Molecular dynamics studies of the STAT3 homodimer:DNA complex: relationships between STAT3 mutations and protein-DNA recognition.

Signal Transducers and Activators of Transcription (STAT) proteins are a group of latent cytoplasmic transcription factors involved in cytokine signaling. STAT3 is a member of the STAT family and is expressed at elevated levels in a large number of diverse human cancers and is now a validated target for anticancer drug discovery.. Understanding the dynamics of the STAT3 dimer interface, accounting for both protein-DNA and protein-protein interactions, with respect to the dynamics of the latent unphosphorylated STAT3 monomer, is important for designing potential small-molecule inhibitors of the activated dimer. Molecular dynamics (MD) simulations have been used to study the activated STAT3 homodimer:DNA complex and the latent unphosphorylated STAT3 monomer in an explicit water environment. Analysis of the data obtained from MD simulations over a 50 ns time frame has suggested how the transcription factor interacts with DNA, the nature of the conformational changes, and ways in which function may be affected. Examination of the dimer interface, focusing on the protein-DNA interactions, including involvement of water molecules, has revealed the key residues contributing to the recognition events involved in STAT3 protein-DNA interactions. This has shown that the majority of mutations in the DNA-binding domain are found at the protein-DNA interface. These mutations have been mapped in detail and related to specific protein-DNA contacts. Their structural stability is described, together with an analysis of the model as a starting-point for the discovery of novel small-molecule STAT3 inhibitors.

Signal and variability within a Holocene peat bog - Chronological uncertainties of pollen, macrofossil and fungal proxies

A single raised bog from the eastern Netherlands has been repeatedly analysed and ¹⁴C dated over the past few decades. Here we assess the within-site variability of fossil proxy data through comparing the regional
pollen, macrofossils and non-pollen palynomorphs of four of these profiles. High-resolution chronologies were obtained using ¹⁴C dating and Bayesian age-depth modelling. Where chronologies of profiles overlap, proxy curves are compared between the profiles using greyscale graphs that visualise chronological uncertainties. Even at this small spatial scale, there is considerable variability of the fossil proxy curves. Implications regarding signal (climate) and noise (internal dynamics) of the different types of fossil proxies are discussed. Single cores are of limited value for reconstructing centennial-scale climate change, and only by combining multiple cores and proxies can we obtain a reliable understanding of past environmental change and possible forcing factors (e.g., solar variability).

Stability studies of the metabolites of nitrofuran antibiotics during storage and cooking

Nitrofuran antibiotics cannot be used in food production within the European Union because of their potential health risks to consumers. The recent discovery of their widespread use in global food industries and the finding of semicarbazide in baby food as a result of packaging contamination have focused attention on the toxicity and stability of these drugs and their metabolites. The stability of the nitrofuran marker residues 3-amino-2-oxazolidinone (AOZ), 3-amino-5-morpholinomethyl-2-oxazolidone (AMOZ), 1-aminohydantoin (AHD) and semicarbazide (SEM) were tested. Muscle and liver of nitrofuran treated pigs were cooked by frying, grilling, roasting and microwaving. Between 67 and 100% of the residues remained after cooking, demonstrating that these metabolites are largely resistant to conventional cooking techniques and will continue to pose a health risk. The concentration of metabolites in pig muscle and liver did not drop significantly during 8 months of storage at -20 degrees C. Metabolite stock and working standard solutions in methanol were also stable for 10 months at 4 degrees C. Only a 10 ng ml(-1) solution of SEM showed a small drop in concentration over this extended storage period.

Frequency Stability Issues for Islanded Power Systems

Frequency stability has not necessarily been a major problem for the majority of power systems in the past. However, for economic and environmental reasons, power systems are now operated closer to stability limits to maximise the use of the existing networks. Therefore, introduction of new, more efficient and renewable generation technologies, and their effect on the power system must be fully understood if a reliable and secure electricity supply is to be maintained. Using the Northern Ireland, and interconnected Republic of Ireland electricity networks as a case study, this paper addresses some of the issues regarding integration and modelling of combined cycle gas turbines (CCGT), and wind turbine generator (WTG) technology on a small islanded power system.

Received signal characteristics of outdoor body-to-body communications channels at 2.45 GHz

In this paper we conduct a number of experiments to assess the impact of typical human body movements on the signal characteristics of outdoor body-to-body communications channels using flexible patch antennas. A modified log-distance path loss model which accounts for body shadowing and signal fading due to small movements is used to model the measured data. For line of sight channels, in which both ends of the body-to-body link are stationary, the path loss exponent is close to that for free space, although the received signal is noticeably affected by involuntary or physiological-related movements of both persons. When one person moves to obstruct the direct signal path between nodes, attenuation by the person's body can be as great as 40 dB, with even greater variation observed due to fading. The effects of movements such as rotation, tilt, walking in line of sight and non-line of sight on body-to-body communications channels are also investigated in this study. © 2011 IEEE.

The effect of nozzle geometry on the flow characteristics of small water jets

A wide variety of processes make use of plain orifice nozzles. Fuel injectors for internal combustion engines incorporate these nozzles to generate finely atomized sprays. Processes such as jet cutting, jet cleaning, and hydroentanglement, on the other hand, use similar nozzles, but require coherent jets. The spray or jet characteristics depend on the stability of the flow emerging from the orifice. This problem has been extensively researched for nozzles with diameters above 300 μm. Much less is known about the characteristics of jets produced by nozzles with smaller diameters, where viscous effects and small geometric variations due to manufacturing tolerances are likely to play an increasing role. Results are presented of a wide-ranging investigation of geometry effects on the flow parameters and jet characteristics of nozzles with diameters between 120 and 170 μm. Nozzles with circular cross-section and conical, cone-capillary and capillary axial designs were investigated. For conical and cone-capillary nozzles, the effect of cone angle and effects due to interactions between adjacent nozzles in the multi-hole cone-capillary nozzles were studied. For capillary nozzles, the effects of diameter variations and inlet edge roundness for capillary nozzles were considered. Furthermore, the effect of varying the aspect ratio (ratio of major and minor axes) of elliptical nozzles was studied. Flowrate and jet impact force measurements were carried out to determine the discharge coefficient C, velocity coefficient C, and contraction coefficient C of the nozzles for supply pressures between 3 and 12 MPa. Visualizations of the jet flow were carried out in the vicinity of the nozzle exit in order to identify near-nozzle flow regimes and to study jet coherence. The relationship between nozzle geometry, discharge characteristics, and jet coherence is examined. © IMechE 2006.

S100A2 is a BRCA1/p63 coregulated tumour suppressor gene with roles in the regulation of mutant p53 stability

Here, we show for the first time that the familial breast/ovarian cancer susceptibility gene, BRCA1, along with interacting ΔNp63 proteins, transcriptionally upregulate the putative tumour suppressor protein, S100A2. Both BRCA1 and ΔNp63 proteins are required for S100A2 expression. BRCA1 requires ΔNp63 proteins for recruitment to the S100A2 proximal promoter region, while exogenous expression of individual ΔNp63 proteins cannot activate S100A2 transcription in the absence of a functional BRCA1. Consequently, mutation of the ΔNp63/p53 response element within the S100A2 promoter completely abrogates the ability of BRCA1 to upregulate S100A2. S100A2 shows growth control features in a range of cell models. Transient or stable exogenous S100A2 expression inhibits the growth of BRCA1 mutant and basal-like breast cancer cell lines, while short interfering RNA (siRNA) knockdown of S100A2 in non-tumorigenic cells results in enhanced proliferation. S100A2 modulates binding of mutant p53 to HSP90, which is required for efficient folding of mutant p53 proteins, by competing for binding to HSP70/HSP90 organising protein (HOP). HOP is a cochaperone that is required for the efficient transfer of proteins from HSP70 to HSP90. Loss of S100A2 leads to an HSP90-dependent stabilisation of mutant p53 with a concomitant loss of p63. Accordingly, S100A2-deficient cells are more sensitive to the HSP-90 inhibitor, 17-N-allylamino-17-demethoxygeldanamycin, potentially representing a novel therapeutic strategy for S100A2- and BRCA1-deficient cancers. Taken together, these data demonstrate the importance of S100A2 downstream of the BRCA1/ΔNp63 signalling axis in modulating transcriptional responses and enforcing growth control mechanisms through destabilisation of mutant p53.

Compressive Sensing based Detector for Sparse Signal Modulation in Precoded OFDM

In this paper, we propose a sparse signal modulation (SSM) method for precoded orthogonal frequency division multiplexing (OFDM) systems and study the signal detection. Although a receiver is able to exploit a path diversity gain with random precoding in OFDM, the complexity of the receiver is usually high as the orthogonality is not retained due to precoding. However, with SSM, we can derive a low-complexity detector that can provide reasonably good performances with a low sparsity ratio based on the notion of compressive sensing (CS). An important feature of a CS detector is that it can estimate SSM signals with a small fraction of the received signals over sub-carriers. This feature can allow us to build a low cost receiver with a small number of demodulators.

SURFACE ENHANCED RAMAN-SCATTERING FROM MILDLY ROUGHENED SURFACES - VARIATION OF SIGNAL WITH METAL GRAIN-SIZE

The intensity of surface enhanced Raman scattering from benzoic acid derivatives on mildly roughened, thermally evaporated Ag films shows a remarkably strong dependence on metal grain size. Large grained (slowly deposited) films give a superior response, by up to a factor of 10, to small grained (quickly deposited) films, with films of intermediate grain size yielding intermediate results. The optical field amplification underlying the enhancement mechanism is due to the excitation of surface plasmon polaritons (SPPs). Since surface roughness characteristics, as determined by STM, remain relatively constant as a function of deposition rate, it is argued that the contrast in Raman scattering is due to differences in elastic grain boundary scattering of SPPs (leading to different degrees of internal SPP damping), rather than differences in the interaction of SPPs with surface inhomogeneities.

Received Signal Characteristics of the Indoor Off-Body Communications Channel at 5.8 GHz

In this paper we investigate the received signal characteristics of a mobile chest-worn transmitter at 5.8 GHz within a high multipath indoor environment. The off-body channel measurements considered both the co- and cross-polarized received signal for both line-of-sight (LOS) and non-LOS (NLOS) conditions. A straightforward channel model based upon the estimated path loss, a lognormal slow fading component and Ricean small-scale fading contribution is developed and used to perform simulations which allow the generation of first order received signal power characteristics.

A co-operative formation-based collision avoidance approach for a group of autonomous vehicles (Special Issue on Adaptive Control and Signal Processing in Marine System)

This paper employs a unique decentralised cooperative control method to realise a formation-based collision avoidance strategy for a group of autonomous vehicles. In this approach, the vehicles' role in the formation and their alert and danger areas are first defined, and the formation-based intra-group and external collision avoidance methods are then proposed to translate the collision avoidance problem into the formation stability problem. The extension–decomposition–aggregation formation control method is next employed to stabilise the original and modified formations, whilst manoeuvring, and subsequently solve their collision avoidance problem indirectly. Simulation study verifies the feasibility and effectiveness of the intra-group and external collision avoidance strategy. It is demonstrated that both formation control and collision avoidance problems can be simultaneously solved if the stability of the expanded formation including external obstacles can be satisfied.

Stability of Short-span Bridges Subject to Overtopping during Floods: Case Studies from UK and the USA

As a consequence of increased levels of flooding, largely attributable to urbanization of watersheds (and perhaps climate change, more frequent extreme rainfall events are occurring and threatening existing critical infrastructure. Many of which are short-span bridges over relatively small waterways (e.g., small rivers, streams and canals). Whilst these short-span bridges were designed, often many years ago, to pass relatively minor the then standard return-period floods, in recenttimes the failure incidence of such short-span bridges has been noticeably increasing. This is suggestive of insufficient hydraulic capacity or alternative failure mechanism not envisaged at the time of design e.g. foundation scour or undermining. This paper presen ts, and draws lessons, from bridge failures in Ireland and the USA. For example, in November 2009, the UK and Ireland were subjected to extraordinarily severe weather conditions for several days. The resulting flooding led to the collapse of three UK bridges that were generally 19th century masonry arch bridges, withrelatively shallow foundations. Parallel failure events have been observed in the USA. To date, knowledge of the combined effect of waterway erosion, bridge submergence, and geotechnical collapse has not been adequately studied. Recent research carried out considered the hydraulic analysis of short span bridges under flood conditions, but no consideration was given towards the likely damage to these structures due to erosive coupling of hydraulic and geotechnical factors. Some work has been done to predict the discharge downstream of an inundated arch, focusing onpredicting afflux, as opposed to bridge scour, under both pressurized and free-surface flows, but no ! predictive equation for scour under pressurized conditions was ever considered. The case studies this paper presents will be augmented by the initial findings from the laboratory experiments investigating the effects of surcharged flow and subsequent scour within the vicinity of single span arch bridges. Velocities profiles will be shown within the vicinity of the arch, in addition to the depth of consequent scour, for a series of flows and model spans. The data will be presented and correlated to the most recent predictive equations for submerged contraction and abutment scour. The accuracy of these equations is examined, and the findings used as a basis for developing further studies in relation to short span bridges.

O-GlcNAc transferase integrates metabolic pathways to regulate the stability of c-MYC in human prostate cancer cells

Metabolic disruptions that occur widely in cancers offer an attractive focus for generalized treatment strategies. The hexosamine biosynthetic pathway (HBP) senses metabolic status and produces an essential substrate for O-linked β-N-acetylglucosamine transferase (OGT), which glycosylates and thereby modulates the function of its target proteins. Here, we report that the HBP is activated in prostate cancer cells and that OGT is a central regulator of c-Myc stability in this setting. HBP genes were overexpressed in human prostate cancers and androgen regulated in cultured human cancer cell lines. Immunohistochemical analysis of human specimens (n = 1987) established that OGT is upregulated at the protein level and that its expression correlates with high Gleason score, pT and pN stages, and biochemical recurrence. RNA interference-mediated siliencing or pharmacologic inhibition of OGT was sufficient to decrease prostate cancer cell growth. Microarray profiling showed that the principal effects of OGT inhibition in prostate cancer cells were related to cell-cycle progression and DNA replication. In particular, c-MYC was identified as a candidate upstream regulator of OGT target genes and OGT inhibition elicited a dose-dependent decrease in the levels of c-MYC protein but not c-MYC mRNA in cell lines. Supporting this relationship, expression of c-MYC and OGT was tightly correlated in human prostate cancer samples (n = 1306). Our findings identify HBP as a modulator of prostate cancer growth and c-MYC as a key target of OGT function in prostate cancer cells.

Petals of Resonance: A performance system for the transformation of small body sounds

A system of software and hardware that combines signal processing and contact microphones using normally inaudible body sounds, including heartbeat/pulse, respiration and internal sounds from the vocal tract that can be heard internally by the performer but not externally by others, to drive resonant filters. Performance at SARC Sonic Lab, Belfast, 19 Feb 2015 in collaboration with Birgit Ulher.

High-temperature stability study of 1 nm Al2O3 deposited on InAs surfaces investigated by synchrotron radiation based photoemission spectroscopy

High-resolution soft x-ray photoemission spectroscopy (SXPS) has been used to study the high-temperature thermal stability of ultra-thin atomic layer deposited (ALD) Al2O3 layers (~1 nm) on sulfur passivated and native oxide covered InAs surfaces. While the arsenic oxides were removed from both interfaces following a 600 °C anneal, a residual indium oxide signal remained. No significant differences were observed between the sulfur passivated and native oxide surfaces other than the thickness of the interfacial oxide layer while the Al2O3 stoichiometry remained unaffected by the anneals. The energy band offsets were determined for the Al2O3 on the sulfur passivated InAs surface using both valence band edge and shallow core-level photoemission measurements.