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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)
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)
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)
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)
Simulated combination screens with Gaussian noise To describe how selectivity bias depends on single agent activities, synergistic interactions and analysis parameters, we simulated sets of combinations in two assays (Fig. S1). We examined synthetic screens with only noise (Fig. S2), as well as different levels of single agent and combination activity, and(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)
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)
Phenotypes that might otherwise reveal a gene's function can be obscured by genes with overlapping function. This phenomenon is best known within gene families, in which an important shared function may only be revealed by mutating all family members. Here we describe the 'green monster' technology that enables precise deletion of many genes. In this(More)