TT2013 meeting report: the transgenic technology meeting visits Asia for the first time

The 11th Transgenic Technology meeting was held in Guangzhou, China on 25th–27th February 2013. Over 300 scientists and students from round the world gathered to hear the latest developments in the technologies underpinning the creation of transgenic and knockout animals and their application to biological sciences in areas such as the modeling human diseases and biotechnology. As well as informative presentations from leading researchers in the field, an excellent selection of short talks selected from abstracts and posters, attendees were also treated to an inspiring talk from Allan Bradley who was awarded the 9th International Society of Transgenic Technologies Prize for outstanding contributions to the field of transgenic technologies

Shaping Future Generations

Due to the extent and variety of research available on the topic of child-targeted advertising, it was determined that an appraisal of the current state of the situation was necessary in order to determine the best course of action. After summarizing the history of children’s advertising and considering the arguments on both sides of the debate – from the children’s advocates and the advertising industry – the previously recommended solutions were evaluated in the paper. Each of these possible solutions were considered, and led to the proposal of a best solution. Supported by research, the best solution advocated a joint effort between the children’s advocates, parents and the advertising industry that emphasized education over government restriction

Mouse tafazzin is required for male germ cell meiosis and spermatogenesis

Barth syndrome is an X-linked mitochondrial disease, symptoms of which include neutropenia and cardiac myopathy. These symptoms are the most significant clinical consequences of a disease, which is increasingly recognised to have a variable presentation. Mutation in the Taz gene in Xq28 is thought to be responsible for the condition, by altering mitochondrial lipid content and mitochondrial function. Male chimeras carrying a targeted mutation of Taz on their X-chromosome were infertile. Testes from the Taz knockout chimeras were smaller than their control counterparts and this was associated with a disruption of the progression of spermatocytes through meiosis to spermiogenesis. Taz knockout ES cells also showed a defect when differentiated to germ cells in vitro. Mutant spermatocytes failed to progress past the pachytene stage of meiosis and had higher levels of DNA double strand damage and increased levels of endogenous retrotransposon activity. Altogether these data revealed a novel role for Taz in helping to maintain genome integrity in meiosis and facilitating germ cell differentiation. We have unravelled a novel function for the Taz protein, which should contribute to an understanding of how a disruption of the Taz gene results in the complex symptoms underlying Barth Syndrome

From Words to Action: Comparing the Disparities Between National Drug Policy and Local Implementation in Tijuana, Mexico and Vancouver, Canada

In 2009, Mexico passed a national drug policy reform decriminalizing the possession of small amounts of certain drugs for personal use with the aim of diverting drug-dependent individuals from prison and towards addiction treatment. However, the public health approach codified by the reform has not yet led to a meaningful change in local police practices nor contributed to the meaningful scale-up of harm reduction and addiction treatment services in many Mexican cities. Specifically, in Tijuana, Baja California, there continues to be a variety of local level barriers – including arbitrary police behaviours – that hinder the ability of people who inject drugs (PWID) from accessing vital harm reduction services. This has implications for the growing HIV epidemic in Mexico’s northern border region, given that access to harm reduction interventions has been shown to effectively reduce the risk of HIV infection among PWID. In contrast to the largely enforcement-based local response seen in Tijuana, the municipal Four Pillars approach implemented in Vancouver, Canada in 2001 was passed as a public-health oriented response to the rising prevalence of HIV/AIDS among PWID in the Downtown Eastside of Vancouver. Centered on the balancing of four approaches – harm reduction, treatment, prevention and enforcement – the Four Pillars approach in Vancouver has led to a well-resourced local harm reduction and addiction treatment system. This local emphasis on harm reduction contrasts with the Canadian Conservative federal government’s opposition to harm reduction approaches. However, police-public health partnerships along with strong political support have led to the substantial scale up of harm reduction services as well as the reduction of HIV/AIDS among PWID in Vancouver, unlike what has been observed in Tijuana. This commentary therefore aims to assess the discrepancies between federal policy and local responses to drug-related harms in order to fully understand the impact and implications of national drug policies in shaping local response to drug related harms among populations of PWID. Through a comparison of the drug policy landscape in two cities linked by a large North American drug trafficking route - Tijuana, Mexico and Vancouver, Canada, - this commentary suggests that drug policy reform in and of itself will have little impact at the local level unless it is appropriately resourced and meaningfully supported by key stakeholders

Dissociative Autoionization in (1+2)-photon Above Threshold Excitation of H2 Molecules

We have theoretically studied the effect of dissociative autoionization on the photoelectron energy spectrum in (1+2)-photon above threshold ionization(ATI) of H2 molecules. We have considered excitation from the ground state X-singlet-Sigma-g+(v=0,j) to the doubly excited autoionizing states of singlet-Sigma-u+ and singlet-Pi-u+ symmetry, via the intermediate resonant B-singlet-Sigma-u+(v=5,j) states. We have shown that the photoelectron energy spectrum is oscillatory in nature and shows three distinct peaks above the photoelectron energy 0.7 eV. This feature has been observed in a recent experiment by Rottke et al, J. Phys. B, Vol. 30, p-4049 (1997).Comment: 11 pages and 4 figure

The initiator methionine tRNA drives cell migration and invasion leading to increased metastatic potential in melanoma

The cell's repertoire of transfer RNAs (tRNAs) has been linked to cancer. Recently, levels of the initiator methionine tRNA (tRNAiMet) in stromal fibroblasts have been shown to influence extracellular matrix (ECM) secretion to drive tumour growth and angiogenesis. Here we show that increased tRNAiMet within cancer cells does not influence tumour growth, but drives cell migration and invasion via a mechanism that is independent from ECM synthesis and dependent on α5β1 integrin and levels of the translation initiation ternary complex. In vivo and ex vivo migration (but not proliferation) of melanoblasts is significantly enhanced in transgenic mice which express additional copies of the tRNAiMet gene. We show that increased tRNAiMet in melanoma drives migratory, invasive behaviour and metastatic potential without affecting cell proliferation and primary tumour growth, and that expression of RNA polymerase III-associated genes (which drive tRNA expression) are elevated in metastases by comparison with primary tumours. Thus specific alterations to the cancer cell tRNA repertoire drive a migration/invasion programme that may lead to metastasis

Reconciling Incongruous Qualitative and Quantitative Findings in Mixed Methods Research: Exemplars from Research with Drug Using Populations

Mixed methods research is increasingly being promoted in the health sciences as a way to gain more comprehensive understandings of how social processes and individual behaviours shape human health. Mixed methods research most commonly combines qualitative and quantitative data collection and analysis strategies. Often, integrating findings from multiple methods is assumed to confirm or validate the findings from one method with the findings from another, seeking convergence or agreement between methods. Cases in which findings from different methods are congruous are generally thought of as ideal, whilst conflicting findings may, at first glance, appear problematic. However, the latter situation provides the opportunity for a process through which apparently discordant results are reconciled, potentially leading to new emergent understandings of complex social phenomena. This paper presents three case studies drawn from the authors’ research on HIV risk amongst injection drug users in which mixed methods studies yielded apparently discrepant results. We use these case studies (involving injection drug users [IDUs] using a Needle/Syringe Exchange Program in Los Angeles, CA, USA; IDUs seeking to purchase needle/syringes at pharmacies in Tijuana, Mexico; and young street-based IDUs in San Francisco, CA, USA) to identify challenges associated with integrating findings from mixed methods projects, summarize lessons learned, and make recommendations for how to more successfully anticipate and manage the integration of findings. Despite the challenges inherent in reconciling apparently conflicting findings from qualitative and quantitative approaches, in keeping with others who have argued in favour of integrating mixed methods findings, we contend that such an undertaking has the potential to yield benefits that emerge only through the struggle to reconcile discrepant results and may provide a sum that is greater than the individual qualitative and quantitative parts

Differential Effects of Migration and Deportation on HIV Infection among Male and Female Injection Drug Users in Tijuana, Mexico

HIV prevalence is rising, especially among high risk females in Tijuana, Baja California, a Mexico-US border city situated on major migration and drug trafficking routes. We compared factors associated with HIV infection among male and female injection drug users (IDUs) in Tijuana in an effort to inform HIV prevention and treatment programs. IDUs aged ≥18 years were recruited using respondent-driven sampling and underwent testing for HIV, syphilis and structured interviews. Logistic regression identified correlates of HIV infection, stratified by gender. Among 1056 IDUs, most were Mexican-born but 67% were born outside Tijuana. Reasons for moving to Tijuana included deportation from the US (56% for males, 29% for females), and looking for work/better life (34% for females, 15% for males). HIV prevalence was higher in females versus males (10.2% vs. 3.5%, p = 0.001). Among females (N = 158), factors independently associated with higher HIV prevalence included younger age, lifetime syphilis infection and living in Tijuana for longer durations. Among males (N = 898), factors independently associated with higher HIV prevalence were syphilis titers consistent with active infection, being arrested for having ‘track-marks’, having larger numbers of recent injection partners and living in Tijuana for shorter durations. An interaction between gender and number of years lived in Tijuana regressed on HIV infection was significant (p = 0.03). Upon further analysis, deportation from the U.S. explained the association between shorter duration lived in Tijuana and HIV infection among males; odds of HIV infection were four-fold higher among male injectors deported from the US, compared to other males, adjusting for all other significant correlates (p = 0.002). Geographic mobility has a profound influence on Tijuana's evolving HIV epidemic, and its impact is significantly modified by gender. Future studies are needed to elucidate the context of mobility and HIV acquisition in this region, and whether US immigration policies adversely affect HIV risk

Higher Loop Spin Field Correlators in Various Dimensions

We compute higher-point superstring correlators involving spin fields in various even space-time dimensions D at tree-level and to arbitrary loop order. This generalizes previous work in D=4 space-time dimensions. The main focus are D=6,8 and D=10 superstring compactifications for which correlation functions with four and more spin fields are computed. More precisely, we present every non-vanishing six-point function. A number of results can even be derived for arbitrary D. A closed formula for the correlators with any number of fermions psi and two spin fields S in D space-time dimensions is given for arbitrary genus. Moreover, in D=6 and for arbitrary genus, we find a general formula for the correlators . The latter serve as basic building blocks to construct higher-point fermionic correlation functions. In D=8 we can profit from the SO(8)-triality to derive further tree-level correlators with a large numbers of spin fields.Comment: 47 pages, 1 figure; v2: typos corrected; submitted to JHE

P08.36 Radioresistance of glioblastoma stem-like cells is associated with DNA replication stress, which is a promising therapeutic target

Introduction: The inevitability of tumour recurrence in glioblastoma (GBM) patients despite multi-modality treatment consisting of surgery, radiotherapy and chemotherapy, is reflected by a median survival of only 14 months. Tumour recurrence is thought to be driven by a small population of glioblastoma stem-like cells (GSCs) that are resistant to conventional therapies. DNA damage response (DDR) pathways have been shown to be up-regulated in GSCs and implicated in radioresistance and treatment failure. However the precise cause of enhanced DDR signalling in GSCs and the extent to which these signalling networks contribute to therapy resistance remains elusive. The objectives of this study were to investigate the underlying cause of DDR upregulation and treatment resistance in GSCs with a view to identifying novel and promising therapeutic targets. Materials and Methods: A panel of primary patient derived GBM cell lines cultured under conditions to enrich for or deplete the tumour stem cell population (GSC vs bulk respectively) were utilised in order to investigate enhanced GSC DDR under basal conditions and in response to ionising radiation. Confirmatory studies were also performed in cells sorted for the putative GSC marker CD133. The effects of a panel of small molecule DDR inhibitor agents on cell survival in GSC and bulk cells were quantified. Results: GSCs exhibited higher levels of total and activated DDR targets ATR, CHK1, ATM and PARP1 under basal conditions and were radioresistant compared to paired bulk populations. This was not due to increased levels of reactive oxygen species (ROS). Instead, we show that RPA is significantly higher in replicating GSCs and confirm by DNA fibre assays that GSCs and CD133+ cells have increased numbers of stalled replication forks, fewer new origins and slower DNA replication compared to bulk or CD133- populations, demonstrating for the first time that replication stress (RS) is a hallmark of GSCs. We identify increased expression of long neural genes as a likely mechanism for RS and DNA double strand breaks (DSBs) in GSCs and show that their radioresistance is reversed by dual inhibition of key RS and DDR proteins ATR and PARP. Conclusions: This study demonstrates the novel finding that replication stress is a hallmark of GSCs and resonates with recently published studies in neural progenitor cells showing that RS preferentially induces DNA DSB in long neural genes. Taken together, we implicate RS as a driver of enhanced DDR in GSCs and identify novel therapeutics with potential to improve clinical outcomes by overcoming the radioresistance of GB