Assessment of community efforts to advance network-based prediction of protein-protein interactions.

Comprehensive understanding of the human protein-protein interaction (PPI) network, aka the human interactome, can provide important insights into the molecular mechanisms of complex biological processes and diseases. Despite the remarkable experimental efforts undertaken to date to determine the structure of the human interactome, many PPIs remain unmapped. Computational approaches, especially network-based methods, can facilitate the identification of previously uncharacterized PPIs. Many such methods have been proposed. Yet, a systematic evaluation of existing network-based methods in predicting PPIs is still lacking. Here, we report community efforts initiated by the International Network Medicine Consortium to benchmark the ability of 26 representative network-based methods to predict PPIs across six different interactomes of four different organisms: A. thaliana, C. elegans, S. cerevisiae, and H. sapiens. Through extensive computational and experimental validations, we found that advanced similarity-based methods, which leverage the underlying network characteristics of PPIs, show superior performance over other general link prediction methods in the interactomes we considered.

Discovery of Novel GR Ligands toward Druggable GR Antagonist Conformations Identified by MD Simulations and Markov State Model Analysis.

Binding of different ligands to glucocorticoid receptor (GR) may induce different conformational changes and even trigger completely opposite biological functions. To understand the allosteric communication within the GR ligand binding domain, the folding pathway of helix 12 (H12) induced by the binding of the agonist dexamethasone (DEX), antagonist RU486, and modulator AZD9567 are explored by molecular dynamics simulations and Markov state model analysis. The ligands can regulate the volume of the activation function-2 through the residues Phe737 and Gln738. Without ligand or with agonist binding, H12 swings from inward to outward to visit different folding positions. However, the binding of RU486 or AZD9567 perturbs the structural state, and the passive antagonist state appears more stable. Structure-based virtual screening and in vitro bioassays are used to discover novel GR ligands that bias the conformation equilibria toward the passive antagonist state. HP-19 exhibits the best anti-inflammatory activity (IC50 = 0.041 ± 0.011 µm) in nuclear factor-kappa B signaling pathway, which is comparable to that of DEX. HP-19 also does not induce adverse effect-related transactivation functions of GR. The novel ligands discovered here may serve as promising starting points for the development of GR modulators.

Economic evaluation of varicella vaccination strategies in Jiangsu province, China: a decision-tree Markov model.

This study evaluated different varicella vaccination strategies in Jiangsu province, China. A decision-tree Markov model was used to evaluate the cost effectiveness of various varicella vaccination strategies for children, including direct and selective vaccination (serotesting pre-vaccination). A cohort of one-year-old children was followed through 60 one-year Markov cycles. The parameter estimation was based on field work, the literature, and statistical yearbooks. We calculated the incremental cost-utility ratio (ICUR) using the saved quality-adjusted life year (QALY). One-way and probability sensitivity analyses were performed to assess uncertainty. Among 100,000 cohort members, one-dose and two-dose direct vaccination averted 8061 and 10,701 varicella cases, respectively, compared with no vaccination. Furthermore, compared with no vaccination, one-dose and two-dose direct vaccination saved one QALY at the ICUR of USD 21,401.33 and USD 35,420.81, respectively, at less than three times the per capita gross domestic product (USD 47,626.86) of Jiangsu. The ICURs of the one-dose and two-dose selective strategies versus no vaccination were USD 42,623.62 and USD 51,406.35 per QALY gained, respectively. The cost effectiveness results were most sensitive to the QALY loss of outpatients and vaccine prices. Thus, in Jiangsu, one-dose and two-dose direct varicella vaccination in children could be cost effective at the willingness to pay threshold of three times provincial GDP per capita from a societal perspective. The findings were sensitive to the vaccine price and health utility of varicella cases.