beta-strand mimicking macrocyclic amino acids: Templates for protease inhibitors with antiviral activity

New amino acids are reported in which component macrocycles are constrained to mimic tripeptides locked in a beta-strand conformation. The novel amino acids involve macrocycles functionalized with both an N- and a C-terminus enabling addition of appendages at either end to modify receptor affinity, selectivity, or membrane permeability. We show that the cycles herein are effective templates within inhibitors of HIV-1 protease. Eleven compounds originating from such bifunctionalized cyclic templates are potent inhibitors of HIV-1 protease (Ki 0.3-50 nM; pH 6.5, I = 0.1 M). Unlike normal peptides comprising amino acids, five of these macrocycle-containing compounds are potent antiviral agents with sub-micromolar potencies (IC50 170-900 nM) against HIV-1 replication in human MT2 cells. The most active antiviral agents are the most lipophilic, with calculated values of LogD(6.5) greater than or equal to 4. All molecules have a conformationally constrained 17-membered macrocyclic ring that has been shown to structurally mimic a tripeptide segment (Xaa)-(Val/Ile)-(Phe/Tyr) of a peptide substrate in the extended conformation. The presence of two trans amide bonds and a para-substituted aromatic ring prevents intramolecular hydrogen bonds and fixes the macrocycle in the extended conformation. Similarly constrained macrocycles may be useful templates for the creation of inhibitors for the many other proteins and proteases that recognize peptide beta-strands.

Predation of brown tree snakes (Boiga irregularis) in Australia

We conducted a literature review to address the potential for using a native, vertebrate predator of brown tree snakes (Boiga irregularis) as a biological control method on Guam. Both actual and potential predators were included in our review. We located two actual predators (red-bellied black snakes (Pseudechis porphyriacus) and cane toads (Bufo marinus)) and 55 potential predators of brown tree snakes. However, none of the native predators of brown tree snakes appear likely candidates as a biological control method on Guam due to their lack of selectivity in their feeding habits and unknown aspects of their natural history. (C) 2002 Elsevier Science Ltd. All rights reserved.

Recoverable reserves and support effects when optimizing open pit mine designs

Orebody modelling, support effects and the estimation of recoverable reserves are key parts of open pit optimization studies. A case study is presented on the estimation of recoverable reserves using an implementation of indicator kriging where metal quantity is used to select cutoffs, and support corrections founded on a conditional simulation approach. Mining selectivity is explored in the subsequent optimization study to compare results from indicator kriging of grade estimates on a regular size blocks and indicator kriging estimates on small size blocks. The use of indicator kriging models adjusted for a given selectivity and the use of grade proportions in each block for the optimization study, provide a presentation of the expected ore recovery for a predefined level of selectivity. The case study shows that indicator kriging estimation with full accounting of block grade distributions generates substantially better results in the pit optimization study. In addition, the adverse effects of small blocks and over-smoothing on optimization results are illustrated.

Circular proteins - no end in sight

Circular proteins are a recently discovered phenomenon. They presumably evolved to confer advantages over ancestral linear proteins while maintaining the intrinsic biological functions of those proteins. In general, these advantages include a reduced sensitivity to proteolytic cleavage and enhanced stability. In one remarkable family of circular proteins, the cyclotides, the cyclic backbone is additionally braced by a knotted arrangement of disulfide bonds that confers additional stability and topological complexity upon the family. This article describes the discovery, structure, function and biosynthesis of the currently known circular proteins. The discovery of naturally occurring circular proteins in the past few years has been complemented by new chemical and biochemical methods to make synthetic circular proteins; these are also briefly described.

Present and future pharmacotherapy for benign prostatic hyperplasia

Around 50% of men 51-60 years of age have pathological benign prostatic hyperplasia (BPH). Pharmacotherapy for BPH includes the 5alpha-reductase inhibitor finasteride, and alpha(1)-adrenoceptor antagonists. Finasteride reduces prostate volume and symptom scores, while increasing peak urinary flow rates. The main problem with finasteride treatment is that it increases the incidence of ejaculation disorders. All of the alpha(1)-adrenoceptor antagonists have been shown to reduce symptom scores and increase peak urinary flow rates in BPH. The nonselective alpha(1)-adrenoceptor antagonists (prazosin, terazosin and doxazosin) were developed as antihypertensives, and hypotensive-related side effects are the main problem with these agents in BPH. These side effects can be diminished by reducing peak concentrations of the drugs, as with once-daily alfuzosin, or by using the uroselective antagonist tamsulosin. Phytopharmaceuticals are commonly used in the treatment of BPH, such as saw palmetto berry which has been shown to improve the symptoms and peak urinary flow rate. Androgen receptor antagonists are not used in BPH because of their adverse effects. Newer drugs under development for the treatment of BPH include alpha(1)-adrenoceptor antagonists that show more selectivity for alpha(1A)-adrenoceptors than tamsulosin, combined 5alpha-reductase/alpha(1)-adrenoceptor inhibitors and combined type 1/type 2 5alpha-reductase inhibitors. New targets for the drug treatment of BPH include indothelin, growth factors, estrogens and the phosphodiesterase isoenzymes.

Acoustic analysis of speech through a hearing aid: perceptual effects of changes with two-channel compression

Compression amplification significantly alters the acoustic speech signal in comparison to linear amplification. The central hypothesis of the present study was that the compression settings of a two-channel aid that best preserved the acoustic properties of speech compared to linear amplification would yield the best perceptual results, and that the compression settings that most altered the acoustic properties of speech compared to linear would yield significantly poorer speech perception. On the basis of initial acoustic analysis of the test stimuli recorded through a hearing aid, two different compression amplification settings were chosen for the perceptual study. Participants were 74 adults with mild to moderate sensorineural hearing impairment. Overall, the speech perception results supported the hypothesis. A further aim of the study was to determine if variation in participants' speech perception with compression amplification (compared to linear amplification) could be explained by the individual characteristics of age, degree of loss, dynamic range, temporal resolution, and frequency selectivity; however, no significant relationships were found.

alpha-conotoxins PnIA and [A10L] PnIA stabilize different states of the alpha 7-L247T nicotinic acetylcholine receptor

The effects of the native alpha-conotoxin PnIA, its synthetic derivative [ A10L] PnIA and alanine scan derivatives of [ A10L] PnIA were investigated on chick wild type alpha7 and alpha7-L247T mutant nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus oocytes. PnIA and [A10L] PnIA inhibited acetylcholine (ACh)-activated currents at wtalpha7 receptors with IC50 values of 349 and 168 nM, respectively. Rates of onset of inhibition were similar for PnIA and [ A10L] PnIA; however, the rate of recovery was slower for [ A10L] PnIA, indicating that the increased potency of [ A10L] PnIA at alpha7 receptors is conveyed by its slower rate of dissociation from the receptors. All the alanine mutants of [ A10L] PnIA inhibited ACh-activated currents at wtalpha7 receptors. Insertion of an alanine residue between position 5 and 13 and at position 15 significantly reduced the ability of [ A10L] PnIA to inhibit ACh-evoked currents. PnIA inhibited the non-desensitizing ACh-activated currents at alpha7-L247T receptors with an IC50 194 nM. In contrast, [ A10L] PnIA and the alanine mutants potentiated the ACh-activated current alpha7-L247T receptors and in addition [ A10L] PnIA acted as an agonist. PnIA stabilized the receptor in a state that is non-conducting in both the wild type and mutant receptors, whereas [ A10L] PnIA stabilized a state that is non-conducting in the wild type receptor and conducting in the alpha7-L247T mutant. These data indicate that the change of a single amino acid side-chain, at position 10, is sufficient to change the toxin specificity for receptor states in the alpha7-L247T mutant.

Effects of herbicides diuron and atrazine on corals of the Great Barrier Reef, Australia

In response to recent reports of contamination of the nearshore marine environment along the Queensland coast by herbicides (including areas inside the Great Barrier Reef Marine Park), an ecotoxicological assessment was conducted of the impact of the herbicides diuron and atrazine on scleractinian corals. Pulse-amplitude modulated (PAM) chlorophyll fluorescence techniques were used to assess the herbicide effects on the symbiotic dinoflagellates within the tissues (in hospite) of 4 species of coral (Acropora formosa, Montipora digitata, Porites cylindrica, Seriatopora hystrix) in static toxicity tests, and in freshly isolated symbiotic dinoflagellates from Stylophora pistillata. Using change in the effective quantum yield (DeltaF/F-m') as an effect criterion, diuron (no observable effect concentration, NOEC = 0.3 mug 1(-1); lowest observable effect concentration, LOEC = 1 mug 1(-1); median effective concentration, EC50 4 to 6 mug 1(-1)) was found to be more toxic than atrazine (NOEC = 1 mug 1(-1), LOEC = 3 mug 1(-1), EC50 40 to 90 mug 1(-1)) in short-term (10 h) toxicity tests. In the tests with isolated algae, significant reductions in DeltaF/F-m' were recorded as low as 0.25 mug 1(-1) diuron (LOEC, EC50 = 5 mug 1(-1)). Time-course experiments indicated that the effects of diuron were rapid and reversible. At 10 mug 1(-1) diuron, DeltaF/F-m' was reduced by 25% in 20 to 30 min, and by 50% in 60 to 90 min. Recovery of DeltaF/F-m' in corals exposed to 10 mug 1(-1) diuron and then transferred to running seawater was slower, returning to within 10% of control values inside 1 to 7 h. The effect of a reduction in salinity (35 to 27%) on diuron toxicity (at 1 and 3 mug 1(-1) diuron) was tested to examine the potential consequences of contaminated coastal flood plumes inundating inshore reefs. DeltaF/F-m' was reduced in the diuron-exposed corals, but there was no significant interaction between diuron and reduced salinity seawater within the 10 h duration of the test. Exposure to higher (100 and 1000 mug 1(-1)) diuron concentrations for 96 h caused a reduction in DeltaF/F-m' the ratio variable to maximal fluorescence (F,1F.), significant loss of symbiotic dinoflagellates and pronounced tissue retraction, causing the corals to pale or bleach. The significance of the results in relation to diuron contamination of the coastal marine environment from terrestrial sources (mainly agricultural) and marine sources (antifouling paints) are discussed.

Chemical characterisation of deep profile Ferrosols under sugarcane in wet tropical northern Queensland

The chemical properties of deep profile samples ( up to 12 m) of Ferrosols from northern Queensland were investigated to provide an understanding of the accumulation of nitrate ( NO3) within these soil profiles. The influence of other cations and anions present in the soil solution or on the exchange and the charge chemistry of the profiles were examined with respect to the NO3 accumulations. The major ions in the soil solution were Na, NO3, and chloride ( Cl). Distinct regions of anion accumulation were observed; SO4 accumulated in the upper profile of all cores, whereas NO3 and Cl accumulations were restricted to the lower profile of cores with appreciable AEC (> 1 cmol(c)/kg). Gaines-Thomas selectivity coefficients were used to indicate exchange preference for cations and anions, and are as follows: Al > Ca similar to Mg > K > Na and sulfate (SO4) > Cl similar to NO3. The selectivity of SO4 increased and the extractable SO4 decreased in the lower profile of all cores. This has important implications for the adsorption of NO3 and Cl. The NO3 and Cl accumulations were shown to correspond to a region of low SO4 occupancy of the exchange sites in the lower profile. Along with the high SO4 selectivity, this suggests that SO4 may control the positioning of the NO3 accumulations. It was concluded that the NO3 accumulations were relatively stable under current management practices, although the reduction in NO3 inputs would likely see the gradual replacement of NO3 with Cl as a result of their comparable selectivity for exchange sites.

SPAnDX: a process-based population dynamics model to explore management and climate change impacts on an invasive alien plant, Acacia nilotica

This paper describes a process-based metapopulation dynamics and phenology model of prickly acacia, Acacia nilotica, an invasive alien species in Australia. The model, SPAnDX, describes the interactions between riparian and upland sub-populations of A. nilotica within livestock paddocks, including the effects of extrinsic factors such as temperature, soil moisture availability and atmospheric concentrations of carbon dioxide. The model includes the effects of management events such as changing the livestock species or stocking rate, applying fire, and herbicide application. The predicted population behaviour of A. nilotica was sensitive to climate. Using 35 years daily weather datasets for five representative sites spanning the range of conditions that A. nilotica is found in Australia, the model predicted biomass levels that closely accord with expected values at each site. SPAnDX can be used as a decision-support tool in integrated weed management, and to explore the sensitivity of cultural management practices to climate change throughout the range of A. nilotica. The cohort-based DYMEX modelling package used to build and run SPAnDX provided several advantages over more traditional population modelling approaches (e.g. an appropriate specific formalism (discrete time, cohort-based, process-oriented), user-friendly graphical environment, extensible library of reusable components, and useful and flexible input/output support framework). (C) 2003 Published by Elsevier Science B.V.

Dendritic branching of pyramidal cells in the visual cortex of the nocturnal owl monkey: A fractal analysis

The branching structure of neurones is thought to influence patterns of connectivity and how inputs are integrated within the arbor. Recent studies have revealed a remarkable degree of variation in the branching structure of pyramidal cells in the cerebral cortex of diurnal primates, suggesting regional specialization in neuronal function. Such specialization in pyramidal cell structure may be important for various aspects of visual function, such as object recognition and color processing. To better understand the functional role of regional variation in the pyramidal cell phenotype in visual processing, we determined the complexity of the dendritic branching pattern of pyramidal cells in visual cortex of the nocturnal New World owl monkey. We used the fractal dilation method to quantify the branching structure of pyramidal cells in the primary visual area (V1), the second visual area (V2) and the caudal and rostral subdivisions of inferotemporal cortex (ITc and ITr, respectively), which are often associated with color processing. We found that, as in diurnal monkeys, there was a trend for cells of increasing fractal dimension with progression through these cortical areas. The increasing complexity paralleled a trend for increasing symmetry. That we found a similar trend in both diurnal and nocturnal monkeys suggests that it was a feature of a common anthropoid ancestor.

Effect of pore-network connectivity on multicomponent adsorption of large molecules

The effect of pore-network connectivity on binary liquid-phase adsorption equilibria using the ideal adsorbed solution theory (LAST) was studied. The liquid-phase binary adsorption experiments used ethyl propionate, ethyl butyrate, and ethyl isovalerate as the adsorbates and commercial activated carbons Filtrasorb-400 and Norit ROW 0.8 as adsorbents. As the single-component isotherm, a modified Dubinin-Radushkevich equation was used. A comparison with experimental data shows that incorporating the connectivity of the pore network and considering percolation processes associated with different molecular sizes of the adsorptives in the mixture, as well as their different corresponding accessibility, can improve the prediction of binary adsorption equilibria using the LAST Selectivity of adsorption for the larger molecule in binary systems increases with an increase in the pore-network coordination number, as well with an increase in the mean pore width and in the spread of the pore-size distribution.

Ação transovariana de lufenuron (50 g/l) sobre adultos de Spodoptera Frugiperda (j. e. smith) (Lepidoptera: Noctuidae) e seu efeito sobre o parasitóide de ovos Trichogramma pretiosum Riley (Hymenoptera: Trichogrammatidae)

Avaliaram-se a ação transovariana do lufenuron em Spodoptera frugiperda e sua seletividade ao parasitóide de ovos Trichogramma pretiosum. Casais da praga foram isolados em gaiolas de PVC e alimentados com solução de mel a 10% na testemunha, e nos outros tratamentos, foi adicionado à solução de mel o regulador de crescimento de insetos Match® CE nas proporções de 12,5; 15,0 e 17,5 g i.a/l. Para verificação da ação transovariana, diariamente foram coletadas as posturas, contado o número de ovos e, posteriormente, o número de larvas eclodidas. Quarenta ovos provenientes de cada tratamento foram colados em cartelas de papel (cartolina) e expostos ao parasitismo, dentro de tubos de vidro de 1,0 x 3,5 cm, contendo uma fêmea de T. pretiosum no seu interior. Cartelas contendo 40 ovos de S. frugiperda foram imersas em soluções de lufenuron com a mesma concentração dos tratamentos anteriores e, posteriormente, expostas ao parasitismo por T. pretiosum. O lufenuron afetou consideravelmente a viabilidade dos ovos de S. frugiperda. Pelos resultados obtidos nos ensaios, relativos ao parasitóide, demonstram-se a seletividade do regulador de crescimento lufenuron e a possibilidade de sua utilização em programas de Manejo Integrado, juntamente com o parasitóide de ovos T. pretiosum.

Fitorremediação de solo contaminado com picloram por capim-pé-de-galinha-gigante (Eleusine coracana)

O longo efeito residual do herbicida picloram no solo aumenta o risco de lixiviação e de fitotoxicidade em culturas sucedâneas; sua presença no solo pode ser abreviada com o uso da fitorremediação. O objetivo deste trabalho foi avaliar a influência da densidade populacional de capim-pé-de-galinha-gigante (Eleusine coracana) sobre a fitorremediação de solo contaminado com o herbicida picloram. O experimento foi realizado em casa de vegetação localizada no município de Rio Verde-GO, no período de setembro de 2006 a fevereiro de 2007. Os tratamentos foram compostos pela combinação entre quatro densidades populacionais da espécie vegetal Eleusine coracana (capim-pé-de-galinha-gigante) (0, 7, 14 e 21 plantas por vaso, correspondendo a 0, 172, 344 e 516 plantas m-2, respectivamente) e três doses do picloram (0, 80 e 160 g ha-1 - aplicadas diretamente nos vasos, simulando níveis de contaminação do solo). Após o cultivo da espécie vegetal fitorremediadora no substrato por 100 dias, efetuou-se, no próprio vaso, a semeadura da soja (Glycine max L.), espécie utilizada como bioindicadora da presença do picloram. A espécie Eleusine coracana mostrou ter capacidade de remediar solos contaminados com o herbicida picloram. A partir de 172 plantas m-2, aumentos na densidade populacional da espécie fitorremediadora não proporcionaram redução de carryover do herbicida picloram sobre a cultura da soja semeada em sucessão.

Toxicidade de óleo de mamona a Helicoverpa zea e a Trichogramma pretiosum

O objetivo deste trabalho foi avaliar os efeitos do óleo de mamona sobre a broca-grande do tomateiro, Helicoverpa zea, e sobre o parasitoide de ovos Trichogramma pretiosum. Foi determinada a mortalidade larval da broca, que foi submetida ao óleo de mamona por ingestão e contato às concentrações 0,5, 1,0, 1,5, 2,0, 2,5 e 3,0% (v v-1). A ação do óleo de mamona sobre T. pretiosum foi determinada mediante testes de seletividade e suscetibilidade. As maiores mortalidades de larvas foram observadas no tratamento por contato com as menores concentrações (0,5 e 1,0%), enquanto com as concentrações intermediárias (1,5; 2,0 e 2,5%), não houve diferença entre as vias de aplicação. À maior concentração testada (3,0%), o tratamento por ingestão proporcionou mortalidade superior àquela obtida por contato. O número de ovos parasitados por T. pretiosum, no teste de seletividade, foi afetado negativamente pelo óleo de mamona, contudo, os demais parâmetros avaliados quanto à seletividade e à suscetibilidade não foram afetados. O óleo de mamona reduz a sobrevivência de larvas de H. zea tanto por ingestão quanto por contato. Além disso, não prejudica o desenvolvimento de T. pretiosum, desde que as pulverizações sejam realizadas após as liberações do parasitoide.