Volume crystallization of this glass is nucleated by Li3P04. On heating from room temperature, Li,SiO, appears around 650°C and then converts to LizSi205 around 850°C by reaction with SiOz from the melt. Preheating the glass at 1000°C forms larger Li3P04 nuclei that promote additional crystallization of cristobalite in the 650" to 850°C range. Crystallization activation energies calculated from scan-rate dependence of DTA peaks are 270 kJ/mol for Li2Si03 and 360 to 570 kJ/mol for Li2Si205.
Overall rate constants for the removal of N2(A,v) by O2 and O were measured at 298 K in a rapidly pumped flow reactor using laser-induced fluorescence (LIF) detection of N2(A,v) by excitation in the first positive system of N2, B(3πg)←A(3Σ+u). O atoms were generated in microwave discharges of pure O2 prepared by thermal decomposition of KMnO4. Measured rate constants for N2(A,v)+O2 increased from 2.5×10−12(v=0) to 5.7×10−12 cm3 s−1(v=3). For N2(A,v)+O(3P), they were an order of magnitude larger, rising from 3.5×10−11(v=(0) to 5.2×10−11 cm3 s−1(v=3). They are compared with previous work and discussed in terms of the likely molecular interaction that they represent.
Mutations in the leucine-rich repeat kinase-2 (LRRK2) gene cause autosomal-dominant Parkinson's disease (PD) and contribute to sporadic PD. LRRK2 contains Guanosine-5'-triphosphate (GTP) binding, GTPase and kinase activities that have been implicated in the neuronal degeneration of PD pathogenesis, making LRRK2, a potential drug target. To date, there is no disease-modifying drug to slow the neuronal degeneration of PD and no published LRRK2 GTP domain inhibitor. Here, the biological functions of two novel GTP-binding inhibitors of LRRK2 were examined in PD cell and mouse models. Through a combination of computer-aided drug design (CADD) and LRRK2 bio-functional screens, two novel compounds, 68: and 70: , were shown to reduce LRRK2 GTP binding and to inhibit LRRK2 kinase activity in vitro and in cultured cell assays. Moreover, these two compounds attenuated neuronal degeneration in human SH-SY5Y neuroblastoma cells and mouse primary neurons expressing mutant LRRK2 variants. Although both compounds inhibited LRRK2 kinase activity and reduced neuronal degeneration, solubility problems with 70: prevented further testing in mice. Thus, only 68: was tested in a LRRK2-based lipopolysaccharide (LPS)-induced pre-inflammatory mouse model. 68: reduced LRRK2 GTP-binding activity and kinase activity in brains of LRRK2 transgenic mice after intraperitoneal injection. Moreover, LPS induced LRRK2 upregulation and microglia activation in mouse brains. These findings suggest that disruption of GTP binding to LRRK2 represents a potential novel therapeutic approach for PD intervention and that these novel GTP-binding inhibitors provide both tools and lead compounds for future drug development.
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