Discovery of selective urokinase plasminogen activator (uPA) inhibitors as a potential treatment for multiple sclerosis

We report here the design and synthesis of a novel series of benzylamines that are potent and selective inhibitors of uPA with promising oral availability in rat. Further evaluation of one representative (ZK824859) of the new structural class showed that this compound lowered clinical scores when dosed in either acute or chronic mouse EAE models, suggesting that uPA inhibitors of this type could be useful for the treatment of multiple sclerosis.     

Sexual cannibalism and population viability

Some behaviours that typically increase fitness at the individual level may reduce population persistence, particularly in the face of environmental changes. Sexual cannibalism is an extreme mating behaviour which typically involves a male being devoured by the female immediately before, during or after copulation, and is widespread amongst predatory invertebrates. Although the individual‐level effects of sexual cannibalism are reasonably well understood, very little is known about the population‐level effects. We constructed both a mathematical model and an individual‐based model to predict how sexual cannibalism might affect population growth rate and extinction risk. We found that in the absence of any cannibalism‐derived fecundity benefit, sexual cannibalism is always detrimental to population growth rate and leads to a higher population extinction risk. Increasing the fecundity benefits of sexual cannibalism leads to a consistently higher population growth rate and likely a lower extinction risk. However, even if cannibalism‐derived fecundity benefits are large, very high rates of sexual cannibalism (>70%) can still drive the population to negative growth and potential extinction. Pre‐copulatory cannibalism was particularly damaging for population growth rates and was the main predictor of growth declining below the replacement rate. Surprisingly, post‐copulatory cannibalism had a largely positive effect on population growth rate when fecundity benefits were present. This study is the first to formally estimate the population‐level effects of sexual cannibalism. We highlight the detrimental effect sexual cannibalism may have on population viability if (1) cannibalism rates become high, and/or (2) cannibalism‐derived fecundity benefits become low. Decreased food availability could plausibly both increase the frequency of cannibalism, and reduce the fecundity benefit of cannibalism, suggesting that sexual cannibalism may increase the risk of population collapse in the face of environmental change.     

Analysis of copia sequence variation within and between Drosophila species

The sequences of the 5' long-terminal repeat (LTR) and adjacent leader regions of 27 full-length copia elements isolated from natural populations of Drosophila melanogaster, D. simulans, and D. mauritiana are presented. Phylogenetic analyses indicate that although D. melanogaster copia elements are distinct from those of D. simulans and D. mauritiana, the elements of these latter two species are not distinguishable from one another. LTRs and adjacent 5' leader regions of elements isolated from D. simulans and D. mauritiana are structurally similar to one another and carry substantial deletional variation mapping to regions previously identified as being of potential importance for copia expression.      

Comparisons of the molecular evolutionary process at rbcL and ndhF in the grass family (Poaceae)

We examine rate heterogeneity among evolutionary lineages of the grass family at two plasmid loci, ndhF and rbcL, and we introduce a method to determine whether patterns of rate heterogeneity are correlated between loci. We show both that rates of synonymous evolution are heterogeneous among grass lineages and that are heterogeneity is correlated between loci at synonymous sites. At nonsynonymous sites, the pattern of rate heterogeneity is not correlated between loci, primarily due to an aberrant pattern of rate heterogeneity at nonsynonymous sites of rbcL. We compare patterns of synonymous rate heterogeneity to predictors based on the generation time effect and the speciation rate hypotheses. Although there is some evidence for generation time effects, neither generation time effects nor speciation rates appear to be sufficient to explain patterns of rate heterogeneity in the grass plastid sequences.      

Determination of the structure of a membrane-incorporated ion channel. Solid-state nuclear magnetic resonance studies of gramicidin A.

Solid-state nuclear magnetic resonance (NMR) measurements on 13C-labeled analogues of the ion channel-forming peptide, gramicidin A, have been used to directly determine the structure of this peptide in lipid membranes. Seven gramicidin analogues, each labeled in a single carbonyl group of gly2, L-ala3, D-leu4, L-val7, D-leu10, D-leu12, or D-leu14 were synthesized by the solid-phase method. These gramicidin analogues were incorporated into aligned multilayers of dimyristoylphosphatidylcholine, or diether lipid bearing 14- or 16-carbon chains, at a 1:15 peptide:lipid mole ratio. Proton-enhanced, 13C, solid-state spectra were obtained at several temperatures and over a range of sample orientations with respect to the spectrometer magnetic field to permit accurate measurement of the chemical shift anisotropies. The observed anisotropies indicate that all of the labeled carbonyl bonds are oriented almost parallel to the molecular long axis and perpendicular to the lipid bilayer plane. These orientations are consistent with gramicidin forming a beta 6.3 single-strand helix that is oriented parallel to the methylene chains of the lipid molecules. Comparison of the linewidths from labeled residues that are in the innermost turn of the helix (gly2, ala3, and D-leu4), in the center of the molecule (val7), and in the turn nearest the lipid bilayer surface (D-leu10, D-leu12, and D-leu14) suggests that although the peptide behaves largely as a rigid barrel, segments of the peptide close to the membrane surface possess greater motional freedom.(ABSTRACT TRUNCATED AT 250 WORDS)     

God's magnificent law: The bad influence of theistic metaphysics on Darwin's estimation of natural selection

Conclusion It is natural for us — living after the Darwinian Revolution and the neo-Darwinian synthesis — to consider the adoption of evolution by natural selection as unconditionally rational, because it now seems the best theory or explanation of many phenomena. Nonetheless, if we take historical inquiry seriously, as allowing us to probe into the ground of our knowledge, the roots of even this rational Darwinism might be unearthed. Darwinian doctrine betrays a deceptive desire for unity and simplicity of principle, and belief that the mechanistic aspect of nature is of the highest significance. Such crucial but questionable presuppositions are more easily discerned historically, insofar as they chronologically preceded Darwin's particular theoretical conviction and were even set off as a metaphysics of divine law.We have seen how Darwin's teaching about nature emerged within that theistic metaphysics. It emerged in a prior metaphysical debate in his mind between the contemporary belief in special creations and the belief in a designed hierarchy of physical laws. One can hardly deny that Darwin favored the superior side in this contest; but the contest was a narrow one whose basic premises he never clearly criticized. On the one hand, of course, his conviction about a lawful genesis inspired him to take a broad view of things and to seek out important general phenomena. But, on the other hand, it ensured that his new empirical notions would be easily drawn into the preferred cosmology. Historically, this seems to have occurred in Darwin's adoption of Malthus' principle of population and his extension of it to the whole account of descent: Malthusianism was readily attached to an ultimate scheme of things. Consequently, the key concepts that Darwin developed out of his Malthusian views — perfect adaptation and selection — reflect his cosmological prepossession, his desire to express a total and teleological process of creation. Perhaps our most valuable, and most undervalued, token of Darwin's metaphysical orientation is his reliance on a human technique (selective breeding) to explain Nature's way. In sum, to understand Darwin's faith in his grand view of life, we should not ignore the metaphysics that preceded and structured it, the metaphysics that linked the principles of contemporary science to primordial creation. Nor should we fail to see that such a metaphysics leads natural philosophy into a shadowy realm, where system can come to look like science, and one insight like an absolute.     

NMR study of synthetic lecithin bilayers in the vicinity of the gel-liquid--crystal transition.

1H, 2H, and 31P NMR methods have been employed in the study of dimyristoyl lecithin bilayers hydrated with D2O in the gel (L beta'), intermediate (P beta') and liquid-crystalline (L alpha) phases. For D2O/lipid molar ratios, n, in the range 7 less than or equal to n less than or equal to 11 discontinuities are observed in the deuterium NMR splittings at both main and pretransitions. A partial phase diagram based on NMR and differential scanning calorimetry data is presented. 1H NMR dipolar splittings are observed for macroscopically oriented samples in all three phases. Changes in the 1H splittings are correlated with 2H and 31P data and interpreted to show that the chain tilt in the gel phase undergoes a discontinuous change on transition to the intermediate phase, which brings the chain axes closer to the bilayer normal. An estimate of chain tilt in the gel phase is made on the basis of NMR data and found to be approximately 23 degrees for a sample with n = 11 at 18 degrees C.     

The use of meperidine hydrochloride for chemical restraint in certain cetaceans and pinnipeds

Meperidine HCl was administered intramuscularly by hand-syringe to a number of individuals representing several species of cetaceans (n = 95) and pinnipeds (n = 36). Dosage administered was 0.11 mg/kg, 0.23 mg/kg or 0.45 mg/kg, with the majority of animals receiving the middle dosage. Meperidine HCl provided moderate restraint in cetaceans without obvious deleterious effects. Restraint was achieved rapidly, with maximum effect occurring 20 min after intramuscular injection and lasting for 2 to 3 hr. Analgesia appeared to last as long as 4 hr and was sometimes accompanied by a restoration of appetite in animals suffering from physical discomfort. Higher doses produced increased sedation and analgesia without noticeably depressing respiration. Meperidine HCl provided moderate restraint for phocids and walrus (Odobenus rosmarus) without apparent detriment. California sea lions (Zalophus californianus) showed little restraint, but demonstrated profound respiratory depression.     

Hematology and serum chemistry values in the beluga (Delphinapterus leucas)

Normal values and ranges for 31 clinical hematology and serum chemistry tests are reported for the beluga or white whale (Delphinapterus leucas). The values were collected over a 6-yr period from eight belugas maintained for display at Sea World (San Diego, California, USA) facilities and represent long-term evaluations for each animal in a controlled environment. They represent the first report for a number of serum chemistry values for the beluga. Normal values such as these provide an important data base from which to detect diagnostically important changes in health status for belugas in a zoological setting. They also establish a baseline from which to evaluate differences in normal values in free-ranging belugas and from which to diagnose disease problems in wild populations.