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Trimethylamine (TMA) is a gut microbiota-derived metabolite which comes from diets rich of choline, betaine or l-carnitine and could be further converted to Trimethylamine-N-oxide (TMAO) in the liver. As the function of gut microbiota and its metabolites being explored so far, studies suggest that TMAO may be a potential risk factor of cardiovascular diseases independent of other traditional risk factors. However, the precise role of TMAO is controversial as some converse results were discovered. In recent studies, it is hypothesized that TMA may also participate in the progression of cardiovascular diseases and some cytotoxic effect of TMA has been discovered. Thus, exploring the relationship between TMA, TMAO and CVD may bring a novel insight into the diagnosis and therapy of cardiovascular diseases. In this review, we discussed the factors which influence the TMA/TMAO’s process of metabolism in the human body. We have also summarized the pathogenic effect of TMA/TMAO in cardiovascular diseases, as well as the limitation of some controversial discoveries.

The significant role of VEGF (vascular endothelial growth factor) as an angiogenesis inducer is well recognized. Besides VEGF, EphrinB2/EphB4 also plays essential roles in vascular development and postnatal angiogenesis. Compared with classical proangiogenic factors, not only does EphrinB2/EphB4 promote sprouting of new vessels, it is also involved in the vessel maturation. Given their involvement in many physiologic and pathological conditions, EphB4 and EphrinB2 are increasingly recognized as attractive therapeutic targets for angiogenesis-related diseases through modulating their expression and function. Previous works mainly focused on the individual role of VEGF and EphrinB2/EphB4 in angiogenesis, respectively, but the correlation between EphrinB2/EphB4 and VEGF in angiogenesis has not been fully disclosed. Here, we summarize the structure and bidirectional signaling of EphrinB2/EphB4, provide an overview on the relationship between EphrinB2/EphB4 signaling and VEGF pathway in angiogenesis and highlight the associated potential usefulness in anti-angiogenetic therapy.

Methanobactins (Mbns) are a family of copper-binding peptides involved in copper uptake by methanotrophs, and are potential therapeutic agents for treating diseases characterized by disordered copper accumulation. Mbns are produced via modification of MbnA precursor peptides at cysteine residues catalyzed by the core biosynthetic machinery containing MbnB, an iron-dependent enzyme, and MbnC. However, mechanistic details underlying the catalysis of the MbnBC holoenzyme remain unclear. Here, we present crystal structures of MbnABC complexes from two distinct species, revealing that the leader peptide of the substrate MbnA binds MbnC for recruitment of the MbnBC holoenzyme, while the core peptide of MbnA resides in the catalytic cavity created by the MbnB–MbnC interaction which harbors a unique tri-iron cluster. Ligation of the substrate sulfhydryl group to the tri-iron center achieves a dioxygen-dependent reaction for oxazolone-thioamide installation. Structural analysis of the MbnABC complexes together with functional investigation of MbnB variants identified a conserved catalytic aspartate residue as a general base required for MbnBC-mediated MbnA modification. Together, our study reveals the similar architecture and function of MbnBC complexes from different species, demonstrating an evolutionarily conserved catalytic mechanism of the MbnBC holoenzymes.

Exercise is usually regarded to have short-term beneficial effects on immune health. Here we show that early-life regular exercise exerts long-term beneficial effects on inflammatory immunity. Swimming training for 3 months in male mice starting from 1-month-old curbs cytokine response and mitigates sepsis when exposed to lipopolysaccharide challenge, even after an 11-month interval of detraining. Metabolomics analysis of serum and liver identifies pipecolic acid, a non-encoded amino acid, as a pivotal metabolite responding to early-life regular exercise. Importantly, pipecolic acid reduces inflammatory cytokines in bone marrow-derived macrophages and alleviates sepsis via inhibiting mTOR complex 1 signaling. Moreover, early-life exercise increases histone 3 lysine 4 trimethylation at the promoter of Crym in the liver, an enzyme responsible for catalyzing pipecolic acid production. Liver-specific knockdown of Crym in adult mice abolishes this early exercise-induced protective effects. Our findings demonstrate that early-life regular exercise enhances anti-inflammatory immunity during middle-aged phase in male mice via epigenetic immunometabolic modulation, in which hepatic pipecolic acid production has a pivotal function. Exercise could affect the immune system, but whether early-life exercise could benefit immune health in adulthood is not fully understood. Here the authors show that early-life exercise promotes epi-metabolic changes in the liver to potentially benefit immunity in older age and characterise the involvement of pipecolic acid in this process.

Quantum-dot light-emitting diodes promise a new generation of high-performance and solution-processed electroluminescent light sources. Understanding the operational degradation mechanisms of quantum-dot light-emitting diodes is crucial for their practical applications. Here, we show that quantum-dot light-emitting diodes may exhibit an anomalous degradation pattern characterized by a continuous increase in electroluminescent efficiency upon electrical stressing, which deviates from the typical decrease in electroluminescent efficiency observed in other light-emitting diodes. Various in-situ/operando characterizations were performed to investigate the evolutions of charge dynamics during the efficiency elevation, and the alterations in electric potential landscapes in the active devices. Furthermore, we carried out selective peel-off-and-rebuild experiments and depth-profiling analyses to pinpoint the critical degradation site and reveal the underlying microscopic mechanism. The results indicate that the operation-induced efficiency increase results from the degradation of electron-injection capability at the electron-transport layer/cathode interface, which in turn leads to gradually improved charge balance. Our work provides new insights into the degradation of red quantum-dot light-emitting diodes and has far-reaching implications for the design of charge-injection interfaces in solution-processed light-emitting diodes. Quantum-dot light-emitting diodes may exhibit anomalous efficiency enhancement upon electrical stress, as revealed by the authors, resulting from the continuous deterioration of cathode contacts.

Background Pyroptosis is a form of programmed cell death involved in the pathophysiological progression of hypoxic pulmonary hypertension (HPH). Emerging evidence suggests that N6-methyladenosine (m6A)-modified transcripts of long noncoding RNAs (lncRNAs) are important regulators that participate in many diseases. However, whether m6A modified transcripts of lncRNAs can regulate pyroptosis in HPH progression remains unexplored. Methods The expression levels of FENDRR in hypoxic pulmonary artery endothelial cells (HPAECs) were detected by using quantitative real-time polymerase chain reaction (qRT-PCR) and fluorescence in situ hybridization (FISH). Western blot, Lactate dehydrogenase (LDH) release assay, Annexin V-FITC/PI double staining, Hoechst 33342/PI fluorescence staining and Caspase-1 activity assay were used to detect the role of FENDRR in HPAEC pyroptosis. The relationship between FENDRR and dynamin-related protein 1 (DRP1) was explored using bioinformatics analysis, Chromatin Isolation by RNA Purification (CHIRP), Electrophoretic mobility shift assay (EMSA) and Methylation-Specific PCR (MSP) assays. RNA immunoprecipitation (RIP) and m6A dot blot were used to detect the m6A modification levels of FENDRR. A hypoxia-induced mouse model of pulmonary hypertension (PH) was used to test preventive effect of conserved fragment TFO2 of FENDRR. Results We found that FENDRR was significantly downregulated in the nucleus of hypoxic HPAECs. FENDRR overexpression inhibited hypoxia-induced HPAEC pyroptosis. Additionally, DRP1 is a downstream target gene of FENDRR, and FENDRR formed an RNA–DNA triplex with the promoter of DRP1, which led to an increase in DRP1 promoter methylation that decreased the transcriptional level of DRP1. Notably, we illustrated that the m6A reader YTHDC1 plays an important role in m6A-modified FENDRR degradation. Additionally, conserved fragment TFO2 of FENDEE overexpression prevented HPH in vivo. Conclusion In summary, our results demonstrated that m6A-induced decay of FENDRR promotes HPAEC pyroptosis by regulating DRP1 promoter methylation and thereby provides a novel potential target for HPH therapy.

Fire detection is crucial for safeguarding human life and property. To address the limitations of existing deep learning-based detectors—such as weak feature perception, information loss, high computational cost, and poor performance on small targets—this paper proposes an enhanced YOLOv7 model named CGDS-YOLO. The model introduces three key innovations: a CDP-ELAN module (fusing Coordinate Convolution, Diverse Branch Block, and Partial Convolution) for strengthened feature extraction, a Gathering-Distributing mechanism for improved multi-scale information fusion, and a SlimNeck structure to reduce parameters while retaining fine-grained details. Additionally, Normalized Wasserstein Distance is adopted to enhance small target detection. Experiments on a homemade smoke and flame dataset and the public Visdrone dataset show that CGDS-YOLO outperforms baseline models, improving mAP by 2.0% and 1.7%, respectively, while maintaining high computational efficiency.

Background: High mobility group box 2 (HMGB2), one of the HMGB domain proteins, may play a significant role in cancer development and progression. Recent scientific investigations have hinted at the potential clinical relevance of HMGB2, particularly in cancer patients where its expression levels have been observed to be elevated. However, the precise impact of HMGB2 on the prognosis of tumors remains an area of ongoing research. To the best of our understanding, our study represents a meta-analysis that elucidates a connection between HMGB2 expression and the clinical outcomes of diverse cancer types. Method: We executed a thorough and systematic search of literature across PubMed, Web of Science, Embase, CNKI, and Wanfang databases. Following this, we conducted a quantitative meta-analysis using statistical tools such as StataMP16 and RevMan5.3. The primary focus of our analysis was to assess the relationship between HMGB2 expression levels and overall survival (OS), disease-free survival (DFS), as well as various clinicopathological characteristics of cancer patients by calculating the hazard ratio (HR). Additionally, we validated our findings by examining HMGB2 expression patterns across different cancer types using the Gene Expression Profiling Interactive Analysis (GEPIA) online platform. Result: Our meta-analysis incorporated data from 17 studies, encompassing a total of 2555 cancer patients. The results revealed a statistically significant association between high HMGB2 expression and shorter OS (HR, 1.40 ;95% CI: 1.10–1.70; P  < 0.001), especially in digestive cancer ( HR, 2.09 (95% CI: 1.54–2.63; I 2  = 0.0%, P  = 0.424). Furthermore, GEPIA analysis demonstrated a consistent upregulation of HMGB2 in most cancer types, with a downregulation between HMGB2 and LAML. Conclusion: Our findings underscore a detrimental correlation between the upregulation of HMGB2 and the prognosis of various cancers. This discovery could pave the way for the development of innovative prognostic biomarkers and therapeutic targets that specifically target HMGB2, offering new avenues for the management and treatment of cancer patients.

Cullin 4B (CUL4B), a pivotal member of the Cullins protein family, plays a crucial role in immune regulation and has garnered significant research attention. CUL4B, through the Cullin 4B-RING E3 ubiquitin ligase (CRL4B) complex, regulates CD4+ T cell differentiation, fostering a balance between TH1 and TH2 subsets, and expedites DNA damage repair to bolster T cell persistence. In B cells, CUL4B upregulation stimulates immune responses but is linked to an unfavorable prognosis in lymphoma. In innate immunity, CUL4B modulates Toll-like receptor (TLR)-mediated anti-inflammatory responses, enhancing macrophage migration and adhesion. CUL4B also plays a role in potentiating anti-tumor immunity by restricting the activity of myeloid-derived suppressor cells (MDSCs). In disease pathogenesis, CUL4B limits MDSCs to enhance anti-tumor effects, and its inhibition in experimental autoimmune encephalomyelitis (EAE) models have demonstrated beneficial effects, underscoring its potential therapeutic significance in autoimmune diseases. Furthermore, CUL4B is involved in various immune-related cancers and inflammation, including pleural mesothelioma, human osteosarcoma, and colitis-associated cancer. In metabolic diseases, CUL4B regulates adipose tissue and insulin sensitivity, with its depletion improving metabolic phenotypes. This review highlights the pivotal role of CUL4B in maintaining immune homeostasis and provides novel perspectives and insights into the understanding and development of treatments for immune-related disorders.

Social isolation is common and associated with many adverse outcomes. The evidence regarding social isolation and mortality among middle-aged and older adults with arthritis was lacking. The study aimed to examine the association between social isolation and mortality in this population. This study used data from four prospective cohorts: National Health and Aging Trends Study (NHATS), English Longitudinal Study of Ageing (ELSA), China Health and Retirement Longitudinal Study (CHARLS), and Chinese Longitudinal Healthy Longevity Survey (CLHLS). Individuals with arthritis (including osteoarthritis and rheumatoid arthritis) in these cohorts were included. Social isolation was assessed using self-reported questionnaires. Cox proportional hazards regression models were conducted to evaluate these associations. At baseline, a total of 16,035 individuals with arthritis (3872 from NHATS, 3259 from ELSA, 5645 CHARLS, and 3259 from CLHLS) were included. Social isolation was associated with increased risk of mortality in meta-analysis (hazard ratio [HR] 1.42, 95% confidence interval [CI]: 1.26–1.59), and individual cohorts (NHATS: HR 1.53, 95% CI 1.19–1.97; ELSA: HR 1.31, 95% CI 1.02–1.67; CLHLS: HR 1.50, 95% CI 1.36–1.64) after being adjusted for confounder factors. Additionally, with increasing social isolation score, the risk of mortality also increased in meta-analysis (HR 1.19, 95% CI 1.15–1.24), as well as in individual cohorts (NHATS: HR 1.22, 95% CI 1.14–1.30; CLHLS: HR 1.19, 95% CI 1.13–1.26). Subgroups analysis results suggested that social isolation was independently associated with a higher likelihood of mortality in middle-aged and older adults with arthritis, regardless of gender, lifestyles, and chronic diseases.