Mechanisms of force-mediated regulation of transcription, chromatin remodeling and cell fate decisions

Tissue mechanics and cellular interactions influence every single cell in our bodies to drive morphogenesis. However, little is known about mechanisms by which cells sense physical forces and transduce them from the cytoskeleton to the nucleus to control gene expression and stem cell fate. We have identified a novel nuclear-mechanosensor complex, consisting of the nuclear membrane protein emerin (Emd), actin and non-muscle myosin IIA (NMIIA), that regulates transcription, chromatin remodeling and lineage commitment. Force-induced enrichment of Emd at the outer nuclear membrane leads to a compensation between H3K9me2,3 and H3K27me3 on constitutive heterochromatin. This strain-induced epigenetic switch is accompanied by the global rearrangement of chromatin. In parallel, forces promote local F-actin polymerization at the outer nuclear membrane, which limits the availability of nuclear G-actin. Subsequently, the reduction of nuclear G-actin results in attenuated global transcription and therefore increased H3K27me3 occupancy to reinforce gene silencing. Restoring nuclear actin levels in the presence of mechanical strain counteracts PRC2-mediated silencing of transcribed genes. This mechanosensory circuit is also observed in vivo. Depletion of NMIIA in mouse epidermis leads to decreased H3K27me3 levels and precocious lineage commitment, thus abrogating organ growth and patterning. Our results reveal how mechanical signals regulate nuclear architecture, chromatin organization and transcription to control cell fate decisions.

On the fundamental mechanisms of active screen plasma nitriding

The nitriding mechanisms of conventional DC plasma treatments have been extensively studied and discussed, but no general agreement has been reached thus far. The sputtering and redeposition theory is among the most accepted ones but, even though this mechanism is feasible, its contribution to the nitriding effect is under question. Furthermore, the novel active screen plasma nitriding technique has been successful in treating samples left at floating potential, where sputtering can not be considered to play a major role. Therefore, it has been proposed that the material sputtered from the cathodic mesh of the active screen furnace (auxiliary cathode) and deposited onto the treated specimens is involved in the mass transfer of nitrogen. The contribution made by this transferred material is the focus of attention of the present study. The hardening effect on the treated specimens showed considerable correlation with the deposition layer, and the XRD analysis of this deposited material yielded possible FeN and FexN peaks. This finding supports the deposition of iron nitrides and their subsequent decomposition on the treated substrate as a mechanism of significance to the plasma nitriding treatments conducted in active screen experimental settings.

Coaching or gaming? Implications of strategy choice for home based stroke rehabilitation

Background: The enduring aging of the world population and prospective increase of age-related chronic diseases urge the implementation of new models for healthcare delivery. One strategy relies on ICT (Information and Communications Technology) home-based solutions allowing clients to pursue their treatments without institutionalization. Stroke survivors are a particular population that could strongly benefit from such solutions, but is not yet clear what the best approach is for bringing forth an adequate and sustainable usage of home-based rehabilitation systems. Here we explore two possible approaches: coaching and gaming. Methods: We performed trials with 20 healthy participants and 5 chronic stroke survivors to study and compare execution of an elbow flexion and extension task when performed within a coaching mode that provides encouragement or within a gaming mode. For each mode we analyzed compliance, arm movement kinematics and task scores. In addition, we assessed the usability and acceptance of the proposed modes through a customized self-report questionnaire. Results: In the healthy participants sample, 13/20 preferred the gaming mode and rated it as being significantly more fun (p < .05), but the feedback delivered by the coaching mode was subjectively perceived as being more useful (p < .01). In addition, the activity level (number of repetitions and total movement of the end effector) was significantly higher (p <.001) during coaching. However, the quality of movements was superior in gaming with a trend towards shorter movement duration (p=.074), significantly shorter travel distance (p <.001), higher movement efficiency (p <.001) and higher performance scores (p <.001). Stroke survivors also showed a trend towards higher activity levels in coaching, but with more movement quality during gaming. Finally, both training modes showed overall high acceptance. Conclusions: Gaming led to higher enjoyment and increased quality in movement execution in healthy participants. However, we observed that game mechanics strongly determined user behavior and limited activity levels. In contrast, coaching generated higher activity levels. Hence, the purpose of treatment and profile of end-users has to be considered when deciding on the most adequate approach for home based stroke rehabilitation.

Leveraging R&D Investment for the Australian Built Environment : Industry Report

The overarching goal of this project is to better match funding strategies to industry needs to maximise the benefits of R&D to Australia’s infrastructure and building industry. Project partners are: Queensland Department of Public Works; Queensland Transport and Main Roads; Western Australian Department of Treasury and Finance; John Holland; Queensland University of Technology; Swinburne University of Technology; and VTT Technical Research Centre of Finland (Prof Göran Roos). This project has been endorsed by the Australian Built Environment Industry Innovation Council (BEIIC) with Council member Prof Catherin Bull serving on this project’s Steering Committee. This project seeks to: (i) maximise the value of R&D investment in this sector through improved understanding of future industry research needs; and (ii) address the perceived problem of a disproportionately low R&D investment in this sector, relative to the size and national importance of the sector. This research will develop new theory built on open innovation, dynamic capabilities and absorptive capacity theories in the context of strategic foresighting and roadmapping activities. Four project phases have been designed to address this research: 1: Audit and analysis of R&D investment in the Australian built environment since 1990 - access publically available data relating to R&D investments across Australia from public and private organisations to understand past trends. 2: Examine diffusion mechanisms of research and innovation and its impact on public and private organisations – investigate specific R&D investments to determine the process of realising research support, direction-setting, project engagement, impacts and pathways to adoption. 3: Develop a strategic roadmap for the future of this critical Australian industry - assess the likely future landscapes that R&D investment will both respond to and anticipate. 4: Develop policy to maximise the value of R&D investments to public and private organisations – through translating project learnings into policy guidelines.

Toward an effective strategy in glioblastoma treatment. Part I: resistance mechanisms and strategies to overcome resistance of glioblastoma to temozolomide.

International audience

Mathematical modelling of controlled drug release from polymer micro-spheres : incorporating the effects of swelling, diffusion and dissolution via moving boundary problems

Controlled drug delivery is a key topic in modern pharmacotherapy, where controlled drug delivery devices are required to prolong the period of release, maintain a constant release rate, or release the drug with a predetermined release profile. In the pharmaceutical industry, the development process of a controlled drug delivery device may be facilitated enormously by the mathematical modelling of drug release mechanisms, directly decreasing the number of necessary experiments. Such mathematical modelling is difficult because several mechanisms are involved during the drug release process. The main drug release mechanisms of a controlled release device are based on the device’s physiochemical properties, and include diffusion, swelling and erosion. In this thesis, four controlled drug delivery models are investigated. These four models selectively involve the solvent penetration into the polymeric device, the swelling of the polymer, the polymer erosion and the drug diffusion out of the device but all share two common key features. The first is that the solvent penetration into the polymer causes the transition of the polymer from a glassy state into a rubbery state. The interface between the two states of the polymer is modelled as a moving boundary and the speed of this interface is governed by a kinetic law. The second feature is that drug diffusion only happens in the rubbery region of the polymer, with a nonlinear diffusion coefficient which is dependent on the concentration of solvent. These models are analysed by using both formal asymptotics and numerical computation, where front-fixing methods and the method of lines with finite difference approximations are used to solve these models numerically. This numerical scheme is conservative, accurate and easily implemented to the moving boundary problems and is thoroughly explained in Section 3.2. From the small time asymptotic analysis in Sections 5.3.1, 6.3.1 and 7.2.1, these models exhibit the non-Fickian behaviour referred to as Case II diffusion, and an initial constant rate of drug release which is appealing to the pharmaceutical industry because this indicates zeroorder release. The numerical results of the models qualitatively confirms the experimental behaviour identified in the literature. The knowledge obtained from investigating these models can help to develop more complex multi-layered drug delivery devices in order to achieve sophisticated drug release profiles. A multi-layer matrix tablet, which consists of a number of polymer layers designed to provide sustainable and constant drug release or bimodal drug release, is also discussed in this research. The moving boundary problem describing the solvent penetration into the polymer also arises in melting and freezing problems which have been modelled as the classical onephase Stefan problem. The classical one-phase Stefan problem has unrealistic singularities existed in the problem at the complete melting time. Hence we investigate the effect of including the kinetic undercooling to the melting problem and this problem is called the one-phase Stefan problem with kinetic undercooling. Interestingly we discover the unrealistic singularities existed in the classical one-phase Stefan problem at the complete melting time are regularised and also find out the small time behaviour of the one-phase Stefan problem with kinetic undercooling is different to the classical one-phase Stefan problem from the small time asymptotic analysis in Section 3.3. In the case of melting very small particles, it is known that surface tension effects are important. The effect of including the surface tension to the melting problem for nanoparticles (no kinetic undercooling) has been investigated in the past, however the one-phase Stefan problem with surface tension exhibits finite-time blow-up. Therefore we investigate the effect of including both the surface tension and kinetic undercooling to the melting problem for nanoparticles and find out the the solution continues to exist until complete melting. The investigation of including kinetic undercooling and surface tension to the melting problems reveals more insight into the regularisations of unphysical singularities in the classical one-phase Stefan problem. This investigation gives a better understanding of melting a particle, and contributes to the current body of knowledge related to melting and freezing due to heat conduction.

Influence of drying conditions on the moisture diffusion and fluidization quality during multi-stage fluidized bed drying of bovine intestine for pet food

In order to establish the influence of the drying air characteristics on the drying performance and fluidization quality of bovine intestine for pet food, several drying tests have been carried out in a laboratory scale heat pump assisted fluid bed dryer. Bovine intestine samples were heat pump fluidized bed dried at atmospheric pressure and at temperatures below and above the materials freezing points, equipped with a continuous monitoring system. The investigation of the drying characteristics have been conducted in the temperature range −10 to 25 ◦C and the airflow in the range 1.5–2.5 m/s. Some experiments were conducted as single temperature drying experiments and others as two stage drying experiments employing two temperatures. An Arrhenius-type equation was used to interpret the influence of the drying air temperature on the effective diffusivity, calculated with the method of slopes in terms of energy activation, and this was found to be sensitive to the temperature. The effective diffusion coefficient of moisture transfer was determined by the Fickian method using uni-dimensional moisture movement in both moisture, removal by evaporation and combined sublimation and evaporation. Correlations expressing the effective moisture diffusivity and drying temperature are reported. Bovine particles were characterized according to the Geldart classification and the minimum fluidization velocity was calculated using the Ergun Equation and generalized equation for all drying conditions at the beginning and end of the trials. Walli’s model was used to categorize stability of the fluidization at the beginning and end of the dryingv for each trial. The determined Walli’s values were positive at the beginning and end of all trials indicating stable fluidization at the beginning and end for each drying condition.

Development of insula connectivity between ages 12 and 30 revealed by high angular resolution diffusion imaging

The insula, hidden deep within the Sylvian fissures, has proven difficult to study from a connectivity perspective. Most of our current information on the anatomical connectivity of the insula comes from studies of nonhuman primates and post mortem human dissections. To date, only two neuroimaging studies have successfully examined the connectivity of the insula. Here we examine how the connectivity of the insula develops between ages 12 and 30, in 307 young adolescent and adult subjects scanned with 4-Tesla high angular resolution diffusion imaging (HARDI). The density of fiber connections between the insula and the frontal and parietal cortex decreased with age, but the connection density between the insula and the temporal cortex generally increased with age. This trajectory is in line with well-known patterns of cortical development in these regions. In addition, males and females showed different developmental trajectories for the connection between the left insula and the left precentral gyrus. The insula plays many different roles, some of them affected in neuropsychiatric disorders; this information on the insula's connectivity may help efforts to elucidate mechanisms of brain disorders in which it is implicated.

Grazing impacts on the susceptibility of rangelands to wind erosion: The effects of stocking rate, stocking strategy and land condition

An estimated 110 Mt of dust is eroded by wind from the Australian land surface each year, most of which originates from the arid and semi-arid rangelands. Livestock production is thought to increase the susceptibility of the rangelands to wind erosion by reducing vegetation cover and modifying surface soil stability. However, research is yet to quantify the impacts of grazing land management on the erodibility of the Australian rangelands, or determine how these impacts vary among land types and over time. We present a simulation analysis that links a pasture growth and animal production model (GRASP) to the Australian Land Erodibility Model (AUSLEM) to evaluate the impacts of stocking rate, stocking strategy and land condition on the erodibility of four land types in western Queensland, Australia. Our results show that declining land condition, over stocking, and using inflexible stocking strategies have potential to increase land erodibility and amplify accelerated soil erosion. However, land erodibility responses to grazing are complex and influenced by land type sensitivities to different grazing strategies and local climate characteristics. Our simulations show that land types which are more resilient to livestock grazing tend to be least susceptible to accelerated wind erosion. Increases in land erodibility are found to occur most often during climatic transitions when vegetation cover is most sensitive to grazing pressure. However, grazing effects are limited during extreme wet and dry periods when the influence of climate on vegetation cover is strongest. Our research provides the opportunity to estimate the effects of different land management practices across a range of land types, and provides a better understanding of the mechanisms of accelerated erosion resulting from pastoral activities. The approach could help further assessment of land erodibility at a broader scale notably if combined with wind erosion models.

Diffusion of sorbates in zeolites Y and A novel dependence on sorbate size and strength of sor ba t e-Zeoli t e interaction

A systematic investigation of monatomic spherical sorbates in the supercages of zeolites Y and A by molecular dynamics technique is presented. Rates of intercage diffusion, rates of cage visits, and the diffusion coefficients have been calculated as a function of the sorbate-zeolite interaction strength. These properties exhibit markedly different dependences on interaction strength for the two zeolites. The observed behavior is shown to be a consequence of the two principal mechanisms of intercage diffusion and the energetic barrier associated with them. The diffusion coefficient and other properties associated with intercage diffusion are found to be directly proportional to the reciprocal of the square of the sorbate diameter when the sorbate diameter is significantly smaller than the window diameter. As the sorbate diameter increases, a peak is observed in all the transport properties investigated including the diffusion coefficient. We call this surprising effect as the ring or levitation effect and it explains several anomalous results reported in the literature and suggests a breakdown of the geometrical criterion for diffusion of sorbates. It shows that under certain conditions nongeometrical factors play a major role and geometrical factors become secondary in the determination of the molecular sieve property. A generalized parameter has been proposed which suggests conditions under which one can expect the ring or levitation effect in any porous medium. Inverse size selectivity becomes operative under these conditions.

Dislocation mechanisms for plastic flow of nickel in the temperature range 4.2 – 1200 K

The temperature ranges of thermal and athermal deformation behaviour of nickel are identified by employing the temperature-dependence of flow-stress and strain-rate cycling data. The results are used to present a unified view of dislocation mechanisms of glide encompassing the two thermally activated and the intermediate athermal regimes of plastic flow.In the low-temperature thermally activated region (<250 K) the strain rate is found to be controlled by the repulsive intersection of glide and forest dislocations, in accordance with current ideas. The athermal stress in this region can be attributed mainly to the presence of strong attractive junctions which are overcome by means of Orowan bowing, a small contribution also coming from the elastic interactions between dislocations. The values of activation area and activation energy obtained in the high-temperature region (> 750 K) negate the operation of a diffusion-controlled mechanism. Instead, the data support a thermal activation model involving unzipping of the attractive junctions. The internal (long-range) stress contribution here results solely from the elastic interactions between dislocations. This view concerning the high-temperature plastic flow is further supported by the observation that the Cottrell–Stokes law is obeyed over large strains in the range 750–1200 K.

Diffusion of components via different modes during growth of the A15-V(3)Gaphase

Based on an interdiffusion study using an incremental diffusion couple in the V-Ga binary system, we have shown that V diffuses via the lattice, whereas Ga does so via grain boundaries, for the growth of the V3Ga phase. We estimate the contributions from the two different mechanisms, which are usually difficult to delineate in an interdiffusion study. Available tracer diffusion studies and the atomic arrangement in the crystal structure have been considered for a discussion on the diffusion mechanisms.

Evaluation and modeling of lanthanum diffusion in TiN/La 2O 3/HfSiON/SiO 2/Si high-k stacks

In this study, TiN/La 2O 3/HfSiON/SiO 2/Si gate stacks with thick high-k (HK) and thick pedestal oxide were used. Samples were annealed at different temperatures and times in order to characterize in detail the interaction mechanisms between La and the gate stack layers. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) measurements performed on these samples show a time diffusion saturation of La in the high-k insulator, indicating an La front immobilization due to LaSiO formation at the high-k/interfacial layer. Based on the SIMS data, a technology computer aided design (TCAD) diffusion model including La time diffusion saturation effect was developed. © 2012 American Institute of Physics.

History, an Exit Strategy: The Retrofuture Fabulations of kara lynch

A cartographer constructs a map of an individual creative history, that of the American artist kara lynch, as it emerges in connection to a collective history of African American cultural expression. Positioning history as complex, dynamic systems of interwoven memory networks, the map follows lynch’s traversals through various “zones of cultural haunting”: places where collective memories made invisible through systematic processes of cultural erasure may be recovered and revived. Through these traversals, which are inspired by lynch’s “forever project” Invisible, the map covers such terrains as haunted narratives, mechanisms of abstraction and coding within African American media production, water as an informational technology, the distribution of memory in blood, the dialectics of materiality and immateriality that frame considerations of black subjectivity, and the possibility that place of music might not be the site of sound but instead the social production of memory.

The Diffusion of Risks in Public Private Partnership Contracts

Purpose The UK government argues that the benefits of public private partnership (PPP) in delivering public infrastructure stem from: transferring risks to the private sector within a structure in which financiers put their own capital at risk; and, the performance based payment mechanism, reinforced by the due diligence requirements imposed by the lenders financing the projects (HM Treasury, 2010). Prior studies of risk in PPPs have investigated ‘what’ risks are allocated and to ‘whom’, that is to the public or the private sector. The purpose of this study is to examine ‘how’ and ‘why’ PPP risks are diffused by their financiers. Design/methodology/approach This study focuses on the financial structure of PPPs and on their financiers. Empirical evidence comes from interviews conducted with equity and debt financiers. Findings The findings show that the financial structure of the deals generates risk aversion in both debt and equity financiers and that the need to attract affordable finance leads to risk diffusion through a network of companies using various means that include contractual mitigation through insurance, performance support guarantees, interest rate swaps and inflation hedges. Because of the complexity this process generates, both procurers and suppliers need expensive expert advice. The risk aversion and diffusion and the consequent need for advice add cost to the projects impacting on the government’s economic argument for risk transfer. Limitations and implications The empirical work covers the private finance initiative (PFI) type of PPP arrangements and therefore the risk diffusion mechanisms may not be generalisable to other forms of PPP, especially those that do not involve the use of high leverage or private finance. Moreover, the scope of this research is limited to exploring the diffusion of risk in the private sector. Further research is needed on how risk is diffused in other settings and on the value for money implication of risk diffusion in PPP contracts. Originality/value The expectation inherent in PPP is that the private sector will better manage those risks allocated to it and because private capital is at risk, financiers will perform due diligence with the ultimate outcome that only viable projects will proceed. This paper presents empirical evidence that raises questions about these expectations. Key words: public private partnership, risk management, diffusion, private finance initiative, financiers