KAT5 (Tip60) is a potential therapeutic target in malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is a rare aggressive cancer of the pleura. Asbestos exposure (through inhalation) is the most well established risk factor for mesothelioma. The current standard of care for patients suffering from MPM is a combination of cisplatin and pemetrexed (or alternatively cisplatin and raltitrexed). Most patients, however, die within 24 months of diagnosis. New therapies are therefore urgently required for this disease. Lysine acetyltransferases (KATs) including KAT5 have been linked with the development of cisplatin resistance. This gene may therefore be altered in MPM and could represent a novel candidate target for intervention. Using RT-PCR screening the expression of all known KAT5 variants was found to be markedly increased in malignant tumors compared to benign pleura. When separated according to histological subtype, KAT5 was significantly overexpressed in both the sarcomatoid and biphasic subgroups for all transcript variants. A panel of MPM cell lines including the normal pleural cells LP9 and Met5A was screened for expression of KAT5 variants. Treatment of cells with a small molecule inhibitor of KAT5 (MG-149) caused significant inhibition of cellular proliferation (p<0.0001), induction of apoptosis and was accompanied by significant induction of pro-inflammatory cytokines/chemokines.

Modelling Cued-Target Recall using Quantum Inspired Models of Target Activation

This article presents and evaluates Quantum Inspired models of Target Activation using Cued-Target Recall Memory Modelling over multiple sources of Free Association data. Two components were evaluated: Whether Quantum Inspired models of Target Activation would provide a better framework than their classical psychological counterparts and how robust these models are across the different sources of Free Association data. In previous work, a formal model of cued-target recall did not exist and as such Target Activation was unable to be assessed directly. Further to that, the data source used was suspected of suffering from temporal and geographical bias. As a consequence, Target Activation was measured against cued-target recall data as an approximation of performance. Since then, a formal model of cued-target recall (PIER3) has been developed [10] with alternative sources of data also becoming available. This allowed us to directly model target activation in cued-target recall with human cued-target recall pairs and use multiply sources of Free Association Data. Featural Characteristics known to be important to Target Activation were measured for each of the data sources to identify any major differences that may explain variations in performance for each of the models. Each of the activation models were used in the PIER3 memory model for each of the data sources and was benchmarked against cued-target recall pairs provided by the University of South Florida (USF). Two methods where used to evaluate performance. The first involved measuring the divergence between the sets of results using the Kullback Leibler (KL) divergence with the second utilizing a previous statistical analysis of the errors [9]. Of the three sources of data, two were sourced from human subjects being the USF Free Association Norms and the University of Leuven (UL) Free Association Networks. The third was sourced from a new method put forward by Galea and Bruza, 2015 in which pseudo Free Association Networks (Corpus Based Association Networks - CANs) are built using co-occurrence statistics on large text corpus. It was found that the Quantum Inspired Models of Target Activation not only outperformed the classical psychological model but was more robust across a variety of data sources.

The determinants of fair value measurements of banks: International evidence

The purpose of this study is to investigate the accounting choice decisions of banks to employ Level 3 inputs in estimating the value of their financial assets and liabilities. Using a sample of 146 bank-year observations from 18 countries over 2009-2012, this study finds banks’ incentives to use Level 3 valuation inputs are associated with both firm-level and country-level determinants. At the firm-level, leverage, profitability (in term of net income), Tier 1 capital ratio, size and audit committee independence are associated with the percentage of Level 3 valuation inputs. At the country-level, economy development, legal region, legal enforcement and investor rights are also associated with the Level 3 classification choice. Lastly, ‘secrecy’, the proxy for culture dimensions and values, is found to be positively associated with the use of Level 3 valuation inputs. Altogether, these findings suggest that banks use the discretion available under Level 3 inputs opportunistically to avoid violating debt covenants limits, to increase earnings and manage their capital ratios. Results of this study also highlight that corporate governance quality at the firm-level (e.g. audit committee independence) and institutional features can constrain banks’ opportunistic behaviors in using the discretion available under Level 3 inputs. The results of this study have important implications for standard setters and contribute to the debate on the use of fair value accounting in an international context.

The determinants of fair value measurements of banks: International evidence

The purpose of this study is to investigate the accounting choice decisions of banks to employ Level 3 inputs in estimating the value of their financial assets and liabilities. Using a sample of 146 bank-year observations from 18 countries over 2009-2012, this study finds banks’ incentives to use Level 3 valuation inputs are associated with both firm-level and country-level determinants. At the firm-level, leverage, profitability (in term of net income), Tier 1 capital ratio, size and audit committee independence are associated with the percentage of Level 3 valuation inputs. At the country-level, economy development, legal region, legal enforcement and investor rights are also associated with the Level 3 classification choice. Lastly, ‘secrecy’, the proxy for culture dimensions and values, is found to be positively associated with the use of Level 3 valuation inputs. Altogether, these findings suggest that banks use the discretion available under Level 3 inputs opportunistically to avoid violating debt covenants limits, to increase earnings and manage their capital ratios. Results of this study also highlight that corporate governance quality at the firm-level (e.g. audit committee independence) and institutional features can constrain banks’ opportunistic behaviors in using the discretion available under Level 3 inputs. The results of this study have important implications for standard setters and contribute to the debate on the use of fair value accounting in an international context.

Evidence for an association with type 2 diabetes mellitus at the PPARG locus in a South Indian population

Peroxisome proliferator activated receptor-gamma 2 (PPARG2) is a nuclear hormone receptor of ligand-dependent ranscription factor involved in adipogenesis and a molecular target of the insulin sensitizers thiazolidinediones. We addressed the question of whether the 3 variants (-1279G/A, Pro12Ala, and His478His) in the PPARG2 gene are associated with type 2 diabetes mellitus and its related traits in a South Indian population. The study subjects (1000 type 2 diabetes mellitus and 1000 normal glucose-tolerant subjects) were chosen randomly from the Chennai Urban Rural Epidemiology Study, an ongoing population-based study in southern India. The variants were screened by single-stranded conformational variant, direct sequencing, and restriction fragment length polymorphism. Linkage disequilibrium was estimated from the estimates of haplotypic frequencies. The -1279G/A, Pro12Ala, and His478His variants of the PPARG2 gene were not associated with type 2 diabetes mellitus. However, the 2-loci analyses showed that, in the presence of Pro/Pro genotype of the Pro12Ala variant, the -1279G/A promoter variant showed increased susceptibility to type 2 diabetes mellitus (odds ratio, 2.092; 95% confidence interval, 1.22-3.59; P = .008), whereas in the presence of 12Ala allele, the -1279G/A showed a protective effect against type 2 diabetes mellitus (odds ratio, 0.270; 95% confidence interval, 0.15-0.49; P < .0001). The 3-loci haplotype analysis showed that the A-Ala-T (-1279G/A-Pro12Ala-His478His) haplotype was associated with a reduced risk of type 2 diabetes mellitus (P < .0001). Although our data indicate that the PPARG2 gene variants, independently, have no association with type 2 diabetes mellitus, the 2-loci genotype analysis involving -1279G/A and Pro12Ala variants and the 3-loci haplotype analysis have shown a significant association with type 2 diabetes mellitus in this South Indian population. (C) 2010 Elsevier Inc. All rights reserved.

Decomposition analysis to examine Australia’s 2030 GHGs emissions target: How hard will it be to achieve?

The Australian government has recently pledged a reduction in GHGs emissions of 26–28% below the 2005 level by 2030. How big is the challenge for the country to achieve this target in terms of its present emissions profile, recent historical trends, and the contributions to those trends from key proximate factors contributing to emissions? In this paper, we attempt a quantitative judgement of the challenge by using decomposition analysis. Based on the analysis it appears the announced target will be quite challenging to achieve if the average annual mitigating effects from economic restructuring, energy efficiency improvements and movement towards less emissions-intensive energy sources in evidence over 2002–2013 continued through to 2030; however, if the contribution from these mitigating sources in evidence over 2006–2013 can be sustained, achievement of the target will be much less challenging. The challenge for government then will be to provide a policy framework to ensure the more pronounced beneficial impacts of the mitigating factors evidenced during 2006–2013 can be maintained over the years to 2030.

Proteomic identification of putative microRNA394 target genes in Arabidopsis thaliana identifies MLP family members critical for normal development

Expression of the F-Box protein Leaf Curling Responsiveness (LCR) is regulated by microRNA, miR394, and alterations to this interplay in Arabidopsis thaliana produce defects in leaf polarity and shoot apical meristem (SAM) organisation. Although the miR394-LCR node has been documented in Arabidopsis, the identification of proteins targeted by LCR F-box itself has proven problematic. Here, a proteomic analysis of shoot apices from plants with altered LCR levels identified a member of the Major Latex Protein (MLP) family gene as a potential LCR F-box target. Bioinformatic and molecular analyses also suggested that other MLP family members are likely to be targets for this post-translational regulation. Direct interaction between LCR F-Box and MLP423 was validated. Additional MLP members had reduction in protein accumulation, in varying degrees, mediated by LCR F-Box. Transgenic Arabidopsis lines, in which MLP28 expression was reduced through an artificial miRNA technology, displayed severe developmental defects, including changes in leaf patterning and morphology, shoot apex defects, and eventual premature death. These phenotypic characteristics resemble those of Arabidopsis plants modified to over-express LCR. Taken together, the results demonstrate that MLPs are driven to degradation by LCR, and indicate that MLP gene family is target of miR394-LCR regulatory node, representing potential targets for directly post-translational regulation mediated by LCR F-Box. In addition, MLP28 family member is associated with the LCR regulation that is critical for normal Arabidopsis development.

Stadilaispojat, rikokset ja lastensuojelu : Viisi tapaustutkimusta kuudelta vuosikymmeneltä

Societal reactions to norm breaking behavior of children reveal, how we understand childhood, the relations between generations and communitie's ratio of tolerance. In Finland the children that repeatedly commit crimes receive social service measures that are based on Child Welfare Act. In the city of Helsinki (Stadi in the slang of Helsinki) existed an agency specifically established for ill-behaving children until the 1980's, agter which an unified agency for the maltreated and maladjusted children was founded. Through five boys' welfare cases, this research aims at defining what kind of positions, social relations and structures are constructed in the social dynamics of these children's everyday lives. The cases cover different decades from the 1940s to the present. At the same time the cases reflect the child welfare and societal practices, and reveal how the communities have participated in constructing deviance in different eras. The research is meta-theoretically based on critical realism and specifically on Roy Bhaskar's transformative model of social activity. The cases are analyzed in the framework of Edwin M. Lemert's societal reaction theory. Thus the focus of the study is on the wide structural context of the institutional and societal definitions of deviance. The research is methodologically based on a qualitative multiple case study research. The primary data consist of classified child welfare case files collected from the archives of the city of Helsinki. The data of the institutional level consist of the annual reports from 1943 to 2004 and the ordinances from 1907 onwards, and of various committee documents produced in the law-making process of child welfare, youth and criminal legislation of the 20th century. Empirical finding are interpreted in a dialogue with previous historical and child welfare research, contemporary literature and studies on the urban development. The analysis is based on Derek Layder's model of adaptive theory. The research forms a viewpoint to the historical study of child welfare, in which the historical era, its agents and the dynamics of their mutual relations are studied through an individual level reconstruction based on the societal reaction theory. The case analyses reveal how the positions of the children form differently in the different eras of child welfare practices. In the 1940s the child is positioned as a psychopath and a criminal type. The measures are aimed at protecting the community from the disturbed child, and at adjusting the individual by isolation. From 1960s to 1980s the child is positioned as a child in need of help and support. The child becomes a victim, a subject that occupies rights, and a target of protection. In the turn of the millennium a norm breaking child is positioned as a dangerous individual that, in the name of the community safety, has to be confined. The case analyses also reveal the prevailing academic and practical paradigms of the time. Keywords: childhood, youth, child protection, child welfare, delinquency, crime, deviance, history, critical realism, case study research

Kinetics and the Mechanism of Interaction of the Endoplasmic Reticulum Chaperone, Calreticulin, with Monoglucosylated (Glc1Man9GlcNAc2) Substrate

Calreticulin is a lectin-like molecular chaperone of the endoplasmic reticulum in eukaryotes. Its interaction with N-glycosylated polypeptides is mediated by the glycan, Glc(1)Man(9)GlcNAc(2), present on the target glycoproteins. In this work, binding of monoglucosyl IgG (chicken) substrate to calreticulin has been studied using real time association kinetics of the interaction with the biosensor based on surface plasmon resonance (SPR). By SPR, accurate association and dissociation rate constants were determined, and these yielded a micromolar association constant. The nature of reaction was unaffected by immobilization of either of the reactants. The Scatchard analysis values for K-a agreed web crith the one obtained by the ratio k(1)/k(-1). The interaction was completely inhibited by free oligosaccharide, Glc(1)Man(9)GlcNAc(2), whereas Man(9)GlcNAc(2) did not bind to the calreticulin-substrate complex, attesting to the exquisite specificity of this interaction. The binding of calreticulin to IgG was used for the development of immunoassay and the relative affinity of the lectin-substrate association was indirectly measured. The values are in agreement with those obtained with SPR. Although the reactions are several orders of magnitude slower than the diffusion controlled processes, the data are qualitatively and quantitatively consistent with single-step bimolecular association and dissociation reaction. Analyses of the activation parameters indicate that reaction is enthalpically driven and does not involve a highly ordered transition state. Based on these data, the mechanism of its chaperone activity is briefly discussed.

Large latitudinal gradients and temporal heterogeneity in aerosol black carbon and its mass mixing ratio over southern and northern oceans observed during a trans-continental cruise experiment

Extensive, and collocated measurements of the mass concentrations (M-B) of aerosol black carbon (BC) and (M-T) of composite aerosols were made over the Arabian Sea, tropical Indian Ocean and the Southern Ocean during a trans-continental cruise experiment. Our investigations show that MB remains extremely low(<50 ng m(-3)) and remarkably steady (in space and time) in the Southern Ocean (20 degrees S to 56 degrees S). In contrast, large latitudinal gradients exist north of similar to 20 degrees S; M-B increasing exponentially to reach as high as 2000 ng m(-3) in the Arabian Sea (similar to 8 degrees N). Interestingly, the share of BC showed a distinctly different latitudinal variation, with a peak close to the equator and decreasing on either side. Large fluctuations were seen in M-T over Southern Ocean associated with enhanced production of sea-salt aerosols in response to sea-surface wind speed. These spatio-temporal changes in M-B and its mixing ratio have important implications to regional and global climate.

First Measurement of the Ratio of Branching Fractions B(Lambda_b to Lambda_c mu nu)/B(Lambda_b to Lambda_c pi)

The analysis uses data from an integrated luminosity of approximately 172 pb-1 of ppbar collisions at sqrt(s)=1.96 TeV, collected with the CDF II detector at the Fermilab Tevatron. The Lambda_b and B0 relative branching fractions are measured to be: B(Lambda_b to Lambda_c+ mu nu)/B(Lambda_b to Lambda_c+ pi) = 16.6 +- 3.0 (stat) +- 1.0 (syst) +2.6 -3.4 (PDG) +- 0.3 (EBR), B(B0 to D+ mu nu)/B(B0 to D+ pi) = 9.9 +- 1.0 (stat) +- 0.6 (syst) +- 0.4 (PDG) +- 0.5 (EBR), B(B0 to D*+ mu nu)/B(B0 to D*+ pi) = 16.5 +- 2.3 (stat) +- 0.6 (syst) +- 0.5 (PDG) +- 0.8 (EBR) This article also presents measurements of the branching fractions of four new Lambda_b semileptonic decays: Lambda_b to Lambda_c(2595)+ mu nu, Lambda_b to Lambda_c(2625)+ mu nu, Lambda_b to Sigma_c(2455)0 pi mu nu, Lambda_b to Sigma_c(2455)++ pi mu nu, relative to the branching fraction of the Lambda_b to Lambda_c mu nu decay. Finally, the transverse-momentum distribution of Lambda_b baryons produced in p-pbar collisions is measured and found to be significantly different from that of B0 mesons.