TCO evaluation in physical asset management : benefits and limitations for industrial adoption

Part 1: Knowledge-Based Performance ImprovementInternational audienceNowadays, the evaluation of the total cost of ownership (TCO) of an asset for supporting informed decision-making both for investments and managerial issues within the asset management framework is gaining increasing attention in industry. Nevertheless its application in practice is still limited. The aim of this paper is to analyze the benefits and limitations of the adoption of TCO evaluation in asset management. Based on a literature review, the paper defines a framework that categorizes the benefits and potential applications that a TCO model can have for different stakeholders. Together with that, industry related issues that influence its implementation are also considered. Finally, empirical evidences are analyzed through a multiple case study to understand if those benefits are recognized in practice and which are the limitations for the practical adoption of a TCO model that should allow exploiting such benefits

Contrasting levels of absorption of intense femtosecond laser pulses by solids

The absorption of ultraintense, femtosecond laser pulses by a solid unleashes relativistic electrons, thereby creating a regime of relativistic optics. This has enabled exciting applications of relativistic particle beams and coherent X-ray radiation, and fundamental leaps in high energy density science and laboratory astrophysics. Obviously, central to these possibilities lies the basic problem of understanding and if possible, manipulating laser absorption. Surprisingly, the absorption of intense light largely remains an open question, despite the extensive variations in target and laser pulse structures. Moreover, there are only few experimental measurements of laser absorption carried out under very limited parameter ranges. Here we present an extensive investigation of absorption of intense 30 femtosecond laser pulses by solid metal targets. The study, performed under varying laser intensity and contrast ratio over four orders of magnitude, reveals a significant and non-intuitive dependence on these parameters. For contrast ratio of 10-9 and intensity of 2 × 1019W cm-2, three observations are revealed: preferential acceleration of electrons along the laser axis, a ponderomotive scaling of electron temperature, and red shifting of emitted second-harmonic. These point towards the role of J × B absorption mechanism at relativistic intensity. The experimental results are supported by particle-in-cell simulations

Filamins Regulate Cell Spreading and Initiation of Cell Migration

Mammalian filamins (FLNs) are a family of three large actin-binding proteins. FLNa, the founding member of the family, was implicated in migration by cell biological analyses and the identification of FLNA mutations in the neuronal migration disorder periventricular heterotopia. However, recent knockout studies have questioned the relevance of FLNa to cell migration. Here we have used shRNA-mediated knockdown of FLNa, FLNb or FLNa and FLNb, or, alternatively, acute proteasomal degradation of all three FLNs, to generate FLN-deficient cells and assess their ability to migrate. We report that loss of FLNa or FLNb has little effect on migration but that knockdown of FLNa and FLNb, or proteolysis of all three FLNs, impairs migration. The observed defect is primarily a deficiency in initiation of motility rather than a problem with maintenance of locomotion speed. FLN-deficient cells are also impaired in spreading. Re-expression of full length FLNa, but not re-expression of a mutated FLNa lacking immunoglobulin domains 19 to 21, reverts both the spreading and the inhibition of initiation of migration

Influence of C-5 substituted cytosine and related nucleoside analogs on the formation of benzo[a]pyrene diol epoxide-dG adducts at CG base pairs of DNA

Endogenous 5-methylcytosine (MeC) residues are found at all CG dinucleotides of the p53 tumor suppressor gene, including the mutational ‘hotspots' for smoking induced lung cancer. MeC enhances the reactivity of its base paired guanine towards carcinogenic diolepoxide metabolites of polycyclic aromatic hydrocarbons (PAH) present in cigarette smoke. In the present study, the structural basis for these effects was investigated using a series of unnatural nucleoside analogs and a representative PAH diolepoxide, benzo[a]pyrene diolepoxide (BPDE). Synthetic DNA duplexes derived from a frequently mutated region of the p53 gene (5′-CCCGGCACCC GC[15N3,13C1-G]TCCGCG-3′, + strand) were prepared containing [15N3, 13C1]-guanine opposite unsubstituted cytosine, MeC, abasic site, or unnatural nucleobase analogs. Following BPDE treatment and hydrolysis of the modified DNA to 2′-deoxynucleosides, N2-BPDE-dG adducts formed at the [15N3, 13C1]-labeled guanine and elsewhere in the sequence were quantified by mass spectrometry. We found that C-5 alkylcytosines and related structural analogs specifically enhance the reactivity of the base paired guanine towards BPDE and modify the diastereomeric composition of N2-BPDE-dG adducts. Fluorescence and molecular docking studies revealed that 5-alkylcytosines and unnatural nucleobase analogs with extended aromatic systems facilitate the formation of intercalative BPDE-DNA complexes, placing BPDE in a favorable orientation for nucleophilic attack by the N2 position of guanin

Tissue Proteome of 2-Hydroxyacyl-CoA Lyase Deficient Mice Reveals Peroxisome Proliferation and Activation of ω-Oxidation

Peroxisomal fatty acid α-oxidation is an essential pathway for the degradation of β-carbon methylated fatty acids such as phytanic acid. One enzyme in this pathway is 2-hydroxyacyl CoA lyase (HACL1), which is responsible for the cleavage of 2-hydroxyphytanoyl-CoA into pristanal and formyl-CoA. Hacl1 deficient mice do not present with a severe phenotype, unlike mice deficient in other α-oxidation enzymes such as phytanoyl-CoA hydroxylase deficiency (Refsum disease) in which neuropathy and ataxia are present. Tissues from wild-type and Hacl1−/− mice fed a high phytol diet were obtained for proteomic and lipidomic analysis. There was no phenotype observed in these mice. Liver, brain, and kidney tissues underwent trypsin digestion for untargeted proteomic liquid chromatography-mass spectrometry analysis, while liver tissues also underwent fatty acid hydrolysis, extraction, and derivatisation for fatty acid gas chromatography-mass spectrometry analysis. The liver fatty acid profile demonstrated an accumulation of phytanic and 2-hydroxyphytanic acid in the Hacl1−/− liver and significant decrease in heptadecanoic acid. The liver proteome showed a significant decrease in the abundance of Hacl1 and a significant increase in the abundance of proteins involved in PPAR signalling, peroxisome proliferation, and omega oxidation, particularly Cyp4a10 and Cyp4a14. In addition, the pathway associated with arachidonic acid metabolism was affected; Cyp2c55 was upregulated and Cyp4f14 and Cyp2b9 were downregulated. The kidney proteome revealed fewer significantly upregulated peroxisomal proteins and the brain proteome was not significantly different in Hacl1−/− mice. This study demonstrates the powerful insight brought by proteomic and metabolomic profiling of Hacl1−/− mice in better understanding disease mechanism in fatty acid α-oxidation disorders

Tissue Proteome of 2-Hydroxyacyl-CoA Lyase Deficient Mice Reveals Peroxisome Proliferation and Activation of ω-Oxidation

Peroxisomal fatty acid α-oxidation is an essential pathway for the degradation of β-carbon methylated fatty acids such as phytanic acid. One enzyme in this pathway is 2-hydroxyacyl CoA lyase (HACL1), which is responsible for the cleavage of 2-hydroxyphytanoyl-CoA into pristanal and formyl-CoA. Hacl1 deficient mice do not present with a severe phenotype, unlike mice deficient in other α-oxidation enzymes such as phytanoyl-CoA hydroxylase deficiency (Refsum disease) in which neuropathy and ataxia are present. Tissues from wild-type and Hacl1−/− mice fed a high phytol diet were obtained for proteomic and lipidomic analysis. There was no phenotype observed in these mice. Liver, brain, and kidney tissues underwent trypsin digestion for untargeted proteomic liquid chromatography-mass spectrometry analysis, while liver tissues also underwent fatty acid hydrolysis, extraction, and derivatisation for fatty acid gas chromatography-mass spectrometry analysis. The liver fatty acid profile demonstrated an accumulation of phytanic and 2-hydroxyphytanic acid in the Hacl1−/− liver and significant decrease in heptadecanoic acid. The liver proteome showed a significant decrease in the abundance of Hacl1 and a significant increase in the abundance of proteins involved in PPAR signalling, peroxisome proliferation, and omega oxidation, particularly Cyp4a10 and Cyp4a14. In addition, the pathway associated with arachidonic acid metabolism was affected; Cyp2c55 was upregulated and Cyp4f14 and Cyp2b9 were downregulated. The kidney proteome revealed fewer significantly upregulated peroxisomal proteins and the brain proteome was not significantly different in Hacl1−/− mice. This study demonstrates the powerful insight brought by proteomic and metabolomic profiling of Hacl1−/− mice in better understanding disease mechanism in fatty acid α-oxidation disorders

Dynamical mean-field approach to materials with strong electronic correlations

We review recent results on the properties of materials with correlated electrons obtained within the LDA+DMFT approach, a combination of a conventional band structure approach based on the local density approximation (LDA) and the dynamical mean-field theory (DMFT). The application to four outstanding problems in this field is discussed: (i) we compute the full valence band structure of the charge-transfer insulator NiO by explicitly including the p-d hybridization, (ii) we explain the origin for the simultaneously occuring metal-insulator transition and collapse of the magnetic moment in MnO and Fe2O3, (iii) we describe a novel GGA+DMFT scheme in terms of plane-wave pseudopotentials which allows us to compute the orbital order and cooperative Jahn-Teller distortion in KCuF3 and LaMnO3, and (iv) we provide a general explanation for the appearance of kinks in the effective dispersion of correlated electrons in systems with a pronounced three-peak spectral function without having to resort to the coupling of electrons to bosonic excitations. These results provide a considerable progress in the fully microscopic investigations of correlated electron materials.Comment: 24 pages, 14 figures, final version, submitted to Eur. Phys. J. for publication in the Special Topics volume "Cooperative Phenomena in Solids: Metal-Insulator Transitions and Ordering of Microscopic Degrees of Freedom

Branch Mode Selection during Early Lung Development

Many organs of higher organisms, such as the vascular system, lung, kidney, pancreas, liver and glands, are heavily branched structures. The branching process during lung development has been studied in great detail and is remarkably stereotyped. The branched tree is generated by the sequential, non-random use of three geometrically simple modes of branching (domain branching, planar and orthogonal bifurcation). While many regulatory components and local interactions have been defined an integrated understanding of the regulatory network that controls the branching process is lacking. We have developed a deterministic, spatio-temporal differential-equation based model of the core signaling network that governs lung branching morphogenesis. The model focuses on the two key signaling factors that have been identified in experiments, fibroblast growth factor (FGF10) and sonic hedgehog (SHH) as well as the SHH receptor patched (Ptc). We show that the reported biochemical interactions give rise to a Schnakenberg-type Turing patterning mechanisms that allows us to reproduce experimental observations in wildtype and mutant mice. The kinetic parameters as well as the domain shape are based on experimental data where available. The developed model is robust to small absolute and large relative changes in the parameter values. At the same time there is a strong regulatory potential in that the switching between branching modes can be achieved by targeted changes in the parameter values. We note that the sequence of different branching events may also be the result of different growth speeds: fast growth triggers lateral branching while slow growth favours bifurcations in our model. We conclude that the FGF10-SHH-Ptc1 module is sufficient to generate pattern that correspond to the observed branching modesComment: Initially published at PLoS Comput Bio

P04.74 Preclinical evaluation of combinations targeting the DNA damage response in 2D and 3D models of glioblastoma stem cells

Background Despite surgical resection followed by DNA-damaging adjuvant therapies, glioblastoma remain incurable. Increasing evidence demonstrates that aberrations within the DNA damage response (DDR) of cancer stem cells contribute to treatment resistance. We have previously shown that the Fanconi Anaemia (FA) pathway, a key DDR process, remains inactive in normal brain but is re-activated in glioblastoma, making it an appealing foundational target for cancer-specific combination therapies. Since intratumoural heterogeneity in glioblastoma and inherent capacity for functional redundancy within DDR networks are established concepts - we aimed to determine whether combined and hypothesis-driven targeting of the FA pathway along with interconnected DDR processes could form a basis for effective multimodal therapies. Material and Methods Bioinformatic analysis of mRNA expression data (REMBRANDT database) was used to confirm the relevance of FA pathway activity in glioma. Subsequently, immunofluorescence and cell viability assays were used to validate and establish the therapeutic potential of novel FA pathway inhibitors (nFAPi) and inhibition of related DDR targets in established cell models. Finally, combinations targeting the DDR were optimised using immunoblotting, and assessed using clonogenic survival in 2D and novel 3D patient-derived glioblastoma stem cell models. Results High expression of downstream FA pathway genes is strongly associated with poor survival (-17.1% 5-year OS, n=329, Log-rank, P Conclusion Simultaneously targeting the FA pathway and interconnected DDR processes in glioblastoma represents a promising therapeutic strategy. Early mechanistic studies suggest this approach augments DNA damage and enhances IR-induced cell cycle arrest in G2/M, however further preclinical evaluation is ongoing