Prior research suggests that liberals are more complex than conservatives. However, it may be that liberals are not more complex in general, but rather only more complex on certain topic domains (while conservatives are more complex in other domains). Four studies (comprised of over 2,500 participants) evaluated this idea. Study 1 involves the domain specificity of a self-report questionnaire related to complexity (dogmatism). By making only small adjustments to a popularly used dogmatism scale, results show that liberals can be significantly more dogmatic if a liberal domain is made salient. Studies 2-4 involve the domain specificity of integrative complexity. A large number of open-ended responses from college students (Studies 2 and 3) and candidates in the 2004 Presidential election (Study 4) across an array of topic domains reveals little or no main effect of political ideology on integrative complexity, but rather topic domain by ideology interactions. Liberals are higher in complexity on some topics, but conservatives are higher on others. Overall, this large dataset calls into question the typical interpretation that conservatives are less complex than liberals in a domain-general way.

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Several neuropeptide systems in the hypothalamus, including neuropeptide Y and agouti-related protein (AgRP), control food intake. Peptides derived from proSAAS, a precursor implicated in the regulation of body weight, also control food intake. GPR171 is a heterotrimeric guanine nucleotide–binding protein (G protein)– coupled receptor (GPCR) for BigLEN (b-LEN), a peptide derived from proSAAS. To facilitate studies exploring the physiological role of GPR171, we sought to identify small-molecule ligands for this receptor by performing a virtual screen of a compound library for interaction with a homology model of GPR171. We identified MS0015203 as an agonist of GPR171 and demonstrated the selectivity of MS0015203 for GPR171 by testing the binding of this compound to 80 other membrane proteins, including family A GPCRs. Reducing the expression of GPR171 by shRNA (short hairpin RNA)–mediated knockdown blunted the cellular and tissue response to MS0015203. Peripheral injection of MS0015203 into mice increased food intake and body weight, and these responses were significantly attenuated in mice with decreased expression of GPR171 in the hypothalamus. Together, these results suggest that MS0015203 is a useful tool to probe the pharmacological and functional properties of GPR171 and that ligands targeting GPR171 may eventually lead to therapeutics for food-related disorders.

G-protein coupled receptors (GPCRs) are popular biological targets for drug discovery and development. To date there are more than 140 orphan GPCRs, i.e., receptors whose endogenous ligands are unknown. Traditionally orphan GPCRs have been difficult to study and the development of therapeutic compounds targeting these receptors has been extremely slow although these GPCRs are considered important targets based on their distribution and behavioral phenotype as revealed by animals lacking the receptor. Recent advances in several methods used to study orphan receptors, including protein crystallography and homology modeling are likely to be useful in the identification of therapeutics targeting these receptors. In the past 13 years, over a dozen different Class A GPCRs have been crystallized; this trend is exciting, since homology modeling of GPCRs has previously been limited by the availability of solved structures. As the number of solved GPCR structures continues to grow so does the number of templates that can be used to generate increasingly accurate models of phylogenetically related orphan GPCRs. The availability of solved structures along with the advances in using multiple templates to build models (in combination with molecular dynamics simulations that reveal structural information not provided by crystallographic data and methods for modeling hard-to-predict flexible loop regions) have improved the quality of GPCR homology models. This, in turn, has improved the success rates of virtual ligand screens that use homology models to identify potential receptor binding compounds. Experimental testing of the predicted hits and validation using traditional GPCR pharmacological approaches can be used to drive ligand-based efforts to probe orphan receptor biology as well as to define the chemotypes and chemical scaffolds important for binding. As a result of these advances, orphan GPCRs are emerging from relative obscurity as a new class of drug targets.

Chronic inflammation resulting from infections, altered metabolism, inflammatory diseases or other environmental factors can be a major contributor to the development of several types of cancer. In fact around 20% of all cancers are linked to some form of inflammation. Evidence gathered from genetic, epidemiological and molecular pathological studies suggest that inflammation plays a crucial role at various stages of prostatic carcinogenesis and tumor progression. These include initiation, promotion, malignant conversion, invasion, and metastasis. Detailed basic and clinical research in these areas, focused towards understanding the etiology of prostatic inflammation, as well as the exact roles that various signaling pathways play in promoting tumor growth, is critical for understanding this complex process. The information gained would be useful in developing novel therapeutic strategies such as molecular targeting of inflammatory mediators and immunotherapy-based approaches.