A theoretical entropy score as a single value to express inhibitor selectivity

Background  

Designing maximally selective ligands that act on individual targets is the dominant paradigm in drug discovery. Poor selectivity can underlie toxicity and side effects in the clinic, and for this reason compound selectivity is increasingly monitored from very early on in the drug discovery process. To make sense of large amounts of profiling data, and to determine when a compound is sufficiently selective, there is a need for a proper quantitative measure of selectivity.     

New Silurian cooksonias from dolostones of north-eastern North America

New specimens of Cooksonia and Hostinella are described from the Bertie Group of Ontario and New York State, which is dated by faunas as latest Silurian (Přídolí). The rare plant fossils are unusual in that they are preserved in fine-grained, slightly argillaceous dolostones ('waterlime') rather than clastic rocks. At least two species of Cooksonia are present, one with ± globular sporangial morphology close to C. hemisphaerica Lang. Those with ellipsoidal/discoidal sporangia are compared with C. pertoni Lang, C .  paranensis Gerrienne et al . and C. bohemica Schweitzer, the latter represented by a single specimen from the Přídolí of the Czech Republic. However, the paucity of specimens, which prevents assessment of taphonomic influences on shape, combined with the absence of any anatomical features and the gross morphological simplicity of the fossils, precludes specific assignment. Specimens of Hostinella include one in which apices and a lateral basal structure resembling a root are preserved. It is concluded that the Laurentian assemblage of Ontario and New York State is less diverse and disparate than coeval assemblages, which are also preserved in marine rocks. Its preservation in limestones may have been facilitated by the hypersalinity inferred from various sedimentary features, which would restrict the activity of many decomposers.  © 2004 The Linnean Society of London, Botanical Journal of the Linnean Society , 2004, 146 , 399–413.     

The South American catfish genus Auchenipterus Valenciennes, 1840 (Ostariophysi: Siluriformes: Auchenipteridae): monophyly and relationships, with a revisionary study

The Neotropical catfishes of the genus Auchenipterus Valenciennes (1840) are reviewed. The genus is hypothesized to be a monophyletic assemblage on the basis of the shared presence of grooves in the ventral surface of the head that accommodate adducted mental barbels. A possible second synapomorphy, the presence of papillae on the dorsal and medial surface of the ossified maxillary barbel of mature males, is tentatively advanced pending discovery of adult males of three species. Contrary to previous hypotheses which considered Auchenipterus to consist of a maximum of five species, we recognize 11 species, including two previously undescribed forms, A. britskii and A. menezesi: Auchenipterus is broadly distributed through the Rio Orinoco, Rio Amazonas, and Rio de La Plata basins, and the coastal drainages of the Guianas, with one species in the Rio Pindare-Mirim and Rio Parnaiba basins of northeastern Brazil. Auchenipterus nuchalis, previously thought to be broadly distributed across the range of the genus, is found to rather have a restricted distribution in the eastern portions of the Amazon basin, the lower portions of the Rio Tocantins, and lower courses of some rivers in Suriname and French Guiana. Citations of A. nuchalis from elsewhere in the range of the genus are of other species. Euanemus Müller & Troschel (1842) and Ceratocheilus Miranda Ribeiro (1918) are considered synonyms of Auchenipterus. Euanemus colymbetes Müller & Troschel (1842) is considered a synonym of Auchenipterus (fen/ata Valenciennes (1840), and A. paysanduanus Devincenzi (1933) is placed into the synonymy of A. nigripinnis Boulenger (1895). A neotype is designated for Hypopthalmus nuchalis Spix & Agassiz (1829). Lectotypes are designated for Euanemus colymbetes and Auchenipterus nigripinnis.     

Host preferences in a phonotactic parasitoid of field crickets: the relative importance of host song characters

Abstract.  1. Predators, including insect parasitoids, often eavesdrop on prey signals, and as a result, predation can have important effects on the evolution of prey signalling behaviour.
2. The phonotactic parasitoid fly, Ormia ochracea , uses the calling songs of male field crickets to locate their field crickets hosts. In the western USA, this fly parasitises the variable field cricket, Gryllus lineaticeps . Previous work with one fly population suggested that female flies, like female field crickets, preferentially orient to male songs with higher chirp rates and longer chirp durations, although a limited range of male song types was used in this previous study. The current study, with a different fly population, used field-based, two-speaker choice tests to examine: (1) the effect of male chirp rate and chirp duration on fly attraction, using a natural range of song types; and (2) the relative importance of these song types in host selection by the flies.
3. Three lines of evidence suggested that chirp rate is more important than chirp duration in host selection. (a) The flies consistently preferred higher chirp rates but only sometimes preferred longer chirp durations. (b) The flies consistently preferred higher chirp rate/shorter chirp duration songs to lower chirp rate/longer chirp duration songs. (c) Preferences for longer chirp durations could be eliminated by increasing the amplitude of the less attractive song type, while preferences for higher chirp rates could only sometimes be eliminated by increasing the amplitude of the less attractive song type.
4. Fly predation may favour lower chirp rates and shorter chirp durations in G. lineaticeps , and may have resulted in stronger selection on chirp rate than on chirp duration.     

Complex determinants in human immunodeficiency virus type 1 envelope gp120 mediate CXCR4-dependent infection of macrophages

Host cell range, or tropism, combined with coreceptor usage defines viral phenotypes as macrophage tropic using CCR5 (M-R5), T-cell-line tropic using CXCR4 (T-X4), or dually lymphocyte and macrophage tropic using CXCR4 alone or in combination with CCR5 (D-X4 or D-R5X4). Although envelope gp120 V3 is necessary and sufficient for M-R5 and T-X4 phenotypes, the clarity of V3 as a dominant phenotypic determinant diminishes in the case of dualtropic viruses. We evaluated D-X4 phenotype, pathogenesis, and emergence of D-X4 viruses in vivo and mapped genetic determinants in gp120 that mediate use of CXCR4 on macrophages ex vivo. Viral quasispecies with D-X4 phenotypes were associated significantly with advanced CD4+-T-cell attrition and commingled with M-R5 or T-X4 viruses in postmortem thymic tissue and peripheral blood. A D-X4 phenotype required complex discontinuous genetic determinants in gp120, including charged and uncharged amino acids in V3, the V5 hypervariable domain, and novel V1/V2 regions distinct from prototypic M-R5 or T-X4 viruses. The D-X4 phenotype was associated with efficient use of CXCR4 and CD4 for fusion and entry but unrelated to levels of virion-associated gp120, indicating that gp120 conformation contributes to cell-specific tropism. The D-X4 phenotype describes a complex and heterogeneous class of envelopes that accumulate multiple amino acid changes along an evolutionary continuum. Unique gp120 determinants required for the use of CXCR4 on macrophages, in contrast to cells of lymphocytic lineage, can provide targets for development of novel strategies to block emergence of X4 quasispecies of human immunodeficiency virus type 1.     

Immunological characterization of tristetraprolin as a low abundance, inducible, stable cytosolic protein

Tristetraprolin (TTP) is a zinc finger protein that can bind to AU-rich elements within certain mRNAs, resulting in deadenylation and destabilization of those mRNAs. Its physiological targets include the mRNAs encoding the cytokines tumor necrosis factor alpha (TNF) and granulocyte-macrophage colony-stimulating factor. TTP was originally identified on the basis of its massive but transient increase in mRNA levels following mitogen stimulation of fibroblasts. It has been difficult to reconcile this transient mRNA profile with the presumed continuing "need" for TTP protein, for example, to reverse the effects of lipopolysaccharide (LPS)-stimulated TNF secretion. To investigate this and other questions concerning endogenous TTP protein in cells and tissues, we raised a high titer rabbit antiserum against full-length mouse TTP. TTP could be detected on immunoblots of mouse cytosolic tissue extracts; it was most highly expressed in spleen, but its concentration in that tissue was only about 1.5 nm. TTP could be detected readily in splenic macrophages and stromal cells from LPS-injected rats. In both LPS-treated RAW 264.7 macrophages and fetal calf serum-treated mouse embryonic fibroblasts, TTP protein was stable after induction, with minimal degradation occurring for several hours after treatment of the cells with cycloheximide. The biosynthesis of TTP was accompanied by large changes in electrophoretic mobility consistent with progressive phosphorylation. Confocal microscopy revealed that TTP accumulated in a vesicular pattern in the cytosol of the LPS-stimulated RAW 264.7 cells, and was occasionally seen in the cytosol of unstimulated dividing cells. Gel filtration of the endogenous protein suggested that its predominant structure was monomeric. TTP appears to be a low abundance, cytosolic protein in unstimulated cells and tissues, but once induced is relatively stable, in contrast to its very labile mRNA.     

Influence of biologically inspired nanometer surface roughness on antigen-antibody interactions for immunoassay-biosensor applications

Current research efforts to improve immunoassay-biosensor functionality have centered on detection through the optimal design of microfluidic chambers, electrical circuitry, optical sensing elements, and so on. To date, little attention has been paid to the immunoassay-biosensor membrane surface on which interactions between antibodies and antigens must occur. For this reason, the objective of the present study was to manipulate the nanometer surface roughness of a model immunoassay-biosensor membrane to determine its role on sensitivity and specificity. It was hypothesized that surface roughness characteristics similar to those used by the body's own immune system with B-lymphocyte cell membranes would promote antigen-antibody interactions and minimize non-specific binding. To test this hypothesis, polystyrene 96-well plate surfaces were modified to possess similar topographies as those of B-lymphocyte cell membranes. This was accomplished by immobilizing Protein A conjugated gold particles and Protein A conjugated polystyrene particles ranging in sizes from 40 to 860 nm to the bottom of polystyrene wells. Atomic force microscopy results provided evidence of well-dispersed immunoassay-biosensor surfaces for all particles tested with high degrees of biologically inspired nanometer roughness. Testing the functionality of these immunosurfaces using antigenic fluorescent microspheres showed that specific antigen capture increased with greater nanometer surface roughness while nonspecific antigen capture did not correlate with surface roughness. In this manner, results from this study suggest that large degrees of biologically inspired nanometer surface roughness not only increases the amount of immobilized antibodies onto the immunosurface membrane, but it also enhances the functionality of those antibodies for optimal antigen capture, criteria critical for improving immunoassay-biosensor sensitivity and specificity.