Structure-based optimization of 1H-imidazole-2-carboxamides as Axl kinase inhibitors utilizing a Mer mutant surrogate

Axl has been a target of interest in the oncology field for several years based on its role in various oncogenic processes. To date, no wild-type Axl crystal structure has been reported. Herein, we describe the structure-based optimization of a novel chemotype of Axl inhibitors, 1H-imidazole-2-carboxamide, using a mutated kinase homolog, Mer(I650M), as a crystallographic surrogate. Iterative optimization of the initial lead compound (1) led to compound (21), a selective and potent inhibitor of wild-type Axl. Compound (21) will serve as a useful compound for further in vivo studies.     

Project portfolio selection under uncertainty with outsourcing opportunities

The paper presents a stochastic optimization model for project portfolio selection under uncertainty about the real efforts required for the execution of the work packages contained in the projects. As a subproblem, the assignment of the work to human resources and the distribution of work over time is addressed. The available workforce is assumed as multi-skilled. Required efforts are modeled as random variables. The recourse action for the case where the available capacities of the internal human resources do not suffice to cover the actual work times consists in delegating parts of the work to external human resources. The staffing-and-scheduling subproblem is solved by means of a Frank-Wolfe type algorithm. To solve the upper-level problem of project portfolio determination, a modification of the Variable Neighborhood Search (VNS) algorithm is applied. Experimental results for a benchmark of synthetically generated test instances and for an illustrative example from the E-Commerce Competence Center Austria are provided.     

GP-9s Are Ubiquitous Proteins Unlikely Involved in Olfactory Mediation of Social Organization in the Red Imported Fire Ant,Solenopsis invicta

The red imported fire ant (RIFA), Solenopsis invicta, is an invasive species, accidentally introduced in the United States that can cause painful (sometimes life-threatening) stings to human, pets, and livestock. Their colonies have two social forms: monogyne and polygyne that have a single and multiple functional queens, respectively. A major gene (Gp-9), identified as a putative pheromone-binding protein on the basis of a modest amino acid sequence identity, has been suggested to influence the expression of colony social organization. Monogyne queens are reported to possess only the GP-9B alleles, whereas polygyne queens possess both GP-9B and GP-9b. Thus, both social forms are reported to express GP-9B, with GP-9b being a marker expressed in polygynes but it is absent in monogynes. Here, we report two types of polygyne colonies, one that does not express GP-9b (monogyne-like) and the other expressing both proteins, GP-9B and GP-9b. Given their expression pattern, GP-9s are hemolymph proteins, which are more likely to be involved in the transport of lipids and small ligands within the homocoel. GP-9B existed in two forms, one of them is phosphorylated. The helical-rich content of the protein resembles the secondary structures of a beetle hemolymph protein and moth pheromone-binding proteins. An olfactory role is unlikely given the lack of specific expression in the sensillar lymph. In marked contrast to GP-9s, a chemosensory protein, SinvCSP, is demonstrated to be specifically expressed in the antennae. Within the antennae, expression of SinvCSP is restricted to the last two segments, which are known to house olfactory sensilla.     

Setting up and running molecular dynamics simulations of membrane proteins

Molecular dynamics simulations have become a popular and powerful technique to study lipids and membrane proteins. We present some general questions and issues that should be considered prior to embarking on molecular dynamics simulation studies of membrane proteins and review common simulation methods. We suggest a practical approach to setting up and running simulations of membrane proteins, and introduce two new (related) methods to embed a protein in a lipid bilayer. Both methods rely on placing lipids and the protein(s) on a widely spaced grid and then 'shrinking' the grid until the bilayer with the protein has the desired density, with lipids neatly packed around the protein. When starting from a grid based on a single lipid structure, or several potentially different lipid structures (method 1), the bilayer will start well-packed but requires more equilibration. When starting from a pre-equilibrated bilayer, either pure or mixed, most of the structure of the bilayer stays intact, reducing equilibration time (method 2). The main advantages of these methods are that they minimize equilibration time and can be almost completely automated, nearly eliminating one time consuming step in MD simulations of membrane proteins.     

Physiological Elevations of Glucocorticoids Potentiate Glutamate Accumulation in the Hippocampus

Abstract: Glucocorticoids (GCs) are secreted during stress and can damage the hippocampus over the course of aging and impair the capacity of hippocampal neurons to survive excitotoxic insults. Using microdialysis, we have previously observed that GCs augment the extracellular accumulation of glutamate and aspartate in the hippocampus following kainic acid-induced seizures. In that study, adrenalectomized rats maintained on minimal GC concentrations were compared with those exposed to GCs elevated to near-pharmacological levels. We wished to gain insight into the physiological relevance of these observations. Thus, we have examined the effects of GCs over the normal physiological range on glutamate and aspartate profiles; this was done by implanting adrenalectomized rats with GC-secreting pellets, which produce stable and controllable circulating GC concentrations. We observe that incremental increases in GC concentrations cause incremental increases in glutamate accumulation before the kainic acid insult, as well as in the magnitude of the glutamate response to kainic acid. Elevating GC concentrations from the circadian trough to peak doubled cumulative glutamate accumulation, whereas a rise into the stress range caused a fourfold increase in accumulation. Similar, although smaller, effects also occurred with aspartate accumulation (as well as with taurine but not glutamine accumulation). These data show that the highly elevated GC concentrations that accompany neurological insults such as seizure or hypoxia-ischemia will greatly exacerbate the glutamate accumulation at that time. Furthermore, stress levels of GCs augmented glutamate accumulation even in the absence of an excitotoxic insult, perhaps explaining how sustained stress itself damages the hippocampus. Finally, even the moderately ?levated basal GC concentrations that typically occur in aged rats augmented glutamate accumulation, perhaps explaining how GCs damage the hippocampus over the course of normal aging.     

A new kinosternoid from the Late Cretaceous Hell Creek Formation of North Dakota and Montana and the origin of the <Emphasis Type="Italic">Dermatemys mawii</Emphasis> lineage

A nearly complete turtle shell from the Late Cretaceous (Maastrichtian) Hell Creek Formation of Slope County, North Dakota, represents the most complete remains to date of a Mesozoic kinosternoid turtle and a new species, Hoplochelys clark nov. sp. The new taxon is diagnosable from other representatives of Hoplochelys by the plesiomorphic placement of the humeral/femoral sulcus behind the hyo/hypoplastral suture and the autapomorphic development of an interrupted median (neural) keel. All six previously named Paleocene (Puercan and Torrejonian) representatives of Hoplochelys lack diagnostic characters and are synonymized as Hoplochelys crassa. A phylogenetic analysis reveals that Hoplochelys spp. and Agomphus pectoralis are most parsimoniously placed within Kinosternoidea along the phylogenetic stem of the extant Mesoamerican River Turtle Dermatemys mawii, extending that taxon’s stem lineage from the early Eocene to the late Maastrichtian. The two primary crown lineages of Kinosternoidea are thus known from the Mesozoic and split prior to the late Campanian. The presence of a thickened cruciform plastron, true costiform processes, only three inframarginals, and the reduction of the medial contact of the abdominals are synapomorphies of Chelydroidea, the clade formed by Chelydridae and Kinosternoidae.     

Global classification of natural terrestrial ecosystems

Summary A global classification system of natural terrestrial ecosystems (including systematic notation), based on the climate zones of Walter, is presented. The basic units of the system are the ecological units biome and biogeocoene. The zonobiomes, which are climate zones corresponding to the largest vegetation units, are subdivided into subzonobiomes and these into individual biomes. The biomes are thus natural, geographical units within the climate zones. They are in turn subdivided into individual biogeocoenes and their constituent synusiae. In addition, the coordinate concepts of pedobiome and orobiome are introduced. These are distinguished from the zonobiomes as follows:1. the pedobiomes by extreme edaphic conditions which cause azonal vegetation.2. the orobiomes, as mountain ranges, by their vertical climate zonation and the altitudinal belts of vegetation.These relationships are explained, and two subseries of pedo-and oro-subunits are established. Transitional zones (zono-ecotones) between individual zonobiomes are also distinguished. The classification system is summarized in a schematic, and a world map of zonobiomes and zono-ecotones is included. More details are presented in Walter (1976).

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Zusammenfassung Ein globales Gliederungssystem der natürlichen terrestrischen Ökosysteme (einschließlich systematischen Bezeichnungen) wird in Beziehung zu den Walter'schen Klimazonen gesetzt. Grundeinheiten des Systems sind die ökologischen Einheiten Biom und Biogeozön. Die Zonobiome werden unterteilt in Subzonobiome und diese in Biome. Die Zonobiome sind Klimazonen und entsprechen den größten Vegetationseinheiten. Die Biome sind natürliche, geographische Einheiten innerhalb der Klimazonen. Sie werden bis zu einzelnen Biogeozönen und ihren Synusien (Teilsytemen) unterteilt. Parallel dazu werden die Begriffe Pedobiom und Orobiom eingeführt. Diese heben sich aus den Zonobiomen heraus: die Pedobiomen durch extreme Böden, die eine azonale Vegetation bedingen, die Orobiome als Gebirge durch die vertikale Klimagliederung und die Höhenstufen der Vegetation. Diese Beziehungen werden erklärt, und zwei Nebenreihen der Pedo- bzw. Orobiom-Untereinheiten werden aufgestellt. Zwischen den einzelnen Zonobiomen werden Übergangszonen (Zonoökotone) unterschieden. Das Gliederungssytem wird bereits in einem Schema zusammengefaßt, und eine Weltkarte der Zonobiome und Zonoökotone wird beigefügt. Ausführlich werden alle diese Fragen bei WALTER (1976) behandelt.

     

Induced Expression of Trimerized Intracellular Domains of the Human Tumor Necrosis Factor (TNF) p55 Receptor Elicits TNF Effects

The various biological activities of tumor necrosis factor (TNF) are mediated by two receptors, one of 55 kD (TNF-R55) and one of 75 kD (TNF-R75). Although the phenotypic and molecular responses elicited by TNF in different cell types are fairly well characterized, the signaling pathways leading to them are so far only partly understood. To further unravel these processes, we focused on TNF-R55, which is responsible for mediating most of the known TNF effects. Since several studies have demonstrated the importance of receptor clustering and consequently of close association of the intracellular domains for signaling, we addressed the question of whether clustering of the intracellular domains of TNF-R55 (TNF-R55i) needs to occur in structural association with the inner side of the cell membrane, where many signaling mediators are known to reside. Therefore, we investigated whether induced intracellular clustering of only TNF-R55i would be sufficient to initiate and generate a full TNF response, without the need for a full-length receptor molecule or a transmembrane region. Our results provide clear evidence that inducible forced trimerization of either TNF-R55i or only the death domain elicits an efficient TNF response, comprising activation of the nuclear factor κB, induction of interleukin-6, and cell killing.     

Allosteric water and phosphate effects in Hoplosternum littorale hemoglobins.

This paper reports the results obtained using the osmotic stress method applied to the purified cathodic and anodic hemoglobins (Hbs) from the catfish Hoplosternum littorale, a species that displays facultative accessorial air oxygenation. We demonstrate that water potential affects the oxygen affinity of H. littorale Hbs in the presence of an inert solute (sucrose). Oxygen affinity increases when water activity increases, indicating that water molecules stabilize the high-affinity state of the Hb. This effect is the same as that observed in tetrameric vertebrate Hbs. We show that both anodic and cathodic Hbs show conformational substrates similar to other vertebrate Hbs. For both Hbs, addition of anionic effectors, especially chloride, strongly increases the number of water molecules bound, although anodic Hb did not exhibit sensitivity to saturating levels of ATP. Accordingly, for both Hbs, we propose that the deoxy conformations coexist in at least two anion-dependent allosteric states, T(o) and T(x), as occurs for human Hb. We found a single phosphate binding site for the cathodic Hb.