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Effect of the PakCat program on nutrition status, dietary pattern and nutrition knowledge and skills of Pakistani women living in Catalonia evaluated by a mixed-method randomized control trial (RCT)
Background Pakistani women are among the most affected groups by obesity and heart failure in Catalonia. Due to cultural and linguistic barriers, their participation in standard health promotion programs is limited. To address this issue, we implemented a culturally and linguistically appropriate food education program called the PakCat Program. Methods The study employed a community-based participatory research (CBPR) design, utilizing a two-arm, cluster-assignment, non-blinded mixed-method randomized control trial (RCT) implemented in Badalona and Santa Coloma de Gramenet, two neighboring municipalities with a substantial Pakistani population. Participants were randomly assigned to the control group (n = 67) and the intervention group (n = 70). The intervention group received ten weekly culturally and linguistically appropriate food education sessions over ten weeks, while the control group attended three general sessions. The main outcome measures included nutritional status, nutrition knowledge and skills, dietary patterns, and satisfaction with the intervention, which were assessed pre-and post-intervention combining quantitative methods based on a survey and qualitative approaches consisting of conducting focus group discussions (FGDs). Results The quantitative analysis conducted through a two-factor analysis of variance (ANOVA) for repeated measures indicated a significant improvement in the study variables across the entire sample (p < 0.001 within group), with the intervention group experiencing greater improvements in nutrition knowledge and skills and dietary pattern (p <0.001 for interaction and between groups). These findings were corroborated by thematically analyzed qualitative data confirming a more pronounced improvement in the study outcomes of the intervention group. Furthermore, both groups reported a high level of satisfaction with the intervention. Conclusions The PakCat Program effectively improved the nutrition knowledge, skills, and dietary patterns of immigrant women of Pakistani origin residing in Catalonia. However, future research involving a larger sample size and combining the behavioral and clinical parameters is needed to enhance the generalizability of the results.
DCFE-YOLO: A novel fabric defect detection method
Accurate detection of fabric defects is crucial for quality control in the textile industry. However, the task of fabric defect detection remains highly challenging due to the complex textures and diverse defect patterns. To address the issues of inaccurate localization and false positives caused by complex textures and varying defect sizes, this paper proposes an improved YOLOv8-based fabric defect detection method. First, Dynamic Snake Convolution is introduced into the backbone network to enhance sensitivity to elongated and subtle defects, improving the extraction of edge and texture details. Second, a Channel Priority Convolutional Attention mechanism is incorporated after the Spatial Pyramid Pooling layer to enable more precise defect localization by leveraging multi-scale structures and channel priors. Finally, the feature fusion network integrates Partial Convolution and Efficient Multi-scale Attention, optimizing the fusion of information across different feature levels and spatial scales, which enhances the richness and accuracy of feature representations while reducing computational complexity. Experimental results demonstrate a significant improvement in detection performance. Specifically, mAP@0.5 increased by 2.9%, precision improved by 3.5%, and mAP@0.5:0.95 rose by 2.3%, highlighting the model’s superior capability in detecting complex defects. The project is available at https://github.com/lilian998/fabric.
Classification and spatial characteristics of different development stages in China: Evidence from the contribution rate of production factors
This paper aims to reveal the changing characteristics of the contribution rates of different production factors in China since the reform and opening up from two dimensions: stage and space. The study used national data from 1978 to 2021 and provincial data from 2000 to 2020, combined with methods such as C-D production function and spatial econometrics for analysis. Research has found that: (1) In terms of stage characteristics, during the structural adjustment stage (1978–1998), economic growth mainly relies on capital and labor input, and the contribution rate of land factors gradually decreases. During the high-speed development stage (1998–2012), the contribution rate of technological factors gradually increased, while the contribution rate of land factors remained relatively stable. In the stage of high-quality development (2012 present), the contribution rate of technological factors continued to rise and become the dominant factor, while the contribution rate of land factors has decreased to a lower level. (2) Regarding spatial characteristics, the spatial econometric model reveals significant spatial agglomeration characteristics of capital and labor, and land factors positively affect local and neighboring economic growth. From 2000 to 2020, the contribution rate of capital factors in various provinces showed a difference of "low in the east and high in the west," which decreased year by year. The contribution rates of labor and land factors have declined to low levels in all provinces; The contribution rate of technological elements has significantly increased, with a higher contribution rate in the southeast region; High-quality development progress in each province can be identified based on the contribution rates of different production factors. The research findings help to understand the impact of varying production factors on economic development at a temporal and spatial scale and provide a scientific basis for achieving a high-quality development pattern of rational allocation of factors and regional coordinated development.
Concomitant formation of protocells and prebiotic compounds under a plausible early Earth atmosphere
Revealing the origin of life and unambiguously detecting fossil remains of the earliest organisms are closely related aspects of the same scientific research. The synthesis of prebiotic molecular building blocks of life and the first compartmentalization into protocells have been considered two events apart in time, space, or both. We conducted lightning experiments in borosilicate reactors filled with a mixture of gases mimicking plausible geochemical conditions of early Earth. In addition to the variety of prebiotic organic molecules synthesized in these experiments, we investigated the micrometer-thick silica-induced organic film that covers the walls of the reactors and floats at the water–gas interface. We found that the film is formed by aggregation of HCN-polymer nanoclusters whenever water is present, either in the liquid or vapor phase. The organic film morphs into micrometer-scale biomorphic vesicular structures hanging from the organic film into the water. We also show that these structures are hollow and may act as microreactors facilitating chemical pathways toward increasing complexity. We propose that these organic biomorphs form through a bubble-driven mechanism and interfacial precipitation of HCN-polymers. The concomitant synthesis of biomorphic poly-HCN protocells and prebiotic molecules under plausible geochemical conditions of early Earth-like planets and moons and opens a different geochemical scenario for the emergence of life. Our results suggest that the coexistence of molecular building blocks of life and submicron biomorphic structures in the oldest rocks on Earth or any other celestial body does not necessarily mean evidence of life.
A prospective observational study on persistent postoperative pediatric pain, 4P: The study protocol
Background Access to adequate pain treatment is a fundamental right, yet international data suggest that a considerable number of children experience acute and persistent pain. Little is known about the occurrence of both acute and persistent pain in children. The incidence of persistent postoperative pain in children is an unexplored area but international studies suggest that many children experience long-term pain after surgery, with a major impact on daily life. In 4P, Persistent Postoperative Pediatric Pain, we want to estimate the incidence of acute and persistent postoperative pediatric pain. The European Society for Paediatric Anaesthesiology has developed guidelines for perioperative pain management. We aim to examine how well these guidelines are followed and whether adherence to guidelines influences the pain experienced after surgery. Method 4P is a prospective observational study of children aged 1–17, planned for surgery in southern Sweden 2023–2024. After agreement from all caregivers, data concerning preoperative pain, pre-emptive analgesia, perioperative management and postoperative pain will be collected. Via an electronic management software, pain will be evaluated at home (or in hospital) at 24h, 3, 6 and 12 months after surgery. We will include 1000 patients. Discussion 4P will prospectively follow a large number of children after general pediatric surgeries and evaluate the occurrence of postoperative pain, both acute (APOP) and persistent (PPOP). The study will assess pain treatment regimens and identify risk factors associated with the development of acute and persistent pediatric postoperative pain. Trial registration Prospectively posted at ClinicalTrials.gov, identifier NCT06035042.
Asynchronous effects of heat stress on growth rates of massive corals and damselfish in the Red Sea
Climate change is imposing multiple stressors on marine life, leading to a restructuring of ecological communities as species exhibit differential sensitivities to these stressors. With the ocean warming and wind patterns shifting, processes that drive thermal variations in coastal regions, such as marine heatwaves and upwelling events, can change in frequency, timing, duration, and severity. These changes in environmental parameters can physiologically impact organisms residing in these habitats. Here, we investigate the synchrony of coral and reef fish responses to environmental disturbance in the Red Sea, including an unprecedented combination of heat stress and upwelling that led to mass coral bleaching in 2015. We developed cross-dated growth chronologies from otoliths of 156 individuals of two planktivorous damselfish species, Pomacentrus sulfureus and Amblyglyphidodon flavilatus, and from skeletal cores of 48 Porites spp. coral colonies. During and immediately after the 2015 upwelling and bleaching event, damselfishes exhibited a positive growth anomaly but corals displayed reduced growth. Yet, after 2015–2016, these patterns were reversed with damselfishes showing a decline in growth and corals rebounding to pre-disturbance growth rates. Our results reveal an asynchronous response between corals and reef fish, with corals succumbing to the direct effects of heat stress, and then quickly recovering when the heat stress subsided—at least, for those corals that survived the bleaching event. Conversely, damselfish growth temporarily benefited from the events of 2015, potentially due to the increased metabolic demand from increased temperature and increased food supply from the upwelling event, before declining over four years, possibly related to indirect effects associated with habitat degradation following coral mortality. Overall, our study highlights the increasingly complex, often asynchronous, ecological ramifications of climate extremes on the diverse species assemblages of coral reefs.
The importance of organisational culture for health system resilience: A qualitative analysis of factors that supported health care workers in Germany during the COVID-19 pandemic
Health system resilience is defined as the ability of a system to prepare, manage, and learn from shocks. This study investigates the resilience of the German health system by analysing the system-related factors that supported health care workers, a key building block of the system, during the COVID-19 pandemic. We thematically analysed data from 18 semi-structured interviews with key informants from management, policy and academia, 17 in-depth interviews with health care workers, and 10 focus group discussions with health care workers. We identified six categories of factors which supported health care workers during the pandemic: (1) appreciation and encouragement; (2) team support and communication; (3) collaboration across professions and institutions; (4) informational, material and technical support; (5) leadership and participation; and (6) creativity and innovation. The analysis highlights the importance of systemic and organisational factors for maintaining health system resilience. The need to improvise and develop pragmatic solutions to deal with COVID-related challenges offered ample opportunities for participation, self-determination, innovation, and alternative work processes. Learning from adaptations made during the pandemic and implementing sustainable organisational and systemic changes to increase participation, conducive organisational cultures, and non-hierarchical working styles hold promising potential for health system transformation and health system strengthening.
A scoping review of interventions on middle school students’ attitudes towards science
The aim of the study was to review the scientific literature on educational interventions to promote positive attitudes towards science in middle school students. Due to the decline in positive attitudes towards science observed in this critical age group of students and the implementation of training programmes aimed at changing this situation, we sought to identify components of training proposals that have received attention from researchers. This paper presents a scoping review of 37 papers published in English and Spanish over the last 10 years. The review aims to describe the research outputs and analyse the effectiveness and characteristics of program interventions, drawing from various databases. The results show the need to examine the operational definition of the constructs used in the programmes, to focus attention on the influence of intrinsic variables on middle school students’ attitudes towards science, such as racial group or self-efficacy, and to conduct follow-up evaluations to assess the permanence of attitudes. While acknowledging limitations related to construct clarity or language restrictions in the search process the findings suggest that middle school students’ attitudes towards science remain an open area of research, as there is no consensus on the characteristics of effective programmes.
Research on the ordering strategy problem in supply chain with profit allocation under two-level price-fluctuation sales
This paper investigates optimal ordering strategies in supply chains under two-level price fluctuations and initial profit allocation. By utilizing Copula functions to model the complex relationship between fluctuating prices and uncertain demand, the study develops both continuous and discrete decision models for practical applications. A discrete algorithm is proposed to approximate the optimal solution, with its convergence rigorously proven. Numerical experiments demonstrate that profit allocation ratios significantly impact optimal order quantities and overall supply chain profit. Price fluctuations, particularly at the discount level, present critical challenges, necessitating flexible and adaptive ordering strategies. The study also investigates the influence of different Copula relationships on optimal ordering decisions, revealing how varying market conditions—from moderate price sensitivity to high volatility—affect optimal order quantities. By examining ordering strategies in the context of profit allocation contracts, this research offers a new perspective on how supply chain members can collaboratively navigate uncertain markets. The findings provide actionable insights for managers to mitigate risks, improve coordination, and seize new opportunities. Extending traditional models to incorporate price fluctuations and profit allocation, this study makes theoretical and practical contributions to supply chain management, offering robust strategies to strengthen supply chain resilience.
Illustration image style transfer method design based on improved cyclic consistent adversarial network
To improve the expressiveness and realism of illustration images, the experiment innovatively combines the attention mechanism with the cycle consistency adversarial network and proposes an efficient style transfer method for illustration images. The model comprehensively utilizes the image restoration and style transfer capabilities of the attention mechanism and the cycle consistency adversarial network, and introduces an improved attention module, which can adaptively highlight the key visual elements in the illustration, thereby maintaining artistic integrity during the style transfer process. Through a series of quantitative and qualitative experiments, high-quality style transfer is achieved, especially while retaining the original features of the illustration. The results show that when running on the Monet2photo dataset, when the system iterates to 72 times, the loss function value of the research method approaches the target value of 0.00. On the Horse2zebra dataset, as the sample size increases, the research method has the smallest FID value, and the value approaches 40.00 infinitely. With the change of peak signal-to-noise ratio, the accuracy of the research algorithm has been greater than 95.00%. Practical application found that the color of the image obtained by the research method is more gorgeous and the line features are more obvious. The above results all show that the research method has achieved more satisfactory results in the task of style transfer of illustration images, especially in terms of the accuracy of style transfer and the retention of image details.
Identifying depression subtypes and investigating their consistency and transitions in a 1-year cohort analysis
Major depressive disorder (MDD) is defined by an array of symptoms that make it challenging to understand the condition at a population level. Subtyping offers a way to unpick this phenotypic diversity for improved disorder characterisation. We aimed to identify depression subtypes longitudinally using the Inventory of Depressive Symptomatology: Self-Report (IDS-SR). A secondary analysis of a two-year cohort study called Remote Assessment of Disease and Relapse in Major Depressive Disorder (RADAR-MDD), which collected data every three months from patients with a history of recurrent MDD in the United Kingdom, the Netherlands, and Spain (N = 619). We used latent class and latent transition analysis to identify subtypes at baseline, determined their consistency at 6- and 12-month follow-ups, and examined transitions over time. We identified a 4-class solution: (1) severe with appetite decrease, (2) severe with appetite increase, (3) moderate severity and (4) low severity. These same classes were identified at 6- and 12-month follow-ups, and participants tended to remain in the same class over time. We found no statistically significant differences between the two severe subtypes regarding baseline clinical and sociodemographic characteristics. Our findings emphasize severity differences over symptom types, suggesting that current subtyping methods provide insights akin to existing severity measures. When examining transitions, participants were most likely to remain in their respective classes over 1-year, indicating chronicity rather than oscillations in depression severity. Future work recommendations are made.
Integrating intuitionistic fuzzy and MCDM methods for sustainable energy management in smart factories
Improving energy efficiency is crucial for smart factories that want to meet sustainability goals and operational excellence. This study introduces a novel decision-making framework to optimize energy efficiency in smart manufacturing environments, integrating Intuitionistic Fuzzy Sets (IFS) with Multi-Criteria Decision-Making (MCDM) techniques. The proposed approach addresses key challenges, including reducing carbon footprints, managing operating costs, and adhering to stringent environmental standards. Eight essential criteria are identified, such as the use of renewable energy, the efficiency of production, and the health and safety of workers, to evaluate energy performance. Using the entropy method for criterion weighting and the CRADIS technique for alternative ranking, we prioritize a range of energy-efficient solutions. The novelty of our approach lies in its comprehensive assessment of complex real-world energy management scenarios within smart factories, offering a robust and adaptable decision-support tool. Our empirical results, validated through sensitivity analysis, show that alternative 5 delivers the most significant improvement in energy efficiency. This study provides valuable information for industry practitioners seeking to transition to more sustainable production methods and supports the broader sustainability agenda.
Saffron’s protective role against atherosclerosis-induced cataract progression in New Zealand white rabbits with phytochemical analysis of saffron’s extract
Cataracts are significant causes of blindness, closely linked to prolonged hypercholesterolemia. While saffron has the potential for eye health, its effects on lens lesions remain understudied. This study aimed to investigate the effect of saffron on the lens changes in atherosclerotic-induced New Zealand white rabbits (NZWR). Thirty-five NZWRs were subjected to four to eight weeks of high-cholesterol diet to induce atherosclerosis, resulting in cataractous lens changes. The rabbits were categorised randomly into three groups: normal diet group, pre-treated group and treated group. The pre-treated group was divided into early atherosclerosis(HC4) and established atherosclerosis (HC8). The saffron-treated group was fed with the HCD diet followed by saffron treatment of 50mg/kg/day (TG450, TG840) and 100mg/kg/day (TG4100, TG8100) of saffron ethanolic extract (SEE) respectively. The normal diet group was given a normal diet over the 8 weeks. After completing the 16-week experimental protocol, the NZWR were euthanized, and their lenses were extracted for histopathological evaluation. The pre-treated group exhibited cataractous lens changes of grade 2, characterized by increased homogenisation, swollen lens fibers, and intracellular vacuolisation. Interestingly, these cataract changes showed a positive trend from grade 2 to grade 1 post-treatment with SEE. In the saffron-treated group, vacuoles and pinkish homogenised areas were reduced. Additionally, a uniform layer of anterior epithelium and decreased non-swollen lens fibers indicated significant cataract lesion improvement. The normal diet group displayed minimal to zero cataractous changes (Grade 0). HPLC analysis demonstrated the presence of crocin, crocetin, and picocrocin in the saffron ethanolic extract, with peak absorptions at 440nm (12.817min), 440nm (1.620min), and 254nm (6.553min) respectively. The phytochemical screening of saffron ethanolic extract was conducted and showed the presence of phytochemical compounds including saponins, flavonoids, tannins, and steroids. The positive effects on lenses in the TG groups could be due to crocin and crocetin, bioactive components of saffron, and its phytochemical compounds. This study highlights saffron’s potential in managing cataract-induced conditions, emphasizing the importance of further research for its full therapeutic potential in cataract management.
Anti-inflammatory effects of moxifloxacin and levofloxacin on cadmium-activated human astrocytes: Inhibition of proinflammatory cytokine release, TLR4/STAT3, and ERK/NF-κB signaling pathway
Cadmium is a non-essential element and neurotoxin that causes neuroinflammation, which leads to neurodegenerative diseases and brain cancer. To date, there are no specific or effective therapeutic agents to control inflammation and alleviate cadmium-induced progressive destruction of brain cells. Fluoroquinolones (FQs), widely used antimicrobials with effective blood-brain barrier penetration, show promise in being repurposed as anti-inflammatory drugs. Therefore, we aimed to test the efficacy of repurposed FQs for the treatment of cadmium-induced inflammation using cultures of U-87 MG human astrocytes and primary human astrocytes. Both FQs abrogated cadmium-induced interleukin (IL)-6 and IL-8 release from human astrocytes in a concentration and time-dependent manner, although levofloxacin had a stronger inhibitory effect than moxifloxacin. The downregulation of inflammatory cytokine release occurred with a concomitant reduction in cadmium-induced elevations in p65 nuclear factor-κB (NF-κB) and extracellular signal-regulated kinases (ERKs) 1/2 phosphorylation. Additionally, levofloxacin treatment significantly alleviated cadmium-induced activation of phosphorylated NF-κB translocation and toll-like receptor (TLR)-4/signal transducer and activator of transcription (STAT) 3 signaling. Transcriptome analysis revealed that modulation of inflammation-related pathways was the most enriched after FQ treatment. Our data suggest that FQs, particularly levofloxacin, attenuate the inflammatory process mediated by cadmium in human astrocytes. These effects may be mediated, at least in part, by inhibition of immune pathways regulated by TLR4, STAT3, ERK MAPK, and NF-κB.
Boreal forests are heading for an open state
The boreal forest biome is warming four times faster than the global average. Changes so far are moderate, but time lags in responses may transiently maintain forest states which are no longer supported by current environmental conditions. Here, we explore whether tree cover dynamics hint at the state to which the biome may be shifting. Our results suggest that global boreal tree cover is heading for a unimodal state of open forest (30 to 50%), contrasting starkly to the bimodal distribution of dense forests (>60%) and sparse woodlands (5 to 15%) found today. A future open forest in a warmer world would likely increase the risk of forest fires, leading to potentially substantial releases of stored carbon.
Flexibility in choosing decision policies in gathering discrete evidence over time
The brain can remarkably adapt its decision-making process to suit the dynamic environment and diverse aims and demands. The brain’s flexibility can be classified into three categories: flexibility in choosing solutions, decision policies, and actions. We employ two experiments to explore flexibility in decision policy: a visual object categorization task and an auditory object categorization task. Both tasks required participants to accumulate discrete evidence over time, with the only difference being the sensory state of the stimuli. We aim to investigate how the brain demonstrates flexibility in selecting decision policies in different sensory contexts when the solution and action remain the same. Our results indicate that the decision policy of the brain in integrating information is independent of inter-pulse interval across these two tasks. However, the decision policy based on how the brain ranks the first and second pulse of evidence changes flexibly. We show that the sequence of pulses does not affect the choice accuracy in the auditory mode. However, in the visual mode, the first pulse had the larger leverage on decisions. Our research underscores the importance of incorporating diverse contexts to improve our understanding of the brain’s flexibility in real-world decision-making.
Plant community and structural pattern analyses of Abraham Sacred Forest in Amhara Regional State, northwest Ethiopia
Owing to its topographic variations, Ethiopia is a biodiversity-rich country. However, the long-term degradation of resources has resulted in isolated forest patches largely around sacred places. Thus, this work was aimed to evaluate the plant community formation and structural dynamics of the Abraham Sacred Forest patch. Data were collected from 60 plots located on transect lines. Five subplots (4 m2), four at each corner and center, were set to collect juveniles’ data. Individuals of each species and cover abundance were recorded, and adults’ stem girth was measured. Hierarchical cluster analysis was used to identify plant communities. A Kruskal-Wallis followed by Tukey’s honestly significant difference test was performed to check the statistical significance among the plant communities. Shannon-Wiener diversity index, equitability index, and non-parametric species richness estimators were used to quantify species diversity, evenness, and richness, respectively. Structural parameters and size class ratios were used to analyze the vegetation structure and regeneration status. Seventy wood species, distributed in 62 genera and 38 families, were recorded. Fabaceae was the most species-rich (10 species) family. Three plant communities were identified. A Kruskal-Wallis test indicated that the community types showed significant differences (P < 0.05) with respect to altitude and slope. The density and basal area of the forest were 4580.4 ha-1 and 35.18 m2ha-1 respectively. The inverted J-shaped pattern in DBH classes implies a good reproduction status. However, importance value index and regeneration status analyses revealed that certain species, like Astropanax abyssinicum (Hochst. ex. A. Rich) Seem, Myrica salicifolia Hochst. ex. A. Rich and Dombeya torrida (G.F.Gmel) Bamps, require conservation priority.
Effect of one dose of ceftriaxone during endotracheal intubation on the incidence of aspiration pneumonia in cerebral hemorrhage patients: A randomized, controlled, double-blind clinical study protocol
Introduction Patients with cerebral hemorrhage often require a tracheal intubation to protect the airway and maintain oxygenation. Due to the use of analgesic and sedative drugs during endotracheal intubation and the opening of the glottis may easily cause aspiration pneumonia. Ceftriaxone is a semi-synthetic third-generation cephalosporin with strong antimicrobial activity against most gram-positive and gram-negative bacteria. It can effectively prevent and treat aspiration pneumonia. Methods and analysis This is a prospective, randomized, controlled, double-blind clinical study. Patients with intracerebral hemorrhage (ICH) undergoing endotracheal intubation in Dong E Hospital of Shandong Province from April 2023 to April 2025 will be enrolled and randomly assigned to the intervention group or control group. The intervention group will be treated using 100mL 0.9% sodium chloride with 2g ceftriaxone intravenously over the course of one hour beginning within two hours after endotracheal intubation. The control group will be given 100mL 0.9% sodium chloride injection intravenously of the course of one hour beginning within two hours after endotracheal intubation. The primary outcome is the incidence of aspiration pneumonia within 48 hours after endotracheal intubation. Secondary outcomes include: intensity of antimicrobial use, length of hospital stay, duration without mechanical ventilation, and 28-day mortality. Discussion The primary objective of this study is to explore whether a single dose of ceftriaxone administered during endotracheal intubation in patients with ICH reduced the incidence of pneumonia within 48 hours and provide evidence for the prevention of aspiration pneumonia in patients with ICH with endotracheal intubation. Trial registration The trial is registered at the Chinese Clinical Trial Registry: ChiCTR2200066837. Registered on December 19, 2022.
Plant-derived Pembrolizumab in conjugation with IL-15Rα-IL-15 complex shows effective anti-tumor activity
Anti-programmed cell death 1 (PD-1) monoclonal antibodies (mAbs) have proven to be effective in treating various cancers, including colorectal, lung, and melanoma. Despite their clinical success, some patients develop resistance to mAbs, requiring co-treatments with radio- or chemotherapy. Interleukin-15 (IL-15) is an immunostimulatory cytokine that promotes immune cell production and proliferation. It has been combined with mAbs and other immunotherapies to improve efficacy and reduce side effects. Fusion of anti-PD-1 mAb and IL-15 streamlines drug administration and management. In this study, we developed a prototype by conjugating the IL-15 receptor subunit alpha (IL-15Rα) and IL-15 complex to the C-terminus of anti-PD-1 Pembrolizumab (Pembrolizumab-IL-15Rα-IL15) using plant molecular farming for production. LC-MS revealed the presence of plant N-glycans (GnGnXF, GnXF and Man9GlcNAc2) on the molecule, which may affect receptor-binding avidity. However, ELISA demonstrated comparable binding efficacy of Pembrolizumab-IL-15Rα-IL15 to human PD-1 protein as commercial Pembrolizumab. In a mouse anti-cancer study, Pembrolizumab-IL-15Rα-IL15 (3 mg kg-1) exhibited slightly improved tumor-growth inhibition, reducing tumor size by 94% compared to commercial Pembrolizumab (5 mg kg-1) with an 83% reduction, regardless of statistically significant difference. In conclusion, Pembrolizumab-IL-15Rα-IL-15 was successfully produced using plant molecular farming and shows promise in addressing mAb drug resistance and enhancing the immunomodulatory effects of IL-15 payload.
Fracture-healing effects of Rhizoma Musae ethanolic extract: An integrated study using UHPLC-Q-Exactive-MS/MS, network pharmacology, and molecular docking
Background Fracture disrupts the integrity and continuity of the bone, leading to symptoms such as pain, tenderness, swelling, and bruising. Rhizoma Musae is a medicinal material frequently utilized in the Miao ethnic region of Guizhou Province, China. However, its specific mechanism of action in treating fractures remains unknown. This study aimed to elucidate the chemical constituents of the ethanol extract of Rhizoma Musae (EERM) and investigate its fracture-healing mechanism using network pharmacology. Methods The chemical profile of EERM was characterized via UHPLC-Q-Exactive-MS/MS. Subsequently, a comprehensive network of compounds, targets, and pathways was constructed using network pharmacology approaches. The interactions between the active compounds of EERM and their targets were validated through molecular docking, molecular dynamics simulation and in vitro cell experiments. Results EERM contained 522 identified compounds. Topological analysis of the protein-protein interaction (PPI) network identified 59 core targets, including key proteins like AKT1, IL-6, and EGFR, known for their anti-inflammatory properties and ability to enhance bone cell proliferation and differentiation. Gene Ontology analysis indicated the involvement of EERM in biological processes such as peptidyl-serine phosphorylation, response to xenobiotic stimulus, and nutrient level regulation. KEGG analysis suggested that EERM’s mechanism may involve signaling pathways such as PI3K-Akt, lipid and atherosclerosis, EGFR tyrosine kinase inhibitor resistance, and MAPK pathways. Molecular docking and molecular dynamics simulations results demonstrated a strong binding affinity between the main compounds of EERM and key targets. In vitro cell experiments demonstrate that EERM enhances cell proliferation by upregulating the expression levels of EGFR and STAT3, while simultaneously downregulating AKT1 and CASP3. Conclusion This study investigates the potential active compounds of EERM and its key targets in regulating multiple pathways of fracture, leading to promoting bone cell proliferation. These results offer valuable insights for the future development and clinical application of Rhizoma Musae.