Hadronic Cross-sections in two photon Processes at a Future Linear Collider

In this note we address the issue of measurability of the hadronic cross-sections at a future photon collider as well as for the two-photon processes at a future high energy linear $e^+e^-$ collider. We extend, to higher energy, our previous estimates of the accuracy with which the \gamgam\ cross-section needs to be measured, in order to distinguish between different theoretical models of energy dependence of the total cross-sections. We show that the necessary precision to discriminate among these models is indeed possible at future linear colliders in the Photon Collider option. Further we note that even in the $e^+e^-$ option a measurement of the hadron production cross-section via \gamgam processes, with an accuracy necessary to allow discrimination between different theoretical models, should be possible. We also comment briefly on the implications of these predictions for hadronic backgrounds at the future TeV energy $e^+e^-$ collider CLIC.Comment: 20 pages, 5 figures, LaTeX. Added an acknowledgemen

COMPRENDO: Focus and approach

Tens of thousands of man-made chemicals are in regular use and discharged into the environment. Many of them are known to interfere with the hormonal systems in humans and wildlife. Given the complexity of endocrine systems, there are many ways in which endocrine-disrupting chemicals (EDCs) can affect the body’s signaling system, and this makes unraveling the mechanisms of action of these chemicals difficult. A major concern is that some of these EDCs appear to be biologically active at extremely low concentrations. There is growing evidence to indicate that the guiding principle of traditional toxicology that “the dose makes the poison” may not always be the case because some EDCs do not induce the classical dose–response relationships. The European Union project COMPRENDO (Comparative Research on Endocrine Disrupters—Phylogenetic Approach and Common Principles focussing on Androgenic/Antiandrogenic Compounds) therefore aims to develop an understanding of potential health problems posed by androgenic and antiandrogenic compounds (AACs) to wildlife and humans by focusing on the commonalities and differences in responses to AACs across the animal kingdom (from invertebrates to vertebrates)

The slings and arrows of communication on nanotechnology

According to numerous surveys the perceived risk of nanotechnology is low and most people feel that the benefits outweigh the risks. This article provides greater insight into risk perception and concludes that the positive attitude to nanotechnology is based not on knowledge but on hope and fascination. The perceived risk is low because of a lack of vivid and frightening images of possible hazards. If news flashes were to link nanotechnology to concrete hazards or actual harm to people, attitudes might suddenly change. Risk communication faces the problem of dealing with a public at large that has little or no knowledge about the technology. As it takes time and extensive additional research to develop appropriate communication strategies and disseminate them to the relevant institutions, this exercise should be started immediately

Use of radiolabelled choline as a pharmacodynamic marker for the signal transduction inhibitor geldanamycin

There is an urgent need to develop non-invasive pharmacodynamic endpoints for the evaluation of new molecular therapeutics that inhibit signal transduction. We hypothesised that, when labelled appropriately, changes in choline kinetics could be used to assess geldanamycin pharmacodynamics, which involves inhibition of the HSP90 molecular chaperone→Raf1→Mitogenic Extracellular Kinase→Extracellular Signal-Regulated Kinase 1 and 2 signal transduction pathway. Towards identifying a potential pharmacodynamic marker response, we have studied radiolabelled choline metabolism in HT29 human colon carcinoma cells following treatment with geldanamycin. We studied the effects of geldanamycin, on net cellular accumulation of (methyl-14C)choline and (methyl-14C)phosphocholine production. In parallel experiments, the effects of geldanamycin on extracellular signal-regulated kinase 1 and 2 phosphorylation and cell viability were also assessed. Additional validation studies were carried out with the mitogenic extracellular kinase inhibitor U0126 as a positive control; a cyclin-dependent kinase-2 inhibitor roscovitine and the phosphatidylinositol 3-kinase inhibitor LY294002 as negative controls. Hemicholinium-3, an inhibitor of choline transport and choline kinase activity was included as an additional control. In exponentially growing HT29 cells, geldanamycin inhibited extracellular signal-regulated kinase 1 and 2 phosphorylation in a concentration- and time-dependent manner. These changes were associated with a reduction in (methyl-14C)choline uptake, (methyl-14C) phosphocholine production and cell viability. Brief exposure to U0126, suppressed phosphocholine production to the same extent as Hemicholinium-3. In contrast to geldanamycin and U0126, which act upstream of extracellular signal-regulated kinase 1 and 2, roscovitine and LY294002 failed to suppress phosphocholine production. Our results suggest that when labelled with carbon-11 isotope, (methyl-11C)choline may be a useful pharmacodynamic marker for the non-invasive evaluation of geldanamycin analogues

Ewing Sarcoma Protein Ewsr1 Maintains Mitotic Integrity and Proneural Cell Survival in the Zebrafish Embryo

BACKGROUND:The Ewing sarcoma breakpoint region 1 gene (EWSR1), also known as EWS, is fused to a number of different partner genes as a result of chromosomal translocation in diverse sarcomas. Despite the involvement of EWSR1 in these diverse sarcomas, the in vivo function of wild type EWSR1 remains unclear. PRINCIPAL FINDINGS:We identified two zebrafish EWSR1 orthologues, ewsr1a and ewsr1b, and demonstrate that both genes are expressed maternally, and are expressed ubiquitously throughout zebrafish embryonic development. Morpholino induced knockdown of both zebrafish ewsr1 genes led to mitotic defects with multipolar or otherwise abnormal mitotic spindles starting from the bud stage (10 hour post-fertilization (hpf)). The abnormalities in mitotic spindles were followed by p53-mediated apoptosis in the developing central nervous system (CNS) leading to a reduction in the number of proneural cells, disorganization of neuronal networks, and embryonic lethality by 5 days post-fertilization. siRNA silencing of EWSR1 in Hela cells resulted in mitotic defects accompanied by apoptotic cell death, indicating that the role of EWSR1 is conserved between zebrafish and human. CONCLUSIONS:Ewsr1 maintains mitotic integrity and proneural cell survival in early zebrafish development

Imaging of acute appendicitis in children: EU versus US ... or US versus CT? A European perspective

There is substantial evidence that imaging may reduce the negative appendectomy rate, also in children. However, controversy exists about the preferred method: US or CT, and the choice appears to be determined by the side of the Atlantic Ocean. This review brings forth several arguments in favour of U

WNT signalling in prostate cancer

Genome sequencing and gene expression analyses of prostate tumours have highlighted the potential importance of genetic and epigenetic changes observed in WNT signalling pathway components in prostate tumours-particularly in the development of castration-resistant prostate cancer. WNT signalling is also important in the prostate tumour microenvironment, in which WNT proteins secreted by the tumour stroma promote resistance to therapy, and in prostate cancer stem or progenitor cells, in which WNT-β-catenin signals promote self-renewal or expansion. Preclinical studies have demonstrated the potential of inhibitors that target WNT receptor complexes at the cell membrane or that block the interaction of β-catenin with lymphoid enhancer-binding factor 1 and the androgen receptor, in preventing prostate cancer progression. Some WNT signalling inhibitors are in phase I trials, but they have yet to be tested in patients with prostate cancer

Mammary stem cells have myoepithelial cell properties.

Contractile myoepithelial cells dominate the basal layer of the mammary epithelium and are considered to be differentiated cells. However, we observe that up to 54% of single basal cells can form colonies when seeded into adherent culture in the presence of agents that disrupt actin-myosin interactions, and on average, 65% of the single-cell-derived basal colonies can repopulate a mammary gland when transplanted in vivo. This indicates that a high proportion of basal myoepithelial cells can give rise to a mammary repopulating unit (MRU). We demonstrate that myoepithelial cells, flow-sorted using two independent myoepithelial-specific reporter strategies, have MRU capacity. Using an inducible lineage-tracing approach we follow the progeny of myoepithelial cells that express α-smooth muscle actin and show that they function as long-lived lineage-restricted stem cells in the virgin state and during pregnancy.This work was funded by Cancer Research UK, Breast Cancer Campaign, the University of Cambridge, Hutchison Whampoa Limited, La Ligue Nationale Contre le Cancer (Equipe Labelisée 2013) and a grant from Agence Nationale de la Recherche ANR- 08-BLAN-0078-01 to M.A.G.This is the author accepted manuscript. The final version is available from Nature at http://www.nature.com/ncb/journal/vaop/ncurrent/full/ncb3025.html

Nucleolin Inhibits G4 Oligonucleotide Unwinding by Werner Helicase

The Werner protein (WRNp), a member of the RecQ helicase family, is strongly associated with the nucleolus, as is nucleolin (NCL), an important nucleolar constituent protein. Both WRNp and NCL respond to the effects of DNA damaging agents. Therefore, we have investigated if these nuclear proteins interact and if this interaction has a possible functional significance in DNA damage repair.Here we report that WRNp interacts with the RNA-binding protein, NCL, based on immunoprecipitation, immunofluorescent co-localization in live and fixed cells, and direct binding of purified WRNp to nucleolin. We also map the binding region to the C-terminal domains of both proteins. Furthermore, treatment of U2OS cells with 15 µM of the Topoisomerase I inhibitor, camptothecin, causes the dissociation of the nucleolin-Werner complex in the nucleolus, followed by partial re-association in the nucleoplasm. Other DNA damaging agents, such as hydroxyurea, Mitomycin C, and aphidicolin do not have these effects. Nucleolin or its C-terminal fragment affected the helicase, but not the exonuclease activity of WRNp, by inhibiting WRN unwinding of G4 tetraplex DNA structures, as seen in activity assays and electrophoretic mobility shift assays (EMSA).These data suggest that nucleolin may regulate G4 DNA unwinding by WRNp, possibly in response to certain DNA damaging agents. We postulate that the NCL-WRNp complex may contain an inactive form of WRNp, which is released from the nucleolus upon DNA damage. Then, when required, WRNp is released from inhibition and can participate in the DNA repair processes

Travel-related schistosomiasis, strongyloidiasis, filariasis, and toxocariasis: the risk of infection and the diagnostic relevance of blood eosinophilia

<p>Abstract</p> <p>Background</p> <p>This study prospectively assessed the occurrence of clinical and subclinical schistosomiasis, strongyloidiasis, filariasis, and toxocariasis, and the screening value of eosinophilia in adult short-term travelers to helminth-endemic countries.</p> <p>Methods</p> <p>Visitors of a pre-travel health advice centre donated blood samples for serology and blood cell count before and after travel. Samples were tested for eosinophilia, and for antibodies against schistosomiasis, strongyloidiasis, filariasis, and toxocariasis. Previous infection was defined as seropositivity in pre- and post-travel samples. Recent infection was defined as a seroconversion. Symptoms of parasitic disease were recorded in a structured diary.</p> <p>Results</p> <p>Previous infection was found in 112 of 1207 subjects: schistosomiasis in 2.7%, strongyloidiasis in 2.4%, filariasis in 3.4%, and toxocariasis in 1.8%. Recent schistosomiasis was found in 0.51% of susceptible subjects at risk, strongyloidiasis in 0.25%, filariasis in 0.09%, and toxocariasis in 0.08%. The incidence rate per 1000 person-months was 6.4, 3.2, 1.1, and 1.1, respectively. Recent infections were largely contracted in Asia. The positive predictive value of eosinophilia for diagnosis was 15% for previous infection and 0% for recent infection. None of the symptoms studied had any positive predictive value.</p> <p>Conclusion</p> <p>The chance of infection with schistosomiasis, strongyloidiasis, filariasis, and toxocariasis during one short-term journey to an endemic area is low. However, previous stay leads to a cumulative risk of infection. Testing for eosinophilia appeared to be of no value in routine screening of asymptomatic travelers for the four helminthic infections. Findings need to be replicated in larger prospective studies.</p