Abstract FBXO31, a member of F-box family to comprise of SCF complex, contributes to a pivotal role in cancer progression. However, the possible involvements of FBXO31 in PC are unelucidated. Here, we reported that FBXO31 was overexpressed in PC patients, which was negatively associated with survival in PC patients. Furthermore, FBXO31 significantly enhanced growth, migration and invasion of PC cells in vitro. Consistently, FBXO31 overexpression promoted tumor growth in nude mice. Mechanistically, SIRT2 was a target of FBXO31 and interacted with FBXO31. Protein half-life and ubiquitination analysis demonstrated that FBXO31 promoted proteasome-dependent degradation of SIRT2. In addition, FBXO31 binds to sirtuin-type domain of SIRT2. Moreover, SIRT2 is required for the oncogenic role of FBXO31 in PC progression. Impressively, METTL3 induced m6A modification of FBXO31 and up-regulated FBXO31 expression, subsequently leading to SIRT2 down-regulation in PC cells. The results showed that METTL3 enhanced FBXO31 mRNA translation in YTHDF1-dependent manner. Taken together, we suggest that METTL3–FBXO31–SIRT2 axis was involved in PC tumorigenesis, which could identify new targets for PC treatment.
Abstract The pharynx is an endoderm innovation in deuterostome ancestors, the vertebrate descendent structure of which is a pharyngeal developmental organizer involving multi-germ layer and organ derivatives. However, the evolutionary origination of complicated pharynx organs in vertebrates is still largely unknown. Endostyle, a transitional pharyngeal organ exclusively in basal chordates provides an opportunity to reveal the origin of pharyngeal organs. Here, utilizing cutting-edged Stereo-seq and single-cell RNA-seq, we constructed the first spatially-resolved single-cell atlas in the endostyle of urochordate ascidian Styela clava , where the spatial location of Stereo-seq and high capture efficiency of single-cell RNA-seq complement each other and identified 23 highly differentiated cell types. We identified a previously overlooked hemolymphoid region (HLR), which harbors immune and blood cell clusters with enriched stemness capacities, illuminating a mixed rudiment and stem-cell niches for the blood and lymphoid system. More excitingly, we discovered a mechanical-sensitive hair cell candidate in zone 3 homologous to vertebrate acoustico-lateralis system, which was supported by the expression of in situ hybridization-verified inner ear-specific markers, including PTPRQ , USH2A , WHRN , and ADGRV1 , ultracellular structure evidence and cross-species comparison. These results thoroughly renewed the comprehension of the basal-chordate pharynx and provides expressional evidence for multiplexed pharyngeal organ evolution.
The direct nucleic acid repair dioxygenase FTO is an enzyme that demethylates N6-methyladenosine (m6A) residues in mRNA in vitro and inside cells. FTO is the first RNA demethylase discovered that also serves a major regulatory function in mammals. Together with structure-based virtual screening and biochemical analyses, we report the first identification of several small-molecule inhibitors of human FTO demethylase. The most potent compound, the natural product rhein, which is neither a structural mimic of 2-oxoglutarate nor a chelator of metal ion, competitively binds to the FTO active site in vitro. Rhein also exhibits good inhibitory activity on m6A demethylation inside cells. These studies shed light on the development of powerful probes and new therapies for use in RNA biology and drug discovery.
Single-cell RNA sequencing (scRNA-seq) analysis have provided an unprecedented resolution for the studies on diabetic retinopathy (DR). However, the early changes in the retina in diabetes remain unclear. A total of 8 human and mouse scRNA-seq datasets, containing 276,402 cells were analyzed individually to comprehensively delineate the retinal cell atlas. The neural retinas were isolated from the type 2 diabetes (T2D) and control mice, and scRNA-seq analysis was conducted to evaluate the early effects of diabetes on the retina. Bipolar cell (BC) heterogeneity were identified. We found some stable BCs across multiple datasets, and explored their biological functions. A new RBC subtype (Car8_RBC) in the mouse retina was validated using the multi-color immunohistochemistry. AC149090.1 was significantly upregulated in the rod cells, ON cone BCs (CBCs), OFF CBCs, and RBCs in T2D mice. Additionally, the interneurons, especially BCs, were the most vulnerable cells to diabetes by integrating scRNA-seq and genome-wide association studies (GWAS) analyses. In conclusion, this study delineated a cross-species retinal cell atlas and uncovered the early pathological alterations in the retina of T2D mice.
Osteosarcoma is a common malignancy seen mainly in children and adolescents. The disease is characterized by poor overall prognosis and lower survival due to a lack of predictive markers. Many gene signatures with diagnostic, prognostic, and predictive values were evaluated to achieve better clinical outcomes. Two public data series, GSE21257 and UCSC Xena, were used to identify the minimum number of robust genes needed for a predictive signature to guide prognosis of patients with osteosarcoma. The lasso regression algorithm was used to analyze sequencing data from TCGA-TARGET, and methods such as Cox regression analysis, risk factor scoring, receiving operating curve, KMplot prognosis analysis, and nomogram were used to characterize the prognostic predictive power of the identified genes. Their utility was assessed using the GEO osteosarcoma dataset. Finally, the functional enrichment analysis of the identified genes was performed. A total of twenty-gene signatures were found to have a good prognostic value for predicting patient survival. Gene ontology analysis showed that the key genes related to osteosarcoma were categorized as peptide–antigen binding, clathrin-coated endocytic vesicle membrane, peptide binding, and MHC class II protein complex. The osteosarcoma related genes in these modules were significantly enriched in the processes of antigen processing and presentation, phagocytosis, cell adhesion molecules, Staphylococcus aureus infection. Twenty gene signatures were identified related to osteosarcoma, which would be helpful for predicting prognosis of patients with OS. Further, these signatures can be used to determine the subtypes of osteosarcoma.
ABSTRACT Stenotrophomonas maltophilia strain B418 was isolated from a barley rhizosphere in China. This bacterium exhibits broad-spectrum inhibitory activities against plant pathogens and root-knot nematode along with growth-promoting effects. Here, we present the draft genome sequence of S. maltophilia B418.
Metaplastic breast carcinoma (MpBC) is a rare histological subtype of breast cancer, and its prognosis is relatively poor. The survival trend of MpBC with different hormone receptor statuses has remained unclear over the past two decades. MpBC patient data were collected from the Surveillance, Epidemiology, and End Results database from 2000 to 2019. Patients were divided into two groups according to their hormone receptor status (negative and positive). The survival probabilities were calculated via Kaplan‒Meier curves. Logistic regression analysis was used to obtain odds ratios for treatment and demographic characteristics. Multivariate Cox regression was used to identify prognostic factors. A total of 3,076 patients were enrolled, and a significant improvement in survival was observed over the last 10 years. For HR-negative MpBC patients, both overall survival and breast cancer-specific survival improved, whereas no survival improvement was observed for HR-positive patients. Compared with those in the time period from 2000 to 2009, the proportion of negative nodes and the likelihood of receiving chemotherapy increased for HR-negative patients from 2010 to 2019. In the HR-negative subgroup, the survival of Whites improved significantly, whereas the survival of Blacks improved in the HR-positive subgroup. The survival of HR-negative MpBC patients has improved significantly in the past 20 years, which may be related to early diagnosis, increased adjuvant therapy and medical development, but no trend towards improvement has been observed in HR-positive patients. Racial disparities in different HR statuses also need to be addressed.
Epigenetics include two main forms: DNA methylation and histon acetylation. For present, it is considered that histon acetylation and DNA hypomethylation can promote gene expression, while histon deacetylation and DNA hypermethylation can inhibite gene expression. The phenomena of universal hypomethylation of genome and region specific permethylation present in tumor tissues. DNA methylation represents the third mechanism by which antioncogenes are inactivated. Epigenetics are significantly associated with genesis of gynecological tumors.
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