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.

Marketing cultural attractions : understanding non-attendance and visitation barriers

Purpose – The purpose of this paper is to draw together the previous academic and industry research on non-attendance of cultural attractions, followed by qualitative in-depth interviews to identify commonalities or gaps in the previous research on barriers, constraints and inhibitors, as well as to propose linkages between these.

Design/methodology/approach – A multi-method approach is used – where barriers, constraints and inhibitors are identified by means of thematic content analysis of the literature. A set of probing questions is developed based on these themes and is then examined in in-depth interviews with individuals that had not visited cultural attractions in the past two years, in an attempt to triangulate data, as well as to identify connections between barriers.

Findings – From the literature, eight interconnected barriers to visitation are identified: physical access; personal access; cost; time and timing; product; personal interest and peer group; socialisation and understanding; and information. The in-depth interviews generally support these, although it is also identified that there are complex interrelationships between the issues.

Originality/value – This paper addresses the neglected question of why people do not attend cultural attractions by triangulating thematic findings from the content analysis of diverse literature with in-depth interview responses from one non-visitor segment. This results in an interconnected model of barriers that can be used to assist managers to develop strategies addressing low visitation rates within targeted segments.

Measuring non-economic well-being achievement

Income per capita and most widely reported, non- or non-exclusively income based human well-being indicators are highly correlated among countries. Yet many countries exhibit higher achievement in the latter than predicted by the former. The reverse is true for many other countries. This paper commences by extracting the inter-country variation in a composite of various widely-reported, non-income-based well-being indices not accounted for by variations in income pre capita. This extraction is interpreted inter alia as a measure of non-economic well-being. The paper then looks at correlations between this extraction and a number of new or less widely-used well-being measures, in an attempt to find the measure that best captures these achievements. A number of indicators are examined, including measures of poverty, inequality, health status, education status, gender bias, empowerment, governance and subjective well-being.

Non-economic well-being achievement in Pacific Asia

It is well known that income per capita and most widely reported non-economic well-being achievement measures are highly correlated among countries. Yet many countries exhibit higher achievement in the latter than predicted by the former. The reverse is true for many other countries. This paper commences by extracting the inter-country variation in a composite of three widely reported educational and health status indicators not accounted for by variations in income per capita. This extraction is interpreted inter alia as a measure of non-economic well-being. Using data for a sample of Pacific Asian countries, the paper then looks at correlations between this extraction and a number of new or less widely-used well-being measures, in an attempt to find the measure that best captures these achievements.

Recent developments in corrosion inhibitors based on rare earth metal compounds

Rare earth organic compounds can provide an environmentally safe and non-toxic alternative to chromates as corrosion inhibitors for some steel and aluminium applications. For steel lanthanum 4-hydroxy cinnamate offers corrosion protection and reduces the susceptibility to hydrogen embrittlement. Recent work has also indicated that it inhibits the corrosion of steel in environments containing high levels of carbon dioxide. For aluminium alloys, cerium diphenyl phosphate provides excellent corrosion inhibition in chloride environments, and reduces susceptibly to stress corrosion cracking. Furthermore, for both steel and aluminium alloys filiform corrosion can be suppressed when rare earth inhibitor compounds are added as pigments to polymer coatings. The levels of inhibition observed are thought to be due to synergistic effects between the rare earth and organic parts of these novel compounds, and are related to the various species that may be present in the complex chemical conditions that develop in solution close to a metal surface. This paper reviews some of the published research conducted by the group at Deakin University over recent years.

Recent developments in corrosion inhibitors based on rare earth metal compounds

Rare earth organic compounds can provide an environmentally safe and non-toxic alternative to chromates as corrosion inhibitors for some steel and aluminium applications. For steel lanthanum 4-hydroxy cinnamate offers corrosion protection and reduces the susceptibility to hydrogen embrittlement. Recent work has also indicated that it inhibits the corrosion of steel in environments containing high levels of carbon dioxide. For aluminium alloys, cerium diphenyl phosphate provides excellent corrosion inhibition in chloride environments, and reduces susceptibly to stress corrosion cracking. Furthermore, for both steel and aluminium alloys filiform corrosion can be suppressed when rare earth inhibitor compounds are added as pigments to polymer coatings. The levels of inhibition observed are thought to be due to synergistic effects between the rare earth and organic parts of these novel compounds, and are related to the various species that may be present in the complex chemical conditions that develop in solution close to a metal surface. This paper reviews some of the published research conducted by the group at Deakin University over recent years.©2014 Institute of Materials, Minerals and Mining.

Anisotropic hardening model based on non-associated flow rule and combined nonlinear kinematic hardening for sheet materials

 A material model for more effective analysis of plastic deformation of sheet materials is presented in this paper. The model is capable of considering the following aspects of plastic deformation behavior of sheet materials: the anisotropy in yielding stresses in different directions by using a quadratic yield function (based on Hill’s 1948 model and stress ratios), the anisotropy in work hardening by introducing non-constant flow stress hardening in different directions, the anisotropy in plastic strains in different directions by using a quadratic plastic potential function and non-associated flow rule (based on Hill’s 1948 model and plastic strain ratios, r-values), and finally some of the cyclic hardening phenomena such as Bauschinger’s effect and transient behavior for reverse loading by using a coupled nonlinear kinematic hardening (so-called Armstrong-Frederick-Chaboche model). Basic fundamentals of the plasticity of the model are presented in a general framework. Then, the model adjustment procedure is derived for the plasticity formulations. Also, a generic numerical stress integration procedure is developed based on backward-Euler method (so-called multistage return mapping algorithm). Different aspects of the model are verified for DP600 steel sheet. Results show that the new model is able to predict the sheet material behavior in both anisotropic hardening and cyclic hardening regimes more accurately. By featuring the above-mentioned facts in the presented constitutive model, it is expected that more accurate results can be obtained by implementing this model in computational simulations of sheet material forming processes. For instance, more precise results of springback prediction of the parts formed from highly anisotropic hardened materials or that of determining the forming limit diagrams is highly expected by using the developed material model.

A non-associated plasticity model with anisotropic and nonlinear kinematic hardening for simulation of sheet metal forming

A material model for more thorough analysis of plastic deformation of sheet materials is presented in this paper. This model considers the following aspects of plastic deformation behavior of sheet materials: (1) the anisotropy in yield stresses and in work hardening by using Hill's 1948 quadratic yield function and non-constant stress ratios which leads to different flow stress hardening in different directions, (2) the anisotropy in plastic strains by using a quadratic plastic potential function and non-associated flow rule, also based on Hill's 1948 model and r-values, and (3) the cyclic hardening phenomena such as the Bauschinger effect, permanent softening and transient behavior for reverse loading by using a coupled nonlinear kinematic hardening model. Plasticity fundamentals of the model were derived in a general framework and the model calibration procedure was presented for the plasticity formulations. Also, a generic numerical stress integration procedure was developed based on backward-Euler method, so-called multi-stage return mapping algorithm. The model was implemented in the framework of the finite element method to evaluate the simulation results of sheet metal forming processes. Different aspects of the model were verified for two sheet metals, namely DP600 steel and AA6022 aluminum alloy. Results show that the new model is able to accurately predict the sheet material behavior for both anisotropic hardening and cyclic hardening conditions. The drawing of channel sections and the subsequent springback were also simulated with this model for different drawbead configurations. Simulation results show that the current non-associated anisotropic hardening model is able to accurately predict the sidewall curl in the drawn channel sections.

A non-destructive test to assess the axial heterogeneity of in situ modified monoliths for HPLC

This paper describes a non-destructive "peak parking" protocol in order to assess the axial heterogeneity of an in situ modified monolithic column for high performance liquid chromatography; a "gradient stationary phase" was designed whereby the ligand density decreases along the length of the rod in the "forward flow" configuration. The results of multi-location peak parking demonstrated a consistent increase in peak variance from the 1 cm position of the column to the 9 cm location. This increase in band broadening supported the theory of a decreasing ligand density along the length of this gradient column. This is consistent with efficiency measurements performed in both the forward and reverse flow directions, with an improved efficiency (15% increase in N m^-1) in the reverse direction. These results are consistent with theoretical investigations into stationary phase gradients.

Cancer risk among people with type 1 and type 2 diabetes: disentangling true associations, detection bias, and reverse causation

 OBJECTIVE: Evidence indicates an increased risk of certain cancers among people with type 2 diabetes. Evidence for rarer cancers and for type 1 diabetes is limited. We explored the excess risk of site-specific cancer incidence and mortality among people with type 1 and type 2 diabetes, compared with the general Australian population. RESEARCH DESIGN AND METHODS: Registrants of a national diabetes registry (953,382) between 1997 and 2008 were linked to national death and cancer registries. Standardized incidence and mortality ratios (SIRs/SMRs) are reported. RESULTS: For type 1 diabetes, significant elevated SIRs were observed for pancreas, liver, esophagus, colon and rectum (females only [F]), stomach (F), thyroid (F), brain (F), lung (F), endometrium, and ovary, and decreased SIRs were observed for prostate in males. Significantly increased SMRs were observed for pancreas, liver, and kidney (males only), non-Hodgkin's lymphoma, brain (F), and endometrium. For type 2 diabetes, significant SIRs were observed for almost all site-specific cancers, with highest SIRs observed for liver and pancreas, and decreased risks for prostate and melanoma. Significant SMRs were observed for liver, pancreas, kidney, Hodgkin's lymphoma, gallbladder (F), stomach (F), and non-Hodgkin's lymphoma (F). Cancer risk was significantly elevated throughout follow-up time but was higher in the first 3 months postregistration, suggesting the presence of detection bias and/or reverse causation. CONCLUSIONS: Type 1 and type 2 diabetes are associated with an excess risk of incidence and mortality for overall and a number of site-specific cancers, and this is only partially explained by bias. We suggest that screening for cancers in diabetic patients is important.

Dangerous practices : the practicum experiences of non-Indigenous pre-service teachers in remote communities

This paper seeks to explore the risks of providing preserviceteachers with professional experiences in remote communities.In particular this paper focuses on the risks associated with this kindof professional experience. Twelve pre-service teachers wereinterviewed whilst on a three-week practicum around Katherine andin Maningrida in the Northern Territory during 2012. The dangersoutlined in this paper relate to the way their experiences continued tobe mediated by stereotypes and perpetuating colonial practices. Thepre-service teachers’ limited understandings of Indigenousknowledges and languages are discussed before exploring the vexedissue of reverse culture shock that some of the participants identifiedwhen they returned home. The paper concludes by exploring thenotion of ‘allies’ as a way to negotiate the problematic nature of thiswork.