A common polymorphism in the oxygen-dependent degradation (ODD) domain of hypoxia inducible factor-1α (HIF-1α) does not impair Pro-564 hydroxylation

BACKGROUND: The hypoxia-inducible factor (HIF) transcription complex, which is activated by low oxygen tension, controls a diverse range of cellular processes including angiogenesis and erythropoiesis. Under normoxic conditions, the α subunit of HIF is rapidly degraded in a manner dependent on hydroxylation of two conserved proline residues at positions 402 and 564 in HIF-1α in the oxygen-dependent degradation (ODD) domain. This allows subsequent recognition by the von Hippel-Lindau (VHL) tumor suppressor protein, which targets HIF for degradation by the ubiquitin-proteasome pathway. Under hypoxic conditions, prolyl hydroxylation of HIF is inhibited, allowing it to escape VHL-mediated degradation. The transcriptional regulation of the erythropoietin gene by HIF raises the possibility that HIF may play a role in disorders of erythropoiesis, such as idiopathic erythrocytosis (IE). RESULTS: Patients with IE were screened for changes in the HIF-1α coding sequence, and a change in the ODD domain that converts Pro-582 to Ser was identified in several patients. This same change, however, was also detected at a significant frequency, 0.073, in unaffected controls compared to 0.109 in the IE patient group. In vitro hydroxylation assays examining this amino acid change failed to reveal a discernible effect on HIF hydroxylation at Pro-564. CONCLUSION: The Pro582Ser change represents a common polymorphism of HIF-1α that does not impair HIF-1α prolyl hydroxylation. Although the Pro582Ser polymorphism is located in the ODD domain of HIF-1α it does not diminish the association of HIF-1α with VHL. Thus, it is unlikely that this polymorphism accounts for the erythrocytosis in the group of IE patients studied

Microscale Quantification of the Absorption by Dissolved and Particulate Material in Coastal Waters with an ac-9

Measuring coastal and oceanic absorption coefficients of dissolved and particulate matter in the visible domain usually requires a methodology for amplifying the natural signal because conventional spectrophotometers lack the necessary sensitivity. The WET Labs ac-9 is a recently developed in situ absorption and attenuation meter with a precision better than ±0.001 m−1 in the raw signal, which is sufficient to make these measurements in pristine samples. Whereas the superior sensitivity of the ac-9 has been well documented, the accuracy of in situ measurements for bio-optical applications has not been rigorously evaluated. Obtaining accurate results with an ac-9 requires careful attention to calibration procedures because baselines drift as a result of the changing optical properties of several ac-9 components. To correct in situ measurements for instrument drift, a pressurized flow procedure was developed for calibrating an ac-9 with optically clean water. In situ, micro- (cm) to fine- (m) scale vertical profiles of spectral total absorption, at(λ), and spectral absorption of dissolved materials, ag(λ), were then measured concurrently using multiple meters, corrected for drift, temperature, salinity, and scattering errors and subsequently compared. Particulate absorption, ap(λ), was obtained from at(λ) − ag(λ). CTD microstructure was simultaneously recorded. Vertical profiles of ag(λ), at(λ), and ap(λ) were replicated with different meters within ±0.005 m−1, and spectral relationships compared well with laboratory measurements and hydrographic structure

Thin layers and camouflage: hidden \u3cem\u3ePseudo-nitzschia\u3c/em\u3e spp. (Bacillariophyceae) populations in a fjord in the San Juan Islands, Washington, USA

Two sets of observations were made on the distribution of Pseudo-nitzschia taxa in a fjord in the San Juan Islands, Washington, USA. From May 21 to 31, 1996, we observed the spatio-temporal distribution of a dense bloom of P. fraudulenta. Microscopic observations of live material were compared to physical-optical water-column structure, currents and wind. At the start of the study, dense concentrations of Pseudo-nitzschia spp. were observed directly at the surface. Optical profiles indicated that most cells were concentrated in a thin layer at ~5 m depth, which appeared to be contiguous throughout the sound. Several days later, sustained winds forced a plume of lighter water over the surface of the sound, displacing the original water mass, with its entrained flora, to depth. The resulting near-bottom thin layer persisted for several days, and contained \u3e106 Pseudo-nitzschia spp. cells l-1. Microscopic examination of live cells from the deep layer revealed that colonies were alive and motile. In 1996 and again in 1998, we observed P. pseudodelicatissima living within colonies of Chaetoceros socialis. Water-column thin layers, near-bottom thin layers and populations of Pseudo-nitzschia spp. within C. socialis colonies could easily escape detection by routine monitoring procedures, and may be a potential source of unexplained toxicity events

Not in my back yard! Sports stadia location and the property market

In recent years sports stadia have been built in the UK, not only for their intended sporting purpose but with the twin aim of stimulating economic and physical regeneration. However, proposals to locate stadia in urban areas often prompt a negative reaction from local communities, fearing a decline in property prices. This paper will use a case study of the Millennium Stadium in Cardiff and the City of Manchester Stadium to illustrate that in contrast to this widely held belief, sports stadia can actually enhance the value of residential property. Furthermore, it will argue that stadia also contribute indirectly to property value through the creation of pride, confidence and enhanced image of an area.</p

A Merger Scenario for the Dynamics of Abell 665

We present new redshift measurements for 55 galaxies in the vicinity of the rich galaxy cluster Abell 665. When combined with results from the literature, we have good velocity measurements for a sample of 77 confirmed cluster members from which we derive the cluster's redshift z=0.1829 +/- 0.0005 and line-of-sight velocity dispersion of 1390 +/- 120 km/s. Our analysis of the kinematical and spatial data for the subset of galaxies located within the central 750 kpc reveals only subtle evidence for substructure and non-Gaussianity in the velocity distribution. We find that the brightest cluster member is not moving significantly relative to the other galaxies near the center of the cluster. On the other hand, our deep ROSAT high resolution image of A665 shows strong evidence for isophotal twisting and centroid variation, thereby confirming previous suggestions of significant substructure in the hot X-ray--emitting intracluster gas. In light of this evident substructure, we have compared the optical velocity data with N-body simulations of head-on cluster mergers. We find that a merger of two similar mass subclusters (mass ratios of 1:1 or 1:2) seen close to the time of core-crossing produces velocity distributions that are consistent with that observed.Comment: 30 pages and 7 figures. Accepted by the Astrophysical Journal Full resoultion figures 1 and 3 available in postscript at http://www.physics.rutgers.edu/~percy/A665paper.htm

Toward a simulation approach for alkene ring-closing metathesis : scope and limitations of a model for RCM

A published model for revealing solvent effects on the ring-closing metathesis (RCM) reaction of di-Et diallylmalonate 7 has been evaluated over a wider range of conditions, to assess its suitability for new applications. Unfortunately, the model is too flexible and the published rate consts. do not agree with exptl. studies in the literature. However, by fixing the values of important rate consts. and restricting the concn. ranges studied, useful conclusions can be drawn about the relative rates of RCM of different substrates, precatalyst concn. can be simulated accurately and the effect of precatalyst loading can be anticipated. Progress has also been made toward applying the model to precatalyst evaluation, but further modifications to the model are necessary to achieve much broader aims

Application of a single-objective, hybrid genetic algorithm approach to pharmacokinetic model building.

A limitation in traditional stepwise population pharmacokinetic model building is the difficulty in handling interactions between model components. To address this issue, a method was previously introduced which couples NONMEM parameter estimation and model fitness evaluation to a single-objective, hybrid genetic algorithm for global optimization of the model structure. In this study, the generalizability of this approach for pharmacokinetic model building is evaluated by comparing (1) correct and spurious covariate relationships in a simulated dataset resulting from automated stepwise covariate modeling, Lasso methods, and single-objective hybrid genetic algorithm approaches to covariate identification and (2) information criteria values, model structures, convergence, and model parameter values resulting from manual stepwise versus single-objective, hybrid genetic algorithm approaches to model building for seven compounds. Both manual stepwise and single-objective, hybrid genetic algorithm approaches to model building were applied, blinded to the results of the other approach, for selection of the compartment structure as well as inclusion and model form of inter-individual and inter-occasion variability, residual error, and covariates from a common set of model options. For the simulated dataset, stepwise covariate modeling identified three of four true covariates and two spurious covariates; Lasso identified two of four true and 0 spurious covariates; and the single-objective, hybrid genetic algorithm identified three of four true covariates and one spurious covariate. For the clinical datasets, the Akaike information criterion was a median of 22.3 points lower (range of 470.5 point decrease to 0.1 point decrease) for the best single-objective hybrid genetic-algorithm candidate model versus the final manual stepwise model: the Akaike information criterion was lower by greater than 10 points for four compounds and differed by less than 10 points for three compounds. The root mean squared error and absolute mean prediction error of the best single-objective hybrid genetic algorithm candidates were a median of 0.2 points higher (range of 38.9 point decrease to 27.3 point increase) and 0.02 points lower (range of 0.98 point decrease to 0.74 point increase), respectively, than that of the final stepwise models. In addition, the best single-objective, hybrid genetic algorithm candidate models had successful convergence and covariance steps for each compound, used the same compartment structure as the manual stepwise approach for 6 of 7 (86 %) compounds, and identified 54 % (7 of 13) of covariates included by the manual stepwise approach and 16 covariate relationships not included by manual stepwise models. The model parameter values between the final manual stepwise and best single-objective, hybrid genetic algorithm models differed by a median of 26.7 % (q₁ = 4.9 % and q₃ = 57.1 %). Finally, the single-objective, hybrid genetic algorithm approach was able to identify models capable of estimating absorption rate parameters for four compounds that the manual stepwise approach did not identify. The single-objective, hybrid genetic algorithm represents a general pharmacokinetic model building methodology whose ability to rapidly search the feasible solution space leads to nearly equivalent or superior model fits to pharmacokinetic data