4-amidinobenzylamine-based inhibitors of urokinase

A series of 4-amidinobenzylamine-based peptidomimetic inhibitors of urokinase was synthesized. The most potent one, benzylsulfonyl-D-Ser-Ala-4-amidinobenzylamide 16, inhibits uPA with a K(i) of 7.7 nM but is less selective than 10 with a Gly as P2 residue. Hydroxyamidine and carbonate prodrugs were prepared, which are rapidly converted into the active inhibitors in rats after subcutaneous application.     

A synthetic TLR4 antagonist has anti-inflammatory effects in two murine models of inflammatory bowel disease

Current evidence indicates that the chronic inflammation observed in the intestines of patients with inflammatory bowel disease is due to an aberrant immune response to enteric flora. We have developed a lipid A-mimetic, CRX-526, which has antagonistic activity for TLR4 and can block the interaction of LPS with the immune system. CRX-526 can prevent the expression of proinflammatory genes stimulated by LPS in vitro. This antagonist activity of CRX-526 is directly related to its structure, particularly secondary fatty acyl chain length. In vivo, CRX-526 treatment blocks the ability of LPS to induce TNF-alpha release. Importantly, treatment with CRX-526 inhibits the development of moderate-to-severe disease in two mouse models of colonic inflammation: the dextran sodium sulfate model and multidrug resistance gene 1a-deficient mice. By blocking the interaction between enteric bacteria and the innate immune system, CRX-526 may be an effective therapeutic molecule for inflammatory bowel disease.     

The Effect of Fish Introductions on the Diatom and Cladoceran Communities of Lake Opeongo,Ontario, Canada

Fish introductions are one of the most widespread anthropogenic perturbations to aquatic ecosystems. Paradoxically, the effects of these introductions on aquatic ecosystems are typically poorly documented. This project studied the effect of fish introductions on Lake Opeongo, an oligotrophic lake in Algonquin Provincial Park, Ontario, Canada (45° 42′ N, 78° 22′ W), using the remains of algae (diatoms) and zooplankton (cladocerans) preserved in the sediments. It was hypothesized that the introduction of cisco or lake herring (Coregonus artedii Lesueur) in 1948, which filled the underutilized pelagic forage fish niche, should have altered nutrient availability for phytoplankton. Prior to cisco introduction, the diatom community of Lake Opeongo reflected a relatively stable oligotrophic state established before European settlement, and consisted of the Cyclotella stelligera complex with subdominants Tabellaria flocculosa IIIp and the Aulacoseira distans complex. No marked changes occurred until ca. 1962 when the diatom community shifted to an assemblage with increased total phosphorus preferences, consisting of Asterionella formosa and lesser amounts of Cyclotella bodanica var lemanica, the C. stelligera complex, Fragilaria crotonensis and T. flocculosa IIIp. The dominant cladoceran Bosmina longirostris increased significantly in relative abundance since the introduction of cisco. The most likely cause of this shift was increased nutrient recycling and/or trophic level changes caused by human manipulation of the fish community of the lake.     

Comparison of Binding Properties and Early Biological Effects of Elicitins in Tobacco Cells

Elicitins are a family of small proteins secreted by Phytophthora species that have a high degree of homology and elicit defense reactions in tobacco (Nicotiana tabacum). They display acidic or basic characteristics, the acidic elicitins being less efficient in inducing plant necrosis. In this study we compared the binding properties of four elicitins (two basic and two acidic) and early-induced signal transduction events (Ca²⁺ influx, extracellular medium alkalinization, and active oxygen species production). The affinity for tobacco plasma membrane-binding sites and the number of binding sites were similar for all four elicitins. Furthermore, elicitins compete with one another for binding sites, suggesting that they interact with the same receptor. The four elicitins induced Ca²⁺ influx, extracellular medium alkalinization, and the production of active oxygen species in tobacco cell suspensions, but the intensity and kinetics of these effects were different from one elicitin to another. As a general observation the concentrations that induce similar levels of biological activities were lower for basic elicitins (with the exception of cinnamomin-induced Ca²⁺ uptake). The qualitative similarity of early events induced by elicitins indicates a common transduction scheme, whereas fine signal transduction tuning is different in each elicitin.     

Mitochondrial haplotypes and the New Zealand origin of clonal European Potamopyrgus, an invasive aquatic snail

The small aquatic snail Potamopyrgus antipodarum is an important invading species in Europe, Australia and North America. European populations are generally believed to derive from accidental introductions from New Zealand, probably dating back to the mid-19th century. We have employed mitochondrial DNA sequences to test the proposed New Zealand origin of European Potamopyrgus, and to learn more about its genealogical history. Using a 481-bp region of the 16S ribosomal RNA gene, we identified 17 distinct haplotypes among 65 snails from New Zealand. In marked contrast, only two haplotypes were found across all European samples, which cover a large geographical area. Importantly, these two haplotypes are shared with snails from the North Island of New Zealand. Due to sampling limitations we cannot rule out a South Island origin for one of the haplotypes, but our results clearly demonstrate the New Zealand origin of European populations. The marked divergence among the two European haplotypes implies the successful colonization by two distinct mitochondrial lineages, which is consistent with previous data based on nuclear markers.     

A single point mutation confers tetrodotoxin and saxitoxin insensitivity on the sodium channel II

A single point mutation of the rat sodium channel II reduces its sensitivity to tetrodotoxin and saxitoxin by more than three orders of magnitude. The mutation replaces glutamic acid 387 with a glutamine and has only slight effects on the macroscopic current properties, as measured under voltage-clamp in Xenopus oocytes injected with the corresponding cDNA-derived mRNA.     

Genetic Evidence That Captured Retroviral Envelope syncytins Contribute to Myoblast Fusion and Muscle Sexual Dimorphism in Mice

Syncytins are envelope genes from endogenous retroviruses, “captured” for a role in placentation. They mediate cell-cell fusion, resulting in the formation of a syncytium (the syncytiotrophoblast) at the fetomaternal interface. These genes have been found in all placental mammals in which they have been searched for. Cell-cell fusion is also pivotal for muscle fiber formation and repair, where the myotubes are formed from the fusion of mononucleated myoblasts into large multinucleated structures. Here we show, taking advantage of mice knocked out for syncytins, that these captured genes contribute to myoblast fusion, with a >20% reduction in muscle mass, mean muscle fiber area and number of nuclei per fiber in knocked out mice for one of the two murine syncytin genes. Remarkably, this reduction is only observed in males, which subsequently show muscle quantitative traits more similar to those of females. In addition, we show that syncytins also contribute to muscle repair after cardiotoxin-induced injury, with again a male-specific effect on the rate and extent of regeneration. Finally, ex vivo experiments carried out on murine myoblasts demonstrate the direct involvement of syncytins in fusion, with a >40% reduction in fusion index upon addition of siRNA against both syncytins. Importantly, similar effects are observed with primary myoblasts from sheep, dog and human, with a 20–40% reduction upon addition of siRNA against the corresponding syncytins. Altogether, these results show a direct contribution of the fusogenic syncytins to myogenesis, with a demonstrated male-dependence of the effect in mice, suggesting that these captured genes could be responsible for the muscle sexual dimorphism observed in placental mammals.     

Revision of the genus Menevia Schaus, 1928 (Lepidoptera,Mimallonoidea, Mimallonidae) with the description of 11 new species

The Neotropical genus Menevia Schaus, 1928 is revised to include 18 species, 11 of which are new. Two species, Menevia ostia comb. n. and Menevia parostia comb. n. are transferred from Pamea Walker, 1855 to Menevia. Four species-groups are diagnosed for the first time based on external characters and male genitalia morphology. The following new species are described: Menevia rosea sp. n., Menevia torvamessoria sp. n., Menevia magna sp. n., Menevia menapia sp. n., Menevia mielkei sp. n., Menevia australis sp. n., Menevia vulgaris sp. n., Menevia franclemonti sp. n., Menevia vulgaricula sp. n., Menevia cordillera sp. n., and Menevia delphinus sp. n.. A neotype is designated for Mimallo plagiata Walker, 1855, which has since been placed in Menevia. Mimallo saturata Walker, 1855 is interpreted to be a nomen dubium.     

Characterization of Novel Simian Immunodeficiency Viruses from Red-Capped Mangabeys from Nigeria (SIVrcmNG409 and -NG411)

Two novel simian immunodeficiency virus (SIV) strains from wild-caught red-capped mangabeys (Cercocebus torquatus torquatus) from Nigeria were characterized. Sequence analysis of the fully sequenced SIV strain rcmNG411 (SIVrcmNG411) and gag and pol sequence of SIVrcmNG409 revealed that they were genetically most closely related to the recently characterized SIVrcm from Gabon (SIVrcmGB1). Thus, red-capped mangabeys from distant geographic locations harbor a common lineage of SIV. SIVrcmNG411 carried a vpx gene in addition to vpr, suggesting a common evolutionary ancestor with SIVsm (from sooty mangabeys). However, SIVrcm was only marginally closer to SIVsm in that region than to any of the other lentiviruses. SIVrcm showed the highest similarity in pol with SIVdrl, isolated from a drill, a primate that is phylogenetically distinct from mangabey monkeys, and clustered with other primate lentiviruses (primarily SIVcpz [from chimpanzees] and SIVagmSab [from African green monkeys]) discordantly in different regions of the genome, suggesting a history of recombination. Despite the genetic relationship to SIVcpz in the pol gene, SIVrcmNG411 did not replicate in chimpanzee peripheral blood mononuclear cells (PBMC), although two other viruses unrelated to SIVcpz, SIVmndGB1 (from mandrills) and SIVlhoest (from L'Hoest monkeys), were able to grow in chimpanzee PBMC. The CCR5 24-bp deletion previously described in red-capped mangabeys from Gabon was also observed in Nigerian red-capped mangabeys, and SIVrcmNG411, like SIVrcmGB1, used CCR2B and STRL33 as coreceptors for virus entry. SIVrcm, SIVsm, SIVmndGB1, and all four SIVlhoest isolates but not SIVsun (from sun-tailed monkeys) replicated efficiently in human PBMC, suggesting that the ability to infect the human host can vary within one lineage.