Computed spatial homology between the L12 protein of chloroplast ribosome and 1.7 A structure of Escherichia coli L12 domain

A computer-graphic model of the tertiary structure of a functional domain in an organelle ribosomal protein was generated using the amino acid sequence of chloroplast ribosomal protein L12 from spinach (Bartsch, Kimura and Subramanian, Proc. Natl. Acad. Sci. USA 79, 6871-6875, 1982) and 1.7 A resolution coordinates of the E. coli L12 C-terminal fragment crystal (Leijonmarck, Eriksson and Liljas, Nature 286, 824-826, 1980). A comparison between the model and the experimentally derived structure shows that although 40% of the primary structure of this part of the two proteins has undergone amino acid replacements, the gross spatial structure of the domain is maintained and the character of the surfaces of possible functional importance are not significantly altered.     

Selective separation procedure for determination of ribosomal proteins L7 and L12.

An electrophoretic procedure for the selective separation and determination of the closely similar ribosomal proteins L7 and L12 (which are specifically involved in the GTPase reactions of the ribosome) from the total protein mixture extracted from unwashed ribosomes is described. In this procedure, which takes advantage of their unusually low isoelectric points. L7 and L12 (and a few other acidic proteins) migrate into gel asanions, while the bulk of ribosomal proteins which are basic remain behind. The positions of L7 and L12 were determined with authentic, pure proteins. It was further determined by means of 2-dimensional gel electrophoresis that no other protein components present in unwashed ribosomes comigrate with the bands of L7 and L12.     

Dispersal Behavior of Tetranychus evansi and T. urticae on Tomato at Several Spatial Scales and Densities: Implications for Integrated Pest Management

Studying distribution is necessary to understand and manage the dynamics of species with spatially structured populations. Here we studied the distribution in Tetranychus evansi and T. urticae, two mite pests of tomato, in the scope of evaluating factors that can influence the effectiveness of Integrated Pest Management strategies. We found greater positive density-dependent distribution with T. evansi than T. urticae when assayed on single, detached tomato leaves. Indeed, T. evansi distribution among leaflets increased with initial population density while it was high even at low T. urticae densities. Intensity and rate of damage to whole plants was higher with T. evansi than T. urticae. We further studied the circadian migration of T. evansi within plant. When T. evansi density was high the distribution behavior peaked between 8 am and 3 pm and between 8 pm and 3 am local time of Kenya. Over 24 h the total number of mites ascending and descending was always similar and close to the total population size. The gregarious behavior of T. evansi combined with its rapid population growth rate, may explain why few tomato plants can be severely damaged by T. evansi and how suddenly all the crop can be highly infested. However the localisation and elimination of the first infested plants damaged by T. evansi could reduce the risk of outbreaks in the entire crop. These findings suggest also that an acaricide treated net placed on the first infested plants could be very effective to control T. evansi. Moreover circadian migration would therefore accentuate the efficiency of an acaricide treated net covering the infested plants.     

Development of a cyclosporin A derivative with excellent anti-hepatitis C virus potency

Synthetic modification of cyclosporin A at P3-P4 positions led to the discovery of NIM258, a next generation cyclophilin inhibitor with excellent anti-hepatitis C virus potency, with decreased transporter inhibition, and pharmacokinetics suitable for coadministration with other drugs. Herein is disclosed the evolution of the synthetic strategy to from the original medicinal chemistry route, designed for late diversification, to a convergent and robust development synthesis. The chiral centers in the P4 fragment were constructed by an asymmetric chelated Claisen rearrangement in the presence of quinidine as the chiral ligand. Identification of advanced crystalline intermediates enabled practical supply of key intermediates. Finally, macrocyclization was carried out at 10% weight concentration by a general and unconventional “slow release” concept.     

Design and synthesis of potent RSK inhibitors

Utilizing the already described 3,4-bi-aryl pyridine series as a starting point, incorporation of a second ring system with a hydrogen bond donor and additional hydrophobic contacts yielded the azaindole series which exhibited potent, picomolar RSK2 inhibition and the most potent in vitro target modulation seen thus far for a RSK inhibitor. In the context of the more potent core, several changes at the phenol moiety were assessed to potentially find a tool molecule appropriate for in vivo evaluation.