Fragment-Based Drug Discovery for RNA Targets

Rapid development within the fields of both fragment-based drug discovery (FBDD) and medicinal targeting of RNA provides possibilities for combining technologies and methods in novel ways. This review provides an overview of fragment-based screening (FBS) against RNA targets, including a discussion of the most recently used screening and hit validation methods such as NMR spectroscopy, X-ray crystallography, and virtual screening methods. A discussion of fragment library design based on research from small-molecule RNA binders provides an overview on both the currently limited guidelines within RNA-targeting fragment library design, and future possibilities. Finally, future perspectives are provided on screening and hit validation methods not yet used in combination with both fragment screening and RNA targets.     

On the effect of peroxisomal β-oxidation and carnitine palmitoyltransferase activity by eicosapentaenoic acid in liver and heart from rats

Repeated administration of highly purified eicosapentaenoic acid (as ethyl ester) resulted in a decrease in plasma triglycerides and high density lipoprotein (HDL) cholesterol. This was accompanied by a stimulation in the activities of carnitine palmitoyltransferase, fatty acyl-CoA oxidase and peroxisomal β-oxidation in the liver. The results suggest that the triglyceride-lowering effect observed with eicosapentaenoic acid may be due to a reduced supply of fatty acids for hepatic triglyceride synthesis because of increased fatty acid oxidation. Eicosapentaenoic acid feeding marginally affected the triglyceride content of heart and mitochondrial and peroxisomal enzyme activities.     

Platinum crystallite size effects on oxide formation and reduction parameters—II

A detailed examination of the electrochemical formation and reduction of surface oxides on platinum crystallites shows a sensitivity for the oxidation rate at constant potential and the mechanism of the oxide reduction on the platinum crystallite size. In the crystallite regions under consideration, the percentage of Pt atoms located in the surfaces of the crystallites changes from 45% at 92 m²/g (30 Å dia.) to 4% at 10 m²/g (280 Å dia.) so that very small crystallites exhibit surface physical properties different from bulk metal surfaces. This is reflected in the changes in electrocatalytic behavior shown here. The oxide reduction mechanisms show two separate “Tafel” slopes of 30 mV and 55 mV, dependent on the oxide coverage. Transitions between the two mechanisms as a function of oxide coverage are linearly dependent upon the percentage of platinum atoms located in the surfaces of the crystallites. Electrocatalytic reaction parameters obtained at bulk platinum metal electrodes may not be applied to high surface area platinum electrocatalysts.     

Effects of moisture content of complete diets on feed intake and milk production by cows

In two trials, 47 and 54 Holstein cows were fed diets containing ensiled forages, ensiled and dry forages, or diets of different moisture contents. In trial 1, diets were fed during a preliminary dry period, early lactation, late lactation, a second dry period, and a second early lactation. In trial 2, four diets identical except for moisture content (78, 64, 52, and 40% dry matter) were fed for the first 200 days of lactation. Substitution of dry hay for alfalfa silage increased dry matter intake during the first early lactation, whereas partial substitution of corn silage with straw did not affect intake during dry periods. Dry matter intake increased linearly as dry matter content of diet increased in trial 2. Neither milk production nor body weight were affected by treatment in either trial. Percentage total solids increased linearly as dry matter content of diet decreased in trial 2. Volatile fatty acids differed slightly, but no trends were consistent. No differences of daily chewing time were observed. From these trials, diets of less than 60 to 65% dry matter may reduce intake by lactating dairy cows.     

Occurrence of Gasterophilus intestinalis and some parasitic nematodes of horses in Sweden

The biological accuracy of a nonlinear compartmental model describing the in vivo kinetics of L-3,4-dihydroxy-6-[18F]fluorophenylalanine ([18F]FDOPA) metabolism was investigated. Tissue activities for [18F]FDOPA and its labeled metabolites 3-O-methyl-[18F]FDOPA ([18F]OMFD), 6-[18F]fluorodopamine ([18F]FDA), L-3,4-dihydroxy-6-[18F]fluorophenylacetic acid ([18F]FDOPAC), and 6-[18F]fluorohomovanillic acid ([18F]FHVA) were calculated using a plasma [18F]FDOPA input function, and kinetic constants estimated previously by chromatographic fractionation of 18F-labeled compounds in plasma and brain extracts from rat. Present data accurately reflected the measured radiochemical composition in rat brain for tracer circulation times past 10 min. We formulated the hypothesis that the discrepancy between calculated and measured fractions of [18F]FDOPA and the deaminated metabolite [18F]FDOPAC at times earlier than 10 min reflected storage of [18F]FDA in vesicles without monoamine oxidase. This hypothesis explained the initially rapid appearance of [18F]FDOPAC in striatum by delayed transfer of [18F]FDA from cytosol into vesicles. We conclude that the simpler model of [18F]FDOPA compartmentation is accurate when the cytosolic and vesicular fractions of [18F]FDA are at steady-state; the approach to equilibrium has a time constant of 15-30 min. The present model is valid for positron emission tomography studies of [18F]FDOPA metabolism in living brain.     

Absolute Configuration of β- and α-Asymmetric Carbons within β-O-4-Structures in Hardwood Lignin

In this study, we investigated the proportion of erythro- and threo-forms of β-O-4-ether structures and their enantiomeric compositions in hardwood lignin by applying the ozonation method to birch wood meal. Optical activity was not substantially observed in either the erythronic or threonic acids obtained as the ozonation products of β-O-4-structures in birch wood meal. The proportions of the four stereoisomeric forms {(αS,βR)-erythro, (αR,βR)-threo, (αS,βS)-threo, and (αR,βS)-erythro forms} were estimated to be 37-38%, 13-14%, 12-13%, and 36-37% based on the yields of erythronic and threonic acids, and on their optical activities. The proportions suggest that the entire components of β-O-4-ether structures in birch wood lignin have R- and S-configurations at the β-carbon in approximately the same quantities {(βR)-β-O-4-structure: (βS)-β-O-4-structure = 50–52:48–50}; i.e., that the β-ether structures are essentially racemic. This estimation implies that, during lignin biosynthesis, an equal number of enantiomeric forms of β-O-4-bonded quinone methides were formed by radical coupling reactions.     

Energy stress on transmission line arresters considering the totallightning charge distribution

Transmission line arresters may be subjected to high energy stresses caused by lightning. Calculations of energy stresses were carried out for a typical line arrester installation. Three line configurations with different degrees of shielding efficiency were used for the study. The primary statistical parameter was the charge of the flash, including multiple strokes. The effect of stroke current magnitude was also investigated. The calculated results were compared with energy stresses in standardized tests on surge arresters     

Computer-assisted measurement of lumbar spine radiographs

RATIONALE AND OBJECTIVES: The authors evaluated a method for obtaining reproducible, reliable measurements from standard lumbar spine radiographs for determining the degree of spondylolisthesis, vertebral body height, intervertebral disk space height, disk space angle, and degree of vertebral body wedging. MATERIALS AND METHODS: Four to six easily defined points were identified on each vertebral body on anteroposterior and lateral plain radiographs of the lumbosacral spine of patients. From these points, the degree of spondylolisthesis, the vertebral body height, the intervertebral disk space height, the disk space angle, and the degree of vertebral body wedging were easily calculated by using well-known geometric relationships. This method requires the use of a personal computer and a standard spreadsheet program but does not require the use of any other specialized radiographic equipment, computer hardware, or custom software. RESULTS: Calculations of intra- and interobserver variability for the measurement of spondylolisthesis, disk space height, disk space angle, and vertebral body height measurement showed that the technique is extremely reproducible. CONCLUSION: This technique may prove useful in the prospective evaluation of potential candidates for lumbar spinal stenosis surgery.     

Why some capuchin monkeys (Cebus apella) use probing tools (and others do not).

Tufted capuchins (Cebus apella) were provided with a task that facilitated the use and modification of sticks as probing tools. It was found that subjects aged 10 years or older at initial task exposure were less likely to use tools than were younger subjects. Furthermore, juveniles whose mothers died before the subjects were aged 3 years were less likely to use tools than were juveniles whose mothers survived through this period. The ability to use tools was not related to subject sex or to access to the tool site or raw tool materials. Subjects modified tools both before and during their use, and the relative percentage of tools modified increased with subject age. Thus, it appears that capuchins most readily acquire tool use before the age of 10 years and that early disruption of the mother–infant relationship has deleterious effects on the emergence of instrumental behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)