Optimal Power Allocation by Imperfect Hardware Analysis in Untrusted Relaying Networks

CCBY By taking a variety of realistic hardware imperfections into consideration, we propose an optimal power allocation (OPA) strategy to maximize the instantaneous secrecy rate of a cooperative wireless network comprised of a source, a destination and an untrusted amplify-and-forward (AF) relay. We assume that either the source or the destination is equipped with a large-scale multiple antennas (LSMA) system, while the rest are equipped with a single-antenna. To prevent the untrusted relay from intercepting the source message, the destination sends an intended jamming noise to the relay, which is referred to as destination-based cooperative jamming (DBCJ). Given this system model, novel closed-form expressions are presented in the high signal-to-noise ratio (SNR) regime for the ergodic secrecy rate (ESR) and the secrecy outage probability (SOP). We further improve the secrecy performance of the system by optimizing the associated hardware design. The results reveal that by beneficially distributing the tolerable hardware imperfections across the transmission and reception radio-frequency (RF) front ends of each node, the system & #x2019;s secrecy rate may be improved. The engineering insight is that equally sharing the total imperfections at the relay between the transmitter and the receiver provides the best secrecy performance. Numerical results illustrate that the proposed OPA together with the most appropriate hardware design significantly increases the secrecy rate

Factors Influencing the Statistical Power of Complex Data Analysis Protocols for Molecular Signature Development from Microarray Data

Critical to the development of molecular signatures from microarray and other high-throughput data is testing the statistical significance of the produced signature in order to ensure its statistical reproducibility. While current best practices emphasize sufficiently powered univariate tests of differential expression, little is known about the factors that affect the statistical power of complex multivariate analysis protocols for high-dimensional molecular signature development.We show that choices of specific components of the analysis (i.e., error metric, classifier, error estimator and event balancing) have large and compounding effects on statistical power. The effects are demonstrated empirically by an analysis of 7 of the largest microarray cancer outcome prediction datasets and supplementary simulations, and by contrasting them to prior analyses of the same data.THE FINDINGS OF THE PRESENT STUDY HAVE TWO IMPORTANT PRACTICAL IMPLICATIONS: First, high-throughput studies by avoiding under-powered data analysis protocols, can achieve substantial economies in sample required to demonstrate statistical significance of predictive signal. Factors that affect power are identified and studied. Much less sample than previously thought may be sufficient for exploratory studies as long as these factors are taken into consideration when designing and executing the analysis. Second, previous highly-cited claims that microarray assays may not be able to predict disease outcomes better than chance are shown by our experiments to be due to under-powered data analysis combined with inappropriate statistical tests

Diagnostic potential of near-infrared Raman spectroscopy in the stomach: differentiating dysplasia from normal tissue

Raman spectroscopy is a molecular vibrational spectroscopic technique that is capable of optically probing the biomolecular changes associated with diseased transformation. The purpose of this study was to explore near-infrared (NIR) Raman spectroscopy for identifying dysplasia from normal gastric mucosa tissue. A rapid-acquisition dispersive-type NIR Raman system was utilised for tissue Raman spectroscopic measurements at 785 nm laser excitation. A total of 76 gastric tissue samples obtained from 44 patients who underwent endoscopy investigation or gastrectomy operation were used in this study. The histopathological examinations showed that 55 tissue specimens were normal and 21 were dysplasia. Both the empirical approach and multivariate statistical techniques, including principal components analysis (PCA), and linear discriminant analysis (LDA), together with the leave-one-sample-out cross-validation method, were employed to develop effective diagnostic algorithms for classification of Raman spectra between normal and dysplastic gastric tissues. High-quality Raman spectra in the range of 800–1800 cm−1 can be acquired from gastric tissue within 5 s. There are specific spectral differences in Raman spectra between normal and dysplasia tissue, particularly in the spectral ranges of 1200–1500 cm−1 and 1600–1800 cm−1, which contained signals related to amide III and amide I of proteins, CH3CH2 twisting of proteins/nucleic acids, and the C=C stretching mode of phospholipids, respectively. The empirical diagnostic algorithm based on the ratio of the Raman peak intensity at 875 cm−1 to the peak intensity at 1450 cm−1 gave the diagnostic sensitivity of 85.7% and specificity of 80.0%, whereas the diagnostic algorithms based on PCA-LDA yielded the diagnostic sensitivity of 95.2% and specificity 90.9% for separating dysplasia from normal gastric tissue. Receiver operating characteristic (ROC) curves further confirmed that the most effective diagnostic algorithm can be derived from the PCA-LDA technique. Therefore, NIR Raman spectroscopy in conjunction with multivariate statistical technique has potential for rapid diagnosis of dysplasia in the stomach based on the optical evaluation of spectral features of biomolecules

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Studies on the inhibition of human hypoxia inducible factor (HIF) hydroxylases

Hypoxia inducible factor (HIF) is an α/β-heterodimeric transcription factor that regulates cellular responses to hypoxia in metazoans. The activity and stability of the HIF-α subunits are regulated by prolyl and asparaginyl hydroxylation. Human HIF-1α prolyl hydroxylation occurs at Pro402 and Pro564 while asparaginyl hydroxylation occurs at Asn803. Asparaginyl hydroxylation blocks the HIF-1α interaction with the p300/CBP co-activator, thus inhibiting HIF transcriptional activation. Prolyl hydroxylation promotes the HIF-1α interaction with the von Hippel-Lindau (VHL) ubiquitin E3 ligase complex and targets it for proteasomal degradation. HIF prolyl hydroxylation is catalysed by the PHDs (prolyl hydroxylase domain) 1, 2 and 3, whereas asparaginyl hydroxylation is catalysed by FIH (factor inhibiting HIF). Both the PHDs and FIH are Fe(II) and 2-oxoglutarate (2OG) dependent oxygenases, which utilise oxygen as a co-substrate. In hypoxia, the activity of the PHDs and FIH are suppressed, thus enabling HIF-α subunits to form a productive transcriptional complex. There is widespread interest in developing HIF hydroxylase inhibitors for the treatment of ischemic/hypoxic diseases. The extent to which HIF-1α prolyl and asparaginyl hydroxylation are differentially regulated by chemical reagents is an important question. This thesis describes the development of methods employing immunoblotting and HIF hydroxy-residue specific antibodies to enable the simultaneous measurement of the effects of chemical inhibition at all three HIF-1α hydroxylation sites in cells. The findings reveal that HIF prolyl hydroxylation is substantially more sensitive than asparaginyl hydroxylation to inhibition by iron chelators and transition metal ions, in contrast to predictions from in vitro studies. Studies on a range of 2OG analogue inhibitors resulted in the identification of several cell-permeable PHD specific inhibitors as well as an FIH specific inhibitor that is active in cells. Excessive accumulation of R-2-hydroxyglutarate (R-2HG) in mutated isocitrate dehydrogenase (IDH)-mediated cancers has led R-2HG to be recognised as an 'oncometabolite'. The newly developed antibody assays were used to investigate the effects of cell-permeable 2HG derivatives on the activity of the HIF hydroxylases in cells. This indicated that direct R-2HG inhibition of PHDs does not play a role in mutated IDH-mediated tumourgenesis. The PHDs have been proposed to play a general role as metabolic sensors besides their function as intracellular oxygen sensors. The Krebs cycle metabolite 2OG (a co-substrate of HIF hydroxylases) was therefore investigated as a potential regulator of the PHDs. The cell-based results demonstrate that 2OG elevation results in HIF-α induction, a mechanism suggested to be, at least in part, through PHD inhibition as supported by in vitro and cell-based results. This thesis also describes the first attempt to apply a chemical-genetic approach to functional studies of the PHD isoforms. The in vitro results demonstrate the feasibility of selective inhibition of PHD2 by employing small-molecule-sensitive PHD2 variants. However, attempts to test this approach in mammalian cells have not been successful to date due to the lack of a suitable cell-system. Work on PHD inhibition then describes the development of a new class of diacylhydrazine-based PHD inhibitors. Findings show that some of these compounds are capable of binding to the PHD2 active site and simultaneously inducing the binding of a second iron to PHD2. The reported PHD inhibitor, aspirin metabolite 2,3-dihydroxybenzoylglycine (DHBG), was unexpectedly found to exhibit a concentration-dependent dichotomous effect on HIF stabilisation and HIF suppression in VHL-competent cells. DHBG and other aspirin metabolites including gentisuric acid (GUA) were subsequently found to suppress HIF-1α and HIF-2α levels in renal carcinoma RCC4 VHL-defective cells, suggesting that therapeutic effects of aspirin in cancers may involve potential regulation of HIF-α activity. </p

Probing replacement of pyrophosphate via click chemistry; synthesis of UDP-sugar analogues as potential glycosyl transferase inhibitors.

A series of potential UDP-sugar mimics were readily synthesised by copper(I) catalysed modified Huisgen cycloaddition of the corresponding alpha-propargyl glycosides with 5-azido uridine in aqueous solution. None of the compounds accessed displayed significant inhibitory activity at concentrations of up to 4.5mM in an assay against bovine milk beta-1,4-galactosyltransferase

Investigating the dependence of the hypoxia-inducible factor hydroxylases (factor inhibiting HIF and prolyl hydroxylase domain 2) on ascorbate and other reducing agents.

The HIF (hypoxia-inducible factor) hydroxylases [PHDs or EGLNs (prolyl hydroxylases), which in humans are PHD isoforms 1-3, and FIH (factor inhibiting HIF)] regulate HIF levels and activity. These enzymes are Fe(II)/2-oxoglutarate-dependent oxygenases, many of which are stimulated by ascorbate. We have investigated the ascorbate dependence of PHD2-catalysed hydroxylation of two prolyl hydroxylation sites in human HIF-1alpha, and of FIH-catalysed hydroxylation of asparaginyl hydroxylation sites in HIF-1alpha and in a consensus ankyrin repeat domain peptide. The initial rate and extent of hydroxylation was increased in the presence of ascorbate for each of these reactions. When ascorbate was replaced with structural analogues, the results revealed that the ascorbate side chain was not important in its contribution to HIF hydroxylase catalysis, whereas modifications to the ene-diol portion of the molecule negated the ability to promote hydroxylation. We investigated whether alternative reducing agents (glutathione and dithiothreitol) could be used to promote HIF hydroxylase activity, and found partial stimulation of hydroxylation in an apparently enzyme- and substrate-specific manner. The results raise the possibility of developing reducing agents targeted to specific HIF hydroxylase-catalysed reactions