tRNA splicing

Introns interrupt the continuity of many eukaryal genes, and therefore their removal by splicing is a crucial step in gene expression. Interestingly, even within Eukarya there are at least four splicing mechanisms. mRNA splicing in the nucleus takes place in two phosphotransfer reactions on a complex and dynamic machine, the spliceosome. This reaction is related in mechanism to the two self-splicing mechanisms for Group 1 and Group 2 introns. In fact the Group 2 introns are spliced by an identical mechanism to mRNA splicing, although there is no general requirement for either proteins or co-factors. Thus it seems likely that the Group 2 and nuclear mRNA splicing reactions have diverged from a common ancestor. tRNA genes are also interrupted by introns, but here the splicing mechanism is quite different because it is catalyzed by three enzymes, all proteins and with an intrinsic requirement for ATP hydrolysis. tRNA splicing occurs in all three major lines of descent, the Bacteria, the Archaea, and the Eukarya. In bacteria the introns are self-splicing (1-3). Until recently it was thought that the mechanisms of tRNA splicing in Eukarya and Archaea were unrelated as well. In the past year, however, it has been found that the first enzyme in the tRNA splicing pathway, the tRNA endonuclease, has been conserved in evolution since the divergence of the Eukarya and the Archaea. Surprising insights have been obtained by comparison of the structures and mechanisms of tRNA endonuclease from these two divergent lines

Bayesian Calibrated Significance Levels Applied to the Spectral Tilt and Hemispherical Asymmetry

Bayesian model selection provides a formal method of determining the level of support for new parameters in a model. However, if there is not a specific enough underlying physical motivation for the new parameters it can be hard to assign them meaningful priors, an essential ingredient of Bayesian model selection. Here we look at methods maximizing the prior so as to work out what is the maximum support the data could give for the new parameters. If the maximum support is not high enough then one can confidently conclude that the new parameters are unnecessary without needing to worry that some other prior may make them significant. We discuss a computationally efficient means of doing this which involves mapping p-values onto upper bounds of the Bayes factor (or odds) for the new parameters. A p-value of 0.05 ($1.96\sigma$) corresponds to odds less than or equal to 5:2 which is below the `weak' support at best threshold. A p-value of 0.0003 ($3.6\sigma$) corresponds to odds of less than or equal to 150:1 which is the `strong' support at best threshold. Applying this method we find that the odds on the scalar spectral index being different from one are 49:1 at best. We also find that the odds that there is primordial hemispherical asymmetry in the cosmic microwave background are 9:1 at best.Comment: 5 pages. V2: clarifying comments added in response to referee report. Matches version to appear in MNRA

Backstreaming ions at a high Mach number interplanetary shock: Solar Orbiter measurements during the nominal mission phase

Solar Orbiter, a mission developed by the European Space Agency, explores in situ plasma across the inner heliosphere while providing remote-sensing observations of the Sun. Our study examines particle observations for the 30 October 2021 shock. The particles provide clear evidence of ion reflection up to several minutes upstream of the shock. Additionally, the magnetic and electric field observations contain complex electromagnetic structures near the shock, and we aim to investigate how they are connected to ion dynamics. The main goal of this study is to advance our understanding of the complex coupling between particles and the shock structure in high Mach number regimes of interplanetary shocks. We used observations of magnetic and electric fields, probe-spacecraft potential, and thermal and energetic particles to characterize the structure of the shock front and particle dynamics. Furthermore, ion velocity distribution functions were used to study reflected ions and their coupling to the shock. To determine shock parameters and study waves, we used several methods, including cold plasma theory, singular-value decomposition, minimum variance analysis, and shock Rankine-Hugoniot relations. To support the analysis and interpretation of the experimental data, test-particle analysis, and hybrid particle in-cell simulations were used. The ion velocity distribution functions show clear evidence of particle reflection in the form of backstreaming ions several minutes upstream. The shock structure has complex features at the ramp and whistler precursors. The backstreaming ions may be modulated by the complex shock structure, and the whistler waves are likely driven by gyrating ions in the foot. Supra-thermal ions up to 20 keV were observed, but shock-accelerated particles with energies above this were not

Observational constraints on the curvaton model of inflation

Simple curvaton models can generate a mixture of of correlated primordial adiabatic and isocurvature perturbations. The baryon and cold dark matter isocurvature modes differ only by an observationally null mode in which the two perturbations almost exactly compensate, and therefore have proportional effects at linear order. We discuss the CMB anisotropy in general mixed models, and give a simple approximate analytic result for the large scale CMB anisotropy. Working numerically we use the latest WMAP observations and a variety of other data to constrain the curvaton model. We find that models with an isocurvature contribution are not favored relative to simple purely adiabatic models. However a significant primordial totally correlated baryon isocurvature perturbation is not ruled out. Certain classes of curvaton model are thereby ruled out, other classes predict enough non-Gaussianity to be detectable by the Planck satellite. In the appendices we review the relevant equations in the covariant formulation and give series solutions for the radiation dominated era.Comment: Minor changes and corrections to match version accepted by PR

Statistical coverage for supersymmetric parameter estimation: a case study with direct detection of dark matter

Models of weak-scale supersymmetry offer viable dark matter (DM) candidates. Their parameter spaces are however rather large and complex, such that pinning down the actual parameter values from experimental data can depend strongly on the employed statistical framework and scanning algorithm. In frequentist parameter estimation, a central requirement for properly constructed confidence intervals is that they cover true parameter values, preferably at exactly the stated confidence level when experiments are repeated infinitely many times. Since most widely-used scanning techniques are optimised for Bayesian statistics, one needs to assess their abilities in providing correct confidence intervals in terms of the statistical coverage. Here we investigate this for the Constrained Minimal Supersymmetric Standard Model (CMSSM) when only constrained by data from direct searches for dark matter. We construct confidence intervals from one-dimensional profile likelihoods and study the coverage by generating several pseudo-experiments for a few benchmark sets of pseudo-true parameters. We use nested sampling to scan the parameter space and evaluate the coverage for the benchmarks when either flat or logarithmic priors are imposed on gaugino and scalar mass parameters. The sampling algorithm has been used in the configuration usually adopted for exploration of the Bayesian posterior. We observe both under- and over-coverage, which in some cases vary quite dramatically when benchmarks or priors are modified. We show how most of the variation can be explained as the impact of explicit priors as well as sampling effects, where the latter are indirectly imposed by physicality conditions. For comparison, we also evaluate the coverage for Bayesian credible intervals, and observe significant under-coverage in those cases.Comment: 30 pages, 5 figures; v2 includes major updates in response to referee's comments; extra scans and tables added, discussion expanded, typos corrected; matches published versio

Ataluren stimulates ribosomal selection of near-cognate tRNAs to promote nonsense suppression

A premature termination codon (PTC) in the ORF of an mRNA generally leads to production of a truncated polypeptide, accelerated degradation of the mRNA, and depression of overall mRNA expression. Accordingly, nonsense mutations cause some of the most severe forms of inherited disorders. The small-molecule drug ataluren promotes therapeutic nonsense suppression and has been thought to mediate the insertion of near-cognate tRNAs at PTCs. However, direct evidence for this activity has been lacking. Here, we expressed multiple nonsense mutation reporters in human cells and yeast and identified the amino acids inserted when a PTC occupies the ribosomal A site in control, ataluren-treated, and aminoglycoside-treated cells. We find that ataluren\u27s likely target is the ribosome and that it produces full-length protein by promoting insertion of near-cognate tRNAs at the site of the nonsense codon without apparent effects on transcription, mRNA processing, mRNA stability, or protein stability. The resulting readthrough proteins retain function and contain amino acid replacements similar to those derived from endogenous readthrough, namely Gln, Lys, or Tyr at UAA or UAG PTCs and Trp, Arg, or Cys at UGA PTCs. These insertion biases arise primarily from mRNA:tRNA mispairing at codon positions 1 and 3 and reflect, in part, the preferred use of certain nonstandard base pairs, e.g., U-G. Ataluren\u27s retention of similar specificity of near-cognate tRNA insertion as occurs endogenously has important implications for its general use in therapeutic nonsense suppression

Cognitive bias modification for paranoia (CBM-pa): a randomised controlled feasibility study in patients with distressing paranoid beliefs

Background: Cognitive Bias Modification for paranoia (CBM-pa) is a novel, theory-driven psychological intervention targeting the biased interpretation of emotional ambiguity associated with paranoia. Study objectives were (i) test the intervention's feasibility, (ii) provide effect size estimates, (iii) assess dose-response and (iv) select primary outcomes for future trials. Methods: In a double-blind randomised controlled trial, sixty-three outpatients with clinically significant paranoia were randomised to either CBM-pa or an active control (text reading) between April 2016 and September 2017. Patients received one 40 min session per week for 6 weeks. Assessments were given at baseline, after each interim session, post-treatment, and at 1- and 3-months post-treatment. Results: A total of 122 patients were screened and 63 were randomised. The recruitment rate was 51.2%, with few dropouts (four out of 63) and follow-up rates were 90.5% (1-month) and 93.7% (3-months). Each session took 30-40 min to complete. There was no statistical evidence of harmful effects of the intervention. Preliminary data were consistent with efficacy of CBM-pa over text-reading control: patients randomised to the intervention, compared to control patients, reported reduced interpretation bias (d = -0.48 to -0.76), improved symptoms of paranoia (d = -0.19 to -0.38), and lower depressed and anxious mood (d = -0.03 to -0.29). The intervention effect was evident after the third session. Conclusions: CBM-pa is feasible for patients with paranoia. A fully powered randomised control trial is warranted

Correlated perturbations from inflation and the cosmic microwave background

We compare the latest cosmic microwave background data with theoretical predictions including correlated adiabatic and CDM isocurvature perturbations with a simple power-law dependence. We find that there is a degeneracy between the amplitude of correlated isocurvature perturbations and the spectral tilt. A negative (red) tilt is found to be compatible with a larger isocurvature contribution. Estimates of the baryon and CDM densities are found to be almost independent of the isocurvature amplitude. The main result is that current microwave background data do not exclude a dominant contribution from CDM isocurvature fluctuations on large scales.Comment: 5 pages, revtex, 3 figures. V3 - DASI data added and reionization taken into account. New figure 2. Matches version to appear in PR

Cosmological parameters from SDSS and WMAP

We measure cosmological parameters using the three-dimensional power spectrum P(k) from over 200,000 galaxies in the Sloan Digital Sky Survey (SDSS) in combination with WMAP and other data. Our results are consistent with a ``vanilla'' flat adiabatic Lambda-CDM model without tilt (n=1), running tilt, tensor modes or massive neutrinos. Adding SDSS information more than halves the WMAP-only error bars on some parameters, tightening 1 sigma constraints on the Hubble parameter from h~0.74+0.18-0.07 to h~0.70+0.04-0.03, on the matter density from Omega_m~0.25+/-0.10 to Omega_m~0.30+/-0.04 (1 sigma) and on neutrino masses from <11 eV to <0.6 eV (95%). SDSS helps even more when dropping prior assumptions about curvature, neutrinos, tensor modes and the equation of state. Our results are in substantial agreement with the joint analysis of WMAP and the 2dF Galaxy Redshift Survey, which is an impressive consistency check with independent redshift survey data and analysis techniques. In this paper, we place particular emphasis on clarifying the physical origin of the constraints, i.e., what we do and do not know when using different data sets and prior assumptions. For instance, dropping the assumption that space is perfectly flat, the WMAP-only constraint on the measured age of the Universe tightens from t0~16.3+2.3-1.8 Gyr to t0~14.1+1.0-0.9 Gyr by adding SDSS and SN Ia data. Including tensors, running tilt, neutrino mass and equation of state in the list of free parameters, many constraints are still quite weak, but future cosmological measurements from SDSS and other sources should allow these to be substantially tightened.Comment: Minor revisions to match accepted PRD version. SDSS data and ppt figures available at http://www.hep.upenn.edu/~max/sdsspars.htm

CLP1 Founder Mutation Links tRNA Splicing and Maturation to Cerebellar Development and Neurodegeneration

SummaryNeurodegenerative diseases can occur so early as to affect neurodevelopment. From a cohort of more than 2,000 consanguineous families with childhood neurological disease, we identified a founder mutation in four independent pedigrees in cleavage and polyadenylation factor I subunit 1 (CLP1). CLP1 is a multifunctional kinase implicated in tRNA, mRNA, and siRNA maturation. Kinase activity of the CLP1 mutant protein was defective, and the tRNA endonuclease complex (TSEN) was destabilized, resulting in impaired pre-tRNA cleavage. Germline clp1 null zebrafish showed cerebellar neurodegeneration that was rescued by wild-type, but not mutant, human CLP1 expression. Patient-derived induced neurons displayed both depletion of mature tRNAs and accumulation of unspliced pre-tRNAs. Transfection of partially processed tRNA fragments into patient cells exacerbated an oxidative stress-induced reduction in cell survival. Our data link tRNA maturation to neuronal development and neurodegeneration through defective CLP1 function in humans