Wave propagation in cardiac tissue and effects of intracellular calcium dynamics (computer simulation study)

Computer simulation using Luo-Rudy I1 model of ventricular myocyte showed that intracellular calcium dynamics become irregular in case of high rate stimulation. This causes the transition from stationary to nonstationary spiral wave and its breakup in 2D model of cardiac tissue. Obtained results suggest how ventricular fibrillation may occur due to the abnormalities of intracellular calcium dynamics. The short review of existing cardiac cell models with calcium dynamics is presented.     

Strikingly high levels of heterozygosity despite 20 years of inbreeding in a clonal honey bee

Inbreeding (the mating between closely related individuals) often has detrimental effects that are associated with loss of heterozygosity at overdominant loci, and the expression of deleterious recessive alleles. However, determining which loci are detrimental when homozygous, and the extent of their phenotypic effects, remains poorly understood. Here, we utilize a unique inbred population of clonal (thelytokous) honey bees, Apis mellifera capensis, to determine which loci reduce individual fitness when homozygous. This asexual population arose from a single worker ancestor approximately 20 years ago and has persisted for at least 100 generations. Thelytokous parthenogenesis results in a 1/3 of loss of heterozygosity with each generation. Yet, this population retains heterozygosity throughout its genome due to selection against homozygotes. Deep sequencing of one bee from each of the three known sub‐lineages of the population revealed that 3,766 of 10,884 genes (34%) have retained heterozygosity across all sub‐lineages, suggesting that these genes have heterozygote advantage. The maintenance of heterozygosity in the same genes and genomic regions in all three sub‐lineages suggests that nearly every chromosome carries genes that show sufficient heterozygote advantage to be selectively detrimental when homozygous.     

Multi-objective optimal control of dynamic bioprocesses using ACADO Toolkit

The optimal design and operation of dynamic bioprocesses gives in practice often rise to optimisation problems with multiple and conflicting objectives. As a result typically not a single optimal solution but a set of Pareto optimal solutions exist. From this set of Pareto optimal solutions, one has to be chosen by the decision maker. Hence, efficient approaches are required for a fast and accurate generation of the Pareto set such that the decision maker can easily and systematically evaluate optimal alternatives. In the current paper the multi-objective optimisation of several dynamic bioprocess examples is performed using the freely available ACADO Multi-Objective Toolkit (http://www.acadotoolkit.org). This toolkit integrates efficient multiple objective scalarisation strategies (e.g., Normal Boundary Intersection and (Enhanced) Normalised Normal Constraint) with fast deterministic approaches for dynamic optimisation (e.g., single and multiple shooting). It has been found that the toolkit is able to efficiently and accurately produce the Pareto sets for all bioprocess examples. The resulting Pareto sets are added as supplementary material to this paper.     

Male reproductive investment and queen mating-frequency in fungus-growing ants

Sperm number and male accessory gland compounds are often importantdeterminants of male mating success but have been little studiedin social insects. This is because mating in social insectsis often difficult to manipulate experimentally, and first evidencefor an explicit influence of accessory gland secretions on malemating success in social insects was obtained only recently.Here we perform a comparative analysis of male sexual organsacross 11 species of attine fungus-growing ants, representingboth genera with single- and multiple-queen mating. We foundthat the general morphology of the male sexual organs was verysimilar across all species, but the relative sizes of the accessoryglands and the sperm-containing accessory testes vary significantlyacross species. Small testes and large accessory glands characterizespecies with singly mated queens, whereas the opposite is foundin species with multiply mated queens. However, in the socialparasite Acromyrmex insinuator, in which queens have secondarilyreverted to single mating, males have accessory gland characteristicsreminiscent of the lower attine ants, but without having significantlyreduced their investment in sperm production. We hypothesizethat the main function of accessory gland compounds in attineants is to monopolize male paternity in similar ways as knownfrom other social insects. This would imply that the evolutionof polyandry in the terminal clade of the fungus-growing ants(the leafcutter ants) has resulted in selection for decreasedinvestment by males in accessory gland secretions and increasedinvestment in sperm number, in response to sperm competitionfor sperm storage.     

Selective release and function of one of the two FMN groups in the cytoplasmic NAD+-reducing [NiFe]-hydrogenase from Ralstonia eutropha.

The soluble, cytoplasmic NAD+-reducing [NiFe]-hydrogenase from Ralstonia eutropha is a heterotetrameric enzyme (HoxFUYH) and contains two FMN groups. The purified oxidized enzyme is inactive in the H2-NAD+ reaction, but can be activated by catalytic amounts of NADH. It was discovered that one of the FMN groups (FMN-a) is selectively released upon prolonged reduction of the enzyme with NADH. During this process, the enzyme maintained its tetrameric form, with one FMN group (FMN-b) firmly bound, but it lost its physiological activity--the reduction of NAD+ by H2. This activity could be reconstituted by the addition of excess FMN to the reduced enzyme. The rate of reduction of benzyl viologen by H2 was not dependent on the presence of FMN-a. Enzyme devoid of FMN-a could not be activated by NADH. As NADH-dehydrogenase activity was not dependent on the presence of FMN-a, and because FMN-b did not dissociate from the reduced enzyme, we conclude that FMN-b is functional in the NADH-dehydrogenase activity catalyzed by the HoxFU dimer. The possible function of FMN-a as a hydride acceptor in the hydrogenase reaction catalyzed by the HoxHY dimer is discussed.     

3-Amido-4-anilinoquinolines as CSF-1R kinase inhibitors 2: Optimization of the PK profile

The optimization of compounds from the 3-amido-4-anilinoquinolines series of CSF-1R kinase inhibitors is described. The series has excellent activity and kinase selectivity. Excellent physical properties and rodent PK profiles were achieved through the introduction of cyclic amines at the quinoline 6-position. Compounds with good activity in a mouse PD model measuring inhibition of pCSF-1R were identified.     

Screening for antiviral inhibitors of the HIV integrase-LEDGF/p75 interaction using the AlphaScreen luminescent proximity assay

Small-molecule inhibitors of HIV integrase (HIV IN) have emerged as a promising new class of antivirals for the treatment of HIV/AIDS. The compounds currently approved or in clinical development specifically target HIV DNA integration and were identified using strand-transfer assays targeting the HIV IN/viral DNA complex. The authors have developed a second biochemical assay for identification of HIV integrase inhibitors, targeting the interaction between HIV IN and the cellular cofactor LEDGF/p75. They developed a luminescent proximity assay (AlphaScreen) designed to measure the association of the 80-amino-acid integrase binding domain of LEDGF/p75 with the 163-amino-acid catalytic core domain of HIV IN. This assay proved to be quite robust (with a Z' factor of 0.84 in screening libraries arrayed as orthogonal mixtures) and successfully identified several compounds specific for this protein-protein interaction.