Mapping piezoelectric nonlinearity in the Rayleigh regime using band excitation piezoresponse force microscopy

Band excitation piezoresponse force microscopy enables local investigation of the nonlinear piezoelectric behavior of ferroelectric thin films. However, the presence of additional nonlinearity associated with the dynamic resonant response of the tip-surface junction can complicate the study of a material's nonlinearity. Here, the relative importance of the two nonlinearity sources was examined as a function of the excitation function. It was found that in order to minimize the effects of nonlinear tip-surface interactions but achieve good signal to noise level, an optimal excitation function must be used. (C) 2011 American Institute of Physics. [doi: 10.1063/1.3593138]

Insulin-like growth factor binding protein-3 mediates vascular repair by enhancing nitric oxide generation

Insulin-like growth factor binding protein (IGFBP)-3 modulates vascular development by regulating endothelial progenitor cell (EPC) behavior, specifically stimulating EPC cell migration. This study was undertaken to investigate the mechanism of IGFBP-3 effects on EPC function and how IGFBP-3 mediates cytoprotection following vascular injury.

The IQGAP-myosin light chain interaction: what is its function?

The first members of the IQGAP family of proteins were
characterised over 15 years ago. It is now known that these molecules act
at the interface between cellular signalling pathways and the actin
cytoskeleton. They bind to a diverse range of signalling molecules –
including those involved in calcium, GTPase, kinase and growth factor
signalling. One intriguing interaction is that between mammalian
IQGAP1 and the myosin essential light chain isoform, Mlc1sa. Although
this has been demonstrated in vitro, its in vivo role is not known. Indeed,
it would be tempting to dismiss it as an experimental artefact, except for
the existence of a parallel interaction in the budding yeast,
Saccharomyces cerevisae. In this organism, the IQGAP-like protein
(Iqg1p) interacts with a myosin essential light chain (Mlc1p). This interaction is critical for the correct execution of cytokinesis. IQGAP-like
proteins also play key roles in cytokinesis in other fungi. Recent work
implicating mammalian IQGAP1 in cytokinesis may help explain the role
of the interaction in higher eukarytotes.

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.

Regulation of c-SRC activity and function by the adapter protein CAS

SRC family kinases play essential roles in a variety of cellular functions, including proliferation, survival, differentiation, and apoptosis. The activities of these kinases are regulated by intramolecular interactions and by heterologous binding partners that modulate the transition between active and inactive structural conformations. p130(CAS) (CAS) binds directly to both the SH2 and SH3 domains of c-SRC and therefore has the potential to structurally alter and activate this kinase. In this report, we demonstrate that overexpression of full-length CAS in COS-1 cells induces c-SRC-dependent tyrosine phosphorylation of multiple endogenous cellular proteins. A carboxy-terminal fragment of CAS (CAS-CT), which contains the c-SRC binding site, was sufficient to induce c-SRC-dependent protein tyrosine kinase activity, as measured by tyrosine phosphorylation of cortactin, paxillin, and, to a lesser extent, focal adhesion kinase. A single amino acid substitution located in the binding site for the SRC SH3 domain of CAS-CT disrupted CAS-CT's interaction with c-SRC and inhibited its ability to induce tyrosine phosphorylation of cortactin and paxillin. Murine C3H10T1/2 fibroblasts that expressed elevated levels of tyrosine phosphorylated CAS and c-SRC-CAS complexes exhibited an enhanced ability to form colonies in soft agar and to proliferate in the absence of serum or growth factors. CAS-CT fully substituted for CAS in mediating growth in soft agar but was less effective in promoting serum-independent growth. These data suggest that CAS plays an important role in regulating specific signaling pathways governing cell growth and/or survival, in part through its ability to interact with and modulate the activity of c-SRC.

Theory of phonon dissipation in the conduction of stressed Au nanowires

Recent experiments on Au break junctions [Phys. Rev. Lett. 88 (2002) 216803] have characterized the nonlinear conductance of stretched short Au nanowires. They reveal in the voltage range 10-20 meV the signatures of dissipation effects, likely due to phonons in the nanowire, reducing the conductance below the quantized value of 2e(2)/h. We present here a theory, based on a model tight-binding Hamiltonian and on non-equilibrium Green's function techniques, which accounts for the main features of the experiment. The theory helps in revealing details of the experiment which need to be addressed with a more realistic, less idealized, theoretical framework. (C) 2004 Elsevier B.V. All rights reserved.

Detecting the work statistics through Ramsey-like interferometry

Out-of-equilibrium statistical mechanics is attracting considerable interest due to the recent advances in the control and manipulations of systems at the quantum level. Recently, an interferometric scheme for the detection of the characteristic function of the work distribution following a time-dependent process has been proposed [L. Mazzola et al., Phys. Rev. Lett. 110 (2013) 230602]. There, it was demonstrated that the work statistics of a quantum system undergoing a process can be reconstructed by effectively mapping the characteristic function of work on the state of an ancillary qubit. Here, we expand that work in two important directions. We first apply the protocol to an interesting specific physical example consisting of a superconducting qubit dispersively coupled to the field of a microwave resonator, thus enlarging the class of situations for which our scheme would be key in the task highlighted above. We then account for the interaction of the system with an additional one (which might embody an environment), and generalize the protocol accordingly.

A novel radial basis function neural network principal component analysis scheme for PMU-based wide-area power system monitoring

A novel model-based principal component analysis (PCA) method is proposed in this paper for wide-area power system monitoring, aiming to tackle one of the critical drawbacks of the conventional PCA, i.e. the incapability to handle non-Gaussian distributed variables. It is a significant extension of the original PCA method which has already shown to outperform traditional methods like rate-of-change-of-frequency (ROCOF). The ROCOF method is quick for processing local information, but its threshold is difficult to determine and nuisance tripping may easily occur. The proposed model-based PCA method uses a radial basis function neural network (RBFNN) model to handle the nonlinearity in the data set to solve the no-Gaussian issue, before the PCA method is used for islanding detection. To build an effective RBFNN model, this paper first uses a fast input selection method to remove insignificant neural inputs. Next, a heuristic optimization technique namely Teaching-Learning-Based-Optimization (TLBO) is adopted to tune the nonlinear parameters in the RBF neurons to build the optimized model. The novel RBFNN based PCA monitoring scheme is then employed for wide-area monitoring using the residuals between the model outputs and the real PMU measurements. Experimental results confirm the efficiency and effectiveness of the proposed method in monitoring a suite of process variables with different distribution characteristics, showing that the proposed RBFNN PCA method is a reliable scheme as an effective extension to the linear PCA method.

A chromatin-independent role of Polycomb-like 1 to stabilize p53 and promote cellular quiescence

Polycomb-like proteins 1-3 (PCL1-3) are substoichiometric components of the Polycomb-repressive complex 2 (PRC2) that are essential for association of the complex with chromatin. However, it remains unclear why three proteins with such apparent functional redundancy exist in mammals. Here we characterize their divergent roles in both positively and negatively regulating cellular proliferation. We show that while PCL2 and PCL3 are E2F-regulated genes expressed in proliferating cells, PCL1 is a p53 target gene predominantly expressed in quiescent cells. Ectopic expression of any PCL protein recruits PRC2 to repress the INK4A gene; however, only PCL2 and PCL3 confer an INK4A-dependent proliferative advantage. Remarkably, PCL1 has evolved a PRC2- and chromatin-independent function to negatively regulate proliferation. We show that PCL1 binds to and stabilizes p53 to induce cellular quiescence. Moreover, depletion of PCL1 phenocopies the defects in maintaining cellular quiescence associated with p53 loss. This newly evolved function is achieved by the binding of the PCL1 N-terminal PHD domain to the C-terminal domain of p53 through two unique serine residues, which were acquired during recent vertebrate evolution. This study illustrates the functional bifurcation of PCL proteins, which act in both a chromatin-dependent and a chromatin-independent manner to regulate the INK4A and p53 pathways.

INFLUENCE OF NOX4 NADPH OXIDASE ON GENERATION AND ANGIOGENIC FUNCTION OF INDUCED PLURIPOTENT STEM CELL-DERIVED ENDOTHELIAL CELLS

Human induced pluripotent stem (iPS) cell-derived endothelial cells (ECs) hold clear potential for therapeutic angiogenesis as a novel strategy for ischaemic disease. Recently, we have developed a novel method for direct reprogramming of partial iPS (PiPS) cells, which unlike iPS cells, are generated before pluripotency so do not form tumours, and may be differentiated into ECs with characteristic morphology and pro-angiogenic actions. Our previous work showed that PiPS-derived ECs are capable of forming vascular-like tubes both in vitro and in vivo and promoting re-endothelialisation of ischemic tissue, with greater effectiveness versus mature ECs.

Interestingly, our preliminary data demonstrate that Nox NADPH oxidases, which are reported to influence stem cell function, are progressively induced during PiPs/PiPS-EC differentiation and in response to hypoxia, with Nox4 demonstrating highest expression. As this isoform is an established regulator of angiogenesis, we hypothesize that Nox4 plays a key role in modulating PiPS-EC generation and angiogenic function.

The aim of this project is therefore to investigate: (1) the specific role of Nox4 in direct reprogramming of PiPS cells and differentiation to PiPS-ECs; (2) whether genetic manipulation of Nox4 influences in vitro function of PiPs-ECs and their ability to promote in vivo angiogenesis. This will be achieved by employing established in vitro functional assays and an experimental model of hindlimb ischaemia with assessment of relevant end-points. Identification of a key role for Nox4 in regulating PiPS-EC generation/function may inform selective targeting of this isoform to enhance the efficiency of PiPS-EC differentiation and their capacity to treat ischemic disease.

Metabolically-inactive glucagon-like peptide-1(9-36)amide confers selective protective actions against post-myocardial infarction remodelling

BACKGROUND: Glucagon-like peptide-1 (GLP-1) therapies are routinely used for glycaemic control in diabetes and their emerging cardiovascular actions have been a major recent research focus. In addition to GLP-1 receptor activation, the metabolically-inactive breakdown product, GLP-1(9-36)amide, also appears to exert notable cardiovascular effects, including protection against acute cardiac ischaemia. Here, we specifically studied the influence of GLP-1(9-36)amide on chronic post-myocardial infarction (MI) remodelling, which is a major driver of heart failure progression.

METHODS: Adult female C57BL/6 J mice were subjected to permanent coronary artery ligation or sham surgery prior to continuous infusion with GLP-1(9-36)amide or vehicle control for 4 weeks.

RESULTS: Infarct size was similar between groups with no effect of GLP-1(9-36)amide on MI-induced cardiac hypertrophy, although modest reduction of in vitro phenylephrine-induced H9c2 cardiomyoblast hypertrophy was observed. Whilst echocardiographic systolic dysfunction post-MI remained unchanged, diastolic dysfunction (decreased mitral valve E/A ratio, increased E wave deceleration rate) was improved by GLP-1(9-36)amide treatment. This was associated with modulation of genes related to extracellular matrix turnover (MMP-2, MMP-9, TIMP-2), although interstitial fibrosis and pro-fibrotic gene expression were unaltered by GLP-1(9-36)amide. Cardiac macrophage infiltration was also reduced by GLP-1(9-36)amide together with pro-inflammatory cytokine expression (IL-1β, IL-6, MCP-1), whilst in vitro studies using RAW264.7 macrophages revealed global potentiation of basal pro-inflammatory and tissue protective cytokines (e.g. IL-1β, TNF-α, IL-10, Fizz1) in the presence of GLP-1(9-36)amide versus exendin-4.

CONCLUSIONS: These data suggest that GLP-1(9-36)amide confers selective protection against post-MI remodelling via preferential preservation of diastolic function, most likely due to modulation of infiltrating macrophages, indicating that this often overlooked GLP-1 breakdown product may exert significant actions in this setting which should be considered in the context of GLP-1 therapy in patients with cardiovascular disease.

Threshold Optimization for Energy Detection-Based Spectrum Sensing Over Hyper-Rayleigh Fading Channels

Spectrum sensing is a key function of cognitive radio systems. Sensing performance is determined by three main factors including the wireless channel between the primary system and the cognitive radio nodes, the detection threshold, and the sensing time. In this letter a closed-form expression for the average probability of detection for energy detection based spectrum sensing over two-wave with diffuse power fading channels is derived. This expression is then used to optimize the detection threshold for cognitive radio nodes, which operate in confined structures that exhibit worse than Rayleigh fading conditions. Such fading conditions can represent a behavioral model of cognitive machine-to-machine systems deployed in enclosed structures such as in-vehicular environments.

A Rare Loss-of-Function Variant in Scavenger Receptor Class B Type I (SCARB1) Raises HDL Cholesterol and Increases Risk of Coronary Disease

Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL)
cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a
lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI
knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased
atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains
unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328
individuals with extremely high plasma HDL-C levels, we identified a homozygote for a lossof-function
variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene
encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and
abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells
derived from induced pluripotent stem cells from the homozygous subject, and in mice.
Large population-based studies revealed that subjects who are heterozygous carriers of
the P376L variant have significantly increased levels of plasma HDL-C. P376L carriers have
a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is
statistically significant).