Enteric coronavirus nsp2 is a virulence determinant that recruits NBR1 for autophagic targeting of TBK1 to diminish the innate immune response.

Non-structural protein 2 (nsp2) exists in all coronaviruses (CoVs), while its primary function in viral pathogenicity, is largely unclear. One such enteric CoV, porcine epidemic diarrhea virus (PEDV), causes high mortality in neonatal piglets worldwide. To determine the biological role of nsp2, we generated a PEDV mutant containing a complete nsp2 deletion (rPEDV-Δnsp2) from a highly pathogenic strain by reverse genetics, showing that nsp2 was dispensable for PEDV infection, while its deficiency reduced viral replication in vitro. Intriguingly, rPEDV-Δnsp2 was entirely avirulent in vivo, with significantly increased productions of IFNB (interferon beta) and IFN-stimulated genes (ISGs) in various intestinal tissues of challenged newborn piglets. Notably, nsp2 targets and degrades TBK1 (TANK binding kinase 1), the critical kinase in the innate immune response. Mechanistically, nsp2 induced the macroautophagy/autophagy process and recruited a selective autophagic receptor, NBR1 (NBR1 autophagy cargo receptor). NBR1 subsequently facilitated the K48-linked ubiquitination of TBK1 and delivered it for autophagosome-mediated degradation. Accordingly, the replication of rPEDV-Δnsp2 CoV was restrained by reduced autophagy and excess productions of type I IFNs and ISGs. Our data collectively define enteric CoV nsp2 as a novel virulence determinant, propose a crucial role of nsp2 in diminishing innate antiviral immunity by targeting TBK1 for NBR1-mediated selective autophagy, and pave the way to develop a new type of nsp2-based attenuated PEDV vaccine. The study also provides new insights into the prevention and treatment of other pathogenic CoVs.Abbreviations: 3-MA: 3-methyladenine; Baf A1: bafilomycin A1; CoV: coronavirus; CQ: chloroquine; dpi: days post-inoculation; DMVs: double-membrane vesicles; GABARAP: GABA type A receptor-associated protein; GFP: green fluorescent protein; GIGYF2: GRB10 interacting GYF protein 2; hpi: hours post-infection; IFA: immunofluorescence assay; IFIH1: interferon induced with helicase C domain 1; IFIT2: interferon induced protein with tetratricopeptide repeats 2; IFITM1: interferon induced transmembrane protein 1; IFNB: interferon beta; IRF3: interferon regulatory factor 3; ISGs: interferon-stimulated genes; mAb: monoclonal antibody; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAVS: mitochondrial antiviral signaling protein; NBR1: NBR1 autophagy cargo receptor; nsp2: non-structural protein 2; OAS1: 2'-5'-oligoadenylate synthetase 1; PEDV: porcine epidemic diarrhea virus; PRRs: pattern recognition receptors; RIGI: RNA sensor RIG-I; RT-qPCR: reverse transcription quantitative polymerase chain reaction; SQSTM1: sequestosome 1; TBK1: TANK binding kinase 1; TCID50: 50% tissue culture infectious doses; VSV: vesicular stomatitis virus.

Human ß-defensin-1 affects the mammalian target of rapamycin pathway and autophagy in colon cancer cells through long non-coding RNA TCONS_00014506.

BACKGROUND: Colorectal cancer has a low 5-year survival rate and high mortality. Human ß-defensin-1 (hBD-1) may play an integral function in the innate immune system, contributing to the recognition and destruction of cancer cells. Long non-coding RNAs (lncRNAs) are involved in the process of cell differentiation and growth. AIM: To investigate the effect of hBD-1 on the mammalian target of rapamycin (mTOR) pathway and autophagy in human colon cancer SW620 cells. METHODS: CCK8 assay was utilized for the detection of cell proliferation and determination of the optimal drug concentration. Colony formation assay was employed to assess the effect of hBD-1 on SW620 cell proliferation. Bioinformatics was used to screen potentially biologically significant lncRNAs related to the mTOR pathway. Additionally, p-mTOR (Ser2448), Beclin1, and LC3II/I expression levels in SW620 cells were assessed through Western blot analysis. RESULTS: hBD-1 inhibited the proliferative ability of SW620 cells, as evidenced by the reduction in the colony formation capacity of SW620 cells upon exposure to hBD-1. hBD-1 decreased the expression of p-mTOR (Ser2448) protein and increased the expression of Beclin1 and LC3II/I protein. Furthermore, bioinformatics analysis identified seven lncRNAs (2 upregulated and 5 downregulated) related to the mTOR pathway. The lncRNA TCONS_00014506 was ultimately selected. Following the inhibition of the lncRNA TCONS_00014506, exposure to hBD-1 inhibited p-mTOR (Ser2448) and promoted Beclin1 and LC3II/I protein expression. CONCLUSION: hBD-1 inhibits the mTOR pathway and promotes autophagy by upregulating the expression of the lncRNA TCONS_00014506 in SW620 cells.

FXR controls duodenogastric reflux-induced gastric inflammation through negatively regulating ER stress-associated TNXIP/NLPR3 inflammasome.

Duodenogastric reflux (DGR) is closely associated with gastric inflammation and tumorigenesis; however, the precise mechanism is unclear. Hence, we aim to clarify this molecular mechanism and design an effective therapeutic strategy based on it. The present study found that DGR induced TXNIP/NLRP3 inflammasome activation and triggered pyroptosis in gastric mucosa in vitro and in vivo, in which endoplasmic reticulum (ER) stress via PERK/eIF2α/CHOP signaling was involved. Mechanistically, farnesoid X receptor (FXR) antagonized the DGR-induced PERK/eIF2α/CHOP pathway and reduced TXNIP and NLRP3 expression. Moreover, FXR suppressed NLRP3 inflammasome activation by physically interacting with NLRP3 and caspase-1. Administration of the FXR agonist OCA protected the gastric mucosa from DGR-induced barrier disruption and mucosal inflammation. In conclusion, our study demonstrates the involvement of TXNIP/NLRP3 inflammasome-mediated pyroptosis in DGR-induced gastric inflammation. FXR antagonizes gastric barrier disruption and mucosal inflammation induced by DGR. Restoration of FXR activity may be a therapeutic strategy for DGR-associated gastric tumorigenesis.

Upregulation of p300 in paclitaxel-resistant TNBC: implications for cell proliferation via the PCK1/AMPK axis.

OBJECTIVE: To explore the role of p300 in the context of paclitaxel (PTX) resistance in triple-negative breast cancer (TNBC) cells, focusing on its interaction with the phosphoenolpyruvate carboxykinase 1 (PCK1)/adenosine monophosphate-activated protein kinase (AMPK) pathway. METHODS: The expression of p300 and PCK1 at the messenger ribonucleic acid (mRNA) level was detected using a quantitative polymerase chain reaction. The GeneCards and GEPIA databases were used to investigate the relationship between p300 and PCK1. The MDA-MB-231/PTX cell line, known for its PTX resistance, was chosen to understand the specific role of p300 in such cells. The Lipofectamine™ 3000 reagent was used to transfer the p300 small interfering RNA and the overexpression of PCK1 plasmid into MDA-MB-231/PTX. The expression levels of p300, PCK1, 5'AMPK and phosphorylated AMPK (p-AMPK) were determined using the western blot test. RESULTS: In TNBC cancer tissue, the expression of p300 was increased compared with TNBC paracancerous tissue (P < 0.05). In the MDA-MB-231 cell line of TNBC, the expression of p300 was lower than in the PTX-resistant TNBC cells (MDA-MB-231/PTX) (P < 0.05). The PCK1 expression was decreased in the TNBC cancer tissue compared with TNBC paracancerous tissue, and the PCK1 expression was reduced in MDA-MB-231/PTX than in MDA-MB-231 (P < 0.05) indicating that PCK1 was involved in the resistance function. Additionally, p-AMPK was decreased in MDA-MB-231/PTX compared with MDA-MB-231 (P < 0.05). The adenosine triphosphate (ATP) level was also detected and was significantly lower in MDA-MB-231/PTX than in MDA-MB-231 (P < 0.05). Additionally, cell proliferation increased significantly in MDA-MB-231/PTX at 48 and 72 h (P < 0.05) suggesting that MDA-MB-231/PTX cells obtained the resistance function which was associated with AMPK and ATP level. When p300 was inhibited, p-AMPK and ATP levels elevated in MDA-MB-231/PTX (P < 0.05). When PCK1 was suppressed, the ATP consumption rate decreased, and cell proliferation increased (P < 0.05). However, there were no changes in p300. CONCLUSIONS: In MDA-MB-231/PTX, p300 can inhibit p-AMPK and ATP levels by inhibiting PCK1 expression. Our findings suggest that targeting p300 could modulate the PCK1/AMPK axis, offering a potential therapeutic avenue for overcoming PTX resistance in TNBC.

Collagen study advances for photoaging skin.

BACKGROUND: Collagen dominates the skin's extracellular matrix (ECM). Type I collagen comprises 80%-90% of the skin's collagen, followed by type III (8%-12%) and type V (5%). Reactive oxygen species, matrix metalloproteinases, and collagen degradation all increase during photoaging, which disrupts the ECM's dynamic balance and lowers the amount of total collagen in the body. In recent years, domestic and foreign researchers have conducted multidimensional and multifaceted studies on collagen and skin photoaging. Collagen and the peptides that are derivates of it are currently being used more and more in biomedicine and medical esthetics. OBJECTIVE: Offering new suggestions for both the avoidance and remedy of photoaging. METHODS: This article reviews collagen and its potential connection to skin photoaging, illustrates the effects of collagen and peptide supplementation derivatives on photoaged skin, and briefly describes other compounds that can also be used to fight photoaging by increasing collagen synthesis in the skin. RESULT: Both internal and external aging are inevitable, and as the main component of extracellular matrix, collagen plays a variety of functions in maintaining skin structure and fighting skin aging, and its role in photoaging is undeniable. Ultraviolet radiation can induce increased fragmentation and degradation of cutaneous collagen, while conversely, supplementation with collagen can effectively counteract photodamage-induced skin impairment. CONCLUSION: Collagen and its derived peptides are indispensable in photoaging skin, holding promising prospects for applications in skin aging.

Compound Bacillus alleviates diarrhea by regulating gut microbes, metabolites, and inflammatory responses in pet cats.

BACKGROUND: Pet cats frequently have diarrhea in their daily life. Bacillus has a protective role that has crucial beneficial functions on intestinal homeostasis. The aim of this research was to investigate the effects of the compound Bacillus on the prevention of diarrhea, microbiota and metabolism in pet cats. A total of 20 pet cats (1-2 years old, 3.91 ± 0.92 kg) were randomly divided into two groups and fed with a basal diet (Control group), or a basal diet supplemented with 3 × 109 CFU/kg compound Bacillus (Probiotics group). The experiment lasted 33 days. RESULTS: Results showed that the compound Bacillus significantly reduced the rate of soft stools and diarrhea in pet cats compared with the control group (P < 0.05, n = 10). Meanwhile, compared with the control group, the probiotics group significantly decreased the content of IL-1ß and IL-6 and significantly increased IL-10 (P < 0.05, n = 6) in the serum. In addition, feeding probiotics significantly increased the abundance of p_Patescibacter and g_Plectosphaerella, decreased the abundance of p_Firmicutes, p_Gemmatimonadetes, g_Ruminococcaceae_UCG-005, g_Ascochytahe and g_Saccharomyces in the feces of the pet cats (P < 0.05, n = 6). And it also can significantly increase the content of total SCFAs, acetic acid and butyric acid in the feces (P < 0.05, n = 6). The fecal and serum metabolomics analyses revealed that most fecal and serum compounds were involved in metabolism, particularly in chemical structure transformation maps and amino acid metabolism. Also, eugenitol and methyl sulfate were the most significantly increased serum metabolites, and log2FC were 38.73 and 37.12, respectively. Pearson's correlation analysis showed that changes in serum metabolism and fecal microbiota were closely related to immune factors. There was also a strong correlation between serum metabolites and microbiota composition. CONCLUSIONS: The results of this research highlight the potential of the compound Bacillus as a dietary supplement to alleviate diarrhea in pet cats.

Inhibitory effect of exogenous mineral elements (Si, P, Zn, Ca, Mn, Se, Fe, S) on rice Cd accumulation and soil Cd bioavailability in Cd-contaminated farmlands: A meta-analysis.

A promising strategy for safely remediating Cd-contaminated farmland has been the application of mineral elements, which can reduce Cd accumulation in rice and inhibit its bioavailability in Cd-contaminated farmlands. However, there is still a lack of systematic and quantitative evaluations regarding how different mineral elements affect rice Cd accumulation and soil Cd bioavailability. Here, a meta-analysis was conducted based on 1062 individual observations from 137 published works to explore the effects of Si, P, Zn, Ca, Mn, Se, Fe and S in rice Cd accumulation and soil Cd bioavailability, we aimed to identify key factors that control the reduction of Cd concentration in rice grains. The results showed that the presence of exogenous elements had dramatically reduced rice grains Cd concentrations in the following decreasing order: Fe (43.03%) > P (38.45%) > Si (33.24%) > Ca (31.90%) > Se (29.83%) > Zn (25.95%) > Mn (23.26%) > S (18.78%). The elements of Ca, P and Si had strongly reduced Cd bioavailability in soils by 29.87%, 27.80% and 22.70%, respectively. The effects of these elements on Cd bioavailability appeared to be controlled by soil physio-chemical properties, such as pH, soil organic carbon (SOC) but also water management, application amounts and elemental forms. Overall, this study provides valuable insights into the potential of using exogenous mineral elements to mitigate Cd contamination in rice and farmlands, and facilitates the selection and application of mineral elements for the safe utilization of Cd-contaminated farmlands, taking into account soil properties and other factors that affect their effect.

TOR-mediated Ypt1 phosphorylation regulates autophagy initiation complex assembly.

The regulation of autophagy initiation is a key step in autophagosome biogenesis. However, our understanding of the molecular mechanisms underlying the stepwise assembly of ATG proteins during this process remains incomplete. The Rab GTPase Ypt1/Rab1 is recognized as an essential autophagy regulator. Here, we identify Atg23 and Atg17 as binding partners of Ypt1, with their direct interaction proving crucial for the stepwise assembly of autophagy initiation complexes. Disruption of Ypt1-Atg23 binding results in significantly reduced Atg9 interactions with Atg11, Atg13, and Atg17, thus preventing the recruitment of Atg9 vesicles to the phagophore assembly site (PAS). Likewise, Ypt1-Atg17 binding contributes to the PAS recruitment of Ypt1 and Atg1. Importantly, we found that Ypt1 is phosphorylated by TOR at the Ser174 residue. Converting this residue to alanine blocks Ypt1 phosphorylation by TOR and enhances autophagy. Conversely, the Ypt1S174D phosphorylation mimic impairs both PAS recruitment and activation of Atg1, thus inhibiting subsequent autophagy. Thus, we propose TOR-mediated Ypt1 as a multifunctional assembly factor that controls autophagy initiation via its regulation of the stepwise assembly of ATG proteins.

Coupled Co-Doped MoS2 and CoS2 as the Dual-Active Site Catalyst for Chemoselective Hydrogenation.

Catalytic hydrogenation plays an important role in the industrial production of fine chemicals. Herein, we report a Co-doped MoS2 and CoS2 composite with a coupling interface and successfully apply it for the chemoselective hydrogenation of p-chloronitrobenzene to p-chloroaniline. The target catalyst 0.5CoMoS has ∼100% conversion and ∼100% selectivity. Experiments and theoretical calculations reveal that CoS2 is more favorable for adsorbing and activating H2 and provides active hydrogen (Ha) to Co-doped MoS2 by the coupling interface. By matching the production and consumption rates of Ha, the maximization of the reaction yield was achieved. This work may promote the study of MoS2-based catalysts for chemoselective hydrogenation.

Mec1 regulates PAS recruitment of Atg13 via direct binding with Atg13 during glucose starvation-induced autophagy.

Mec1 is a DNA damage sensor, which performs an essential role in the DNA damage response pathway and glucose starvation-induced autophagy. However, the functions of Mec1 in autophagy remain unclear. In response to glucose starvation, Mec1 forms puncta, which are recruited to mitochondria through the adaptor protein Ggc1. Here, we show that Mec1 puncta also contact the phagophore assembly site (PAS) via direct binding with Atg13. Functional analysis of the Atg13-Mec1 interaction revealed two previously unrecognized protein regions, the Mec1-Binding Region (MBR) on Atg13 and the Atg13-Binding Region (ABR) on Mec1, which mediate their mutual association under glucose starvation conditions. Disruption of the MBR or ABR impairs the recruitment of Mec1 puncta and Atg13 to the PAS, consequently blocking glucose starvation-induced autophagy. Additionally, the MBR and ABR regions are also crucial for DNA damage-induced autophagy. We thus propose that Mec1 regulates glucose starvation-induced autophagy by controlling Atg13 recruitment to the PAS.

Stabilization of Dinuclear Rhodium and Iridium Clusters on Layered Titanate and Niobate Supports.

Atomically dispersed organometallic clusters can provide well-defined nuclearity of active sites for both fundamental studies as well as new regimes of activity and selectivity in chemical transformations. More recently, dinuclear clusters adsorbed onto solid surfaces have shown novel catalytic properties resulting from the synergistic effect of two metal centers to anchor different reactant species. Difficulty in synthesizing, stabilizing, and characterizing isolated atoms and clusters without agglomeration challenges allocating catalytic performance to atomic structure. Here, we explore the stability of dinuclear rhodium and iridium clusters adsorbed onto layered titanate and niobate supports using molecular precursors. Both systems maintain their nuclearity when characterized using aberration-corrected high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM). Statistical analysis of HAADF-STEM images revealed that rhodium and iridium dimers had mean cluster-to-cluster distances very similar to what is expected from a random distribution of atoms over a large area, indicating that they are dispersed without aggregation. The stability of dinuclear rhodium clusters supported on titanate nanosheets was also investigated by X-ray absorption fine structure (EXAFS), DRIFTS, and first-principles calculations. Both X-ray absorption spectroscopy and HAADF-STEM simulations, guided by density functional theory (DFT)-optimized structure models, suggested that rhodium dimers adsorb onto the nanosheets in an end-on binding mode that is stable up to 100 °C under reducing conditions. This study highlights that crystalline nanosheets derived from layered metal oxides can be used as model supports to selectively stabilize dinuclear clusters, which could have implications for heterogeneous catalysis.

Amide Linkages in Pyrene-Based Covalent Organic Frameworks toward Efficient Photocatalytic Reduction of Uranyl.

The bond linkages in covalent organic frameworks (COFs) partly determine its physical and chemical properties, thus affecting the photoreactive activity by influencing the generation of photoelectrons and the separation of excitons. Herein, pyrene-based amide COF 4,4',4″,4‴-(pyrene-1,3,6,8-tetrayl)tetrabenzaldehyde-3,8-diamino-6-phenylphenanthridine (TFPPy-DP) was synthesized by postsynthetic modification of imine COFs. Due to the introduction of oxygen atoms into the framework and the change in polarity, an increased number of photogenerated electrons and a wide band gap for amide COFs were found, hydrophilicity and dispersibility were prompted as well. Both imine and amide COF TFPPy-DP were applied in the photocatalytic reduction and removal of toxic U(VI) under visible light, the catalytic reduction equilibrium (91% removal percentage of 238 ppm U at pH 3) was achieved by imine COFs with 10 h of irradiation, while amide COFs only took 2 h of irradiation (82% removal percentage). The much faster photocatalytic reduction rate of U(VI) can be attributed to the fact that amide COF TFPPy-DP retained crystallinity and permanent porosity and exhibited lower electrochemical impedance and enhanced charge separation and accumulation. Further electronic excitation analysis based on time-dependent density functional theory calculations revealed that the intramolecular charge-transfer effect in amide TFPPy-DP enhanced its photocatalytic rate.

Enabling the drug combination of celecoxib through a spherical co-agglomeration strategy with controllable and stable drug content and good powder properties.

Combining celecoxib with other chemopreventive drugs is a promising method of chemoprevention for cancer, especially for colorectal cancer. However, the traditional drug combination approaches are restricted with high-cost apparatus, complex and numerous unit operations. This work aims to develop an efficient spherical co-agglomeration strategy for celecoxib in combination with lovastatin, which can achieve drug combination in a single crystallization unit. The ternary solvent system was determined based on molecular simulation, and then a stable spherical agglomeration process was developed through the design of molar fraction of anti-solvent (MFA) and stirring rate to produce spherical agglomerates with high sphericity (84.2-89.9 %) and narrow size distribution. On this basis, celecoxib-benzoic acid spherical co-agglomerates were designed to form a complete spherical co-agglomeration strategy, which includes solvent system selection, spherical agglomeration and spherical co-agglomeration. Finally, celecoxib-lovastatin spherical co-agglomerates with synergistic efficacy were successfully produced by this strategy, with controllable and stable drug content (fluctuation < 2.7 %), good powder properties, and improved tabletability.

Review detection of Newcastle disease virus.

Newcastle disease (ND) is an acute and highly contagious disease caused by the Newcastle disease virus (NDV) infecting poultry, which has caused great harm to the poultry industry around the world. Rapid diagnosis of NDV is important to early treatment and early institution of control measures. In this review, we comprehensively summarize the most recent research into NDV, including historical overview, molecular structure, and infection mechanism. We then focus on detection strategies for NDV, including virus isolation, serological assays (such as hemagglutination and hemagglutination-inhibition tests, enzyme linked immunosorbent assay, reporter virus neutralization test, Immunofluorescence assay, and Immune colloidal gold technique), molecular assays (such as reverse transcription polymerase chain reaction, real-time quantitative PCR, and loop-mediated isothermal amplification) and other assays. The performance of the different serological and molecular biology assays currently available was also analyzed. To conclude, we examine the limitations of currently available strategies for the detection of NDV to lay the groundwork for new detection assays.

Bacillus amyloliquefaciens SC06 alleviates the obesity of ob/ob mice and improves their intestinal microbiota and bile acid metabolism.

Dietary interventions with probiotics have been widely reported to be effective in regulating obesity, and the intestinal microbiota is considered to be an important environmental factor. However, few reports focus on the interactions of microbiota-metabolites-phenotypic variables in ob/ob mice, and they have not been characterized in great detail. In this study, we investigated the effects of Bacillus amyloliquefaciens SC06 on obesity, the intestinal microbiota and the bile acid metabolism of ob/ob mice using biochemical testing, histochemical staining, high-throughput sequencing of the 16S rRNA gene, LC-MS/MS analysis and qRT-PCR. The results showed that SC06 ameliorated the fat mass percentage, hepatic steatosis and liver lipid metabolism disorders and reshaped the gut microbiota and metabolites in male ob/ob mice, specifically deceasing f_S24-7, p_TM7, s_Alistipes massiliensis, f_Rikenellaceae, f_Prevotellaceae, f_Lactobacillaceae, g_Alistipes, g_Flexispira, g_Lactobacillus, g_Odoribacter, g_AF12 and g_Prevotella and increasing f_Bacteroidaceae, g_Bacteroides and f_Desulfovibrionaceae. Meanwhile, SC06 treatment groups had lower ibuprofen and higher glycodeoxycholic acid and 7-dehydrocholesterol. Correlation analysis further clarified the relationships between compositional changes in the microbiota and alterations in the metabolites and phenotypes of ob/ob mice. Moreover, SC06 downregulated bile acid synthesis, export and re-absorption in the liver and increased ileum re-absorption into the blood in ob/ob mice, which may be mediated by the FXR-SHP/FGF15 signaling pathway. These results suggest that Bacillus amyloliquefaciens SC06 can ameliorate obesity in male ob/ob mice by reshaping the intestinal microbial composition, changing metabolites and regulating bile acid metabolism via the FXR signaling pathway.

Activation of FXR and inhibition of EZH2 synergistically inhibit colorectal cancer through cooperatively accelerating FXR nuclear location and upregulating CDX2 expression.

Our previous study indicated that colon cancer cells varied in sensitivity to pharmacological farnesoid X receptor (FXR) activation. Herein, we explore the regulatory mechanism of FXR in colorectal cancer (CRC) development and aim to design effective strategies of combined treatment based on the regulatory axis. We found that the expression of FXR was negatively correlated with enhancer of zeste homolog 2 (EZH2) in colon cancer tissues. EZH2 transcriptionally suppressed FXR via H3K27me3. The combination of FXR agonist OCA plus EZH2 inhibitor GSK126 acted in a synergistic manner across four colon cancer cells, efficiently inhibiting clonogenic growth and invasion in vitro, retarding tumor growth in vivo, preventing the G0/G1 to S phase transition, and inducing caspase-dependent apoptosis. Benign control cells FHC were growth-arrested without apoptosis induction, but retained long-term proliferation and invasion capacity. Mechanistically, the drug combination dramatically accelerated FXR nuclear location and cooperatively upregulated caudal-related homeobox transcription factor 2 (CDX2) expression. The depletion of CDX2 antagonized the synergistic effects of the drug combination on tumor inhibition. In conclusion, our study demonstrated histone modification-mediated FXR silencing by EZH2 in colorectal tumorigenesis, which offers useful evidence for the clinical use of FXR agonists combined with EZH2 inhibitors in combating CRC.

Molecular detection and phylogenetic analysis of pigeon circovirus from racing pigeons in Northern China.

BACKGROUND: Pigeon circovirus (PiCV) infections in pigeons (Columba livia) have been reported worldwide. Currently, pigeon racing is becoming increasingly popular and considered to be a national sport in China, and even, the greatest competitions of racing pigeons are taking place in China. However, there are still no epidemiologic data regarding PiCV infections among racing pigeons in China. The purpose of our study was to provide information of prevalence, genetic variation and evolution of PiCV from racing pigeons in China. RESULTS: To trace the prevalence, genetic variation and evolution of PiCV in sick and healthy racing pigeons, 622 samples were collected from 11 provinces or municipalities in China from 2016 to 2019. The results showed that the positive rate of PiCV was 19.3% (120/622) at the sample level and 59.0% (23/39) at the club level, thus suggesting that the virus was prevalent in Chinese racing pigeons. A sequence analysis revealed that the cap genes of the PiCV strains identified in our study displayed a high genetic diversity and shared nucleotide homologies of 71.9%-100% and amino acid homologies of 71.7%-100%. 28 and 36 unique amino acid substitutions were observed in the Cap and Rep proteins derived from our PiCV strains, respectively. A cladogram representation of PiCV strains phylogeny based on 90 cap gene sequences showed that the strains in this study could be further divided into seven clades (A, B, C, E, G, H, and I) and some of them were closely related to worldwide strains from different types of pigeons. A large number of recombination events (31 events) were also detected in the PiCV genomes from Chinese racing pigeons. CONCLUSIONS: These findings indicate that PiCV strains circulating in China exhibit a high genetic diversity and also contribute to information of prevalence, genetic variation and evolution of PiCV from racing pigeons in China.

Characterization of four novel H5N6 avian influenza viruses with the internal genes from H5N1 and H9N2 viruses and experimental challenge of chickens vaccinated with current commercially available H5 vaccines.

Since 2014, highly pathogenic avian influenza H5N6 viruses have been responsible for outbreaks in poultry. In this study, four H5N6 virus strains were isolated from faecal samples of sick white ducks and dead chickens in Shandong in 2019. These H5N6 viruses were triple-reassortant viruses that have not been previously characterized. Their HA genes were derived from the H5 viruses and were closely related to the vaccine strain Re-11. Their NA genes all fell into the N6-like lineage and the internal gene were derived from H5N1 and H9N2 viruses. They all showed high pathogenicity in mice and caused lethal infection with high rates of transmission in chickens. Moreover, the SPF chickens inoculated with the currently used H5 (Re-11 and Re-12 strains)/H7 (H7-Re-2 strain) trivalent inactivated vaccines in China were completely protected from these four H5N6 viruses. Our study indicated the necessity of continued surveillance for H5 influenza A viruses and the importance of timely update of vaccine strains in poultry industry.