Investigation of the relationship between the changes in vaginal microecological enzymes and human papillomavirus (HPV) infection.

This study aims to investigate the relationship between the human papillomavirus (HPV) infection and the altered vaginal microecological environment of patients. Initially, HPV genotyping and microecological detection were performed in 1281 subjects in the Department of Obstetrics and Gynecology of The First Hospital of Qinhuangdao (Qinhuangdao, China). The relationship between the enzymes of vaginal microecology, that is, proline aminopeptidase and acetylglucosaminidase, and vaginal inflammatory diseases, as well as the prognosis of HPV infection, was analyzed. The experimental findings indicated a close relationship between the expression of positive prolyl aminopeptidase and trichomonas vaginitis, as well as bacterial vaginitis. In addition, the expression of acetylglucosaminidase is closely associated with trichomonas vaginitis and vulvovaginal candidiasis. Furthermore, the observations indicated that positive prolyl aminopeptidase and acetylglucosaminidase could increase the risk of various subtypes of HPV infection in patients. The receiver operating characteristic curve analysis presented that the expression of prolyl aminopeptidase and acetylglucosaminidase could offer exceptional diagnostic efficacy, indicating their association with persistent HPV infection. In summary, our results highlighted that the expression of positive prolyl aminopeptidase and acetylglucosaminidase in the vaginal microecology could be substantially correlated to the occurrence and the development of vaginal inflammatory diseases, as well as the outcome and the risk of persistent HPV infection.

Reconnoitering correlation between human papillomavirus infection-induced vaginal microecological abnormality and squamous intraepithelial lesion (SIL) progression.

OBJECTIVE: This study aims to investigate the relationship between abnormal vaginal microecology and human papillomavirus (HPV) infection, as well as the squamous intraepithelial lesions (SIL) progression. METHODS: A total of 383 patients diagnosed with HPV infection in our hospital between March 2017 and February 2022 were selected as the experimental group. In addition, several volunteers (n = 898) who underwent physical examination during the same period were randomly selected as the control group. Subsequently, we conducted several investigations, such as HPV detection and gene typing, examined vaginal microecological imbalances, and performed cytological examinations to analyze the correlation between microecological changes, different types of HPV infection, and SIL progression. RESULTS: HPV detection primarily included single and high-risk types of HPV infections. Moreover, significant disparities in the vaginal microecological environment between patients with persistent HPV infection and the control group, as well as patients with low-grade and high-grade SIL (LSIL and HSIL), were observed. The regression analysis revealed a correlation between LSIL and microflora density, diversity, bacteriological vaginosis (BV), vulvovaginal candidiasis (VVC), trichomonas vaginalis (TV), sialidase, as well as Lactobacillus. In addition, we identified an association between HSIL and pH, flora density, diversity, BV, VVC, candida vaginitis (CV), leukocyte esterase, catalase, and Lactobacillus levels. CONCLUSION: These findings revealed a significant association between abnormal vaginal microecology and both HPV infection and the SIL progression.

Expression and clinical significance of RHCG in endometrial cancer.

Endometrial cancer (EC) is the most common gynecological cancer. Rhesus family, C glycoprotein (RHCG) has been evidenced to be involved in the occurrence and development of various tumors. This study aimed to investigate the expression and clinical significance of RHCG in EC. Bioinformatics analysis was based on the RNAseq counts data from TCGA database, and the prognosis analysis was performed using the Kaplan-Meier method; 4 cases of endometrioid adenocarcinomas samples and 4 cases of normal proliferative endometrium were collected for qPCR and western blot; immunohistochemistry analysis was employed to assess the expression of RHCG in a tissue microarray; the correlation between RHCG and clinicopathological factors was analyzed through Mann-Whitney U test. The lentiviral interference vector was further constructed. The results demonstrated that RHCG was highly expressed in EC tissues, and RHCG was an independent factor affecting the overall survival of patients. Additionally, the expression of RHCG was related to FIGO stage and tumor infiltrate. After interfering with shRHCG, the proliferation activity of EC cells decreased, the migration ability of cells decreased, the apoptosis of cells increased, and the tumor outgrowth was arrested. In summary, RHCG promotes the malignant proliferation and migration of EC, and makes the cells have anti-apoptotic activity. Our study provides a theoretical basis for RHCG to become a potential therapeutic target for EC in the future.

Corrigendum: Modifying SnS2 with carbon quantum dots to improve photocatalytic performance for Cr(VI) reduction.

[This corrects the article DOI: 10.3389/fchem.2022.911291.].

Structure-guided design and characterization of a clickable, covalent PARP16 inhibitor.

PARP16-the sole ER-resident PARP family member-is gaining attention as a potential therapeutic target for cancer treatment. Nevertheless, the precise function of the catalytic activity of PARP16 is poorly understood. This is primarily due to the lack of inhibitors that are selective for PARP16 over other PARP family members. Herein, we describe a structure-guided strategy for generating a selective PARP16 inhibitor by incorporating two selectivity determinants into a phthalazinone pan-PARP inhibitor scaffold: (i) an acrylamide-based inhibitor (DB008) designed to covalently react with a non-conserved cysteine (Cys169, human numbering) in the NAD+ binding pocket of PARP16 and (ii) a dual-purpose ethynyl group designed to bind in a unique hydrophobic cavity adjacent to the NAD+ binding pocket as well as serve as a click handle. DB008 exhibits good selectivity for PARP16 versus other PARP family members. Copper-catalyzed azide-alkyne cycloaddition (CuAAC) confirmed that covalent labeling of PARP16 by DB008 in cells is dependent on Cys169. DB008 exhibits excellent proteome-wide selectivity at concentrations required to achieve saturable labeling of endogenous PARP16. In-cell competition labeling experiments using DB008 provided a facile strategy for evaluating putative PARP16 inhibitors. Lastly, we found that PARP16 is sequestered into a detergent-insoluble fraction under prolonged amino acid starvation, and surprisingly, treatment with PARP16 inhibitors prevented this effect. These results suggest that the catalytic activity of PARP16 regulates its solubility in response to nutrient stress.

Deaza-modification of MR1 ligands modulates recognition by MR1-restricted T cells.

MR1-restricted T (MR1T) cells recognize microbial small molecule metabolites presented on the MHC Class I-like molecule MR1 and have been implicated in early effector responses to microbial infection. As a result, there is considerable interest in identifying chemical properties of metabolite ligands that permit recognition by MR1T cells, for consideration in therapeutic or vaccine applications. Here, we made chemical modifications to known MR1 ligands to evaluate the effect on MR1T cell activation. Specifically, we modified 6,7-dimethyl-8-D-ribityllumazine (DMRL) to generate 6,7-dimethyl-8-D-ribityldeazalumazine (DZ), and then further derivatized DZ to determine the requirements for retaining MR1 surface stabilization and agonistic properties. Interestingly, the IFN-γ response toward DZ varied widely across a panel of T cell receptor (TCR)-diverse MR1T cell clones; while one clone was agnostic toward the modification, most displayed either an enhancement or depletion of IFN-γ production when compared with its response to DMRL. To gain insight into a putative mechanism behind this phenomenon, we used in silico molecular docking techniques for DMRL and its derivatives and performed molecular dynamics simulations of the complexes. In assessing the dynamics of each ligand in the MR1 pocket, we found that DMRL and DZ exhibit differential dynamics of both the ribityl moiety and the aromatic backbone, which may contribute to ligand recognition. Together, our results support an emerging hypothesis for flexibility in MR1:ligand-MR1T TCR interactions and enable further exploration of the relationship between MR1:ligand structures and MR1T cell recognition for downstream applications targeting MR1T cells.

Artificial Intelligence Based Study Association between p53 Gene Polymorphism and Endometriosis: A Systematic Review and Meta-analysis.

Background: The P53 gene is critical to the onset and progression of cancers. Currently, relevant study findings indicate that the p53 gene may have a strong association with the risk of endometriosis, but these findings have not been united. To gather more statistically meaningful clinical data, we used meta-analysis to examine the relationship between the rs1042522 single nucleotide polymorphism of the tumor suppressor gene p53 and the incidence of endometriosis. Methods: Through a comprehensive literature survey of PubMed, MEDLINE, EMBASE, Springer, and Web of Science literature databases, we obtained a clinical control case study on the relationship between p53 gene polymorphism and the prevalence of female endometriosis and finally traced the relevant references included. The quality of the literature included in this study was evaluated, and Revman5.3 was used to complete the meta-analysis. Results: This research includes eight publications. The total number of cases in the study group was 1551, whereas the total number of cases in the control group was 1440. The findings of the sensitivity analyses of each omitted piece of the literature revealed no significant difference. The results of the meta-analysis showed that there were significant differences in the GG gene frequency (OR = 0.56, 95%CI (0.38, 0.92), P = 0.003), allele G (OR = 2.46, 95%CI (1.41,4.29), P = 0.002), and allele C (OR = 0.62, 95%CI (0.46, 0.84), P = 0.002) between the study group and the control group (P < 0.01), but there was no significant difference in the GC gene frequency (OR = 1.17, 95%CI (1.01,1.36), P = 0.03), and the CC gene frequency (OR = 1.25, 95%CI (0.85,1.82), P = 0.26) (P > 0.01). Conclusion: Our study results show that there is a significant correlation between the single nucleotide of the p53 gene and the incidence rate of female endometriosis, in which the decrease of the GG gene frequency and the increase of allele C are likely to increase the risk of such diseases.

Therapeutics That Promote Sympathetic Reinnervation Modulate the Inflammatory Response After Myocardial Infarction.

Myocardial infarction (MI) triggers an inflammatory response that transitions from pro-inflammatory to reparative over time. Restoring sympathetic nerves in the heart after MI prevents arrhythmias. This study investigated if reinnervation altered the immune response after MI. This study used quantitative multiplex immunohistochemistry to identify the immune cells present in the heart 2 weeks after ischemia-reperfusion. Two therapeutics stimulated reinnervation, preventing arrhythmias and shifting the immune response from inflammatory to reparative, with fewer pro-inflammatory macrophages and more regulatory T cells and reparative macrophages. Treatments did not alter macrophage phenotype in vitro, which suggested reinnervation contributed to the altered immune response.

Reconstruction algorithm of haze image based on blind separation model of polarized orthogonal airlight.

Polarization-based dehazing methods can enhance the quality of haze images. However, existing methods tend to a manual selection of sky area and bias coefficient to estimate the degree of polarization (DoP) of the airlight, which leads to inaccurate estimation of the airlight. Aiming at the problem, a reconstruction algorithm based on the blind separation model of polarized orthogonal airlight is proposed. Importantly, the depth-dependent DoP of the airlight is automatically estimated without manual selection of sky area and bias coefficient. To reduce the interference of white objects on the estimation of airlight at infinity, an adaptive estimation method using the deviation between the DoP of the airlight and incident light is proposed. In order to accurate estimate the airlight from the airlight at infinity, a blind separation model of the airlight with multi-regularization constraints is established based on the decomposition of the airlight at infinity into a pair of polarized components with orthogonal angles. The experimental results show that the method effectively improves the visibility of scenes under different haze concentrations, especially in dense or heavy haze weather.

Local linear model and restoration method of underwater images.

When light transports in water, it will be scattered and absorbed by the water body and water particles, resulting in blurred images and color distortion. In order to improve the quality of underwater imaging, the local linear model and restoration method of underwater images are proposed in this paper. Based on the distance-invariant feature in the local region, the local linear model is established, and the slope and intercept of the model represent the transmission rate and the backscattered light of the local region of the image, respectively. Utilizing this model, the problem of underwater image restoration has been transformed into the problem of solving the slope and intercept of linear equations. To solve the linear imaging model, the concept of local special-value is defined in this paper, and several fitting points can be obtained through the special-value. Then the linear model is solved by the fitting method, and the restoration of underwater images is completed. The restoration results of different underwater scene images verify that the linear model has a good effect in improving the image clarity and removing the color distortion.

CDCA3 exhibits a role in promoting the progression of ovarian cancer.

OBJECTIVE: Ovarian cancer (OC) is one of the common gynecological malignant tumors. Cell division cycle-associated protein-3 (CDCA3) is involved in the regulation of cell cycle progression. The role of CDCA3 in OC was explored in this study. METHODS: The expression of CDCA3 in OC was evaluated in the Gene Expression Omnibus (GEO) database and further verified by qRT-PCR and Western blot (WB). Subsequently, we established lentivirus-mediated CDCA3 knockdown in OC cell lines HO-8910 and A2780. The biological roles of CDCA3 on proliferation, sensitivity to cisplatin, apoptosis, migration and tumor formation of OC were investigated using loss-of-function assays. RESULTS: CDCA3 was frequently up-regulated in OC. Knockdown of CDAC3 inhibited proliferation and migration, and enhanced apoptosis as well as sensitivity of OC cells to cisplatin. In vivo results further confirmed the inhibitory effect of CDCA3 knockdown on tumor growth. CONCLUSIONS: Our findings indicated that CDCA3 may play an important role in OC progression, and may serve as a potential therapeutic target for the OC treatment.

Anlotinib combined with TQB2450 in patients with platinum-resistant or -refractory ovarian cancer: A multi-center, single-arm, phase 1b trial.

This is a phase Ib study of anlotinib plus a programmed death-ligand 1 (PD-L1) inhibitor TQB2450 for platinum-resistant or -refractory ovarian cancer. Thirty-four patients are enrolled and receive treatment. The objective response rate (ORR) is 47.1%, and the disease control rate is 97.1%. The median duration of response (DOR) has not been reached, and 61.3% of patients have a DOR of at least 8 months. The median progression-free survival (PFS) is 7.8 months, and the median overall survival (OS) has not been reached. The PD-L1-positive group has an ORR of 25.0%, whereas the PD-L1-negative group has an ORR of 92.9%. Treatment-related grade 3 or 4 adverse events (AEs) occur in 70.6% of patients, with the most common being hypertension (29.4%) and palmar-plantar erythrodysesthesia syndrome (29.4%). Anlotinib plus TQB2450 show promising antitumor activity and manageable toxicities in patients with platinum-resistant or -refractory ovarian cancer. A phase 3 randomized controlled trial to further validate our findings is ongoing.

Modifying SnS2 With Carbon Quantum Dots to Improve Photocatalytic Performance for Cr(VI) Reduction.

The photoreduction for hazardous Cr(VI) in industrial wastewater has been considered a "green" approach with low-cost and easy-to-go operation. SnS2 is a promising narrow bandgap photocatalyst, but its low charge carrier separation efficiency should be solved first. In this work, N-doped carbon quantum dots (CQDs) were prepared and loaded onto SnS2 nanoparticles via an in situ method. The resulting composite samples (NC@SnS2) were characterized, and their photocatalytic performance was discussed. SnS2 nanoparticles were obtained as hexagonal ones with a bandgap of 2.19 eV. The optimal doping level for NC@SnS2 was citric acid: urea:SnS2 = 1.2 mmol:1.8 mmol:3.0 mmol. It showed an average diameter of 40 nm and improved photocatalytic performance, compared to pure SnS2, following a pseudo-first-order reaction with a kinetic rate constant of 0.1144 min-1. Over 97% of Cr(VI) was photo-reduced after 30 min. It was confirmed that modification of SnS2 with CQDs can not only improve the light-harvesting ability but also stimulate the charge separation, which therefore can enhance the photoreactivity of SnS2 toward Cr(VI) reduction. The excellent stability of NC@SnS2 indicates that it is promising to be practically used in industrial wastewater purification.

Identification and Characterization of Small-Molecule IRF3-Dependent Immune Activators for Pharmaceutical Development.

We sought to develop a small-molecule activator of interferon regulatory factor 3 (IRF3), an essential innate immune transcription factor, which could potentially be used therapeutically in multiple disease settings. Using a high-throughput screen, we identified small-molecule entities that activate a type I interferon response, with minimal off-target NFκB activation. We identified 399 compounds at a hit rate of 0.24% from singlicate primary screening. Secondary screening included the primary hits and additional compounds with similar chemical structures obtained from other library sources and resulted in 142 candidate compounds. The hit compounds were sorted and ranked to identify compound groups with activity in both human and mouse backgrounds to facilitate animal model engagement for translational development. Chemical modifications within two groups of small molecules produced leads with improved activity over original hits. Furthermore, these leads demonstrated activity in ex vivo cytokine release assays from human blood- and mouse bone marrow-derived macrophages. Dependence on IRF3 was demonstrated using bone marrow-derived macrophages from IRF3-deficient mice, which were not responsive to the molecules. To identify the upstream pathway leading to IRF3 activation, we used a library of CRISPR knockout cell lines to test the key innate immune adaptor and receptor molecules. These studies indicated a surprising toll-interleukin-1 receptor-domain-containing-adapter-inducing interferon-ß-dependent but TLR3/4-independent mechanism of IRF3 activation.

Small Molecules Targeting PTPσ-Trk Interactions Promote Sympathetic Nerve Regeneration.

Chondroitin sulfate proteoglycans (CSPGs) prevent sympathetic nerve regeneration in the heart after myocardial infarction and prevent central nerve regrowth after traumatic brain injury and spinal cord injury. Currently, there are no small-molecule therapeutics to promote nerve regeneration through CSPG-containing scars. CSPGs bind to monomers of receptor protein tyrosine phosphatase sigma (PTPσ) on the surface of neurons, enhancing the ability of PTPσ to bind and dephosphorylate tropomyosin receptor kinases (Trks), inhibiting their activity and preventing axon outgrowth. Targeting PTPσ-Trk interactions is thus a potential therapeutic target. Here, we describe the development and synthesis of small molecules (HJ-01 and HJ-02) that disrupt PTPσ interactions with Trks, enhance Trk signaling, and promote sympathetic nerve regeneration over CSPGs.

LncRNA KCNQ1OT1-mediated cervical cancer progression by sponging miR-1270 as a ceRNA of LOXL2 through PI3k/Akt pathway.

BACKGROUND: Dysregulated noncoding RNAs participated in progressions of cervical cancer. PURPOSE: To verify impacts of KCNQ1OT1 on modulating progressions of cervical cancer cells. METHOD: Expressions of KCNQ1OT1, miR-1270, and LOXL2 were analyzed through RT-qPCR and protein expressions of LOXL2, p-AKT, and AKT were validated using western blot. Bindings of miR-1270 with KCNQ1OT1 or LOXL2 were verified using luciferase reporter assay. CCK-8 and flow cytometry evaluated cell viability and apoptosis, respectively. The PI3K/AKT signaling pathway suppressor, LY294002, was applied to treat the cells and the changes of KCNQ1OT1 expression and LOXL2, p-AKT, and AKT protein expressions were examined. RESULTS: KCNQ1OT1 expression was the highest in HeLa cells but lowest in SiHa cells whose upregulation improved the viability but inhibited the apoptosis in SiHa cells while knockdown of KCNQ1OT1 caused opposite results in HeLa cells. MiR-1270 was sponged and negatively modulated by KCNQ1OT1. MiR-1270 mimics caused low viability and high apoptosis of SiHa cells but miR-1270 inhibitor reverse its roles in HeLa cells. LOXL2, the target of miR-1270, positively interplayed with KCNQ1OT1 but had negative interaction with miR-1270. LOXL2 overexpression promoted viability and decreased apoptosis of SiHa cells but knockdown of LOXL2 restored its effects in HeLa cells. Moreover, LOXL2 and phosphorylated AKT (p-AKT) protein expressions were downregulated by suppressed KCNQ1OT1 and LOXL2 and miR-1270 mimics but promoted by overexpressed KCNQ1OT1 and LOXL2 and miR-1270 inhibitor. Additionally, LY294002 treatment caused low KCNQ1OT1 RNA expression and decreased LOXL2 and p-AKT protein expressions. CONCLUSION: KCNQ1OT1/miR-1270/LOXL2 axis modulated viability and apoptosis of cervical cancer cells.

Evolution of sulfate reduction behavior in leachate saturated zones in landfills.

The sulfate reduction behavior of the landfill leachate saturated zone under different temperatures was investigated. The results showed that temperature had significant effects on sulfate reduction behavior. The sulfate reduction efficiency was the highest at high temperatures (55 °C and 45 °C), followed by mesophilic temperature (35 °C). Normal temperature 25 °C was far less effective than 55 °C, 45 °C and 35 °C. High abundances of aprA and dsrA genes were distributed under high temperatures. Through indicator species analysis and functional comparison, some key taxa were identified as putative key genera for sulfate reduction. Under high temperature, Paenibacillus could effectively degrade dimethyl sulfide. DsrAB is present in the genome of Tissierella. Gordonia, Syntrophomonas, and Lysinibacillus under mesophilic temperature indicates the potential of these organisms to degrade heterogenous biomass, environmental pollutants or other natural polymers with slow biodegradation. This microbial function is similar to that of the putative key genera under normal (25 °C) temperature. Most of the putative key genera belong to Firmicutes, Proteobacteria and Myxococcota. This study provides theoretical support for the control of hydrogen sulfide release from landfills.

Neutral point detection using the AOP of polarized skylight patterns.

The neutral points are one of the most significant characteristics of the polarized skylight pattern in the whole sky. At present, detection of the neutral points mostly utilizes ellipse fitting of the degree of polarization. However, because the degree of polarization distribution characteristics of a polarized skylight pattern is easily affected by the environment, the robustness of the detection is unstable. Aiming at the problem, we analyzed the angle of polarization distribution characteristics of polarized skylight patterns in the region around the neutral point by measurement experiments. Based on this, we proposed an automatic detection method of neutral points using the angle of polarization of the polarized skylight pattern. The experimental results of different times in a continuous period of time show that compared with ellipse fitting of the degree of polarization, the detection accuracy of the proposed method is almost the same, but the robustness is better. It provides a novel method for the position detecting of the neutral point, which is in favor of the measurement applications of polarization technology.

A New Scalable Synthesis of ELQ-300, ELQ-316, and other Antiparasitic Quinolones.

The Endochin-Like Quinolone (ELQ) compound class may yield effective, safe treatments for a range of important human and animal afflictions. However, to access the public health potential of this compound series, a synthetic route needed to be devised that lowers costs and is amenable to large scale production. In the new synthetic route described here, a substituted ß-keto ester, formed by an Ullmann reaction and subsequent acylation, is reacted with an aniline via a Conrad-Limpach reaction to produce 3-substituted 4(1H)-quinolones such as ELQ-300 and ELQ-316. This synthetic route, the first described to be truly amenable to industrial scale production, is relatively short (5 reaction steps), does not require palladium, chromatographic separation or protecting group chemistry, and may be performed without high vacuum distillation.

Characterization of a Novel Compound That Stimulates STING-Mediated Innate Immune Activity in an Allele-Specific Manner.

The innate immune response to cytosolic DNA involves transcriptional activation of type I interferons (IFN-I) and proinflammatory cytokines. This represents the culmination of intracellular signaling pathways that are initiated by pattern recognition receptors that engage DNA and require the adaptor protein Stimulator of Interferon Genes (STING). These responses lead to the generation of cellular and tissue states that impair microbial replication and facilitate the establishment of long-lived, antigen-specific adaptive immunity. Ultimately this can lead to immune-mediated protection from infection but also to the cytotoxic T cell-mediated clearance of tumor cells. Intriguingly, pharmacologic activation of STING-dependent phenotypes is known to enhance both vaccine-associated immunogenicity and immune-based anti-tumor therapies. Unfortunately, the STING protein exists as multiple variant forms in the human population that exhibit differences in their reactivity to chemical stimuli and in the intensity of molecular signaling they induce. In light of this, STING-targeting drug discovery efforts require an accounting of protein variant-specific activity. Herein we describe a small molecule termed M04 that behaves as a novel agonist of human STING. Importantly, we find that the molecule exhibits a differential ability to activate STING based on the allelic variant examined. Furthermore, while M04 is inactive in mice, expression of human STING in mouse cells rescues reactivity to the compound. Using primary human cells in ex vivo assays we were also able to show that M04 is capable of simulating innate responses important for adaptive immune activation such as cytokine secretion, dendritic cell maturation, and T cell cross-priming. Collectively, this work demonstrates the conceivable utility of a novel agonist of human STING both as a research tool for exploring STING biology and as an immune potentiating molecule.