Search Results (126)

Break-bulk cargo operations are characterized by high variability and complex resource synchronization, yet they have received limited research attention compared to containerized logistics. This paper proposes an integrated lean-informed simulation framework for evaluating vessel service time (VST) in multipurpose terminals handling break-bulk cargo. The framework sequences three analytical stages: Value Stream Mapping paired with Ohno’s waste taxonomy to diagnose non-value-adding activities, a discrete-event simulation model built in Simio to quantify their impact on VST, and Sobol sensitivity analysis to decompose the remaining variability across operational factors. Demonstrated at DP World Lirquén, a multipurpose terminal in Chile, the lean diagnostic identified 101 min of waste per cycle across waiting, motion, and overproduction categories. Scenario evaluation showed that eliminating shift-transition delays and standardizing load composition reduced VST by 14.3% and 10.6%, respectively, without capital investment. The sensitivity decomposition revealed that warehouse machinery composition, particularly the interaction between equipment types, dominates VST variability, while truck fleet size operates as an independent factor. These findings demonstrate that coordination-related policy interventions outperform incremental resource additions. More specifically, machinery allocation must be optimized jointly rather than by equipment type in isolation. Full article

Therapy resistance remains a major obstacle to successful cancer treatment and is driven by complex interactions between tumor-intrinsic adaptive mechanisms and signals originating from the tumor microenvironment. Among the molecular regulators implicated in these processes, the transcription factor FOXM1 has emerged as a key mediator of DNA damage repair, cell cycle progression, and stress adaptation. Although FOXM1 has traditionally been studied as a regulator of intracellular signaling pathways, accumulating evidence suggests that its functions extend beyond canonical transcriptional control. In this review, we analyze current knowledge on the mechanisms regulating FOXM1 expression and activity and discuss how FOXM1 contributes to therapy resistance. We propose that FOXM1 should be viewed not merely as a regulator of individual oncogenic pathways but as a systems-level coordinator that integrates intracellular stress adaptation with microenvironment-driven resistance mechanisms. Particular attention is given to the FOXM1 interactome, complemented by an analysis of protein interaction data from BioGRID. We also discuss emerging evidence implicating FOXM1 in intercellular communication. To identify potential links between FOXM1 signaling and extracellular vesicle cargo, we analyzed the overlap between FOXM1 target genes and proteins identified in extracellular vesicle proteome databases. These emerging regulatory networks may represent previously underappreciated contributors to therapy resistance. Full article

Port decarbonization strategies often prioritize emissions under direct port authority control while overlooking dominant indirect sources. This study proposes an approach that combines Life-Cycle Assessment (LCA) and expert elicitation. While existing studies often rely on descriptive emission inventories, this paper demonstrates the value of combining quantitative life-cycle data with expert judgment. The methodology is applied to the Port of Sines, Portugal’s largest port by cargo volume and handling capacity. The LCA revealed that Scope 3 emissions account for over 99% of total greenhouse gas emissions, with ocean-going vessels as the main contributors. The expert elicitation process prioritized energy-related measures such as renewable energy, alternative fuels, electrification, and energy efficiency, while onshore power supply and ship–port interface measures received lower priority. By comparing the results, the study reveals a misalignment between the most significant emission sources (Scope 3 emissions, particularly ocean-going vessels) and commonly prioritized decarbonization measures (measures addressing Scopes 1 and 2). The main contribution lies in combining LCA findings and expert inputs to actively inform strategic decision making, helping ports realign decarbonization strategies toward high-impact measures and providing transferable insights for other ports pursuing net-zero objectives. Full article

The family of Nek kinases has 11 human members that are conserved in their kinase domains but diverse in their regulatory domains. Functionally, they can be associated with diverse aspects of cell cycle regulation, from mitosis and primary cilia function to centrosome disjunction in the G2 phase and checkpoints of the DNA damage response. However, novel functional contexts have emerged in recent years, including regulatory roles of Neks 1, 4, 5, and 10 in mitochondrial metabolic and morphological homeostasis. We recently generated, by CRISPR-Cas9 technology, a DU-145 prostate cancer cell line, with an NEK6 gene knockout. Here, we focus on a detailed characterization of changes in this cell line, in mitochondrial respiration function and morphology. DU-145 NEK6 knockout cells exhibited reduced mitochondrial respiration and a fragmented phenotype in electron microscopy, with reduced mitochondrial cristae numbers. Alterations in mitochondrial architecture and respiration were correlated with increased expression of anaerobic glycolytic proteins (HK2, PFKP, and LDHA) and decreased expression of PDH, an enzyme of aerobic glycolysis. Molecular analysis by Western blot revealed decreased levels of mitochondrial mass and biogenesis protein markers (TOM20, TFAM), without alterations in other markers such as VDAC1/3 or mtDNA copy number in the NEK6 knockout cells. Furthermore, the regulators of mitochondrial fusion/fission are altered in the knockout cells (decrease in the Long-OPA1:Short-OPA1 ratio and DRP1 total level), which is associated with an increase in endoplasmic reticulum–mitochondria contact at ≤20 nm observed in transmission electron microscopy (TEM) image analysis. Using analysis of TEM micrographs, we found an increase in the autophagic structures (autophagosome, amphisome, and autolysosome), with mitochondria as cargo in some structures, which was correlated with a decrease in LC3A/B and an increase in the BECLIN1 total level, and with an increase in acidic vesicles approximation, suggesting that reduction in TOM20 and TFAM without alterations in VDAC1/3 and mtDNA copy number might be related to mitochondrial degradation through autophagy. Together, our data suggest a new role for NEK6 in regulating mitochondrial homeostasis, where its loss alters mitochondrial morphology and respiration, and could be associated with an increase in the degradation of the dysfunctional mitochondria through autophagy. Full article

International and regional decarbonisation policies are accelerating the deployment of hybrid electric propulsion systems (HEPSs) in short-sea and coastal trades, yet most existing design studies focus on ferries or tugs, rely on stylised duty cycles, and treat battery degradation only superficially. This paper proposes an integrated, data-driven framework for the design and dynamic performance optimisation of a diesel–battery HEPS for a coastal general cargo vessel operating on short-sea routes. A multi-year automatic identification system (AIS) and logbook data are processed to derive route-specific, time-resolved operating profiles, which drive a DC-based hybrid propulsion model comprising diesel generator sets, propulsion motors and a lithium-ion battery energy storage system (ESS). A degradation-aware ESS model is embedded in a life-cycle cost (LCC) formulation that explicitly accounts for battery replacement timing and residual value. The hybrid design problem is cast as a bi-level optimisation: an upper level determines engine rating and ESS capacity to minimise LCC, while fuel savings and emissions are evaluated as key parallel performance indicators, while a lower level uses dynamic programming to compute optimal power split trajectories under state-of-charge, C-rate and power constraints. A surrogate-assisted global search with Kriging and Expected Improvement is employed to manage the computational burden of repeated lower-level optimisations. Case-study results for representative coastal routes show that the optimised hybrid configurations achieve fuel savings of 16–21%, CO₂ reductions of 17–20%, and LCC reductions of 8–14% relative to a conventional mechanical baseline, outperforming a rule-based hybrid design. Sensitivity analyses with varying fuel prices and ESS costs confirm the robustness of the proposed framework and highlight the importance of explicitly coupling degradation-aware ESS. Full article

Prevalent cancers primarily include breast, lung and bronchus, prostate, and colorectal cancers. In contrast, cancer of the epididymis is very rare, and we propose that this tissue could carry inherent anticancer components, in particular, small extracellular vesicles (EVs) with antineoplastic properties. All cell types release extracellular vesicles (EVs) into their intercellular space, which act in the crosstalk required to achieve homeostasis. Among these, small EVs, which are membrane-bound vesicles with an average diameter of 30–200 nm, can transfer cell-specific cargo, such as lipids, proteins, DNA and RNA, which can be selectively received by neighboring or distant cells, and trigger specific cell processes, such as growth, division, or apoptosis. Here, we isolated small EVs from epididymis tissue, and examined their effect on morphology, viability, apoptosis, cell cycle phases, and certain gene and protein expression levels, particularly of the pro-apoptotic p53 protein, in HCC38 and MCF-7 breast cancer cell lines, as well as in a normal fibroblast cell line. The various analyses demonstrated effects on breast cancer cells but not on normal cells. Specifically, epididymis-derived EVs (Ep-EVs) selectively induced apoptosis and cell cycle arrest in cancer cells, while normal cells were unaffected. Moreover, the relative uptake of Ep-EVs in HCC38 and MCF-7 breast cancer cells was significant, indicating a direct association between vesicle internalization and the biological response. Taken together, these findings demonstrate a solid experimental foundation supporting the therapeutic potential of Ep-EVs in breast cancer, with promising implications for their development as a broader anticancer platform. Full article

In recent years, electric cargo (e-cargo) bikes have been increasingly adopted as a sustainable alternative for urban logistics and last-mile delivery, particularly in densely populated areas where traditional vehicles face traffic congestion and access limitations. This study aims to develop a representative driving cycle for e-cargo bikes based on real-world cycling data. An instrumented Long John-type e-cargo bike was used to collect naturalistic data from four different riders covering a total of 50 km along a predefined route in the city center of Florence, selected in collaboration with the Italian postal service provider (i.e., Poste Italiane) to reflect typical delivery operations. The driving cycle was generated using a Markov chain Monte Carlo (MCMC) method, modeling the stochastic transitions of vehicle speed and acceleration values. The resulting driving cycle, defined as the Florence cargo bike driving cycle (FCBDC), achieved an error of 2.1% on the Speed Acceleration Probability Distribution (SAPD) root sum square difference; although minor losses in peak acceleration values were observed due to data smoothing and discretization, the synthesized driving cycle effectively reproduces the dynamic characteristics of e-cargo bike riding. While the study is limited to a single route and is equivalent to simulated postman behavior, it provides valuable insights to guide the future development and optimization of e-cargo bikes for sustainable mobility operations. Full article

Extracellular vesicles (EVs), particularly exosomes, have emerged as critical mediators of intercellular communication, yet the metabolite fraction of their cargo remains substantially underexplored relative to proteins and nucleic acids. This review synthesizes current knowledge on the exosomal metabolome as a functionally distinct intercellular signaling system with unique biophysical properties. We review the mechanisms proposed to govern metabolite encapsulation into exosomes, encompassing membrane transporter involvement, lipid raft partitioning, and binding to luminal proteins, and discuss the unresolved question of whether metabolite loading is selective or stochastic. Critically, we present a quantitative framework evaluating whether delivered metabolite quantities are sufficient to alter recipient cell metabolic pools, distinguishing receptor-mediated signaling from bulk substrate delivery. We also address methodological considerations including contamination artifacts and isolation-method biases that complicate interpretation of EV metabolomics data. Exosomal metabolites are reviewed across four functional categories: energy substrates (ATP, lactate, amino acids), signaling molecules (TCA cycle intermediates, eicosanoids, nucleotides), redox cofactors and antioxidants (NADH, glutathione), and oncometabolites. For each category, available evidence is critically appraised, distinguishing metabolites with direct mass spectrometric detection from those whose roles are inferred from parent-cell biology. The review examines the roles of exosomal metabolites in tumor-stroma metabolic symbiosis, immunometabolic regulation, inter-organ crosstalk in metabolic diseases including type 2 diabetes and non-alcoholic fatty liver disease, cancer metastasis, viral infections, and immune evasion. A quantitative framework is discussed to evaluate whether delivered metabolite quantities are sufficient to alter recipient cell metabolic pools, distinguishing receptor-mediated signaling from bulk substrate delivery. Technical challenges in exosomal metabolomics are reviewed, including the impact of isolation method on data quality, contamination artifacts, and current standardization gaps. Therapeutic implications of exosomal metabolite signaling are discussed, encompassing metabolite-loaded exosomes as therapeutic vehicles and exosomal metabolite loading as a pharmacological target. Integration of single-vesicle technologies with systems biology approaches is highlighted as a promising direction for advancing this field toward precision medicine applications in oncological and metabolic disorders. Full article

Background: Extracellular vesicles (EVs) are increasingly explored as nanocarriers in drug delivery; however, selecting an appropriate loading strategy for a given small-molecule cargo still relies largely on empirical, resource-intensive parallel screening within EV formulation workflows. Despite the widespread application of passive incubation, electroporation, saponin-mediated permeabilization, freeze–thaw cycling, and sonication, there is currently no mechanistically grounded, descriptor-informed framework that enables rational prioritization of loading methods during the early design stage of EV-based dosage forms, leading to inefficient trial-and-error experimentation. Methods: We assembled a chemically diverse dataset of 21 compounds with experimentally determined loading efficiencies across five EV loading methods and calculated seven mechanistically motivated physicochemical descriptors (LogP, molecular weight, aqueous solubility, hydrogen bond donors/acceptors, polar surface area, and formal charge) for each drug. Separate Elastic Net regression models were trained for each loading strategy. Model performance was evaluated using leave-one-out cross-validation, a predefined external validation set (n = 4), and 50 repeated random train–test splits. The analysis emphasized decision-level ranking of loading methods rather than the precise prediction of absolute efficiencies. The applicability domain was assessed via leverage analysis to define the supported chemical space for prospective implementation in EV-based formulation development. Results: As anticipated for biologically heterogeneous EV systems, continuous regression performance remained modest (LOOCV R² = 0.06–0.41). In contrast, decision-level accuracy for identifying the experimentally optimal loading method was consistently high across validation schemes (internal: 76.5%; predefined external: 75%; repeated random validation: 80.5 ± 16.8%). Mechanical disruption methods (freeze–thaw and sonication) demonstrated comparatively greater predictive stability, while misclassification patterns suggested potential nonlinear behavior for highly polar, ionizable cargos. All compounds resided within the leverage-defined applicability domain, confirming adequate descriptor-space representation. Conclusions: This study establishes a mechanistically interpretable, descriptor-based decision-support framework capable of reliably prioritizing EV loading strategies for small-molecule cargos beyond empirical chance without altering standard protocols. By reframing the modeling objective from high-precision efficiency prediction to robust ranking of candidate methods, the approach offers a practical tool to triage between commonly used techniques, thereby reducing experimental burden in early-stage EV formulation development. The framework provides a quantitative basis for integrating molecular-descriptor-guided method selection into rational EV-based drug delivery design and can be expanded with membrane-specific descriptors and larger datasets. Full article

Androgenetic alopecia (AGA) and telogen effluvium (TE) are common hair loss disorders characterized by dysregulated hair follicle cycling and impaired dermal papilla cell function. Emerging evidence indicates that exosomes are key mediators of intercellular communication, largely through their microRNA (miRNA) cargo. Milk-derived exosomes (Mi-Exos) represent an accessible and biologically active source of regulatory miRNAs with potential relevance for hair disorders. This study evaluated the in vitro effects of bovine milk-derived exosomes (MEV-miRNAs) on human hair follicles. MEV-miRNAs were enriched in miRNA families (Let-7, miR-21, miR-30, miR-200, and miR-148/152) previously implicated in hair follicle regulation. Viability/metabolic activity of hair follicle dermal papilla (HFDP) cells was assessed, and human hair follicles were cultured ex vivo to measure shaft elongation and modulation of the WNT signaling pathway by qRT-PCR. MEV-miRNAs significantly increased HFDP cell viability after 24 h compared with controls. Human hair follicles showed a non-significant trend toward increased elongation following treatment. Gene expression analysis revealed significant up-regulation of key WNT pathway components, including WNT2, WNT5B, WNT10A, WNT11, MMP7, WISP1, and NKD1, indicating modulation of WNT-associated pathways implicated in hair follicle growth and cycling. Overall, MEV-miRNAs exhibit positive modulatory effects on signaling pathways, supporting their potential as a novel therapeutic strategy for AGA and TE. Full article

Oncosomes, a distinct subclass of extracellular vesicles released predominantly by tumor cells, have attracted increasing interest as potential carriers for targeted drug delivery in cancer research. Characterized by their large size (1–10 µm) and complex molecular cargo, including oncogenic proteins, nucleic acids, and lipids, oncosomes provide a biologically relevant platform for investigating tumor-associated communication and cargo transport. Preclinical studies suggest that oncosomes may enable tumor-associated delivery of therapeutic agents; however, evidence to date remains largely proof-of-concept and derived from in vitro and animal models. This review summarizes current knowledge on oncosome biogenesis and molecular composition; discusses their roles in cancer progression and metastasis; and critically evaluates existing methodologies for oncosome isolation, characterization, and cargo loading, including incubation, electroporation, sonication, freeze–thaw cycling, and transfection. Potential advantages such as cargo capacity and biological compatibility are discussed alongside key challenges, including vesicle heterogeneity, limited loading efficiency, large-scale manufacturing constraints, safety considerations, and regulatory uncertainty. Future perspectives focus on addressing these technical and translational barriers to support the systematic evaluation of engineered oncosomes as an experimental platform for personalized and precision-oriented cancer research. Full article

Exosomes are small extracellular vesicles that package DNA fragments, several classes of RNA, lipids, and proteins, and are now regarded as active messengers between cells rather than as cellular debris. This narrative review synthesizes dermatologic and related regenerative applications reported between 2020 and 2025, drawing on PubMed and Scopus searches. In skin, exosomes regulate inflammation, angiogenesis, matrix remodeling, pigmentation, and hair cycling. Preclinical models show faster wound closure, improved scar architecture, attenuation of photoaging changes, and stimulation of hair growth, with additional signals in inflammatory dermatoses and fungal skin disease. Early human studies in wound care, rejuvenation, scars, and alopecia suggest acceptable safety and a recurring pattern of benefit when exosomes are used as adjuncts to microneedling, lasers, or standard dressings, although products, dosing, and outcome measures remain heterogeneous. Beyond dermatology, early work in osteoarticular and soft tissue repair points toward meaningful regenerative potential, but clinical programs are still at an early stage. In practice, exosomes are being positioned as acellular alternatives or add-ons to platelet-rich plasma, bone marrow aspirate concentrate, and conventional topicals and as emerging carriers for small molecules and biologics. Key limitations include low yields, product and cargo heterogeneity, lack of agreed quality and potency metrics, and uncertain regulatory status. Whether exosomes remain boutique adjuncts or become part of standard dermatologic and musculoskeletal practice will depend on what happens next: consistent manufacturing, agreed-upon characterization panels, meaningful potency assays, robust pharmacokinetic and biodistribution data, and comparative trials that track outcomes and safety over years rather than weeks. Full article

Defrost cycles in shipboard refrigeration plants are typically initiated on fixed schedules or by operator judgement, which can lead to unnecessary energy use and temperature variability during the transport of frozen products. This study proposes a data-driven predictive maintenance approach to trigger defrost on demand in a merchant reefer vessel carrying frozen tuna. A total of 76,692 operational records from cargo-hold air coolers and holds were analysed, including delivery and return air temperatures, hold air temperature and relative humidity. The records were modelled to show their behaviour under real voyage conditions. The modelled strategy indicates that 66.55% of defrost cycles performed during the study period were unnecessary, suggesting substantial scope to reduce defrost frequency and associated disturbances. These findings demonstrate the feasibility of implementing machine learning (ML)-based decision support for maritime refrigeration. This enables defrost-on-demand scheduling, which has the potential to enhance operational efficiency while supporting product quality, sustainability and traceability in the frozen tuna supply chain. Full article

Despite treatments such as pentosan polysulfate, hyaluronic acid, botulinum toxin A, and platelet-rich plasma, many interstitial cystitis/bladder pain syndrome (IC/BPS) patients experience persistent symptoms. Urinary extracellular vesicles (uEVs) carry molecular cargo reflecting disease pathophysiology, yet their proteomic profiles in treated IC/BPS remain unexplored. This pilot study examined uEV proteomics in refractory IC/BPS cases to test the “Toxic Urine Hypothesis”—a vicious cycle, whereby urothelial dysfunction enables EV-mediated toxin penetration, triggering inflammation that further impairs the bladder barrier. Urinary EVs were isolated from six female IC/BPS patients on active treatments and four healthy female controls. Mass spectrometry-based proteomics identified differential protein expressions, followed by pathway enrichment analysis and functional validation using NF-κB reporter assays in HEK293T cells and Western blot in primary human bladder epithelial cells. IC/BPS EVs exhibited 31 upregulated proteins (including HPGD, KRT8, HSPA4, 14-3-3 family members) and 19 downregulated proteins (including neutrophil granule proteins MPO and ELANE), indicating suppressed acute neutrophil inflammation but enriched homeostatic, metabolic, and regenerative pathways. Patient EVs induced significantly higher NF-κB activation than in the controls, with upregulated 14-3-3ζ and phosphorylated NF-κB p65 in bladder epithelial cells. These findings support the “Toxic Urine Hypothesis”, revealing persistent NF-κB-mediated chronic epithelial stress despite suppressed acute inflammation in treated IC/BPS patients, suggesting that therapies targeting inflammation and regeneration may help break this vicious cycle. Full article

A promising approach to advancing sustainable urban mobility is the increased use of light electric vehicles, such as e-cycles and their cargo-carrying variants: e-cargo cycles. These micromobility vehicles fall between e-cycles and conventional vehicles in terms of transport capacity, range, and cost. A key advantage of e-cargo cycles over their non-electrified counterparts is the electric powertrain, which enables them to carry heavier payloads, travel longer distances, and reduce driver fatigue. Since the primary use of e-cargo cycles is urban parchment deliveries, trip efficiency plays a critical role in their effectiveness within urban logistics. This efficiency is influenced by factors such as travel distance, traffic density, and the weight and volume of the delivery payload. While higher delivery capacity generally enhances efficiency, studies have shown that as the drop size increases, the efficiency of e-cargo cycle delivery trips tends to decline. A practical way to address this limitation is the use of cargo attachments, such as trailers. These micromobility solutions are already widely implemented globally and significantly enhance transport capacity. This paper reports the process of designing and testing the control algorithm of an electrical system for an experimental attachment demonstrator that can be used to convert most cycle vehicles into cargo variants. The system integrates two 250 W BLDC hub motors, two 576 Wh lithium-ion batteries, dual load-cell sensing in the coupling element, and an STM32-based controller to provide independent propulsion and synchronization with the leading cycle. The force-based control strategy enables automatic adaptation to varying payloads typically encountered in urban logistics, which is supported by the variable storage volume capable of transporting payloads of up to 200 kg. Full article