Total Synthesis of Paracaseolide A

The total synthesis of paracaseolide A, a valuable cell-cycle progression inhibitor, was accomplished in 8 steps from known compounds, with 6.6% overall yield. The synthetic strategy creates strong potential for diversification

Toxicology evaluation of radiotracer doses of 3'-deoxy-3'-[18F]fluorothymidine (18F-FLT) for human PET imaging: Laboratory analysis of serial blood samples and comparison to previously investigated therapeutic FLT doses

Background: 18F-FLT is a novel PET radiotracer which has demonstrated a strong potential utility for imaging cellular proliferation in human tumors in vivo. To facilitate future regulatory approval of 18F-FLT for clinical use, we wished to demonstrate the safety of radiotracer doses of 18F-FLT administered to human subjects, by: 1) performing an evaluation of the toxicity of 18F-FLT administered in radiotracer amounts for PET imaging, 2) comparing a radiotracer dose of FLT to clinical trial doses of FLT. Methods: Twenty patients gave consent to a 18F-FLT injection, subsequent PET imaging, and blood draws. For each patient, blood samples were collected at multiple times before and after 18F-FLT PET. These samples were assayed for a comprehensive metabolic panel, total bilirubin, complete blood and platelet counts. 18F-FLT doses of 2.59 MBq/Kg with a maximal dose of 185 MBq (5 mCi) were used. Blood time-activity curves were generated for each patient from dynamic PET data, providing a measure of the area under the FLT concentration curve for 12 hours (AUC12). Results: No side effects were reported. Only albumin, red blood cell count, hematocrit and hemoglobin showed a statistically significant decrease over time. These changes are attributed to IV hydration during PET imaging and to subsequent blood loss at surgery. The AUC12 values estimated from imaging data are not significantly different from those found from serial measures of FLT blood concentrations (p = 0.66). The blood samples-derived AUC12 values range from 0.232 ng*h/mL to 1.339 ng*h/mL with a mean of 0.802 � 0.303 ng*h/mL. This corresponds to 0.46% to 2.68% of the lowest and least toxic clinical trial AUC12 of 50 ng*h/mL reported by Flexner et al (1994). This single injection also corresponds to a nearly 3,000-fold lower cumulative dose than in Flexner's twice daily trial. Conclusion: This study shows no evidence of toxicity or complications attributable to 18F-FLT injected intravenously.This study was supported by NIH grant R01 CA115559, 1R01 CA107264, and 1R01 CA80907

Use of molecular modelling to probe the mechanism of the nucleoside transporter NupG.

Nucleosides play key roles in biology as precursors for salvage pathways of nucleotide synthesis. Prokaryotes import nucleosides across the cytoplasmic membrane by proton- or sodium-driven transporters belonging to the Concentrative Nucleoside Transporter (CNT) family or the Nucleoside:H(+) Symporter (NHS) family of the Major Facilitator Superfamily. The high resolution structure of a CNT from Vibrio cholerae has recently been determined, but no similar structural information is available for the NHS family. To gain a better understanding of the molecular mechanism of nucleoside transport, in the present study the structures of two conformations of the archetypical NHS transporter NupG from Escherichia coli were modelled on the inward- and outward-facing conformations of the lactose transporter LacY from E. coli, a member of the Oligosaccharide:H(+) Symporter (OHS) family. Sequence alignment of these distantly related proteins (∼ 10% sequence identity), was facilitated by comparison of the patterns of residue conservation within the NHS and OHS families. Despite the low sequence similarity, the accessibilities of endogenous and introduced cysteine residues to thiol reagents were found to be consistent with the predictions of the models, supporting their validity. For example C358, located within the predicted nucleoside binding site, was shown to be responsible for the sensitivity of NupG to inhibition by p-chloromercuribenzene sulphonate. Functional analysis of mutants in residues predicted by the models to be involved in the translocation mechanism, including Q261, E264 and N228, supported the hypothesis that they play important roles, and suggested that the transport mechanisms of NupG and LacY, while different, share common features

Sulfide geochronology along the Endeavour Segment of the Juan de Fuca Ridge

Forty-nine hydrothermal sulfide-sulfate rock samples from the Endeavour Segment of the Juan de Fuca Ridge, northeastern Pacific Ocean, were dated by measuring the decay of 226Ra (half-life of 1600 years) in hydrothermal barite to provide a history of hydrothermal venting at the site over the past 6000 years. This dating method is effective for samples ranging in age from ∼200 to 20,000 years old and effectively bridges an age gap between shorter- and longer-lived U-series dating techniques for hydrothermal deposits. Results show that hydrothermal venting at the active High Rise, Sasquatch, and Main Endeavour fields began at least 850, 1450, and 2300 years ago, respectively. Barite ages of other inactive deposits on the axial valley floor are between ∼1200 and ∼2200 years old, indicating past widespread hydrothermal venting outside of the currently active vent fields. Samples from the half-graben on the eastern slope of the axial valley range in age from ∼1700 to ∼2925 years, and a single sample from outside the axial valley, near the westernmost valley fault scarp is ∼5850 ± 205 years old. The spatial relationship between hydrothermal venting and normal faulting suggests a temporal relationship, with progressive younging of sulfide deposits from the edges of the axial valley toward the center of the rift. These relationships are consistent with the inward migration of normal faulting toward the center of the valley over time and a minimum age of onset of hydrothermal activity in this region of 5850 years

SRH and HrQOL: does social position impact differently on their link with health status?

<p>Abstract</p> <p>Background</p> <p>Self-rated Health (SRH) and health-related quality of life (HRQoL) are used to evaluate health disparities. Like all subjective measures of health, they are dependent on health expectations that are associated with socioeconomic characteristics. It is thus needed to analyse the influence played by socioeconomic position (SEP) on the relationship between these two indicators and health conditions if we aim to use them to study health disparities. Our objective is to assess the influence of SEP on the relationship between physical health status and subjective health status, measured by SRH and HRQoL using the SF-36 scale.</p> <p>Methods</p> <p>We used data from the French National Health Survey. SEP was assessed by years of education and household annual income. Physical health status was measured by functional limitations and chronic low back pain.</p> <p>Results</p> <p>Regardless of their health status, people with lower SEP were more likely than their more socially advantaged counterparts to report poor SRH and poorer HRQoL, using any of the indicators of SEP. The negative impact of chronic low back pain on SRH was relatively greater in people with a high SEP than in those with a low SEP. In contrast, chronic low back pain and functional limitations had less impact on physical and mental component scores of quality of life for socially advantaged men and women.</p> <p>Conclusions</p> <p>Both SRH and HRQoL were lower among those reporting functional limitations or chronic low back pain. However, the change varied according SEP and the measure. In relative term, the negative impact of a given health condition seems to be greater on SRH and lower on HRQoL for people with higher SEP in comparison with people with low SEP. Using SRH could thus decrease socioeconomic differences. In contrast using HRQoL could increase these differences, suggesting being cautious when using these indicators for analyzing health disparities.</p

Triad pattern algorithm for predicting strong promoter candidates in bacterial genomes

Abstract Background Bacterial promoters, which increase the efficiency of gene expression, differ from other promoters by several characteristics. This difference, not yet widely exploited in bioinformatics, looks promising for the development of relevant computational tools to search for strong promoters in bacterial genomes. Results We describe a new triad pattern algorithm that predicts strong promoter candidates in annotated bacterial genomes by matching specific patterns for the group I σ70 factors of Escherichia coli RNA polymerase. It detects promoter-specific motifs by consecutively matching three patterns, consisting of an UP-element, required for interaction with the α subunit, and then optimally-separated patterns of -35 and -10 boxes, required for interaction with the σ70 subunit of RNA polymerase. Analysis of 43 bacterial genomes revealed that the frequency of candidate sequences depends on the A+T content of the DNA under examination. The accuracy of in silico prediction was experimentally validated for the genome of a hyperthermophilic bacterium, Thermotoga maritima, by applying a cell-free expression assay using the predicted strong promoters. In this organism, the strong promoters govern genes for translation, energy metabolism, transport, cell movement, and other as-yet unidentified functions. Conclusion The triad pattern algorithm developed for predicting strong bacterial promoters is well suited for analyzing bacterial genomes with an A+T content of less than 62%. This computational tool opens new prospects for investigating global gene expression, and individual strong promoters in bacteria of medical and/or economic significance.</p

All-sky search for gravitational-wave bursts in the second joint LIGO-Virgo run

We present results from a search for gravitational-wave bursts in the data collected by the LIGO and Virgo detectors between July 7, 2009 and October 20, 2010: data are analyzed when at least two of the three LIGO-Virgo detectors are in coincident operation, with a total observation time of 207 days. The analysis searches for transients of duration < 1 s over the frequency band 64-5000 Hz, without other assumptions on the signal waveform, polarization, direction or occurrence time. All identified events are consistent with the expected accidental background. We set frequentist upper limits on the rate of gravitational-wave bursts by combining this search with the previous LIGO-Virgo search on the data collected between November 2005 and October 2007. The upper limit on the rate of strong gravitational-wave bursts at the Earth is 1.3 events per year at 90% confidence. We also present upper limits on source rate density per year and Mpc^3 for sample populations of standard-candle sources. As in the previous joint run, typical sensitivities of the search in terms of the root-sum-squared strain amplitude for these waveforms lie in the range 5 10^-22 Hz^-1/2 to 1 10^-20 Hz^-1/2. The combination of the two joint runs entails the most sensitive all-sky search for generic gravitational-wave bursts and synthesizes the results achieved by the initial generation of interferometric detectors.Comment: 15 pages, 7 figures: data for plots and archived public version at https://dcc.ligo.org/cgi-bin/DocDB/ShowDocument?docid=70814&version=19, see also the public announcement at http://www.ligo.org/science/Publication-S6BurstAllSky