Design, synthesis and structure-activity relationships of (indo-3-yl) heterocyclic derivatives as agonists of the CB1 receptor. Discovery of a clinical candidate

We report an expansion of the structure-activity relationship (SAR) of a novel series of indole-3-heterocyclic CB1 receptor agonists. Starting from the potent but poorly soluble lead, 1, a rational approach was taken in order to balance solubility, hERG activity and potency while retaining the desired long duration of action within the mouse tail flick test. This led to the discovery of compound 38 which successfully progressed into clinical development.     

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.     

Suppression of statin effectiveness by copper and zinc in yeast and human cells

Lovastatin and other statins inhibit HMG-CoA reductase, which carries out an early step in the sterol biosynthesis pathway. Statins lower cholesterol and are widely prescribed to prevent heart disease, but like many drugs, they can interact with nutritionally acquired metabolites. To probe these interactions, we explored the effect of a diverse library of metabolites on statin effectiveness using a Saccharomyces cerevisiae model. In yeast, treatment with lovastatin results in reduced growth. We combined lovastatin with the library of metabolites, and found that copper and zinc ions impaired the ability of the statin to inhibit yeast growth. Using an integrated genomic and metabolomic approach, we found that lovastatin plus metal synergistically upregulated some sterol biosynthesis genes. This altered pattern of gene expression resulted in greater flux through the sterol biosynthesis pathway and an increase in ergosterol levels. Each sterol intermediate level was correlated with expression of the upstream gene. Thus, the ergosterol biosynthetic response induced by statin is enhanced by copper and zinc. In cultured mammalian cells, these metals also rescued statin growth inhibition. Because copper and zinc impair the ability of statin to reduce sterol biosynthesis, dietary intake of these metals could have clinical relevance for statin treatment in humans.     

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.     

Empirical establishment of oligonucleotide probe design criteria

Criteria for the design of gene-specific and group-specific oligonucleotide probes were established experimentally via an oligonucleotide array that contained perfect match (PM) and mismatch probes (50-mers and 70-mers) based upon four genes. The effects of probe-target identity, continuous stretch, mismatch position, and hybridization free energy on specificity were tested. Little hybridization was observed at a probe-target identity of < or =85% for both 50-mer and 70-mer probes. PM signal intensities (33 to 48%) were detected at a probe-target identity of 94% for 50-mer oligonucleotides and 43 to 55% for 70-mer probes at a probe-target identity of 96%. When the effects of sequence identity and continuous stretch were considered independently, a stretch probe (>15 bases) contributed an additional 9% of the PM signal intensity compared to a nonstretch probe (< or =15 bases) at the same identity level. Cross-hybridization increased as the length of continuous stretch increased. A 35-base stretch for 50-mer probes or a 50-base stretch for 70-mer probes had approximately 55% of the PM signal. Little cross-hybridization was observed for probes with a minimal binding free energy greater than -30 kcal/mol for 50-mer probes or -40 kcal/mol for 70-mer probes. Based on the experimental results, a set of criteria are suggested for the design of gene-specific and group-specific oligonucleotide probes, and the experimentally established criteria should provide valuable information for new software and algorithms for microarray-based studies.     

Effect of short schemes on body composition measurements using Air-Displacement Plethysmography

Background

Air-displacement plethysmography (ADP) is becoming a popular method to assess body composition. Several studies have shown certain types of clothing can affect measurements of body density, however no study has specifically investigated the effect of cotton gym shorts and spandex bicycle shorts on body density.

Methods

Thirty-seven males (23.0 ± 3.2 yr., 177.3 ± 5.4 cm., 74.8 ± 7.5 kg.) and thirty-eight females (23.7 ± 5.3 yr., 163.6 ± 8.4 cm., 57.1 ± 7.0 kg.) had their body density measured by ADP in three clothing schemes: 1) a tight fitting Speedo^® swim suit (criterion measure), 2) cotton gym shorts, and 3) spandex bicycle shorts. The clothing was provided by the University of Oklahoma Body Composition Laboratory and the testing schemes were performed in random order.

Results

The regression of body density by the criterion measure against body density while wearing cotton gym shorts for the entire group (y = 0.001 + 0.991x, SEE = 0.003 g/cm³) and the females (y = 0.059 + 0.934x, SEE = 0.003 g/cm³) did not significantly deviate from the line of identity. However in males the regression significantly deviated from the line of identity (y = 0.052 + 0.944x, SEE = 0.002 g/cm³). Body density by the criterion measure and body density while wearing spandex bicycle shorts did not significantly differ from the line of identity for the entire group (y = -0.018 + 1.013x SEE = 0.003 g/cm³), in males (y = -0.002 + 1.001x, SEE = 0.003 g/cm³), or females (y = 0.073 + 0.925x, SEE = 0.003 g/cm³). Residual plot analysis revealed no group or gender bias in either the cotton gym shorts or in the spandex bicycle shorts.

Conclusion

It would appear bicycle spandex shorts are an acceptable alternative to a Speedo^® like swim suit, however we advise that subjects adhere to the strict clothing protocol that is recommended by the manufacturer.