AbstractNon-small cell lung cancer (NSCLC) constitutes one of the deadliest and most common malignancies. The LKB1/STK11 tumour suppressor is mutated in ∼ 30% of NSCLCs, typically lung adenocarcinomas (LUAD). We implemented zebrafish and human lung organoids as synergistic platforms to pre-clinically screen for metabolic compounds selectively targeting LKB1-deficient tumours. Interestingly, two kinase inhibitors, Piceatannol and Tyrphostin 23, appeared to exert synthetic lethality with LKB1 mutations. Although LKB1 loss alone accelerates energy expenditure, unexpectedly we find that it additionally alters regulation of the key energy homeostasis maintenance player leptin (LEP), further increasing the energetic burden and exposing a vulnerable point; acquired sensitivity to the identified compounds. We show that compound treatment stabilises Hypoxia-inducible factor 1-alpha (HIF1A) by antagonising Von Hippel-Lindau (VHL)-mediated HIF1A ubiquitination, driving LEP hyperactivation. Importantly, we demonstrate that sensitivity to piceatannol/tyrphostin 23 epistatically relies on a HIF1A-LEP-Uncoupling Protein 2 (UCP2) signaling axis lowering cellular energy beyond survival, in already challenged LKB1-deficient cells. Thus, we uncover a pivotal metabolic vulnerability of LKB1-deficient tumours, which may be therapeutically exploited using our identified compounds as mitochondrial uncouplers.
The threat of antimicrobial resistance (AMR) and the need for sustainable disinfectants have spurred interest in natural antimicrobials such as essential oils (EOs). However, their application is limited by volatility, poor water solubility, and cytotoxicity. Herein, we present the development of bio-based core-shell sub-micro-/nanocapsules (NCs) with encapsulated oregano (OO), thyme (TO), eucalyptus (EuO), and tea tree (TTO) oils to enhance antimicrobial (AM) performance and reduce cytotoxicity. NCs were synthesized via a nanoencapsulation method using chemically modified zein or poly(methyl vinyl ether-co-maleic anhydride) (GZA) as shell polymers, with selected EOs encapsulated in their core (encapsulation efficacy > 98%). Chemical modification of zein with vanillin (VA) and GZA with either dodecyl amine (DDA) or 3-(glycidyloxypropyl)trimethoxysilane (EPTMS) resulted in improvement in particle size distributions, polydispersity indices (PDIs) of synthesized NCs, and in the stability of the NC-dispersions in water. Antibacterial testing against Staphylococcus aureus and cytotoxicity assays showed that encapsulation significantly reduced toxicity while preserving their antibacterial activity. Among the formulations, GZA-based NCs modified with EPTMS provided the best balance between safety and efficacy. Despite this, life cycle assessment revealed that zein-based NCs were more environmentally sustainable due to lower energy use and material impact. Overall, the approach offers a promising strategy for developing sustainable, effective, and safe EO-based antibacterial agents for AM applications.
Tacrolimus, a calcineurin inhibitor with a narrow therapeutic index, requires precise dosing to optimize efficacy and minimize adverse effects in kidney transplant recipients. Although CYP3A5 genetic variants influence tacrolimus pharmacokinetics, they do not fully explain inter-individual differences. This retrospective study evaluated the combined impact of CYP3A4 [*1B (rs2740574), *1 G (rs2242480), *22 (rs35599367)] and CYP3A5 [*3 (rs776746), *6 (rs10264272), *7 (rs41303343)] genetic variants, as CYP3A phenotypes, on tacrolimus dose-adjusted trough concentrations (C0/D), in 94 Greek kidney transplant recipients at five time points during the first-year post-transplantation. Significant differences in tacrolimus C0/D ratios were observed across the groups. Group 4 (CYP3A5 expressers, carriers of CYP3A4*1B or *1 G) had consistently lower C0/D ratios compared to Groups 1 and 2 (CYP3A5 nonexpressers, carriers of CYP3A4*22 or CYP3A4 *1/*1) at multiple timepoints (p ≤ 0.022 and p ≤ 0.004, respectively). These findings suggest that CYP3A phenotypes could improve tacrolimus dosing decisions in kidney transplant recipients.
Aerosol source apportionment is a key tool for understanding the origins of atmospheric particulate matter and for guiding effective air quality management strategies. However, source apportionment techniques still struggle to properly separate highly correlated sources without relying on restrictive a priori information, possibly skewing the solution and adding subjective operator input, with varying degrees of benefit. This study introduces sparsity into the Bayesian Autocorrelated Matrix Factorisation (BAMF) model with the aim of removing non-essential species contribution in the unconstrained profiles, which is expected to improve the separation of factors compared to BAMF. The regularised horseshoe prior (HS) has been added to BAMF (BAMF+HS) to promote composition matrix F sparsity, shrinking low-signal contributions to the solutions. BAMF+HS was evaluated using three synthetic datasets designed to reflect increasing levels of data complexity (Toy, representing a highly simplified dataset; Offline, representing a filter dataset; and Online, representing an Aerosol Chemical Speciation Monitor (ACSM)-like dataset), and a real-world multi-site filter dataset. The results demonstrate that BAMF+HS effectively enforces sparsity in offline datasets and that this improves accuracy in reconstructing source profiles and time series compared to BAMF and Positive Matrix Factorisation (PMF). However, its application to higher-complexity ACSM datasets revealed sensitivity to sampling instability hindering sparsification. With that, even though sparsity was not achieved, the quality of the BAMF+HS solution metrics were not deprecated compared to BAMF. Overall, this work underscores the value of incorporating profile sparsity as a solution property in Bayesian source apportionment, and positions BAMF+HS as a promising model for source apportionment.
Central Greece once contained over 200 medieval towers, approximately two-thirds of which were located on Euboea. Many still dominate the landscape around Chalcis, either within village centers or on isolated hilltops. From the early medieval period onward, the region underwent successive political transitions, from Byzantine authority centered at Thebes to Latin, Catalan, Florentine, and Venetian control after 1204, culminating in the Ottoman conquest of Chalcis in 1470. Within this context of political instability between the late thirteenth and early fifteenth centuries, this pilot study investigates the chronology and construction phases of the Euboean towers. An integrated approach was applied, combining radiocarbon dating of wooden structural elements with the analytical characterization of mortars to assess their chronology and manufacturing technology. Radiocarbon dating indicates that all towers were constructed between 1270 and 1434 cal AD. More precise construction phases were established for three towers through wiggle-matching: Mistros (1283–1323 cal AD), North Mytikas (1330–1374 cal AD), and Skounteri (1391–1414 cal AD). Complementary analyses of mortars, including optical microscopy, portable X-ray fluorescence (pXRF), petrography, scanning electron microscopy with energy-dispersive spectroscopy (SEM–EDS), and X-ray diffraction (XRD), reveal compositional variability reflecting different preparation techniques and the selective use of local resources. Evidence for two construction phases was identified at Bailelekas and North Mytikas. The integration of high-resolution radiocarbon dating with mineralogical and geochemical analyses provides new insights into the multi-phased construction history of Euboean towers and demonstrates the value of an interdisciplinary approach for the study of medieval fortifications.
