Novel Furin Inhibitors with Potent Anti‐infectious Activity

New peptidomimetic furin inhibitors with unnatural amino acid residues in the P3 position were synthesized. The most potent compound 4‐guanidinomethyl‐phenylacteyl‐Arg‐Tle‐Arg‐4‐amidinobenzylamide (MI‐1148) inhibits furin with a K_i value of 5.5 pM . The derivatives also strongly inhibit PC1/3, whereas PC2 is less affected. Selected inhibitors were tested in cell culture for antibacterial and antiviral activity against infectious agents known to be dependent on furin activity. A significant protective effect against anthrax and diphtheria toxin was observed in the presence of the furin inhibitors. Furthermore, the spread of the highly pathogenic H5N1 and H7N1 avian influenza viruses and propagation of canine distemper virus was strongly inhibited. Inhibitor MI‐1148 was crystallized in complex with human furin. Its N‐terminal guanidinomethyl group in the para position of the P5 phenyl ring occupies the same position as that found previously for a structurally related inhibitor containing this substitution in the meta position, thereby maintaining all of the important P5 interactions. Our results confirm that the inhibition of furin is a promising strategy for a short‐term treatment of acute infectious diseases.     

Genetic Variation in Jasmonic Acid- and Spider Mite-Induced Plant Volatile Emission of Cucumber Accessions and Attraction of the Predator <Emphasis Type="Italic">Phytoseiulus persimilis</Emphasis>

Cucumber plants (Cucumis sativus L.) respond to spider–mite (Tetranychus urticae) damage with the release of specific volatiles that are exploited by predatory mites, the natural enemies of the spider mites, to locate their prey. The production of volatiles also can be induced by exposing plants to the plant hormone jasmonic acid. We analyzed volatile emissions from 15 cucumber accessions upon herbivory by spider mites and upon exposure to jasmonic acid using gas chromatography—mass spectrometry. Upon induction, cucumber plants emitted over 24 different compounds, and the blend of induced volatiles consisted predominantly of terpenoids. The total amount of volatiles was higher in plants treated with jasmonic acid than in those infested with spider mites, with (E)-4,8-dimethyl-1,3,7-nonatriene, (E,E)-α-farnesene, and (E)-β-ocimene as the most abundant compounds in all accessions in both treatments. Significant variation among the accessions was found for the 24 major volatile compounds. The accessions differed strongly in total amount of volatiles emitted, and displayed very different odor profiles. Principal component analysis performed on the relative quantities of particular compounds within the blend revealed clusters of highly correlated volatiles, which is suggestive of common metabolic pathways. A number of cucumber accessions also were tested for their attractiveness to Phytoseiulus persimilis, a specialist predator of spider mites. Differences in the attraction of predatory mites by the various accessions correlated to differences in the individual chemical profiles of these accessions. The presence of genetic variation in induced plant volatile emission in cucumber shows that it is possible to breed for cucumber varieties that are more attractive to predatory mites and other biological control agents.     

Feed water pretreatment for desalination plants

Effective membrane pretreatment is a crucial requirement for trouble free and cost effective RO desalination. Pretreatment construction costs are significant and may reach as much as 10%-20% of the total desalination plant capital costs. This paper presents a general review of the central factors involved in assessing raw water quality. The main foulant categories are described and the various unit operations commonly applied are reviewed. Pretreatment aspects of desalination offer fertile grounds for advancing desalination technologies. Promising research directions are highlighted.     

Nutraceutical properties and toxicity studies of fruits from four Cactaceae species grown in Argentine Northwestern

Fruits are known as good sources of phytochemicals, essential to prevent degenerative diseases like cancer and cardiovascular diseases. They contain a variety of antioxidants, which are useful to scavenge radical oxygen species (ROS). Considering the importance of natural products as a functional food, comparative studies between the antioxidant activity (AOA) and antimutagenic properties as well as phytochemical profile of Cactaceae fruits (Lepismium lorentzianum, Lepismium lumbricoides, Rhipsalis floccosa, and Pfeiffera ianthothele) from Argentinean Yungas, were performed. Different assays were applied: ABTS radical scavenging capacity, inhibition of lipid peroxidation using ??-carotene-linoleate model system and mutagenicity/antimutagenicity by Ames test. A pigment like betalain was detected in fruits of both Lepismium species; L. lorentzianum aqueous extracts showed a higher pigment content (60.6 mg BE/100 g FM) than L. lumbricoides (9.2 mg BE/100 g FM). Fruit preparations of L. lorentzianum (aqueous and ethanolic extractions) showed significantly higher total phenolic compound and pigments content than the other berries. In all preparations, high antioxidant activity was demonstrated. Lepismium species were more active than Rhipsalis and Pfeiffera (SC_50ABTS values between 1.3 and 4.5 ??g/ml and IC_{50 ??-carotene-linoleate} values between 9 and 45.8 ??g/ml). A significant correlation between pigment and phenolic compounds content and AOA was observed. The preparations showed no sign of mutagenicity at tested concentrations (until 50 ??g/plate). A significant antimutagenic effect was observed for L. lumbricoides, and a weak effect was shown for P. ianthothele and R. floccosa. Because of the diversity and abundance of bioactive phytochemicals found in these species, food, cosmetic, and pharmaceutical applications could be proposed.     

Compact multiphoton/single photon laser scanning microscope for spectral imaging and fluorescence lifetime imaging

An inverted fluorescence microscope was upgraded into a compact three-dimensional laser scanning microscope (LSM) of 65 x 62 x 48 cm dimensions by means of a fast kHz galvoscanner unit, a piezodriven z-stage, and a picosecond (ps) 50 MHz laser diode at 405 nm. In addition, compact turn-key near infrared femtosecond lasers have been employed to perform multiphoton fluorescence and second harmonic generation (SHG) microscopy. To expand the features of the compact LSM, a time-correlated single photon counting unit as well as a Sagnac interferometer have been added to realize fluorescence lifetime imaging (FLIM) and spectral imaging. Using this unique five-dimensional microscope, TauMap, single-photon excited (SPE), and two-photon excited (TPE) cellular fluorescence as well as intratissue autofluorescence of water plant leaves have been investigated with submicron spatial resolution, <270 ps temporal resolution, and 10 nm spectral resolution.     

Recombinant tropomyosin from Penaeus aztecus (rPen a 1) for measurement of specific immunoglobulin E antibodies relevant in food allergy to crustaceans and other invertebrates

Immunoglobulin E (IgE)-mediated food allergy to crustaceans and mollusks is relatively common and affected individuals typically react to a range of different species. The only known major allergen of shrimp was first described over 20 years ago and later identified as the muscle protein tropomyosin. This protein may be useful as a defined and relevant diagnostic marker for allergic sensitization to invertebrate foods. In order to generate an assay reagent suitable for this purpose, tropomyosin from the shrimp Penaeus aztecus (Pen a 1) was produced as a recombinant protein in Escherichia coli and characterized with respect to IgE antibody binding properties in comparison to natural shrimp tropomyosin. Hexahistidine-tagged rPen a 1 accumulated as a predominantly soluble protein in the E. coli expression host and a two-step chromatographic procedure provided a high yield of pure and homogeneous protein. rPen a 1 displayed chromatographic and folding characteristics similar to those of purified natural shrimp tropomyosin. Serum preincubation with serial protein dilutions revealed similar capacity of recombinant and natural tropomyosin to compete with immobilized shrimp extract for IgE binding. rPen a 1 was further shown to extensively and specifically compete for IgE binding to extracts of other crustacean species, house dust mite and German cockroach.     

Probing the structure of nanograined CuO powders

The microstructural properties of polycrystalline CuO powders and their evolution during controlled high energetic ball milling (HEBM) were studied using conventional X-ray diffraction (XRD) techniques and in situ temperature-dependent small and wide angle scattering (SAXS–WAXS) synchrotron radiation experiments. Volume weighted average grain size, unit cell expansion, oxygen deficiency, and microstrain values as a function of milling time were obtained from XRD. SAXS data revealed different nanostructures for samples synthesized by one-step solid-state reaction (SSR) or HEBM-treated powders. The latter presented the characteristics of a multilayered nanoscale solid system with surface fractal behavior. Correlation of the XRD microstructural parameters and the power law exponent of the SAXS curves as a function of temperature and milling time provided a coherent picture of the structure of HEBM-treated powders. The overall structural information presented in this article may shed some light on the macroscopic physical properties of CuO nanostructures.     

Architectures for Silicon Nanoelectronics and Beyond

Although nanoelectronics won't replace CMOS for some time, research is needed now to develop the architectures, methods, and tools to maximally leverage nanoscale devices and terascale capacity. Addressing the complementary architectural and system issues involved requires greater collaboration at all levels. The effective use of nanotechnology calls for total system solutions     

Design,Synthesis, and Characterization of Macrocyclic Inhibitors of the Proprotein Convertase Furin

The activation of viral glycoproteins by the host protease furin is an essential step in the replication of numerous pathogenic viruses. Thus, effective inhibitors of furin could serve as broad-spectrum antiviral drugs. A crystal structure of an inhibitory hexapeptide derivative in complex with furin served as template for the rational design of various types of new cyclic inhibitors. Most of the prepared derivatives are relatively potent furin inhibitors with inhibition constants in the low nanomolar or even sub-nanomolar range. For seven derivatives the crystal structures in complex with furin could be determined. In three complexes, electron density was found for the entire inhibitor. In the other cases the structures could be determined only for the P6/P5-P1 segments, which directly interact with furin. The cyclic derivatives together with two non-cyclic reference compounds were tested as inhibitors of the proteolytic activation and replication of respiratory syncytial virus in cells. Significant antiviral activity was found for both linear reference inhibitors, whereas a negligible efficacy was determined for the cyclic derivatives.     

Scale and scope of environmental planning transformations: The Israeli case

This paper explores the scale and scope of transformations in the environmental planning field, and the factors that may advance or impede their widespread adoption. A conceptual model is offered which examines scope (defined as type, breadth and structure of the transformation), and the scale of its impact (categorized as stakeholder, organizational, institutional or societal) and applies it to the analysis of several cases in Israel where environmental transformations, affecting the way in which planning is conducted, have been adopted. Conclusions include identification of conditions for facilitating and advancing transformations, including knowledge of innovative alternatives, initiative, willingness to adopt new practices, and identification of policy windows that emerge during conflict, reform, or crisis. The fostering of relations between environmental non-government organizations and planning systems and leadership roles are also significant in catalyzing environmental transformation.