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The Kinase Chemogenomic Set (KCGS): An open science resource for kinase vulnerability identification
(2019)
We describe the assembly and annotation of a chemogenomic set of protein kinase inhibitors as an open science resource for studying kinase biology. The set only includes inhibitors that show potent kinase inhibition and a narrow spectrum of activity when screened across a large panel of kinase biochemical assays. Currently, the set contains 187 inhibitors that cover 215 human kinases. The kinase chemogenomic set (KCGS) is the most highly annotated set of selective kinase inhibitors available to researchers for use in cell-based screens.
Long non-coding RNAs (lncRNAs) contribute to cardiac (patho)physiology. Aging is the major risk factor for cardiovascular disease with cardiomyocyte apoptosis as one underlying cause. Here, we report the identification of the aging-regulated lncRNA Sarrah (ENSMUST00000140003) that is anti-apoptotic in cardiomyocytes. Importantly, loss of SARRAH (OXCT1-AS1) in human engineered heart tissue results in impaired contractile force development. SARRAH directly binds to the promoters of genes downregulated after SARRAH silencing via RNA-DNA triple helix formation and cardiomyocytes lacking the triple helix forming domain of Sarrah show an increase in apoptosis. One of the direct SARRAH targets is NRF2, and restoration of NRF2 levels after SARRAH silencing partially rescues the reduction in cell viability. Overexpression of Sarrah in mice shows better recovery of cardiac contractile function after AMI compared to control mice. In summary, we identified the anti-apoptotic evolutionary conserved lncRNA Sarrah, which is downregulated by aging, as a regulator of cardiomyocyte survival.
Epigenetic neural glioblastoma enhances synaptic integration and predicts therapeutic vulnerability
(2023)
Neural-tumor interactions drive glioma growth as evidenced in preclinical models, but clinical validation is nascent. We present an epigenetically defined neural signature of glioblastoma that independently affects patients survival. We use reference signatures of neural cells to deconvolve tumor DNA and classify samples into low- or high-neural tumors. High-neural glioblastomas exhibit hypomethylated CpG sites and upregulation of genes associated with synaptic integration. Single-cell transcriptomic analysis reveals high abundance of stem cell-like malignant cells classified as oligodendrocyte precursor and neural precursor cell-like in high-neural glioblastoma. High-neural glioblastoma cells engender neuron-to-glioma synapse formation in vitro and in vivo and show an unfavorable survival after xenografting. In patients, a high-neural signature associates with decreased survival as well as increased functional connectivity and can be detected via DNA analytes and brain-derived neurotrophic factor in plasma. Our study presents an epigenetically defined malignant neural signature in high-grade gliomas that is prognostically relevant.
Purpose: The stomachs and spiral valves of sharks and rays were examined for their trypanorhynch (Cestoda) parasite fauna and dietary items to infer feeding ecology. In Indonesia, sharks and rays have been experiencing increasing awareness and conservation in the recent years due to high fisheries activities and to avoid future species extinction.
Methods: The samples were collected in 2009 from two different sampling sites at the southern coasts of Java and Bali in Indonesia. The parasite fauna was studied for 41 elasmobranch fishes. Amongst these, three shark species, Carcharhinus sorrah, Carcharhinus sp. I and Squalus megalops and seven ray species, Brevitrygon heterura, B. cf. heterura, Gymnura zonura, Maculabatis gerrardi, Mobula kuhlii, Neotrygon cauruleopuncatata and Rhinobatos penggali were studied. Four additional specimens, belonging to the shark species Carcharhinus sp. II and Mustelus cf. manazo and the ray species Maculabatis gerrardi were studied from the waters of South Bali.
Results: Analyses of the feeding ecology of the ray M. gerrardi revealed distinct differences between both sampling sites, indicating the presence of ecological differences between the geographically independent regions. A total of 11 different trypanorhynch species/taxa belonging to the five families Eutetrarhynchidae (5), Gilquiniidae (1), Lacistorhynchidae (1), Pterobothriidae (1) and Tentaculariidae (3) were found. Ten trypanorhynch species from Penyu Bay and four species from South Bali could be identified. Two taxa that might represent new species were collected: Dollfusiella sp. from Brevitrygon heterura and Prochristianella sp. from Maculabatis gerrardi.
Conclusions: The present paper gives insights in using the trypanorhynch cestode community in combination with feeding ecology analyses to support conservation of elasmobranchs in Indonesian waters.