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Background Previous research has demonstrated flavonoid intake was closely related to hyperuricemia. The purpose of this study was to examine whether flavonoid intake was associated with serum uric acid and hyperuricemia in U.S. adults. Methods The study sample consisted of 8,760 participants enrolled in the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2010. Flavonoid consumption was measured using a two-day recall questionnaire on dietary intake. Hyperuricemia was defined based on the serum uric acid levels, determined as ≥ 7 mg/dL for males and ≥ 6 mg/dL for females. The study utilized multivariate linear regression to determine the correlation between flavonoid consumption and serum uric acid levels. Additionally, analyses involving multivariate logistic regression and restricted cubic splines (RCS) were conducted to evaluate the potential link between flavonoid consumption and hyperuricemia. All analyses were adjusted for possible confounding variables. Results The study revealed a negative correlation between serum uric acid levels and elevated levels of anthocyanidins and flavanones, with significant p-trends of < 0.001 and 0.02 respectively. The multivariate analysis showed that anthocyanidins and flavanones intake had a significant negative association with the risk of hyperuricemia, with p-trend value being < 0.001 and 0.01, respectively. Flavan-3-ols, flavonols, and all flavonoids exhibited a non-linear association with the incidence of hyperuricemia, with significant p-nonlinear values of < 0.001, 0.04, and 0.01 respectively. Conclusion Our study demonstrated that individuals who follow a diet rich in anthocyanins and flavanones had significantly lower serum uric acid levels and a lower incidence of hyperuricemia.

Post-operative recurrence rates of stage I non-small cell lung cancer (NSCLC) range from 20% to 40%. Nonetheless, the molecular mechanisms underlying recurrence hitherto remain largely elusive. Here, we generate genomic, epigenomic and transcriptomic profiles of paired tumors and adjacent tissues from 122 stage I NSCLC patients, among which 57 patients develop recurrence after surgery during follow-up. Integrated analyses illustrate that the presence of predominantly solid or micropapillary histological subtypes, increased genomic instability, and APOBEC-related signature are associated with recurrence. Furthermore, TP53 missense mutation in DNA-binding domain could contribute to shorter time to recurrence. DNA hypomethylation is pronounced in recurrent NSCLC, and PRAME is the significantly hypomethylated and overexpressed gene in recurrent lung adenocarcinoma (LUAD). Mechanistically, hypomethylation at TEAD1 binding site facilitates the transcriptional activation of PRAME . Inhibition of PRAME restrains the tumor metastasis via downregulation of epithelial–mesenchymal transition-related genes. We also identify that enrichment of AT2 cells with higher copy number variation burden, exhausted CD8 + T cells and Macro_SPP1, along with the reduced interaction between AT2 and immune cells, is essential for the formation of ecosystem in recurrent LUAD. Finally, multi-omics clustering could stratify the NSCLC patients into 4 subclusters with varying recurrence risk and subcluster-specific therapeutic vulnerabilities. Collectively, this study constitutes a promising resource enabling insights into the biological mechanisms and clinical management for post-operative recurrence of stage I NSCLC. The molecular mechanisms underlying stage I non-small cell lung cancer (NSCLC) remain poorly understood. Here, the authors do multi-omics profiling of paired tumor and normal adjacent tissues from NSCLC patients, finding molecular processes and cell type proportions that are associated with recurrence.

ClpX and ClpP are involved in many important functions, including stress responses and energy metabolism, in microorganisms. However, the ClpX and ClpP of microbes used in industrial scale have rarely been studied. Industrial bacterial fermentation experiences a variety of stresses, and energy metabolism is extremely important for industrial bacteria. Thus, the role played by the ClpX and ClpP of industrial bacteria in fermentation should be investigated. Most microorganisms have a single clpP gene, while Corynebacterium crenatum AS 1.542 possesses two clpPs. Herein, the clpX, clpP1, and clpP2 of C. crenatum were cloned, and its fusion protein was expressed and characterized. We also constructed clpX deletion mutant and complementation strain. Results indicate that ClpX serves an important function in thermal, pH, and ethanol stresses. It is also involved in NADPH synthesis and glucose consumption during fermentation.

Background L -Tyrosine ( L -Tyr) is a significant aromatic amino acid that is experiencing an increasing demand in the market due to its distinctive characteristics. Traditional production methods exhibit various limitations, prompting researchers to place greater emphasis on microbial synthesis as an alternative approach. Results Here, we developed a metabolic engineering-based method for efficient production of L -Tyr from Corynebacterium crenatum , including the elimination of competing pathways, the overexpression of aroB , aroD , and aroE , and the introduction of the mutated E. coli tyrA fbr gene for elevating L -Tyr generation. Moreover, the mtlR gene was knocked out, and the mtlD and pfkB genes were overexpressed, allowing C. crenatum to produce L -Tyr from mannitol. The L -Tyr production achieved 6.42 g/L at a glucose-to-mannitol ratio of 3:1 in a shake flask, which was 16.9% higher than that of glucose alone. Notably, the L -Tyr production of the fed-batch fermentation was elevated to 34.6 g/L, exhibiting the highest titers among those of C. glutamicum previously reported. Conclusion The importance of this research is underscored by its pioneering application of mannitol as a carbon source for the biosynthesis of L -Tyr, as well as its examination of the influence of mannitol-associated genes in microbial metabolism. A promising platform is provided for the production of target compounds that does not compete with human food source.

Dental fluorosis is a very prevalent endemic disease. Although oral microbiome has been reported to correlate with different oral diseases, there appears to be an absence of research recognizing any relationship between the severity of dental fluorosis and the oral microbiome. To this end, we investigated the changes in oral microbial community structure and identified bacterial species associated with moderate and severe dental fluorosis. Salivary samples of 42 individuals, assigned into Healthy (N = 9), Mild (N = 14) and Moderate/Severe (M&S, N = 19), were investigated using the V4 region of 16S rRNA gene. The oral microbial community structure based on Bray Curtis and Weighted Unifrac were significantly changed in the M&S group compared with both of Healthy and Mild. As the predominant phyla, Firmicutes and Bacteroidetes showed variation in the relative abundance among groups. The Firmicutes/Bacteroidetes (F/B) ratio was significantly higher in the M&S group. LEfSe analysis was used to identify differentially represented taxa at the species level. Several genera such as Streptococcus mitis, Gemella parahaemolysans, Lactococcus lactis, and Fusobacterium nucleatum , were significantly more abundant in patients with moderate/severe dental fluorosis, while Prevotella melaninogenica and Schaalia odontolytica were enriched in the Healthy group. In conclusion, our study indicates oral microbiome shift in patients with moderate/severe dental fluorosis. We identified several differentially represented bacterial species enriched in moderate and severe fluorosis. Findings from this study suggests that the roles of these bacteria in oral health and related diseases warrant more consideration in patients with moderate and severe fluorosis.

The cell identity of malignant cells and how they acquire it are fundamental for our understanding of cancer. Here, we report that esophageal squamous cell carcinoma (ESCC) cells display molecular features equally similar but distinct to all three types of normal esophageal epithelial cells, which we term as confused cell identity (CCI). CCI is an independent prognostic marker associated with poor prognosis in ESCC. Further, we identify tropomyosin 4 (TPM4) as a critical CCI gene that promotes the aggressiveness of ESCC in vitro and in vivo. And TPM4 creates CCI through activating the Jak/STAT-SOX2 pathway. Thus, our study suggests an unrecognized feature of ESCC cells, which might be of value for clinic prognosis and potential interference.

Transcriptional elongation is a universal and critical step during gene expression. The super elongation complex (SEC) regulates the rapid transcriptional induction by mobilizing paused RNA polymerase II (Pol II). Dysregulation of SEC is closely associated with human diseases. However, the physiological role of SEC during development and homeostasis remains largely unexplored. Here we studied the function of SEC in adipogenesis by manipulating an essential scaffold protein AF4/FMR2 family member 4 (AFF4), which assembles and stabilizes SEC. Knockdown of AFF4 in human mesenchymal stem cells (hMSCs) and mouse 3T3-L1 preadipocytes inhibits cellular adipogenic differentiation. Overexpression of AFF4 enhances adipogenesis and ectopic adipose tissue formation. We further generate Fabp4-cre driven adipose-specific Aff4 knockout mice and find that AFF4 deficiency impedes adipocyte development and white fat depot formation. Mechanistically, we discover AFF4 regulates autophagy during adipogenesis. AFF4 directly binds to autophagy-related protein ATG5 and ATG16L1, and promotes their transcription. Depleting ATG5 or ATG16L1 abrogates adipogenesis in AFF4-overepressing cells, while overexpression of ATG5 and ATG16L1 rescues the impaired adipogenesis in Aff4 -knockout cells. Collectively, our results unveil the functional importance of AFF4 in regulating autophagy and adipogenic differentiation, which broaden our understanding of the transcriptional regulation of adipogenesis.

Background Osteoarthritis (OA) is a joint disorder that is characterized, among other features, by abnormal subchondral bone remodeling. Moxibustion, a traditional Chinese medicine treatment, has a long history in the clinical treatment of osteoarthritis and has demonstrated significant efficacy. However, the impact mechanisms of moxibustion on subchondral bone in osteoarthritis have yet to be elucidated. Purpose This study investigated the specific effects and mechanisms of moxibustion on abnormal subchondral bone remodeling in OA. Methods Anterior cruciate ligament transection (ACLT) surgery was performed on mice to establish an OA model, and moxibustion intervention for 4 weeks. The effects of moxibustion on knee osteoarthritis symptoms and walking ability were assessed by knee joint diameter measurement, von Frey test and footprint analysis. Micro-CT, TEM, immunofluorescence staining, and western blot were used to detect the contact between autophagy–lysosomal pathway and NLRP3 inflammasome in subchondral bone remodeling. Subsequently, proteomic analysis was performed on mouse subchondral bone. Results We first discovered that moxibustion intervention effectively reduced inflammation in the subchondral bone, thereby balancing the activities of osteoblasts and osteoclasts. Moxibustion, with its warming and medicinal properties, significantly alleviated pain and swelling and enhanced walking ability in OA mice. The findings also suggested that moxibustion counteracted subchondral bone imbalance by inhibiting the activation of the NLRP3 inflammasome through increased autolysosome levels. Proteomic analysis and experimental validation revealed that moxibustion promoted ACSL1 expression to regulate autophagy in OA subchondral bone. Conclusion Our study elucidated the molecular mechanism by which moxibustion improved the inflammatory environment and abnormal subchondral bone remodeling in OA mice by activating ACSL1-mediated autophagy, providing the basis and new insights for  advancing moxibustion therapy in OA.

Gastric Squamous Cell Carcinoma (GSCC) is a rare but aggressive subtype of gastric cancer with unique histopathology, whose etiology remains poorly understood. Here, we perform genomics analyses of twenty GSCC samples and find that epigenetic regulation genes are among the most frequently mutated genes, including Enhancer of zeste homolog 2 ( EZH2 ). Ezh2 loss induces squamous feature both in gastric organoids in vitro and in vivo mouse model. Ezh2 deficiency, together with Trp53 and Pten loss, both of which are also frequently mutated in GSCC, give rise to full-blown GSCC in mice. Mechanistically, we find that Ezh2 could repress the expression of Transcription factor AP-2 gamma ( Tfap2c ), a transcription factor with the ability to initiate epidermal squamous differentiation, through H3K27 methylation. Disruption of Tfap2c reduces the squamous characteristics of the Ezh2 loss-driven GSCC and reverses its resistance to chemo treatment. Our findings elucidate key molecular mechanisms underlying GSCC pathogenesis and identify potential therapeutic targets for this aggressive malignancy. Gastric Squamous Cell Carcinoma (GSCC) is a rare subtype of gastric cancer with unknown etiology. Here, the authors identify frequent mutations in epigenetic regulation genes including EZH2 in twenty GSCC patient samples, and demonstrate that EZH2 loss, along with TP53 and PTEN loss, leads to GSCC in mouse models.

The study, published in Nature, incorporates click chemistry into global run-on and sequencing (GRO-seq) to create a single-cell GRO-seq (scGRO-seq) technique.1 This method allows for the precise capture of the episodic and coordinated nature of transcription at high resolution, revealing critical dynamics such as burst size and enhancer-gene interactions. Enhancers, specific to cell types and states, regulate genes over long distances and are often linked to disease regions, making them potential targets for cancer therapies.2 Current genomic tools provide insights into gene activation precursors but lack real-time transcription event capture. scGRO-seq addresses this gap, offering a dynamic view of regulatory mechanisms for targeted cancer treatment. Focusing on a 10 kb central gene region and excluding the ends with paused polymerases, it utilizes an RNA Polymerase II elongation rate of 2.5 kb/min, limiting the burst detection window to just 4 min. Through stringent analysis within a 4-min window, it was found that only 0.7% of over 112 million gene pairs tested were significantly co-transcribed, forming a network of 59 distinct modules with roles in cell cycle regulation, RNA splicing, and DNA repair.