Search Results (827)

Background: Pain is a complex phenomenon characterized by unpleasant experiences with profound heterogeneity influenced by biological, psychological, and social factors. According to the National Health Interview Survey, 50.2 million U.S. adults (20.5%) experience pain on most days, with the annual cost of prescription medication for pain reaching approximately USD 17.8 billion. Theranostic pain nanomedicine therefore emerges as an attractive analgesic strategy with the potential for increased efficacy, reduced side-effects, and treatment personalization. Theranostic nanomedicine combines drug delivery and diagnostic features, allowing for real-time monitoring of analgesic efficacy in vivo using molecular imaging. However, clinical translation of these nanomedicines are challenging due to complex manufacturing methodologies, lack of standardized quality control, and potentially high costs. Quality by Design (QbD) can navigate these challenges and lead to the development of an optimal pain nanomedicine. Our lab previously reported a macrophage-targeted perfluorocarbon nanoemulsion (PFC NE) that demonstrated analgesic efficacy across multiple rodent pain models in both sexes. Here, we report PFC-free, biphasic nanoemulsions formulated with a biocompatible and non-immunogenic plant-based coconut oil loaded with a COX-2 inhibitor and a clinical-grade, indocyanine green (ICG) near-infrared fluorescent (NIRF) dye for parenteral theranostic analgesic nanomedicine. Methods: Critical process parameters and material attributes were identified through the FMECA (Failure, Modes, Effects, and Criticality Analysis) method and optimized using a 3 × 2 full-factorial design of experiments. We investigated the impact of the oil-to-surfactant ratio (w/w) with three different surfactant systems on the colloidal properties of NE. Small-scale (100 mL) batches were manufactured using sonication and microfluidization, and the final formulation was scaled up to 500 mL with microfluidization. The colloidal stability of NE was assessed using dynamic light scattering (DLS) and drug quantification was conducted through reverse-phase HPLC. An in vitro drug release study was conducted using the dialysis bag method, accompanied by HPLC quantification. The formulation was further evaluated for cell viability, cellular uptake, and COX-2 inhibition in the RAW 264.7 macrophage cell line. Results: Nanoemulsion droplet size increased with a higher oil-to-surfactant ratio (w/w) but was no significant impact by the type of surfactant system used. Thermal cycling and serum stability studies confirmed NE colloidal stability upon exposure to high and low temperatures and biological fluids. We also demonstrated the necessity of a solubilizer for long-term fluorescence stability of ICG. The nanoemulsion showed no cellular toxicity and effectively inhibited PGE2 in activated macrophages. Conclusions: To our knowledge, this is the first instance of a celecoxib-loaded theranostic platform developed using a plant-derived hydrocarbon oil, applying the QbD approach that demonstrated COX-2 inhibition. Full article

Human-Robot Collaboration (HRC) is pivotal for flexible, worker-centric manufacturing in Industry 5.0, yet dynamic task allocation remains difficult because operator states—fatigue and skill—fluctuate abruptly. I address this gap with a hybrid framework that couples real-time perception and double-estimating reinforcement learning. A Convolutional Neural Network (CNN) classifies nine fatigue–skill combinations from synthetic physiological cues (heart-rate, blink rate, posture, wrist acceleration); its outputs feed a Double Deep Q-Network (DDQN) whose state vector also includes task-queue and robot-status features. The DDQN optimises a multi-objective reward balancing throughput, workload and safety and executes at 10 Hz within a closed-loop pipeline implemented in MATLAB R2025a and RoboDK v5.9. Benchmarking on a 1000-episode HRC dataset (2500 allocations·episode⁻¹) shows the hybrid CNN+DDQN controller raises throughput to 60.48 ± 0.08 tasks·min⁻¹ (+21% vs. rule-based, +12% vs. SARSA, +8% vs. Dueling DQN, +5% vs. PPO), trims operator fatigue by 7% and sustains 99.9% collision-free operation (one-way ANOVA, p < 0.05; post-hoc power 1 − β = 0.87). Visual analyses confirm responsive task reallocation as fatigue rises or skill varies. The approach outperforms strong baselines (PPO, A3C, Dueling DQN) by mitigating Q-value over-estimation through double learning, providing robust policies under stochastic human states and offering a reproducible blueprint for multi-robot, Industry 5.0 factories. Future work will validate the controller on a physical Doosan H2017 cell and incorporate fairness constraints to avoid workload bias across multiple operators. Full article

This study investigates the influence of process parameters on the fabrication and mechanical performance of Scalmalloy^® lattice structures produced via laser powder bed fusion (PBF-LB) and their mechanical responses at different cell size. A full-factorial design of experiments was employed to evaluate the effect of scan speed, hatch distance, and downskin power on internal porosity and dimensional accuracy. Regression models revealed significant relationships, with optimised parameters identified at a scan speed of 700 mm/s, hatch distance of 0.13 mm, and downskin power of 80 W. Mechanical characterisation through tensile tests of bulk samples and compression tests of lattice structures highlighted the strengthening effects of the heat treatment. Experimental data on quasi-elastic gradient and yield strength were compared to predictions from the Ashby–Gibson model, revealing a partial agreement but noticeable deviations attributed to cell geometry and manufacturing defects. The scaling laws observed differed from the classical model, particularly in the yield strength exponent, indicating the need for empirical models tailored to metallic lattices. This work provides key insights into the optimisation of PBF-LB parameters for Scalmalloy^® and underlines the complex interplay between process parameters, structural design, and mechanical behaviour. Full article

Infectious diseases have been treated using plants and their compounds for thousands of years. This knowledge has enabled modern techniques to identify specific antiviral remedies and to understand their molecular mechanism of action. Numerous active phytochemicals, such as alkaloids, terpenoids, polyphenols (phenolic acids, flavonoids, stilbenes, and lignans), coumarins, thiophenes, saponins, furyl compounds, small proteins, and peptides, are promising options for treating and preventing viral infections. It has been shown that plant-derived products can prevent or inhibit viral entry into and replication by host cells. Biotechnological advances have made it possible to engineer plants with an increased capacity for the production and accumulation of natural antiviral compounds. Plants can also be engineered to produce various types of antivirals (cytokines, antibodies, vaccines, and lectins). This study summarizes the current understanding of the antiviral activity of specific plant-derived metabolites, emphasizing their mechanisms of action and exploring the enormous potential of plants as biological factories. Full article

Microalgal biomass has emerged as a valuable and nutrient-rich source of novel plant-based foods of the future, with several demonstrated benefits. In addition to their green and health-promoting characteristics, these foods exhibit bioactive properties that contribute to a range of physiological benefits. Photoautotrophic microalgae are particularly important as a source of food products due to their ability to biosynthesize high-value compounds. Their photosynthetic efficiency and biosynthetic activity are directly influenced by light conditions. The primary goal of this study is to track the changes in the light requirements of various high-value microalgae species and use advanced systems to regulate these conditions. Artificial intelligence (AI) and machine learning (ML) models have emerged as pivotal tools for intelligent microalgal cultivation. This approach involves the continuous monitoring of microalgal growth, along with the real-time optimization of environmental factors and light conditions. By accumulating data through cultivation experiments and training AI models, the development of intelligent microalgae cell factories is becoming increasingly feasible. This review provides a concise overview of the regulatory mechanisms that govern microalgae growth in response to light conditions, explores the utilization of microalgae-based products in plant-based foods, and highlights the potential for future research on intelligent microalgae cultivation systems. Full article

Background: Progressive multifocal leukoencephalopathy (PML) is a rare but fatal disease caused by John Cunningham virus (JCV) in immunocompromised individuals, with no effective antiviral treatment currently available. This study aimed to evaluate the feasibility of adoptive JCV-specific T lymphocyte therapy in patients with PML. Methods: Nineteen patients meeting the 2013 consensus criteria for “definite PML” were included, and JCV-specific T lymphocytes expanded from autologous or allogeneic peripheral blood mononuclear cells (PBMCs) using JCV antigen-derived peptides were administered. Clinical outcomes were monitored through neuroimaging and biological markers. Results: The mean age at diagnosis was 56.5 years, with a mean time to treatment of three months. Patients received a median of two infusions. At 12 months, six patients (31.6%) survived, while 13 (68.4%) had died, primarily due to PML progression. Survivors had a higher median baseline Karnofsky performance scale (KPS) score (50% vs. 30%, p = 0.41) and a significantly shorter diagnosis delay. MRI assessment showed a reduced disease burden in survivors, and JCV-DNA copy numbers decreased overall. One case of immune reconstitution inflammatory syndrome (IRIS) was observed. Conclusions: Adoptive JCV-specific T lymphocytes may represent a safe therapeutic option for PML patients, and the MRI burden and JCV-DNA copy may serve as biomarkers for disease monitoring. Full article

This study investigated the effects of Trichoderma harzianum inoculation on the growth, physiological responses, and soil nutrient uptake of three turfgrass species cultivated on eco-concrete—Axonopus compressus (Sw.) Beauv., Cynodon dactylon (L.) Pers., and Zoysia sinica Hance. A 2 × 2 factorial design was used to evaluate plant growth, physiological responses, and soil metrics under cement stress, incorporating T. harzianum inoculation (inoculated vs. control) and substrate composition (eco-concrete vs. pastoral soil). Our results indicate that inoculation with Trichoderma harzianum significantly enhanced the growth potential of the three turfgrass species compared to uninoculated controls. Furthermore, under cement stress conditions in vegetated concrete, inoculation with T. harzianum significantly alleviated the inhibition of growth and development. More specifically, in the vegetated concrete habitat, inoculated plants exhibited significantly increased root length and surface area. This enhancement promoted the uptake of available nitrogen (AN), available phosphorus (AP), and available potassium (AK) from the soil. Concurrently, inoculated plants showed higher leaf epidermal cell density, stomatal width, soluble sugar content, and antioxidant enzyme activity (SOD, POD, CAT, and APX). Additionally, significant reductions were observed in root activity, relative conductivity, and malondialdehyde (MDA) and proline contents. In conclusion, T. harzianum inoculation promotes the growth of the three turfgrass species under cement stress, likely by enhancing root development, increasing osmoregulatory substance accumulation, and elevating antioxidant enzyme activities. Full article

Sarcomyxa edulis is a characteristic low-temperature, edible mushroom in Northeast China. It has a delicious taste and rich nutritional and medicinal value. S. edulis can undergo explosive fruiting, neat fruiting, and unified harvesting, making it suitable for factory production. The molecular mechanisms underlying fruiting body development in S. edulis remain poorly understood. This study employed transcriptome analysis to compare the post-ripening mycelium (NPM) and primordial fruiting bodies (PRMs) of the thermostable S. edulis strain PQ650759, which uniquely forms primordia under constant temperature. A total of 4862 differentially expressed genes (DEGs) (|log2(fold change)| ≥ 1) were identified and found to be predominantly enriched in biological processes such as cell wall organization, DNA replication, and carbohydrate metabolism. KEGG pathway analysis revealed significant enrichment in 20 metabolic pathways, including mismatch repair, yeast cell cycle, and starch/sucrose metabolism. Ten candidate genes (e.g., SKP1, MRE11, GPI) linked to cell cycle regulation, DNA repair, and energy metabolism were randomly selected and prioritized for functional analysis. Quantitative PCR validation confirmed the reliability of transcriptome data, with expression trends consistent across both methods. Our findings provide critical insights into the molecular regulation of fruiting body development in S. edulis and establish a foundation for future mechanistic studies and strain optimization in industrial cultivation. Full article

Skin aging is a multi-factorial process characterized by the progressive deterioration of biomechanical properties and cellular functionality. One such factor is the formation of advanced glycation end products (AGEs), which are known to have detrimental effects on the skin, including stiffening of the extracellular matrix (ECM) and reduction of cellular proliferation. AGEs accumulate because of sugar metabolism dysfunction; however, the direct impact of elevated sugar levels on cellular physiology requires further investigation. Here, we elucidated the effects of elevated fructose levels on skin cell function using in vitro models and hypothesized that high fructose levels adversely impact cell function. By fluorescence microscopy, we observed that high fructose induced different cellularity, cell morphology, and stress fiber appearance than the controls. Skin cells exposed to high fructose levels showed impaired growth and delayed closure in an artificial wound model. Mechanistically, high fructose conditions induce inflammatory cytokines and activate the NFκB pathway. Furthermore, we observed for the first time an increase in the senescence markers p16, p21, and p53 in response to high fructose levels. Taken together, we show that high fructose levels affect many critical skin functions that contribute to the aging process and recapitulate several aspects of aging related to AGEs. Full article

The aromatic C₁₃ apocarotenoid β-ionone is a high-value natural-flavor and -fragrance compound derived from the oxidative cleavage of carotenoids. Carotenoid cleavage dioxygenases (CCDs) play a pivotal role in the biosynthesis of volatile apocarotenoids, particularly β-ionone. In this study, we report the identification, cloning, and functional characterization of two CCD1 homologs: OeCCD1 from Olea europaea and InCCD1 from Ipomoea nil. These two species, which, respectively, represent a woody perennial and a herbaceous annual, were selected to explore the potential functional divergence of CCD1 enzymes across different plant growth forms. These CCD1 genes were synthesized using codon optimization for Escherichia coli expression, followed by heterologous expression and purification using a GST-fusion system. In vitro assays confirmed that both enzymes cleave β-carotene at the 9,10 (9′,10′) double bond to yield β-ionone, but only OeCCD1 exhibits detectable activity on zeaxanthin; InCCD1 shows no in vitro cleavage of zeaxanthin. Kinetic characterization using β-apo-8′-carotenal as substrate revealed, for OeCCD1, a K_m of 0.82 mM, V_max of 2.30 U/mg (k_cat = 3.35 s⁻¹), and k_cat/K_m of 4.09 mM⁻¹·s⁻¹, whereas InCCD1 displayed K_m = 0.69 mM, V_max = 1.22 U/mg (k_cat = 1.82 s⁻¹), and k_cat/K_m = 2.64 mM⁻¹·s⁻¹. The optimization of expression parameters, as well as the systematic evaluation of temperature, pH, solvent, and metal ion effects, provided further insights into the stability and functional diversity within the plant CCD1 family. Overall, these findings offer promising enzymatic tools for the sustainable production of β-ionone and related apocarotenoids in engineered microbial cell factories. Full article

Microcystis aeruginosa is a cyanobacterium frequently associated with toxic blooms in eutrophic freshwater systems. Certain strains produce microcystins (MCs), a group of hepatotoxins with significant ecological and public health implications. In this study, we examined the quantitative response of a temperate native M. aeruginosa strain to combinations of temperature (26, 30, and 36 °C), light intensity (30, 50, and 70 µmol photons·m⁻²·s⁻¹), and N:P ratio (10, 100, 150), using a full-factorial experimental design. Growth parameters (µ, lag phase duration, and maximum cell density), chlorophyll-a production, and MC-LR synthesis were modeled using Gompertz, linear, and dynamic approaches. High temperature and irradiance increased the specific growth rate but decreased final biomass, while elevated N:P ratios shortened the lag phase. MC-LR production peaked under low temperature, low irradiance, and low N:P ratio. Although MC-LR synthesis did not correlate positively with growth rate, and the environmental conditions maximizing growth differed from those enhancing toxin production, a population-level coupling between both processes was observed using the Long model. These findings suggest that MC-LR synthesis in M. aeruginosa is not merely a metabolic by-product of growth, but a context-dependent trait with potential adaptive significance. Full article

The development of yeast cell factories for efficient xylose utilization and xylitol production is crucial for advancing sustainable biotechnological processes. Xylose, a major component of lignocellulosic biomass, presents challenges for microbial conversion due to its complex metabolic pathways. This study presents the genomic perspective and xylitol production capability of a novel xylose utilizing yeast Cyberlindnera fabianii TBRC 4498. Genome sequencing and functional annotation revealed key metabolic networks and genes involved in the xylose metabolism pathway, providing insights into the strain’s performance. The Cy. fabianii TBRC 4498 had excellent growth and xylose assimilation at a broad range of xylose concentrations from 40 to 140 g/L, with the highest growth rate at 80 g/L of xylose. The highest xylitol production yield (83.19 g/L) was detected from 120 g/L of xylose at 30 °C for 72 h, equivalent to 0.65 g xylitol/g xylose and 1.16 g/L/h productivity. Remarkably, Cy. fabianii TBRC 4498 produced high-purity xylitol, achieving over 95% homogeneity without forming undesirable byproducts, such as acid or ethanol. These results demonstrated the potential of Cy. fabianii TBRC 4498 as a whole-cell biocatalyst for xylitol production using high xylose concentrations, offering a promising microbial cell factory for large-scale xylitol production from lignocellulosic sugar. Full article

Mandelic acid (MA) is a valuable α-hydroxy acid with applications in pharmaceuticals, cosmetics, and fine chemicals. While chemical synthesis is well established, concerns over toxicity and sustainability have driven interest in microbial production. Here, we engineered Escherichia coli for de novo MA biosynthesis by integrating enzyme screening, metabolic flux optimization, and pathway regulation. We first screened and identified an efficient hydroxymandelate synthase (HMAS) homolog from Actinosynnema mirum for MA synthesis, and subsequently enhanced the shikimate pathway along with the supply of the precursors erythrose-4-phosphate (E4P) and phosphoenolpyruvate (PEP). Additionally, CRISPR interference (CRISPRi) was employed to repress competing pathways and redirect flux toward MA production. High-cell-density cultivation (HCDC) in a 5 L bioreactor demonstrated the strain’s industrial potential, achieving an MA titer of 9.58 g/L, the highest reported for microbial production. This study provides a systematic metabolic engineering approach for efficient MA biosynthesis from glucose, offering a foundation for sustainable large-scale production, demonstrating not only genetic-level optimizations, but also effective process scaling through high-cell-density cultivation, highlighting the power of pathway engineering in microbial cell factories. Full article

In a susceptible individual, persistent, low-level injury to the airway epithelium initiates an exaggerated wound repair response, ultimately leading to idiopathic pulmonary fibrosis (IPF). The mechanisms driving this fibroproliferative response are not fully understood. Here, we review recent spatially resolved transcriptomics and proteomics studies that provide insight into two distinct matricellular microenvironments important in this pathological fibroproliferation. First, in response to alveolar epithelial injury, alveolar differentiation intermediate (ADI) basal cells arising from Secretoglobin (Scgb1a1) progenitors re-populate the injured alveolus remodeling the extracellular matrix (ECM). ADI cells exhibit an interconnected cellular stress response involving the unfolded protein response (UPR), epithelial–mesenchymal transition (EMT) and senescence pathways. These pathways reprogram cellular metabolism to support fibrillogenic ECM remodeling. In turn, the remodeled ECM tonically stimulates EMT in the ADI population, perpetuating the transitional cell state. Second, fibroblastic foci (FF) are a distinct microenvironment composed of activated aberrant “basaloid” cells supporting transition of adjacent mesenchyme into hyaluronan synthase (HAS^hi)-expressing fibroblasts and myofibroblasts. Once formed, FF are the major matrix-producing factories that invade and disrupt the alveolar airspace, forming a mature scar. In both microenvironments, the composition and characteristics of the ECM drive persistence of atypical epithelium sustaining matrix production. New approaches to monitor cellular trans-differentiation and matrix characteristics using positron emission tomography (PET)–magnetic resonance imaging (MRI) and optical imaging are described, which hold the potential to monitor the effects of therapeutic interventions to modify the ECM. Greater understanding of the bidirectional interrelationships between matrix and cellular phenotypes will identify new therapeutics and diagnostics to affect the outcomes of this lethal disease. Full article

Solitary fibrous tumors (SFTs) are rare mesenchymal neoplasms of fibroblastic origin. In this study, we report a rare case of cervical SFT in a pediatric patient, a rare phenomenon since the incidence is particularly rare in pediatric patients according to the literature. Typical radiological features of the lesion may lead to misdiagnosis. Image study and immunohistochemistry are crucial for its correct diagnosis. Their imaging characteristics often resemble meningiomas or schwannomas, making differential diagnosis challenging. Immunohistochemical markers such as CD34 and STAT6 remain essential for definitive diagnosis. Full article