Killing Themselves Slowly: India and China's Bad Habits

The world has experienced a public-health miracle in the past half century, as cleaner water, new health technologies, better diet and a host of other improvements have sharply reduced mortality and extended life expectancy in poor countries by as much as 20 years. A substantial portion of those gains has been realized through improvements in infant and child survival. However, the increase in income that was both a cause and effect of this miracle brought with it a new and ironic threat: a steep rise in non-communicable diseases (NCDs) like heart ailments and cancer.

Granular gland transcriptomes in stimulated amphibian skin secretions.

Amphibian defensive skin secretions are complex, species-specific cocktails of biologically active molecules, including many uncharacterized peptides. The study of such secretions for novel peptide discovery is time-limited, as amphibians are in rapid global decline. While secretion proteome analysis is non-lethal, transcriptome analysis has until now required killing of specimens prior to skin dissection for cDNA library construction. Here we present the discovery that polyadenylated mRNAs encoding dermal granular gland peptides are present in defensive skin secretions, stabilized by endogenous nucleic acid-binding amphipathic peptides. Thus parallel secretory proteome and transcriptome analyses can be performed without killing the specimen in this model amphibian system--a finding that has important implications in conservation of biodiversity within this threatened vertebrate taxon and whose mechanistics may have broader implications in biomolecular science.

Peacebuilding at the Local Level: Refugee Return to Prijedor'

During the 1992-95 war, Prijedor was synonymous with mass killing, ethnic cleansing and detention camps. A decade after the end of the war, international agencies consider this town to be an example of successful foreign intervention. Thousands of Muslim displaced persons (DPs) returned to their pre-war homes, mosques have been rebuilt, and hard-line Serb nationalists have lost much influence. How could Prijedor turn from a hopeless case of ethnic violence to an example of successful intervention? This essay argues that Prijedor's (relative) success is due more to the determination of Muslim DPs than to the international peacebuilding strategy. The initial post-Dayton international intervention exacerbated the problem of internal displacement, raised ethnic tensions and left Prijedor in the hands of the same indicted war criminals responsible for the war. Against the advice of international agencies, which feared a backlash among the Bosnian Serbs, in 1998 Muslim DPs began returning home. Eventually, large-scale return improved ethnic relations and helped marginalize Bosnian Serb extremists. The essay concludes by highlighting the lessons from Prijedor, and identifies the domestic and international contribution to Prijedor's post-settlement success.

Antimicrobial activity of truncated alpha-defensin (human neutrophil peptide (HNP)-1) analogues without disulphide bridges.

Antimicrobial peptides play an important role in host defence, particularly in the oral cavity where there is constant challenge by microorganisms. The a-defensin antimicrobial peptides comprise 30–50% of the total protein in the azurophilic granules of human neutrophils, the most abundant of which is human neutrophil peptide 1 (HNP-1). Despite its antimicrobial activity, a limiting factor in the potential therapeutic use of HNP-1 is its chemical synthesis with the correct disulphide topology. In the present study, we synthesised a range of truncated defensin analogues lacking disulphide bridges. All the analogues were modelled on the C-terminal region of HNP-1 and their antimicrobial activity was tested against a range of microorganisms, including oral pathogens. Although there was variability in the antimicrobial activity of the truncated analogues synthesised, a truncated peptide named 2Abz23S29 displayed a broad spectrum of antibacterial activity, effectively killing all the bacterial strains tested. The finding that truncated peptides, modelled on the C-terminal ß-hairpin region of HNP-1 but lacking disulphide bridges, display antimicrobial activity could aid their potential use in therapeutic interventions.

Functional domains of the human epididymal protease inhibitor, eppin

Eppin has two potential protease inhibitory domains: a whey acid protein or four disulfide core domain and a Kunitz domain. The protein is also reported to have antibacterial activity against Gram-negative bacteria. Eppin and its whey acid protein and Kunitz domains were expressed in Escherichia coli and their ability to inhibit proteases and kill bacteria compared. The Kunitz domain inhibits elastase (EC 3.4.21.37) to a similar extent as intact eppin, whereas the whey acid protein domain has no such activity. None of these fragments inhibits trypsin (EC 3.4.21.4) or chymotrypsin (EC 3.4.21.1) at the concentrations tested. In a colony forming unit assay, both domains have some antibacterial activity against E. coli, but this was not to the same degree as intact eppin or the two domains together. When bacterial respiratory electron transport was measured using a 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide assay, eppin and its domains caused an increase in the rate of respiration. This suggests that the mechanism of cell killing may be partly through the permeablization of the bacterial inner membrane, resulting in uncoupling of respiratory electron transport and consequent collapse of the proton motive force. Thus, we conclude that although both of eppin’s domains are involved in the protein’s antibacterial activity, only the Kunitz domain is required for selective protease inhibition.

Predatory nature of the littoral amphipod Echinogammarus marinus: gut content analysis and effects of alternative food and substrate heterogeneity

Interspecific interactions are major structuring forces in marine littoral communities; however, it is unclear which of these interactions are exhibited by many key-component species. Gut content analysis showed that the ubiquitous rocky/cobble shore amphipod Echinogammarus marinas, often ascribed as a mesograzer, consumes both algae and macroinvertebrates. Further, laboratory experiments showed that E. marinus is an active predator of such macroinvertebrates, killing and consuming the isopod Jaera nordmanni and the oligochaete Tubificoides benedii. Predatory impacts of E. marinus were not alleviated by the presence of alternative food in the form of alga discs. However, in the presence of prey, consumption of alga by E. marinus was significantly reduced. Further, survival of prey was significantly higher when substrate was provided, but predation remained significant and did not decline with further increases in substrate heterogeneity. We conclude that such amphipods can have pervasive predatory impacts on a range of species, with implications for community structure, diversity and functioning.

Effects of the acanthocephalan parasite Echinorhynchus truttae on the feeding ecology of Gammarus pulex (Crustacea : Amphipoda)

The amphipod Gammarus pulex is an intermediate host to the acanthocephalan fish parasite Echinorhynchus truttae. Gammarus pulex has a wide trophic repertoire, feeding as a herbivore, detritivore and predator. In this study an examination was made of the effects of E. truttae parasitism on components of the G. pulex diet: stream-conditioned leaves, dead chironomids and live juvenile isopods Asellus aquaticus. Over 21 days, parasitism had no effect on daily feeding rates or wet weights of G. pulex fed on leaves or chironomids. Parasitism had a significant effect on the number of A. aquaticus killed by G. pulex, with parasitized individuals killing significantly fewer than their unparasitized counterparts. In addition, unparasitized amphipods killed all size classes of A. aquaticus indiscriminately, whereas parasitized animals tended to kill the smaller size classes. The impacts of the parasitism of G. pulex throughout the wider freshwater community are discussed.

Histone H2AX phosphorylation as a molecular pharmacological marker for DNA interstrand crosslink cancer chemotherapy

The aims of this study were to investigate mechanisms of action involved in H2AX phosphorylation by DNA interstrand crosslinking (ICL) agents and determine whether gamma H2AX could be a suitable pharmacological marker for identifying potential ICL cellular chemosensitivity. In normal human fibroblasts, after treatment with nitrogen mustard (HN2) or cisplatin, the peak gamma H2AX response was detected 2-3 h after the peak of DNA ICLs measured using the comet assay, a validated method for detecting ICLs in vitro or in clinical samples. Detection of gamma H2AX foci by immunofluorescence microscopy could be routinely detected with 6-10 times lower concentrations of both drugs compared to detection of ICLs using the comet assay. A major pathway for repairing DNA ICLs is the initial unhooking of the ICL by the ERCC1-XPF endonuclease followed by homologous recombination. HN2 or cisplatin-induced gamma H2AX foci persisted significantly longer in both, ERCC1 or XRCC3 (homologous recombination) defective Chinese hamster cells that are highly sensitive to cell killing by ICL agents compared to wild type or ionising radiation sensitive XRCC5 cells. An advantage of using gamma H2AX immunofluorescence over the comet assay is that it appears to detect ICL chemosensitivity in both ERCC1 and HR defective cells. With HN2 and cisplatin, gamma H2AX foci also persisted in chemosensitive human ovarian cancer cells (A2780) compared to chemoresistant (A2780cisR) cells. These results show that gamma H2AX can act as a highly sensitive and general marker of DNA damage induced by HN2 or cisplatin and shows promise for predicting potential cellular chemosensitivity to ICL agents. (c) 2008 Elsevier Inc. All rights reserved.

Exile or emigrant? Female ex-prisoners who left Ireland 1850-1921

In the popular mind, the concept of 'emigration' usually refers to people voluntarily leaving one country to go to another in search of a new and better life. It presupposes some degree of choice, although it is accepted that for many emigrants, such as those who left Ireland during the nineteenth century, there were few incentives to stay at home. Current scholarship on voluntary and forced movements of people demonstrates that the distinction between the categories of 'voluntary emigrant' and 'forced exile' is often blurred. Orm Overland's study of refugee communities in the United States highlights the fact that, although the differences between the 'emigrant' and the 'exile' may be clear in extreme cases, this is not always true, as there may be 'pressing political or economic reasons behind a decision to emigrate'. Migration scholars Jan Lucassen and Leo Lucassen also question the adequacy of conceptual models of migration based on what Lindsay Proudfoot and Dianne Hall refer to as the 'straightforward binarism between free and unfree emigration'. The questions raised by these scholars are very relevant to the study of Irish people who left their country during the second half of the nineteenth century immediately after they had been discharged from prison or from Dundrum. Their stories are discussed here against a background of substantial scholarship on emigration from Ireland and on the criminal justice system within Ireland. According to David Fitzpatrick, at least eight million men, women and children emigrated from Ireland between 1801 and 1921. This large-scale movement of people was generally characterised by the voluntary emigration of individuals who funded their own passages. However, it also included schemes of assisted emigration, funded variously by governments, landlords, the poor law authorities, earlier emigrants, and philanthropists. In addition, it included people who were transported from Ireland by means of the criminal justice system a practice that had originated in the seventeenth century. What is less well known is that after the end of transportation from Ireland to eastern Australia in 1853, to Bermuda in 1863 and to Western Australia in 1868, Irish convicts continued to be channelled towards emigration by being offered early release if they agreed to leave Ireland. These people, and especially the women among them, are the subject of this article.

Murder and the Ruthless Risk-Taker

The main focus of this article is the ways in which the problem of reckless murder is dealt with in the common law world. In a case of reckless murder it may not be possible to prove that the accused set out to kill or do serious injury; but the killing is nevertheless thought to merit classification as murder rather than manslaughter. This may be because the case is thought to be analytically indistinguishable from murder, or because the level of culpability demonstrated by the conduct in question is thought to deserve that stigma on other grounds. This article seeks, by reference to various common law systems, to analyse the different techniques used to classify the reckless killer as a murderer, and to compare their advantages and disadvantages in the light of the different rationales used to justify such a classification. The article concludes by arguing that the question whether reckless killers should be classified as murderers—and if so how—can only be decided by reference to broader conceptions of the nature of criminal culpability.

Drug delivery strategies for photodynamic antimicrobial chemotherapy: From benchtop to clinical practice

Light and photosensitizer-mediated killing of many pathogens, termed photodynamic antimicrobial chemotherapy (PACT), has been extensively investigated in vitro. A wide range of organisms from the Gram-positive Staphylococcus aureus to the Gram-negative Pseudomonas aeruginosa have been proven to be susceptible to PACT. Multidrug-resistant strains are just as susceptible to this treatment as their naive counterparts. Both enveloped and non-enveloped viruses have demonstrated susceptibility in vitro, in addition to fungi and protozoa. Significantly, however, no clinical treatments based on PACT are currently licensed. This paper provides a comprehensive review of work carried out to date on delivery of photosensitizers for use in PACT, including topical, intranasal and oral/buccal delivery, as well as targeted delivery. We have also reviewed photo-antimicrobial surfaces. It is hoped that, through a rational approach to formulation design and subsequent success in small-scale clinical trials, more widespread use will be made of PACT in the clinic, to the benefit of patients worldwide. (C) 2009 Elsevier B.V. All rights reserved.

New molecular targets in radiotherapy: DNA damage signalling and repair in targeted and non-targeted cells

Ionising radiation plays a key role in therapy due to its ability to directly induce DNA damage, in particular DNA double-strand breaks leading to cell death. Cells have multiple repair pathways which attempt to maintain genomic stability. DNA repair proteins have become key targets for therapy, using small molecule inhibitors, in combination with radiation and or chemotherapeutic agents as a means of enhancing cell killing. Significant advances in our understanding of the response of cells to radiation exposures has come from the observation of non-targeted effects where cells respond via mechanisms other than those which are a direct consequence of energy-dependent DNA damage. Typical of these is bystander signalling where cells respond to the fact that their neighbours have been irradiated. Bystander cells show a DNA damage response which is distinct from directly irradiated cells. In bystander cells, ATM- and Rad3-related (ATR) protein kinase-dependent signalling in response to stalled replication forks is an early event in the DNA damage response. The ATM protein kinase is activated downstream of ATR in bystander cells. This offers the potential for differential approaches for the modulation of bystander and direct effects with repair inhibitors which may impact on the response of tumours and on the protection of normal tissues during radiotherapy. (C) 2009 Elsevier B.V. All rights reserved.