Antiviral activity of a small-molecule inhibitor of arenavirus glycoprotein processing by the cellular site 1 protease.

Arenaviruses merit interest as clinically important human pathogens and include several causative agents, chiefly Lassa virus (LASV), of hemorrhagic fever disease in humans. There are no licensed LASV vaccines, and current antiarenavirus therapy is limited to the use of ribavirin, which is only partially effective and is associated with significant side effects. The arenavirus glycoprotein (GP) precursor GPC is processed by the cellular site 1 protease (S1P) to generate the peripheral virion attachment protein GP1 and the fusion-active transmembrane protein GP2, which is critical for production of infectious progeny and virus propagation. Therefore, S1P-mediated processing of arenavirus GPC is a promising target for therapeutic intervention. To this end, we have evaluated the antiarenaviral activity of PF-429242, a recently described small-molecule inhibitor of S1P. PF-429242 efficiently prevented the processing of GPC from the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) and LASV, which correlated with the compound's potent antiviral activity against LCMV and LASV in cultured cells. In contrast, a recombinant LCMV expressing a GPC whose processing into GP1 and GP2 was mediated by furin, instead of S1P, was highly resistant to PF-429242 treatment. PF-429242 did not affect virus RNA replication or budding but had a modest effect on virus cell entry, indicating that the antiarenaviral activity of PF-429242 was mostly related to its ability to inhibit S1P-mediated processing of arenavirus GPC. Our findings support the feasibility of using small-molecule inhibitors of S1P-mediated processing of arenavirus GPC as a novel antiviral strategy.

Current drug discovery strategies against arenavirus infections.

Arenaviruses are a large group of emerging viruses including several causative agents of severe hemorrhagic fevers with high mortality in man. Considering the number of people affected and the currently limited therapeutic options, novel efficacious therapeutics against arenaviruses are urgently needed. Over the past decade, significant advances in knowledge about the basic virology of arenaviruses have been accompanied by the development of novel therapeutics targeting different steps of the arenaviral life cycle. High-throughput, small-molecule screens identified potent and broadly active inhibitors of arenavirus entry that were instrumental for the dissection of unique features of arenavirus fusion. Novel inhibitors of arenavirus replication have been successfully tested in animal models and hold promise for application in humans. Late in the arenavirus life cycle, the proteolytic processing of the arenavirus envelope glycoprotein precursor and cellular factors critically involved virion assembly and budding provide further promising 'druggable' targets for novel therapeutics to combat human arenavirus infection.

New palaeontological investigations in the Jurassic of western Thailand

The paleontological investigations of the Jurassic of Western Thailand, districts of Mae Sot (Tak-Mae Sot highway, Padaeng Tak and Ban Mae Kut Luang Zinc mines) and Umphang (Klo Tho), provide age constraints for the Late Indosinian orogeny, the Paleotethys closure and the timing of the marine Jurassic inundation of Sundaland. The basal conglomerate of the Jurassic is derived from the pelagic Triassic Mae Sariang substratum. Stratigraphy, microfacies and paleontology of the Jurassic marine strata focus especially on ammonites, bivalves, large benthic foraminifera and algae. Among ammonites, the Tethyan Catulloceras perisphinctoides Gemmellaro marks the Upper Toarcian (Aalensis Zone) along the Tak-Mae Sot highway and Riccardiceras longalvum (Vacek). Malladaites pertinax (Vacek), Abbasites sp. and Vacekia sp. indicate Middle Aalenian to lowermost Bajocian in the Padaeng Mine (SE of Mae Sot) and Klo-Tho (Umphang). Vacekia sp., Spinammatoceras schindewolfi Linares and Sandoval and Malladaites vaceki Linares and Sandoval indicate Middle Aalenian to lowermost Upper Aalenian at Ban Mae Kut Luang (NE of Mae Sot). Among foraminifers, the large benthic foraminifer Timidonella sarda Bassoullet, Chabrier and Fourcade in the Western Tethys is indicative for Aalenian-Bajocian times, as characterized in the section at the Tak-Padaeng Zinc mine and the Klo-Tho Formation near Umphang. The endemic foraminifer Gutnicella kaempferi characterizes the Pu Khloe Khi Formation near Umphang. Among bivalves, shallow marine, dominantly endemic fauna includes Parvamussium donaiense (Mansuy) and Bositra ornate (Quenstedt), from the Toarcian to the Early Bajocian. A consideration of the faunal affinity shows that the fauna is partly endemic with Northern Tethyan (Eurasian) affinity. Crown Copyright (C) 2010 Published by Elsevier B.V. on behalf of International Association for Gondwana Research. All rights reserved.

Kemikaaliriskien kartoitus

Tämä insinöörityö tehtiin Crown Pakkaus Oy:n Helsingin tehtaalle. Työ toteutettiin kemikaalilainsäädännön tietojen sekä muun kirjallisuuden pohjalta. Työn tarkoituksena oli tehdä kemikaaliriskien kartoitus johdatuksena turvalliseen työskentelyyn tehtaalla. Insinöörityö jakautuu kolmeen osioon. Ensimmäinen osa sisältää taustaa Crown Pakkaus Oy:stä, tietoa työn tavoitteista, kemikaalitietojen tarjonnasta sekä siitä, minkälaista tietoa kannattaa hankkia kemikaaliriskien kartoituksessa. Työn toisessa osassa käydään läpi, mitä vaaralliset kemikaalit ovat ja miten niitä tulisi käsitellä. Lisäksi tarkastellaan kemikaalivarastoa, mitä näkökohtia täytyy ottaa huomioon kemikaalivarastoa suunniteltaessa. Lopussa käsitellään henkilönsuojaimia sekä torjuntavälineistöä. Kolmannessa osassa käsitellään kemikaaliriskien arviointia, toimenpide-ehdotuksia sekä tulevaisuutta. Tulevaisuusnäkökohta liittyy uuteen kemikaaliasetukseen, joka astuu voimaan kesäkuussa 2007.

Degradation of pathogen quorum-sensing molecules by soil bacteria: a preventive and curative biological control mechanism.

Abstract The plasmid pME6863, carrying the aiiA gene from the soil bacterium Bacillus sp. A24 that encodes a lactonase enzyme able to degrade N-acyl-homoserine lactones (AHLs), was introduced into the rhizosphere isolate Pseudomonas fluorescens P3. This strain is not an effective biological control agent against plant pathogens. The transformant P. fluorescens P3/pME6863 acquired the ability to degrade AHLs. In planta, P. fluorescens P3/pME6863 significantly reduced potato soft rot caused by Erwinia carotovora and crown gall of tomato caused by Agrobacterium tumefaciens to a similar level as Bacillus sp. A24. Little or no disease reduction was observed for the wild-type strain P3 carrying the vector plasmid without aiiA. Suppression of potato soft rot was observed even when the AHL-degrading P. fluorescens P3/pME6863 was applied to tubers 2 days after the pathogen, indicating that biocontrol was not only preventive but also curative. When antagonists were applied individually with the bacterial plant pathogens, biocontrol activity of the AHL degraders was greater than that observed with several Pseudomonas 2,4-diacetylphloroglucinol-producing strains and with Pseudomonas chlororaphis PCL1391, which relies on production of phenazine antibiotic for disease suppression. Phenazine production by this well characterized biological control strain P. chlororaphis PCL1391 is regulated by AHL-mediated quorum sensing. When P. chlororaphis PCL1391 was co-inoculated with P. fluorescens P3/pME6863 in a strain mixture, the AHL degrader interfered with the normally excellent ability of the antibiotic producer to suppress tomato vascular wilt caused by Fusarium oxysporum f. sp. lycopersici. Our results demonstrate AHL degradation as a novel biocontrol mechanism, but also demonstrate the potential for non-target interactions that can interfere with the biocontrol efficacy of other strains.

Risk sharing with the monarch: Excusable defaults and contingent debt in the age of Philip II, 1556-1598

Contingent sovereign debt can create important welfare gains. Nonetheless,there is almost no issuance today. Using hand-collected archival data, we examine thefirst known case of large-scale use of state-contingent sovereign debt in history. Philip IIof Spain entered into hundreds of contracts whose value and due date depended onverifiable, exogenous events such as the arrival of silver fleets. We show that this allowedfor effective risk-sharing between the king and his bankers. The data also stronglysuggest that the defaults that occurred were excusable they were simply contingenciesover which Crown and bankers had not contracted previously.

Microsatellites reveal high population viscosity and limited dispersal in the ant Formica paralugubris

We used microsatellites to study the fine-scale genetic structure of a highly polygynous and largely uni-colonial population of the ant Formica paralugubris. Genetic data indicate that long-distance gene flow between established nests is limited and new queens are primarily recruited from within their natal nest. Most matings occur between nestmates and are random at this level. In the center of the study area, budding and permanent connections between nests result in strong population viscosity, with close nests being more similar generically than distant nests. In contrast, nests located outside of this supercolony show no isolation by distance, suggesting that they have been initiated by queens that participated in mating flights rather than by budding from nearby nests in our sample population. Recruitment of nestmates as new reproductive individuals and population viscosity in the supercolony increase genetic differentiation between nests. This in turn inflates relatedness estimates among worker nestmates (r = 0.17) above what is due to close pedigree links. Local spatial genetic differentiation may favor the maintenance of altruism when workers raise queens that will disperse on foot and compete with less related queens from neighboring nests or disperse on the wing and compete with unrelated queens.

Nestmate recognition and the genetic relatedness of nests in the ant Formica pratensis

Genetic relatedness of the mound-building ant Formica pratensis was determined by means of microsatellite DNA polymorphism, and its impact on nestmate recognition was tested in a population in Southern Sweden (Oeland). Recognition between nests was measured by testing aggression levels between single pairs of workers. The genetic distances of nests (Nei's genetic distance) and the spatial distance of nests were correlated and both showed a strong relation to the aggression behavior. Multiple regression analysis revealed a stronger impact of genetic relatedness rather than spatial distances on aggression behavior. Neighbouring nests were more closely related than distant nests, which may reflect budding as a possible spreading mechanism. The genetic distance data showed that nestmate recognition was strongly genetically influenced in F. pratensis.

Within tree distribution of a gall-inducing Eurytoma (Hymenoptera, Eurytomidae) on Caryocar brasiliense (Caryocaraceae)

For the first time, we identified the insect herbivore that induces one of the most conspicuous galls on the leaves of Caryocar brasiliense Camb. (Caryocaraceae), a widespread, typical cerrado woody plant of large economic importance. The gall inducing organism is a new and undescribed species of Eurytoma sp. (Hymenoptera, Eurytomidae). Furthermore, we recorded its spatial distribution within C. brasiliense trees. More Eurytoma galls were found on the eastern tree slope, followed the southern and northern slopes. More galls were found in the interior of the tree crown, i.e., on the proximal portion of the stems compared to the terminal portion. At the leaf level, more galls were found on the median region compared to the distal or proximal, perhaps due to the lower trichome density found in there. Leaf colonization by Eurytoma sp. may initiate at the leaf margin but after colonization reaches 50% the central portion starts to be colonized.

A new species of Aurigoniella Takiya, Mejdalani & Felix (Hemiptera, Cicadellidae, Cicadellini) from southern Brazil

Aurigoniella meridionalis, sp. nov. is described and illustrated from Morretes and São José dos Pinhais, Paraná State, southern Brazil. It can be easily distinguished from the Aurigoniella type-species, A. dutrai, by its distinct color pattern, smaller size, shorter crown, hindleg knees attaining lateral lobe of pronotum, aedeagus broadest height around mid-length, and paraphyses ramus biramous.

Serial defaults, serial profits: Returns to sovereign lending in Habsburg Spain, 1566-1600

Philip II of Spain accumulated debts equivalent to 60% of GDP. He also defaulted four times onhis short-term loans, thus becoming the first serial defaulter in history. Contrary to a commonview in the literature, we show that lending to the king was profitable even under worst-casescenario assumptions. Lenders maintained long-term relationships with the crown. Lossessustained during defaults were more than compensated by profits in normal times. Defaultswere not catastrophic events. In effect, short-term lending acted as an insurance mechanism,allowing the king to reduce his payments in harsh times in exchange for paying a premium intranquil periods. © 2010 Elsevier Inc. All rights reserved.

Spatial distribution of a spherical gall (Hymenoptera, Eulophidae) on Caryocar brasiliense (Caryocaraceae)

We obtained the first data on spatial distribution of a spherical galling insect (Hymenoptera, Eulophidae) at the Caryocar brasiliense Camb. (Caryocaraceae) tree level. This work was developed in two pastures in Montes Claros, Minas Gerais State, Brazil. The areas studied were: pasture 1 (in activity) and pasture 2 (abandoned pasture = savanna in recovery). We evaluated the distribution of spherical galls in: foliage orientation (slope), among leaves (border and interior of the tree crown), among leaflets (right, central, left), distal, median, and proximal as well as border, central area, and adjacent to the mid leaf vein of the leaflet, and difference between areas in 10 infested trees per area. The smaller number of spherical gall/leaflet was observed in pasture 1 than in pasture 2. More spherical galls were found on the northern in pasture 1, but in the pasture 2, the lower spherical galls were observed on the northeast than other slopes. The average number of spherical galls did not differ statistically among the three leaflets of C. brasiliense in pasture 2. However, in pasture 1, we observed highest number of spherical galls in the central leaflet. More spherical galls were found in the border than interior of the tree crown. The average number of spherical galls did not differ statistically among the longitudinal region on leaflet of C. brasiliense. The spherical gall insect preferred to colonize the leaf margin than the central portion or near mid vein on transversal regions on a leaflet.

Market institutions and judicial rulemaking

Assuming that the degree of discretion granted to judges was the main distinguishing feature between common and civil law until the 19th century, we argue that constraining judicial discretion was instrumental in protecting freedom of contract and developing the market order in civil law. We test this hypothesis by analyzing the history of Western law. In England, a unique institutional balance between the Crown and the Parliament guaranteed private property and prompted the gradual evolution towards a legal framework that facilitated market relationships, a process that was supported by the English judiciary. On the Continent, however, legal constraints on the market were suppressed in a top-down fashion by the founders of the liberal state, often against the will of the incumbent judiciary. Constraining judicial discretion there was essential for enforcing freedom of contract and establishing the legal order of the market economy. In line with this evidence, our selection hypothesis casts doubts on the normative interpretation of empirical results that proclaim the superiority of one legal system over another, disregarding the local conditions and institutional interdependencies on which each legal system was grounded.

Here’s The Skinny on Asparagus..., 2009

Three seasons pass before asparagus can be harvested. In its first season of growth a crown forms with six inches of root. In the second season the crown grows a fern. Asparagus can be harvested in its third year, and reaches its prime after 6-8 years. This brochure produced by The Department of Agriculture and Land Stewardship.

Kauppias, kaupunki, kruunu : Turun porvariyhteisö ja talouden organisaatio varhaiskeskiajalta 1570-luvulle

Summary: The merchant, the town and the crown : the burgher community of Turku and economic organization from the early Middle Ages to the 1570's