A morpho-molecular prognostic model for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the third common cause of cancer-related deaths and its prognostication is still suboptimal. The aim of this study was to establish a new prognostication algorithm for HCC.

Inverse Gaussian Modeling of Turbulence-Induced Fading in Free-Space Optical Systems

We propose the inverse Gaussian distribution, as a less complex alternative to the classical log-normal model, to describe turbulence-induced fading in free-space optical (FSO) systems operating in weak turbulence conditions and/or in the presence of aperture averaging effects. By conducting goodness of fit tests, we define the range of values of the scintillation index for various multiple-input multiple-output (MIMO) FSO configurations, where the two distributions approximate each other with a certain significance level. Furthermore, the bit error rate performance of two typical MIMO FSO systems is investigated over the new turbulence model; an intensity-modulation/direct detection MIMO FSO system with Q-ary pulse position modulation that employs repetition coding at the transmitter and equal gain combining at the receiver, and a heterodyne MIMO FSO system with differential phase-shift keying and maximal ratio combining at the receiver. Finally, numerical results are presented that validate the theoretical analysis and provide useful insights into the implications of the model parameters on the overall system performance. © 2011 IEEE.

Killer immunoglobulin-like Receptors (KIR) haplogroups A and B track with Natural Killer Cells and Cytokine Profile in Aged Subjects: Observations from Octo/Nonagenarians in the Belfast Elderly Longitudinal Free-living Aging STudy (BELFAST)

Background: Natural Killer Cells (NK) play an important role in detection and elimination of virus-infected, damaged or cancer cells. NK cell function is guided by expression of Killer Immunoglobulin-like Receptors (KIRs) and contributed to by the cytokine milieu. KIR molecules are grouped on NK cells into stimulatory and inhibitory KIR haplotypes A and B, through which NKs sense and tolerate HLA self-antigens or up-regulate the NK-cytotoxic response to cells with altered HLA self-antigens, damaged by viruses or tumours. We have previously described increased numbers of NK and NK-related subsets in association with sIL-2R cytokine serum levels in BELFAST octo/nonagenarians. We hypothesised that changes in KIR A and B haplotype gene frequencies could explain the increased cytokine profiles and NK compartments previously described in Belfast Elderly Longitudinal Free-living Aging STudy (BELFAST) octo/nonagenarians, who show evidence of ageing well.

Results: In the BELFAST study, 24% of octo/nonagenarians carried the KIR A haplotype and 76% KIR B haplotype with no differences for KIR A haplogroup frequency between male or female subjects (23% v 24%; p=0.88) or for KIR B haplogroup (77% v 76%; p=0.99). Octo/nonagenarian KIR A haplotype carriers showed increased NK numbers and percentage compared to Group B KIR subjects (p=0.003; p=0.016 respectively). There were no KIR A/ B haplogroup-associated changes for related CD57+CD8 (high or low) subsets. Using logistic regression, KIR B carriers were predicted to have higher IL-12 cytokine levels compared to KIR A carriers by about 3% (OR 1.03, confidence limits CI 0.99–1.09; p=0.027) and 14% higher levels for TGF-ß (active), a cytokine with an anti-inflammatory role, (OR 1.14, confidence limits CI 0.99–1.09; p=0.002).

Conclusion: In this observational study, BELFAST octo/nonagenarians carrying KIR A haplotype showed higher NK cell numbers and percentage compared to KIR B carriers. Conversely, KIR B haplotype carriers, with genes encoding for activating KIRs, showed a tendency for higher serum pro-inflammatory cytokines compared to KIR A carriers. While the findings in this study should be considered exploratory they may serve to stimulate debate about the immune signatures of those who appear to age slowly and who represent a model for good quality survivor-hood.© 2013 Rea et al.; licensee BioMed Central Ltd.

Three different types of quasi-model networks: synthesis by group transfer polymerization and characterization

Group transfer polymerization (GTP) chemistry was employed for the preparation of polymethacrylate networks of controlled structure (quasi-model networks) of three different types: (a) regular quasi-model networks, in which all polymer chains were linked at their ends, leaving, in principle, no free chain ends, (b) crosslinked star polymer quasi-model networks, in which star polymers were interlinked via half of their chains, letting the other half free (dangling), and (c) shell-crosslinked polymer quasi-model networks, in which the outer part of the network contained polymer arms (dangling chains). Combination of hydrophilic and hydrophobic monomers led to amphiphilic networks whose aqueous swelling behavior was characterized gravimetrically.

Slip distribution model along the anchorage length of prestressing strands

An analytical model to predict strand slips within both transmission and anchorage lengths in pretensioned prestressed concrete members is presented. This model has been derived from an experimental research work by analysing the bond behavior and determining the transmission and anchorage lengths of seven-wire prestressing steel strands in different concrete mixes. A testing technique based on measuring the prestressing strand force in specimens with different embedment lengths has been used. The testing technique allows measurement of free end slip as well as indirect determination of the strand slip at different cross sections of a member without interfering with bond phenomena. The experimental results and the proposed model for strand slip distribution have been compared with theoretical predictions according to different equations in the literature and with experimental results obtained by other researchers. © 2013 Elsevier Ltd.

A feasibility study testing four hypotheses with phase II outcomes in advanced colorectal cancer (MRC FOCUS3): a model for randomised controlled trials in the era of personalised medicine?

Background: Molecular characteristics of cancer vary between individuals. In future, most trials will require assessment of biomarkers to allocate patients into enriched populations in which targeted therapies are more likely to be effective. The MRC FOCUS3 trial is a feasibility study to assess key elements in the planning of such studies.

Patients and methods: Patients with advanced colorectal cancer were registered from 24 centres between February 2010 and April 2011. With their consent, patients' tumour samples were analysed for KRAS/BRAF oncogene mutation status and topoisomerase 1 (topo-1) immunohistochemistry. Patients were then classified into one of four molecular strata; within each strata patients were randomised to one of two hypothesis-driven experimental therapies or a common control arm (FOLFIRI chemotherapy). A 4-stage suite of patient information sheets (PISs) was developed to avoid patient overload.

Results: A total of 332 patients were registered, 244 randomised. Among randomised patients, biomarker results were provided within 10 working days (w.d.) in 71%, 15 w.d. in 91% and 20 w.d. in 99%. DNA mutation analysis was 100% concordant between two laboratories. Over 90% of participants reported excellent understanding of all aspects of the trial. In this randomised phase II setting, omission of irinotecan in the low topo-1 group was associated with increased response rate and addition of cetuximab in the KRAS, BRAF wild-type cohort was associated with longer progression-free survival.

Conclusions: Patient samples can be collected and analysed within workable time frames and with reproducible mutation results. Complex multi-arm designs are acceptable to patients with good PIS. Randomisation within each cohort provides outcome data that can inform clinical practice.

Assessment of a zoomed global model for the North Sea by comparison with a conventional nested regional model

Assessment of marine downscaling of global model simulations to the regional scale is a prerequisite for understanding ocean feedback to the atmosphere in regional climate downscaling. Major difficulties arise from the coarse grid resolution of global models, which cannot provide sufficiently accurate boundary values for the regional model. In this study, we first setup a stretched global model (MPIOM) to focus on the North Sea by shifting poles. Second, a regional model (HAMSOM) was performed with higher resolution, while the open boundary values were provided by the stretched global model. In general, the sea surface temperatures (SSTs) in the two experiments are similar. Major SST differences are found in coastal regions (root mean square difference of SST is reaching up to 2°C). The higher sea surface salinity in coastal regions in the global model indicates the general limitation of this global model and its configuration (surface layer thickness is 16 m). By comparison, the advantage of the absence of open lateral boundaries in the global model can be demonstrated, in particular for the transition region between the North Sea and Baltic Sea. On long timescales, the North Atlantic Current (NAC) inflow through the northern boundary correlates well between both model simulations (R~0.9). After downscaling with HAMSOM, the NAC inflow through the northern boundary decreases by ~10%, but the circulation in the Skagerrak is stronger in HAMSOM. The circulation patterns of both models are similar in the northern North Sea. The comparison suggests that the stretched global model system is a suitable tool for long-term free climate model simulations, and the only limitations occur in coastal regions. Regarding the regional studies focusing on the coastal zone, nested regional model can be a helpful alternative.

Determination of Non-linear Damping Coefficients of bottom-hinged Oscillating Wave Surge Converters Using Numerical Free Decay Tests

Linear wave theory models are commonly applied to predict the performance of bottom-hinged oscillating wave surge converters (OWSC) in operational sea states. To account for non-linear effects, the additional input of coefficients not included in the model itself becomes necessary. In ocean engineering it is
common practice to obtain damping coefficients of floating structures from free decay tests. This paper presents results obtained from experimental tank tests and numerical computational fluid dynamics simulations of OWSC’s. Agreement between numerical and experimental methods is found to be very good, with CFD providing more data points at small amplitude rotations.
Analysis of the obtained data reveals that linear quadratic-damping, as commonly used in time domain models, is not able to accurately model the occurring damping over the whole regime of rotation amplitudes. The authors
conclude that a hyperbolic function is most suitable to express the instantaneous damping ratio over the rotation amplitude and would be the best choice to be used in coefficient based time domain models.

Feasibility Assessment of Plug and Play Model Predictive Control for use in DC Grids

Distributed control techniques can allow Transmission System Operators (TSOs) to coordinate their responses via TSO-TSO communication, providing a level of control that lies between that of centralised control and communication free decentralised control of interconnected power systems. Recently the Plug and Play Model Predictive Control (PnPMPC) toolbox has been developed in order to allow practitioners to design distributed controllers based on tube-MPC techniques. In this paper, some initial results using the PnPMPC toolbox for the design of distributed controllers to enhance AGC in AC areas connected to Multi-Terminal HVDC (MTDC) grids, are illustrated, in order to evaluate the feasibility of applying PnPMPC for this purpose.

Free fatty acid receptors:structural models and elucidation of ligand binding interactions

BACKGROUND: The free fatty acid receptors (FFAs), including FFA1 (orphan name: GPR40), FFA2 (GPR43) and FFA3 (GPR41) are G protein-coupled receptors (GPCRs) involved in energy and metabolic homeostasis. Understanding the structural basis of ligand binding at FFAs is an essential step toward designing potent and selective small molecule modulators.

RESULTS: We analyse earlier homology models of FFAs in light of the newly published FFA1 crystal structure co-crystallized with TAK-875, an ago-allosteric ligand, focusing on the architecture of the extracellular binding cavity and agonist-receptor interactions. The previous low-resolution homology models of FFAs were helpful in highlighting the location of the ligand binding site and the key residues for ligand anchoring. However, homology models were not accurate in establishing the nature of all ligand-receptor contacts and the precise ligand-binding mode. From analysis of structural models and mutagenesis, it appears that the position of helices 3, 4 and 5 is crucial in ligand docking. The FFA1-based homology models of FFA2 and FFA3 were constructed and used to compare the FFA subtypes. From docking studies we propose an alternative binding mode for orthosteric agonists at FFA1 and FFA2, involving the interhelical space between helices 4 and 5. This binding mode can explain mutagenesis results for residues at positions 4.56 and 5.42. The novel FFAs structural models highlight higher aromaticity of the FFA2 binding cavity and higher hydrophilicity of the FFA3 binding cavity. The role of the residues at the second extracellular loop used in mutagenesis is reanalysed. The third positively-charged residue in the binding cavity of FFAs, located in helix 2, is identified and predicted to coordinate allosteric modulators.

CONCLUSIONS: The novel structural models of FFAs provide information on specific modes of ligand binding at FFA subtypes and new suggestions for mutagenesis and ligand modification, guiding the development of novel orthosteric and allosteric chemical probes to validate the importance of FFAs in metabolic and inflammatory conditions. Using our FFA homology modelling experience, a strategy to model a GPCR, which is phylogenetically distant from GPCRs with the available crystal structures, is discussed.

Element-Free Galerkin Modelling of Crack Migration in Composite Laminates

The development of a virtual testing environment, as a cost-effective industrial design tool in the design and analysis of composite structures, requires the need to create models efficiently, as well as accelerate the analysis by reducing the number of degrees of freedom, while still satisfying the need for accurately tracking the evolution of a debond, delamination or crack front. The eventual aim is to simulate both damage initiation and propagation in components with realistic geometrical features, where crack propagation paths are not trivial. Meshless approaches, and the Element-Free Galerkin (EFG) method, are particularly suitable for problems involving changes in topology and have been successfully applied to simulate damage in homogeneous materials and concrete. In this work, the method is utilized to model initiation and mixed-mode propagation of cracks in composite laminates, and to simulate experimentally-observed crack migration which is difficult to model using standard finite element analysis. N

Feature recognition & tool path generation for 5 axis step-nc machining of free form / irregular contoured surfaces

This research paper presents a five step algorithm to generate tool paths for machining Free form / Irregular Contoured Surface(s) (FICS) by adopting STEP-NC (AP-238) format. In the first step, a parametrized CAD model with FICS is created or imported in UG-NX6.0 CAD package. The second step recognizes the features and calculates a Closeness Index (CI) by comparing them with the B-Splines / Bezier surfaces. The third step utilizes the CI and extracts the necessary data to formulate the blending functions for identified features. In the fourth step Z-level 5 axis tool paths are generated by adopting flat and ball end mill cutters. Finally, in the fifth step, tool paths are integrated with STEP-NC format and validated. All these steps are discussed and explained through a validated industrial component.