Blocked dihydropteridines as nitric oxide synthase activators

It has been shown that 6-acetyl-7,7-dimethyl-5,6,7,8-tetrahydropteridin-4(3H)-one can act as a competent cofactor for the production of nitric oxide by neuronal nitric oxide synthase (nNOS). More information was sought on the structural features that could contribute to strong binding within the enzyme whilst maintaining a fast electron transfer rate. This study was concerned with expansion at the C2-position of the pteridine scaffold. The evidence suggests that expansion at the C2-position had a deleterious effect with respect to Km and as a consequence electron transfer rate. Unexpectedly, several lines of evidence suggested that a methyl substituent on nitrogen at C2 reduced the electron density in the pyrimidine and dihydropterin rings

Bactericidal action of positive and negative ions in air

In recent years there has been renewed interest in the use of air ionisers to control of the spread of airborne infection. One characteristic of air ions which has been widely reported is their apparent biocidal action. However, whilst the body of evidence suggests a biocidal effect in the presence of air ions the physical and biological mechanisms involved remain unclear. In particular, it is not clear which of several possible mechanisms of electrical origin (i.e. the action of the ions, the production of ozone, or the action of the electric field) are responsible for cell death. A study was therefore undertaken to clarify this issue and to determine the physical mechanisms associated with microbial cell death. In the study seven bacterial species (Staphylococcus aureus, Mycobacterium parafortuitum, Pseudomonas aeruginosa, Acinetobacter baumanii, Burkholderia cenocepacia, Bacillus subtilis and Serratia marcescens) were exposed to both positive and negative ions in the presence of air. In order to distinguish between effects arising from: (i) the action of the air ions; (ii) the action of the electric field, and (iii) the action of ozone, two interventions were made. The first intervention involved placing a thin mica sheet between the ionisation source and the bacteria, directly over the agar plates. This intervention, while leaving the electric field unaltered, prevented the air ions from reaching the microbial samples. In addition, the mica plate prevented ozone produced from reaching the bacteria. The second intervention involved placing an earthed wire mesh directly above the agar plates. This prevented both the electric field and the air ions from impacting on the bacteria, while allowing any ozone present to reach the agar plate. With the exception of Mycobacterium parafortuitum, the principal cause of cell death amongst the bacteria studied was exposure to ozone, with electroporation playing a secondary role. However in the case of Mycobacterium parafortuitum, electroporation resulting from exposure to the electric field appears to have been the principal cause of cell inactivation. The results of the study suggest that the bactericidal action attributed to negative air ions by previous researchers may have been overestimated

Quantum interest in two dimensions

The quantum interest conjecture of Ford and Roman asserts that any negative-energy pulse must necessarily be followed by an over-compensating positive-energy one within a certain maximum time delay. Furthermore, the minimum amount of over-compensation increases with the separation between the pulses. In this paper, we first study the case of a negative-energy square pulse followed by a positive-energy one for a minimally coupled, massless scalar field in two-dimensional Minkowski space. We obtain explicit expressions for the maximum time delay and the amount of over-compensation needed, using a previously developed eigenvalue approach. These results are then used to give a proof of the quantum interest conjecture for massless scalar fields in two dimensions, valid for general energy distributions.Comment: 17 pages, 4 figures; final version to appear in PR

Putting social networks to practical use: improving last-mile dissemination systems for climate and market information services in developing countries

Understanding how to improve the accessibility and timely dissemination of weather and market information can help farmers adapt their management to climate change impacts. Our objective is to use Social Network Analysis (SNA) as a tool to identify potential opportunities for improving weather and market advisory dissemination to rural communities and to explore the relationship between farmers' access to information and yield and selling price. As a case study, we applied SNA to 313 farmers in Bangladesh to analyze weather and market information networks and farmers' friendship networks as a potential proxy for information exchange. Farmer access to information, dominant sources of information and potential speed of information transfer were key criteria for our analysis. Our results indicate that weather and market information networks in coastal Bangladesh depended on certain key sources of information, while the friendship network was decentralized and interconnected, with few isolated farmers. We showed that farmers networks are significantly correlated with several socio-agro-economic variables; however, there was little indication of a relationship between information access and yield and selling price. We conclude that a mixed approach of targeting central actors and broadcasting information to farmers may be a suitable strategy to reach a maximum number of farmers as well as the most isolated farmers. Our study highlights that SNA can be a promising tool to reveal hidden structures of information flows in farmer communities and provide valuable insights for developing information dissemination strategies that reach even the most remote and underserved farmers

Quantum inequalities and `quantum interest' as eigenvalue problems

Quantum inequalities (QI's) provide lower bounds on the averaged energy density of a quantum field. We show how the QI's for massless scalar fields in even dimensional Minkowski space may be reformulated in terms of the positivity of a certain self-adjoint operator - a generalised Schroedinger operator with the energy density as the potential - and hence as an eigenvalue problem. We use this idea to verify that the energy density produced by a moving mirror in two dimensions is compatible with the QI's for a large class of mirror trajectories. In addition, we apply this viewpoint to the `quantum interest conjecture' of Ford and Roman, which asserts that the positive part of an energy density always overcompensates for any negative components. For various simple models in two and four dimensions we obtain the best possible bounds on the `quantum interest rate' and on the maximum delay between a negative pulse and a compensating positive pulse. Perhaps surprisingly, we find that - in four dimensions - it is impossible for a positive delta-function pulse of any magnitude to compensate for a negative delta-function pulse, no matter how close together they occur.Comment: 18 pages, RevTeX. One new result added; typos fixed. To appear in Phys. Rev.

Mouse cytotoxic T cell-derived granzyme B activates the mitochondrial cell death pathway in a bim-dependent fashion

Cytotoxic T cells (Tc) use perforin and granzyme B (gzmB) to kill virus-infected cells and cancer cells. Recent evidence suggests that human gzmB primarily induces apoptosis via the intrinsic mitochondrial pathway by either cleaving Bid or activating Bim leading to the activation of Bak/Bax and subsequent generation of active caspase-3. In contrast, mouse gzmB is thought to predominantly induce apoptosis by directly processing pro-caspase-3. However, in certain mouse cell types gzmB-mediated apoptosis mainly occurs via the mitochondrial pathway. To investigate whether Bim is involved under the latter conditions, we have now employed ex vivo virus-immune mouse Tc that selectively kill by using perforin and gzmB (gzmB+Tc) as effector cells and wild type as well as Bim- or Bak/Bax-deficient spontaneously (3T9) or virus-(SV40) transformed mouse embryonic fibroblast cells as targets. We show that gzmB+Tc-mediated apoptosis (phosphatidylserine translocation, mitochondrial depolarization, cytochrome c release, and caspase-3 activation) was severely reduced in 3T9 cells lacking either Bim or both Bak and Bax. This outcome was related to the ability of Tc cells to induce the degradation of Mcl-1 and Bcl-XL, the anti-apoptotic counterparts of Bim. In contrast, gzmB+Tc-mediated apoptosis was not affected in SV40-transformed mouse embryonic fibroblast cells lacking Bak/Bax. The data provide evidence that Bim participates in mouse gzmB+Tc-mediated apoptosis of certain targets by activating the mitochondrial pathway and suggest that the mode of cell death depends on the target cell. Our results suggest that the various molecular events leading to transformation and/or immortalization of cells have an impact on their relative resistance to the multiple gzmB+Tc-induced death pathways

Floc formation reduces the pH stress experienced by microorganisms living in alkaline environments

The survival of microorganisms within a cementitious geological disposal facility for radioactive wastes is heavily dependent on their ability to survive the calcium dominated, hyper-alkaline conditions resulting from the dissolution of the cementitious materials. The present study shows that the formation of flocs, composed of a complex mixture of extracellular polymeric substances (EPS), provides protection against alkaline pH values up to pH 13.0. The flocs were dominated by Alishewanella and Dietzia sp, producing a mannose rich carbohydrate fraction incorporating extracellular DNA, resulting in Ca2+ sequestration. EPS provided a ~10 µm thick layer around the cells within the centre of the flocs, which were capable of growth at pH 11.0 and 11.5, maintaining internal pH values of pH 10.4 and 10.7 respectively. Survival was observed at pH 12.0, where an internal floc pH of 11.6 was observed alongside a reduced associated biomass. Limited floc survival (<2 weeks) was observed at pH 13.0.This study demonstrates that flocs are able to maintain a lower internal pH in response to the hyperalkaline conditions expected to occur within a cementitious, geological disposal facility for radioactive wastes and indicates that floc communities within such a facility would be capable of survival up to a pH of 12.0

The effect of the dynamical state of clusters on gas expulsion and infant mortality

The star formation efficiency (SFE) of a star cluster is thought to be the critical factor in determining if the cluster can survive for a significant (>50 Myr) time. There is an often quoted critical SFE of ~30 per cent for a cluster to survive gas expulsion. I reiterate that the SFE is not the critical factor, rather it is the dynamical state of the stars (as measured by their virial ratio) immediately before gas expulsion that is the critical factor. If the stars in a star cluster are born in an even slightly cold dynamical state then the survivability of a cluster can be greatly increased.Comment: 6 pages, 2 figures. Review talk given at the meeting on "Young massive star clusters - Initial conditions and environments", E. Perez, R. de Grijs, R. M. Gonzalez Delgado, eds., Granada (Spain), September 2007, Springer: Dordrecht. Replacement to correct mistake in a referenc

The VLT-FLAMES survey of massive stars: observations in the Galactic clusters NGC3293, NGC4755 and NGC6611

We introduce a new survey of massive stars in the Galaxy and the Magellanic Clouds using the Fibre Large Array Multi-Element Spectrograph (FLAMES) instrument at the Very Large Telescope (VLT). Here we present observations of 269 Galactic stars with the FLAMES-Giraffe Spectrograph (R ~ 25,000), in fields centered on the open clusters NGC 3293, NGC 4755 and NGC 6611. These data are supplemented by a further 50 targets observed with the Fibre-Fed Extended Range Optical Spectrograph (FEROS, R = 48,000). Following a description of our scientific motivations and target selection criteria, the data reduction methods are described; of critical importance the FLAMES reduction pipeline is found to yield spectra that are in excellent agreement with less automated methods. Spectral classifications and radial velocity measurements are presented for each star, with particular attention paid to morphological peculiarities and evidence of binarity. These observations represent a significant increase in the known spectral content of NGC 3293 and NGC 4755, and will serve as standards against which our subsequent FLAMES observations in the Magellanic Clouds will be compared.Comment: 26 pages, 9 figures (reduced size). Accepted for publication in A&A. A copy with full res. figures is available from http://www.ing.iac.es/~cje/flames_mw.ps.gz. Minor changes following correction of proof