Alternative polyadenylation regulates the translation of metabolic and inflammation-related proteins in adipose tissue of gestational diabetes mellitus.

In gestational diabetes mellitus (GDM), adipose tissue undergoes metabolic disturbances and chronic low-grade inflammation. Alternative polyadenylation (APA) is a post-transcriptional modification mechanism that generates mRNA with variable lengths of 3' untranslated regions (3'UTR), and it is associated with inflammation and metabolism. However, the role of APA in GDM adipose tissue has not been well characterized. In this study, we conducted transcriptomic and proteomic sequencing on subcutaneous and omental adipose tissues from both control and GDM patients. Using Dapars, a novel APA quantitative algorithm, we delineated the APA landscape of adipose tissue, revealing significant 3'UTR elongation of mRNAs in the GDM group. Omental adipose tissue exhibited a significant correlation between elongated 3'UTRs and reduced translation levels of genes related to metabolism and inflammation. Validation experiments in THP-1 derived macrophages (TDMs) demonstrated the impact of APA on translation levels by overexpressing long and short 3'UTR isoforms of a representative gene LRRC25. Additionally, LRRC25 was validated to suppress proinflammatory polarization in TDMs. Further exploration revealed two underexpressed APA trans-acting factors, CSTF3 and PPP1CB, in GDM omental adipose tissue. In conclusion, this study provides preliminary insights into the APA landscape of GDM adipose tissue. Reduced APA regulation in GDM omental adipose tissue may contribute to metabolic disorders and inflammation by downregulating gene translation levels. These findings advance our understanding of the molecular mechanisms underlying GDM-associated adipose tissue changes.

Screening and identification of tissue-infiltrating immune cells and genes for patients with emphysema phenotype of COPD.

Objective: To study the tissue-infiltrating immune cells of the emphysema phenotype of chronic obstructive pulmonary disease (COPD) and find the molecular mechanism related to the development of emphysema to offer potential targets for more precise treatment of patients with COPD. Methods: Combined analyses of COPD emphysema phenotype lung tissue-related datasets, GSE47460 and GSE1122, were performed. CIBERSORT was used to assess the distribution of tissue-infiltrating immune cells. Weighted gene co-expression network analysis (WGCNA) was used to select immune key genes closely related to clinical features. Rt-qPCR experiments were used for the validation of key genes. Emphysema risk prediction models were constructed by logistic regression analysis and a nomogram was developed. Results: In this study, three immune cells significantly associated with clinical features of emphysema (FEV1 post-bronchodilator % predicted, GOLD Stage, and DLCO) were found. The proportion of neutrophils (p=0.025) infiltrating in the emphysema phenotype was significantly increased compared with the non-emphysema phenotype, while the proportions of M2 macrophages (p=0.004) and resting mast cells (p=0.01) were significantly decreased. Five immune-related differentially expressed genes (DEGs) were found. WGCNA and clinical lung tissue validation of patients with emphysema phenotype were performed to further screen immune-related genes closely related to clinical features. A key gene (SERPINA3) was selected and included in the emphysema risk prediction model. Compared with the traditional clinical prediction model (AUC=0.923), the combined prediction model, including SERPINA3 and resting mast cells (AUC=0.941), had better discrimination power and higher net benefit. Conclusion: This study comprehensively analyzed the tissue-infiltrating immune cells significantly associated with emphysema phenotype, including M2 macrophages, neutrophils, and resting mast cells, and identified SERPINA3 as a key immune-related gene.

Screening and Identification of Prognostic Tumor-Infiltrating Immune Cells and Genes of Endometrioid Endometrial Adenocarcinoma: Based on The Cancer Genome Atlas Database and Bioinformatics.

BACKGROUND: Endometrioid endometrial adenocarcinoma (EEA) is one of the most common tumors in the female reproductive system. With the further understanding of immune regulation mechanism in tumor microenvironment, immunotherapy is emerging in tumor treatment. However, there are few systematic studies on EEA immune infiltration. METHODS: In this study, prognostic tumor-infiltrating immune cells (TIICs) and related genes of EEA were comprehensively analyzed for the first time through the bioinformatics method with CIBERSORT algorithm as the core. Gene expression profile data were downloaded from the TCGA database, and the abundance ratio of TIICs was obtained. Kaplan-Meier analysis and Cox regression analysis were used to identify prognostic TIICs. EEA samples were grouped according to the risk score in Cox regression model. Differential analysis and functional enrichment analyses were performed on high- and low-risk groups to find survival-related hub genes, which were verified by Tumor Immune Estimation Resource (TIMER). RESULT: Four TIICs including memory CD4+ T cells, regulatory T cells, natural killer cells and dendritic cells were identified. And two hub gene modules were found, in which six hub genes including APOL1, CCL17, RBP4, KRT15, KRT71, and KRT79 were significantly related to overall survival and were closely correlated with some certain TIICs in the validation of TIMER. CONCLUSION: In this study, four prognostic TIICs and six hub genes were found to be closely related to EEA. These findings provided new potential targets for EEA immunotherapy.

Systematic Identification of Hub Genes in Placenta Accreta Spectrum Based on Integrated Transcriptomic and Proteomic Analysis.

Placenta accreta spectrum (PAS) is a pathological condition of the placenta with abnormal adhesion or invasion of the placental villi to the uterine wall, which is associated with a variety of adverse maternal and fetal outcomes. Although some PAS-related molecules have been reported, the underlying regulatory mechanism is still unclear. Compared with the study of single gene or pathway, omics study, using advanced sequencing technology and bioinformatics methods, can increase our systematic understanding of diseases. In this study, placenta tissues from 5 patients with PAS and 5 healthy pregnant women were collected for transcriptomic and proteomic sequencing and integrated analysis. A total of 728 messenger RNAs and 439 proteins were found to be significantly different between PAS group and non-PAS group, in which 23 hub genes were differentially expressed in both transcriptome and proteome. Functional enrichment analysis showed that the differentially expressed genes were mainly related to cell proliferation, migration and vascular development. Totally 18 long non-coding RNA were found that might regulate the expression of hub genes. Many kinds of single nucleotide polymorphism, alternative splicing and gene fusion of hub genes were detected. This is the first time to systematically explore the hub genes and gene structure variations of PAS through integrated omics analysis, which provided a genetic basis for further in-depth study on the underlying regulatory mechanism of PAS.

Nomogram to predict postpartum hemorrhage in cesarean delivery for women with scarred uterus: A retrospective cohort study in China.

AIM: To develop nomograms predicting the risk of postpartum hemorrhage (PPH) in cesarean delivery for singleton pregnant women with a scarred uterus in the north of China. METHODS: A retrospective cohort study was conducted. Totally 3722 singleton pregnant women with a scarred uterus who underwent a cesarean delivery in a large teaching hospital of north China between January 2013 and December 2017 were enrolled. Nomograms, a kind of user-friendly tool, were developed to predict PPH (blood loss ≥1000 mL or accompanied by signs or symptoms of hypovolemia within 24 h after the birth process) based on the model generated by logistic regression analysis. The discrimination and calibration of models were evaluated, and decision curve analysis was developed. RESULTS: Among 3722 enrolled women, 243 (6.53%) had PPH. There are six identified factors associated with PPH: maternal age, placental location, placenta previa, hypertensive disorders of pregnancy, fetal position and placenta accreta spectrum (PAS). The model achieved a good calibration (Hosmer-Lemeshow test P value 0.77) and discrimination (area under curve c-statistics 0.90, 95% confidence interval 0.86-0.93). Decision curve analysis showed the threshold probability by using our model is between 1.0% and 85.7%. A nomogram was developed accordingly. And another nomogram for women without placenta previa and PAS was also developed. CONCLUSION: Two nomograms were first generated to predict PPH, respectively, for women with a scarred uterus and for women with a scarred uterus who do not have placenta previa or PAS. Placental location and fetal position were found to be closely related to PPH.

Molecular Dynamics Study of Bubble Nucleation on a Substrate with Nonuniform Wettability.

In the present study, the molecular dynamics simulation method is adopted to study bubble nucleation on a platinum substrate with nonuniform wettability. The central region of the substrate has strong hydrophilicity and both sides have weak hydrophobicity. It is interesting that the bubble nucleation happens in the hydrophobic region when the substrate temperature is low, and the nucleation position moves to the hydrophilic region with the increase of the substrate temperature. The intrinsic regime for the change of nucleation position with the substrate temperature is fully illustrated based on the competition between the suffered potential restriction and the absorbed thermal energy of liquid atoms. When the liquid atoms on one region obtain enough thermal energy to break their potential barrier, they convert into a bubble nucleus. Both the potential barrier for liquid atoms clinging to the substrate surface and the solid-liquid heat transfer efficiency improve with the enhancement of substrate hydrophilicity. The potential barrier is decided only by the atomic distribution and interatomic interaction. However, the substrate temperature changes the absorbed thermal energy of the liquid atoms within a specific time, causing the movement of the nucleation position. Furthermore, a hydrophilic nanostructure is introduced to replace the central smooth hydrophilic region and promote lateral heat transfer to the liquid on the hydrophobic region, leading to the improvement of the bubble nucleation efficiency.

The optimal timing of immunotherapy may improve pregnancy outcome in women with unexplained recurrent pregnancy loss: A perspective follow-up study in northeastern China.

PROBLEM: To determine whether patients with unexplained recurrent pregnancy loss (URPL) can benefit from pre-conception immunotherapy or on the early phase of the first trimester. METHOD OF STUDY: The prospective follow-up study which involved pre-conception patients diagnosed with URPL following rigorous etiology screening in the medical center of recurrent pregnancy loss. In this study, pre-conception immunotherapy included lymphocyte immunotherapy (pre-LIT). Post-conception immunotherapy (post-IM) included LIT or intravenous immunoglobulin (IVIG). Patients were recommended to undergo post-IM immediately from human chorionic gonadotrophin (hCG) elevation. Autoimmune antibodies (AIA) and anti-paternal lymphocytotoxic antibodies (APLA) were tested before and after pre-LIT. Favorable outcome was defined as pregnancy over 14 weeks. Unfavorable outcomes included biochemical pregnancy loss (BPL) and pregnancy loss with clear implantation location (PLCIL). RESULTS: In this study, URPL accounted for 12.9% of recurrent pregnancy loss (217/1682). Frequency of BPL was significantly lower in patients with post-IM than that without post-IM [2.8% vs 28.2%; adjusted relative risk (aRR), 0.06; 95% confidence interval (CI), 0.01-0.24]. There was a significant positive conversion in the AIA induced by pre-LIT (0.0% vs 31.0%). Frequency of PLCIL in patients with positive iatrogenic AIA conversion induced by pre-LIT was higher than that in patients without AIA conversion [30.4% vs 5.8%; aRR, 7.53; 95% CI, 1.31-43.34]. CONCLUSION: Pre-LIT of patients with URPL contributed to a positive iatrogenic AIA conversion, which was associated with an increased risk of PLCIL. Post-IM immediately initiated from the time of hCG elevation can reduce the incidence of BPL.

Evaluation of immune responses induced by a novel human papillomavirus type 16 E7 peptide-based vaccine with Candida skin test reagent as an adjuvant in C57BL/6 mice.

Cell mediated immune (CMI) responses are crucial for the clearance of human papillomavirus (HPV) infection and HPV-associated lesions. Activated CD8 T cells are critical effector cells in recognizing and killing HPV-infected or HPV-transformed cells. CD4 T cells provide help for priming the generation and maintenance of CD8 T cells as well as for tumors immunity. An ideal therapeutic HPV peptide-based vaccine should induce both a robust CD8 T-cell response as well as a CD4 T-cell response for ensuring their efficiency. Candida skin test reagent was demonstrated to be able to induce the secretion of IL-12 by Langerhans cells and T-cell proliferation in vitro by our group, which indicated the potential of Candida to enhance CMI response. In this current study, we designed a novel HPV peptide-based vaccine which includes HPV16 E7 peptides and Candida as an adjuvant. The immune responses induced by the vaccine were comprehensively evaluated. The results showed that the vaccine induced significant HPV-specific CD8 T-cell and Th1 CD4 T-cell responses as well as humoral immune response. It is interesting that Candida alone induced a significant polarization of Th1 response an production of IFN-γ, which indicated Candida alone may be used as a potential immunotherapeutic reagent not only for HPV-associated lesions but also for other viral infection or even cancers.