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  • ItemOpen AccessPublished version Peer-reviewed
    Toxification of polycyclic aromatic hydrocarbons by commensal bacteria from human skin.
    (Springer Science and Business Media LLC, 2017-06) Sowada, Juliane; Lemoine, Lisa; Schön, Karsten; Hutzler, Christoph; Luch, Andreas; Tralau, Tewes; Tralau, Tewes [0000-0002-7857-4237]
    The ubiquitous occurrence of polycyclic aromatic hydrocarbons (PAHs) leads to constant human exposure at low levels. Toxicologically relevant are especially the high-molecular weight substances due to their (pro-)carcinogenic potential. Following ingestion or uptake, the eukaryotic phase I metabolism often activates these substances to become potent DNA binders, and unsurprisingly metabolism and DNA-adduct formation of model substances such as benzo[a]pyrene (B[a]P) are well studied. However, apart from being subjected to eukaryotic transformations PAHs are also carbon and energy sources for the myriads of commensal microbes inhabiting man's every surface. Yet, we know little about the microbiome's PAH-metabolism capacity and its potentially adverse impact on the human host. This study now shows that readily isolable skin commensals transform B[a]P into a range of highly cyto- and genotoxic metabolites that are excreted in toxicologically relevant concentrations during growth. The respective bacterial supernatants contain a mixture of established eukaryotic as well as hitherto unknown prokaryotic metabolites, the combination of which leads to an increased toxicity. Altogether we show that PAH metabolism of the microbiome has to be considered a potential hazard.
  • ItemOpen Access
    The mechanistic and evolutionary aspects of the 2'- and 3'-OH paradigm in biosynthetic machinery.
    (Springer Science and Business Media LLC, 2013-07-08) Safro, Mark; Klipcan, Liron
    BACKGROUND: The translation machinery underlies a multitude of biological processes within the cell. The design and implementation of the modern translation apparatus on even the simplest course of action is extremely complex, and involves different RNA and protein factors. According to the "RNA world" idea, the critical link in the translation machinery may be assigned to an adaptor tRNA molecule. Its exceptional functional and structural characteristics are of primary importance in understanding the evolutionary relationships among all these macromolecular components. PRESENTATION OF THE HYPOTHESIS: The 2'-3' hydroxyls of the tRNA A76 constitute chemical groups of critical functional importance, as they are implicated in almost all phases of protein biosynthesis. They contribute to: a) each step of the tRNA aminoacylation reaction catalyzed by aminoacyl-tRNA synthetases (aaRSs); b) the isomerase activity of EF-Tu, involving a mixture of the 2'(3')- aminoacyl tRNA isomers as substrates, thereby producing the required combination of amino acid and tRNA; and c) peptide bond formation at the peptidyl transferase center (PTC) of the ribosome. We hypothesize that specific functions assigned to the 2'-3' hydroxyls during peptide bond formation co-evolved, together with two modes of attack on the aminoacyl-adenylate carbonyl typical for two classes of aaRSs, and alongside the isomerase activity of EF-Tu. Protein components of the translational apparatus are universally recognized as being of ancient origin, possibly replacing RNA-based enzymes that may have existed before the last universal common ancestor (LUCA). We believe that a remnant of these processes is still imprinted on the organization of modern-day translation. TESTING AND IMPLICATIONS OF THE HYPOTHESIS: Earlier publications indicate that it is possible to select ribozymes capable of attaching the aa-AMP moiety to RNA molecules. The scenario described herein would gain general acceptance, if a ribozyme able to activate the amino acid and transfer it onto the terminal ribose of the tRNA, would be found in any life form, or generated in vitro. Interestingly, recent studies have demonstrated the plausibility of using metals, likely abandoned under primordial conditions, as biomimetic catalysts of the aminoacylation reaction.
  • ItemOpen Access
    Genistein promotes cell death of ethanol-stressed HeLa cells through the continuation of apoptosis or secondary necrosis.
    (Springer Science and Business Media LLC, 2013-06-26) Xie, Xin; Wang, Shan Shan; Wong, Timothy Chung Sing; Fung, Ming Chiu
    BACKGROUND: Apoptosis is a major target and treatment effect of multiple chemotherapeutical agents in cancer. A soybean isoflavone, genistein, is a well-studied chemopreventive agent and has been reported to potentiate the anticancer effect of some chemotherapeutics. However, its mechanistic basis of chemo-enhancement effect remains to be fully elucidated. METHODS: Apoptotic features of low concentration stressed cancer cells were studied by microscopic method, western blot, immunostaining and annexin V/PI assay. Genistein's effects on unstressed cells and recovering cells were investigated using MTT cell viability assay and LDH cytotoxicity assay. Quantitative real-time PCR was employed to analyze the possible gene targets involved in the recovery and genistein's effect. RESULTS: Low-concentration ethanol stressed cancer cells showed apoptotic features and could recover after stress removal. In stressed cells, genistein at sub-toxic dosage promoted the cell death. Quantitative real-time PCR revealed the up-regulation of anti-apoptotic genes MDM2 and XIAP during the recovery process in HeLa cells, and genistein treatment suppressed their expression. The application of genistein, MDM2 inhibitor and XIAP inhibitor to the recovering HeLa cells caused persistent caspase activity and enhanced cell death. Flow cytometry study indicated that genistein treatment could lead to persistent phosphatidylserine (PS) externalization and necrotic events in the recovering HeLa cells. Caspase activity inhibition shifted the major effect of genistein to necrosis. CONCLUSIONS: These results suggested two possible mechanisms through which genistein promoted cell death in stressed cancer cells. Genistein could maintain the existing apoptotic signal to enhance apoptotic cell death. It could also disrupt the recovering process in caspase-independent manner, which lead to necrotic events. These effects may be related to the enhanced antitumor effect of chemotherapeutic drugs when they were combined with genistein.
  • ItemOpen Access
    Effects of emotion recognition training on mood among individuals with high levels of depressive symptoms: study protocol for a randomised controlled trial.
    (Springer Science and Business Media LLC, 2013-06-01) Adams, Sally; Penton-Voak, Ian S; Harmer, Catherine J; Holmes, Emily A; Munafò, Marcus R
    BACKGROUND: We have developed a new paradigm that targets the recognition of facial expression of emotions. Here we report the protocol of a randomised controlled trial of the effects of emotion recognition training on mood in a sample of individuals with depressive symptoms over a 6-week follow-up period. METHODS/DESIGN: We will recruit 190 adults from the general population who report high levels of depressive symptoms (defined as a score ≥ 14 on the Beck Depression Inventory-II). Participants will attend a screening session and will be randomised to intervention or control procedures, repeated five times over consecutive days (Monday to Friday). A follow-up session will take place at end-of -treatment, 2-weeks and 6-weeks after training. Our primary study outcome will be depressive symptoms, Beck Depression Inventory- II (rated over the past two weeks). Our secondary outcomes are: depressive symptoms, Hamilton Rating Scale for Depression; anxiety symptoms, Beck Anxiety Inventory (rated over the past month); positive affect, Positive and Negative Affect Schedule (rated as 'how you feel right now'); negative affect, Positive and Negative Affect Schedule (rated as 'how you feel right now'); emotion sensitivity, Emotion Recognition Task (test phase); approach motivation and persistence, the Fishing Game; and depressive interpretation bias, Scrambled Sentences Test. DISCUSSION: This study is of a novel cognitive bias modification technique that targets biases in emotional processing characteristic of depression, and can be delivered automatically via computer, Internet or Smartphone. It therefore has potential to be a valuable cost-effective adjunctive treatment for depression which may be used together with more traditional psychotherapy, cognitive-behavioural therapy and pharmacotherapy. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN17767674.
  • ItemOpen Access
    Campath, calcineurin inhibitor reduction and chronic allograft nephropathy (3C) study: background, rationale, and study protocol.
    (Springer Science and Business Media LLC, 2013-05-06) Haynes, Richard; Baigent, Colin; Harden, Paul; Landray, Martin; Akyol, Murat; Asderakis, Argiris; Baxter, Alex; Bhandari, Sunil; Chowdhury, Paramit; Clancy, Marc; Emberson, Jonathan; Gibbs, Paul; Hammad, Abdul; Herrington, Will; Jayne, Kathy; Jones, Gareth; Krishnan, Nithya; Lay, Michael; Lewis, David; Macdougall, Iain; Nathan, Chidambaram; Neuberger, James; Newstead, Chas; Pararajasingam, Ravi; Puliatti, Carmelo; Rigg, Keith; Rowe, Peter; Sharif, Adnan; Sheerin, Neil; Sinha, Sanjay; Watson, Chris; Friend, Peter; 3C Study Collaborative Group; Watson, Christopher [0000-0002-0590-4901]
    BACKGROUND: Kidney transplantation is the best treatment for patients with end-stage renal failure, but uncertainty remains about the best immunosuppression strategy. Long-term graft survival has not improved substantially, and one possible explanation is calcineurin inhibitor (CNI) nephrotoxicity. CNI exposure could be minimized by using more potent induction therapy or alternative maintenance therapy to remove CNIs completely. However, the safety and efficacy of such strategies are unknown. METHODS/DESIGN: The Campath, Calcineurin inhibitor reduction and Chronic allograft nephropathy (3C) Study is a multicentre, open-label, randomized controlled trial with 852 participants which is addressing two important questions in kidney transplantation. The first question is whether a Campath (alemtuzumab)-based induction therapy strategy is superior to basiliximab-based therapy, and the second is whether, from 6 months after transplantation, a sirolimus-based maintenance therapy strategy is superior to tacrolimus-based therapy. Recruitment is complete, and follow-up will continue for around 5 years post-transplant. The primary endpoint for the induction therapy comparison is biopsy-proven acute rejection by 6 months, and the primary endpoint for the maintenance therapy comparison is change in estimated glomerular filtration rate from baseline to 2 years after transplantation. The study is sponsored by the University of Oxford and endorsed by the British Transplantation Society, and 18 centers for adult kidney transplant are participating. DISCUSSION: Late graft failure is a major issue for kidney-transplant recipients. If our hypothesis that minimizing CNI exposure with Campath-based induction therapy and/or an elective conversion to sirolimus-based maintenance therapy can improve long-term graft function and survival is correct, then patients should experience better graft function for longer. A positive outcome could change clinical practice in kidney transplantation. TRIAL REGISTRATION:, NCT01120028 and ISRCTN88894088.
  • ItemOpen Access
    A structural role for the PHP domain in E. coli DNA polymerase III.
    (Springer Science and Business Media LLC, 2013-05-14) Barros, Tiago; Guenther, Joel; Kelch, Brian; Anaya, Jordan; Prabhakar, Arjun; O'Donnell, Mike; Kuriyan, John; Lamers, Meindert H
    BACKGROUND: In addition to the core catalytic machinery, bacterial replicative DNA polymerases contain a Polymerase and Histidinol Phosphatase (PHP) domain whose function is not entirely understood. The PHP domains of some bacterial replicases are active metal-dependent nucleases that may play a role in proofreading. In E. coli DNA polymerase III, however, the PHP domain has lost several metal-coordinating residues and is likely to be catalytically inactive. RESULTS: Genomic searches show that the loss of metal-coordinating residues in polymerase PHP domains is likely to have coevolved with the presence of a separate proofreading exonuclease that works with the polymerase. Although the E. coli Pol III PHP domain has lost metal-coordinating residues, the structure of the domain has been conserved to a remarkable degree when compared to that of metal-binding PHP domains. This is demonstrated by our ability to restore metal binding with only three point mutations, as confirmed by the metal-bound crystal structure of this mutant determined at 2.9 Å resolution. We also show that Pol III, a large multi-domain protein, unfolds cooperatively and that mutations in the degenerate metal-binding site of the PHP domain decrease the overall stability of Pol III and reduce its activity. CONCLUSIONS: While the presence of a PHP domain in replicative bacterial polymerases is strictly conserved, its ability to coordinate metals and to perform proofreading exonuclease activity is not, suggesting additional non-enzymatic roles for the domain. Our results show that the PHP domain is a major structural element in Pol III and its integrity modulates both the stability and activity of the polymerase.
  • ItemOpen Access
    The histone deacetylase inhibitor sodium valproate causes limited transcriptional change in mouse embryonic stem cells but selectively overrides Polycomb-mediated Hoxb silencing.
    (Springer Science and Business Media LLC, 2013-05-01) Boudadi, Elsa; Stower, Hannah; Halsall, John A; Rutledge, Charlotte E; Leeb, Martin; Wutz, Anton; O'Neill, Laura P; Nightingale, Karl P; Turner, Bryan M
    BACKGROUND: Histone deacetylase inhibitors (HDACi) cause histone hyperacetylation and H3K4 hypermethylation in various cell types. They find clinical application as anti-epileptics and chemotherapeutic agents, but the pathways through which they operate remain unclear. Surprisingly, changes in gene expression caused by HDACi are often limited in extent and can be positive or negative. Here we have explored the ability of the clinically important HDACi valproic acid (VPA) to alter histone modification and gene expression, both globally and at specific genes, in mouse embryonic stem (ES) cells. RESULTS: Microarray expression analysis of ES cells exposed to VPA (1 mM, 8 h), showed that only 2.4% of genes showed a significant, >1.5-fold transcriptional change. Of these, 33% were down-regulated. There was no correlation between gene expression and VPA-induced changes in histone acetylation or H3K4 methylation at gene promoters, which were usually minimal. In contrast, all Hoxb genes showed increased levels of H3K9ac after exposure to VPA, but much less change in other modifications showing bulk increases. VPA-induced changes were lost within 24 h of inhibitor removal. VPA significantly increased the low transcription of Hoxb4 and Hoxb7, but not other Hoxb genes. Expression of Hoxb genes increased in ES cells lacking functional Polycomb silencing complexes PRC1 and PRC2. Surprisingly, VPA caused no further increase in Hoxb transcription in these cells, except for Hoxb1, whose expression increased several fold. Retinoic acid (RA) increased transcription of all Hoxb genes in differentiating ES cells within 24 h, but thereafter transcription remained the same, increased progressively or fell progressively in a locus-specific manner. CONCLUSIONS: Hoxb genes in ES cells are unusual in being sensitive to VPA, with effects on both cluster-wide and locus-specific processes. VPA increases H3K9ac at all Hoxb loci but significantly overrides PRC-mediated silencing only at Hoxb4 and Hoxb7. Hoxb1 is the only Hoxb gene that is further up-regulated by VPA in PRC-deficient cells. Our results demonstrate that VPA can exert both cluster-wide and locus-specific effects on Hoxb regulation.
  • ItemOpen Access
    A combination of mutations in AKR1D1 and SKIV2L in a family with severe infantile liver disease.
    (Springer Science and Business Media LLC, 2013-05-16) Morgan, Neil V; Hartley, Jane L; Setchell, Kenneth DR; Simpson, Michael A; Brown, Rachel; Tee, Louise; Kirkham, Sian; Pasha, Shanaz; Trembath, Richard C; Maher, Eamonn R; Gissen, Paul; Kelly, Deirdre A; Maher, Eamonn [0000-0002-6226-6918]
    Infantile cholestatic diseases can be caused by mutations in a number of genes involved in different hepatocyte molecular pathways. Whilst some of the essential pathways have a well understood function, such as bile biosynthesis and transport, the role of the others is not known. Here we report the findings of a clinical, biochemical and molecular study of a family with three patients affected with a severe infantile cholestatic disease. A novel homozygous frameshift germline mutation (c.587delG) in the AKR1D1 gene; which encodes the enzyme Δ 4-3-oxosteroid 5β-reductase that is required for synthesis of primary bile acids and is crucial for establishment of normal bile flow, was found in all 3 patients. Although the initial bile acid analysis was inconclusive, subsequent testing confirmed the diagnosis of a bile acid biogenesis disorder. An additional novel homozygous frameshift mutation (c.3391delC) was detected in SKIV2L in one of the patients. SKIV2L encodes a homologue of a yeast ski2 protein proposed to be involved in RNA processing and mutations in SKIV2L were recently described in patients with Tricohepatoenteric syndrome (THES). A combination of autozygosity mapping and whole-exome-sequencing allowed the identification of causal mutations in this family with a complex liver phenotype. Although the initial 2 affected cousins died in the first year of life, accurate diagnosis and management of the youngest patient led to successful treatment of the liver disease and disease-free survival.
  • ItemOpen Access
    Sex-biased gene expression in the developing brain: implications for autism spectrum disorders.
    (Springer Science and Business Media LLC, 2013-05-07) Ziats, Mark N; Rennert, Owen M
    Autism spectrum disorders affect significantly more males than females. Understanding sex differences in normal human brain development may provide insight into the mechanism(s) underlying this disparity; however, studies of sex differences in brain development at the genomic level are lacking. Here, we report a re-analysis of sex-specific gene expression from a recent large transcriptomic study of normal human brain development, to determine whether sex-biased genes relate to specific mechanistic processes. We discovered that male-biased genes are enriched for the processes of extracellular matrix formation/glycoproteins, immune response, chromatin, and cell cytoskeleton. We highlight that these pathways have been repeatedly implicated in autism and demonstrate that autism candidate genes are also enriched for these pathways. We propose that the overlap of these male-specific brain transcriptional modules with the same pathways in autism spectrum disorders may partially explain the increased incidence of autism in males.
  • ItemOpen Access
    A phase II randomized clinical trial on cerebral near-infrared spectroscopy plus a treatment guideline versus treatment as usual for extremely preterm infants during the first three days of life (SafeBoosC): study protocol for a randomized controlled trial.
    (Springer Nature, 2013-05-01) Hyttel-Sorensen, Simon; Austin, Topun; van Bel, Frank; Benders, Manon; Claris, Olivier; Dempsey, Eugene; Fumagalli, Monica; Greisen, Gorm; Grevstad, Berit; Hagmann, Cornelia; Hellström-Westas, Lena; Lemmers, Petra; Lindschou, Jane; Naulaers, Gunnar; van Oeveren, Wim; Pellicer, Adelina; Pichler, Gerhard; Roll, Claudia; Skoog, Maria; Winkel, Per; Wolf, Martin; Gluud, Christian; Austin, Topun [0000-0002-8428-8624]
    BACKGROUND: Every year in Europe about 25,000 infants are born extremely preterm. These infants have a 20% mortality rate, and 25% of survivors have severe long-term cerebral impairment. Preventative measures are key to reduce mortality and morbidity in an extremely preterm population. The primary objective of the SafeBoosC phase II trial is to examine if it is possible to stabilize the cerebral oxygenation of extremely preterm infants during the first 72 hours of life through the application of cerebral near-infrared spectroscopy (NIRS) oximetry and implementation of an clinical treatment guideline based on intervention thresholds of cerebral regional tissue saturation rStO2. METHODS/DESIGN: SafeBoosC is a randomized, blinded, multinational, phase II clinical trial. The inclusion criteria are: neonates born more than 12 weeks preterm; decision to conduct full life support; parental informed consent; and possibility to place the cerebral NIRS oximeter within 3 hours after birth. The infants will be randomized into one of two groups. Both groups will have a cerebral oximeter monitoring device placed within three hours of birth. In the experimental group, the cerebral oxygenation reading will supplement the standard treatment using a predefined treatment guideline. In the control group, the cerebral oxygenation reading will not be visible and the infant will be treated according to the local standards. The primary outcome is the multiplication of the duration and magnitude of rStO2 values outside the target ranges of 55% to 85%, that is, the 'burden of hypoxia and hyperoxia' expressed in '%hours'. To detect a 50% difference between the experimental and control group in %hours, 166 infants in total must be randomized. Secondary outcomes are mortality at term date, cerebral ultrasound score, and interburst intervals on an amplitude-integrated electroencephalogram at 64 hours of life and explorative outcomes include neurodevelopmental outcome at 2 years corrected age, magnetic resonance imaging at term, blood biomarkers at 6 and 64 hours after birth, and adverse events. DISCUSSION: Cerebral oximetry guided interventions have the potential to improve neurodevelopmental outcome in extremely preterm infants. It is a logical first step to test if it is possible to reduce the burden of hypoxia and hyperoxia. TRIAL REGISTRATION:, NCT01590316.
  • ItemOpen Access
    Developmental time rather than local environment regulates the schedule of epithelial polarization in the zebrafish neural rod.
    (Springer Science and Business Media LLC, 2013-03-24) Girdler, Gemma C; Araya, Claudio; Ren, Xiaoyun; Clarke, Jonathan DW
    BACKGROUND: Morphogenesis requires developmental processes to occur both at the right time and in the right place. During neural tube formation in the zebrafish embryo, the generation of the apical specializations of the lumen must occur in the center of the neural rod after the neural cells have undergone convergence, invagination and interdigitation across the midline. How this coordination is achieved is uncertain. One possibility is that environmental signaling at the midline of the neural rod controls the schedule of apical polarization. Alternatively, polarization could be regulated by a timing mechanism and then independent morphogenetic processes ensure the cells are in the correct spatial location. RESULTS: Ectopic transplantation demonstrates the local environment of the neural midline is not required for neural cell polarization. Neural cells can self-organize into epithelial cysts in ectopic locations in the embryo and also in three-dimensional gel cultures. Heterochronic transplants demonstrate that the schedule of polarization and the specialized cell divisions characteristic of the neural rod are more strongly regulated by time than local environmental signals. The cells' schedule for polarization is set prior to gastrulation, is stable through several rounds of cell division and appears independent of the morphogenetic movements of gastrulation and neurulation. CONCLUSIONS: Time rather than local environment regulates the schedule of epithelial polarization in zebrafish neural rod.
  • ItemOpen Access
    Actigraphy assessments of circadian sleep-wake cycles in the Vegetative and Minimally Conscious States.
    (Springer Science and Business Media LLC, 2013-01-24) Cruse, Damian; Thibaut, Aurore; Demertzi, Athena; Nantes, Julia C; Bruno, Marie-Aurélie; Gosseries, Olivia; Vanhaudenhuyse, Audrey; Bekinschtein, Tristan A; Owen, Adrian M; Laureys, Steven; Bekinschtein, Tristan [0000-0001-5501-8628]
    BACKGROUND: The Vegetative and Minimally Conscious States (VS; MCS) are characterized by absent or highly disordered signs of awareness alongside preserved sleep-wake cycles. According to international diagnostic guidelines, sleep-wake cycles are assessed by means of observations of variable periods of eye-opening and eye-closure. However, there is little empirical evidence for true circadian sleep-wake cycling in these patients, and there have been no large-scale investigations of the validity of this diagnostic criterion. METHODS: We measured the circadian sleep-wake rhythms of 55 VS and MCS patients by means of wrist actigraphy, an indirect method that is highly correlated with polysomnographic estimates of sleeping/waking. RESULTS: Contrary to the diagnostic guidelines, a significant proportion of patients did not exhibit statistically reliable sleep-wake cycles. The circadian rhythms of VS patients were significantly more impaired than those of MCS patients, as were the circadian rhythms of patients with non-traumatic injuries relative to those with traumatic injuries. The reliability of the circadian rhythms were significantly predicted by the patients' levels of visual and motor functioning, consistent with the putative biological generators of these rhythms. CONCLUSIONS: The high variability across diagnoses and etiologies highlights the need for improved guidelines for the assessment of sleep-wake cycles in VS and MCS, and advocates the use of actigraphy as an inexpensive and non-invasive alternative.
  • ItemOpen Access
    Annotating targets with pathways: extending approaches to mode of action analysis
    (Springer Science and Business Media LLC, 2013-01) Liggi, Sonia; Koutsoukas, Alexios; Motamedi, Yasaman Kalantar; Glen, Robert C; Bender, Andreas; Liggi, Sonia [0000-0003-1802-357X]
  • ItemOpen Access
    The landscape of RNA polymerase II transcription initiation in C. elegans reveals a novel enhancer architecture
    (Springer Science and Business Media LLC, 2013-03) Chen, Ron; Down, Thomas; Ahringer, Julie; Ahringer, Julie [0000-0002-7074-4051]
  • ItemOpen Access
    Gene dosage in mammals: characterization of haploid embryonic stem cells
    (Springer Science and Business Media LLC, 2013-03) Wutz, Anton; Leeb, Martin
  • ItemOpen Access
    Correction to Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: Evidence for an immune-modulated glutamatergic neurotransmission? [Journal of Neuroinflammation (2013) 10, 34] 10.1186/1742-2094-10-34
    (Springer Nature, 2013-03-02) Steiner, J; Walter, M; Gos, T; Guillemin, GJ; Bernstein, HG; Sarnyai, Z; Mawrin, C; Brisch, R; Bielau, H; zu Schwabedissen, LM; Bogerts, B; Myint, AM
  • ItemOpen Access
    The 3rd DBCLS BioHackathon: improving life science data integration with Semantic Web technologies.
    (Springer Science and Business Media LLC, 2013-02-11) Katayama, Toshiaki; Wilkinson, Mark D; Micklem, Gos; Kawashima, Shuichi; Yamaguchi, Atsuko; Nakao, Mitsuteru; Yamamoto, Yasunori; Okamoto, Shinobu; Oouchida, Kenta; Chun, Hong-Woo; Aerts, Jan; Afzal, Hammad; Antezana, Erick; Arakawa, Kazuharu; Aranda, Bruno; Belleau, Francois; Bolleman, Jerven; Bonnal, Raoul Jp; Chapman, Brad; Cock, Peter Ja; Eriksson, Tore; Gordon, Paul Mk; Goto, Naohisa; Hayashi, Kazuhiro; Horn, Heiko; Ishiwata, Ryosuke; Kaminuma, Eli; Kasprzyk, Arek; Kawaji, Hideya; Kido, Nobuhiro; Kim, Young Joo; Kinjo, Akira R; Konishi, Fumikazu; Kwon, Kyung-Hoon; Labarga, Alberto; Lamprecht, Anna-Lena; Lin, Yu; Lindenbaum, Pierre; McCarthy, Luke; Morita, Hideyuki; Murakami, Katsuhiko; Nagao, Koji; Nishida, Kozo; Nishimura, Kunihiro; Nishizawa, Tatsuya; Ogishima, Soichi; Ono, Keiichiro; Oshita, Kazuki; Park, Keun-Joon; Prins, Pjotr; Saito, Taro L; Samwald, Matthias; Satagopam, Venkata P; Shigemoto, Yasumasa; Smith, Richard; Splendiani, Andrea; Sugawara, Hideaki; Taylor, James; Vos, Rutger A; Withers, David; Yamasaki, Chisato; Zmasek, Christian M; Kawamoto, Shoko; Okubo, Kosaku; Asai, Kiyoshi; Takagi, Toshihisa; Micklem, Gos [0000-0002-6883-6168]
    BACKGROUND: BioHackathon 2010 was the third in a series of meetings hosted by the Database Center for Life Sciences (DBCLS) in Tokyo, Japan. The overall goal of the BioHackathon series is to improve the quality and accessibility of life science research data on the Web by bringing together representatives from public databases, analytical tool providers, and cyber-infrastructure researchers to jointly tackle important challenges in the area of in silico biological research. RESULTS: The theme of BioHackathon 2010 was the 'Semantic Web', and all attendees gathered with the shared goal of producing Semantic Web data from their respective resources, and/or consuming or interacting those data using their tools and interfaces. We discussed on topics including guidelines for designing semantic data and interoperability of resources. We consequently developed tools and clients for analysis and visualization. CONCLUSION: We provide a meeting report from BioHackathon 2010, in which we describe the discussions, decisions, and breakthroughs made as we moved towards compliance with Semantic Web technologies - from source provider, through middleware, to the end-consumer.
  • ItemOpen Access
    The V86M mutation in HIV-1 capsid confers resistance to TRIM5α by abrogation of cyclophilin A-dependent restriction and enhancement of viral nuclear import.
    (Springer Science and Business Media LLC, 2013-02-28) Veillette, Maxime; Bichel, Katsiaryna; Pawlica, Paulina; Freund, Stefan MV; Plourde, Mélodie B; Pham, Quang Toan; Reyes-Moreno, Carlos; James, Leo C; Berthoux, Lionel
    BACKGROUND: HIV-1 is inhibited early after entry into cells expressing some simian orthologues of the tripartite motif protein family member TRIM5α. Mutants of the human orthologue (TRIM5αhu) can also provide protection against HIV-1. The host protein cyclophilin A (CypA) binds incoming HIV-1 capsid (CA) proteins and enhances early stages of HIV-1 replication by unknown mechanisms. On the other hand, the CA-CypA interaction is known to increase HIV-1 susceptibility to restriction by TRIM5α. Previously, the mutation V86M in the CypA-binding loop of HIV-1 CA was found to be selected upon serial passaging of HIV-1 in cells expressing Rhesus macaque TRIM5α (TRIM5αrh). The objectives of this study were (i) to analyze whether V86M CA allows HIV-1 to escape mutants of TRIM5αhu, and (ii) to characterize the role of CypA in the resistance to TRIM5α conferred by V86M. RESULTS: We find that in single-cycle HIV-1 vector transduction experiments, V86M confers partial resistance against R332G-R335G TRIM5αhu and other TRIM5αhu variable 1 region mutants previously isolated in mutagenic screens. However, V86M HIV-1 does not seem to be resistant to R332G-R335G TRIM5αhu in a spreading infection context. Strikingly, restriction of V86M HIV-1 vectors by TRIM5αhu mutants is mostly insensitive to the presence of CypA in infected cells. NMR experiments reveal that V86M alters CypA interactions with, and isomerisation of CA. On the other hand, V86M does not affect the CypA-mediated enhancement of HIV-1 replication in permissive human cells. Finally, qPCR experiments show that V86M increases HIV-1 transport to the nucleus of cells expressing restrictive TRIM5α. CONCLUSIONS: Our study shows that V86M de-couples the two functions associated with CA-CypA binding, i.e. the enhancement of restriction by TRIM5α and the enhancement of HIV-1 replication in permissive human cells. V86M enhances the early stages of HIV-1 replication in restrictive cells by improving nuclear import. In summary, our data suggest that HIV-1 escapes restriction by TRIM5α through the selective disruption of CypA-dependent, TRIM5α-mediated inhibition of nuclear import. However, V86M does not seem to relieve restriction of a spreading HIV-1 infection by TRIM5αhu mutants, underscoring context-specific restriction mechanisms.
  • ItemOpen Access
    A world allergy organization international survey on diagnostic procedures and therapies in drug allergy/hypersensitivity.
    (Elsevier BV, 2011-12) Thong, Bernard Yu-Hor; Mirakian, Rita; Castells, Mariana; Pichler, Werner; Romano, Antonino; Bonadonna, Patrizia; Diana, Deleanu; Kowalski, Marek; Yanez, Anahi; Lleonart, Ramon; Sanchez-Borges, Mario; Demoly, Pascal
    OBJECTIVE: To study the diagnostic and treatment modalities used in drug allergy/hypersensitivity among members of the World Allergy Organization (WAO). METHODS: A questionnaire comprising 39 questions was circulated electronically to member societies, associate member societies, and regional and affiliate organizations of WAO between June 29, 2009, and August 9, 2009. RESULTS: Eighty-two responses were received. Skin testing was used by 74.7%, with only 71.4% having access to penicillin skin test reagents. In vitro-specific IgE tests were used by 67.4%, and basophil activation test was used by 54.4%. Lymphocyte transformation tests were used by 36.8% and patch tests by 54.7%. Drug provocation tests were used by 68.4%, the most common indication being to exclude hypersensitivity where history/symptoms were not suggestive of drug hypersensitivity/allergy (76.9%). Rapid desensitization for chemotherapy, antibiotics, or biologic agents was used by 69.6%. Systemic corticosteroid was used in the treatment of Stevens-Johnson syndrome by 72.3%, and high-dose intravenous immunoglobulins in toxic epidermal necrolysis by 50.8%. Human leukocyte antigen screening before prescription of abacavir was used by 92.9% and before prescription of carbamazepine by 21.4%. CONCLUSIONS: Results of this survey form a useful framework for developing educational and training needs and for improving access to drug allergy diagnostic and treatment modalities across WAO member societies.
  • ItemOpen Access
    Open questions: what is there left for cell biologists to do?
    (Springer Science and Business Media LLC, 2013-02-27) Munro, Sean
    AbstractFirst paragraph (this article has no abstract) There is little risk of cell biologists' getting bored in the 21st century, but it is worth considering a few of the questions they might hope to have solved by 2100, if not before.