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Pseudouridines in RNAs: switching atoms means shifting paradigms.

ABSTRACT: The structure, stability, and function of various coding and noncoding RNAs are influenced by chemical modifications. Pseudouridine (Ψ) is one of the most abundant post-transcriptional RNA base modifications and has been detected at individual positions in tRNAs, rRNAs, mRNAs, and snRNAs, which are referred to as Ψ-sites. By allowing formation of additional bonds with neighboring atoms, Ψ strengthens RNA-RNA and RNA-protein interactions. Although many aspects of the underlying modification reactions remain unclear, the advent of new transcriptome-wide methods to quantitatively detect Ψ-sites has recently changed our perception of the functional roles and importance of Ψ. For instance, it is now clear that the occurrence of Ψs appears to be directly linked to the lifetime and the translation efficiency of a given mRNA molecule. Furthermore, the administration of Ψ-containing RNAs reduces innate immune responses, which appears strikingly advantageous for the development of generations of mRNA-based vaccines. In this review, we aim to comprehensively summarize recent discoveries that highlight the impact of Ψ on various types of RNAs and outline possible novel biomedical applications of Ψ.

SUBMITTER: Lin TY

PROVIDER: S-EPMC9290505 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Pseudouridines in RNAs: switching atoms means shifting paradigms.

Lin Ting-Yu TY Mehta Rahul R Glatt Sebastian S

FEBS letters 20210913 18

The structure, stability, and function of various coding and noncoding RNAs are influenced by chemical modifications. Pseudouridine (Ψ) is one of the most abundant post-transcriptional RNA base modifications and has been detected at individual positions in tRNAs, rRNAs, mRNAs, and snRNAs, which are referred to as Ψ-sites. By allowing formation of additional bonds with neighboring atoms, Ψ strengthens RNA-RNA and RNA-protein interactions. Although many aspects of the underlying modification react ...[more]

PMID: 34468991

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Project description:Pulmonary arterial hypertension (PAH) is a long-term condition characterised by increased resistance to blood flow in the pulmonary circulation. The disease has a progressive course and is associated with a poor prognosis. Without treatment, PAH is associated with mortality in <3 years. Over the past decade, many advances have been made in revising the haemodynamic definition, clinical classification, risk calculation score, treatment options etc. Suggestions from the Sixth World Symposium on Pulmonary Hypertension were incorporated into a literature review that was included in the European Society of Cardiology/European Respiratory Society (ESC/ERS)'s most recent iteration of their guidelines in 2022. The traditional cut-off for pulmonary hypertension (PH), i.e., mean pulmonary artery pressure (mPAP) >25 mm Hg, has been challenged by observational cohort studies, which have shown poor outcomes for values of 21-24 mmHg; the new consensus is that PH is defined at mPAP >20 mm Hg. Although the gold standard for diagnosis and the major source of therapy guidance continues to be right cardiac catheterisation, echocardiography remains the initial test of choice. A multidisciplinary approach is highly recommended when treating PH patients and careful evaluation of patients will aid in proper diagnosis and prognosis. Pharmacotherapy for PAH has seen a paradigm shift with the successful use of newer agents in more extensive, longer and more inclusive trials driven by hard endpoints. Macitentan, selexipag and riociguat are three oral agents that have shown astounding success in PAH randomised studies in the past decade. Upfront combination therapy with two agents is now becoming the norm (following the AMBITION, OPTIMA and ITALY trials) and the momentum is shifting towards triple therapy as for essential hypertension. More recently, inhaled treprostinil was shown to improve exercise capacity in PH associated with interstitial lung disease in the phase III INCREASE study and has been granted regulatory approval for World Health Organization group 3 PH. A new class of drug, sotatercept (a tumour growth factor-β signalling inhibitor), has also been recently approved by the Food and Drug Administration for management of PAH based on positive results from the phase III STELLAR study. Pulmonary artery denervation and balloon pulmonary angioplasty have emerged as viable alternatives in PH that are resistant to drug therapy. This article aims to summarise the key changes and recent advances in diagnosis and managing PH in general, with an emphasis on certain subgroups.

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Pseudouridines in RNAs: switching atoms means shifting paradigms.

Publications

Pseudouridines in RNAs: switching atoms means shifting paradigms.

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