Combination of a fusogenic glycoprotein, pro-drug activation and oncolytic HSV as an intravesical therapy for superficial bladder cancer

Background: There are still no effective treatments for superficial bladder cancer (SBC)/non-muscle invasive bladder cancer. Following treatment, 20% of patients still develop metastatic disease. Superficial bladder cancer is often multifocal, has high recurrences after surgical resection and recurs after intravesical live Bacillus Calmette-Guérin. Oncovex GALV/CD, an oncolytic herpes simplex virus-1, has shown enhanced local tumour control by combining oncolysis with the expression of a highly potent pro-drug activating gene and the fusogenic glycoprotein. Methods: In vitro fusion/prodrug/apoptotic cell-based assays. In vivo orthotopic bladder tumour model, visualised by computed microtomography. Results: Treatment of seven human bladder carcinoma cell lines with the virus resulted in tumour cell killing through oncolysis, pro-drug activation and glycoprotein fusion. Oncovex GALV/CD and mitomycin C showed a synergistic effect, whereas the co-administration with cisplatin or gemcitabine showed an antagonistic effect in vitro. Transitional cell cancer (TCC) cells follow an apoptotic cell death pathway after infection with Oncovex GALV/CD + with or without 5-FC. In vivo results showed that intravesical treatment with Oncovex GALV/CD prodrug (5-FC) reduced the average tumour volume by over 95% compared with controls.Discussion: Our in vitro and in vivo results indicate that Oncovex GALV/CD can improve local tumour control within the bladder, and potentially alter its natural history

Anisotropic Structure of the Order Parameter in FeSe0.45Te0.55 Revealed by Angle Resolved Specific Heat

The symmetry and structure of the superconducting gap in the Fe-based superconductors are the central issue for understanding these novel materials. So far the experimental data and theoretical models have been highly controversial. Some experiments favor two or more constant or nearly-constant gaps, others indicate strong anisotropy and yet others suggest gap zeros ("nodes"). Theoretical models also vary, suggesting that the absence or presence of the nodes depends quantitatively on the model parameters. An opinion that has gained substantial currency is that the gap structure, unlike all other known superconductors, including cuprates, may be different in different compounds within the same family. A unique method for addressing this issue, one of the very few methods that are bulk and angle-resolved, calls for measuring the electronic specific heat in a rotating magnetic field, as a function of field orientation with respect to the crystallographic axes. In this Communication we present the first such measurement for an Fe-based high-Tc superconductor (FeBSC). We observed a fourfold oscillation of the specific heat as a function of the in-plane magnetic field direction, which allowed us to identify the locations of the gap minima (or nodes) on the Fermi surface. Our results are consistent with the expectations of an extended s-wave model with a significant gap anisotropy on the electron pockets and the gap minima along the \Gamma M (or Fe-Fe bond) direction.Comment: 32 pages, 7 figure

Ferritins: furnishing proteins with iron

Ferritins are a superfamily of iron oxidation, storage and mineralization proteins found throughout the animal, plant, and microbial kingdoms. The majority of ferritins consist of 24 subunits that individually fold into 4-α-helix bundles and assemble in a highly symmetric manner to form an approximately spherical protein coat around a central cavity into which an iron-containing mineral can be formed. Channels through the coat at inter-subunit contact points facilitate passage of iron ions to and from the central cavity, and intrasubunit catalytic sites, called ferroxidase centers, drive Fe2+ oxidation and O2 reduction. Though the different members of the superfamily share a common structure, there is often little amino acid sequence identity between them. Even where there is a high degree of sequence identity between two ferritins there can be major differences in how the proteins handle iron. In this review we describe some of the important structural features of ferritins and their mineralized iron cores and examine in detail how three selected ferritins oxidise Fe2+ in order to explore the mechanistic variations that exist amongst ferritins. We suggest that the mechanistic differences reflect differing evolutionary pressures on amino acid sequences, and that these differing pressures are a consequence of different primary functions for different ferritins

The development and application of a new tool to assess the adequacy of the content and timing of antenatal care

Abstract Background: Current measures of antenatal care use are limited to initiation of care and number of visits. This study aimed to describe the development and application of a tool to assess the adequacy of the content and timing of antenatal care. Methods: The Content and Timing of care in Pregnancy (CTP) tool was developed based on clinical relevance for ongoing antenatal care and recommendations in national and international guidelines. The tool reflects minimal care recommended in every pregnancy, regardless of parity or risk status. CTP measures timing of initiation of care, content of care (number of blood pressure readings, blood tests and ultrasound scans) and whether the interventions were received at an appropriate time. Antenatal care trajectories for 333 pregnant women were then described using a standard tool (the APNCU index), that measures the quantity of care only, and the new CTP tool. Both tools categorise care into 4 categories, from ‘Inadequate’ (both tools) to ‘Adequate plus’ (APNCU) or ‘Appropriate’ (CTP). Participants recorded the timing and content of their antenatal care prospectively using diaries. Analysis included an examination of similarities and differences in categorisation of care episodes between the tools. Results: According to the CTP tool, the care trajectory of 10,2% of the women was classified as inadequate, 8,4% as intermediate, 36% as sufficient and 45,3% as appropriate. The assessment of quality of care differed significantly between the two tools. Seventeen care trajectories classified as ‘Adequate’ or ‘Adequate plus’ by the APNCU were deemed ‘Inadequate’ by the CTP. This suggests that, despite a high number of visits, these women did not receive the minimal recommended content and timing of care. Conclusions: The CTP tool provides a more detailed assessment of the adequacy of antenatal care than the current standard index. However, guidelines for the content of antenatal care vary, and the tool does not at the moment grade over-use of interventions as ‘Inappropriate’. Further work needs to be done to refine the content items prior to larger scale testing of the impact of the new measure

A Quantitative Analysis of Flight Feather Replacement in the Moustached Tree Swift Hemiprocne mystacea, a Tropical Aerial Forager

The functional life span of feathers is always much less than the potential life span of birds, so feathers must be renewed regularly. But feather renewal entails important energetic, time and performance costs that must be integrated into the annual cycle. Across species the time required to replace flight feather increases disproportionately with body size, resulting in complex, multiple waves of feather replacement in the primaries of many large birds. We describe the rules of flight feather replacement for Hemiprocne mystacea, a small, 60g tree swift from the New Guinea region. This species breeds and molts in all months of the year, and flight feather molt occurs during breeding in some individuals. H. mystacea is one to be the smallest species for which stepwise replacement of the primaries and secondaries has been documented; yet, primary replacement is extremely slow in this aerial forager, requiring more than 300 days if molt is not interrupted. We used growth bands to show that primaries grow at an average rate of 2.86 mm/d. The 10 primaries are a single molt series, while the 11 secondaries and five rectrices are each broken into two molt series. In large birds stepwise replacement of the primaries serves to increase the rate of primary replacement while minimizing gaps in the wing. But stepwise replacement of the wing quills in H. mystacea proceeds so slowly that it may be a consequence of the ontogeny of stepwise molting, rather than an adaptation, because the average number of growing primaries is probably lower than 1.14 feathers per wing

Efficient recovery-based error estimation for the smoothed finite element method for smooth and singular linear elasticity

[EN] An error control technique aimed to assess the quality of smoothed finite element approximations is presented in this paper. Finite element techniques based on strain smoothing appeared in 2007 were shown to provide significant advantages compared to conventional finite element approximations. In particular, a widely cited strength of such methods is improved accuracy for the same computational cost. Yet, few attempts have been made to directly assess the quality of the results obtained during the simulation by evaluating an estimate of the discretization error. Here we propose a recovery type error estimator based on an enhanced recovery technique. The salient features of the recovery are: enforcement of local equilibrium and, for singular problems a ¿smooth + singular¿ decomposition of the recovered stress. We evaluate the proposed estimator on a number of test cases from linear elastic structural mechanics and obtain efficient error estimations whose effectivities, both at local and global levels, are improved compared to recovery procedures not implementing these features.Stephane Bordas would like to thank the partial financial support of the Royal Academy of Engineering and of the Leverhulme Trust for his Senior Research Fellowship Towards the next generation surgical simulators as well as the financial support for Octavio A. Gonzalez-Estrada and Stephane Bordas from the UK Engineering Physical Science Research Council (EPSRC) under grant EP/G042705/1 Increased Reliability for Industrially Relevant Automatic Crack Growth Simulation with the eXtended Finite Element Method. Stephane Bordas also thanks partial financial support of the European Research Council Starting Independent Research Grant (ERC Stg grant agreement No. 279578) and the FP7 Initial Training Network Funding under grant number 289361 "Integrating Numerical Simulation and Geometric Design Technology, INSIST". This work has been carried out within the framework of the research project DPI2010-20542 of the Ministerio de Ciencia e Innovacion (Spain). The financial support from Universitat Politecnica de Valencia, PROMETEO/2012/023 and Generalitat Valenciana are also acknowledged.González Estrada, OA.; Natarajan, S.; J.J. Ródenas; Nguyen-Xuan, H.; Bordas, S. (2013). Efficient recovery-based error estimation for the smoothed finite element method for smooth and singular linear elasticity. Computational Mechanics. 52(1):37-52. https://doi.org/10.1007/s00466-012-0795-6S3752521Liu GR, Dai KY, Nguyen TT (2006) A smoothed finite element method for mechanics problems. 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Int J Numer Methods Eng 78: 324–353Liu G, Nguyen-Thoi T, Lam K (2009) An edge-based smoothed finite element method (ES-FEM) for static, free and forced vibration analyses of solids. J Sound Vib 320: 1100–1130Liu G, Nguyen-Thoi T, Nguyen-Xuan H, Lam K (2009) A node based smoothed finite element method (NS-FEM) for upper bound solution to solid mechanics problems. Comput Struct 87: 14–26Liu G. Smoothed Finite Element Methods. CRC Press, 2010Liu G, Nguyen-Xuan H, Nguyen-Thoi T (2010) A theoretical study on the smoothed FEM (SFEM) models: Properties, accuracy and convergence rates. Int J Numer Methods Biomed Eng 84: 1222–1256Nguyen T, Liu G, Dai K, Lam K (2007) smoothed finite element method. Tsinghua Sci Technol 12: 497–508Hung NX, Bordas S, Hung N (2009) Addressing volumetric locking and instabilities by selective integration in smoothed finite element. Commun Numer Methods Eng 25: 19–34Nguyen-Xuan H, Rabczuk T, Bordas S, Debongnie JF (2008) A smoothed finite element method for plate analysis. Comput Methods Appl Mech Eng 197: 1184–1203Nguyen NT, Rabczuk T, Nguyen-Xuan H, Bordas S (2008) A smoothed finite element method for shell analysis. Comput Methods Appl Mech Eng 198: 165–177Bordas SPA, Rabczuk T, Hung NX, Nguyen VP, Natarajan S, Bog T, óuan DM, Hiep NV (2010) Strain smoothing in FEM and XFEM. Comput Struct 88(23–24): 1419–1443. doi: 10.1016/j.compstruc.2008.07.006Bordas SP, Natarajan S, Kerfriden P, Augarde CE, Mahapatra DR, Rabczuk T, Pont SD (2011) On the performance of strain smoothing for óuadratic and enriched finite element approximations (XFEM/GFEM/PUFEM). Int J Numer Methods Biomed Eng 86: 637–666Liu G, Nguyen-Thoi T, Nguyen-Xuan H, Dai K, Lam K (2009) On the essence and the evaluation of the shape functions for the smoothed finite element method (SFEM). Int J Numer Methods Eng 77: 1863–1869. doi: 10.1002/nme.2587Strouboulis T, Zhang L, Wang D, Babuška I. (2006) A posteriori error estimation for generalized finite element methods. Comput Methods Appl Mech Eng 195(9–12): 852–879Bordas SPA, Duflot M (2007) Derivative recovery and a posteriori error estimate for extended finite elements. Comput Methods Appl Mech Eng 196(35–36): 3381–3399Xiao óZ, Karihaloo BL (2004) Statically admissible stress recovery using the moving least sóuares technique. In: Topping BHV, Soares CAM (eds) Progress in computational structures technology. Saxe-Coburg Publications, Stirling, pp 111–138Ródenas JJ, González-Estrada OA, Tarancón JE, Fuenmayor FJ (2008) A recovery-type error estimator for the extended finite element method based on singular + smooth stress field splitting. Int J Numer Methods Eng 76(4): 545–571. doi: 10.1002/nme.2313Panetier J, Ladevèze P, Chamoin L (2010) Strict and effective bounds in goal-oriented error estimation applied to fracture mechanics problems solved with XFEM. Int J Numer Methods Eng 81(6): 671–700Barros FB, Proenca SPB, de Barcellos CS (2004) On error estimator and p-adaptivity in the generalized finite element method. Int J Numer Methods Eng 60(14):2373–2398. doi: 10.1002/nme.1048Nguyen-Thoi T, Liu G, Nguyen-Xuan H, Nguyen-Tran C (2011) Adaptive analysis using the node-based smoothed finite element method (NS-FEM). Int J Numer Methods Biomed Eng 27(2): 198–218. doi: 10.1002/cnmGonzález-Estrada OA, Ródenas JJ, Bordas SPA, Duflot M, Kerfriden P, Giner E (2012) On the role of enrichment and statical admissibility of recovered fields in a-posteriori error estimation for enriched finite element methods. Eng Comput 29(8)Zienkiewicz OC, Zhu JZ (1987) A simple error estimator and adaptive procedure for practical engineering analysis. Int J Numer Methods Eng 24(2): 337–357Ródenas JJ, González-Estrada OA, Díez P, Fuenmayor FJ (2010) Accurate recovery-based upper error bounds for the extended finite element framework. Comput Methods Appl Mech Eng 199(37–40): 2607–2621Williams ML (1952) Stress singularities resulting from various boundary conditions in angular corners of plate in extension. J Appl Mech 19: 526–534Szabó BA, Babuška I (1991) Finite element analysis. Wiley, New YorkBarber JR. (2010) Elasticity. Series: solid mechanics and its application, 3rd edn. Springer, DordrechtChen JS, Wu CT, Yoon S, You Y (2001) A stabilized conforming nodal integration for Galerki mesh-free methods. Int J Numer Methods Eng 50: 435–466Yoo J, Moran B, Chen J (2004) Stabilized conforming nodal integration in the natural element method. Int J Numer Methods Eng 60: 861–890Zienkiewicz OC, Zhu JZ (1992) The superconvergent patch recovery and a posteriori error estimates. Part 1: The recovery technique. Int J Numer Methods Eng 33(7): 1331–1364Zienkiewicz OC, Zhu JZ (1992) The superconvergent patch recovery and a posteriori error estimates. Part 2: Error estimates and adaptivity. Int J Numer Methods Eng 33(7): 1365–1382Wiberg NE, Abdulwahab F (1993) Patch recovery based on superconvergent derivatives and eóuilibrium. Int J Numer Methods Eng 36(16): 2703–2724. doi: 10.1002/nme.1620361603Blacker T, Belytschko T (1994) Superconvergent patch recovery with eóuilibrium and conjoint interpolant enhancements. Int J Numer Methods Eng 37(3): 517–536Stein E, Ramm E, Rannacher R (2003) Error-controlled adaptive finite elements in solid mechanics. Wiley, ChichesterDuflot M, Bordas SPA (2008) A posteriori error estimation for extended finite elements by an extended global recovery. 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In: Khalili N, Valliappan S, Li ó, Russell A (eds) 9th World congress on computational mechanics (WCCM9). 4th Asian Pacific Congress on computational methods (APCOM2010). Centre for Infrastructure Engineering and SafetyRódenas JJ, González-Estrada OA, Díez P, Fuenmayor FJ (2007) Upper bounds of the error in the extended finite element method by using an eóuilibrated-stress patch recovery technique. In: International conference on adaptive modeling and simulation (ADMOS 2007). International Center for Numerical Methods in Engineering (CIMNE), pp 210–213Menk A, Bordas S (2010) Numerically determined enrichment function for the extended finite element method and applications to bi-material anisotropic fracture and polycrystals. Int J Numer Methods Eng 83: 805–828Menk A, Bordas S (2011) Crack growth calculations in solder joints based on microstructural phenomena with X-FEM. 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How Abnormal Is the Behaviour of Captive, Zoo-Living Chimpanzees?

Background. Many captive chimpanzees (Pan troglodytes) show a variety of serious behavioural abnormalities, some of which have been considered as possible signs of compromised mental health. The provision of environmental enrichments aimed at reducing the performance of abnormal behaviours is increasing the norm, with the housing of individuals in (semi-)natural social groups thought to be the most successful of these. Only a few quantitative studies of abnormal behaviour have been conducted, however, particularly for the captive population held in zoological collections. Consequently, a clear picture of the level of abnormal behaviour in zoo-living chimpanzees is lacking. Methods. We present preliminary findings from a detailed observational study of the behaviour of 40 socially-housed zoo-living chimpanzees from six collections in the United States of America and the United Kingdom. We determined the prevalence, diversity, frequency, and duration of abnormal behaviour from 1200 hours of continuous behavioural data collected by focal animal sampling. Results, conclusion, and significance. Our overall finding was that abnormal behaviour was present in all sampled individuals across six independent groups of zoo-living chimpanzees, despite the differences between these groups in size, composition, housing, etc. We found substantial variation between individuals in the frequency and duration of abnormal behaviour, but all individuals engaged in at least some abnormal behaviour and variation across individuals could not be explained by sex, age, rearing history or background (defined as prior housing conditions). Our data support a conclusion that, while most behaviour of zoo-living chimpanzees is ‘normal’ in that it is typical of their wild counterparts, abnormal behaviour is endemic in this population despite enrichment efforts. We suggest there is an urgent need to understand how the chimpanzee mind copes with captivity, an issue with both scientific and welfare implications

Towards strange metallic holography

We initiate a holographic model building approach to `strange metallic' phenomenology. Our model couples a neutral Lifshitz-invariant quantum critical theory, dual to a bulk gravitational background, to a finite density of gapped probe charge carriers, dually described by D-branes. In the physical regime of temperature much lower than the charge density and gap, we exhibit anomalous scalings of the temperature and frequency dependent conductivity. Choosing the dynamical critical exponent $z$ appropriately we can match the non-Fermi liquid scalings, such as linear resistivity, observed in strange metal regimes. As part of our investigation we outline three distinct string theory realizations of Lifshitz geometries: from F theory, from polarised branes, and from a gravitating charged Fermi gas. We also identify general features of renormalisation group flow in Lifshitz theories, such as the appearance of relevant charge-charge interactions when $z \geq 2$. We outline a program to extend this model building approach to other anomalous observables of interest such as the Hall conductivity.Comment: 71 pages, 8 figure

Cognitive function is associated with risk aversion in community-based older persons

<p>Abstract</p> <p>Background</p> <p>Emerging data from younger and middle-aged persons suggest that cognitive ability is negatively associated with risk aversion, but this association has not been studied among older persons who are at high risk of experiencing loss of cognitive function.</p> <p>Methods</p> <p>Using data from 369 community-dwelling older persons without dementia from the Rush Memory and Aging Project, an ongoing longitudinal epidemiologic study of aging, we examined the correlates of risk aversion and tested the hypothesis that cognition is negatively associated with risk aversion. Global cognition and five specific cognitive abilities were measured via detailed cognitive testing, and risk aversion was measured using standard behavioral economics questions in which participants were asked to choose between a certain monetary payment ($15) versus a gamble in which they could gain more than$15 or gain nothing; potential gamble gains ranged from $21.79 to$151.19 with the gain amounts varied randomly over questions. We first examined the bivariate associations of age, education, sex, income and cognition with risk aversion. Next, we examined the associations between cognition and risk aversion via mixed models adjusted for age, sex, education, and income. Finally, we conducted sensitivity analyses to ensure that our results were not driven by persons with preclinical cognitive impairment.</p> <p>Results</p> <p>In bivariate analyses, sex, education, income and global cognition were associated with risk aversion. However, in a mixed effect model, only sex (estimate = -1.49, standard error (SE) = 0.39, p < 0.001) and global cognitive function (estimate = -1.05, standard error (SE) = 0.34, p < 0.003) were significantly inversely associated with risk aversion. Thus, a lower level of global cognitive function and female sex were associated with greater risk aversion. Moreover, performance on four out of the five cognitive domains was negatively related to risk aversion (<it>i.e</it>., semantic memory, episodic memory, working memory, and perceptual speed); performance on visuospatial abilities was not.</p> <p>Conclusion</p> <p>A lower level of cognitive ability and female sex are associated with greater risk aversion in advanced age.</p

Meta-analysis of four new genome scans for lipid parameters and analysis of positional candidates in positive linkage regions

Lipid levels in plasma strongly influence the risk for coronary heart disease. To localise and subsequently identify genes affecting lipid levels, we performed four genome-wide linkage scans followed by combined linkage/association analysis. Genome-scans were performed in 701 dizygotic twin pairs from four samples with data on plasma levels of HDL- and LDL-cholesterol and their major protein constituents, apolipoprotein AI (ApoAI) and Apolipoprotein B (ApoB). To maximise power, the genome scans were analysed simultaneously using a well-established meta-analysis method that was newly applied to linkage analysis. Overall LOD scores were estimated using the means of the sample-specific quantitative trait locus (QTL) effects inversely weighted by the standard errors obtained using an inverse regression method. Possible heterogeneity was accounted for with a random effects model. Suggestive linkage for HDL-C was observed on 8p23.1 and 12q21.2 and for ApoAI on 1q21.3. For LDL-C and ApoB, linkage regions frequently coincided (2p24.1, 2q32.1, 19p13.2 and 19q13.31). Six of the putative QTLs replicated previous findings. After fine mapping, three maximum LOD scores mapped within 1cM of major candidate genes, namely APOB (LOD =2.1), LDLR (LOD =1.9) and APOE (LOD =1.7). APOB haplotypes explained 27% of the QTL effect observed for LDL-C on 2p24.1 and reduced the LOD-score by 0.82. Accounting for the effect of the LDLR and APOE haplotypes did not change the LOD score close to the LDLR gene but abolished the linkage signal at the APOE gene. In conclusion, application of a new meta-analysis approach maximised the power to detect QTLs for lipid levels and improved the precision of their location estimate. © 2005 Nature Publishing Group. All rights reserved