Comparing the antioxidation and bioavailability of polysaccharides from extruded and unextruded Baijiu vinasses via in vitro digestion and fecal fermentation.

Extrusion has been proven to be a novel approach for modifying the physicochemical characteristic of Baijiu vinasses (BV) to extract polysaccharides, contributing to the sustainable development of brewing industry. However, the comparison of the bioactivity and bioavailability of extruded (EX) and unextruded (UE) BV polysaccharides was unclear, which impended the determination of the efficacy of extrusion in BV resourcing. In this study, in vitro digestion and fecal fermentation experiments were conducted to investigate the bioavailability, and the results showed that EX exhibited less variation in the monosaccharide composition and molecular weight, while exhibiting a stronger antioxidant capacity compared to UE. Moreover, during fermentation EX increased the abundance of Parasutterella and Lachnospiraceae, while UE promoted the proliferation of Bacteroides, Faecalibacterium, and Dialister, resulting in variation in short-chain fatty acids. These findings indicate that extrusion can enhance the capacity of antioxidants and bioavailability of BV polysaccharides.

Multicopper Oxidase from Lactobacillus hilgardii: Mechanism of Degradation of Tyramine and Phenylethylamine in Fermented Food.

Elevated levels of biogenic amines (BAs) in fermented food can have negative effects on both the flavor and health. Mining enzymes that degrade BAs is an effective strategy for controlling their content. The study screened a strain of Lactobacillus hilgardii 1614 from fermented food system that can degrade BAs. The multiple copper oxidase genes LHMCO1614 were successfully mined after the whole genome protein sequences of homologous strains were clustered and followed by homology modeling. The enzyme molecules can interact with BAs to stabilize composite structures for catalytic degradation, as shown by molecular docking results. Ingeniously, the kinetic data showed that purified LHMCO1614 was less sensitive to the substrate inhibition of tyramine and phenylethylamine. The degradation rates of tyramine and phenylethylamine in huangjiu (18% vol) after adding LHMCO1614 were 41.35 and 40.21%, respectively. Furthermore, LHMCO1614 demonstrated universality in degrading tyramine and phenylethylamine present in other fermented foods as well. HS-SPME-GC-MS analysis revealed that, except for aldehydes, the addition of enzyme treatment did not significantly alter the levels of major flavor compounds in enzymatically treated fermented foods (p > 0.05). This study presents an enzymatic approach for regulating tyramine and phenylethylamine levels in fermented foods with potential applications both targeted and universal.

Dominant activities of fear engram cells in the dorsal dentate gyrus underlie fear generalization in mice.

Over-generalized fear is a maladaptive response to harmless stimuli or situations characteristic of posttraumatic stress disorder (PTSD) and other anxiety disorders. The dorsal dentate gyrus (dDG) contains engram cells that play a crucial role in accurate memory retrieval. However, the coordination mechanism of neuronal subpopulations within the dDG network during fear generalization is not well understood. Here, with the Tet-off system combined with immunostaining and two-photon calcium imaging, we report that dDG fear engram cells labeled in the conditioned context constitutes a significantly higher proportion of dDG neurons activated in a similar context where mice show generalized fear. The activation of these dDG fear engram cells encoding the conditioned context is both sufficient and necessary for inducing fear generalization in the similar context. Activities of mossy cells in the ventral dentate gyrus (vMCs) are significantly suppressed in mice showing fear generalization in a similar context, and activating the vMCs-dDG pathway suppresses generalized but not conditioned fear. Finally, modifying fear memory engrams in the dDG with "safety" signals effectively rescues fear generalization. These findings reveal that the competitive advantage of dDG engram cells underlies fear generalization, which can be rescued by activating the vMCs-dDG pathway or modifying fear memory engrams, and provide novel insights into the dDG network as the neuronal basis of fear generalization.

Comparative Analysis of Gracilaria chouae Polysaccharides Derived from Different Geographical Regions: Focusing on Their Chemical Composition, Rheological Properties, and Gel Characteristics.

Polysaccharides derived from diverse sources exhibit distinct rheological and gel properties, exerting a profound impact on their applicability in the food industry. In this study, we collected five Gracilaria chouae samples from distinct geographical regions, namely Rizhao (RZ), Lianyungang (LYG), Ningde (ND), Beihai (BH), and a wild source from Beihai (BHW). We conducted analyses on the chemical composition, viscosity, and rheological properties, as well as gel properties, to investigate the influence of chemical composition on variations in gel properties. The results revealed that the total sugar, sulfate content, and monosaccharide composition of G. chouae polysaccharides exhibit similarity; however, their anhydrogalactose content varies within a range of 15.31% to 18.98%. The molecular weight distribution of G. chouae polysaccharides ranged from 1.85 to 2.09 × 103 kDa. The apparent viscosity of the LYG and BHW polysaccharides was relatively high, whereas that of RZ and ND was comparatively low. The gel strength displayed a similar trend. BHW and LYG exhibited solid-like behavior, while ND, RZ, and BH demonstrated liquid-like characteristics at low frequencies. The redundancy analysis (RDA) analysis revealed a positive correlation between the texture profile analysis (TPA) characteristics and anhydrogalactose. The study could provide recommendations for the diverse applications of G. chouae polysaccharides derived from different geographical regions.

Anti-CTLA-4 m2a Antibody Exacerbates Cardiac Injury in Experimental Autoimmune Myocarditis Mice By Promoting Ccl5-Neutrophil Infiltration.

The risk for suffering immune checkpoint inhibitors (ICIs)-associated myocarditis increases in patients with pre-existing conditions and the mechanisms remain to be clarified. Spatial transcriptomics, single-cell RNA sequencing, and flow cytometry are used to decipher how anti-cytotoxic T lymphocyte antigen-4 m2a antibody (anti-CTLA-4 m2a antibody) aggravated cardiac injury in experimental autoimmune myocarditis (EAM) mice. It is found that anti-CTLA-4 m2a antibody increases cardiac fibroblast-derived C-X-C motif chemokine ligand 1 (Cxcl1), which promots neutrophil infiltration to the myocarditic zones (MZs) of EAM mice via enhanced Cxcl1-Cxcr2 chemotaxis. It is identified that the C-C motif chemokine ligand 5 (Ccl5)-neutrophil subpopulation is responsible for high activity of cytokine production, adaptive immune response, NF-κB signaling, and cellular response to interferon-gamma and that the Ccl5-neutrophil subpopulation and its-associated proinflammatory cytokines/chemokines promoted macrophage (Mφ) polarization to M1 Mφ. These altered infiltrating landscape and phenotypic switch of immune cells, and proinflammatory factors synergistically aggravated anti-CTLA-4 m2a antibody-induced cardiac injury in EAM mice. Neutralizing neutrophils, Cxcl1, and applying Cxcr2 antagonist dramatically alleviates anti-CTLA-4 m2a antibody-induced leukocyte infiltration, cardiac fibrosis, and dysfunction. It is suggested that Ccl5-neutrophil subpopulation plays a critical role in aggravating anti-CTLA-4 m2a antibody-induced cardiac injury in EAM mice. This data may provide a strategic rational for preventing/curing ICIs-associated myocarditis.

Palladium-Catalyzed Synthesis of Nitrones Via Redox Cross-Coupling of Nitro Compounds and Alcohols.

A novel methodology for the synthesis of nitrones via palladium-catalyzed redox cross-coupling of nitro compounds and alcohols is established. The protocol is a mild, convenient, ligand-free, and scalable synthesis method that can be compatible with various nitro compounds and alcohols. Nitrone is a significant multifunctional platform synthon which can be synthesized directly and efficiently via this tactic from commercially available and cheap raw materials.

Si Single-Atom Sites Anchored Carbon Anode Achieving the Zero-Strain Feature and Superior Li+ Storage Performance.

Overcoming the significant volume strain in silicon-based anodes has been the focus of research for decades. The strain/stress in silicon-based anodes is inversely proportional to their size. In this study, we design atomic Si sites to achieve the ultimate size effect, which indeed exhibits a zero-strain feature. Compared with conventional silicon-based anodes with alloying addition reactions, the lithium-ion storage mechanism of atomic Si sites is solid-solution reactions, which brings about the zero-strain feature. Additionally, the ligand structure of atomic Si sites remains constant during cycling. This zero-strain feature results in excellent cycling stability. Furthermore, the exposed atomic Si sites enhance the electrochemical reaction kinetics, leading to outstanding rate performance. Moreover, the anode inherits the advantages of silicon-based anodes, including a low working voltage (~0.21 V) and high specific capacity (~2300 mAh g-1 or ~1203 mAh cm-3). This work establishes a novel pathway for designing low/zero-strain anodes.

Retinal vascular morphological characteristics in diabetic retinopathy: an artificial intelligence study using a transfer learning system to analyze ultra-wide field images.

AIM: To investigate the morphological characteristics of retinal vessels in patients with different severity of diabetic retinopathy (DR) and in patients with or without diabetic macular edema (DME). METHODS: The 239 eyes of DR patients and 100 eyes of healthy individuals were recruited for the study. The severity of DR patients was graded as mild, moderate and severe non-proliferative diabetic retinopathy (NPDR) according to the international clinical diabetic retinopathy (ICDR) disease severity scale classification, and retinal vascular morphology was quantitatively analyzed in ultra-wide field images using RU-net and transfer learning methods. The presence of DME was determined by optical coherence tomography (OCT), and differences in vascular morphological characteristics were compared between patients with and without DME. RESULTS: Retinal vessel segmentation using RU-net and transfer learning system had an accuracy of 99% and a Dice metric of 0.76. Compared with the healthy group, the DR group had smaller vessel angles (33.68±3.01 vs 37.78±1.60), smaller fractal dimension (Df) values (1.33±0.05 vs 1.41±0.03), less vessel density (1.12±0.44 vs 2.09±0.36) and fewer vascular branches (206.1±88.8 vs 396.5±91.3), all P<0.001. As the severity of DR increased, Df values decreased, P=0.031. No significant difference between the DME and non-DME groups were observed in vascular morphological characteristics. CONCLUSION: In this study, an artificial intelligence retinal vessel segmentation system is used with 99% accuracy, thus providing with relatively satisfactory performance in the evaluation of quantitative vascular morphology. DR patients have a tendency of vascular occlusion and dropout. The presence of DME does not compromise the integral retinal vascular pattern.

Highly Regio- and Stereoselective Dehydration of Allylic Alcohols to Conjugated Dienes via 1,4-syn-Elimination with H2 Evolution.

Dehydration of alcohols is one of the most fundamental transformations in the organic chemistry class and one of the most widely used methods for producing alkenes in synthetic research. Numerous methods and reagents have been developed to control the regio- and stereoselectivity as well as the dehydration efficiency of normal alcohols. Despite these achievements, regio- and stereoselective and predictable dehydration of allylic alcohol has seldom been reported, except for limited substrates with a native preferred elimination position, as a result of the challenges that many potential dienes could be formed via 1,2- or 1,4-syn- or anti-elimination. Here, we report a tBuOK/potassium 2,2-difluoroacetate-mediated 1,4-syn-dehydration of allylic alcohol for the synthesis of regio- and stereodefined conjugated dienes via an in situ generated directing group strategy. This reaction exhibits a broad substrate scope and good functional group compatibility for primary-tertiary alcohols. The simple and scalable (up to 0.6 mol) procedure with readily available and inexpensive reagents makes it a practical method for conjugated diene synthesis. Mechanistic studies reveal that an acetate with tert-butoxide and allyloxide acetal moiety is formed as an intermediate, in which the acetate and the acetal act as the directing group for the base-promoted elimination. An unusual H2 evolution is also involved in the reaction.

Real-time predictive model of extrauterine growth retardation in preterm infants with gestational age less than 32 weeks.

The aim of this study was to develop a real-time risk prediction model for extrauterine growth retardation (EUGR). A total of 2514 very preterm infants were allocated into a training set and an external validation set. The most appropriate independent variables were screened using univariate analysis and Lasso regression with tenfold cross-validation, while the prediction model was designed using binary multivariate logistic regression. A visualization of the risk variables was created using a nomogram, while the calibration plot and receiver operating characteristic (ROC) curves were used to calibrate the prediction model. Clinical efficacy was assessed using the decision curve analysis (DCA) curves. Eight optimal predictors that namely birth weight, small for gestation age (SGA), hypertensive disease complicating pregnancy (HDCP), gestational diabetes mellitus (GDM), multiple births, cumulative duration of fasting, growth velocity and postnatal corticosteroids were introduced into the logistic regression equation to construct the EUGR prediction model. The area under the ROC curve of the training set and the external verification set was 83.1% and 84.6%, respectively. The calibration curve indicate that the model fits well. The DCA curve shows that the risk threshold for clinical application is 0-95% in both set. Introducing Birth weight, SGA, HDCP, GDM, Multiple births, Cumulative duration of fasting, Growth velocity and Postnatal corticosteroids into the nomogram increased its usefulness for predicting EUGR risk in very preterm infants.

Serum bile acid and unsaturated fatty acid profiles of non-alcoholic fatty liver disease in type 2 diabetic patients.

BACKGROUND: The understanding of bile acid (BA) and unsaturated fatty acid (UFA) profiles, as well as their dysregulation, remains elusive in individuals with type 2 diabetes mellitus (T2DM) coexisting with non-alcoholic fatty liver disease (NAFLD). Investigating these metabolites could offer valuable insights into the pathophy-siology of NAFLD in T2DM. AIM: To identify potential metabolite biomarkers capable of distinguishing between NAFLD and T2DM. METHODS: A training model was developed involving 399 participants, comprising 113 healthy controls (HCs), 134 individuals with T2DM without NAFLD, and 152 individuals with T2DM and NAFLD. External validation encompassed 172 participants. NAFLD patients were divided based on liver fibrosis scores. The analytical approach employed univariate testing, orthogonal partial least squares-discriminant analysis, logistic regression, receiver operating characteristic curve analysis, and decision curve analysis to pinpoint and assess the diagnostic value of serum biomarkers. RESULTS: Compared to HCs, both T2DM and NAFLD groups exhibited diminished levels of specific BAs. In UFAs, particular acids exhibited a positive correlation with NAFLD risk in T2DM, while the ω-6:ω-3 UFA ratio demonstrated a negative correlation. Levels of α-linolenic acid and γ-linolenic acid were linked to significant liver fibrosis in NAFLD. The validation cohort substantiated the predictive efficacy of these biomarkers for assessing NAFLD risk in T2DM patients. CONCLUSION: This study underscores the connection between altered BA and UFA profiles and the presence of NAFLD in individuals with T2DM, proposing their potential as biomarkers in the pathogenesis of NAFLD.

The role of small RNAs in resistant melon cultivar against Phelipanche aegyptiaca parasitization.

Bidirectional trans-kingdom RNA silencing, a pivotal factor in plant-pathogen interactions, remains less explored in plant host-parasite dynamics. Here, using small RNA sequencing in melon root systems, we investigated microRNA (miRNA) expression variation in resistant and susceptible cultivars pre-and post-infection by the parasitic plant, broomrape. This approach revealed 979 known miRNAs and 110 novel miRNAs across 110 families. When comparing susceptible (F0) and resistant (R0) melon lines with broomrape infection (F25 and R25), 39 significantly differentially expressed miRNAs were observed in F25 vs. F0, 35 in R25 vs. R0, and 5 in R25 vs. F25. Notably, two miRNAs consistently exhibited differential expression across all comparisons, targeting genes linked to plant disease resistance. This suggests their pivotal role in melon's defense against broomrape. The target genes of these miRNAs were confirmed via degradome sequencing and validated by qRT-PCR, ensuring reliable sequencing outcomes. GO and KEGG analyses shed light on the molecular functions and pathways of these differential miRNAs. Furthermore, our study unveiled four trans-kingdom miRNAs, forming a foundation for exploring melon's resistance to broomrape.

Optimization of tracheoesophageal fistula model established with T-shaped magnet system based on magnetic compression technique.

BACKGROUND: The magnetic compression technique has been used to establish an animal model of tracheoesophageal fistula (TEF), but the commonly shaped magnets present limitations of poor homogeneity of TEF and poor model control. We designed a T-shaped magnet system to overcome these problems and verified its effectiveness via animal experiments. AIM: To investigate the effectiveness of a T-shaped magnet system for establishing a TEF model in beagle dogs. METHODS: Twelve beagles were randomly assigned to groups in which magnets of the T-shaped scheme (study group, n = 6) or normal magnets (control group, n = 6) were implanted into the trachea and esophagus separately under gastroscopy. Operation time, operation success rate, and accidental injury were recorded. After operation, the presence and timing of cough and the time of magnet shedding were observed. Dogs in the control group were euthanized after X-ray and gastroscopy to confirm establishment of TEFs after coughing, and gross specimens of TEFs were obtained. Dogs in the study group were euthanized after X-ray and gastroscopy 2 wk after surgery, and gross specimens were obtained. Fistula size was measured in all animals, and then harvested fistula specimens were examined by hematoxylin and eosin (HE) and Masson trichrome staining. RESULTS: The operation success rate was 100% for both groups. Operation time did not differ between the study group (5.25 min ± 1.29 min) and the control group (4.75 min ± 1.70 min; P = 0.331). No bleeding, perforation, or unplanned magnet attraction occurred in any animal during the operation. In the early postoperative period, all dogs ate freely and were generally in good condition. Dogs in the control group had severe cough after drinking water at 6-9 d after surgery. X-ray indicated that the magnets had entered the stomach, and gastroscopy showed TEF formation. Gross specimens of TEFs from the control group showed the formation of fistulas with a diameter of 4.94 mm ± 1.29 mm (range, 3.52-6.56 mm). HE and Masson trichrome staining showed scar tissue formation and hierarchical structural disorder at the fistulas. Dogs in the study group did not exhibit obvious coughing after surgery. X-ray examination 2 wk after surgery indicated fixed magnet positioning, and gastroscopy showed no change in magnet positioning. The magnets were removed using a snare under endoscopy, and TEF was observed. Gross specimens showed well-formed fistulas with a diameter of 6.11 mm ± 0.16 mm (range, 5.92-6.36 mm), which exceeded that in the control group (P < 0.001). Scar formation was observed on the internal surface of fistulas by HE and Masson trichrome staining, and the structure was more regular than that in the control group. CONCLUSION: Use of the modified T-shaped magnet scheme is safe and feasible for establishing TEF and can achieve a more stable and uniform fistula size compared with ordinary magnets. Most importantly, this model offers better controllability, which improves the flexibility of follow-up studies.

The mediation roles of self-regulation and problematic internet use: How maladaptive parenting during the COVID-19 pandemic influenced adolescents' academic procrastination in the postpandemic era.

INTRODUCTION: In the transition to the postpandemic era, adolescents are working to shift their focus back to school. However, the prevalence of academic procrastination is reflective of that the aftereffects of the pandemic are persisting. Literature documents the increases in the negative parenting behaviors and internet use of adolescents during the pandemic. The excessive internet use has to do with adolescents' self-regulatory capabilities and self-regulation is profoundly shaped by parents' parenting practices. Given the connections among these factors, the present study seeks to understand how maladaptive parenting practices during the pandemic influenced adolescents' academic procrastination postpandemic through the mediation of self-regulation and problematic internet use. METHOD: Using three waves of data from a total of 1062 Chinese adolescents (Mage = 14.9 years old, SD = 1.6, 13-18 years old; 45% female), we used structural equation modeling to examine the direct effect of maladaptive parenting on academic procrastination and its indirect effect via self-regulation and problematic internet use. RESULTS: Maladaptive parenting during the pandemic did not directly predict adolescent academic procrastination post-pandemic. Yet, maladaptive parenting indirectly influenced academic procrastination both through self-regulation solely and self-regulation and problematic internet use sequentially. CONCLUSION: The findings demonstrate that parents can contribute to adolescents' academic procrastination by influencing their self-regulation ability, which further impacts their internet use. Self-regulation serves as a robust mediator between parenting and adolescents' problematic behaviors related to internet use and learning. Implications for parents and intervention oriented toward adolescents are discussed.

Plant-LncPipe: a computational pipeline providing significant improvement in plant lncRNA identification.

Long non-coding RNAs (lncRNAs) play essential roles in various biological processes, such as chromatin remodeling, post-transcriptional regulation, and epigenetic modifications. Despite their critical functions in regulating plant growth, root development, and seed dormancy, the identification of plant lncRNAs remains a challenge due to the scarcity of specific and extensively tested identification methods. Most mainstream machine learning-based methods used for plant lncRNA identification were initially developed using human or other animal datasets, and their accuracy and effectiveness in predicting plant lncRNAs have not been fully evaluated or exploited. To overcome this limitation, we retrained several models, including CPAT, PLEK, and LncFinder, using plant datasets and compared their performance with mainstream lncRNA prediction tools such as CPC2, CNCI, RNAplonc, and LncADeep. Retraining these models significantly improved their performance, and two of the retrained models, LncFinder-plant and CPAT-plant, alongside their ensemble, emerged as the most suitable tools for plant lncRNA identification. This underscores the importance of model retraining in tackling the challenges associated with plant lncRNA identification. Finally, we developed a pipeline (Plant-LncPipe) that incorporates an ensemble of the two best-performing models and covers the entire data analysis process, including reads mapping, transcript assembly, lncRNA identification, classification, and origin, for the efficient identification of lncRNAs in plants. The pipeline, Plant-LncPipe, is available at: https://github.com/xuechantian/Plant-LncRNA-pipline.

Detection of tumor marker CA72-4 with an electrochemical immunosensor based on MnO2 nanosheets and HNM-AuPtPd nanocomposites.

To accurately detect tumor marker carbohydrate antigen 72-4 (CA72-4) of serum samples is of great significance for the early diagnosis of malignant tumors. In the present study, MnO2/hollow nanobox metal-organic framework (HNM)-AuPtPd nanocomposites were prepared via multi-step synthesis and superposition method and a series of characterizations were carried out. A highly sensitive immunosensor Ab/MnO2/HNM-AuPtPd/GCE based on the composite nanomaterial was further prepared and used to detect the tumor marker CA72-4. The constructed immunosensor achieved signal amplification by increasing the electrocatalytic activity to H2O2 by means of the synergistic effect of MnO2 ultra-thin nanosheets (MnO2 UNs) and HNM-AuPtPd. At the same time, the electrochemical properties of the immunosensor were analyzed using cyclic voltammetry, electrochemical impedance, amperometry (with the test voltage of -0.4 V), and differential pulse voltammetry. The experimental results showed that the MnO2/HNM-AuPtPd nanocomposites were successfully prepared, and the immunosensor Ab/MnO2/HNM-AuPtPd/GCE demonstrated an excellent electrochemical performance. The electrochemical immunosensor had the highest detection sensitivity under the optimal experimental conditions, such as incubation pH of 7.0, incubation time of 60 min, with the addition of 15 µL of H2O2, and in the concentration range 0.001-500 U/mL. It had a low detection limit of 1.78×10-5 U/mL (S/N = 3). Moreover, the serum sample recovery were in the range from 99.38 to 100.52%. This study provides a new method and experimental basis for the detection of tumor markers in clinical practice.

Investigation of Microstructure and Mechanical Properties of Extruded Mg-6Bi and Mg-6Bi-1Ag Alloys.

The extruded Mg-6Bi alloy and Mg-6Bi-1Ag alloy subjected to extrusion at 300 °C with the extrusion ratio of 25:1 and die-exit speed of 2 m/min were used to investigate microstructure characteristics and mechanical behavior. The experimental results demonstrate that the bimodal microstructure, composed of coarse dynamic unrecrystallized (unDRXed) grains and fine dynamic recrystallized (DRXed) grains, was obtained after extrusion. The Ag addition can obviously promote dynamic recrystallization and average grain size. It also indicates that the dynamic precipitation is significantly promoted by Ag addition during extrusion, obtaining more fraction of the Mg3Bi2 precipitates. Moreover, the extruded Mg-6Bi-1Ag alloy has a high tensile yield strength of 304 ± 2.0 MPa, which is increased by 19% compared to the extruded Mg-6Bi alloy, and elongation of 11.0 ± 1.7%, almost the same as 11.9 ± 0.9% of the extruded Mg-6Bi alloy. This result also shows that the extruded Mg-6Bi-1Ag alloy exhibits better strain hardening capacity. Therefore, Ag exhibits an effective role in promoting dynamic recrystallization and dynamic precipitation, resulting in the enhancement of strength and strain hardening capacity of the extruded Mg-6Bi-1Ag alloy, as well as keeping high ductility.

Epigenetic Activation of Cytochrome P450 1A2 Sensitizes Hepatocellular Carcinoma Cells to Sorafenib.

Cytochrome P450 1A2 (CYP1A2) is a known tumor suppressor in hepatocellular carcinoma (HCC), but its expression is repressed in HCC and the underlying mechanism is unclear. In this study, we investigated the epigenetic mechanisms of CYP1A2 repression and potential therapeutic implications. In HCC tumor tissues, the methylation rates of CYP1A2 CpG island (CGI) and DNA methyltransferase (DNMT) 3A protein levels were significantly higher, and there was a clear negative correlation between DNMT3A and CYP1A2 protein expression. Knockdown of DNMT3A by siRNA significantly increased CYP1A2 expression in HCC cells. Additionally, treating HCC cells with decitabine (DAC) resulted in a dose-dependent upregulation of CYP1A2 expression by reducing the methylation level of CYP1A2 CGI. Furthermore, we observed a decreased enrichment of H3K27Ac in the promoter region of CYP1A2 in HCC tissues. Treatment with the trichostatin A (TSA) restored CYP1A2 expression in HCC cells by increasing H3K27Ac levels in the CYP1A2 promoter region. Importantly, combination treatment of sorafenib with DAC or TSA resulted in a leftward shift of the dose-response curve, lower IC50 values, and reduced colony numbers in HCC cells. Our findings suggest that hypermethylation of the CGI at the promoter, mediated by the high expression of DNMT3A, and hypoacetylation of H3K27 in the CYP1A2 promoter region, leads to CYP1A2 repression in HCC. Epigenetic drugs DAC and TSA increase HCC cell sensitivity to sorafenib by restoring CYP1A2 expression. Our study provides new insights into the epigenetic regulation of CYP1A2 in HCC and highlights the potential of epigenetic drugs as a therapeutic approach for HCC. SIGNIFICANCE STATEMENT: This study marks the first exploration of the epigenetic mechanisms underlying cytochrome P450 (CYP) 1A2 suppression in hepatocellular carcinoma (HCC). Our findings reveal that heightened DNA methyltransferase expression induces hypermethylation of the CpG island at the promoter, coupled with diminished H3K27Ac levels, resulting in the repression of CYP1A2 in HCC. The use of epigenetic drugs such as decitabine and trichostatin A emerges as a novel therapeutic avenue, demonstrating their potential to restore CYP1A2 expression and enhance sorafenib sensitivity in HCC cells.

Risk factors for severe bronchopulmonary dysplasia in a Chinese cohort of very preterm infants.

OBJECTIVES: To examine the risk factors for severe bronchopulmonary dysplasia (BPD) in a cohort of very preterm infants (VPIs) in China, as BPD is common among VPIs and associated with a high mortality rate. METHODS: In this multicenter retrospective study, medical records from infants with BPD born at gestation age (GA) of <32 weeks with birth weight (BW) of <1,500 grams (g) in 7 regions of China were included. The cohort was stratified into different BPD severity groups based on their fraction of inspired oxygen requirement at a modified GA of 36 weeks or post discharge. Risk factors were identified using logistic regression analysis. RESULTS: A significant inverse correlation was revealed between BPD severity and both GA and BW (p<0.001). Independent risk factors for severe BPD (sBPD) were identified as invasive mechanical ventilation (≥7d), multiple blood transfusion (≥3), nosocomial infection (NI), hemodynamically significant patent ductus arteriosus (hsPDA), delayed initiation of enteral nutrition, and longer time to achieve total caloric intake of 110 kcal/kg. Conversely, administration of antenatal steroids was associated with reduced risk of sBPD. CONCLUSION: Our study not only reaffirmed the established risk factors of low GA and BW for sBPD in VPIs, but also identified additional, potentially modifiable risk factors. Further research is warranted to explore whether intervention in these modifiable factors might reduce the risk of sBPD.Clinical Trial Reg. No.: ChiCTR1900023418.

Genetic and microbial determinants of azoxymethane-induced colorectal tumor susceptibility in Collaborative Cross mice and their implication in human cancer.

The insights into interactions between host genetics and gut microbiome (GM) in colorectal tumor susceptibility (CTS) remains lacking. We used Collaborative Cross mouse population model to identify genetic and microbial determinants of Azoxymethane-induced CTS. We identified 4417 CTS-associated single nucleotide polymorphisms (SNPs) containing 334 genes that were transcriptionally altered in human colorectal cancers (CRCs) and consistently clustered independent human CRC cohorts into two subgroups with different prognosis. We discovered a set of genera in early-life associated with CTS and defined a 16-genus signature that accurately predicted CTS, the majority of which were correlated with human CRCs. We identified 547 SNPs associated with abundances of these genera. Mediation analysis revealed GM as mediators partially exerting the effect of SNP UNC3869242 within Duox2 on CTS. Intestine cell-specific depletion of Duox2 altered GM composition and contribution of Duox2 depletion to CTS was significantly influenced by GM. Our findings provide potential novel targets for personalized CRC prevention and treatment.