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.

Semi-empirical procedures for estimation of residual velocity and ballistic limit for impact on mild steel plates by projectiles

This paper deals with the development of simplified semi-empirical relations for the prediction of residual velocities of small calibre projectiles impacting on mild steel target plates, normally or at an angle, and the ballistic limits for such plates. It has been shown, for several impact cases for which test results on perforation of mild steel plates are available, that most of the existing semi-empirical relations which are applicable only to normal projectile impact do not yield satisfactory estimations of residual velocity. Furthermore, it is difficult to quantify some of the empirical parameters present in these relations for a given problem. With an eye towards simplicity and ease of use, two new regression-based relations employing standard material parameters have been discussed here for predicting residual velocity and ballistic limit for both normal and oblique impact. The latter expressions differ in terms of usage of quasi-static or strain rate-dependent average plate material strength. Residual velocities yielded by the present semi-empirical models compare well with the experimental results. Additionally, ballistic limits from these relations show close correlation with the corresponding finite element-based predictions.

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.

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.

Strength design of composite beam using gradient and particle swarm optimization

This work addresses the optimum design of a composite box-beam structure subject to strength constraints. Such box-beams are used as the main load carrying members of helicopter rotor blades. A computationally efficient analytical model for box-beam is used. Optimal ply orientation angles are sought which maximize the failure margins with respect to the applied loading. The Tsai-Wu-Hahn failure criterion is used to calculate the reserve factor for each wall and ply and the minimum reserve factor is maximized. Ply angles are used as design variables and various cases of initial starting design and loadings are investigated. Both gradient-based and particle swarm optimization (PSO) methods are used. It is found that the optimization approach leads to the design of a box-beam with greatly improved reserve factors which can be useful for helicopter rotor structures. While the PSO yields globally best designs, the gradient-based method can also be used with appropriate starting designs to obtain useful designs efficiently. (C) 2006 Elsevier Ltd. All rights reserved.

The Structure and Functions of Hantavirus Nucleocapsid Protein

Hantaviruses, members of the genus Hantavirus in the Bunyaviridae family, are enveloped single-stranded RNA viruses with tri-segmented genome of negative polarity. In humans, hantaviruses cause two diseases, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), which vary in severity depending on the causative agent. Each hantavirus is carried by a specific rodent host and is transmitted to humans through excreta of infected rodents. The genome of hantaviruses encodes four structural proteins: the nucleocapsid protein (N), the glycoproteins (Gn and Gc), and the polymerase (L) and also the nonstructural protein (NSs). This thesis deals with the functional characterization of hantavirus N protein with regard to its structure. Structural studies of the N protein have progressed slowly and the crystal structure of the whole protein is still not available, therefore biochemical assays coupled with bioinformatical modeling proved essential for studying N protein structure and functions. Presumably, during RNA encapsidation, the N protein first forms intermediate trimers and then oligomers. First, we investigated the role of N-terminal domain in the N protein oligomerization. The results suggested that the N-terminal region of the N protein forms a coiled-coil, in which two antiparallel alpha helices interact via their hydrophobic seams. Hydrophobic residues L4, I11, L18, L25 and V32 in the first helix and L44, V51, L58 and L65 in the second helix were crucial for stabilizing the structure. The results were consistent with the head-to-head, tail-to-tail model for hantavirus N protein trimerization. We demonstrated that an intact coiled-coil structure of the N terminus is crucial for the oligomerization capacity of the N protein. We also added new details to the head-to-head, tail-to-tail model of trimerization by suggesting that the initial step is based on interaction(s) between intact intra-molecular coiled-coils of the monomers. We further analyzed the importance of charged aa residues located within the coiled-coil for the N protein oligomerization. To predict the interacting surfaces of the monomers we used an upgraded in silico model of the coiled-coil domain that was docked into a trimer. Next the predicted target residues were mutated. The results obtained using the mammalian two-hybrid assay suggested that conserved charged aa residues within the coiled-coil make a substantial contribution to the N protein oligomerization. This contribution probably involves the formation of interacting surfaces of the N monomers and also stabilization of the coiled-coil via intramolecular ionic bridging. We proposed that the tips of the coiled-coils are the first to come into direct contact and thus initiate tight packing of the three monomers into a compact structure. This was in agreement with the previous results showing that an increase in ionic strength abolished the interaction between N protein molecules. We also showed that residues having the strongest effect on the N protein oligomerization are not scattered randomly throughout the coiled-coil 3D model structure, but form clusters. Next we found evidence for the hantaviral N protein interaction with the cytoplasmic tail of the glycoprotein Gn. In order to study this interaction we used the GST pull-down assay in combination with mutagenesis technique. The results demonstrated that intact, properly folded zinc fingers of the Gn protein cytoplasmic tail as well as the middle domain of the N protein (that includes aa residues 80 248 and supposedly carries the RNA-binding domain) are essential for the interaction. Since hantaviruses do not have a matrix protein that mediates the packaging of the viral RNA in other negatve stranded viruses (NSRV), hantaviral RNPs should be involved in a direct interaction with the intraviral domains of the envelope-embedded glycoproteins. By showing the N-Gn interaction we provided the evidence for one of the crucial steps in the virus replication at which RNPs are directed to the site of the virus assembly. Finally we started analysis of the N protein RNA-binding region, which is supposedly located in the middle domain of the N protein molecule. We developed a model for the initial step of RNA-binding by the hantaviral N protein. We hypothesized that the hantaviral N protein possesses two secondary structure elements that initiate the RNA encapsidation. The results suggest that amino acid residues (172-176) presumably act as a hook to catch vRNA and that the positively charged interaction surface (aa residues 144-160) enhances the initial N-RNA interacation. In conclusion, we elucidated new functions of hantavirus N protein. Using in silico modeling we predicted the domain structure of the protein and using experimental techniques showed that each domain is responsible for executing certain function(s). We showed that intact N terminal coiled-coil domain is crucial for oligomerization and charged residues located on its surface form a interaction surface for the N monomers. The middle domain is essential for interaction with the cytoplasmic tail of the Gn protein and RNA binding.

A model to similate the strength and deformation of concrete in compression

A simple model is developed to represent the strength and deformational characteristics of concrete when subjected to a rate of strain or rate of stress or creep or relaxation testing under uniaxial compression.

Prediction of solid block masonry prism compressive strength using FE model

Masonry strength is dependent upon characteristics of the masonry unit,the mortar and the bond between them. Empirical formulae as well as analytical and finite element (FE) models have been developed to predict structural behaviour of masonry. This paper is focused on developing a three dimensional non-linear FE model based on micro-modelling approach to predict masonry prism compressive strength and crack pattern. The proposed FE model uses multi-linear stress-strain relationships to model the non-linear behaviour of solid masonry unit and the mortar. Willam-Warnke's five parameter failure theory developed for modelling the tri-axial behaviour of concrete has been adopted to model the failure of masonry materials. The post failure regime has been modelled by applying orthotropic constitutive equations based on the smeared crack approach. Compressive strength of the masonry prism predicted by the proposed FE model has been compared with experimental values as well as the values predicted by other failure theories and Eurocode formula. The crack pattern predicted by the FE model shows vertical splitting cracks in the prism. The FE model predicts the ultimate failure compressive stress close to 85 of the mean experimental compressive strength value.

On the theory of the indentation test for the measurement of tensile strength of brittle materials

A theoretical solution has been obtained for the state of stress in a rectangular plate under a pair of symmetrically placed rigid indenters. The stress distributions along the two central axes have been calculated for a square plate assuming the pressure distribution under the indenters as uniform, parabolic and one resulting from 'constant displacement' on a semiinfinite boundary, for different ratios of indenter-width to side of square. The results are compared with those of photoelastic analysis of Berenbaum and Brodie and the validity of the solution is discussed. The solution has been extended to orthotropic materials and numerical results for one type of coal are given.

Diversity of DNA methyltransferases that recognize asymmetric target sequences

DNA methyltransferases (MTases) are a group of enzymes that catalyze the methyl group transfer from S-adenosyl-L-methionine in a sequence-specific manner. Orthodox Type II DNA MTases usually recognize palindromic DNA sequences and add a methyl group to the target base (either adenine or cytosine) on both strands. However, there are a number of MTases that recognize asymmetric target sequences and differ in their subunit organization. In a bacterial cell, after each round of replication, the substrate for any MTase is hemimethylated DNA, and it therefore needs only a single methylation event to restore the fully methylated state. This is in consistent with the fact that most of the DNA MTases studied exist as monomers in solution. Multiple lines of evidence suggest that some DNA MTases function as dimers. Further, functional analysis of many restriction-modification systems showed the presence of more than one or fused MTase genes. It was proposed that presence of two MTases responsible for the recognition and methylation of asymmetric sequences would protect the nascent strands generated during DNA replication from cognate restriction endonuclease. In this review, MTases recognizing asymmetric sequences have been grouped into different subgroups based on their unique properties. Detailed characterization of these unusual MTases would help in better understanding of their specific biological roles and mechanisms of action. The rapid progress made by the genome sequencing of bacteria and archaea may accelerate the identification and study of species- and strain-specific MTases of host-adapted bacteria and their roles in pathogenic mechanisms.

Effect of matrix strength on the mechanical properties of Al-Zn-Mg/SiCp composites

The mechanical properties of Al-Zn-Mg alloy reinforced with SiCP composites prepared by solidification route were studied by altering the matrix strength with different heat treatments. With respect to the control alloy, the composites have shown similar ageing behaviour in terms of microhardness data at 135 degrees C. It was shown that although composites exhibited enhanced modulus values, the strengthening was found to be dependent on the damage that is occurring during straining. Thus the initial matrix strength plays an important role in determining the strengthening. Consequently, compression data had shown a different trend compared to tension. (C) 2000 Elsevier Science Ltd. All rights reserved.

Diversity of DNA methyltransferases that recognize asymmetric target sequences

DNA methyltransferases (MTases) are a group of enzymes that catalyze the methyl group transfer from S-adenosyl-L-methionine in a sequence-specific manner. Orthodox Type II DNA MTases usually recognize palindromic DNA sequences and add a methyl group to the target base (either adenine or cytosine) on both strands. However, there are a number of MTases that recognize asymmetric target sequences and differ in their subunit organization. In a bacterial cell, after each round of replication, the substrate for any MTase is hemimethylated DNA, and it therefore needs only a single methylation event to restore the fully methylated state. This is in consistent with the fact that most of the DNA MTases studied exist as monomers in solution. Multiple lines of evidence suggest that some DNA MTases function as dimers. Further, functional analysis of many restriction-modification systems showed the presence of more than one or fused MTase genes. It was proposed that presence of two MTases responsible for the recognition and methylation of asymmetric sequences would protect the nascent strands generated during DNA replication from cognate restriction endonuclease. In this review, MTases recognizing asymmetric sequences have been grouped into different subgroups based on their unique properties. Detailed characterization of these unusual MTases would help in better understanding of their specific biological roles and mechanisms of action. The rapid progress made by the genome sequencing of bacteria and archaea may accelerate the identification and study of species- and strain-specific MTases of host-adapted bacteria and their roles in pathogenic mechanisms.