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Chronic heart failure (CHF) poses a significant threat to human health. The stress hyperglycemia ratio (SHR) is a novel metric for accurately assessing stress hyperglycemia, which has been correlated with adverse outcomes in various major diseases. However, it remains unclear whether SHR is associated with 28-day mortality in patients with pre-existing CHF who were admitted to intensive care units (ICUs). This study retrospectively recruited patients who were admitted to ICUs with both acute critical illness and pre-existing CHF from the Medical Information Mart for Intensive Care (MIMIC) database. Characteristics were compared between the survival and non-survival groups. The relationship between SHR and 28-day all-cause mortality was analyzed using restricted cubic splines, receiver operating characteristic (ROC) curves, Kaplan–Meier survival analysis, and Cox proportional hazards regression analysis. The importance of the potential risk factors was assessed using the Boruta algorithm. Prediction models were constructed using machine learning algorithms. A total of 913 patients were enrolled. The risk of 28-day mortality increased with higher SHR levels (P < 0.001). SHR was independently associated with 28-day all-cause mortality, with an unadjusted hazard ratio (HR) of 1.45 (P < 0.001) and an adjusted HR of 1.43 (P < 0.001). Subgroup analysis found that none of the potential risk factors, such as demographics, comorbidities, and drugs, affected the relationship (P for interaction > 0.05). The area under the ROC (AUC) curve for SHR was larger than those for admission blood glucose and HbA1c; the cut-off for SHR was 0.57. Patients with SHR higher than the cut-off had a significantly lower 28-day survival probability (P < 0.001). SHR was identified as one of the key factors for 28-day mortality by the Boruta algorithm. The predictive performance was verified through four machine learning algorithms, with the neural network algorithm being the best (AUC 0.801). For patients with both acute critical illness and pre-existing CHF, SHR was an independent predictor of 28-day all-cause mortality. Its prognostic performance surpasses those of HbA1c and blood glucose, and prognostic models based on SHR provide clinicians with an effective tool to make therapeutic decisions. [ABSTRACT FROM AUTHOR]

Hyperuricemia (HUA) is a common complication of chronic kidney disease (CKD). Conversely, HUA can promote the disease progression of CKD. However, the molecular mechanism of HUA in CKD development remains unclear. In the present study, we applied ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) to analyze the serum metabolite profiling of 47 HUA patients, 41 non-hyperuricemic CKD (NUA-CKD) patients, and 51 CKD and HUA (HUA-CKD) patients, and then subjected to multivariate statistical analysis, metabolic pathway analysis and diagnostic performance evaluation. Metabolic profiling of serums showed that 40 differential metabolites (fold-change threshold (FC) > 1.5 or<2/3, variable importance in projection (VIP) > 1, and p < 0.05) were screened in HUA-CKD and HUA patients, and 24 differential metabolites (FC > 1.2 or<0.83, VIP>1, and p < 0.05) were screened in HUA-CKD and NUA-CKD patients. According to the analysis of metabolic pathways, significant changes existed in three metabolic pathways (compared with the HUA group) and two metabolic pathways (compared with the HUA-CKD group) in HUA-CKD patients. Glycerophospholipid metabolism was a significant pathway in HUA-CKD. Our findings show that the metabolic disorder in HUA-CKD patients was more serious than that in NUA-CKD or HUA patients. A theoretical basis is provided for HUA to accelerate CKD progress. [ABSTRACT FROM AUTHOR]

G‐protein‐coupled receptor kinase 2 (GRK2) interacts with Gβγ and Gαq, subunits of G‐protein alpha, to regulate cell signalling. The second messenger inositol trisphosphate, produced by activated Gαq, promotes calcium release from the endoplasmic reticulum (ER) and regulates maturation‐promoting factor (MPF) activity. This study aimed to investigate the role of GRK2 in MPF activity during the meiotic maturation of porcine oocytes. A specific inhibitor of GRK2 (βi) was used in this study. The present study showed that GRK2 inhibition increased the percentage of oocyte arrest at the metaphase I (MI) stage (control: 13.84 ± 0.95%; βi: 31.30 ± 4.18%), which resulted in the reduction of the maturation rate (control: 80.36 ± 1.94%; βi: 65.40 ± 1.14%). The level of phospho‐GRK2 decreased in the treated group, suggesting that GRK2 activity was reduced upon GRK2 inhibition. Furthermore, the addition of βi decreased Ca2+ release from the ER. The protein levels of cyclin B and cyclin‐dependent kinase 1 were higher in the treatment group than those in the control group, indicating that GRK2 inhibition prevented a decrease in MPF activity. Collectively, GRK2 inhibition induced meiotic arrest at the MI stage in porcine oocytes by preventing a decrease in MPF activity, suggesting that GRK2 is essential for oocyte meiotic maturation in pigs. [ABSTRACT FROM AUTHOR]

Assisted reproduction technology (ART) procedures are often impacted by post-ovulatory aging (POA), which can lead to reduced fertilization rates and impaired embryo development. This study used RNA sequencing analysis and experimental validation to study the similarities and differences between in vivo- and vitro-matured porcine oocytes before and after POA. Differentially expressed genes (DEGs) between fresh in vivo-matured oocyte (F_vivo) and aged in vivo-matured oocyte (A_vivo) and DEGs between fresh in vitro-matured oocyte (F_vitro) and aged in vitro-matured oocyte (A_vitro) were intersected to explore the co-effects of POA. It was found that "organelles", especially "mitochondria", were significantly enriched Gene Ontology (GO) terms. The expression of genes related to the "electron transport chain" and "cell redox homeostasis" pathways related to mitochondrial function significantly showed low expression patterns in both A_vivo and A_vitro groups. Weighted correlation network analysis was carried out to explore gene expression modules specific to A_vivo. Trait–module association analysis showed that the red modules were most associated with in vivo aging. There are 959 genes in the red module, mainly enriched in "RNA binding", "mRNA metabolic process", etc., as well as in GO terms, and "spliceosome" and "nucleotide excision repair" pathways. DNAJC7, IK, and DDX18 were at the hub of the gene regulatory network. Subsequently, the functions of DDX18 and DNAJC7 were verified by knocking down their expression at the germinal vesicle (GV) and Metaphase II (MII) stages, respectively. Knockdown at the GV stage caused cell cycle disorders and increase the rate of abnormal spindle. Knockdown at the MII stage resulted in the inefficiency of the antioxidant melatonin, increasing the level of intracellular oxidative stress, and in mitochondrial dysfunction. In summary, POA affects the organelle function of oocytes. A_vivo oocytes have some unique gene expression patterns. These genes may be potential anti-aging targets. This study provides a better understanding of the detailed mechanism of POA and potential strategies for improving the success rates of assisted reproductive technologies in pigs and other mammalian species. [ABSTRACT FROM AUTHOR]

Classical Swine Fever (CSF), caused by the Classical Swine Fever Virus (CSFV), inflicts significant economic losses on the global pig industry. A key factor in the challenge of eradicating this virus is its ability to evade the host's innate immune response, leading to persistent infections. In our study, we elucidate the molecular mechanism through which CSFV exploits m6A modifications to circumvent host immune surveillance, thus facilitating its proliferation. We initially discovered that m6A modifications were elevated both in vivo and in vitro upon CSFV infection, particularly noting an increase in the expression of the methyltransferase METTL14. CSFV non-structural protein 5B was found to hijack HRD1, the E3 ubiquitin ligase for METTL14, preventing METTL14 degradation. MeRIP-seq analysis further revealed that METTL14 specifically targeted and methylated TLRs, notably TLR4. METTL14-mediated regulation of TLR4 degradation, facilitated by YTHDF2, led to the accelerated mRNA decay of TLR4. Consequently, TLR4-mediated NF-κB signaling, a crucial component of the innate immune response, is suppressed by CSFV. Collectively, these data effectively highlight the viral evasion tactics, shedding light on potential antiviral strategies targeting METTL14 to curb CSFV infection. Author summary: A significant concern arises from the enduring infection attributable to the suppression of the host innate immune response subsequent to CSFV infection. Our recent studies have excitingly unveiled the molecular mechanisms by which CSFV manipulates host methylation modifications to evade innate immune surveillance, thereby enhancing viral proliferation. Notably, CSFV non-structural protein 5B strategically commandeered the host factor HRD1. This interaction prevented HRD1 from ubiquitinating METTL14, leading to increased intracellular stability and expression of METTL14. Significantly, MeRIP-seq analysis revealed that METTL14 specifically targeted TLR4, recruiting YTFDH2 to facilitate TLR4 degradation, which in turn inhibited the TLR4 regulated NF-κB pathway. This suppression of the innate immune response resulted in a marked increase in CSFV replication. This distinct regulatory mechanism, unique to CSFV within the Pestivirus genus, illuminates the strategy of virus in exploiting m6A modification to bypass innate immunity, specifically focusing on the suppression of the NF-κB pathway at its source. [ABSTRACT FROM AUTHOR]