ADNP modulates SINE B2-derived CTCF-binding sites during blastocyst formation in mice.

CTCF is crucial for chromatin structure and transcription regulation in early embryonic development. However, the kinetics of CTCF chromatin occupation in preimplantation embryos have remained unclear. In this study, we used CUT&RUN technology to investigate CTCF occupancy in mouse preimplantation development. Our findings revealed that CTCF begins binding to the genome prior to zygotic genome activation (ZGA), with a preference for CTCF-anchored chromatin loops. Although the majority of CTCF occupancy is consistently maintained, we identified a specific set of binding sites enriched in the mouse-specific short interspersed element (SINE) family B2 that are restricted to the cleavage stages. Notably, we discovered that the neuroprotective protein ADNP counteracts the stable association of CTCF at SINE B2-derived CTCF-binding sites. Knockout of Adnp in the zygote led to impaired CTCF binding signal recovery, failed deposition of H3K9me3, and transcriptional derepression of SINE B2 during the morula-to-blastocyst transition, which further led to unfaithful cell differentiation in embryos around implantation. Our analysis highlights an ADNP-dependent restriction of CTCF binding during cell differentiation in preimplantation embryos. Furthermore, our findings shed light on the functional importance of transposable elements (TEs) in promoting genetic innovation and actively shaping the early embryo developmental process specific to mammals.

Cell-surface d-glucuronyl C5-epimerase binds to porcine deltacoronavirus spike protein facilitating viral entry.

Porcine deltacoronavirus (PDCoV) is an emerging swine enteric coronavirus with zoonotic potential. The coronavirus spike (S) glycoprotein, especially the S1 subunit, mediates viral entry by binding to cellular receptors. However, the functional receptor of PDCoV remains poorly understood. In this study, we used the soluble PDCoV S1 protein as bait to capture the S1-binding cellular transmembrane proteins in combined immunoprecipitation and mass spectrometry analyses. A single guide RNA screen identified d-glucuronyl C5-epimerase (GLCE), a heparan sulfate-modifying enzyme, as a proviral host factor for PDCoV infection. GLCE knockout significantly inhibited the attachment and internalization stages of PDCoV infection. We also demonstrated the interaction between GLCE and PDCoV S with coimmunoprecipitation in both an overexpression system and PDCoV-infected cells. GLCE could be localized to the cell membrane, and an anti-GLCE antibody suppressed PDCoV infection. Although GLCE expression alone did not render nonpermissive cells susceptible to PDCoV infection, GLCE promoted the binding of PDCoV S to porcine amino peptidase N (pAPN), acting synergistically with pAPN to enhance PDCoV infection. In conclusion, our results demonstrate that GLCE is a novel cell-surface factor facilitating PDCoV entry and provide new insights into PDCoV infection. IMPORTANCE: The identification of viral receptors is of great significance, potentially extending our understanding of viral infection and pathogenesis. Porcine deltacoronavirus (PDCoV) is an emerging enteropathogenic coronavirus with the potential for cross-species transmission. However, the receptors or coreceptors of PDCoV are still poorly understood. The present study confirms that d-glucuronyl C5-epimerase (GLCE) is a positive regulator of PDCoV infection, promoting viral attachment and internalization. The anti-GLCE antibody suppressed PDCoV infection. Mechanically, GLCE interacts with PDCoV S and promotes the binding of PDCoV S to porcine amino peptidase N (pAPN), acting synergistically with pAPN to enhance PDCoV infection. This work identifies GLCE as a novel cell-surface factor facilitating PDCoV entry and paves the way for further insights into the mechanisms of PDCoV infection.

Sweet cherry TCP gene family analysis reveals potential functions of PavTCP1, PavTCP2 and PavTCP3 in fruit light responses.

BACKGROUND: TCP proteins are plant specific transcription factors that play important roles in plant growth and development. Despite the known significance of these transcription factors in general plant development, their specific role in fruit growth remains largely uncharted. Therefore, this study explores the potential role of TCP transcription factors in the growth and development of sweet cherry fruits. RESULTS: Thirteen members of the PavTCP family were identified within the sweet cherry plant, with two, PavTCP1 and PavTCP4, found to contain potential target sites for Pav-miR159, Pav-miR139a, and Pav-miR139b-3p. Analyses of cis-acting elements and Arabidopsis homology prediction analyses that the PavTCP family comprises many light-responsive elements. Homologs of PavTCP1 and PavTCP3 in Arabidopsis TCP proteins were found to be crucial to light responses. Shading experiments showed distinct correlation patterns between PavTCP1, 2, and 3 and total anthocyanins, soluble sugars, and soluble solids in sweet cherry fruits. These observations suggest that these genes may contribute significantly to sweet cherry light responses. In particular, PavTCP1 could play a key role, potentially mediated through Pav-miR159, Pav-miR139a, and Pav-miR139b-3p. CONCLUSION: This study is the first to unveil the potential function of TCP transcription factors in the light responses of sweet cherry fruits, paving the way for future investigations into the role of this transcription factor family in plant fruit development.

Pgp3 protein of Chlamydia trachomatis inhibits apoptosis via HO-1 upregulation mediated by PI3K/Akt activation.

As an obligate intracellular pathogen, Chlamydia trachomatis assumes various strategies to inhibit host cells apoptosis, thereby providing a suitable intracellular environment to ensure completion of the development cycle. In the current study, we revealed that Pgp3 protein, one of eight plasmid proteins of C. trachomatis that has been illustrated as the key virulence factor, increased HO-1 expression to suppress apoptosis, and downregulation of HO-1 with siRNA-HO-1 failed to exert anti-apoptosis activity of Pgp3 protein. Moreover, treatment of PI3K/Akt pathway inhibitor and Nrf2 inhibitor evidently reduced HO-1 expression and Nrf2 nuclear translocation was blocked by PI3K/Akt pathway inhibitor. These findings highlight that induction of HO-1 expression by Pgp3 protein is probably due to regulation of Nrf2 nuclear translocation activated by PI3K/Akt pathway, which provide clues on how C. trachomatis adjusts apoptosis.

Rapid identification of methicillin-resistant Staphylococcus aureus by MALDI-TOF MS: A meta-analysis.

Invasive infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are associated with high mortality and morbidity. The sooner the pathogen is determined, the better it is beneficial to patient. However, routine laboratory inspections are time-consuming and laborious. A thorough research was conducted in PubMed and Web of Science (until June 2021) to identify studies evaluating the accuracy of MRSA identification by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). STATA 15.0 software was used to analyze the pooled results of sensitivity, specificity, and 95% confidence intervals (CI). The summary receiver operating characteristic curves (SROC) and area under the curve (AUC) were utilized to show the overall performance of MALDI-TOF MS. Fifteen studies involving 2471 isolates were included in this study after the final selection in this meta-analysis. Using the random effects model forest plot to summarize the overall statistics, the sensitivity of MALDI-TOF MS for identifying MRSA was 92% (95% CI: 81%-97%), and the specificity was 97% (95% CI: 89%-99%). In the SROC curve, the AUC reached 0.99 (95% CI: 97%-99%). Deeks' test showed no significant publication bias in this meta-analysis. Compared with clinical reference methods, MALDI-TOF MS identification of MRSA shows a higher degree of sensitivity and specificity.

Synergistic effect of collagen cross-linking and remineralization for improving resin-dentin bond durability.

In this study, the synergistic effect of glutaraldehyde-cross-linking and remineralization on the strength and durability of resin-dentin bonds was investigated. Dentin surfaces were etched with 35% phosphoric acid. The control specimens were bonded with Adper Single Bond 2 using wet bonding without pretreatment. The experimental specimens were pretreated with 5% (v/v) glutaraldehyde solution for 3 min and placed in a remineralizing solution for 0, 12, and 24 h, followed by dry bonding. After performing composite build-ups on the specimens, they were longitudinally sectioned, immediately, and after aging for 3 h with sodium hypochlorite (NaOCl), to evaluate microtensile bond strength (µTBS). The cross-linked specimens exhibited µTBS values comparable with those of the control group, but the µTBS decreased significantly after NaOCl aging. The cross-linked dentin remineralized for 24 h exhibited an increase in µTBS. After aging in NaOCl, the µTBS of the specimens remineralized for 24 h did not decrease and was significantly higher than for the other experimental groups. Cross-linking with dry bonding maintained µTBS in specimens before aging in NaOCl, but the bonding durability was compromised. Remineralization of cross-linked dentin for 24 h followed by dry bonding increased the immediate µTBS and improved bond durability. Therefore, combining cross-linking with remineralization of collagen fibrils progressively increased resistance to degradation, improving bond durability.

Transcriptomic and Metabolomic Analysis of Quality Changes during Sweet Cherry Fruit Development and Mining of Related Genes.

Sweet cherries are economically important fruit trees, and their quality changes during development need to be determined. The mechanism of fruit quality changes in sweet cherries were determined by analyzing sweet cherry fruits at 12 developmental stages. The results showed that the soluble sugar, anthocyanin content, and hormones of sweet cherries all changed drastically during the color transition. Therefore, the fruits at the beginning of color conversion, at the end of color conversion, and at the ripening state were selected for the comprehensive analysis of their metabolome and transcriptome. Different sugars, such as D-glucose, sucrose, and trehalose, were identified in the metabolome. Dihydroquercetin, delphinidin-3-glucoside, cyanidin-3-rutincoside, and other flavonoid species were also identified. D-glucose and cyanidin-3-rutinoside were among the most important components of sweet cherry soluble sugars and anthocyanins, respectively. The transcriptional analysis identified key structural genes and nine transcription factors involved in the ABA, sugar, organic acid, and anthocyanin synthesis pathways, with the following specific regulatory patterns. NAC71, WRKY57, and WRKY3 regulate fruit sugar accumulation mainly by acting on INV, SPS, and SUS. MYC2 is involved in the synthesis of anthocyanin precursors by activating PAL and C4H, whereas TCP7 mainly regulates CHI and F3H. WRKY3, NAC71, and WRKY57 have important positive regulatory significance on anthocyanin accumulation, mainly by activating the expression of DFR, ANS, and 3GT.

Digitally prefabricated versus conventionally fabricated implant-supported full-arch provisional prosthesis: a retrospective cohort study.

BACKGROUND: To evaluate and compare the clinical outcomes of digitally prefabricated and conventionally fabricated implant-supported full-arch provisional prostheses. METHODS: In this retrospective study, a total of 39 patients (22 males and 17 females) who underwent implant-supported full-arch rehabilitation using the All-on-4 concept with an immediate loading protocol were included: 20 patients treated with digitally prefabricated provisional prostheses were assigned into Group A, and 19 patients treated with conventionally fabricated provisional prostheses were assigned into Group B. Implant/provisional prosthesis survival rates and complications were reviewed. Marginal bone loss (MBL) was investigated by CBCT. Surgical time, restorative time, and total operative time were analyzed. Postoperative pain and swelling were evaluated with the visual analog scale (VAS). The oral health impact profile (OHIP) questionnaire was administered before and after surgery. RESULTS: The implant/provisional prosthesis survival rate was 100%, and complications appeared with low frequency in both groups, while the mean MBL was 0.30 ± 0.29 mm in Group A and 0.31 ± 0.41 mm in Group B after 3~ 6 months (P > 0.05). The average restorative time in Group A (116.16 ± 16.61 min) was significantly shorter than that in Group B (242.11 ± 30.14 min) (P < 0.05). Patients in Group A showed lower pain/swelling VAS scores after surgery than Group B (P < 0.05). Low OHIP scores with high satisfaction with the overall effects were shown in both groups. CONCLUSION: Prefabricated prostheses reduced the prosthetic time and postoperative discomfort in patients whose immediate rehabilitation was based on the All-on-4 concept. This prefabrication technology may be a predictable alternative to improve the short-term clinical outcome of implant-supported full-arch provisional rehabilitation.

Research progress on effect of magnetic nanoparticle composite scaffold on osteogenesis.

Magnetic nanoparticles (MNP) have been widely used as biomaterials due to their unique magnetic responsiveness and biocompatibility, which also can promote osteogenic differentiation through their inherent micro-magnetic field. The MNP composite scaffold retains its superparamagnetism, which has good physical, mechanical and biological properties with significant osteogenic effects and . Magnetic field has been proved to promote bone tissue repair by affecting cell metabolic behavior. MNP composite scaffolds under magnetic field can synergically promote bone tissue repair and regeneration, which has great application potential in the field of bone tissue engineering. This article summarizes the performance of magnetic composite scaffold, the research progress on the effect of MNP composite scaffold with magnetic fields on osteogenesis, to provide reference for further research and clinical application.

Anti-Food Allergic Alkaloids from the Lotus Seed Pot.

Lotus seed pod (LSP) has been used as traditional herbal cuisine to modulate immunity. From the AcOEt-soluble extract of LSP, one new aporphine alkaloid, N-[2-(2H-phenanthro[3,4-d][1,3]dioxol-5-yl)ethyl]acetamide (nelunucine A, 1) was obtained along with 19 known ones. Their structures were established by detailed analysis of the 1D-, 2D-NMR, and HR-ESI-MS data. N-Nornuciferine (9) and lirinidine (10) showed potent in vitro anti-food allergic activity with IC50 values of 40.0 and 55.4 µM, respectively, compared to 91.4 µM for loratadine, the positive control.

Sensitive Fluorescent Sensor for Hydrogen Sulfide in Rat Brain Microdialysis via CsPbBr3 Quantum Dots.

The instability and insolubility of perovskite quantum dots in aqueous solution prohibit applications in polar solvents. As a highly toxic gas pollutant and also an endogenous gaseous signaling molecule existing in a variety of physiological processes, hydrogen sulfide (H2S), with high selectivity and high specificity, detection is of great significance. In this study, a simple device has been designed to separate H2S from aqueous solution and CsPbBr3 quantum dots (CsPbBr3 QDs) have been used as the detection probe to develop a novel fluorescent sensor for rapid H2S detection. The addition of hydrogen sulfide to the phosphoric acid solution results in the escape of H2S from the aqueous sample and hence it passing into the n-hexane solution containing CsPbBr3 QDs, resulting in the quenching of the fluorescence of CsPbBr3 QDs. The fluorescence intensity of the system has a linear relationship with the concentration of H2S in the range of 0-100 µM with the detection limit of 0.18 µM. The proposed system has been applied to detection of H2S in rat brain microdialysate with satisfying results. The potential mechanism regarding the quenching of fluorescence from CsPbBr3 QDs by H2S has been studied as well.

[Effect of genipin pretreatment on type â collagen mineralization].

OBJECTIVE: To investigate the effects of bio-crosslinker genipin pretreatment on type Ⅰ collagen mineralization. METHODS: Type Ⅰ collagen gels were prepared and pretreated with 0.5wt%genipin (experimental group) and deionized water (control group) for 2 h, respectively. The pretreated products were subjected to Fourier transform infrared spectroscopy (FT-IR). Reconstituted collagen fibrils were pretreated with genipin or deionized water for 2 h and were mineralized for 4 h. The collagen density and mineralization degree were examined with transmission electron microscopy (TEM) and analyzed with ImageJ software. Then scanning electron microscopy (SEM) and TEM were used to observe the mineralization of cross-linked demineralized dentin collagen. RESULTS: FT-IR spectrum showed that the genipin was crosslinked with collagen. TEM observation and ImageJ results showed that after 4 h mineralization, the mineralization effect of 0.5wt% genipin group was significantly better than that of the control group[(73.3±5.3)%vs.(7.4±3.5)%,P<0.01]. TEM and SEM observation showed that the mineralization rate of type Ⅰ collagen and demineralized dentin pretreated with genipin were significantly faster than that of the control group. CONCLUSIONS: The study demonstrates that 0.5 wt% concentration of genipin can significantly promote the mineralization of type Ⅰ collagen.

Target-Induced Horseradish Peroxidase Deactivation for Multicolor Colorimetric Assay of Hydrogen Sulfide in Rat Brain Microdialysis.

Hydrogen sulfide (H2S) is important for normal neural functions, which involves protecting neurons from oxidative stress and neuronal transmission modulation in brain. The detection of H2S is significant for revealing its role in the diagnosis of various disease. In this study, a novel multicolor colorimetric assay based on the etching of gold nanorods (Au NRs) is proposed to evaluate H2S level with the naked eye. This measurement relies on the catalytic oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) via horseradish peroxidase (HRP) to produce TMB2+, which could etch the Au NRs quickly and accompany with a distinct color change. The vivid colors can be easily distinguished with the naked eye without any sophisticated instruments. The presence of H2S can cause the deactivation of HRP, which affects the amount of TMB2+ produced and consequently affects the color changing of the system. Based on this mechanism, a simple but sensitive multicolor colorimetric assay is developed for H2S detection with a linear range of 0.05-50 µM. The proposed method is demonstrated for monitoring extracellular H2S in rat brain coupled with microdialysate.

miR-495 sensitizes MDR cancer cells to the combination of doxorubicin and taxol by inhibiting MDR1 expression.

MDR1 is highly expressed in MDR A2780DX5 ovarian cancer cells, MDR SGC7901R gastric cancer cells and recurrent tumours. It pumps cytoplasmic agents out of cells, leading to decreased drug accumulation in cells and making cancer cells susceptible to multidrug resistance. Here, we identified that miR-495 was predicted to target ABCB1, which encodes protein MDR1. To reduce the drug efflux and reverse MDR in cancer cells, we overexpressed a miR-495 mimic in SGC7901R and A2780DX cells and in transplanted MDR ovarian tumours in vivo. The results indicated that the expression of MDR1 in the above cells or tumours was suppressed and that subsequently the drug accumulation in the MDR cells was decreased, cell death was increased, and tumour growth was inhibited after treatment with taxol-doxorubicin, demonstrating increased drug sensitivity. This study suggests that pre-treatment with miR-495 before chemotherapy could improve the curative effect on MDR1-based MDR cancer.

The Chromosome-Encoded Hypothetical Protein TC0668 Is an Upper Genital Tract Pathogenicity Factor of Chlamydia muridarum.

We previously associated a missense mutation of the tc0668 gene of serial in vitro-passaged Chlamydia muridarum, a murine model of human urogenital C. trachomatis, with severely attenuated disease development in the upper genital tract of female mice. Since these mutants also contained a TC0237 Q117E missense mutation that enhances their in vitro infectivity, an effort was made here to isolate and characterize a tc0668 single mutant to determine its individual contribution to urogenital pathogenicity. Detailed genetic analysis of C. muridarum passages revealed a truncated variant with a G216* nonsense mutation of the 408-amino-acid TC0668 protein that does not produce a detectable product. Intracellular growth and infectivity of C. muridarum in vitro remain unaffected in the absence of TC0668. Intravaginal inoculation of the TC0668 null mutant into C3H/HeJ mice results in a typical course of lower genital tract infection but, unlike a pathogenic isogenic control, is unable to elicit significant chronic inflammation of the oviduct and fails to induce hydrosalpinx. Thus, TC0668 is demonstrated as an important chromosome-encoded urogenital pathogenicity factor of C. muridarum and the first with these characteristics to be discovered for a Chlamydia pathogen.

Protective immunity induced by recombinant protein CPSIT_p8 of Chlamydia psittaci.

Chlamydia psittaci is a zoonotic pathogen with a broad host range that can lead to severe respiratory and systemic disease in humans. Currently, an effective commercial vaccine against C. psittaci infection is not available. The chlamydial plasmid is an important virulence factor and encodes plasmid proteins that play important roles in chlamydial infection and the corresponding immune response. In this study, we assessed the efficacy of vaccination with plasmid proteins at preventing C. psittaci lung infection in a murine model. BALB/c mice were immunized intraperitoneally, three times at 2-week intervals, with purified recombinant CPSIT_p8 protein and then infected with C. psittaci. Immunization significantly decreased chlamydial load in the lungs of infected mice, resulted in a lower level of IFN-γ, and reduced the extent of inflammation. In vivo or in vitro neutralization of C. psittaci with sera collected from immunized mice did not reduce the amount of viable C. psittaci in the lungs of mice, indicating that CPSIT_p8-specific antibodies do not have neutralizing capacity. Furthermore, confocal fluorescence microscopy using a mouse anti-CPSIT_p8 antibody revealed that CPSIT_p8 was localized inside the inclusion of C. psittaci 6BC-infected cells. Our results demonstrate that CPSIT_p8 protein induces significant protective immunity against challenge with C. psittaci in mice and represents a promising new vaccine candidate for the prevention of C. psittaci infection.

In vitro passage selects for Chlamydia muridarum with enhanced infectivity in cultured cells but attenuated pathogenicity in mouse upper genital tract.

Although modern Chlamydia muridarum has been passaged for decades, there are no reports on the consequences of serial passage with strong selection pressure on its fitness. In order to explore the potential for Pasteurian selection to induce genomic and phenotypic perturbations to C. muridarum, a starter population was passaged in cultured cells for 28 generations without standard infection assistance. The resultant population, designated CMG28, displays markedly reduced in vitro dependence on centrifugation for infection and low incidence and severity of upper genital tract pathology following intravaginal inoculation into mice compared to the parental C. muridarum population, CMG0. Deep sequencing of CMG0 and CMG28 revealed novel protein variants in the hypothetical genes TC0237 (Q117E) and TC0668 (G322R). In vitro attachment assays of isogenic plaque clone pairs with mutations in either TC0237 and TC0668 or only TC0237 reveal that TC0237(Q117E) is solely responsible for enhanced adherence to host cells. Paradoxically, double mutants, but not TC0237(Q117E) single mutants, display severely attenuated in vivo pathogenicity. These findings implicate TC0237 and TC0668 as novel genetic factors involved in chlamydial attachment and pathogenicity, respectively, and show that serial passage under selection pressure remains an effective tool for studying Chlamydia pathogenicity.

Transformation of Chlamydia muridarum reveals a role for Pgp5 in suppression of plasmid-dependent gene expression.

Transformation of Chlamydia trachomatis should greatly advance the chlamydial research. However, significant progress has been hindered by the failure of C. trachomatis to induce clinically relevant pathology in animal models. Chlamydia muridarum, which naturally infects mice, can induce hydrosalpinx in mice, a tubal pathology also seen in women infected with C. trachomatis. We have developed a C. muridarum transformation system and confirmed Pgp1, -2, -6, and -8 as plasmid maintenance factors, Pgp3, -5, and -7 as dispensable for in vitro growth, and Pgp4 as a positive regulator of genes that are dependent on plasmid for expression. More importantly, we have discovered that Pgp5 can negatively regulate the same plasmid-dependent genes. Deletion of Pgp5 led to a significant increase in expression of the plasmid-dependent genes, suggesting that Pgp5 can suppress the expression of these genes. Replacement of pgp5 with a mCherry gene, or premature termination of pgp5 translation, also increased expression of the plasmid-dependent genes, indicating that Pgp5 protein but not its DNA sequence is required for the inhibitory effect. Replacing C. muridarum pgp5 with a C. trachomatis pgp5 still inhibited the plasmid-dependent gene expression, indicating that the negative regulation of plasmid-dependent genes is a common feature of all Pgp5 regardless of its origin. Nevertheless, C. muridarum Pgp5 is more potent than C. trachomatis Pgp5 in suppressing gene expression. Thus, we have uncovered a novel function of Pgp5 and developed a C. muridarum transformation system for further mapping chlamydial pathogenic and protective determinants in animal models.

Plasmid-encoded Pgp3 is a major virulence factor for Chlamydia muridarum to induce hydrosalpinx in mice.

Hydrosalpinx induction in mice by Chlamydia muridarum infection, a model that has been used to study C. trachomatis pathogenesis in women, is known to depend on the cryptic plasmid that encodes eight genes designated pgp1 to pgp8. To identify the plasmid-encoded pathogenic determinants, we evaluated C. muridarum transformants deficient in the plasmid-borne gene pgp3, -4, or -7 for induction of hydrosalpinx. C. muridarum transformants with an in-frame deletion of either pgp3 or -4 but not -7 failed to induce hydrosalpinx. The deletion mutant phenotype was reproduced by using transformants with premature termination codon insertions in the corresponding pgp genes (to minimize polar effects inherent in the deletion mutants). Pgp4 is known to regulate pgp3 expression, while lack of Pgp3 does not significantly affect Pgp4 function. Thus, we conclude that Pgp3 is an effector virulence factor and that lack of Pgp3 may be responsible for the attenuation in C. muridarum pathogenicity described above. This attenuated pathogenicity was further correlated with a rapid decrease in chlamydial survival in the lower genital tract and reduced ascension to the upper genital tract in mice infected with C. muridarum deficient in Pgp3 but not Pgp7. The Pgp3-deficient C. muridarum organisms were also less invasive when delivered directly to the oviduct on day 7 after inoculation. These observations demonstrate that plasmid-encoded Pgp3 is required for C. muridarum survival in the mouse genital tract and represents a major virulence factor in C. muridarum pathogenesis in mice.

Induced dual-target rebalance simultaneously enhances efficient therapeutical efficacy in tumors.

Multiple gene abnormalities are major drivers of tumorigenesis. NF-κB p65 overactivation and cGAS silencing are important triggers and genetic defects that accelerate tumorigenesis. However, the simultaneous correction of NF-κB p65 and cGAS abnormalities remains to be further explored. Here, we propose a novel Induced Dual-Target Rebalance (IDTR) strategy for simultaneously correcting defects in cGAS and NF-κB p65. By using our IDTR approach, we showed for the first time that oncolytic adenovirus H101 could reactivate silenced cGAS, while silencing GAU1 long noncoding RNA (lncRNA) inhibited NF-κB p65 overactivation, resulting in efficient in vitro and in vivo antitumor efficacy in colorectal tumors. Intriguingly, we further demonstrated that oncolytic adenoviruses reactivated cGAS by promoting H3K4 trimethylation of the cGAS promoter. In addition, silencing GAU1 using antisense oligonucleotides significantly reduced H3K27 acetylation at the NF-κB p65 promoter and inhibited NF-κB p65 transcription. Our study revealed an aberrant therapeutic mechanism underlying two tumor defects, cGAS and NF-κB p65, and provided an alternative IDTR approach based on oncolytic adenovirus and antisense oligonucleotides for efficient therapeutic efficacy in tumors.