S100A4 downregulates filopodia formation through increased dynamic instability

Cell migration requires the initial formation of cell protrusions, lamellipodia and/or filopodia, the attachment of the leading lamella to extracellular cues and the formation and efficient recycling of focal contacts at the leading edge. The small calcium binding EF-hand protein S100A4 has been shown to promote cell motility but the direct molecular mechanisms responsible remain to be elucidated. In this work, we provide new evidences indicating that elevated levels of S100A4 affect the stability of filopodia and prevent the maturation of focal complexes. Increasing the levels of S100A4 in a rat mammary benign tumor derived cell line results in acquired cellular migration on the wound healing scratch assay. At the cellular levels, we found that high levels of S100A4 induce the formation of many nascent filopodia, but that only a very small and limited number of those can stably adhere and mature, as opposed to control cells, which generate fewer protrusions but are able to maintain these into more mature projections. This observation was paralleled by the fact that S100A4 overexpressing cells were unable to establish stable focal adhesions. Using different truncated forms of the S100A4 proteins that are unable to bind to myosin IIA, our data suggests that this newly identified functions of S100A4 is myosin-dependent, providing new understanding on the regulatory functions of S100A4 on cellular migration.

Pattern generation by dissipative parametric instability

Nonlinear instabilities are responsible for spontaneous pattern formation in a vast number of natural and engineered systems, ranging from biology to galaxy buildup. We propose a new instability mechanism leading to pattern formation in spatially extended nonlinear systems, which is based on a periodic antiphase modulation of spectrally dependent losses arranged in a zigzag way: an effective filtering is imposed at symmetrically located wave numbers k and -k in alternating order. The properties of the dissipative parametric instability differ from the features of both key classical concepts of modulation instabilities, i.e., the Benjamin-Feir instability and the Faraday instabiltyity. We demonstrate how the dissipative parametric instability can lead to the formation of stable patterns in one- and two-dimensional systems. The proposed instability mechanism is generic and can naturally occur or can be implemented in various physical systems.

Development of a post-mitotic, neuronal-astrocytic cell system, for the prediction of acute neurotoxicity in humans

The human NT2.D1 cell line was differentiated to form both a 1:2 co-culture of post-mitotic NT2 neuronal and NT2 astrocytic (NT2.N/A) cells and a pure NT2.N culture. The respective sensitivities to several test chemicals of the NT2.N/A, the NT2.N, and the NT2.D1 cells were evaluated and compared with the CCF-STTG1 astrocytoma cell line, using a combination of basal cytotoxicity and biochemical endpoints. Using the MTT assay, the basal cytotoxicity data estimated the comparative toxicities of the test chemicals (chronic neurotoxin 2,5-hexanedione, cytotoxins 2,3- and 3,4-hexanedione and acute neurotoxins tributyltin- and trimethyltin- chloride) and also provided the non-cytotoxic concentration-range for each compound. Biochemical endpoints examined over the non-cytotoxic range included assays for ATP levels, oxidative status (H2O2 and GSH levels) and caspase-3 levels as an indicator of apoptosis. although the endpoints did not demonstrate the known neurotoxicants to be consistently more toxic to the cell systems with the greatest number of neuronal properties, the NT2 astrocytes appeared to contribute positively to NT2 neuronal health following exposure to all the test chemicals. The NT2.N/A co-culture generally maintained superior ATP and GSH levels and reduced H2O2 levels in comparison with the NT2.N mono-culture. In addition, the pure NT2.N culture showed a significantly lower level of caspase-3 activation compared with the co-culture, suggesting NT2 astrocytes may be important in modulating the mode of cell death following toxic insult. Overall, these studies provide evidence that an in vitro integrated population of post-mitotic human neurons and astrocytes may offer significant relevance to the human in vivo heterogeneous nervous system, when initially screening compounds for acute neurotoxic potential.

Primary production, financial constraints and economic instability:Zambia since independence.

A systematic analysis is presented of the economic consequences of the abnormally high concentration of Zambia's exports on a commodity whose price is exceptionally unstable. Zambian macro-economic variables in the post-independence years are extensively documented, showing acute instability and decline, particularly after the energy price revolution and the collapse of copper prices. The relevance of stabilization policies designed to correct short-term disequilibrium is questioned. It is, therefore, a pathological case study of externally induced economic instability, complementing other studies in this area which use cross-country analysis of a few selected variables. After a survey of theory and issues pertaining to development, finance and stabilization, the emergence of domestic and foreign financial constraints on the Zambian economy is described. The world copper industry is surveyed and an examination of commodity and world trade prices concludes that copper showed the highest degree of price instability. Specific aspects of Zambia's economy identified for detailed analysis include: its unprofitable mining industry, external payments disequilibrium, a constrained government budget, potentially inflationary monetary growth, and external indebtedness. International comparisons are used extensively, but major copper exporters are subjected to closer scrutiny. An appraisal of policy options concludes the study.

Evaluation of DNA enzymes targeted against the RNA component of human telomerase

Glioblastoma Multiforme (GBM) is a highly malignant form of brain cancer for which there is currently no effective cure. Consequently, developing new therapies and elucidating effective targets is crucial for this fatal disease. In recent years, DNA enzymes, deoxyribonucleic acid molecules with enzymatic activity, have emerged. In the same manner as ribozymes, DNA enzymes are able to effect cleavage of RNA in a sequence-specific manner, and operate with catalytic efficiency. In this study, two DNA enzymes were designed to target the template region of human telomerase RNA (hTR), utilising the 10-23 and 8-17 catalytic motifs elucidated by Santoro and Joyce (1997). Telomerase is an RNA-dependent DNA polymerase, which stabilises telomere lengths by adding hexameric repeats (TTAGGG in humans) to chromosome termini, thus preventing the telomere shortening that usually occurs during mitotic cell division. Telomerase activity, whilst absent in normal somatic tissues, is present in almost 90% of all tumours. Thus, there is speculation that telomerase may be the much sought universal target for therapeutic intervention in cancer. In vitro cleavage assays showed both DNA enzymes to be catalytically competent. Unmodified phosphodiester (PO) backbone DNA enzymes were rapidly degraded in the presence of serum, with a half-life of 10 minutes. The common approach of introducing phosphorothioate (PS) linkages was used in an effort to overcome this instability. As a result of concurrent activity and stability studies on the DNA enzymes with various numbers of PS linkages, the DNA enzymes with a PO core and PS arms were chosen for use in further cell work. The cleavage activity of both was shown to be specific and affected by temperature, pH, MgCI2 concentration and enzyme concentration. Both DNA enzyme motifs reduced telomerase activity in cell lysates, as assessed by the telomerase repeat amplification protocol (TRAP) with an IC50 of 100nM. DNA enzymes being polyanionic molecules do not readily cross biological barriers. Cellular association of naked DNA enzyme was inefficient at less than 2%. Cellular delivery of the DNA enzymes was effectively improved using commercial cationic lipid formulations. However, the lipid-mediated delivery of DNA enzymes to U87-MG cells over a 4-hour period did not significantly inhibit cell proliferation compared to controls. This is possibly due to an expected lag period between the inhibition of telomere maintenance and cell death. Therefore, biodegradable polymer microspheres were investigated as a potential delivery option for prolonged and sustained delivery. In vitro release profiles showed that after an initial burst, sustained release of DNA enzymes was observed over 35 days. Finally, the efficacy and specificity of the DNA enzymes were demonstrated in a luciferase based reporter assay. Specific inhibition of luciferase expression was displayed at 10nM. Thus DNA enzymes have potential against endogenous cellular targets.

Lateral instability of slender reinforced concrete columns in a fire environment

The research concerns the development and application of an analytical computer program, SAFE-ROC, that models material behaviour and structural behaviour of a slender reinforced concrete column that is part of an overall structure and is subjected to elevated temperatures as a result of exposure to fire. The analysis approach used in SAFE-RCC is non-linear. Computer calculations are used that take account of restraint and continuity, and the interaction of the column with the surrounding structure during the fire. Within a given time step an iterative approach is used to find a deformed shape for the column which results in equilibrium between the forces associated with the external loads and internal stresses and degradation. Non-linear geometric effects are taken into account by updating the geometry of the structure during deformation. The structural response program SAFE-ROC includes a total strain model which takes account of the compatibility of strain due to temperature and loading. The total strain model represents a constitutive law that governs the material behaviour for concrete and steel. The material behaviour models employed for concrete and steel take account of the dimensional changes caused by the temperature differentials and changes in the material mechanical properties with changes in temperature. Non-linear stress-strain laws are used that take account of loading to a strain greater than that corresponding to the peak stress of the concrete stress-strain relation, and model the inelastic deformation associated with unloading of the steel stress-strain relation. The cross section temperatures caused by the fire environment are obtained by a preceding non-linear thermal analysis, a computer program FIRES-T.

Purchasing power parity and structural instability in the US/UK exchange rate

The aim of this study is to determine if nonlinearities have affected purchasing power parity (PPP) since 1885. Also using recent advances in the econometrics of structural change we segment the sample space according to the identified breaks and look at whether the PPP condition holds in each sub-sample and whether this involves linear or non-linear adjustment. Our results suggest that during some sub-periods, PPP holds, although whether it holds or not and whether the adjustment is linear or non-linear, depends primarily on the type of exchange rate regime in operation at any point in time.

Stochastically driven instability in rotating shear flows

Origin of hydrodynamic turbulence in rotating shear flows is investigated. The particular emphasis is on flows whose angular velocities decrease but specific angular momenta increase with increasing radial coordinate. Such flows are Rayleigh stable, but must be turbulent in order to explain observed data. Such a mismatch between the linear theory and observations/experiments is more severe when any hydromagnetic/magnetohydrodynamic instability and the corresponding turbulence therein is ruled out. The present work explores the effect of stochastic noise on such hydrodynamic flows. We focus on a small section of such a flow which is essentially a plane shear flow supplemented by the Coriolis effect. This also mimics a small section of an astrophysical accretion disk. It is found that such stochastically driven flows exhibit large temporal and spatial correlations of perturbation velocities, and hence large energy dissipations, that presumably generate instability. A range of angular velocity profiles (for the steady flow), starting with the constant angular momentum to that of the constant circular velocity are explored. It is shown that the growth and roughness exponents calculated from the contour (envelope) of the perturbed flows are all identical, revealing a unique universality class for the stochastically forced hydrodynamics of rotating shear flows. This work, to the best of our knowledge, is the first attempt to understand origin of instability and turbulence in the three-dimensional Rayleigh stable rotating shear flows by introducing additive stochastic noise to the underlying linearized governing equations. This has important implications in resolving the turbulence problem in astrophysical hydrodynamic flows such as accretion disks.

Risk and structural instability in US house prices

This paper employs a Component GARCH in Mean model to show that house prices across a number of major US cities between 1987 and 2009 have displayed asset market properties in terms of both risk-return relationships and asymmetric adjustment to shocks. In addition, tests for structural breaks in the mean and variance indicate structural instability across the data range. Multiple breaks are identified across all cities, particularly for the early 1990s and during the post-2007 financial crisis as housing has become an increasingly risky asset. Estimating the models over the individual sub-samples suggests that over the last 20 years the financial sector has increasingly failed to account for the levels of risk associated with real estate markets. This result has possible implications for the way in which financial institutions should be regulated in the future.

Dual-pump Raman amplification with increased flatness using modulation instability

he application of modulation instability-initiated nonlinear broadening of two CW pumps at different wavelengths, in order to achieve superior gain ripple performance in broadband Raman amplifiers, is demonstrated for the first time experimentally. A particular example using Truewave and LEAF fibers is offered, in which the 0.1 dB gain ripple band is extended from 5 nm to 19 nm. Experimental results are in a good agreement with numerical modeling. Guidelines for optimal broadening are discussed.

Dual-pump Raman amplification with increased flatness using modulation instability

The application of modulation instability-initiated nonlinear broadening of two CW pumps at different wavelengths, in order to achieve superior gain ripple performance in broadband Raman amplifiers, is demonstrated for the first time experimentally. A particular example using Truewave and LEAF fibers is offered, in which the 0.1 dB gain ripple band is extended from 5 nm to 19 nm. Experimental results are in a good agreement with numerical modeling. Guidelines for optimal broadening are discussed. © 2005 Optical Society of America.

Stochastically driven instability in rotating shear flows

Origin of hydrodynamic turbulence in rotating shear flows is investigated. The particular emphasis is on flows whose angular velocities decrease but specific angular momenta increase with increasing radial coordinate. Such flows are Rayleigh stable, but must be turbulent in order to explain observed data. Such a mismatch between the linear theory and observations/experiments is more severe when any hydromagnetic/magnetohydrodynamic instability and the corresponding turbulence therein is ruled out. The present work explores the effect of stochastic noise on such hydrodynamic flows. We focus on a small section of such a flow which is essentially a plane shear flow supplemented by the Coriolis effect. This also mimics a small section of an astrophysical accretion disk. It is found that such stochastically driven flows exhibit large temporal and spatial correlations of perturbation velocities, and hence large energy dissipations, that presumably generate instability. A range of angular velocity profiles (for the steady flow), starting with the constant angular momentum to that of the constant circular velocity are explored. It is shown that the growth and roughness exponents calculated from the contour (envelope) of the perturbed flows are all identical, revealing a unique universality class for the stochastically forced hydrodynamics of rotating shear flows. This work, to the best of our knowledge, is the first attempt to understand origin of instability and turbulence in the three-dimensional Rayleigh stable rotating shear flows by introducing additive stochastic noise to the underlying linearized governing equations. This has important implications in resolving the turbulence problem in astrophysical hydrodynamic flows such as accretion disks.

Development of a neurotoxicity test-system, using human post-mitotic, astrocytic and neuronal cell lines in co-culture

Astrocytes are essential for neuronal function and survival, so both cell types were included in a human neurotoxicity test-system to assess the protective effects of astrocytes on neurons, compared with a culture of neurons alone. The human NT2.D1 cell line was differentiated to form either a co-culture of post-mitotic NT2.N neuronal (TUJ1, NF68 and NSE positive) and NT2.A astrocytic (GFAP positive) cells (∼2:1 NT2.A:NT2.N), or an NT2.N mono-culture. Cultures were exposed to human toxins, for 4 h at sub-cytotoxic concentrations, in order to compare levels of compromised cell function and thus evidence of an astrocytic protective effect. Functional endpoints examined included assays for cellular energy (ATP) and glutathione (GSH) levels, generation of hydrogen peroxide (H2O2) and caspase-3 activation. Generally, the NT2.N/A co-culture was more resistant to toxicity, maintaining superior ATP and GSH levels and sustaining smaller significant increases in H2O2 levels compared with neurons alone. However, the pure neuronal culture showed a significantly lower level of caspase activation. These data suggest that besides their support for neurons through maintenance of ATP and GSH and control of H2O2 levels, following exposure to some substances, astrocytes may promote an apoptotic mode of cell death. Thus, it appears the use of astrocytes in an in vitro predictive neurotoxicity test-system may be more relevant to human CNS structure and function than neuronal cells alone. © 2007 Elsevier Ltd. All rights reserved.

Power-controlled phase-matching and instability of CW propagation in multicore optical fibers with a central core

We present modulation instability analysis including azimuthal perturbations of steady-state continuous wave (CW) propagation in multicore-fiber configurations with a central core. In systems with a central core, a steady CW evolution regime requires power-controlled phase matching, which offers interesting spatial-division applications. Our results have general applicability and are relevant to a range of physical and engineering systems, including high-power fiber lasers, optical transmission in multicore fiber, and systems of coupled nonlinear waveguides. © 2013 Optical Society of America.

Design of a fiber scheme for nonlinear Raman pump broadening through modulation instability

In this work we explore numerically an experimentally the dependence of the broadened spectra on the choice of fibers and we analyze a series of basic rules to be taken into account when using nonlinear broadening to reduce the gain ripple of broadband Raman amplifiers