Canada's foreign policy dilemmas

'Canada plays little part in Europe's Atlantic policy. Yet European and German policy makers should be aware of an emerging debate in the Northern part of North America that could affect Canada's link to Europe and with it European interests. Europeans as yet are not very conscious of the fact that reliable, like-minded, multilateralist partners with enough resources and political will to make a contribution, do not come in such numbers that Canada can be largely ignored. Because of real and acknowledged similarities between Canada and Europe on many foreign and domestic policy issues, Canada has sometimes been referred to as 'a North American country with European instincts.' But that does not mean that, in comparison to the US, the transatlantic cooperation between Canada and Europe is less problematic and goes on unnurtured. Years of very significant Canadian involvement in the Balkans and major contributions in Afghanistan alongside European troops have not been enough to make Europeans aware of the need to address the unique situation of Canada, for instance in NATO. The question therefore is why should either side do what it does not seem naturally inclined to do, i.e. promote a special relationship. The most obvious first step would be a better inclusion of Canada in the transatlantic dialogue. For that to happen, Canada would have to define convincingly the nature of its added value. It would also have to find within Europe a champion. As a new government in Germany is beginning to define its international role in terms of security, energy and transatlantic relations, this is an aspect that it could do well to consider.' (author's abstract)

Guanine Oxidation in Double-stranded DNA by MnTMPyP/KHSO5: At Least Three Independent Reaction Pathways

In order to better define the mechanism and the products of guanine oxidation within DNA, we investigated the details of the mechanism of guanine oxidation by a metalloporphyrin, Mn-TMPyP, associated to KHSO5 on oligonucleotides. We found that the three major products of guanine oxidation are formed by independent reaction routes. The oxidized guanidinohydantoin (1) and the proposed spiro compound 3 derivatives are not precursors of imidazolone lesion (Iz). These guanine lesions as well as their degradation products, may account for non-detected guanine oxidation products on oxidatively damaged DNA

Mechanistic studies on DNA damage by minor groove binding copper–phenanthroline conjugates

Copper–phenanthroline complexes oxidatively damage and cleave nucleic acids. Copper bis-phenanthroline and copper complexes of mono- and bis-phenanthroline conjugates are used as research tools for studying nucleic acid structure and binding interactions. The mechanism of DNA oxidation and cleavage by these complexes was examined using two copper–phenanthroline conjugates of the sequence-specific binding molecule, distamycin. The complexes contained either one or two phenanthroline units that were bonded to the DNA-binding domain through a linker via the 3-position of the copper ligand. A duplex containing independently generated 2-deoxyribonolactone facilitated kinetic analysis of DNA cleavage. Oxidation rate constants were highly dependent upon the ligand environment but rate constants describing elimination of the alkali-labile 2-deoxyribonolactone intermediate were not. Rate constants describing DNA cleavage induced by each molecule were 11–54 times larger than the respective oxidation rate constants. The experiments indicate that DNA cleavage resulting from β-elimination of 2-deoxyribonolactone by copper–phenanthroline complexes is a general mechanism utilized by this family of molecules. In addition, the experiments confirm that DNA damage mediated by mono- and bis-phenanthroline copper complexes proceeds through distinct species, albeit with similar outcomes

Un fléau nommé paludisme

De la recherche fondamentale à l’innovation thérapeutique, des molécules biomimétiques aux antipaludiques... Rien, en apparence, ne prédestinait Bernard Meunier à une telle trajectoire. Pourtant, avec Palumed SA, la société de chimie thérapeutique qu’il a créée en 2000, il a fait preuve d’une polyvalence inestimable et accompagné un transfert technologique réussi

Le désert chrétien, avatar des utopies antiques ?

Dans la littérature chrétienne des premiers siècles se distingue un sous-corpus, la littérature monastique – en particulier celle des apophtegmes –, qui met en scène cet autre monde qu’est le désert, aux frontières du rêve, du mythe et du modèle édifiant, qui suggère des rapprochements avec la littérature utopique. Cet article se propose d’examiner le rapport entre le désert chrétien antique, tel qu’il est raconté dans ces récits, et le genre de l’utopie, pour voir s’il en relève, s’il s’y inscrit tout entier, le renouvelle ou le dénature. Le phénomène singulier qu’est le monachisme ancien a-t-il pensé et réalisé un monde nouveau tel que les utopistes pouvaient le rêver ? A-t-il voulu le faire ? Comment interpréter les thèmes comme le paradis retrouvé, l’homme sauvage, le Royaume des justes à la fin des temps ? L’utopie peut à la fois être interrogée par cette littérature, et l’interroger à son tour pour l’éclairer peut-être sous un angle un peu différent des approches classiques.In the Christian literature of the first centuries, attention is paid to monastic literature, especially to that of the apophthegms, which presents another world, the desert, on the borders of dream, myth and spirituality, and suggests comparisons with utopian literature. This article examines the relationship between the ancient Christian desert, such as it is told in these narratives, and the literary genre of utopia, in order to see if the literature of the desert derives from it, or merges with it entirely, or renews it, or distorts it. Did ancient monasticism create a new world as utopians dreamed it up? How can we interpret the themes as that of paradise regained, the wild man, or the kingdom of just men at the end of time? Utopia can be questioned by this literature of the desert, and question it back, and thus enlighten it from a point of view which is a little different from classical approaches

Double-walled carbon nanotubes trigger IL-1β release in human monocytes through Nlrp3 inflammasome activation

Because of their outstanding physical properties, carbon nanotubes (CNTs) are promising new materials in the field of nanotechnology. It is therefore imperative to assess their adverse effects on human health. Monocytes/macrophages that recognize and eliminate the inert particles constitute the main target of CNTs. In this article, we report our finding that double-walled CNTs (DWCNTs) synergize with Tolllike receptor agonists to enhance IL-1β release in human monocytes. We show that DWCNTs–induced IL-1β secretion is exclusively linked to caspase-1 and to Nlrp3 inflammasome activation in human monocytes. We also establish that this activation requires DWCNTs phagocytosis and potassium efflux, but not reactive oxygen specied (ROS) generation. Moreover, inhibition of lysosomal acidification or cathepsin-B activation reduces DWCNT-induced IL-1β secretion, suggesting that Nlrp3 inflammasome activation occurs via lysosomal destabilization. Thus, DWCNTs present a health hazard due to their capacity to activate Nlrp3 inflammasome, recalling the inflammation caused by asbestos and hence demonstrating that they should be used with caution. From the Clinical Editor: This is a very important biosafety/toxicity study regarding double walled carbon nanotubes. The investigators demonstrate that such nanotubes do represent a health hazard due to their capacity to activate Nlrp3 inflammasome, resembling the inflammation caused by asbestos. While further study of this phenomenon is definitely needed, the above findings clearly suggest that special precautions need to be taken when applying these nanoparticles in human disease research

Effect of long-term exposure of SH-SY5Y cells to morphine: a whole cell proteomic analysis

BACKGROUND: Opiate addiction reflects plastic changes that endurably alter synaptic transmission within relevant neuronal circuits. The biochemical mechanisms of these adaptations remain largely unknown and proteomics-based approaches could lead to a broad characterization of the molecular events underlying adaptations to chronic drug exposure. RESULTS: Thus, we have started proteomic analyses of the effects of chronic morphine exposure in a recombinant human neuroblastoma SH-SY5Y clone that stably overexpresses the μ-opioid receptor. Cells were treated with morphine for 6, 24 and 72 hours, the proteins were separated by 2-D gel electrophoresis and stained with Coomassie blue, and the protein map was compared with that obtained from untreated cells. Spots showing a statistically significant variation were selected for identification using mass spectrometric analyses. CONCLUSION: A total of 45 proteins were identified, including proteins involved in cellular metabolism, cytoskeleton organization, vesicular trafficking, transcriptional and translational regulation, and cell signaling

DNA cleavage and binding selectivity of a heterodinuclear Pt–Cu(3-Clip-Phen) complex

The synthesis and nuclease activity of a new bifunctional heterodinuclear platinum–copper complex are reported. The design of this ditopic coordination compound is based on the specific mode of action of each component, namely, cisplatin and Cu(3-Clip-Phen), where 3-Clip-Phen is 1-(1,10-phenanthrolin-3-yloxy)-3-(1,10-phenanthrolin-8-yloxy)propan-2-amine. Cisplatin is not only able to direct the Cu(3-Clip-Phen) part to the GG or AG site, but also acts as a kinetically inert DNA anchor. The nuclease activity of this complex has been investigated on supercoiled DNA. The dinuclear compound is not only more active than Cu(3-Clip-Phen), but is also capable of inducing direct double-strand breaks. The sequence selectivity of the mononuclear platinum complex has been investigated by primer extension experiments, which reveal that its interaction with DNA occurs at the same sites as for cisplatin. The Taq polymerase recognizes the resulting DNA damage as different from that for unmodified cisplatin. The sequence-selective cleavage has been investigated by high-resolution gel electrophoresis on a 36-bp DNA fragment. Sequence-selective cleavages are observed in the close proximity of the platinum sites for the strand exhibiting the preferential platinum binding sites. The platinum moiety also coordinates to the other DNA strand, most likely leading only to mono guanine or adenine adducts

Pancreatic head cancer in patients with chronic pancreatitis

International audienceBACKGROUND: Chronic pancreatitis (CP) is a risk factor of pancreatic adenocarcinoma (PA). The discovery of a pancreatic head lesion in CP frequently leads to a pancreaticoduodenectomy (PD) which preceded by a multidisciplinary meeting (MM). The aim of this study was to evaluate the relevance between this indication of PD and the definitive pathological results. METHODS: Between 2000 and 2010, all patients with CP who underwent PD for suspicion of PA without any histological proof were retrospectively analyzed. The operative decision has always been made at an MM. The definitive pathological finding was retrospectively confronted with the decision made at an MM, and patients were classified in two groups according to this concordance (group 1) or not (group 2). Clinical and biological parameters were analyzed, preoperative imaging were reread, and confronted to pathological findings in order to identify predictive factors of malignant degeneration. RESULTS: During the study period, five of 18 (group 1) patients with CP had PD were histologically confirmed to have PA, and the other 13 (group 2) did not have PA. The median age was 52.5+/-8.2 years (gender ratio 3.5). The main symptoms were pain (94.4%) and weight loss (72.2%). There was no patient's death. Six (33.3%) patients had a major complication (Clavien-Dindo classification ≥ 3). There was no statistical difference in clinical and biological parameters between the two groups. The rereading of imaging data could not detect efficiently all patients with PA. CONCLUSIONS: Our results confirmed the difficulty in detecting malignant transformation in patients with CP before surgery and therefore an elevated rate of unnecessary PD was found. A uniform imaging protocol is necessary to avoid PD as a less invasive treatment could be proposed