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Metabolism and gene expression, which are two fundamental biological processes that are essential to all living organisms, reciprocally regulate each other to maintain homeostasis and regulate cell growth, survival and differentiation. Metabolism feeds into the regulation of gene expression via metabolic enzymes and metabolites, which can modulate chromatin directly or indirectly — through regulation of the activity of chromatin trans-acting proteins, including histone-modifying enzymes, chromatin-remodelling complexes and transcription regulators. Deregulation of these metabolic activities has been implicated in human diseases, prominently including cancer.

This study investigates the relationship of neutrophil–lymphocyte ratio (NLR) with the risk of all-cause and cardiovascular mortality in patients with cardiovascular disease. The data for this analysis came from 2239 participants with cardiovascular disease of the National Health and Nutrition Examination Survey conducted between 1999–2018. The optimal cutoff point for NLR was determined using maximally selected rank statistics. Survival analysis was performed using Cox regression models to assess the impact of NLR on the risk of all-cause mortality and cardiovascular mortality. Restricted cubic spline was used to visualize the association of NLR with mortality risk. Subgroup analysis was performed to examine the relationship between NLR and mortality within subgroups based on age, sex, diabetes and hypertension. During a median follow-up period of 6.7 (IQR, 3.3–10.9) years, 992 all-cause deaths occurred, including 381 cardiovascular deaths. Our study revealed that NLR is a risk factor for all-cause mortality (HR: 1.15 95%Cl: 1.11 ~ 1.19) and cardiovascular mortality (HR: 1.14 95%Cl: 1.08 ~ 1.2) among patients with cardiovascular disease. The restricted cubic spline regression analysis showed a non-linear association between NLR and all-cause mortality (p < 0.05 for nonlinearity) in cardiovascular patients. This association remained robust in subgroup analyses stratified by age, sex, diabetes, and hypertension. Conclusion NLR stands as a significant risk factor for both all-cause and cardiovascular mortality among patients with cardiovascular disease.

Glucose transporter GLUT1 is a transmembrane protein responsible for the uptake of glucose into the cells of many tissues through facilitative diffusion. Plasma membrane (PM) localization is essential for glucose uptake by GLUT1. However, the mechanism underlying GLUT1 PM localization remains enigmatic. We find that GLUT1 is palmitoylated at Cys207, and S-palmitoylation is required for maintaining GLUT1 PM localization. Furthermore, we identify DHHC9 as the palmitoyl transferase responsible for this critical posttranslational modification. Knockout of DHHC9 or mutation of GLUT1 Cys207 to serine abrogates palmitoylation and PM distribution of GLUT1, and impairs glycolysis, cell proliferation, and glioblastoma (GBM) tumorigenesis. In addition, DHHC9 expression positively correlates with GLUT1 PM localization in GBM specimens and indicates a poor prognosis in GBM patients. These findings underscore that DHHC9-mediated GLUT1 S-palmitoylation is critical for glucose supply during GBM tumorigenesis. The glucose transporter GLUT1 is upregulated in multiple cancers and may contribute to tumour progression, but the underlying mechanisms are poorly understood. Here, the authors show that DHHC9-mediated GLUT1 palmitoylation at Cys207 is crucial for plasma membrane localisation of GLUT1 and for tumourigenesis in glioblastoma cells.

Itaconate is a newly discovered endogenous metabolite promoting an anti-inflammatory program during innate immune response, but the precise mechanisms underlying its effect remains poorly understood owing primarily to the limitations of available itaconate-monitoring techniques. Here, we develop and validate a genetically encoded fluorescent itaconate biosensor, BioITA, for directly monitoring itaconate dynamics in subcellular compartments of living macrophages. Utilizing BioITA, we monitor the itaconate dynamics in response to lipopolysaccharide (LPS) stimulation in the context of modulating itaconate transportation and metabolism. Moreover, we show that STING activation induces itaconate production, and injection of AAVs expressing cytosolic BioITA into mice allows directly reporting elevation of itaconate level in activated macrophages derived from LPS-injected mice. Thus, BioITA enables subcellular resolution imaging of itaconate in living macrophages. Itaconate has been identified as an immunomodulatory metabolite produced by activated macrophages, but methods for detecting itaconate in live cells are lacking. Here, the authors develop a fluorescent biosensor named BioITA for detecting itaconate in subcellular compartments of living macrophages.

Cancer stem cells (CSCs) represent a small portion of tumor cells with self-renewal ability in tumor tissues and are a key factor in tumor resistance, recurrence, and metastasis. CSCs produce a large number of exosomes through various mechanisms, such as paracrine and autocrine signaling. Studies have shown that CSC-derived exosomes (CSC-Exos) carry a variety of gene mutations and specific epigenetic modifications indicative of unique cell phenotypes and metabolic pathways, enabling exchange of information in the tumor microenvironment (TME) to promote tumor invasion and metastasis. In addition, CSC-Exos carry a variety of metabolites, especially proteins and miRNAs, which can activate signaling pathways to further promote tumor development. CSC-Exos have dual effects on cancer development. Due to advances in liquid biopsy technology for early cancer detection, CSCs-Exos may become an important tool for early cancer diagnosis and therapeutic drug delivery. In this article, we will review how CSC-Exos exert the above effects based on the above two aspects and explore their mechanism of action.

Many types of human tumour cells overexpress the dual-specificity phosphatase Cdc25A. Cdc25A dephosphorylates cyclin-dependent kinase and regulates the cell cycle, but other substrates of Cdc25A and their relevant cellular functions have yet to be identified. We demonstrate here that EGFR activation results in c-Src-mediated Cdc25A phosphorylation at Y59, which interacts with nuclear pyruvate kinase M2 (PKM2). Cdc25A dephosphorylates PKM2 at S37, and promotes PKM2-dependent β-catenin transactivation and c-Myc-upregulated expression of the glycolytic genes GLUT1 , PKM2 and LDHA , and of CDC25A ; thus, Cdc25A upregulates itself in a positive feedback loop. Cdc25A-mediated PKM2 dephosphorylation promotes the Warburg effect, cell proliferation and brain tumorigenesis. In addition, we identify positive correlations among Cdc25A Y59 phosphorylation, Cdc25A and PKM2 in human glioblastoma specimens. Furthermore, levels of Cdc25A Y59 phosphorylation correlate with grades of glioma malignancy and prognosis. These findings reveal an instrumental function of Cdc25A in controlling cell metabolism, which is essential for EGFR-promoted tumorigenesis. Protein phosphatase Cdc25 controls cell cycle transitions by dephosphorylating CDK substrates. Here, the authors show that the Cdc25A isoform regulates glycolysis through dephosphorylation of pyruvate kinase PKM2, resulting in β-catenin activation and consequent upregulation of the transcription of glycolytic genes.

Loin muscle area (LMA) is an important production trait in pigs and is highly correlated with lean meat percentage. However, the genetic architecture of LMA has not yet been fully elucidated. This study conducted genome-wide association studies (GWAS) and meta-analyses of LMA in Duroc (n = 337), Landrace (n = 662), and Yorkshire pigs (n = 3,176) using imputed whole-genome sequencing to identify new QTLs and candidate genes associated with LMA traits. A total of 108, 34, and 232 significant variants were identified in the Duroc, Landrace, and Yorkshire populations, respectively. The meta-analysis revealed 143 genome-wide significant SNPs and 276 suggestive SNPs, among which 213 were not identified in single population GWAS. Notably, 229 and 413 SNPs were located on SSC16 in the Yorkshire population and meta-analysis, respectively. Based on the 2-LOD drop-off interval, the SSC16 QTL in the Yorkshire population was further narrowed to a 679.835 kb interval (from 32.818 Mb to 33.498 Mb). The most significant variant within this QTL, 16_33228254 ( P  = 4.45 × 10 –9 ), explained 1.11% phenotypic variance, representing a potential novel locus for LMA. Further bioinformatics analysis determined seven promising candidate genes ( NDUFS4 , ARL15 , FST , ADAM12 , DAB2, PLPP1, and SGMS2 ) with biological processes such as myoblast fusion and positive regulation of transforming growth factor beta receptor signaling pathway. Among them, ARL15 was previously reported in LMA studies, while the other six genes represent novel candidate genes. These findings reveal potential functional genes and pathways associated with LMA, providing valuable insights for future genetic improvement in pigs.

In humans, risk attitude is highly context-dependent, varying with wealth levels or for different potential outcomes, such as gains or losses. These behavioral effects have been modelled using prospect theory, with the key assumption that humans represent the value of each available option asymmetrically as a gain or loss relative to a reference point. It remains unknown how these computations are implemented at the neuronal level. Here we show that macaques, like humans, change their risk attitude across wealth levels and gain/loss contexts using a token gambling task. Neurons in the anterior insular cortex (AIC) encode the ‘reference point’ (i.e., the current wealth level of the monkey) and reflect ‘loss aversion’ (i.e., option value signals are more sensitive to change in the loss than in the gain context) as postulated by prospect theory. In addition, changes in the activity of a subgroup of AIC neurons correlate with the inter-trial fluctuations in choice and risk attitude. Taken together, we show that the primate AIC in risky decision-making may be involved in monitoring contextual information used to guide the animal’s willingness to accept risk. Prospect theory predicts irrational effects in human decision-making, but relies on ad-hoc assumptions. Here, authors provide a neural basis for this by showing that anterior insular cortex encodes key economic variables proposed by prospect theory.

Background Plaque destabilization and rupture are the primary triggers of acute coronary syndrome (ACS). Soluble growth stimulation expressed gene 2 (sST2) has been implicated in cardiovascular disease. We aimed to investigate the association between circulating sST2 levels and features of coronary plaque destabilization assessed by optical coherence tomography (OCT) in patients with unstable angina (UA). Methods This study enrolled 122 patients admitted with UA and 107 age- and sex-matched healthy controls. All UA patients underwent standard coronary angiography and OCT imaging to identify features indicative of plaque destabilization. Plasma sST2 levels were measured in all participants using an immunofluorescence assay. Associations between sST2 levels, clinical characteristics, and factors predicting OCT-defined plaque destabilization were analyzed. Results sST2 levels were significantly higher in UA patients compared to healthy controls ( p  < 0.001). Among UA patients, sST2 levels were significantly elevated in those with OCT-defined plaque destabilization features compared to those without ( p  < 0.001). In multivariable logistic regression analysis, elevated sST2 levels emerged as an independent factor associated with the presence of OCT-defined plaque destabilization ( p  = 0.013). Conclusions Circulating sST2 levels are elevated in UA patients and independently associated with features of coronary plaque destabilization identified by OCT. These findings suggest sST2 may be a novel biomarker reflecting plaque destabilization in patients with UA, potentially aiding in risk stratification.

Hydrogel sensors are widely utilized in soft robotics and tissue engineering due to their excellent mechanical properties and biocompatibility. However, in high‐water environments, traditional hydrogels can experience significant swelling, leading to decreased mechanical and electrical performance, potentially losing shape, and sensing capabilities. This study addresses these challenges by leveraging the Hofmeister effect, coupled with directional freezing and salting‐out techniques, to develop a layered, high‐strength, tough, and antiswelling PVA/MXene hydrogel. In particular, the salting‐out process enhances the self‐entanglement of PVA, resulting in an S‐PM hydrogel with a tensile strength of up to 2.87 MPa. Furthermore, the S‐PM hydrogel retains its structure and strength after 7 d of swelling, with only a 6% change in resistance. Importantly, its sensing performance is improved postswelling, a capability rarely achievable in traditional hydrogels. Moreover, the S‐PM hydrogel demonstrates faster response times and more stable resistance change rates in underwater tests, making it crucial for long‐term continuous monitoring in challenging aquatic environments, ensuring sustained operation and monitoring. Inspired by the Hofmeister effect, PM (PVA/MXene) hydrogel undergo salting‐out to achieve S‐PM hydrogel with excellent mechanical properties and crosslinking ability. Additionally, directional freezing introduces a layered structure, endowing the hydrogel with excellent tear resistance. The hydrogel exhibits a mere 6% change in resistivity after swelling and demonstrated superior sensing performance underwater.