Mechanistic Insights of a p53-Targeting Small Molecule.

Restoring the p53 pathway, particularly by reactivating wild-type (wt) or mutant (mut) p53, is considered a promising approach for cancer treatment. Previously, we identified the tryptophanol-derived oxazoloisoindolinone family as a new scaffold for obtaining wt and mut p53 reactivators. Herein, we report a detailed study on the pharmacokinetic profile and the mechanism of action of , an ()-tryptophanol-derived oxazoloisoindolinone that exhibits six times higher activity and increased selectivity for HCT116 cells with p53 compared to our initial hit, .

Complex bifurcation structures in a Hodgkin-Huxley model of thermally sensitive neurons under periodic perturbation.

In this study, we identify an intricate class of periodic behavior, coined as "fishbone," within the chaotic dynamics induced by external periodic disturbances in a neuronal system. Alongside this structure, we observe well-known patterns such as shrimps and cockroaches, revealing the system's sensitivity to external perturbations. Notably, our work highlights the significant impact of altering biophysical parameters, showing that changes in the ionic conductance of neurons can lead to the cohesion or detachment of complex periodic structures from the primary fishbone-shaped structure.

The British and Brazilian expeditions and the 1919 total solar eclipse: regimes of labour and degrees of invisibility.

In this paper, we dissect how different regimes of labour were crucial to the success of the British and Brazilian expeditions which observed the 1919 total solar eclipse in Príncipe and Sobral. We connect regimes of labour with degrees of invisibility and discuss plausible justifications for various absences/presences in the written records. We discuss reasons for the inclusion of Cottingham, the artisan-technician expert on clockwork mechanisms, into the teams; the entanglements of forced labour with scientific and technical work in Príncipe; and the various regimes of labour in place at Sobral.

The effect of a low transition temperature mixture for enhanced bioavailability of celecoxib in combination with hyaluronic acid in a rat model with post-traumatic knee osteoarthritis.

Osteoarthritis (OA) is the most common form of arthritis and a leading cause of disability worldwide. Current therapies include pain relief with oral uptake of non-steroidal anti-inflammatory drugs (NSAIDs) and intra-articular injections of hyaluronic acid (HA), to restore the lubricant and protective properties of the joint (viscosupplementation). The administration of both therapies is limited, especially for NSAIDs, given the systemic side-effects.

Assessment of the Genotoxic Hazard of Estuarine Sediments Using an Integrative Approach With LacZ Plasmid-Based Transgenic Mice.

Under the influence of multiple anthropogenic pressures, from industrial to agricultural activities, estuaries have long been regarded as particularly sensitive ecosystems to contamination. The present study aimed at investigating the genotoxic potential of a contaminated sediment sample from an urban and industrial area of the Sado Estuary, by combining the analysis of multiple endpoints in the LacZ plasmid-based transgenic mouse model exposed for 28 days to contaminated estuarine sediment extracts through drinking water. The DNA and chromosome damaging effects were monitored in peripheral blood at 7-day intervals using the standard and enzyme-modified Comet assay, as well as the micronucleus assays in peripheral blood cells.

Production of an extract rich in alpha-tomatine from green tomatoes by subcritical water.

Green tomatoes, a by-product of agro-food industry, are rich in the glycoalkaloid alpha-tomatine. This compound presents health benefits including anti-inflammatory and fungicide properties. Subcritical water extraction (SWE), a green and sustainable process, was used to obtain a tomatine-rich extract from fresh or frozen tomatoes.

Cognitive Lab: A dataset of biosignals and HCI features for cognitive process investigation.

Background And Objective: Attention, cognitive workload/fatigue, and emotional states significantly influence learning outcomes, cognitive performance, and human-machine interactions. However, existing assessment methodologies fail to fully capture the multimodal nature of these cognitive processes, limiting their application in adaptive learning environments. This study presents the Cognitive Lab, a comprehensive multimodal dataset designed to investigate these cognitive processes across real-time learning scenarios.

A Multimodal Dataset Addressing Motor Function in Autism.

Autism has primarily been characterized at a social-cognitive level, with evidence suggesting impairments in action-perception and motor function. However, there is a lack of publicly available datasets that specifically address the neural and behavioral mechanisms linking these functions in autism. The Move4AS dataset aims to fill this gap, having been designed to facilitate the study of the underlying mechanisms of motor function in the autism spectrum.

Two major ecological shifts shaped 60 million years of ungulate faunal evolution.

The fossil record provides direct evidence for the behavior of biological systems over millions of years, offering a vital source for studying how ecosystems evolved and responded to major environmental changes. Using network analysis on a dataset of over 3000 fossil species spanning the past 60 Myr, we find that ungulate continental assemblages exhibit prolonged ecological stability interrupted by irreversible reorganizations associated with abiotic events. During the early Cenozoic, continental assemblages are dominated by mid-sized browsers with low-crowned teeth, which show increasing functional diversity.

Tripartite binding mode of cohesin-dockerin complexes from Ruminococcus flavefaciens involving naturally truncated dockerins.

Polysaccharides in plant cell walls serve as a rich carbon and energy source, yet their structural complexity presents a barrier to efficient degradation. To address this, anaerobic microorganisms like R. flavefaciens have developed sophisticated multi-enzyme complexes known as cellulosomes, which enable the efficient breakdown of these recalcitrant polysaccharides.

Hydrophobic Eutectogels for the Removal of Contaminants of Emerging Concern from Water.

Five hydrophobic eutectic solvents based on menthol and thymol were prepared and incorporated into a poly(ethylene glycol) diacrylate (PEGDA) network to form eutectogel membranes. The two most promising eutectogels were further optimized by adding ethyl hexylacrylate (HA) to the eutectogel formulation to improve the compatibility between the eutectic solvent and polymer network and to enhance the water resistance of the resulting membranes. Thermal analysis confirmed the successful formation and integration of eutectic solvents within the polymer network.

Synthesis, characterization and biological activity of methotrexate-derived salts in lung cancer cells.

Lung cancer is one of the deadliest types of cancer, and is a public health problem worldwide. Methotrexate (MTX), a class IV drug in the biopharmaceutical classification system, is a folate antagonist that has demonstrated efficacy in cancer treatment. A suitable combination of MTX as a di-anion and biocompatible counter ions allowed the modulation of their physicochemical properties.

Enhancing Cancer Vaccine Efficacy: Backbone Modification with β‑Amino Acids Alters the Stability and Immunogenicity of MUC1-Derived Glycopeptide Formulations.

Glycopeptides derived from the mucin-1 (MUC1) glycoprotein hold significant promise as cancer vaccine candidates, but their clinical utility is limited by proteolytic degradation and the poor bioavailability of L-α-amino acid-based peptides. In this study, we demonstrate that substitution of multiple α-amino acids with homologous β-amino acids (same side chain, but extended backbone) in -glycosylated MUC1 derivatives significantly enhances their proteolytic stability. We further show that α-to-β substitutions within the most immunogenic epitope of MUC1 impede binding to an anti-MUC1 antibody, while substitutions outside the same epitope preserve antibody recognition.

Protein digestibility of aquafeeds in Sparus aurata: A model for in vitro bioaccessibility validation in fish.

The in vitro assessment of nutrient digestibility in aquaculture offers a fast, affordable, and ethical alternative enabling to optimize the nutritional value of feeds for improved fish health. Although commonly used in human studies, these in vitro models are still scarce for fish. This study aimed to validate an in vitro digestion method for marine fish using both fish crude digestive extracts and commercial digestive enzymes through a comparison with an in vivo assay using gilthead seabream (Sparus aurata) as a biological model.

ZnO Nanorod/Ag NanoparticleFunctionalized Paper Substrate for Sensitive SERS Detection of Environmental Contaminants.

In this work, we functionalize Whatman no 1 paper (WP) substrates with zinc oxide nanorods (ZnO NRs) decorated with silver nanoparticles (AgNPs) for detecting environmental contaminants. ZnO NRs were grown by hydrothermal synthesis assisted by microwave irradiation on WP substrate and subsequently decorated with AgNPs using the dewetting deposition method. WP substrates functionalized with ZnO NRs/AgNPs were used as a SERS platform for detecting rhodamine 6G (R6G) dye and the thiabendazole (TBZ) pesticide, widely used in modern agriculture for fungal disease protection in fruits and vegetables.

Antimicrobial Resistance Profile and Biofilm Formation of Isolated from Meat.

Introduction: is the causative agent of listeriosis, a serious infectious disease with one of the highest case fatality rates among foodborne diseases affecting humans.

Objectives: This study investigated the prevalence, antimicrobial resistance pattern and biofilm production capacity of isolated in meats.

Materials: A total of 75 samples were analyzed, including fresh meats and meat preparations, in Northern Portugal.

Unique trajectory of gene family evolution from genomic analysis of nearly all known species in an ancient yeast lineage.

Gene gains and losses are a major driver of genome evolution; their precise characterization can provide insights into the origin and diversification of major lineages. Here, we examined gene family evolution of 1154 genomes from nearly all known species in the medically and technologically important yeast subphylum Saccharomycotina. We found that yeast gene family evolution differs from that of plants, animals, and filamentous ascomycetes, and is characterized by smaller overall gene numbers yet larger gene family sizes for a given gene number.

Deep Eutectic Systems: A Game Changer for Marine Bioactives Recovery.

The extraction of bioactive compounds from marine natural products has gained increasing attention due to their diverse applications, such as in pharmaceuticals, nutraceuticals, and cosmetics. Yet, low extraction yields and toxicity associated with common solvents are a major bottleneck. Deep eutectic solvents (DESs) and natural deep eutectic solvents (NADESs) have emerged as promising green alternatives to conventional organic solvents, offering advantages such as biodegradability, greater environmental and economic sustainability, low toxicity, and enhanced extraction selectivity.

Manufacturing Order Matters? Exploring the Impact of Heat Treatment and Machining Sequences on the NiTi Instruments Properties.

This study assessed how manufacturing sequence affects the metallurgical and mechanical properties of two nickel-titanium instruments: Procodile Q (heat-treated before machining) and Procodile +HT (heat-treated after machining). Both instruments (n = 74 each, size 25/0.06) were analysed for design, NiTi composition, phase transformation temperatures and mechanical performance (cyclic fatigue at 20°C and 35°C, torsional fatigue, bending load, buckling strength, cutting ability, microhardness and roughness).

Isolation, Fixation and Characterization of Juvenile Gilthead Seabream Head Kidney Leukocytes by Flow Cytometry.

Immunity is crucial for the physiological regulation of organisms, serving as the primary defense against pathogens and environmental stressors. The isolation and analysis of immune cells provide key insights into immune responses to external pressures. However, the lack of harmonized protocols for less studied species, such as marine fish, often leads to technical and analytical challenges that hamper data interpretation and a thorough understanding of species-specific immune responses.

Angiopoietin-TIE2 feedforward circuit promotes PIK3CA-driven venous malformations.

Venous malformations (VMs) are vascular anomalies lacking curative treatments, often caused by somatic PIK3CA mutations that hyperactivate the PI3Kα-AKT-mTOR signaling pathway. Here, we identify a venous-specific signaling circuit driving disease progression, where excessive PI3Kα activity amplifies upstream TIE2 receptor signaling through autocrine and paracrine mechanisms. In Pik3ca-driven VM mouse models, single-cell transcriptomics and lineage tracking revealed clonal expansion of mutant endothelial cells with a post-capillary venous phenotype, characterized by suppression of the AKT-inhibited FOXO1 and its target genes, including the TIE2 antagonist ANGPT2.

Design and evolution of a synthetic small protein scaffold based on the WW domain.

Protein engineering is a powerful tool in biotechnology and the basis to create unprecedented sequences, structures, and functions. The WW domains are a family of naturally occurring proteins involved in the molecular recognition of proline-rich and phosphorylated peptide sequences with relevance in cellular processes involved in human diseases. Due to their small size, WW domains represent appealing small protein domains for protein engineering and to generate novel functions as binders to non-cognate targets.

Comparative analysis of antibiotic resistance and biofilm formation in spp. across One Health domains.

The rise of antibiotic-resistant bacteria is a critical issue across various ecological interfaces, highlighting the need for a One Health approach. spp., known for their ability to acquire and disseminate resistance, serve as an excellent model due to their presence in diverse hosts and environments.

An advanced image processing and multivariate statistical methodology to interpret Micro-EDXRF 2D maps: Uncovering heterogeneity and spatial distribution patterns of rare earth elements in phosphogypsum.

Phosphogypsum (PG), a by-product of the fertilizer industry, is a potential source of rare earth elements (REEs) such as Lanthanum (La), Cerium (Ce), Neodymium (Nd), and Yttrium (Y). These elements were efficiently detected using micro-Energy Dispersive X-Ray Fluorescence (μ-EDXRF). Although a homogeneous REE distribution was expected in μ-EDXRF 2D maps, significant heterogeneity and variations in elemental associations (EA) were observed at a micrometric scale.