Synthesis of the C(7)-C(22)-Sector of (+)-Acutiphycin Via O-Directed Double Free Radical Alkyne Hydrostannation with Ph3SnH/Et3B, Double I-Sn Exchange and Double Stille Coupling

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Herein a new double O-directed free radical hydrostannation reaction is reported on the structurally complex dialkyldiyne 11. Through our use of a conformation-restraining acetal to help prevent stereocenter-compromising 1,5-H-atom abstraction reactions by vinyl radical intermediates, the two vinylstannanes of 10 were concurrently constructed with high stereocontrol using Ph3SnH/Et3B/O2. Distannane 10 was thereafter elaborated into the bis-vinyl iodide 9 via O-silylation and double I–Sn exchange; double Stille coupling of 9, O-desilylation, and oxidation thereafter furnished 8.

Partitioning Heritability of Regulatory and Cell-Type-Specific Variants across 11 Common Diseases

Regulatory and coding variants are known to be enriched with associations identified by genome-wide association studies (GWASs) of complex disease, but their contributions to trait heritability are currently unknown. We applied variance-component methods to imputed genotype data for 11 common diseases to partition the heritability explained by genotyped SNPs () across functional categories (while accounting for shared variance due to linkage disequilibrium). Extensive simulations showed that in contrast to current estimates from GWAS summary statistics, the variance-component approach partitions heritability accurately under a wide range of complex-disease architectures. Across the 11 diseases DNaseI hypersensitivity sites (DHSs) from 217 cell types spanned 16% of imputed SNPs (and 24% of genotyped SNPs) but explained an average of 79% (SE = 8%) of  from imputed SNPs (5.1× enrichment; p = 3.7 × 10⁻¹⁷) and 38% (SE = 4%) of  from genotyped SNPs (1.6× enrichment, p = 1.0 × 10⁻⁴). Further enrichment was observed at enhancer DHSs and cell-type-specific DHSs. In contrast, coding variants, which span 1% of the genome, explained <10% of  despite having the highest enrichment. We replicated these findings but found no significant contribution from rare coding variants in independent schizophrenia cohorts genotyped on GWAS and exome chips. Our results highlight the value of analyzing components of heritability to unravel the functional architecture of common disease.

N-terminal glycation of cholecystokinin-8 abolishes its insulinotropic action on clonal pancreatic B-cells

Monoglycated cholecystokinin octapeptide (Asp(1)-glucitol CCK-X) was prepared under hyperglycaemic reducing conditions and purified by reverse phase-high performance liquid chromatography. Electrospray ionisation mass spectrometry and automated Edman degradation demonstrated that CCK-8 was glycated specifically at the amino-terminal Asp(1) residue. Effects of Asp(1)-glucitol CCK-8 and CCK-8 on insulin secretion were examined using glucose-responsive clonal BRIN-BD11 cells. In acute (20 min) incubations, 10(-10) mol/l CCK-8 enhanced insulin release by 1.2-1.5-fold at 5.6-11.1 mmol/l glucose. The stimulatory effect induced by 10(-10) mom CCK-8 was abolished following glycation. At 5.6 mmol/l glucose, CCK-8 at concentrations ranging from 10(-11) to 10(-7) mol/l induced a significant 1.6-1.9-fold increase in insulin secretion. Insulin output in the presence of Asp(1)-glucitol CCK-8 over the concentration range 10(-11)-10(-7) mol/l was decreased by 21-35% compared with CCK-8, and its insulinotropic action was effectively abolished. Asp(1)-glucitol CCK-8 at 10(-8) mol/l also completely blocked the stimulatory effects of 10(-11)-10(-8) mol/l CCK-8. These data indicate that structural modification by glycation at the amino-terminal Asp(1) residue effectively abolishes and/or antagonises the insulinotropic activity of CCK-8. (C) 1999 Elsevier Science B.V. All rights reserved.

Explaining variation in cancer survival between 11 jurisdictions in the International Cancer Benchmarking Partnership: a primary care vignette survey

OBJECTIVES: The International Cancer Benchmarking Partnership (ICBP) is a collaboration between 6 countries and 12 jurisdictions with similar primary care-led health services. This study investigates primary care physician (PCP) behaviour and systems that may contribute to the timeliness of investigating for cancer and subsequently, international survival differences.

DESIGN: A validated survey administered to PCPs via the internet set out in two parts: direct questions on primary care structure and practice relating to cancer diagnosis, and clinical vignettes, assessing management of scenarios relating to the diagnosis of lung, colorectal or ovarian cancer.

PARTICIPANTS: 2795 PCPs in 11 jurisdictions: New South Wales and Victoria (Australia), British Columbia, Manitoba, Ontario (Canada), England, Northern Ireland, Wales (UK), Denmark, Norway and Sweden.

PRIMARY AND SECONDARY OUTCOME MEASURES: Analysis compared the cumulative proportion of PCPs in each jurisdiction opting to investigate or refer at each phase for each vignette with 1-year survival, and conditional 5-year survival rates for the relevant cancer and jurisdiction. Logistic regression was used to explore whether PCP characteristics or system differences in each jurisdiction affected the readiness to investigate.

RESULTS: 4 of 5 vignettes showed a statistically significant correlation (p<0.05 or better) between readiness to investigate or refer to secondary care at the first phase of each vignette and cancer survival rates for that jurisdiction. No consistent associations were found between readiness to investigate and selected PCP demographics, practice or health system variables.

CONCLUSIONS: We demonstrate a correlation between the readiness of PCPs to investigate symptoms indicative of cancer and cancer survival rates, one of the first possible explanations for the variation in cancer survival between ICBP countries. No specific health system features consistently explained these findings. Some jurisdictions may consider lowering thresholds for PCPs to investigate for cancer-either directly, or by specialist referral, to improve outcomes.

Effect of ultraviolet-B light on lymphocyte activity at doses at which normal bone marrow stem cells are preserved

Ultraviolet B (UVB) light is known to be immunosuppressive, but, probably because of a small UVC component in the emission spectra of some of the UVB lamps used, reports vary on effective dose levels. To prevent potentially lethal graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation, alloreactive donor T-cell activity must be suppressed. In this study, a narrow wavelength UVB lamp (TL01, 312 nm peak emission) was used to determine what doses of UVB were required to abolish rat lymphocyte proliferation while simultaneously preserving rat bone marrow progenitor cell and primitive hematopoietic stem cell viability. Lymphocyte proliferation, as measured by 3H-Thymidine incorporation, in response to lectin stimulation was abolished below detection at doses greater than 3,500 J/m2. When T-cell clonogenicity was measured in a limiting dilution assay, a small fraction (0.6%) was maintained at doses up to 4,000 J/m2. Cytotoxic T-lymphocyte (CTL) activity was reduced after treatment with 4,000 J/m2, but a significant level of cytotoxicity was still maintained. Natural killer cell cytolytic activity was not affected by doses up to 4,000 J/m2. At 4,000 J+m2 there was a 10% survival of colony-forming units-granulocyte-macrophage; a 1% and 4% survival of day-8 and day-12 colony-forming units-spleen, respectively; and 11% survival of marrow repopulating ability cells. Up to 25% of late cobblestone area forming cells (4 to 5 weeks), reflecting the more immature hematopoietic stem cells, were preserved in bone marrow treated with 4,000 J/m2, indicating that early stem cells are less sensitive to UVB damage than are more committed progenitor cells. Thus, a potential therapeutic window was established at approximately 4,000 J/m2 using this light source, whereby the potentially GVHD-inducing T cells were suppressed, but a sufficient proportion of the cells responsible for engraftment was maintained.

The VLT-FLAMES Tarantula Survey XXII. Multiplicity properties of the B-type stars

We investigate the multiplicity properties of 408 B-type stars observed in the 30 Doradus region of the Large Magellanic Cloud with multi-epoch spectroscopy from the VLT-FLAMES Tarantula Survey (VFTS). We use a cross-correlation method to estimate relative radial velocities from the helium and metal absorption lines for each of our targets. Objects with significant radial-velocity variations (and with an amplitude larger than 16 km s^-1) are classified as spectroscopic binaries. We find an observed spectroscopic binary fraction (defined by periods of <10^3.5 d and mass ratios >0.1) for the B-type stars, f<inf>B</inf>(obs) = 0.25 ± 0.02, which appears constant across the field of view, except for the two older clusters (Hodge 301 and SL 639). These two clusters have significantly lower binary fractions of 0.08 ± 0.08 and 0.10 ± 0.09, respectively. Using synthetic populations and a model of our observed epochs and their potential biases, we constrain the intrinsic multiplicity properties of the dwarf and giant (i.e. relatively unevolved) B-type stars in 30 Dor. We obtain a present-day binary fraction f<inf>B</inf>(true) = 0.58 ± 0.11, with a flat period distribution. Within the uncertainties, the multiplicity properties of the B-type stars agree with those for the O stars in 30 Dor from the VFTS.

4.11(EC) Report new instrumentation and field measuring technology for tidal currents

One of the challenges the tidal power industry faces, is the requirement of cost effective, reliable but highly accurate acquisition of flow data. Different methods are required , applications range over different spatial and temporal scales. This report assembles in the first sections, theoretical background information on acoustic Doppler Velocimetry and RADAR measurements. The use of existing expertise in field tests of marine vehicles is discussed next, followed by a discussion of issues relating to recreating field conditions in laboratory environments. The last three sections present practical applications of various methods performed in field conditions. While progress has been made over the last years, this overview highlights the challenges in full scale field measurements and knowledge gaps in the industry.

High-dose therapy and autologous stem cell transplantation in first relapse for diffuse large B cell lymphoma in the rituximab era:an analysis based on data from the European Blood and Marrow Transplantation Registry

Autologous stem cell transplantation (ASCT) consolidation remains the treatment of choice for patients with relapsed diffuse large B cell lymphoma. The impact of rituximab combined with chemotherapy in either first- or second-line therapy on the ultimate results of ASCT remains to be determined, however. This study was designed to evaluate the benefit of ASCT in patients achieving a second complete remission after salvage chemotherapy by retrospectively comparing the disease-free survival (DFS) after ASCT for each patient with the duration of the first complete remission (CR1). Between 1990 and 2005, a total of 470 patients who had undergone ASCT and reported to the European Blood and Bone Transplantation Registry with Medical Essential Data Form B information were evaluated. Of these 470 patients, 351 (74%) had not received rituximab before ASCT, and 119 (25%) had received rituximab before ASCT. The median duration of CR1 was 11 months. The median time from diagnosis to ASCT was 24 months. The BEAM protocol was the most frequently used conditioning regimen (67%). After ASCT, the 5-year overall survival was 63% (95% confidence interval, 58%-67%) and 5-year DFS was 48% (95% confidence interval, 43%-53%) for the entire patient population. Statistical analysis showed a significant increase in DFS after ASCT compared with duration of CR1 (median, 51 months versus 11 months; P < .001). This difference was also highly significant for patients with previous exposure to rituximab (median, 10 months versus not reached; P < .001) and for patients who had experienced relapse before 1 year (median, 6 months versus 47 months; P < .001). Our data indicate that ASCT can significantly increase DFS compared with the duration of CR1 in relapsed diffuse large B cell lymphoma and can alter the disease course even in patients with high-risk disease previously treated with rituximab.

Assessment Of various sensors for structural health monitoring for bridge weigh-in-motion (B-WIM).

In recent years, Structural Health Monitoring (SHM) systems have been developed to monitor bridge deterioration, assess real load levels and hence extend bridge life and safety. A road bridge is only safe if the stresses caused by the passing vehicles are less than the capacity of the bridge to resist them. Conventional SHM systems can be used to improve knowledge of the bridges capacity to resist stresses but generally give no information on the causes of any increase in stresses (based on measuring strain). The concept of in Bridge Weigh-in-Motion (B-WIM) is to establish axle loads, without interruption to traffic flow, by using strain sensors at a bridge soffit and subsequently converting the data to real time axle loads or stresses. Recent studies have shown it would be most beneficial to develop a portable system which can be easily attached to existing and new bridge structures for a specified monitoring period. The sensors could then be left in place while the data acquisition can be moved for various other sites. Therefore it is necessary to find accurate sensors capable of capturing peak strains under dynamic load and suitable methods for attaching these strain sensors to existing and new bridge structures. Additionally, it is important to ensure accurate strain transfer between concrete and steel, the adhesives layer and the strain sensor. This paper describes research investigating the suitably of using various sensors for the monitoring of concrete structures under dynamic vehicle load. Electrical resistance strain (ERS) gauges, vibrating wire (VW) gauges and fibre optic sensors (FOS) are commonly used for SHM. A comparative study will be carried out to select a suitable sensor for a bridge Weigh in Motion System. This study will look at fixing methods, durability, scanning rate and accuracy range. Finite element modeling is used to predict the strains which are then validated in laboratory trials.

Generalized collisional radiative model for light elements. Part B: Data for the Be isonuclear sequence

A first-stage collision database is assembled which contains electron-impact excitation, ionization, and recombination rate coefficients for Be, Be+, Be2+, and Be3+. The first-stage database is constructed using the R-matrix with pseudo-states, time-dependent close-coupling, and perturbative, distorted-wave methods. A second-stage collision database is then assembled which contains generalized collisional-radiative and radiated power loss coefficients. The second-stage database is constructed by solution of collisional-radiative equations in the quasi-static equilibrium approximation using the first-stage database. Both collision database stages reside in electronic form at the ORNL Controlled Fusion Atomic Data Center and in the ADAS database, and are easily accessed over the worldwide internet. © 2007 Elsevier Inc. All rights reserved.