Structure-Based Design of Inhibitors with Improved Selectivity for Steroidogenic Cytochrome P450 17A1 over Cytochrome P450 21A2

Inhibition of androgen biosynthesis is clinically effective for treating androgen-responsive prostate cancer. Abiraterone is a clinical first-in-class inhibitor of cytochrome P450 17A1 (CYP17A1) required for androgen biosynthesis. However, abiraterone also causes hypertension, hypokalemia, and edema, likely due in part to off-target inhibition of another steroidogenic cytochrome P450, CYP21A2. Abiraterone analogs were designed based on structural evidence that B-ring substituents may favorably interact with polar residues in binding CYP17A1 and sterically clash with residues in the CYP21A2 active site. The best analogs increased selectivity of CYP17A1 inhibition up to 84-fold compared with 6.6-fold for abiraterone. Cocrystallization with CYP17A1 validated the intended new contacts with CYP17A1 active site residues. Docking these analogs into CYP21A2 identified steric clashes that likely underlie decreased binding and CYP21A2 inhibition. Overall, these analogs may offer a clinical advantage in the form of reduced side effects

Cooperation Survives and Cheating Pays in a Dynamic Network Structure with Unreliable Reputation

In a networked society like ours, reputation is an indispensable tool to guide decisions about social or economic interactions with individuals otherwise unknown. Usually, information about prospective counterparts is incomplete, often being limited to an average success rate. Uncertainty on reputation is further increased by fraud, which is increasingly becoming a cause of concern. To address these issues, we have designed an experiment based on the Prisoner's Dilemma as a model for social interactions. Participants could spend money to have their observable cooperativeness increased. We find that the aggregate cooperation level is practically unchanged, i.e., global behavior does not seem to be affected by unreliable reputations. However, at the individual level we find two distinct types of behavior, one of reliable subjects and one of cheaters, where the latter artificially fake their reputation in almost every interaction.A. A. gratefully acknowledges financial support by the Swiss National Science Foundation (under grants no. 200020-143224, CR13I1-138032 and P2LAP1-161864) and by the Rectors’ Conference of the Swiss Universities (under grant no. 26058983). All authors acknowledge financial support to carry out the experiments by the Faculty of Business and Economics of the University of Lausanne and the fundamental support by Prof. Rafael Lalive. This work has been supported in part by the European Commission through FET Open RIA 662725 (IBSEN) and by the Ministerio de Economía y Competitividad (Spain) under grant FIS2015-64349-P (VARIANCE)

The emergence of inequality in social groups: network structure and institutions affect the distribution of earnings in cooperation games

From small communities to entire nations and society at large, inequality in wealth, social status, and power is one of the most pervasive and tenacious features of the social world. What causes inequality to emerge and persist? In this study, we investigate how the structure and rules of our interactions can increase inequality in social groups. Specifically, we look into the effects of four structural conditions—network structure, network fluidity, reputation tracking, and punishment institutions—on the distribution of earnings in network cooperation games. We analyze 33 experiments comprising 96 experimental conditions altogether. We find that there is more inequality in clustered networks compared to random networks, in fixed networks compared to randomly rewired and strategically updated networks, and in groups with punishment institutions compared to groups without. Secondary analyses suggest that the reasons inequality emerges under these conditions may have to do with the fact that fixed networks allow exploitation of the poor by the wealthy and clustered networks foster segregation between the poor and the wealthy, while the burden of costly punishment falls onto the poor, leaving them poorer. Surprisingly, we do not find evidence that inequality is affected by reputation in a systematic way but this could be because reputation needs to play out in a particular network environment in order to have an effect. Overall, our findings suggest possible strategies and interventions to decrease inequality and mitigate its negative impact, particularly in the context of mid- and large-sized organizations and online communities

Quality versus quantity of social ties in experimental cooperative networks

Recent studies suggest that allowing individuals to choose their partners can help to maintain cooperation in human social networks; this behaviour can supplement behavioural reciprocity, whereby humans are influenced to cooperate by peer pressure. However, it is unknown how the rate of forming and breaking social ties affects our capacity to cooperate. Here we use a series of online experiments involving 1,529 unique participants embedded in 90 experimental networks, to show that there is a ‘Goldilocks’ effect of network dynamism on cooperation. When the rate of change in social ties is too low, subjects choose to have many ties, even if they attach to defectors. When the rate is too high, cooperators cannot detach from defectors as much as defectors re-attach and, hence, subjects resort to behavioural reciprocity and switch their behaviour to defection. Optimal levels of cooperation are achieved at intermediate levels of change in social ties

Soft x-ray measurements of z

This article reports the experimental characterization of a z-pinch driven-vacuum hohlraum. The authors have measured soft x-ray fluxes of 5 x 10{sup 12} W/cm{sup 2} radiating from the walls of hohlraums which are 2.4--2.5 cm in diameter by 1 cm tall. The x-ray source used to drive these hohlraums was a z-pinch consisting of a 300 wire tungsten array driven by a 2 MA, 100 ns current pulse. In this hohlraum geometry, the z-pinch x-ray source can produce energies in excess of 800 kJ and powers in excess of 100 TW to drive these hohlraums. The x-rays released in these hohlraums represent greater than a factor of 25 in energy and more than a factor of three in x-ray power over previous laboratory-driven hohlraums

Instrumentality and lifetime number of sexual partners

The degree of instrumentality and expressiveness displayed by males and females is known to correlate with a wide range of behaviors. A number of studies have investigated the impact of these personality traits on sexual strategy selection, in particular partner preference. Here we report associations between the lifetime number of sexual partners and the age at first sexual intercourse in relation to personality (as measured by the Bem Sex Role Inventory; BSRI) in a sample of 232 German males and females aged 16-63 years. Significant sex differences were found for BSRI measures such that males scored higher on instrumentality, while females scored higher on expressiveness. Significant positive associations between BSRI instrumentality scores and the reported lifetime number of sexual partners were found in both males and females. In addition, reported age of first sexual intercourse was negatively correlated with BSRI instrumentality scores in males. Finally, females scoring higher on BSRI instrumentality reported to have more lifetime number of sexual partners, even when actual biological age was controlled for. These findings suggest that there are significant within-sex differences in sexual behaviors due to the possession of instrumental personality traits