The First Data Release of the Sloan Digital Sky Survey

The Sloan Digital Sky Survey has validated and made publicly available its First Data Release. This consists of 2099 square degrees of five-band (u, g, r, i, z) imaging data, 186,240 spectra of galaxies, quasars, stars and calibrating blank sky patches selected over 1360 square degrees of this area, and tables of measured parameters from these data. The imaging data go to a depth of r ~ 22.6 and are photometrically and astrometrically calibrated to 2% rms and 100 milli-arcsec rms per coordinate, respectively. The spectra cover the range 3800--9200 A, with a resolution of 1800--2100. Further characteristics of the data are described, as are the data products themselves.Comment: Submitted to The Astronomical Journal. 16 pages. For associated documentation, see http://www.sdss.org/dr

Combinatorial pharmacogenetic interactions of bucindolol and β1, α2C adrenergic receptor polymorphisms.

Pharmacogenetics involves complex interactions of gene products affecting pharmacodynamics and pharmacokinetics, but there is little information on the interaction of multiple genetic modifiers of drug response. Bucindolol is a β-blocker/sympatholytic agent whose efficacy is modulated by polymorphisms in the primary target (β(1) adrenergic receptor [AR] Arg389 Gly on cardiac myocytes) and a secondary target modifier (α(2C) AR Ins [wild-type (Wt)] 322-325 deletion [Del] on cardiac adrenergic neurons). The major allele homozygotes and minor allele carriers of each polymorphism are respectively associated with efficacy enhancement and loss, creating the possibility for genotype combination interactions that can be measured by clinical trial methodology.In a 1,040 patient substudy of a bucindolol vs. placebo heart failure clinical trial, we tested the hypothesis that combinations of β(1)389 and α(2C)322-325 polymorphisms are additive for both efficacy enhancement and loss. Additionally, norepinephrine (NE) affinity for β(1)389 AR variants was measured in human explanted left ventricles.The combination of β(1)389 Arg+α(2C)322-325 Wt major allele homozygotes (47% of the trial population) was non-additive for efficacy enhancement across six clinical endpoints, with an average efficacy increase of 1.70-fold vs. 2.32-fold in β(1)389 Arg homozygotes+α(2C)322-325 Del minor allele carriers. In contrast, the minor allele carrier combination (13% subset) exhibited additive efficacy loss. These disparate effects are likely due to the higher proportion (42% vs. 8.7%, P = 0.009) of high-affinity NE binding sites in β(1)389 Arg vs. Gly ARs, which converts α(2C)Del minor allele-associated NE lowering from a therapeutic liability to a benefit.On combination, the two sets of AR polymorphisms 1) influenced bucindolol efficacy seemingly unpredictably but consistent with their pharmacologic interactions, and 2) identified subpopulations with enhanced (β(1)389 Arg homozygotes), intermediate (β(1)389 Gly carriers+α(2C)322-325 Wt homozygotes), and no (β(1)389 Gly carriers+α(2C)322-325 Del carriers) efficacy

Time to all-cause mortality or cardiac transplantation for Group 1/2 (A), Group 3 (B), and Group 4 (C), and time to heart failure progression (combination endpoint of heart failure mortality, cardiac transplantation, heart failure hospitalization, or emergency department care that includes intravenous therapy not requiring hospitalization) for Group 1/2 (D), Group 3 (E), and Group 4 (F).

<p>Abbreviations: AC, all-cause; BUC, bucindolol; Del, deletion; HF, heart failure; PBO, placebo.</p

Baseline characteristics by genotype combination groups.

<p>Data presented as means ± standard deviations, unless otherwise noted.</p><p>Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; BP, blood pressure; CHF, chronic heart failure; HF, heart failure; LVEF, left ventricular ejection fraction; NE, norepinephrine; NYHA, New York Heart Association.</p>A<p>β<b>₁</b>389 Arg/Arg+α<b>_2C</b>_Wt/Wt.</p>B<p>β<b>₁</b>389 Arg/Arg+α<b>_2C</b>_Del carrier.</p>C<p>β<b>₁</b>389 Gly carrier+α_{2c Wt/}Wt.</p>D<p>β<b>₁</b>389 Gly carrier+α<b>_2C</b>_Del carrier.</p>E<p><i>P</i><0.05 by ANOVA (ANalysis Of Variance).</p>F<p><i>P</i><0.0083 by Bonferroni for all pair wise comparisons.</p>G<p><i>P</i><0.05 by Chi-square test.</p>H<p><i>P</i><0.0083 by Bonferroni vs. Group 4.</p>I<p><i>P</i><0.0083 by Bonferroni vs. Group 1.</p>J<p><i>P</i><0.0083 by Bonferroni vs. Group 2.</p

Hazard ratios or relative change ratios for bucindolol/placebo (95% confidence intervals), number of events, and log-rank <i>P</i> values for clinical endpoints and norepinephrine change by genotype combination groups.

<p>Abbreviations: ACM, all-cause mortality; B, bucindolol; CI, confidence interval; CVH, cardiovascular hospitalization; CVM, cardiovascular mortality; HFH, heart failure hospitalization; HFP, heart failure progression (composite of heart failure death, cardiac transplantation, heart failure hospitalization, or an emergency department visit for treatment of heart failure involving administration of intravenous heart failure medication); HR, hazard ratio; P, placebo; NE, norepinephrine; RCR, relative change ratio; RES, relative effect size.</p>A<p>Number of events presented are using the unadjusted analysis, which differs slightly from covariate-adjusted because adjusted analyses are transplant-censored.</p>B<p>All genotypes.</p>C<p>β₁389 Arg/Arg+α_{2C Wt/}Wt.</p>D<p>β₁389 Arg/Arg+α_{2C Del} carrier.</p>E<p>β₁389 Arg/Arg+any α_2C.</p>F<p>β₁389 Gly carrier+α_{2C Wt/}Wt.</p>G<p>β₁389 Gly carrier+α_{2C Del} carrier.</p>H<p>Interaction <i>P</i> value≤0.20, >0.10.</p>I<p>Interaction <i>P</i> value≤0.10, >0.05.</p>J<p>Relative change ratio.</p>K<p>[1−HR or RCR]×100.</p>L<p>RES = Ln HR (genotype group)/Ln (DNA substudy cohort).</p>M<p>See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044324#s2" target="_blank">Methods</a>.</p

Representative competition curves between 50 pM ¹²⁵[I]CYP and L-NE at increasing concentrations, in the absence and presence of 30 µM Gpp(NH)p in membranes from a non-failing human left ventricle with 77% β₁ AR that was β₁389 Arg/Arg genotype (A) and in membranes from a non-failing human heart with 77% β₁ AR that was β₁389 Arg/Gly genotype (B); mean±SEM (%) of high-affinity L-NE binding sites identified in seven β₁389 Arg/Arg, five β₁389 Arg/Gly, and five β₁389 Gly/Gly left ventricles (C).

<p>Abbreviations: AR, adrenergic receptor; CYP, cyanopindolol; Gpp(NH)p, non-hydrolyzable guanine nucleotide; K_H, dissociation constant; K_L, low-affinity binding constant; L-NE, L-norepinephrine; SEM, standard error measurement.</p