mRNA Suicide: Destabilization by Programmed Ribosomal Frameshifting

Cis-acting mRNA elements that promote programmed -1 ribosomal frameshifting (-1 PRF) redirect a fraction of translating ribosomes into a new translational reading frame. In viruses, these signals typically direct the translation of alternative protein products from a single mRNA. However, programmed frameshifts could also direct elongating ribosomes to premature termination codons, in which case the mRNAs could become targets for degradation by the nonsense mediated mRNA decay pathway (NMD). Computational analyses revealed the presence of 10,340 consensus -1 PRF signals in the <i>Saccharomyces cerevisiae</i> genome. Of the 6,353 yeast open reading frames (ORFs) included in this study, 1,275 are predicted to have at least one strong and statistically significant -1 PRF signal. In contrast to viral frameshifting, the predicted outcomes of nearly all of these genomic frameshift signals would direct ribosomes to premature termination codons, in theory making these mRNAs substrates for NMD. Nine of these predicted -1 PRF signals were tested empirically, eight of which promoted efficient levels of PRF in vivo. This study also demonstrates that viral -1 PRF signals are sufficient to target a reporter mRNA for degradation via NMD. Furthermore, several of -1 PRF signals from the yeast genome were also shown to act as NMD-dependent mRNA destabilizing element. Importantly, these signals are found in genes whose mRNAs are known to be natural targets for NMD. These findings support the hypothesis that PRF may be used by cellular mRNAs to initiate "mRNA suicide". A model is presented in which programmed frameshifting acts as a general post-transcriptional regulatory mechanism to control gene expression by regulating mRNA abundance

PRFdb: A database of computationally predicted eukaryotic programmed -1 ribosomal frameshift signals

The Programmed Ribosomal Frameshift Database (PRFdb) provides an interface to help researchers identify potential programmed -1 ribosomal frameshift (-1 PRF) signals in eukaryotic genes or sequences of interest. To identify putative -1 PRF signals, sequences are first imported from whole genomes or datasets, e.g. the yeast genome project and mammalian gene collection. They are then filtered through multiple algorithms to identify potential -1 PRF signals as defined by a heptameric slippery site followed by an mRNA pseudoknot. The significance of each candidate -1 PRF signal is evaluated by comparing the predicted thermodynamic stability (ΔG°) of the native mRNA sequence against a distribution of ΔG° values of a pool of randomized sequences derived from the original. The data have been compiled in a user-friendly, easily searchable relational database. The PRFdB enables members of the research community to determine whether genes that they are investigating contain potential -1 PRF signals, and can be used as a metasource of information for cross referencing with other databases. It is available on the web at http://dinmanlab.umd.edu/prfdb .https://doi.org/10.1186/1471-2164-9-33

Levels of soluble fms-like tyrosine kinase one in first trimester and outcomes of pregnancy: a systematic review

Angiogenic factors are involved in formation of new blood vessels required for placental development and function; and critical for fetal growth and development. Soluble fms-like tyrosine kinase 1(sFlt-1) is an anti-angiogenic protein that inhibits formation of new blood vessels resulting in potential pregnancy complications. The objective of this study was to undertake a systematic review to assess levels of sFlt-1 in early pregnancy and association with adverse pregnancy outcomes. PubMed and Medline databases and reference lists were searched up to July 2010. Inclusion criteria were pregnant women, blood sample taken during first trimester and assessment/reporting of sFlt-1 concentrations and subsequent pregnancy complications. Twelve relevant studies were identified of 71 to 668 women. No pooling of results was undertaken due to variation in sFlt-1 concentrations (range, 166-6,349 pg/ml amongst controls), samples used (serum, plasma), different summary statistics (mean, median, odds ratio) and outcome definitions applied. Levels of sFlt-1 were generally higher among women who developed preeclampsia (11 studies) or gestational hypertension (two studies), but not significantly different to normotensive women in most studies. There was no consistent pattern in association between sFlt-1 concentrations and fetal growth restriction (4 studies); and levels were non-significantly higher for women with postpartum bleeding (1 study) and significantly lower for stillbirths (1 study).This review found no clear evidence of an association between sFlt-1 levels in first trimester and adverse pregnancy outcomes. However, findings were affected by methodological, biological and testing variations between studies; highlighting the need for consistent testing of new biomarkers and reporting of outcome measures

What Next-Generation 21 cm Power Spectrum Measurements Can Teach Us About the Epoch of Reionization

A number of experiments are currently working towards a measurement of the 21 cm signal from the Epoch of Reionization. Whether or not these experiments deliver a detection of cosmological emission, their limited sensitivity will prevent them from providing detailed information about the astrophysics of reionization. In this work, we consider what types of measurements will be enabled by a next-generation of larger 21 cm EoR telescopes. To calculate the type of constraints that will be possible with such arrays, we use simple models for the instrument, foreground emission, and the reionization history. We focus primarily on an instrument modeled after the $\sim 0.1~\rm{km}^2$ collecting area Hydrogen Epoch of Reionization Array (HERA) concept design, and parameterize the uncertainties with regard to foreground emission by considering different limits to the recently described "wedge" footprint in k-space. Uncertainties in the reionization history are accounted for using a series of simulations which vary the ionizing efficiency and minimum virial temperature of the galaxies responsible for reionization, as well as the mean free path of ionizing photons through the IGM. Given various combinations of models, we consider the significance of the possible power spectrum detections, the ability to trace the power spectrum evolution versus redshift, the detectability of salient power spectrum features, and the achievable level of quantitative constraints on astrophysical parameters. Ultimately, we find that $0.1~\rm{km}^2$ of collecting area is enough to ensure a very high significance ($\gtrsim30\sigma$) detection of the reionization power spectrum in even the most pessimistic scenarios. This sensitivity should allow for meaningful constraints on the reionization history and astrophysical parameters, especially if foreground subtraction techniques can be improved and successfully implemented.Comment: 27 pages, 18 figures, updated SKA numbers in appendi

Development of a Mind Body Program for Obese Knee Osteoarthritis Patients with Comorbid Depression

Knee osteoarthritis (OA) is the most common joint disorder in the U.S. and a leading cause of disability. Depression and obesity are highly comorbid among knee OA patients, and the combination of obesity and depression is associated with decreased physical activity, higher pain and disability, and more rapid cartilage degradation. Depression, obesity and OA exacerbate one another and share a common pathophysiology involving systemic inflammation and pro-inflammatory cytokines, reflecting a complex mind-body interaction. Current treatments for knee OA offer little to no benefit over placebo, and do not emphasize mind-body practices or physical activity to target the underlying pathophysiology. Mind-body interventions to lessen depressive symptoms and increase physical activity offer the ability to target biological, mechanical and psychological mechanisms of OA progression. Our long-term goals are to evaluate the mechanisms by which the Relaxation Response Resiliency Program (3RP) delivered via secure telehealth, and adapted for patients with depression, obesity and knee OA (GetActive-OA) promotes increases in physical activity and improved knee health. We hypothesize that the synergistic interaction between mindfulness, adaptive thinking, positive psychology and healthy living skills of the GetActive-OA will slow the progression of symptomatic knee OA by reducing pro-inflammatory cytokine expression and promoting optimal mechanical loading of the cartilage. Here we present the protocol for a mixed methods study that will adapt the 3RP for the needs of knee OA patients with depression and obesity with a focus on increasing physical activity (GetActive-OA), and iteratively maximize the feasibility, credibility and acceptability of the programs and research procedures