Recent progress in the discovery of macrocyclic compounds as potential anti-infective therapeutics

Novel therapeutic strategies are urgently needed for the treatment of serious diseases caused by viral, bacterial and parasitic infections, because currently used drugs are facing the problem of rapidly emerging resistance. There is also an urgent need for agents that act on novel pathogen-specific targets, in order to expand the repertoire of possible therapies. The high throughput screening of diverse small molecule compound libraries has provided only a limited number of new lead series, and the number of compounds acting on novel targets is even smaller. Natural product screening has traditionally been very successful in the anti-infective area. Several successful drugs on the market as well as other compounds in clinical development are derived from natural products. Amongst these, many are macrocyclic compounds in the 1-2 kDa size range. This review will describe recent advances and novel drug discovery approaches in the anti-infective area, focusing on synthetic and natural macrocyclic compounds for which in vivo proof of concept has been established. The review will also highlight the Protein Epitope Mimetics (PEM) technology as a novel tool in the drug discovery process. Here the structures of naturally occurring antimicrobial and antiviral peptides and proteins are used as starting points to generate novel macrocyclic mimetics, which can be produced and optimized efficiently by combinatorial synthetic methods. Several recent examples highlight the great potential of the PEM approach in the discovery of new anti-infective agents

Fundamental scaling laws of on-off intermittency in a stochastically driven dissipative pattern forming system

Noise driven electroconvection in sandwich cells of nematic liquid crystals exhibits on-off intermittent behaviour at the onset of the instability. We study laser scattering of convection rolls to characterize the wavelengths and the trajectories of the stochastic amplitudes of the intermittent structures. The pattern wavelengths and the statistics of these trajectories are in quantitative agreement with simulations of the linearized electrohydrodynamic equations. The fundamental $\tau^{-3/2}$ distribution law for the durations $\tau$ of laminar phases as well as the power law of the amplitude distribution of intermittent bursts are confirmed in the experiments. Power spectral densities of the experimental and numerically simulated trajectories are discussed.Comment: 20 pages and 17 figure

Modulation of Localized States in Electroconvection

We report on the effects of temporal modulation of the driving force on a particular class of localized states, known as worms, that have been observed in electroconvection in nematic liquid crystals. The worms consist of the superposition of traveling waves and have been observed to have unique, small widths, but to vary in length. The transition from the pure conduction state to worms occurs via a backward bifurcation. A possible explanation of the formation of the worms has been given in terms of coupled amplitude equations. Because the worms consist of the superposition of traveling waves, temporal modulation of the control parameter is a useful probe of the dynamics of the system. We observe that temporal modulation increases the average length of the worms and stabilizes worms below the transition point in the absence of modulation.Comment: 4 pages, 4 figure

Crossover Scaling in Dendritic Evolution at Low Undercooling

We examine scaling in two-dimensional simulations of dendritic growth at low undercooling, as well as in three-dimensional pivalic acid dendrites grown on NASA's USMP-4 Isothermal Dendritic Growth Experiment. We report new results on self-similar evolution in both the experiments and simulations. We find that the time dependent scaling of our low undercooling simulations displays a cross-over scaling from a regime different than that characterizing Laplacian growth to steady-state growth

Co-ordination of local policies for urban development and public transportation in four Swiss cities

The present article aims at assessing the possibility for urban areas to coordinate local policies of urban development and public transportation and at explaining the differences in this achievement between urban regions. In order to do so, the study draws support from two empirical sources: a historical analysis of the "mass-production" generated by the public service sectors in the field of transport and urban development in the cities of Basel, Bern, Geneva, and Lausanne since 1950, and a series of six case studies in these four cities. The study identifies factors located both at context level regarding morphological and geographical conditions as well as institutional settings and case-specific idiosyncrasies regarding organizational structure, past policy decisions, as well as vocational cultures that determine the possibility for urban areas to meet the need for policy coordination

A Randomized Placebo-Controlled Phase Ia Malaria Vaccine Trial of Two Virosome-Formulated Synthetic Peptides in Healthy Adult Volunteers

BACKGROUND AND OBJECTIVES: Influenza virosomes represent an innovative human-compatible antigen delivery system that has already proven its suitability for subunit vaccine design. The aim of the study was to proof the concept that virosomes can also be used to elicit high titers of antibodies against synthetic peptides. The specific objective was to demonstrate the safety and immunogenicity of two virosome-formulated P. falciparum protein derived synthetic peptide antigens given in two different doses alone or in combination. METHODOLOGY/PRINCIPAL FINDINGS: The design was a single blind, randomized, placebo controlled, dose-escalating study involving 46 healthy Caucasian volunteers aged 18-45 years. Five groups of 8 subjects received virosomal formulations containing 10 microg or 50 microg of AMA 49-CPE, an apical membrane antigen-1 (AMA-1) derived synthetic phospatidylethanolamine (PE)-peptide conjugate or 10 ug or 50 ug of UK39, a circumsporozoite protein (CSP) derived synthetic PE-peptide conjugate or 50 ug of both antigens each. A control group of 6 subjects received unmodified virosomes. Virosomal formulations of the antigens (designated PEV301 and PEV302 for the AMA-1 and the CSP virosomal vaccine, respectively) or unmodified virosomes were injected i. m. on days 0, 60 and 180. In terms of safety, no serious or severe adverse events (AEs) related to the vaccine were observed. 11/46 study participants reported 16 vaccine related local AEs. Of these 16 events, all being pain, 4 occurred after the 1(st), 7 after the 2(nd) and 5 after the 3(rd) vaccination. 6 systemic AEs probably related to the study vaccine were reported after the 1(st) injection, 10 after the 2(nd) and 6 after the 3(rd). Generally, no difference in the distribution of the systemic AEs between either the doses applied (10 respectively 50 microg) or the synthetic antigen vaccines (PEV301 and PEV302) used for immunization was found. In terms of immunogenicity, both PEV301 and PEV302 elicited already after two injections a synthetic peptide-specific antibody response in all volunteers immunized with the appropriate dose. In the case of PEV301 the 50 microg antigen dose was associated with a higher mean antibody titer and seroconversion rate than the 10 microg dose. In contrast, for PEV302 mean titer and seroconversion rate were higher with the lower dose. Combined delivery of PEV301 and PEV302 did not interfere with the development of an antibody response to either of the two antigens. No relevant antibody responses against the two malaria antigens were observed in the control group receiving unmodified virosomes. CONCLUSIONS: The present study demonstrates that three immunizations with the virosomal malaria vaccine components PEV301 or/and PEV302 (containing 10 microg or 50 microg of antigen) are safe and well tolerated. At appropriate antigen doses seroconversion rates of 100% were achieved. Two injections may be sufficient for eliciting an appropriate immune response, at least in individuals with pre-existing anti-malarial immunity. These results justify further development of a final multi-stage virosomal vaccine formulation incorporating additional malaria antigens. TRIAL REGISTRATION: ClinicalTrials.gov NCT00400101

A miniature world in decline: European Red List of Mosses, Liverworts and Hornworts

AimThis Red List is a summary of the conservation status of the European species of mosses, liverworts and hornworts, collectively known as bryophytes, evaluated according to IUCN’s Guidelines for Application of IUCN Red List Criteria at Regional Level. It provides the first comprehensive, region-wide assessment of bryophytes and it identifies those species that are threatened with extinction at a European level, so that appropriate policy measures and conservation actions, based on the best available evidence, can be taken to improve their status.ScopeAll bryophytes native to or naturalised in Europe (a total of 1,817 species), have been included in this Red List. In Europe, 1,796 species were assessed, with the remaining 21 species considered Not Applicable (NA). For the EU 28, 1,728 species were assessed, with a remaining 20 species considered NA and 69 species considered Not Evaluated (NE). The geographical scope is continentwide, extending from Iceland in the west to the Urals in the east, and from Franz Josef Land in the north to theCanary Islands in the south. The Caucasus region is not included. Red List assessments were made at two regional levels: for geographical Europe and for the 28 Member States of the European Union.ResultsOverall, 22.5% of European bryophyte species assessed in this study are considered threatened in Europe, with two species classified as Extinct and six assessed as Regionally Extinct (RE). A further 9.6% (173 species) are considered Near Threatened and 63.5% (1,140 species) are assessed as Least Concern. For 93 species (5.3%), there was insufficient information available to be able to evaluate their risk of extinction and thus they were classified as Data Deficient (DD). The main threats identified were natural system modifications (i.e., dam construction, increases in fire frequency/intensity, and water management/use), climate change (mainly increasing frequency of droughts and temperature extremes), agriculture (including pollution from agricultural effluents) and aquaculture.RecommendationsPolicy measures• Use the European Red List as the scientific basis to inform regional/national lists of rare and threatened species and to identify priorities for conservation action in addition to the requirements of the Habitats Directive, thereby highlighting the conservation status of bryophytes at the regional/local level.• Use the European Red List to support the integration of conservation policy with the Common Agricultural Policy (CAP) and other national and international policies. For example, CAP Strategic Plans should include biodiversity recovery commitments that could anticipate, among others, the creation of Important Bryophyte Areas. An increased involvement of national environmental agencies in the preparation of these strategic plans, and more broadly in ongoing discussions on the Future CAP Green Architecture, would likely also ensure the design of conservation measures better tailored to conserve bryophytes in agricultural landscapes.• Update the European Red List every decade to ensure that the data remains current and relevant.• Develop Key Biodiversity Areas for bryophytes in Europe with a view to ensuring adequate site-based protection for bryophytes.Research and monitoring• Use the European Red List as a basis for future targeted fieldwork on possibly extinct and understudied species.• Establish a monitoring programme for targeted species (for example, threatened species and/or arable bryophytes).• Use the European Red List to obtain funding for research into the biology and ecology of key targeted species.Action on the ground• Use the European Red List as evidence to support multi-scale conservation initiatives, including designation of protected areas, reform of agricultural practices and land management, habitat restoration and rewilding, and pollution reduction measures.• Use the European Red List as a tool to target species that would benefit the most from the widespread implementation of the solutions offered by the 1991 Nitrates Directive (Council Directive 91/676/EEC), including the application of correct amounts of nutrients for each crop, only in periods of crop growth under suitable climatic conditions and never during periods of heavy rainfall or on frozen ground, and the creation of buffer zones to protect waters from run-off from the application of fertilizers.Ex situ conservation• Undertake ex situ conservation of species of conservation concern in botanic gardens and spore and gene banks, with a view to reintroduction where appropriate.</p

Comparative constructions of similarity in Northern Samoyedic languages

The purpose of this paper is to analyze the suffixes which are used in Northern Samoyedic languages to build comparative constructions of equality. Depending on the language, the suffixes may perform three functions: word-building, form-building, and inflectional. When they mark the noun, they serve as simulative suffixes and are employed to build object comparison. In the inflectional function, these suffixes mark the verb and are a means of constructing situational comparison. In this case, they signal the formation of a special mood termed the Approximative. This paper provides a detailed description of the Approximative from paradigmatic and syntagmatic perspectives