Nucleosides, Nucleotides & Nucleic Acids最新文献

Eukaryotic cells without telomerase experience progressively shorter telomeres with each round of cell division until cell cycle arrest is initiated, leading to replicative senescence. When yeast TLC1, which encodes the RNA template of telomerase, is deleted, senescence is accompanied by increased expression of TERRA (non-coding telomere repeat-containing RNA). Deletion of Npl3, an RNA-processing protein with telomere maintenance functions, accelerates senescence in tlc1Δ cells and significantly increases TERRA levels. Using genetic approaches, we set out to determine how Npl3 is involved in regulating TERRA expression and maintaining telomere homeostasis. Even though Npl3 regulates hyperrecombination, we found that Npl3 does not help resolve RNA:DNA hybrids formed during TERRA synthesis in the same way as RNase H1 and H2. Furthermore, Rad52 is still required for cells to escape senescence by telomere recombination in the absence of Npl3. Npl3 also works separately from the THO/TREX pathway for processing nascent RNA for nuclear export. However, deleting Dot1, a histone methyltransferase involved in tethering telomeres to the nuclear periphery, rescued the accelerated senescence phenotype of npl3Δ cells. Thus, our study suggests that Npl3 plays an additional role in regulating cellular senescence outside of RNA:DNA hybrid resolution and co-transcriptional processing.

Objective: Type 2 diabetes mellitus (T2DM) is a complex heterogenic metabolic with a wide range of etiology. Purinergic receptors have pivotal roles in different processes and are hypothesized to have roles in the pathogenesis of T2DM.

Materials and methods: Three hundred subjects affected by T2DM and 300 healthy subjects were genotyped by amplification refractory mutation system polymerase chain reaction (ARMS-PCR). SPSS V16.0 was recruited for statistical analysis.

Results: The findings showed that the G allele of rs25644A > G increases the risk of T2DM in our population statistically (OR = 1.51, 95% CI = 1.14-1.99, p = 0.003). This allele in some genotype models, including the dominant model, caused an increase in the risk of T2DM. The interaction of genotypes between studied variants in the P2XR4 gene increased the risk of T2DM. Haplotype analysis showed that A_rs1169727/G_rs25644 haplotype caused an increase in the risk of T2DM.

Conclusions: The findings suggest that rs25644A > G plays a role in our population's increased risk of T2DM.

Background: Identifying subtypes of lung adenocarcinoma (LUAD) patients based on mitochondrial energy metabolism and immunotherapy sensitivity is essential for precision cancer treatment.

Methods: LUAD subtypes were identified using unsupervised consensus clustering, and results were subjected to immune and tumor mutation analyses. DEGs between subtypes were identified by differential analysis. Functional enrichment and PPI network analyses were conducted. Patients were classified into high and low expression groups based on the expression of the top 10 hub genes, and survival analysis was performed. Drugs sensitive to feature genes were screened based on the correlation between hub gene expression and drug IC₅₀ value. qRT-PCR and western blot were used for gene expression detection, and CCK-8 and flow cytometry were for cell viability and apoptosis analysis.

Results: Cluster-1 had significantly higher overall survival and a higher degree of immunoinfiltration and immunophenotypic score, but a lower TIDE score, DEPTH score, and TMB. Enrichment analysis showed that pathways and functions of DEGs between two clusters were mainly related to the interaction of receptor ligands with intracellular proteases. High expression of hub genes corresponded to lower patient survival rates. The predicted drugs with high sensitivity to feature genes were CDK1: Ribavirin (0.476), CCNB2: Hydroxyurea (0.474), Chelerythrine (0.470), and KIF11: Ribavirin (0.471). KIF11 and CCNB2 were highly expressed in LUAD cells and promoted cell viability and inhibited cell apoptosis.

Conclusion: This study identified two subtypes of LUAD, with cluster-1 being more suitable for immunotherapy. These results provided a reference for the development of precision immunotherapy for LUAD patients.

The chemical synthesis of guanosine nucleosides generates both the N9 and N7 regioisomers, which require careful separation to obtain the desired N9 isomer. To preferentially obtain the N9 isomer, a bulky diphenylcarbamoyl (DPC) group can be installed at the O6 position of guanine. However, installation of the DPC group presents a challenging task due to low solubility of the N-acetyl protected guanine. Here we report the usage of commercially available 2-amino-6-chloro purine as a new strategy that offers a more efficient route to the synthesis of the guanine phosphoramidite of threose nucleic acid (TNA).

In this communication, an innovative and straightforward protocol for the one-pot catalytic synthesis of bis(indolyl)pyrimidine derivatives and their DNA binding abilities is presented. The synthesis involves the condensation of indole with diverse substituted pyrimidine-5-carbaldehydes, employing cost-effective and reusable Sr-Al supported nanophosphors, specifically strontium aluminate (SrAl₂O₄), as a catalyst. In particular, this method does not require the use of toxic solvents. The Sr-Al supported nanophosphorus catalyst exhibited sustained activity over multiple cycles and showed no significant decline while maintaining its strictly heterogeneous properties. The bis(indolyl)pyrimidine derivatives were extensively characterized using spectroscopic and analytical techniques. Furthermore, the interaction between these derivatives and CT-DNA was investigated by absorption spectroscopy, viscosity measurement, and in silico molecular docking studies. Photoinduced cleavage studies demonstrated the photonuclease activity of the compound against pUC19 DNA upon exposure to UV-visible radiation.

Deficiency in the breast cancer type 1 (BRCA1) gene expression predisposes to triple-negative breast cancer (TNBC) and ovarian cancer (OC). We previously identified by Comparative Genomic Hybridization (CGH) array a gain in the 17q25.3 genomic region in 90% of the BRCA1 mutated TNBC tissues, where 17 genes were up-regulated. A second region (Chr19_45681759_54221324) was identified as the second most frequent gain in the BRCA1-mutated population and has not yet been described in the context of BRCA1 mutation. We thus aimed to validate the expression of the Casein kinase 1 delta (CSNK1D) gene of Chr17 in TNBC and OC cell lines and to investigate the expression of genes of Chr19 in TNBC cell lines and tissues as well as in OC cell lines. Expression level of the genes of the 17q25.3, 19q13.32,13.33 and 13.41 chromosomal regions was analyzed using RT-PCR in BRCA1 deficient TNBC and OC cell lines, as well as in 10 BRCA1-mutated TNBC tissues versus 10 wild type carriers. Our results revealed a significant upregulation of CSNK1D gene expression in BRCA1 deficient TNBC and OC cell lines when compared to control ones, and a significant aberration in the expression of the other six genes of Chr19 was observed. Interestingly, upregulation of kallikrein-related peptidase 6 (KLK6) was detected among the BRCA1 deficient TNBC (cell lines and tissues) and OC cell lines. In conclusion, our results suggested that CSNK1D and KLK6 expression levels could be very promising in the search for biomarkers for BRCA1 deficient TNBC and OC.

Several studies showed that adipokines are associated with types of cancer which are documented to be effective in cancer biology. This study aimed to determine the relationship between vaspin rs2236242 polymorphism and the vaspin level with papillary thyroid carcinoma (PTC), and multinodular goiter (MNG). In this cross-sectional study, we recruited 170 candidates. Ninety patients with newly diagnosed (PTC 60 patients and MNG 30 patients), and 80 participants as a control group referred to Shariati Hospital, Tehran, Iran, were enrolled in the study. The vaspin hormone measurements were conducted utilizing the Elisa Kit. Using Tetra amplification resistant-mutation system polymerase chain reaction (T-ARMS-PCR), the genotype of single nucleotide polymorphism (SNP) rs2236242 was determined. The statistical analysis was performed using SPSS software version 20. Our findings showed significant age and genotype frequency differences in three groups (p-value < 0.05). There was no significant difference in vaspin levels between PTC, and control groups. The level of vaspin in MNG compared to the control group had significantly different, but there were no differences after adjustment for age. Results showed the genotypes of vaspin rs2236242 polymorphism are not associated with the level of vaspin. The genotypes and allele frequencies of vaspin rs2236242 in the PTC and MNG groups were significant compared to the control group. We have found vaspin rs2236242 gene polymorphism as a potential marker of papillary thyroid cancer. The A allele of the vaspin SNP rs2236242 plays a protective role against PTC and MNG. SNP at rs2236242 was not significantly associated with vaspin levels.

The N¹-methyladenosine (m¹A) epigenetic modification exists in many RNAs and is related to many human diseases. Chemically synthesized RNAs containing the modification are required for projects aimed at studying biological processes, mechanisms, and pathogenesis related to m¹A. Existing methods for the synthesis of m¹A containing RNAs use tetrabutylammonium fluoride (TBAF) for the deprotection of the 2'-silyl protecting groups. Since TBAF is nonvolatile, and is relatively non-polar, its use in the desilylation of RNA requires repeated desalting, which is tedious and gives low yields. Here we report the use of the volatile and neat triethylamine hydrogen fluoride (TEA-HF) for desilylation of m¹A RNA synthesis. We found that the method is much simpler, and-in our hands-give significantly higher yield of RNA. Two major concerns for m¹A RNA synthesis are depurination and Dimroth rearrangement. HPLC and MALDI MS of the RNA indicated that depurination is not a problem for the new method. The absence of Dimroth rearrangement is proven by RNA digestion followed by HPLC analysis of the nucleosides.

Recently, a meta-analysis has shown that a potentially functional genetic polymorphism (rs7158663 A > G) on the cancer-associated lncRNA MEG3 is associated with the risk of many types of cancer. Given the important role of MEG3 in the development of hepatocellular carcinoma (HCC), the current study evaluated the association of the rs7158663 genetic polymorphism with HCC risk. A total of 271 HCC patients and 267 healthy individuals were included in the current case-control study. Direct sequencing was used to detect the rs7158663 locus genotype of the included individuals. The case-control study showed that the MEG3 rs7158663 genetic polymorphism was associated with the increased risk of developing HCC [GA vs. GG: OR = 1.63, 95% CI = 1.14-2.34, p = 0.009; AA vs. GG: OR = 2.10, 95% CI = 1.10-4.08, p = 0.03; (GA + AA) vs. GG: OR = 1.70, 95% CI = 1.21-2.40, p = 0.003; A vs. G: OR = 1.53, 95% CI = 1.17-2.00, p = 0.002]. In addition, the genotype-tissue expression showed that the rs7158663 AA or GA genotype was associated with reduced MEG3 expression. Bioinformatic analysis showed that the rs7158663 genetic polymorphism not only affects the binding of transcription factors but also interacts with multiple genes through chromatin loops. In summary, the current findings suggest that the rs7158663 genetic polymorphism affecting MEG3 expression is associated with HCC risk and may serve as a marker of genetic susceptibility to HCC. However, the specific molecular mechanisms of the rs7158663 genetic polymorphism in the development of HCC need to be further revealed.

One of the mechanisms responsible for antibiotic resistance in Klebsiella pneumoniae is the enzymes produced by the bacteria; another important mechanism is the ability to form biofilm. In this study, antibiotic resistance, genes associated with virulence, and biofilm-forming properties of K. pneumoniae strains were investigated. A total of 100  K. pneumoniae isolates were obtained from different clinical samples identified by Matrix-Assisted Laser Desorption/Ionization time-of-flight Mass Spectrometry. Antimicrobial susceptibility testing was performed with the Phoenix 100 apparatus. The biofilm forming properties of strains were determined by the microtiter plate method. For molecular analysis, genes encoding the carbapenemase enzyme (bla_OXA-48, bla_NDM-1, bla_IMP, and bla_VIM) and biofilm-related genes (treC, luxS, mrkA, and wza) were investigated by polymerase chain reaction (PCR). While 76% of clinical isolates were resistant to three or more antimicrobials, 24% were classified as non-multidrug resistant (non-MDR). When biofilm-forming capacities of clinical isolates were tested, it was determined that the resistant-isolates produced 59.2% strong biofilm, and susceptible-isolates produced 12.5% strong biofilm. According to PCR results, carbapenemase genes were determined as follows: bla_OXA-48-70%, bla_NDM-49%, and bla_KPC-19%, bla_OXA-48/bla_NDM/bla_KPC-12%, bla_OXA-48/bla_NDM-26%, and bla_OXA-48/bla_KPC-4%. The biofilm-associated genes in bacterial isolates were determined as follows: luxS-98%, treC-94%, mrkA-88%, and wza-15%. In addition, Hierarchical Clustering Tree and Heatmap analysis revealed an association between isolates that lacks resistance genes and isolates lacks biofilm-formation related genes that were included in MDR or non-MDR classes. As a result, biofilm should be considered in the treatment of MDR infections, and therapy should be planned accordingly. In addition, pursuing the data and genes of antibiotic resistance is significant for combating resistance.