Lengthening of 3' Untranslated Regions of mRNAs by Alternative Polyadenylation Is Associated With Tumor Progression and Poor Prognosis of Clear Cell Renal Cell Carcinoma.

Alternative polyadenylation (APA) is emerging as a major posttranscriptional mechanism for gene regulation in cancer. A prevailing hypothesis is that shortening of the 3' untranslated region (3'UTR) increases oncoprotein expression because of the loss of miRNA-binding sites (MBSs). We showed that the longer 3'UTR is associated with a more advanced tumor stage in patients with clear cell renal cell carcinoma (ccRCC). More surprisingly, 3'UTR shortening is correlated with better overall survival in patients with ccRCC. Furthermore, we identified a mechanism by which longer transcripts lead to increased oncogenic protein and decreased tumor-suppressive protein expression compared to the shorter transcripts. In our model, shortening of 3'UTRs by APA may increase the mRNA stability of the majority of the potential tumor-suppressor genes due to the loss of MBSs and AU-rich elements (AREs). Unlike potential tumor-suppressor genes, the potential oncogenes display much lower MBS and ARE density and globally much higher m6A density in distal 3'UTRs. As a result, 3'UTRs shortening decreases the mRNA stability of potential oncogenes and enhances the mRNA stability of potential tumor-suppressor genes. Our findings highlight the cancer-specific pattern of APA regulation and extend our understanding of the mechanism of APA-mediated 3'UTR length changes in cancer biology.

Comprehensive analysis of alternative polyadenylation regulators concerning CD276 and immune infiltration in bladder cancer.

Alternative polyadenylation (APA) is emerging as a crucial regulatory mechanism in bladder cancer (BC), while it remains elusive whether APA influences the tumor immune microenvironment (TIME) in BC. We identified two distinct subtypes of BC by APA-related regulatory genes expression profiles. The two subtypes have different pathological grades, prognostic outcomes, tumor immune infiltration characteristics, and pathway enrichment. Subsequently, CPSF3 was identified as a potential immune infiltration-related gene in BC. Highly expressed CPSF3 was positively correlated with unfavorable prognosis and high CD276 expression in BC. Moreover, we verified the expression of CPSF3 in BC tissues and cell lines by qRT-PCR. In conclusion, the study indicates that APA regulatory factors play an important role in immune infiltration of BC, and that CPSF3 was a potentially prognostic marker and immunotherapy target for BC.

miR-190b promotes tumor growth and metastasis via suppressing NLRC3 in bladder carcinoma.

Bladder cancer is one of the most common urogenital malignancies. However, its pathogenesis, especially molecular mechanisms remain elusive. Thus, understanding the molecular mechanisms underlying bladder cancer is important for the discovery of novel therapeutic paradigms for these diseases. In current study, we found that micro-RNA (miR)-190b is highly expressed in bladder cancer tissues and cells. Overexpression of miR-190b enhanced the proliferation, growth, migration and invasion capabilities, and angiogenesis of bladder cancer cells, whereas downregulation of miR-190b reversed these effects. Target prediction and dual luciferase reporter assays identified NLR family CARD domain containing 3 (NLRC3) as a potential target of miR-190b. Pathway analysis indicated that miR-190b promotes bladder cancer progression via the Wnt/ß-catenin and mTOR signaling pathways. Taken together, our findings imply that miR-190b acts as a critical regulator for bladder cancer development by repressing NLRC3 and partly through the Wnt/ß-catenin and mTOR pathways. Our study suggests that miR-190b may be served as a potential therapeutic target for bladder cancer treatment.

Protective Effect of Curcumin on Bone Trauma in a Rat Model via Expansion of Myeloid Derived Suppressor Cells.

BACKGROUND Bone fracture, a common injury to bones leads to various biophysiological changes and pathological responses in the body. The current study investigated curcumin for treatment of bone fracture in a rat model of bone trauma, and evaluated the related mechanism. MATERIAL AND METHODS The rats were separated randomly into 3 groups; sham, model, and curcumin treatment groups. The fracture rat model was established by transverse osteotomy in the right femur bone at the mid-shaft. The osteoblast count was determined using hematoxylin and eosin staining. Vascular endothelial growth factor (VEGF) and proliferating cell nuclear antigen (PCNA) expression were measured by western blotting. RESULTS The rpS6-phosphorylation was suppressed and light chain 3 (LC3II) expression elevated in the curcumin treated group of the fracture rat model. In the curcumin-treated group, mineralization of fracture calluses was markedly higher on day 14 of fracture. The formation of osteoblasts was observed at a greater rate in the curcumin treated group compared to the model rat group. Treatment of rats with curcumin significantly (P<0.05) promoted expression of PCNA and VEGF. The decrease in CD11b+/Gr-1+ cell expansion in rats with bone trauma was alleviated significantly by curcumin treatment. A marked increase in arginase-1 expression in rats with bone trauma was caused by curcumin treatment. CONCLUSIONS In summary, curcumin activates autophagy and inhibits mTOR activation in bone tissues of rats with trauma. The curcumin promoted myeloid-derived suppressor cell (MDSC) proliferation and increased expansion of MDSCs in a rat model of trauma. Therefore, curcumin may have beneficial effect in patients with bone trauma and should be evaluated further for development of treatment.

Diaqua-(5-carb-oxy-benzene-1,3-dicarboxyl-ato-κO(1))[8-ethyl-5-oxo-2-(piperazin-4-ium-1-yl)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxyl-ato-κ(2)O(5),O(6)]zinc monohydrate.

In the title compound, [Zn(C(14)H(17)N(5)O(3))(C(9)H(4)O(6))(H(2)O)(2)]·H(2)O, the complex mol-ecule exists in a zwitterionic form. The Zn(II) ion exhibits a distorted tetra-gonal-pyramidal geometry, being coordinated by two O atoms from the zwitterionic 8-ethyl-5-oxo-2-(piperazin-4-ium-1-yl)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxyl-ate (L) ligand, one O atom from the 5-carb-oxy-benzene-1,3-dicarboxyl-ate dianion, [Hbtc](2-), and two O atoms from two aqua ligands. In the crystal, N-H⋯O and O-H⋯O hydrogen bonds link the components into a three-dimensional structure. The crystal packing exhibits π-π inter-actions between the aromatic rings, with centroid-centroid distances in the range 3.466 (3)-3.667 (3) Å.

Native forests transformed into cash crops reduced soil multi-functionality by modifying the microbial community composition and keystone species' abundance in the Jianghuai Hilly Region.

Conversion of native forest to cash crops is the predominant form of land use change in the Jianghuai Hilly Region. However, how plantations with different cash crops affect the soil multi-functionality is not well documented. In this study, we collected three kinds of cash crops soils (vegetable, orchard, and tea) and forest soil, to systematically review the relationship between soil microbial communities and soil multi-functionality. Soil multi-functionality had decreased in vegetable and orchard as compared to native forest, whereas tea plantation had no significant effects on soil multi-functionality. The results also showed that cash crop plantations decreased soil multi-functionality by shifting keystone species' abundance, for forest, vegetable, and orchard, the keystone species that were classified as module hubs in the bacterial co-occurrence network significantly negatively contributed to soil multi-functionality, but the keystone species categorized as module hubs in fungal co-occurrence network positively affected soil multi-functionality. Multiple soil properties were the drivers of the soil microbial community; thus, indicating that the altered soil properties under cash crop plantations were vital in determining microbial composition and biological processes. These results identified that sustainable management strategy in cash crop plantation needed to be developed for improving soil multi-functionality.

Comprehensive analysis of alternative polyadenylation regulators of CTLA4 and immune infiltration in clear cell renal cell carcinoma.

Background: Clear cell renal cell carcinoma (ccRCC) is the most common renal cancer. Alternative polyadenylation (APA) plays an important role in the progression and immunity of multiple tumors. Although immunotherapy has emerged as an important treatment option for metastatic renal cell carcinoma, whether APA affects the tumor immune microenvironment (TIME) in ccRCC remains unclear. Methods: Patients with ccRCC were classified into two groups by performing a consensus clustering analysis of APA factor expression profiles. The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases were used to assess the association between APA regulators and ccRCC prognosis. Through the use of the R package, GSVA, the correlation between SNRNP70 expression and tumor immune features were analyzed. Results: The TCGA data revealed that APA regulators were associated with Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA4) expression. Cluster 1 exhibited a higher grade and histological tumor stage, as well as a worse prognosis compared to Cluster 2. A ssGSEA analysis demonstrated that Cluster 2 possessed an extensively higher level of immune infiltration. Moreover, high SNRNP70 expression was found to be positively correlated with CTLA4 expression and a poor prognosis in ccRCC. Thus, SNRNP70 might represent a novel immune-related prognostic biomarker in ccRCC. A pan-cancer analysis suggested that SNRNP70 may also play a role in other types of cancer by affecting the TIME. Conclusions: The data from this study indicate that APA regulators play a key role in immune infiltration in ccRCC. SNRNP70 is a promising prognostic biomarker and a potential target for ccRCC's immunotherapy.

cis-Tetra-aqua-bis-{5-[4-(1H-imidazol-1-yl-κN(3))phen-yl]tetra-zolido}manganese(II) dihydrate.

In the title compound, [Mn(C(10)H(7)N(6))(2)(H(2)O)(4)]·2H(2)O, the complex unit comprises an Mn(2+) ion, coordinated by two imidazole N atoms from cis-related monodentate 5-[4-(imidazol-1-yl)phen-yl]tetra-zolide ligands and four water mol-ecules, together with two water mol-ecules of solvation. The Mn(2+) ion lies on a twofold rotation axis and has a slightly distorted octa-hedral geometry. The mol-ecules are connected by O-H⋯N and O-H⋯O hydrogen bonds involving both coordinated and solvent water mol-ecules, generating a three-dimensional structure. Two C atoms of the imidazole ring of the ligand are each disordered over two sites with occupancy factors of 0.75 and 0.25.

Comprehensive analysis of lower mitochondrial complex I expression is associated with cell metastasis of clear cell renal cell carcinoma.

Background: Clear cell renal cell carcinoma (ccRCC) is characterized by high metastasis potential. It is of great importance to explore the mechanisms underlying ccRCC metastasis and to enable development of potent therapeutics. The mitochondrial complex I (CI) had been considered to play an important role in the development of cancers, but less known in ccRCC. Methods: We utilized available public databases of ccRCC, including single-cell RNA sequencing (scRNA-seq) data GSE73121 and The Cancer Genome Atlas-kidney renal clear cell carcinoma (TCGA-KIRC). Principal component analysis (PCA) and t-Distributed Stochastic Neighbor Embedding (tSNE) analysis were evaluated the heterogeneity of metastatic renal cell carcinoma (mRCC) and primary renal cell carcinoma (pRCC). Protein-protein interaction (PPI) network identified critical gene. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) performed to explore the potential biologic pathways. Results: Our study revealed a significant gene expression heterogeneity between pRCC and mRCC. A PPI network based on differentially expressed genes (DEGs) identified electron transport chain (ETC), especially mitochondrial CI, as the key network hub. Further analysis revealed that the role of mitochondrial CI is associated with tumor metastasis and immune responds of ccRCC. Although CI had low frequency mutations in ccRCC, CI expression is associated with the high frequency mutated genes. A prognosis model included 7 CI genes, and these had a significant effect on overall survival (OS). The area under the curve at 1, 3, and 5 years was 0.717, 0.685, and 0.728, respectively. Transcription factor analysis predicted that PPARG possibly is a potential transcription activator of CI genes in ccRCC. Conclusions: Overall, we found that CI expression is associated with ccRCC progress. CI and PPARG may be potential biomarkers for metastatic ccRCC.

catena-Poly[[(2,2'-bipyridine)-manganese(II)]-µ(3)-4,4'-sulfonyl-dibenzoato].

In the title compound, [Mn(C(14)H(8)O(6)S)(C(10)H(8)N(2))](n), the Mn(II) ion is coordinated by four O atoms from three 4,4'-sulfonyl-dibenzoate (sdba) ligands and two N atoms from one 2,2'-bipyridine (2,2'-bipy) ligand in a distorted octa-hedral geometry. The manganese atoms are alternately bridged either by two sdba ligands, with an Mn⋯Mn separation of 12.284 (1) Å, or by two carboxyl-ate groups from two sdba ligands, with an Mn⋯Mn separation of 4.064 (1) Å, thus producing polymeric chains propagated in [101]. Weak inter-molecular C-H⋯O hydrogen bonds and π-π inter-actions [centroid-centroid distance of 3.730 (3) Šbetween the aromatic rings of neighbouring polymeric chains] further stabilize the crystal packing.