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DNA damage in proximal tubules triggers systemic metabolic dysfunction through epigenetically altered macrophages
Innovative AI analysis and experimental study of hydrogen- enriched clean fuel in modern fossil fuel engines
Comprehensive comparison of the third-generation sequencing tools for bacterial 6mA profiling
Identification of new families and variants in autosomal dominant macular dystrophy associated with THRB
Parallel processing of past and future memories through reactivation and synaptic plasticity mechanisms during sleep
When lowering temperature, the in vivo circadian clock in cyanobacteria follows and surpasses the in vitro protein clock trough the Hopf bifurcation
Structural basis for regulation of CELSR1 by a compact module in its extracellular region
Machine learning-based quantification and separation of emissions and meteorological effects on PM2.5 in Greater Bangkok
Angiogenic and immune predictors of neoadjuvant axitinib response in renal cell carcinoma with venous tumour thrombus
Abstract Venous tumour thrombus (VTT), where the primary tumour invades the renal vein and inferior vena cava, affects 10–15% of renal cell carcinoma (RCC) patients. Curative surgery for VTT is high-risk, but neoadjuvant therapy may improve outcomes. The NAXIVA trial demonstrated a 35% VTT response rate after 8 weeks of neoadjuvant axitinib, a VEGFR-directed therapy. However, understanding non-response is critical for better treatment. Here we show that response to axitinib in this setting is characterised by a distinct and predictable set of features. We conduct a multiparametric investigation of samples collected during NAXIVA using digital pathology, flow cytometry, plasma cytokine profiling and RNA sequencing. Responders have higher baseline microvessel density and increased induction of VEGF-A and PlGF during treatment. A multi-modal machine learning model integrating features predict response with an AUC of 0.868, improving to 0.945 when using features from week 3. Key predictive features include plasma CCL17 and IL-12. These findings may guide future treatment strategies for VTT, improving the clinical management of this challenging scenario.
Enhanced alcohol metabolism and sleep quality with continuous positive airway pressure following alcohol consumption
Abstract We aimed to examine the effect of continuous positive airway pressure on sleep quality and alcohol metabolism after alcohol consumption. Men (n = 53) aged ≥ 19 years with sleep disorders who regularly consumed an average of ≥ 1.0 g of alcohol/kg of bodyweight, were free of serious diseases (including liver disorders), and underwent polysomnography and continuous positive airway pressure titration between January 2016 and July 2021 were included. Participants drank a high dose of a traditional Korean liquor at a rate of 1.0 g/kg of bodyweight for 1 h. The main outcome measures included polysomnography results and blood and breath ethanol and acetaldehyde concentrations after alcohol consumption before and after sleep. Statistical analyses were performed using R software, version 4.0.5 (R Foundation, Vienna, Austria). Continuous positive airway pressure enhanced sleep quality after alcohol consumption, with oxygen significantly improving the metabolism of acetaldehyde over that of ethanol. Breath and blood sample analyses and polysomnography results revealed that continuous positive airway pressure improved sleep quality by reducing apnea–hypopnea index by 27.32 ± 24.87 (p < 0.001), increasing rapid eye movement sleep by 2.08 ± 6.74% (p < 0.05), and enhancing acetaldehyde breakdown by 21.2% (p < 0.001), while its effect on ethanol breakdown (4–5%) was not statistically significant. Continuous positive airway pressure is recommended after alcohol consumption for individuals with sleep apnea to enhance sleep quality.
PRPS2 enhances RNA m6A methylation by stimulating SAM synthesis through enzyme-dependent and independent mechanisms
Abstract Cancer cells exploit altered metabolic pathways to dynamically regulate epigenetic methylation and thus promote tumorigenesis and metastasis. In various human cancers, such as lung adenocarcinoma, the level of a key cellular metabolite, S-adenosylmethionine (SAM), is prominently upregulated for RNA hypermethylation as the methyl donor. However, the specific mechanisms by which cancer cells produce SAM to sustain RNA methylation remain elusive. Here, we demonstrate that PRPS2, a phosphoribosyl pyrophosphate synthetase isoform involved in the first and rate-limiting step of the purine biosynthesis pathway, exhibits distinct oncogenic functionality in regulating RNA methylation, unlike its homolog PRPS1. PRPS2 utilizes four non-conserved key residues to bypass the typical ADP/GDP allosteric feedback inhibition, enabling sustained excess production of newly synthesized ATP. Moreover, PRPS2 stabilizes methionine adenosyltransferase 2 A (MAT2A) through direct interactions to positively stimulate ATP utilization and SAM synthesis for RNA m6A specific methylation via the WTAP/METTL3/METTL14 methyltransferase complex, thereby promoting lung tumorigenesis. Our study links nucleotide biosynthesis with RNA epigenetics in cancer progression through the PRPS2-MAT2A-WTAP/METTL3/METTL14 axis, and elucidates both enzyme-dependent and independent functions of PRPS2. These findings have significant implications for developing targeted therapies for cancers associated with PRPS2 abnormalities.