Discovery of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent and selective PI3Kδ inhibitors.

As demonstrated in preclinical animal models, the disruption of PI3Kδ expression or its activity leads to a decrease in inflammatory and immune responses. Therefore, inhibition of PI3Kδ may provide an alternative treatment for autoimmune diseases, such as RA, SLE, and respiratory ailments. Herein, we disclose the identification of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent, selective and orally bioavailable PI3Kδ inhibitors. The lead compound demonstrated efficacy in an in vivo mouse KLH model.

Soil and groundwater nitrogen response to invasion by an exotic nitrogen-fixing shrub.

Autumn-olive (Elaeagnus umbellata Thunb.) is an invasive, exotic shrub that has become naturalized in the eastern United States and can fix nitrogen (N) via a symbiotic relationship with the actinomycete Frankia. Fixed N could potentially influence nutrient cycling rates and N leaching into soil water and groundwater. In situ net N mineralization, net nitrification, and net ammonification rates, as well as soil water and groundwater nitrate N (NO(3)-N) and ammonium N (NH(4)-N) concentrations, were measured under autumn-olive-dominated and herbaceous open field areas in southern Illinois. Soil net N mineralization and net nitrification rates were higher under autumn-olive compared with open field (p < 0.05) and could be driven, in part, by the relatively low C/N ratio (11.41 +/- 0.29) of autumn-olive foliage and subsequent litter. Autumn-olive stands also had greater soil water NO(3)-N (p = 0.003), but soil water NH(4)-N concentrations were similar between autumn-olive and open field. Groundwater NO(3)-N and NH(4)-N concentrations were similar beneath both types of vegetation. Groundwater NO(3)-N concentrations did not reflect patterns in soil N mineralization and soil water NO(3)-N most likely due to a weak hydrologic connection between soil water and groundwater. The increased N levels in soil and soil water indicate that abandoned agroecosystems invaded by autumn-olive may be net sources of N to adjacent terrestrial and aquatic systems rather than net sinks.

Trading people versus trading time: what is the difference?

BACKGROUND: Person trade-off (PTO) elicitations yield different values than standard utility measures, such as time trade-off (TTO) elicitations. Some people believe this difference arises because the PTO captures the importance of distributive principles other than maximizing treatment benefits. We conducted a qualitative study to determine whether people mention considerations related to distributive principles other than QALY-maximization more often in PTO elicitations than in TTO elicitations and whether this could account for the empirical differences. METHODS: 64 members of the general public were randomized to one of three different face-to-face interviews, thinking aloud as they responded to TTO and PTO elicitations. Participants responded to a TTO followed by a PTO elicitation within contexts that compared either: 1) two life-saving treatments; 2) two cure treatments; or 3) a life-saving treatment versus a cure treatment. RESULTS: When people were asked to choose between life-saving treatments, non-maximizing principles were more common with the PTO than the TTO task. Only 5% of participants considered non-maximizing principles as they responded to the TTO elicitation compared to 68% of participants who did so when responding to the PTO elicitation. Non-maximizing principles that emerged included importance of equality of life and a desire to avoid discrimination. However, these principles were less common in the other two contexts. Regardless of context, though, participants were significantly more likely to respond from a societal perspective with the PTO compared to the TTO elicitation. CONCLUSION: When lives are at stake, within the context of a PTO elicitation, people are more likely to consider non-maximizing principles, including the importance of equal access to a life-saving treatment, avoiding prejudice or discrimination, and in rare cases giving treatment priority based purely on the position of being worse-off.

Behavioral confirmation in the interrogation room: on the dangers of presuming guilt.

A two-phased experiment tested the hypothesis that the presumption of guilt that underlies police interrogations activates a process of behavioral confirmation. In Phase I, 52 suspects guilty or innocent of a mock theft were questioned by 52 interrogators led to believe that most suspects were guilty or innocent. Interrogators armed with guilty as opposed to innocent expectations selected more guilt-presumptive questions, used more interrogation techniques, judged the suspect to be guilty, and exerted more pressure to get a confession--particularly when paired with innocent suspects. In Phase II, neutral observers listened to audiotapes of the suspect, interrogator, or both. They perceived suspects in the guilty expectations condition as more defensive--and as somewhat more guilty. Results indicate that a presumption of guilt sets in motion a process of behavioral confirmation by which expectations influence the interrogator's behavior, the suspect's behavior, and ultimately the judgments of neutral observers.