerability of five representative block ciphers—DES, SDES, AES-128, SAES, and SPECK32/64—under two neural attack models: Encryption Emulation (EE) and Plaintext Recovery (PR), using both fully connected neural networks and Recurrent Neural Networks (RNNs) based on bidirectional Long Short-Term Memory (BiLSTM). Our experimental results show that the proposed federated learning-based cryptanalysis framework achieves performance nearly identical to that of centralized attacks, particularly for ciphers with low round complexity. Even as the number of edge servers increases to 32, the attack models maintain high accuracy in reduced-round settings. We validate our security assessments through formal statistical significance testing using two-tailed binomial tests with 99% confidence intervals. Additionally, our scalability analysis demonstrates that aggregation times remain negligible (<0.01% of total training time), confirming the computational efficiency of the federated framework. Overall, this work provides both a scalable cryptanalysis framework and valuable insights into the design of cryptographic algorithms that are resilient to distributed, deep learning-based threats. Full article

Background: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease and affects male patients more often than women. Prior studies, however, suggested that women are diagnosed later and at advanced stages of the disease, present with more pronounced symptoms, and experience worse outcomes. Objectives: To investigate sex-specific differences in clinical, laboratory, and comprehensive imaging characteristics in a contemporary cohort of HCM patients from a tertiary referral center in Austria. Methods: We retrospectively analyzed 321 HCM patients enrolled in a prospective registry (2018–2024). All patients underwent a comprehensive baseline evaluation, including medical history, laboratory assessment, transthoracic echocardiography, and cardiac magnetic resonance imaging. Results: At diagnosis, women were significantly older (62 vs. 53 years, p < 0.001) and presented with more advanced functional class (NYHA ≥ II: 80% vs. 49%, p < 0.001). Six-minute walking distance was lower and obstructive HCM was more prevalent in women (425 vs. 505 m, p < 0.001, and 55% vs. 32%, p < 0.001, respectively). Echocardiographic assessment revealed higher diastolic filling pressures (E/E′ 18 vs. 10, p < 0.001), larger indexed atrial volumes (29.5 vs. 26.6 mL/m², p < 0.001), a higher left ventricular ejection fraction (70% vs. 62%, p < 0.001), and a larger indexed interventricular septal thickness in women (10.2 vs. 9.3 mm/m², p = 0.004). Moreover, serum levels of NT-proBNP were significantly higher in women (760 vs. 338 pg/L, p < 0.001). Conclusions: Female patients with HCM were diagnosed at an older age, presented with more advanced symptoms, had higher rates of obstructive physiology, and a phenotype characterized by diastolic dysfunction and elevated biomarkers, closely resembling heart failure with preserved ejection fraction. Recognizing these sex-specific disparities is crucial in improving diagnostic awareness and individualized therapeutic management. Full article

Mitochondrial dysfunction contributes to impaired myocardial energetics and performance in heart failure with preserved ejection fraction (HFpEF). Elamipretide (Ela) enhances mitochondrial bioenergetics in preclinical models, yet its relevance in HFpEF remains unclear. This study examined the effects of Ela on cardiac mitochondrial function, structure, and cardiovascular performance in a rodent HFpEF model. Female obese ZSF1 rats received vehicle or Ela for 12 weeks, with age-matched lean rats as controls. Cardiac function and hemodynamics were assessed by echocardiography and pressure–volume analysis. Mitochondrial respiration was measured in permeabilized fibers and ultrastructure evaluated by transmission electron microscopy. Molecular and histological analyses included cardiolipin lipidomics and mRNA/protein profiling of hypertrophic, fibrotic, and inflammatory markers. Ela modestly improved complex I and II respiration, whereas mitochondrial ultrastructure, cardiolipin composition, and tafazzin expression were unchanged. Diastolic dysfunction persisted, reflected by unchanged E/é, ventricular stiffness factor β, and titin phosphorylation. Compared to untreated HFpEF, systolic performance showed a mild decline, with small reductions in LV ejection fraction and end-systolic elastance. Accordingly, cardiac remodeling, including hypertrophy, fibrosis, and inflammatory activation, remained unaltered. Vascular stiffness slightly increased, while carotid reactivity and morphology were preserved. In conclusion, despite enhanced mitochondrial respiration following Ela treatment, no functional or structural benefits were observed in experimental HFpEF, suggesting limited therapeutic efficacy once HFpEF is established. Full article

Medium-milled rice is increasingly valued for its health benefits and distinctive aroma, which differs from that of white rice because differences in milling degree modify the content of lipids and other aroma precursors. However, its aroma profile remains underexplored. This study aimed to systematically analyze aroma differences among four Simiao rice cultivars after medium milling (8% degree of milling) and to elucidate the chemical basis underlying consumer preference. Odor sensory evaluation identified Xiangzhuxiang as the cultivar with the highest aroma acceptance. Subsequently, gas chromatography–olfactometry–mass spectrometry and odor activity value analysis characterized the volatile profile, identifying 45 volatile compounds across the four cultivars, including 17 key odor-active components. Multivariate statistical analysis pinpointed the discriminating key odor-active compounds responsible for the superior aroma quality of Xiangzhuxiang. The results showed that (E,E)-2,4-decadienal and indole (VIP > 1.0, FDR-adjusted q < 0.05, FC > 1.2, OAV > 1.0, confirmed by GC-O) significantly increased the aroma scores of Xiangzhuxiang; imparted nutty, fatty, and sweet notes; and thus played a decisive role in shaping its characteristic aroma. Moreover, the moderate levels of hexanal and octanal in Xiangzhuxiang facilitated its characteristic aroma expression. These findings provide a basis for developing premium fragrant Simiao rice cultivars optimized for medium milling. Full article

High accuracy and time synchronous aerosol optical depth (AOD) is essential for atmospheric correction (AC) of medium and high spatial resolution (MHSR) remote sensing data. However, existing high-resolution AOD retrieval methods often rely on sparsely distributed ground-based measurements, which limits their capacity to resolve fine-scale spatial heterogeneity and consequently constrains retrieval performance. To address this limitation, we propose a framework that takes GF-1 top-of-atmosphere (TOA) reflectance as input, where the model is first pre-trained using MCD19A2 as Pseudo-labels, with high-confidence samples weighted according to their spatial consistency and temporal stability, and then fine-tuned using Aerosol Robotic Network (AERONET) observations. This approach enables improved retrieval accuracy while better capturing surface variability. Validation across multiple regions demonstrates strong agreement with AOD measurements, achieving the correlation coefficient (R) of 0.941 and RMSE of 0.113. Compared to models without pretraining, the proportion of AOD retrievals within EE improves by 13%. While applied to AC, the corrected surface reflectance also shows strong consistency with in situ observations (R > 0.93, RMSE < 0.04). The proposed Trans-AODnet significantly enhances the accuracy and reliability of AOD inputs for AC of high-resolution wide-field sensors (e.g., GF-WFV), offering robust support for regional environmental monitoring and exhibiting strong potential for broader remote sensing applications. Full article

Polymeric micelles have the potential to improve the efficacy and safety of drug delivery by improving drug solubility, enhancing bioaccumulation and reducing off-target toxicity. Despite excellent safety profiles, a major limitation with polymeric micelles is their inability to rapidly release their payload once they have reached their target, leading to the inadequate delivery of therapeutic doses. To address this limitation, we have developed a novel strategy to impart pH-responsiveness in non-responsive micelles through the co-encapsulation of oligoelectrolytes with drugs. Herein, we investigate the influence of copolymer composition and drug identity in combination with oligoelectrolyte—oligo(2-vinyl pyridine) (OVP)—loading on pH-triggered drug release from micelles and their cytotoxicity. A library of OVP-loaded micelles was prepared using conventional and well-established non-responsive block copolymers. Dynamic light scattering (DLS) was used to monitor the changes in the micelles as a function of pH. Regardless of the copolymer composition, an abrupt decrease in the hydrodynamic diameter (D_h) was observed as the pH was reduced due to OVP expulsion from the core, which was also confirmed by release studies. In general, co-encapsulation of OVP and model drugs (doxorubicin (DOX), gossypol (GP), paclitaxel (PX), and 7-ethyl-10-hydroxycamptothecin (SN38)) in the micelles provided good to excellent encapsulation efficiency percentage (EE%) values. In vitro studies revealed the pH triggered release of drugs from the OVP-loaded micelles regardless of the drug identity, which increased as the OVP loading increased. This general behaviour was observed in all cases, largely independent of the copolymer composition, albeit with subtle differences in the release profile for different drugs. Compared to their blank counterparts, the drug-loaded micelles displayed a slight increase in cytotoxicity against a panel of cancer cell lines, in a dose dependent manner. However, drug- and OVP-loaded micelles displayed a significant increase in cytotoxicity (up to 8-fold increase) that was independent of the copolymer composition. These results demonstrate the versatility of the oligoelectrolyte-mediated approach to furnish non-responsive micelles with a pH-trigger that allows the rapid release of drugs, regardless of the micelle composition or the drug identity. Full article