Quantitative analysis of snoRNA association with pre-ribosomes and release of snR30 by Rok1 helicase

In yeast, three small nucleolar RNAs (snoRNAs) are essential for the processing of pre-ribosomal RNA—U3, U14 and snR30—whereas 72 non-essential snoRNAs direct site-specific modification of pre-rRNA. We applied a quantitative screen for alterations in the pre-ribosome association to all 75 yeast snoRNAs in strains depleted of eight putative helicases implicated in 40S subunit synthesis. For the modification-guide snoRNAs, we found no clear evidence for the involvement of these helicases in the association or dissociation of pre-ribosomes. However, the DEAD box helicase Rok1 was required specifically for the release of snR30. Point mutations in motif I, but not in motif III, of the helicase domain of Rok1 impaired the release of snR30, but this was less marked than in strains depleted of Rok1, and resulted in a dominant-negative growth phenotype. Dissociation of U3 and U14 from pre-ribosomes is also dependent on helicases, suggesting that release of the essential snoRNAs might differ mechanistically from release of the modification-guide snoRNAs

Modelling co-transcriptional cleavage in the synthesis of yeast pre-rRNA

AbstractIn this paper we present a quantified model of the synthesis of pre-rRNAs in yeast. The chemical kinetics simulation software Dizzy has been used as both the modelling and simulation framework of our study. The simulations have been used to investigate the mechanism of co-transcriptional cleavage which can occur during the synthesis of pre-rRNAs.Throughout the paper we emphasise the strong role of experimental data both in shaping the model and in guiding the analysis which is carried out. Parameter estimation procedures have been used to fit the model to the data and we discuss the validation of the model against the available experimental data. Simulation based on Gillespie’s algorithm is considered to be the reference method for our analysis and a comparison with other simulators is reported. Finally, we define an extended model, that relaxes one of the assumptions of the initial model

Specific heat at the transition in a superconductor with fluctuating magnetic moments

In the heavy-fermion materials CeCoIn$_5$ and UBe$_{13}$, the superconducting order parameter is coupled to flucutating magnetization of the uncompensated part of the localized $f$-moments. We find that this coupling decreases the superconducting transition temperature and increases the jump of the specific-heat coefficient, which indicates entropy transfer from the magnetic to the superconducting degree of freedom at the transition temperature. Below the transition, we find that the magnetic fluctuations are suppressed. We discuss the relation of our results to experiments on CeCoIn$_5$ under pressure.Comment: 4 pages, 1 figur

Post-transcriptional regulation of ribosome biogenesis in yeast

Most microorganisms are exposed to the constantly and often rapidly changing environment. As such they evolved mechanisms to balance their metabolism and energy expenditure with the resources available to them. When resources become scarce or conditions turn out to be unfavourable for growth, cells reduce their metabolism and energy usage to survive. One of the major energy consuming processes in the cell is ribosome biogenesis. Unsurprisingly, cells encountering adverse conditions immediately shut down production of new ribosomes. It is well established that nutrient depletion leads to a rapid repression of transcription of the genes encoding ribosomal proteins, ribosome biogenesis factors as well as ribosomal RNA (rRNA). However, if pre-rRNA processing and ribosome assembly are regulated post-transcriptionally remains largely unclear. We have recently uncovered that the yeast Saccharomyces cerevisiae rapidly switches between two alternative pre-rRNA processing pathways depending on the environmental conditions. Our findings reveal a new level of complexity in the regulation of ribosome biogenesis

Modulation of mammalian translation by a ribosome-associated tRNA half

Originally considered futile degradation products, tRNA-derived RNA fragments (tdRs) have been shown over the recent past to be crucial players in orchestrating various cellular functions. Unlike other small non-coding RNA (ncRNA) classes, tdRs possess a multifaceted functional repertoire ranging from regulating transcription, apoptosis, RNA interference, ribosome biogenesis to controlling translation efficiency. A subset of the latter tdRs has been shown to directly target the ribosome, the central molecular machine of protein biosynthesis. Here we describe the function of the mammalian tRNAPro 5ʹ half, a 35 residue long ncRNA associated with ribosomes and polysomes in several mammalian cell lines. Addition of tRNAPro halves to mammalian in vitro translation systems results in global translation inhibition and concomitantly causes the upregulation of a specific low molecular weight translational product. This tRNAPro 5ʹ half-dependent translation product consists of both RNA and amino acids. Transfection of the tRNAPro half into HeLa cells leads to the formation of the same product in vivo. The migration of this product in acidic gels, the insensitivity to copper sulphate treatment, the resistance to 3ʹ polyadenylation, and the association with 80S monosomes indicate that the accumulated product is peptidyl-tRNA. Our data thus suggest that binding of the tRNAPro 5ʹ half to the ribosome leads to ribosome stalling and to the formation of peptidyl-tRNA. Our findings revealed a so far unknown functional role of a tdR thus further enlarging the functional heterogeneity of this emerging class of ribo-regulators

Sedative load and frailty among community-dwelling population aged ≥65 years

OBJECTIVE: To explore the association between use of sedative drugs and frailty. DESIGN: Cross-sectional study. SETTING: First wave of The Irish Longitudinal Study on Ageing (TILDA), a nationally representative cohort of the community-dwelling population aged 50 years or older in Ireland. PARTICIPANTS: Participants were 1642 men and 1804 women aged 65 years or older. MEASUREMENTS: Regular use of sedative drugs determined according to the sedative load (SL) model, frailty phenotype status, and frailty deficit index (FI) score assessed using validated, established protocols. RESULTS: Overall, 19% of the participants took sedative drugs, most frequently hypnotics and antidepressants. Sedative drug use was at 46% for frail, 23% for prefrail, and 9% for nonfrail participants. After adjustment for covariates, SL was positively associated with being prefrail (odds ratio [OR] 1.27; 95% confidence interval [CI] 1.11-1.46) and frail (OR 1.30; 95% CI 1.02-1.64). Advancing age but not sex remained significant (P < .001). After adjustment for covariates, the association between SL and the FI was also significant at P ≤ .001 (β = 1.77; 95% CI 1.13-2.42). CONCLUSION: Higher SL was positively associated with phenotype frailty and the FI. This suggests that careful consideration must be given when prescribing sedatives to frail older adults, who are most vulnerable to adverse drug reactions and adverse health outcomes