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.     

Plasma progesterone response following ACTH administration during mid-gestation in the pregnant Brahman heifer

Previous reports of adrenal progesterone (P4) contributions during late gestation in cattle, and ACTH-induced P4 responses in the non-pregnant heifer, prompted a retrospective investigation to evaluate the plasma P4 response and the relative ratio of plasma cortisol (CT) to P4 following ACTH administration during mid-gestation in pregnant Brahman heifers. Twenty-three pregnant (139.0 +/- 5.0 days of gestation) Brahman heifers received one of the following treatments: 0 (saline; n = 5), 0.125 (n = 4), 0.25 (n = 5), 0.5 (n = 4), or 1.0 (n = 5)IU of ACTH per kg BW. Blood samples were collected at -15 and -0.5 (time 0), 15, 30, 45, 60, 75, 105, 135, 165, 195, and 255-min post-ACTH challenge. Plasma P4 and CT were quantified by RIA. Pre-ACTH P4 did not differ (P > 0.10) among ACTH treatment groups (pooled, 12.1 +/- 0.6 ng/mL). Among peak P4 values at 15-min post-ACTH infusion, control P4 (9.6 +/- 1.2 ng/mL) tended to be lower (P < 0.07) than 0.5 IU ACTH-treated heifers (13.3 +/- 1.1 ng/mL); and were lower (P < 0.02) than 0.25 and 1.0 IU ACTH-treated heifers (14.7 +/- 1.1 and 22.2 +/- 3.7 ng/mL, respectively). During the primary P4 response period (0 to 75-min post-ACTH), the area under the curve (AUC) was greater (P < 0.05) for 1.0 IU ACTH-treated heifers than all other groups. The CT:P4 ratios were lower (time x treatment, P < 0.01) for control heifers than all ACTH-treated heifers. Among ACTH-treated heifers, CT:P4 ratio response and CT:P4 ratio AUC were similar (P > 0.10) following ACTH challenge. In conclusion, acute increases in ACTH elevated plasma P4, likely of adrenal origin, in mid-gestation pregnant heifers, while the CT:P4 ratio (relative output) remained constant irrespective of ACTH dose (0.125-1.0 IU). Whether ACTH-induced increases in P4 in pregnant animals are of physiological significance (e.g., an accessory role in the maintenance of pregnancy during periods of acute stress) remains to be determined.     

IgE enhances parasite clearance and regulates mast cell responses in mice infected with Trichinella spiralis

Trichinella spiralis infection elicits a vigorous IgE response and pronounced intestinal and splenic mastocytosis in mice. Since IgE both activates mast cells (MC) and promotes their survival in culture, we examined its role in MC responses and parasite elimination in T. spiralis-infected mice. During primary infection, wild-type but not IgE-deficient (IgE(-/-)) BALB/c mice mounted a strong IgE response peaking 14 days into infection. The splenic mastocytosis observed in BALB/c mice following infection with T. spiralis was significantly diminished in IgE(-/-) mice while eosinophil responses were not diminished in either the blood or jejunum. Similar levels of peripheral blood eosinophilia and jejunal mastocytosis occurred in wild-type and IgE-deficient animals. Despite the normal MC response in the small intestine, serum levels of mouse MC protease-1 also were lower in parasite-infected IgE(-/-) animals and these animals were slower to eliminate the adult worms from the small intestine. The number of T. spiralis larvae present in the skeletal muscle of IgE(-/-) mice 28 days after primary infection was about twice that in BALB/c controls, and the fraction of larvae that was necrotic was reduced in the IgE-deficient animals. An intense deposition of IgE in and around the muscle larvae was observed in wild-type but not in IgE null mice. We conclude that IgE promotes parasite expulsion from the gut following T. spiralis infection and participates in the response to larval stages of the parasite. Furthermore, our observations support a role for IgE in the regulation of MC homeostasis in vivo.     

Designing cyclic peptide inhibitor of dengue virus NS3-NS2B protease by using molecular docking approach

Peptides are preferred for designing inhibitors because of their high activity and specificity. Seven cyclopentapeptide inhibitors were designed in this study against dengue virus type 2 (DEN-2) NS3-NS2B protease: CKRRC, CGRRC, CRGRC, CRTRC, CTRRC, CKRKC and CRRKC. Docking analysis was performed to study the enzyme-inhibitor binding interactions. The free energy binding and estimated Ki values for all the inhibitors were found to be small (within micromolar range), indicating that the inhibitors bind considerably well to the binding site. The results showed that the cyclopentapeptide CKRKC was the best peptide inhibitor candidate with estimated free binding energy of -8.39 kcal/mol and Ki of 0.707 μM when compared to the standard inhibitor Bz-Nle-Lys-Arg-Arg-H that has been experimentally tested and shown to exhibit Ki value of 5.8 μM. Several modes of weak interactions were observed between the cyclopentapeptide CKRKC and the active site of DEN-2 NS3-NS2B protease. Thus, the cyclopentapeptide is proposed as a potential inhibitor to the NS3-NS2B protease activities of DEN-2. While these preliminary results are promising, further experimental investigation is necessary to validate the results.     

Making water flow: a comparison of the hydrodynamic characteristics of 12 different benthic biological flumes

Flume tanks are becoming increasingly important research tools in aquatic ecology, to link biological to hydrodynamical processes. There is no such thing as a “standard flume tank”, and no flume tank is suitable for every type of research question. A series of experiments has been carried out to characterise and compare the hydrodynamic characteristics of 12 different flume tanks that are designed specifically for biological research. These facilities are part of the EU network BioFlow. The flumes could be divided into four basic design types: straight, racetrack, annular and field flumes. In each facility, two vertical velocity profiles were measured: one at 0.05 m s⁻¹ and one at 0.25 m s⁻¹. In those flumes equipped with Acoustic Doppler Velocimeters (ADV), time series were also recorded for each velocity at two heights above the bottom: 0.05 m and 20% of the water depth. From these measurements turbulence characteristics, such as TKE and Reynolds stress, were derived, and autocorrelation spectra of the horizontal along-stream velocity component were plotted. The flume measurements were compared to two sets of velocity profiles measured in the field.Despite the fact that some flumes were relatively small, turbulence was fully developed in all channels. Straight and racetrack flumes generally produced boundary layers with a clearly definable logarithmic layer, similar to measurements in the field taken under steady flow conditions. The two annular flumes produced relatively thin boundary layers, presumably due to secondary flows developing in the curved channels. The profiles in the field flumes also differed considerably from the expected log profile. This may either have been due the construction of the flume, or due to unsteady conditions during measurement. Constraints imposed by the different flume designs on the suitability for different types of boundary layer research, as well as scaling issues are discussed.     

Small interfering RNA screens reveal enhanced cisplatin cytotoxicity in tumor cells having both BRCA network and TP53 disruptions

RNA interference technology allows the systematic genetic analysis of the molecular alterations in cancer cells and how these alterations affect response to therapies. Here we used small interfering RNA (siRNA) screens to identify genes that enhance the cytotoxicity (enhancers) of established anticancer chemotherapeutics. Hits identified in drug enhancer screens of cisplatin, gemcitabine, and paclitaxel were largely unique to the drug being tested and could be linked to the drug's mechanism of action. Hits identified by screening of a genome-scale siRNA library for cisplatin enhancers in TP53-deficient HeLa cells were significantly enriched for genes with annotated functions in DNA damage repair as well as poorly characterized genes likely having novel functions in this process. We followed up on a subset of the hits from the cisplatin enhancer screen and validated a number of enhancers whose products interact with BRCA1 and/or BRCA2. TP53(+/-) matched-pair cell lines were used to determine if knockdown of BRCA1, BRCA2, or validated hits that associate with BRCA1 and BRCA2 selectively enhances cisplatin cytotoxicity in TP53-deficient cells. Silencing of BRCA1, BRCA2, or BRCA1/2-associated genes enhanced cisplatin cytotoxicity approximately 4- to 7-fold more in TP53-deficient cells than in matched TP53 wild-type cells. Thus, tumor cells having disruptions in BRCA1/2 network genes and TP53 together are more sensitive to cisplatin than cells with either disruption alone.