A conserved and essential basic region mediates tRNA binding to the Elp1 subunit of the <em>Saccharomyces cerevisiae</em> Elongator complex

Elongator is a conserved, multi-protein complex discovered in Saccharomyces cerevisiae, loss of which confers a range of pleiotropic phenotypes. Elongator in higher eukaryotes is required for normal growth and development and a mutation in the largest subunit of human Elongator (Elp1) causes familial dysautonomia, a severe recessive neuropathy. Elongator promotes addition of mcm(5) and ncm(5) modifications to uridine in the tRNA anticodon ‘wobble’ position in both yeast and higher eukaryotes. Since these modifications are required for the tRNAs to function efficiently, a translation defect caused by hypomodified tRNAs may therefore underlie the variety of phenotypes associated with Elongator dysfunction. The Elp1 carboxy-terminal domain contains a highly conserved arginine/lysine-rich region that resembles a nuclear localization sequence (NLS). Using alanine substitution mutagenesis, we show that this region is essential for Elongator's function in tRNA wobble uridine modification. However, rather than acting to determine the nucleo-cytoplasmic distribution of Elongator, we find that the basic region plays a critical role in a novel interaction between tRNA and the Elp1 carboxy-terminal domain. Thus the conserved basic region in Elp1 may be essential for tRNA wobble uridine modification by acting as tRNA binding motif

Cosmology at the Millennium

One hundred years ago we did not know how stars generate energy, the age of the Universe was thought to be only millions of years, and our Milky Way galaxy was the only galaxy known. Today, we know that we live in an evolving and expanding Universe comprising billions of galaxies, all held together by dark matter. With the hot big-bang model, we can trace the evolution of the Universe from the hot soup of quarks and leptons that existed a fraction of a second after the beginning to the formation of galaxies a few billion years later, and finally to the Universe we see today 13 billion years after the big bang, with its clusters of galaxies, superclusters, voids, and great walls. The attractive force of gravity acting on tiny primeval inhomogeneities in the distribution of matter gave rise to all the structure seen today. A paradigm based upon deep connections between cosmology and elementary particle physics -- inflation + cold dark matter -- holds the promise of extending our understanding to an even more fundamental level and much earlier times, as well as shedding light on the unification of the forces and particles of nature. As we enter the 21st century, a flood of observations is testing this paradigm.Comment: 44 pages LaTeX with 14 eps figures. To be published in the Centennial Volume of Reviews of Modern Physic

Phase Dynamics of Nearly Stationary Patterns in Activator-Inhibitor Systems

The slow dynamics of nearly stationary patterns in a FitzHugh-Nagumo model are studied using a phase dynamics approach. A Cross-Newell phase equation describing slow and weak modulations of periodic stationary solutions is derived. The derivation applies to the bistable, excitable, and the Turing unstable regimes. In the bistable case stability thresholds are obtained for the Eckhaus and the zigzag instabilities and for the transition to traveling waves. Neutral stability curves demonstrate the destabilization of stationary planar patterns at low wavenumbers to zigzag and traveling modes. Numerical solutions of the model system support the theoretical findings

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo