Sulfamethoxazole (SMX) is frequently found in aquatic environments, causing ecological toxicity and accelerating the spread of antibiotic resistance genes (ARGs). The conventional constructed wetlands (CWs) face challenges in removing antibiotics and recovering energy. Constructed wetland-microbial fuel cells (CW-MFCs) are a combination of constructed wetlands and bio-electrochemical technology, enhancing pollutant removal and bioelectricity production. In this study, an iron-carbon particle-enhanced CW-MFC (FCCW) was constructed for SMX removal. The decontamination performance, electrochemical properties, metagenomic profiles, ARG distribution, and transformation products of SMX were analyzed. The results showed that the FCCW displayed superiority in power generation performance with an average voltage of 286.16 mV, a peak power density of 5.40 mW·m-2, a peak current density of 32.48 mW·m2, and a low internal resistance of 382.10 Ω. The FCCW achieved the highest removal rates of TN (51.66±1.63%), NH4+-N (65.49±1.96%), TP (96.69±2.46%), COD (80.90±2.98%), and SMX (96.49±2.77%). Metagenomic analysis revealed that Proteobacteria and Actinobacteria dominated in the three systems and the iron-carbon particles increased the relative abundance of genes associated with energy metabolism and pollutant transformation. Additionally, the FCCW showed a more diffuse distribution of ARGs and no localized accumulation. The analysis of transformation intermediates showed that the FCCW may rely on a glutathione (GSH)-related conjugation pathway associated with lower accumulation of certain toxic intermediates. Overall, the enhanced performance of the FCCW was attributed to improved redox conditions, more efficient electron transfer, and changes in microbial functional composition. Therefore, the FCCW system offers a promising approach for in-situ electricity generation and stable pollutant treatment performance.

White matter integrity is a sensitive marker of cerebrovascular health and aging. Physical activity may promote white matter health, but previous studies were limited by self-reported activity and small sample sizes. We examined the association between accelerometer-based physical activity and novel indices of white matter integrity while identifying potential mediators. We analyzed cross-sectional baseline data from 4188 participants (58% women, mean age: 55.4 years) of the Rhineland Study, a prospective cohort study in Bonn, Germany. Physical activity measures (independent variables) were derived from activPAL3 micro-accelerometers. Fractional anisotropy, mean diffusivity, free water fraction, orientation dispersion, and neurite density (outcomes) were obtained from 3 T MR images for the whole brain and across 27 white matter tracts. We performed multivariable polynomial regression and mediation analyses for cardiometabolic and inflammatory factors. Higher energy expenditure was related to lower orientation dispersion, with the association leveling off at higher amounts (standardized βlinear = -0.153 [-0.183; -0.122]; βquadratic = 0.034 [0.017; 0.051]; both p < 0.001). Physical activity was linked to lower neurite density in motor tracts (βs between -0.133 and -0.056, all p < 0.001). However, with advancing age, physical activity became more strongly associated with higher neurite density and lower mean diffusivity of supratentorial fibers. Body weight, cardiometabolic, and inflammatory factors partly mediated effects of physical activity on white matter microstructure. Physical activity is related to white matter integrity in a nonlinear, age- and region-specific way. Physical activity's effects are greatest in sedentary and older individuals, likely mediated through its impact on body composition, cardiometabolic health, and systemic inflammation.

Dementia arises from multifactorial neurodegenerative processes, with growing evidence implicating blood-brain barrier dysfunction, neuroinflammation, and vascular injury as contributors to progressive brain tissue damage. Because decline in white matter microstructural integrity is a prominent feature of brain aging, biomarkers that capture this process may improve dementia risk stratification beyond conventional clinical factors. Fractional anisotropy (FA), derived from diffusion tensor imaging, reflects white matter microstructural integrity and may provide a sensitive marker of downstream injury associated with chronic vascular and barrier dysfunction. We conducted a retrospective single-center study of 528 participants, including individuals with dementia (n = 176), age-matched cognitively normal older adults (n = 176), and a young healthy reference cohort (n = 176), all of whom underwent standardized 3-Tesla diffusion MRI. Dementia prediction was evaluated using elastic net-regularized logistic regression with nested tenfold cross-validation, incorporating 16 prespecified clinical and imaging predictors. Corpus callosum FA showed the largest standardized coefficient within the penalized model, exceeding all demographic and clinical variables. The model demonstrated strong discrimination between dementia and age-matched controls (area under the receiver operating characteristic curve [AUC] = 0.970; sensitivity = 90.9%; specificity = 93.2%). FA also declined stepwise from young adults to cognitively normal older adults to participants with dementia, consistent with progressive white matter microstructural injury across the aging-dementia continuum. These findings indicate that corpus callosum FA provides additional predictive value beyond conventional risk factors and support diffusion MRI as a potentially scalable biomarker of age-related white matter microstructural injury with potential utility for dementia risk stratification and biologically informed prevention strategies.

Remote diffusion-weighted imaging lesions (RDWILs) after intracerebral hemorrhage (ICH) are associated with unfavorable outcomes and reflect secondary microvascular injury in the setting of systemic stress responses and autonomic dysfunction due to ICH. However, association of RDWILs with neuroendocrine stress markers and acute blood pressure (BP) control remain unclear. We evaluated whether stress hormone levels and the duration of intravenous nicardipine infusion, as an index of post-ICH BP management burden, were associated with RDWILs. Patients with ICH enrolled in a prospective study (October 2020-December 2022) were analyzed. RDWILs were defined as diffusion restriction located ≥ 10 mm from the hematoma. Plasma concentrations of the hypothalamic-pituitary-adrenal (HPA) axis markers-adrenocorticotropic hormone and cortisol-and the sympathetic-adrenomedullary (SAM) axis markers-dopamine, adrenaline, noradrenaline, and urinary total metanephrine-were measured in the subacute phase. Post-ICH BP management burden was indexed by days of intravenous nicardipine required to achieve and maintain systolic BP < 140 mmHg. Among 39 patients (median age 54 years; 67% male), 7 (18%) had RDWILs. In unadjusted analyses, dysregulated HPA-axis- (lower adrenocorticotropic hormone and higher cortisol) and higher SAM-axis-related stress markers (higher dopamine, noradrenaline, and urinary total metanephrine), and longer nicardipine duration were significantly associated with RDWILs. These associations were consistent in exploratory adjusted models. Dopamine, noradrenaline, and urinary total metanephrine were also positively associated with nicardipine infusion duration. Dysregulated HPA-axis- and higher SAM-axis-related stress markers, and longer nicardipine duration were each associated with RDWILs. Higher SAM-axis-related stress markers were also associated with post-ICH BP management burden.

Diarrhoea is the primary cause of nintedanib discontinuation in idiopathic pulmonary fibrosis. We investigated predictors in 100 prospective patients; 46% experienced diarrhoea, defined as common terminology criteria for adverse events V.5.0 grade ≥1. In a multivariable model (area under the curve 0.9056), lower standardised body surface area (adjusted OR 0.20, 95% CI 0.06 to 0.55, p=0.004) emerged as a significant independent predictor. A linear mixed model showed that dose adjustments managed symptoms without compromising 12-month forced vital capacity or diffusing capacity of the lungs for carbon monoxide trajectories (p>0.05). Small body size influences drug tolerability, suggesting that simple anthropometric measures can aid in baseline risk stratification to improve adherence.

BackgroundEar infections affect millions worldwide, causing significant hearing loss, particularly in developing countries. Bacterial infections play a major role, necessitating studies on causative agents, risk factors, and antibiotic resistance.ObjectiveThis study aimed to assess the prevalence, associated factors, and antibiotic susceptibility of the bacterial isolates among patients in suspected ear infections at the University of Gondar Hospital, Ethiopia.MethodsA hospital-based prospective cross-sectional study was conducted from May to July 2023, involving 303 participants with clinical diagnosis of having ear infections. Ear discharge samples were cultured on blood agar, chocolate agar, and MacConkey agar. Antibiotic susceptibility was determined using the Kirby-Bauer disk diffusion method. Cefoxitin disc and double-disc synergy tests detected methicillin-resistant Staphylococcus aureus and extended-spectrum beta-lactamase (ESBL) production in Enterobacterales respectively. Data were analyzed using SPSS version 27, with logistic regression to identify associations. A p-value < 0.05 was considered statistically significant.ResultsBacterial culture was positive in 48.5% (147/303; 95% CI: 42.8-54.3) of cases, yielding 172 isolates with Proteus mirabilis 30.2 % (52/172), Pseudomonas aeruginosa 13.9% (24/172) and S. aureus 13.9% (24/172) as the common isolated pathogens. Multidrug resistance was observed in 64.5% (111/172) of isolates, while 29.2% (7/24) of S. aureus exhibited methicillin resistance. ESBL production was detected in 19.1% (14/82) of Enterobacterales, particularly Klebsiella pneumoniae 27.3% (3/11). Associated factors included age under five (AOR = 1.19, p = 0.013) and upper respiratory tract infections (URTI) (AOR = 3.27, p < 0.001) in children. Among adults, diabetes mellitus (AOR = 2.73, p = 0.032), URTI (AOR = 1.97, p < 0.001), and frequent earphone use (AOR = 11.4, p < 0.001) were significantly associated.ConclusionP. mirabilis, P. aeruginosa, and S. aureus were predominant and exhibited high antibiotic resistance. Targeted antimicrobial stewardship, culture-based therapy, and public health interventions are essential, particularly for high-risk groups.

MAP2 has been widely used as a marker of neuronal dendrites because of its extensive restriction in the somatodendritic region. Despite that, how the precise localization of such a soluble protein is established and maintained against diffusion has been elusive and long remained a mystery in neuroscience. In this study, using GFP-tagged MAP2 expressed in cultured hippocampal neurons, we discovered a crucial protein region responsible for the localization of MAP2, the serine/proline-rich (S/P) region. Our pulse-chase live-cell imaging revealed the slow but steady migration of MAP2 toward distal dendrites, which was not observed in the presence of a Dynein inhibitor. By integrating these experimental parameters into a mathematical model, we demonstrated that an intermittent active transport mechanism by Dynein is sufficient to explain the observed MAP2 dynamics. In addition, our experiments using a Dynein inhibitor as well as Dynein knockdown, showed that impaired Dynein function leads to mislocalization of MAP2 in the axon. Furthermore, we verified that cytoplasmic Dynein binds to MAP2 through the S/P region in heterologous cells. Finally, we show that the failure of this Dynein-mediated transport mechanism results in the ectopic stabilization of axonal microtubules, thereby disrupting axonal identity. Thus, we propose that the cytoplasmic Dynein recruits and transports free MAP2 toward distal dendrites, thereby maintaining the precise dendritic localization of MAP2. Our findings shed light on the previously unknown mechanism behind MAP2 localization and provide a new direction for soluble protein trafficking research in the field of cell biology of neurons.

Gastric adenocarcinoma (GAC) remains a leading cause of cancer-related mortality, particularly in patients with peritoneal carcinomatosis, for whom effective therapies are limited. We investigated the therapeutic efficacy and molecular mechanism of CYD-4-61, a BAX activator, using human GAC cell lines, patient-derived xenograft models, genetically engineered mouse models, and a syngeneic mouse model. CYD-4-61 potently inhibited tumor cell proliferation, induced apoptosis, and suppressed cancer stem cell-like properties, with enhanced activity in radiation-resistant GAC cells. Mechanistically, CYD-4-61 activated the BAX-caspase pathway, leading to SOX9 protein reduction. Integrated bulk and single-cell transcriptomic analyses identified SOX9-dependent transcriptional programs as major targets of CYD-4-61. Functional rescue experiments together with chromatin immunoprecipitation and CUT&RUN analyses supported CDK4 as a SOX9-regulated gene and demonstrated suppression of the SOX9-CDK4 regulatory axis following CYD-4-61 treatment. In multiple preclinical models, CYD-4-61 significantly inhibited tumor growth and improved the therapeutic response to anti-programmed cell death protein 1 (PD-1) therapy while modulating the tumor immune microenvironment. Clinically, co-expression of SOX9 and CDK4 was associated with diffuse-type GAC and poor patient outcomes. These findings identify the BAX-SOX9-CDK4 axis as an important mechanism contributing to the antitumor activity of CYD-4-61 and provide a strong preclinical rationale for its further development as a therapeutic strategy for aggressive GAC.

Despite advances in chemotherapy, the clinical efficacy of docetaxel (Doc) in breast cancer treatment is limited by systemic toxicity and poor delivery efficiency. In this study, electrospun poly(lactic acid) (PLA):gelatin (Gel) core-shell nanofibers were developed as a dual drug delivery system for the co-delivery of Doc and heparin (HP). The core-shell architecture enabled the spatial compartmentalization of hydrophobic Doc within the PLA core and hydrophilic HP within the gelatin shell, allowing independent and controlled release profiles. Nanofibers containing 2, 3, and 5 wt% Doc in the core and corresponding amounts of HP in the shell were successfully fabricated. In vitro release studies performed at pH 3.0, 5.5, and 7.4 (37 °C) demonstrated a compartment-dependent release behavior, where HP exhibited rapid release (̴ 10 h), while Doc showed sustained release (̴ 80 h). These results indicate that the core-shell structure effectively regulates drug diffusion and enables distinct release kinetics for each therapeutic agent. Increased drug loading resulted in higher cumulative release for both agents. Cytotoxicity studies on MCF-7 breast cancer cells revealed that dual drug-loaded nanofibers (5 wt%, 2 mg) significantly reduced cell viability after 72 h, indicating enhanced in vitro antiproliferative activity. While Doc alone exhibited limited cytotoxic effect and HP showed negligible direct cytotoxicity, their combined delivery within the core-shell nanofiber system resulted in a markedly enhanced antiproliferative response. This enhanced effect indicates improved antiproliferative activity associated with dual-drug delivery through the core-shell nanofiber system. Overall, the developed PLA:Gel core-shell nanofibers represent a promising biomaterial-based platform for dual drug delivery of hydrophobic and hydrophilic agents, offering controlled release and promising in vitro antiproliferative activity.

The use of environmentally friendly technologies and renewable sources in bioplastic production offers an alternative to conventional chemical methods for modifying biopolymers and limits the formation of hazardous byproducts. Thus, this study examined how acrylic (AA) and hexamethyldisiloxane (HMDSO) plasma treatments altered the morphology and structure of sorghum starch, thereby influencing chemical interactions and molecular arrangement during film formation and determining water barrier performance. AA plasma species altered both the outer and inner layers of the granules, changing the intermolecular structural arrangement within starch molecules, whereas HMDSO plasma species altered only the granule periphery. As hypothesized, these changes promoted low chemical oxidation during sorghum starch film (F-SS) formation, favoring CC bonds within starch molecules in films containing AA- and HMDSO-plasma-modified starches (F-SSA and F-SSH) rather than C-OH interactions, thereby also enabling their binding within the crystalline fraction in F-SSH. Thus, polar sites on starch molecules were occupied by links and double helices, limiting interactions with water molecules in phenomena such as diffusion, swelling, absorbed water, and solubility. The work provides new insights into the use of plasma-modified sorghum starches as a prospect for developing packaging films for perishable foods susceptible to damage in high-humidity environments.

Corneal neovascularization (CoNV) treatment via ocular drug delivery remains challenging because rapid ocular clearance and limited tissue penetration result in low bioavailability, reduced therapeutic efficacy, and the need for frequent administration. Although polymer-based delivery systems can provide sustained release, their clinical translation may be limited by low drug loading, suboptimal release kinetics, and potential toxicity associated with polymer degradation products. Here, we developed a carrier-free subconjunctival depot platform composed of pure regorafenib crystals, including microcrystals (∼5 µm) and nanocrystals (∼260 nm), to achieve sustained release through a dissolution/diffusion-controlled mechanism without the need for a polymer matrix. Both formulations maintained crystallinity and their initial particle size during 12 months of storage at 4 °C. Nanocrystals exhibited faster dissolution and clearance, whereas microcrystals provided prolonged local retention, maintaining detectable regorafenib levels through eight months after a single administration. In vivo imaging and histological analyses demonstrated the formation of dense monolithic depots within the subconjunctival space, supporting sustained release and local retention. In prophylactic CoNV models, nanocrystals enhanced tissue penetration and produced greater early inhibition of angiogenic sprouting than microcrystals (p < 0.05). In therapeutic models of established neovascularization, a single 2 mg subconjunctival injection of either formulation induced comparable and sustained regression of neovessels for up to eight months, with efficacy significantly greater than that of 0.5 mg bevacizumab administered at 2-month intervals (p < 0.01). In addition, the 1 mg microcrystal formulation reduced TNF-α, IL-1β, and VEGF expression relative to saline-treated controls and were associated with improved corneal epithelial healing compared with bevacizumab. Collectively, these findings demonstrate that carrier-free pure drug crystal depots can provide sustained ocular delivery for at least eight months following a single administration, while crystal size governs the balance between initial tissue exposure and long-term retention.