Nonsense-mediated mRNA decay in human cells: mechanistic insights, functions beyond quality control and the double-life of NMD factors

Nonsense-mediated decay is well known by the lucid definition of being a RNA surveillance mechanism that ensures the speedy degradation of mRNAs containing premature translation termination codons. However, as we review here, NMD is far from being a simple quality control mechanism; it also regulates the stability of many wild-type transcripts. We summarise the abundance of research that has characterised each of the NMD factors and present a unified model for the recognition of NMD substrates. The contentious issue of how and where NMD occurs is also discussed, particularly with regard to P-bodies and SMG6-driven endonucleolytic degradation. In recent years, the discovery of additional functions played by several of the NMD factors has further complicated the picture. Therefore, we also review the reported roles of UPF1, SMG1 and SMG6 in other cellular processe

Persistently Elevated Right Ventricular Index of Myocardial Performance in Preterm Infants with Incipient Bronchopulmonary Dysplasia

OBJECTIVES: Elevated pulmonary vascular resistance occurs during the first days after birth in all newborn infants and persists in infants at risk for bronchopulmonary dysplasia (BPD). It is difficult to measure in a non-invasive fashion. We assessed the usefulness of the right ventricular index of myocardial performance (RIMP) to estimate pulmonary vascular resistance in very low birth weight infants. STUDY DESIGN: Prospective echocardiography on day of life (DOL) 2, 7, 14, and 28 in 121 preterm infants (median [quartiles] gestational age 28 [26]-[29] weeks, birth weight 998 [743-1225] g) of whom 36 developed BPD (oxygen supplementation at 36 postmenstrual weeks). RESULTS: RIMP derived by conventional pulsed Doppler technique was unrelated to heart rate or mean blood pressure. RIMP on DOL 2 was similar in infants who subsequently did (0.39 [0.33-0.55]) and did not develop BPD (0.39 [0.28-0.51], p = 0.467). RIMP declined steadily in non-BPD infants but not in BPD infants (DOL 7: 0.31[0.22-0.39] vs. 0.35[0.29-0.48], p = 0.014; DOL 14: 0.23[0.17-0.30] vs. 0.35[0.25-0.43], p<0.001; DOL 28: 0.21[0.15-0.28] vs. 0.31 [0.21-0.35], p = 0.015). CONCLUSIONS: In preterm infants, a decline in RIMP after birth was not observed in those with incipient BPD. The pattern of RIMP measured in preterm infants is commensurate with that of pulmonary vascular resistance

An imperial enlightenment? : notions of India and the literati of Edinburgh, 1723-1791

This dissertation highlights the influence of the extension of Empire in India on Enlightenment in Scotland. It argues, consistently, that an ever increasing contact with the Eastern parts of Empire over the eighteenth century created productive tensions between the personal, material and intellectual worlds of the Edinburgh literati. Scottish thinkers stood in close contact to one another and congregated in the Select Society and the Poker Club. Beyond the domestic boundaries, they had practical and personal interests in contemporary events in the East Indies. All had relatives or acquaintances in India and were all correspondents of Sir John Macpherson, Governor-General of India (1785-6). The dissertation shows that a revision of civic humanism on the one hand and scientific Whiggism on the other, found their main dilemma in “luxury” and “despotism” respectively. Both of these concepts were intrinsically connected with the perception of India at the beginning of the eighteenth century. One of the outcomes of the literati’s personal and intellectual engagement with India was the different solutions for the regulation of Empire. Ferguson, following the tradition of civic humanism, argued for the importance of civic virtue in order to maintain Empire. His thoughts stood in stark contrast to Smith, Hume and particularly Robertson. Vigour, instead of civic virtue, needed to be developed and strengthened. No monolithic canon of how Empire could be sustained was developed by these men, but all were involved in squaring the circle of improvement through Empire. The constant interplay between domestic, cosmopolitan and imperial spheres suggests that Enlightenment had an imperial nature, which is highlighted in relation to the literati’s particular investigation of “luxury” and “despotism” and their positive perception of Nabobs. Moreover, the dissertation emphasises that Edinburgh associations can not only be viewed as pillars of Enlightenment in Scotland, but also as networks and the gateways to Empire from at least the 1760s. The evidence assembled suggests that men like Ferguson and Robertson were active players in a world which was intellectually and practically shaped by Empire.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Comparison of EJC-enhanced and EJC-independent NMD in human cells reveals two partially redundant degradation pathways

Nonsense-mediated mRNA decay (NMD) is a eukaryotic post-transcriptional gene regulation mechanism that eliminates mRNAs with the termination codon (TC) located in an unfavorable environment for efficient translation termination. The best-studied NMD-targeted mRNAs contain premature termination codons (PTCs); however, NMD regulates even many physiological mRNAs. An exon-junction complex (EJC) located downstream from a TC acts as an NMD-enhancing signal, but is not generally required for NMD. Here, we compared these “EJC-enhanced” and “EJC-independent” modes of NMD with regard to their requirement for seven known NMD factors in human cells using two well-characterized NMD reporter genes (immunoglobulin μ and β-Globin) with or without an intron downstream from the PTC. We show that both NMD modes depend on UPF1 and SMG1, but detected transcript-specific differences with respect to the requirement for UPF2 and UPF3b, consistent with previously reported UPF2- and UPF3-independent branches of NMD. In addition and contrary to expectation, a higher sensitivity of EJC-independent NMD to reduced UPF2 and UPF3b concentrations was observed. Our data further revealed a redundancy of the endo- and exonucleolytic mRNA degradation pathways in both modes of NMD. Moreover, the relative contributions of both decay pathways differed between the reporters, with PTC-containing immunoglobulin μ transcripts being preferentially subjected to SMG6-mediated endonucleolytic cleavage, whereas β-Globin transcripts were predominantly degraded by the SMG5/SMG7-dependent pathway. Overall, the surprising heterogeneity observed with only two NMD reporter pairs suggests the existence of several mechanistically distinct branches of NMD in human cells