Clear-cell carcinomas (CCCs) are a histological group of highly aggressive malignancies commonly originating in the kidney and ovary. CCCs are distinguished by aberrant lipid and glycogen ...accumulation and are refractory to a broad range of anti-cancer therapies. Here we identify an intrinsic vulnerability to ferroptosis associated with the unique metabolic state in CCCs. This vulnerability transcends lineage and genetic landscape, and can be exploited by inhibiting glutathione peroxidase 4 (GPX4) with small-molecules. Using CRISPR screening and lipidomic profiling, we identify the hypoxia-inducible factor (HIF) pathway as a driver of this vulnerability. In renal CCCs, HIF-2α selectively enriches polyunsaturated lipids, the rate-limiting substrates for lipid peroxidation, by activating the expression of hypoxia-inducible, lipid droplet-associated protein (HILPDA). Our study suggests targeting GPX4 as a therapeutic opportunity in CCCs, and highlights that therapeutic approaches can be identified on the basis of cell states manifested by morphological and metabolic features in hard-to-treat cancers.
Despite considerable efforts to identify cancer metabolic alterations that might unveil druggable vulnerabilities, systematic characterizations of metabolism as it relates to functional genomic ...features and associated dependencies remain uncommon. To further understand the metabolic diversity of cancer, we profiled 225 metabolites in 928 cell lines from more than 20 cancer types in the Cancer Cell Line Encyclopedia (CCLE) using liquid chromatography-mass spectrometry (LC-MS). This resource enables unbiased association analysis linking the cancer metabolome to genetic alterations, epigenetic features and gene dependencies. Additionally, by screening barcoded cell lines, we demonstrated that aberrant ASNS hypermethylation sensitizes subsets of gastric and hepatic cancers to asparaginase therapy. Finally, our analysis revealed distinct synthesis and secretion patterns of kynurenine, an immune-suppressive metabolite, in model cancer cell lines. Together, these findings and related methodology provide comprehensive resources that will help clarify the landscape of cancer metabolism.
Novel antibiotics are urgently needed to address the looming global crisis of antibiotic resistance. Historically, the primary source of clinically used antibiotics has been microbial secondary ...metabolism. Microbial genome sequencing has revealed a plethora of uncharacterized natural antibiotics that remain to be discovered. However, the isolation of these molecules is hindered by the challenge of linking sequence information to the chemical structures of the encoded molecules. Here, we present PRISM 4, a comprehensive platform for prediction of the chemical structures of genomically encoded antibiotics, including all classes of bacterial antibiotics currently in clinical use. The accuracy of chemical structure prediction enables the development of machine-learning methods to predict the likely biological activity of encoded molecules. We apply PRISM 4 to chart secondary metabolite biosynthesis in a collection of over 10,000 bacterial genomes from both cultured isolates and metagenomic datasets, revealing thousands of encoded antibiotics. PRISM 4 is freely available as an interactive web application at http://prism.adapsyn.com .
Self‐healing is a natural phenomenon whereby living organisms respond to damage. Recently, considerable research efforts have been invested in self‐healing cementitious materials that are capable of ...restoring structural integrity and mechanical properties after being damaged. Inspired by nature, a variety of creative approaches are explored here based on the intrinsic or extrinsic healing mechanism. Research on new intrinsic self‐healing cementitious materials with biomimetic features is on the forefront of material science, which provides a promising way to construct resilient and sustainable concrete infrastructures. Here, the current advances in the development of the intrinsic healing cementitious materials are described, and a new definition of intrinsic self‐healing discussed. The methods to assess the efficiency of different healing mechanisms are briefly summarized. The critical insights are emphasized to guide the future research on the development of new self‐healing cementitious materials.
Recent advances in intrinsic self‐healing cementitious materials that favor high compatibility and chemical interactions with the cementitious matrix according to its essential healing mechanism are summarized, and the methods to assess the efficiency briefly discussed. The critical insights on this promising research field are provided to guide the future development of self‐healing of cementitious materials.
Ferroptosis is widely involved in degenerative diseases in various tissues including kidney, liver and brain, and is a targetable vulnerability in multiple primary and therapy-resistant cancers. ...Accumulation of phospholipid hydroperoxides in cellular membranes is the hallmark and rate-limiting step of ferroptosis; however, the enzymes contributing to lipid peroxidation remain poorly characterized. Using genome-wide, CRISPR-Cas9-mediated suppressor screens, we identify cytochrome P450 oxidoreductase (POR) as necessary for ferroptotic cell death in cancer cells exhibiting inherent and induced susceptibility to ferroptosis. By genetic depletion of POR in cancer cells, we reveal that POR contributes to ferroptosis across a wide range of lineages and cell states, and in response to distinct mechanisms of ferroptosis induction. Using systematic lipidomic profiling, we further map POR's activity to the lipid peroxidation step in ferroptosis. Hence, our work suggests that POR is a key mediator of ferroptosis and potential druggable target for developing antiferroptosis therapeutics.
Butternut squash is greatly consumed in United Kingdom and as by‐products of its processing are produced large amounts of skin and seeds. However, little research has been reported on the antioxidant ...properties and bioactive peptides from butternut squash seeds and skin. This study focused on assessing the potential of these wastes as sources of beneficial and bioactive compounds. The results indicated that the squash skin phenolic extract showed higher values of antioxidant activity and phenolic content compared with the values of phenolic for the seed material (3.20 mg GAE/g, 1.82 mg GAE/g, respectively). Furthermore, both squash seed protein hydrolysate and skin phenolic extract inhibited α‐amylase activity in a dose‐dependent manner (5–20 mg/ml). Hydrolyzed peptides from squash seeds possess antihypertensive ability (which was significantly different from the control group p < .05). Therefore, it can be demonstrated that these squash residues are potentially good sources of bioactive compounds with health benefits.
This study focused on assessing the potential of these wastes as sources of beneficial and bioactive compounds. The results indicated that the squash skin phenolic extract showed higher values of antioxidant activity and phenolic content compared with the values of phenolic for the seed material. It can be demonstrated that these squash residues are potentially good sources of bioactive compounds with health benefits.
Polyphenols are the largest group of phytochemicals with important biological properties. Their presence in conveniently available low-cost sources, such as agri-food by-products, has gained ...considerable attention in their recovery and further exploitation. Retrieving polyphenols in a green and sustainable way is crucial. Recently, deep eutectic solvents (DESs) have been identified as a safe and environmentally benign medium capable of extracting polyphenols efficiently. This review encompasses the current knowledge and applications of DESs and assisted technologies to extract polyphenols from agri-food by-products. Particular attention has been paid to fundamental mechanisms and potential applications in the food, cosmetic, and pharmaceutical industries. In this way, DESs and DESs-assisted with advanced techniques offer promising opportunities to recover polyphenols from agri-food by-products efficiently, contributing to a circular and sustainable economy.
•Develop a framework to evaluate supply and demand of temperature regulation service.•Discover imbalanced supply and demand of temperature regulation service of urban forests.•Propose place-based ...greening strategies according to the imbalance of TRS supply–demand.
Urban forests can provide temperature regulation service (TRS) by lowering the local temperature and further mitigating the urban heat island effect. Numerous studies have focused on how to better realize or enhance the cooling function of urban forests, but have not considered that from the perspective of supply and demand. Here, we develop a framework to quantify the supply and demand of temperature regulation service provided by urban forests, using remote sensing, meteorological and socio-economic data. Taking Shenzhen city as a case study, we analyzed the spatial distribution of both TRS supply and demand as well as their relationship in Shenzhen. We found: 1) TRS supply varied greatly in space, with areas of high supply generally located in the southeast of Shenzhen, which is mainly covered by forests, and around the boundaries of administrative districts that are distant from the urban centers. 2) TRS demand had even more significant spatial heterogeneity, showing that high-demand areas were primarily distributed in the southwest but occupied a relatively small amount of land in Shenzhen. We then categorized the spatial relationship between TRS supply and demand into four types, and identified the hotspots of highly mismatched supply and demand of TRS. Targeted urban forests planning and management measures were further proposed for each type of region. This study provides spatial tools and insights for urban forests design and planning towards better urban heat mitigation and adaptation.
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