Synergistic phage-antibiotic combinations for the control of Escherichia coli biofilms in vitro.

The potential application of phage therapy for the control of bacterial biofilms has received increasing attention as resistance to conventional antibiotic agents continues to increase. The present study identifies antimicrobial synergy between bacteriophage T4 and a conventional antibiotic, cefotaxime, via standard plaque assay and, importantly, in the in vitro eradication of biofilms of the T4 host strain Escherichia coli 11303. Phage-antibiotic synergy (PAS) is defined as the phenomenon whereby sub-lethal concentrations of certain antibiotics can substantially stimulate the host bacteria's production of virulent phage. Increasing sub-lethal concentrations of cefotaxime resulted in an observed increase in T4 plaque size and T4 concentration. The application of PAS to the T4 one-step growth curve also resulted in an increased burst size and reduced latent period. Combinations of T4 bacteriophage and cefotaxime significantly enhanced the eradication of bacterial biofilms when compared to treatment with cefotaxime alone. The addition of medium (10(4) PFU mL(-1) ) and high (10(7) PFU mL(-1) ) phage titres reduced the minimum biofilm eradication concentration value of cefotaxime against E. coli ATCC 11303 biofilms from 256 to 128 and 32 µg mL(-1) , respectively. Although further investigation is needed to confirm PAS, this study demonstrates, for the first time, that synergy between bacteriophage and conventional antibiotics can significantly improve biofilm control in vitro.

Nuclear factor-kappaB as a potential therapeutic target for the novel cytotoxic agent LC-1 in acute myeloid leukaemia

Nuclear factor-kappaB (NF-kappaB) has been implicated in a number of malignancies and has been suggested to be a potential molecular target in the treatment of leukaemia. This study demonstrated the constitutive activation of NF-kappaB in human myeloid blasts and a clear correlation between NF-kappaB expression and in vitro cytoprotection. High NF-kappaB expression was found in many of the poor prognostic acute myeloid leukaemia (AML) subtypes, such as French-American-British classification M0 and M7, and the poor cytogenetic risk group. The in vitro effects of LC-1, a novel dimethylamino-parthenolide analogue, were assessed in 62 primary untreated AML samples. LC-1 was found to be cytotoxic to AML cells in a dose-dependent manner, mediated through the induction of apoptosis. The median drug concentration necessary to kill 50% of the cells was 4.5 micromol/l for AML cells, compared with 12.8 micromol/l for normal marrow cells. LC-1 was shown to reduce the five individual human NF-kappaB Rel proteins in a dose-dependent manner. The subsequent inhibition of many NF-kappaB-regulated cytokines was also demonstrated. Importantly, sensitivity to LC-1 was correlated with the basal NF-kappaB activity. Consequently, LC-1 treatment provides a proof of principle for the use of NF-kappaB inhibitors in the treatment of AML.

Moxifloxacin sensitivity of respiratory pathogens in the United Kingdom

The in vitro activity of moxifloxacin and comparator agents against respiratory isolates from a range of geographically distinct centres around the United Kingdom was investigated in the following study. Clinical isolates of Streptococcus pneumoniae (n = 257), Haemophilus influenzae (n = 399) and Moraxella catarrhalis (n = 253) were obtained between March 1998 and April 1999 from nine centres in the United Kingdom. Sensitivity was determined by testing each isolate for its minimum inhibitory concentration (MIC) by agar dilution. Against Streptococcus pneumoniae moxifloxacin and grepafloxacin were the most active (MIC90 = 0.25 mg/l). Trovafloxacin and sparfloxacin were the next most active (MIC90 = 0.5 mg/l) followed by levofloxacin and ciprofloxacin. MIC90 values of the six fluoroquinolones versus H. influenzae ranged from ciprofloxacin > levofloxacin. Against M. catarrhalis the lowest MIC90 was that of grepafloxacin at 0.0625 mg/l followed by moxifloxacin, sparfloxacin, levofloxacin and ciprofloxacin. Trovafloxacin demonstrated the highest MIC90 at 0.5 mg/l. These results demonstrate that moxifloxacin has superior in vitro activity against respiratory tract pathogens than any other comparator quinolones available for clinical use.

Design and Practice in Architectural Theory Education

Benefiting from design in theory learning is not common in architecture schools. The general practice is to design in studio and to theorise in lectures. In the undergraduate module History and Theory in Architecture II at Queen’s University Belfast, students attend interactive lectures, participate in reading group discussions, design TextObjects, and write essays. TextObjects contain textual, audio and/or graphic representations that highlight a single concept or a complex set of issues derived from readings. Students experiment with diverse media, such as filmmaking, photography, and graphic design, some of which they experience for the first time. Lectures and readings revolve around theories of architectural representation, media and communication, which are practiced through TextObjects. This is a new way to link theory and practice in architectural education. Through action research, this study analyses this innovative teaching method called TextObject, which brings design and practice into architectural theory education to stimulate students towards critical thinking. The pedagogical research of architectural theoretician Necdet Teymur (1992, 1996, 2002) underlies the study.

Intra-epithelial T cells in coeliac disease

Coeliac disease is an enteropathy associated with dietary gluten which occurs in individuals with a genetic predisposition. The pathogenesis remains obscure although it is clear that only certain parts of the gliadin molecule are toxic and there is considerable evidence of immunological activity, including antibody production. In this issue of European Journal of Gastroenterology and Hepatology Carton et al. present evidence in favour of an inherent depletion of CD4CD8 T cells, which could result in a loss of oral tolerance to ingested gliadin. Using flow cytometry they also demonstrated that the classic T-cell infiltration of coeliac disease is not due to an increase in T cells but is an apparent increase associated with a relative decrease in enterocytes as a result of the change in architecture of the mucosa. These could be important fundamental observations in helping to unravel the pathogenesis of coeliac disease.

The effect of hypobaric hypoxia on misonidazole binding in normal and tumour-bearing mice

The effect of hypobaric hypoxia on the in vivo binding of misonidazole was investigated in normal mice and mice bearing T50/80 or CA NT mammary carcinomas. After the intraperitoneal injection of radiolabelled misonidazole, mice were randomised to breathe either room air or air at 0.5 atmospheres. The distribution of misonidazole in liver, kidney, heart, spleen and tumour tissue, 24 h later, was studied by scintillation counting and by autoradiography. Significantly higher misonidazole binding occurred in the livers (x2.5), kidneys (x2.4), spleens (x2.9) and hearts (x1.8) of hypoxic mice compared to controls. Hypobaric hypoxia was associated with a greater than four-fold increase in misonidazole binding within T50/80 tumours. However, significantly higher binding was not demonstrated within CA NT tumours after exposure of tumour-bearing animals to hypoxic conditions. In autoradiographs of hypoxic liver, labelling was intense in regions near to hepatic veins but sparse in areas surrounding portal tracts. This pattern was striking and consistent. In hypoxic kidney, labelling was most intense over tubular cells, less intense over glomeruli and sparse in the renal medulla. It is likely that the hepatic and renal cortical distributions of misonidazole binding reflect local oxygen gradients.

In-vitro investigation of out-of-field cell survival following the delivery of conformal, intensity-modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) plans

The aim of this work is to determine the out-of-field survival of cells irradiated with either the primary field or scattered radiation in the presence and absence of intercellular communication following delivery of conformal, IMRT and VMAT treatment plans. Single beam, conformal, IMRT and VMAT plans were created to deliver 3 Gy to half the area of a T80 flask containing either DU-145 or AGO-1522 cells allowing intercellular communication between the in-and out-of-field cell populations. The same plans were delivered to a similar custom made phantom used to hold two T25 culture flasks, one flask in-field and one out-of-field to allow comparison of cell survival responses when intercellular communication is physically inhibited. Plans were created for the delivery of 8 Gy to the more radio-resistant DU-145 cells only in the presence and absence of intercellular communication. Cell survival was determined by clonogenic assay. In both cell lines, the out-of-field survival was not statistically different between delivery techniques for either cell line or dose. There was however, a statistically significant difference between survival out-of-field when intercellular communication was intact (single T80 culture flask) or inhibited (multiple T25 culture flasks) to in-field for all plans. No statistically significant difference was observed in-field with or without cellular communication to out-of-field for all plans. These data demonstrate out-of-field effects as important determinants of cell survival following exposure to modulated irradiation fields when cellular communication between differentially irradiated cell populations is present. This data is further evidence that refinement of existing radiobiological models to include indirect cell killing effects is required.

Recombinant canine distemper virus strain Snyder Hill expressing green or red fluorescent proteins causes meningoencephalitis in the ferret

The propensity of canine distemper virus (CDV) to spread to the central nervous system is one of the primary features of distemper. Therefore, we developed a reverse genetics system based on the neurovirulent Snyder Hill (SH) strain of CDV (CDV(SH)) and show that this virus rapidly circumvents the blood-brain and blood-cerebrospinal fluid (CSF) barriers to spread into the subarachnoid space to induce dramatic viral meningoencephalitis. The use of recombinant CDV(SH) (rCDV(SH)) expressing enhanced green fluorescent protein (EGFP) or red fluorescent protein (dTomato) facilitated the sensitive pathological assessment of routes of virus spread in vivo. Infection of ferrets with these viruses led to the full spectrum of clinical signs typically associated with distemper in dogs during a rapid, fatal disease course of approximately 2 weeks. Comparison with the ferret-adapted CDV(5804P) and the prototypic wild-type CDV(R252) showed that hematogenous infection of the choroid plexus is not a significant route of virus spread into the CSF. Instead, viral spread into the subarachnoid space in rCDV(SH)-infected animals was triggered by infection of vascular endothelial cells and the hematogenous spread of virus-infected leukocytes from meningeal blood vessels into the subarachnoid space. This resulted in widespread infection of cells of the pia and arachnoid mater of the leptomeninges over large areas of the cerebral hemispheres. The ability to sensitively assess the in vivo spread of a neurovirulent strain of CDV provides a novel model system to study the mechanisms of virus spread into the CSF and the pathogenesis of acute viral meningitis.

Bit-level systolic architecture for very high performance IIR filters

A novel bit-level systolic array architecture for implementing bit-parallel IIR filter sections is presented. The authors have shown previously how the fundamental obstacle of pipeline latency in recursive structures can be overcome by the use of redundant arithmetic in combination with bit-level feedback. These ideas are extended by optimizing the degree of redundancy used in different parts of the circuit and combining redundant circuit techniques with those of conventional arithmetic. The resultant architecture offers significant improvements in hardware complexity and throughput rate.

Between Sound and Sight: Framing the Exotic in Roysten Abel's The Manganiyar Seduction

Roysten Abel’s The Manganiyar Seduction is perhaps the most popular performance of Indian folk music on the global festival market today. This performance of Rajasthani folk music is an apt exemplification of an auto-exoticism framed as cultural commodity. Its mise en scéne of musicians framed, literally, by illuminated red square boxes ‘theatricalises’ Rajasthan’s folk culture of orality and renders such a tradition the quality of strangeness that borders on theatre and music, contemporary and traditional. The ‘dazzling’ union of the Manganiyar’s music and scenography of Amsterdam’s red light district engendered an exotic seduction that garnered raving reviews on its global tour. This paper then examines the production’s performative interstices: the in betweenness of sound and sight where aural tradition is ‘spectacularised’, and the shifting convergences of tradition and cultural consumption. It further interrogates the role of reception in the construction of such ‘exotic’ spectacles.

Changing Paradigms in Space Theories:Recapturing 20th Century Architectural History

The concept of space entered architectural history as late as 1893. Studies in art opened up the discussion, and it has been studied in various ways in architecture ever since. This article aims to instigate an additional reading to architectural history, one that is not supported by "isms" but based on space theories in the 20th century. Objectives of the article are to bring the concept of space and its changing paradigms to the attention of architectural researchers, to introduce a conceptual framework to classify and clarify theories of space, and to enrich the discussions on the 20th century architecture through theories that are beyond styles. The introduction of space in architecture will revolve around subject-object relationships, three-dimensionality and senses. Modern space will be discussed through concepts such as empathy, perception, abstraction, and geometry. A scientific approach will follow to study the concept of place through environment, event, behavior, and design methods. Finally, the research will look at contemporary approaches related to digitally supported space via concepts like reality-virtuality, mediated experience, and relationship with machines.

Behavioural skeletons in GCM: autonomic management of grid components

Autonomic management can be used to improve the QoS provided by parallel/distributed applications. We discuss behavioural skeletons introduced in earlier work: rather than relying on programmer ability to design “from scratch” efficient autonomic policies, we encapsulate general autonomic controller features into algorithmic skeletons. Then we leave to the programmer the duty of specifying the parameters needed to specialise the skeletons to the needs of the particular application at hand. This results in the programmer having the ability to fast prototype and tune distributed/parallel applications with non-trivial autonomic management capabilities. We discuss how behavioural skeletons have been implemented in the framework of GCM(the Grid ComponentModel developed within the CoreGRID NoE and currently being implemented within the GridCOMP STREP project). We present results evaluating the overhead introduced by autonomic management activities as well as the overall behaviour of the skeletons. We also present results achieved with a long running application subject to autonomic management and dynamically adapting to changing features of the target architecture.
Overall the results demonstrate both the feasibility of implementing autonomic control via behavioural skeletons and the effectiveness of our sample behavioural skeletons in managing the “functional replication” pattern(s).

A Generic Reference Software Architecture for Load Balancing over Mirrored Web Servers: NaSr Case Study

With the rapid expansion of the internet and the increasing demand on Web servers, many techniques were developed to overcome the servers' hardware performance limitation. Mirrored Web Servers is one of the techniques used where a number of servers carrying the same "mirrored" set of services are deployed. Client access requests are then distributed over the set of mirrored servers to even up the load. In this paper we present a generic reference software architecture for load balancing over mirrored web servers. The architecture was designed adopting the latest NaSr architectural style [1] and described using the ADLARS [2] architecture description language. With minimal effort, different tailored product architectures can be generated from the reference architecture to serve different network protocols and server operating systems. An example product system is described and a sample Java implementation is presented.

Shifting Ground:Beyond National Architecture

The Irish Pavilion at the Venice Architecture Biennale 2012 charts a position for Irish architecture in a global culture where the modes of production of architecture are radically altered. Ireland is one of the most globalised countries in the world, yet it has developed a national culture of architecture derived from local place as a material construct. We now have to evolve our understanding in the light of the globalised nature of economic processes and architectural production which is largely dependent on internationally networked flows of products, data, and knowledge. We have just begun to represent this situation to ourselves and others. How should a global architecture be grounded culturally and philosophically? How does it position itself outside of shared national reference points?
heneghan peng architects were selected as participants because they are working across three continents on a range of competition-winning projects. Several of these are in sensitive and/or symbolic sites that include three UNESCO World Heritage sites, including the Grand Egyptian Museum in Cairo, the Giants Causeway Visitor Centre in Northern Ireland, and the new Rhine Bridge near Lorelei.
Our dialogue led us to discussing the universal languages of projective geometry and number are been shared by architects and related professionals. In the work of heneghan peng, the specific embodiment of these geometries is carefully calibrated by the choice of materials and the detailed design of their physical performance on site. The stone facade of the Giant’s Causeway Visitor Centre takes precise measure of the properties of the volcanic basalt seams from which it is hewn. The extraction of the stone is the subject of the pavilion wall drawings which record the cutting of stones to create the façade of the causeway centre.
We also identified water as an element which is shared across the different sites. Venice is a perfect place to take measure of this element which suggests links to another site – the Nile Valley which was enriched by the annual flooding of the River Nile. An ancient Egyptian rod for measuring the water level of the Nile inspired the design of the Nilometre - a responsive oscillating bench that invites visitors to balance their respective weights. This action embodies the ways of thinking that are evolving to operate in the globalised world, where the autonomous architectural object is dissolving into an expanded field of conceptual rules and systems. The bench constitutes a shifting ground located in the unstable field of Venice. It is about measurement and calibration of the weight of the body in relation to other bodies; in relation to the site of the installation; and in relation to water. The exhibit is located in the Artiglierie section of the Arsenale. Its level is calibrated against the mark of the acqua alta in the adjacent brickwork of the building which embodies a liminal moment in the fluctuating level of the lagoon.
The weights of bodies, the level of water, changes over time, are constant aspects of design across cultures and collectively they constitute a common ground for architecture - a ground shared with other design professionals. The movement of the bench required complex engineering design and active collaboration between the architects, engineers and fabricators. It is a kind of prototype – a physical object produced from digital data that explores the mathematics at play – the see-saw motion invites the observer to become a participant, to give it a test drive. It shows how a simple principle can generate complex effects that are difficult to predict and invites visitors to experiment and play with them.