High stability interleaved fibre Michelson interferometer for on-line precision displacement measurements

A self-reference fiber Michelson interferometer measurement system, which employs fiber Bragg gratings (FBGs) as in-fiber reflective mirrors and interleaves together two fiber Michelson interferometers that share the common-interferometric-optical path, is presented. One of the fiber interferometers is used to stabilise the system by the use of an electronic feedback loop to compensate the influences resulting from the environmental disturbances, while the other one is used to perform the measurement task. The influences resulting from the environmental disturbances have been eliminated by the compensating action of the electronic feedback loop, this makes the system suitable for on-line precision measurement. By means of the homodyne phase-tracking technique, the linearity of the measurement results of displacement measurements has been very high.

MicroRNA-155 promotes resolution of hypoxia-inducible factor 1α activity during prolonged hypoxia

The hypoxia-inducible factor (HIF) is a key regulator of the transcriptional response to hypoxia. While the mechanism underpinning HIF activation is well understood, little is known about its resolution. Both the protein and the mRNA levels of HIF-1a (but not HIF-2a) were decreased in intestinal epithelial cells exposed to prolonged hypoxia. Coincident with this, microRNA (miRNA) array analysis revealed multiple hypoxiainducible miRNAs. Among these was miRNA-155 (miR-155), which is predicted to target HIF-1a mRNA. We confirmed the hypoxic upregulation of miR-155 in cultured cells and intestinal tissue from mice exposed to hypoxia. Furthermore, a role for HIF-1a in the induction of miR-155 in hypoxia was suggested by the identification of hypoxia response elements in the miR-155 promoter and confirmed experimentally. Application of miR-155 decreased the HIF-1a mRNA, protein, and transcriptional activity in hypoxia, and neutralization of endogenous miR-155 reversed the resolution of HIF-1a stabilization and activity. Based on these data and a mathematical model of HIF-1a suppression by miR-155, we propose that miR-155 induction contributes to an isoform-specific negative-feedback loop for the resolution of HIF-1a activity in cells exposed to prolonged hypoxia, leading to oscillatory behavior of HIF-1a-dependent transcription. © 2011, American Society for Microbiology.

Inhibition of collagen I accumulation reduces glomerulosclerosis by a Hic-5-dependent mechanism in experimental diabetic nephropathy

Glomerulosclerosis of any cause is characterized by loss of functional glomerular cells and deposition of excessive amounts of interstitial collagens including collagen I. We have previously reported that mesangial cell attachment to collagen I leads to upregulation of Hic-5 in vitro, which mediates mesangial cell apoptosis. Furthermore, glomerular Hic-5 expression was increased during the progression of experimental glomerulosclerosis. We hypothesized that reducing collagen I accumulation in glomerulosclerosis would in turn lower Hic-5 expression, reducing mesangial cell apoptosis, and thus maintaining glomerular integrity. We examined archive renal tissue from rats undergoing experimental diabetic glomerulosclerosis, treated with the transglutaminase-2 inhibitor NTU281. Untreated animals exhibited increased glomerular collagen I accumulation, associated with increased glomerular Hic-5 expression, apoptosis, and mesangial myofibroblast transdifferentiation characterized by a-smooth muscle actin (a-SMA) expression. NTU281 treatment reduced glomerular collagen I accumulation, Hic-5 and a-SMA expression, and apoptosis. Proteinurea and serum creatinine levels were significantly reduced in animals with reduced Hic-5 expression. In vitro studies of Hic-5 knockdown or overexpression show that mesangial cell apoptosis and expression of both a-SMA and collagen I are Hic-5 dependent. Together, these data suggest that there exists, in vitro and in vivo, a positive feedback loop whereby increased levels of collagen I lead to increased mesangial Hic-5 expression favoring not only increased apoptosis, but also mesangial myofibroblast transdifferentiation and increased collagen I expression. Prevention of collagen I accumulation interrupts this Hic-5-dependent positive feedback loop, preserving glomerular architecture, cellular phenotype, and function. © 2013 USCAP, Inc All rights reserved.

Tissue Transglutaminase (TG2) is a potential therapeutic target in the treatment of chemoresistant breast cancer

Tissue transglutaminase (TG2) has been suggested to be a key player in the progression and metastasis of chemoresistant breast cancer. One of the foremost survival signalling pathways implicated in causing drug resistance in breast cancer is the constitutive activation of NFκB (Nuclear Factor -kappa B) induced by TG2. This study provides a mechanism by which TG2 constitutively activates NFκB which in turn confers chemoresistance to breast cancer cells against doxorubicin. Breast cancer cell lines with varying expression levels of TG2 as well as TG2 null breast cancer cells transfected with TG2 were used as the major cell models for this study. This study made use of cell permeable and impermeable TG2 inhibitors, specific TG2 and Rel A/ p65 targeting siRNA, TG2 functional blocking antibodies, IKK inhibitors and a specific targeting peptide against Rel A/p65 to investigate the pathway of activation involved in the constitutive activation of NFκB by TG2 leading to drug resistance. Crucial to the activation of Rel A/p65 and drug resistance in the breast cancer cells is the interaction between the complex of IκBα and Rel A/p65 with TG2 which results in the dimerization of Rel A/p65 and polymerization of IκBα. The association of TG2 with the IκBα-NFκB complex was determined to be independent of IKKα/β function. The polymerized IκBα is degraded in the cytoplasm by the μ-calpain pathway which allows the cross linked Rel A/ p65 dimers to translocate into the nucleus. Using R283 and ZDON (cell permeable TG2 activity inhibitors) and specific TG2 targeting siRNA, the Rel A/ p65 dimer formation could be inhibited. Co-immunoprecipitation studies confirmed that the phosphorylation of the Rel A/p65 dimers at the Ser536 residue by IKKε took place in the cell nucleus. Importantly, this study also investigated the transcriptional regulation of the TGM2 gene by the pSer536 Rel A/ p65 dimer and the importance of this TG2-NFκB feedback loop in conferring drug resistance to breast cancer cells. This data provides evidence that TG2 could be a key therapeutic target in the treatment of chemoresistant breast cancer.

Reporting and managing risk:a look at current practice at Tesco, RBS, local and central government

These case studies from CIMA highlight the need to embed risk management within more easily understood behaviours, consistent with the overall organisational culture. In each case, some form of internal audit team provides either an oversight function or acts as an expert link in that feedback loop. Frontline staff, managers and specialists should be completely aligned on risk, in part just to ensure that there is a consistency of approach. They should understand instinctively that good performance includes good risk management. Tesco has continued to thrive during the recession and remains a robust and efficient group of businesses despite the emergence of potential threats around consumer spending and the supply chain. RBS, by contrast, has suffered catastrophic and very public failures of risk management despite a large in-house function and stiff regulation of risk controls. Birmingham City Council, like all local authorities, is adapting to more commercial modes of operation and is facing diverse threats and opportunities emerging as a result of social change. And DCMS, like many other public sector organisations, has to handle an incredibly complex network of delivery partners within the context of a relatively recent overhaul of central government risk management processes. Key Findings: •Risk management is no longer solely a financial discipline, nor is it simply a concern for the internal control function. •Where organisations retain a discrete risk management cadre – often specialists at monitoring and evaluating a range of risks – their success is dependent on embedding risk awareness in the wider culture of the enterprise. •Risk management is most successful when it is explicitly linked to operational performance. •Clear leadership, specific goals, excellent influencing skills and open-mindedness to potential threats and opportunities are essential for effective risk management. •Bureaucratic processes and systems can hamper good risk management – either as a result of a ‘box-ticking mentality’ or because managers and staff believe they do not need to consider risk themselves.

The antecedents and consequences of anticipatory identification

The aim of this thesis was to investigate anticipatory identification: newcomers’ identification with an organisation prior to entry; in particular by exploring the antecedents and consequences of the construct. Although organisational identification has been frequently investigated over the past 25 years, surprisingly little is known about what causes an individual to identify with a new organisation before entry and whether this has an impact on their relationship with the organisation after formally taking up membership. Drawing on a Social Identity approach to organisational identification, it was hypothesised that newcomers would more closely identify with an organisation prior to entry when the organisation was seen as a source of positive social identity and was situationally relevant and meaningful to the newcomer, i.e. salient, during the pre-entry period. It was also hypothesised that anticipatory identification would have post-entry consequences and would predict newcomers’ post-entry identification, turnover intentions and job satisfaction. An indirect relationship between anticipatory identification and post-entry identification through post-entry social identity judgements (termed a “feedback loop” mechanism) was additionally proposed. Finally anticipatory identification was also predicted to moderate the relationship between post-entry social identity judgements and post-entry identification (termed a “buffering” mechanism). Four studies were conducted to test these hypotheses. Study One served as a pilot study, using a retrospective self-report design with s sample of 124 university students to initially test the proposed conceptual model. Studies Two and Three adopted experimental designs. Each used a unique sample of 72 staff and students from Aston University to respectively test the hypothesised positive social identity motive and salience antecedents of anticipatory identification. Study Four explored the relationship between anticipatory identification, its antecedents and consequences longitudinally, using an organisational sample of 45 employees. Overall, these studies found support for a social identity motive antecedent of anticipatory identification, as well as more limited evidence that anticipatory identification was associated with the salience of an organisation prior to entry. Support was inconsistent for a direct relationship between anticipatory identification and post-entry identification and there was no evidence that anticipatory identification was a significant direct predictor of turnover intention and job satisfaction. Anticipatory identification was however found to act as a buffer in the relationship between post-entry social identity judgements and post-entry identification in all but one of the four samples measured. A feedback loop mechanism was observed within the experimental designs of Studies Two and Three, but not within the organisational samples of Studies One and Four. Overall the findings of these four studies highlight key ways through which anticipatory identification can develop prior to entry into an organisation. Moreover, the research observed several important post-entry consequences of anticipatory identification, indicating that an understanding of post-entry identification may be enriched by attending more closely to the extent to which newcomers identify with an organisation prior to entry.

APP controls the formation of PI(3,5)P2 vesicles through its binding of the PIKfyve complex

Phosphoinositides are signalling lipids that are crucial for major signalling events as well as established regulators of membrane trafficking. Control of endosomal sorting and endosomal homeostasis requires phosphatidylinositol-3-phosphate (PI(3)P) and phosphatidylinositol-3,5-bisphosphate (PI(3,5)P2), the latter a lipid of low abundance but significant physiological relevance. PI(3,5)P2 is formed by phosphorylation of PI(3)P by the PIKfyve complex which is crucial for maintaining endosomal homeostasis. Interestingly, loss of PIKfyve function results in dramatic neurodegeneration. Despite the significance of PIKfyve, its regulation is still poorly understood. Here we show that the Amyloid Precursor Protein (APP), a central molecule in Alzheimer’s disease, associates with the PIKfyve complex (consisting of Vac14, PIKfyve and Fig4) and that the APP intracellular domain directly binds purified Vac14. We also show that the closely related APP paralogues, APLP1 and 2 associate with the PIKfyve complex. Whether APP family proteins can additionally form direct protein–protein interaction with PIKfyve or Fig4 remains to be explored. We show that APP binding to the PIKfyve complex drives formation of PI(3,5)P2 positive vesicles and that APP gene family members are required for supporting PIKfyve function. Interestingly, the PIKfyve complex is required for APP trafficking, suggesting a feedback loop in which APP, by binding to and stimulating PI(3,5)P2 vesicle formation may control its own trafficking. These data suggest that altered APP processing, as observed in Alzheimer’s disease, may disrupt PI(3,5)P2 metabolism, endosomal sorting and homeostasis with important implications for our understanding of the mechanism of neurodegeneration in Alzheimer’s disease.

Blind phase noise estimation for CO-OFDM transmissions

In this paper, we discuss in detail the performance of different blind phase noise estimation schemes for coherent optical orthogonal frequency-division multiplexing transmissions. We first derive a general model of such systems with phase noise. Based on this model, the phase cycle slip probability in blind phase noise estimation is calculated. For blind phase tracking, we present and discuss the implementation of feedback loop and digital phase tracking. We then analyze in detail the performance of a decision-direct-free blind scheme, in which only three test phases are required for phase noise compensation. We show that the decision-direct-free blind scheme is transparent to QAM formats, and can provide a similar performance to the conventional blind phase search employing 16 test phases. We also propose two novel cost functions to further reduce the complexity of this scheme.

Semiconductor optical amplifier-based nonlinear optical-loop mirror with feedback

The behavior of a semiconductor optical amplifier (SOA)-based nonlinear loop mirror with feedback has been investigated as a potential device for all-optical signal processing. In the feedback device, input signal pulses (ones) are injected into the loop, and amplified reflected pulses are fed back into the loop as switching pulses. The feedback device has two stable modes of operation - block mode, where alternating blocks of ones and zeros are observed, and spontaneous clock division mode, where halving of the input repetition rate is achieved. Improved models of the feedback device have been developed to study its performance in different operating conditions. The feedback device could be optimized to give a choice of either of the two stable modes by shifting the arrival time of the switching pulses at the SOA. Theoretically, it was found possible to operate the device at only tens of fJ switching pulse energies if the SOA is biased to produce very high gain in the presence of internal loss. The clock division regime arises from the combination of incomplete SOA gain recovery and memory of the startup sequence that is provided by the feedback. Clock division requires a sufficiently high differential phase shift per unit differential gain, which is related to the SOA linewidth enhancement factor.

Picosecond soliton transmission using concatenated nonlinear optical loop-mirror intensity filters

The issues involved in employing nonlinear optical loop mirrors (NOLMs) as intensity filters in picosecond soliton transmission were examined in detail. It was shown that inserting NOLMs into a periodically amplified transmission line allowed picosecond solitons to be transmitted under conditions considered infeasible until now. The loop mirrors gave dual function, removing low-power background dispersive waves through saturable absorption and applying a negative feedback mechanism to control the amplitude of the solitons. The stochastic characteristics of the pulses that were due to amplifier spontaneous-emission noise were investigated, and a number of new properties were determined. In addition, the mutual interaction between pulses was also significantly different from that observed for longer-duration solitons. The impact of Raman scattering in the computations was included and it was shown that soliton self-frequency shifts may be eliminated by appropriate bandwidth restrictions.

Travelling-wave model of semiconductor optical amplifier based non-linear loop mirror

A travelling-wave model of a semiconductor optical amplifier based non-linear loop mirror is developed to investigate the importance of travelling-wave effects and gain/phase dynamics in predicting device behaviour. A constant effective carrier recovery lifetime approximation is found to be reasonably accurate (±10%) within a wide range of control pulse energies. Based on this approximation, a heuristic model is developed for maximum computational efficiency. The models are applied to a particular configuration involving feedback.