Multi-omics and immunogenomics analysis revealed PFKFB3 as a targetable hallmark and mediates sunitinib resistance in papillary renal cell carcinoma: in silico study with laboratory verification.

Glycolysis-related metabolic reprogramming is a central hallmark of human cancers, especially in renal cell carcinoma. However, the regulatory function of glycolytic signature in papillary RCC has not been well elucidated. In the present study, the glycolysis-immune predictive signature was constructed and validated using WGCNA, glycolysis-immune clustering analysis. PPI network of DEGs was constructed and visualized. Functional enrichments and patients' overall survival were analyzed. QRT-PCR experiments were performed to detect hub genes' expression and distribution, siRNA technology was used to silence targeted genes; cell proliferation and migration assays were applied to evaluate the biological function. Glucose concentration, lactate secretion, and ATP production were measured. Glycolysis-Immune Related Prognostic Index (GIRPI) was constructed and combined analyzed with single-cell RNA-seq. High-GIRPI signature predicted significantly poorer outcomes and relevant clinical features of pRCC patients. Moreover, GIRPI also participated in several pathways, which affected tumor immune microenvironment and provided potential therapeutic strategy. As a key glycolysis regulator, PFKFB3 could promote renal cancer cell proliferation and migration in vitro. Blocking of PFKFB3 by selective inhibitor PFK-015 or glycolytic inhibitor 2-DG significantly restrained renal cancer cells' neoplastic potential. PFK-015 and sunitinib could synergistically inhibit pRCC cells proliferation. Glycolysis-Immune Risk Signature is closely associated with pRCC prognosis, progression, immune infiltration, and therapeutic response. PFKFB3 may serve as a pivotal glycolysis regulator and mediates Sunitinib resistance in pRCC patients.

Interaction of immune cells with renal cancer development: Mendelian randomization (MR) study.

BACKGROUND: Renal cell carcinoma (RCC) is a prevalent and extensively immune-infiltrated malignancy of the urinary system. Immune cells play a crucial role in both the progression and therapeutic interventions targeting RCC. Nevertheless, the interplay between RCC and immune cells remains understudied, lacking substantial evidence supporting their causal relationship. METHODS: For the purpose of investigating the causal connection between RCC and immune cell characteristics, a two-way two-sample Mendelian randomization (MR) analysis was carried out in this study. The aim was to determine whether specific immune cell traits have a causal impact on the risk of RCC. In order to achieve this, publicly accessible genetic data was utilized to examine and establish the potential relationship between 731 immune cell characteristics and the likelihood of developing RCC. Additionally, various techniques were applied to verify the reliability, variability, and presence of horizontal pleiotropy in the outcomes. RESULTS: We found a bidirectional causal relationship between RCC and immune cells according to the MR analysis results. It should be noted that CD4-CD8-T cells (OR = 1.61, 95%CI = 1.02-2.55, P = 4.07 × 10-2) pose a risk for RCC, whereas BAFF-R (OR = 0.69, 95%CI = 0.53-0.89, P = 5.74 × 10-3) and CD19 (OR = 0.59, 95%CI = 1.02-2.55, P = 4.07 × 10-2) on B cells act as protective factors. Furthermore, the presence of RCC reduces the levels of B cells (OR = 1.05, 95%CI = 1.01-1.09, P = 1.19 × 10-2) and CD8 + T cells (OR = 1.04, 95%CI = 1.00-1.08, P = 2.83 × 10-2). CONCLUSIONS: Our research illustrates the intricate correlation between immune cells and RCC, presenting novel insights for the prospective safeguarding against RCC risk and the exploration of fresh therapeutic targets.

Bisphenol A promote the cell proliferation and invasion ability of prostate cancer cells via regulating the androgen receptor.

A synthetic organic substance called bisphenol A (BPA) is used to make polyester, epoxy resin, polyacrylate, and polycarbonate plastic. BPA exposure on a regular basis has increased the risk of developing cancer. Recent research has shown that there is a strong link between BPA exposure and a number of malignancies. We want to investigate any connections between BPA and prostate cancer in this work. The scores of bisphenols in the prostate cancer cohort were obtained using the ssGSEA algorithm. The analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment was used to investigate probable pathways that are closely related to the genes tied to BPA. The BPA-based risk model was built using regression analysis. Additionally, the molecular docking method was employed to assess BPA's capacity to attach to important genes. Finally, we were able to successfully get the BPA cohort ratings for prostate cancer patients. Additionally, the KEGG enrichment study showed that of the malignancies linked to BPA, prostate cancer is the most highly enriched. In a group of men with prostate cancer, the BPA-related prognostic prediction model exhibits good predictive value. The BPA demonstrated strong and efficient binding to the androgen receptor, according to the molecular docking studies. According to cell proliferation and invasion experiments, exposing prostate cancer cells to BPA at a dosage of 10-7 uM could greatly enhance their ability to proliferate and invade.

Comprehensive analysis of the impact of emerging flame retardants on prostate cancer progression: The potential molecular mechanisms and immune infiltration landscape.

Emerging flame retardants have been used to replace traditional flame retardants, but their potential impact on cancer, especially prostate cancer, is not well understood. Our study aimed to explore the link between flame retardants and prostate cancer, and identify potential carcinogenic mechanisms among populations exposed to emerging flame retardants. We screened flame retardant interacting genes differentially expressed in prostate cancer patients and identified hub genes by protein-protein interaction (PPI) analysis based on the STRING database. Univariate and multivariate Cox regression analyses were performed to construct risk models and identify flame retardant-related prognostic genes. We calculated the proportion of immune cell infiltration to explore the potential mechanism of the prognostic gene, and verified the target cell population of the prognostic gene in the single-cell transcriptome dataset. Our study revealed a significant link between emerging flame retardants and prostate cancer. We constructed a risk model with good predictive ability for prostate cancer prognosis using TCGA dataset, and identified six flame retardant-related prognostic genes validated in the GSE70769 dataset. We found that the expression of M2 macrophages was up-regulated in patients with high expression of prognostic genes, and the single-cell dataset confirmed the expression of prognostic genes in macrophages. Our study confirms the link between emerging flame retardants and prostate cancer, and highlights the role of immune-related pathways in the high-risk population exposed to these flame retardants.

Silencing of CPNE1-TRAF2 Axis Restrains the Development of Pancreatic Cancer.

BACKGROUND: Copine 1 (CPNE1) acts as a promoter in the progression of many kinds of cancers with the exception of pancreatic cancer (PC). This research is designed to probe the function of the CPNE1-tumor necrosis factor receptor-associated factor 2 (TRAF2) axis in PC. METHODS: In vivo and in vitro models of PC were constructed, and a series of biological function tests, including MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide], colony formation, flow cytometry, and immunohistochemistry, were performed. RESULTS: The level of CPNE1 elevated dramatically in PC cells. Downregulation of CPNE1in PC cells resulted in the inhibition of colony formation and proliferation. In addition, the silencing of CPNE1 induced the G1/S arrest and apoptosis in PC cells. Additionally, TRAF2 positively interacted with CPNE1 in PANC cells. CPNE1 silencing also inhibited the growth of tumors in in vivo mouse models. Functional experiments revealed that the anti-tumor effect of CPNE1 silencing was counteracted by TRAF2 overexpression, and the tumor-promoting effect of TRAF2 overexpression was reversed by CPNE1 silencing. CONCLUSIONS: In summary, our findings indicate that the silencing of the CPNE1-TRAF2 axis restrains PC development.

Exploring the pathogenesis of depression and potential antidepressants through the integration of reverse network pharmacology, molecular docking, and molecular dynamics.

Depression is characterized by a significant and persistent decline in mood and is currently a major threat to physical and mental health. Traditional Chinese medicine can effectively treat depression with few adverse effects. Therefore, this study aimed to examine the use of reverse network pharmacology and computer simulations to identify effective ingredients and herbs for treating depression. Differentially expressed genes associated with depression were obtained from the Gene Expression Omnibus database, after which enrichment analyses were performed. A protein-protein interaction network was constructed using the STRING database to screen core targets. The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform database was used to screen ingredients related to these core targets, and the core ingredients were screened by constructing the "Targets-Ingredients-Herbs" network. Drug evaluation analysis was performed using the SwissADME and ADMETlab platforms, according to Lipinski Rule of 5. The binding between the targets and ingredients was simulated using molecular docking software. The binding stability was determined using molecular dynamics analysis. The "Ingredients-Herbs" network was constructed, and we annotated it for its characteristics and meridians. Finally, the selected herbs were classified to determine the formulation for treating depression in traditional Chinese medicine. The pathogenesis of depression was associated with changes in SPP1, Plasminogen activator inhibitor 1, CCNB1 protein, CCL3, and other genes. Computer simulations have verified the use of quercetin, luteolin, apigenin, and other ingredients as drugs for treating depression. Most of the top 10 herbs containing these ingredients were attributed to the liver meridian, and their taste was symplectic. Perilla Frutescen, Cyperi Rhizoma, and Linderae Radix, the main components of "Tianxiang Zhengqi Powder," can treat depression owing to Qi stagnation. Epimedium and Citicola, the main traditional Chinese herbs in "Wenshen Yiqi Decoction," have a positive effect on depression of the Yang asthenia type. Fructus Ligustri Lucidi and Ecliptae Herba are from the classic prescription "Erzhi Pills" and can treat depression of the Yin deficiency type. This study identified the key targets and effective medicinal herbs for treating depression. It provides herbal blend references for treating different types of depression according to the theory of traditional Chinese medicine.

Cuproptosis in ccRCC: key player in therapeutic and prognostic targets.

Background: Classical biomarkers have been used to classify clear cell renal cell carcinoma (ccRCC) patients in a variety of ways, and emerging evidences have indicated that cuproptosis is closely related to mitochondrial metabolism, thereby accelerating the development and progression of ccRCC. Nevertheless, the specific relationship between cuproptosis and the prognosis and treatment of ccRCC remains unclear. Methods: We comprehensively integrated several ccRCC patient datasets into a large cohort. Following that, we systematically analyzed multi-omics data to demonstrate the differences between two cuproptosis clusters. Results: We identified two cuproptosis clusters in ccRCC patients. Among the two clusters, cluster 1 patients showed favorable prognosis. We then confirmed the significant differences between the two clusters, including more typical cancer hallmarks were enriched in cluster 2 patients; cluster 2 patients were more susceptible to develop mutations and had a lower level of gistic score and mRNAsi. Importantly, both Tumor Immune Dysfunction and Exclusion analysis and subclass mapping algorithm showed that cuproptosis 1 patients were more susceptible to be responded to immunotherapy. In addition, a prognostic signature was successfully developed and also showed prominent predictive power in response to immunotherapy. Conclusion: As a result of our findings, we were able to classify ccRCC patients according to cuproptosis in a novel way. By constructing the cuproptosis clusters and developing the signature, patients with ccRCC could have a more accurate prognosis prediction and better immunotherapy options.

Systems biology approaches to identify potential targets and inhibitors of the intestinal microbiota to treat depression.

Depression is a common mental disease, with some patients exhibiting ideas and behaviors such as self-harm and suicide. The drugs currently used to treat depression have not achieved good results. It has been reported that metabolites produced by intestinal microbiota affect the development of depression. In this study, core targets and core compounds were screened by specific algorithms in the database, and three-dimensional structures of these compounds and proteins were simulated by molecular docking and molecular dynamics software to further study the influence of intestinal microbiota metabolites on the pathogenesis of depression. By analyzing the RMSD gyration radius and RMSF, it was finally determined that NR1H4 had the best binding effect with genistein. Finally, according to Lipinski's five rules, equol, genistein, quercetin and glycocholic acid were identified as effective drugs for the treatment of depression. In conclusion, the intestinal microbiota can affect the development of depression through the metabolites equol, genistein and quercetin, which act on the critical targets of DPP4, CYP3A4, EP300, MGAM and NR1H4.

Exploring the potential mechanisms of impairment on genitourinary system associated with coronavirus disease 2019 infection: Bioinformatics and molecular simulation analyses.

Objective: The novel coronavirus (severe acute respiratory syndrome coronavirus 2) has been spreading worldwide since December 2019, posing a serious danger to human health and socioeconomic development. A large number of clinical trials have revealed that coronavirus disease 2019 (COVID-19) results in multi-organ damage including the urogenital system. This study aimed to explore the potential mechanisms of genitourinary damage associated with COVID-19 infection through bioinformatics and molecular simulation analysis. Methods: We used multiple publicly available databases to explore the expression patterns of ACE2, TMPRSS2, and CD147 (Basigin [BSG]) in major organs in the healthy and disease-specific populations, particularly the genitourinary organs. Single-cell RNA sequencing was used to analyze the cell-specific expression patterns of ACE2, TMPRSS2, CD147, cytokine receptors, and cytokine interacting proteins in genitourinary organs, such as the bladder, kidney, prostate, and testis. Additionally, gene set enrichment analysis was used to investigate the relationship between testosterone levels and COVID-19 vulnerability in patients with prostate cancer. Results: The results revealed that ACE2, TMPRSS2, and CD147 were highly expressed in normal urogenital organs. Then, they were also highly expressed in multiple tumors and chronic kidney diseases. Additionally, ACE2, TMPRSS2, and CD147 were significantly expressed in a range of cells in urogenital organs according to single-cell RNA sequencing. Cytokine receptors and cytokine interacting proteins, especially CCL2, JUN, and TIMP1, were commonly highly expressed in urogenital organs. Finally, gene set enrichment analysis results showed that high testosterone levels in prostate cancer patients were significantly related to the JAK/STAT signaling pathway and the Toll-like receptor signaling pathway which were associated with COVID-19. Conclusion: Our study provides new insights into the potential mechanisms of severe acute respiratory syndrome coronavirus 2 damage to urogenital organs from multiple perspectives, which may draw the attention of urologists to COVID-19 and contribute to the development of targeted drugs.

Prognostic Role of DNA Damage Response Genes Mutations and their Association With the Sensitivity of Olaparib in Prostate Cancer Patients.

OBJECTIVE: Evidence shows that gene mutation is a significant proportion of genetic factors associated with prostate cancer. The DNA damage response (DDR) is a signal cascade network that aims to maintain genomic integrity in cells. This comprehensive study was performed to determine the link between different DNA damage response gene mutations and prostate cancer. MATERIALS AND METHODS: A systematic literature search was performed using PubMed, Web of Science, and Embase. Papers published up to February 1, 2022 were retrieved. The DDR gene mutations associated with prostate cancer were identified by referring to relevant research and review articles. Data of prostate cancer patients from multiple PCa cohorts were obtained from cBioPortal. The OR or HR and 95% CIs were calculated using both fixed-effects models (FEMs) and random-effects models (REMs). RESULTS: Seventy-four studies were included in this research, and the frequency of 13 DDR genes was examined. Through the analysis of 33 articles that focused on the risk estimates of DDR genes between normal people and PCa patients, DDR genes were found to be more common in prostate cancer patients (OR = 3.6293 95% CI [2.4992; 5.2705]). Also, patients in the mutated group had a worse OS and DFS outcome than those in the unmutated group (P < .05). Of the 13 DDR genes, the frequency of 9 DDR genes in prostate cancer was less than 1%, and despite differences in race, BRCA2 was the potential gene with the highest frequency (REM Frequency = .0400, 95% CI .0324 - .0541). The findings suggest that mutations in genes such as ATR, BLM, and MLH1 in PCa patients may increase the sensitivity of Olaparib, a PARP inhibitor. CONCLUSION: These results demonstrate that mutation in any DDR pathway results in a poor prognosis for PCa patients. Furthermore, mutations in ATR, BLM, and MLH1 or the expression of POLR2L, PMS1, FANCE, and other genes significantly influence Olaparib sensitivity, which may be underlying therapeutic targets in the future.

AC010973.2 promotes cell proliferation and is one of six stemness-related genes that predict overall survival of renal clear cell carcinoma.

Extensive research indicates that tumor stemness promotes tumor progression. Nonetheless, the underlying roles of stemness-related genes in renal clear cell carcinoma (ccRCC) are unclear. Data used in bioinformatics analysis were downloaded from The Cancer Genome Atlas (TCGA) database. Moreover, the R software, SPSS, and GraphPad Prism 8 were used for mapping and statistical analysis. First, the stemness index of each patient was quantified using a machine learning algorithm. Subsequently, the differentially expressed genes between high and low stemness index were identified as stemness-related genes. Based on these genes, a stable and effective prognostic model was identified to predict the overall survival of patients using a random forest algorithm (Training cohort; 1-year AUC: 0.67; 3-year AUC: 0.79; 5-year AUC: 0.73; Validation cohort; 1-year AUC: 0.66; 3-year AUC: 0.71; 5-year AUC: 0.7). The model genes comprised AC010973.2, RNU6-125P, AP001209.2, Z98885.1, KDM5C-IT1, and AL021368.3. Due to its highest importance evaluated by randomforst analysis, the AC010973.2 gene was selected for further research. In vitro experiments demonstrated that AC010973.2 is highly expressed in ccRCC tissue and cell lines. Meanwhile, its knockdown could significantly inhibit the proliferation of ccRCC cells based on colony formation and CCK8 assays. In summary, our findings reveal that the stemness-related gene AC01097.3 is closely associated with the survival of patients. Besides, it remarkably promotes cell proliferation in ccRCC, hence a novel potential therapeutic target.

Predictive factors for successful sperm retrieval by microdissection testicular sperm extraction in men with nonobstructive azoospermia and a history of cryptorchidism.

This study aims to explore the factors influencing the success rate of the microdissection testicular sperm extraction (Micro-TESE) in patients with nonobstructive azoospermia (NOA) and cryptorchidism. Clinical data of 162 patients with cryptorchidism who underwent Micro-TESE due to infertility from December 2015 to May 2020 in the First Affiliated Hospital of Nanjing Medical University were analyzed retrospectively. In the univariate analysis, significant differences in the age of patient at the time of orchidopexy (median [interquartile range, IQR]: 7.0 [4.0-11.0] years vs 11.5 [9.0-14.5] years, P < 0.001), interval between orchidopexy and Micro-TESE (mean ± standard deviation: 17.5 ± 5.0 years vs 14.4 ± 4.4 years, P < 0.001), severity of cryptorchidism (unilateral [62.8%] vs bilateral [31.6%], P < 0.001; location of cryptorchidism, intra-abdominal [27.3%] vs inguinal [44.8%] vs suprascrotal [66.7%], P < 0.001), volume of the dominant testis (median [IQR]: 17.00 [15.00-19.00] ml vs 14.50 [11.75-16.25] ml, P < 0.001), and levels of follicle-stimulating hormone (FSH; P = 0.004) and testosterone (P = 0.006) were observed between the successful and failed sperm extraction groups. After conducting the multivariate analysis, four of these factors, including unilateral/bilateral cryptorchidism (P < 0.001), location of cryptorchidism (P = 0.032), age of orchidopexy (P < 0.001), and dominant testicular volume, were adopted in the clinical prediction model to evaluate preoperatively the success rate of Micro-TESE for patients with NOA and cryptorchidism. The likelihood of successful sperm retrieval by Micro-TESE in men with NOA and cryptorchidism increased in patients with mild forms of cryptorchidism.

Immune Microenvironment and Response in Prostate Cancer Using Large Population Cohorts.

Immune microenvironment of prostate cancer (PCa) is implicated in disease progression. However, previous studies have not fully explored PCa immune microenvironment. This study used ssGSEA algorithm to explore expression levels of 53 immune terms in a combined PCa cohort (eight cohorts; 1,597 samples). The top 10 immune terms were selected based on the random forest analysis and used for immune-related risk score (IRS) calculation. Furthermore, we explored differences in clinical and genomic features between high and low IRS groups. An IRS signature based on the 10 immune terms showed high prediction potential for PCa prognosis. Patients in the high IRS group showed significantly higher percentage of immunotherapy response factors, implying that IRS is effective in predicting immunotherapy response rate. Furthermore, consensus clustering was performed to separate the population into three IRSclusters with different clinical outcomes. Patients in IRScluster3 showed the worst prognosis and highest immunotherapy response rate. On the other hand, patients in IRScluster2 showed better prognosis and low immunotherapy response rate. In addition, VGLL3, ANPEP, CD38, CCK, DPYS, CST2, COMP, CRISP3, NKAIN1, and F5 genes were differentially expressed in the three IRSclusters. Furthermore, CMap analysis showed that five compounds targeted IRS signature, thioridazine, trifluoperazine, 0175029-0000, trichostatin A, and fluphenazine. In summary, immune characteristics of PCa tumor microenvironment was explored and an IRS signature was constructed based on 10 immune terms. Analysis showed that this signature is a useful tool for prognosis and prediction of immunotherapy response rate of PCa.

Genetic comprehension of organophosphate flame retardants, an emerging threat to prostate cancer.

In recent years, organophosphate ester flame retardants (OPFRs), which have been regarded as alternatives for brominated flame retardants (BFRs), have become widely used in building materials, textiles, and electric equipment. Elucidating the relationship between OPFRs and tumors holds great significance for the treatment and prevention of diseases. In this work, we found a new method for predicting the correlation between the interactive genes of OPFRs and tumors. Transcriptome profiles and OPFR information were obtained from The Cancer Genome Atlas and the Genotype-Tissue Expression, Comparative Toxicogenomics, and PharmMapper databases. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis showed that interactive genes were mainly enriched in prostate cancer, steroid metabolic process, and steroid hormone regulation. Furthermore, protein-protein interaction network analysis revealed 33 biological hub genes. The operating characteristic curves and survival analysis showed the role of key genes in predicting the prognosis of prostate cancer. Gene target prediction and gene set variation analysis proved that OPFRs and their metabolites exert potential effects on prostate cancer. Colony formation assay showed that the cells with AR, mTOR and DDIT3 knockdown could remarkably mitigate the cell proliferation ability in both PC-3 and LNCap cells. Transwell assay demonstrated that the silencing of AR, mTOR and DDIT3 could significantly inhibit the cell invasion capacity of prostate cells. Triphenyl phosphate (TPP) significantly increase the cell proliferation ability and promote cell invasion capacity. AR, mTOR and DDIT3 in the PC-3 and LNCap cells were significantly upregulated with 10-6 M TPP treated.

COL5A2 Promotes Proliferation and Invasion in Prostate Cancer and Is One of Seven Gleason-Related Genes That Predict Recurrence-Free Survival.

Extensive research has revealed that the score derived from the Gleason grading system plays a pivotal role in predicting prostate cancer (PCa) progression. However, the underlying involvement of Gleason-related genes in PCa requires further investigation. This study aimed to identify Gleason-related genes with the potential to guide PCa therapy and future research. Differentially expressed genes (DEGs) were identified by comparing PCa tissues with high or low Gleason scores using the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) databases. R v3.6.1, SPSS v23, and ImageJ software were used for all analyses. An effective recurrence-free survival (RFS) predictive model based on seven Gleason-related genes was established and validated (TCGA, AUC = 0.803; five years, AUC = 0.740; three years, AUC = 0.722; one year, AUC = 0.711; GSE46602, AUC = 0.766; five years, AUC = 0.808; three years, AUC = 0.723; one year, AUC = 0.656; GSE116918, AUC = 0.788; five years, AUC = 0.704; three years, AUC = 0.693; one year, AUC = 0.996). Calibration and nomogram plots were conducted. Weighted correlation network analysis (WGCNA) was used, and COL5A2 was selected for further analysis. The results from in vitro experiments demonstrated that COL5A2 was upregulated in PCa with high Gleason scores. The knockdown of COL5A2 inhibited cell proliferation and invasion in PC-3 and LNCaP cell lines. Meanwhile, COL5A2 displayed a strong association with immune infiltration, which might be an underlying immunotherapy target for PCa. We successfully established a robust RFS predictive model. The findings from this study indicated that COL5A2 could promote cell proliferation and invasion in PCa.

Role of Hakai in m6A modification pathway in Drosophila.

N6-methyladenosine (m6A), the most abundant internal modification in eukaryotic mRNA, is installed by a multi-component writer complex; however, the exact roles of each component remain poorly understood. Here we show that a potential E3 ubiquitin ligase Hakai colocalizes and interacts with other m6A writer components, and Hakai mutants exhibit typical m6A pathway defects in Drosophila, such as lowered m6A levels in mRNA, aberrant Sxl alternative splicing, wing and behavior defects. Hakai, Vir, Fl(2)d and Flacc form a stable complex, and disruption of either Hakai, Vir or Fl(2)d led to the degradation of the other three components. Furthermore, MeRIP-seq indicates that the effective m6A modification is mostly distributed in 5' UTRs in Drosophila, in contrast to the mammalian system. Interestingly, we demonstrate that m6A modification is deposited onto the Sxl mRNA in a sex-specific fashion, which depends on the m6A writer. Together, our work not only advances the understanding of mechanism and regulation of the m6A writer complex, but also provides insights into how Sxl cooperate with the m6A pathway to control its own splicing.

Integrated Analysis of the Prognosis-Associated RNA-Binding Protein Genes and Candidate Drugs in Renal Papillary Cell Carcinoma.

RNA-binding proteins (RBPs) play significant roles in various cancer types. However, the functions of RBPs have not been clarified in renal papillary cell carcinoma (pRCC). In this study, we identified 31 downregulated and 89 upregulated differentially expressed RBPs on the basis of the cancer genome atlas (TCGA) database and performed functional enrichment analyses. Subsequently, through univariate Cox, random survival forest, and multivariate Cox regression analysis, six RBPs of SNRPN, RRS1, INTS8, RBPMS2, IGF2BP3, and PIH1D2 were screened out, and the prognostic model was then established. Further analyses revealed that the high-risk group had poor overall survival. The area under the curve values were 0.87 and 0.75 at 3 years and 0.78 and 0.69 at 5 years in the training set and test set, respectively. We then plotted a nomogram on the basis of the six RBPs and tumor stage with the substantiation in the TCGA cohort. Moreover, we selected two intersectant RBPs and evaluate their biological effects by GSEA and predicted three drugs, including STOCK1N-28457, pyrimethamine, and trapidil by using the Connectivity Map. Our research provided a novel insight into pRCC and improved the determination of prognosis and individualized therapeutic strategies.

Multiple Expression Assessments of ACE2 and TMPRSS2 SARS-CoV-2 Entry Molecules in the Urinary Tract and Their Associations with Clinical Manifestations of COVID-19.

BACKGROUND: Since December 2019, the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first spread quickly in Wuhan, China, then globally. Based on previously published evidence, ACE2 and TMPRSS2 are both pivotal entry molecules that enable cellular infection by SARS-CoV-2. Also, increased expression of pro-inflammatory cytokines, or a "cytokine storm," is associated with multiple organ dysfunction syndrome often observed in critically ill patients. METHODS: We investigated the expression pattern of ACE2 and TMPRSS2 in major organs in the human body, especially in specific disease conditions. Multiple sequence alignment of ACE2 in different species was used to explain animal susceptibility. Moreover, the cell-specific expression patterns of ACE2 and cytokine receptors in the urinary tract were assessed using single-cell RNA sequencing (scRNA-seq). Additional biological relevance was determined through Gene Set Enrichment Analysis (GSEA) using an ACE2-specific signature. RESULTS: Our results revealed that ACE2 and TMPRSS2 were highly expressed in genitourinary organs. ACE2 was highly and significantly expressed in the kidney among individuals with chronic kidney diseases or diabetic nephropathy. In single cells, ACE2 was primarily enriched in gametocytes in the testis and renal proximal tubules. The receptors for pro-inflammatory cytokines, especially IL6ST, were notably concentrated in endothelial cells, macrophages, spermatogonial stem cells in the testis, and renal endothelial cells, which suggested the occurrence of alternative damaging autoimmune mechanisms. CONCLUSION: This study provided new insights into the pathogenic mechanisms of SARS-CoV-2 that underlie the clinical manifestations observed in the human testis and kidney. These observations might substantially facilitate the development of effective treatments for this rapidly spreading disease.

Predictive value of preoperative comprehensive evaluation on the efficacy of HoLEP.

BACKGROUND: With the aging of the population, prostate hyperplasia is more and more perplexing to the old men. This study aimed to evaluate the predictive value of international prostatic symptom score-voiding/storage score ratio (IPSS-V/S), urodynamic examination, intravesical prostatic protrusion (IPP) and residual urine volume (RUV) on the efficacy of holmium laser enucleation of the prostate (HoLEP) before operation. METHODS: Ninety-six patients with benign prostatic hyperplasia (BPH) were enrolled in this study. Each patient was diagnosed as BPH and completed all the evaluations as described above before the same urologist surgeon performed HoLEP. Three months later, another IPSS questionnaire would be finished by each patient to assess the efficacy of the operation. According to the results of IPSS after operation, the group with significant effect and the group with poor effect were divided. Then compare the difference of preoperative examination results between the two groups. RESULTS: In single factor analysis, the differences of the age, voiding symptom score, V/S, RUV, Qmax and IPP between the two groups were statistically significant (P<0.05). While there was no significant difference in IPSS score and score of urine storage period. In the logistic regression analysis, the age of patients, V/S, RUV, IPP and Qmax can establish a good prediction model. In this model, the younger the patients are, the less the RUV is, the larger the V/S and IPP are, the more likely they are to achieve good efficacy of HoLEP. CONCLUSIONS: In conclusion, HoLEP was more effective in BPH patients with younger age, more IPP, less RUV, less Qmax and those whose IPSS score was mainly based on voiding symptoms.

Annealing effects on microstructure and laser-induced damage threshold of quasi-rugate filters.

Ta2O5/SiO2 quasi-rugate filters with high damage thresholds were deposited by ion-beam sputtering and then annealed at temperature of 200-800°C. The relations between microstructure, optical properties, chemical composition, weak absorption, and laser-induced damage threshold (LIDT) were studied. It was found that the transmittance spectra shifted to short wavelength as the annealing temperature increased. Three evolution courses of the films in the annealing process were analyzed by Atomic Force microscopy (AFM), Zygo interferometer measurement and Focused Ion Beam microscope (FIB). The decreased weak absorption during annealing process was found with significant effect on the LIDT. As the annealing temperature increased to 600°C, the weak absorption of films decreased from 39.99 to 7.2 ppm and the 50%-LIDTs increased from 59.32 to 158.87J/cm2. Distinct damage micrographs of the films annealed at different temperature were obtained. A combination of substoichiometric defect and structural defect dominant description was used to illustrate the aggravation of laser-induced damage.