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Abstract Background and objective The aim of this study was to investigate potential hub genes for dilated cardiomyopathy (DCM). Methods Five DCM-related microarray datasets were downloaded from the Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) were used for identification. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, disease ontology, gene ontology annotation and protein-protein interaction (PPI) network analysis were then performed, while a random forest was constructed to explore central genes. Artificial neural networks were used to compare with known genes and to develop new diagnostic models. 240 population blood samples were collected and expression of hub genes was verified in these samples using RT-PCR and demonstrated by Nomogram. Results After differential analysis, 33 genes were statistically significant (adjusted P

Abstract How the lung achieves immune homeostasis after a pulmonary infection is not fully understood. Here, we analyzed the spatiotemporal changes in the lungs over a 2-week natural recovery from severe pneumonia in a Syrian hamster model of SARS-CoV-2 infection. We find that SARS-CoV-2 infects multiple cell types and causes massive cell death at the early stage, including alveolar macrophages. We identify a group of monocyte-derived Slamf9 + macrophages, which are induced after SARS-CoV-2 infection and resistant to impairment caused by SARS-CoV-2. Slamf9 + macrophages contain SARS-CoV-2, recruit and interact with Isg12 + Cst7 + neutrophils to clear the viruses. After viral clearance, Slamf9 + macrophages differentiate into Trem2 + and Fbp1 + macrophages, contributing to inflammation resolution at the late stage, and finally replenish alveolar macrophages. These findings are validated in a SARS-CoV-2-infected hACE2 mouse model and confirmed with publicly available human autopsy single-cell RNA-seq data, demonstrating the potential role of Slamf9 + macrophages and their coordination with neutrophils in post-injury tissue repair and inflammation resolution.

Abstract How immune cells are spatiotemporally coordinated in the lung to effectively monitor, respond to, and resolve infection and inflammation in primed form needs to be fully illustrated. Here we apply immunocartography, a high-resolution technique that integrates spatial and single-cell RNA sequencing (scRNA-seq) through deconvolution and co-localization analyses, to the SARS-CoV-2-infected Syrian hamster model. We generate a comprehensive transcriptome map of the whole process of pulmonary infection from physiological condition, infection initiation, severe pneumonia to natural recovery at organ scale and single-cell resolution, with 142,965 cells and 45 lung lobes from 25 hamsters at 5 time points. Integrative analysis identifies that alveolar dendritic cell–T cell immunity hubs, where Ccr7 + Ido1 + dendritic cells, Cd160 + Cd8 + T cells, and Tnfrsf4 + Cd4 + T cells physiologically co-localize, rapidly expand during SARS-CoV-2 infection, eliminate SARS-CoV-2 with the aid of Slamf9 + macrophages, and then restore to physiological levels after viral clearance. We verify the presence of these cell subpopulations in the immunity hubs in normal and SARS-CoV-2-infected hACE2 mouse models, as well as in publicly available human scRNA-seq datasets, demonstrating the potential broad relevance of our findings in lung immunity.

Abstract Background Dual bronchodilator therapy, consisting of a long-acting beta-agonist (LABA) and a long-acting muscarinic antagonist (LAMA), has proven effective for patients with chronic obstructive pulmonary disease (COPD). However, it remains uncertain whether there are efficacy differences between current and former smokers with COPD. This study aims to explore the effectiveness of LABA/LAMA therapies in both these groups. Methods The TOReTO trial assessed lung function, symptoms, health status, the occurrence of exacerbations, clinically significant exacerbations, and the use of LABA/LAMA therapies. These therapies include Tio/Olo, umeclidinium/vilanterol (Umec/Vi), and umeclidinium/vilanterol (Umec/Vi) are used in patients with COPD. The study examined the differences in outcomes between current and former smokers. To balance the baseline characteristics, propensity score matching (PSM) was employed. Results Data from 967 patients were collected. After PSM, the time to the first acute exacerbation in current smokers was analyzed separately for the three treatment groups and was significantly different between them (p = 0.0457). Among, there are differences in the occurrence of acute exacerbation between treatment and smoking status in Umec/Vi (p = 0.0114). There is no significant difference in the treatment of former smokers among the three different groups of LABA/LAMA fixed-dose combinations (p = 0.3079). COPD-related symptoms remained stable throughout the treatment period. There were no significant differences in symptom scores, including CAT and mMRC, among the three groups at the end of the study. Conclusions The three fixed-dose combinations of LABA/LAMA showed no difference in reducing exacerbations in former smokers but did show differences in current smokers. This trend has clinical significance, and future research will be conducted to control influencing variables to validate this point. However, due to the non-randomized study design, these findings should be interpreted with caution.

Acute kidney injury （AKI） is a diverse group of renal diseases characterized by a dramatic decline in renal function. Not only AKI has a high mortality rate， but also poor renal adaptation or incomplete repair after acute phase may also lead to renal fibrosis and eventually to chronic kidney disease （CKD）. Currently there are no effective measures for limiting damage， promoting recovery and improving survival. Proteolysis targeting chimeras （PROTACs） provide a novel strategy for AKI drug development through ubiquitin-proteasome system of degrading target proteins. This review summarized promising therapeutic targets for AKI and the application of PROTACs technology.

Primula medogensis W.B Ju, B. Xu & X.F. Gao 2023, a new species categorized under P. sect. Cordifoliae, was officially described in 2023. Given its recent classification, the genetic resources for this species are currently very limited. Here, we sequenced and assembled the first complete chloroplast genome of P. medogensis using Illumina sequencing technology. The complete chloroplast genome of P. medogensis is 151,486 bp in length, exhibiting a typical quadripartite structure. It consists of a large single-copy region (LSC; 83,407 bp) and a small single-copy region (SSC;17675 bp), separated by a pair of inverted repeat regions (IRs; 25202 bp). A total of 131 genes were annotated, including 86 protein-coding, 37 tRNA, and eight rRNA genes. The overall GC content was 37.1%. Phylogenetic analysis of 59 Primula species revealed a close relationship between P. medogensis and P. calliantha subsp. bryophila.

Abstract Background Cancer patients’ vulnerability to QT prolongation contradicts certain anti-cancer drug usage. Until now, the QT prolongation’s impact on CV mortality in cancer patients remains unclear, potentially biasing therapeutic decisions. Methods This retrospective observational cohort included adult cancer patients with an electrocardiogram (ECG) performed in a tertiary hospital in Taiwan. The first performed ECGs after cancer diagnosis (n = 59,568) were analyzed. The corrected QT intervals by Bazett (QTcB), Fridericia (QTcFri), and Framingham (QTcFra) formulae were used to predict the 90-day and one-year CV mortality according to the Taiwan death registry. Results The AUC of QTcB (90 days: 0.70, 1 year: 0.68) for predicting CV mortality was better than QTcFri and QTcFra (90 days: 0.63 and 0.50, 1 year: 0.65 and 0.56). Using the restricted cubic spline regression model adjusted by age and comorbidities, QTcB increased a significant but trivial risk of CV mortality at 90 days (hazard ratio, 1.007, P = 0.02) and one year (1.006, P

Abstract Background Modified furosemide responsiveness index (mFRI) is a novel biomarker for assessing diuretic response and AKI progression in patients with early AKI. However, the comparative predictive performance of mFRI and novel renal biomarkers for adverse renal outcomes remains unclear. In a single-center prospective study, we aimed to evaluate the discriminatory abilities of mFRI and other novel renal biomarkers in predicting AKI progression and prognosis in patients with initial mild and moderate AKI (KDIGO stage 1 to 2). Results Patients with initial mild and moderate AKI within 48 h following cardiac surgery were included in this study. The mFRI, renal biomarkers (including serum or urinary neutrophil gelatinase-associated lipocalin [sNGAL or uNGAL], serum cystatin C, urinary N-acetyl-beta-D-glycosaminidase [uNAG], urinary albumin-to-creatinine ratio) and cytokines (TNF, IL-1β, IL-2R, IL-6, IL-8, and IL-10) were measured at AKI diagnosis. The mFRI was calculated for each patient, which was defined as 2-hour urine output divided by furosemide dose and body weight. Of 1013 included patients, 154 (15.2%) experienced AKI progression, with 59 (5.8%) progressing to stage 3 and 33 (3.3%) meeting the composite outcome of hospital mortality or receipt of renal replacement therapy (RRT). The mFRI showed non-inferiority or potential superiority to renal biomarkers and cytokines in predicting AKI progression (area under the curve [AUC] 0.80, 95% confidence interval [CI] 0.77–0.82), progression to stage 3 (AUC 0.87, 95% CI 0.85–0.89), and composite outcome of death and receipt of RRT (AUC 0.85, 95% CI 0.82–0.87). Furthermore, the combination of a functional biomarker (mFRI) and a urinary injury biomarker (uNAG or uNGAL) resulted in a significant improvement in the prediction of adverse renal outcomes than either individual biomarker (all P

Abstract Nucleotide-binding oligomerization domain 2 (NOD2) is an immune sensor crucial for eliciting the innate immune responses. Nevertheless, discrepancies exist regarding the effect of NOD2 on different types of cancer. This study aimed to investigate these function of NOD2 in melanoma and its underlying mechanisms. We have validated the tumor suppressor effect of NOD2 in melanoma. NOD2 inhibited the proliferation of melanoma cells, hindering their migration and invasion while promoting the onset of apoptosis. Our study showed that NOD2 expression is closely related to pyrimidine and folate metabolism. NOD2 inhibits thymidylate synthase (TYMS) expression by promoting K48-type ubiquitination modification of TYMS, thereby decreasing the resistance of melanoma cells to 5-fluorouracil (5-FU) and capecitabine (CAP). TYMS was identified to form a complex with Polo-like Kinase 1 (PLK1) and activate the PLK1 signaling pathway. Furthermore, we revealed that the combination of the PLK1 inhibitor volasertib (BI6727) with 5-FU or CAP had a synergistic effect repressing the proliferation, migration, and autophagy of melanoma cells. Overall, our research highlights the protective role of NOD2 in melanoma and suggests that targeting NOD2 and the TYMS/PLK1 signaling axis is a high-profile therapy that could be a prospect for melanoma treatment.

BACKGROUND AND AIMS: Neuroprotection plays an important role in the treatment of brain disorders. In recent years, studies using rat models and clinical trials have demonstrated the positive effects of hydrogen treatment on neurological disorders and brain injuries. Hence, it is of great significance to shed light on this issue. In this article, CiteSpace is employed for visualization and bibliometric analysis of the research frontiers and evolving trends related to the neuroprotective effect of hydrogen. METHODS: All articles published from 2009 to 2023 that discussed the neuroprotective effects of hydrogen in cerebrovascular diseases were retrieved from the Web of Science. Using CiteSpace, a visualization analysis was conducted on aspects such as countries, institutions, authors, keywords, and Co cited references, which enables an intuitive observation of current research hotspots. RESULTS: After manual screening, a total of 106 articles were retrieved. Over time, The number of publications has increased annually. Regarding national contributions, the top three countries with the highest number of publications include China, the United States, and Japan. The Second Military Medical University is the institution that publishes the most articles and has significant influence in the field of hydrogen neuroprotection. Sun, Xuejun and Domoki, Ferenc were the most productive. The most common keywords include hydrogen, oxidative stress, inflammation, and apoptosis. Potential areas of focus for future research consist of early brain injury, hydrogen, ischemia-reperfusion injury and hypothermia treatment. CONCLUSION: The bibliometric study presented herein offers insights into the current status and trends of research on hydrogen in the field of cerebrovascular diseases. Future research trends suggest that hydrogen contributes significantly to the cerebrovascular domain through its anti-inflammatory, antioxidative, and anti-apoptotic mechanisms. This study can aid researchers in identifying hot topics and exploring new research directions.

Abstract Background Mitochondria and endoplasmic reticulum (ER) contact sites (MERCS) constitute a functional communication platform for ER and mitochondria, and they play a crucial role in the lipid homeostasis of the liver. However, it remains unclear about the exact effects of MERCs on the neutral lipid synthesis of the liver. Methods In this study, the role and mechanism of MERCS in palmitic acid (PA)-induced neutral lipid imbalance in the liver was explored by constructing a lipid metabolism animal model based on yellow catfish. Given that the structural integrity of MERCS cannot be disrupted by the si-mitochondrial calcium uniporter (si-mcu), the MERCS-mediated Ca2+ signaling in isolated hepatocytes was intercepted by transfecting them with si-mcu in some in vitro experiments. Results The key findings were: (1) Hepatocellular MERCs sub-proteome analysis confirmed that, via activating Ip3r-Grp75-voltage-dependent anion channel (Vdac) complexes, excessive dietary PA intake enhanced hepatic MERCs. (2) Dietary PA intake caused hepatic neutral lipid deposition by MERCs recruiting Seipin, which promoted lipid droplet biogenesis. (3) Our findings provide the first proof that MERCs recruited Seipin and controlled hepatic lipid homeostasis, depending on Ip3r-Grp75-Vdac-controlled Ca2+ signaling, apart from MERCs’s structural integrity. Noteworthy, our results also confirmed these mechanisms are conservative from fish to mammals. Conclusions The findings of this study provide a new insight into the regulatory role of MERCS-recruited SEIPIN in hepatic lipid synthesis via Ip3r-Grp75-Vdac complex-mediated Ca2+ signaling, highlighting the critical contribution of MERCS in hepatic lipid homeostasis.