Multifunctional rare earth organic corrosion inhibitors

All rights reserved.Chromium (VI) compounds are commonly used in paint systems to provide corrosion protection, particularly for aerospace alloys. These compounds are toxic, carcinogenic and environmentally detrimental, therefore alternatives that are safe, environmentally benign and meet or exceed current levels of corrosion protection are vital. Multifunctional rare earth organic compounds incorporate known inhibitor species, achieving synergistic inhibition in corrosive environments. The mechanism, efficiency and surface interactions of these complexes are explored. The complexes were effective inhibitors for steel and aluminium alloys, through mixed inhibition. Advantages and limitations of these inhibitor complexes, along with applications and future research direction, are discussed.

Rare earth-based corrosion inhibitors

Corrosion inhibitors are an important method for minimizing corrosion; however traditional inhibitors such as chromates pose environmental problems. Rare earth metals provide an important, environmentally-friendly alternative. This book provides a comprehensive review of current research and examines how rare earth metals can be used to prevent corrosion and applied to protect metals in such industries as aerospace and construction. Chapter 1 begins by examining the important need to replace chromate, and then goes on to discuss the chemistry of the rare earth metals and their related compounds. Chapter 2 considers the techniques that can be used to identify corrosion inhibition mechanisms and to test the levels of protection offered to different metals by rare earth compounds. Subsequent chapters consider in more detail how rare earth elements can be used as corrosion inhibitors in different forms and for different metals. This includes discussion on the potential of rare earth elements for self-healing, tunable and multifunctional coatings. Finally, chapter 10 considers the cost and availability of the rare earths and the potential health and environmental risks associated with extracting them. Provides a review of current research and examines how rare earth metals can be used to prevent corrosion and applied to protect metals in such industries as aerospace and construction. Includes discussion on the potential of rare earth elements for self-healing, tunable and multifunctional coatings. Considers the cost and availability of the rare earths and the potential health and environmental risks associated with extracting them.

Inhibitors and facilitators for mobile payment adoption in Australia: a preliminary study

With the seamless diffusion and acceptance of mobile phones into people's everyday life as trusted communication devices, businesses have begun exploring their potential as payment devices. In this paper, we report on the findings from a pioneering study conducted in Australia, which explored inhibitors and facilitators in the adoption of mobile phones as payment devices.

Severity of ED : relationship to treatment-seeking and satisfaction with treatment using PDE5 inhibitors

Introduction. Research in the past 20 years has demonstrated that erectile dysfunction (ED) is an area of concern for men and their partners.

Aim. The current study was designed to evaluate the impact of the perceived severity of ED on treatment-seeking behavior and satisfaction with treatment among men with ED.

Main Outcome Measures. Participants completed a questionnaire to assess the above variables, as well as the duration of ED.

Methods. Participants were 410 men with ED who were primarily recruited over the Internet via men's health websites.

Results. The results demonstrated that men with more severe ED compared with men with milder ED were more likely to have discussed their ED with their partner and doctor, have sought assistance for their ED problem, but they were also less satisfied with the effectiveness of phosphodiesterase type 5 inhibitors, and said they were less likely to use them in the future. Men with more severe ED were also less likely to want ED medication to last for 24 hours.

Conclusions. Implications of these findings for the treatment of men with different levels of ED are discussed.

Cost-effectiveness of cognitive behavioural therapy and selective serotonin reuptake inhibitors for major depression in children and adolescents

Objective:
To assess from a health sector perspective the incremental cost-effectiveness of cognitive behavioural therapy (CBT) and selective serotonin reuptake inhibitors (SSRIs) for the treatment of major depressive disorder (MDD) in children and adolescents, compared to ‘current practice’.
Method:
The health benefit is measured as a reduction in disability-adjusted life years (DALYs), based on effect size calculations from meta-analysis of randomised controlled trials. An assessment on second stage filter criteria (‘equity’; ‘strength of evidence’, ‘feasibility’ and ‘acceptability to stakeholders’) is also undertaken to incorporate additional factors that impact on resource allocation decisions. Costs and benefits are tracked for the duration of a new episode of MDD arising in eligible children (age 6–17 years) in the Australian population in the year 2000. Simulation-modelling techniques are used to present a 95% uncertainty interval (UI) around the cost-effectiveness ratios.
Results:
Compared to current practice, CBT by public psychologists is the most costeffective intervention for MDD in children and adolescents at A$9000 per DALY saved (95% UI A$3900 to A$24 000). SSRIs and CBT by other providers are less cost-effective but likely to be less than A$50 000 per DALY saved (> 80% chance). CBT is more effective than SSRIs in children and adolescents, resulting in a greater total health benefit (DALYs saved) than could be achieved with SSRIs. Issues that require attention for the CBT intervention include equity concerns, ensuring an adequate workforce, funding arrangements and acceptability to various stakeholders.
Conclusions:
Cognitive behavioural therapy provided by a public psychologist is the most
effective and cost-effective option for the first-line treatment of MDD in children and adolescents. However, this option is not currently accessible by all patients and will require change in policy to allow more widespread uptake. It will also require ‘start-up’ costs and attention to ensuring an adequate workforce.

Duration of erectile dysfunction and its relationship to treatment seeking and satisfaction with treatment using PDE5 inhibitors

Objectives: This cross-sectional study was designed to evaluate whether the duration of erectile dysfunction (ED) influenced treatment seeking and satisfaction with treatment using PDE5 inhibitors.
Methods: Participants were 409 men with ED who were primarily recruited over the internet via men's health web sites. Participants completed a questionnaire to assess the duration and perceived severity of ED, information and help-seeking behaviors for ED, and treatment usage and satisfaction with PDE5 inhibitor medication.
Results: The results demonstrated that men with ED of longer duration were more likely to have discussed their ED with their partner and doctor and to have sought information and treatment for their ED problem. No differences were found in reported satisfaction with ED medication usage or expected future medication use across the varying levels of ED duration, once variance attributable to age was accounted for.
Conclusions: These results suggest that men are more likely to accept that they have ED and seek treatment for their ED with increasing duration of the condition, although these men are not more satisfied with PDE5 inhibitors as a treatment option.

Dissecting isoform selectivity of P13K inhibitors: the role of non-conserved residues in the catalytic pocket

The last few years have seen the identification of numerous small molecules that selectively inhibit specific class I isoforms of PI3K (phosphoinositide 3-kinase), yet little has been revealed about the molecular basis for the observed selectivities. Using site-directed mutagenesis, we have investigated one of the areas postulated as being critical to the observed selectivity. The residues Thr⁸⁸⁶ and Lys⁸⁹⁰ of the PI3Kγ isoform project towards the ATP-binding pocket at the entrance to the catalytic site, but are not conserved. We have made reciprocal mutations between those residues in the β isoform (Glu⁸⁵⁸ and Asp⁸⁶²) and those in the α isoform (His⁸⁵⁵ and Gln⁸⁵⁹) and evaluated the potency of a range of reported PI3K inhibitors. The results show that the potencies of β-selective inhibitors TGX221 and TGX286 are unaffected by this change. In contrast, close analogues of these compounds, particularly the α-isoform-selective compound (III), are markedly influenced by the point mutations. The collected data suggests two distinct binding poses for these inhibitor classes, one of which is associated with potent PI3Kβ activity and is not associated with the mutated residues, and a second that, in accord with earlier hypotheses, does involve this pair of non-conserved amino acids at the catalytic site entrance and contributes to the α-isoform-selectivity of the compounds studied.

Substrates and inhibitors of human multidrug resistance associated proteins and the implications in drug development

Human contains 49 ATP-binding cassette (ABC) transporter genes and the multidrug resistance associated proteins (MRP1/ABCC1, MRP2/ABCC2, MRP3/ABCC3, MRP4/ABCC4, MRP5/ABCC5, MRP6/ABCC6, MRP7/ABCC10, MRP8/ABCC11 and MRP9/ABCC12) belong to the ABCC family which contains 13 members. ABCC7 is cystic fibrosis transmembrane conductance regulator; ABCC8 and ABCC9 are the sulfonylurea receptors which constitute the ATP-sensing subunits of a complex potassium channel. MRP10/ABCC13 is clearly a pseudo-gene which encodes a truncated protein that is highly expressed in fetal human liver with the highest similarity to MRP2/ABCC2 but without transporting activity. These transporters are localized to the apical and/or basolateral membrane of the hepatocytes, enterocytes, renal proximal tubule cells and endothelial cells of the blood-brain barrier. MRP/ABCC members transport a structurally diverse array of important endogenous substances and xenobiotics and their metabolites (in particular conjugates) with different substrate specificity and transport kinetics. The human MRP/ABCC transporters except MRP9/ABCC12 are all able to transport organic anions, such as drugs conjugated to glutathione, sulphate or glucuronate. In addition, selected MRP/ABCC members may transport a variety of endogenous compounds, such as leukotriene C(4) (LTC(4) by MRP1/ABCC1), bilirubin glucuronides (MRP2/ABCC2, and MRP3/ABCC3), prostaglandins E1 and E2 (MRP4/ABCC4), cGMP (MRP4/ABCC4, MRP5/ABCC5, and MRP8/ABCC11), and several glucuronosyl-, or sulfatidyl steroids. In vitro, the MRP/ABCC transporters can collectively confer resistance to natural product anticancer drugs and their conjugated metabolites, platinum compounds, folate antimetabolites, nucleoside and nucleotide analogs, arsenical and antimonial oxyanions, peptide-based agents, and in concert with alterations in phase II conjugating or biosynthetic enzymes, classical alkylating agents, alkylating agents. Several MRP/ABCC members (MRPs 1-3) are associated with tumor resistance which is often caused by an increased efflux and decreased intracellular accumulation of natural product anticancer drugs and other anticancer agents. Drug targeting of these transporters to overcome MRP/ABCC-mediated multidrug resistance may play a role in cancer chemotherapy. Most MRP/ABCC transporters are subject to inhibition by a variety of compounds. Based on currently available preclinical and limited clinical data, it can be expected that modulation of MRP members may represent a useful approach in the management of anticancer and antimicrobial drug resistance and possibly of inflammatory diseases and other diseases. A better understanding of their substrates and inhibitors has important implications in development of drugs for treatment of cancer and inflammation.

Mapping and molecular modeling of S-adenosyl-L-methionine binding sites in N-methyltransferase domains of the multifunctional polypeptide cyclosporin synthetase

We employed a highly specific photoaffinity labeling procedure, using 14C-labeled S-adenosyl-L-methionine (AdoMet) to define the chemical structure of the AdoMet binding centers on cyclosporin synthetase (CySyn). Tryptic digestion of CySyn photolabeled with either [methyl-14C]AdoMet or [carboxyl-14C]AdoMet yielded the sequence H2N-Asn-Asp-Gly-Leu-Glu-Ser-Tyr-Val-Gly-Ile-Glu-Pro-Ser-Arg-COOH (residues 10644-10657), situated within the N-methyltransferase domain of module 8 of CySyn. Radiosequencing detected Glu10654 and Pro10655 as the major sites of derivatization. [carboxyl-14C]AdoMet in addition labeled Tyr10650. Chymotryptic digestion generated the radiolabeled peptide H2N-Ile-Gly-Leu-Glu-Pro-Ser-Gln-Ser-Ala-Val-Gln-Phe-COOH, corresponding to amino acids 2125-2136 of the N-methyltransferase domain of module 2. The radiolabeled amino acids were identified as Glu2128 and Pro2129, which are equivalent in position and function to the modified residues identified with tryptic digestions in module 8. Homology modeling of the N-methyltransferase domains indicates that these regions conserve the consensus topology of the AdoMet binding fold and consensus cofactor interactions seen in structurally characterized AdoMet-dependent methyltransferases. The modified sequence regions correspond to the motif II consensus sequence element, which is involved in directly complexing the adenine and ribose components of AdoMet. We conclude that the AdoMet binding to nonribosomal peptide synthetase N-methyltransferase domains obeys the consensus cofactor interactions seen among most structurally characterized low molecular weight AdoMet-dependent methyltransferases.

Study on thermoplastic-modified multifunctional epoxies : influence of heating rate on cure behaviour and phase separation

The effect of heating rate on the cure behaviour and phase separation of thermoplastic-modified epoxy systems was investigated. Polyethersulphone (PES) modified multifunctional epoxies, triglycidyl-aminophenol (TGAP) and tetraglycidyldiaminodiphenylmethane (TGDDM), as well T300/914 prepreg were used. It was shown that heating rate had a significant influence on the cure kinetics and phase structures of investigated systems. Greater heating rate causes higher epoxy conversion. The domain size of the macrophases formed from phase separation increases with the increase of heating rate. A more complete phase separation is achieved by fast heated thermoplastic-modified epoxy blends.

Targeting Hsp90 with small molecule inhibitors induces the over-expression of the anti-apoptotic molecule, survivin, in human A549, HONE-1 and HT-29 cancer cells

Survivin is a dual functioning protein. It inhibits the apoptosis of cancer cells by inhibiting caspases, and also promotes cancer cell growth by stabilizing microtubules during mitosis. Since the molecular chaperone Hsp90 binds and stabilizes survivin, it is widely believed that down-regulation of survivin is one of the important therapeutic functions of Hsp90 inhibitors such as the phase III clinically trialed compound 17-AAG. However, Hsp90 interferes with a number of molecules that up-regulate the intracellular level of survivin, raising the question that clinical use of Hsp90 inhibitors may indirectly induce survivin expression and subsequently enhance cancer anti-drug responses. The purpose of this study is to determine whether targeting Hsp90 can alter survivin expression differently in different cancer cell lines and to explore possible mechanisms that cause the alteration in survivin expression.

The impact of the use of PDE5 inhibitors for erectile dysfunction on the lives of Australian men

This article presents findings from a recent cross-sectional study that was designed to evaluate both the impact of erectile dysfunction (ED) on the lives of Australian men, and explore whether the use of PDE5 inhibitors was able to alter this impact. The sample comprised 410 men with ED, and 242 men who did not have ED. All men were primarily recruited over the internet via men's health web sites. Participants completed a questionnaire to assess their self-esteem, masculinity, quality of life, sexual satisfaction, relationship satisfaction and usage of oral ED medication. The results demonstrated that men with ED experienced deficits on all of the psychosocial areas when compared to men without ED. Moreover, treatment with ED medication did not alleviate this deficit. Implications of these findings for the treatment of men with ED are discussed in the context of the biopsychosocial model of health and the need for a multidisciplinary approach to ED management is highlighted.

Evaluation of novel hyphodermin derivatives as glycogen phosphorylase a inhibitors

The lipophilicity, permeability, solubility, polar surface area and ‘rule-of-five’ properties were assessed, using QikProp v2.5 (Schrödinger, Inc.) and ALOGPS 2.1 calculations, for 25 Hyphodermin derivatives. These compounds obeyed the ‘rule-of-five’, and the calculated physicochemical values were generally within desired limits. All compounds were tested against Glycogen Phosphorylase a (GPa). Four phenyl and benzyl substituted 2-oxo-hexahydro and tetrahydrobenzo[cd]indole carboxylic acids were identified as novel inhibitors of GPa with estimated IC50 values in the range 0.8–1.3 mM. Molecular modelling of these novel inhibitors was used to obtain the main structural features of this class of molecule for future structure–activity relationship studies.