Identification of potential drug targets in Salmonella Typhimurium using metabolic modelling and experimental validation

almonella enterica serovar Typhimurium is an established model organism for Gram-negative, intracellular pathogens. Owing to the rapid spread of resistance to antibiotics among this group of pathogens, new approaches to identify suitable target proteins are required. Based on the genome sequence of Salmonella Typhimurium and associated databases, a genome-scale metabolic model was constructed. Output was based on an experimental determination of the biomass of Salmonella when growing in glucose minimal medium. Linear programming was used to simulate variations in energy demand, while growing in glucose minimal medium. By grouping reactions with similar flux responses, a sub-network of 34 reactions responding to this variation was identified (the catabolic core). This network was used to identify sets of one and two reactions, that when removed from the genome-scale model interfered with energy and biomass generation. 11 such sets were found to be essential for the production of biomass precursors. Experimental investigation of 7 of these showed that knock-outs of the associated genes resulted in attenuated growth for 4 pairs of reactions, while 3 single reactions were shown to be essential for growth.

A Lab-in-a-briefcase for rapid prostate specific antigen (PSA) screening from whole blood

We present a new concept for rapid and fully portable Prostate Specific Antigen (PSA) measurement, termed “Lab-in-a-Briefcase”, which integrates an affordable microfluidic ELISA platform utilising a melt-extruded fluoropolymer Micro Capillary Film (MCF) containing 10 bore, 200 μm internal diameter capillaries, a disposable multi-syringe aspirator (MSA) plus a sample tray pre-loaded with all required immunoassay reagents, and a portable film scanner for colorimetric signal digital quantitation. Each MSA can perform 10 replicate microfluidic immunoassays on 8 samples, allowing 80measurements to be made in less than 15 minutes based on semi-automated operation and norequirement of additional fluid handling equipment. An assay was optimised for measurement of a clinically relevant range of PSA from 0.9 to 60.0 ng/ml in 15 minutes with CVs in the order of 5% based on intra-assay variability when read using a consumer flatbed film scanner. The PSA assay performance in the MSA remained robust in the presence of undiluted or 1:2 diluted human serum or whole blood, and the matrix effect could simply be overcome by extending sample incubation times. The PSA "Lab-in-a-briefcase" is particularly suited to a low-resource health setting where diagnostic labs and automated immunoassay systems are not accessible, by allowing PSA measurement outside the laboratory using affordable equipment.

Rapid assessment of historic, current and future habitat quality for biodiversity around UK Natura 2000 sites

Changes in landscape composition and structure may impact the conservation and management of protected areas. Species that depend on specific habitats are at risk of extinction when these habitats are degraded or lost. Designing robust methods to evaluate landscape composition will assist decision- and policy-making in emerging landscapes. This paper describes a rapid assessment methodology aimed at evaluating landcover quality for birds, plants, butterflies and bees around seven UK Natura 2000 sites. An expert panel assigned quality values to standard Coordination of Information on the Environment (CORINE) landcover classes for each taxonomic group. Quality was assessed based on historical (1950, 1990), current (2000) and future (2030) land-cover data, the last projected using three alternative scenarios: a growth applied strategy (GRAS), a business-as-might-beusual (BAMBU) scenario, and sustainable European development goal (SEDG) scenario. A quantitative quality index weighted the area of each land-cover parcel with a taxa-specific quality measure. Land parcels with high quality for all taxonomic groups were evaluated for temporal changes in area, size and adjacency. For all sites and taxonomic groups, the rate of deterioration of land-cover quality was greater between 1950 and 1990 than current rates or as modelled using the alternative future scenarios (2000– 2030). Model predictions indicated land-cover quality stabilized over time under the GRAS scenario, and was close to stable for the BAMBU scenario. The SEDG scenario suggested an ongoing loss of quality, though this was lower than the historical rate of c. 1% loss per decade. None of the future scenarios showed accelerated fragmentation, but rather increases in the area, adjacency and diversity of high quality land parcels in the landscape.

Contributions of different cloud types to feedbacks and rapid adjustments in CMIP5

Using five climate model simulations of the response to an abrupt quadrupling of CO2, the authors perform the first simultaneous model intercomparison of cloud feedbacks and rapid radiative adjustments with cloud masking effects removed, partitioned among changes in cloud types and gross cloud properties. Upon CO2 quadrupling, clouds exhibit a rapid reduction in fractional coverage, cloud-top pressure, and optical depth, with each contributing equally to a 1.1 W m−2 net cloud radiative adjustment, primarily from shortwave radiation. Rapid reductions in midlevel clouds and optically thick clouds are important in reducing planetary albedo in every model. As the planet warms, clouds become fewer, higher, and thicker, and global mean net cloud feedback is positive in all but one model and results primarily from increased trapping of longwave radiation. As was true for earlier models, high cloud changes are the largest contributor to intermodel spread in longwave and shortwave cloud feedbacks, but low cloud changes are the largest contributor to the mean and spread in net cloud feedback. The importance of the negative optical depth feedback relative to the amount feedback at high latitudes is even more marked than in earlier models. The authors show that the negative longwave cloud adjustment inferred in previous studies is primarily caused by a 1.3 W m−2 cloud masking of CO2 forcing. Properly accounting for cloud masking increases net cloud feedback by 0.3 W m−2 K−1, whereas accounting for rapid adjustments reduces by 0.14 W m−2 K−1 the ensemble mean net cloud feedback through a combination of smaller positive cloud amount and altitude feedbacks and larger negative optical depth feedbacks.

Rapid changes in LLBL thickness

We employ data from two spacecraft, at the dawn flank of the magnetopause, to investigate fluctuations in the thickness of the low-latitude boundary layer (LLBL). We show the LLBL is considerably thinner shortly after the detection of a flux transfer event than it was during the event. These data are shown to be consistent with the theory of transient increases in the open LLBL thickness caused by a pulse of enhanced reconnection at the magnetopause.

The effect of rapid changes in ionospheric flow on velocity vectors deduced from radar beam-swinging experiments

The effects on the horizontal ionospheric velocity vectors deduced from radar beam-swinging experiments, which occur when changes in the flow take place on short time scales compared with the experiment cycle time, are analysed in detail. The further complications which arise in the interpretation of beam-swinging data, due to longitudinal gradients in the flow and to field-aligned flows, are also considered. It is concluded that these effects are unlikely to seriously compromise statistical determinations of the response time of the flow, e.g. to changes in the north-south component of the IMF, such as have been recently reported by Etemadiet al. (1988, Planet. Space Sci.36, 471), using EISCAT ‘Polar’ data.

EISCAT observations of bursts of rapid flow in the high latitude dayside ionosphere

Observations are presented of short-lived, highly structured bursts of rapid plasma flow observed with the EISCAT radar in the high latitude dayside ionosphere. It is shown that the properties of the bursts are consistent with ionospheric perturbations caused by impulsive, localized reconnection at the Earth's magnetopause, i.e. by flux transfer events.

Virtualization for cost-effective teaching of assembly language programming

A virtual system that emulates an ARM-based processor machine has been created to replace a traditional hardware-based system for teaching assembly language. The proposed virtual system integrates, in a single environment, all the development tools necessary to deliver introductory or advanced courses on modern assembly language programming. The virtual system runs a Linux operating system in either a graphical or console mode on a Windows or Linux host machine. No software licenses or extra hardware are required to use the virtual system, thus students are free to carry their own ARM emulator with them on a USB memory stick. Institutions adopting this, or a similar virtual system, can also benefit by reducing capital investment in hardware-based development kits and enable distance learning courses.

Rapid preconditioning of data for accelerating convex hull algorithms

Given a dataset of two-dimensional points in the plane with integer coordinates, the method proposed reduces a set of n points down to a set of s points s ≤ n, such that the convex hull on the set of s points is the same as the convex hull of the original set of n points. The method is O(n). It helps any convex hull algorithm run faster. The empirical analysis of a practical case shows a percentage reduction in points of over 98%, that is reflected as a faster computation with a speedup factor of at least 4.

Rapid changes in the redox conditions of the western Tethys Ocean during the early Aptian oceanic anoxic event

The early Aptian (125 to 121 Ma) records an episode of severe environmental change including a major perturbation of the carbon cycle, an oceanic anoxic event (OAE 1a, 122.5 Ma), a platform drowning episode and a biocalcification crisis. We propose to trace changes in the oxygenation state of the ocean during the early Aptian anoxic event using the redox-sensitive trace-element (RSTE) distribution, phosphorus accumulation rates (PARs) and organic-matter characterization in three different basins of the western Tethys. The following sections have been investigated: Gorgo a Cerbara (central Italy) in the Umbria Marche basin, Glaise (SE France) in the Vocontian basin and Cassis/La Bédoule (SE France) located in the Provencal basin. In the Gorgo a Cerbara section, RSTE distributions show a low background level along the main part of the section, contrasted by different maxima in concentrations within the Selli level. In the Glaise section, the Goguel level displays a weak increase in RSTE contents coeval with moderate TOC values. At Cassis/La Bédoule, no significant RSTE enrichments have been observed in sediments equivalent to the Selli level. These differences in the records of the geochemical proxies of the Selli level or its equivalent indicate the deposition under different redox conditions, probably related to the paleogeography. Our data indicate the development of anoxic–euxinic conditions in the deeper part of the Tethys during OAE 1a, whereas in the shallower environments, conditions were less reducing. Moreover, at Gorgo a Cerbara, the Selli level is characterized by rapid changes in the intensity of reducing conditions in the water column. Ocean eutrophication seems to be a major factor in the development and the persistence of anoxia as suggested by the PAR evolution. Higher PAR values at the onset of OAE 1a suggest an increase in nutrient input, whereas the return to lower values through the first part of the OAE 1a interval may be related to the weakened capacity to retain P in the sedimentary reservoir due to bottom-water oxygen depletion. This general pattern is contrasted by the data of Gorgo a Cerbara, where the sediments deposited during the OAE 1a interval show P-enrichments (mainly authigenic P). This is associated with maxima in TOC values and Corg:Ptot ratios, suggesting that a part of the remobilized P was trapped in the sediments and as such prevented from returning to the water column.

Thermoelectric materials: a new rapid synthesis process for non-toxic and high-performance tetrahedrite compounds

The feasibility to synthesize, in large quantity, pure and non-toxic tetrahedrite compounds using high-energy mechanical-alloying from only elemental precursors is reported in the present paper for the first time. Our processing technique allows a better control of the final product composition and leads to high thermoelectric performances (ZT of 0.75 at 700 K), comparable to that reported on sealed tube synthesis samples. Combined with spark plasma sintering, the production of highly pure and dense samples is achieved in a very short time, at least 8 times shorter than in conventional liquid-solid-vapor synthesis process. The process described in this paper is a promising way to produce high performance tetrahedrite materials for cost-effective and large-scale thermoelectric applications.

Asymmetric cyclopropanation of conjugated cyanosulfones using a novel cupreine organocatalyst: rapid access to d3-amino acids

An organocatalytic asymmetric synthesis of a novel, highly functionalised cyclopropane system furnished with versatile substituents and containing a quaternary centre is described. The process utilises a new bifunctional catalyst based on the cinchona alkaloid framework and the products made using this catalyst were obtained as single diastereoisomers, with very high enantioselectivities (up to 96% ee). We have also demonstrated that these resulting cyclopropanes are very useful synthetic intermediates to interesting products, such as the difficult to access d3-amino acids.

Sex differences in the programming effects of prenatal stress on psychopathology and stress responses: an evolutionary perspective

There is strong evidence from animal studies that prenatal stress has different effects on male and female offspring. In general, although not always, prenatal stress increases anxiety, depression and stress responses, both hypothalamic–pituitary–adrenal and cardiovascular, in female offspring rather than in male. Males are more likely to show learning and memory deficits. There have been few studies so far in humans which differentiate effects of prenatal stress on male and female psychopathology. Some studies support the animal models, but the evidence is inconsistent. The mediating mechanisms for any sex specific effects are little understood, but there is evidence that placental function can differ depending on the sex of the fetus. We suggest that there may be an evolutionary reason for any sex differences in the long term effects of prenatal stress. In a stressful environment it may be adaptive for females, who are more likely to stay in one place and look after children, to be more vigilant, alert to danger and thus show more stress responsiveness. This can give rise to a more anxious or depressed phenotype. With males it may be more adaptive to go out and explore new environments, compete with other males, and be more aggressive. For this it may help to be less responsive to external stressors. More research is needed into sex differences in the effects of prenatal stress in humans, to test these ideas.