Predictive modelling of thermo-active tunnels in London Clay

Thermo-active structures are underground facilities which enable the exchange of thermal energy between the ground and the overlying buildings, thus providing renewable means of space heating and cooling. Although this technology is becoming increasingly popular, the behaviour of geotechnical structures under additional thermal loading is still not fully understood. This paper focuses on the use of underground tunnels as thermo-active structures and explains their behaviour through a series of finite element analyses based on an existing case study of isothermal tunnels in London Clay. The bespoke finite element codeI CFEP is adopted which is capable of simulating the fully coupled thermo-hydro-mechanical behaviour of porous materials. The complex coupled interactions between the tunnel and the surrounding soil are explored bycomparing results from selected types of coupledand uncoupled simulations. It is demonstratedthat: (1) the thermally-induceddeformation of the tunnel and the ground are more critical design aspects than the thermally-induced forces in the tunnel lining, and (2) the modelling approach in terms of the type of analysis, as well as the assumed permeability of the tunnel lining, have a significant effect on the computed tunnel response and,hence, must be chosen carefull

Finite element modelling of heat transfer in ground source energy systems with heat exchanger pipes

Ground source energy systems (GSES) utilise low enthalpy geothermal energy and have been recognised as an efficient means of providing low carbon space heating and cooling. This study focuses on GSES where the exchange of heat between the ground and the building is achieved by circulating a fluid through heat exchanger pipes. Although numerical analysis is a powerful tool for exploring the performance of such systems, simulating the highly advective flows inside the heat exchanger pipes can be problematic. This paper presents an efficient approach for modelling these systems using the finite element method (FEM). The pipes are discretised with line elements and the conductive-advective heat flux along them is solved using the Petrov-Galerkin FEM instead of the conventional Galerkin FEM. Following extensive numerical studies, a modelling approach for simulating heat exchanger pipes, which employs line elements and a special material with enhanced thermal properties, is developed. The modelling approach is then adopted in three-dimensional simulations of two thermal response tests, with an excellent match between the computed and measured temperatures being obtained

R-Ras Regulates Migration through an Interaction with Filamin A in Melanoma Cells

Changes in cell adhesion and migration in the tumor microenvironment are key in the initiation and progression of metastasis. R-Ras is one of several small GTPases that regulate cell adhesion and migration on the extracellular matrix, however the mechanism has not been completely elucidated. Using a yeast two-hybrid approach we sought to identify novel R-Ras binding proteins that might mediate its effects on integrins.We identified Filamin A (FLNa) as a candidate interacting protein. FLNa is an actin-binding scaffold protein that also binds to integrin β1, β2 and β7 tails and is associated with diverse cell processes including cell migration. Indeed, M2 melanoma cells require FLNa for motility. We further show that R-Ras and FLNa interact in co-immunoprecipitations and pull-down assays. Deletion of FLNa repeat 3 (FLNaΔ3) abrogated this interaction. In M2 melanoma cells active R-Ras co-localized with FLNa but did not co-localize with FLNa lacking repeat 3. Thus, activated R-Ras binds repeat 3 of FLNa. The functional consequence of this interaction was that active R-Ras and FLNa coordinately increased cell migration. In contrast, co-expression of R-Ras and FLNaΔ3 had a significantly reduced effect on migration. While there was enhancement of integrin activation and fibronectin matrix assembly, cell adhesion was not altered. Finally, siRNA knockdown of endogenous R-Ras impaired FLNa-dependent fibronectin matrix assembly.These data support a model in which R-Ras functionally associates with FLNa and thereby regulates integrin-dependent migration. Thus in melanoma cells R-Ras and FLNa may cooperatively promote metastasis by enhancing cell migration

Gene Expression Profiles of the NCI-60 Human Tumor Cell Lines Define Molecular Interaction Networks Governing Cell Migration Processes

Although there is extensive information on gene expression and molecular interactions in various cell types, integrating those data in a functionally coherent manner remains challenging. This study explores the premise that genes whose expression at the mRNA level is correlated over diverse cell lines are likely to function together in a network of molecular interactions. We previously derived expression-correlated gene clusters from the database of the NCI-60 human tumor cell lines and associated each cluster with function categories of the Gene Ontology (GO) database. From a cluster rich in genes associated with GO categories related to cell migration, we extracted 15 genes that were highly cross-correlated; prominent among them were RRAS, AXL, ADAM9, FN14, and integrin-beta1. We then used those 15 genes as bait to identify other correlated genes in the NCI-60 database. A survey of current literature disclosed, not only that many of the expression-correlated genes engaged in molecular interactions related to migration, invasion, and metastasis, but that highly cross-correlated subsets of those genes engaged in specific cell migration processes. We assembled this information in molecular interaction maps (MIMs) that depict networks governing 3 cell migration processes: degradation of extracellular matrix, production of transient focal complexes at the leading edge of the cell, and retraction of the rear part of the cell. Also depicted are interactions controlling the release and effects of calcium ions, which may regulate migration in a spaciotemporal manner in the cell. The MIMs and associated text comprise a detailed and integrated summary of what is currently known or surmised about the role of the expression cross-correlated genes in molecular networks governing those processes

A proteomic approach reveals integrin activation state-dependent control of microtubule cortical targeting

Integrin activation, which is regulated by allosteric changes in receptor conformation, enables cellular responses to the chemical, mechanical and topological features of the extracellular microenvironment. A global view of how activation state converts the molecular composition of the region proximal to integrins into functional readouts is, however, lacking. Here, using conformation-specific monoclonal antibodies, we report the isolation of integrin activation state-dependent complexes and their characterization by mass spectrometry. Quantitative comparisons, integrating network, clustering, pathway and image analyses, define multiple functional protein modules enriched in a conformation-specific manner. Notably, active integrin complexes are specifically enriched for proteins associated with microtubule-based functions. Visualization of microtubules on micropatterned surfaces and live cell imaging demonstrate that active integrins establish an environment that stabilizes microtubules at the cell periphery. These data provide a resource for the interrogation of the global molecular connections that link integrin activation to adhesion signalling

The role of the p90 ribosomal S6 kinase family in prostate cancer progression and therapy resistance.

Prostate cancer (PCa) is the second most commonly occurring cancer in men, with over a million new cases every year worldwide. Tumor growth and disease progression is mainly dependent on the Androgen Receptor (AR), a ligand dependent transcription factor. Standard PCa therapeutic treatments include androgen-deprivation therapy and AR signaling inhibitors. Despite being successful in controlling the disease in the majority of men, the high frequency of disease progression to aggressive and therapy resistant stages (termed castrate resistant prostate cancer) has led to the search for new therapeutic targets. The p90 ribosomal S6 kinase (RSK1-4) family is a group of highly conserved Ser/Thr kinases that holds promise as a novel target. RSKs are effector kinases that lay downstream of the Ras/Raf/MEK/ERK signaling pathway, and aberrant activation or expression of RSKs has been reported in several malignancies, including PCa. Despite their structural similarities, RSK isoforms have been shown to perform nonredundant functions and target a wide range of substrates involved in regulation of transcription and translation. In this article we review the roles of the RSKs in proliferation and motility, cell cycle control and therapy resistance in PCa, highlighting the possible interplay between RSKs and AR in mediating disease progression. In addition, we summarize the current advances in RSK inhibitor development and discuss their potential clinical benefits

Numerical modelling of time-dependent thermally induced excess pore fluid pressures in a saturated soil

A temperature rise in soils is usually accompanied by an increase in excess pore fluid pressure due to the differential thermal expansion coefficients of the pore fluid and the soil particles. To model the transient behaviour of this thermally induced excess pore fluid pressure in geotechnical problems, a coupled THM formulation was employed in this study, which accounts for the non-linear temperature-dependent behaviour of both the soil permeability and the thermal expansion coefficient of the pore fluid. Numerical analyses of validation exercises (where there is an analytical solution), as well as of existing triaxial and centrifuge heating tests on Kaolin clay, were carried out in the current paper. The obtained numerical results exhibited good agreement with the analytical solution and experimental measurements respectively, demonstrating good capabilities of the applied numerical facilities and providing insight into the mechanism behind the observed evolution of the thermally induced pore fluid pressure. The numerical results further highlighted the importance of accounting for the temperature-dependent nature of the soil permeability and the thermal expansion coefficient of the pore fluid, commonly ignored in geotechnical numerical analysis

A coupled thermo-hydro-mechanical finite element formulation for curved beams in two-dimensions

To enable the use of beam elements in the modelling of coupled thermo-hydro-mechanical (THM) geotechnical problems, a fully coupled and robust THM formulation is required. This paper presents such a formulation which allows both fluid flow and heat transfer along a 2D curved beam, while ensuring compatibility with coupled THM solid elements commonly used to discretise soils. Verification exercises and application with the proposed coupled beam element are carried out to demonstrate its satisfactory behaviour. The results of these analyses are compared against closed form solutions, solutions obtained using solid elements, and field measurements, showing an excellent agreement