Discovery and antiplatelet activity of a selective PI3Kß inhibitor (MIPS-9922).

A series of amino-substituted triazines were developed and examined for PI3Kß inhibition and anti-platelet function. Structural adaptations of a morpholine ring of the prototype pan-PI3K inhibitor ZSTK474 yielded PI3Kß selective compounds, where the selectivity largely derives from an interaction with the non-conserved Asp862 residue, as shown by site directed mutagenesis. The most PI3Kß selective inhibitor from the series was studied in detail through a series of in vitro and in vivo functional studies. MIPS-9922, 10 potently inhibited ADP-induced washed platelet aggregation. It also inhibited integrin αIIbß3 activation and αIIbß3 dependent platelet adhesion to immobilized vWF under high shear. It prevented arterial thrombus formation in the in vivo electrolytic mouse model of thrombosis without inducing prolonged bleeding or excess blood loss.

Tracking a complete voltage-sensor cycle with metal-ion bridges.

Voltage-gated ion channels open and close in response to changes in membrane potential, thereby enabling electrical signaling in excitable cells. The voltage sensitivity is conferred through four voltage-sensor domains (VSDs) where positively charged residues in the fourth transmembrane segment (S4) sense the potential. While an open state is known from the Kv1.2/2.1 X-ray structure, the conformational changes underlying voltage sensing have not been resolved. We present 20 additional interactions in one open and four different closed conformations based on metal-ion bridges between all four segments of the VSD in the voltage-gated Shaker K channel. A subset of the experimental constraints was used to generate Rosetta models of the conformations that were subjected to molecular simulation and tested against the remaining constraints. This achieves a detailed model of intermediate conformations during VSD gating. The results provide molecular insight into the transition, suggesting that S4 slides at least 12 Å along its axis to open the channel with a 3(10) helix region present that moves in sequence in S4 in order to occupy the same position in space opposite F290 from open through the three first closed states.

Establishing and maintaining a volunteer victim advocate program to assist victims of domestic violence in the U.S. Army.

A descriptive evaluation of a volunteer victim advocacy (VA) program was conducted to assist domestic violence victims on the scene of a domestic violence incident on a 24-hour per day basis at a U.S. Army installation. A total of 87 volunteers contributed data to this evaluation. The VAs conducted on-the-spot client safety planning using risk factor assessment. Additional information was given to the client about post programs and services. VAs were evaluated and monitored through initial, periodic, and exit interviews. They were asked about their training needs, the most difficult situations they confronted, what they did best, and whether the VA program met their personal needs. While the Army supports victim advocacy by regulation, it often does not provide sufficient funds to support the hiring of the necessary staff. Hence, a volunteer program may be the only feasible approach to provide advocacy assistance for abused spouses in the Army above a minimum level. Drawing on the services of trained volunteers allowed the Family Advocacy Program at this installation to accomplish its mandated mission. Suggestions for further research in VA programs are presented.

Characteristics of domestic violence incidents reported at the scene by volunteer victim advocates.

At a single U.S. Army installation from 1997 to 2005, domestic violence volunteer victim advocates assisted 1,417 clients in 1,380 physical and 301 verbal abuse incidents. The average soldier and spouse population during this time was slightly less than 10,000. Advocates went to the scene of the incident to talk to the victim to ensure that her/his rights were observed, to determine whether the victim was safe, was referred to the hospital social work service for assessment, and had the information necessary to negotiate the complex military and community systems. The advocate inquired of the victim the characteristics of the incident and risk factors in the history of the relationship. In many incidents, risk factors indicated a history of serious violence by the offender including an increasing level of violence, stalking, and assaults. Frequently reported precipitants of incidents were relationship problems, jealously, and infidelity. Spouses often reported previous attempts to leave and to get help. Advocates play an important role in gathering information uniquely available at the scene that can be useful in planning education and intervention programs to reduce domestic violence in the Army, the military services, and civilian society.