Bisphosphonates are effective for the treatment of osteoporosis despite recent reports of safety concerns such as atypical femur fracture. We conducted an ecological analysis of relevant media reports, oral bisphosphonate use, and fracture outcomes in the United States. Trends in media reports and public interest of bisphosphonates were quantified using data from Google Trends. Data from the Medical Expenditure Panel Survey (MEPS) and the National Inpatient Sample (NIS) were used to estimate the trends in oral bisphosphonate use among patients aged 55 years and older and hospitalizations for intertrochanteric and subtrochanteric fractures, respectively. These trends in the prevalence of oral bisphosphonate use and the age-adjusted incidence rate of intertrochanteric and subtrochanteric fractures were examined from 1996 to 2012. A series of spikes in Internet search activity for alendronate (Fosamax) occurred between 2006 and 2010 immediately following media reports of safety concerns. Oral bisphosphonate use declined by greater than 50% between 2008 and 2012 (p < 0.001) after increasing use for more than a decade.

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Chromosome I from the yeast Saccharomyces cerevisiae contains a DNA molecule of -231 kbp and is the smallest naturally occurring functional eukaryotic nuclear chromosome so far characterized. The nucleotide sequence of this chromosome has been determined as part of an international collaboration to sequence the entire yeast genome. The yeast Saccharomyces cerevisiae has been the focus of intensive study as a model eukaryote. As part of this effort, an international program is under way to determine the nucleotide sequence of the 16 chromosomes that constitute its 13.5-Mbp nuclear genome. This endeavor will provide both a complete eukaryotic gene set and a reference set of experimentally amenable genes for comparison with those of other organisms. Currently, four yeast chromosomes have been sequenced (1-4); all have a high gene density, and a majority of the genes found are newly sequenced and of unknown function. Chromosome I is the smallest S. cerevisiae chromosome. It contains a DNA molecule that is only 231 kbp, making it the smallest known fully functional nuclear chromosome. This chromosome has been studied intensively, and mutants are available for a large number of its genes (5-7). Here we report the nucleotide sequence of chromosome I and describe several unusual features of its gene organization and chromosome structure as well as many newly discovered genes.** MATERIALS AND METHODS DNA Sources. Four sources of chromosome I DNA, all from S288C-derived yeast strains, were used to generate the tem-The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.plates for DNA sequencing. These were the library of Riles et aL (8), a cosmid from the collection of Dujon (9), chromosome walking (10), and PCR amplified fragments of genomic DNA. DNA fragments, except those generated by PCR which were used directly, were subcloned into the Bluescript KS(+) plasmid from Stratagene prior to sequencing. All DNA sequencing was performed using double-stranded DNA templates.DNA Sequencing. Two methods were used for sequencing DNA templates: manual sequencing and machine-based sequencing with an Applied Biosystems sequencing machine (model 373A). Our manual sequencing used unidirectional nested deletions and was carried out as described (11, 12). For machine-based sequencing, three sets of templates were used: unidirectional nested deletions, PCR amplified chromosomal DNA, and, for the region spanning YAL062 to CDC24, cosmid DNA was shotgun cloned into Bluescript KS(+). In summary, the procedure for the Applied Biosystems machine (model 373A) used dye-labeled dideoxynucleotide terminators and a cycle sequencing kit (Prism Ready reaction dye terminator kit; Perkin-Elmer) and the protocol provided by the supplier. This method allowed us to process all four sequencing reactions in a single reaction tube. The cycle amplification reactions were performed with a Perkin-Elmer ...

Translational control mediated by an upstream open reading frame (uORF) in the 5'-leader of the Neurospora crassa arg-2 mRNA was reconstituted in a homologous, cell-free in vitro translation system. A cell-free N. crassa system was developed that required the presence of cap and poly(A) on RNA for maximal translation and that was amino acid-dependent. The 24-codon arg-2 uORF, when placed in the 5'-leader region of capped and adenylated synthetic luciferase RNAs, conferred Arg-specific negative regulation in this system. Improving the uORF translation initiation context decreased luciferase production and only slightly increased the magnitude of Arg-specific regulation. Mutation of uORF Asp codon 12 to Asn, which eliminates Arg-specific regulation in vivo, eliminated regulation in vitro. Elimination of the uORF translation initiation codon also eliminated Arg-specific regulation. Arg-specific regulation in vitro appeared to be reversible. Control of RNA stability did not appear to be a primary component of Arg-specific regulation in vitro. Comparison of the effects of adding Arg to in vitro translation reactions with adding compounds related to Arg indicated that Arg-specific translational regulation was specific for L-arginine.