Modifications of the chemical structure of terpenes in antiplasmodial and antifungal drug research

Pure natural monoterpenes were evaluated in vitro for their antiplasmodial activities against Plasmodium falciparum. Chemically modified terpenes were also tested to see whether the introduction of an alkyne, a cyclopropane, a diene, or a cyclopentenone moiety had an influence on the biological activity. The IC(50) obtained on a chloroquine-resistant strain of Plasmodium (FcM29-Cameroon) showed moderate activity, but with the alkyne and the cyclopentenone derivatives showing a promising enhancement of activity compared with the parent molecules. On the contrary, no antifungal activity was found in vitro using Candida albicans. Given the observed antiplasmodial activity of some of these modified monoterpenes, new monoterpene derivatives could be the basis for new antimalarial drugs to be researched.     

Anatomical and histological changes in the alimentary tract of migrating blackcaps (Sylvia atricapilla): a comparison among fed, fasted, food-restricted, and refed birds

During northward migration, blackcaps that arrive to refuel at stopover sites in Israel's Negev Desert have reduced masses of organs that are important in food digestion and assimilation. We tested several predictions from the general hypothesis that smaller organs of digestion (small intestine and pancreas) and nutrient assimilation (liver) bring about a lower capacity to consume food and that the organs must be restored before blackcaps can feed and digest at a high rate. We used a fasting protocol to create a group of blackcaps with reduced intestine and liver mass (reduced by 45% and 36%, respectively) compared with controls fed ad lib. Because most of the small intestine's biochemical digestive capacity reside in enterocytes found on villi, we predicted and found that reduced intestinal mass in fasted blackcaps related mainly to changes in enterocytes rather than other cells and tissues such as nonabsorptive crypt cells or underlying muscle. Because migrating blackcaps that stop over to feed begin to increase in body mass only 2 d after arrival, we predicted and found a similar recovery period in blackcaps that were first fasted but then refed--the organ mass, structure, function, and ability to consume food was restored after 2 d of feeding. Another group of food-restricted blackcaps (fed at one-third ad lib. level) lost similar amounts of body mass as fasted blackcaps but had much greater capacity to consume food than fasted blackcaps, and so we predicted that they would exhibit little or no reduction in alimentary organs relative to controls fed ad lib. A surprising result was that, as in fasted blackcaps, in food-restricted blackcaps, the decreases in masses of small intestine, liver, and pancreas were proportionally greater than the decreases in body mass or in masses of nonalimentary organs (heart, pectoralis). Food restriction, like fasting, caused a decrease in amount of intestinal mucosa and an alteration in the phenotype of enterocytes. These results are thus not consistent with the general hypothesis, and although they can be rationalized by assuming that blackcaps fed ad lib. have excess digestive capacity, it may also be that the physiological process or processes limiting very high feeding rate lie elsewhere than in the digestive system.     

Genomic survey of prepulse inhibition in mouse chromosome substitution strains

Prepulse inhibition (PPI) is a measure of sensorimotor gating, a pre-attentional inhibitory brain mechanism that filters extraneous stimuli. Prepulse inhibition is correlated with measures of cognition and executive functioning, and is considered an endophenotype of schizophrenia and other psychiatric illnesses in which patients show PPI impairments. As a first step toward identifying genes that regulate PPI, we performed a quantitative trait locus (QTL) screen of PPI phenotypes in a panel of mouse chromosome substitution strains (CSSs). We identified five CSSs with altered PPI compared with the host C57BL/6J strain: CSS-4 exhibited decreased PPI, whereas CSS-10, -11, -16 and -Y exhibited higher PPI compared with C57BL/6J. These data indicate that A/J chromosomes 4, 10, 11, 16 and Y harbor at least one QTL region that modulates PPI in these CSSs. Quantitative trait loci for the acoustic startle response were identified on seven chromosomes. Like PPI, habituation of the startle response is also disrupted in schizophrenia, and in the present study CSS-7 and -8 exhibited deficits in startle habituation. Linkage analysis of an F₂ intercross identified a highly significant QTL for PPI on chromosome 11 between positions 101.5 and 114.4 Mb (peak LOD = 4.54). Future studies will map the specific genes contributing to these QTLs using congenic strains and other genomic approaches. Identification of genes that modulate PPI will provide insight into the neural mechanisms underlying sensorimotor gating, as well as the psychopathology of disorders characterized by gating deficits.     

Predicting global change impacts on plant species’ distributions: Future challenges

Given the rate of projected environmental change for the 21st century, urgent adaptation and mitigation measures are required to slow down the on-going erosion of biodiversity. Even though increasing evidence shows that recent human-induced environmental changes have already triggered species’ range shifts, changes in phenology and species’ extinctions, accurate projections of species’ responses to future environmental changes are more difficult to ascertain. This is problematic, since there is a growing awareness of the need to adopt proactive conservation planning measures using forecasts of species’ responses to future environmental changes.

There is a substantial body of literature describing and assessing the impacts of various scenarios of climate and land-use change on species’ distributions. Model predictions include a wide range of assumptions and limitations that are widely acknowledged but compromise their use for developing reliable adaptation and mitigation strategies for biodiversity. Indeed, amongst the most used models, few, if any, explicitly deal with migration processes, the dynamics of population at the “trailing edge” of shifting populations, species’ interactions and the interaction between the effects of climate and land-use.

In this review, we propose two main avenues to progress the understanding and prediction of the different processes occurring on the leading and trailing edge of the species’ distribution in response to any global change phenomena. Deliberately focusing on plant species, we first explore the different ways to incorporate species’ migration in the existing modelling approaches, given data and knowledge limitations and the dual effects of climate and land-use factors. Secondly, we explore the mechanisms and processes happening at the trailing edge of a shifting species’ distribution and how to implement them into a modelling approach. We finally conclude this review with clear guidelines on how such modelling improvements will benefit conservation strategies in a changing world.     

The p85alpha subunit of phosphatidylinositol 3'-kinase binds to and stimulates the GTPase activity of Rab proteins

Rab5 and Rab4 are small monomeric GTPases localized on early endosomes and function in vesicle fusion events. These Rab proteins regulate the endocytosis and recycling or degradation of activated receptor tyrosine kinases such as the platelet-derived growth factor receptor (PDGFR). The p85alpha subunit of phosphatidylinositol 3'-kinase contains a BH domain with sequence homology to GTPase activating proteins (GAPs), but has not previously been shown to possess GAP activity. In this report, we demonstrate that p85alpha has GAP activity toward Rab5, Rab4, Cdc42, Rac1 and to a lesser extent Rab6, with little GAP activity toward Rab11. Purified recombinant Rab5 and p85alpha can bind directly to each other and not surprisingly, the p85alpha-encoded GAP activity is present in the BH domain. Because p85alpha stays bound to the PDGFR during receptor endocytosis, p85alpha will also be localized to the same early endosomal compartment as Rab5 and Rab4. Taken together, the physical co-localization and the ability of p85alpha to preferentially stimulate the down-regulation of Rab5 and Rab4 GTPases suggests that p85alpha regulates how long Rab5 and Rab4 remain in their GTP-bound active state. Cells expressing BH domain mutants of p85 show a reduced rate of PDGFR degradation as compared with wild type p85 expressing cells. These cells also show sustained activation of the mitogen-activated protein kinase and Akt pathways. Thus, the p85alpha protein may play a role in the down-regulation of activated receptors through its temporal control of the GTPase cycles of Rab5 and Rab4.     

The origin of long-range attraction between hydrophobes in water

When water-coated hydrophobic surfaces meet, direct contacts form between the surfaces, driving water out. However, long-range attractive forces first bring those surfaces close. This analysis reveals the source and strength of the long-range attraction between water-coated hydrophobic surfaces. The origin is in the polarization field produced by the strong correlation and coupling of the dipoles of the water molecules at the surfaces. We show that this polarization field gives rise to dipoles on the surface of the hydrophobic solutes that generate long-range hydrophobic attractions. Thus, hydrophobic aggregation begins with a step in which water-coated nonpolar solutes approach one another due to long-range electrostatic forces. This precursor regime occurs before the entropy increase of releasing the water layers and the short-range van der Waals attraction provide the driving force to "dry out" the contact surface. The effective force of attraction is derived from basic molecular principles, without assumptions of the structure of the hydrophobe-water interaction. The strength of this force can be measured directly from atomic force microscopy images of a hydrophobic molecule tethered to a surface but extending into water, and another hydrophobe attached to an atomic force probe. The phenomenon can be observed in the transverse relaxation rates in water proton magnetic resonance as well. The results shed light on the way water mediates chemical and biological self-assembly, a long outstanding problem.     

Impacts of forest fragmentation on orchid bee (Hymenoptera: Apidae: Euglossini) communities in the Chocó biodiversity hotspot of northwest Ecuador

Habitat loss is a major driver of bee declines worldwide, and is of key relevance in the tropics given high deforestation rates, but we continue to have a poor understanding of the impact of land-cover change on tropical bee communities. Orchid bees (Apidae: Euglossini) are critical long-distance pollinators and may be highly susceptible to forest fragmentation given their reliance on forest habitat. Previous studies on the impact of forest fragmentation on euglossines have been geographically limited, have largely ignored β-diversity, and have not compared fragments with continuous forest. To contribute to addressing these gaps, we sampled male euglossine bees in 18 forest fragments (area range: 2.5–33 ha) and at eight locations within a large (3500 ha) continuous forest in the Chocó biodiversity hotspot of Ecuador during the dry season in 2014. We assessed how euglossine abundance, richness, and evenness related to fragment area, isolation, and edge:area ratio. We also compared fragments to continuous forest, in terms of α- and β-diversity. In fragments, a single species (Euglossa tridentata) comprised 78% of captures, and we found no significant effect of fragment area, isolation, or edge on abundance, richness, or evenness among fragments. Forest fragments and continuous forest differed in both community composition and evenness, but not in abundance or species richness. Spatial turnover (β-diversity) showed a non-significant trend toward changing more rapidly in continuous forest relative to fragments. These results underscore the conservation value of continuous forest for orchid bee diversity.     

A hybrid protein of urokinase growth-factor domain and plasminogen-activator inhibitor type 2 inhibits urokinase activity and binds to the urokinase receptor.

The binding of urokinase-type plasminogen activator (uPA) to its specific cell-surface receptor (uPAR) localises the proteolytic cascade initiated by uPA to the pericellular environment. Inhibition of uPA activity or prevention of uPA binding to uPAR might have a beneficial effect on disease states wherein this activity is deregulated, e.g. cancer and some inflammatory diseases. To this end, a bifunctional hybrid molecule consisting of the uPAR-binding growth-factor domain of uPA (amino acids 1-47; GFuPA) at the N-terminus of plasminogen-activator inhibitor type 2 (PAI-2) was produced in Saccharomyces cerevisiae. The purified protein inhibited uPA with kinetics similar to placental or recombinant PAI-2 and was also found to bind to U937 cells and to FL amnion cells. GFuPA-PAI-2 competed with uPA, the N-terminal fragment of uPA and a proteolytic fragment of uPA (amino acids 4-43) in cell binding experiments, indicating that the molecule bound to the cells via uPAR. Hence, both the uPA-inhibitory and uPAR-binding domains of the hybrid molecule were functional, demonstrating the feasibility of the novel concept of introducing an unrelated, functional domain onto a member of the serine-protease-inhibitor superfamily.