Photoantimicrobials-are we afraid of the light?

Although conventional antimicrobial drugs have been viewed as miraculous cure-alls for the past 80 years, increasing antimicrobial drug resistance requires a major and rapid intervention. However, the development of novel but still conventional systemic antimicrobial agents, having only a single mode or site of action, will not alleviate the situation because it is probably only a matter of time until any such agents will also become ineffective. To continue to produce new agents based on this notion is unacceptable, and there is an increasing need for alternative approaches to the problem. By contrast, light-activated molecules called photoantimicrobials act locally via the in-situ production of highly reactive oxygen species, which simultaneously attack various biomolecular sites in the pathogenic target and therefore offer both multiple and variable sites of action. This non-specificity at the target circumvents conventional mechanisms of resistance and inhibits the development of resistance to the agents themselves. Photoantimicrobial therapy is safe and easy to implement and, unlike conventional agents, the activity spectrum of photoantimicrobials covers bacteria, fungi, viruses, and protozoa. However, clinical trials of these new, truly broad-spectrum, and minimally toxic agents have been few, and the funding for research and development is almost non-existent. Photoantimicrobials constitute one of the few ways forward through the morass of drug-resistant infectious disease and should be fully explored. In this Personal View, we raise awareness of the novel photoantimicrobial technologies that offer a viable alternative to conventional drugs in many relevant application fields, and could thus slow the pace of resistance development

THE TOOLS AND MONTE CARLO WORKING GROUP Summary Report from the Les Houches 2009 Workshop on TeV Colliders

This is the summary and introduction to the proceedings contributions for the Les Houches 2009 "Tools and Monte Carlo" working group.Comment: 144 Pages. Workshop site http://wwwlapp.in2p3.fr/conferences/LesHouches/Houches2009/ . Conveners were Butterworth, Maltoni, Moortgat, Richardson, Schumann and Skand

Timing the multiple cell death pathways initiated by Rose Bengal acetate photodynamic therapy

Rose Bengal acetate photodynamic therapy (RBAc–PDT) induced multiple cell death pathways in HeLa cells through ROS and ER stress. Indeed, apoptosis was the first preferred mechanism of death, and it was triggered by at least four different pathways, whose independent temporal activation ensures cell killing when one or several of the pathways are inactivated. Apoptosis occurred as early as 1 h after PDT through activation of intrinsic pathways, followed by activation of extrinsic, caspase-12-dependent and caspase-independent pathways, and by autophagy. The onset of the different apoptotic pathways and autophagy, that in our system had a pro-death role, was timed by determining the levels of caspases 9, 8, 3 and 12; Bcl-2 family; Hsp70; LC3B; GRP78 and phospho-eIF2α proteins. Interestingly, inhibition of one pathway, that is, caspase-9 (Z-LEHD-FMK), caspase-8 (Z-IETD-FMK), pan-caspases (Z-VAD-FMK), autophagy (3-MA) and necrosis (Nec-1), did not impair the activation of the others, suggesting that the independent onset of the different apoptotic pathways and autophagy did not occur in a subordinated manner. Altogether, our data indicate RBAc as a powerful photosensitiser that induces a prolonged cytotoxicity and time-related cell death onset by signals originating from or converging on almost all intracellular organelles. The fact that cancer cells can die through different mechanisms is a relevant clue in the choice and design of anticancer PDT

Non-monotonic changes in clonogenic cell survival induced by disulphonated aluminum phthalocyanine photodynamic treatment in a human glioma cell line

<p>Abstract</p> <p>Background</p> <p>Photodynamic therapy (PDT) involves excitation of sensitizer molecules by visible light in the presence of molecular oxygen, thereby generating reactive oxygen species (ROS) through electron/energy transfer processes. The ROS, thus produced can cause damage to both the structure and the function of the cellular constituents resulting in cell death. Our preliminary investigations of dose-response relationships in a human glioma cell line (BMG-1) showed that disulphonated aluminum phthalocyanine (AlPcS₂) photodynamically induced loss of cell survival in a concentration dependent manner up to 1 μM, further increases in AlPcS₂concentration (>1 μM) were, however, observed to decrease the photodynamic toxicity. Considering the fact that for most photosensitizers only monotonic dose-response (survival) relationships have been reported, this result was unexpected. The present studies were, therefore, undertaken to further investigate the concentration dependent photodynamic effects of AlPcS₂.</p> <p>Methods</p> <p>Concentration-dependent cellular uptake, sub-cellular localization, proliferation and photodynamic effects of AlPcS₂were investigated in BMG-1 cells by absorbance and fluorescence measurements, image analysis, cell counting and colony forming assays, flow cytometry and micronuclei formation respectively.</p> <p>Results</p> <p>The cellular uptake as a function of extra-cellular AlPcS₂concentrations was observed to be biphasic. AlPcS₂was distributed throughout the cytoplasm with intense fluorescence in the perinuclear regions at a concentration of 1 μM, while a weak diffuse fluorescence was observed at higher concentrations. A concentration-dependent decrease in cell proliferation with accumulation of cells in G₂+M phase was observed after PDT. The response of clonogenic survival after AlPcS₂-PDT was non-monotonic with respect to AlPcS₂concentration.</p> <p>Conclusions</p> <p>Based on the results we conclude that concentration-dependent changes in physico-chemical properties of sensitizer such as aggregation may influence intracellular transport and localization of photosensitizer. Consequent modifications in the photodynamic induction of lesions and their repair leading to different modes of cell death may contribute to the observed non-linear effects.</p

The microbial experience of environmental phosphate fluctuations. An essay on the possibility of putting intentions into cell biochemistry

International audienceWe present a model of microbial information processing that contains characteristic features of the phenomenon of physiological adaptation. The backbone of the model is the "`adaptive event"&apos; in which energy-converting subsystems of the cell interact with the changing environment. In this process, the subsystems pass, via an adaptive operation mode, from one adapted state to the next. An adaptive operation mode takes place when an adapted state is disturbed by an environmental alteration. These two manifestations of an adaptive event were differently treated in the simulation, based on an application of linear irreversible thermodynamics to the energy transduction of adaptive subsystems. In adapted states, the conductivity coefficients of the flow-force relationships employed remained constant, whereas during an adaptive operation mode, these coefficients were altered in a directional manner during the simulation. An example dealing with the complex relationship between phosphate uptake and cyanobacterial growth is given. In this example, the simulation of adapted states of two subsystems of the incorporating machinery, namely the phosphate carrier in the cell membrane and the F-ATPase in the thylakoid membrane, was in accordance with the measured uptake kinetics, and when fixed, predetermined conductivity coefficients were used. In the adaptive operation mode, however, the simulated behavior was in agreement with experimental observations when the program was able to interpret its own performance in the light of environmental phosphate fluctuations, experienced by the cell in the past, and to reconstruct the two subsystems according to this interpretation. Via transitions between adapted states and adaptive modes, information is transferred from one adaptive event to the next: the latter inherits the results of former interpretations. By appropriating them selectively, it is entering into a future in which its own interpretation is passed on to the following adaptive event. The model is discussed with respect to the concept of autopoiesis

Vergleich von Zwischenlagerungskonzepten fuer Forschungsreaktor-Brennelemente Schlussbericht

Target of the study was to conduct a comparative examination of different schemes for interim storage of German research reactor fuel elements taking into consideration the costs, schedules and licensing. Four schemes have been investigated: - Interim storage in a central interim store; - Interim storage in an extended cask store; - Interim storage in a new interim store; - Interim storage by exchanging capacities between two interim stores. The investigation has shown promising chances for the realization of the two schemes ''interim storage in an extended cask store'', respectively ''interim storage by exchanging capacities between two interim stores''. On the basis of these results, the study group ''MTR Fuel Cycle'' recommends to conduct further investigations into these two schemes, and to investigate additionally the reloading of MTR fuel elements in a central reloading plant. A comparison of the two waste management alternatives ''reprocessing'' and ''direct disposal'' for MTR fuel elements has shown substantial advantages of the alternative ''direct disposal'' with regard to costs. (orig./HP)Beruecksichtigt wird der Entsorgungsbedarf aller deutschen Forschungsreaktoren von 1996 bis 2010. Der Zwischenlagerbedarf betraegt ohne die Brennelemente der TRIGA-Reaktoren (Stand: Januar 1993): 1.511 bestrahlte Brennelemente. Zur Deckung des Bedarfs werden ca. 60 Transport- und Lagerbehaelter der Referenz-Behaelter CASTOR-MTR 2 benoetigt. Als Zwischenlagerkonzept ist die Behaelterlagerung vorgesehen. Eine Einlagerung in das Zwischenlager Ahaus wird als Referenzloesung verfolgt. Beim RFR Rossendorf sind zusaetzlich ca. 2.100 Brennelemente zu entsorgen, fuer die 21 CASTOR-MTR 2 benoetigt werden. Die Variantenuntersuchung ergibt unter Beruecksichtigung von Kosten, Genehmigungsaspekten und Realisierungszeitraeumen als guenstigste Loesung eine Erweiterung des AVR-Behaelterlagers in Juelich. Die Kosten dieser Zwischenlagerungsalternative werden auf ca. 30 Mio. DM abgeschaetzt. Die Variante weist durch die Moeglichkeit einer Nutzung der in Juelich bereits vorhandenen Anlagen und durch eine Minimierung von ausserbetrieblichen Transporten aufgrund des eigenen Entsorgungsbedarfs der KFA wesentliche Vorteile auf. Ein weiterer Vorteil dieser Variante besteht darin, dass die in der KFA vorhandenen Einrichtungen als zentrale Reparaturstelle fuer die CASTOR-MTR 2 Behaelter genutzt werden koennten. Ein Vergleich der Entsorgungswege ''Wiederaufarbeitung'' und ''Zwischenlagerung/Direkte Endlagerung'' weist wesentliche Kostenvorteile fuer die Endlagerung auf. (orig./HP)SIGLEAvailable from TIB Hannover: F94B1721+a / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Forschung und Technologie (BMFT), Bonn (Germany)DEGerman

Supramolecular and base-induced singlet oxygen generation enhancement of a water-soluble phthalocyanine

Investigation into the reactive oxygen species (ROS) generating abilities of photosensitizers outside of in-vitro/vivo conditions is a crucial element in the wider study of photodynamic therapy (PDT) in clinical settings. Zinc (II) phthalocyanine tetrasulfonic acid (ZnPcTS) is a water-soluble photosensitizer that can generate ROS as singlet oxygen (SO) under irradiation in the red and far-red region of the electromagnetic spectrum. The incorporation of ZnPcTS into nano-fibers of a bis-imidazolium hydrogel was demonstrated and the material was characterized with photophysical, rheological, and microscopy techniques. This supramolecular material containing ZnPcTS (named ZnPcTS_nEqBase@ Gels) was found to significantly enhance the SO generation rate with respect to that of ZnPcTS in an aqueous solution. The effect is attributed mainly to reduced aggregation within the gel microenvironment compared with

Initial state QED radiation aspects for future e+e−e^+e^- colliders

This white paper concerns theoretical and phenomenological aspects relevant to the physics of future $e^+e^-$ colliders, in particular regarding initial-state QED radiation. The contributions each contain key technical aspects, and are formulated in a pedagogical manner so as to render them accessible also to those who are not directly working on these and immediately-related topics. This should help both experts and non-experts understand the theoretical challenges that we shall face at future $e^+e^-$ colliders. Specifically, this paper contains descriptions of the treatment of initial state radiation from several Monte Carlo collaborations, as well as contributions that explain a number of more theoretical developments with promise of future phenomenological impact