Modular approach to select bacteriophages targeting Pseudomonas aeruginosa for their application to children suffering with cystic fibrosis

This review discusses the potential application of bacterial viruses (phage therapy) towards the eradication of antibiotic resistant Pseudomonas aeruginosa in children with cystic fibrosis (CF). In this regard, several potential relationships between bacteria and their bacteriophages are considered. The most important aspect that must be addressed with respect to phage therapy of bacterial infections in the lungs of CF patients is in ensuring the continuity of treatment in light of the continual occurrence of resistant bacteria. This depends on the ability to rapidly select phages exhibiting an enhanced spectrum of lytic activity among several well-studied phage groups of proven safety. We propose a modular based approach, utilizing both mono-species and hetero-species phage mixtures. With an approach involving the visual recognition of characteristics exhibited by phages of well studied phage groups on lawns of the standard P. aeruginosa PAO1 strain, the simple and rapid enhancement of the lytic spectrum of cocktails is permitted, allowing the development of tailored preparations for patients capable of circumventing problems associated with phage resistant bacterial mutants.

Hypoxia selects for androgen independent LNCaP cells with a more malignant geno- and phenotype.

Hypoxia confers resistance to common cancer therapies, however, it has also has been shown to result in genetic alterations which may allow a survival advantage and increase the tumorigenic properties of cancer cells. Additionally, it may exert a selection pressure, allowing expansion of tumor cells with a more aggressive phenotype. To further assess the role of hypoxia in malignant progression in prostate cancer we exposed human androgen dependent prostate cancer cells (LNCaP) to cycles of chronic hypoxia and isolated a subline, LNCaP-H1. This article describes the partial characterization of this cell line. The LNCaP-H1 subline showed altered growth characteristics and exhibited androgen independent growth both in vitro and in vivo. Furthermore, these cells were resistant to mitochondrial-mediated apoptosis, probably since the endogenous levels of Bax was lower and Bcl-2 higher than in the parental LNCaP cells. Microarray analysis revealed that a complex array of pathways had differential gene expression between the 2 cell lines, with LNCaP-H1 cells exhibiting a genetic profile which suggests that they may be more likely metastasize to distant organs, especially bone. This was supported by an in vitro invasion assay, and an in vivo metastasis study. This study shows that hypoxia can select for androgen independent prostate cancer cells which have a survival advantage and are more likely to invade and metastasize.

Do multinationals really prefer to enter culturally distant countries through greenfields rather than through acquisitions? The role of parent experience and subsidiary autonomy.

Prior research has argued that multinational enterprises (MNEs) prefer to enter culturally distant countries through greenfields rather than through acquisitions, since acquisitions in such countries are costlier to manage. This argument contains two hidden assumptions: (1) the additional costs of acquisitions in culturally distant countries are the same for all MNEs; and (2) such acquisitions have no benefits over their greenfield counterparts. In this paper we relax these two assumptions by arguing that an MNE's preference for greenfields in culturally distant countries depends on its international and host-country experience, and on the level of autonomy it plans to grant the focal subsidiary. Analyzing 171 wholly owned greenfield investments and full acquisitions made by Dutch MNEs in 35 countries, we find that these MNEs prefer to enter culturally distant countries through greenfields, but that this preference is lower when they have little international experience, or plan to grant the focal subsidiary considerable autonomy in marketing. [ABSTRACT FROM AUTHOR]

Enhancement of optically thick to thin line intensities in solar and stellar coronal plasmas through radiative transfer effects: an angularly resolved study.

An analysis of radiative transfer effects present in the Fe XV ion stage of solar and stellar coronal plasmas provides a general explanation of line radiation intensity enhancement above the optically thin limit. Full linearization radiation transfer is compared with the escape factor method and found to be in good agreement at the lower column densities. An angular study of the enhancement shows that symmetry factors are of great importance. This gives a possible reason for the indeterminate status of opacity in relation to coronal lines of distant stellar sources, where only emission integrated across the whole surface is detected.

CCD photometry of distant comets. III - Ensemble properties of Jupiter-family comets

We describe the results of a ground-based observational "snapshot" study of Jupiter-family comets in the heliocentric range 2.29 AU less than or equal to R-h less than or equal to 5.72 AU. Results are presented based on observations from the 1m JKT on the island of La Palma. A total of 25 comets were targeted with 15 being positively detected. Broad-band VRI photometry was performed to determine dimensions, colour indices, and dust production rates in terms of the "A frho" formalism. The results for selected comets are compared with previous investigations. Ensemble properties of the Jupiter- family population have been investigated by combining the results presented here with those of Lowry et al. (1999), and Lowry & Fitzsimmons (2001). We find that the cumulative size distribution of the Jupiter-family comets can be described by a power law of the form; Sigma(> r) proportional to r(-1.6+/- 0.1). This size distribution is considerably shallower than that found for the observed Edgeworth-Kuiper belt objects, which may reflect either an intrinsic difference at small km- sizes in the belt, or the various processes affecting the nuclei of comets as their orbits evolve from the Edgeworth- Kuiper belt to the inner Solar system. Also, there would appear to be no correlation between nuclear absolute magnitude and perihelion distance. Finally, for the sample of active comets, there is a distinct correlation between absolute R band magnitude and perihelion distance, which can be explained by either a discovery bias towards brighter comets or in terms of "rubble" mantle formation.

CCD photometry of distant comets II

R band CCD photometric observations of short period Jupiter family comets in the heliocentric region of 2.11 AU less than or equal to R-h less than or equal to 5.63 AU were performed using the 4.2 m William Herschel Telescope on La Palma in December 1998. 22 comets were targeted, including the comet- asteroid transition object 49P/Arend-Rigaux. Out of a total of ten detected comets. six were seen to display substantial outgassing (48P, 65P, 74P, 103Pt 128P, and 139P), with the remaining four comets (7P. 9P, 22P. and 49P) being stellar in appearance. Nuclear radius measurements and relative dust production rates in terms of Af rho were measured for these comets, along with upper limits for the remaining twelve undetected comets (6P, 44P, 51P, 54P, 57P: 63P, 71P, 73P, 79P, 86P, 87P, and 100P). The inactive comets had nuclear radii in the range 1.8 km less than or equal to r(N) less than or equal to 4.4 km, while upper limits for the active and undetected comets (assuming they all lay within the held of view) were between 0.6 km and 12.7 km, for an assumed albedo of 0.04. Even if one applies the previously measured maximum axis ratio of 2.6:1 and the minimum measured albedo of 0.02 to the undetected comets. their projected semi-major axes are all constrained to below 8 km. For the active comets, photometric profiles of their dust comae were measured and are consistent with those of steady state coma models.

An analytic geometry-variant approach to line ratio enhancement above the optically thin limit

We describe a simple theoretical model to investigate the anomalous effects of opacity on spectral line ratios, as previously studied in elements such as Fe XV and Fe XVII. The model developed is general: it is not specific to a particular atomic system, thus giving applicability to a number of coronal and chromospheric plasmas; furthermore, it may be applied to a variety of astrophysically relevant geometries. The analysis is underpinned by geometrical arguments, and we outline a technique for it to be used as a tool for the explicit diagnosis of plasma geometry in distant astrophysical objects.

William Herschel Telescope observations of distant comets

We present results from broad-band V- and R-filter observations obtained at the 4.2-m William Herschel Telescope on La Palma on 2002 July 12-14. A total of six comets were imaged, and their heliocentric distances ranged from 2.8 to 6.1 au. The comets observed were 43P/Wolf-Harrington, 129P/Shoemaker-Levy 3, 133P/Elst-Pizarro, 143P/Kowal-Mrkos, P/1998 U4 (Spahr) and P/2001 H5 (NEAT). A detailed surface brightness profile analysis indicates that three of the targeted comets (43P/Wolf-Harrington, 129P/Shoemaker-Levy 3 and P/1998 U4) were visibly active, and the remaining three comets were stellar in appearance. Further analysis shows that for the three `stellar-like' comets the possible coma contribution to the observed flux does not exceed 12.2 per cent, and in the case of comet 143P/Kowal-Mrkos the coma contribution is expected to be as low as 1 per cent, and so the resulting photometry most likely represents that of the projected nucleus surface. Effective radii for the inactive comets range from 1.02 to 4.56 km, and the effective radius upper limits for the active comets range from 1.94 to 4.15 km. We assume an albedo and phase coefficient of 0.04 and 0.035 mag deg-1, respectively, with the exception of comets 133P/Elst-Pizarro and 143P/Kowal-Mrkos for which phase coefficients were previously measured. These values are compared with previous measurements, and for comet 43P/Wolf-Harrington we find that the nucleus axial ratio a/b could be as large as 2.44. For the active comets we measured dust production levels in terms of the Af? quantity. Spectral gradients were extracted for two of the inactive comets from their measured broad-band colour indices, and compared with the rest of the comet population for which (V-R) colour and spectral gradient values exist. We find a spectral gradient for 143P/Kowal-Mrkos of 9.9 +/- 8.1 per cent/100 nm, which is very typical of Jupiter-family comets, the majority of which have reflectivity gradients in the range 0-13 per cent (100 nm)-1. The spectral gradient for comet 133P/Elst-Pizarro is amongst the bluest yet measured. We measure a (V-R) colour index value of 0.14 +/- 0.11 for the nucleus of 133P/Elst-Pizarro which is considerably lower than previous measurements. A possible explanation for this difference is considered.

Optical observations of 23 distant Jupiter Family Comets, including 36P/Whipple at multiple phase angles

We present photometry on 23 Jupiter Family Comets (JFCs) observed at large heliocentric distance, primarily using the 2.5-m Isaac Newton Telescope (INT). Snapshot images were taken of 17 comets, of which five were not detected, three were active and nine were unresolved and apparently inactive. These include 103P/Hartley 2, the target of the NASA Deep Impact extended mission, EPOXI. For six comets we obtained time-series photometry and use this to constrain the shape and rotation period of these nuclei. The data are not of sufficient quantity or quality to measure precise rotation periods, but the time-series do allow us to measure accurate effective radii and surface colours. Of the comets observed over an extended period, 40P/Väisälä 1, 47P/Ashbrook-Jackson and P/2004 H2 (Larsen) showed faint activity which limited the study of the nucleus. Light curves for 94P/Russell 4 and 121P/Shoemaker-Holt 2 reveal rotation periods of around 33 and 10h, respectively, although in both cases these are not unique solutions. 94P was observed to have a large range in magnitudes implying that it is one of the most elongated nuclei known, with an axial ratio a/b >= 3. 36P/Whipple was observed at five different epochs, with the INT and ESO's 3.6-m NTT, primarily in an attempt to confirm the preliminary short rotation period apparent in the first data set. The combined data set shows that the rotation period is actually longer than 24h. A measurement of the phase function of 36P's nucleus gives a relatively steep ß = 0.060 +/- 0.019. Finally, we discuss the distribution of surface colours observed in JFC nuclei, and show that it is possible to trace the evolution of colours from the Kuiper Belt Object (KBO) population to the JFC population by applying a `dereddening' function to the KBO colour distribution.

A set of primers for plastid indels and nuclear microsatellites in the invasive plant Heracleum mantegazzianum (Apiaceae) and their transferability to Heracleum sphondylium

This study reports the isolation and polymorphism characterization of four plastid indels and six nuclear microsatellite loci in the invasive plant Heracleum mantegazzianum. These markers were tested in 27 individuals from two distant H. mantegazzianum populations. Plastid indels revealed the presence of five chlorotypes while five nuclear microsatellite loci rendered polymorphism. Applications of these markers include population genetics and phylogeography of H. mantegazzianum. A very good transferability of markers to Heracleum sphondylium was demonstrated.

FKBPL regulates estrogen receptor signaling and determines response to endocrine therapy

The HSP90 chaperone and immunophilin FKBPL is an estrogen-responsive gene that interacts with estogen receptor a (ERa) and regulates its levels. In this study, we explored the effects of FKBPL on breast cancer proliferation. Breast cancer cells stably overexpressing FKBPL became dependent on estrogen for their growth and were dramatically more sensitive to the antiestrogens tamoxifen and fulvestrant, whereas FKBPL knockdown reverses this phenotype. FKBPL knockdown also decreased the levels of the cell cycle inhibitor p21WAF1 and increased ERa phosphorylation on Ser118 in response to 17ß-estradiol and tamoxifen. In support of the likelihood that these effects explained FKBPL-mediated cell growth inhibition and sensitivity to endocrine therapies, FKBPL expression was correlated with increased overall survival and distant metastasis-free survival in breast cancer patients. Our findings suggest that FKBPL may have prognostic value based on its impact on tumor proliferative capacity and sensitivity to endocrine therapies, which improve outcome.

The politics of ethical foreign policy::A responsibility to protect whom?

Ethical foreign policy persists as a problem of international relations, especially regarding humanitarian intervention. However, despite apparent international upheavals, the debate about the ethics of humanitarian intervention has remained fundamentally unchanged. To escape the limits of this debate, this article deconstructs British claims to ethical foreign policy since 1997, reading these claims against themselves and against contemporary humanitarian intervention literature. It finds that Britain’s ethical framework, the ‘doctrine of international community’, which justifies interventions in Kosovo, Sierra Leone and Afghanistan, is undone by the anomalous, yet exemplary, invasion of Iraq. This demonstrates the politics of ethical foreign policy: first, that any intervention, no matter how ‘ethical’ or ‘right’, produces suffering and death; and, second, that we cannot know for sure whether we are doing the right thing by intervening. Embracing, rather than effacing, the political nature of ethical foreign policy opens up a more intellectually honest and positive potential future for relating to the foreign in a responsible manner.

On Suffering and Sympathy: Jude the Obscure, Evolution and Ethics

This article links Thomas Hardy’s exploration of sympathy in Jude the Obscure to contemporary scientific debates over moral evolution. Tracing the relationship between pessimism, progressivism, and determinism in Hardy’s understanding of sympathy, it also considers Hardy’s conception of the author as enlarger of “social sympathies”--a position, I argue, that was shaped by Leslie Stephen’s advocacy of novel writing as moral art. Considering Hardy’s engagement with writings by Charles Darwin, T. H. Huxley, Herbert Spencer, and others, I explore the novel’s participation in a debate about the evolutionary significance of sympathy and its implications for Hardy’s understanding of moral agency. Hardy, I suggest, offered a stronger defence of morality based on biological determinism than Darwin, but this determinism was linked to an unexpected evolutionary optimism.