15th Annual Environmental Law Institute

Materials from the 15th Annual Environmental Law Institute held by UK/CLE in March 1999

16th Annual Environmental Law Institute

Materials from the 16th Annual Environmental Law Institute held by UK/CLE in May 2000

Use of 5-α-Reductase Inhibitors for Prostate Cancer Chemoprevention: American Society of Clinical Oncology/American Urological Association 2008 Clinical Practice Guideline

To develop an evidence-based guideline on the use of 5-α-reductase inhibitors (5-ARIs) for prostate cancer chemoprevention

Use of 5-α-Reductase Inhibitors for Prostate Cancer Chemoprevention: American Society of Clinical Oncology/American Urological Association 2008 Clinical Practice Guideline

To develop an evidence-based guideline on the use of 5-α-reductase inhibitors (5-ARIs) for prostate cancer chemoprevention

Fluorescence Linked Enzyme Chemoproteomic Strategy for Discovery of a Potent and Selective DAPK1 and ZIPK Inhibitor

DAPK1 and ZIPK (also called DAPK3) are closely related serine/threonine protein kinases that regulate programmed cell death and phosphorylation of non-muscle and smooth muscle myosin. We have developed a fluorescence linked enzyme chemoproteomic strategy (FLECS) for the rapid identification of inhibitors for any element of the purinome and identified a selective pyrazolo­[3,4-<i>d</i>]­pyrimidinone (HS38) that inhibits DAPK1 and ZIPK in an ATP-competitive manner at nanomolar concentrations. In cellular studies, HS38 decreased RLC20 phosphorylation. In <i>ex vivo</i> studies, HS38 decreased contractile force generated in mouse aorta, rabbit ileum, and calyculin A stimulated arterial muscle by decreasing RLC20 and MYPT1 phosphorylation. The inhibitor also promoted relaxation in Ca²⁺-sensitized vessels. A close structural analogue (HS43) with 5-fold lower affinity for ZIPK produced no effect on cells or tissues. These findings are consistent with a mechanism of action wherein HS38 specifically targets ZIPK in smooth muscle. The discovery of HS38 provides a lead scaffold for the development of therapeutic agents for smooth muscle related disorders and a chemical means to probe the function of DAPK1 and ZIPK across species

Fluorescence Linked Enzyme Chemoproteomic Strategy for Discovery of a Potent and Selective DAPK1 and ZIPK Inhibitor

DAPK1 and ZIPK (also called DAPK3) are closely related serine/threonine protein kinases that regulate programmed cell death and phosphorylation of non-muscle and smooth muscle myosin. We have developed a fluorescence linked enzyme chemoproteomic strategy (FLECS) for the rapid identification of inhibitors for any element of the purinome and identified a selective pyrazolo­[3,4-<i>d</i>]­pyrimidinone (HS38) that inhibits DAPK1 and ZIPK in an ATP-competitive manner at nanomolar concentrations. In cellular studies, HS38 decreased RLC20 phosphorylation. In <i>ex vivo</i> studies, HS38 decreased contractile force generated in mouse aorta, rabbit ileum, and calyculin A stimulated arterial muscle by decreasing RLC20 and MYPT1 phosphorylation. The inhibitor also promoted relaxation in Ca²⁺-sensitized vessels. A close structural analogue (HS43) with 5-fold lower affinity for ZIPK produced no effect on cells or tissues. These findings are consistent with a mechanism of action wherein HS38 specifically targets ZIPK in smooth muscle. The discovery of HS38 provides a lead scaffold for the development of therapeutic agents for smooth muscle related disorders and a chemical means to probe the function of DAPK1 and ZIPK across species

Non-mare silicic volcanism on the lunar farside at Compton–Belkovich

Non-basaltic volcanism is rare on the Moon. The best known examples occur on the lunar nearside in the compositionally evolved Procellarum KREEP terrane. However, there is an isolated thorium-rich area—the Compton–Belkovich thorium anomaly—on the lunar farside for which the origin is enigmatic. Here we use images from the Lunar Reconnaissance Orbiter Cameras, digital terrain models and spectral data from the Diviner lunar radiometer to assess the morphology and composition of this region. We identify a central feature, 25 by 35 km across, that is characterized by elevated topography and relatively high reflectance. The topography includes a series of domes that range from less than 1 km to more than 6 km across, some with steeply sloping sides. We interpret these as volcanic domes formed from viscous lava. We also observe arcuate to irregular circular depressions, which we suggest result from collapse associated with volcanism. We find that the volcanic feature is also enriched in silica or alkali-feldspar, indicative of compositionally evolved, rhyolitic volcanic materials. We suggest that the Compton–Belkovich thorium anomaly represents a rare occurrence of non-basaltic volcanism on the lunar farside. We conclude that compositionally evolved volcanism did occur far removed from the Procellarum KREEP terrane