Untersuchungen zur transkriptionellen Regulation des Chromogranin A Gens und seine Anwendung zum zellspezifischen therapeutischen Gentransfer in neuroendokrine Pankreastumorzellen

Die Therapieoptionen zur Behandlung metastasierter neuroendokriner Tumore sind bisher ineffektiv. Der regulierte Gentransfer könnte eine weitere Möglichkeit eröffnen, metastasierte neuroendokrine Tumore zu behandeln. In der vorliegenden Arbeit wurde daher die transkriptionelle Regulation von Chromogranin A als Basis zur Gentherapie durch eine regulierte Genexpression in neuroendokrinen Tumorzellen untersucht. Chromogranin A (CgA) besitzt vielfältige Funktionen in der regulierten Sekretion von Peptidhormonen und Neurotransmittern. Es wird spezifisch in nahezu allen endokrinen und neuroendokrinen Zellen exprimiert und diagnostisch als Marker bei neuroendokrinen Tumorerkrankungen eingesetzt. Zur Identifizierung wichtiger cis-regulatorischer Elemente im humanen Chromogranin A Promotor wurde die 5'-flankierende Sequenz des hCgA Gens auf putative Transkriptionsfaktorbindungsseiten untersucht und eine Interspezieshomologie des humanen, bovinen, murinen und des Rattenchromogranin A Promotors erstellt. Es fand sich eine konservierte Sequenzhomologie in den proximalen Chromogranin A Promotorbereichen mit den putativen Transkriptionsfaktor-Bindungsseiten Egr-1/Sp1, CRE und TATA-Box. Untersuchungen zur zelltypspezifischen Regulation des Chromogranin A Promotors ergaben eine starke Expression von Chromogranin A in neuroendokrinen Pankreastumorzellen BON-1 und der Lungenkarzinomzelllinie EPLC 32M1, während sich nur eine geringe Expression in nicht neuroendokrinen Zelllinien wie z.B. der Fibroblastenzelllinie MSTO-211H zeigte. Die neuroendokrin-spezifische Regulation wurde im hCgA Promotor durch das im proximalen Promotorbereich gelegene CRE vermittelt. Ebenso konnte gezeigt werden, dass Gastrin und cAMP den hCgA Promotor über das CRE regulieren. Unter Anwendung des charakterisierten hCgA Promotors konnte die funktionelle Expression des Natriumjodidsymporters unter der Kontrolle des humanen CgA Promotors in BON 1 Zellen nachgewiesen werden. Dies bildet einen vielversprechenden neuen Therapieansatz, durch einen regulierten Gentransfer neuroendokrine Tumorzellen mittels einer Radiojodtherapie in Analogie zu Schilddrüsenkarzinomen zu behandeln

Assessment of a conduction-repolarisation metric to predict Arrhythmogenesis in right ventricular disorders

Background: The re-entry vulnerability index (RVI) is a recently proposed activation-repolarization metric designed to quantify tissue susceptibility to re-entry. This study aimed to test feasibility of an RVI-based algorithm to predict the earliest endocardial activation site of ventricular tachycardia (VT) during electrophysiological studies and occurrence of haemodynamically significant ventricular arrhythmias in follow-up. Methods: Patients with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) (n = 11), Brugada Syndrome (BrS) (n = 13) and focal RV outflow tract VT (n = 9) underwent programmed stimulation with unipolar electrograms recorded from a non-contact array in the RV. Results: Lowest values of RVI co-localised with VT earliest activation site in ARVC/BrS but not in focal VT. The distance between region of lowest RVI and site of VT earliest site (D min ) was lower in ARVC/BrS than in focal VT (6.8 ± 6.7 mm vs 26.9 ± 13.3 mm, p = 0.005). ARVC/BrS patients with inducible VT had lower Global-RVI (RVI G ) than those who were non-inducible (−54.9 ± 13.0 ms vs −35.9 ± 8.6 ms, p = 0.005) or those with focal VT (−30.6 ± 11.5 ms, p = 0.001). Patients were followed up for 112 ± 19 months. Those with clinical VT events had lower Global-RVI than both ARVC and BrS patients without VT (−54.5 ± 13.5 ms vs −36.2 ± 8.8 ms, p = 0.007) and focal VT patients (−30.6 ± 11.5 ms, p = 0.002). Conclusions: RVI reliably identifies the earliest RV endocardial activation site of VT in BrS and ARVC but not focal ventricular arrhythmias and predicts the incidence of haemodynamically significant arrhythmias. Therefore, RVI may be of value in predicting VT exit sites and hence targeting of re-entrant arrhythmias

Questionnaire study to gain an insight into the manufacturing and fitting process of artificial eyes in children: an ocularist perspective

Purpose To gain an insight into the manufacturing and fitting of artificial eyes in children and potential improvements to the process. Method An online qualitative survey was distributed to 39 ocularists/prosthetists in Europe and Canada. Participants were recruited through purposive sampling, specifically maximum variation sampling from the researcher’s contacts and an online search. Results The findings highlighted the current impression technique as being the most difficult yet most important part of the current process for both the ocularist and child patient. Negatively affecting obtaining a good impression, the child patients distress can be reduced by their parents by providing encouragement, reassurance, practicing the insertion and removal of the artificial eye and being matter of fact. Whilst improvements to the current process provided mixed views, the incorporation of current technology was perceived as not being able to meet the requirements to produce aesthetically pleasing artificial eyes. Conclusion The current artificial eye process can be seen as an interaction with its success being dependent on the child patient’s acceptance and adjustment which is dependent on the factors associated to the process. Investigation into the needs of the patient and whether technology can improve the process are the next steps in its advancement

Altruism can proliferate through group/kin selection despite high random gene flow

The ways in which natural selection can allow the proliferation of cooperative behavior have long been seen as a central problem in evolutionary biology. Most of the literature has focused on interactions between pairs of individuals and on linear public goods games. This emphasis led to the conclusion that even modest levels of migration would pose a serious problem to the spread of altruism in group structured populations. Here we challenge this conclusion, by analyzing evolution in a framework which allows for complex group interactions and random migration among groups. We conclude that contingent forms of strong altruism can spread when rare under realistic group sizes and levels of migration. Our analysis combines group-centric and gene-centric perspectives, allows for arbitrary strength of selection, and leads to extensions of Hamilton's rule for the spread of altruistic alleles, applicable under broad conditions.Comment: 5 pages, 2 figures. Supplementary material with 50 pages and 26 figure

Antonio Gramsci’s impact on critical pedagogy

This paper provides an account of Antonio Gramsci’s impact on the area of critical pedagogy. It indicates the Gramscian influence on the thinking of major exponents of the field. It foregrounds Gramsci's ideas and then indicates how they have been taken up by a selection of critical pedagogy exponents who were chosen on the strength of their identification and engagement with Gramsci's ideas, some of them even having written entire essays on Gramsci. The essay concludes with a discussion concerning an aspect of Gramsci's concerns, the question of powerful knowledge, which, in the present author's view, provides a formidable challenge to critical pedagogues.peer-reviewe

Conditional statistics of electron transport in interacting nanoscale conductors

Interactions between nanoscale semiconductor structures form the basis for charge detectors in the solid state. Recent experimental advances have demonstrated the on-chip detection of single electron transport through a quantum dot (QD). The discreteness of charge in units of e leads to intrinsic fluctuations in the electrical current, known as shot noise. To measure these single-electron fluctuations a nearby coherent conductor, called a quantum point contact (QPC), interacts with the QD and acts as a detector. An important property of the QPC charge detector is noninvasiveness: the system physically affects the detector, not visa-versa. Here we predict that even for ideal noninvasive detectors such as the QPC, when a particular detector result is observed, the system suffers an informational backaction, radically altering the statistics of transport through the QD as compared to the unconditional shot noise. We develop a theoretical model to make predictions about the joint current probability distributions and conditional transport statistics. The experimental findings reported here demonstrate the reality of informational backaction in nanoscale systems as well as a variety of new effects, such as conditional noise enhancement, which are in essentially perfect agreement with our model calculations. This type of switching telegraph process occurs abundantly in nature, indicating that these results are applicable to a wide variety of systems.Comment: 16 pages, 3 figures, to appear in Nature Physic

Publishing and sharing multi-dimensional image data with OMERO

Imaging data are used in the life and biomedical sciences to measure the molecular and structural composition and dynamics of cells, tissues, and organisms. Datasets range in size from megabytes to terabytes and usually contain a combination of binary pixel data and metadata that describe the acquisition process and any derived results. The OMERO image data management platform allows users to securely share image datasets according to specific permissions levels: data can be held privately, shared with a set of colleagues, or made available via a public URL. Users control access by assigning data to specific Groups with defined membership and access rights. OMERO’s Permission system supports simple data sharing in a lab, collaborative data analysis, and even teaching environments. OMERO software is open source and released by the OME Consortium at www.openmicroscopy.org

Evidence of the Generation of Isosaccharinic Acids and Their Subsequent Degradation by Local Microbial Consortia within Hyper-Alkaline Contaminated Soils, with Relevance to Intermediate Level Radioactive Waste Disposal

The contamination of surface environments with hydroxide rich wastes leads to the formation of high pH (>11.0) soil profiles. One such site is a legacy lime works at Harpur Hill, Derbyshire where soil profile indicated in-situ pH values up to pH 12. Soil and porewater profiles around the site indicated clear evidence of the presence of the α and β stereoisomers of isosaccharinic acid (ISA) resulting from the anoxic, alkaline degradation of cellulosic material. ISAs are of particular interest with regards to the disposal of cellulosic materials contained within the intermediate level waste (ILW) inventory of the United Kingdom, where they may influence radionuclide mobility via complexation events occurring within a geological disposal facility (GDF) concept. The mixing of uncontaminated soils with the alkaline leachate of the site resulted in ISA generation, where the rate of generation in-situ is likely to be dependent upon the prevailing temperature of the soil. Microbial consortia present in the uncontaminated soil were capable of surviving conditions imposed by the alkaline leachate and demonstrated the ability to utilise ISAs as a carbon source. Leachate-contaminated soil was sub-cultured in a cellulose degradation product driven microcosm operating at pH 11, the consortia present were capable of the degradation of ISAs and the generation of methane from the resultant H2/CO2 produced from fermentation processes. Following microbial community analysis, fermentation processes appear to be predominated by Clostridia from the genus Alkaliphilus sp, with methanogenesis being attributed to Methanobacterium and Methanomassiliicoccus sp. The study is the first to identify the generation of ISA within an anthropogenic environment and advocates the notion that microbial activity within an ILW-GDF is likely to influence the impact of ISAs upon radionuclide migration

Increased shear in the North Atlantic upper-level jet stream over the past four decades

Earth’s equator-to-pole temperature gradient drives westerly mid-latitude jet streams through thermal wind balance. In the upper atmosphere, anthropogenic climate change is strengthening this meridional temperature gradient by cooling the polar lower stratosphere and warming the tropical upper troposphere acting to strengthen the upper-level jet stream. In contrast, in the lower atmosphere, Arctic amplification of global warming is weakening the meridional temperature gradient acting to weaken the upper-level jet stream. Therefore, trends in the speed of the upper-level jet stream represent a closely balanced tug-of-war between two competing effects at different altitudes. It is possible to isolate one of the competing effects by analysing the vertical shear—the change in wind speed with height—instead of the wind speed, but this approach has not previously been taken. Here we show that, although the zonal wind speed in the North Atlantic polar jet stream at 250 hectopascals has not changed since the start of the observational satellite era in 1979, the vertical shear has increased by 15 per cent (with a range of 11–17 per cent) according to three different reanalysis datasets. We further show that this trend is attributable to the thermal wind response to the enhanced upper-level meridional temperature gradient. Our results indicate that climate change may be having a larger impact on the North Atlantic jet stream than previously thought. The increased vertical shear is consistent with the intensification of shear-driven clear-air turbulence expected from climate change which will affect aviation in the busy transatlantic flight corridor by creating a more turbulent flying environment for aircraft. We conclude that the effects of climate change and variability on the upper-level jet stream are being partly obscured by the traditional focus on wind speed rather than wind shear

Cancer symptom awareness and barriers to symptomatic presentation in England – Are we clear on cancer?

Background: Low cancer awareness may contribute to delayed diagnosis and poor cancer survival. We aimed to quantify socio-demographic differences in cancer symptom awareness and barriers to symptomatic presentation in the English population. Methods: Using a uniquely large data set (n=49?270), we examined the association of cancer symptom awareness and barriers to presentation with age, gender, marital status and socio-economic position (SEP), using logistic regression models to control for confounders. Results: The youngest and oldest, the single and participants with the lowest SEP recognised the fewest cancer symptoms, and reported most barriers to presentation. Recognition of nine common cancer symptoms was significantly lower, and embarrassment, fear and difficulties in arranging transport to the doctor’s surgery were significantly more common in participants living in the most deprived areas than in the most affluent areas. Women were significantly more likely than men to both recognise common cancer symptoms and to report barriers. Women were much more likely compared with men to report that fear would put them off from going to the doctor. Conclusions: Large and robust socio-demographic differences in recognition of some cancer symptoms, and perception of some barriers to presentation, highlight the need for targeted campaigns to encourage early presentation and improve cancer outcomes