The ubiquitin E3 ligase TRIM31 promotes aggregation and activation of the signaling adaptor MAVS through Lys63-linked polyubiquitination.

The signaling adaptor MAVS forms prion-like aggregates to activate an innate antiviral immune response after viral infection. However, the molecular mechanisms that regulate MAVS aggregation are poorly understood. Here we identified TRIM31, an E3 ubiquitin ligase of the TRIM family of proteins, as a regulator of MAVS aggregation. TRIM31 was recruited to mitochondria after viral infection and specifically regulated antiviral signaling mediated by RLR pattern-recognition receptors. TRIM31-deficient mice were more susceptible to infection with RNA virus than were wild-type mice. TRIM31 interacted with MAVS and catalyzed the Lys63 (K63)-linked polyubiquitination of Lys10, Lys311 and Lys461 on MAVS. This modification promoted the formation of prion-like aggregates of MAVS after viral infection. Our findings reveal new insights in the molecular regulation of MAVS aggregation and the cellular antiviral response through TRIM31-mediated K63-linked polyubiquitination of MAVS.

Ferroptosis and its role in gastric and colorectal cancers.

Ferroptosis is a novel mechanism of programmed cell death, characterized by intracellular iron overload, intensified lipid peroxidation, and abnormal accumulation of reactive oxygen species, which ultimately resulting in cell membrane impairment and demise. Research has revealed that cancer cells exhibit a greater demand for iron compared to normal cells, indicating a potential susceptibility of cancer cells to ferroptosis. Stomach and colorectal cancers are common gastrointestinal malignancies, and their elevated occurrence and mortality rates render them a global health concern. Despite significant advancements in medical treatments, certain unfavorable consequences and drug resistance persist. Consequently, directing attention towards the phenomenon of ferroptosis in gastric and colorectal cancers holds promise for enhancing therapeutic efficacy. This review aims to elucidate the intricate cellular metabolism associated with ferroptosis, encompassing lipid and amino acid metabolism, as well as iron metabolic processes. Furthermore, the significance of ferroptosis in the context of gastric and colorectal cancer is thoroughly examined and discussed.

Identification of Anesthetic-Induced Cardiovascular Biomarkers in Off-Pump Coronary Artery Bypass Grafting Surgery Using Weighted Gene Co-Expression Network Analysis and Machine Learning.

BACKGROUND: This study aimed to select anesthesia-induced zinc finger protein-related gene biomarkers that predict cardiovascular function during off-pump coronary artery bypass grafting (OPCABG). METHODS: Gene expression data from GSE4386 included 20 post-anesthesia and 20 pre-anesthesia atrial tissue samples. Zinc finger protein-related genes (ZFPRGs) were searched in the UniProt database and anesthesia-induced differentially expressed genes (DEGs) were identified Weighted gene co-expression network analysis (WGCNA) was used to screen hub genes, and three machine learning algorithms were used to further screen for cardiovascular biomarkers. Diagnostic accuracy was evaluated using a nomogram model. Gene set enrichment analysis was used to analyze the pathways enriched by the biomarkers. A microRNA (miRNA)-mRNA-transcription factor (TF) regulatory network was established to explore the potential regulatory mechanisms of these biomarkers. Disease-related drugs were predicted using the Comparative Toxicogenomics Database (CTD). RESULTS: A total of 1102 cardioprotection-related DEGs were selected between the pre- and post-anesthesia groups. Additionally, 1095 hub genes were obtained based on WGCNA, and 2274 ZFPRGs were downloaded from the UniProt database. After Venn analysis and machine learning, ZNF420, RNF135, and BNC2 were selected as cardioprotection-related zinc finger biomarkers during OPCABG. Receiver operating characteristic (ROC) curves and nomogram models confirmed the diagnostic value and accuracy of the three cardioprotective biomarkers. Pathway enrichment analysis revealed that ZNF420 is involved in the cell cycle and the tricarboxylic acid cycle. RNF135 and BNC2 were enriched in the oxidative phosphorylation pathway. In the constructed miRNA-mRNA-TF network, miR-182-5p and miR-16-5p simultaneously regulated three cardioprotective biomarkers. CONCLUSION: Three cardioprotection-related zinc finger protein biomarkers (ZNF420, RNF135, and BNC2) were identified using OPCABG samples.

Loss of bioactive microRNAs in cow's milk by ultra-high-temperature treatment but not by pasteurization treatment.

BACKGROUND: Milk microRNA (miRNA) with bioactivity is beneficial for human health. However, the effect of heat treatment on miRNA in milk is still not clear. In this study, the miRNAs in raw (RM), pasteurized (PM) and ultra-high-temperature (UHT) milk (UM) from the same batch were extracted, sequenced and analyzed. RESULTS: The results showed that there was a significant difference in miRNAs between RM and UM, but not between RM and PM. The total read counts of milk miRNAs were significantly decreased by heat treatment, with the least counts in UM (P < 0.05). The average length and GC percentage of miRNAs were significantly reduced by heat treatment (P < 0.05), while there was no significant difference in these terms between RM and PM. The content of miRNAs was verified by qPCR, finding that miR-17-5p, miR-25, miR-27b and miR-9-5p were significantly reduced in UM (P < 0.05) but not significantly affected in PM (except miR-27b). In addition, the targeting gene ontology enrichment functions of the different presented miRNAs were mostly enriched in biological process, cellular component and molecular function. The top 20 enriched miRNAs with different levels in heat-treated milk were identified by the Kyoto Encyclopedia of Genes and Genomes enrichment analysis. Interestingly, most of the functions of these miRNA targeting genes are involved in cancer or inflammation activity. CONCLUSION: This study revealed that the bioactive miRNA in RM was lost after UHT treatment but not in pasteurized treatment. © 2021 Society of Chemical Industry.

Two novel protein chips for the detection of antibodies against porcine parvovirus.

BACKGROUND: PPV is one of the most important pathogens causing porcine reproductive disorder. It has been shown in clinical cases to be a commonly mixed infection with other important swine diseases which can aggravate the severity of the disease and bring serious economic losses to the pig industry. Serological methods, such as hemagglutination inhibition assays (HAI), serum neutralization (SN), and the modified direct complement-fixation (MDCF) test were utilized earlier, whereas the enzyme-linked immunosorbent assay (ELISA) is the most frequently applied assay to detect PPV-specific antibodies. RESULTS: We establish the visible protein chip and the cyanine dye 3 (Cy3)-labeled protein chip to detect the clinical serum from pigs. In this study, the recombinant protein VP2 of PPV was expressed in E.coli, purified with nickel magnetic beads, and then printed onto epoxy-coated glass slides for preparation of the protein chip. After a series of experiments, the conditions of antigen protein concentration, incubation time of primary antibody or secondary antibody, and optimal serum dilution fold were optimized, resulting in a successful visible protein chip and Cy3-labeled protein chip. The results showed that the positive serum, diluted up to 6000-fold, can be detected by the visible protein chip, and the positive serum, diluted up to 12,800-fold, can be detected by the Cy3-labeled protein chip, suggesting the high sensitivity of these protein chips. Moreover, the positive detection ratio, sensitivity, and specificity of these two kinds of protein chips were higher than those of commercial ELISA antibody detection kits. CONCLUSION: Overall, these two protein chips can be used to rapidly diagnose clinical samples with high throughput.

Porcine Mx1 Protein Inhibits Classical Swine Fever Virus Replication by Targeting Nonstructural Protein NS5B.

Mx proteins are interferon (IFN)-induced GTPases that have broad antiviral activity against a wide range of RNA and DNA viruses; they belong to the dynamin superfamily of large GTPases. In this study, we confirmed the anti-classical swine fever virus (CSFV) activity of porcine Mx1 in vitro and showed that porcine Mx2 (poMx2), human MxA (huMxA), and mouse Mx1 (mmMx1) also have anti-CSFV activity in vitro Small interfering RNA (siRNA) experiments revealed that depletion of endogenous poMx1 or poMx2 enhanced CSFV replication, suggesting that porcine Mx proteins are responsible for the antiviral activity of interferon alpha (IFN-α) against CSFV infection. Confocal microscopy, immunoprecipitation, glutathione S-transferase (GST) pulldown, and bimolecular fluorescence complementation (BiFC) demonstrated that poMx1 associated with NS5B, the RNA-dependent RNA polymerase (RdRp) of CSFV. We used mutations in the poMx1 protein to elucidate the mechanism of their anti-CSFV activity and found that mutants that disrupted the association with NS5B lost all anti-CSV activity. Moreover, an RdRp activity assay further revealed that poMx1 undermined the RdRp activities of NS5B. Together, these results indicate that porcine Mx proteins exert their antiviral activity against CSFV by interacting with NS5B.IMPORTANCE Our previous studies have shown that porcine Mx1 (poMx1) inhibits classical swine fever virus (CSFV) replication in vitro and in vivo, but the molecular mechanism of action remains largely unknown. In this study, we dissect the molecular mechanism of porcine Mx1 and Mx2 against CSFV in vitro Our results show that poMx1 associates with NS5B, the RNA-dependent RNA polymerase of CSFV, resulting in the reduction of CSFV replication. Moreover, the mutants of poMx1 further elucidate the mechanism of their anti-CSFV activities.

Rab5 and Rab11 Are Required for Clathrin-Dependent Endocytosis of Japanese Encephalitis Virus in BHK-21 Cells.

During infection Japanese encephalitis virus (JEV) generally enters host cells via receptor-mediated clathrin-dependent endocytosis. The trafficking of JEV within endosomes is controlled by Rab GTPases, but which Rab proteins are involved in JEV entry into BHK-21 cells is unknown. In this study, entry and postinternalization of JEV were analyzed using biochemical inhibitors, RNA interference, and dominant negative (DN) mutants. Our data demonstrate that JEV entry into BHK-21 cells depends on clathrin, dynamin, and cholesterol but not on caveolae or macropinocytosis. The effect on JEV infection of dominant negative (DN) mutants of four Rab proteins that regulate endosomal trafficking was examined. Expression of DN Rab5 and DN Rab11, but not DN Rab7 and DN Rab9, significantly inhibited JEV replication. These results were further tested by silencing Rab5 or Rab11 expression before viral infection. Confocal microscopy showed that virus particles colocalized with Rab5 or Rab11 within 15 min after virus entry, suggesting that after internalization JEV moves to early and recycling endosomes before the release of the viral genome. Our findings demonstrate the roles of Rab5 and Rab11 on JEV infection of BHK-21 cells through the endocytic pathway, providing new insights into the life cycle of flaviviruses.IMPORTANCE Although Japanese encephalitis virus (JEV) utilizes different endocytic pathways depending on the cell type being infected, the detailed mechanism of its entry into BHK-21 cells is unknown. Understanding the process of JEV endocytosis and postinternalization will advance our knowledge of JEV infection and pathogenesis as well as provide potential novel drug targets for antiviral intervention. With this objective, we used systematic approaches to dissect this process. The results show that entry of JEV into BHK-21 cells requires a low-pH environment and that the process occurs through dynamin-, actin-, and cholesterol-dependent clathrin-mediated endocytosis that requires Rab5 and Rab11. Our work provides a detailed picture of the entry of JEV into BHK-21 cells and the cellular events that follow.

Stress granule-localized USP8 potentiates cGAS-mediated type I interferonopathies through deubiquitination of DDX3X.

Cyclic GMP-AMP synthase (cGAS) undergoes liquid-liquid phase separation (LLPS) to trigger downstream signaling upon double-stranded DNA (dsDNA) stimulation, and the condensed cGAS colocalizes with stress granules (SGs). However, the molecular mechanism underlying the modulation of cGAS activation by SGs remains elusive. In this study, we show that USP8 is localized to SGs upon dsDNA stimulation and potentiates cGAS-stimulator of interferon genes (STING) signaling. A USP8 inhibitor ameliorates pathological inflammation in Trex1-/- mice. Systemic lupus erythematosus (SLE) databases indicate a positive correlation between USP8 expression and SLE. Mechanistic study shows that the SG protein DDX3X promotes cGAS phase separation and activation in a manner dependent on its intrinsic LLPS. USP8 cleaves K27-linked ubiquitin chains from the intrinsically disordered region (IDR) of DDX3X to enhance its condensation. In conclusion, we demonstrate that USP8 catalyzes the deubiquitination of DDX3X to facilitate cGAS condensation and activation and that inhibiting USP8 is a promising strategy for alleviating cGAS-mediated autoimmune diseases.

Regulation of cellular senescence by innate immunity.

During the COVID-19 pandemic, the interplay between the processes of immunity and senescence is drawing more and more intensive attention. SARS-CoV-2 infection induces senescence in lung cells, failure to clear infected cells and increased presence of inflammatory factors could lead to a cytokine storm and acute respiratory disease syndrome (ARDS), which together with aging and age-associated disease lead to 70% of COVID-19-related deaths. Studies on how senescence initiates upon viral infection and how to restrict excessive accumulation of senescent cells to avoid harmful inflammation are crucially important. Senescence can induce innate immune signaling, and innate immunity can engage cell senescence. Here, we mainly review the innate immune pathways, such as cGAS-STING, TLRs, NF-κB, and NLRP3 inflammasome, participating in the senescence process. In these pathways, IFN-I and inflammatory factors play key roles. At the end of the review, we propose the strategies by which we can improve the immune function and reduce inflammation based on these findings.

Effects of milk-derived bioactive peptide VPP on diarrhea of pre-weaning calves.

A well-known milk-derived bioactive tripeptide, VPP (Val-Pro-Pro) has good anti-inflammatory, anti-hypertension, and anti-hydrolysis properties. However, whether VPP can alleviate calf intestinal inflammation is unclear. In this experiment, the effects of VPP on growth, diarrhea incidence, serum biochemical indices, short-chain fatty acids, and fecal microorganisms were examined in pre-weaning Holstein calves. Eighteen calves with similar birth date, body weight, and genetic background were randomly assigned equally to two groups (n = 9). The control group was given 50 mL of phosphate buffer saline before morning feeding, whereas the VPP group received 50 mL of VPP solution (100 mg/kg body weight/d). The study lasted for 17 days, with the first 3 days used for adaptation. Initial and final body weights were determined, and daily dry matter intake and fecal score were recorded throughout the study. Serum hormone levels and antioxidant and immune indices were measured on day 14. Fecal microorganisms were collected on days 0, 7, and 14, and 16S rDNA sequencing was performed. Oral administration of VPP did not significantly affect calf average daily feed intake and body weight, but the growth rate in body weight was significantly higher in the VPP group than in the control group on day 7 (P < 0.05). Compared with the control, VPP significantly decreased serum TNF-α and IL-6 contents (P < 0.05), and concentrations of nitric oxide and IL-1ß also decreased but not significantly (0.05 < P < 0.1). After seven days of VPP, relative abundances of g_Lachnoclostridium, uncultured_bacterium_, and g_Streptococcus in fecal samples increased significantly (P < 0.05). Compared with the control, VPP significantly increased concentrations of the fecal short-chain fatty acids n-butyric acid and isovaleric acid (P < 0.05). In conclusion, VPP can relieve intestinal inflammation and alleviate the degree of diarrhea in pre-weaning calves.

The hindgut microbiome contributes to host oxidative stress in postpartum dairy cows by affecting glutathione synthesis process.

BACKGROUND: Dairy cows are susceptible to postpartum systemic oxidative stress (OS), which leads to significant production loss and metabolic disorders. The gut microbiota has been linked to host health and stress levels. However, to what extent the gut microbiota is associated with postpartum OS remains unknown. In this study, the contribution of the fecal microbiota to postpartum systemic OS and its underlying mechanisms were investigated by integrating 16S rRNA gene sequencing, metagenomics, and metabolomics in postpartum dairy cattle and by transplanting fecal microbiota from cattle to mice. RESULTS: A strong link was found between fecal microbial composition and postpartum OS, with an explainability of 43.1%. A total of 17 significantly differential bacterial genera and 19 species were identified between cows with high (HOS) and low OS (LOS). Among them, 9 genera and 16 species showed significant negative correlations with OS, and Marasmitruncus and Ruminococcus_sp._CAG:724 had the strongest correlations. The microbial functional analysis showed that the fecal microbial metabolism of glutamine, glutamate, glycine, and cysteine involved in glutathione synthesis was lower in HOS cows. Moreover, 58 significantly different metabolites were identified between HOS and LOS cows, and of these metabolites, 19 were produced from microbiota or cometabolism of microbiota and host. Furthermore, these microbial metabolites were enriched in the metabolism of glutamine, glutamate, glycine, and cysteine. The mice gavaged with HOS fecal microbiota had significantly higher OS and lower plasma glutathione peroxidase and glutathione content than those orally administered saline or LOS fecal microbiota. CONCLUSIONS: Integrated results suggest that the fecal microbiota is responsible for OS and that lower glutathione production plays a causative role in HOS. These findings provide novel insights into the mechanisms of postpartum OS and potential regulatory strategies to alleviate OS in dairy cows. Video Abstract.

Rapid and reliable ultrasensitive detection of pathogenic H9N2 viruses through virus-binding phage nanofibers decorated with gold nanoparticles.

The rapid and sensitive detection of pathogenic viruses is important for controlling pandemics. Herein, a rapid, ultrasensitive, optical biosensing scheme was developed to detect avian influenza virus H9N2 using a genetically engineered filamentous M13 phage probe. The M13 phage was genetically engineered to bear an H9N2-binding peptide (H9N2BP) at the tip and a gold nanoparticle (AuNP)-binding peptide (AuBP) on the sidewall to form an engineered phage nanofiber, M13@H9N2BP@AuBP. Simulated modelling showed that M13@H9N2BP@AuBP enabled a 40-fold enhancement of the electric field enhancement in surface plasmon resonance (SPR) compared to conventional AuNPs. Experimentally, this signal enhancement scheme was employed for detecting H9N2 particles with a sensitivity down to 6.3 copies/mL (1.04 × 10-5 fM). The phage-based SPR scheme can detect H9N2 viruses in real allantoic samples within 10 min, even at very low concentrations beyond the detection limit of quantitative polymerase chain reaction (qPCR). Moreover, after capturing the H9N2 viruses on the sensor chip, the H9N2-binding phage nanofibers can be quantitatively converted into plaques that are visible to the naked eye for further quantification, thereby allowing us to enumerate the H9N2 virus particles through a second mode to cross-validate the SPR results. This novel phage-based biosensing strategy can be employed to detect other pathogens because the H9N2-binding peptides can be easily switched with other pathogen-binding peptides using phage display technology.

Colonization and development of the gut microbiome in calves.

Colonization and development of the gut microbiome are crucial for the growth and health of calves. In this review, we summarized the colonization, beneficial nutrition, immune function of gut microbiota, function of the gut barrier, and the evolution of core microbiota in the gut of calves of different ages. Homeostasis of gut microbiome is beneficial for nutritional and immune system development of calves. Disruption of the gut microbiome leads to digestive diseases in calves, such as diarrhea and intestinal inflammation. Microbiota already exists in the gut of calf fetuses, and the colonization of microbiota continues to change dynamically under the influence of various factors, which include probiotics, diet, age, and genotype. Colonization depends on the interaction between the gut microbiota and the immune system of calves. The abundance and diversity of these commensal microbiota stabilize and play a critical role in the health of calves.

Modulating gastrointestinal microbiota to alleviate diarrhea in calves.

The calf stage is a critical period for the development of heifers. Newborn calves have low gastrointestinal barrier function and immunity before weaning, making them highly susceptible to infection by various intestinal pathogens. Diarrhea in calves poses a significant threat to the health of young ruminants and may cause serious economic losses to livestock farms. Antibiotics are commonly used to treat diarrhea and promote calf growth, leading to bacterial resistance and increasing antibiotic residues in meat. Therefore, finding new technologies to improve the diarrhea of newborn calves is a challenge for livestock production and public health. The operation of the gut microbiota in the early stages after birth is crucial for optimizing immune function and body growth. Microbiota colonization of newborn animals is crucial for healthy development. Early intervention of the calf gastrointestinal microbiota, such as oral probiotics, fecal microbiota transplantation and rumen microbiota transplantation can effectively relieve calf diarrhea. This review focuses on the role and mechanisms of oral probiotics such as Lactobacillus, Bifidobacterium and Faecalibacterium in relieving calf diarrhea. The aim is to develop appropriate antibiotic alternatives to improve calf health in a sustainable and responsible manner, while addressing public health issues related to the use of antibiotics in livestock.

Gut Microbiota and Their Role in Health and Metabolic Disease of Dairy Cow.

Ruminants are mostly herbivorous animals that employ rumen fermentation for the digestion of feed materials, including dairy cows. Ruminants consume plant fibre as their regular diet, but lack the machinery for their digestion. For this reason, ruminants maintain a symbiotic relation with microorganisms that are capable of producing enzymes to degrade plant polymers. Various species of microflora including bacteria, protozoa, fungi, archaea, and bacteriophages are hosted at distinct concentrations for accomplishing complete digestion. The ingested feed is digested at a defined stratum. The polysaccharic plant fibrils are degraded by cellulolytic bacteria, and the substrate formed is acted upon by other bacteria. This sequential degradative mechanism forms the base of complete digestion as well as harvesting energy from the ingested feed. The composition of microbiota readily gets tuned to the changes in the feed habits of the dairy cow. The overall energy production as well as digestion is decided by the intactness of the resident communal flora. Disturbances in the homogeneity gastrointestinal microflora has severe effects on the digestive system and various other organs. This disharmony in communal relationship also causes various metabolic disorders. The dominance of methanogens sometimes lead to bloating, and high sugar feed culminates in ruminal acidosis. Likewise, disruptive microfloral constitution also ignites reticuloperitonitis, ulcers, diarrhoea, etc. The role of symbiotic microflora in the occurrence and progress of a few important metabolic diseases are discussed in this review. Future studies in multiomics provides platform to determine the physiological and phenotypical upgradation of dairy cow for milk production.

Dietary Bioactive Peptide Alanyl-Glutamine Attenuates Dextran Sodium Sulfate-Induced Colitis by Modulating Gut Microbiota.

Inflammatory bowel disease (IBD) is a chronic intestinal disorder threatening human health. Di-peptide alanyl-glutamine (Ala-Gln) has various beneficial effects on gut health. However, its role and functional mechanism in treating IBD are still not clear. Therefore, the protective effects of Ala-Gln and glutamine (Gln) on dextran sulfate sodium- (DSS-) induced colitic mice were investigated in this study. The results showed that oral supplementation of Ala-Gln or Gln significantly attenuated the colitis symptoms in mice, including body weight loss, colon length, disease activity index, histological scores, and tissue apoptosis. The concentrations of interleukin- (IL-) 1ß, IL-6, tumor necrosis factor-α, and myeloperoxidase were significantly decreased, while the concentrations of immunoglobulins (IgA, IgG, and IgM) and superoxide dismutase were significantly increased by Ala-Gln or Gln supplementation. The expression of occludin and peptide transporter 1 (PepT1) was significantly increased by Ala-Gln or Gln. Interestingly, Ala-Gln had better beneficial effects than Gln in alleviating colitis. In addition, 16S rDNA sequencing showed that the DSS-induced shifts of the microbiome (community diversity, evenness, richness, and composition) in the mouse colon were restored by Gln and Ala-Gln, including Lactobacillus, Bacteroides_acidifaciens, Bacteroidales, Firmicutes, Clostridia, Helicobacter, and Bacteroides. Correspondingly, the functions of the microflora metabolism pathways were also rescued by Ala-Gln, including fatty acid metabolism, membrane transporters, infectious diseases, and immune system. In conclusion, the results revealed that Ala-Gln can prevent colitis through PepT1, enhancing the intestinal barrier and modulating gut microbiota and microflora metabolites.

USP18 positively regulates innate antiviral immunity by promoting K63-linked polyubiquitination of MAVS.

Activation of MAVS, an adaptor molecule in Rig-I-like receptor (RLR) signaling, is indispensable for antiviral immunity, yet the molecular mechanisms modulating MAVS activation are not completely understood. Ubiquitination has a central function in regulating the activity of MAVS. Here, we demonstrate that a mitochondria-localized deubiquitinase USP18 specifically interacts with MAVS, promotes K63-linked polyubiquitination and subsequent aggregation of MAVS. USP18 upregulates the expression and production of type I interferon following infection with Sendai virus (SeV) or Encephalomyocarditis virus (EMCV). Mice with a deficiency of USP18 are more susceptible to RNA virus infection. USP18 functions as a scaffold protein to facilitate the re-localization of TRIM31 and enhances the interaction between TRIM31 and MAVS in mitochondria. Our results indicate that USP18 functions as a post-translational modulator of MAVS-mediated antiviral signaling.

TRIM31 facilitates K27-linked polyubiquitination of SYK to regulate antifungal immunity.

Spleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase, which plays an essential role in both innate and adaptive immunity. However, the key molecular mechanisms that regulate SYK activity are poorly understood. Here we identified the E3 ligase TRIM31 as a crucial regulator of SYK activation. We found that TRIM31 interacted with SYK and catalyzed K27-linked polyubiquitination at Lys375 and Lys517 of SYK. This K27-linked polyubiquitination of SYK promoted its plasma membrane translocation and binding with the C-type lectin receptors (CLRs), and also prevented the interaction with the phosphatase SHP-1. Therefore, deficiency of Trim31 in bone marrow-derived dendritic cells (BMDCs) and macrophages (BMDMs) dampened SYK-mediated signaling and inhibited the secretion of proinflammatory cytokines and chemokines against the fungal pathogen Candida albicans infection. Trim31-/- mice were also more sensitive to C. albicans systemic infection than Trim31+/+ mice and exhibited reduced Th1 and Th17 responses. Overall, our study uncovered the pivotal role of TRIM31-mediated K27-linked polyubiquitination on SYK activation and highlighted the significance of TRIM31 in anti-C. albicans immunity.

Robust Assessment of Controllable Operating Parameters of Entrained Flow Cogasification of Petcoke with Coal: Considering Some Uncertainties.

This paper is focused on the effects of some controllable operating parameters on the robustness of the coke/coal entrained flow cogasification process considering some uncertainties in it. In the present work, the operating variables were categorized into controllable parameters (CPs) (oxygen and steam concentrations, OC and SC) and hard-to-control parameters (temperature and coal/coke blending ratio) according to the actual modes during the cogasification process. Then, some robust response surface methodology (RSM) models, that is, mean RSM model and variance RSM model, for some important performance indexes [H2, CO, and (H2 + CO) production] with the CPs as independent variables, were found using combined array methodology. Then, the effects of OC and SC not only on the mean but also on the variance of each performance index were systematically investigated. Finally, the cogasification process was robustly optimized using the mean square criterion and desirability function. The result shows that the average production of H2 and that of (H2+ CO) increases with increasing OC but decreases with increasing SC. Additionally, higher OC suppresses the fluctuations in H2 and (H2 + CO) production, while higher SC enlarges the fluctuations in H2 production. Assuming that the variance of temperature in a gasifier is 20 °C and the variance of the coal/coke blending ratio is 5%, the multiobjective robust optimization solutions of OC and SC are 1.56 and 50%, respectively, and a satisfactory performance for high syngas production with low fluctuation can be gained.

Dietary Taxifolin Protects Against Dextran Sulfate Sodium-Induced Colitis via NF-κB Signaling, Enhancing Intestinal Barrier and Modulating Gut Microbiota.

Taxifolin is a natural antioxidant polyphenol with various bioactivities and has many beneficial effects on human gut health. However, little is known of its function on colitis. In this study, the protective effects of taxifolin on colitis symptoms, inflammation, signaling pathways, and colon microbiota were investigated using dextran sulfate sodium (DSS)-induced colitis mice. Intriguingly, pre-administration of taxifolin alleviated the colitis symptoms and histological changes of the DSS-challenged mice. Supplementation of taxifolin significantly inhibited the secretions of tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6 and significantly increased the secretions of IL-10, secretory immunoglobulin A, superoxide dismutase, and immunoglobulins (IgA, IgG, and IgM) in DSS-induced colitis mice. In addition, the activation of nuclear factor kappa B (NF-κB; p65 and IκBα) signaling was significantly suppressed by taxifolin supplementation. The expression of tight junction proteins (claudin-1 and occludin) was significantly increased by taxifolin. Moreover, 16S rDNA sequencing revealed that the DSS-induced changes of colon microbiota composition and microbial functions (amino acid metabolism and MAPK signaling) were restored by taxifolin, including the decreases of the abundances of Bacteroides, Clostridium ramosum, Clostridium saccharogumia, Sphingobacterium multivorum, and the ratio of Bacteroidetes/Firmicutes, and the increases of the abundances of Desulfovibrio C21 c20 and Gemmiger formicilis at species level. In conclusion, these results revealed that dietary taxifolin has a great potential to prevent colitis by inhibiting the NF-κB signaling pathway, enhancing intestinal barrier, and modulating gut microbiota.