Use of NMR metabolomic plasma profiling methodologies to identify illicit growth-promoting administrations

Detection of growth-promoter use in animal production systems still proves to be an analytical challenge despite years of activity in the field. This study reports on the capability of NMR metabolomic profiling techniques to discriminate between plasma samples obtained from cattle treated with different groups of growth-promoting hormones (dexamethasone, prednisolone, oestradiol) based on recorded metabolite profiles. Two methods of NMR analysis were investigated—a Carr–Purcell–Meiboom–Gill (CPMG)-pulse sequence technique and a conventional 1H NMR method using pre-extracted plasma. Using the CPMG method, 17 distinct metabolites could be identified from the spectra. 1H NMR analysis of extracted plasma facilitated identification of 23 metabolites—six more than the alternative method and all within the aromatic region. Multivariate statistical analysis of acquired data from both forms of NMR analysis separated the plasma metabolite profiles into distinct sample cluster sets representative of the different animal study groups. Samples from both sets of corticosteroid-treated animals—dexamethasone and prednisolone—were found to be clustered relatively closely and had similar alterations to identified metabolite panels. Distinctive metabolite profiles, different from those observed within plasma from corticosteroid-treated animal plasma, were observed in oestradiol-treated animals and samples from these animals formed a cluster spatially isolated from control animal plasma samples. These findings suggest the potential use of NMR methodologies of plasma metabolite analysis as a high-throughput screening technique to aid detection of growth promoter use.

Rational design of a dual-mode optical and chemical prodrug

Purpose. The purpose of this study is to demonstrate the rational design and behaviour of the first dual mode optical and chemical prodrug, exemplified by an acetyl salicylic acid-based system. Methods. A cyclic 1,4-benzodioxinone prodrug was synthesised by reaction of 3,5-dimethoxybenzoin and acetyl salicoyl chloride with pyridine. After purification by column chromatography and recrystallization, characterization was achieved using infrared and NMR spectroscopies, mass spectrometry, elemental analysis and single crystal X-ray diffraction. Light-triggered drug liberation was characterised via UV-visible spectroscopy following low-power 365 nm irradiation for controlled times. Chemical drug liberation was characterised via UV-visible spectroscopy in pH 5.5 solution. Results. The synthetic method yielded pure prodrug, with full supporting characterisation. Light-triggered drug liberation proceeded at a rate of 8.30 10j2 sj1, while chemical, hydrolytic liberation proceeded independently at 1.89 10j3 sj1. The photochemical and hydrolytic reactions were both quantitative. Conclusions. This study demonstrates the first rational dual-mode optical and chemical prodrug, using acetyl salicylic acid as a model, acting as a paradigm for future dual-mode systems. Photochemical drug liberation proceeds 44 times faster than chemical liberation, suggesting potential use in drug-eluting medical devices where an additional burst of drug is required at the onset of infection.

Application of Heuristic Evaluation Method by Universal Design Experts

This study highlights how heuristic evaluation as a usability evaluation method can feed into current building design practice to conform to universal design principles. It provides a definition of universal usability that is applicable to an architectural design context. It takes the seven universal design principles as a set of heuristics and applies an iterative sequence of heuristic evaluation in a shopping mall, aiming to achieve a cost-effective evaluation process. The evaluation was composed of three consecutive sessions. First, five evaluators from different professions were interviewed regarding the construction drawings in terms of universal design principles. Then, each evaluator was asked to perform the predefined task scenarios. In subsequent interviews, the evaluators were asked to re-analyze the construction drawings. The results showed that heuristic evaluation could successfully integrate universal usability into current building design practice in two ways: (i) it promoted an iterative evaluation process combined with multi-sessions rather than relying on one evaluator and on one evaluation session to find the maximum number of usability problems, and (ii) it highlighted the necessity of an interdisciplinary ad hoc committee regarding the heuristic abilities of each profession. A multi-session and interdisciplinary heuristic evaluation method can save both the project budget and the required time, while ensuring a reduced error rate for the universal usage of the built environments.

Evolution of Clay Morphology in Polypropylene/Montmorillonite Nanocomposites upon Equi-biaxial Stretching: A Solid-State NMR and TEM Approach

Solid-state NMR and TEM were used to quantitatively examine the evolution of clay morphology upon equibiaxial stretching of polypropylene/montmorillonite (PP-MMT) nanocomposites up to a stretch ratio (?= final length/initial length) of 3.5. 1 H spin-lattice relaxation times were measured by the saturation-recovery sequence. For the nanocomposites, initial portions of the magnetization recovery
curves (e~20 ms) were found to depend on v t, indicative of diffusion-limited relaxation and in agreement with calculations based on estimates of the spin-diffusion barrier radius surrounding the paramagnetic centers in the clay, the electron-nucleus coupling constant, and the spin-diffusion coefficient. Initial slopes of these magnetization recovery curves directly correlated with the fraction of clay/polymer interface. New clay surface was exposed as a near linear function of strain. Long-time portions of the magnetization recovery curves yielded information on the average interparticle separations, which decreased slowly before reaching a plateau at ?=~2.5 as particles aligned. TEM images supported these findings and were used to define and quantify degrees of exfoliation and homogeneity from the NMR data. Exfoliation, defined as (platelets/ stack)-1, increased from 0.38 (unstretched) to 0.80 at ? = 3.5 for PP-MMT nanocomposites stretched at
150 C and 16 s-1. A lower stretch temperature, 145 C, which is slightly below melting onset, led to an exfoliation degree of 0.87 at ?= 2.8, consistent with the ability of higher melt viscosities to allow for higher shear stress transfer. Exposure of new clay surface is attributed to aggregate breakup and orientation at low strains (? e ~2) and to platelets sliding apart at higher strains.

The design and performance of a 2.5-GHz telecommand link for wireless biomedical monitoring

This paper details the implementation and operational performance of a minimum-power 2.45-GHz pulse receiver and a companion on-off keyed transmitter for use in a semi-active duplex RF biomedical transponder. A 50-Ohm microstrip stub-matched zero-bias diode detector forms the heart of a body-worn receiver that has a CMOS baseband amplifier consuming 20 microamps from +3 V and achieves a tangential sensitivity of -53 dBm. The base transmitter generates 0.5 W of peak RF output power into 50 Ohms. Both linear and right-hand circularly polarized Tx-Rx antenna sets were employed in system reliability trials carried out in a hospital Coronary Care Unit, For transmitting antenna heights between 0.3 and 2.2 m above floor level, transponder interrogations were 95% reliable within the 67-m-sq area of the ward, falling to an average of 46 % in the surrounding rooms and corridors. Overall, the circular antenna set gave the higher reliability and lower propagation power decay index.

Multi-pulse scheme for enhancing electron localization through vibrational wavepacket manipulation

A novel scheme for enhancing electron localization in intense-field dissociation is outlined. Through manipulation of a bound vibrational wavepacket in the exemplar deuterium molecular ion, simulations demonstrate that the application of multiple phase-locked, few-cycle IR pulses can provide a powerful scheme for directing the molecular dissociation pathway. By tuning the time delay and carrier–envelope–phase for a sequence of pulse interactions, the probability of the electron being localized to a chosen nucleus can be enhanced to above 80%.

Characterisation of virus transport and attenuation in epikarst using short pulse and prolonged injection multi-tracer testing

Attenuation processes controlling virus fate and transport in the vadose zone of karstified systems can strongly influence groundwater quality. This research compares the breakthrough of two bacteriophage tracers (H40/1 and T7), with contrasting properties, at subsurface monitoring points following application onto an overlying composite sequence of thin organic soil and weathered limestone (epikarst). Short pulse multi-tracer test results revealed that T7 (Source concentration, Co=1.8x106pfu/mL) and H40/1(Co=5.9x106pfu/mL) could reach sampling points 10m below ground less than 30 minutes after tracer application. Contrasting deposition rates, determined from simulated tracer responses, reflected the potential of the ground to differentially attenuate viruses. Prolonged application of both T7 (Co=2.3x104pfu/mL) and H40/1 (Co=1.3x105pfu/mL) over a five hour period during a subsequent test, in which ionic strength levels observed at monitoring points rose consistently, corresponded to a rapid rise in T7 levels, followed by a gradual decline before the end of tracer injection; this reflected reaction-limited deposition in the system. T7’s response contrasted with that of H40/1, whose concentration remained constant over a three hour period before declining dramatically prior to the end of tracer injection. Subsequent application of lower ionic strength tracer-free flush water generated a rapid rise in H40/1 levels and a more gradual release of T7. Results highlight the benefits of employing prolonged injection multi-tracer tests for identifying processes not apparent from conventional short pulse tests. Study findings demonstrate that despite rapid transport rates, the epikarst is capable of physicochemical filtration of viruses and their remobilization, depending on virus type and hydrochemical conditions.

Unraveling the Structure and Function of G Protein-Coupled Receptors Through NMR Spectroscopy

G protein-coupled receptors (GPCRs) are a large superfamily of signaling proteins expressed on the plasma membrane. They are involved in a wide range of physiological processes and, therefore, are exploited as drug targets in a multitude of therapeutic areas. In this extent, knowledge of structural and functional properties of GPCRs may greatly facilitate rational design of modulator compounds. Solution and solid-state nuclear magnetic resonance (NMR) spectroscopy represents a powerful method to gather atomistic insights into protein structure and dynamics. In spite of the difficulties inherent the solution of the structure of membrane proteins through NMR, these methods have been successfully applied, sometimes in combination with molecular modeling, to the determination of the structure of GPCR fragments, the mapping of receptor-ligand interactions, and the study of the conformational changes associated with the activation of the receptors. In this review, we provide a summary of the NMR contributions to the study of the structure and function of GPCRs, also in light of the published crystal structures.

THE MARINE RADIOCARBON BOMB PULSE ACROSS THE TEMPERATE NORTH ATLANTIC: A COMPILATION OF Delta C-14 TIME HISTORIES FROM ARCTICA ISLANDICA GROWTH INCREMENTS

Marine radiocarbon bomb-pulse time histories of annually resolved archives from temperate regions have been underexploited. We present here series of Delta C-14 excess from known-age annual increments of the long-lived bivalve mollusk Arctica islandica from 4 sites across the coastal North Atlantic (German Bight, North Sea; Tromso, north Norway; Siglufjordur, north Icelandic shelf; Grimsey, north Icelandic shelf) combined with published series from Georges Bank and Sable Bank (NW Atlantic) and the Oyster Ground (North Sea). The atmospheric bomb pulse is shown to be a step-function whose response in the marine environment is immediate but of smaller amplitude and which has a longer decay time as a result of the much larger marine carbon reservoir. Attenuation is determined by the regional hydrographic setting of the sites, vertical mixing, processes controlling the isotopic exchange of C-14 at the air-sea boundary, C-14 content of the freshwater flux, primary productivity, and the residence time of organic matter in the sediment mixed layer. The inventories form a sequence from high magnitude-early peak (German Bight) to low magnitude-late peak (Grimsey). All series show a rapid response to the increase in atmospheric Delta C-14 excess but a slow response to the subsequent decline resulting from the succession of rapid isotopic air-sea exchange followed by the more gradual isotopic equilibration in the mixed layer due to the variable marine carbon reservoir and incorporation of organic carbon from the sediment mixed layer. The data constitute calibration series for the use of the bomb pulse as a high-resolution dating tool in the marine environment and as a tracer of coastal ocean water masses.

Conformational Dynamics of the Human Propeller Telomeric DNA Quadruplex on a Microsecond Time Scale

The human telomeric DNA sequence with four repeats can fold into a parallel-stranded propeller-type topology. NMR structures solved under molecular crowding experiments correlate with the crystal structures found with crystal-packing interactions that are effectively equivalent to molecular crowding. This topology has been used for rationalization of ligand design and occurs experimentally in a number of complexes with a diversity of ligands, at least in the crystalline state. While G-quartet stems have been well characterised, the interactions of the TTA loop with the G-quartets are much less defined. To better understand the conformational variability and structural dynamics of the propeller-type topology, we performed molecular dynamics simulations in explicit solvent up to 1.5 µs. The analysis provides a detailed atomistic account of the dynamic nature of the TTA loops highlighting their interactions with the G-quartets including formation of an A:A base pair, triad, pentad and hexad. The results present a threshold in quadruplex simulations, with regards to understanding the flexible nature of the sugar-phosphate backbone in formation of unusual architecture within the topology. Furthermore, this study stresses the importance of simulation time in sampling conformational space for this topology.

Transmit and receive filter design for OFDM based WLAN systems

We analyze the effect of different pulse shaping filters on the orthogonal frequency division multiplexing (OFDM) based wireless local area network (LAN) systems in this paper. In particular, the performances of the square root raised cosine (RRC) pulses with different rolloff factors are evaluated and compared. This work provides some guidances on how to choose RRC pulses in practical WLAN systems, e.g., the selection of rolloff factor, truncation length, oversampling rate, quantization levels, etc.

The efficacy of a CDIO based integrated curriculum as preparation for professional practice in product design and development

The School of Mechanical and Aerospace Engineering at Queen’s University Belfast started BEng and MEng degree programmes in Product Design and Development (PDD) in 2004. Intended from the outset to be significantly different from the existing programmes within the School the PDD degrees used the syllabus and standards defined by the CDIO Initiative as the basis for an integrated curriculum. Students are taught in the context of conceiving, designing, implementing and operating a product. Fundamental to this approach is a core sequence of Design-Build-Test (DBT) experiences which facilitates the development of a range of professional skills as well as the immediate application of technical knowledge gained in strategically aligned supporting modules.
The key objective of the degree programmes is to better prepare students for professional practice. PDD graduates were surveyed using a questionnaire developed by the CDIO founders and interviewed to examine the efficacy of these degree programmes, particularly in this key objective. Graduate employment rates, self assessment of graduate attributes and examples of work produced by MEng graduates provided positive evidence that their capabilities met the requirements of the profession. The 24% questionnaire response rate from the 96 graduates to date did not however facilitate statistically significant conclusions to be drawn and particularly not for BEng graduates who were under represented in the response group. While not providing proof of efficacy the investigation did provide a good amount of useful data for consideration as part of a continuous improvement process.

Multi-level wordline driver for robust SRAM design in nano-scale CMOS technology

In this paper, a multi-level wordline driver scheme is presented to improve 6T-SRAM read and write stability. The proposed wordline driver generates a shaped pulse during the read mode and a boosted wordline during the write mode. During read, the shaped pulse is tuned at nominal voltage for a short period of time, whereas for the remaining access time, the wordline voltage is reduced to save the power consumption of the cell. This shaped wordline pulse results in improved read noise margin without any degradation in access time for small wordline load. The improvement is explained by examining the dynamic and nonlinear behavior of the SRAM cell. Furthermore, during the hold mode, for a short time (depending on the size of boosting capacitance), wordline voltage becomes negative and charges up to zero after a specific time that results in a lower leakage current compared to conventional SRAM. The proposed technique results in at least 2× improvement in read noise margin while it improves write margin by 3× for lower supply voltages than 0.7 V. The leakage power for the proposed SRAM is reduced by 2% while the total power is improved by 3% in the worst case scenario for an SRAM array. The main advantage of the proposed wordline driver is the improvement of dynamic noise margin with less than 2.5% penalty in area. TSMC 65 nm technology models are used for simulations.