PDGF regulates the actin cytoskeleton through hnRNP-K-mediated activation of the ubiquitin E-3-ligase MIR

PDGF is a potent chemotactic mitogen and a strong inductor of fibroblast motility. In Swiss 3T3 fibroblasts, exposure to PDGF but not EGF or IGF-1 causes a rapid loss of actin stress fibers (SFs) and focal adhesions (FAs), which is followed by the development of retractile dendritic protrusions and induction of motility. The PDGF-specific actin reorganization was blocked by inhibition of Src-kinase and the 26S proteasome. PDGF induced Src-dependent association between the multifunctional transcription/translation regulator hnRNP-K and the mRNA-encoding myosin regulatory light-chain (MRLC)-interacting protein (MIR), a E3-ubiquitin ligase that is MRLC specific. This in turn rapidly increased MIR expression, and led to ubiquitination and proteasome-mediated degradation of MRLC. Downregulation of MIR by RNA muting prevented the reorganization of actin structures and severely reduced the migratory and wound-healing potential of PDGF-treated cells. The results show that activation of MIR and the resulting removal of diphosphorylated MRLC are essential for PDGF to instigate and maintain control over the actin-myosin-based contractile system in Swiss 3T3 fibroblasts. The PDGF induced protein destabilization through the regulation of hnRNP-K controlled ubiquitin-ligase translation identifies a novel pathway by which external stimuli can regulate phenotypic development through rapid, organelle-specific changes in the activity and stability of cytoskeletal regulators.

Good practice transfer within small construction specialist trade contractors

Government and institutionally-driven ‘good practice transfer’ initiatives are consistently presented as a means to enhance construction firm and industry performance. Two implicit tenets of these initiatives appear to be: knowledge embedded in good practice will transfer automatically; and, the potential of implementing good practice will be capitalised regardless of the context where it is to be used. The validity of these tenets is increasingly being questioned and, concurrently, more nuanced knowledge production understandings are being developed which recognise and incorporate context-specificity. This research contributes to this growing, more critical agenda by examining the actual benefits accrued from good practice transfer from the perspective of a small specialist trade contracting firm. A concept model for successful good practice transfer is developed from a single longitudinal case study within a small heating and plumbing firm. The concept model consists of five key variables: environment, strategy, people, technology, and organisation of work. The key findings challenge the implicit assumptions prevailing in the existing literature and support a contingency approach that argues successful good practice transfer is not just adopting and mechanistically inserting into the firm, but requires addressing ‘behavioural’ aspects. For successful good practice transfer, small specialist trade contracting firms need to develop and operationalise organisation slack, mechanisms for scanning external stimuli and absorbing knowledge. They also need to formulate and communicate client-driven external strategies; to motive and educate people at all levels; to possess internal or accessible complementary skills and knowledge; to have ‘soft focus’ immediate/mid-term benefits at a project level; and, to embed good practice in current work practices.

Associating spontaneous with evoked activity in a neural mass model of cat visual cortex

Spontaneous activity of the brain at rest frequently has been considered a mere backdrop to the salient activity evoked by external stimuli or tasks. However, the resting state of the brain consumes most of its energy budget, which suggests a far more important role. An intriguing hint comes from experimental observations of spontaneous activity patterns, which closely resemble those evoked by visual stimulation with oriented gratings, except that cortex appeared to cycle between different orientation maps. Moreover, patterns similar to those evoked by the behaviorally most relevant horizontal and vertical orientations occurred more often than those corresponding to oblique angles. We hypothesize that this kind of spontaneous activity develops at least to some degree autonomously, providing a dynamical reservoir of cortical states, which are then associated with visual stimuli through learning. To test this hypothesis, we use a biologically inspired neural mass model to simulate a patch of cat visual cortex. Spontaneous transitions between orientation states were induced by modest modifications of the neural connectivity, establishing a stable heteroclinic channel. Significantly, the experimentally observed greater frequency of states representing the behaviorally important horizontal and vertical orientations emerged spontaneously from these simulations. We then applied bar-shaped inputs to the model cortex and used Hebbian learning rules to modify the corresponding synaptic strengths. After unsupervised learning, different bar inputs reliably and exclusively evoked their associated orientation state; whereas in the absence of input, the model cortex resumed its spontaneous cycling. We conclude that the experimentally observed similarities between spontaneous and evoked activity in visual cortex can be explained as the outcome of a learning process that associates external stimuli with a preexisting reservoir of autonomous neural activity states. Our findings hence demonstrate how cortical connectivity can link the maintenance of spontaneous activity in the brain mechanistically to its core cognitive functions.

Healable supramolecular polymers

This mini-review details the recent development of self-healing and mendable polymeric materials which take advantage of the reversible characteristics of non-covalent interactions during their physical recovery process. Supramolecular polymer systems which undergo spontaneous (autonomous) healing, as well as those which require external stimuli to initiate the healing process (healable/mendable), are introduced and discussed. Supramolecular polymers offer key advantages over alternative approaches, as these materials can typically withstand multiple healing cycles without substantial loss of performance, as a consequence of the highly directional and fully reversible non-covalent interactions present within the polymer matrix.

RE1 silencing transcription factor/neuron-restrictive silencing factor regulates expansion of adult mouse subventricular zone-derived neural stem/progenitor cells in vitro

Adult neural stem cell (aNSC) activity is tuned by external stimuli through the recruitment of transcription factors. This study examines the RE1 silencing transcription factor (REST) in neural stem/progenitor cells isolated from the subventricular zone of adult mouse brain and provides the first extensive characterization of REST-mediated control of the cellular and molecular properties. This study shows that REST knockdown affects the capacity of progenitor cells to generate neurospheres, reduces cell proliferation, and triggers cell differentiation despite the presence of growth factors. Genome- and transcriptome-wide analyses show that REST binding sites are significantly enriched in genes associated with synaptic transmission and nervous system development and function. Seeking candidate regulators of aNSC function, this study identifies a member of the bone morphogenetic protein (BMP) family, BMP6, the mRNA and protein of which increased after REST knockdown. The results of this study extend previous findings, demonstrating a reciprocal control of REST expression by BMPs. Administration of exogenous BMP6 inhibits aNSC proliferation and induces the expression of the astrocytic marker glial fibrillary acidic protein, highlighting its antimitogenic and prodifferentiative effects. This study suggests that BMP6 produced in a REST-regulated manner together with other signals can contribute to regulation of NSC maintenance and fate. © 2015 Wiley Periodicals, Inc.

Response of the lower St. Lawrence Estuary to external forcing in winter

Mostly because of a lack of observations, fundamental aspects of the St. Lawrence Estuary's wintertime response to forcing remain poorly understood. The results of a field campaign over the winter of 2002/03 in the estuary are presented. The response of the system to tidal forcing is assessed through the use of harmonic analyses of temperature, salinity, sea level, and current observations. The analyses confirm previous evidence for the presence of semidiurnal internal tides, albeit at greater depths than previously observed for ice-free months. The low-frequency tidal streams were found to be mostly baroclinic in character and to produce an important neap tide intensification of the estuarine circulation. Despite stronger atmospheric momentum forcing in winter, the response is found to be less coherent with the winds than seen in previous studies of ice-free months. The tidal residuals show the cold intermediate layer in the estuary is renewed rapidly ( 14 days) in late March by the advection of a wedge of near-freezing waters from the Gulf of St. Lawrence. In situ processes appeared to play a lesser role in the renewal of this layer. In particular, significant wintertime deepening of the estuarine surface mixed layer was prevented by surface stability, which remained high throughout the winter. The observations also suggest that the bottom circulation was intensified during winter, with the intrusion in the deep layer of relatively warm Atlantic waters, such that the 3 C isotherm rose from below 150 m to near 60 m.

Converting the nanodomains of a diblock-copolymer thin film from spheres to cylinders with an external electric field

We investigate the ability of an applied electric field to convert the morphology of a diblock-copolymer thin film from a monolayer of spherical domains embedded in the matrix to cylindrical domains that penetrate through the matrix. As expected, the applied field increases the relative stability of cylindrical domains, while simultaneously reducing the energy barrier that impedes the transition to cylinders. The effectiveness of the field is enhanced by a large dielectric contrast between the two block-copolymer components, particularly when the low-dielectric contrast component forms the matrix. Furthermore, the energy barrier is minimized by selecting sphere-forming diblock copolymers that are as compositionally symmetric as possible. Our calculations, which are the most quantitatively reliable to date, are performed using a numerically precise spectral algorithm based on self-consistent-field theory supplemented with an exact treatment for linear dielectric materials.

Curbing agricultural exceptionalism: The EU's response to external challenge

From 1948 to 1994, the agricultural sector was afforded special treatment in the GATT. We analyse the extent to which this agricultural exceptionalism was curbed as a result of the GATT Uruguay Round Agreement on Agriculture, discuss why it was curbed and finally explore the implication of this for EU policy making. We argue that, in particular, two major changes in GATT institutions brought about restrictions on agricultural exceptionalism. First, the Uruguay Round was a 'single undertaking' in which progress on other dossiers was contingent upon an outcome on agriculture. The EU had keenly supported this new decision rule in the GATT. Within the EU this led to the MacSharry reforms of the Common Agricultural Policy (CAP) in 1992, paving the way for a trade agreement on agriculture within the GATT. Second, under the new quasi-judicial dispute settlement procedure, countries are expected to bring their policies into conformity with WTO rules or face retaliatory trade sanctions. This has brought about a greater willingness on the part of the EU to submit its farm policy to WTO disciplines.

Myocyte remodeling in response to hypertrophic stimuli requires nucleocytoplasmic shuttling of muscle LIM protein

CSRP3 or muscle LIM protein (MLP) is a nucleocytoplasmic shuttling protein and a mechanosensor in cardiac myocytes. MLP regulation and function was studied in cultured neonatal rat myocytes treated with pharmacological or mechanical stimuli. Either verapamil or BDM decreased nuclear MLP while phenylephrine and cyclic strain increased it. These results suggest that myocyte contractility regulates MLP subcellular localization. When RNA polymerase II was inhibited with alpha-amanitin, nuclear MLP was reduced by 30%. However, when both RNA polymerase I and II were inhibited with actinomycin D, there was a 90% decrease in nuclear MLP suggesting that its nuclear translocation is regulated by both nuclear and nucleolar transcriptional activity. Using cell permeable synthetic peptides containing the putative nuclear localization signal (NLS) of MLP, nuclear import of the protein in cultured rat neonatal myocytes was inhibited. The NLS of MLP also localizes to the nucleolus. Inhibition of nuclear translocation prevented the increased protein accumulation in response to phenylephrine. Furthermore, cyclic strain of myocytes after prior NLS treatment to remove nuclear MLP resulted in disarrayed sarcomeres. Increased protein synthesis and brain natriuretic peptide expression were also prevented suggesting that MLP is required for remodeling of the myo filaments and gene expression. These findings suggest that nucleocytoplasmic shuttling MLP plays an important role in the regulation of the myocyte remodeling and hypertrophy and is required for adaptation to hypertrophic stimuli. (C) 2009 Elsevier Inc. All rights reserved.

Skeletal muscle fibre plasticity in response to selected environmental and physiological stimuli

Skeletal muscle constitutes a highly adaptable and malleable tissue that responds to environmental and physiological challenges by changing its phenotype in terms of size and composition, outcomes that are brought about by changes in gene expression, biochemical and metabolic properties. Both the short- and long-term effects of nutritional alterations on skeletal muscle homeostasis have been defined as the object of intensive research over the last thirty years. This review focuses predominantly on assimilating our understanding of the changes in muscle fibre phenotype and functional properties induced by either food restriction or alternatively existing on a high fat diet. Firstly, food restriction has been shown in a number of studies to decrease the myofibre cross sectional area and consistently, it has been found that glycolytic type IIB fibres are more prone to atrophy than oxidative fibres. Secondly, in rodents, a high fat diet has been shown to induce an oxidative profile in skeletal muscle, although obese humans usually show higher numbers of glycolytic type IIB fibres. Moreover, attention is paid to the effect of prenatal maternal food restriction on muscle development of the offspring in various species. A key point related to these experiments is the timing of food restriction for the mother. Furthermore, we explore extensively the seemingly species-specific response to maternal malnutrition. Finally, key signalling molecules that play a pivotal role in energy metabolism, fibre type transitions and muscle hypertrophy are discussed in detail.

Hemispace differences in the visual perception of size in left hemi-Parkinson's disease

The visual perception of size in different regions of external space was studied in Parkinson's disease (PD). A group of patients with worse left-sided symptoms (LPD) was compared with a group with worse right-sided symptoms (RPD) and with a group of age-matched controls on judgements of the relative height or width of two rectangles presented in different regions of external space. The relevant dimension of one rectangle (the 'standard') was held constant, while that of the other (the 'variable') was varied in a method of constant stimuli. The point of subjective equality (PSE) of rectangle width or height was obtained by probit analysis as the mean of the resulting psychometric function. When the standard was in left space, the PSE of the LPD group occurred when the variable was smaller, and when the standard was in right space, when the variable was larger. Similarly, when the standard rectangle was presented in upper space, and the variable in lower space, the PSE occurred when the variable was smaller, an effect which was similar in both left and right spaces. In all these experiments, the PSEs for both the controls and the RPD group did not differ significantly, and were close to a physical match, and the slopes of the psychometric functions were steeper in the controls than the patients, though not significantly so. The data suggest that objects appear smaller in the left and upper visual spaces in LPD, probably because of right hemisphere impairment. (C) 2002 Elsevier Science Ltd. All rights reserved.