Advancing Open Science

Background: Skin cancer progression is driven by the dysregulation of key oncogenic signaling pathways, including EGFR, BRAF V600E, and TGF-β, which collectively promote tumor proliferation, invasion, and metastatic progression. Targeting these pathways using multitarget natural modulators represents a promising therapeutic strategy. Methods: In this study, forty-nine phytoconstituents from Cannabis sativa were evaluated using an integrated computational approach to explore their inhibitory potential against EGFR, BRAF V600E, and the TGF-β receptor. Molecular docking was performed to assess binding affinities and interaction profiles, followed by ADMET analysis to evaluate pharmacokinetic and safety properties. The top-ranked compounds were further investigated using 200 ns molecular dynamics simulations and MM-GBSA binding free energy calculations to assess the stability and strength of protein–ligand interactions. Results: Several phytoconstituents exhibited strong binding affinities toward the target proteins, formed stable interactions with key active-site residues, and demonstrated favorable pharmacokinetic profiles with acceptable safety characteristics. Molecular dynamics simulations confirmed the structural stability of the selected protein–ligand complexes, while MM-GBSA analysis supported their favorable binding energetics. Conclusions: These findings suggest that Cannabis sativa phytoconstituents may represent a promising source of multitarget modulators capable of attenuating EGFR, BRAF V600E, and TGF-β driven oncogenic signaling in skin cancer. This study provides a mechanistic framework that supports further in vitro validation and the development of cannabis-derived therapeutic candidates for targeted skin cancer management.

The convergence of Lean manufacturing and Industry 4.0 requires digital infrastructures capable of transforming high-frequency telemetry into actionable insights. However, architectures that integrate near real-time data with closed-loop process control remain scarce, particularly in the food-processing industry. This study proposes a “Lean 4.0” framework based on a six-layer Digital Twin (DT) architecture to digitise waste detection and optimise a medium-scale bakery. The methodology integrates a heterogeneous Industrial Internet of Things (IIoT) network comprising 17 ESP32 (Espressif Systems, Shanghai, China)-based monitoring nodes. Data collection is managed via an edge-centric MQTT–InfluxDB (version 2.7, InfluxData, San Francisco, CA, USA) data pipeline. Furthermore, the analytics layer employs discrete-event simulation in Siemens Plant Simulation (version 2302, Siemens Digital Industries Software, Plano, TX, USA), constraint programming with Google OR-Tools (version 9.8, Google LLC, Mountain View, CA, USA), and machine learning models (Isolation Forest and SARIMA). Multi-month validation in a brownfield bakery, including a 60-day continuous monitoring test, demonstrated that the proposed architecture reduced production cycle time by 24.4% and inter-operational waiting time by 51.2%. Moreover, manual planning time decreased by 87.4% through the use of low-code scheduling interfaces. In addition, state-based control of critical ovens reduced energy consumption by 23.06%. These findings indicate that combining deterministic simulation and combinatorial optimisation with data-driven analytics provides a scalable blueprint for implementing cyber-physical systems in food-processing SMEs. This approach effectively bridges the gap between traditional Lean principles and data-driven smart manufacturing.

Background: Axonal misdirection remains a major limitation in peripheral nerve repair. While nerve guidance conduits (NGCs) and nerve scaffolds (NSCs) have advanced structurally, it is unclear whether these designs effectively reduce misdirection compared to autografts (ANGs). This systematic review evaluates the impact of NGC and NSC structural features on axonal dispersion and reinnervation accuracy using retrograde tracing animal models. Methods: A systematic search was performed through Medline (PubMed), Scopus (EBSCOhost), and the Cochrane Library from inception to December 2024. Eligible studies included mammalian in vivo models of peripheral nerve transection repaired by direct coaptation, autografts, or artificial conduits and assessed with retrograde axonal tracing. Data on neurons labeling, innervation accuracy, and histomorphometric parameters were extracted, and misdirection rates were calculated. Risk of bias was assessed using the SYRCLE tool. Due to heterogeneity, data were synthesized narratively following the SWiM framework. Results: Out of 4043 records identified through database searching and 37 through citation searching, 19 studies (49 experimental groups) met the inclusion criteria. Motoneuron counts were consistently reported across all arms, but no outcome assessing axonal misdirection was reported in more than half. Structured designs resulted in outcomes more closely aligned with ANG repair, while unstructured generally underperformed, and certainty of evidence was very low. Discussion: The evidence in this study was limited by high risk of bias, substantial inconsistency across heterogeneous study designs and outcomes, and imprecision from small animal models with sparse outcome measures. Despite the trend for structured designs to improve over basic hollow designs, current evidence does not support any structure as superior. Future research should be more standardized to provide reliable knowledge translational into clinical practice.

Despite the aesthetic potential of free-form envelopes in large-scale public buildings, geometric interlacing complexity, ambiguous façade boundaries, and constructability translation gaps persist as systemic barriers. This study addresses these challenges through a Design Science Research (DSR) approach, developing a rule-based digital twin methodology that maintains parametric intelligence across the building life cycle. Implemented via a five-layer integrated framework, i.e., geometric, parametric, BIM, coordination, and fabrication, the methodology was validated through a revelatory case study of the Shenzhen Bay Culture Plaza. Results demonstrate 91.2% clash resolution prior to construction, 20.3 million RMB in cost savings (10.8% reduction), and 35.4% schedule compression, while preserving rule-based relationships into operational facility management. The study advances BIM theory by operationalizing life-cycle digital twins for non-standard geometries, offering a replicable framework for future special-shaped construction projects.

Botrytis cinerea poses a major threat to postharvest strawberries, causing significant losses due to gray mold. As a plant-derived antifungal agent, Rhodiola rosea L. essential oil (REO) possesses considerable healthcare benefits. However, its effectiveness and underlying mechanisms in the maintenance of postharvest products remain poorly understood. This study demonstrated that REO at 0.5 µL/mL completely inhibited the growth of B. cinerea under in vitro conditions. In vivo fumigation treatment with REO alleviated the severity of gray mold in strawberry fruit. Additionally, REO decreased natural decay and positively impacted marketability, as evidenced by higher firmness, total soluble solids, and ascorbic acid contents, as well as more favorable color attributes. Further investigations involving scanning electron microscopy, calcofluor white (CFW) staining, propidium iodide (PI) staining, 2′,7′-dichlorodihydrofluorescein diacetate assay, and cellular leakage tests were conducted to investigate the effects of REO treatment on gray mold mycelium. Results showed that REO treatment induced severe morphological distortions and collapse of mycelium. Within 30 min of exposure, REO triggered a sharp increase in PI fluorescence accompanied by a decrease in CFW fluorescence, without inducing an elevation in intracellular reactive oxygen species levels. The elevated leakage of nucleic acids and soluble proteins further confirmed that REO compromised the integrity of the cell barrier in B. cinerea. Collectively, these findings indicate that REO exerts potent antifungal activity by disrupting the integrity and functionality of B. cinerea cellular barriers, thereby reducing postharvest decay and positively impacting the marketability of strawberry fruit. Taken together, our findings suggest that REO represents a promising natural alternative for environmentally sustainable postharvest protection of strawberries.

Carpinus betulus is an important ornamental landscape tree species with colorful foliage. It is widely used in landscaping due to its upright tree shape, significant seasonal changes, and good tolerance to pruning. Propagation methods for C. betulus include grafting, cutting, and seeding. However, the germination rate of seeding is low, and the rooting of cuttings is difficult; moreover, plant tissue culture techniques are complex, and the key technologies have not been disclosed. Grafting has therefore become the primary means of propagation. However, enabling the rapid reproduction of C. betulus through appropriate grafting methods and in appropriate environments remains an urgent issue to be addressed. In this study, Carpinus turczaninowii was used as a rootstock to graft C. betulus, and the effects of the grafting periods, technique, and environmental conditions on the survival rate of grafted C. betulus were discussed. The results showed that branch grafting (cleft graft and whip-and-tongue graft) performed in March to April and August to November resulted in the highest survival rates, whereas budding grafts (chip budding and patch budding) were more suitable in May and June. Increasing ambient humidity was a key measure for improving graft survival rates and germination rates. In terms of grafting survival rate, germination rate, and leaf growth, humidification and treatment with 60–70% light transmission had better results than treatment with natural humidity or 20–30% light transmission and full light treatment under humidification conditions. Under low-light conditions, increasing air humidity had a particularly pronounced effect on promoting the growth of grafted seedling branches. In the future, further research should be conducted on the molecular mechanism mediated by soil environment and temperature changes for the successful grafting of C. betulus, providing a theoretical basis for the propagation and cultivation of C. betulus.

The optimal dietary balance between n-6 and n-3 polyunsaturated fatty acids (PUFAs), the safe upper intake of n-6 PUFAs—particularly linoleic acid—and the physiological consequences of their metabolic competition remain unresolved in the context of the Western diet. Since the 1980s, Bill Lands and colleagues have argued that high n-6 PUFA intake can shift the balance of n-3-derived pathways and eicosanoid signaling, potentially influencing processes relevant to non-communicable diseases. Across human populations, the proportion of n-6 in tissue HUFA spans a broad range—from roughly 20% in traditional dietary patterns to nearly 80% in typical Western diets—illustrating the predictable impact of dietary precursor supply on HUFA composition. Despite its potential public health implications, this hypothesis has received limited systematic attention. In this narrative review, we synthesize key aspects of Lands’ work, evaluate supportive and contradictory evidence, and highlight mechanistic insights into lipid competition and inflammatory regulation. We conclude that these unresolved but testable hypotheses warrant renewed investigation, as their corroboration could reshape dietary guidelines and strategies for chronic disease prevention.

Background/Objectives: Botanical and nutraceutical approaches have increasingly been considered as alternatives or complements to conventional lipid-lowering therapies, particularly in individuals with mild-to-moderate dyslipidemia or statin intolerance. This study aimed to evaluate a multi-botanical formulation, combining black garlic, sesame, Gastrodia elata, and Primula veris extracts, for its effects on hepatic cholesterol regulation and the PCSK9–LDLr–SREBP-2 axis in vitro. Methods: Each extract was chemically characterised for its polysaccharide, polyphenol, flavonoid, and sesamin content. HepG2 cells were exposed to normal (5 mM) or high-glucose (30 mM) conditions to mimic metabolic stress. Dose–response studies identified optimal concentrations for cell viability. Hepatic safety was assessed via MTT and ROS assays, while cholesterol metabolism was evaluated by measuring HMG-CoA reductase levels, total cholesterol, LDL levels, bile acid production, free cholesterol levels, and the expression of PCSK9, LDLr, and SREBP-2 using ELISA and Western blot. Results: All individual extracts improved cell viability, reduced oxidative stress, and moderately modulated cholesterol metabolism. The multi-botanical combination exhibited synergistic effects, enhancing cell viability (+47.5% vs. untreated), suppressing ROS, reducing HMGR levels, and lowering total intracellular cholesterol more effectively than single extracts or the statin-like reference RYRF. Importantly, the combination strongly downregulated PCSK9 and inhibited SREBP-2 proteolytic activation while upregulating LDLr, indicating coordinated transcriptional and post-translational regulation. Bile acid production and free cholesterol excretion were also significantly increased, supporting improved cholesterol clearance. Conclusions: This four-botanical formulation effectively modulates hepatic cholesterol homeostasis via a multifactorial, synergistic mechanism distinct from statin-like agents. The results suggest its potential as a safe, non-statin strategy to support cardiometabolic health. Future studies are warranted to confirm long-term efficacy and clinical relevance.