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DNA microarrays can be used to identify gene expression changes characteristic of human disease. This is challenging, however, when relevant differences are subtle at the level of individual genes. We introduce an analytical strategy, Gene Set Enrichment Analysis, designed to detect modest but coordinate changes in the expression of groups of functionally(More)
The systematic translation of cancer genomic data into knowledge of tumour biology and therapeutic possibilities remains challenging. Such efforts should be greatly aided by robust preclinical model systems that reflect the genomic diversity of human cancers and for which detailed genetic and pharmacological annotation is available. Here we describe the(More)
Type 2 diabetes mellitus (DM2) affects over 110 million people worldwide and is a principal contributor to atherosclerotic vascular disease, blindness, amputation and kidney failure 1. Defects in insulin secretion are observed early in individuals with maturity-onset diabetes of the young, a monogenic form of type 2 diabetes 2 ; insulin resistance at(More)
Multicomponent therapies, originating through deliberate mixing of drugs in a clinical setting, through happenstance, and through rational design, have a successful history in a number of areas of medicine, including cancer, infectious diseases, and CNS disorders. We have developed a high-throughput screening method for identifying effective combinations of(More)
Efforts to construct therapeutically useful models of biological systems require large and diverse sets of data on functional connections between their components. Here we show that cellular responses to combinations of chemicals reveal how their biological targets are connected. Simulations of pathways with pairs of inhibitors at varying doses predict(More)
Predicting the behavior of living organisms is an enormous challenge given their vast complexity. Efforts to model biological systems require large datasets generated by physical binding experiments and perturbation studies. Genetic perturbations have proven important and are greatly facilitated by the advent of comprehensive mutant libraries in model(More)
In the present-day universe, supermassive black hole masses (M BH) appear to be strongly correlated with their galaxy's bulge luminosity, among other properties. In this study, we explore the analogous relationship between M BH , derived using the virial method, and the stellar R-band bulge luminosity (L R) or stellar bulge mass (M *) at epochs of 1 z 4.5(More)
We have obtained and modeled new NICMOS images of the lens system MG 1131+0456 , which show that its lens galaxy is an H= 18.6 mag, transparent, early-type galaxy at a redshift of z l ≃ 0.85; it has a major axis effective radius R e = 0. ′′ 68 ± 0. ′′ 05, projected axis ratio b/a = 0.77 ± 0.02, and major axis PA= 60 • ± 2 •. The lens is the brightest member(More)
Drug combinations are a promising strategy to overcome the compensatory mechanisms and unwanted off-target effects that limit the utility of many potential drugs. However, enthusiasm for this approach is tempered by concerns that the therapeutic synergy of a combination will be accompanied by synergistic side effects. Using large scale simulations of(More)
Biological systems are robust, in that they can maintain stable phenotypes under varying conditions or attacks. Biological systems are also complex, being organized into many functional modules that communicate through interlocking pathways and feedback mechanisms. In these systems, robustness and complexity are linked because both qualities arise from the(More)