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The ability to translate three nucleotide sequences, or codons, into amino acids to form proteins is conserved across all organisms. All but two amino acids have multiple codons, and the frequency that such synonymous codons occur in genomes ranges from rare to common. Transcripts enriched in rare codons are typically associated with poor translation, but in certain settings can be robustly expressed, suggestive of codon-dependent regulation. Given this, we screened a gain-of-function library for human genes that increase the expression of a GFP rare reporter encoded by rare codons. This screen identified multiple components of the mitogen activated protein kinase (MAPK) pathway enhancing GFP rare expression. This effect was reversed with inhibitors of this pathway and confirmed to be both codon-dependent and occur with ectopic transcripts naturally coded with rare codons. Finally, this effect was associated, at least in part, with enhanced translation. We thus identify a potential regulatory module that takes advantage of the redundancy in the genetic code to modulate protein expression.

Ubiquitin modification and alternative polyadenylation play crucial roles in the onset and progression of cancer. Hence, this study aims to comprehensively and deeply understand gene regulation and associated biological processes in lung adenocarcinoma (LUAD) by integrating both mechanisms. Alternative polyadenylation (APA)-related E3 ubiquitin ligases in LUAD were identified through multiple databases, and the association between selected genetic loci influencing gene expression (apaQTL-SNPs) and LUAD risk were evaluated through the GWAS database of the Female Lung Cancer Consortium in Asia (FLCCA). Subsequently, the interaction between RNF213 and ZBTB20, as well as their functional mechanisms in LUAD, were investigated using bioinformatics analysis, Western blot, co-immunoprecipitation, and colony formation experiments. A total of five apaQTL-SNPs (rs41301932, rs4494603, rs9890400, rs56066320, and rs41301932), located on RNF213, were significantly associated with LUAD risk (p < 0.05), and they inhibit tumor growth through ubiquitin-mediated degradation of ZBTB20. [ABSTRACT FROM AUTHOR]

The genetic disorder Prader-Willi syndrome (PWS) is mainly caused by the loss of multiple paternally expressed genes in chromosome 15q11-q13 (the PWS region). Early diagnosis of PWS is essential for timely treatment, leading to effectively easing some clinical symptoms. Molecular approaches for PWS diagnosis at the DNA level are available, but the diagnosis of PWS at the RNA level has been limited. Here, we show that a cluster of paternally transcribed snoRNA-ended long noncoding RNAs (sno-lncRNAs, sno-lncRNA1–5) derived from the SNORD116 locus in the PWS region can serve as diagnostic markers. In particular, quantification analysis has revealed that 6,000 copies of sno-lncRNA3 are present in 1 μL whole blood samples from non-PWS individuals. sno-lncRNA3 is absent in all examined whole blood samples of 8 PWS individuals compared to 42 non-PWS individuals and dried blood samples of 35 PWS individuals compared to 24 non-PWS individuals. Further developing a new CRISPR-MhdCas13c system for RNA detection with a sensitivity of 10 molecules per μL has ensured sno-lncRNA3 detection in non-PWS, but not PWS individuals. Together, we suggest that the absence of sno-lncRNA3 represents a potential marker for PWS diagnosis that can be detected by both RT-qPCR and CRISPR-MhdCas13c systems with only microlitre amount of blood samples. Such an RNA-based sensitive and convenient approach may facilitate the early detection of PWS. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) are important components of the innate and adaptive immune systems, and abnormal TLR expression has been linked to a variety of cancers. However, there was a lack of clarity on the association of TLR stimulation with the carcinogenesis of cancer. The study's goal was to analyse the clinical importance of TLRs expression at the mRNA level in pan-cancer datasets, as well as the link between TLR expression and carcinogenesis, progression, and clinical prognosis. The expression profile of TLRs derived from UCSC pan-cancer data was analysed in multiple dimensions, including clinical analysis, immunological subtype analysis, tumour microenvironment (TME) analysis, tumour stem cell correlation analysis, and drug sensitivity analysis. Additionally, we analyse protein-protein interactions, functional enrichment, and chromatin accessibility, as well as TLR expression in single-cell sequencing data. Our multi-omics analysis results imply that TLRs may operate as a biological marker for carcinogenesis and progression, a potential target for anti-tumour therapy, and a prognostic biomarker, laying the theoretical groundwork for future translational medicine research. TLRs are involved in the formation of malignancies and can be explored in further detail as potential prognostic indicators. Toll-like receptors (TLRs) are key factors in the process of the innate and adaptive immune response, and their aberrant expression of TLRs have been widely reported in various cancer. However, the association between TLRs stimulation and tumorigenesis of cancer has not been well clarified. In this study, in the pan-cancer data, integrated TLR family gene expression analysis, clinical correlation analysis, immune subtype correlation analysis, tumour microenvironment correlation analysis, tumour stem cell correlation analysis, and drug sensitivity correlation analysis were performed. TLRs play an important role in the development of tumours and can be studied in depth as potential prognostic markers. [ABSTRACT FROM AUTHOR]

Lateral organ boundary Domain (LBD) proteins are plant-specific transcription factors that play a key role in plant lateral organ development and stress tolerance. However, LBD gene has not been identified in the common bean (Phaseolus vulgaris L.). Here, a total of 47 common bean LBD genes (PvLBDs) were identified. Members of the same subfamily had similar genetic structures. Synteny analysis indicated that LBDs in the common bean genome have greater collinearity with soybean (Glycine max L.) than with Arabidopsis and rice (Oryza sativa L.). Additionally, 9 pair of segmental duplication genes were identified by collinearity analysis. Phytozome data analysis showed significant differences in PvLBD gene expression abundance between different developmental stages of the same tissue. The qRT-PCR results showed that NaCl, CdCl2, and HgCl2 stresses up-regulated 19% and down-regulated 81% of the PvLBD genes. This study provides a basis for further analysis of the function of the PvLBD gene family. [ABSTRACT FROM AUTHOR]

Sugar Will Eventually be Exported Transporters (SWEET) proteins function as sugar transporters that play key roles in plant growth, development, and biotic and abiotic stress responses. However, little is known about the SWEET gene family in common bean (Phaseolus vulgaris L.). In this study, 24 putative PvSWEET genes were identified. They can be categorized into four subgroups based on a phylogenetic analysis, exon–intron structure, cis-regulatory elements, and MEME motifs. A collinearity analysis showed that three pairs of segmental duplicated events were identified. The Phytozome database showed that 16 PvSWEET genes were highly expressed in reproductive organs. PvSWEET5 was expressed the most highly in all the tissues tested, while PvSWEET8/9/10/13 were undetectable in the datasets. The results of qRT-PCR analysis showed that PvSWEET24 was significantly up-regulated following treatment with NaCl, CdCl2, and HgCl2, whereas the PvSWEET5 and PvSWEET20 genes displayed a specific negative response to CdCl2 stress. Collectively, this study provides comprehensive information for the role of SWEET gene family in common bean and lays a solid foundation to elucidate the biological function of the PvSWEET gene family, as well as provide insights into the correlation between the PvSWEET genes and responses to metal stresses. [ABSTRACT FROM AUTHOR]

Understanding the response and tolerance mechanisms of nitrogen (N) stress is essential for the taproot plant of sugar beet. Hence, in this study, low (0.5 and 3 mmol/L; N0.5 and N3), moderate (5 mmol/L; N5; control) and high (10 and 12 mmol/L; N10 and N12) N were imposed to sugar beet to comparatively investigate the growth and physiological changes, and expression pattern of the gene involving ammonia transporting at different seedling stages. The results showed that, different from N5 which could induce maximum biomass of beet seedlings, low N was more likely to inhibit the growth of beet seedlings than high N treatments. Morphological differences and adverse factors increased significantly with extension of stress time, but sugar beet seedlings displayed a variety of physical responses to different N concentrations to adapt to N abnormal. At 14 d, the chlorophyll content, leaf and root surface area, total dry weight and nitrogen content of seedlings treated with N0.5 decreased 15.83%, 53.65%, 73.94%, 78.08% and 24.88% respectively, compared with N12; however, the root shoot ratio increased significantly as well as superoxide dismutase (SOD), peroxidase (POD), glutamine synthetase (GS) activity and malondialdehyde (MDA) and proline content, especially in root. The expression of BvAMT1.2 was also regulated in an N concentration-dependent manner, and was mainly involved in the tolerance of beet leaves to N stress, which significantly positively correlated to GS activity on the basis of its high affinity to N. It can be deduced that the stored nutrients under low N could only maintain relatively stable root growth, and faced difficulty in being transported to the shoots. Sugar beet was relatively resilient to N0.5 stress according to the mean affiliation function analysis. These results provide a theoretical basis for the extensive cultivation of sugar beet in N-stressed soil. [ABSTRACT FROM AUTHOR]

Sulfate transporters (SULTRs) are responsible for the absorption and transport of sulfate in higher plants. They also play a key role in plant growth, development and abiotic stress responses. However, the SULTR gene family in common bean (Phaseolus vulgaris L.) is still not well studied. In this study, 15 PvSULTRs were identified. Phylogenetic analysis divided the PvSULTR genes into four subgroups. Cis-regulatory element analysis of the promoter sequence of the PvSULTR genes showed that many cis-regulatory elements were related to hormone and environmental stresses. Collinearity analysis showed that two PvSULTR gene pairs are duplicated in common bean. Tissue-specific expression analysis of the 15 PvSULTR genes showed different expression patterns in various tissues. Furthermore, real-time fluorescence quantitative polymerase chain reaction (qRT-PCR) analysis showed that PvSULTR1/2/7 genes displayed specific responses to CdCl2 and HgCl2 stresses, whereas PvSULTR11/12 were explicitly induced by NaCl and HgCl2 stresses. These results suggest that PvSULTR family members might function under different mechanisms in response to specific metal stress. This study provides the basis for elucidating the functional diversity of PvSULTR gene family and reveals its role in metal stress response in common bean. [ABSTRACT FROM AUTHOR]

Background. Emerging evidence has indicated that circular RNAs (circRNAs), recognized as functional noncoding transcripts in eukaryotic cells, may be involved in regulating many physiological or pathological processes. However, the regulation and function of circular RNA circITGA7 in thyroid cancer (TC) remains unknown. Methods. In this study, we found that circITGA7 is upregulated in TC cell lines. We then performed functional analyses in the cell lines to support clinical findings. Mechanistically, we demonstrated that circITGA7 can directly bind to miR-198 and reduce the inhibition effect of miR-198 on target FGFR1 expression. Results. We reported an upregulation of circITGA7 in patients with TC. Silencing of circITGA7 inhibits metastasis and proliferation of TC cell lines in vitro. In addition, in the TC cell lines, the knockdown of circITGA7 or overexpression of miR-198 significantly suppressed FGFR1 levels. Mechanistically, we found that circITGA7 acts as miR-198 competitive endogenous RNA (ceRNA) to regulate FGFR1 expression. Conclusions. In summary, circRNA circITGA7 may play a regulatory role in TC and may be a potential marker for TC diagnosis or progression. [ABSTRACT FROM AUTHOR]

Beiging of white adipose tissue (WAT) is a particularly appealing target for therapeutics in the treatment of metabolic diseases through norepinephrine (NE)-mediated signaling pathways. Although previous studies report NE clearance mechanisms via SLC6A2 on sympathetic neurons or proinflammatory macrophages in adipose tissues (ATs), the low catecholamine clearance capacity of SLC6A2 may limit the cleaning efficiency. Here, we report that mouse organic cation transporter 3 (Oct3; Slc22a3) is highly expressed in WAT and displays the greatest uptake rate of NE as a selective non-neural route of NE clearance in white adipocytes, which differs from other known routes such as adjacent neurons or macrophages. We further show that adipocytes express high levels of NE degradation enzymes Maoa, Maob, and Comt, providing the molecular basis on NE clearance by adipocytes together with its reuptake transporter Oct3. Under NE administration, ablation of Oct3 induces higher body temperature, thermogenesis, and lipolysis compared with littermate controls. After prolonged cold challenge, inguinal WAT (ingWAT) in adipose-specific Oct3-deficient mice shows much stronger browning characteristics and significantly elevated expression of thermogenic and mitochondrial biogenesis genes than in littermate controls, and this response involves enhanced β-adrenergic receptor (β-AR)/protein kinase A (PKA)/cyclic adenosine monophosphate (cAMP)-responsive element binding protein (Creb) pathway activation. Glycolytic genes are reprogrammed to significantly higher levels to compensate for the loss of ATP production in adipose-specific Oct3 knockout (KO) mice, indicating the fundamental role of glucose metabolism during beiging. Inhibition of β-AR largely abolishes the higher lipolytic and thermogenic activities in Oct3-deficient ingWAT, indicating the NE overload in the vicinity of adipocytes in Oct3 KO adipocytes. Of note, reduced functional alleles in human OCT3 are also identified to be associated with increased basal metabolic rate (BMR). Collectively, our results demonstrate that Oct3 governs β-AR activity as a NE recycling transporter in white adipocytes, offering potential therapeutic applications for metabolic disorders. [ABSTRACT FROM AUTHOR]

Duck enteritis virus (DEV) can infect ducks, geese, and many other poultry species and leads to acute, septic and highly fatal infectious disease. Autophagy is an evolutionarily ancient pathway that plays an important role in many viral infections. We previously reported that DEV infection induces autophagy for its own benefit, but how this occurs remains unclear. In this study, endoplasmic reticulum (ER) stress was triggered by DEV infection, as demonstrated by the increased expression of the ER stress marker glucose-regulated protein 78 (GRP78) and the dilated morphology of the ER. Pathways associated with the unfolded protein response (UPR), including the PKR-like ER protein kinase (PERK) and inositol-requiring enzyme 1 (IRE1) pathways, but not the activating transcription factor 6 (ATF6) pathway, were activated in DEV-infected duck embryo fibroblast (DEF) cells. In addition, the knockdown of both PERK and IRE1 by small interfering RNAs (siRNAs) reduced the level of LC3-II and viral yields, which suggested that the PERK-eukaryotic initiation factor 2α (eIF2α) and IRE1-x-box protein1 (XBP1) pathways may contribute to DEV-induced autophagy. Collectively, these data offer new insight into the mechanisms of DEV -induced autophagy through activation of the ER stress-related UPR pathway. [ABSTRACT FROM AUTHOR]

Mercury chloride can cause severe liver injury, which involves multiple mechanisms. Ferroptosis plays an important role in regulating the development and progression of liver pathology. Oleanolic acid (OA), a triterpenoid compound widely exists in fruits, has liver protective properties. In this study, we investigated the role of ferroptosis in mercury chloride-induced liver injury and the intervention effect of OA, and clarified the potential mechanism. We found that mercury chloride-induced oxidative stress in liver tissues and cells, leading to lipid peroxidation and iron overload, thereby reducing the expression levels of GPX4 and SLC7A11, and increasing the expression level of TRF1, OA pretreatment improved the changes of GPX4, SLC7A11 and TRF1 induced by mercury chloride, which were related to its inhibition of oxidative stress. Furthermore, We pretreated cells with OA, VC, and Fer-1, respectively and found that VC pretreatment reduced oxidative stress and significantly reversed the gene and protein expressions of GPX4, SLC7A11, and TRF1 in mercury chloride-exposed cells (P < 0.05, vs. HgCl 2 group), however, the protein expression level of GPX4 in OA pre-treatment group was lower than that in VC pre-treatment group (P < 0.05). Fer-1 pretreatment decreased the level of iron ions in cells, increased the gene and protein expression levels of GPX4 and SLC7A11, and decreased the gene and protein expression levels of TRF1 (P < 0.05, vs. HgCl 2 group), however, the protein expression levels of GPX4 and SLC7A11 in OA pre-treatment group were lower than those in Fer-1 pre-treatment group (P < 0.05). Moreover, vivo experiments also demonstrated that pre-treatment with OA, VC, and Fer-1 reversed the changes in gene expression levels of Nrf2 and SOD1, and protein expression of GPX4 induced by mercury chloride (P < 0.05, vs. HgCl 2 group), meanwhile, the difference was not statistically significant among OA, VC, and Fer-1 pretreatment. The improvement effect of OA pretreatment on the change in TFR1 protein expression caused by mercury chloride was similar to that of Fer-1 and VC, however, the intervention effect of OA on SLC7A11 protein expression was not as good as Fer-1 and VC pre-treatment. To sum up, all these results suggest that ferroptosis is involved in mercury chloride-induced liver injury, OA pretreatment alleviated mercury chloride-induced ferroptosis by inhibiting ROS production and iron ion overload, and then alleviate the liver injury. • Mercury chloride induces liver injury, involving ferroptosis. • OA improves mercury chloride-induced liver injury is related to the inhibition of iron overload. • Inhibited ROS/iron overload play a key role in ameliorated mercury chloride-induced liver injury. [ABSTRACT FROM AUTHOR]

Object: Trop2 plays an important role in proliferation and invasion of tumors. Extensive research has shown that the expression level of Trop2 is closely related to the progress of cervical diseases. This study was to explore the effects of Trop2 on cell proliferation and apoptosis in cervical cancer. Methods: Trop2 was knocked down by shRNA in CaSki cells. The expression level of mRNA and protein was detected by real-time PCR and western blot, respectively. Cell proliferation was determined by CCK-8 and clone formation assay; apoptosis was measured by flow cytometry; cell cycle and apoptosis-related proteins cyclinD1, P53, bcl-2, bax, caspase 3, 8 and 9 were analyzed as well to investigate possible mechanism. Results: Trop2 expression was effectively repressed in CaSki cells by Trop2 shRNA, which resulted in inhibition of proliferation and colony formation, whereas apoptosis rate was significantly increased. Furthermore, in Trop2 knockdown CaSki cells, the expression of cyclinD1 and bcl-2 was significantly down-regulated, while that of P53 and bax was up-regulated accompanied by increased activities of caspase 9 and 3 but not caspase 8. Conclusions: Trop2 is important in proliferation and apoptosis regulation in CaSki cells, which may become a novel target for cervical cancer treatment. [ABSTRACT FROM AUTHOR]

Reference 1 Feng D., Xu D., Murakoshi N., Tajiri K., Qin R., Yonebayashi S., Okabe Y., Li S., Yuan Z., Aonuma K. Nicotinamide Phosphoribosyltransferase (Nampt)/Nicotinamide Adenine Dinucleotide (NAD) Axis Suppresses Atrial Fibrillation by Modulating the Calcium Handling Pathway. Nicotinamide Phosphoribosyltransferase (Nampt)/Nicotinamide Adenine Dinucleotide (NAD) Axis Suppresses Atrial Fibrillation by Modulating the Calcium Handling Pathway. Figures Graph: Figure 1 Gene and protein expressions of Nampt and Sirt1 in the atrial tissues. [Extracted from the article]