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Schiff base complexes of Mn have garnered significant attention as homogeneous catalysts. Among that class of compounds, bis(imino)pyridine-supported variants feature prominently. Synthesis of these species typically entails multistep, multiday processes and often under forcing conditions to drive condensation of less favorable nucleophiles. We report the multigram-scale one-pot, one-step synthesis of bis(imino)pyridine-Mn complexes using ultrasound-assisted synthesis, or sonochemistry, via acoustic cavitation. Complexes are assembled from their ligand components (diacetylpyridine, anilines, and MnCl2·(H2O)4), without the aid of an additional acid catalyst, using methanol as a solvent, and without any effort to remove H2O, in only 30 min of reaction time. The process is additionally amenable to electron-poor fluorinated anilines, giving rise to new complexes with novel steric and electronic environments around the Mn center.
Chronic rhinosinusitis (CRS) is a common comorbidity in bronchiectasis. Previous studies suggested that bronchiectasis with CRS is associated with elevated type 2 biomarkers, representing an "eosinophilic bronchiectasis" phenotype. However, whether the association with type 2 inflammation exists in rare aetiologies of bronchiectasis such as primary ciliary dyskinesia (PCD) or immune deficiency is unknown. Our aim was to explore the prevalence of CRS with and without nasal polyposis (CRSwNP and CRSnNP), their impact on bronchiectasis outcomes, and their association with type 2 inflammatory biomarkers in patients with bronchiectasis of various aetiologies. Using data from the EMBARC bronchiectasis registry, we classified patients with bronchiectasis as having no CRS, CRSnNP or CRSwNP. Regression models were used to test the effect of CRS on symptom scores and long-term outcomes. Multivariate models were created for elevated "type 2 biomarkers", defined as elevated blood eosinophil count or total IgE. Among 16 640 people with bronchiectasis, 2703 (20.9%) had CRSnNP and 1223 (7.3%) had CRSwNP. CRSwNP and CRSnNP were associated with worse symptoms and more frequent exacerbations, but lower hospitalisations and mortality. Type 2 biomarkers were elevated in people with comorbid CRSwNP in idiopathic bronchiectasis, but not in bronchiectasis secondary to PCD or immune deficiency. In multivariable analysis, CRSwNP was independently associated with elevated type 2 biomarkers. CRS and nasal polyposis are common comorbidities in bronchiectasis, associated with worse symptoms and exacerbations. Elevated type 2 biomarkers are associated with CRS, but this finding is dependent on the aetiology of bronchiectasis.
Colloidal quantum dots (QDs) offer size-tunable optoelectronic properties and solution processability, yet achieving uniformly packed emissive layers remains a bottleneck for high-performance quantum-dot light-emitting diodes (QLEDs). Here, we report a machine learning -guided solvent optimization strategy to produce homogeneous QD films. Five representative solvent parameters are evaluated, and multiple regression models are trained against film uniformity derived from atomic force microscopy. Among them, support vector regression provides the highest predictive accuracy for film homogeneity. Guided by these predictions, we formulate a mixed solvent that closely matches the target profile, yielding superior packing homogeneity, which is confirmed by grazing-incidence small-angle x-ray scattering. QLEDs fabricated with this formulation exhibit an external quantum efficiency of 20.6% and an operational lifetime of 468.5 h at 20 000 cd m-2, surpassing all single-solvent controls. These findings establish packing homogeneity as a decisive factor for device performance and introduce a generalizable and scalable framework for data-driven design of solution-processed devices, holding strong potential for next-generation optoelectronic systems.
Uveal melanoma (UM) is one of the most prevalent types of intraocular melanomas, which has relatively high morbidity and mortality rates despite being a rare disease. Genetic modifications are one of the prime driving forces behind cellular growth, proliferation, and migration in UM, among which mutation of driver genes (e.g., GNA11, GNAQ, BAP1, EIF1AX, and SF3B1, etc.) and epigenetic modifications (e.g., DNA methylation, histone modifications, and non-coding RNAs) are the key drivers behind oncogenesis. A feasible treatment approach for UM could be gene therapy targeting these genetic mutations and implicated pathways. In this review, current therapeutic options for the treatment of primary and metastatic UM will be briefly discussed in the context of the major driver gene and epigenetic mutations in UM. Primary focus will be on the current state of RNA interference, non-coding RNA, gene editing, gene replacement, and suicide gene therapies for UM, including prospective targeting strategies.
Capillary rise occurs when a thin tube contacts a liquid, which rises against gravity due to the capillary force. This phenomenon is present in a wide range of everyday and industrial settings and provides the means to measure the physical properties of liquids. Here, we report on the unusual ultra-slow capillary rise on a solid-like material of agarose hydrogels. The observed meniscus motion cannot be described with classical capillary rise models, and we develop a new model based on the fluid transport through the porous hydrogel network. Our model is in good agreement with the temporal scaling observed in our experiments with agarose gels made with five different concentrations and with two different viscosities of the liquid flowing inside the gel. Our results provide a non-invasive technique to directly estimate the permeability of hydrogel interfaces with high spatial resolution, which is important in the implementation of hydrogels in advanced biomedical applications.
Osteosarcoma (OS) is a highly aggressive primary bone malignancy in adolescents, with poor prognosis due to limited diagnostic and therapeutic strategies. Mitochondrial dysfunction is a hallmark of cancer, and mitophagy, the selective clearance of damaged mitochondria, critically maintains cellular homeostasis. However, the specific role of mitophagy in shaping the OS tumor microenvironment (TME) at single-cell resolution remains poorly understood. This study aims to systematically characterize mitophagy patterns within the OS TME and investigate their impact on intercellular communication, tumor progression, and patient prognosis. We analyzed single-cell RNA sequencing data from OS samples using non-negative matrix factorization to cluster cells based on mitophagy-related genes. We characterized distinct mitophagy-associated subtypes of TME cells. Pseudotime trajectory, cell-cell communication), gene regulatory network, and functional enrichment analyses were performed. Prognostic significance was evaluated using GSVA and Cox regression in bulk RNA-seq cohort. Immunotherapy response was predicted using the TIDE algorithm. We identified diverse mitophagy-activated cellular subtypes within the TME. Mitophagy-active CAFs and macrophages exhibited enhanced angiogenic signaling to endothelial cells. Mitophagy-associated CD8+ T cells displayed marked exhaustion features, while macrophages showed metabolic reprogramming. Clinically, higher infiltration of these mitophagy-related subtypes was consistently associated with poorer overall survival. TIDE analysis indicated that mitophagy patterns potentially correlate with immune checkpoint blockade response. Our findings reveal that mitophagy drives complex intercellular crosstalk in the OS TME, promoting angiogenesis and immunosuppression. Mitophagy-related signatures serve as robust prognostic biomarkers. These insights suggest that targeted inhibition of mitophagy, rather than activation, represents a promising therapeutic strategy, providing a novel framework for improving OS patient outcomes.
Variability is an inherent feature of human force output, and its temporal structure provides insights into motor control. In young adults, this structure has been associated with efficient motor behavior. Conversely, aging-related physiological changes may constrain neuromuscular adaptability, leading to less effective response to perturbations. We tested this hypothesis using a perturbation-based paradigm that quantified the time required to return to baseline force following unexpected target shifts during an isometric grip task. Sixteen young and eighteen older adults performed steady contractions and sudden upward (30→45% maximum voluntary contraction; MVC) and downward (30→15% MVC) force perturbations. Force regularity and variability magnitude were assessed using Sample Entropy (SaEn) and standard deviation (SD) across contraction intensities ranging from 5% to 80% MVC. Older adults exhibited significantly longer adaptation times and greater force regularity than young adults, whereas SD did not differ between age groups. Across both groups, downward perturbations resulted in slower recovery than upward perturbations, indicating direction-specific constraints in force control. These findings demonstrate that aging prolongs adaptation to force perturbations and increases force output regularity, highlighting perturbation-based assessments as a sensitive approach for probing adaptive motor control. Force regularity may represent a more informative marker of aging-related changes in motor control than variability magnitude.
This research aims to analyze and compare the biomechanical and histological characteristics of temporal fascia (TF) and dura mater grafts (DM); both obtained from adult human cadavers preserved in 10% formalin solution. TF and DM samples (bilateral, n = 3 strips per tissue) were obtained from 12 adult human cadavers (6 males, 6 females, age 46-86, mean 73) preserved in 10% formalin solution. Biomechanical tensile test was used to measure the maximum force, stiffness, energy absorption, and maximum deformation, maximum stress, maximum strain, elastic (Young's) modulus, and toughness. Histological analysis assessed collagen and elastic fiber densities using standard staining methods via Pentachrome, Masson Trichrome and Verhoeff staining. The elastic modulus, ultimate stress, and toughness were higher in formalin-fixed temporalis fascia than in formalin-fixed dura mater, indicating a stiffer material behavior. Histologically, collagen fiber and elastic fiber densities of grafts were similar. Formalin-fixed temporal fascia exhibited higher stiffness and tensile strength than formalin-fixed dura mater, likely due to fixation-induced structural alterations rather than differences in elastic fiber content.
Hybrid nanostructures that combine semiconducting and metallic components offer great potential for photothermal therapy, optoelectronics, and sensing, by integrating tunable optical properties with enhanced light absorption and charge transport. Boosting the integrated performance of these hybrid systems demands techniques capable of probing local variations of the physical properties inaccessible to bulk analysis. Here, we report the single-particle dielectric characterization of hybrid, semiconducting bismuth sulfide (Bi2S3) nanorods (NR) decorated with metallic Au nanoparticles (NP), employing scanning dielectric microscopy, which uses electrostatic force microscopy in combination with finite-element numerical simulations. We reveal a pronounced enhancement in the local dielectric response of Bi2S3 upon Au decoration, attributed to interfacial polarization and electron transfer from Au to the Bi2S3 matrix, thus suggesting a enhanced metallic-like polarizability at the single-particle level. Numerical simulations show that the response is dominated by the vertical component of the permittivity and that the decorating metallic Au NP produce only moderate shielding of the semiconductor Bi2S3 NR core, indicating that the large increase in the dielectric response originates primarily from intrinsic modifications within the NR. Overall, these findings provide direct insight into structure-property relationships at the single-particle level, supporting the rational design of advanced hybrid nanostructures with tailored electronic functionalities.
Oligonucleotide therapeutics are becoming representatives of the "Third Wave" of pharmaceutical innovation, expending from initial rare diseases to oncology and chronic indications, following small molecules and proteins. Globally, hundreds of clinical trials are currently underway, in addition to the 26 oligonucleotide drugs that have already been approved. Although nearly thirty years have elapsed since the initial approval of Fomivirsen, oligonucleotide therapeutics continue to pose unique CMC (Chemistry, Manufacturing, and Controls) challenges that are distinct from small molecules. Furthermore, the lack of harmonized ICH guidelines specifically for oligonucleotides forces developers to navigate a "regulatory grey area" between new molecular entities (NMEs) and biologics. This perspective focuses on the technical and regulatory hurdles of API (Active Pharmaceutical Ingredient) CMC development, covering synthesis (including conjugation strategies with delivery systems), analysis and regulatory aspects, with a specific emphasis on stage-appropriate requirements from the Investigational New Drug (IND) application to the New Drug Application (NDA).
Protein lactylation is an emerging lactate-derived modification, coupling metabolic reprogramming to inflammatory regulation while modulating cellular responses to the microenvironment. However, the role of macrophage lactylation in orthodontic tooth movement (OTM) remains unclear. Transcriptomic and metabolomic profiling of compressed macrophages identified glycolytic reprogramming as the core regulatory axis, with elevated lactate levels validated in macrophages, mice, and human saliva. Exogenous lactate promoted M1 polarization and NF-κB signaling activation in compressed macrophages, identifying lactate dehydrogenase A (LDHA) as a critical regulatory node. Myeloid-specific Ldha deficiency inhibited OTM and attenuated sterile inflammation, confirming the critical link between lactate metabolism and OTM progression. Mechanistically, we utilized lactylation proteomics and identified that lactate induces specific lactylation of TRAF6 at lysine residues 171, 180, and 388 (K171, K180, K388). Molecular dynamics simulations and site-directed mutagenesis revealed that K171/K180 lactylation enhances TRAF6 K63-linked ubiquitination, thereby driving NF-κB signaling activation. Consistently, mutation of K171 and K180 diminished TRAF6 K63-linked ubiquitination and suppressed NF-κB activation. Collectively, our findings demonstrate that sustained compressive force reprograms macrophage metabolism toward glycolysis and drives lactylation of TRAF6 at K171/K180, which serves as a core regulatory node that amplifies NF-κB signaling, thereby facilitating OTM-associated sterile inflammation and alveolar bone remodeling.
The aim of this study was to evaluate the biomechanical consequences of performing an anteromedializing tibial tubercle osteotomy on a cadaveric knee model with increased femoral anteversion. A controlled biomechanical study was performed on 16 human cadaveric knees. Intra-articular pressures were measured under four conditions. The first group was the native knee (n = 16). Subsequently, the sample was divided into two equal groups: a group in which 30 degrees of internal femoral rotation was experimentally induced (n = 8), and a group in which a Fulkerson osteotomy was performed (n = 8). Finally, the group in which an internal rotation of 30 degrees was experimentally induced underwent a Fulkerson osteotomy (n = 8). Measurements were obtained at 0°, 30°, 60° and 90° of knee flexion under a simulated weight-bearing squat condition using a 1000 N ground reaction force combined with independent quadriceps (218 N) and hamstring (80 N) loading. Patellofemoral and tibiofemoral compartments were analysed using intra-articular pressure sensors. Compared with the native knee, internal femoral rotation significantly increased lateral patellofemoral pressure (1.220 ± 0.016 vs. 1.342 ± 0.032 MPa at 30° of flexion; p = 0.05) and lateral tibiofemoral pressure (1.110 ± 0.020 vs. 1.489 ± 0.054 MPa at 90° of flexion; p = 0.004). The anteromedialization of the tibial tubercle partially reversed those changes. However, the technique failed to restore the pressure distribution to native values (all p < 0.05). Our findings indicate that while anteromedialization of the tibial tubercle partially mitigates the biomechanical alterations induced by increased internal femoral torsion, it does not fully restore native joint pressure distribution. These findings suggest that isolated distal realignment may be insufficient in the presence of significant rotational deformity and that surgical strategies should also address proximal rotational abnormalities to optimise joint loading. NA.
Only Congress can amend the statutory definition of eligible food for the Supplemental Nutrition Assistance Program, but states are actively engaged on this topic. The aim of this study was to identify state strategies to address Supplemental Nutrition Assistance Program-eligible food and inform future Supplemental Nutrition Assistance Program policy. Using Lexis+, a legal research platform, in 2025 and 2026, state strategies-including legislative actions (bills and laws) and executive orders and U.S. Department of Agriculture state waivers-to restrict Supplemental Nutrition Assistance Program-eligible foods in 2025 were identified. Data were evaluated in 2026. In 2025, 31 states engaged in relevant activities. There were 40 unique policies that sought to exclude: sugar-sweetened beverages and candy (12 bills, 3 laws, 3 executive orders); sugar-sweetened beverages, candy, snacks, and/or prepared desserts (7 bills); sugar-sweetened beverages (3 bills, 1 law, 1 executive order); food based on broad nutrition criteria (4 bills, 1 executive order); ultraprocessed food (1 bill, 1 law, 1 executive order); and specific additives (2 bills). One law included evaluation requirements. In 2025, U.S. Department of Agriculture granted 18 state waivers to exclude sugar-sweetened beverages and candy (n=9); sugar-sweetened beverages (n=6); and sugar-sweetened beverages, candy, snacks, and/or prepared desserts (n=3); all of which contained evaluation requirements. The majority of state activity focused on sugar-sweetened beverages and candy. Although bills were proposed by states with diverse political party make-ups, activities with the force of law (laws, executive orders, and U.S. Department of Agriculture waivers) were predominantly passed or issued by Republican trifectas (when the governor and both legislative houses are of the same political party), with 2 waivers granted to Democratic trifectas. The waivers' evaluation requirements are essential to understanding the impacts of Supplemental Nutrition Assistance Program food-eligibility exclusions.
Staphylococcus epidermidis (SE) is a Gram-positive bacterium that is a major cause of healthcare-associated infections (HAIs), largely due to its ability to form biofilms on medical devices and its resistance to many antibiotics. Cholesteryl linoleate (CL) is a lipid secreted by epithelial cells that has been shown to have antimicrobial effects against SE, but how it interacts with the bacteria remains poorly understood. In this study, we developed a surface plasmon resonance microscopy (SPRm) protocol to observe the interaction between CL formulated in phospholipid (CL-PL) liposomes and live stationary phase SE cells in real time. Buffer control experiments showed that the bacteria remained viable throughout the SPRm procedure. Our results provide evidence that CL directly binds to surface of SE and showed that CL-PL binding to SE is concentration-dependent and much more pronounced than binding of PL only. The binding was not uniform but instead varied from one SE cell region to another, with some cell regions showing strong binding and others showing much less indicative of a heterogenous bacterial population as expected for stationary phase bacteria. This work supports further exploration of CL and similar lipids to treat antibiotic-resistant infections caused by SE and other pathogens associated with HAIs, and presents a novel approach of studying antimicrobial activities capable to discern heterogeneity within live bacterial populations.
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DNA methylation plays a key role in non-small cell lung cancer (NSCLC) pathogenesis. This study aimed to explore the global research landscape and frontier trends of DNA methylation and NSCLC through bibliometric analysis. A literature search was conducted in the Web of Science Core Collection (WoSCC), focusing on articles published from January 2008 to April 2025. The bibliometric analysis utilized VOSviewer, CiteSpace, and the R package "bibliometrix" to visualize collaborations, keyword co-occurrences, and emerging research trends. The analysis identified 573 articles authored by 4,356 researchers across 2,524 institutions in 174 countries. China (n=288), the USA (n=77), and South Korea (n=33) were the countries with the highest number of published articles, with Nanjing Medical University in China (n=74) emerging as the leading institution. Clinical Cancer Research had the highest total link strength in co-occurrence networks. High-impact authors included Esteller Manel and Herman James G. Keyword clustering identified seven major themes: Hypermethylation in NSCLC, DNA methylation in therapy against NSCLC, DNA methyltransferases (DNMTs) in NSCLC, DNA methylation as a biomarker in early diagnosis for NSCLC, single nucleotide polymorphisms (SNPs) in NSCLC, cigarette smoke-related abnormal DNA methylation, and DNA methylation in other cancers. Notably, since 2022, the emergence of "activation" and "transcription" continued through to 2025. This bibliometric analysis highlights the important role of DNA methylation in NSCLC. Moving forward, research efforts should focus on elucidating the specific molecular mechanisms within the broader epigenetic network of NSCLC, rather than studying DNA methylation in isolation. Such an approach may enhance the efficacy of therapies targeting epigenetic regulators and modifiers.
This study aimed to examine the association between cumulative occupational noise exposure, using high-frequency hearing loss as an objective marker, and hypertension among Air Force ground staff. Active-duty Air Force ground staff ( n  = 451) completed standardized questionnaires and underwent pure-tone audiometry, and their blood pressure (BP) and laboratory profiles were measured. High-frequency hearing loss was defined as the average 4-kHz hearing threshold in both ears and was categorized into low (< 7.5 decibels [dB], 2nd quartile), medium (7.5-12.5 dB), and high (≥ 12.5 dB, 3rd quartile) groups. Hypertension was defined as systolic blood pressure (SBP) ≥140 mmHg, diastolic blood pressure (DBP) ≥90 mmHg, or a previous diagnosis. Multiple logistic and linear regression models were used to estimate associations. The prevalence of hypertension increased progressively across the hearing loss categories (40.9%, 63.5%, and 82.1%, respectively). Compared with the low group, the odds of hypertension were significantly higher in the medium (adjusted odds ratio [aOR] = 1.90, 95% confidence interval [CI]: 1.08-3.34) and high (aOR = 4.81, 95% CI: 2.51-9.02) groups. Each 5-dB increase in the 4-kHz hearing threshold was associated with double the likelihood of hypertension (aOR = 2.15, 95% CI: 1.57-2.94) and with increases in SBP and DBP (adjusted beta coefficients [aβ] = 0.63 and 0.46 mmHg, respectively). High-frequency hearing loss as a proxy for cumulative noise exposure was strongly associated with hypertension among the Air Force ground staff. These findings suggest that occupational noise may be associated with an increased risk of hypertension.
Engineering skeletal muscle tissues with controllable bioactuation is essential for advances in biohybrid robotics, regenerative medicine, and high-fidelity disease models. Mechanical stimulation has been shown to replicate the effects of physical exercise, while magnetic stimulation allows the manipulation of cells in a non-invasive manner. Here, a platform based on Helmholtz coil pair for magnetic stimulation is developed. To focus the stimulation through mechanotransduction, magnetic microspheres (MMS) were conjugated to myoblast integrins at defined MMS-to-cell ratios, functioning as microscale actuators under alternating magnetic fields. Exposure of non-labeled C2C12 cells to ∼2.9 mT, 50 Hz magnetic fields enhanced myogenic differentiation, with significantly increased fusion indices after 10 and 30 min of daily stimulation. Remarkably, MMS-labeled cells (1:1 ratio) required only 2 min of daily stimulation to achieve comparable enhancement, demonstrating the efficacy of targeted microactuation. Mechanistic analysis revealed elevated nuclear localization of Yes-associated protein (YAP) in stimulated MMS-labeled cells, confirming activation of force-dependent signaling pathways. qRT-PCR analysis further supported these findings, showing stimulation-associated upregulation of myogenic genes, particularly in MMS-labeled cells. The integration of cell labeling with dynamic magnetic fields offers new opportunities for remote stimulation strategies in biofabrication, muscle tissue engineering, and therapeutic approaches for muscle tissue.
Flexible pressure sensors have recently aroused increasing interests for fields of electronic skin, intelligent robotics, and human-machine interactions (HMI). Preserving high sensitivity of flexible pressure sensors across a broad range is essential prerequisite to ensure signal-to-noise reliability for multiple applications. However, this remains challenging due to the inherent sensing saturation when flexible matrix is exposed to varying pressure. Herein, a flexible pressure sensor based on design of binary micro-dome pixels is proposed. Triple-gradient of conductivity, modulus, and dimension is precisely designed in binary pixels, ensuring mechanical and electrical compensation during the entire deformation process. With well-developed CNT/PDMS matrix, significant sensing enhancement is realized, showcasing a linear sensitivity of 974.1 kPa-1 across range up to 1.8 MPa (R2 > 0.99). Thanks to the preserved sensitivity, the wearable device can recognize body information such as pulse, joint motion, and even foot pressure. The broad linearity also allows HMI establishment that applies force level as one basic clue to reflect human intension, e.g. dual-factor authentication system. Along with superiorities of low detection limit, fast response, and mechanical robustness, the principle of triple-gradient in binary pixels can be of significance for development of high-performance flexible sensors in the future is expected.
Regarded as one of the most complex membrane protein folds, CLCs form a large family of membrane proteins that function as anion channels and secondary active anion/proton transporters. Despite low sequence similarity, available structures are remarkably similar, maintaining the same inverted topology and fold, with subunits assembled as dimers in wild-type structures. Because of these strong structural features, CLC-ec1, a prokaryotic homologue from E. coli, has become a highly valuable model system for studying membrane protein folding and oligomerization assembly. Associating via a membrane-embedded dimerization interface, the subunits participate in a dynamic equilibrium between monomers and dimers in lipid bilayers, enabling investigation of the physical driving forces underlying the formation of stable membrane complexes. Like soluble protein assembly, studies indicate that CLC-ec1 dimerization is driven by a solvophobic force arising from the free energy gained by burying lipid bilayer defects. Dimerization stability is influenced by lipid composition and pH, which, in turn, provide a mechanism for functional regulation through oligomerization. In this review, I provide an overview of how the exploration of CLC folding and oligomerization advances our understanding of membrane protein self-assembly in general and the role of oligomerization in regulating function.