Ageing increases vulnerability to aβ42 toxicity in Drosophila

Age is the major risk factor for many neurodegenerative diseases, including Alzheimer's Disease (AD), for reasons that are not clear. The association could indicate that the duration or degree of exposure to toxic proteins is important for pathology, or that age itself increases susceptibility to protein toxicity. Using an inducible Drosophila model of AD, we investigated these possibilities by varying the expression of an Aβ42 transgene in neurons at different adult ages and measuring the effects on Aβ42 levels and associated pathological phenotypes. Acute induction of Arctic Aβ42 in young adult flies resulted in rapid expression and clearance of mRNA and soluble Arctic Aβ42 protein, but in irreversible expression of insoluble Arctic Aβ42 peptide. Arctic Aβ42 peptide levels accumulated with longer durations of induction, and this led to a dose-dependent reduction in negative geotaxis and lifespan. For a standardised level of mRNA expression, older flies had higher levels of Arctic Aβ42 peptide and associated toxicity, and this correlated with an age-dependent reduction in proteasome activity. Equalising Aβ42 protein at different ages shortened lifespan in correlation with the duration of exposure to the peptide, suggesting that Aβ42 expression accumulates damage over time. However, the relative reduction in lifespan compared to controls was greater in flies first exposed to the peptide at older ages, suggesting that ageing itself also increases susceptibility to Aβ42 toxicity. Indeed older flies were more vulnerable to chronic Aβ42 toxicity even with a much lower lifetime exposure to the peptide. Finally, the persistence of insoluble Aβ42 in both young and old induced flies suggests that aggregated forms of the peptide cause toxicity in later life. Our results suggest that reduced protein turnover, increased duration of exposure and increased vulnerability to protein toxicity at later ages in combination could explain the late age-of-onset of neurodegenerative phenotypes.     

Efficiency Enhancement of Organic Solar Cells Using Hydrophobic Antireflective Inverted Moth‐Eye Nanopatterned PDMS Films

Poly‐dimethylsiloxane (PDMS) films with 2D periodic inverted moth‐eye nanopatterns on one surface are implemented as antireflection (AR) layers on a glass substrate for efficient light capture in encapsulated organic solar cells (OSCs). The inverted moth‐eye nanopatterned PDMS (IMN PDMS) films are fabricated by a soft imprint lithographic method using conical subwavelength grating patterns formed by laser interference lithography/dry etching. Their optical characteristics, together with theoretical analysis using rigorous coupled‐wave analysis simulation, and wetting behaviors are investigated. For a period of 380 nm, IMN PDMS films laminated on glass substrates exhibit a hydrophobic surface with a water contact angle (θ_CA) of ≈120° and solar weighted transmittance (SWT) of ≈94.2%, both significantly higher than those (θ_CA≈ 36° and SWT ≈ 90.3%) of bare glass substrates. By employing IMN PDMS films with a period of 380 nm on glass substrates for OSCs, an enhanced power conversion efficiency (PCE) of 6.19% is obtained mainly due to the increased short‐circuit current density (J_sc) of 19.74 mA cm^‐2 compared to the OSCs with the bare glass substrates (PCE = 5.16% and J_sc = 17.25 mA cm^‐2). For the OSCs, the device stability is also studied.     

Review of elevated atmospheric CO2 effects on agro-ecosystems: residue decomposition processes and soil C storage

A series of studies using major crops (cotton [Gossypium hirsutum L.], wheat [Triticum aestivum L.], grain sorghum [Sorghum bicolor (L.) Moench.] and soybean [Glycine max (L.) Merr.]) were reviewed to examine the impact of elevated atmospheric CO₂ on crop residue decomposition within agro-ecosystems. Experiments evaluated utilized plant and soil material collected from CO₂ study sites using Free Air CO₂ Enrichment (FACE) and open top chambers (OTC). A incubation study of FACE residue revealed that CO₂-induced changes in cotton residue composition could alter decomposition processes, with a decrease in N mineralization observed with FACE, which was dependent on plant organ and soil series. Incubation studies utilizing plant material grown in OTC considered CO₂-induced changes in relation to quantity and quality of crop residue for two species, soybean and grain sorghum. As with cotton, N mineralization was reduced with elevated CO₂ in both species, however, difference in both quantity and quality of residue impacted patterns of C mineralization. Over the short-term (14 d), little difference was observed for CO₂ treatments in soybean, but C mineralization was reduced with elevated CO₂ in grain sorghum. For longer incubation periods (60 d), a significant reduction in CO₂-C mineralized per g of residue added was observed with the elevated atmospheric CO₂ treatment in both crop species. Results from incubation studies agreed with those from the OTC field observations for both measurements of short-term CO₂ efflux following spring tillage and the cumulative effect of elevated CO₂ (> 2 years) in this study. Observations from field and laboratory studies indicate that with elevated atmospheric CO₂, the rate of plant residue decomposition may be limited by N and the release of N from decomposing plant material may be slowed. This indicates that understanding N cycling as affected by elevated CO₂ is fundamental to understanding the potential for soil C storage on a global scale. This revised version was published online in June 2006 with corrections to the Cover Date.     

Genome Scale Evolution of Myxoma Virus Reveals Host-Pathogen Adaptation and Rapid Geographic Spread

The evolutionary interplay between myxoma virus (MYXV) and the European rabbit (Oryctolagus cuniculus) following release of the virus in Australia in 1950 as a biological control is a classic example of host-pathogen coevolution. We present a detailed genomic and phylogeographic analysis of 30 strains of MYXV, including the Australian progenitor strain Standard Laboratory Strain (SLS), 24 Australian viruses isolated from 1951 to 1999, and three isolates from the early radiation in Britain from 1954 and 1955. We show that in Australia MYXV has spread rapidly on a spatial scale, with multiple lineages cocirculating within individual localities, and that both highly virulent and attenuated viruses were still present in the field through the 1990s. In addition, the detection of closely related virus lineages at sites 1,000 km apart suggests that MYXV moves freely in geographic space, with mosquitoes, fleas, and rabbit migration all providing means of transport. Strikingly, despite multiple introductions, all modern viruses appear to be ultimately derived from the original introductions of SLS. The rapidity of MYXV evolution was also apparent at the genomic scale, with gene duplications documented in a number of viruses. Duplication of potential virulence genes may be important in increasing the expression of virulence proteins and provides the basis for the evolution of novel functions. Mutations leading to loss of open reading frames were surprisingly frequent and in some cases may explain attenuation, but no common mutations that correlated with virulence or attenuation were identified.     

Investigating the permanent electric dipole moment of beta-lactoglobulin fibrils, using transient electric birefringence

Amyloid fibrils, which are polymeric assemblies of protein molecules, have been intensively studied on a structural level, yet due to complications such as the disorder within the molecules, several aspects of their structure remain mysterious. Similarly, the kinetics of assembly are not well understood. Here we investigate the electric dipole moment of beta-lactoglobulin fibrils, a model amyloid fibril system, by applying the technique of transient electric birefringence. This moment appears to be large, and comparable to the total moment of the constituent protein monomers if they were joined in a chain, head-to-tail, without changing conformation, suggesting an ordered joining of monomers in the fibril. Such an ordered assembly may have implications for the assembly mechanism of beta-lactoglobulin fibrils in particular, and amyloid fibrils in general.     

Allosteric Inhibition of Epac: COMPUTATIONAL MODELING AND EXPERIMENTAL VALIDATION TO IDENTIFY ALLOSTERIC SITES AND INHIBITORS*

Epac, a guanine nucleotide exchange factor for the low molecular weight G protein Rap, is an effector of cAMP signaling and has been implicated to have roles in numerous diseases, including diabetes mellitus, heart failure, and cancer. We used a computational molecular modeling approach to predict potential binding sites for allosteric modulators of Epac and to identify molecules that might bind to these regions. This approach revealed that the conserved hinge region of the cyclic nucleotide-binding domain of Epac1 is a potentially druggable region of the protein. Using a bioluminescence resonance energy transfer-based assay (CAMYEL, cAMP sensor using YFP-Epac-Rluc), we assessed the predicted compounds for their ability to bind Epac and modulate its activity. We identified a thiobarbituric acid derivative, 5376753, that allosterically inhibits Epac activity and used Swiss 3T3 and HEK293 cells to test the ability of this compound to modulate the activity of Epac and PKA, as determined by Rap1 activity and vasodilator-stimulated phosphoprotein phosphorylation, respectively. Compound 5376753 selectively inhibited Epac in biochemical and cell migration studies. These results document the utility of a computational approach to identify a domain for allosteric regulation of Epac and a novel compound that prevents the activation of Epac1 by cAMP.     

Effects of growth hormone on diaphragmatic recovery from malnutrition.

A 25% weight loss was induced in adult Fisher 344 rats by nutritional deprivation. Subsequently, normal feeding was resumed. Refed animals were divided into three groups and received recombinant human growth hormone (rhGH) injections during 5 wk of refeeding, saline injections during 5 wk of refeeding, or 9 wk of refeeding without injections. The effects of nutritional deprivation and the various refeeding protocols on the cross-sectional areas (CSA) of each of the four types of myofibers [typed immunohistochemically with antibodies against four myosin heavy chain (MHC) isoforms known to be present in the rat diaphragm] were determined. Malnutrition decreased the CSA of myofibers containing MHC2X, MHC2B, and MHC2A (i.e., fast myofibers), with the greatest effect on muscle mass being due to the atrophy of fibers containing MHC2X. Fibers containing MHC beta/slow failed to undergo malnutrition-induced atrophy. Whereas refeeding for 5 wk in the absence of rhGH allowed the recovery of CSA of fibers containing MHC2A, fibers containing MHC2B and MHC2X remained smaller than fibers of similar type in control animals. In contrast, 5 wk of refeeding supplemented with rhGH returned all fiber CSAs to control values. Even when refeeding alone was extended to 9 wk to allow for weight stabilization, the CSA of the fibers containing MHC2B and MHC2X remained smaller than similar fibers in control muscle. Serum insulin-like growth factor, a marker of malnutrition (R. Reeves and J. Elders, J. Nutr. 109: 613-620, 1979), was significantly decreased after nutritional deprivation and returned to normal after 5 wk of refeeding and GH supplementation.