Lysine acetyltransferase 5 in EGFR mutated non-small cell lung cancer

Histone modifications are crucial in activities such as transcriptional activation, gene silencing, and epigenetic cellular memory. In particular, lysine acetylation via lysine (K) acetyltransferases (KATs) has been implicated in cancer development. Interestingly, KAT5, also known as Tip60 (tat-interactive protein-60kDa), has been reported to possess both tumor promoting and tumor suppressing properties depending on the context of malignancy. Herein we report that KAT5 contributes to tumorigenesis in epidermal growth factor receptor (EGFR) mutated lung cancer, and Kat5-knockout mice models demonstrate significantly reduced lung tumor burden. To probe the aberrant modification of KAT5, we demonstrated that KAT5 binds to and is phosphorylated by oncogenic EGFR in co-immunoprecipitation experiments. Next, to investigate whether KAT5 is involved in cell proliferation and survival, H1975 cells harboring L858R-T790M double-activating mutations were transfected with doxycycline inducible short helical RNA (shRNA) targeting KAT5 (shKAT5). Following treatment, shKAT5 cells were observed to have suppressed proliferation rates. Pharmacological inhibition using TH1834, a known KAT5 inhibitor, also suppressed proliferation rates in shKAT5 cells; in contrast BEAS2B cells, an immortalized normal human bronchial cell line, surprisingly exhibited increased viability compared to transformed human lung H1975 cells. This finding supports KAT5’s context-dependent role in in normal and abnormal cell homeostasis. To further investigate KAT5 in lung tumorigenesis in vivo, we generated EGFR-mutant conditional Kat5 knockout mice using a tetracycline-induced Cre/loxP system. Following doxycycline treatment for 10 weeks, isolated mice lungs for EGFRTL/CCSP-rtTA/Cre/Kat5F/F possessed significantly lower tumor volume compared to EGFRTL/CCSP-rtTA/Cre/Kat5wt/F and EGFRTL/CCSP-rtTA/Cre/Kat5wt/wt mice lungs. Hemotoxylin and eosin staining showed no evident hyperproliferation in lungs isolated from EGFRTL/CCSP-rtTA/Cre/Kat5F/F mice whereas lungs isolated from EGFRTL/CCSP-rtTA/Cre/Kat5wt/wt and EGFRTL/CCSP-rtTA/Cre/Kat5wt/F did, signifying that KAT5 has a potential regulatory role in cellular proliferation. RNA-Seq analysis of shKAT5 H1975 cells identified downstream targets involved in tumorigenic pathways. Subsequent quantitative polymerase chain reaction (PCR) of shKAT5 cells served to validate the reported targets. Taken together, these data offer insight into a KAT5 mediated oncogenic pathway that can provide novel therapeutic approaches in treating lung cancer

A Multivariate Control Chart for Autocorrelated Tool Wear Processes

Full automation of metal cutting processes has been a long held goal of the manufacturing industry. One key obstacle to achieving this ambition has been the inability to monitor completely the condition of the cutting tool in real time, as premature tool breakage and heavy tool wear can result in substantial costs through damage to the machinery and increasing the risk of non-conforming items that have to be scrapped or reworked. Instead, the condition of the tool has to be indirectly monitored using modern sensor technology that measures the acoustic emission, sound, spindle power and vibration of the tool during a cut. An on-line monitoring procedure for such data is proposed. Firstly, the standard deviation is extracted from each sensor signal to summarise the state of the tool after each cut. Secondly, a multivariate autoregressive state space model is specified for estimating the joint effects and cross-correlation of the sensor variables in Phase I. Then we apply a distribution-free monitoring scheme to the model residuals in Phase II, based on binomial type statistics. The proposed methodology is illustrated using a case study of titanium alloy milling (a machining process used in the manufacture of aircraft landing gears) from the Advanced Manufacturing Research Centre in Sheffield, UK, and is demonstrated to outperform alternative residual control charts in this application

Electron correlation energy in confined two-electron systems

Radial, angular and total correlation energies are calculated for four two-electron systems with atomic numbers Z=0-3 confined within an impenetrable sphere of radius R. We report accurate results for the non-relativistic, restricted Hartree-Fock and radial limit energies over a range of confinement radii from 0.05 - 10 a0. At small R, the correlation energies approach limiting values that are independent of Z while at intermediate R, systems with Z > 1 exhibit a characteristic maximum in the correlation energy resulting from an increase in the angular correlation energy which is offset by a decrease in the radial correlation energy

Geometric reconstruction methods for electron tomography

Electron tomography is becoming an increasingly important tool in materials science for studying the three-dimensional morphologies and chemical compositions of nanostructures. The image quality obtained by many current algorithms is seriously affected by the problems of missing wedge artefacts and nonlinear projection intensities due to diffraction effects. The former refers to the fact that data cannot be acquired over the full $180^\circ$ tilt range; the latter implies that for some orientations, crystalline structures can show strong contrast changes. To overcome these problems we introduce and discuss several algorithms from the mathematical fields of geometric and discrete tomography. The algorithms incorporate geometric prior knowledge (mainly convexity and homogeneity), which also in principle considerably reduces the number of tilt angles required. Results are discussed for the reconstruction of an InAs nanowire

Embodying compassion: A virtual reality paradigm for overcoming excessive self-criticism

Virtual reality has been successfully used to study and treat psychological disorders such as phobias and posttraumatic stress disorder but has rarely been applied to clinically-relevant emotions other than fear and anxiety. Self-criticism is a ubiquitous feature of psychopathology and can be treated by increasing levels of self-compassion. We exploited the known effects of identification with a virtual body to arrange for healthy female volunteers high in self-criticism to experience self-compassion from an embodied first-person perspective within immersive virtual reality. Whereas observation and practice of compassionate responses reduced self-criticism, the additional experience of embodiment also increased self-compassion and feelings of being safe. The results suggest potential new uses for immersive virtual reality in a range of clinical conditions.N/

Changes in food neophobia and dietary habits of international students

Background International study is becoming more prevalent, yet aspects such as food neophobia often militate against the consumption of a nutritionally balanced diet of visiting students. The purpose of this paper, therefore, was to evaluate the extent to which international postgraduate students experience food neophobia, how this might vary by nationality and other demographic characteristics, and how acculturation might manifest itself in students’ dietary behaviour. Methods International postgraduate students were invited to complete a validated questionnaire during their first week at university. The questionnaire was subsequently re-administered to the same students approximately four and eight months later. Results In total, 226 usable responses were analysed, 124, 58 and 44, respectively, for the first, second and final data collection. Perhaps surprisingly, the overall food neophobia scores increased from an initial value of 27.95 (SD ± 16.95) to 33.67 (SD ± 33.67) after 3 months although when comparing European and Asian students, only the former were significantly different (p<0.05). Both Asian and European students reported small but not significant changes in their eating habits, although after 3 months significantly (p=< 0.05) less changes were reported. No significant changes were reported in students’ perceived healthiness of their diets either by nationality or over time. Conclusions Understanding the complexities of food neophobia, other aspects of dietary change and at what point these changes might take place in the acculturation process when students arrive in the UK needs to be fully understood if a climate for positive learning is to be established

Increased risk of HPV-associated genital cancers in men and women as a consequence of pre-invasive disease

To assess the excess risk of HPV‐associated cancer (HPVaC) in two at‐risk groups – women with a previous diagnosis of high grade cervical intraepithelial neoplasia (CIN3) and both men and women treated for non‐cervical pre‐invasive ano‐genital disease. All CIN3 cases diagnosed in 1989‐2015 in Scotland were extracted from the Scottish cancer registry (SMR06). All cases of pre‐invasive penile, anal, vulval, and vaginal disease diagnosed in 1990‐2015 were identified within the NHS pathology databases in the two largest NHS health boards in Scotland. Both were linked to SMR06 to extract subsequent incidence of HPVaC following the diagnosis of CIN3 or pre‐invasive disease. Standardised incidence ratios were calculated for the risk of acquiring HPVaC for the two at‐risk groups compared with the general Scottish population. Among 69714 females in Scotland diagnosed with CIN3 (890360.9 person‐years), 179 developed non‐cervical HPVaC. CIN3 cases were at 3.2‐fold (95% CI: 2.7 to 3.7) increased risk of developing non‐cervical HPVaC, compared to the general female population. Among 1235 patients diagnosed with non‐cervical pre‐invasive disease (9667.4 person‐years), 47 developed HPVaC. Individuals with non‐cervical pre‐invasive disease had a substantially increased risk of developing HPVaC ‐ 15.5‐fold (95% CI: 11.1 to 21.1) increased risk for females and 28‐fold (11.3 to 57.7) increased risk for males. We report a significant additional risk of HPV‐associated cancer in those have been diagnosed with pre‐invasive HPV‐associated lesions including but not confined to the cervix. Uncovering the natural history of pre‐invasive disease has potential for determining screening, prevention and treatment

Googling the brain: discovering hierarchical and asymmetric network structures, with applications in neuroscience

Hierarchical organisation is a common feature of many directed networks arising in nature and technology. For example, a well-defined message-passing framework based on managerial status typically exists in a business organisation. However, in many real-world networks such patterns of hierarchy are unlikely to be quite so transparent. Due to the nature in which empirical data is collated the nodes will often be ordered so as to obscure any underlying structure. In addition, the possibility of even a small number of links violating any overall “chain of command” makes the determination of such structures extremely challenging. Here we address the issue of how to reorder a directed network in order to reveal this type of hierarchy. In doing so we also look at the task of quantifying the level of hierarchy, given a particular node ordering. We look at a variety of approaches. Using ideas from the graph Laplacian literature, we show that a relevant discrete optimization problem leads to a natural hierarchical node ranking. We also show that this ranking arises via a maximum likelihood problem associated with a new range-dependent hierarchical random graph model. This random graph insight allows us to compute a likelihood ratio that quantifies the overall tendency for a given network to be hierarchical. We also develop a generalization of this node ordering algorithm based on the combinatorics of directed walks. In passing, we note that Google’s PageRank algorithm tackles a closely related problem, and may also be motivated from a combinatoric, walk-counting viewpoint. We illustrate the performance of the resulting algorithms on synthetic network data, and on a real-world network from neuroscience where results may be validated biologically

SPT-3G: A Next-Generation Cosmic Microwave Background Polarization Experiment on the South Pole Telescope

We describe the design of a new polarization sensitive receiver, SPT-3G, for the 10-meter South Pole Telescope (SPT). The SPT-3G receiver will deliver a factor of ~20 improvement in mapping speed over the current receiver, SPTpol. The sensitivity of the SPT-3G receiver will enable the advance from statistical detection of B-mode polarization anisotropy power to high signal-to-noise measurements of the individual modes, i.e., maps. This will lead to precise (~0.06 eV) constraints on the sum of neutrino masses with the potential to directly address the neutrino mass hierarchy. It will allow a separation of the lensing and inflationary B-mode power spectra, improving constraints on the amplitude and shape of the primordial signal, either through SPT-3G data alone or in combination with BICEP-2/KECK, which is observing the same area of sky. The measurement of small-scale temperature anisotropy will provide new constraints on the epoch of reionization. Additional science from the SPT-3G survey will be significantly enhanced by the synergy with the ongoing optical Dark Energy Survey (DES), including: a 1% constraint on the bias of optical tracers of large-scale structure, a measurement of the differential Doppler signal from pairs of galaxy clusters that will test General Relativity on ~200 Mpc scales, and improved cosmological constraints from the abundance of clusters of galaxies.Comment: 21 pages, 9 figures. To be published in Proceedings of SPIE Volume 9153. Presented at SPIE Astronomical Telescopes + Instrumentation 2014, conference 915

COBRA framework to evaluate e-government services: A citizen-centric perspective

E-government services involve many stakeholders who have different objectives that can have an impact on success. Among these stakeholders, citizens are the primary stakeholders of government activities. Accordingly, their satisfaction plays an important role in e-government success. Although several models have been proposed to assess the success of e-government services through measuring users' satisfaction levels, they fail to provide a comprehensive evaluation model. This study provides an insight and critical analysis of the extant literature to identify the most critical factors and their manifested variables for user satisfaction in the provision of e-government services. The various manifested variables are then grouped into a new quantitative analysis framework consisting of four main constructs: cost; benefit; risk and opportunity (COBRA) by analogy to the well-known SWOT qualitative analysis framework. The COBRA measurement scale is developed, tested, refined and validated on a sample group of e-government service users in Turkey. A structured equation model is used to establish relationships among the identified constructs, associated variables and users' satisfaction. The results confirm that COBRA framework is a useful approach for evaluating the success of e-government services from citizens' perspective and it can be generalised to other perspectives and measurement contexts. Crown Copyright © 2014.PIAP-GA-2008-230658) from the European Union Framework Program and another grant (NPRP 09-1023-5-158) from the Qatar National Research Fund (amember of Qatar Foundation