Utility of peak torque and rate of torque development characteristics to identify walking performance ability in older women

Objectives:It is unclear whether peak torque and rate of torque development (RTD) measurements can characterize functional differences in older adults according to their performance on a six-minute walk test. This study aimed to examine the efficacy of isometric peak torque and RTD characteristics of the knee extensors to differentiate between functional status in older women who are able (higher functioning) versus those who are unable (lower functioning) to walk 550 m in six minutes.Methods:Ten higher functioning (67±4 years) and 10 lower functioning (68±4 years) older women performed three isometric knee extension maximal voluntary contractions followed by a six-minute walk test. Peak torque and early (RTD100), late (RTD200), and maximum (Peak RTD) RTD measurements were obtained from each contraction.Results:The higher functioning group exhibited greater peak torque, Peak RTD, RTD100, and RTD200 compared to the lower functioning group (P≤0.011), with larger differences occurring for RTD characteristics (39.9-54.9%) than peak torque (20.3%). Multiple regression analysis indicated that RTD200 was the single best predictor of the distance covered during the six-minute walk test (R²=0.437, P=0.002).Conclusions:These findings suggest that knee extensor muscle strength, and in particular RTD, may be an effective discriminator and predictor of walking performance ability in older women.     

Design and synthesis of substituted nicotinamides as inhibitors of soluble epoxide hydrolase

A series of potent nicotinamide inhibitors of soluble epoxides hydrolase (sEH) is disclosed. This series was designed using structure-based deconstruction and a combination of two HTS hit series, resulting in hybrid analogs that retained the optimal potency from one series, and acceptable in vitro metabolic stability from the other. Structure-guided optimization of these analogs gave rise to nanomolar inhibitors of human sEH that had acceptable plasma exposure to qualify them as probes to determine the in vivo phenotypic consequences of sEH inhibition.     

Improving potency and selectivity of a new class of non-Zn-chelating MMP-13 inhibitors

Discovery and optimization of potency and selectivity of a non-Zn-chelating MMP-13 inhibitor with the aid of protein co-crystal structural information is reported. This inhibitor was observed to have a binding mode distinct from previously published MMP-13 inhibitors. Potency and selectivity were improved by extending the hit structure out from the active site into the S1′ pocket.     

Optogenetic fUSI for brain-wide mapping of neural activity mediating collicular-dependent behaviors

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Protease nexin-2/amyloid beta-protein precursor in blood is a platelet-specific protein

The protease inhibitor, protease nexin-2 (PN-2), is the secreted form of the amyloid beta-protein precursor (APP) which contains the Kunitz protease inhibitor domain. PN-2/APP is an abundant platelet alpha-granule protein which is secreted upon platelet activation. PN-2/APP mRNA is present in cultured endothelial cells and the protein has been detected in plasma. In the present studies we quantitated PN-2/APP in platelets, plasma and several different cell types of the vasculature to identify the repository of the protein in the circulatory system. We report that PN-2/APP is predominantly a platelet protein in the vascular compartment. Lysates of unstimulated umbilical vein endothelial cells, granulocytes or monocytes contained little PN-2/APP based on sensitive functional protease binding and immunoblotting assays. Quantitative immunoblotting studies demonstrated that normal citrated-plasma contains less than or equal to 60 pM PN-2/APP. In contrast, platelets can contribute up to 30 nM PN-2/APP, indicating that they are the major source of the protein in blood.