The emergence of insect resistance in Bt-corn: implication of resistance management information under uncertainty

"The successful management of transgenic technology is likely to depend on the economic behavioral response of farmers to the regulated use of transgenic crops. A well-studied example is the widespread use of Bt-corn, in the United States, and elsewhere, to control the European Corn Borer, a major corn pest. The extensive use of Bt-corn has led to concerns about the emergence of insect resistance. The United States Environment Protection Agency addressed this potential problem by developing an insect resistance management strategy, based, in part, on complex mathematical models using detailed biological assumptions about the population genetics and life history of the European Corn Borer. However, seed companies and others have sometimes used simpler deterministic profit models to justify the economics of Bt-corn to potential growers. Therefore an over reliance, by regulatory agencies, on complex modeling approaches may obscure the likely economic behavioral response of farmers who rely on these less complex models. However, the determinants of adoption are numerous, profit being one of them. We develop a simple model for the spread of resistance based on the logistic growth equation and use it to investigate the effect of uncertainty on farmer decisions to plant Bt-corn and follow EPA management rules. The model results suggest that planting Bt-corn is an optimal strategy under the type of uncertainty assumed in the model and that short-term economic behavior is likely to lead to the Environment Protection Agency management rules not being followed. Our results add weight to existing work on this problem." Authors' AbstractBt-corn, logistic growth, Monte Carlo methods, Corn, Environmental protection, Economics Methodology,

Expression proteomics identifies biochemical adaptations and defense responses in transgenic plants with perturbed polyamine metabolism

AbstractSoluble proteins from leaves of transgenic tobacco plants with perturbed polyamine metabolism, caused by S-adenosylmethionine decarboxylase overexpression, were analysed by comparative proteomics. A group of proteins was found to be increasingly repressed, in parallel with the degree of polyamine perturbation, in each of the three independent transgenic lines. These were identified as isoforms of chloroplast ribonucleoproteins, known to be involved in chloroplast mRNA stability, processing and translation. Another group of eight proteins strongly induced in the most metabolically perturbed line was identified as multiple, uncharacterised isoforms of the defense protein PR-1, a known marker for systemic acquired resistance

Polymer-drug conjugates as nano-sized multi-targeting systems for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive, neurodegenerative condition. There are clear markers for the presence and progression of the disease, including β-amyloid (Aβ) plaques and Tau tangles, with many potential causes debated in the scientific community. Most existing treatments only provide symptomatic solutions. Due to poor aqueous solubility and possibly limited uptake across the blood–brain barrier (BBB), medications targeting the hallmarks of AD are still under study despite enormous efforts. Recently, nanoparticle-based drug delivery systems have demonstrated remarkable promise as precision medicines that may effectively increase bioavailability, permeate the BBB, and improve the targeting ability of a variety of pharmaceuticals. Polymer therapeutics have made tremendous progress in recent years, particularly in cancer treatment. Polymer–drug conjugates (PDCs) typically have a longer half-life, higher stability, and enhanced water solubility. Polymers serve as carriers for the administration of drugs, proteins, targeting moieties, and imaging agents in polymeric and macromolecular prodrugs. Numerous commercially viable PDCs for the treatment of various diseases have already proved their potential. This paper focuses mainly on the rationale for the design, synthesis, and potential use of PDCs as a multi-target treatment for neurodegenerative diseases

Bitopic binding mode of an M1 muscarinic acetylcholine receptor agonist associated with adverse clinical trial outcomes

The realisation of the therapeutic potential of targeting the M1 muscarinic acetylcholine receptor (M1 mAChR) for the treatment of cognitive decline in Alzheimer's disease has prompted the discovery of M1 mAChR ligands showing efficacy in alleviating cognitive dysfunction in both rodents and humans. Among these is GSK1034702, described previously as a potent M1 receptor allosteric agonist, which showed pro-cognitive effects in rodents and improved immediate memory in a clinical nicotine withdrawal test but induced significant side-effects. Here we provide evidence using ligand binding, chemical biology and functional assays to establish that rather than the allosteric mechanism claimed, GSK1034702 interacts in a bitopic manner at the M1 mAChR such that it can concomitantly span both the orthosteric and an allosteric binding site. The bitopic nature of GSK1034702 together with the intrinsic agonist activity and a lack of muscarinic receptor subtype selectivity reported here, all likely contribute to the adverse effects of this molecule in clinical trials. We conclude that these properties, whilst imparting beneficial effects on learning and memory, are undesirable in a clinical candidate due to the likelihood of adverse side effects. Rather, our data supports the notion that "pure" positive allosteric modulators showing selectivity for the M1 mAChR with low levels of intrinsic activity would be preferable to provide clinical efficacy with low adverse responses

Semi-quantitative mass spectrometry in AML cells identifies new non-genomic targets of the EZH2 methyltransferase

Alterations to the gene encoding the EZH2 (KMT6A) methyltransferase, including both gain-of-function and loss-of-function, have been linked to a variety of haematological malignancies and solid tumours, suggesting a complex, context-dependent role of this methyltransferase. The successful implementation of molecularly targeted therapies against EZH2 requires a greater understanding of the potential mechanisms by which EZH2 contributes to cancer. One aspect of this effort is the mapping of EZH2 partner proteins and cellular targets. To this end we performed affinity-purification mass spectrometry in the FAB-M2 HL-60 acute myeloid leukaemia (AML) cell line before and after all-transretinoic acid-induced differentiation. These studies identified new EZH2 interaction partners and potential non-histone substrates for EZH2-mediated methylation. Our results suggest that EZH2 is involved in the regulation of translation through interactions with a number of RNA binding proteins and by methylating key components of protein synthesis such as eEF1A1. Given that deregulated mRNA translation is a frequent feature of cancer and that eEF1A1 is highly expressed in many human tumours, these findings present new possibilities for the therapeutic targeting of EZH2 in AML

Effect of Airborne-particle Abrasion on 3-dimensional Surface Roughness and Characteristic Failure Load of Fiber-reinforced Posts

Statement of problem Debonding is the most common complication of fiber-reinforced posts (FRPs). Airborne-particle abrasion (APA) has been suggested to increase resin cement adhesion to the surface of FRPs. However, which abrasion protocol is the most favorable is unclear. Purpose The purpose of this in vitro study was to compare the surface roughness and characteristic failure load of three FRP systems following different APA protocols. Material and methods A total of 150 posts from 3 manufacturers (glass FRP, quartz FRP, and zirconia-enriched glass FRP) were randomly assigned to different surface treatments (NT: no treatment—control; E0: cleaned with 96% ethanol solution; E2: APA for 2 seconds/mm2—ethanol cleaned, E5: APA for 5 seconds/mm2—ethanol cleaned; and E10: APA for 10 seconds/mm2—ethanol cleaned) forming 15 groups in total. APA was performed with 50-μm aluminum oxide. Each post was observed under a 3-dimensional (3D) laser microscope, and average 3D surface roughness (Sa) was measured. Failure was induced with a universal testing machine. Two specimens per group were evaluated under the same microscope to evaluate failure patterns. Surface roughness data were analyzed with the Welch ANOVA (α=.05), followed by the post hoc Games-Howell test. Failure load differences were determined by 2-parameter Weibull statistics and likelihood ratio contour plots (95% confidence bounds). Results Statistically significant differences were found in the mean surface roughness among the groups (Welch ANOVA, P Conclusions APA significantly increased surface roughness in all post systems. APA effects on characteristic failure load were dependent on the material used

Comparing computer-generated and pathologist-generated tumour segmentations for immunohistochemical scoring of breast tissue microarrays

BACKGROUND: Tissue microarrays (TMAs) have become a valuable resource for biomarker expression in translational research. Immunohistochemical (IHC) assessment of TMAs is the principal method for analysing large numbers of patient samples, but manual IHC assessment of TMAs remains a challenging and laborious task. With advances in image analysis, computer-generated analyses of TMAs have the potential to lessen the burden of expert pathologist review. METHODS: In current commercial software computerised oestrogen receptor (ER) scoring relies on tumour localisation in the form of hand-drawn annotations. In this study, tumour localisation for ER scoring was evaluated comparing computer-generated segmentation masks with those of two specialist breast pathologists. Automatically and manually obtained segmentation masks were used to obtain IHC scores for thirty-two ER-stained invasive breast cancer TMA samples using FDA-approved IHC scoring software. RESULTS: Although pixel-level comparisons showed lower agreement between automated and manual segmentation masks (κ=0.81) than between pathologists' masks (κ=0.91), this had little impact on computed IHC scores (Allred; [Image: see text]=0.91, Quickscore; [Image: see text]=0.92). CONCLUSIONS: The proposed automated system provides consistent measurements thus ensuring standardisation, and shows promise for increasing IHC analysis of nuclear staining in TMAs from large clinical trials