Temperature dependence of turnover in a Sc(OTf)3-catalyzed intramolecular Schmidt reaction Dedicated to the memory of Harry Wasserman, an inspirational person and a most elegant scholar

The intramolecular Schmidt reaction of ketones and tethered azides is an efficient method for the generation of amides and lactams. This reaction is catalyzed by Lewis acids, which tightly bind the strongly basic amide product and result in product inhibition. We report herein conditions to achieve a catalytic Schmidt reaction using substoichiometric amounts of the heat-stable Lewis acid Sc(OTf)3. This species was shown to effectively release products of the Schmidt reaction in a temperature-dependent fashion. Thus, heat was able to promote catalyst turnover. A brief substrate scope was conducted using these conditions

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

Overcoming product inhibition in catalysis of the intramolecular Schmidt reaction

A method for carrying out the intramolecular Schmidt reaction of alkyl azides and ketones using a substoichiometric amount of catalyst is reported. Following extensive screening, the use of the strong hydrogen-bond-donating solvent hexafluoro-2-propanol was found to be consistent with low catalyst loadings, which ranged from 2.5 mol % for favorable substrates to 25 mol % for more difficult cases. Reaction optimization, broad substrate scope, and preliminary mechanistic studies of this improved version of the reaction are described

Seeing without Seeing? Degraded Conscious Vision in a Blindsight Patient

Blindsight patients, whose primary visual cortex is lesioned, exhibit preserved ability to discriminate visual stimuli presented in their “blind” field, yet report no visual awareness hereof. Blindsight is generally studied in experimental investigations of single patients, as very few patients have been given this “diagnosis”. In our single case study of patient GR, we ask whether blindsight is best described as unconscious vision, or rather as conscious, yet severely degraded vision. In experiment 1 and 2, we successfully replicate the typical findings of previous studies on blindsight. The third experiment, however, suggests that GR's ability to discriminate amongst visual stimuli does not reflect unconscious vision, but rather degraded, yet conscious vision. As our finding results from using a method for obtaining subjective reports that has not previously used in blindsight studies (but validated in studies of healthy subjects and other patients with brain injury), our results call for a reconsideration of blindsight, and, arguably also of many previous studies of unconscious perception in healthy subjects

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)

Fast resistive bolometry

Resistive bolometry is an accurate, robust, spectrally broadband technique for measuring absolute x-ray fluence and flux. Bolometry is an independent technique for x-ray measurements that is based on a different set of physical properties than other diagnostics such as x-ray diodes, photoconducting detectors, and P-I-N diodes. Bolometers use the temperature-driven change in element resistivity to determine the total deposited energy. The calibration of such a device is based on fundamental material properties and its physical dimensions. We describe the use of nickel and gold bolometers to measure x rays generated by high-power z pinches on Sandia's Saturn and Z accelerators. The Sandia bolometer design described herein has a pulse response of {approximately}1 ns. We describe in detail the fabrication, fielding, and data analysis issues leading to highly accurate x-ray measurements. The fundamental accuracy of resistive bolometry will be discussed

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

High-temperature dynamic hohlraums on the pulsed power driver Z

In the concept of the dynamic hohlraum an imploding z-pinch is optically thick to its own radiation. Radiation may be trapped inside the pinch to give a radiation temperature inside the pinch greater than that outside the pinch. The radiation is typically produced by colliding an outer Z-pinch liner onto an inner liner. The collision generates a strongly radiating shock, and the radiation is trapped by the outer liner. As the implosion continues after the collision the radiation temperature may continue to increase due to ongoing PdV (pressure times change in volume) work done by the implosion. In principal the radiation temperature may increase to the point at which the outer liner burns through, becomes optically thin, and no longer traps the radiation. One application of the dynamic hohlraum is to drive an ICF (inertial confinement fusion) pellet with the trapped radiation field. Members of the dynamic hohlraum team at Sandia National Labs have used the pulsed power driver Z (20 LMA, 100 ns) to create a dynamic hohlraum with temperature linearly ramping from 100 to 180 eV over 5 ns. On this shot zp214 a nested tungsten wire array of 4 and 2 cm diameters with masses of 2 and 1 mg imploded onto a 2.5 mg plastic annulus at 5 mm diameter. The current return can on this shot was slotted. It is likely the radiation temperature may be increased to over 200 CV by stabilizing the pinch with a solid current return can. A current return can with 9 slots imprints 9 filaments onto the imploding pinch. This degrades the optical trapping and the quality of the liner collision. A 1.6 mm diameter capsule situated inside this dynamic hohlraum of zp214 would see 15 kJ of radiation impinging on its surface before the pinch itself collapses to a 1.6 mm diameter. Dynamic hohlraum shots including pellets are scheduled to take place on Z in September of 1998