A Network of SLC and ABC Transporter and DME Genes Involved in Remote Sensing and Signaling in the Gut-Liver-Kidney Axis.

Genes central to drug absorption, distribution, metabolism and elimination (ADME) also regulate numerous endogenous molecules. The Remote Sensing and Signaling Hypothesis argues that an ADME gene-centered network-including SLC and ABC "drug" transporters, "drug" metabolizing enzymes (DMEs), and regulatory genes-is essential for inter-organ communication via metabolites, signaling molecules, antioxidants, gut microbiome products, uremic solutes, and uremic toxins. By cross-tissue co-expression network analysis, the gut, liver, and kidney (GLK) formed highly connected tissue-specific clusters of SLC transporters, ABC transporters, and DMEs. SLC22, SLC25 and SLC35 families were network hubs, having more inter-organ and intra-organ connections than other families. Analysis of the GLK network revealed key physiological pathways (e.g., involving bile acids and uric acid). A search for additional genes interacting with the network identified HNF4α, HNF1α, and PXR. Knockout gene expression data confirmed ~60-70% of predictions of ADME gene regulation by these transcription factors. Using the GLK network and known ADME genes, we built a tentative gut-liver-kidney "remote sensing and signaling network" consisting of SLC and ABC transporters, as well as DMEs and regulatory proteins. Together with protein-protein interactions to prioritize likely functional connections, this network suggests how multi-specificity combines with oligo-specificity and mono-specificity to regulate homeostasis of numerous endogenous small molecules

The Polarization of American Politics

Elected officials in the United States appear to represent relatively extreme support coalitions rather than the interests of middle-of-the-road voters. This contention is supported by analysis of variance of liberal-conservative positions in the United States Senate from 1959 to 1980. Within both the Democratic and the Republican parties, there is considerable variation in liberal-conservative positions, but two senators from the same state and party tend to be very similar. In contrast, senators from the same state but from different parties are highly dissimilar, suggesting that each party represents an extreme support coalition in the state. Moreover, the distribution of senators is now consistent with the hypothesis that, in the long run, both parties have an equal chance of winning any seat in the Senate. This result suggests that there is now competition between equally balanced but extreme support coalitions throughout most of the United States

A Spatial Model for Legislative Roll Call Analysis

A general nonlinear logit model is used to analyze political choice data. The model assumes probabilistic voting based on a spatial utility function. The parameters of the utility function and the spatial coordinates of the choices and the choosers can all be estimated on the basis of observed choices. Ordinary Guttman scaling is a degenerate case of this model. Estimation of the model is implemented in the NOMINATE program for one dimensional analysis of two alternative choices with no nonvoting. The robustness and face validity of the program outputs are evaluated on the basis of roll call voting data for the U.S. House and Senate. Extensive Monte Carlo studies are also presented. Substantive applications using the results for the Senate are briefly illustrated