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Abstract Background Breast cancer manifests as a heterogeneous pathology marked by complex metabolic reprogramming essential to satisfy its energy demands. Oncogenic signals boost the metabolism, modifying fatty acid synthesis and glucose use from the onset to progression and therapy resistant-forms. However, the exact contribution of metabolic dependencies during tumor evolution remains unclear. Methods In this study, we elucidate the connection between FASN and LDHA, pivotal metabolic genes, and their correlation with tumor grade and therapy response using datasets from public repositories. Subsequently, we evaluated the metabolic and proliferative functions upon FASN and LDHA inhibition in breast cancer models. Lastly, we integrated metabolomic and lipidomic analysis to define the contributions of metabolites, lipids, and precursors to the metabolic phenotypes. Results Collectively, our findings indicate metabolic shifts during breast cancer progression, unvealling two distinct functional energy phenotypes associated with aggressiveness and therapy response. Specifically, FASN exhibits reduced expression in advance-grade tumors and therapy-resistant forms, whereas LDHA demonstrates higher expression. Additionally, the biological and metabolic impact of blocking the enzymatic activity of FASN and LDHA was correlated with resistant conditions. Conclusions These observations emphasize the intrinsic metabolic heterogeneity within breast cancer, thereby highlighting the relevance of metabolic interventions in the field of precision medicine.

IntroductionThe contribution of Cannabinoid type 1 receptor (CB1) in mitochondrial energy transduction mechanisms and mitochondrial activities awaits deeper investigations. Our study aims to assess the impact of CB1 absence on the mitochondrial compartment in the liver, focusing on both functional aspects and remodeling processes.MethodsWe used CB1−/− and CB1+/+ male mice. Cytochrome C Oxidase activity was determined polarographically. The expression and the activities of separated mitochondrial complexes and supercomplexes were performed by using Blue-Native Page, Western blotting and histochemical staining for in-gel activity. Key players of Mitochondrial Quality Control processes were measured using RT-qPCR and Western blotting. Liver fine sub-cellular ultrastructural features were analyzed by TEM analysis.Results and discussionIn the absence of CB1, several changes in the liver occur, including increased oxidative capacity, reduced complex I activity, enhanced complex IV activity, general upregulation of respiratory supercomplexes, as well as higher levels of oxidative stress. The mitochondria and cellular metabolism may be affected by these changes, increasing the risk of ROS-related damage. CB1−/− mice show upregulation of mitochondrial fusion, fission and biogenesis processes which suggests a dynamic response to the absence of CB1. Furthermore, oxidative stress disturbs mitochondrial proteostasis, initiating the mitochondrial unfolded protein response (UPRmt). We noted heightened levels of pivotal enzymes responsible for maintaining mitochondrial integrity, along with heightened expression of molecular chaperones and transcription factors associated with cellular stress reactions. Additionally, our discoveries demonstrate a synchronized reaction to cellular stress, involving both UPRmt and UPRER pathways.

The conclusions on the best available techniques for waste incineration implemented in Europe by EU Decision 2019/2010 introduce ambitious targets for emission control. Provisions such as higher removal efficiency requirements for HCl and SO2 and the continuous measurement of Hg emissions can induce operators of existing waste-to-energy plants to contemplate a revamping of their flue gas cleaning lines to wet treatment, a guarantee of high abatement performance for both acid gases and micropollutants. However, wet treatment is associated with high investment costs and a relevant energy penalty related to the management of temperatures along the flue gas cleaning line, especially in the presence of tail-end deNOX treatments. The present study examines a possible alternative, represented by the integration of a wet scrubbing system as a final flue gas treatment downstream of an existing dry acid gas removal system. An economic and environmental analysis is performed in order to assess the potential benefit conferred by the retrofit. Noteworthy reductions in operational costs, diminished consumption of reactants, and a concurrent decrease in waste generation are observed, depending on the SO2 load in the flue gas and the compatibility constraints with deNOX operation in the selective catalytic reduction reactor.

Food plant diversity in bioactive compounds makes them an exploitable resource in the search for effective natural products to prevent or treat viral infections. Therefore, in the framework aimed at studying the antiviral properties of extractive mixtures from fruits (and their waste) grown in the Campania Region (Italy), jujube drupes (Zizyphus jujuba Mill.) were our focus. The drupes were dissected into their peel, pulp and seed parts, each of which was extracted by ultrasound-assisted maceration and further fractionated, thus obtaining, beyond the sugar fraction, a polyphenolic fraction and a lipid fraction. UHPLC-HR MS/MS tools highlighted that the polyphenolic component of the seed was strongly dissimilar from that of the edible parts, being constituted by swertisin and its derivatives. Moreover, the peel mostly accounted for triglycosylated flavonols, whereas the pulp was rich in volatile aromatic glycosides. Among lipids, p-coumaroyl triterpenes mainly characterized the peel. All fractions were screened for their cytotoxicity, and non-toxic concentrations of each extract were tested against herpes simplex virus type 1 (HSV-1) by plaque assays. Molecular tests and Western blot analyses were also carried out. The jujube mixtures, in detail the peel and pulp polyphenolic fractions, and peel lipophilic fraction (the latter enriched mainly in ursane-type triterpenes), showed a marked inhibitory activity against HSV-1 acting in the early stages of viral infection and preventing attachment of the virus to the host cell. The acquired data suggest jujube active mixtures as promising candidates for the prevention and treatment of herpetic lesions.

Wastewater from livestock farms contains high concentrations of suspended solids, organic contaminants, and nitrogen compounds, such as ammoniacal nitrogen. Discharging livestock effluents into water bodies without appropriate treatment leads to severe environmental pollution. Compared to conventional treatment methods, electrochemical oxidation exhibits higher nitrogen removal efficiencies. In the present work, the electrochemical removal of ammoniacal nitrogen from real livestock wastewater was investigated through a lab-scale reactor. Preliminary experiments were carried out to investigate the effects of different anode materials, including boron-doped diamond and iridium/ruthenium-coated titanium, on the total nitrogen removal efficiency using synthetic wastewater. Boron-doped diamond, a well-known non-active electrode, allowed to obtain 63.7 ± 1.21 % of total nitrogen degradation efficiency. However, the iridium/ruthenium-coated titanium electrode, belonging to the class of active anodes, showed a higher performance, achieving 78.8 ± 0.76 % contaminant degradation. Coupling iridium/ruthenium-coated titanium anode with a stainless-steel cathode improved the performance of the system, achieving even 96.2 ± 2.73 % of total nitrogen removal. The optimized cell configuration was used to treat livestock wastewater, resulting in the degradation of 67.0 ± 2.25 % of total nitrogen and 37.3 ± 0.68 % of total organic carbon when sodium chloride was added. At the end of the process, the ammonium content was completely removed, and only 17.7 ± 0.51 % of the initial nitrogen turned into nitrate. The results show that the proposed system is a promising approach to treating livestock wastewater by coupling high contaminant removal efficiencies with low operational costs. Anyway, further studies on process optimization with an emphasis on power requirements and electrode costs need to be carried out.

Abstract Efficient predictive biomarkers are needed for immune checkpoint inhibitor (ICI)-based immunotherapy in non-small cell lung cancer (NSCLC). Testing the predictive value of single nucleotide polymorphisms (SNPs) in programmed cell death 1 (PD-1) or its ligand 1 (PD-L1) has shown contrasting results. Here, we aim to validate the predictive value of PD-L1 SNPs in advanced NSCLC patients treated with ICIs as well as to define the molecular mechanisms underlying the role of the identified SNP candidate. rs822336 efficiently predicted response to anti-PD-1/PD-L1 immunotherapy in advanced non-oncogene addicted NSCLC patients as compared to rs2282055 and rs4143815. rs822336 mapped to the promoter/enhancer region of PD-L1, differentially affecting the induction of PD-L1 expression in human NSCLC cell lines as well as their susceptibility to HLA class I antigen matched PBMCs incubated with anti-PD-1 monoclonal antibody nivolumab. The induction of PD-L1 expression by rs822336 was mediated by a competitive allele-specificity binding of two identified transcription factors: C/EBPβ and NFIC. As a result, silencing of C/EBPβ and NFIC differentially regulated the induction of PD-L1 expression in human NSCLC cell lines carrying different rs822336 genotypes. Analysis by binding microarray further validated the competitive allele-specificity binding of C/EBPβ and NFIC to PD-L1 promoter/enhancer region based on rs822336 genotype in human NSCLC cell lines. These findings have high clinical relevance since identify rs822336 and induction of PD-L1 expression as novel biomarkers for predicting anti-PD-1/PD-L1-based immunotherapy in advanced NSCLC patients.

Abstract The critical roles of CD4+ T cells have been understudied for cancer vaccines. Here we report long-term clinical outcomes of a randomized multicenter phase II clinical trial (NCT00118274), where patients with high-risk melanoma received a multipeptide vaccine targeting CD8+ T cells (12MP) and were randomized to receive either of two vaccines for CD4+ (helper) T cells: 6MHP (6 melanoma-specific helper peptides), or tet (a nonspecific helper peptide from tetanus toxoid). Cyclophosphamide (Cy) pre-treatment was also assessed. Primary outcomes for T cell responses to 12MP, 6MHP, and tet were previously reported, suggesting immunogenicity of both vaccines but that CD8 T cell responses to 12MP were lower when tet was replaced with 6MHP. Here, in post-hoc analyses, we report durable prolongation of overall survival by adding 6MHP instead of tet. That benefit was experienced only by male patients. A favorable interaction of 6MHP and Cy is also suggested. Multivariable Cox regression analysis of the intent-to-treat population identify vaccine arm (12MP + 6MHP+Cy) and patient sex (male) as the two significant predictors of enhanced survival. These findings support the value of adding cognate T cell help to cancer vaccines and also suggest a need to assess the impact of patient sex on immune therapy outcomes.

Abstract Multiple oncogenic alterations contribute to breast cancer development. Metabolic reprogramming, deeply contributing to tumor microenvironment (TME) education, is now widely recognized as a hallmark of cancer. The reverse Warburg effect induces cancer-associated fibroblasts (CAFs) to produce and secrete L-lactate, enhancing malignant characteristics such as neoangiogenesis, metastatic dissemination, and treatment resistance. Monocarboxylate transporter (MCT) 4 is involved in lactate efflux from CAFs into stromal and epithelial cells. Here, we first assess the expression of miR-425-5p and its target MCT4 in breast cancer CAFs and normal fibroblasts. We analyzed the metabolic changes induced by miR-425-5p in CAFs and its role in the education of breast cancer epithelial cells. We show that miR-425-5p-induced MCT4 knockdown decreased lactate extrusion from CAFs and its availability in the TME. miR-425-5p overexpression induced profound metabolic transformation in CAFs, ultimately influencing breast cancer metabolism. Furthermore, miR-425-5p impaired the capacity of CAFs to sustain vessel formation and breast cancer cell migration, viability, and proliferation. These findings emphasize the key role of miR-425-5p in breast cancer metabolism and aggressiveness, and its possible importance for breast cancer therapy and monitoring.

Abstract We study the phenomenology of superheavy decaying dark matter with mass around 1010 GeV which can arise in the low-energy limit of string compactifications. Generic features of string theory setups (such as high scale supersymmetry breaking and epochs of early matter domination driven by string moduli) can accommodate superheavy dark matter with the correct relic abundance. In addition, stringy instantons induce tiny R-parity violating couplings which make dark matter unstable with a lifetime well above the age of the Universe. Adopting a model-independent approach, we compute the flux and spectrum of high-energy gamma rays and neutrinos from three-body decays of superheavy dark matter and constrain its mass-lifetime plane with current observations and future experiments. We show that these bounds have only a mild dependence on the exact nature of neutralino dark matter and its decay channels. Applying these constraints to an explicit string model sets an upper bound of O $$ \mathcal{O} $$ (0.1) on the string coupling, ensuring that the effective field theory is in the perturbative regime.

Starting from the regional air quality forecasts produced by the Copernicus Atmosphere Monitoring Service (CAMS), we propose a novel post-processing approach to improve and downscale results on a finer scale. Our approach is based on the combination of ensemble model output statistics (EMOS) with a spatio-temporal interpolation process performed through the stochastic partial differential equation–integrated nested laplace approximation (SPDE-INLA). Our interpolation approach includes several spatial and spatio-temporal predictors, including meteorological variables. A use case is provided that scales down the CAMS forecasts on the Italian peninsula. The calibration is focused on the concentrations of several air quality pollutants (PM10, PM2.5, NO2, and O3) at a daily resolution from a set of 750 monitoring sites, distributed throughout the Italian country. Our results show the key role that conditioning variables play in improving the forecast capabilities of ensemble predictions, thus allowing for a net improvement in the calibration with respect to ordinary EMOS strategies. From a deterministic point of view, the performance of the predictive model shows a significant improvement in the performance of the raw ensemble forecast, with an almost-zero bias, significantly reduced root mean square errors, and correlations that are almost always higher than 0.9 for each pollutant; moreover, the post-processing approach is able to significantly improve the prediction of exceedances, even for very low thresholds, such as those recently recommended by the World Health Organisation. This is particularly significant if a forecasting approach is used to predict air quality conditions and plan adequate human health protection measures, even for low alert thresholds. From a probabilistic point of view, the quality of the forecast was verified in terms of reliability and credible intervals. After post-processing, the predictive probability density functions were sharp and much better calibrated than the raw ensemble forecast. Finally, we present some additional results based on a set of gridded (4 km × 4 km) maps covering the entire Italian country for the detection of areas where pollution peaks occur (exceedances of the current and/or proposed regulatory thresholds).

Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) is a biodegradable polymer with excellent thermal and mechanical properties comparable to fossil-based plastics. Scaling up the production of this polymer could provide a viable solution for reducing the use of fossil-based materials. However, its current production capacities are limited, with only a few facilities implementing the process at pilot or semi-industrial scales. The primary challenge lies in the high production costs, with 40% of the expenses attributed to the feedstock used for fermentation. Additionally, the energy required for sterilization in processes using pure methanotrophic cultures further reduces its economic viability. In this study, the economic aspects of the PHBV production process were assessed at an industrial level (100,000 t/y PHBV), using cheap and renewable substrates such as valeric acid and methane. A mixed methanotrophic consortium was used to reduce the need for sterility. The techno-economic analysis was based on estimating both fixed investment and operating costs. Then, a sensitivity analysis was performed to analyse the effect that the polymer content has on the final selling price: the initial biomass concentration was set to 30 g L-1, and the PHBV content was considered to be 20, 30, 40, 50 and 70% wt on a dry weight basis. The results revealed that increasing the polymer content beyond 40% wt led to a more competitive PHBV selling price, thus opening significant market opportunities.

As the demand for rare earth elements (REEs) continues to surge in diverse industrial and medical domains, the ecological consequences of their ubiquitous presence have garnered heightened attention. Among the REEs, gadolinium (Gd), commonly used in medical imaging contrast agents, has emerged as a pivotal concern due to its inadvertent introduction into marine ecosystems via wastewater release. This study delves into the complex ecotoxicological implications of Gd contamination, focusing on its impact on the embryonic development and sperm functionality of Mytilus galloprovincialis. The findings from this study underscore the potential hazards posed by this rare element, offering a critical perspective on the ecological risks associated with Gd. Notably, this exploratory work reveals that Gd exerts a significant embryotoxic effect at elevated concentrations, with an observed half maximal effective concentration (EC50) value of 0.026 mg/L. Additionally, Gd exposure leads to a considerable reduction in sperm motility and alters sperm morfo-kinetic parameters, especially at a concentration of 5.6 mg/L. The results highlight a dose-dependent relationship between Gd exposure and the prevalence of specific malformation types in Mytilus embryos, further providing crucial insights into the potential risks imposed by this rare earth element.

Listeria monocytogenes is a gram-positive, primarily foodborne pathogen responsible for severe invasive infections (1), especially in immunocompromised patients. The treatment for some immunodeficiency conditions can require the administration of blood [...]

Microplastics (MPs) persist for long periods in the environment, causing adverse effects on aquatic and terrestrial ecosystems. The accumulation of MPs in various trophic levels mostly depends on weathering phenomena, their reduced dimensions and the improved bioavailability; this ultimately causes their ingestion by organisms living in different niches. The modern concern about MPs toxicity collides with the current unavailability of standardized and reliable methodologies to assess the risks associated with the exposure of organisms from different habitats. Hence, the identification and selection of appropriate biomonitors for MPs pollution risk assessment should focus on the identification of easy-to-implement assays, rapidly interpretable results (e.g., based on the MPs bioaccumulation capabilities in their tissues) and standardizable methodologies. The present review analyzed some emerging biomonitors exploited for MPs evaluation, selected and examined according to their potential use as specific biological indicators for diverse environments. The research was focused on plants, as biological models for airborne microfibers toxicity evaluation; mussels, as key organisms for the establishment of MPs accumulation in marine environments; land snails, representing emerging organisms selected for studies of MPs’ impact on soil. Furthermore, recent findings evidenced the influence of microplastics on the composition of environmental microbiota, enhancing pathogenic biofilms formation, leading to increased water, soil, food, crops and waste contamination. Disposing of harmonized and validated methods to study MPs’ impact on the environment, integrated with promising machine learning tools, might sensibly support the risk management strategies protecting human and animal health.

The implementation of morphing wing mechanisms shows significant potential for improving aircraft performance, as highlighted in the recent literature. The Clean Sky 2 AirGreen 2 European project team is currently performing ground and wind tunnel tests to validate improvements in morphing wing structures. The project aims to demonstrate the effectiveness of these morphing designs on a full-scale flying prototype. This article describes the design methodology and structural testing of a scaled morphing-flap structure, which can adapt to three different morphing modes for various flight conditions: low-speed (take-off and landing) and high-speed (cruise). A scale factor of 1:3 was selected for the wind tunnel test campaign. Due to challenges in scaling the embedded mechanisms and actuators necessary for shape-changing, a full geometrical scale of the real flap prototype was not feasible. Static analyses were performed using the finite element method to address critical load conditions determined through three-dimensional computational fluid dynamic (CFD) analysis. The finite element (FE) analysis was conducted and the results were compared with the empirical data from the structural test. Good correlations were found between the structural testing results and numerical predictions, including static deflections and elastic deformations under applied loads. This indicates that the modeling approaches used during the design and testing phases were highly successful. Based on simulations for the ultimate load conditions tested during the wind tunnel tests, the scaled flap prototype has been deemed suitable for further testing.

Fatigue damage represents a key failure mode in ship structures. Such damage typically begins at vulnerable points in the structure, like welded joints, stress concentration areas, and cracks. Cyclic loading, particularly from waves, encountered by ships during their operational life is a major cause of fatigue damage, which is the main focus of this study. There are various methods to address different sea state conditions, though they can sometimes be approximate. This paper aims to review the most commonly used methods to highlight their strengths and weaknesses and to provide essential background knowledge for developing reliable theoretical and numerical models for predicting the fatigue life of ship structures exposed to various sea states over their lifetime. The primary theoretical approaches discussed include energy spectral methods in both time and frequency domains, which are used to quantify wave-related energy and amplitude characteristics and evaluate wave loads for predicting the fatigue life of structures and welded joints. The discussion also covers the determination of cyclic stress in specific structural details of the hull girder and welded joints to identify the relevant maximum stress range for subsequent fatigue studies conducted using finite element analysis.