Interaction between tetraethylammonium and amino acid residues in the pore of cloned voltage-dependent potassium channels

Extracellular tetraethylammonium (TEA) inhibits currents in Xenopus oocytes that have been injected with mRNAs encoding voltage-dependent potassium channels. Concentration-response curves were used to measure the affinity of TEA; this differed up to 700-fold among channels RBK1 (KD 0.3 mM), RGK5 (KD 11 mM), and RBK2 (KD greater than 200 mM). Studies in which chimeric channels were expressed localized TEA binding to the putative extracellular loop between trans-membrane domains S5 and S6. Site-directed mutagenesis of residues in this region identified the residue Tyr379 of RBK1 as a crucial determinant of TEA sensitivity; substitution of Tyr in the equivalent positions of RBK2 (Val381) and RGK5 (His401) made these channels as sensitive to TEA as RBK1. Nonionic forces are involved in TEA binding because (i) substitution of the Phe for Tyr379 in RBK1 increased its affinity, (ii) protonation of His401 in RGK5 selectively reduced its affinity, and (iii) the affinity of TEA was unaffected by changes in ionic strength. The results suggest an explanation for the marked differences in TEA sensitivity that have been observed among naturally occurring and cloned potassium channels and indicate that the amino acid corresponding to residue 379 in RBK1 lies within the external mouth of the ion channel

Evidence for Non-perturbative String Symmetries

String theory appears to admit a group of discrete field transformations -- called $S$ dualities -- as exact non-perturbative quantum symmetries. Mathematically, they are rather analogous to the better-known $T$ duality symmetries, which hold perturbatively. In this talk the evidence for $S$ duality is reviewed and some speculations are presented.Comment: Error corrected and reference added; 10 pages, latex, no figures, conference Repor

A randomized trial of vertebroplasty for painful osteoporotic vertebral fractures

Background Vertebroplasty has become a common treatment for painful osteoporotic vertebral fractures, but there is limited evidence to support its use. Methods We performed a multicenter, randomized, double-blind, placebo-controlled trial in which participants with one or two painful osteoporotic vertebral fractures that were of less than 12 months\u27 duration and unhealed, as confirmed by magnetic resonance imaging, were randomly assigned to undergo vertebroplasty or a sham procedure. Participants were stratified according to treatment center, sex, and duration of symptoms (&lt;6 weeks or 6 weeks). Outcomes were assessed at 1 week and at 1, 3, and 6 months. The primary outcome was overall pain (on a scale of 0 to 10, with 10 being the maximum imaginable pain) at 3 months. Results A total of 78 participants were enrolled, and 71 (35 of 38 in the vertebroplasty group and 36 of 40 in the placebo group) completed the 6-month follow-up (91%). Vertebroplasty did not result in a significant advantage in any measured outcome at any time point. There were significant reductions in overall pain in both study groups at each follow-up assessment. At 3 months, the mean (&plusmn;SD) reductions in the score for pain in the vertebroplasty and control groups were 2.6&plusmn;2.9 and 1.9&plusmn;3.3, respectively (adjusted between-group difference, 0.6; 95% confidence interval, &ndash;0.7 to 1.8). Similar improvements were seen in both groups with respect to pain at night and at rest, physical functioning, quality of life, and perceived improvement. Seven incident vertebral fractures (three in the vertebroplasty group and four in the placebo group) occurred during the 6-month follow-up period. Conclusions We found no beneficial effect of vertebroplasty as compared with a sham procedure in patients with painful osteoporotic vertebral fractures, at 1 week or at 1, 3, or 6 months after treatment. (Australian New Zealand Clinical Trials Registry number, ACTRN012605000079640.)<br /

A novel method to derive a human safety limit for PFOA by gene expression profiling and modelling

Perfluorooctanoic acid (PFOA) is a persistent environmental contaminant that can accumulate in the human body due to its long half-life. This substance has been associated with liver, pancreatic, testicular and breast cancers, liver steatosis and endocrine disruption. PFOA is a member of a large group of substances also known as “forever chemicals” and the vast majority of substances of this group lack toxicological data that would enable their effective risk assessment in terms of human health hazards. This study aimed to derive a health-based guidance value for PFOA intake (ng/kg BW/day) from in vitro transcriptomics data. To this end, we developed an in silico workflow comprising five components: (i) sourcing in vitro hepatic transcriptomics concentration-response data; (ii) deriving molecular points of departure using BMDExpress3 and performing pathway analysis using gene set enrichment analysis (GSEA) to identify the most sensitive molecular pathways to PFOA exposure; (iii) estimating freely-dissolved PFOA concentrations in vitro using a mass balance model; (iv) estimating in vivo doses by reverse dosimetry using a PBK model for PFOA as part of a quantitative in vitro to in vivo extrapolation (QIVIVE) algorithm; and (v) calculating a tolerable daily intake (TDI) for PFOA. Fourteen percent of interrogated genes exhibited in vitro concentration-response relationships. GSEA pathway enrichment analysis revealed that “fatty acid metabolism” was the most sensitive pathway to PFOA exposure. In vitro free PFOA concentrations were calculated to be 2.9% of the nominal applied concentrations, and these free concentrations were input into the QIVIVE workflow. Exposure doses for a virtual population of 3,000 individuals were estimated, from which a TDI of 0.15 ng/kg BW/day for PFOA was calculated using the benchmark dose modelling software, PROAST. This TDI is comparable to previously published values of 1.16, 0.69, and 0.86 ng/kg BW/day by the European Food Safety Authority. In conclusion, this study demonstrates the combined utility of an “omics”-derived molecular point of departure and in silico QIVIVE workflow for setting health-based guidance values in anticipation of the acceptance of in vitro concentration-response molecular measurements in chemical risk assessment

Annotating the human genome with Disease Ontology

<p>Abstract</p> <p>Background</p> <p>The human genome has been extensively annotated with Gene Ontology for biological functions, but minimally computationally annotated for diseases.</p> <p>Results</p> <p>We used the Unified Medical Language System (UMLS) MetaMap Transfer tool (MMTx) to discover gene-disease relationships from the GeneRIF database. We utilized a comprehensive subset of UMLS, which is disease-focused and structured as a directed acyclic graph (the Disease Ontology), to filter and interpret results from MMTx. The results were validated against the Homayouni gene collection using recall and precision measurements. We compared our results with the widely used Online Mendelian Inheritance in Man (OMIM) annotations.</p> <p>Conclusion</p> <p>The validation data set suggests a 91% recall rate and 97% precision rate of disease annotation using GeneRIF, in contrast with a 22% recall and 98% precision using OMIM. Our thesaurus-based approach allows for comparisons to be made between disease containing databases and allows for increased accuracy in disease identification through synonym matching. The much higher recall rate of our approach demonstrates that annotating human genome with Disease Ontology and GeneRIF for diseases dramatically increases the coverage of the disease annotation of human genome.</p

Swift Observations of GRB 050603: An afterglow with a steep late time decay slope

We report the results of Swift observations of the Gamma Ray Burst GRB 050603. With a V magnitude V=18.2 about 10 hours after the burst the optical afterglow was the brightest so far detected by Swift and one of the brightest optical afterglows ever seen. The Burst Alert Telescope (BAT) light curves show three fast-rise-exponential-decay spikes with $T_{90}$=12s and a fluence of 7.6$\times 10^{-6}$ ergs cm$^{-2}$ in the 15-150 keV band. With an $E_{\rm \gamma, iso} = 1.26 \times 10^{54}$ ergs it was also one of the most energetic bursts of all times. The Swift spacecraft began observing of the afterglow with the narrow-field instruments about 10 hours after the detection of the burst. The burst was bright enough to be detected by the Swift UV/Optical telescope (UVOT) for almost 3 days and by the X-ray Telescope (XRT) for a week after the burst. The X-ray light curve shows a rapidly fading afterglow with a decay index $\alpha$=1.76$^{+0.15}_{-0.07}$. The X-ray energy spectral index was $\beta_{\rm X}$=0.71\plm0.10 with the column density in agreement with the Galactic value. The spectral analysis does not show an obvious change in the X-ray spectral slope over time. The optical UVOT light curve decays with a slope of $\alpha$=1.8\plm0.2. The steepness and the similarity of the optical and X-ray decay rates suggest that the afterglow was observed after the jet break. We estimate a jet opening angle of about 1-2$^{\circ}$Comment: 14 pages, accepted for publication in Ap

Work characteristics and employee outcomes in local government

The overall objective of this study was to examine the work characteristics that make significant contributions to extra-role performance (as measured by the helping dimension of citizenship behaviour) and employee wellbeing (measured by job satisfaction and psychological health) in a local government. The work characteristics examined were based on the demand-control-support (DCS) model, augmented by organization-specific characteristics. The results indicate that characteristics described in the core DCS are just as relevant to extra-role performance as they are to more traditional indicators of job stress. Although the more situation-specific conditions were not predictive of citizenship behaviour, they made unique contributions to job satisfaction<br /

GRB 060313: A New Paradigm for Short-Hard Bursts?

We report the simultaneous observations of the prompt emission in the gamma-ray and hard X-ray bands by the Swift-BAT and the KONUS-Wind instruments of the short-hard burst, GRB 060313. The observations reveal multiple peaks in both the gamma-ray and hard X-ray bands suggesting a highly variable outflow from the central explosion. We also describe the early-time observations of the X-ray and UV/Optical afterglows by the Swift XRT and UVOT instruments. The combination of the X-ray and UV/Optical observations provide the most comprehensive lightcurves to date of a short-hard burst at such an early epoch. The afterglows exhibit complex structure with different decay indices and flaring. This behavior can be explained by the combination of a structured jet, radiative loss of energy, and decreasing microphysics parameters occurring in a circum-burst medium with densities varying by a factor of approximately two on a length scale of 10^17 cm. These density variations are normally associated with the environment of a massive star and inhomogeneities in its windy medium. However, the mean density of the observed medium (n approximately 10^&#8722;4 cm^3) is much less than that expected for a massive star. Although the collapse of a massive star as the origin of GRB 060313 is unlikely, the merger of a compact binary also poses problems for explaining the behavior of this burst. Two possible suggestions for explaining this scenario are: some short bursts may arise from a mechanism that does not invoke the conventional compact binary model, or soft late-time central engine activity is producing UV/optical but no X-ray flaring.Comment: 28 pages, 6 figures. Accepted for publication in ApJ. Clarifications made and typos correcte

Photothermal perylene bisimide hydrogels

Gels formed using a perylene bisimide (PBI) as a low molecular weight gelator can show the photothermal effect. Formation of the PBI radical anion results in new absorption bands forming, meaning that subsequent irradiation with a wavelength of light overlapping with the new absorption band leads to heating of the gel. This approach can be used to heat the gel, as well as the surrounding milieu. We show how we can use electrochemical methods as well as multicomponent systems to form the radical anion without the need for UV light, and how we can use the photothermal effect to induce phase transitions in the solutions above the gels by exploiting photothermal behavior