Probiotic consumption and hepatic steatosis: results from the NHANES 2011-2016 and Mendelian randomization study.

Background: Recent research showed that probiotics treatment may reduce insulin resistance, regulate lipid metabolism, raise liver enzyme levels, and ameliorate inflammation in individuals with metabolic associated fatty liver disease (MAFLD). However, the possible effects of probiotic use on the progression of hepatic steatosis (HS) have not been identified. The purpose of this study was to investigate this in a large population database. Methods: The cross-sectional research was conducted among adults with complete data on probiotic yogurt consumption and HS in the 2011-2016 National Health and Nutrition Examination Survey (NHANES). Probiotic yogurt consumption was assessed using a dietary supplement questionnaire, while HS was evaluated with HS index (HSI). To explore their relationship, weighted univariate regression analysis, subgroup analysis, and interaction analysis were conducted. To evaluate the causal association between yogurt consumption and NAFLD, mendelian randomization analysis (MR) were performed. A restricted cubic spline (RCS) was used to analyze the relationship curve between the leves of yogurt consumption and hepatic steatosis. Results: A total of 7,891 participants were included in the study represented 146.7 million non-institutionalized residents of the United States, of whom 4,322 (54.77%) were diagnosed with HS. Multivariable logistic regression showed probiotic yogurt consumption had significantly inverse relationship for HS (OR = 0.84, 95% CI: 0.72-0.97, p = 0.02) after adjusting for all covariates. Once more, the independent relationship between probiotic yogurt consumption and HS was verified by subgroup analysis and interaction analysis. The MR analysis results indicate that there is no causal relationship between yogurt consumption and NAFLD. The RCS model demonstrated a robust J-shaped link between yogurt consumption and HS, revealing a significant decrease in risk within the lower range of yogurt consumption, which attained the lowest risk close to 0.4 cup. Conclusion: According to the NHANES data, the consumption of probiotics and yogurt has a beneficial effect on HS, whereas the MR results indicated it was not related to NAFLD. The RCS analysis indicates a J-shaped relationship between yogurt consumption and HS, which may account for the inconsistency in the results. Based on these findings, we recommend that adults take half a cup of yogurt daily.

FADD promotes type I interferon production to suppress porcine reproductive and respiratory syndrome virus infection.

Porcine reproductive and respiratory syndrome (PRRS) is an epidemic animal infectious disease worldwide, causing huge economic losses to the global swine industry. Fas-associated death domain (FADD) was previously reported to be an adaptor protein that functions in transferring the apoptotic signals regulated by the death receptors. In the current study, we unravel its unidentified role in promoting type I interferon (IFN) production during PRRS virus (PRRSV) infection. We identified that FADD inhibited PRRSV infection via promotion of type I IFN transcription. Overexpression of FADD suppressed the replication of PRRSV, while knockout of FADD increased viral titer and nucleocapsid protein expression. Mechanistically, FADD promoted mitochondrial antiviral signaling protein (MAVS)-mediated production of IFN-ß and some IFN-stimulated genes (ISGs). Furthermore, FADD exerted anti-PRRSV effects in a MAVS-dependent manner and increased the type I IFN signaling during PRRSV infection. This study highlights the importance of FADD in PRRSV replication, which may have implications for the future control of PRRS.

A flexible 'plug and play' bicistronic construct and its application in the screening of protein expression system in Escherichia coli.

The bicistronic expression system that utilizes fluorescent reporters has been demonstrated to be a straightforward method for detecting recombinant protein expression levels, particularly when compared to polyacrylamide gel electrophoresis and immunoblot analysis, which are tedious and labor-intensive. However, existing bicistronic reporter systems are less capable of quantitative measurement due to the lag in reporter expression and its negative impact on target protein. In this work, a plug and play bicistronic construct using mCherry as reporter was applied in the screening of optimal replicon and promoter for Sortase expression in Escherichia coli (E. coli). The bicistronic construct allowed the reporter gene and target open reading frame (ORF) to be co-transcribed under the same promoter, resulting in a highly positive quantitative correlation between the expression titer of Sortase and the fluorescent intensity (R2 > 0.97). With the correlation model, the titer of target protein can be quantified by noninvasively measuring the fluorescent intensity. On top of this, the expression of reporter has no significant effect on the yield of target protein, thus favoring a plug and play design for removing reporter gene to generate a plain plasmid for industrial use.

Somatic mutations that affect early genetic progression and immune microenvironment in gastric carcinoma.

Gastric carcinoma (GC) is a high heterogeneity and malignant tumor with a poor prognosis. The current implementation of immunotherapy in GC is limited due to the insufficient exploration of immune-related mutations and speculated early mutation events. Therefore, we performed whole-exome sequencing on 40 patients with GC to explore their genetic characteristics, shedding light on the order of genetic events, somatic mutations impacting the immune microenvironment, and potential biomarkers for immunotherapy. Regarding genetic events, TP53 disruptions were identified as frequent and early events in GC progression, often occurring alongside other gene mutations. The mutations occurring in GANS, SMAD4, and POLE were early independent events. Patients harboring CSMD3, FAT4, FLG, KMT2C, LRP1B, MUC5B, MUC16, PLEC, RNF43, SYNE1, TP53, TTN, XIRP2, and ZFHX4 mutations tended to have decreased B cells, T cells, macrophage, neutrophil, and dendritic cells infiltration, except for the ARID1A gene mutations. We also found patients with microsatellite instability-high tumors had higher homologous recombination deficiency (HRD) scores. HRD showed a positive correlation with tumor mutational burden, which might serve as indirect evidence supporting the potential of HRD as a biomarker for GC. These findings highlighted GC's high heterogeneity and complexity and provided valuable insights into the somatic mutations that affect early genetic progression and immune microenvironment.

CRKL but not CRKII contributes to hemin-induced erythroid differentiation of CML.

Destruction of erythropoiesis process leads to various diseases, including thrombocytopenia, anaemia, and leukaemia. miR-429-CT10 regulation of kinase-like (CRKL) axis involved in development, progression and metastasis of cancers. However, the exact role of miR-429-CRKL axis in leukaemic cell differentiation are still unknown. The current work aimed to uncover the effect of miR-429-CRKL axis on erythropoiesis. In the present study, CRKL upregulation was negatively correlated with miR-429 downregulation in both chronic myeloid leukaemia (CML) patient and CR patient samples. Moreover, CRKL expression level was significantly decreased while miR-429 expression level was increased during the erythroid differentiation of K562 cells following hemin treatment. Functional investigations revealed that overexpression and knockdown of CRKL was remarkably effective in suppressing and promoting hemin-induced erythroid differentiation of K562 cells, whereas, miR-429 exhibited opposite effects to CRKL. Mechanistically, miR-429 regulates erythroid differentiation of K562 cells by downregulating CRKL via selectively targeting CRKL-3'-untranslated region (UTR) through Raf/MEK/ERK pathway. Conversely, CRKII had no effect on erythroid differentiation of K562 cells. Taken together, our data demonstrated that CRKL (but not CRKII) and miR-429 contribute to development, progression and erythropoiesis of CML, miR-429-CRKL axis regulates erythropoiesis of K562 cells via Raf/MEK/ERK pathway, providing novel insights into effective diagnosis and therapy for CML patients.

Efficient nitrogen removal by multi-stage A/O mud membrane composite process with segmented influent: Performance and microbial community structure.

In this paper, a multi-stage A/O mud membrane composite process with segmented influent was constructed for the first time and compared with the traditional activated sludge process and the multi-stage A/O pure membrane process with segmented influent. The nitrogen removal efficiency of the process under different influencing factors was studied. Under the optimum conditions, the highest removal rate of ammonia nitrogen can reach 99%, and the average removal rate of total nitrogen was 80%. The removal rate of COD in effluent reached 93%. The relative abundance of Proteobacteria was the highest in the multi-stage A/O mud membrane composite reactor with segmented influent. The community diversity and richness of activated sludge and biofilm in aerobic pool were the highest. Dechloromonas, Flavobacterium and Rhodobacter were dominant bacteria, and they were aerobic denitrifying bacteria that significantly contributed to the removal rate of ammonia nitrogen.

Composite Quasi-Solid-State Electrolytes with Organic-Inorganic Interface Engineering for Fast Ion Transport in Dendrite-Free Sodium Metal Batteries.

Quasi-solid-state electrolytes (QSSE) are a promising candidate for addressing the limitations of liquid and solid electrolytes. However, different ion transport capacities between liquid solvents and polymers can cause localized heterogeneous distribution of Na+ fluxes. In addition, the continuous side reactions occurring at the interface between QSSE and sodium anode lead to uncontrollable dendrites growth. Herein, a novel strategy is designed to integrate the composite electrospun membrane of Na3Zr2Si2PO12 and poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) into QSSE, aiming to introduce new fast ion conducting channels at the organic-inorganic interface. The efficient ion transfer pathways can effectively promote the homogenization of ion migration, enabling composite QSSE to achieve an ultrahigh ionic conductivity of 4.1 mS cm-1 at room temperature, with a Na+ transference number as high as 0.54. Moreover, the PVDF-HFP is preferentially reduced upon contact with the sodium anode to form a "NaF-rich" solid electrolyte interphase, which effectively suppresses the growth of dendrites. The synergistic combination of multiple strategies can realize exceptional long-term cycling stability in both sodium symmetric batteries (≈700 h) and full batteries (2100 cycles). This study provides a new insight for constructing high performance and dendrite-free solid-state sodium metal batteries.

Chidamide and Oxaliplatin Synergistically Inhibit Colorectal Cancer Growth by Regulating the RPS27A-MDM2-P53 Axis.

Purpose: The present study explored the anti-tumor effects of chidamide plus oxaliplatin on colorectal cancer (CRC) and examined its underlying mechanism. Material and Methods: First, the Combination Index (CI) of chidamide and oxaliplatin was evaluated via CCK-8 assay. Second, the effects of chidamide and oxaliplatin monotherapy and the combined treatment on cell proliferation, invasion, migration, and apoptosis were detected. Third, whole-transcriptome RNA sequencing (RNA-seq) was performed to seek the potential targeted gene by which chidamide plus oxaliplatin exerted anti-tumor effects. Fourth, the validation of the targeted gene and the signal pathway it regulated were performed. Finally, the anti-tumor effect of chidamide plus oxaliplatin on mice xenograft was examined. Results: Chidamide and oxaliplatin acted synergistically to inhibit CRC growth in vitro and in vivo (CI<1). Besides, compared with oxaliplatin monotherapy, chidamide could significantly enhance oxaliplatin-induced inhibition in cell proliferation, invasion, and migration, and promotion in HCT-116 and RKO cell apoptosis (P<0.05). The RNA-seq displayed that, compared to oxaliplatin monotherapy, RPS27A mRNA was evidently decreased in HCT-116 cells treated with chidamide plus oxaliplatin (P<0.001). Then, we found RPS27A was highly expressed in CRC tissues and CRC cell lines (P<0.001). Silence of RPS27A attenuated proliferation and induced apoptosis in HCT-116 and RKO cells via downregulation of MDM2 expression and upregulation of P53. Next, RPS27A overexpression could partially reverse chidamide plus oxaliplatin induced growth inhibition and apoptosis in HCT-116 and RKO cells (P<0.01). RPS27A overexpression could promote the upregulation of MDM2 and downregulation of P53 after the combined treatment of chidamide with oxaliplatin. Conclusion: Chidamide and oxaliplatin acted synergistically to suppress CRC growth by the inhibition of the RPS27A-MDM2-p53 axis.

Low-dose antimony exposure promotes prostate cancer proliferation by inhibiting ferroptosis via activation of the Nrf2-SLC7A11-GPX4 pathway.

Antimony (Sb) is a typical environmental pollutant. With the development of industrialization, antimony is widely used in daily life and enters the human body through the food chain, water source, air pollution, and other channels. The risk of antimony exposure has emerged as one of the public's major health concerns. Current research on antimony shows that antimony has certain biological toxicity, and antimony exposure may be one of the carcinogenic risk factors for bladder cancer, prostate cancer (PCa), and other cancers. But the molecular mechanism of antimony exposure in PCa is still unclear. Our results showed that serum antimony levels were significantly higher in PCa patients than in benign prostatic hyperplasia (BPH), and high levels of serum antimony were associated with poorer prognosis in PCa. We demonstrate that antimony exposure promotes PCa progression in vivo and in vitro. In addition, our results also showed that low-dose antimony exposure resulted in increased GSH, increased GPX4 expression, and decreased Fe2+. Since GPX4 and Fe2+ are important molecular features in the mechanism of ferroptosis, we further found that low-dose antimony exposure can inhibit RSL3-induced ferroptosis and promote PCa proliferation. Finally, our study demonstrates that low-dose antimony exposure promotes Nrf2 expression, increases the expression level of SLC7A11, and then increases the expression of GPX4, inhibits ferroptosis, and promotes PCa progression. Taken together, our experimental results suggest that low-dose antimony exposure promotes PCa cell proliferation by inhibiting ferroptosis through activation of the Nrf2-SLC7A11-GPX4 pathway. These findings highlight the link between low-dose antimony exposure and the Nrf2-SLC7A11-GPX4 ferroptosis pathway, providing a new potential direction for the prevention and treatment of PCa.

The Present and Future of Artificial Intelligence in Urological Cancer.

Artificial intelligence has drawn more and more attention for both research and application in the field of medicine. It has considerable potential for urological cancer detection, therapy, and prognosis prediction due to its ability to choose features in data to complete a particular task autonomously. Although the clinical application of AI is still immature and faces drawbacks such as insufficient data and a lack of prospective clinical trials, AI will play an essential role in individualization and the whole management of cancers as research progresses. In this review, we summarize the applications and studies of AI in major urological cancers, including tumor diagnosis, treatment, and prognosis prediction. Moreover, we discuss the current challenges and future applications of AI.

The mixed-order chlorine decay model with an analytical solution and corresponding trihalomethane generation model in drinking water.

Ensuring effective drinking water disinfection, remaining a certain amount of residual chlorine, and controlling disinfection by-product formation were very important for guarantying water quality safety and protecting public health; thus, the chlorine decay model and corresponding disinfection by-product formation model were necessary. This paper proposed a mixed-order chlorine bulk decay model (two parameters) based on Taylor's formula and derived its analytical solution. The accuracy of the mixed-order model was evaluated by comparing it with the nth-order model. To optimize the model and reduce the number of parameters required to be calibrated, the relationship of parameters with temperature, initial chlorine concentration, TOC and inorganic substance (ammonia nitrogen and iodide ion) was explored. The result proved that one of the parameters could be regarded as temperature dependent only. Meanwhile, the temperature equation of the model parameters was established by the Arrhenius formula. Subsequently, this paper selected trihalomethane as the target and study the linear relationship between chlorine consumption and trihalomethane formation. The results indicated that the liner slope had little correlation with initial chlorine concentration and temperature. On this basis, the corresponding trihalomethane model was built and its performance was proven to be good. The modeling developed in this work could be applied to drinking water distribution systems for residual chlorine and trihalomethane prediction, and provided a reference for the decision involving water quality.

Splitting ore from X-ray image based on improved robust concave-point algorithm.

Image segmentation is a key part of ore separation process based on X-ray images, and its segmentation result directly affects the accuracy of ore classification. In the field of ore production, the conventional segmentation method is difficult to meet the requirements of real-time, robustness and accuracy during ore segmentation process. In order to solve the above problems, this article proposes an ore segmentation method dealing with pseudo-dual-energy X-ray image which is composed of contour extraction module, concave point detection module and concave point matching module. In the contour extraction module, the image is firstly cut into two parts with high and low energy, then the adaptive threshold is used to obtain the ore binary image. After filtering and morphological operation, the image contour is obtained from the binary image. Concave point detection module uses vector to detect concave points on contour. As the main contribution of this article, the concave point matching module can remove the influence of boundary interference concave points by drawing the auxiliary line and judging the relative position of auxiliary line and ore contour. With the matching concave points connected, the whole ore segmentation is completed. In order to verify the effectiveness of this method, a comparative experiment was conducted between the proposed method and conventional segmentation method using X-ray images of antimony ore as data samples. The result of industrial experiment shows that the proposed intelligent segmentation method can remove the interference of pseudo concave points on the contour, achieve accuracy segmentation result, and satisfy the requirements of processing X-ray image of ore.

An integrated nitrogen utilization gene network and transcriptome analysis reveal candidate genes in response to nitrogen deficiency in Brassica napus.

Nitrogen (N) is an essential factor for crop yield. Here, we characterized 605 genes from 25 gene families that form the complex gene networks of N utilization pathway in Brassica napus. We found unequal gene distribution between the An- and Cn-sub-genomes, and that genes derived from Brassica rapa were more retained. Transcriptome analysis indicated that N utilization pathway gene activity shifted in a spatio-temporal manner in B. napus. A low N (LN) stress RNA-seq of B. napus seedling leaves and roots was generated, which proved that most N utilization related genes were sensitive to LN stress, thereby forming co-expression network modules. Nine candidate genes in N utilization pathway were confirmed to be significantly induced under N deficiency conditions in B. napus roots, indicating their potential roles in LN stress response process. Analyses of 22 representative species confirmed that the N utilization gene networks were widely present in plants ranging from Chlorophyta to angiosperms with a rapid expansion trend. Consistent with B. napus, the genes in this pathway commonly showed a wide and conserved expression profile in response to N stress in other plants. The network, genes, and gene-regulatory modules identified here represent resources that may enhance the N utilization efficiency or the LN tolerance of B. napus.

Accelerated electron transfer process via MOF-derived FeCo/C for enhanced degradation of antibiotic contaminants towards heterogeneous electro-Fenton system.

The Fe(III) to Fe(II) process limits the rate of the electro-Fenton system. In this study, MIL-101(Fe) derived porous carbon skeleton-coated FeCo bimetallic catalyst Fe4/Co@PC-700 was prepared as a heterogeneous electro-Fenton (EF) catalytic process. The experimental results showed its good performance in catalytic removal of antibiotic contaminants, the rate constant of tetracycline (TC) degradation catalyzed by Fe4/Co@PC-700 was 8.93 times higher than that of Fe@PC-700 under the pH conditions of raw water (pH = 5.86), exhibited good removal of TC, oxytetracycline (OTC), hygromycin (CTC), chloramphenicol (CAP) and ciprofloxacin (CIP). It was shown that the introduction of Co promoted more Fe0 production, allowing the material to exhibit faster Fe(III)/Fe(II) cycling rates. 1O2 and high-priced metal oxygen species were identified as the main active species of the system, in addition to the analysis of possible degradation pathways and toxicity of intermediates of TC. Finally, the stability and adaptability of Fe4/Co@PC-700 and EF systems to different water matrices were evaluated, showing that Fe4/Co@PC-700 was easy to recover and could be applied to different water matrices. This study provides a reference for the design and system application of heterogeneous EF catalysts.

UBE4A catalyzes NRF1 ubiquitination and facilitates DDI2-mediated NRF1 cleavage.

The transcription factor nuclear factor erythroid 2 like 1 (NFE2L1 or NRF1) regulates constitutive and inducible expression of proteasome subunits and assembly chaperones. The precursor of NRF1 is integrated into the endoplasmic reticulum (ER) and can be retrotranslocated from the ER to the cytosol where it is processed by ubiquitin-directed endoprotease DDI2. DDI2 cleaves and activates NRF1 only when NRF1 is highly polyubiquitinated. It remains unclear how retrotranslocated NRF1 is primed with large amount of ubiquitin and/or very long polyubiquitin chain for subsequent processing. Here, we report that E3 ligase UBE4A catalyzes ubiquitination of retrotranslocated NRF1 and promotes its cleavage. Depletion of UBE4A reduces the amount of ubiquitin modified on NRF1, shortens the average length of polyubiquitin chain, decreases NRF1 cleavage efficiency and causes accumulation of non-cleaved, inactivated NRF1. Expression of a UBE4A mutant lacking ligase activity impairs the cleavage, likely due to a dominant negative effect. UBE4A interacts with NRF1 and the recombinant UBE4A can promote ubiquitination of retrotranslocated NRF1 in vitro. In addition, knocking out UBE4A reduces transcription of proteasomal subunits in cells. Our results indicate that UBE4A primes NRF1 for DDI2-mediated activation to facilitate expression of proteasomal genes.

Systemic immune-inflammation index is associated with hepatic steatosis: Evidence from NHANES 2015-2018.

Background: As a novel inflammatory marker, Systemic Immune-Inflammation Index (SII) has not been studied with hepatic steatosis. The aim of this study was to investigate the possible relationship between SII and hepatic steatosis. Methods: In the cross-sectional investigation, adults having complete information on SII, hepatic steatosis, and bariatric surgery from the 2015-2018 National Health and Nutrition Examination Survey (NHANES) were included. Hepatic steatosis was evaluated with heaptic steatosis index (HSI). The platelet count × neutrophil count/lymphocyte count was used to compute SII. We investigated the independent interaction between SII and hepatic steatosis using weighted multivariable regression analysis and subgroup analysis. To explore the potential relationship between SII, bariatric surgery and hepatic steatosis by controlling potential confounders by propensity score matching. Results: The study involved 10505 participants in total, 5937 (56.5%) of whom had hepatic steatosis according to the diagnosis. After adjusted for covariates, multivariable logistic regression revealed that high SII level was an independent risk factor for hepatic steatosis (OR = 1.30, 95% CI: 1.10-1.52, P 0.01). Unexpectedly, bariatric surgery reduced SII even after PSM corrected for differences of BMI and HSI. Conclusions: In US adults, SII was positively correlated with an increase in hepatic steatosis. The SII may be a simple and affordable way to identify hepatic steatosis. Bariatric surgery may reduce SII without resorting to weight loss. This needs to be verified in additional prospective research.

Exploring the landscape, hot topics, and trends of bariatric metabolic surgery with machine learning and bibliometric analysis.

Background: This study aimed to analyze the landscape of publications on bariatric metabolic surgery through machine learning and help experts and scholars from various disciplines better understand bariatric metabolic surgery's hot topics and trends. Methods: In January 2021, publications indexed in PubMed under the Medical Subject Headings (MeSH) term 'Bariatric Surgery' from 1946 to 2020 were downloaded. Python was used to extract publication dates, abstracts, and research topics from the metadata of publications for bibliometric evaluation. Descriptive statistical analysis, social network analysis (SNA), and topic modeling with latent Dirichlet allocation (LDA) were used to reveal bariatric metabolic surgery publication growth trends, landscape, and research topics. Results: A total of 21,798 records of bariatric metabolic surgery-related literature data were collected from PubMed. The number of publications indexed to bariatric metabolic surgery had expanded rapidly. Obesity Surgery and Surgery for Obesity and Related Diseases are currently the most published journals in bariatric metabolic surgery. The bariatric metabolic surgery research mainly included five topics: bariatric surgery intervention, clinical case management, basic research, body contour, and surgical risk study. Conclusion: Despite a rapid increase in bariatric metabolic surgery-related publications, few studies were still on quality of life, psychological status, and long-term follow-up. In addition, basic research has gradually increased, but the mechanism of bariatric metabolic surgery remains to be further studied. It is predicted that the above research fields may become potential hot topics in the future.

Identification of Novel Characteristics in TP53-Mutant Hepatocellular Carcinoma Using Bioinformatics.

Background: TP53 mutations are the most frequent mutations in hepatocellular carcinoma (HCC) and affect the occurrence and development of this cancer type. Therefore, it is essential to clarify the function and mechanism of TP53 mutations in HCC. Methods: We performed a sequence of bioinformatic analyses to elucidate the characteristics of TP53 mutations in HCC. We downloaded the data of hepatocellular carcinoma from The Cancer Genome Atlas database and used different R packages for serial analyses, including gene mutation analysis, copy number variation analysis, analysis of the tumor mutational burden and microsatellite instability, differential gene expression analysis, and functional enrichment analysis of TP53 mutations, and performed gene set enrichment analysis. We established a protein-protein interaction network using the STRING online database and used the Cytoscape software for network visualization, and hub gene screening. In addition, we performed anticancer drug sensitivity analysis using data from the Genomics of Drug Sensitivity in Cancer. Immune infiltration and prognosis analyses were also performed. Results: Missense mutations accounted for a great proportion of HCC mutations, the frequency of single nucleotide polymorphisms was high, and C > T was the most common form of single nucleotide variations. TP53 had a mutation rate of 30% and was the most commonly mutated gene in HCC. In the TP53 mutant group, the tumor mutational burden (p < 0.001), drug sensitivity (p < 0.05), ESTIMATE score (p = 0.038), and stromal score (p < 0.001) dramatically decreased. The Cytoscape software screened ten hub genes, including CT45A1, XAGE1B, CT55, GAGE2A, PASD1, MAGEA4, CTAG2, MAGEA10, MAGEC1, and SAGE1. The prognostic model showed a poor prognosis in the TP53 mutation group compared with that in the wild-type group (overall survival, p = 0.023). Univariate and multivariate cox regression analyses revealed that TP53 mutation was an independent risk factor for the prognosis of HCC patients (p <0.05). The constructed prognostic model had a favorable forecast value for the prognosis of HCC patients at 1 and 3 years (1-year AUC = 0.752, 3-years AUC = 0.702). Conclusion: This study further deepened our understanding of TP53-mutated HCC, provided new insights into a precise individualized therapy for HCC, and has particular significance for prognosis prediction.

Is energy excess the initial trigger of carbon overflow metabolism? Transcriptional network response of carbon-limited Escherichia coli to transient carbon excess.

BACKGROUND: Escherichia coli adapted to carbon-limiting conditions is generally geared for energy-efficient carbon utilization. This includes also the efficient utilization of glucose, which serves as a source for cellular building blocks as well as energy. Thus, catabolic and anabolic functions are balanced under these conditions to minimize wasteful carbon utilization. Exposure to glucose excess interferes with the fine-tuned coupling of anabolism and catabolism leading to the so-called carbon overflow metabolism noticeable through acetate formation and eventually growth inhibition. RESULTS: Cellular adaptations towards sudden but timely limited carbon excess conditions were analyzed by exposing slow-growing cells in steady state glucose-limited continuous culture to a single glucose pulse. Concentrations of metabolites as well as time-dependent transcriptome alterations were analyzed and a transcriptional network analysis performed to determine the most relevant transcription and sigma factor combinations which govern these adaptations. Down-regulation of genes related to carbon catabolism is observed mainly at the level of substrate uptake and downstream of pyruvate and not in between in the glycolytic pathway. It is mainly accomplished through the reduced activity of CRP-cAMP and through an increased influence of phosphorylated ArcA. The initiated transcriptomic change is directed towards down-regulation of genes, which contribute to active movement, carbon uptake and catabolic carbon processing, in particular to down-regulation of genes which contribute to efficient energy generation. Long-term changes persisting after glucose depletion and consumption of acetete encompassed reduced expression of genes related to active cell movement and enhanced expression of genes related to acid resistance, in particular acid resistance system 2 (GABA shunt) which can be also considered as an inefficient bypass of the TCA cycle. CONCLUSIONS: Our analysis revealed that the major part of the trancriptomic response towards the glucose pulse is not directed towards enhanced cell proliferation but towards protection against excessive intracellular accumulation of potentially harmful concentration of metabolites including among others energy rich compounds such as ATP. Thus, resources are mainly utilized to cope with "overfeeding" and not for growth including long-lasting changes which may compromise the cells future ability to perform optimally under carbon-limiting conditions (reduced motility and ineffective substrate utilization).