Guanine specific binding at a DNA junction formed by d[CG(5-BrU)ACG]2 with a topoisomerase poison in the presence of Co2+Ions†,‡

The structure of the duplex d[CG(5-BrU)ACG]2 bound to 9-bromophenazine-4-carboxamide has been solved through MAD phasing at 2.0 Å resolution. It shows an unexpected and previously unreported intercalation cavity stabilized by the drug and novel binding modes of Co2+ ions at certain guanine N7 sites. For the intercalation cavity the terminal cytosine is rotated to pair with the guanine of a symmetry-related duplex to create a pseudo-Holliday junction geometry, with two such cavities linked through the minor groove interactions of the N2/N3 guanine sites at an angle of 40°, creating a quadruplex-like structure. The mode of binding of the drug is shown to be disordered, with the major conformations showing the side chain bound to the N7 position of adjacent guanines. The other end of the duplex exhibits a terminal base fraying in the presence of Co2+ ions linking symmetry-related guanines, causing the helices to intertwine through the minor groove. The stabilization of the structure by the intercalating drug shows that this class of compound may bind to DNA junctions as well as duplex DNA or to strand-nicked DNA (‘hemi-intercalated'), as in the cleavable complex. This suggests a structural basis for the dual poisoning of topoisomerase I and II enzymes by this family of drugs.

Evaluation of field wetlands for mitigation of diffuse pollution from agriculture: sediment retention, cost and effectiveness

Diffuse pollution, and the contribution from agriculture in particular, has become increasingly important as pollution from point sources has been addressed by wastewater treatment. Land management approaches, such as construction of field wetlands, provide one group of mitigation options available to farmers. Although field wetlands are widely used for diffuse pollution control in temperate environments worldwide, there is a shortage of evidence for the effectiveness and viability of these mitigation options in the UK. The Mitigation Options for Phosphorus and Sediment Project aims to make recommendations regarding the design and effectiveness of field wetlands for diffuse pollution control in UK landscapes. Ten wetlands have been built on four farms in Cumbria and Leicestershire. This paper focuses on sediment retention within the wetlands, estimated from annual sediment surveys in the first two years, and discusses establishment costs. It is clear that the wetlands are effective in trapping a substantial amount of sediment. Estimates of annual sediment retention suggest higher trapping rates at sandy sites (0.5–6 t ha�1 yr�1), compared to silty sites (0.02–0.4 t ha�1 yr�1) and clay sites (0.01–0.07 t ha�1 yr�1). Establishment costs for the wetlands ranged from £280 to £3100 and depended more on site specific factors, such as fencing and gateways on livestock farms, rather than on wetland size or design. Wetlands with lower trapping rates would also have lower maintenance costs, as dredging would be required less frequently. The results indicate that field wetlands show promise for inclusion in agri-environment schemes, particularly if capital payments can be provided for establishment, to encourage uptake of these multi-functional features.

Connecting mean field models of neural activity to EEG and fMRI data

Progress in functional neuroimaging of the brain increasingly relies on the integration of data from complementary imaging modalities in order to improve spatiotemporal resolution and interpretability. However, the usefulness of merely statistical combinations is limited, since neural signal sources differ between modalities and are related non-trivially. We demonstrate here that a mean field model of brain activity can simultaneously predict EEG and fMRI BOLD with proper signal generation and expression. Simulations are shown using a realistic head model based on structural MRI, which includes both dense short-range background connectivity and long-range specific connectivity between brain regions. The distribution of modeled neural masses is comparable to the spatial resolution of fMRI BOLD, and the temporal resolution of the modeled dynamics, importantly including activity conduction, matches the fastest known EEG phenomena. The creation of a cortical mean field model with anatomically sound geometry, extensive connectivity, and proper signal expression is an important first step towards the model-based integration of multimodal neuroimages.

Realistic mean field forward predictions for the integration of co-registered EEG/fMRI

Brain activity can be measured non-invasively with functional imaging techniques. Each pixel in such an image represents a neural mass of about 105 to 107 neurons. Mean field models (MFMs) approximate their activity by averaging out neural variability while retaining salient underlying features, like neurotransmitter kinetics. However, MFMs incorporating the regional variability, realistic geometry and connectivity of cortex have so far appeared intractable. This lack of biological realism has led to a focus on gross temporal features of the EEG. We address these impediments and showcase a "proof of principle" forward prediction of co-registered EEG/fMRI for a full-size human cortex in a realistic head model with anatomical connectivity, see figure 1. MFMs usually assume homogeneous neural masses, isotropic long-range connectivity and simplistic signal expression to allow rapid computation with partial differential equations. But these approximations are insufficient in particular for the high spatial resolution obtained with fMRI, since different cortical areas vary in their architectonic and dynamical properties, have complex connectivity, and can contribute non-trivially to the measured signal. Our code instead supports the local variation of model parameters and freely chosen connectivity for many thousand triangulation nodes spanning a cortical surface extracted from structural MRI. This allows the introduction of realistic anatomical and physiological parameters for cortical areas and their connectivity, including both intra- and inter-area connections. Proper cortical folding and conduction through a realistic head model is then added to obtain accurate signal expression for a comparison to experimental data. To showcase the synergy of these computational developments, we predict simultaneously EEG and fMRI BOLD responses by adding an established model for neurovascular coupling and convolving "Balloon-Windkessel" hemodynamics. We also incorporate regional connectivity extracted from the CoCoMac database [1]. Importantly, these extensions can be easily adapted according to future insights and data. Furthermore, while our own simulation is based on one specific MFM [2], the computational framework is general and can be applied to models favored by the user. Finally, we provide a brief outlook on improving the integration of multi-modal imaging data through iterative fits of a single underlying MFM in this realistic simulation framework.

Balanced excitation and inhibition: Model based analysis of local field potentials

We have developed a model of the local field potential (LFP) based on the conservation of charge, the independence principle of ionic flows and the classical Hodgkin–Huxley (HH) type intracellular model of synaptic activity. Insights were gained through the simulation of the HH intracellular model on the nonlinear relationship between the balance of synaptic conductances and that of post-synaptic currents. The latter is dependent not only on the former, but also on the temporal lag between the excitatory and inhibitory conductances, as well as the strength of the afferent signal. The proposed LFP model provides a method for decomposing the LFP recordings near the soma of layer IV pyramidal neurons in the barrel cortex of anaesthetised rats into two highly correlated components with opposite polarity. The temporal dynamics and the proportional balance of the two components are comparable to the excitatory and inhibitory post-synaptic currents computed from the HH model. This suggests that the two components of the LFP reflect the underlying excitatory and inhibitory post-synaptic currents of the local neural population. We further used the model to decompose a sequence of evoked LFP responses under repetitive electrical stimulation (5 Hz) of the whisker pad. We found that as neural responses adapted, the excitatory and inhibitory components also adapted proportionately, while the temporal lag between the onsets of the two components increased during frequency adaptation. Our results demonstrated that the balance between neural excitation and inhibition can be investigated using extracellular recordings. Extension of the model to incorporate multiple compartments should allow more quantitative interpretations of surface Electroencephalography (EEG) recordings into components reflecting the excitatory, inhibitory and passive ionic current flows generated by local neural populations.

MALDI MS profiling of post-DRE urine samples highlights the potential of b-Microseminoprotein as a marker for prostatic diseases

BACKGROUND. To use spectra acquired by matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) from pre- and post-digital rectal examination (DRE) urine samples to search for discriminating peaks that can adequately distinguish between benign and malignant prostate conditions, and identify the peaks’ underlying biomolecules. METHODS. Twenty-five participants with prostate cancer (PCa) and 27 participants with a variety of benign prostatic conditions as confirmed by a 10-core tissue biopsy were included. Pre- and post-DRE urine samples were prepared for MALDI MS profiling using an automated clean-up procedure. Following mass spectra collection and processing, peak mass and intensity were extracted and subjected to statistical analysis to identify peaks capable of distinguishing between benign and cancer. Logistic regression was used to combine markers to create a sensitive and specific test. RESULTS. A peak at m/z 10,760 was identified as b-microseminoprotein (b-MSMB) and found to be statistically lower in urine from PCa participants using the peak’s average areas. By combining serum prostate-specific antigen (PSA) levels with MALDI MS-measured b-MSMB levels, optimum threshold values obtained from Receiver Operator characteristics curves gave an increased sensitivity of 96% at a specificity of 26%. CONCLUSIONS. These results demonstrate that with a simple sample clean-up followed by MALDI MS profiling, significant differences of MSMB abundance were found in post-DRE urine samples. In combination with PSA serum levels, obtained from a classic clinical assay led to high classification accuracy for PCa in the studied sample set. Our results need to be validated in a larger multicenter prospective randomized clinical trial.

Within, but not between hands interactions in vibrotactile detection thresholds reflect somatosensory receptive field organization

Detection of a tactile stimulus on one finger is impaired when a concurrent stimulus (masker) is presented on an additional finger of the same or the opposite hand. This phenomenon is known to be finger-specific at the within-hand level. However, whether this specificity is also maintained at the between-hand level is not known. In four experiments, we addressed this issue by combining a Bayesian adaptive staircase procedure (QUEST) with a two-interval forced choice (2IFC) design in order to establish threshold for detecting 200ms, 100Hz sinusoidal vibrations applied to the index or little fingertip of either hand (targets). We systematically varied the masker finger (index, middle, ring, or little finger of either hand), while controlling the spatial location of the target and masker stimuli. Detection thresholds varied consistently as a function of the masker finger when the latter was on the same hand (Experiments 1 and 2), but not when on different hands (Experiments 3 and 4). Within the hand, detection thresholds increased for masker fingers closest to the target finger (i.e., middle>ring when the target was index). Between the hands, detection thresholds were higher only when the masker was present on any finger as compared to when the target was presented in isolation. The within hand effect of masker finger is consistent with the segregation of different fingers at the early stages of somatosensory processing, from the periphery to the primary somatosensory cortex (SI). We propose that detection is finger-specific and reflects the organisation of somatosensory receptive fields in SI within, but not between the hands.

Characterization and antimicrobial efficacy against E. coli of a helium/air plasma at atmospheric pressure created in a plastic package

A plasma source, sustained by the application of a floating high voltage (±15 kV) to parallel-plate electrodes at 50 Hz, has been achieved in a helium/air mixture at atmospheric pressure (P = 105 Pa) contained in a zip-locked plastic package placed in the electrode gap. Some of the physical and antimicrobial properties of this apparatus were established with a view to ascertain its performance as a prototype for the disinfection of fresh produce. The current–voltage (I–V) and charge–voltage (Q–V) characteristics of the system were measured as a function of gap distance d, in the range (3 × 103 ≤ Pd ≤ 1.0 × 104 Pa m). The electrical measurements showed this plasma source to exhibit the characteristic behaviour of a dielectric barrier discharge in the filamentary mode and its properties could be accurately interpreted by the two-capacitance in series model. The power consumed by the discharge and the reduced field strength were found to decrease quadratically from 12.0 W to 4.5 W and linearly from 140 Td to 50 Td, respectively, in the range studied. Emission spectra of the discharge were recorded on a relative intensity scale and the dominant spectral features could be assigned to strong vibrational bands in the 2+ and 1− systems of N2 and ${\rm N}_2^+$ , respectively, with other weak signatures from the NO and OH radicals and the N+, He and O atomic species. Absolute spectral intensities were also recorded and interpreted by comparison with the non-equilibrium synthetic spectra generated by the computer code SPECAIR. At an inter-electrode gap of 0.04 m, this comparison yielded typical values for the electron, vibrational and translational (gas) temperatures of (4980 ± 100) K, (2700 ± 200) K and (300 ± 100) K, respectively and an electron density of 1.0 × 1017 m−3. A Boltzmann plot also provided a value of (3200 ± 200 K) for the vibrational temperature. The antimicrobial efficacy was assessed by studying the resistance of both Escherichia coli K12 its isogenic mutants in soxR, soxS, oxyR, rpoS and dnaK selected to identify possible cellular responses and targets related with 5 min exposure to the active gas in proximity of, but not directly in, the path of the discharge filaments. Both the parent strain and mutants populations were significantly reduced by more than 1.5 log cycles in these conditions, showing the potential of the system. Post-treatment storage studies showed that some transcription regulators and specific genes related to oxidative stress play an important role in the E. coli repair mechanism and that plasma exposure affects specific cell regulator systems.

The rulB gene of plasmid pWW0 is a hotspot for the site-specific insertion of integron-like elements found in the chromosomes of environmental Pseudomonas fluorescens group bacteria

The rulAB operon of Pseudomonas spp. confers fitness traits on the host and has been suggested to be a hotspot for insertion of mobile elements that carry avirulence genes. Here, for the first time, we show that rulB on plasmid pWW0 is a hotspot for the active site-specific integration of related integron-like elements (ILEs) found in six environmental pseudomonads (strains FH1–FH6). Integration into rulB on pWW0 occurred at position 6488 generating a 3 bp direct repeat. ILEs from FH1 and FH5 were 9403 bp in length and contained eight open reading frames (ORFs), while the ILE from FH4 was 16 233 bp in length and contained 16 ORFs. In all three ILEs, the first 5.1 kb (containing ORFs 1–4) were structurally conserved and contained three predicted site-specific recombinases/integrases and a tetR homologue. Downstream of these resided ORFs of the ‘variable side’ with structural and sequence similarity to those encoding survival traits on the fitness enhancing plasmid pGRT1 (ILEFH1 and ILEFH5) and the NR-II virulence region of genomic island PAGI-5 (ILEFH4). Collectively, these ILEs share features with the previously described type III protein secretion system effector ILEs and are considered important to host survival and transfer of fitness enhancing and (a)virulence genes between bacteria.

A new South American network to study the atmospheric electric field and its variations related to geophysical phenomena

In this paper we present the capability of a new network of field mill sensors to monitor the atmospheric electric field at various locations in South America; we also show some early results. The main objective of the new network is to obtain the characteristic Universal Time diurnal curve of the atmospheric electric field in fair weather, known as the Carnegie curve. The Carnegie curve is closely related to the current sources flowing in the Global Atmospheric Electric Circuit so that another goal is the study of this relationship on various time scales (transient/monthly/seasonal/annual). Also, by operating this new network, we may also study departures of the Carnegie curve from its long term average value related to various solar, geophysical and atmospheric phenomena such as the solar cycle, solar flares and energetic charged particles, galactic cosmic rays, seismic activity and specific meteorological events. We then expect to have a better understanding of the influence of these phenomena on the Global Atmospheric Electric Circuit and its time-varying behavior.

Bdellovibrio bacteriovorus HD100 guards against Pseudomonas tolaasii brown-blotch lesions on the surface of post-harvest Agaricus bisporus supermarket mushrooms

BACKGROUND: Pseudomonas tolaasii is a problematic pathogen of cultured mushrooms, forming dark brown 'blotches' on mushroom surfaces and causing spoilage during crop growth and post-harvest . Treating P. tolaasii infection is difficult, as other, commensal bacterial species such as Pseudomonas putida are necessary for mushroom growth, so treatments must be relatively specific. RESULTS: We have found that P. tolaasii is susceptible to predation in vitro by the δ-proteobacterium Bdellovibrio bacteriovorus. This effect also occurred in funga, where B. bacteriovorus was administered to post-harvest mushroom caps before and after administration of the P. tolaasii pathogen. A significant, visible improvement in blotch appearance, after incubation, was observed on administration of Bdellovibrio. A significant reduction in viable P. tolaasii cell numbers, recovered from the mushroom tissue, was detected. This was accompanied by a more marked reduction in blotch severity on Bdellovibrio administration. We found that there was in some cases an accompanying overgrowth of presumed-commensal, non-Pseudomonas bacteria on post-harvest mushroom caps after Bdellovibrio-treatment. These bacteria were identified (by 16SrRNA gene sequencing) as Enterobacter species, which were seemingly resistant to predation. We visualised predatory interactions occuring between B. bacteriovorus and P. tolaasii on the post-harvest mushroom cap surface by Scanning Electron Microscopy, seeing predatory invasion of P. tolaasii by B. bacteriovorus in funga. This anti-P. tolaasii effect worked well in post-harvest supermarket mushrooms, thus Bdellovibrio was not affected by any pre-treatment of mushrooms for commercial/consumer purposes. CONCLUSIONS: The soil-dwelling B. bacteriovorus HD100 preys upon and kills P. tolaasii, on mushroom surfaces, and could therefore be applied to prevent spoilage in post-harvest situations where mushrooms are stored and packaged for sale.

Modulation of UK lightning by heliospheric magnetic field polarity

Observational studies have reported solar magnetic modulation of terrestrial lightning on a range of time scales, from days to decades. The proposed mechanism is two-step: lightning rates vary with galactic cosmic ray (GCR) flux incident on Earth, either via changes in atmospheric conductivity and/or direct triggering of lightning. GCR flux is, in turn, primarily controlled by the heliospheric magnetic field (HMF) intensity. Consequently, global changes in lightning rates are expected. This study instead considers HMF polarity, which doesnʼt greatly affect total GCR flux. Opposing HMF polarities are, however, associated with a 40–60% difference in observed UK lightning and thunder rates. As HMF polarity skews the terrestrial magnetosphere from its nominal position, this perturbs local ionospheric potential at high latitudes and local exposure to energetic charged particles from the magnetosphere. We speculate as to the mechanism(s) by which this may, in turn, redistribute the global location and/or intensity of thunderstorm activity.

Dependence of convective flows and particle precipitation in the high-latitude dayside ionosphere on theXandYcomponents of the interplanetary magnetic field

The asymmetries in the convective flows, current systems, and particle precipitation in the high-latitude dayside ionosphere which are related to the equatorial plane components of the interplanetary magnetic field (IMF) are discussed in relation to the results of several recent observational studies. It is argued that all of the effects reported to date which are ascribed to the y component of the IMF can be understood, at least qualitatively, in terms of a simple theoretical picture in which the effects result from the stresses exerted on the magnetosphere consequent on the interconnection of terrestrial and interplanetary fields. In particular, relaxation under the action of these stresses allows, in effect, a partial penetration of the IMF into the magnetospheric cavity, such that the sense of the expected asymmetry effects on closed field lines can be understood, to zeroth order, in terms of the “dipole plus uniform field” model. In particular, in response to IMF By, the dayside cusp should be displaced in longitude about noon in the same sense as By in the northern hemisphere, and in the opposite sense to By in the southern hemisphere, while simultaneously the auroral oval as a whole should be shifted in the dawn-dusk direction in the opposite sense with respect to By. These expected displacements are found to be consistent with recently published observations. Similar considerations lead to the suggestion that the auroral oval may also undergo displacements in the noon-midnight direction which are associated with the x component of the IMF. We show that a previously published study of the position of the auroral oval contains strong initial evidence for the existence of this effect. However, recent results on variations in the latitude of the cusp are more ambiguous. This topic therefore requires further study before definitive conclusions can be drawn.

Financial viability appraisals for site-specific planning decisions in England

In England, appraisals of the financial viability of development schemes have become an integral part of planning policy-making, initially in determining the amount of planning obligations that might be obtained via legal agreements (known as Section 106 agreements) and latterly as a basis for establishing charging schedules for the Community Infrastructure Levy (CIL). Local planning authorities set these policies on an area-wide basis but ultimately development proposals require consent on a site-by-site basis. It is at this site-specific level that issues of viability are hotly contested. This paper examines case documents, proofs of evidence and decisions from a sample of planning disputes in order to address major issues within development viability, the application of the models and the distribution of the development gain between the developer, landowner and community. The results have specific application to viability assessment in England and should impact on future policy and practice guidance in this field. They also have relevance to other countries that incorporate assessments of economic viability in their planning systems.

Negotiating the British landscape

According to many accounts, a key paradigm for understanding art in Post WWII Britain is one of Englishness versus internationalism or abstraction versus realism . These terms have a rich inflection of meanings that have been subject to interrogation over the last few decades. Anwar Shemza came to Britain and practiced his art at a time when these competing claims were at their height. In a postcolonial reading entitled “Black Diaspora Artists in Britain: Three ‘Moments’ in Post-War Britain” Stuart Hall recently used David Scott’s framework of a ‘problem space’, that is discursively defined through questions, tensions and conjunctures, that couched the entry of what he describes as first waive British commonwealth artists into critical visibility in Britain. This can be characterized in part by the reviews of WG Archer and GM Butcher, both supporters of Shemza and prominent critics of the period. Hall includes Shemza in this framework that defines the work and his aspirations as constituted through the tensions of what was perceived to be anti-colonialist aims of modernism through universalism and the ‘nativist’ current in anti-colonial nationalism . This text will focus particularly on the problematic of Landscape as a ‘problem space’ of vernacular and modernism, over here and over there. The aim is not to define Shemza within the tradition of English landscape nor to exclude him but to position him within a discursive field of landscape and modernism in mid twentieth Century art.