Metabolic and mitochondria alterations induced by SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10.

Antiviral signaling, immune response and cell metabolism are dysregulated by SARS-CoV-2, the causative agent of COVID-19. Here, we show that SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10 induce a significant mitochondrial and metabolic reprogramming in A549 lung epithelial cells. While ORF9b, ORF9c and ORF10 induced largely overlapping transcriptomes, ORF3a induced a distinct transcriptome, including the downregulation of numerous genes with critical roles in mitochondrial function and morphology. On the other hand, all four ORFs altered mitochondrial dynamics and function, but only ORF3a and ORF9c induced a marked alteration in mitochondrial cristae structure. Genome-Scale Metabolic Models identified both metabolic flux reprogramming features both shared across all accessory proteins and specific for each accessory protein. Notably, a downregulated amino acid metabolism was observed in ORF9b, ORF9c and ORF10, while an upregulated lipid metabolism was distinctly induced by ORF3a. These findings reveal metabolic dependencies and vulnerabilities prompted by SARS-CoV-2 accessory proteins that may be exploited to identify new targets for intervention.

Shedding Light on Dark Chemical Matter: The Discovery of a SARS-CoV-2 Mpro Main Protease Inhibitor through Intensive Virtual Screening and In Vitro Evaluation.

The development of specific antiviral therapies targeting SARS-CoV-2 remains fundamental because of the continued high incidence of COVID-19 and limited accessibility to antivirals in some countries. In this context, dark chemical matter (DCM), a set of drug-like compounds with outstanding selectivity profiles that have never shown bioactivity despite being extensively assayed, appears to be an excellent starting point for drug development. Accordingly, in this study, we performed a high-throughput screening to identify inhibitors of the SARS-CoV-2 main protease (Mpro) using DCM compounds as ligands. Multiple receptors and two different docking scoring functions were employed to identify the best molecular docking poses. The selected structures were subjected to extensive conventional and Gaussian accelerated molecular dynamics. From the results, four compounds with the best molecular behavior and binding energy were selected for experimental testing, one of which presented inhibitory activity with a Ki value of 48 ± 5 µM. Through virtual screening, we identified a significant starting point for drug development, shedding new light on DCM compounds.

Effects of catchment land use on temperate mangrove forests.

Human land use changes are threatening the integrity and health of coastal ecosystems worldwide. Intensified land use for anthropogenic purposes increases sedimentation rates, pollutants, and nutrient concentrations into adjacent coastal areas, often with detrimental effects on marine life and ecosystem functioning. However, how these factors interact to influence ecosystem health in mangrove forests is poorly understood. This study investigates the effects of catchment human land use on mangrove forest architecture and sedimentary attributes at a landscape-scale. Thirty sites were selected along a gradient of human land use within a narrow latitudinal range, to minimise the effects of varying climatic conditions. Land use was quantified using spatial analysis tools with existing land use databases (LCDB5). Twenty-six forest architectural and sedimentary variables were collected from each site. The results revealed a significant effect of human land use on ten out of 26 environmental variables. Eutrophication, characterised by changes in redox potential, pH, and sediment nutrient concentrations, was strongly associated with increasing human land use. The δ15N values of sediments and leaves also indicated increased anthropogenic nitrogen input. Furthermore, the study identified a positive correlation between human land use and tree density, indicating that increased nutrient delivery from catchments contributes to enhanced mangrove growth. Propagule and seedling densities were also positively correlated with human land use, suggesting potential recruitment success mechanisms. This research underpins the complex interactions between human land use and mangrove ecosystems, revealing changes in carbon dynamics, potential alterations in ecosystem services, and a need for holistic management approaches that consider the interconnectedness of species and their environment. These findings provide essential insights for regional ecosystem models, coastal management, and restoration strategies to address the impacts of human pressures on temperate mangrove forests, even in estuaries that may be relatively healthy.

Células madre en cáncer de próstata / Stem cells in prostate cancer

LLos tumores constituyen ecosistemas complejos con múltiples interacciones entre las células neoplásicas, que muestran diferentes fenotipos y funciones, y en los que el nicho tumoral se construye con una participación activa del ambiente del huésped, que también impacta la progresión maligna de las células tumorales. Independientemente del origen de la célula del adenocarcinoma prostático, evidencias crecientes apoyan la existencia de una jerarquía dentro de las células neoplásicas prostáticas que contribuye a la heterogeneidad de estos tumores. En el origen de esta jerarquía están pequeñas poblaciones de células tumorales con un alto potencial de autorrenovación, y también capaces de generar progenie de células tumorales que pierden las propiedades de autorrenovación al adquirir fenotipos más diferenciados. Estas células truncales neoplásicas dependen de redes de genes activos que les confieren su capacidad de autorrenovación por medio de divisiones simétricas mientras que también pueden sufrir división asimétrica y diferenciación bien como eventos estocásticos o en respuesta a señales ambientales. Aunque nuevas evidencias experimentales indican que este puede ser un proceso reversible, difuminando así la distinción entre células truncales neoplásicas y células neoplásicas no truncales, las primeras se consideran las motoras del crecimiento y evolución tumorales, siendo por tanto, objetivo primordial de intervención terapéutica. De particular importancia en cáncer de próstata, las células truncales neoplásicas pueden constituir la población que albergue a las células andrógeno-insensibles y quimiorresistentes responsables del desarrollo de tumores resisitentes a la castración y a la quimioterapia, por lo que su identificación y cuantificación en tumores primarios y metastásicos puede jugar un papel importante en la toma de decisiones terapéuticas en cáncer de próstata (AU)

Tumors constitute complex ecosystems with multiple interactions among neoplastic cells displaying various phenotypes and functions and where the tumoral niche is built with an active participation of the host environment that also impacts the malignant progression of the tumor cells. Irrespective of the cell of origin of prostate adenocarcinoma, mounting evidences support the existence of a hierarchy within neoplastic prostate cells that contributes to the heterogeneity of these tumors. At the origin of this hierarchy are small populations of tumor cells with high self-renewal potential and also capable of generating progeny tumor cells that lose self-renewal properties as they acquire more differentiated phenotypes. These cancer stem cells (CSC) depend on active gene networks that confer them with their self-renewal capacity through symmetrical divisions whereas they can also undergo asymmetrical division and differentiation either as stochastic events or in response to environmental cues. Although new experimental evidences indicate that this is can be a reversible process, thus blurring the distinction between CSCs and non-CSCs, the former are considered as the drivers of tumor growth and evolution, and thus a prime target for therapeutic intervention. Of particular importance in prostate cancer, CSCs may constitute the repository population of androgen-insensitive and chemotherapy-resistant tumor cells responsible for castration-resistant and chemotherapy-insensitive tumors, thus their identification and quantification in primary and metastatic neoplasms could play important roles in the management of this disease (AU)